Barranco, 07 de diciembre de 2016

Seores. -
MINISTERIO DE AGRICULTURA - SENASA
M.V. Martn Vicente Ortiz Morera
Director de la Sub Direccin de Insumos Pecuarios SENASA
Presente

Ref.: Exp. 1601-00002870

Por medio de la presente me dirijo a usted para saludarlo y a la vez hacerle llegar
la subsanacin de observaciones al expediente del producto DECTOVERM 3.15
solicitadas por su representada mediante CARTA-4604-2016-MINAGRI-
SENASA-DIAIA-SIP del 29 de noviembre de 2016.

Sin otro particular, quedo de usted.

Atentamente,
1. AGENTES ETIOLOGICOS SUSCEPTIBLES

Ivermectina:

Ganado vacuno

Nematodos (adultos y larvas): Haemonchus spp., Ostertagia spp., Cooperia

spp., Trichostrongylus spp., Strongyloides papillosus; Bunostomum spp.,
Nematodirus spp., Trichuris spp., Oesophagostomum spp., Dictyocaulus
viviparus.

Artrpodos: Hypoderma spp., Sarcoptes scabiei var. bovis, Psoroptes ovis,

Linognathus spp. y Haematopinus spp.

Ovinos

Nematodos (adultos y larvas): Haemonchus spp., Chabertia ovina, Ostertagia

spp., Cooperia spp., Trichostrongylus spp., Strongyloides papillosus,
Bunostomum spp., Nematodirus spp., Trichuris ovis, Oesophagostomum spp.,
Dictyocaulus filaria.

Artrpodos: Oestrus ovis Sarcoptes scabiei, Psoroptes ovis, Melanophagus

ovinus.

Fuentes:

The pharmacokinetics and metabolism of ivermectin in domestic animal species. The Veterinary
Journal 179 (2009) Pagina: 11.

CFR. 522.1192. IVERMECTIN. 2016. Pgina 22.

http://www.ecfr.gov/cgi-bin/text-
idx?SID=6d8815dd398417c1defc8429eefd2296&mc=true&node=se21.6.522_11192&rgn=div8

Camlidos sudamericanos

Nematodos: Graphinema aucheniae, Spirulopteragia peruvianus,

Nematodirus lamae ,Camellustrongylus mentulatus y Lamanema chavezi.
Otras especies son propias de vacunos y ovinos pueden afectar a los
camlidos, tales como aquellos de los gneros Ostertagia, Trichostrongylus,
Cooperia, Haemoncus, Oesophagostomum y Dyctiocaulus.
 Artrpodos: Chorioptes, Psoroptes sp., Sarcoptes scabiei var auchinae.
Piojera causada por parasitos masticadores del genero Microthoracius y
Damalinia.

Fuente:

British Veterinary Zoological Sociey Proceedings May 2008. SKIN DISEASES OF SOUTH
AMERICAN CAMELIDS. Pgina 24-26.
http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.469.4216&rep=rep1&type=pdf

Situacin Actual de Camelidos Sudamericanos en el Peru. FAO. 2005. Pginas: 74 y 76.

http://tarwi.lamolina.edu.pe/~emellisho/zootecnia_archivos/situacion%20alpcas%20peru.pdf

Manejo sanitario de la vicua. Ministerio de Agricultura SAC Chile. 2007. Pginas 93, 95 y 96.
http://www2.sag.gob.cl/Pecuaria/bvo/BVO_9_I_semestre_2009/articulos/manejo_sanitario_vicuna.pdf

Se adjunta sustento bibliogrfico en el anexo 1.

2. EFECTOS BIOLOGICOS NO DESEADOS

Evaluacin toxicolgica y microbiolgica

El estudio humano Se llev a cabo de acuerdo con los principios de la

Declaracin de Helsinki. El Comit consider que la base de datos era
adecuada para la evaluacin.

Datos bioqumicos

Los datos farmacocinticos se obtuvieron de la seguridad, tolerabilidad y

farmacocintica en humanos. A doce individuos en ayunas por grupo de
dosificacin se les administr una dosis oral nica de 30, 60, 90 120 mg de
ivermectina o dosis mltiples de 30 60 mg de ivermectina durante 7 das. El
anlisis farmacocintico revel que las concentraciones de ivermectina en
plasma eran generalmente proporcionales hasta una dosis oral nica de 120
mg en pacientes en ayunas. La linealidad de dosis de la mxima
Concentracin en el plasma (Cmax) y el rea por debajo de la curva de
concentracin plasma-tiempo (AUC) se confirm despus de la normalizacin
de la dosis. No hubo diferencias en variables farmacocinticas entre hombres
y mujeres. Se observ mnima acumulacin con dosis repetidas, y el tiempo
promedio de eliminacin vari de
18,8 a 20,1 horas en sujetos en ayuno. El AUC de ivermectina fue 2,57 veces
mayor
en sujetos alimentados frente a los que ayunaron al recibir una dosis nica de
30 mg, pero el tiempo promedio de eliminacin ms corto fue de 15 horas.

Datos toxicolgicos

Los estudios de toxicidad oral a largo plazo o de carcinogenicidad con

ivermectina no estuvieron disponibles, pero el Comit en su 36 reunin
(Anexo 1, 91) lleg a la conclusin de que, dadas las similitudes estructurales
y Perfiles de ivermectina y abamectina, tales estudios no fueron necesarios.
En un estudio de carcinogenicidad de 94-semanas en ratones con dosis de
abamectina de 0, 2, 4 y 8 mg / kg de peso corporal por da, no fue identificado
algn nivel de efecto no observado: NOEL o NOAEL a dosis de 4,0 mg / kg
de peso corporal por da.

Adems, en un estudio de Carcinogenicidad en la dieta de 105 semanas de

duracin en ratas con dosis de 0, 0,75, 1,5 y 2,0 mg / kg de peso corporal /
da de abamectina, se identific un NOEL (NOAEL) de 1,5 mg / kg de peso
corporal por da. La Comisin presente est de acuerdo con estas
conclusiones.

En un estudio de toxicidad reproductiva, la ivermectina se administr

oralmente a ratas hembra a una dosis de 0, 0,4, 0,8 1,6 mg / kg de peso
corporal por da a partir de 15 das antes del apareamiento hasta 20 das
postparto. Dos grupos de control recibieron el vehculo (aceite de ssamo).
Basados en la usencia de resultados adversos en las madres, se identific
una dosis de toxicidad materna NOAEL de 1,6 mg / Kg de peso corporal por
da, la dosis ms alta probada.

Un aumento estadsticamente significativo relacionado con el tratamiento en

la mortalidad de los cachorros en el grupo de 1,6 mg / kg de peso corporal por
da fue observado en el da 1 y en los das 7-14 postparto. Se identific una
toxicidad de descendencia LOAEL de 1,6 mg / kg de peso corporal por da y
la toxicidad NOAEL de la descendencia fue de 0,8 mg / kg de peso corporal
por da.

Se llevaron a cabo tres estudios multi generacionales de toxicidad

reproductiva en ratas. Los dos primeros estudios fallaron en establecer una
NOAEL para la ivermectina cuando se administr oralmente a ratas a dosis
de 0,4, 1,2 y 3,6 mg / kg de peso corporal por da o 2,0 mg / kg de peso
corporal por da, respectivamente. En un tercer estudio de multi generacin,
las ratas recibieron ivermectina por va oral a dosis de 0,05, 0,1, 0,2 0,4 mg
/ kg de peso corporal por da. Un grupo control recibi el vehculo aceite de
ssamo. Los efectos relacionados con el tratamiento se limitaron a una ligera,
pero estadsticamente significativa, disminucin de la ganancia de peso
corporal durante el perodo posterior al destete en las hembras F1b en el grupo
de 0,4 mg / kg de peso corporal por da y los machos F2b en los grupos de 0,2
y 0,4 mg / kg de peso corporal por da. No hubo efectos relacionados con el
tratamiento en el rendimiento de ratas macho o hembra en cualquier grupo de
dosis. No hubo evidencia de Teratogenicidad en la descendencia F3. Se
identific una dosis de Toxicidad NOAEL de los padres y de los hijos a una
dosis de 0,4 mg / kg de peso corporal por da, la dosis ms alta ensayada.

Observaciones en seres humanos

En un estudio doble ciego, aleatorizado, controlado con placebo, dosis de

aumento mltiple
(0, 30, 60, 90 y 120 mg, equivalente a 0, 0,4, 0,8, 1,2 y 1,5 mg / kg de peso
corporal, respectivamente, basado en el peso corporal medio) para investigar
la seguridad, tolerabilidad y la farmacocintica de dosis mltiples de
ivermectina. A grupos de 12 sujetos humanos sanos sujetos por dosis se
administraron dosis orales de ivermectina de 30 60 mg en los das 1, 4 y 7
o dosis nicas de 90 120 mg. A un grupo adicional de cuatro sujetos
saludables se les administr un placebo. Todos los sujetos estuvieron en
ayuno antes de la dosificacin. A un grupo de sujetos que recibieron 30 mg
se les aplico un lavado gstrico durante una semana, luego se alimentaron
antes de la administracin de una dosis oral nica de 30 mg de ivermectina.
Todas las dosis de ivermectina fueron bien toleradas. No se observaron
efectos adversos sobre la salud humana, en particular sobre el sistema
neurolgico. Se determin que la NOAEL para toxicidad oral aguda de
ivermectina era de 120 mg, equivalente a 1,5 mg / kg de peso corporal, la
dosis ms alta probada, basada en un cuerpo mediano de 77,9 kg de peso.

La ivermectina se ha administrado a varios millones de pacientes para el

tratamiento de la oncocercosis a un nivel de dosis oral recomendado de 150
g / kg de peso corporal administrado una vez cada 12 meses. No hay signos
de toxicidad aguda del sistema nervioso central. Las reacciones adversas que
se han observado en los pacientes tratados han sido descritas como
respuestas alrgicas o inflamatorias resultante de la muerte de microfilarias,
denominada "reaccin de Mazotti". No se han reportado efectos adversos
significativos en los fetos durante el embarazo en mujeres fueron tratadas
inadvertidamente con ivermectina.

Ivermectina tambin se puede utilizar en el tratamiento de la filariasis linftica,

la estrongiloidiasis y la sarna. El tratamiento de la sarna generalmente
requiere una dosis oral de 200 g / kg de peso corporal, pero pueden ser
necesarias dos o tres dosis repetidas, separadas por un intervalo de 1 2
semanas, para ser totalmente eficaces. El patrocinador identific una serie de
estudios publicados en los que los pacientes parasitados recibieron hasta 13
dosis de ivermectina (800 g / kg de peso corporal) durante el curso del
tratamiento. Estos estudios indicaron que la ivermectina fue bien tolerada y
que no se observaron efectos adversos graves para la salud. Una reciente
revisin de la toxicidad aguda de las lactonas macrocclicas indico que los
efectos adversos para la salud del tratamiento del tratamiento con ivermectina
en pacientes con oncocercosis se relacionaron no con la dosis de ivermectina,
sino con la carga microfilarial de la piel.

Datos microbiolgicos

Teniendo en cuenta la estructura qumica y el modo de accin, el Comit no

previo anticipo algn efecto adverso causado por los residuos de ivermectina
en el sistema gastrointestinal humano.
Fuente: Evaluation of certain veterinary drug residues in food. Eighty-first report of the Joint
FAO/WHO Expert Committee on food aditives. FAO-WHO. 2016. Pgina 165-168.
http://apps.who.int/iris/bitstream/10665/204670/1/9789240695504_eng.pdf

Se adjunta el sustento bibliogrfico en el anexo 2.

3. LIMITE MXIMO DE RESIDUOS (LMR)

3.5. Conclusiones y recomendaciones para el establecimiento de Lmites de

residuos.

Habiendo considerado que:

se ha establecido previamente una IDA toxicolgica de 10 g / kg de peso

corporal / da (600 g / persona / da) como IDA global para la ivermectina;
Se mantuvo la 22,23-dihidroavermectina B 1a como residuo marcador en
todos los tejidos y especies animales diana;
la distribucin tisular de los residuos y las relaciones globales del marcador
con los residuos totales fueron generalmente similares, siendo los niveles de
residuos los ms altos en tejidos grasos e hgado;
las concentraciones de residuos eran persistentemente bajos en el msculo
que no era sitio de inyeccin;
los residuos en el lugar de la inyeccin se agotan lentamente y deben
considerarse para
Perodos de retiro;
se calcularon los promedios del total de residuos en las diferentes especies
animales y tejidos;
la Comisin y las autoridades de control de residuos consideran que, para
garantizar la
el control de residuos, un solo lmite de residuos para msculo debe publicarse
en el Reglamento (UE) No 37/2010;
Se establece un Valor de Referencia de Residuos en el Sitio de Inyeccin
(ISRRV) de 1250 g / kg para todas las especies animales mamferas
productoras de alimentos - este valor debe tenerse en cuenta para establecer
el periodo de retiro;
una porcin de la IDA debe reservarse para una posible necesidad futura de
establecer un LMR para la leche,
con el propsito de monitorear los residuos de ivermectina se recomienda
que, cuando la
carcasa entera est disponible, el hgado o grasa (piel + grasa de los cerdos)
deben ser muestreado de preferencia al musculo, ya que los residuos en estos
tejidos se agotan ms lentamente que los residuos en el msculo y por lo tanto
proporcionar una mejor base para verificar el cumplimiento del perodo de
retiro;
est disponible un mtodo analtico validado para el monitoreo de residuos
de ivermectina en tejidos comestibles de bovinos, ovejas, cerdos y caballo
(hgado, rin, grasa y msculo) est disponible;

El CVMP (Comit de Medicamentos de Uso Veterinario) recomienda que se

modifique la entrada correspondiente a la ivermectina en el cuadro 1 del
Reglamento (UE) no 37/2010 de la Comisin de conformidad con el cuadro
siguiente:
 En el cuadro de arriba se est fijando un nivel de residuos de ivermectina para
los tejidos de todas las especies de mamferos productores de alimentos
(donde se incluyen los camlidos sudamericanos), que es el siguiente:

30 g/kg Msculo
100 g/kg Grasa
100 g/kg Hgado
30 g/kg Rin

Fuente: EMEA. EPMAR. Ivermectin (All mammalian food producing species). 2014. Paginas: 251-252.
http://www.ema.europa.eu/docs/en_GB/document_library/Maximum_Residue_Limits_-
_Report/2014/05/WC500167329.pdf

Se adjunta el sustento bibliogrfico en el anexo 3.

4. ROTULADO

adjunta la etiqueta en arte final con las correcciones solicitadas.

ANEXO 1
 Available online at www.sciencedirect.com

The
Veterinary Journal
The Veterinary Journal 179 (2009) 2537
www.elsevier.com/locate/tvjl

Review

The pharmacokinetics and metabolism of ivermectin

in domestic animal species
Aranzazu Gonzalez Canga *, Ana M. Sahagun Prieto, M. Jose Diez Liebana,
Nelida Fernandez Martnez, Matilde Sierra Vega, Juan J. Garca Vieitez
Department of Biomedical Sciences, Veterinary Faculty, University of Leon, Spain

Accepted 17 July 2007

Abstract

The pharmacokinetic properties of drugs are closely related to their pharmacological ecacy. The kinetics of ivermectin are charac-
terised, in general terms, by a slow absorption process, a broad distribution in the organism, low metabolism, and slow excretion. The
kinetics vary according to the route of administration, formulation, animal species, body condition, age, and physiological status, all of
which contribute to dierences in drug ecacy. Characterisation of ivermectin kinetics can be used to predict and optimise the value of
the parasiticide eects and to design programmes for parasite control. This article reviews the pharmacokinetics of ivermectin in several
domestic animal species.
2007 Elsevier Ltd. All rights reserved.

Keywords: Ivermectin; Pharmacokinetics; Animal species; Absorption; Distribution; Metabolism; Excretion; Cattle; Sheep; Goat; Pig; Dog; Review

Introduction tin-B1a and >20% 22,23-dihydroavermectin-B1b (Fig. 1).

The rational use of a drug requires knowledge of its
basic pharmacokinetics in the target animal species, and
this helps to optimise clinical ecacy. Ivermectin is proba-
bly one of the most widely used antiparasitic drugs world-
wide, and its ecacy is well established. However, the
pharmacokinetic parameters of ivermectin vary extensively
and in accordance with many factors that can all inuence
the drugs plasma concentration. These factors, which
include the species, route of administration, vehicle used
in the commercial formulation, bodyweight, body condi-
tion, physiological status, and amount and type of nutri-
tion, create diculties when extrapolating data from one
species to another and should be considered in clinical
practice in order to achieve eective levels that will last
as long as possible.
Ivermectin is a mixture of two chemically modied aver-
mectins that contain at least 80% of 22,23-dihydroavermec-
*
Corresponding author. Tel.: +34 987 29 18 46; fax: +34 987 29 12 67.
E-mail address: agonc@unileon.es (A. Gonzalez Canga).
It is a highly lipophilic substance that dissolves in most
organic solvents, but is practically insoluble in water
(0.0004% m/v). Ivermectin was rst marketed in 1981 by
Merck Sharp and Dohme as an antiparasitic agent (Steel,
1993), and it remains the leading worldwide antiparasitic
agent for livestock. It has exceptional potency against
endo- and ectoparasites at extremely low doses (doses rec-
ommended are expressed as lg/kg); this accounts for its
large margin of safety.
Ivermectin is highly active against a wide spectrum of
nematode species, including most larvae and adult forms;
it is also highly eective against many arthropod parasites
of domestic animals (Table 1). All important gastrointesti-
nal and lung nematodes are susceptible to the drug, includ-
ing sensitive mites, ticks, biting ies, and parasitic dipteran
larvae (Campbell and Benz, 1984; Campbell, 1989; McKel-
lar and Benchaoui, 1996). In dogs, ivermectin is also active
against developing larvae of Dirolaria immitis and is used
in heartworm prophylaxis.
Toxicity to ivermectin is rare across animal species. The
signs of toxicosis are mydriasis and depression, followed by

1090-0233/$ - see front matter 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tvjl.2007.07.011
26 A. Gonzalez Canga et al. / The Veterinary Journal 179 (2009) 2537
Fig. 1. Chemical structure of ivermectin.
ataxia, recumbency, and death. It has no adverse eects on
breeding performance. Some Collie dogs and other herding
breeds are remarkably susceptible, but even these animals
will tolerate doses of 50 lg/kg, which are nearly 10-fold
greater than the therapeutic dose in dogs. The central ner-
vous system side-eects in sensitive Collie dogs have been
linked to the absence or functional deciency of P-glyco-
protein, which functions as a transmembrane eux pump
and plays a central role in limiting drug uptake by the
brain, thereby protecting against ivermectin neurotoxicity.
Many rumino-reticular delivery systems, as well as oral,
topical, and injectable formulations of ivermectin, are cur-
rently available at the dosage recommended by manufac-
turers, namely, 200 lg/kg in ruminants (500 lg/kg for
topical application) and equines, 300 lg/kg in pigs, and
6 lg/kg in dogs. This paper reviews the most important
aspects of ivermectin pharmacokinetics, including absorp-
tion, distribution, metabolism, and excretion (Fig. 2).
General overview of ivermectin pharmacokinetics and
metabolism
Since its introduction in 1981, there have been numerous
pharmacokinetic studies of ivermectin. The drug can be
administered by oral, intramuscular (IM), subcutaneous
(SC), or topical routes, depending on the species. The phar-
macokinetic properties are dose-dependent, with a linear
increase in the area under the curve (AUC) with increasing
dose.
The route of administration and the formulation
strongly aect ivermectins pharmacokinetics. The greatest
bioavailability is achieved with the SC injection, followed
by the oral route. The lowest AUC values are obtained
after topical administration, even if the dose is 500 lg/kg
instead of 200 lg/kg. Parenteral administration delays iver-
mectins absorption compared to the oral route, but leads
to an overall higher availability in plasma, a longer dura-
tion of activity, and better ecacy. Molento et al. (2004)
pointed out that the lower absorption of ivermectin after
oral administration could be inuenced by P-glycoprotein,
which is also present on the intestinal epithelium; when
ivermectin is co-administered with verapamil (a P-glyco-
protein blocker), the maximum plasma concentration
(Cmax) and bioavailability increased, leading to an
improvement in antiparasitic ecacy.
Ivermectins extremely low water solubility and its pre-
cipitation in SC tissues favour slow absorption from the
injection site, resulting in a prolonged presence in the
bloodstream. On the other hand, the erratic SC absorption
of ivermectin could relate to variability in pharmacokinetic
parameters.
In ruminant species, intraruminal (IR) administration
yields a lower systemic availability and could explain its
lesser ecacy against ectoparasites (Benz et al., 1989;
McKellar and Benchaoui, 1996) and shorter duration of
activity against gastrointestinal nematodes.
Small dierences in formulations may result in substan-
tial changes in the antiparasitic activity of ivermectin. This
property has been extensively studied in cattle. Absorption
is greater and faster with an aqueous vehicle than with pro-
pylene glycol:glycerol-formal (60:40 v/v), and the drugs
biological half-life is also longer, prolonging its clinical e-
cacy (Lo et al., 1985). Moreover, when using an oil-based
formulation, absorption is faster after IM versus SC admin-
istration due to greater blood ow in muscle. SC absorption
is delayed with an oil-based vehicle compared with propyl-
ene glycol:glycerol-formal due to slower release of the iver-
mectin from the SC depot (Lifschitz et al., 1999b).
Results do however vary. In one study, no dierences
were observed after SC administration of two commercial
formulations with the same vehicle (propylene glycol:glyc-
erol-formal 60:40 v/v) (Lifschitz et al., 1999a), whereas in
another study from the same group there were signicant
dierences in the absorption pattern (rate and extent)
between four formulations with the same vehicle (Lifschitz
et al., 2004).
Due to its high lipophilic nature, ivermectin is exten-
sively distributed with broad volumes of distribution (Vd)
in all species. It tends to accumulate in fat tissue, which acts
as a drug reservoir and the highest levels of ivermectin are
found in liver and fat, and the lowest in brain tissue.
Binding studies in dogs have shown that ivermectin binds
extensively to plasma albumin and lipoproteins (Rohrer
and Evans, 1990), and this should be considered in
undernourished animals or in diseases in which plasma
proteins decrease, as there would be a higher free fraction
of the drug. Ivermectin persists in the body for a prolonged
period, due not only to low plasma clearance but also to
this accumulation in fat tissue. Plasma clearance appears
to be greater in pigs than in polygastric species
(goats > sheep > cattle).
 A. Gonzalez Canga et al. / The Veterinary Journal 179 (2009) 2537 27

Table 1
Ivermectin spectrum of activity in several domestic animals
Animal species Nematodes Arthropods Dose
Cattle Haemonchus spp. Hypoderma spp. 200 lg/kg subcutaneous and
Ostertagia spp. Sarcoptes bovis oral 500 lg/kg topical
Cooperia spp. Psoroptes ovis
Trichostrongylus spp. Linognathus spp.
Strongyloides papillosus; Haematopinus spp.
Bunostomum spp.
Nematodirus spp.
Trichuris spp.
Oesophagostomum spp.
Dictyocaulus viviparus
Sheep Haemonchus spp. Oestrus ovis 200 lg/kg subcutaneous and oral
Chabertia ovina Sarcoptes scabiei
Ostertagia spp. Psoroptes ovis
Cooperia spp. Melanophagus ovinus
Trichostrongylus spp.
Strongyloides papillosus
Bunostomum spp.
Nematodirus spp.
Trichuris ovis
Oesophagostomum spp.
Dictyocaulus laria
Goat Haemonchus spp. Sarcoptes spp. 200 lg/kg subcutaneous
Chabertia ovina Psoroptes ovis
Teladorsagia spp.
Cooperia spp.
Trichostrongylus spp.
Strongyloides papillosus
Oesophagostomum spp.
Dictyocaulus laria
Pig Ascaris suum Sarcoptes scabiei 300 lg/kg subcutaneous
Hyostrongylus rubidus
Strongyloides ransomi Haematopinus suis
Oesophagostomum spp.
Metastrongylus spp.
Stephanurus dentatus
Trichinella spiralis (intestinal)
Horse Strongylus spp. Gasterophilus spp. 200 lg/kg oral
Parascaris equorum Sarcoptes scabiei
Oxyuris equi
Draschia spp.
Habronema spp.
Trichostrongylus axei
Parascaris equorum (microlaria)
Strongyloides westeri
Dictyocaulus arneldi
Onchocerca spp.
Dog Dirolaria immitis Sarcoptes scabiei 6 lg/kg oral
(microlaria and fourth-stage larvae)
Toxocara canis Otodectes cynotis
Toxascaris leonine
Ancylostoma caninum
Uncinaria stenocephala
Trichuris vulpis

Ivermectin undergoes little metabolism; most of the dose
is excreted unchanged. Metabolic studies have been per-
formed in rats, cattle, sheep, goats, and pigs. The major
metabolites isolated in vivo are 24-OH-H2B1a and 24-
OH-H2B1b in cattle, sheep, and rats (Chiu et al., 1986),
whereas in pigs O-demethylation derivatives are the major
metabolites that have been isolated (300 -O-desmethyl-
H2B1a and 300 -O-desmethyl-H2B1b); 3-O-desmethyl
metabolite was found in goats (Alvinerie et al., 1994). In
sheep and cattle, less polar metabolites have been found
in fat tissue, suggesting that in both species liver metabo-
lites are esteried with fatty acids and stored in fat as
non-polar entities (Chiu et al., 1988). These non-polar
metabolites have not been described in pigs, as their
28 A. Gonzalez Canga et al. / The Veterinary Journal 179 (2009) 2537
Fig. 2. Pharmacokinetics of ivermectin.
hepatic metabolites lack a primary hydroxyl functional
group, and would be less favourable substrates for esteri-
cation in fat.
Ivermectin is mainly eliminated in the faeces in all spe-
cies regardless of the route of administration, and faecal
excretion accounts for 90% of the dose administered with
<2% of the dose excreted in urine. Bile is the main route
of excretion. As P-glycoprotein is also present in biliary
canalicules, it could contribute to the drugs high faecal
excretion (Laont et al., 2002). Ivermectin is also excreted
by the mammary gland in dairy cows, sheep, and goats;
this mode of excretion is related to its high lipophilicity.
After intravenous (IV) administration, the plasma elimina-
tion half-life appears to be longer for ruminant species than
for monogastric animals.
Excretion is also aected by the formulation and is
slower in cattle treated SC with non-aqueous vehicles com-
pared with aqueous vehicles (Table 5); retention in the
body is also increased due to slow absorption from the
injection site (elimination half-lives are 2.0, 3.7, and 8.3
days with aqueous, aqueous:glycerol-formal 50:50 v/v,
and propylene glycol:glycerol-formal 60:40 v/v formula-
tions, respectively) (Lo et al., 1985). Furthermore, excre-
tion is slower with an oily solvent compared with
propylene glycol:glycerol-formal (Lifschitz et al., 1999b).
Even with the same vehicle, however, the elimination
half-life varies depending on the pharmaceutical prepara-
tion (Lifschitz et al., 1999a). The half-life of the non-aque-
ous formulation of ivermectin is longer after SC than IV
administration, reecting the rate-limiting eect of the
absorption process on the drugs overall kinetics (Lo
et al., 1985; Echeverra et al., 1997).
There are large interspecies and inter-individual varia-
tions in ivermectin pharmacokinetics. Regarding interspe-
cies variability, the AUC values after SC and oral
administration are almost 2.5 times less in sheep compared
to horses, and the time to reach the maximum plasma con-
centration (tmax) is longer (Marriner et al., 1987). On the
other hand, the Vd could inuence plasma concentrations,
as after IV administration the Vd increases in the following
manner: cattle < sheep and pigs < goats. Inter-individual
variation can also be attributed to dierences in body con-
dition, age, sex, and physiological status (McKellar and
Marriner, 1987; Bogan and McKellar, 1988; Scott et al.,
1990; McKellar et al., 1991; Scott and McKellar, 1992;
Lanusse et al., 1997; Gayrard et al., 1999; Cerkvenik
et al., 2002; Barber et al., 2003).
The eect of malnutrition on ivermectin kinetics has
been studied in cattle (Lifschitz et al., 1997). When admin-
istered SC, plasma availability was greater in calves with a
restricted diet for 21 days compared to cattle fed ad libitum,
(undernourished: AUC = 443 ng day/mL, Cmax = 53.9 ng/
mL; ad libitum: AUC = 286 ng day/mL, Cmax = 48.5 ng/
mL). Lifschitz et al. (1997) hypothesised that due to the
lipid solubility of ivermectin, the mobilisation of free fatty
acids from adipose tissue could modify the plasma-adipose
tissue exchange pattern. Moreover, ivermectin elimination
is delayed in undernourished (elimination half-life: 9.7
days; clearance: 0.465 L/kg day) versus regularly fed calves
(elimination half-life: 5.6 days; clearance: 0.733 L/kg day),
with signicant dierences in the elimination half-life and
clearance. Lifschitz et al. (1997) proposed that dietary
restrictions could reduce bile ow and, subsequently, bili-
ary excretion of ivermectin.
 A. Gonzalez Canga et al. / The Veterinary Journal 179 (2009) 2537 29

Table 2
Pharmacokinetic models followed by ivermectin in dierent animal species after the administration of the drug by various routes
Animal species Route Model References
Cattle Intravenous Two-compartmental Lo et al. (1985); Bousquet-Melou et al. (2004);
Echeverria et al. (1997)
Subcutaneous One-compartmental Lifschitz et al. (1999b); Toutain et al. (1988)
Two-compartmental Lanusse et al. (1997)
Intraruminal Two-compartmental Alvinerie et al. (1998)
Topical One-compartmental Gayrard et al. (1999)
Sheep Intravenous Two-compartmental Lo et al. (1985); Gonzalez et al. (2007)
Subcutaneous One-compartmental Cerkvenik et al. (2002); Barber et al. (2003);
Echeverra et al. (2002)
Two-compartmental Marriner et al. (1987); Atta and Abo-Shihada (2000)
Goat Intravenous Two-compartmental Gonzalez et al. (2006)
Subcutaneous One-compartmental Alvinerie et al. (1993)
Intraruminal One or two-compartmentala Escudero et al. (1997)
Pig Intravenous Two-compartmental Craven et al. (2001)
Horse Subcutaneous Two-compartmental Marriner et al. (1987)
Oral Two-compartmental Perez et al. (2002)
Dog Intravenous Two-compartmental Lo et al. (1985)
a
Depending on the individual animal.

McKellar et al. (1991) showed that infestation with
Nematodirus battus did not modify the kinetics of ivermec-
tin administered SC or orally to sheep. Nevertheless, Ech-
everra et al. (2002) observed that infestation with
Psoroptes spp. resulted in faster absorption with a higher
Cmax value after SC treatment, probably due to the smaller
amount of body fat compared to healthy animals.
The pharmacokinetic model describing the kinetics of
ivermectin varies according to the animal species and route
of administration (Table 2). The choice of one model over
another involves a consideration of pharmacokinetic
parameters and the ways in which they are calculated.
Species considerations
Cattle
Table 3 summarises the pharmacokinetic parameters
calculated for dierent routes of administration in cattle.
SC administration is the most studied, and the results show
a high degree of variability, which may be due to dier-
ences in breed, body condition, number of samples or data
points, methods of quantication, and kinetic treatment of
the data, or to erratic absorption from the injection site.
Despite this variability, Campbell and Benz (1984) and
Benz et al. (1989) showed that the plasma concentrations
achieved in cattle are clinically eective against some spe-
cies of endo- and ectoparasites. It is known that ivermectin
administered SC has persistent anthelmintic activity
against most gastrointestinal nematodes, lasting for
approximately 10 days, and it is active against Dictyocaulus
viviparus for 21 days (Barth, 1983; Bremner et al., 1983;
Armour et al., 1985). In cattle, plasma concentrations of
0.51 ng/mL are required for optimal anthelmintic activity
against most gastrointestinal and lung nematodes (Lifs-
chitz et al., 1999b); plasma concentrations of 0.5 ng/mL
also control Hypoderma spp. ies (Alvinerie et al., 1994).
Intra-ruminal administration has also been tested in cat-
tle and results in a lower and earlier plasma peak concen-
tration and reduced bioavailability. With a single IR
dose, the bioavailability was 26% of that following SC
administration (Chiu et al., 1990a). However, a sus-
tained-release bolus (SRB) that delivered 12 mg/day to
the cattle rumen for 135 days yielded a high steady-state
concentration (20 ng/mL) between days 4 and 120 after
treatment, oering a desirable drug-release prole for par-
asite control throughout an entire grazing season (Alviner-
ie et al., 1998).
Pour-on formulations are used in cattle, as their applica-
tion is less stressful for handlers and animals. Bioavailabil-
ity is low and does not exceed 15% of that for SC injection
possibly due to wastage or the drug being trapped in the
skin and released very slowly over a longer period of time
(Gayrard et al., 1999). Thus, the choice of a SC or pour-on
route could be important clinically, as topical formulations
(with a longer action) would be more eective against most
sensitive parasite species (D. viviparus or Oesophagostomum
radiatum), whereas SC administration should be considered
for less sensitive nematodes (Nematodirus helvetianus or
Trichostrongylus colubriformis).
With topical application, attention should be paid to the
animals licking behaviour. Laont et al. (2001) observed
that the bioavailability of ivermectin was lower in calves
when licking was prevented (19%) compared to when it
was not (33%). Thus, with licking, a substantial amount
of topically applied ivermectin could access the systemic
circulation via oral consumption resulting in subtherapeu-
tic concentrations in untreated and licked animals, which
can contribute to the development of resistance. Bous-
quet-Melou et al. (2004) reported that 6.380.4 lg/kg
30 A. Gonzalez Canga et al. / The Veterinary Journal 179 (2009) 2537

Table 3
Absorption pharmacokinetic parameters obtained after ivermectin administration to ruminants
Reference Route Cmax (ng/mL) tmax (h) AUC (ng day/mL) F (%)
Cattle
Lifschitz et al. (1999b)a IM 22.6p 54p 189n,p
Lanusse et al. (1997)e SC 42.8 96 459n
Lo et al. (1985)
Formulation Ab SC 84 24 246(04d) 55
Formulation Bc SC 25 48 186(04d) 41
Formulation Cd SC 13 48 149(04d) 33
Lifschitz et al. (1999b)
Formulation 1a SC 19.9o,p 96o,p 206n,o,p
Formulation 2d SC 35.4o 39.1o 207n,o
Lifschitz et al. (1999a)d
Formulation 3 SC 40.5 48 244n
Formulation 4 SC 46.4 50.9 266n
Lifschitz et al. (2004)d
Formulation D SC 23.6 27.4 231
Formulation E SC 32.7 62 308
Formulation F SC 22 103 262
Formulation G SC 28.4 44.6 242
Chiu et al. (1990a)f SC 133.2 24
Lifschitz et al. (2000) SC 40 24 278n
Echeverria et al. (1997)g SC 33.1 55.9 328.8
Toutain et al. (1988) SC 54.6 34.8
Alvinerie et al. (1998)r IR 28.5 364 247.6 (0160d)
Gayrard et al. (1999)g T 12.2 81.6 121.5(050d)
Laont et al. (2001)
Lickers T 39o 147 595.1o
Non-lickers T 16o 191 381.1o
Sheep
Prichard et al. (1985) IV 375
Gonzalez et al. (2007) IV 197
Bogan and McKellar (1988) SC 32.2 36
McKellar et al. (1991)
Healthy animals SC 30 46 101.7
Parasitized animals SC 35 38.2 175
Cerkvenik et al. (2002)g,h SC 11.9 40.8 64n
Barber et al. (2003)g SC 25.8 29.8 82.1(015d)
Lo et al. (1985)f SC 12 22
Echeverra et al. (2002)g
Healthy animals SC 24.1o 64.1o 207.5o
Parasitized animals SC 41.2o 21.6o 180o
Marriner et al. (1987)e SC 30.8 60 238
Atta and Abo-Shihada (2000)e SC 16.3 62.4 281n
Gonzalez et al. (2007) SC 19.6 3.1 190.7 98.2
Bogan and McKellar (1988)
Ewes O 14.7 24 36.3(07d)
Lambs O 23.6 36 93.7(07d)
McKellar et al. (1991)
Healthy animals O 29 19.3 74.6
Parasitized animals O 21 20 88.8
Mestorino et al. (2003)
Solution O 11.3 31.9 44.7
Tablets O 8.5 43.9 52
Marriner et al. (1987)e O 22 16.4 85 35.7l
Chiu et al. (1990a)f IR 12.5 24
Prichard et al. (1985) IR 17.6 23.5 94.2 25.1m
Prichard et al. (1985) IAB 60.6 4.8 440
Goat
Gonzalez et al. (2006)e IV 153
Gonzalez et al. (2006) SC 21.8 72 144 91.8
 A. Gonzalez Canga et al. / The Veterinary Journal 179 (2009) 2537 31

Table 3 (continued)
Reference Route Cmax (ng/mL) tmax (h) AUC (ng day/mL) F (%)
Alvinerie et al. (1993)g,h SC 6.1 68.4 60
Scott et al. (1990)h O 15.9 24 21.5
Escudero et al. (1997)h,p,i IR 9.3 31.2 34.4
Escudero et al. (1997)h,k IR 10.6 29 34.6
Scott et al. (1990)h T 3.9 48 13.2
Cmax = maximum plasma concentration; tmax = time to reach Cmax; AUC = area under the plasma concentrationtime curve; F = bioavailability;
d = day(s); = unknown data.
IM = intramuscular; SC = subcutaneous; IR = intraruminal; T = topical; IV = intravenous (200 lg/kg); O = oral; IAB = intra-abomasal. Doses are
always those recommended by manufacturers, except if indicated.
a
Oily vehicle.
b
Aqueous vehicle.
c
Aqueous-glycerol-formal vehicle (50:50, v/v).
d
Propyleneglycol:glycerol-formal vehicle (60:40, v/v).
e
Two-compartmental model.
f
300 lg/kg.
g
One-compartmental model.
h
Lactating animals.
i
Animals fasted for 36 h before ivermectin administration.
k
Animals fed ad libitum.
l
Relative to subcutaneous.
m
Relative to intra-abomasal.
n
AUC01; if other, it is indicated as superscript in brackets.
o
Signicant dierences within the study.
p
Signicant dierences within the study.
r
Sustained release bolus.

(1.316.1% of a pour-on dose) was ingested by untreated
cattle licking treated cattle.
The distribution of ivermectin is slow in cattle but
broad, as demonstrated by the high Vd and the high mean
residence time (MRT) (Table 5). When administered SC
and IR, [3H]ivermectin was detected in all sampled tissues:
the highest concentrations were found in liver and fat; high
levels were also recorded in the kidney and muscle (Chiu
et al., 1990a). Availability was higher in tissues where par-
asites usually reside than in plasma at 167%, 163%, and
244% in lungs, intestinal mucosae, and abomasal mucosae,
respectively, and persisted in most organs for 48 days (Lifs-
chitz et al., 2000). This could explain the strong ecacy of
ivermectin against parasites in these locations.
As in other species, ivermectin metabolism is minimal.
In studies using radiolabelled ivermectin, unchanged drug
represented 52% of the radioactivity in liver and fat (day
14 after SC treatment). Twenty-eight days after administra-
tion, these levels decreased to 40% in liver and 19% in fat
(Chiu et al., 1986). Liver metabolites were hydroxylated
derivatives of ivermectin (Chiu et al., 1986), whereas non-
polar metabolites were detected in fat tissue (Chiu et al.,
1988). In another study, such non-polar derivatives repre-
sented 64% of the radioactivity detected in fat on day 28
after treatment, and lengthened the depletion time of the
residues in fat compared to residues in liver (Chiu et al.,
1990a).
After SC injection, Chiu et al. (1990a) found that on day
7 after treatment, 1.5% and 62% of ivermectin was found in
urine and faeces, respectively (Chiu et al., 1990a). Toutain
et al. (1988) found that 5.5% of a SC dose was secreted via
the mammary gland and because of these high concentra-
tions milk from dairy cows treated with ivermectin must
be excluded from human consumption.
Chiu et al. (1990a) found that with IR treatment, the
percentage of ivermectin excreted in faeces and urine 7 days
after administration was 79.7% and 0.5%, respectively, and
its concentration in bile was high (273 ng/mL). Alvinerie
et al. (1998) reported that 8090% of drug delivered via
SRB systems was excreted faecally and the drug was
detected in faeces until day 160. This persistent excretion
could pose a threat to the ecosystem (through, for example,
dung-breeding/dung-feeding invertebrates).
Following topical application, ivermectin has a longer
plasma half-life in cattle prevented from licking (15.1 days)
than in those that are permitted to lick themselves (6.4
days); the half-life is also longer than after IV injection (6
days) reecting slow absorption through the skin, which
limits later elimination. Laont et al. (2001) measured
69% of the dose in faeces from lickers after 28 days of treat-
ment, and only 6.6% of the dose in faeces from non-lickers.
These results are consistent with ivermectin transiting
directly through the digestive tract into faeces, which con-
tributes greatly to the drugs faecal output (Laont et al.,
2001).
Sheep
Plasma levels of ivermectin are lower in sheep than in
cattle. The SC bioavailability is highly variable, ranging
from 22% (Lo et al., 1985) to 98.2% (Gonzalez et al.,
2007). Plasma concentrations are lower after oral versus
32 A. Gonzalez Canga et al. / The Veterinary Journal 179 (2009) 2537
SC administration (McKellar and Marriner, 1987). Thus,
as in other animal species, oral administration yields
poorer ecacy and a shorter duration of action.
As expected, absorption of ivermectin is faster after oral
administration of a solution versus tablets (Mestorino
et al., 2003). The Cmax and AUC obtained after oral
administration was greater in lambs versus ewes, probably
reecting dierences in body composition (especially fat
content) and to impaired elimination in lambs (Bogan
and McKellar, 1988). Ali and Hennessy (1996) demon-
strated that reducing feed intake for 24 h before IR admin-
istration could be a valid option to ensure the ecacy of
ivermectin, as it should increase the drugs bioavailability
and extend its residence time.
Distribution in the sheep (Table 5) is faster and broader
than in cattle or dogs (Lo et al., 1985) due to substantial
deposition into adipose tissue, which may act as a drug
depot (Prichard et al., 1985). The larger fat reservoir in
sheep compared to cattle could contribute to not only the
more extensive distribution but also the greater persistence
in plasma at lower concentrations, probably because less
blood is supplied to fatty tissues (Atta and Abo-Shihada,
2000). Likewise, the higher Vd in sheep versus cattle corre-
lates well with the lower plasma concentrations observed in
sheep.
As with cattle, Chiu et al. (1986) reported that
unchanged ivermectin represented >50% of the radioactiv-
ity in liver and fat, but in this case on day 3 after IR admin-
istration. Ivermectin levels decrease faster in sheep than in
cattle (Chiu et al., 1986). The main metabolites isolated in
the liver are the same in the two species and accounted for
55% of the radioactivity on day 7 after IR treatment. A sig-
nicant rst-pass eect was not evident in sheep, as intra-
abomasal bioavailability was 100% (Prichard et al., 1985).
Prichard et al. (1985) reported that IR administration in
sheep resulted in a low bioavailability (25%), similar to that
obtained in cattle. They also proposed that the ruminal
microora metabolise ivermectin, as 50% disappeared from
the rumen uid after 2-h incubation. Andrew and Halley
(1996) however attributed this disappearance to the high
level of binding to solids and surfaces. More recently, Lifs-
chitz et al. (2005) conrmed that ivermectin was thor-
oughly bound to solid ruminal contents (> 90%) without
suering degradation.
The IV half-life of ivermectin is similar in sheep and cat-
tle (Table 5); thus, the lower plasma levels in sheep are due
to a broader distribution rather than to faster elimination
(Lo et al., 1985). In sheep, concentrations in milk are sim-
ilar to those in plasma (Bogan and McKellar, 1988), and
only 0.71% of a SC dose was excreted through milk (less
than in cattle, probably due to species dierences in the vol-
ume and fat content of milk). However, Cerkvenik et al.
(2001) observed that ivermectin remains stable following
thermal treatment, conrming that residues in dairy prod-
ucts would be an issue for consumers.
Indirect exposure of untreated sucking lambs to iver-
mectin via milk ingestion is negligible; Cerkvenik et al.
(2002) found that only 2.1% of the dose was transferred
by treated ewes; this is lower than the oral value (10%).
Furthermore, the plasma concentration derived from trea-
ted dams was only 4% of that found in the same lambs trea-
ted orally. Although this seems low, it could have benecial
eects for lambs due to the high ecacy of ivermectin at a
low dosage. On the other hand, treatment of ewes over the
periparturient period has been recommended to reduce fae-
cal egg output and after only one SC dose this reduced fae-
cal output persists for approximately 1 week.
Goats
Studies in goats are limited but plasma levels tend to be
lower than those obtained in cattle and in sheep (Table 3).
The SC bioavailability is very high (91.8%) (Gonzalez
et al., 2006) and Scott et al. (1990) demonstrated that the
bioavailability of topically administered ivermectin was
61.5% of that found when the drug was orally adminis-
tered; persistence in plasma was, however, more prolonged
following the percutaneous route.
Ivermectin associates with lipoproteins in goats, prefer-
entially high density lipoprotein (88.1%), with binding per-
centages of 7.3% for low density lipoprotein, 1.8% for very
low density lipoprotein, and 2.7% for albumin and a-1 gly-
coprotein (Bassissi et al., 2004). This extensive binding to
lipoproteins could aect the delivery of ivermectin to fat
tissue and consequently relate to its extended presence in
the body.
Total body clearance after IV administration (Table 5)
demonstrated the slow elimination process in goats (Gonz-
alez et al., 2006). Excretion in milk is even lower than in
sheep with only 0.31% of the dose recovered in milk 25
days after SC treatment (Alvinerie et al., 1993). Scott
et al. (1990) observed that the concentrations excreted in
milk were similar after oral and topical administration.
Pigs
In pigs treated SC (Table 4), the Cmax and AUC are sig-
nicantly lower than in calves; this could be related to the
higher distribution and deposition of the drug in fat tissue,
which diminishes plasma levels in this animal species (Lifs-
chitz et al., 1999a). The inuence of body fat levels on iver-
mectin kinetics has been investigated in pigs, but the results
are not clear. Craven et al. (2001) reported that fat content
had no detectable inuence on ivermectin disposition and
they found no signicant dierences in the pharmacoki-
netic parameters representative of the distribution process
between two groups of pigs with dierent body conditions
(Table 6). In another study, these workers compared two
groups of animals diering in back-fat thickness and
weight (71.6 and 38.3 kg) and found that absorption was
slower and availability higher in fat pigs. Plasma levels
were >2 ng/mL until 18 days after treatment in fat pigs
and 11 days in thin pigs, suggesting a longer period of drug
ecacy (Craven et al., 2002a). When animals with an inter-
 A. Gonzalez Canga et al. / The Veterinary Journal 179 (2009) 2537 33

Table 4 domestic species have been found in hepatic and fat metab-
Absorption pharmacokinetic parameters obtained after ivermectin admin- olism; O-demethylation products were the metabolites
istration to monogastric species
found in liver. In contrast to other species, the same deriv-
Reference Route Cmax tmax AUC atives were also present in fat, accounting for the similar
(ng/mL) (h) (ng d/mL)
elimination half-lives (5 days) of residues from liver and
Pigs fat in swine (Chiu et al., 1990).
Scott and McKellar (1992) SC 28.4 27.2 71.41
Lifschitz et al. (1999a)a
Taking into account the half-life, the disappearance of
Formulation 1 SC 33.3 66d 165c ivermectin from plasma (Table 6) is faster in pigs than in
Formulation 2 SC 39.6 22.6d 132c cattle or sheep (Lo et al., 1985), suggesting briefer protec-
Craven et al. (2002a) tion against parasites in this animal species. Clearance is
Animals weighing 38.3 kg SC 9.7 33.2d 85.7d also higher than in ruminant species, which correlates well
Animals weighing 71.6 kg SC 7.4 71.9d 111.7d with the shorter half-life in pigs. On the other hand, body
Craven et al. (2002b) condition does not aect clearance when ivermectin is
Animals weighing 51 kg SC 8 75.1 70.5 administered IV (Craven et al., 2001) or SC (Craven
Animals weighing 60 kg SC 7.2 48 87.7 et al., 2002a,b). Chiu et al. (1990b) reported that on day
7 after SC treatment, the concentrations excreted in faeces
Horse
and urine were half those found in cattle (30% and 0.6% of
Marriner et al. (1987)b SC 60.7 80 550.4
Marriner et al. (1987) O 82.3 3.1 200.9 the dose, respectively). One day after treatment, high con-
Gokbulut et al. (2001) O 21.4 7.9 centrations were found in bile (210 ng/mL) and faeces
Perez et al. (2002)b O 51.3 3.6 137.1(0-30d) (178.5 ng/g) (Scott and McKellar, 1992).
Donkey
Horses
Gokbulut et al. (2005) O 23.6 24.0 119.3

Dog In contrast to ruminants, the absorption process in

Daurio et al. (1992) horses is faster after oral versus SC administration. More-
Standard tablet O 2.97 5.3 4.5 over, although SC injection results in greater bioavailabil-
Chewable tablet O 3.37 8.5 5.5
ity than does oral administration (AUCoral = 36.5% of
Daurio et al. (1992)e
Standard tablet O 44.3 4.2 43.1 the AUCsc), the oral route is preferred, as parenteral
Modied tablet (crystalline) O 48.4 3.8 41.7 administration can produce local swelling and other
Cmax = maximum plasma concentration; tmax = time to reach Cmax; adverse reactions (Anderson, 1984). Plasma concentrations
AUC = area under the plasma concentrationtime curve; = unknown are higher and more rapidly achieved in horses compared
data. SC = subcutaneous; O = oral; d = day(s). Doses are always those to sheep (Marriner et al., 1987) (Table 4), probably because
recommended by manufacturers, except if indicated. the rumen delays absorption in ruminant species. Never-
a
Propyleneglycol:glycerol-formal vehicle.
b theless, the elimination half-lives after SC and oral treat-
Two-compartmental model.
c
AUC01; if other, it is indicated as superscript in brackets. ment are 3.7 and 2.8 days, respectively, and similar to
d
Signicant dierences within the study. sheep (Marriner et al., 1987).
e
100 lg/kg. In horses, the MRT is also longer after oral administra-
tion (4.2 days) (Perez et al., 2002) versus SC injection (3
days) (Gokbulut et al., 2001); it is longer still in donkeys
mediate bodyweight were used, no dierences in kinetic dis- treated orally with ivermectin (6.5 days) (Gokbulut et al.,
position were observed (Craven et al., 2002b). 2005), where the elimination of ivermectin is slower, with
A higher Vd after IV administration was observed in a half-life of 7.4 days (Gokbulut et al., 2005). In horses
pigs when compared to sheep or cattle. Ivermectin also dis- treated SC, most of the dose (90%) is faecally excreted in
tributed widely in this species after SC administration, with 4 days. The higher concentrations found in equine faeces
the highest levels in liver and fat (Chiu et al., 1990b). compared to cattle faeces have been attributed to a lower
Twenty-four hours after injection, a large amount remains production of more concentrated faeces (Perez et al., 2001).
at the injection site, indicating a slow release process. Iver-
mectin has been detected at all levels of the gastrointestinal Dogs
tract (contents and mucus), with high concentrations in the
lungs, skin, and also earwax (accounting for its eective- In dogs, the oral route is preferred for heartworm pre-
ness against ectoparasites, particularly ear mites) (Scott vention. Absorption of ivermectin is faster in dogs than
and McKellar, 1992). in ruminants and pigs, and similar to horses. Peak plasma
Chiu et al. (1990) reported that on day 7 the parent drug levels are attained in 35 h (Table 4). Oral bioavailability is
represented 45% of radioactivity in the liver and the per- greater if the tablets are chewable. The amount absorbed
centage was slightly higher in fat tissue (63%). These levels follows a linear dose-relationship, as Cmax and AUC
decreased to 30% and 35%, respectively, on day 14 after increase proportionally with dose (Daurio et al., 1992).
drug administration. Dierences with respect to other The Vc (volume of distribution in the central compart-
34 A. Gonzalez Canga et al. / The Veterinary Journal 179 (2009) 2537

Table 5
Distribution and elimination pharmacokinetic parameters obtained after ivermectin administration to ruminants
Reference Route Vd (L/kg) t1/2a (d) t1/2b (d) MRT (d) t1/2 (d) Cl (L/kg d)
Cattle
Lo et al. (1985)a,b IV 1.9l 2.8
Echeverra et al. (1997)b IV 1.2m 3.4
Laont et al. (2001) IV 6 0.27
Bousquet-Melou et al. (2004)c IV 2.7m 8.1 7.8 0.35
Lifschitz et al. (1999b)d IM 5.2k
Chiu et al. (1990a)a SC 4.3
Echeverra et al. (1997)d SC 5.7
Lanusse et al. (1997)b SC 3.4m 4.2 17.2 7.4 0.48i
Lifschitz et al. (1999b)
Formulation 1d SC 5.9i
Formulation 2e SC 3.99i,k
Lifschitz et al. (1999a)e
Formulation 3 SC 5.3
Formulation 4 SC 6.3
Lifschitz et al. (2000) SC 5.8
Toutain et al. (1988)f,g SC 6.5
Chiu et al. (1990a) IR 3.7
Gayrard et al. (1999) T 8.4

Sheep
Lo et al. (1985)b IV 4.6l 2.7
Prichard et al. (1985) IV 5.3m 7.4 0.56
Gonzalez et al. (2007) IV 3.0l 0.7 9.6 10.3 1.11
Marriner et al. (1987)b SC 3.7
Atta and Abo-Shihada (2000)b SC 5.9 7
Cerkvenik et al. (2002)f,g SC 12.8m 5.2 2.9 3.24i
Echeverra et al. (2002)f
Healthy animals SC 8.8n 8.6 5.6
Parasitized animals SC 6.5n 6.7 5.5
Barber et al. (2003)f SC 1.7
Gonzalez et al. (2007) SC 17.6n 10.3 11 1.11
Marriner et al. (1987)b O 2.6
Atta and Abo-Shihada (2000) O 2.1
Mestorino et al. (2003)
Solution O 3.45 3.6
Tablets O 3.78 3.7
Chiu et al. (1990a)a IR 2.4
Prichard et al. (1985) IR 4.3

Goats
Gonzalez et al. (2006)b IV 2.8l 0.7 7.4 1.56
Gonzalez et al. (2006) SC 12.8n 8.3 5.6 1.43
Alvinerie et al. (1993)m,g SC 7.9 4.03
Escudero et al. (1997)g IR 2.62.8 1.181.24
Vd = volume of distribution; Vss = volume of distribution at steady state; t1/2a = half-life associated with a phase; t1/2b = half-life associated with b phase;
MRT = mean residence time; t1/2 = half-life; Cl = total body clearance; = unknown data. IV = intravenous; IM = intramuscular; SC = subcutaneous;
IR = intraruminal; T = topical; O = oral; d = day. Doses are always those recommended by manufacturers, except if indicated.
h
VSS/F.
a
300 lg/kg.
b
Two-compartment model.
c
70 lg/kg.
d
Oily vehicle.
e
Propyleneglycol:glycerol-formal vehicle (60:40, v/v).
f
One-compartment model.
g
Lactating animals.
i
Signicant dierences within the study.
k
Signicant dierences within the study.
l
Vc (volume of distribution in the central compartment).
m
Vss.
n
Va (volume of distribution of the area).
 A. Gonzalez Canga et al. / The Veterinary Journal 179 (2009) 2537 35

Table 6
Distribution and elimination pharmacokinetic parameters obtained after ivermectin administration to pigs
Reference Route Vc (L/kg) t1/2a (d) t1/2b (d) MRT (d) t1/2 (d) Cl (L/kg d)
a
Craven et al. (2001)
Animals weighing 28.5 kg IV 2.7 (5.1*) 0.14 1.18 0.5b 4.15
Animals weighing 41.7 kg IV 2.1 (5.3*) 0.15 1.33 0.7b 4.01
Lo et al. (1985) SC 0.5
Scott and McKellar (1992) SC 1.5
Lifschitz et al. (1999a) SC 3.53.8
Craven et al. (2002a)
Animals weighing 38.3 kg SC 8.1 3.55
Animals weighing 71.6 kg SC 9.8 2.75
Craven et al. (2002 b)
Animals weighing 50 kg SC 8.4 2.28 4.47
Animals weighing 60 kg SC 9.6 2.55 3.64
Vc; = volume of distribution in the central compartment; t1/2a = half-life associated with a phase; t1/2b = half-life associated with b phase; MRT = mean
residence time; t1/2 = half-life; Cl = total body clearance.
a
Two-compartmental model.
b
Signicant dierences within the study; = unknown data. IV = intravenous; SC = subcutaneous. Doses are always those recommended by man-
ufacturers, except if indicated.
*
Vss = volume of distribution at steady state.

ment) is 2.4 L/kg in dogs injected IV, intermediate between
values obtained in cattle and sheep (Lo et al., 1985). On the
other hand, excretion is more rapid in dogs versus cattle or
sheep (IV elimination half-life = 1.8 days) (Lo et al., 1985).
Conclusions
Although the ecacy of ivermectin has been established
across a variety of domestic species, its pharmacokinetic
properties dier between them, and the factors responsible
for modifying ivermectins pharmacokinetics should be
taken into account to ensure its clinical ecacy, prevent
subtherapeutic levels, and minimise the development of
resistance.
References
Ali, D.N., Hennessy, D.R., 1996. The eect of level of feed intake on
the pharmacokinetic disposition and ecacy of ivermectin in
sheep. Journal of Veterinary Pharmacology and Therapeutics 19,
8994.
Alvinerie, M., Sutra, J.F., Galtier, P., 1993. Ivermectin in goat plasma and
milk after subcutaneous injection. Annales de Recherches Veterinaires
24, 417421.
Alvinerie, M., Sutra, J.F., Galtier, P., Lifschitz, A., Virkel, G., Sallovitz,
J., Lanusse, C., 1998. Persistence of ivermectin in plasma and faeces
following administration of a sustained-release bolus to cattle.
Research in Veterinary Science 66, 5761.
Alvinerie, M., Sutra, J.F., Galtier, P., Toutain, P.L., 1994. Microdose
divermectine chez la vaca laitiere: concentrations plasmatiques et
residus dans le lait. Recueil de Medecine Veterinaire 145, 761764.
Alvinerie, M., Tardieu, D., Sutra, J.F., Bojensen, G., Galtier, P., 1994.
Metabolic prole of ivermectin in goats: an in vivo and in vitro
evaluation. In: Lees, P. (Ed.), European Association for Veterinary
Pharmacology and Toxicology. Proceedings of the 6th International
Congress. Blackwell Scientic Publications, Edinburgh, p. 262.
Anderson, R.R., 1984. The use of ivermectin in horses: research and
clinical observations. Compendium on Continuing Education 6, S517
S520.
Andrew, N.W., Halley, B.A., 1996. Stability of ivermectin in rumen uids.
Journal of Veterinary Pharmacology and Therapeutics 19, 295299.
Armour, J., Bairden, K., Batty, A.F., Davison, C.C., Ross, D.B., 1985.
Persistent anthelmintic activity of ivermectin in cattle. The Veterinary
Record 116, 151153.
Atta, A.H., Abo-Shihada, M.N., 2000. Comparative pharmacokinetics of
doramectin and ivermectin in sheep. Journal of Veterinary Pharma-
cology and Therapeutics 23, 4952.
Barber, S., Bowles, V., Lespine, A., Alvinerie, M., 2003. The comparative
serum disposition kinetics of subcutaneous administration of dora-
mectin, ivermectin and moxidectin in the Australian merino sheep.
Journal of Veterinary Pharmacology and Therapeutics 26, 343348.
Barth, D., 1983. Persistent anthelmintic eect of ivermectin in cattle. The
Veterinary Record 113, 300.
Bassissi, M.F., Alvinerie, M., Lespine, A., 2004. Macrocyclic lactones:
distribution in plasma lipoproteins of several animal species including
humans. Comparative Biochemistry and Physiology 138, 437444.
Benz, G.W., Roncalli, R.A., Gross, S.J., 1989. Use of ivermectin in cattle,
sheep, goats, and swine. In: Campbell, W.C. (Ed.), Ivermectin and
Abamectin. Springer-Verlag, New York, pp. 215229.
Bogan, J.A., McKellar, Q.A., 1988. The pharmacodynamics of ivermectin
in sheep and cattle. Journal of Veterinary Pharmacology and Ther-
apeutics 11, 260268.
Bousquet-Melou, A., Mercadier, S., Alvinerie, M., Toutain, P.L., 2004.
Endectocide exchanges between grazing cattle after pour-on adminis-
tration of doramectin, ivermectin and moxidectin. International
Journal of Parasitology 34, 12991307.
Bremner, K.C., Berrie, D.A., Hotson, I.K., 1983. Persistence of the
anthelmintic activity of ivermectin in calves. The Veterinary Record
113, 569.
Campbell, W.C., 1989. Ivermectin and Abamectin. Springer-Verlag, New
York.
Campbell, W.C., Benz, G.W., 1984. Ivermectin: a review of ecacy
and safety. Journal of Veterinary Pharmacology and Therapeutics
7, 116.
Cerkvenik, V., Doganoc, D.Z., Skubic, V., Beek, W.M.J., Keukens,
H.J., 2001. Thermal and long-term freezing stability of ivermectin
residues in sheep milk. European Food Research and Technology
213, 7276.
Cerkvenik, V., Grabnar, I., Skubic, V., Doganoc, D.Z., Beek, W.M.,
Keukens, H.J., Drobnic, M., Pogacnik, M., 2002. Ivermectin phar-
macokinetics in lactating sheep. Veterinary Parasitology 104, 175185.
36 A. Gonzalez Canga et al. / The Veterinary Journal 179 (2009) 2537
Chiu, S.H.L., Carlin, R., Taub, R., Sestokas, E., Zweig, J., Vandenheuvel,
W.J., Jacob, T.A., 1988. Comparative metabolic disposition of
ivermectin in fat tissues of cattle, sheep, and rats. Drug Metabolism
and Disposition 16, 728736.
Chiu, S.H.L., Green, M.L., Baylis, F.P., Eline, D., Rosegay, A.,
Meriwether, H., Jacob, T.A., 1990a. Absorption, tissue distribu-
tion, and excretion of tritium-labeled ivermectin in cattle, sheep,
and rat. Journal of Agricultural and Food Chemistry 38, 2072
2078.
Chiu, S.H.L., Sestokas, E., Taub, R., Buhs, R.P., Green, M., Sestokas, R.,
Vandenheuvel, W.J., Arison, B.H., Jacob, T.A., 1986. Metabolic
disposition of ivermectin in tissues of cattle, sheep, and rats. Drug
Metabolism and Disposition 14, 590600.
Chiu, S.H.L., Sestokas, E., Taub, R., Green, M.L., Baylis, F.P., Jacob,
T.A., Lu, A.Y.H., 1990b. Metabolic disposition of ivermectin in swine.
Journal of Agricultural and Food Chemistry 38, 20792085.
Craven, J., Bjrn, H., Hennesy, D., Friis, C., Nansen, P., 2001.
Pharmacokinetics of moxidectin and ivermectin following intravenous
injection in pigs with dierent body compositions. Journal of Veter-
inary Pharmacology and Therapeutics 24, 99104.
Craven, J., Bjrn, H., Hennesy, D.R., Friis, C., 2002a. The eects of body
composition on the pharmacokinetics of subcutaneously injected
ivermectin and moxidectin in pigs. Journal of Veterinary Pharmacol-
ogy and Therapeutics 25, 227232.
Craven, J., Hennessy, D.R., Friis, C., 2002b. Does the rate of fat
deposition inuence the pharmacokinetic disposition of subcutane-
ously administered moxidectin and ivermectin in pigs? Journal of
Veterinary Pharmacology and Therapeutics 25, 351357.
Daurio, C.P., Cheung, E.N., Jecoat, A.R., Skelly, B.J., 1992. Bioavail-
ability of ivermectin administered orally to dogs. Veterinary Research
Communications 16, 125130.
Echeverra, J., Mestorino, N., Errecalde, J., 2002. Comparative pharma-
cokinetics of ivermectin after its subcutaneous administration in
healthy sheep and sheep infected with mange. Journal of Veterinary
Pharmacology and Therapeutics 25, 159160.
Echeverra, J., Mestorino, N., Giorgieri, S., Turic, E., Alt, M., Errecalde,
J., 1997. Pharmacokinetics of ivermectin after its intravenous and
subcutaneous administration to cattle. Journal of Veterinary Pharma-
cology and Therapeutics 20, 7778.
Escudero, E., Carceles, C.M., Galtier, P., Alvinerie, M., 1997. Inuence of
fasting on the pharmacokinetics of ivermectin in goats. Journal of
Veterinary Pharmacology and Therapeutics 20, 7172.
Gayrard, V., Alvinerie, M., Toutain, P.L., 1999. Comparison of pharma-
cokinetic proles of doramectin and ivermectin pour-on formulations
in cattle. Veterinary Parasitology 81, 4755.
Gokbulut, C., Boyacioglu, M., Karademir, U., 2005. Plasma pharmaco-
kinetics and faecal excretion of ivermectin (Eqvalan paste) and
doramectin (Dectomax, 1%) following oral administration in don-
keys. Research in Veterinary Science 79, 233238.
Gokbulut, C., Nolan, A.M., McKellar, Q.A., 2001. Plasma pharmacoki-
netics and faecal excretion of ivermectin, doramectin and moxidectin
following oral administration in horses. Equine Veterinary Journal 33,
494498.
Gonzalez, A., Sahagun, A., Diez, M.J., Fernandez, N., Sierra, M., Garcia,
J.J., 2007. Bioavailability of a commercial formulation of ivermectin
after subcutaneous administration to sheep. American Journal of
Veterinary Research 68, 101106.
Gonzalez, A., Sahagun, A.M., Diez, M.J., Fernandez, N., Sierra, M.,
Garcia, J.J., 2006. Pharmacokinetics of a novel formulation of
ivermectin after administration to goats. American Journal of Veter-
inary Research 67, 323328.
Laont, C.M., Alvinerie, M., Bousquet-Melou, A., Toutain, P.L., 2001.
Licking behaviour and environmental contamination arising from
pour-on ivermectin for cattle. International Journal of Parasitology 3,
16871692.
Laont, C.M., Toutain, P.L., Alvinerie, M., Bousquet-Melou, A., 2002.
Intestinal secretion is a major route for parent ivermectin elimination
in the rat. Drug Metabolism and Disposition 30, 626630.
Lanusse, C., Lifschitz, A., Virkel, G., Alvarez, L., Sanchez, S., Sutra,
J.F., Galtier, P., Alvinerie, M., 1997. Comparative plasma
disposition kinetics of ivermectin, moxidectin and doramectin in
cattle. Journal of Veterinary Pharmacology and Therapeutics 20,
9199.
Lifschitz, A., Murno, G., Pis, A., Sallovitz, J., Virkel, G., Lanusse, C.,
1997. Malnutrition modies the disposition kinetics of ivermectin in
calves. Journal of Veterinary Pharmacology and Therapeutics 20, 71
72.
Lifschitz, A., Pis, A., Alvarez, L., Virkel, G., Sanchez, S., Sallovitz, J.,
Kujanek, R., Lanusse, C., 1999a. Bioequivalence of ivermectin
formulations in pigs and cattle. Journal of Veterinary Pharmacology
and Therapeutics 22, 2734.
Lifschitz, A., Sallovitz, J., Imperiale, F., Pis, A., Lorda, J., Lanusse, C.,
2004. Pharmacokinetic evaluation of four generic formulations in
calves. Veterinary Parasitology 119, 247257.
Lifschitz, A., Virkel, G., Ballent, M., Sallovitz, J., Pis, A., Lanusse, C.,
2005. Moxidectin and ivermectin metabolic stability in sheep ruminal
and abomasal contents. Journal of Veterinary Pharmacology and
Therapeutics 28, 411418.
Lifschitz, A., Virkel, G., Pis, A., Imperiale, F., Sanchez, S., Alvarez, L.,
Kujanek, R., Lanusse, C., 1999b. Ivermectin disposition kinetics after
subcutaneous and intramuscular administration of an oil-based
formulation to cattle. Veterinary Parasitology 86, 203215.
Lifschitz, A., Virkel, G., Sallovitz, J., Sutra, J.F., Galtier, P., Alvinerie,
M., Lanusse, C., 2000. Comparative distribution of ivermectin and
doramectin to parasite location tissues in cattle. Veterinary Parasitol-
ogy 87, 327338.
Lo, P.K.A., Fink, D.W., Williams, J.B., Blodinger, J., 1985. Pharmaco-
kinetic studies of ivermectin: eects of formulation. Veterinary
Research Communications 9, 251258.
Marriner, S.E., McKinnon, I., Bogan, J.A., 1987. The pharmacokinetics
of ivermectin after oral and subcutaneous administration to sheep and
horses. Journal of Veterinary Pharmacology and Therapeutics 10, 175
179.
McKellar, Q.A., Benchaoui, H.A., 1996. Avermectins and milbemyc-
ins. Journal of Veterinary Pharmacology and Therapeutics 19,
331351.
McKellar, Q.A., Jackson, F., Coop, R.L., Jackson, E., Scott, E., 1991.
Eect of parasitism with Nematodirus battus on the pharmacokinetics
of levamisole, ivermectin, and netobimin. Veterinary Parasitology 39,
123136.
McKellar, Q.A., Marriner, S.E., 1987. Comparison of the anthelmintic
ecacy of oxfendazole or ivermectin administered orally and ivermec-
tin administered subcutaneously to sheep during the periparturient
period. The Veterinary Record 18, 383386.
Mestorino, N., Turic, E., Pesoa, J., Echeverra, J., Errecalde, J.O., 2003.
Pharmacokinetics in plasma of ivermectin after its oral (solution and
tablets) administration to sheep. Journal of Veterinary Pharmacology
and Therapeutics 26, 307309.
Molento, M.B., Lifschitz, A., Sallovitz, J., Lanusse, C., Prichard, R., 2004.
Inuence of verapamil on the pharmacokinetics of the antiparasitic
drugs ivermectin and moxidectin in sheep. Parasitology Research 92,
121127.
Perez, R., Cabezas, I., Godoy, C., Rubilar, L., Munoz, L., Arboix, M.,
Castells, G., Alvinerie, M., 2002. Pharmacokinetics of doramectin and
ivermectin after oral administration in horses. The Veterinary Journal
163, 161167.
Perez, R., Cabezas, I., Sutra, J.F., Galtier, P., Alvinerie, M., 2001. Fecal
excretion prole of moxidectin and ivermectin after oral administra-
tion in horses. The Veterinary Journal 161, 8592.
Prichard, R.K., Steel, J.W., Lacey, E., Hennessy, D.R., 1985. Pharmaco-
kinetics of ivermectin in sheep following intravenous, intra-abomasal
or intraruminal administration. Journal of Veterinary Pharmacology
and Therapeutics 8, 8894.
Rohrer, S.P., Evans, D.V., 1990. Binding characteristics of ivermectin in
plasma from Collie dogs. Veterinary Research Communications 14,
157165.
 A. Gonzalez Canga et al. / The Veterinary Journal 179 (2009) 2537 37

Scott, E.W., Kinabo, L.D., McKellar, Q.A., 1990. Pharmacokinetics of
ivermectin after oral administration to adult milking goats. Journal of
Veterinary Pharmacology and Therapeutics 13, 432435.
Scott, E.W., McKellar, Q.A., 1992. The distribution and some pharma-
cokinetic parameters of ivermectin in pigs. Veterinary Research
Communications 16, 139146.
Steel, J.W., 1993. Pharmacokinetics and metabolism of avermectins in
livestock. Veterinary Parasitology 48, 4547.
Toutain, P.L., Campan, M., Galtier, P., Alvinerie, M., 1988. Kinetic
and insecticidal properties of ivermectin residues in the milk of
dairy cows. Journal of Veterinary Pharmacology and Therapeutics
11, 288291.


ELECTRONICCODEOFFEDERALREGULATIONS

eCFRdataiscurrentasofDecember1,2016

Title21ChapterISubchapterEPart522522.1192

Title21:FoodandDrugs
PART522IMPLANTATIONORINJECTABLEDOSAGEFORMNEWANIMALDRUGS

522.1192Ivermectin.

(a)Specifications(1)Eachmilliliter(mL)ofsolutioncontains20milligrams(mg)ivermectin.

(2)EachmLofsolutioncontains10mgivermectin.

(3)EachmLofsolutioncontains2.7mgivermectin.

(b)Sponsors.Seesponsorsin510.600(c)ofthischapterforuseasinparagraph(e)ofthissection.

(1)No.050604foruseoftheproductdescribedinparagraph(a)(1)ofthissectionasinparagraph(e)(1)ofthis
sectiontheproductdescribedinparagraph(a)(2)ofthissectionasinparagraphs(e)(2),(e)(3),(e)(4),and(e)(5)ofthis
sectionandtheproductdescribedinparagraph(a)(3)ofthissectionasinparagraphs(e)(3)and(e)(6)ofthissection.

(2)Nos.016592,055529,058005,and061623foruseoftheproductdescribedinparagraph(a)(2)ofthissectionas
inparagraphs(e)(2),(e)(3),(e)(4),and(e)(5)ofthissection.

(d)Specialconsiderations(1)See500.25ofthischapter.

(2)Labelingshallbearthefollowingprecaution:Thisproductshouldnotbeusedinotheranimalspeciesassevere
adversereactions,includingfatalitiesindogs,mayresult.

(e)Conditionsofuse(1)Horses(i)Amount.200microgramsperkilogram(g/kg)ofbodyweightbyintramuscular
injection.

(ii)Indicationsforuse.Forthetreatmentandcontroloflargestrongyles(adult)(Strongylusvulgaris,S.edentatus,
Triodontophorusspp.),smallstrongyles(adultandfourthstagelarvae)(Cyathostomumspp.,Cylicocyclusspp.,
Cylicostephanusspp.),pinworms(adultandfourthstagelarvae)(Oxyurisequi),largeroundworms(adult)(Parascaris
equorum),hairworms(adult)(Trichostrongylusaxei),largemouthstomachworms(adult)(Habronemamuscae),neck
threadworms(microfilariae)(Onchocercaspp.),andstomachbots(Gastrophilusspp.).

(iii)Limitations.Notforuseinhorsesintendedforhumanconsumption.Federallawrestrictsthisdrugtousebyoron
theorderofalicensedveterinarian.

(2)Cattle(i)Amount.200g/kgofbodyweightbysubcutaneousinjection.

(ii)Indicationsforuse.Forthetreatmentandcontrolofgastrointestinalnematodes(adultsandfourthstagelarvae)
(Haemonchusplacei,Ostertagiaostertagi(includinginhibitedlarvae),O.lyrata,Trichostrongylusaxei,T.colubriformis,
Cooperiaoncophora,C.punctata,C.pectinata,Oesophagostomumradiatum,Nematodirushelvetianus(adultsonly),N.
spathiger(adultsonly),Bunostomumphlebotomum)lungworms(adultsandfourthstagelarvae)(Dictyocaulusviviparus)
grubs(parasiticstages)(Hypodermabovis,H.lineatum)suckinglice(Linognathusvituli,Haematopinuseurysternus,
Solenopotescapillatus)mites(scabies)(Psoroptesovis(syn.P.communisvar.bovis),Sarcoptesscabieivar.bovis).For
controlofinfectionsandtoprotectfromreinfectionwithD.viviparusandO.radiatumfor28daysaftertreatmentO.
ostertagi,T.axei,andC.punctatafor21daysaftertreatmentH.placeiandC.oncophorafor14daysaftertreatment.

(iii)Limitations.Donottreatcattlewithin35daysofslaughter.Becauseawithdrawaltimeinmilkhasnotbeen
established,donotuseinfemaledairycattleofbreedingage.Awithdrawalperiodhasnotbeenestablishedforthis
productinpreruminatingcalves.Donotuseincalvestobeprocessedforveal.

(3)Swine(i)Amount.300g/kgofbodyweightbysubcutaneousinjection.

(ii)Indicationsforuse.Forthetreatmentandcontrolofgastrointestinalroundworms(adultsandfourthstagelarvae)
(largeroundworm,Ascarissuumredstomachworm,Hyostrongylusrubidusnodularworm,Oesophagostomumspp.
threadworm,Strongyloidesransomi(adultsonly))somaticroundwormlarvae(threadworm,S.ransomi(somaticlarvae))
lungworms(Metastrongylusspp.(adultsonly))lice(H.suis)andmites(S.scabieivar.suis).

(iii)Limitations.Donottreatswinewithin18daysofslaughter.
 (4)Americanbison(i)Amount.200g/kgofbodyweightbysubcutaneousinjection.

(ii)Indicationsforuse.Forthetreatmentandcontrolofgrubs(H.bovis).

(iii)Limitations.Donotslaughterwithin56daysoflasttreatment.

(5)Reindeer(i)Amount.200g/kgofbodyweightbysubcutaneousinjection.

(ii)Indicationsforuse.Forthetreatmentandcontrolofwarbles(Oedemagenatarandi).

(iii)Limitations.Donottreatreindeerwithin56daysofslaughter.

(6)Ranchraisedfoxes(i)Amount.200g/kgofbodyweightbysubcutaneousinjection.Repeatin3weeks.

(ii)Indicationsforuse.Fortreatmentandcontrolofearmites(Otodectescynotis).

[72FR27735,May17,2007,asamendedat72FR62771,Nov.7,200774FR9049,Mar.2,200975FR26647,May12,201076
FR57906,Sept.19,201178FR17597,Mar.22,201381FR59134,Aug.29,2016]

Needassistance?
 British Veterinary Zoological Sociey Proceedings May 2008

SKIN DISEASES OF SOUTH AMERICAN CAMELIDS

Aiden Foster
a.foster@vla.defra.gsi.gov.uk

Introduction
The South American camelids (SACs): Lama glama (llama), L. quanicoe (guanaco), Vicugna
pacos (alpaca), and V. vicugna (vicua) have been growing in popularity as sources of hair (fibre) in
North America and Europe. Dermatological problems can be a major challenge for veterinary
clinicians dealing with alpaca herds. The aim of this article is to review some of the ectoparasitic skin
conditions that may be found in alpacas and llamas in the United Kingdom. Other aspects of skin
conditions in SACs have been briefly reviewed elsewhere (Foster et al. 2007).

Chorioptic Mange
Chorioptic mange in SACs is usually assumed to involve Chorioptes bovis. Clinical signs
may include mild pruritus, alopecia and scaling of the feet and tail base with extension to the ventral
abdomen, medial limbs, and the ears. Chorioptes mites may be found by collecting superficial skin
scrapings from animals with or without overt signs of skin disease. While the distribution of clinical
signs may be similar to Sarcoptic mange some authors propose that one difference is that the skin can
be very thickened in sarcoptic mange. However, like many chronic skin problems, thickening may
also be a feature of idiopathic hyperkeratosis syndromes and chronic Chorioptic mange. Ideally all
animals in the group should be sampled because like horses with Chorioptic mange there may be mild
or absent clinical signs but mites could still be present consistent with asymptomatic carriage. This
may reflect that some animals like horses may harbour low-level infestations with no ill effect, while
some other animals with severe skin problems may be suffering from a hypersensitivity response.
Good sites for collecting scrapings are the dorsal interdigital and axilla areas. Skin scale and
debris can be collected with a blunted size 10 scalpel blade and mounted with a cover slip in liquid
paraffin. The mites are quite large and can be seen with the naked eye when present in large numbers,
although low power microscopic examination will be required to identify the mites.

Psoroptic mange
The typical lesion of infestation is crusting associated with papules and serum exudate from
the site of where the mites have been feeding on superficial exudate and skin debris by abrading the
stratum corneum of the epidermis with their mouthparts. Pruritus and fibre loss is particularly
associated with the pinna and ear canal, although the pruritus and mite distribution has also been
reported to be generalised and not to include the ear canal. Other locations may include the shoulders,
back, sides, tail head, perineum, nares, axillae, groin, neck and legs.
There is currently some debate about the identification of Psoroptes mites and so it is prudent
to call SAC isolates Psoroptes sp. until further analysis has been carried out. There is an obvious
concern about SACs being a potential reservoir for the infestation of sheep with sheep scab mites.
Microscopic examination of superficial skin scrapes and ear swabs rubbed into the vertical ear canal
and then rolled into liquid paraffin on a slide should enable identification of the mites with their
characteristic morphology. Chorioptes mites may also be found in the ear canal and on the pinnae.

The University of Bristol have a PhD study looking at goats, llamas and alpacas as potential reservoir hosts of
Psoroptes ovis in the UK; for more information please contact Dr Eric Morgan or Prof Richard Wall (School of
Biological Sciences).

Sarcoptic mange
Clinical signs of infestation with Sarcoptes scabiei var auchinae include pruritus (which can
be severe) with hyperaemia, papules, pustules with crusting present on limbs including between the
toes, medial thighs, ventral abdomen, chest, axilla, perineum and prepuce. There is a significant
zoonotic risk of spread to human handlers with this disease. Again microscopic examination of
superficial skin scrapings should allow identification of mites. Infestation may arise from other
species.

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 British Veterinary Zoological Sociey Proceedings May 2008

Lice
Infestation with biting lice (Bovicola breviceps) has been reported in Australia, New Zealand
and the UK (Duff et al. 1999) while sucking lice (Microthoracius sp) have not been reported in the
UK. Clinical signs may include pruritus with matted hair and alopecia in heavy infestations. Lesions
are most likely to be observed at the base of the tail and along the neck and trunk in biting lice, and
around the head, neck and withers in sucking lice. While sucking lice may respond to injectable
ivermectin-based products, the topical therapies available for biting lice are limited. In the UK,
alpacas could be treated with topical permethrin-based products such as deltamethrin as a spot-on/pour
on product. The prevalence of lice in SACs in the UK is unknown.

Treatment for mites

All three species of mites (Sarcoptes, Chorioptes and Psoroptes) have been observed in
alpacas in the UK. Some SACs may have concurrent infestation with Chorioptes and either
Psoroptes or Sarcoptes mites; or even with all three types of mite.
Llama and alpaca fibre does not contain lanolin; consequently topical applications of
insecticidal/acaricidal products used on other ruminants may not be as effective in SACs.
Consequently there may be reliance upon the use of systemic therapies particularly
macrocyclic lactones.
In order to achieve a high rate of successful treatment with any form of suspected or
confirmed mite infestation owners should weigh and treat all animals within a herd with an
accurately measured dose.
In the case of the surface-dwelling Chorioptes mites - that feed on epidermal debris - repeated
administration of injectable or topical macrocyclic lactone products may substantially reduce
but not always totally eradicate infestation in a herd. Consequently eliminating such
infestations may also require application of acaricidal sprays such as fipronil-based products.
In one study there was a good response (but not complete eradication of mites) to weekly
topical application of an eprinomectin-based product at a dose of 500 micrograms/kg, for four
treatments (DAlterio et al. 2005a).
Some SACs are treated with sprays or even dips used for the control of flies or mites in sheep.
Dipping can be stressful for SACs and there is no information about safety of dip products
(particularly organophosphates) in SACs, so it is not recommended.
Topical application of fly repellents including pyrethroid-based products should be used with
care, especially in crias, because of the potential risk of neurological side effects.
Chorioptes mites appear to be very common in herds unlike other ectoparasites (DAlterio et
al. 2005b).
In one recent report (Lau et al. 2007) alpacas severely and chronically infested with sarcoptes
mites were treated with amitraz because there had been a poor response to application of
eprinomectin and administration of doramectin. Similar studies from Belgium suggest that
scabies may not be easy to treat and deaths from severe skin disease may be observed. In
South America large scale epidemics with deaths in llamas may be attributable to scabies.
Pharmacokinetic studies of macrocyclic lactones in SACs are limited in number but suggest
that compared with other ruminants that absorption is somewhat lower whatever route of
administration. The clinical impact of the potential differences between SACs and other
ruminants in the metabolism of macrocyclic lactones is unclear.
There have also been suggestions of using higher than label doses of ivermectin-based
products for ectoparasites in alpacas and llamas such as 400 micrograms / kg subcutaneously
on a weekly basis because of perceived ineffectiveness of standard dosages used in other
ruminants.

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 British Veterinary Zoological Sociey Proceedings May 2008

Despite the apparent poor absorption of topical and subcutaneous injections of ivermectin a number of
authors have used ivermectin at 200 micrograms / kg by subcutaneous injection with variable, but
usually good, effect for the treatment of various parasite species including psoroptic and sarcoptic
mange, and sucking lice in SACs. Similarly good responses may be observed with the topical use of
products containing eprinomectin, doramectin and moxidectin.
There is clearly a need for controlled clinical trial work to clarify the dosing regimen for
macrocyclic lactones and other products for alpacas and llamas with various types of mite (or lice)
infestation.

References
DAlterio GL, Jackson AP, Knowles TG Foster AP (2005a) Comparative study of the efficacy of
eprinomectin versus ivermectin, and field efficacy of eprinomectin only, for the treatment of
Chorioptes mange in alpacas. Veterinary Parasitology 130, 267-275.
D Alterio GL, Callaghan C, Just C, Manner-Smith A, Foster AP, Knowles TG (2005b) Prevalence of
Chorioptes sp. mite infestation in alpaca (Lama pacos) in the south-west of England:
implications for skin health. Small Ruminant Research 57, 221-228.
Duff JP, Maxwell AJ, Claxton JR (1999) Chronic and fatal fascioliasis in llamas in the UK. Veterinary
Record 145: 315-6.
Foster AP, Jackson AP, D' Alterio GL (2007) Skin diseases of South American camelids. In Practice
29, 216-223.
Lau P, Hill PB, Rybnek J, Steel L (2007) Sarcoptic mange in three alpacas treated successfully with
amitraz. Veterinary Dermatology 18: 272277.

- 32 -
 SITUACIN ACTUAL DE LOS CAMLIDOS
SUDAMERICANOS EN PER

Proyecto de Cooperacin Tcnica

en apoyo a la crianza y aprovechamiento de los
Camlidos Sudamericanos en la Regin Andina
TCP/RLA/2914

Junio, 2005

ORGANIZACIN DE LAS NACIONES UNIDAS PARA LA AGRICULTURA Y LA

ALIMENTACIN
 1

Las denominaciones empleadas en esta publicacin y la forma en que

aparecen presentados los datos que contiene no implican, de parte de la
Organizacin de las Naciones Unidas para la Agricultura y la
Alimentacin, juicio alguno sobre la condicin jurdica de pases,
territorios, ciudades o zonas, o de sus autoridades, ni respecto de la
delimitacin de sus fronteras y lmites.

Todos lo derechos reservados. Se autoriza la reproduccin y difusin

del material contenido en este producto informativo para fines
educativos u otros fines no comerciales sin previa autorizacin escrita
de los titulares de los derechos de autor, siempre que se especifique
claramente la fuente. Se prohbe la reproduccin de material contenido
en este producto informativo para reventa u otros fines comerciales sin
previa autorizacin escrita de los titulares de los derechos de autor. Las
peticiones para obtener tal autorizacin debern dirigirse al Jefe del
Servicio de Gestin de las Publicaciones de la Direccin de
Informacin de la FAO, Viale delle Terme di Caracalla, 00100 Roma,
Italia, o por correo electrnico a copyright@fao.org.

(c) FAO 2005

 2

INDICE

INDICE................................................................................................................................... 2
PROLOGO ............................................................................................................................. 3
RESUMEN EJECUTIVO ...................................................................................................... 5
EXECUTIVE SUMMARY .................................................................................................... 7
1. INTRODUCCIN........................................................................................................... 11
2. CENSO Y DISTRIBUCION DE LOS CAMELIDOS SUDAMERICANOS ......... 13
2.1 ALPACAS ............................................................................................................. 13
2.2 LLAMAS.............................................................................................................. 15
2.3 VICUAS Y GUANACOS .................................................................................. 16
3. CARACTERIZACIN SOCIOECONMICA DE LOS PRODUCTORES DE
CAMLIDOS................................................................................................................... 19
4. SISTEMAS DE EXPLOTACIN: ESPECIES DOMESTICAS............................. 21
4.1. ESTRUCTURA DE LOS REBAOS POR EDAD Y SEXO ........................... 22
4.2. PRACTICAS DE MANEJO................................................................................. 23
4.2.1. Alimentacin ................................................................................................. 23
4.2.2. Empadre (Manejo reproductivo) ................................................................... 24
4.2.3 Paricin y destete............................................................................................ 26
4.2.4 Esquila ............................................................................................................ 26
4.2.5 Seleccin y mejoramiento gentico................................................................ 28
5. MANEJO DE LA VICUA........................................................................................ 31
6. APROVECHAMIENTO DE LA FIBRA.................................................................... 33
6.1 Fibra de alpaca........................................................................................................ 33
6.2 Fibra de llama. ........................................................................................................ 36
6.3 Fibra de vicua ....................................................................................................... 37
7. APROVECHAMIENTO DE LA CARNE .................................................................. 39
8. PREVENCION Y CONTROL DE ENFERMEDADES.............................................. 43
8.1 ENFERMEDADES INFECCIOSAS ..................................................................... 44
8.1.1 ENFERMEDADES DE CRIAS. ..................................................................... 44
8.1.2 ENFERMEDADES DE TUIS Y ADULTOS ................................................ 46
8.2 ENFERMEDADES PARASITARIAS ................................................................. 46
8.2.1 NEUMOGASTROENTERITIS PARASITARIA.......................................... 47
8.2.2 SARCOCISTIOSIS ........................................................................................ 48
8.2.3 HIDATIDOSIS............................................................................................... 49
8.2.4 DISTOMATOSIS.......................................................................................... 49
8.2.5 ENFERMEDADES PRODUCIDAS POR ECTOPARSITOS.................... 49
9. CONCLUSIONES Y PERSPECTIVAS ...................................................................... 51
REFERENCIAS BIBLIOGRAFICAS ............................................................................. 53
ANEXO I.............................................................................................................................. 56
ANEXO II ............................................................................................................................ 60
 3

PROLOGO

Los Camlidos Sudamericanos (CSA) son una riqueza pecuaria y gentica de las poblaciones
andinas. Bajo el trmino CSA se incluyen dos especies domsticas, la alpaca (Lama pacos) y la
llama (Lama glama), y a dos silvestres, la vicua (Lama vicugna) y el guanaco (Lama guanicoe).

Los CSA son fuente de fibra, carne, de trabajo y de muchos productos que son indispensables para
la subsistencia de un amplio sector de la poblacin alto andina, destacndose su eficiencia en el uso
de la tierra en un ambiente adverso como lo son las frgiles praderas de los pramos andinos de los
cinco pases donde se concentra la mayor poblacin natural de estas especies; Argentina, Bolivia,
Chile, Ecuador y Per.

El rol de los CSA en la seguridad alimentaria es de gran importancia en las poblaciones asentadas
en las zonas alto-andinas, por ser un medio de carga y transporte, por su fibra para vestimenta, la
carne como fuente de protena, los excrementos como combustible y fertilizante. Se estima que el
90 por ciento de las alpacas y la totalidad de las llamas se encuentra en manos de pequeos
productores de subsistencia de estos asentamientos.

La crianza de alpacas y llamas es una actividad econmica relevante para las regiones andinas,
destacando la produccin de fibra fundamentalmente la de alpaca que posee una alta valoracin en
los mercados internacionales por su fina textura.

La carne en forma contraria, tanto de llama como de alpaca, posee un consumo bajsimo en los
medios urbanos, pese a sus extraordinarias cualidades nutritivas, como lo son el bajo porcentaje de
grasa y un nivel de protena ms alto en relacin a otras especies, caractersticas adecuadas para los
perfiles nutricionales de las sociedades modernas.

El mayor problema que limita la aceptacin de la carne de camlidos para el consumo humano, es el
de la sarcocistiosis, enfermedad parasitaria que no afecta al hombre pero altera su aceptabilidad al
generar un aspecto desagradable al producto, y ser confundida con otra parasitosis de alto potencial
zoontico. Se suma a ello que se considera a la carne de camlidos como alimento nico de
campesinos y no para las poblaciones urbanas debido a la idiosincrasia entre las personas del
burgo.

Debido a lo manifestado y a que la produccin y aprovechamiento de los camlidos constituyen

grandes posibilidades para el desarrollo socioeconmico del sector peculio de las comunidades alto-
andinas en diferentes aspectos de seguridad alimentaria, alivio de la pobreza, y calidad higinica
nutritiva, la FAO, a solicitud de los pases andinos aprob el proyecto de cooperacin tcnica
Apoyo a la crianza y aprovechamiento de los camlidos sudamericanos en la Regin Andina
(TCP/RLA/2914).
 4

La FAO desea agradecer al Sr. Sal Fernndez-Baca autor de este documento, por la dedicacin
empleada para su elaboracin, el que recopila informacin actualizada de la biologa, la patologa y
estado situacional de los CSA en Per. Este documento pertenece a una serie de cinco trabajos
realizados bajo el marco del proyecto, que describen las condiciones actuales de los CSA en
Argentina, Bolivia, Chile, Ecuador y Per.

M. Vargas-Tern
Oficial de Salud Animal FAO/RLC
 5

RESUMEN EJECUTIVO

Este informe es el resultado de una consultora dentro del Proyecto TCP/RLA/2914, Apoyo a la
crianza y aprovechamiento de los camlidos sudamericanos en la Regin Andina, financiado por la
Organizacin de las Naciones Unidas para la Agricultura y la Alimentacin (FAO) y ejecutado por
la Universidad Peruana Cayetano Heredia, en colaboracin con el Consejo Nacional de Camlidos
Sudamericanos.

El informe seala la importancia econmica, social, cultural y cientfica de los camlidos

sudamericanos (CSA). Las especies domsticas, alpaca y llama, constituyen el principal medio de
subsistencia de un vasto sector de la poblacin de las zonas alto andinas del Per, a travs del aporte
de fibra, carne, energa de trabajo y otros subproductos. Entre las especies silvestres, la ms
importante es la vicua que aporta una fibra de excepcional calidad. El Per posee alrededor de 3
millones de alpacas, un milln de llamas y alrededor de 125 mil vicuas; la mayora se encuentra en
los Departamentos de la sierra sur, particularmente Puno y Cusco. El Per ocupa el primer lugar en
el mundo en cuanto a nmero de alpacas y vicuas. La poblacin de guanacos es muy reducida,
alrededor de 5 mil cabezas.

Ms del 80 por ciento de las alpacas y la casi totalidad de llamas son de propiedad de comunidades
campesinas y pequeos productores de muy escasos recursos y carentes de servicios y vas de
comunicacin adecuados. El resto de alpacas se distribuye entre los medianos productores y las
empresas asociativas.

Las prcticas de manejo de alpacas y llamas, en la mayora de casos, son de tipo tradicional,
carentes de innovaciones tecnolgicas. Enfrentan problemas de diversa ndole siendo las ms
relevantes la alta mortalidad de cras y la deficiente calidad de la carne debido a la presencia de
sarcocistes. A esto se agregan las bajas tasas de natalidad debido a la mortalidad embrionaria y
deficiente manejo reproductivo, el empobrecimiento de las praderas de pastos naturales debido al
sobrepastoreo, la baja calidad de la fibra debido a la falta de programas de seleccin. Todo ello
resulta en baja produccin y pobre rentabilidad para el productor.

La vicua est considerada como un patrimonio nacional pero est autorizado su usufructo por las
comunidades campesinas y otras personas naturales o jurdicas en cuyo territorio pastan las vicuas,
bajo estricta supervisin y control del Consejo Nacional de Camlidos Sudamericanos (CONACS)
y el Instituto Nacional de Recursos Naturales (INRENA), ambos organismos del Estado. La fibra de
vicua, procedente de la esquila de animales vivos, alcanza alrededor de 5 000 k por ao. Se
comercializa bajo el sello de Vicua-Per en el caso de empresas industriales textiles y Vicua-
Per-Artesana en el caso de las empresas artesanales.

La fibra de alpaca, cuya produccin alcanza cerca de 3 400 toneladas anuales, es destinada en un
85 por ciento a la industria, la mayora para exportacin, y el 15 por ciento a la artesana y
autoconsumo. La fibra de llama (alrededor de 800 toneladas por ao) se destina mayormente a
artesana y autoconsumo.

La carne de alpaca y llama se consume ya sea fresca o deshidratada (charqui y chalona). Tambin se
usa en embutidos en forma an limitada. La matanza se realiza en mataderos destinados a otras
especies animales; sin embargo una parte considerable se beneficia en forma casera y bajo
condiciones higinicas deficientes. La carne de camlidos tiene una composicin nutritiva similar a
otras carnes por lo que tiene un gran potencial para consumo humano tanto en el mercado local
 6

como en el de exportacin. La limitacin principal es la presencia de sarcocistes en la musculatura

esqueltica y cardiaca de la casi totalidad de animales mayores de dos aos de edad, lo que da lugar
a decomiso.

Las enfermedades ocasionan grandes prdidas tanto por muerte de los animales como por la
disminucin de su productividad. La enterotoxemia causada por el Clostridium perfringens es la
principal causa de muerte de las cras dentro del primer mes de vida, pudiendo alcanzar niveles
mayores del 50% en algunos aos. Se estudia la produccin de una vacuna que permita prevenir la
enfermedad. Otra entidad nosolgica importante es la enterocolitis.

Las enfermedades parasitarias, tanto internas como externas, si bien no producen muerte, causan
trastornos digestivos que repercuten negativamente sobre funciones productivas como el
crecimiento y la produccin de fibra. Entre estas afecciones, la sarcocistiosis ocupa un lugar
importante por sus graves repercusiones econmicas. Los ectoparsitos, como la sarna, pueden
ocasionar daos graves a la fibra si no se controlan adecuadamente.

Diversos organismos pblicos y privados desarrollan actividades en apoyo a la produccin de los

CSA, tales como promocin, investigacin y asistencia tcnica. Sin embargo, su impacto es an
muy limitado y requieren de un reforzamiento considerable.

En conclusin, es evidente que el Per tiene una ventaja comparativa importante al ocupar el primer
lugar en el mundo en cuanto a poblacin de alpacas y vicuas y el segundo lugar en cuanto a
llamas. Para que esta ventaja se convierta en un factor de desarrollo y lucha contra la pobreza del
sector de pequeos productores que poseen este valioso recurso, se requieren acciones efectivas que
conduzcan a la superacin de los factores limitantes tanto de naturaleza tecnolgica como social y
econmica.
 7

EXECUTIVE SUMMARY

This report is the result of a consultancy that was carried out within the framework of the Regional
TCP project TCP/RLA/2914 Support to the breeding and utilization of South American Camelids
in the Andean Region. The project is executed by the University Cayetano Heredia and the
Nacional South American Council (CONACS) of Per. The report points out the economic,
social, cultural and scientific importance of South American Camelids (SAC) in the Andean region
of Latin American countries in general and of Peru in particular. There are four species of SAC; two
domestic: alpaca and llama, and two wild: vicua and guanaco. Alpacas and llamas play a very
important role in the economy of a large population located at altitudes ranging from 3 800 to more
than 4 500 m above sea level. They provide fiber, meat, pelts and dung which is used as fuel and
fertilizer. Llamas are also utilized as pack animals in some isolated regions. Vicuas are the most
important of the wild species as they produce a very fine quality fiber that command high prices in
the international market.

There are about 3 million alpacas, one million llamas, 125 thousand vicuas and 5 thousand
guanacos in Peru. Thus, Peru possesses the largest number of alpacas and vicuas in the world.
More than 80 percent of alpacas and the whole population of llamas belong to small farmers and
peasant communities with very limited resources, located in isolated areas of the Andes with out
access to basic services such as health care and education. The remaining 20 per cent of alpacas are
distributed between medium size farmers and communal enterprises. Management of alpacas and
llamas is very poor in most cases, with no technical innovations. They are mostly low input-low
productivity systems. They face a variety of problems such as low reproduction rates and high
mortality of the newborn. Nutritional deficiencies derived from inadequate management of feed
resources result in poor growth and deterioration of natural resources. Added to these is the lack of
properly designed selection programs which prevents the improvement of economically important
traits such as fiber quality. On the other hand the high incidence of Sarcocysts in the muscles
seriously affects the quality and public acceptance of the meat. Producers also face limitations for
the commercialization of their products because they are not properly organized for collective
action. The final outcome of all these limitations is poor income, low profits, poverty and food
insecurity.

The vicua is considered a national property; however the law permits the harvest and sale of their
fiber by those communities or individuals that are the owners of the land where the vicuas graze.
This is done under the close supervision of CONACS and the National Institute of Natural
Resources (INRENA). Annual harvest of vicua fiber amounts to about 5 000 kg which is marketed
under the seal of Vicua-Peru when it goes to the textile industry, and Vicua-Per-Artesana
when the destination is the artisan industry.

Annual alpaca fiber production is around 3 400 tons, 85 percent of which goes to industry, mostly
for export, and the remaining 15 percent to artisan industry and home use. Llama fiber production
is around 800 tons per year, mostly for home use and handy crafts.

Alpaca and llama meat is of high nutritive value, similar to that of other animals; it is consumed
either fresh or dehydrated in the form of charqui or chalona. Other forms of utilization are still
limited. Alpacas and llamas are slaughtered in the same slaughter houses used for other animal
species under acceptable hygienic conditions. However, a sizeable portion of animals are sacrificed
elsewhere with no veterinary supervision. Even though the camelid meat is of high quality the main
 8

limitation for its wider acceptance is the presence of Sarcocysts in the muscle of most animals older
than two years of age. This makes the meat inappropriate for human consumption.

The prevalence of diseases is the cause of heavy losses either due to death of the animals or the
negative effect of the illnesses on productive functions such as growth, reproduction and fiber yield
and quality.

Among infectious diseases, Enterotoxemia caused by Clostridium perfringens, is the main killer of
new born alpacas within their first month of live. Annual losses due to this disease may be as high
as 50 percent and over in some years. Efforts are being made for the development of a vaccine to
prevent the disease. Enterocolitis is another condition which may cause high mortality in young
alpacas and llamas.

Even though internal parasites usually do not cause high mortality, they have a negative impact on
productive functions such as body growth, reproduction and fiber production. In addition, external
parasites have a damaging effect on fiber quality.

Several public and private institutions carry out research, extension and technical assistance
programmes in support of the development and conservation of camelids in Peru. However, their
impact so far has been very limited. More effective and coordinated actions are needed in order to
obtain more benefits from this unique genetic resource that has a great potential for the reduction of
poverty and the improvement of the quality of life of the inhabitants of the Andean region of Peru
which are one of the poorest sectors of the countrys population.
 9

INDICE

1. INTRODUCCIN 8
2. CENSO Y DISTRIBUCIN DE LOS CAMELIDOS SUDAMERICANOS
2.1 Alpacas . 9
2.2 Llamas 12
2.3 Vicuas y guanacos .. 13
3. CARACTERIZACIN SOCIOECONOMICA DE LOS PRODUCTORES DE
CAMLIDOS 15
4. SISTEMAS DE EXPLOTACIN: CAMLIDOS DOMESTICOS. 17
4.1 Estructura de los rebaos por edad y sexo 18
4.2 Prcticas de manejo .. 19
4.2.1 Alimentacin 19
4.2.2 Empadre: manejo reproductivo . 20
4.2.3 Paricin y destete .. 22
4.2.4 Esquila 23
4.2.5 Seleccin y mejoramiento gentico 24
5. MANEJO DE LA VICUA 27
6. APROVECHAMIENTO DE LA FIBRA
6.1 Fibra de alpaca 29
6.2 Fibra de llama . 31
6.3 Fibra de vicua 32
7. APROVECHAMIENTO DE LA CARNE ... 33
8. PREVENCION Y CONTROL DE ENFERMEDADES.. 37
8.1 Enfermedades infecciosas
8.1.1 Causas de mortalidad en cras . 38
8.1.2 Enfermedades de tuis y adultos ... 40
8.2 Enfermedades parasitarias 41
8.2.1 Neumogastroenteritis parasitaria .. 42
8.2.2 Sarcocistiosis 42
8.2.3 Hidatidosis .. 44
8.2.4 Distomatosis 44
8.2.5 Enfermedades producidas por ectoparsitos 44
9. Conclusiones y perspectivas 45

REFERENCIAS BIBLIOGRAFICAS. 47
ANEXOS
ANEXO I: Instituciones e institucionalidad local. 50
ANEXO II: Legislacin y polticas 54
10
 11

1. INTRODUCCIN

Los camlidos sudamericanos (CSA), constituyen un recurso gentico de gran importancia social,
econmica, cultural y cientfica para el Per y algunos de los pases de la Regin Andina.

Las especies domsticas, alpaca y llama, proveen productos de alta calidad, como son la fibra y la
carne y, a menudo, constituyen el nico medio de subsistencia de un vasto sector de la poblacin
alto andina. Las especies silvestres, vicua y guanaco, que se consideran antecesoras de las especies
domsticas, ofrecen igualmente un importante potencial de aprovechamiento sustentable dentro de
los marcos legales establecidos.

La domesticacin de la llama y alpaca data de hace unos 6 a 7 mil aos; sin embargo el auge de su
crianza y aprovechamiento se alcanz durante el imperio incaico del Tawantinsuyo. Se estima que
la poblacin de estos camlidos en aquella poca fue de varios millones de cabezas, distribuidos a
lo largo de todo su territorio, incluyendo la costa. Las especies silvestres, en particular la vicua,
fueron objeto de cuidadosa proteccin aprovechndose su valiosa fibra para indumentarias de la
realeza.

La introduccin en el nuevo mundo de especies forneas de animales domsticos provenientes del

viejo mundo, como los ovinos y bovinos, hizo que las especies nativas no slo fueran descuidadas,
sino desplazadas a las zonas ms inhspitas de los Andes donde sobrevivieron gracias a su enorme
poder de adaptacin. Esto tambin trajo consigo la prdida de los conocimientos tradicionales sobre
la crianza de estas especies y, en su lugar, la adopcin de prcticas de crianza similares a las del
ganado ovino, por desconocimiento de las marcadas diferencias biolgicas existentes entre estos
dos grupos de animales. Por otra parte, la caza indiscriminada de las especies silvestres, las condujo
al borde de su extincin, en particular de las vicuas, altamente deseada por su valiosa fibra.

En la actualidad, los CSA constituyen el nico medio de utilizacin productiva de las extensas reas
de pastos naturales de las zonas alto andinas donde no es posible la agricultura ni la crianza
econmica de otras especies de animales domsticos. Los CSA convierten, con inusual eficiencia,
los pastos pobres de estas alturas en productos de alta calidad como son la fibra y la carne, adems
de los subproductos como las pieles y cueros que tienen mltiples usos industriales y artesanales.
El estircol es otro subproducto valioso que se usa como combustible para la coccin de los
alimentos y como fertilizante para los cultivos. La llama, por otra parte, cumple una funcin muy
importante como medio de transporte en los lugares carentes de una adecuada infraestructura vial
que, desafortunadamente, son muchos.

El Per tiene el privilegio de ocupar el primer lugar en el mundo en la tenencia de alpacas y vicuas
y el segundo lugar en llamas, despus de Bolivia. El aprovechamiento racional de esta ventaja
comparativa es el reto que el pas encara como el medio ms efectivo de lucha contra la pobreza y
la inseguridad alimentaria que afecta a las comunidades campesinas que viven de la crianza de
estas especies.

Los CSA presentan una serie de particularidades anatmicas y fisiolgicas que probablemente
tienen que ver con su gran capacidad de adaptacin a las condiciones de hipoxia y de escasez de
recursos forrajeros de las grandes alturas. Destacan entre ellas, la forma elptica de los glbulos
rojos que supuestamente facilita el transporte de oxgeno en un medio hipxico, mientras que la
mayor capacidad de digestin de la fibra, les permite derivar una mayor proporcin de nutrientes de
los pastos lignificados de las grandes altitudes. Concomitante con esta mayor capacidad de
 12

digestin est la estructura anatmica peculiar de su tracto digestivo, an cuando se desconoce la

relacin que pueda existir entre estas dos caractersticas. Por otro lado, la conformacin anatmica
del cuerpo y de las extremidades, les permite movilizarse con un consumo mnimo de energa, lo
que es importante en las condiciones de hipoxia de las grandes alturas. La conducta de depositar los
excrementos en lugares determinados, formando los llamados estercoleros o letrinas, juega un papel
importante en el control de las infestaciones parasitarias. La configuracin de la porcin distal de
las extremidades que, en lugar de pezuas propias de otros ungulados, termina en una almohadilla
plantar, hace que las pisadas no maltraten el pasto ni causen erosin.

Desde el punto de vista de su comportamiento reproductivo, los CSA presentan caractersticas

peculiares, muy diferentes a otros rumiantes. Presentan actividad sexual estacional entre diciembre
y marzo, con ausencia de ciclos estrales; muestran un estado de receptividad sexual continua; la
ovulacin es inducida por el estmulo coital; la gestacin se desarrolla en ms del 90 por ciento de
los casos en el cuerno uterino izquierdo pese a que ambos ovarios son igualmente activos en el
aporte de vulos. Otras caractersticas incluyen el tipo y extensin de la placenta; el largo perodo
de gestacin lo que resulta en el nacimiento de la cra en un estado avanzado de desarrollo y con
mayor posibilidad de sobre vivencia en un medio inhspito como el alto andino. Estas
peculiaridades hacen que estos animales despierten tambin gran inters cientfico a nivel mundial,
por constituir modelos biolgicos muy singulares.

No es de extraar entonces que se haya despertado un marcado inters, de parte de otros pases de
ste y otros continentes, en la crianza de alpacas y llamas, con resultados satisfactorios lo que
confirma la gran capacidad de adaptacin de estos animales a otros mbitos geogrficos. Lo que al
comienzo constituy un inters puramente recreativo se va convirtiendo en una actividad econmica
importante en algunos pases como los Estados Unidos de Norte Amrica, Australia y Nueva
Zelanda, entre otros. Esto ha ocasionado tambin la apertura de un mercado de exportacin
creciente de pie de cra, lo que, debidamente orientado y canalizado, podra constituir una ventaja
para los productores locales. Pero tambin hay que sealar que el surgimiento de la crianza en otros
pases constituye un gran desafo para los pases andinos, que en un futuro cercano podran
enfrentar una marcada competencia. Es necesario entonces que se tomen las medidas necesarias
para impulsar el desarrollo de los camlidos sobre bases tcnicas y ser cada vez ms competitivos.
 13

2. CENSO Y DISTRIBUCION DE LOS CAMELIDOS SUDAMERICANOS

2.1 ALPACAS
La alpaca (Lama pacos), es la especie de mayor existencia numrica en el Per y la ms cotizada
por la produccin de fibra. Existen dos razas de alpacas: Suri y Huacaya. Se diferencian claramente
por sus caractersticas fenotpicas. La alpaca Suri presenta fibras de gran longitud que se organizan
en rizos que caen por los costados del cuerpo, similar a lo que se observa en los ovinos de raza
Lincoln; esto le da al animal una apariencia angulosa. En cambio la alpaca Huacaya presenta un
velln de apariencia esponjosa, con fibras de menor longitud, similar al velln del ovino de raza
Corriedale, lo que le da una apariencia ms voluminosa al animal. Pese a la diferencia de aspecto,
no hay diferencias marcadas en el peso de las cras al nacer (7,5 a 8,0 kg) ni en el peso vivo adulto
entre individuos de las dos razas (Promedio de 65 kg en hembras y 70 kg en machos).

El producto principal que se obtiene de la alpaca es la fibra que tiene caractersticas textiles muy
apreciadas. La carne tiene un valor nutritivo similar o superior a otras carnes; desafortunadamente,
an no est debidamente aprovechada por limitaciones que sern tratadas posteriormente. Adems
los subproductos como las pieles y cueros tienen mltiples aplicaciones, sobre todo en la industria
artesanal.

Ambas razas presentan una gama de colores de fibra que van del blanco al negro pasando por los
colores intermedios. Hay una mayor demanda del mercado por la fibra blanca, de ah que hay una
tendencia al predominio de animales blancos en los rebaos por la seleccin orientada a esa
caracterstica. Sin embargo, los colores naturales son cada vez ms apreciados por la industria por
lo que se impone la necesidad de preservar este material gentico.

La poblacin de alpacas de las dos razas as como su distribucin en el territorio nacional se

presenta en el Cuadro 1. Segn estimado de CONACS, en el ao 2001 habra una poblacin de 3
041 598 alpacas.

Cuadro 1
Existencia y distribucin geogrfica de alpacas en el Per

Regin Huacaya % Suri % Total %

Puno 1 392 600 56.5 289 319 66.6 1 681 919 58.0
Cusco 304 797 12.4 41 431 9.5 346 228 11.9
Junn 47 620 1.9 7 970 1.8 55 590 1.9
Arequipa 207 810 8.4 26 561 6.1 234 371 8.1
Ayacucho 113 332 4.6 16 174 3.7 129 506 4.5
Apurmac 66 744 2.7 18 204 4.2 84 948 2.9
Huancavelica 306 968 12.4 23 660 5.4 330 628 11.4
Lima 26 333 1.1 11 377 2.6 37 710 1.3
TOTAL 2 466 204 100.0 434 696 99.9 2 900 900 100.0
Notas: Junn incluye los departamentos de Pasco y Huanuco
Huancavelica incluye el departamento de Ica
Lima incluye Ancash, Cajamarca y La Libertad.
Fuente: INEI CENAGRO (1995) y CONACS (2004)
 14

El Departamento de Puno es el que posee la mayor proporcin de alpacas seguido por Cusco,
Huancavelica y Arequipa. Esto est en relacin con la extensin de las praderas alto andinas
existentes. Las poblaciones de alpacas de los Departamentos ubicados en las regiones de Lima y
Junn son en gran parte el resultado del proyecto Repoblamiento de Alpacas de la Sierra Norte y
Centro del Pasque entre 1992 y 1996 llev a cabo el Ministerio de Agricultura a travs de
FONAFOG (Fondo Nacional de Fomento Ganadero) con financiamiento del Fondo de
Compensacin y Desarrollo Social (FONCODES).

La estrategia de esta operacin fue seleccionar y adquirir alpacas en zonas de alta produccin
(Puno, Cusco y Arequipa) y trasladarlas a zonas de escasa o nula produccin pero con piso forrajero
y fuentes de agua adecuados. Al beneficiario se le otorgaba un crdito constituido por un ncleo de
110 alpacas (100 hembras y 10 machos) que tenan que ser devueltas en semovientes (alpacas) en
un periodo de diez aos. Durante las cinco etapas del proyecto, se movilizaron aproximadamente
25 000 alpacas y se beneficiaron alrededor de 250 criadores. Desde 1997 al 2003, las
recuperaciones fueron utilizadas para continuar otorgando crditos bajo el esquema de fondos
rotatorios. El seguimiento del programa est ahora a cargo del CONACS.

En el Cuadro 1 se puede apreciar tambin que predomina la raza Huacaya con un 85% mientras
que Suri slo representa el 15% de la poblacin total. Esto indica que ha habido una recuperacin
notable de la raza Suri pues hace algunos aos hubo una preocupacin por su marcada disminucin,
sobre todo en las partes ms altas de la sierra, lo que se atribuy a la menor resistencia de estos
animales a las inclemencias climticas severas, lo que haca que los productores tuvieran
preferencia por la raza Huacaya. Se estima que por el ao 1991, la proporcin de Suris no era mayor
del 5% (Barreda, 1991). Esa informacin fue en cierta medida corroborada por una encuesta
realizada en el Departamento de Puno, en el marco del Programa de Conservacin de Recursos
Genticos Animales de la FAO, donde se encontr que la proporcin de Suri efectivamente apenas
llegaba al 5% (Smar, 1991). El hecho de que la fibra de Suri se cotiza en algunos casos a un
precio mayor en el mercado, junto a la creciente demanda de animales de esta raza para
exportacin, son factores que probablemente reactivan el inters por Suri.

En la encuesta antes mencionada, en el Departamento de Puno no se encontraron tipos raciales

intermedios (Suri/Huacaya) a pesar de que los pequeos productores mantienen todos los animales
en un solo rebao, donde existe la posibilidad de cruces entre razas. A este respecto, surge la
pregunta de si las caractersticas de Suri y Huacaya se mantienen invariables en cruces sucesivos
dentro de la misma raza. Al parecer esto es cierto en el caso de Huacaya pero no en Suri.
Observaciones de campo indican que cruces de Huacaya por Huacaya siempre dan como resultado
cras Huacaya, mientras que cruces de Suri por Suri dan como resultado alrededor de un 75 por
ciento de cras Suri y 25 por ciento de Huacaya (Velasco, 1980). Similares observaciones han sido
hechas en Australia por Ponzoni y col. (1998) en una serie de combinaciones de cruces entre
ambas razas. Basados en los resultados de esos cruzamientos, postulan la hiptesis de que la
caracterstica fenotpica de estas dos razas estara controlada por un solo gen, siendo dominante el
alelo responsable del tipo Suri sobre el tipo Huacaya . De esta manera, cruces de Huacaya entre s
dara 100 por ciento de cras Huacaya, mientras que cruces de Suri por Suri podra dar lugar a cien
por ciento de Suri en caso de que ambos progenitores sean homocigotos, o una proporcin de
Huacaya (adems de Suri) en caso de que uno o ambos progenitores sean heterocigotos. An
cuando el nmero de animales utilizados en los cruzamientos llevados a cabo en Australia, no es
muy alto, es un aspecto interesante que amerita ser estudiado. De ser ratificados estos resultados, se
contara con un mecanismo prctico de incrementar rpidamente la poblacin de Suri.
 15

Tradicionalmente, los productores peruanos son reacios a hacer cruces entre Suri y Huacaya; por lo
tanto no ha sido posible obtener datos sobre resultados de cruces a escala comercial. Sin embargo,
datos obtenidos de la antigua Granja Modelo de Auqunidos de La Raya en el Departamento de
Puno (Fernndez-Baca, 1971), pareceran corroborar los resultados de Velasco y los reportados de
Australia. En un total de 738 cras obtenidas del cruce de Huacaya por Huacaya, se observaron 15
cras Suri (2%), mientras que en un total de 511 cras obtenidas del cruce de Suri por Suri, hubieron
89 cras Huacaya (17.4%). Aunque resulta difcil explicar el resultado de los cruces de Huacaya
por Huacaya (a menos que haya ocurrido una incursin clandestina de un macho Suri en el rebao
de hembras Huacaya, hecho no descartable), el resultado de los cruces de Suri por Suri, es
coherente con la hiptesis. Si ambos progenitores son heterocigotos, se esperara un 25% de cras
Huacaya, que no es significativamente diferente de la cifra observada de 17.4%. En todo caso, es un
tema muy importante que amerita mayor investigacin.

En cuanto a herencia de los colores, no se conoce a ciencia cierta el mecanismo de transmisin;

hay una serie de hiptesis pero nada concreto hasta el momento. Se trata de una caracterstica que
parece cobrar cada vez mayor importancia por el inters de la industria en colores naturales.

2.2 LLAMAS
La llama (Lama glama) es el camlido de mayor tamao; puede alcanzar un peso adulto de 100 a
120 kg. Fue desarrollado fundamentalmente para el transporte y el abastecimiento de carne.
Produce fibra de menor calidad que la de alpaca y en menor cantidad. Presenta dos capas de fibra:
una interior, fina y otra exterior, gruesa. En muchos lugares alejados de los Andes, carentes de vas
de comunicacin, la llama sigue prestando valiosos servicios como animal de carga. Se le utiliza
para el transporte de insumos para las labores agrcolas as como de los productos a los lugares de
comercializacin.

En otros pases se han encontrado otros usos para la llama, fuera de los mencionados. Por ejemplo
se les utiliza como mascotas y, en las excursiones, para el transporte del equipo de campo. Tambin
las llamas han demostrado ser excelentes guardianes para dar proteccin a las ovejas contra el
ataque de predatores como el coyote y los zorros, cuyo control constituye un problema en las zonas
de crianza de ovinos de los EE.UU. de Norte Amrica (Franklin, 1994). En dicho pas no est
permitido el empleo de veneno por las implicancias ambientales, ni las trampas por considerarse un
acto de crueldad. Frente a ello han encontrado la solucin en la llama, la que al ser mantenida en un
rebao de ovejas se convierte en la conductora del grupo y las protege contra la incursin de
animales extraos.

Existen dos razas, Chaku y Kara, conocidas tambin con las denominaciones Lanuda y Pelada,
respectivamente. Se diferencian una de otra por la magnitud de cobertura del cuerpo. Mientras que
Chaku tiene mayor cobertura de fibra, incluyendo las extremidades, Kara tiene una apariencia de
mayor fortaleza corporal con poca cobertura de cuerpo y extremidades. Existen tipos intermedios
que pueden confundirse con el Huarizo, producto del cruce de llama con alpaca, que ocurre
frecuentemente en sistemas de crianza mixta como es el caso de la mayora de pequeos
productores.

En el Cuadro 2 se puede apreciar la poblacin y distribucin geogrfica de la llama en el Per. Al

igual que en el caso de las alpacas, la mayor concentracin de llamas se encuentra en el
Departamento de Puno, seguido por Cusco y Huancavelica. La regin Junn ocupa el cuarto lugar a
diferencia de lo que ocurre en el caso de las alpacas en que esta regin ocupa uno de los ltimos
 16

lugares. La mayor concentracin de llamas en un determinado departamento tiene que ver con las
necesidades de uso de estos animales para el transporte de insumos agrcolas y de las cosechas pero
al mismo tiempo constituyen una importante fuente de protenas para consumo humano.

Cuadro 2
Existencia y distribucin geogrfica de llamas en el Per
Regin Nmero Porcentaje
Puno 359 786 35,7
Cusco 178 040 17,7
Junn 111 909 11,2
Arequipa 96 963 9,6
Ayacucho 57 003 5,7
Apurimac 49 655 4,9
Huancavelica 130 068 12,9
Lima 23 190 2,3
TOTAL 1 006 614 100,0
Notas: Regin Junn incluye departamentos de Pasco y Hunuco
Regin Huancavelica incluye Ica
Regin Lima incluye Ancash, Cajamarca y La Libertad
Fuente: INEI, CENAGRO (1995) y CONACS (2004)

En lo que respecta a razas, segn la informacin disponible hay cierto grado de equilibrio entre las
dos con un ligero predominio de Kara que representa el 58 por ciento de la poblacin de llamas a
nivel nacional. A diferencia de la alpaca cuyo nmero aument de 2,7 millones de cabezas en 1990
a poco ms de 3 millones en el 2001, la poblacin de llamas se ha mantenido ms o menos
constante durante ese tiempo, segn datos de CONACS.

2.3 VICUAS Y GUANACOS

La vicua (Vicugna vicugna) es el camlido silvestre de mayor presencia en el Per, apreciada por
la alta calidad y finura de su fibra. Se describen dos sub-especies de vicuas: Vicugna vicugna
vicugna Molina, 1782, que se encuentra al sur de los 18 de latitud Sur, y V.v.mensalis
Thomas,1917, que se encuentra ms al Norte. Ambas poseen fibras extremadamente finas de un
color canela claro o ligeramente oscuro (color vicua), que cubren todo el cuerpo excepto las partes
inferiores y el vientre que son de color blanco. Slo la V.v. mensalis presenta un mechn de pelos
blancos en el pecho (Wheeler, 1991).

Despus de un perodo de disminucin debido a la caza indiscriminada, la poblacin de vicuas ha

experimentado una marcada recuperacin durante los ltimos 30 aos, pasando de una situacin de
especie en peligro de extincin, en 1969, al status de especie vulnerable en 1972, lo que se debi a
las medidas de proteccin tomadas por los pases andinos. La existencia de vicuas en el Per para
el ao 1969 se estimaba solamente en 10 mil cabezas, cifra que subi a 62 mil animales en 1982
gracias a un programa de conservacin que el Per inici en 1968 con el establecimiento de la
Reserva Nacional de Pampa Galeras, en el Departamento de Ayacucho (Wheeler, 1991). De ah en
adelante ha habido un incremento continuado de la poblacin de vicuas, estimndose al ao 2 000
la cifra de 118 678 cabezas (Cuadro 3). Segn proyecciones de CONACS e INRENA, esta cifra se
habra incrementado a 161 460 cabezas en el ao 2004.
 17

En el Cuadro 3, que corresponde a los datos del censo nacional de vicuas del ao 2000, se aprecia
que la poblacin mayor de estos animales se encuentra en el Departamento de Ayacucho, sede de la
Reserva Nacional ms importante, que hoy se conoce con el nombre de Reserva Nacional Brbara
DAquiles de Pampa Galeras.

Cuadro 3
Existencia y distribucin geogrfica de vicuas en el Per

DEPARTAMENTO N VICUAS
Ancash 684
Apurimac 10 020
Arequipa 3 681
Ayacucho 40 390
Cajamarca 235
Cusco 4 209
Huancavelica 8 745
Hunuco 51
Ica 1 583
Junn 11 408
La Libertad 26
Lima 17 689
Moquegua 293
Pasco 343
Puno 18 107
Tacna 1 214
TOTAL 118 678

Fuente: CONACS (2000)

El guanaco (Lama guanicoe), es el camlido silvestre de mayor tamao y el que muestra el mayor
grado de adaptabilidad ya que su distribucin va desde las partes ms altas de la cordillera de los
Andes hasta la Patagonia. Se considera que es la forma ancestral de la llama domstica. La
poblacin de guanacos en el Per es bastante reducida. Segn el Censo Nacional de guanacos
(CONACS) haba un total de 3 810 animales en el ao 1996.

En 1977 el guanaco fue declarado como especie en extincin en el Per (Resolucin Ministerial N
0170-77-AG-DGFF). Adems, en 1981, se estableci la Reserva Nacional de Calipuy ubicado en
Santiago de Chuco, Departamento de La Libertad (Decreto Supremo N 0004-81-AA) donde hay
alrededor de medio millar de animales ( Cuadro 4).

La mayor poblacin de guanacos en Arequipa y Ayacucho obedece probablemente a una mayor

vigilancia que ejercen las comunidades campesinas para prevenir la caza furtiva.
 18

Ambas especies silvestres son patrimonio nacional. En el caso de la vicua, la ley permite su
usufructo por las comunidades donde ellas habitan, mediante capturas programadas y esquila,
previa autorizacin y bajo estricta vigilancia del CONACS y el INTRENA.

Cuadro 4
Existencia y distribucin geogrfica de guanacos en el Per

DEPARTAMENTO N ANIMALES
Apurmac 9
Arequipa 1 124
Ayacucho 1 167
Huancavelica 211
Ica 516
La Libertad 538
Moquegua 79
Puno 71
Tacna 95
TOTAL 3 810
 19

3. CARACTERIZACIN SOCIOECONMICA DE LOS PRODUCTORES DE

CAMLIDOS.

La crianza de alpacas y llamas en el Per se desarrolla en la regin andina de la sierra,

particularmente sur y central, a altitudes que van de los 3 800 hasta ms de 5 000 metros sobre el
nivel del mar.

Entre los 3 800 y 4 000 m de altitud, la crianza de alpacas y llamas por lo general se combina con la
de otras especies animales y algunos cultivos, pero encima de los 4 000 m la actividad
predominante es la crianza de camlidos, en particular alpacas.

Alrededor del 90 por ciento de las alpacas y la totalidad de las llamas est en manos de pequeos
productores que paradjicamente constituyen uno de los segmentos menos favorecidos de la
poblacin peruana, la misma que vive en estado de extrema pobreza. Habitan las zonas ms
apartadas del pas, carentes de servicios bsicos como educacin y cuidado de la salud, as como
de obras de infraestructura vial que faciliten la comunicacin y la adecuada conduccin de las
actividades tanto de produccin como de comercializacin de sus productos.

Se estima que al ao 2000, al menos un milln y medio de personas de las zonas alto andinas de los
Departamentos de Apurimac, Arequipa, Ayacucho, Cusco, Huancavelica, Junn, Lima y Puno, se
dedicaban a la crianza de CSA domsticos como actividad principal. Los ingresos per cpita en
estas zonas productoras de camlidos son los menores del pas. As, el ingreso anual per cpita en
Puno, Huancavelica, Ayacucho y Apurmac es menor a 800 dlares de los EE.UU. El rendimiento
de fibra de alpaca en esta poblacin, en el ao 2000, era slo alrededor de 3,5 libras por animal,
segn datos de CONACS.

La mujer cumple una actividad primordial en la sociedad ganadera alto andina, pues es ella quien se
dedica al pastoreo y vigilancia de los animales. El hombre apoya en las actividades de esquila,
paricin y empadre; comparte las labores de pastoreo y se encarga de realizar las transacciones para
el intercambio de mercaderas, previa coordinacin con los miembros de la familia.

Al no disponer de suficientes recursos provenientes de la actividad ganadera para solventar los

gastos de la familia, los padres e hijos varones por lo general se ven obligados a migrar temporal o
definitivamente a los centros urbanos en busca de trabajo, quedando el cuidado de los animales, y
cualquier otra labor agrcola, en manos de las mujeres y de los nios. Este importante papel de la
mujer en el manejo de la unidad productiva, con frecuencia no se toma en cuenta en los programas
de capacitacin y extensin en los que generalmente slo se considera a los varones dejando de lado
a las mujeres. La situacin de pobreza en que vive este segmento de la poblacin es tambin un
factor que determina la migracin masiva del campo a los centros urbanos en busca de otros medios
de vida, especialmente de los jvenes, lo que hace que la actividad de crianza quede en manos de
personas mayores. Por ejemplo en el Departamento de Arequipa, el 43 por ciento de productores de
camlidos se ubica en el estrato de 45 a 64 aos..

El Cuadro 5 muestra la distribucin de las alpacas y llamas en relacin con el tamao de los predios
en el Per.
 20

Cuadro 5
Distribucin de alpacas y llamas segn tamao de los predios

Terrenos de
<3 ha 3-10 ha 10-50 ha >50 ha
TOTAL ----------------- ------------------------------------------------

Alpacas (000) 2 456 796 248 354 983

-------------------------------------------------------------------------------------
% 32,4 10,1 14,4 40,0
Llamas (000) 1 006 405 175 159 238
------------------------------------------------------------------------------------
% 40,2 17,5 15,8 23,6
Pastos Nat.
(000 ha) 15 950 85 341 829 14 695
----------------------------------------------------------------------------------------------------------------------
Fuente: INEI - CENAGRO, 1996

Se puede notar en este Cuadro que el 60 por ciento de las alpacas y 76 por ciento de las llamas se
cran en unidades agropecuarias de una extensin menor de 50 hectreas. Lo que llama tambin la
atencin es que el 32 por ciento de las alpacas y el 46 por ciento de las llamas se ubican en unidades
agropecuarias menores de 3 hectreas que representan slo el 0,5 por ciento del total de la
superficie de pastos. Esto implica una alta carga animal por hectrea cuyas consecuencias son, por
un lado el sobre pastoreo con la consiguiente erosin y deterioro de las praderas y, por otro, una
insuficiente disponibilidad de alimento lo que conduce a una mayor incidencia de enfermedades,
bajas tasas de natalidad, mayor mortalidad de cras, y retardo en el crecimiento. La consecuencia
final no es slo una baja productividad y escasa rentabilidad, sino que pone en riesgo la
sostenibilidad del sistema con graves consecuencias para el bienestar de las generaciones futuras.

El aislamiento en que viven los productores de camlidos por la falta de una infraestructura vial
adecuada y de mecanismos de participacin grupal, hace que tengan grandes dificultades de acceso
al mercado para la comercializacin de la fibra, que es la principal fuente de ingreso, por lo que se
ven obligados a depender de los intermediarios con grave perjuicio econmico. Por otro lado, la
carne, pese a su enorme potencial para contribuir de manera significativa al ingreso familiar, an
tiene limitaciones en su comercializacin y en el grado de aceptacin por parte de la poblacin
urbana. Sin embargo, la carne contribuye de manera notable a la alimentacin familiar por ser la
nica fuente de protena animal de que disponen.

Las actividades que muchos organismos oficiales y privados vienen realizando con miras a
incentivar la organizacin de los productores con un enfoque empresarial, se espera que ir
fortaleciendo su capacidad de gestin y negociacin tanto para la comercializacin de los
productos como para facilitar su acceso a otros servicios esenciales que conduzcan al mejoramiento
de sus ingresos y la calidad de vida.

Es realmente paradjico que el sector de la poblacin que posee un recurso gentico tan singular y
valioso, como son los camlidos sudamericanos, sea el que muestra los mayores grados de pobreza
extrema.
 21

4. SISTEMAS DE EXPLOTACIN: ESPECIES DOMESTICAS.

Hay notables diferencias en el tamao, grado de organizacin y nivel tecnolgico de las

explotaciones de alpacas y llamas. Se pueden distinguir al menos tres categoras bien diferenciadas
de productores: a) Comunidades, parcialidades y minifundios; b) Pequeos y medianos productores;
y c) Empresas asociativas.

a) Comunidades, parcialidades y minifundios.

Este sector engloba no menos del 80 por ciento de las alpacas y la casi totalidad de las
llamas. Los sistemas de explotacin de este sector se caracterizan por la precariedad en el
manejo de los animales y de los recursos naturales. Los animales se manejan en un solo
rebao sin separacin por especie, raza o sexo. A menudo se trata de rebaos mixtos
compuestos por alpacas, llamas y en algunos casos tambin ovinos y vacunos. Las medidas
de control de enfermedades son inexistentes en la mayora de casos y no se sigue un
calendario definido de faenas ganaderas, tales como esquila o tratamientos antiparasitarios,
ni un manejo racional de los pastos.

En las comunidades, donde la propiedad de la tierra es comunal mientras que la de los

animales es privada, hay una tendencia a poseer un nmero de animales por encima de la
capacidad receptiva de los pastos lo que conduce al sobre pastoreo y la consiguiente
degradacin de este recurso. La ausencia de medidas de control y prevencin de
enfermedades resulta en altos ndices de morbilidad y mortalidad as como bajas tasas de
crecimiento y de natalidad, todo lo cual resulta en bajos niveles de produccin y
productividad. A eso se suman las dificultades para la comercializacin de los productos
que dependen de una cadena de intermediarios. El resultado final es un bajo nivel de
ingreso para las familias que repercute en su nivel de vida.

Este es el sector ms relegado y desprotegido de los criadores de camlidos pero al mismo

tiempo el que tiene el mayor potencial de desarrollo por la elevada masa ganadera que
posee. Para ello se requiere un apoyo decidido y efectivo del Estado y de los organismos de
cooperacin, en las diferentes etapas de produccin y comercializacin, as como la
dotacin de infraestructura y servicios bsicos.

b) Pequeos y medianos productores.

En este sector se ubica aproximadamente el 10 a 12 por ciento de la poblacin de alpacas en

unidades de produccin de 500 a 2 000 cabezas o ms. Los criadores de este sector por lo
general tienen un enfoque empresarial; realizan prcticas de manejo y control sanitario
aceptables y hacen de la crianza de alpacas una actividad rentable. Se trata en la mayora de
casos de productores progresistas, consumidores de tecnologa y vidos de nuevos
conocimientos. Sus parmetros de produccin se ubican por encima del promedio. Algunos
de ellos llevan a cabo programas de seleccin y son fuente de material gentico de calidad y
se han beneficiado con la apertura de las exportaciones de animales.

c) Empresas asociativas.

Estas son el fruto del proceso de reforma agraria llevada a cabo en la dcada de los 70s y
corresponden a las antiguas haciendas alpaqueras de propiedad privada afectadas por el
 22

proceso y convertidas en Cooperativas o Sociedades Agrcolas de Inters Social (SAIS). Se

estima que este sector engloba alrededor del 8 por ciento del total de alpacas en unidades de
produccin de varios miles de cabezas.

El nivel tecnolgico de estas explotaciones es similar al de las medianas empresas; hay

clasificacin de los animales por edad y sexo y en algunos casos por raza. Se sigue un
calendario de operaciones ms o menos definido durante el ao con prcticas ms
evolucionadas como la esquila mecnica, rotacin de pastos, control del empadre, etc. Sin
embargo, en algunos casos hay todava la tendencia a seguir prcticas de manejo similares a
las de ovinos, sobre todo en el empadre, sin tener en consideracin las diferencias
fisiolgicas entre las dos especies. Por los volmenes de produccin que manejan por lo
general gozan de mayor poder de negociacin para la comercializacin de los productos.
Este es un sector que ofrece el mayor potencial para la produccin de carne de calidad tanto
para el mercado interno como para el externo, adems de la produccin de fibra que
actualmente es la mayor fuente de ingreso.

Las prcticas de manejo que a continuacin se presentan corresponden mayormente a los

sectores b y c de productores aun cuando se van tratando de introducir en el sector a.

4.1. ESTRUCTURA DE LOS REBAOS POR EDAD Y SEXO

La composicin de los rebaos de alpacas es variable. En el Cuadro 6 se muestra el promedio de
composicin de los rebaos de 13 explotaciones del Departamento de Puno, que es la regin que
alberga la mayor poblacin de alpacas. Los trminos que se utilizan para denominar a los animales
segn edad y sexo son: cras (machos y hembras) del nacimiento hasta el ao de edad; tuis, machos
y hembras, animales de uno a dos aos de edad; madres, hembras mayores de dos aos, aptas para
la reproduccin; padres, machos mayores de dos aos, aptos para la reproduccin; capones, machos
castrados. El trmino tui es un vocablo local, probablemente de origen quechua o aymara, que es de
uso comn en el Departamento de Puno y que hoy se ha generalizado a otras zonas.

Cuadro 6
Estructura de rebaos de alpacas en el Departamento de Puno

Porcentaje

Hembras (>2 aos de edad) 42,0

Machos reproductores 4,3
Tuis, machos y hembras,
1-2 aos de edad 17,3
Cras, hasta 1 ao de edad 21,1
Machos castrados 15,3
--------------------------------------------------------
Fuente: Novoa (1987)

Como se puede ver en el Cuadro, la proporcin de hembras es relativamente baja debido a la

tendencia a mantener machos castrados como productores de fibra por todo el tiempo que dure su
vida productiva, que puede llegar hasta diez o doce aos. Esta prctica resta espacio a las hembras y
 23

tiene una repercusin negativa en la economa de la explotacin, puesto que el costo de crianza de
un animal castrado es similar al de una hembra con la diferencia de que sta, adems de fibra, puede
producir una cra. El bajo porcentaje de cras que se aprecia en el Cuadro 6 es un reflejo de la baja
proporcin de hembras en edad reproductiva y de las bajas tasas de natalidad y alta mortalidad
neonatal. Lo deseable es mantener un porcentaje mayor de hembras en los rebaos y reducir tanto
como sea posible el nmero de machos castrados a fin de obtener un mayor nmero de cras e
incrementar as el porcentaje de saca anual a un nivel de 25 a 30 por ciento en lugar del 10 o 15%
actual.

4.2. PRACTICAS DE MANEJO

4.2.1. Alimentacin
La base de la alimentacin de los camlidos sudamericanos en general lo constituyen las praderas
de pastos naturales las que se caracterizan por un predominio de gramneas con escasa presencia de
leguminosas. Hay una gran variacin estacional tanto en la produccin de biomasa como en el
contenido de protena, con relativa abundancia en la estacin de lluvias y marcada escasez en la
poca seca. La precipitacin pluvial vara de un ao a otro, entre 900 a 1 200 mm y est
circunscrita a 4 meses del ao: diciembre a marzo; los ocho meses restantes son prcticamente de
una sequa completa con un alto ndice de evaporacin. La temperatura ambiental vara de una
mxima de 18 a 20 C en el da a -12 C durante la noche en los meses invernales. Con cierta
frecuencia, la sierra alta es afectada por tormentas de nieve que al cubrir los pastos dejan sin
alimento a los animales por varios das. Otros aos hay sequas prolongadas que, igualmente,
afectan la disponibilidad de forraje lo que repercute en el comportamiento productivo de los
animales.

Para lograr una produccin sostenible y obtener un mayor beneficio de las praderas, hay necesidad
de un manejo racional; desafortunadamente eso no ocurre en la mayora de casos, sobre todo a
nivel de comunidades y pequeos productores. En el caso de las comunidades, donde la propiedad
de la tierra es comunal mientras que la de los animales es individual o familiar, con frecuencia hay
una fuerte tendencia al sobrepastoreo lo que va en detrimento de una produccin sostenible.

El establecimiento de pastos cultivados para complementar las praderas naturales no es una prctica
comn pese a haber experiencias exitosas a este respecto. Se ha logrado establecer exitosamente
pastos cultivados en zonas ubicadas a altitudes de 4 000 metros y ms, con rendimientos excelentes,
tal como demuestran los trabajos realizados en la Estacin de Camlidos Sudamericanos de La
Raya. Especies de gramneas del gnero Lolium y de leguminosas del gnero Trifolium, han dado
excelentes resultados y son plenamente aceptados por las alpacas y llamas. Son notables tambin
los logros obtenidos en el Departamento de Puno con el Proyecto de Cooperacin de Nueva
Zelanda en el Per, que se llev a cabo en la dcada de los 70s. Se obtuvieron respuestas dramticas
en ganancia de peso de alpacas al pastoreo en una asociacin de alfalfa y Dactylis glomerata con
cargas de hasta 60 cabezas por hectrea, similar a lo obtenido con ovinos. Adems, con la ventaja
de que no se observaron problemas de timpanismo en alpacas debido al consumo de leguminosas, a
diferencia de ovinos y vacunos en los que esta afeccin constituy un verdadero problema. Estas
experiencias demuestran la factibilidad de establecer pastos cultivados a altitudes de 4 000 m o ms,
lo que constituye una alternativa importante para aliviar la presin sobre los pastos naturales y al
mismo tiempo obtener una mayor productividad por unidad de superficie con los consiguientes
beneficios econmicos para los productores.
 24

No se han reportado deficiencias minerales en alpacas y llamas; es probable que existan. No es

usual el suministro de mezclas minerales como es el caso en otros animales; adems los camlidos
no tienen el hbito de lamer.

4.2.2. Empadre (Manejo reproductivo)

El adecuado manejo reproductivo de cualquier especie animal requiere del conocimiento de su
fisiologa reproductiva. Las investigaciones sobre la fisiologa de la reproduccin de los camlidos,
en especial alpacas, iniciadas en el Per hace ms de 40 aos, seguidas luego por trabajos en otros
pases, han permitido lograr los conocimientos bsicos sobre su comportamiento reproductivo. Con
base en estos conocimientos se han diseado sistemas de empadre acordes con las caractersticas
peculiares de estos animales. Pese a que la mayor parte de los trabajos han sido realizados en
alpacas, hay suficientes evidencias de que el patrn de comportamiento reproductivo es similar en
la llama y probablemente en las dems especies.

La hembra de los camlidos presenta actividad sexual entre los meses de diciembre a marzo o abril,
que corresponde a la poca de lluvias y de mayor disponibilidad de pastos. Durante este perodo, la
hembra no presenta ciclos ovulatorios peridicos, como ocurre en otros ungulados, sino que
permanece en celo continuo hasta que es tomada por el macho. La ovulacin es inducida por el
estmulo coital. En caso de no ocurrir fertilizacin, la hembra vuelve a entrar en celo 13 a 15 das
despus del servicio estril. En caso de gestacin, la hembra deja de presentar celo por todo el
tiempo que dura sta (345 das en la alpaca), a menos que se produzca muerte del embrin o que
aborte, en cuyo caso la hembra vuelve a presentar receptividad sexual. Se ha reportado que cerca
del 50 por ciento de las gestaciones terminan dentro de los primeros 30 das por muerte del
embrin. Adems, se ha observado que la asociacin continua de machos y hembras por un tiempo
prolongado inhibe el deseo sexual de los machos por lo que an habiendo hembras en celo no
ocurren montas (Fernndez-Baca, 1993). Toda esta informacin es importante para un manejo
adecuado del empadre.

En las explotaciones con cierto grado de organizacin, como son aquellas que pertenecen a la
categora de los medianos productores y empresas asociativas, donde hay separacin de los
animales por edad y sexo, el empadre se realiza entre los meses de diciembre y abril. Durante este
tiempo, los machos, en una proporcin de 3-4 por ciento, permanecen con las hembras durante un
lapso variable de 45 a 60 das.

La edad del primer servicio de las hembras, vara en funcin del desarrollo corporal. Hembras con
adecuado desarrollo estn aptas para el servicio a partir del ao de edad. Se ha demostrado que
hembras de un ao tienen un comportamiento similar a las de dos o ms aos de edad en cuanto a
tasas de ovulacin, fertilizacin y sobrevivencia del embrin. No obstante, la prctica usual de los
productores es demorar el primer empadre hasta la edad de 2 a 3 aos, lo que obedece al pobre
desarrollo corporal de los animales.

Los machos entran en servicio a partir de los tres aos, edad en que ya se ha producido la completa
separacin de la adherencia pene-prepucial. Su persistencia es signo de inmadurez sexual.

En las explotaciones donde no hay separacin por edad ni sexo, las oportunidades de empadre se
extienden a lo largo del ao. Sin embargo, las pariciones se circunscriben slo al perodo
diciembre-marzo, lo que indicara que a pesar de haber hembras vacas no ocurren servicios. Ocurre
lo mismo en las especies silvestres donde la paricin es estacional. Esto es atribuible al efecto
 25

inhibitorio que sobre la actividad sexual de los machos ejerce su asociacin continua con las
mismas hembras, ya mencionado ms arriba. Se ha demostrado experimentalmente, que hembras
mantenidas en separacin del macho, muestran actividad sexual durante todo el ao. Al hacerse los
apareamientos a lo largo de los meses considerados como de quietud sexual (mayo a diciembre) la
conducta sexual de machos y hembras fue similar al observado entre enero y abril y no hubo
diferencias significativas atribuibles a la poca del ao, en lo que respecta tasas de ovulacin y
fertilizacin (Fernndez-Baca, 1993).

Con base en los hallazgos mencionados, se dise y puso en prctica un nuevo mtodo de empadre,
conocido como empadre alternado con el que fue posible elevar las tasas de paricin de un
promedio de 50% a 70% en pruebas a escala comercial.

El empadre alternado consiste en dividir a los machos a ser utilizados (en la proporcin de 6 por
ciento) en dos grupos de igual nmero, los que se van alternando en el rebao de las hembras a
intervalos de 5 a 7 das hasta la finalizacin del empadre, que generalmente dura 60 das. De esta
manera se logra mantener constante la actividad de los machos y permite que todas las hembras que
retornen en celo, ya sea despus de una cpula estril o la prdida temprana del embrin, vuelvan a
ser servidas.

Las tasas de paricin anual que se obtienen en las explotaciones tanto grandes como pequeas con
los sistemas tradicionales de empadre son del orden del 50 por ciento; comparado con ms del 80
por ciento con el empadre alternado (Cuadro 7).

Cuadro 7
Efecto del empadre alternado sobre la natalidad en alpacas

Clase Nmero Porcentaje

Empadradas
paridas paridas
Adultas
540 486 90,0
con cra
Adultas
384 281 73,2
vacas
Primerizas 475 367 77,3

Total 1 399 1 134 81,2

Fuente: Novoa, 1981

La baja tasa de natalidad que se obtiene con el empadre tradicional tiene estrecha relacin con la
alta mortalidad embrionaria que alcanza hasta un 50 por ciento durante los primeros 30 das de
gestacin. Las hembras que pierden el embrin vuelven a presentar celo pero no tienen la
posibilidad de ser servidas nuevamente por el efecto inhibitorio que la asociacin continua de
ambos sexos ejerce sobre los machos. En las explotaciones pequeas, con pocos animales, los
porcentajes de paricin tienden a ser mayores que en las grandes, alrededor del 60 a 70 por ciento,
lo que obedece a que el manejo del empadre es casi individual. Sin embargo, la mortalidad de cras
suele ser muy elevada, llegando con frecuencia al 50 por ciento.
 26

Se han descrito una serie de anomalas de los rganos genitales de machos y hembras (Smar,
1989) que pueden ser causa de baja eficacia reproductiva por lo que se recomienda hacer la revisin
correspondiente antes del empadre. Es indispensable que los machos destinados a la reproduccin,
adems de las caractersticas fenotpicas deseables, renan las condiciones necesarias para asegurar
altas tasas de fertilidad.

4.2.3 Paricin y destete

Despus de un perodo de gestacin de alrededor de 345 das (alrededor de 350 en llamas), la cra
nace en un estado avanzado de desarrollo lo que le permite movilizarse con facilidad poco tiempo
despus del nacimiento. Los partos ocurren generalmente por la maana lo que se atribuye a un
mecanismo de adaptacin para resistir mejor los cambios bruscos de temperatura de las grandes
altitudes.

Los cuidados que se prodigan a las cras recin nacidas se reducen bsicamente a la desinfeccin
del ombligo y la ingestin del calostro materno tan pronto como sea posible despus del nacimiento.
Hay evidencias de que la tarda o insuficiente ingestin del calostro es una de las causas
principales de muerte de las cras de alpacas (Garmendia y Col., 1987). Este es un aspecto
importante del manejo durante la paricin, que frecuentemente no recibe la debida atencin.

La mortalidad neonatal es uno de los problemas de mayor impacto econmico que enfrentan los
productores de alpacas. Las prdidas de cras dentro de los primeros tres o cuatro meses de vida,
alcanza cifras elevadas; en algunos aos puede superar el 50 por ciento. Esto, combinado con la
baja tasa de natalidad constituye un freno para cualquier programa de mejoramiento gentico por
seleccin debido a la poca disponibilidad de animales que reemplacen a los que se desechen. Las
causas de esta alta mortalidad son una combinacin de factores tales como las enfermedades, las
inclemencias climticas, la salud de las madres, etc. Ms adelante se trata esto en mayor detalle.

El destete se realiza alrededor de los 7 meses de edad, tiempo en el cual la madre ya debera estar
nuevamente con una gestacin de alrededor de cuatro meses. Esto se espera en al menos en un 50
por ciento de los casos. Por lo tanto la demanda de nutrientes va en aumento para el mantenimiento
de ambas funciones: gestacin y lactancia.

4.2.4 Esquila
La esquila en las alpacas se efecta entre los meses de octubre y noviembre que son los ms
benignos desde el punto de vista climtico. Se hace anualmente aunque hay productores que an
prefieren hacerlo cada dos aos. Se considera que la esquila anual es ms ventajosa porque permite
ejercer un control ms efectivo sobre los ectoparsitos que constituyen un serio problema en la
mayora de explotaciones. Adems, con la esquila anual se cosecha mayor cantidad de fibra que con
la efectuada cada dos aos.

Los pequeos productores, ubicados en las partes ms altas y aisladas, no siempre tienen un
calendario definido de esquila; lo hacen conforme van surgiendo sus necesidades las que son
satisfechas con la venta de fibra que a veces slo procede de una parte del animal. A menudo
utilizan la modalidad de trueque de la fibra por alimentos u otros enseres domsticos, en el mercado
local.

En las explotaciones grandes (empresas asociativas) y medianas, se va generalizando la esquila

mecnica a diferencia de las pequeas en las que es ms frecuente el uso de tijeras y an de
 27

cuchillos. La ventaja de las mquinas de esquilar es que el corte resulta mucho ms parejo lo que
facilita tambin el crecimiento posterior uniforme. Segn Villarroel (1991) la secuencia de la
esquila es importante para obtener un velln de alta calidad. Primero se corta el velln principal
aquel que cubre la lnea inferior, cuello, espalda, brazo, costillas, grupa y pierna hasta el corvejn
el que se separa cuidadosamente. Luego se corta la fibra cerdosa que cubre la regin pectoral,
vientre, flancos, extremidades, cola y cabeza, constituyendo en conjunto las bragas. La prctica de
esta secuencia, ya sea en esquila con tijeras o con mquina, significa un mejoramiento notable de la
fibra.

La clasificacin de la fibra es hecha por personal debidamente entrenado y es un paso muy

importante, previo a la comercializacin. Desafortunadamente, es una prctica an poco comn
entre los pequeos productores. Sin embargo, hay un inters creciente, de parte del sector industrial,
en promover esta prctica mediante la capacitacin de personal auxiliar que apoye a los pequeos
productores en la adopcin de prcticas mejoradas de esquila y clasificacin lo que est siendo
facilitado con el establecimiento de centros de acopio y clasificacin. La clasificacin se hace por
color, finura y longitud.

La produccin de fibra de alpaca muestra notables variaciones tanto entre unidades de produccin
como entre individuos dentro de la misma unidad. En explotaciones con un nivel tecnolgico
medio, como es el caso de la Estacin de Camlidos de La Raya, se reportan cifras de produccin
que van de 1,2 a 2,8 kg por animal, en esquila anual, sin mayores diferencias entre Suri y Huacaya
(Chvez, 1991). Por otro lado, una encuesta realizada en el Departamento de Puno, reporta cifras
de produccin anual que van de 1,8 a 2,0 kg por animal para ambas razas, con finuras de fibra de
23,8 micras en Suri y 24,0 en Huacaya (Smar, 1991).

La fibra de llama es de mayor dimetro que la de alpaca; los correspondientes valores para Kcara y
Chaku son de 33,9 y 28,1 micras, respectivamente. En cuanto a peso de velln en llamas, los
valores reportados son variables lo que se debe en parte a la frecuencia de esquila; las llamas no
siempre son esquiladas anualmente. Las cifras reportadas van de 1,0 a 1,5 kg por animal siendo
mayor en Chaku.

Cuadro 8
Porcentajes de colores en alpacas y llamas del Departamento de Puno

Color Alpacas Llamas

Caf 27,7 26,0
Negro 3,5 2,0
Blanco 53,0 35,0
Gris 1,0 9,0
Roano 0,5 --
Manchado 14,0 28,0
Total 100,0 100,0
Fuente: Adaptado de Smar(1991)
 28

4.2.5 Seleccin y mejoramiento gentico

En la actualidad, la seleccin que se practica en alpacas con miras a mejoramiento gentico, es muy
limitada y, mucho ms limitada an en llamas. Una de las razones es la poca disponibilidad de
reemplazos debido al bajo porcentaje de vientres madres en edad reproductiva en los rebaos, a la
baja tasa de natalidad y alta mortalidad de cras. Todo ello no permite hacer una adecuada
renovacin de los rebaos y ejercer una alta presin de seleccin. Por otro lado, la ya mencionada
tendencia a mantener los machos castrados como productores de fibra por todo el tiempo de
duracin de su vida productiva (10 a 12 aos), impide imprimir un ritmo ms dinmico al proceso
productivo mediante la renovacin de animales.

El principal criterio que se ha tomado en cuenta en la seleccin de alpacas ha sido el peso de velln
y el color de la fibra. La industria prefiere el color blanco; en consecuencia, ha habido una
tendencia al aumento de la proporcin del color blanco en los rebaos de alpacas y tambin de
llamas, aunque en menor proporcin (Cuadro 8).

Esta tendencia a la disminucin de los animales de color, que podra significar la desaparicin de
otras caractersticas deseables, probablemente asociadas al color, ha causado cierta preocupacin lo
que ha dado lugar al establecimiento, por parte de las entidades del Estado, de un centro de
conservacin de recursos genticos de camlidos que actualmente funciona en la localidad de
Quimsachata, Departamento de Puno. En este Centro, que est a cargo del Instituto Nacional de
Investigacin y Extensin Agraria (INIEA) del Ministerio de Agricultura, se mantiene
germoplasma de llamas y alpacas de color. El mantenimiento de los colores en la alpaca es tambin
importante por la creciente tendencia a dar preferencia a los colores naturales en lugar del uso de
tintes.

La finura o dimetro de la fibra es otra caracterstica de importancia para la industria textil y que
tiene influencia en el precio. La fibra de alpaca tiene una finura media de 28 micras siendo posible
distinguir lotes finos de 22 a 25 micras (baby alpaca) y gruesos de 30 micras que corresponden a la
calidad denominada Huarizo (Villarroel, 1991). Con la exigencia creciente de la industria por
materia prima de calidad, ser necesario que los productores presten mayor atencin, entre otros
aspectos, a la finura, lo que implica optar por mediciones ms objetivas a diferencia de las
evaluaciones subjetivas que hoy se hacen.

Fuera de la fibra, la produccin de carne es un rengln importante en la crianza de alpacas y ms

an en el caso de las llamas por su mayor tamao. Por lo tanto debera tomarse en cuenta la
velocidad de crecimiento o ganancia de peso, como uno de los parmetros de seleccin. La
produccin de carne tiene un potencial de contribuir de manera significativa a los ingresos de la
explotacin; su aporte se estima que puede superar un 50% del ingreso total de la unidad de
produccin en el caso de las alpacas y probablemente un aporte superior en el caso de la llama.
Adems, la carne cumple un papel importante en la alimentacin del campesino.

La dificultad que se afronta en la seleccin de alpacas y llamas y el consiguiente mejoramiento

gentico, es la falta de informacin sobre la correlacin gentica que existe entre las diferentes
caractersticas de importancia econmica. Por otro lado, los valores del ndice de herencia
(heredabilidad) de la mayora de ellas, no son conocidos lo que imposibilita emprender programas
de mejoramiento gentico con slidas bases cientficas. Un factor limitante para esto es la carencia
de registros de produccin en la mayora de explotaciones lo que no permite seleccionar a los
animales de acuerdo a criterios objetivos. Por lo general las evaluaciones se hacen sobre la base de
 29

apreciaciones visuales de carcter subjetivo en las que no se toma en cuenta las correlaciones entre
las diferentes caractersticas.

El Consejo Nacional de Camlidos Sudamericanos (CONACS), un organismo del Ministerio de

Agricultura, est desarrollando actualmente un programa de mejoramiento gentico de alpacas
basado en el establecimiento de registros genealgicos y la formacin de ncleos de reproductores.
El programa de registros genealgicos consiste en la evaluacin e inscripcin de los mejores
ejemplares en una sucesin de libros que van desde el libro de animales identificados hasta el libro
cerrado de pedigree. El objetivo es identificar a los ejemplares de superior calidad y hacer un
seguimiento de su descendencia antes de su ingreso en el libro cerrado. Actualmente, la evaluacin
de los ejemplares se basa en apreciacin visual subjetiva que desafortunadamente tiene
limitaciones. El programa alcanzar sus objetivos cuando las evaluaciones de los ejemplares se
hagan sobre bases objetivas lo que implica el establecimiento de programas de control de
produccin y registros de datos.

Recientemente hay un mayor inters de parte del sector industrial para apoyar a los productores de
alpaca en el mejoramiento de la calidad de la fibra. Con este propsito los industriales de productos
de alpaca, con el apoyo de la Comisin para la Promocin de Exportaciones (Prompex) y de la
Asociacin Internacional de la Alpaca (AIA), han creado el Instituto Peruano de la Alpaca y
Camlidos (IPAC) cuyas acciones incluyen la capacitacin de agentes de extensin para la
prestacin de asistencia tcnica a los productores, y el mejoramiento de los sistemas de
comercializacin mediante el establecimiento de centros de acopio. Si estas acciones se traducen en
una mayor rentabilidad para el productor, es muy probable que sean un incentivo para introducir
mejoras tecnolgicas en los sistemas de produccin, incluido el mejoramiento gentico.

Las biotecnologas aplicadas a la reproduccin, como son la inseminacin artificial y la

transferencia de embriones, son herramientas que podran tener un impacto considerable en el
proceso de mejoramiento gentico, al permitir la diseminacin masiva de caractersticas deseables
por parte tanto del macho como de la hembra. Pese a los esfuerzos realizados desde hace varios
aos, no se ha logrado an desarrollar una metodologa que asegure resultados tales que justifiquen
econmicamente la aplicacin masiva de estas tcnicas que tendran un impacto notable en el
proceso de mejoramiento gentico.

La inseminacin artificial que es un valioso instrumento para el mejoramiento gentico, an no es

posible aplicarlo en forma masiva. Uno de los escollos sigue siendo la carencia de un mtodo
confiable de coleccin de semen lo que se dificulta por la posicin en que se lleva a cabo la cpula
en los camlidos (con la hembra en posicin decbito ventral). Hay experiencias exitosas con la
inseminacin, pero no las suficientes como para aplicarlas en forma masiva. Algo similar ocurre
con la transferencia de embriones. Hay que sealar, sin embargo, que por sus caractersticas
reproductivas, los camlidos ofrecen mayores ventajas que otras especies de animales domsticos
para la implementacin de estas tcnicas.

El hecho de que las cuatro especies de CSA tengan igual nmero de cromosomas hace posible los
cruces entre especies. Cruzamientos entre llamas y alpacas, que dan lugar al Huarizo, ocurren con
frecuencia, sobre todo en las comunidades pequeas donde se practica la crianza mixta. Pese a que
los animales resultantes son de mayor tamao que la alpaca, hay un desmejoramiento de la calidad
de la fibra, por lo que no se considera muy deseable. Menos frecuentes son los cruces entre alpaca y
vicua que dan como resultado la paco vicua. Estos animales tienen un mayor peso de velln y
tamao corporal que las vicuas y una fibra de mayor finura que la alpaca, lo que podra ser muy
 30

deseable. Estudios realizados en los pocos ejemplares obtenidos, sobre todo a nivel de estacin
experimental, demuestran que el dimetro de fibra vara entre 13,3 y 17,3 micras. Se atribuye esta
variacin a la posible diferencia en dimetro de la fibra de los progenitores alpaca puesto que en las
vicuas el dimetro es ms uniforme (Carpio, 1991). Se requieren ms estudios de seguimiento del
comportamiento de las generaciones resultantes de estos cruzamientos antes de intentar la
implementacin de programas en escala comercial.
 31

5. MANEJO DE LA VICUA

La vicua tiene un patrn de organizacin social muy peculiar que ha sido motivo de numerosos
estudios. Se caracteriza por la existencia de grupos familiares polgamos consistentes en un macho
dominante (jaiacho) y cinco o seis hembras con sus cras; tropillas de machos y machos solitarios.
El macho establece y mantiene un territorio permanente a lo largo de su vida reproductiva. Este
territorio, normalmente contiene un dormidero en el sector ms alto, un territorio de alimentacin
ubicado en una parte ms baja, y una fuente de agua (Wheeler, 1991). La extensin de los territorios
de alimentacin de los grupos familiares vara segn su ubicacin. En la Reserva de Pampa Galeras,
se encontr un promedio de 18,4 ha en las zonas de mejores recursos y extensiones mayores en las
zonas ms pobres. Los lmites territoriales estn demarcados por estercoleros que sirven para la
orientacin de los miembros del grupo familiar y como puntos desde los cuales el macho dominante
defiende su territorio contra la incursin de individuos extraos. El macho, mediante defecacin
ritual, refuerza los lmites de su territorio y expulsa a sus propias cras machos y hembras antes del
inicio de la siguiente paricin. Los machos excluidos se juntan a tropillas no territoriales y las
hembras se unen a otros grupos familiares. Algunos machos eventualmente se separan de las
tropillas y viven solitarios hasta establecer su propio territorio.

El periodo de gestacin de la vicua es de 330 a 350 das; la paricin comienza en la segunda

quincena de febrero y termina en abril con un pico de nacimientos en marzo, lo que refleja la
estacionalidad marcada de su actividad reproductiva. An cuando algunas hembras son capaces de
empadrarse al ao de edad, la mayora lo hace a los dos aos, de manera que producen la primera
cra a los tres aos. Las tasas de preez que se reportan son variables; se informa, por ejemplo, que
en la Reserva de Pampa Galeras lleg hasta un 80% al comienzo de las operaciones en la dcada de
los 70, cuando haba abundancia de recursos alimenticios; luego disminuy a un 58% cuando
sobrevino el dficit debido a la sobrepoblacin y la sequa (Wheeler, 1991). Sin embargo, en una
evaluacin realizada en 9 localidades de la Regin Jos Carlos Maritegui que involucra los
Departamentos de Puno, Tacna y Moquegua durante un lapso de 10 aos, se encontr un promedio
de 31,7 por ciento de natalidad con variaciones de 25 a 42 por ciento.

La paricin siempre ocurre por las maanas (similar a las alpacas) lo que se considera como un
mecanismo de supervivencia frente a las inclemencias climticas propias de las zonas alto andinas.
El peso al nacer vara entre 4 y 6 kg. La mortalidad durante los primeros cuatro meses de vida
vara entre 10 y 30% debido a neumonas, caza ilegal y predatores, como zorros y pumas. Para su
alimentacin, las vicuas prefieren los pastos cortos no siendo ramoneadores.

De acuerdo con la legislacin peruana vigente, el manejo, conservacin y aprovechamiento

racional de la vicua est ahora a cargo de comunidades campesinas y empresas asociativas que
tienen el derecho al usufructo de la poblacin animal existente en sus territorios. El manejo de este
recurso se lleva a cabo bajo los lineamientos y la supervisin del Instituto Nacional de Recursos
Naturales (INRENA) y del CONACS. Hay actualmente 259 entidades titulares de manejo y
aprovechamiento de la vicua, distribuidos como sigue: 197 comunidades campesinas; 12 empresas
comunales; 12 empresas asociativas; y 12 propietarios particulares. Hay adems, 178 mdulos de
uso sustentable con una poblacin de 27 405 vicuas. Estos operadores se cien a lo establecido
por la Convencin para el Comercio Internacional de Especies Amenazadas de Flora y Fauna
(CITES) de la cual Per es signatario, que ubica a la vicua en el Apndice II, permitiendo el
comercio de telas fabricadas con fibra proveniente de vicuas esquiladas vivas.
 32

La cosecha de la fibra se realiza mediante la operacin denominada chaku que puede llevarse a
cabo entre el 15 de mayo y el 15 de noviembre de cada ao. El chaku es una tcnica de manejo
ancestral de la vicua que se remonta a la poca prehispnica y que alcanz su apogeo durante el
imperio incaico. Consiste en el arreo de las vicuas hacia un lugar especfico de captura con el
propsito de realizar la esquila. Se aprovecha tambin para la revisin de los animales y los
tratamientos que sean requeridos.

Parte importante del proceso de manejo y aprovechamiento de la vicua es la vigilancia constante

para prevenir la accin delictiva de los cazadores furtivos. Actualmente 134 ncleos comunales
cuentan con un servicio de guarda parques y se prev el incremento de este nmero en el futuro.
 33

6. APROVECHAMIENTO DE LA FIBRA

Las fibras de alpaca y vicua tienen un mercado importante de exportacin, fuera de los usos
artesanales, mientras que la de llama se destina mayormente a consumo interno.

Cuadro 9
Evolucin de la produccin de fibra de alpaca y vicua en el Per

AO ALPACAS VICUAS
Toneladas Toneladas
1994 3 728 0,842
1995 2 775 2,222
1996 3 365 1,466
1997 3 337 1,907
1998 3 450 2,531
1999 3 272 3,076
2000 3 317 3,428
2001 3 399 4,332
2002 3 165 5,150
2003 3 103 6,093
2004 3 200 5,084
Fuente: CONACS (2005)

6.1 Fibra de alpaca

En el Cuadro 9 se observa que la produccin de fibra de alpaca se ha mantenido ms o menos
constante desde el ao 1994 a diferencia de la de vicua que ha ido en aumento, debido a la
incorporacin de un nmero cada vez mayor de comunidades al manejo de este recurso as como al
mejoramiento de los mtodos de captura para la esquila. No obstante, segn informacin reciente
de CONACS, la produccin actual de fibra de alpaca alcanzara la cifra de 6 440 toneladas mtricas.
Lo evidente es que no se dispone en el pas de un mecanismo efectivo de monitoreo y control de
produccin que mantenga la informacin al da.

El relativo estancamiento de la produccin de fibra de alpaca, segn estos datos, en contraste con el
incremento numrico de esta especie en los ltimos diez aos, podra ser una indicacin de que los
niveles individuales de produccin han disminuido o, en el peor de los casos, no han variado. Esto
sera atribuible a la ausencia de trabajos de seleccin sistematizados y con objetivos concretos, a la
deficiente alimentacin y al impacto de las enfermedades. Es una realidad que el sector de pequeos
productores que posee ms del 80 por ciento de alpacas, no tiene ni los medios ni los incentivos
para mejorar su sistema de produccin, de ah que los rendimientos en lugar de aumentar sigan una
tendencia descendente.

La fibra de alpaca pasa por un proceso de clasificacin previa a la comercializacin. Los principales
parmetros que se toman en cuenta son la finura o dimetro, la longitud de mecha, y la resistencia
(Velarde, 1993). Cada empresa textil tiene su propio sistema de clasificacin, al no existir un
sistema estandarizado. Recientemente, CONACS ha anunciado la pronta implementacin de normas
tcnicas para la fibra y carne de alpaca.
 34

El sistema de comercializacin de la fibra de alpaca se diferencia segn su origen. La que proviene

de las comunidades campesinas y es recolectada por intermediarios se denomina de colecta,
mientras que la que proviene de las empresas asociativas y medianos propietarios se denomina de
finca. La primera, por lo general contiene mayor cantidad de impurezas y es menos homognea
por las condiciones precarias en que se realiza la esquila; en cambio la fibra de finca es ms
homognea y con menor contenido de impurezas.

En la cadena de comercializacin de la fibra de alpaca hay una serie de eslabones de intermediacin

hasta llegar a su destino final. Esta cadena est compuesta por:

Alcanzadores: Se encargan de alcanzar a los productores antes de que lleguen al lugar de

venta y adquieren la fibra a bajo precio aprovechando la desinformacin del productor.

Rescatistas: Acopian la fibra de los productores manteniendo con ellos una relacin de
dominio a travs de diversos mecanismos como el compadrazgo o el adelanto en vveres o
dinero. Hay diversas categoras de rescatistas segn la escala en la que operan. Ellos, por lo
general, cuentan con los llamados jaladores que son los encargados de hacer el contacto con
los productores y hacer que vendan su fibra al rescatista para el que trabajan.

Los agentes comerciales: Trabajan para las empresas comercializadoras percibiendo un

sueldo fijo y una comisin por volumen acopiado.

Las empresas comercializadoras: Constituyen el ltimo eslabn de la cadena de

intermediacin. Gracias a su capacidad econmico financiera, pueden controlar el circuito
desde la compra hasta el procesamiento del producto, orientndolo principalmente hacia el
mercado externo.

Se estima que un 85 por ciento de la produccin total de fibra de alpaca va a la industria (para
exportacin en su mayora) y el 15 por ciento restante se destina a la artesana y el autoconsumo.

Los pasos que se siguen en el procesamiento de la fibra, una vez que es recepcionada en la fbrica,
son los siguientes (Lazarte, 1990):

Clasificacin por colores;

a) Cardado. La fibra cardada recibe el nombre de Slivers y el descarte, Noils;
b) Peinado, que se repite tres veces consecutivas;
c) Peinado termina cuando se pasa a la mquina de embobinado, lo que constituye el Top de
alpaca;
d) Hilado: conversin de mechas de tops en hilo que se presenta en conos de unos 73 kg de
peso.

En la conversin de fibra a tops hay una prdida por desperdicio de 21 por ciento; por lo tanto, se
utiliza 1,265 kg de fibra por cada kilogramo de tops.

El desperdicio en la conversin de tops a hilo es de 5,5%. Por lo tanto, por cada kilogramo de hilo
se utiliza 1,0582 kg de tops; por consiguiente, la conversin de fibra a hilo es de 75%, por lo que se
 35

demanda 1,333 kg de fibra por cada kilogramo de hilo y 1,5682 kg de fibra por kilogramo de tejido
plano (1,1765 kg de hilo/kg de tejido plano).

La fibra de alpaca, ingres al mercado mundial a principios del siglo XIX, destacndose por su gran
suavidad y resistencia. Hoy sigue siendo un producto importante de exportacin. Sin embargo,
debido a los bajos volmenes de oferta en comparacin con otras fibras de origen animal, como el
mohair, cashmere, o pelo de camello, la fibra de alpaca est sujeta a fluctuaciones considerables de
precio en el mercado internacional lo que naturalmente se refleja en los precios que la industria
paga al productor. Por ejemplo, la produccin mundial de fibra de alpaca en 1993 slo representaba
el 19 por ciento del mohair y 42 por ciento del pelo de camello (Velarde, 1993). Es probable que las
proporciones no hayan variado mucho en los ltimos aos.

Por otro lado, cuando la alpaca se pone de moda, lo que ocurre cada cinco aos aproximadamente,
se producen situaciones extremas de inestabilidad y volatilidad en los precios, que suben
rpidamente por efecto de una demanda que supera la oferta, lo que causa gran especulacin interna
y un incremento estacional de precios en toda la cadena. Esto obliga a los compradores finales a
sustituir la alpaca por otras fibras con mayor masa crtica y estabilidad. La consecuencia final es
que el precio de la alpaca baja a niveles de sub-rentabilidad para el productor.

En el Cuadro 10 se presentan los precios referenciales de alpaca y otras fibras animales en el

mercado internacional, segn datos del Instituto Peruano de la Alpaca y Camlidos (IPAC).

Cuadro 10
Precios internacionales de la alpaca y de otras fibras animales

TIPO DE FIBRA FINURA PRECIO

(Top) (Micras) $EE.UU./Kg

Alpaca baby 22,5 14,00

Alpaca superfine 26,5 9,00
Alpaca huarizo 31,0 4,30
Alpaca adult 34,0 2,90
Cashmere 16,0 80,00
Mohair kid 25,0 27,00
Mohair young 28-31 21,00
Mohair adult 35-37 6,00-11,50
Fuente: IPAC (2004)

Los principales mercados de exportacin son: China, Italia, Reino Unido y los Estados Unidos, para
los Tops e hilados, y los Estados Unidos, Alemania, Reino Unido y Japn, para las prendas
terminadas de alpaca. El 80 por ciento de la fibra se exporta en la forma de productos de bajo valor
agregado (tops, hilados y telas) y solamente el 20% en prendas terminadas.

El sector representa el 1,35 por ciento de las exportaciones totales del Per y el 5 por ciento de las
exportaciones no tradicionales. El ao 2001 se export por un valor total de 75 millones de dlares
EE.UU. Su contribucin al Producto Bruto Interno manufacturero ha fluctuado de 2 a 2,5 por ciento
 36

en los ltimos diez aos y en las exportaciones de productos textiles y confecciones tiene una
participacin del 15 por ciento. Absorbe el 2 por ciento de la poblacin econmicamente activa
(PEA) ocupada en la industria manufacturera, aproximadamente 22 000 personas. De las empresas
del sector el 96 por ciento son micro y pequeas empresas con menos de 40 empleados, el 3 por
ciento son medianas (41 a 200 empleados) y slo el 1 por ciento son empresas grandes. Los tres
principales grupos empresariales dedicados al procesamiento de la fibra de alpaca se encuentran
localizados en la ciudad de Arequipa: Grupo Mitchell, Grupo Inca, y Grupo Sarfaty. Son las
empresas que dominan el espectro de la industria alpaquera en el Per.

6.2 Fibra de llama.

Las estadsticas sobre volumen de produccin anual de fibra de llama son referenciales. La esquila
no es una prctica que se rija por un calendario como en el caso de la alpaca. Se estima que slo el
40 por ciento de la fibra va a los artesanos y la industria y el 60 por ciento se orienta al
autoconsumo, para la fabricacin de una serie de productos de uso domstico como sogas, costales
o bolsas, hondas, ponchos, chompas, tapices, etc.

La produccin total en el ao 2001 fue de 800 toneladas segn estimado de la Direccin General de
Asuntos Econmicos y Sociales del Ministerio de Economa y Finanzas (DGAES, 2005). Con una
produccin media anual de alrededor de 1,2 kg por animal, tal como indican los datos de La Raya
(Cuadro 11), la cantidad registrada equivaldra a la produccin de aproximadamente 600 000
animales, o sea el equivalente al 60 por ciento de la poblacin total de llamas. Esto, bajo el supuesto
de que los rendimientos corresponden a esquila anual.

Cuadro 11
Peso de velln por tipo de llama y procedencia

Edad CAT Gigante C.E. La Raya

Aos
Kara Lanuda Kara Lanuda
1 -- -- -- --
2 -- -- 0,92 1,12
3 2,04 2,36 1,15 1,43
4 1,40 3,22 1,07 1,38
5 1,23 3,20 1,05 1,42
6 1,58 -- 1,15 1,34
7 1,50 -- 1,20 1,46
8 1,43 -- 1,15 1,35
9 2,00 -- -- --
Media 1,59 2,92 1,10 1,35
Fuente: Chvez (1991)

En las cifras del Cuadro 11 se ve la diferencia entre las dos razas de llamas. La Lanuda posee un
velln ms voluminoso, con fibras que se parecen a la alpaca con poca presencia de cerda; en
cambio la pelada o Kara tiene fibra corta con alto contenido de cerda. El dimetro de la fibra vara
de 25,6 a 27,6 micras en Lanuda y de 29,2 a 30,7 micras en Kara (Vidal, citado por Chvez, 1991).
 37

La mayor parte de la fibra de llama que se destina a la artesana y autoconsumo se comercializa de

manera informal; en la comercializacin de aquella porcin que va a la industria, se sigue el mismo
patrn que con la fibra de alpaca.

6.3 Fibra de vicua

La produccin de fibra de vicua (Cuadro 9) ha ido en aumento con la incorporacin de nuevos
ncleos de manejo sustentable a cargo de organizaciones comunales y operadores privados. El
nmero de titulares de manejo sustentable se increment de 219 en el ao 2002 a 259 en el 2004.
Segn las cifras de CONACS en el ao 2002, la captura total de vicuas en los 219 ncleos de
manejo fue de 58 754 cabezas de las cuales fueron esquiladas 26 457, o sea el 44,9 por ciento, con
una produccin total de 5 150 kg. La produccin promedio de fibra de los animales esquilados fue
de 195 g por animal. Se trata de una fibra sumamente fina con un dimetro de 10 a 12 micras.

El acopio de la produccin de fibra de vicua, segn las disposiciones legales vigentes, est a cargo
de las comunidades campesinas y otras personas jurdicas titulares del manejo de las vicuas, bajo
la supervisin de CONACS. Esta produccin debe ser debidamente registrada como paso previo a
su transformacin y comercializacin.

La transformacin y comercializacin de los productos derivados de la fibra de vicuas esquiladas

vivas, se hace con la marca VICUA-PERU en el caso de las empresas industriales textiles, y
VICUA-PERU-ARTESANIA, en el caso de las empresas artesanales.

La mayora de la produccin de fibra de vicua es comprada por dos compaas nacionales: Prosur
S.A. y Michell y Cia S.A. Los precios referenciales pagados por estas compaas, segn
informacin de CONACS, se presentan en el Cuadro 12.

Cuadro 12
Precios pagados por las empresas industriales por la fibra de vicua
(Fuente: CONACS)

FIBRA DE VICUA
SUCIA CORTA
N EMPRESA PREDESCERDAD DESCERDADA
CLASIFICADA (EEUU$
A. (EEUU$ x Kg) (EEUU$ x Kg)
(EEUU$ x Kg) x Kg)
1 LEAF INC (-) 475.00
2 JOHNSTONS OD ELGIN (-) 507.00 650.00
3 PROSUR S.A. (-) 437.00 70.00
4 MICHELL & CIA. S.A. (-) 437.00 507.00
Z. HINCHILIFFE & SONS
5 507.00
LTDA. (+)
INTERNATIONAL VICUA
6 380.00
CONSORTIUM (-)
7 INCALPACA TPX (*) 450.00 625.00
(-) Ao 2003-2004
(+) Ao 2004
(*) Ao 2005
 38

La industria artesanal basada en la fibra de alpaca, llama y vicua, cobra cada vez mayor
importancia en el Per debido a la creciente demanda de los productos artesanales tanto en el
mercado externo como en el interno. El crecimiento del flujo turstico al Per es de suponer que
cree an una mayor demanda. El artesanal es un sector que engloba una considerable cantidad de
micro empresarios que constituyen una importante fuente de trabajo que absorbe gran cantidad de
mano de obra. Su crecimiento debe favorecer a los productores de camlidos al crearse mayor
demanda para sus productos.
 39

7. APROVECHAMIENTO DE LA CARNE

La produccin de carne es un rengln importante en la crianza de camlidos. Primero, porque se

trata de un alimento de alto valor nutritivo que contribuye de manera importante a la nutricin de
los pueblos alto andinos, y segundo, porque con un debido reordenamiento de la estructura de los
rebaos y mejora del manejo y la sanidad, es posible obtener beneficios econmicos comparables
con el aporte de la fibra.

La produccin total de carne depende naturalmente de la saca anual, es decir, del nmero de
animales que anualmente se descartan del rebao para ser destinados a sacrificio. Aunque no hay
datos concretos, se estima que el porcentaje de saca anual, tanto en alpacas como en llamas, es del
orden del 10 a 12 por ciento que, como ya se mencion, se debe al bajo porcentaje de hembras que
se suele mantener en los rebaos as como a las bajas tasas de natalidad y alta mortalidad de cras.
La saca, en gran mayora, est constituida por animales viejos, hembras y machos, que han llegado
al final de su vida productiva. Esto hace que la presencia de sarcocistes en la musculatura sea
elevada y que la carne sea de inferior calidad.

No existen estadsticas precisas sobre el nmero de llamas y alpacas que se destinan al sacrificio
anualmente ni sobre la cantidad total de carne que se produce. Una considerable proporcin de
animales son beneficiados sin pasar necesariamente por los mataderos y que por lo tanto no pueden
ser contabilizados oficialmente. Tomando como base una saca de 12 por ciento anual y las
poblaciones existentes de alpacas y llamas (Cuadros 1 y 2), se estima que el nmero de animales
destinados cada ao a beneficio ascendera a 348 000 alpacas y 120 000 llamas. Con un peso de
canal de 30 kg para las alpacas y 55 kg para las llamas, las correspondientes cifras de produccin de
carne seran de 10 440 toneladas para alpaca y 6 600 toneladas para llama. Cunto de esto pasa por
los mataderos y cuantos se sacrifican fuera de ellos, no se conoce.

No existen mataderos destinados exclusivamente al sacrificio de camlidos; se utilizan los mismos

donde tambin se sacrifican otras especies. El nico centro de beneficio y procesamiento de carne
de camlidos que fue establecido y puesto en funcionamiento en la sierra de Arequipa, mediante un
proyecto apoyado por la Agencia Espaola de Cooperacin Internacional (AECI), fue desactivado
por falta de mercado para los productos. Otro matadero modular construido especialmente para
alpacas en el Municipio de Marangan, Departamento de Cusco, con apoyo financiero y tcnico de
la FAO, no funciona a plenitud por el momento.

La mayor afluencia de alpacas y llamas a los mataderos ocurre en las zonas de mayor poblacin de
estos animales como son los Departamentos de Punto, Huancavelica, Apurmac, Cusco, en los que
tambin hay mayor demanda de la poblacin por estas carnes.

Las condiciones higinicas de los mataderos formales, aunque varan de un lugar a otro, son en
general aceptables y cuentan con los servicios de inspeccin veterinaria. Por el contrario, el
beneficio clandestino, fuera de los mataderos, se lleva a cabo en condiciones higinicas poco
adecuadas y carentes de control sanitario e inspeccin veterinaria, lo que constituye un medio de
propagacin de enfermedades.

El rendimiento de canal es relativamente alto en comparacin con otras especies: un promedio de

55 por ciento en alpacas y 57 por ciento en llamas, con una media de pesos adultos de 116 kg para
llamas y 60 kg para alpacas. Para los estimados de produccin total de carne antes mencionados, se
han tomado pesos corporales menores por tratarse de animales de desecho.
 40

La carne de camlidos tiene una composicin nutritiva similar a la de otras especies domsticas; es,
por lo tanto una importante fuente de protenas y otros elementos esenciales como minerales y
vitaminas (Cuadro 13). Sus caractersticas organolpticas no difieren de la carne de otras especies
aunque la procedente de machos enteros adultos puede tener un olor y sabor ms fuertes.

Su consumo es en la forma de carne fresca o procesada (carne deshidratada o embutidos). El

procesamiento tanto de la carne fresca como la deshidratada se hace de manera artesanal, siguiendo
en muchos casos tcnicas ancestrales.

Cuadro 13
Composicin bromatolgica de la carne de alpaca y llama

ALPACA LLAMA
Humedad (%) 71,9 -77,3 69,2 73,8
Protena (%) 18,9 - 21,7 19,4 24,8
Grasa (%) 1,1 7,2 1,2 4,8
Cenizas (%) 1,1 1,6 1,2 1,7
Colesterol (%) 0,20 0,16
Fuente: Vilca, 1991

La carne que proviene de los mataderos se destina mayormente al consumo directo en la forma de
carne fresca y, en menor proporcin a la elaboracin de otros productos, como embutidos. Por lo
general no se practica la clasificacin de canales por calidad y tampoco existe un sistema
estandarizado de cortes. Se sigue un sistema similar al de ovinos, an cuando hay diferentes
propuestas para la canal de los camlidos. Una de ellas consiste en dividir la canal en tres partes
principales: el bistec (pierna y brazuelo) que representa el 47 por ciento; el churrasco (lomo,
churrasco de costilla) que representa el 15 por ciento, y el sancochado (pescuezo, pecho, osobuco,
costillar y falda) que constituye el 38 por ciento restante (Vilca, 1991). Hay otras propuestas que
consideran mayor nmero de cortes.

Una parte considerable de la carne de llamas y alpacas se comercializa previo proceso de

deshidratacin, en forma de charqui o chalona. En ambos casos se utilizan tecnologas ancestrales
que se remontan a la poca pre-hispnica y consisten bsicamente en el secado de la carne con la
adicin de sal y algunos condimentos. La diferencia entre el charqui y la chalona consiste en que
para la primera se utiliza mayormente carne deshuesada, cortes de las porciones musculares,
mientras que para la segunda se utiliza la canal ntegra, sin deshuesar. La poca ms apropiada para
ambos procesos es entre los meses de mayo y agosto, que son los ms secos, con abundante
radiacin solar y bajas temperaturas nocturnas.

Las tcnicas de elaboracin de charqui tienen algunas variaciones de un lugar a otro aunque el
principio es el mismo. En un estudio realizado en 16 comunidades campesinas de Ayacucho y
Huancavelica se encontr que los pasos que se siguen en la elaboracin familiar de charqui son: a)
laminado de la carne; b) espolvoreo con sal granulada y c) secado natural, con exposicin directa al
sol. En la mayora de casos la duracin total del proceso vari de 15 a 25 das.

Para la elaboracin de la chalona, en el canal ntegro se practican cortes en las regiones musculares
a fin de introducir la sal; adems, se cubre de sal toda la superficie de la carcasa. El secado se hace
 41

exponiendo al sol durante el da y al fro en las noches, hasta lograr la deshidratacin. El proceso
dura entre 7 y 8 das. Es un proceso de deshidratacin y desecado por congelamiento.

El charqui procede en mayor escala de carne de llama pues es practicada ms a nivel de pequeos
productores. En las explotaciones de alpacas de mayor magnitud, como son las empresas
asociativas y medianos productores, se suele hacer la matanza colectiva de los animales destinados
a saca para luego procesarlos en forma de chalona.

Las menudencias son en parte consumidas en forma fresca y, en parte, procesadas como carne seca
salada para su conservacin.

En cuanto al destino del charqui y de la chalona, se estima que un 30 por ciento es para
autoconsumo y un 70 por ciento para el comercio siendo los destinos finales las poblaciones de la
selva, los centros mineros y ciudades de la costa, en orden de importancia. Estudios hechos sobre
rendimiento de charqui y chalona indican porcentajes que varan de 25 a 46 por ciento (Vilca,
1991).

La elaboracin de embutidos a base de carne de camlidos an no ha alcanzado gran magnitud pese

el potencial que tiene esta forma de uso para abrir un mayor mercado a este tipo de carne y
promover sistemas de crianza orientados al suministro de animales ms tiernos y de mayor calidad
al mercado. Hay experiencias exitosas en la preparacin de embutidos a base de carne de camlidos.
El proyecto TCP/RLA 2914, apoyado por FAO y ejecutado por la Universidad Peruana Cayetano
Heredia , en cooperacin con CONACS, tiene entre sus finalidades la capacitacin de tcnicos en la
elaboracin de embutidos de carne de camlidos con la adicin de extensores a base de productos
nativos de la regin. De esta forma se pretende abaratar costos sin sacrificar el valor nutritivo, y
poner los productos al alcance de las personas de menores ingresos. Los resultados obtenidos en los
ensayos preliminares son muy promisorios.

Actualmente la utilizacin de la carne de camlidos en la produccin comercial de embutidos es

todava limitada. Algunas empresas particulares las estn utilizando en combinacin con otras
carnes para la elaboracin de chorizo.

Otros productos crnicos que eventualmente se fabrican a partir de carne de camlidos incluyen el
jamn y las conservas enlatadas. Se han logrado resultados promisorios en los ensayos realizados
sobre preparacin de estos productos; sin embargo an no se han desarrollado en escala comercial.
Subproductos como la sangre y vsceras tambin son aprovechadas a nivel domstico.

El consumo de carne fresca de camlidos en los centros urbanos es limitado; es ms generalizado en

las ciudades ubicadas en las zonas de produccin de alpacas y llamas y, dentro de ellas, entre el
sector de poblacin de menores ingresos. Por lo general el precio de venta es equivalente a la mitad
del precio de la carne de ovino o vacuno. En general, hay una cierta discriminacin debido
principalmente a prejuicios sobre su calidad nutritiva y estado de higiene y de sanidad. A esto
contribuye la baja calidad de carne procedente de animales viejos y la presencia de los sarcocistes.

Hay un inters creciente en promover el consumo de carne de alpaca a travs de la oferta de recetas
y platos especiales en el men de restaurantes tanto de Lima como de provincias, sobre todo de los
lugares que reciben un flujo turstico elevado como es el caso del Cusco. Tambin es posible
encontrar en algunos supermercados de Lima carne de alpaca; as mismo, algunos restaurantes
ofrecen potajes especiales a base de esta carne
 42

Con el suministro al mercado de una carne de mejor calidad, proveniente de animales jvenes y
libres de parsitos como la sarcocistiosis, es posible esperar la apertura de un mercado mucho
mayor y ms equitativo en precio, para la carne de los camlidos. Existe tambin un importante
potencial de exportacin por la creciente demanda por carnes exticas producidas bajo condiciones
de pastoreo como es el caso de las alpacas y llamas. Adems, se trata de carnes magras con un bajo
contenido de colesterol.

Fuera de las vsceras, los principales subproductos del beneficio de los animales son las pieles y
cueros. Las vsceras, frescas o deshidratadas, se destinan a autoconsumo. Con frecuencia, en la
matanza clandestina, se alimenta a los perros con algunas vsceras lo que constituye el vehculo de
transmisin de muchas de las afecciones parasitarias como la sarcocistiosis y la hidatidosis.

Las pieles se destinan mayormente a usos artesanales. Son particularmente cotizadas las pieles de
animales jvenes, menores de 6 meses de edad, por la calidad de su fibra. Los cueros se utilizan
para la curtiembre y la fabricacin de una serie de productos como zapatos, chaquetas, bolsas,
correas, etc. El cuero de llama es especialmente cotizado para la confeccin de lazos o reatas, por
su gran resistencia a la traccin.
 43

8. PREVENCION Y CONTROL DE ENFERMEDADES.

Las enfermedades infecciosas y parasitarias constituyen un factor limitante de gran magnitud en la

produccin de camlidos domsticos y en la conservacin y aprovechamiento de las especies
silvestres. Las enfermedades infecciosas son causa de la alta mortalidad y morbilidad de cras y
adultos, que se traduce en graves prdidas econmicas, mientras que las enfermedades parasitarias
afectan el estado general de los animales lo que reduce su produccin y productividad, o afectan la
calidad de los productos como es el caso de la sarcocistiosis que afecta la carne, o los ectoparsitos
que afectan la calidad de la fibra.

Tal como se observa en el Cuadro 14, las mayores tasas de mortalidad se observan en cras con
valores extremos que van de 9,3 a 56,6 por ciento, lo que representa prdidas econmicas
considerables. Adems, esta alta mortalidad de cras, combinada con la alta incidencia de muerte
embrionaria temprana y baja tasa de natalidad anual (alrededor del 50%), trae como consecuencia
una escasa disponibilidad de reemplazos lo que limita las posibilidades de seleccin y mejoramiento
gentico, tal como ya se ha mencionado en secciones anteriores.

Cuadro 14
Porcentajes de mortalidad anual por edad en alpacas de la regin del Altiplano de Per

Edad Media Valores Extremos

Cra 26,7 9,3 56,6
Tui 5,1 4,1 - 6,6
Adulto 2,9 2,0 3,6
Fuente: Ramrez, 1991

Entre las causas de mortalidad, tanto de cras como de adultos, ocupan el primer lugar las
enfermedades infecciosas, seguidas por las metablicas (Cuadro 15). Las enfermedades parasitarias
no son causa importante de muerte pero s ocasionan alta morbilidad.

Cuadro 15
Causas de mortalidad en alpacas segn edad, en un sistema de produccin del Altiplano de
Per (%)
Categora Cra Tui Adulto
Enf. Infecciosas 66,5 53,1 52,4
Enf. Parasitarias 0,1 5,5 3,2
Enf. Metablicas 22,8 21,0 22,8
Causas fortuitas 4,0 11,7 11,4

Fuente: Ramrez, 1991

 44

8.1 ENFERMEDADES INFECCIOSAS

8.1.1 ENFERMEDADES DE CRIAS.

Tal como se indica en el Cuadro 14, la causa principal de muerte en cras de alpacas son las
enfermedades infecciosas. Entre ellas ocupa el primer lugar la enterotoxemia que en algunos aos
puede ocasionar la muerte de hasta un 86 por ciento de las cras de alpaca. No se dispone de datos
muy precisos en lo que respecta a llamas pero hay informes de que la situacin es similar, aunque
los porcentajes de muerte de cras de esta especie parecen ser menores que en el caso de las alpacas.

8.1.1.1 Enterotoxemia
La enterotoxemia es una enfermedad infecciosa aguda que afecta a las cras de alpaca
principalmente dentro del primer mes de vida. Es la enfermedad ms devastadora y es producida
por la accin de las enterotoxinas provenientes de una bacteria anaerbica, el Clostridium
perfringens tipo A (antes llamada C. welchii) las cuales rpidamente causan dao severo a nivel
intestinal y rganos vitales que termina con la muerte repentina del animal. La mortalidad de cras
supera largamente el 50 por ciento en algunos aos.

Las primeras observaciones sobre esta enfermedad datan de la dcada de los cincuentas. En 1955,
fue Moro, un profesor de la Facultad de Medicina Veterinaria de la Universidad Nacional de San
Marcos, quien realiz los primeros estudios y denomin a la enfermedad diarrea bacilar, al
observar la presencia de un bacilo anaerbico en heces diarreicas de cras muertas. La confirmacin
final del agente etiolgico, C. perfringens tipo A, fue realizada tomando como base la deteccin de
la alfa toxina. Antes de eso, la enfermedad fue considerada como una forma aguda de la
denominada fiebre de alpaca producida por el Strepcoccus zooepidemicus (Ramrez, 19991).
Estudios posteriores han dado mayores luces sobre el agente etiolgico de la enfermedad aun
cuando quedan muchas interrogantes, que son materia de estudio.

La enfermedad se presenta en forma cclica, conforme demuestran los estudios de seguimiento

hechos durante ms de 10 aos en explotaciones comerciales y a nivel del Centro Nacional de
Camlidos Sudamericanos de La Raya. De una tasa de mortalidad de cras por enterotoxemia de 15
a 20 por ciento en el primer ao de un ciclo, aumenta a 30 o 40 por ciento en el siguiente ao hasta
alcanzar un nivel mximo de 50 por ciento o ms hacia el quinto o sexto ao. Luego baja
abruptamente a 6 o 10 por ciento el siguiente ao. La posible explicacin de estas variaciones
parece radicar en los cambios del nivel inmunolgico de la madre. Durante el ciclo de alta
mortalidad de cras por enterotoxemia, las madres son expuestas a altos niveles de cepas de C.
perfringens tipo A, productoras de enterotoxinas. De esa forma las madres recibiran una suerte de
vacuna natural contra el patgeno, que estimulara su respuesta inmune y permitira el pasaje de
una mayor concentracin de anticuerpos a las cras a travs del calostro. Al disminuir la incidencia
de la enfermedad y bajar la mortalidad, habra tambin una disminucin de los niveles de
anticuerpos de la madre y la consiguiente menor concentracin en el calostro, lo que
desencadenara un nuevo ciclo (Ellis, 1997). Los ciclos son de cinco a seis aos y la severidad de la
enfermedad puede ser exacerbada por las condiciones climticas adversas y la falta de medidas
higinicas que desafortunadamente son de comn ocurrencia.

Actualmente no se cuenta con una vacuna que conceda una proteccin efectiva a las cras contra la
enterotoxemia. Hay investigaciones en marcha y se espera tener resultados positivos en un futuro
cercano. El proyecto TCP/RLA/2914 que como se mencion, ejecuta la UPCH en colaboracin
con CONACS, tiene como uno de sus objetivos el estudio de las causas de mortalidad neonatal
 45

entre las cuales, sin duda, la enterotoxemia ocupa un lugar de primer orden. Se espera que pueda
llegarse a la produccin de una vacuna contra esta enfermedad.

El manejo de los animales es un factor muy importante en la prevencin de la enfermedad. El

hacinamiento, la falta de limpieza de los corrales de paricin y de los dormideros, la falta de
proteccin contra las inclemencias climticas, la insuficiente o tarda ingestin de calostro por las
cras, as como la inadecuada nutricin de las madres en los ltimos meses de gestacin, entre otros,
son factores que crean las condiciones propicias para la presentacin de la enterotoxemia. Ha sido
demostrado en otras especies animales que la insuficiente alimentacin de las madres en el ltimo
tercio de gestacin, adems de afectar el nivel de anticuerpos de la madre, ocasiona un desarrollo
inadecuado del sistema nervioso de la cra lo que hace que no reaccione rpidamente despus del
nacimiento para acceder al calostro en el momento de mxima concentracin de inmunoglobulinas.
Esto lo hace susceptible a procesos entricos y neumnicos.
En efecto, Garmendia y col. (1987) encontraron que la falla en la transferencia de
inmunoglobulinas provenientes del calostro, constituye la causa principal de muerte neonatal en
alpacas, debido a su incapacidad de defenderse contra las infecciones. Ellos encontraron que en
cras a punto de morir la concentracin de inmunoglobulina srica fue significativamente menor
que en aquellas cras que sobrevivieron.

Todo lo anterior demuestra lo mucho que queda por investigar en el tema de la enterotoxemia en
particular y de las causas concomitantes que intervienen en la mortalidad de cras de camlidos, en
general. Lo que se requiere realmente es un enfoque integral que incluya los factores tanto
infecciosos como los del medio ambiente y el manejo, a efectos de establecer medidas efectivas con
una base cientfica slida, que conduzcan a la reduccin de las prdidas ocasionadas por la
mortalidad neonatal.

8.1.1.2 Colibacilosis
Bajo este nombre se agrupan las formas diarreicas y septicmicas causadas por cepas de
Escherichia coli que afectan a las cras. Su presentacin es estimada en 15 por ciento. En la forma
entrica las cras presentan un cuadro diarreico por 3 a 8 das, deshidratacin, prdida de peso y, en
ocasiones, sobreviene la muerte, aunque algunas cras se recuperan. Los cuadros septicmicos, que
se presentan principalmente durante la primera semana de vida, se caracterizan por muerte
repentina.

8.1.1.3 Otras enfermedades

Otras enfermedades infecciosas que afectan a las cras y que pueden ocasionar la muerte incluyen
las afecciones respiratorias y las septicemias. La neumona es una afeccin respiratoria aguda cuya
frecuencia vara de 2 a 22 por ciento, segn los aos. Casi siempre se relaciona con algn tipo de
estrs que baja las defensas del animal y da lugar a la proliferacin de grmenes. La entidad
bacteriana involucrada pertenece al gnero Pasteurella .

La neumona aguda tiene un curso rpido que compromete al parnquima pulmonar; se presenta en
neonatos y animales jvenes. Las muertes de cras por esta causa van de 2 a 27 por ciento tanto en
alpacas como en llamas (Ramrez, 1991).

Los cuadros septicmicos pueden tener causas variadas dentro de las cuales una de las ms
frecuentes es la onfaloflebitis que es consecuencia de una desinfeccin deficiente del ombligo y
falta de higiene.
 46

Se describen otras afecciones patolgicas de las cras pero que no tienen una connotacin mortal
tales como la querato conjuntivitis, los absesos y la necrobacilosis.

8.1.2 ENFERMEDADES DE TUIS Y ADULTOS

Como ya se mencion anteriormente, las tasas de mortalidad atribuibles a enfermedades infecciosas
son relativamente bajas en tuis y adultos. Se reportan, sin embargo, un buen nmero de entidades
nosolgicas de frecuencia variable. Entre ellas se incluyen:

a) La fiebre de las alpacas o estrepcocosis. Es una enfermedad bacteriana asociada a factores

de estrs ambiental y de manejo; el agente causal es el Streptococcus zooepidemicus . La
morbilidad es relativamente baja (5 a 10%) pudiendo alcanzar cifras mayores en animales
sometidos a manejo inadecuado. La mortalidad reportada es del orden del 2 a 5 por ciento
de los afectados.

b) Osteomielitis. Es una inflamacin de la mandbula, inicialmente proliferativa y luego

osteoltica que produce un abultamiento detectable a simple vista. Generalmente se
presenta en la poca de sequa y se le relaciona con las lesiones producidas por el pasto
seco de la poca invernal, que sirven de sustento para la proliferacin de micro organismos
de los gneros Actinomices y Fusobacterium. El efecto de la enfermedad es que dificulta la
ingestin de alimentos por lo que generalmente hay que sacrificarlos.

c) Edema maligno o Braxy. Producida por Clostridium septicum; se caracteriza por la

formacin de edema severo alrededor de alguna herida. Se ha observado espordicamente
en alpacas pero al presentarse puede provocar la muerte del animal.

d) Otras enfermedades incluyen la fiebre aftosa, el ttano. antrax, otitis, etc. cuyas
prevalencias son menores aunque ocasionalmente podran revestir cierta importancia.
An cuando no se han reportado brotes masivos de fiebre aftosa en alpacas o llamas,
similares a los que ocurren en otros ungulados, los animales pueden ser portadores lo que
es un factor que limita las exportaciones de animales vivos. Recientemente la OIE ha
declarado la regin sur del pas, donde se encuentra la mayor poblacin de alpacas, como
libre de aftosa lo que podr facilitar los procedimientos a seguir para la exportacin de
animales vivos. Tambin se han reportado casos de afecciones micticas en llamas y
alpacas, que son tratables y sin mayor relevancia.

8.2 ENFERMEDADES PARASITARIAS

Un elevado nmero de enfermedades parasitarias afectan a los camlidos sudamericanos. Si bien
stas no son causa de elevada mortalidad como las infecciosas, y a menudo pasan desapercibidas
por los productores, son responsables de prdidas considerables por afectar una serie de funciones
productivas. Por ejemplo, los parsitos gastrointestinales, adems de ocasionar un drenaje constante
de sangre, interfieren con el proceso digestivo de utilizacin de los alimentos lo que se traduce en
deficiente desarrollo corporal y baja produccin de fibra y carne. Adems, el debilitamiento del
animal hace que este sea ms susceptible a contraer enfermedades infecciosas. Los ectoparsitos,
por otro lado, afectan la produccin de fibra tanto en cantidad como en calidad. A todo esto hay
 47

que sumar las prdidas por decomiso de carnes y vsceras parasitadas como es el caso de la
sarcocistiosis y los quistes hidticos.

Resulta difcil hacer un estimado de las prdidas econmicas causadas por las afecciones
parasitarias por la falta de estadsticas confiables; se estima, sin embargo, que alcanzan varios
millones de dlares al ao, lo que evidentemente va en detrimento de la economa de los
productores.

Los efectos positivos de un adecuado control parasitario han sido demostrados por varios
investigadores en el Per. Por ejemplo, en uno de los trabajos se observ que alpacas sometidas a
un programa de dosificacin estratgica con ivermectina, superaron al grupo testigo no tratado, en
6,9 kg en peso corporal y 0,45 kg en peso de velln. Por otro lado, la incidencia de sarna fue de
slo 1 por ciento en el grupo tratado en comparacin con 22 por ciento en el grupo testigo
(Guerrero y col., 1986). La relacin costo/beneficio fue favorable para el grupo tratado. Similares
resultados fueron encontrados en otro trabajo realizado en las zonas altas del Departamento de
Arequipa por Windsor y col. (1992).

8.2.1 NEUMOGASTROENTERITIS PARASITARIA

Este complejo nosolgico es producido por infecciones mixtas de nemtodes que parasitan el tracto
gastrointestinal y respiratorio. Algunas especies de parsitos son propias de los camlidos, tales
como: Graphinema aucheniae, Spirulopteragia peruvianus, Nematodirus lamae,Camellustrongylus
mentulatus y Lamanema chavezi. En cambio, otras especies son propias de vacunos y ovinos pero
pueden afectar a los camlidos, tales como aquellos de los gneros Ostertagia, Trichostrongylus,
Cooperia, Haemoncus, Oesophagostomum y Dyctiocaulus. La prevalencia de parsitos en alpacas,
llamas, vicuas y guanacos es del orden de 70 a 100 por ciento, con una mortalidad relativamente
baja, alrededor del uno por ciento, segn numerosos estudios llevados a cabo, pero ocasionan una
alta morbilidad con las consecuencias negativas en la productividad de los animales.

Hay una serie de factores que contribuyen a la infestacin parasitaria, tales como el pastoreo de
animales en ambientes reducidos y altamente contaminados por heces y huevos de parsitos, sin la
adecuada rotacin de pastos; la disminucin de defensas de los animales por factores estresantes
tales como la paricin y lactancia en el caso de las madres y el destete en el caso de las cras; el
mantenimiento de los estercoleros sin la limpieza adecuada, entre otros. El hbito de los camlidos
de depositar sus deyecciones en un determinado lugar, formando estercoleros, es probablemente
una forma de prevenir la diseminacin de parsitos en los pastizales; sin embargo, cuando hay
sobrepoblacin esta aparente ventaja puede convertirse en desventaja.

Los parsitos que se localizan en el tubo digestivo, ya sea en el abomaso o en los intestinos,
producen alteraciones estructurales y funcionales de la mucosa con grave interferencia en la
digestin y absorcin de los alimentos lo que va en detrimento de las funciones productivas como
son crecimiento, reproduccin y produccin de fibra. Adems las larvas de Lamanema al migrar al
hgado ocasionan lesiones cirrticas que se visualizan externamente como pequeos abscesos de
color blanquecino, dando al rgano un aspecto moteado que puede dar lugar a su decomiso.

La prevencin de las infestaciones parasitarias debe consistir bsicamente en la reduccin o

eliminacin de los factores predisponentes mencionados anteriormente. Se recomienda tambin
tratamientos preventivos con drogas antiparasitarias, de acuerdo a un esquema en funcin de la
edad de los animales y la poca del ao.
 48

8.2.2 SARCOCISTIOSIS
Esta es una enfermedad que tiene una gran repercusin econmica y que constituye actualmente un
freno para la comercializacin de la carne de CSA. Es producida por una coccidia del gnero
Sarcocystis del que existen tres especies: S. tilopodi (o S. guanicoecanis) en guanacos; S. aucheniae
en alpacas, llamas y vicuas, que producen quistes macroscpicos en la musculatura esqueltica; y
el S. lamacanis, encontrado en alpacas, que forma quistes microscpicos infectivos en corto tiempo,
en la musculatura miocrdica y esqueltica.

Hasta hace poco haba duda acerca de si se trataba de una sola especie de Sarcocystis que era
responsable de la formacin de los dos tipos de quistes y que los microquistes no seran sino un
estadio temprano de desarrollo de los macroquistes. Mediante tcnicas de biologa molecular se ha
llegado a establecer recientemente y en forma concluyente que se trata efectivamente de dos
especies genticamente diferentes: S. aucheniae y S. lamacanis (Hung, 2005; comunicacin
personal).

La coccidia causante de esta enfermedad es de ciclo indirecto, donde los perros y carnvoros
silvestres son los hospederos definitivos en cuyo intestino se efecta la reproduccin sexual
mientras que la reproduccin asexual se realiza en los capilares, arteriolas y msculo esqueltico y
cardaco de los CSA, que son los hospederos intermediarios.

La enfermedad es conocida vulgarmente con el nombre de arrocillo y triquina y a menudo se la

confunde con la cisticercosis. Se ha encontrado una prevalencia de 70 a 80 por ciento de micro o
macroquistes en la musculatura de los animales, particularmente en mayores de dos aos de edad.
En animales jvenes no es frecuente la presencia de macroquistes pero s de microquistes que slo
pueden detectarse mediante examen microscpico.

El dao que ocasiona el parsito est relacionado fundamentalmente con el decomiso de la carne
con presencia de los quistes en la musculatura, lo que da lugar a prdidas econmicas. Adems crea
una imagen negativa de la carne de los camlidos lo que repercute en el grado de aceptacin por el
pblico. Al ser ingerida por el humano, la carne con sarcocistes, insuficientemente cocida, produce
un cuadro de gastroenteritis con nusea, diarrea, clicos y escalofros, sntomas que se deberan a
una toxina presente en los quistes, la misma que es desactivada mediante la coccin. Por lo tanto, la
carne con sarcocistes, debidamente cocida, no constituye un problema de salud pblica.

La propagacin de la enfermedad se ve favorecida por la ingestin de carne con sarcocistes por los
perros que son los compaeros inseparables de los pastores de alpacas y llamas. A ellos se agregan
los carnvoros silvestres, como los zorros, que al consumir carne con el parsito, eliminan millones
de ooquistes diseminndolos por los pastizales. Entonces la forma de controlar la sarcocistiosis es
evitando el consumo de carne contaminada por los perros y controlando la accin de los carnvoros
silvestres. Ambas acciones no son nada fciles dadas las condiciones en que se desarrolla la crianza
de los camlidos. Frente a esta situacin se est trabajando actualmente en la produccin de una
vacuna que aplicada a los animales en pastoreo ofrezca una proteccin efectiva contra esta
enfermedad. Estos trabajos, al igual que la tipificacin gentica de los sarcocistes, estn siendo
realizados por la Facultad de Veterinaria y Zootecnia de la Universidad Peruana Cayetano Heredia
con apoyo de la FAO a travs del proyecto TCP/RLA/2914, ya mencionado.

Habida cuenta de que la mayor incidencia de macroquistes se observa en animales mayores de dos
aos, una forma de disminuir los decomisos es haciendo la saca temprana, es decir, destinando al
 49

sacrificio animales jvenes no aptos para la reproduccin, antes de que se hagan visibles los
macroquistes. Esto implica incrementar la proporcin de vientres y hacer la saca de los capones a la
edad ms temprana posible, antes de los dos aos. Esto permite no slo disminuir las perdidas por
decomiso de carcasas sino tambin la oferta de una carne de calidad superior y de mayor aceptacin
por los consumidores.

8.2.3 HIDATIDOSIS
Es producida por los estadios csticos de de la tenia Echinococcus granulosus cuya forma adulta se
encuentra en el intestino delgado del perro y carnvoros silvestres. Los quistes por lo general se
localizan en el hgado y pulmones lo que da lugar al decomiso de dichos rganos y las
consiguientes prdidas econmicas. Desde el punto de vista de la salud pblica tiene tambin
importancia por tratarse de una zoonosis que tiene relativamente una alta incidencia en las zonas de
crianza de camlidos.

El control de la enfermedad, al igual que en el caso de sarcocistiosis, consiste en evitar que los
perros consuman vsceras con los quistes y la dosificacin peridica de stos contra el
Echinococcus.

8.2.4 DISTOMATOSIS
Es causada por la Fasciola heptica que parasita los conductos biliares del hgado. Su ciclo
evolutivo involucra la participacin de un hospedero intermediario, un caracol del gnero Limnea,
que habita las zonas hmedas y pantanosas. En las regiones altas de la puna, la incidencia de
distomatosis en alpacas y llamas parece ser baja, lo cual se atribuye a que las condiciones climticas
no seran adecuadas para el desarrollo del caracol. Sin embargo cuando los animales son
trasladados a zonas ms bajas, donde por lo general abundan los caracoles, pueden ocurrir
infestaciones masivas produciendo cuadros agudos y elevada mortalidad. Esto ocurri con alpacas
que fueron trasladadas del Departamento de Puno a Cajamarca, en las etapas iniciales del
Programa de Repoblamiento de Alpacas, referido anteriormente.

8.2.5 ENFERMEDADES PRODUCIDAS POR ECTOPARSITOS

En este grupo la enfermedad ms importante es la sarna, por afectar el crecimiento de la fibra y su
calidad, adems de causar retardo en el crecimiento y alteracin de otras funciones productivas. La
afeccin es producida por la presencia y multiplicacin de ectoparsitos conocidos con el nombre
de caros. Se han encontrado dos especies de ellos en alpacas, llamas y vicuas: Sarcoptes scabiei
var aucheniae y el Psoroptes aucheniae.

La prevalencia de la enfermedad vara en funcin del nivel tecnolgico de la explotacin y. de la

poca del ao. Es ms alta a nivel de pequeos productores en los que la afeccin puede ser masiva;
los meses de primavera-verano, son los ms propicios para la presentacin de la enfermedad. Su
control es relativamente simple siempre y cuando se hagan los tratamientos de manera oportuna.
Hoy en da, con el desarrollo de frmacos sistmicos de administracin parenteral, el tratamiento y
control de los ectoparsitos es mucho ms simple. Sin embargo, el problema que afrontan los
pequeos productores es la falta de recursos para la compra de los medicamentos y, a menudo, el
inadecuado uso de ellos por falta de acceso a servicios de asistencia tcnica.

La piojera es otra enfermedad producida por parsitos de los gneros Microthoracius y Damalinia.
Son parsitos suctopicadores o masticadores que se alimentan de la sangre en el primer caso y de
las clulas epiteliales descamadas en el segundo, causando prurito lo que hace que los animales se
 50

froten y daen la fibra. La piojera puede adquirir caractersticas enzoticas en comunidades

campesinas y pequeos criadores (30% a 100%).
 51

9. CONCLUSIONES Y PERSPECTIVAS

Los camlidos sudamericanos representan un recurso gentico de gran importancia tanto desde el
punto de vista econmico como social, cultural y cientfico. La alpaca y la llama constituyen la base
de sustento de un vasto sector de la poblacin de la regin alto andina del Per.

Pese a su gran importancia el aprovechamiento pleno de este recurso est limitado por factores de
naturaleza tanto tcnica como social y econmica. Para lograr un mayor beneficio de la crianza de
alpacas y llamas y contribuir al bienestar de los pequeos productores, en su mayora de muy
escasos recursos, hay necesidad de prestar la debida atencin a los siguientes aspectos:

Reduccin de la mortalidad de cras y adultos as como el impacto de las enfermedades

parasitarias sobre las funciones productivas. Esto implica el desarrollo, mediante la
investigacin, de mtodos efectivos e integrales de control y prevencin de enfermedades,
entre las cuales la enterotoxemia y la sarcocistiosis ocupan un lugar preponderante.

Elevacin de las tasas de natalidad mediante la adopcin de sistemas adecuados de empadre

compatibles con las caractersticas fisiolgicas de estas especies. An cuando muchos
aspectos de la reproduccin de camlidos son an desconocidos, se dispone de
conocimientos bsicos que aplicados adecuadamente podran elevar las tasas actuales de
paricin.

Uso racional y sostenible de los recursos naturales. Puesto que las praderas constituyen
actualmente la base de la alimentacin de los camlidos, la sostenibilidad del sistema
depende en gran medida del manejo racional de este recurso.

Implementacin de sistemas eficaces de alimentacin. Fuera de las praderas nativas existen

evidencias experimentales sobre la posibilidad del cultivo de especies forrajeras de mayor
rendimiento y valor nutritivo en regiones cercanas a los 4 000 m de altitud. La
implementacin ms generalizada de esta opcin resultar en mejoramiento de los niveles
de nutricin de los animales y la obtencin de una mayor produccin por unidad de
superficie a la vez que permitir disminuir la presin de pastoreo sobre las praderas
naturales.

Mejoramiento del potencial gentico de produccin. Esto implica la necesidad de

implementar sistemas de seleccin por caractersticas de importancia econmica que
puedan ser medidas de manera objetiva y que sean compatibles con las exigencias del
mercado.

Hay un inters creciente en la aplicacin de biotecnologas reproductivas tales como la

inseminacin artificial y la transferencia de embriones, en el mejoramiento de la calidad
gentica de los camlidos domsticos. Sin duda se trata de herramientas poderosas para ese
efecto siempre que se cuente con material gentico altamente deseable debidamente
identificado. Para ello es requisito indispensable contar con un programa de seleccin que
permita identificar a los animales genticamente ms valiosos cuyo genotipo se pretende
diseminar en forma masiva ya sea a travs de la lnea materna o paterna.
 52

Adopcin de tecnologas mejoradas de obtencin y utilizacin de los productos, en especial

las operaciones de esquila, sacrificio de animales y procesamiento de la carne as como el
aprovechamiento de las pieles y cueros.

Muchos de los aspectos mencionados han sido materia de investigacin y se dispone de informacin
razonable; sin embargo, la adopcin de las tecnologas por parte del productor es muy limitada.
Esto obedece a la ausencia de un servicio de informacin y asistencia tcnica que se encargue de la
difusin de los resultados. Por otro lado, el pequeo productor a menudo carece de recursos e
incentivos econmicos que hagan atractivos los cambios.

La comercializacin de los productos es otro aspecto donde los productores enfrentan dificultades
debido al aislamiento en que se encuentran en relacin a los centros de venta; esto hace que tengan
que depender de los intermediarios que no necesariamente resultan ventajosos. De ah que la
organizacin de productores con fines productivos es esencial para lograr un mayor poder de
negociacin no slo para la comercializacin de los productos (Fibra, carne, animales en pie, etc)
sino tambin para acceder a servicios de asistencia tcnica, salud y educacin as como para facilitar
la adquisicin de insumos. La incorporacin de los pequeos productores a cadenas productivas de
mayor escala, debidamente articulados con el sector industrial, es probablemente el camino ms
deseable a seguir en el futuro, en lugar de que cada uno acte aisladamente.

La conservacin y aprovechamiento racional de la vicua ser cada vez ms exitoso en la medida en

que se vayan desarrollando mtodos ms eficientes de manejo y captura ya sea en sistemas de plena
libertad o en semi cautiverio. La caza furtiva de la vicua sigue siendo un problema y una amenaza
para la especie; se espera que las comunidades y personas jurdicas autorizadas para el usufructo de
esta especie ejerzan acciones preventivas ms eficaces.

Finalmente, cabe sealar que hay un creciente inters en la crianza de camlidos sudamericanos
domsticos en otras partes del mundo lo que est dando lugar a un incremento numrico
considerable de la poblacin de alpacas y llamas as como al desarrollo de programas de
investigacin de largo plazo. Tal es el caso de Australia, para citar un ejemplo. Esto constituye por
una parte una ventaja por la mayor demanda de animales en edad reproductiva para abastecer ese
mercado creciente lo que puede favorecer a los productores nacionales, pero por otro lado podra
constituir, en un plazo no muy lejano, un desafo para los pases andinos sino se toman las medidas
del caso para ser cada vez ms competitivos en el aporte de los productos de estas especies al
mercado internacional.
 53

REFERENCIAS BIBLIOGRAFICAS

1. Barreda, J. E. 1991. La alpaca y sus problemas en la Zona Nororiental del Departamento de

Puno. En: Seminario Taller: La Alpaca, Ventaja Comparativa Peruana. Fundacin para el
Desarrollo del Agro, Lima (Per).

2. Carpio, M. 1991. Aspectos tecnolgicos de la fibra de los camlidos andinos. En: C.Novoa y
A. Florez, ed. Produccin de rumiantes menores: alpaca. RERUMEN, SR-CRSP-INIA, Lima
(Per).

3. Chvez, J.F. 1991. Mejoramiento gentico de alpacas y llamas. En: S. Fernndez-Baca, ed.
Avances y Perspectivas del Conocimiento de los Camlidos Sudamericanos. FAO/RLA,
Santiago (Chile).

4. DGAES, 2005. Agricultura peruana 1990-2001: evolucin y perspectivas. Ministerio de

Economa y Finanzas, Per.

5. Ellis, R.P. 1997. Sleuthing Clostridium perfringens enterotoxemia: the number one killer of
young Peruvian alpacas. The Alpaca Registry Journal, Vol. II (2): 1-7.

6. Esponda, R., Avalos, P., Huanco, C. y Huaco, Y. 2004. Situacin de los camlidos
sudamericanos en el Per. En: Bases para un Programa Macro regional de Ciencia, Tecnologa
e Innovacin. CONCYTEC-CONACS. Lima (Per)

7. Fernndez-Baca, S, y Novoa, C. 1966. Estudio comparativo de la digestibilidad de los forrajes

en ovinos y alpacas. Rev. Fac. Med. Vet., UNMSM, Vol. 18-20: 88-96, Lima (Per).

8. Fernndez-Baca, S. 1971. La Alpaca: reproduccin y crianza. Boletn de Divulgacin N 7.

Instituto Veterinario de Investigaciones Tropicales y de Altura, Lima (Per).

9. Fernndez-Baca, S. 1993. Manipulation of reproductive functions in male and female New World
camelids. An. Reprod. Sci. 33: 307-323.

10. Franklin, W.L. y Powell, K.J. 1994. Guard llamas: a part of integrated sheep protection. Iowa
State University. University Extension. Ames, IA,USA.

11. Garmendia, A.E., Palmer, G.H, De Martn, J.C. y McGuire, T.C. 1987. Failure of passive
immunoglobulin transfer: a major determinant of mortality in newborn alpacas (L.pacos). Am.J.
Vet. Res., Vol. 48, No.10: 1472-1476.

12. Guerrero, C., Alva, J. y Nez, A. 1986. Evaluacin antihelmntica de la ivermectina contra
infecciones naturales de nemtodes gastrointestinales de alpacas. MV Rev. Cienc. Vet. 2:15-18,
Lima (Per).

13. Instituto Nacional de Estadstica e Informtica (INEI). 1996. III Censo Nacional
Agropecuario (III CENAGRO), Lima (Per).

14. Lazarte, J. 1990. Corriente comercial y precios relativos del complejo textil alpaquero peruano
1980-1989. Proyecto Alpacas, COTESU, Lima (Per).
 54

15. Legua, G. 1991. Enfermedades parasitarias. En: S. Fernndez-Baca, ed. Avances y

Perspectivas del Conocimiento de los Camlidos Sudamericanos. FAO/RLA, Santiago (Chile).

16. Novoa, C. 1981. Camlidos sudamericanos. En: B. Muller-Haye y J. Gelman, ed. Recursos
genticos animales en Amrica Latina. Estudio FAO, Produccin y Sanidad Animal N 22.
Roma.

17. Novoa, C. 1987. Improvement of Andean camelids. En: J. Hodges, ed. Animal genetic
resources. Strategies for improved use and conservation. FAO, Animal Prod. and Health Paper
N 66. Rome (Italy).

18. Novoa, C. and Wilson,T. 1992. A global review of the genetic resources of Camelidae. En:
J.Hodges, ed. The Management of Global Animal Genetic Resources. Proc. FAO Expert
Consultation. Rome, Italy, 1992.

19. Ponzoni, R. y col. 1998. Phenotypes resulting from Huacaya by Huacaya, Suri by Huacaya and
Suri by Suri alpaca crossings. Proceedings of the Association for the Advancement of Animal
Breeding and Genetics. Vol. 12, Part 1, pp. 136-139. Australia.

20. Ramrez, A. 1991. Enfermedades infecciosas. En: S.Fernndez-Baca, ed. Avances y

Perspectivas del Conocimiento de los Camlidos Sudamericanos. FAO/RLA, Santiago (Chile).

21. Smar, J. 1989. Defectos congnitos y hereditarios de la alpaca: Teratologa. CONCYTEC,

Lima (Per).

22. Sumar, J. 1991. Caractersticas de las poblaciones de llamas y alpacas en la sierra sur del Per.
En: Informe de la Mesa Redonda sobre Camlidos Sudamericanos. Lima, Sept. 1991, GAN-37.
RLA, Santiago (Chile).

23. Velarde, R. 1993. Comercializacin de productos derivados de los camlidos sudamericanos.

En: Informe del Simposio sobre Camlidos Sudamericanos Domsticos. Oct. 1992, GAN- 42,
FAO/RLA, Santiago (Chile).

24. Velasco, J. 1980. Mejoramiento gentico de alpacas. Anales III Reunin Cientfica Anual. Soc.
Peruana de Prod. Animal. Lima (Per).

25. Vilca, M.A. 1991.Produccin, tecnologa e higiene de la carne. En: S. Fernndez-Baca, ed.
Avances y Perspectivas del Conocimiento de los Camlidos Sudamericanos. FAO/RLA,
Santiago (Chile).

26. Villarroel, J. 1991. Las fibras. En: S.Fernndez-Baca, ed. Avances y Perspectivas del
Conocimiento de los Camlidos Sudamericanos. FAO/RLA, Santiago (Chile).

27. Wheeler, J.C. 1991. Origen, evolucin y status actual (de los camlidos). En: S. Fernndez-
Baca, ed. Avances y Perspectivas del Conocimiento de los Camlidos Sudamericanos.
FAO/RLA. Santiago (Chile).
 55

28. Windsor, R.H.S., Tern, M. y Windsor, R.S. 1992. Effects of parasitic infestation on the
productivity of alpacas (Lama pacos). Trop. Anim. Hlth. Prod., 24, 57-62.
 56

ANEXO I

INSTITUCIONES E INSTITUCIONALIDAD

Numerosas instituciones, tanto pblicas como privadas, brindan apoyo a las actividades
relacionadas con los camlidos sudamericanos.

A. INSTITUCIONES PBLICAS

Consejo Nacional de Camlidos Sudamericanos (CONACS)

Creado en 1992 por Decreto Supremo N 029-92- AG. Es un organismo pblico descentralizado del
Ministerio de Agricultura, encargado de promover, asesorar y supervisar el desarrollo, la
conservacin, manejo y mejoramiento en el mbito nacional, de todas las especies de camlidos
sudamericanos y sus hbridos.

Sus lineamientos de poltica institucional son:

Fortalecimiento institucional y organizacional de los actores locales, regionales y
nacionales;
Proteccin y uso racional de los recursos naturales en los ecosistemas alto andinos;
Desarrollo y fortalecimiento de las cadenas productivas de los CSA;
Apoyo a la generacin de plataformas de servicios para la produccin, comercializacin y
transformacin;
Impulso al desarrollo de los recursos humanos del sector en sus capacidades tcnicas y
liderazgo social;
Promocin y articulacin de las instituciones que desarrollan ciencia, tecnologa e
innovacin en el sector de los CSA;
Apoyo a la afirmacin cultural, identidad y racionalidad andina.

Para el cumplimiento de sus funciones, CONACS cuenta con 8 Oficinas Regionales localizadas en
los Departamentos de Apurmac, Arequipa, Ayacucho, Cusco, Huancavelica, Junn, Puno y Lima.
Cuenta as mismo, con un Consejo Directivo como rgano consultivo, integrado por: dos
representantes del Ministerio de Agricultura; un representante de los gobiernos regionales y otro de
las universidades del pas; un representante de cada una de las organizaciones de base (Sociedad
Nacional de Criadores de Vicua y Sociedad de Alpacas y Llamas registradas); y un representante
de los industriales textiles. Dicho consejo est dirigido por el Presidente del CONACS.

Instituto Nacional de Recursos Naturales (INRENA)

Es otro Organismo pblico descentralizado del Ministerio de Agricultura cuya misin es velar por
la conservacin y uso sostenible de los recursos naturales. En coordinacin con CONACS, cumple
la funcin de supervisar la conservacin, manejo y utilizacin racional de las especies silvestres:
vicua y guanaco.
 57

Servicio Nacional de Sanidad Agropecuaria (SENASA).

El SENASA es otro organismo del Ministerio de Agricultura que como su nombre indica es la
responsable de resguardar la sanidad tanto animal como vegetal. Cuenta con una Direccin General
de Sanidad Animal, encargada del control y prevencin de las enfermedades de los animales a nivel
nacional, lo que incluye a los camlidos sudamericanos.

Instituto Nacional de Investigacin y Extensin Agraria (INIEA)

Es el organismo oficial del Gobierno, dependiente del Ministerio de Agricultura, cuya misin es la
investigacin y la transferencia de tecnologa. Cuenta con estaciones experimentales a lo largo del
pas, una de ellas dedicada exclusivamente a la investigacin y conservacin de recursos genticos
de camlidos sudamericanos. Esta es la Estacin de Quimsachata, ubicada en el Departamento de
Puno.

Consejo Nacional de Ciencia, Tecnologa e Innovacin (CONCYTEC)

Institucin nacional que, en coordinacin con el CONACS, impulsa la creacin e implementacin

de un programa macro regional en ciencia, tecnologa e innovacin en el campo de los camlidos
sudamericanos. Provee, asimismo, financiamiento para proyectos de investigacin en el campo de
los camlidos sudamericanos, que se adjudican por concurso a instituciones tanto pblicas como
privadas.

Universidades pblicas

Universidad Nacional Mayor de San Marcos, Facultad de Medicina Veterinaria.

La Facultad de Medicina Veterinaria de la Universidad de San Marcos es la pionera en las

investigaciones sobre camlidos sudamericanos, en especial alpacas. Las primeras investigaciones
datan de la dcada de los 50s. Posteriormente, con la creacin del Instituto Veterinario de
Investigaciones Tropicales y de Altura (IVITA), a comienzos de los 60s, las investigaciones en
alpacas alcanzaron una mayor intensidad. Este Instituto cont, en sus etapas iniciales, con el apoyo
del Programa de las Naciones Unidas para el Desarrollo, a travs de la FAO. Los trabajos realizados
por este Instituto condujeron al logro de conocimientos importantes en los diferentes aspectos de los
camlidos, tales como la anatoma y la fisiologa, la reproduccin, enfermedades infecciosas y
parasitarias, nutricin, establecimiento de pastos cultivados, etc. La mayora de estos trabajos se
realizaron en la antiguamente denominada Granja Modelo de Auqunidos de La Raya que luego
pas a llamarse Centro Nacional de Camlidos Sudamericanos de La Raya, situado entre los
Departamentos de Cusco y Puno a una altitud de 4 100 m sobre el nivel del mar. Este Centro
perteneci inicialmente al Ministerio de Agricultura, luego pas a la Universidad Nacional del
Altiplano, Puno y, finalmente, se dividi en dos fracciones, una mitad para la Universidad del
Cusco y la otra para la Universidad de Puno, hecho que caus un debilitamiento de la capacidad
operativa y disminucin del impulso a las investigaciones. IVITA, por otro lado, se vio en la
necesidad de implementar una estacin ubicada en la localidad de Marangan, Departamento del
Cusco, donde se realizan investigaciones campo y laboratorio en camlidos.
 58

Universidad Nacional Agraria de La Molina (UNA-La Molina).

Ubicada en Lima; a travs de sus Facultades de Agronoma y Zootecnia, realiza trabajos de
investigacin en manejo de praderas, tecnologa de carnes y fibras de camlidos, nutricin, entre
otros.

Otras instituciones que realizan investigaciones en camlidos son: la Universidad Nacional San
Antonio Abad del Cusco y la Universidad Nacional del Altiplano, Puno, ambas con facilidades en
la Estacin de Camlidos de La Raya; la Universidad Nacional de San Agustn, de Arequipa; la
Universidad Federico Basadre de Tacna, Universidad de Ayacucho, el Instituto Peruano de Energa
Nuclear (IPEN), entre otras.

Desafortunadamente hay poca vinculacin entre universidades y la mayora de ella realiza

proyectos de investigacin en forma aislada.

Otras instituciones pblicas relacionadas de una forma u otra con los camlidos sudamericanos son:
Ministerio de la Produccin; Ministerio de Comercio Exterior y Turismo; el Fondo de
Compensacin Econmica y Social (FONCODES); el Programa Nacional de Manejo de las
Cuencas Hidrogrficas (PRONAMACHS); Comisin para la Promocin de las Exportaciones
(PROMPEX); Comisin de Promocin de la Pequea y Mediana Empresa (PROMPYME); Instituto
Nacional de Defensa Civil, Gobiernos Regionales y Locales.

B. INSTITUCIONES PRIVADAS

Las instituciones privadas involucradas en el sector de camlidos incluyen, entre otras, las
siguientes:

Sociedad de Productores de Alpacas Registradas (SPAR). Lo conforman los criadores que

participan en el Programa de Registros Genealgicos que lleva a cabo el CONACS.
Sociedad Nacional de la Vicua (SNV). Agrupa a las comunidades campesinas y personas
naturales o jurdicas que tienen el derecho al usufructo de las vicuas.
Instituto Peruano de la Alpaca y Camlidos (IPAC). Representa al sector industrial y su
papel incluye, entre otros, impulsar el mejoramiento de la calidad de la fibra ofertada a la
industria a travs de asistencia tcnica y organizacin de la comercializacin.
Asociacin Internacional de la Alpaca (AIA). Una institucin del sector privado fundada en
1984 con el objeto de promover, fomentar y salvaguardar los intereses de los sectores
involucrados con la produccin e industrializacin de la fibra de alpaca.
Organismos no Gubernamentales (ONGs). Su principal funcin es la provisin de asistencia
tcnica a los productores con financiamiento proveniente de diferentes fuentes,
principalmente internacionales. Tambin hay algunas que desarrollan actividades de
investigacin y desarrollo.
Universidades particulares tales como la Universidad Peruana Cayetano Heredia (UPCH) y
la Universidad San Martn de Porres. La UPCH desarrolla actualmente un proyecto de
investigacin orientado a la prevencin de la sarcocistiosis y el control de la mortalidad
neonatal en alpacas, con el financiamiento de FAO a travs del proyecto TCP/RLA/ 2914.
 59

Proyecto UE-PASA . Proyecto de Apoyo a la Seguridad Alimentaria (con base en el

desarrollo de los camlidos); cuenta con financiamiento de la Unin Europea y es
ejecutado por CONACS a travs de ONGs.
 60

ANEXO II

LEGISLACION Y POLITICAS

La legislacin sobre camlidos sudamericanos en el Per es bastante extensa y ha venido variando

con el tiempo, sobre todo en lo que respecta a las responsabilidades institucionales, pero siempre se
ha mantenido dentro del marco de la promocin del desarrollo sostenible, conservacin y
utilizacin racional tanto de las especies domsticas como de las silvestres. Algunas de las leyes y
Decretos que rigen la actividad se mencionan a continuacin.

Ley de promocin de las inversiones en el sector agrario. Expedido mediante Decreto

Legislativo N 653, del 1 de agosto de 1991.

Segn esta ley se declara a la vicua y el guanaco, especies de fauna silvestre sujetas a proteccin
por el Estado. La crianza, al igual que la transformacin y comercializacin de sus productos,
pueden ser efectuados por cualquier persona natural o jurdica bajo supervisin del Estado el que
garantiza a las comunidades campesinas, empresas asociativas y otros propietarios de tierras de la
regin andina, el derecho a participar en el aprovechamiento de los hatos de vicuas y guanacos que
se encuentran en sus tierras. La Ley seala tambin que el Estado fomenta e incentiva la
investigacin para el mejoramiento gentico de los Camlidos Sudamericanos.
En el Reglamento de esta Ley se hacen algunas precisiones tales como las restricciones al comercio
exterior de alpacas de la raza Suri en todos sus colores, del hbrido paco-vicua y de alpacas de raza
Huacaya en todos sus colores excepto el blanco, en vista del reducido nmero de las poblaciones de
estos animales.

Decreto Supremo N 026-92-AG, del 9 de julio de 1992.

Crea el Consejo Nacional de Camlidos Sudamericanos (CONACS), que reemplaza al Consejo
Nacional de Camlidos Sudamericanos Domsticos creado por el Decreto Legislativo 653 y
expande su responsabilidad a las especies silvestres. Decreta, asimismo, la conclusin del Proyecto
Especial Utilizacin Racional de la Vicua y la disolucin del Consejo Nacional de la Vicua,
cuyos patrimonios, recursos y acervo documentario se transfieren al CONACS.

Decreto Supremo N 017.93.PCM, del 6 de abril de 1993, que dispone que la Reserva Nacional
Pampa Galeras ubicada en la Provincia de Lucanas, se conozca bajo la denominacin
RESERVA NACIONAL PAMPA GALERAS BARBARA DACHILLE en homenaje a la Seora
Brbara DAchille quien se destac por su constante preocupacin por la proteccin y conservacin
del medio ambiente.

Resolucin Jefatural N 017-94-AG-CONACS del 2 de mayo de 1994. Autoriza a las

comunidades campesinas beneficiarias del usufructo de las vicuas ubicadas en sus territorios,
realizar la campaa anual de captura y esquila de vicuas vivas entre los meses de mayo y octubre.

Decreto Supremo N 007-96-AG, del 7 de junio de 1996.

Aprueba el Reglamento de la Ley 26496, referido al uso sustentable de los CSA silvestres. Seala
que stos son patrimonio de la nacin y que es responsabilidad del CONACS, en coordinacin con
la autoridad administrativa CITES-Per, representada por INRENA, fijar las normas de
conservacin, utilizacin y comercializacin de los productos con el logo VICUANDES-
PERU. Se declara reas de manejo de vicuas y guanacos a los territorios de propiedad de las
 61

comunidades campesinas donde se hallan los animales y se autoriza a las comunidades beneficiarse
de los animales previo cumplimiento de requisitos establecidos por CONACS.

Decreto Supremo N 053-2000-AG, del 23 de setiembre del 2000.

Faculta al Ministerio de Agricultura, a travs del CONACS, entregar en custodia y usufructo, hatos
de vicuas y/o guanacos a personas naturales y jurdicas distintas de comunidades campesinas, en
concordancia con el Decreto Legislativo 653- Ley de Promocin de las Inversiones en el sector
agrario.

Decreto Supremo N 004-2004-AG, del 3 de febrero del 2004.

Declara de inters nacional la produccin de fibra de alpaca, llama y vicua.

Decreto Supremo N 008-2004-AG, del 20 de febrero del 2004.

Introduce, entre otras, las siguientes modificaciones al DS N 007-96-AG:

a) INRENA, en su calidad de Autoridad Administrativa CITES-PERU, coordinar con

CONACS los asuntos especficos en materia de CSA silvestres (CSAS).
b) Los Comits de Uso Sustentable de CSAS podrn constituir una organizacin por regin,
con el objetivo de garantizar la supervivencia de la especie.
c) Se otorga concesin de la marca VICUA-PERU y VICUA-PERU ARTESANIA, a
favor de las empresas encargadas de la transformacin y comercializacin de productos
obtenidos de vicuas esquiladas vivas, beneficiadas con la buena pro en la adquisicin de
fibra y acreditadas mediante el respectivo contrato.
d) Se establece que las comunidades campesinas y otras personas jurdicas de origen comunal,
titulares del manejo de los CSAS, sern las encargadas del acopio de la produccin de fibra
para su registro y posterior transformacin y comercializacin. Para ello, podrn
establecerse centros de acopio de la fibra por cuenta de las comunidades campesinas
autorizadas por CONACS.
El Decreto seala tambin los aspectos relativos a la transformacin de fibra y la
comercializacin de telas provenientes de las vicuas.

Ley N 283350 de Promocin del Mejoramiento Gentico y Conservacin de las Razas de

Camlidos Sudamericanos Domsticos (Promulgada el 30 de setiembre del 2004).
El objetivo de esta Ley es promover el mejoramiento gentico y preservacin de la alpaca y llama y
declararlas como Recurso Gentico del Per. Se seala que las acciones de promocin y
conservacin de germoplasma quedan a cargo del CONACS y del INIEA y que el Estado
promueve, a travs de estas dos instituciones, el establecimiento e implementacin de mecanismos
de mejoramiento gentico de los CSA domsticos tales como:

Registros genealgicos de razas de alpacas y llamas;

Control de produccin y productividad;
Ncleos de reproductores;
Biotecnologa reproductiva y molecular.

La ley establece adems normas generales sobre los registros genealgicos, la identificacin de los
animales de superior calidad gentica, las regulaciones sobre la exportacin de la reserva gentica
de alpacas y llamas, etc.
 62

Decreto Supremo N 006-2005-AG, del 24 de enero del 2005.

Otorga licencia de las marcas:

a) VICUA-PERU, a favor de empresas industriales textiles encargadas de la transformacin

y comercializacin de productos obtenidos de vicua esquilada viva, previa autorizacin
del CONACS.

b) VICUA-PERU ARTESANIA, a favor de empresas artesanales encargadas de la

transformacin y comercializacin de la fibra obtenida de vicua esquilada viva, con
autorizacin del CONACS.
 Manejo sanitario de la vicua

Claudio Prez1, M.V., claudio.perez@sag.gob.cl

Francisco Arredondo2, M.V., francisco.arredondo@sag.gob.cl
Leonardo Turra3, M.V., leonardo.turra@sag.gob.cl

1. Introduccin

Para realizar un adecuado y exitoso manejo de la vicua se requiere considerar que existen
enfermedades que pueden provocar importantes prdidas que afectan la productividad de un
rebao; por lo tanto se requiere establecer algn tipo de manejo sanitario que permita un
adecuado control de las variables que inciden en la presentacin de cuadros patolgicos
causados por diferentes tipos de agentes.

Fotografa: R. Denegri

1
Encargado de Proteccin Pecuaria, Regin de Arica y Parinacota. Servicio Agrcola y Ganadero.
2
Sectorial de Controles Fronterizos, Regin de Arica y Parinacota. Servicio Agrcola y Ganadero.
3
Proteccin de los Recursos Naturales Renovables, Regin de Arica y Parinacota. Servicio Agrcola y Ganadero.
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Existen enfermedades infecciosas y parasitarias que afectan a los camlidos sudamericanos,
que deben ser consideradas al momento de planificar un desarrollo adecuado de los animales,
especial atencin merecen las enfermedades parasitarias, que sin llegar a provocar la muerte,
son capaces de mermar notoriamente el rendimiento productivo de un animal, como es el caso
de parsitos externos como la sarna y garrapatas y otros internos como los gastrointestinales.
Para su control se debe implementar un plan teraputico rutinario, en conjunto con prcticas
ganaderas que minimicen las probabilidades de reinfestacin.

Por otra parte, para el manejo de las enfermedades infecciosas, cobra mayor validez la
aplicacin de medidas profilcticas, que incluyan todos los aspectos necesarios para prevenir la
aparicin de una patologa, considerando, inclusive, la inmunizacin activa.

A continuacin se tratan algunas enfermedades que afectan con ms frecuencia a las vicuas y
otras que pudieran adquirir importancia al realizarse manejos que impliquen una crianza de
estos animales en reas delimitadas de terreno.

2. Enfermedades ectoparasitarias

Son aquellas en que los parsitos se encuentren en la piel y sus anexos tegumentarios.

2.1 Sarna

Es una enfermedad infesto-contagiosa que afecta la piel y es producida por caros. En alpacas,
llamas y vicuas se ha reportado la presencia de Sarcoptes scabiei aucheniae, la cual produce
la sarna sarcptica y Psoroptes aucheniae, que produce la sarna psorptica (Legua, 1999).

Ciclo biolgico

Corresponde a un ciclo directo, constituido por tres fases evolutivas con metamorfosis completa.
Las hembras depositan huevos en galeras fabricadas en la piel en el caso de Sarcoptes y
sobre la piel en el caso de Psoroptes. De los huevos emergen hembras hexpodas que mudan
transformndose en ninfas octpodas, para posteriormente diferenciarse en machos y hembras.
El ciclo completo de Sarcoptes es de 18 a 26 das y de Psoroptes, 10 a 12 das (Snchez et al.,
1985).

Fotografa: R. Denegri
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 CICLO BIOLGICO DE SARCOPTES

Contagio (ninfas o adultos)

Ninfas
12-15 das Muere
Adultos
3-8 das
fecundacin en la

EPIDERMIS

HUEVOS
(2 a 3 por da)
por 30 das DERMIS
Muere

Epidemiologa

La principal va de propagacin es el contacto directo entre animales enfermos y sanos, siendo

en general los jvenes los ms afectados. La presentacin en animales adultos est
comnmente asociada a situaciones de estrs nutricional o sobrepoblacin. La segunda va de
propagacin es la indirecta, producida principalmente en revolcaderos, donde los caros
pueden permanecer vivos hasta por 7 das.

La enfermedad muestra una presentacin estacional, observndose con mayor gravedad y

extensin las lesiones durante la primavera y verano, existiendo un periodo de latencia durante
otoo e invierno con pequeas poblaciones de caros localizadas en zonas protegidas del
cuerpo como axilas, entrepiernas, pliegues inguinales y orejas. (Rojas, 2004).

Sintomatologa

Sarcoptes se introduce en la piel y forma tneles o galeras. Mediante su aparato bucal y saliva
produce una accin mecnica, txica e irritativa que se traduce en una intensa reaccin
inflamatoria, la cual es ms dramtica en animales reinfestados, en los que se desarrollan
cuadros de dermatitis hipersensible. Este tipo de sarna se localiza primariamente en zonas
desprovistas de piel (axilas, entrepiernas, vientre, etc.) inicindose la lesin como pequeos
focos eritematosos, con bastante prurito y exudado seroso que al coagularse da lugar a costras
agrietadas, sangrantes y dolorosas. Estas lesiones pueden extenderse progresivamente a otras
regiones, llegando a veces a generalizarse en todo el cuerpo. El intenso prurito, ocasiona que
los animales se muerdan o rasquen las zonas afectadas o se soben contra superficies duras, lo
que induce un mayor dao traumtico que puede complicarse con infecciones bacterianas
secundarias, produciendo heridas pigenas que agravan el cuadro clnico. (Legua, 1999).

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La sarna psorptica es menos importante por su baja difusin y accin patgena, localizndose
en el cuello y orejas, donde produce lesiones superficiales (Legua, op.cit.).

Diagnstico

Se realiza mediante observacin de las lesiones en la piel del animal, sumado a la presencia de
prurito. El diagnstico definitivo se realiza mediante un examen microscpico de raspado de piel
de las zonas afectadas, a fin de determinar la presencia de los caros.

Tratamiento

Uno de los tratamientos posibles es la aplicacin de un bao acaricida, el cual se debe repetir a
los 15 das para eliminar a los individuos recin eclosionados. Los insecticidas menos txicos
son los piretroides, como la permetrina, la cipermetrina, el d-fenotrn y la tetrametrina. Esos
productos alteran la transmisin nerviosa del parsito, interfieren en los canales de sodio y
causan su parlisis; presentan, adems, una accin repelente y residual al tratamiento.
Sin embargo el mtodo mas efectivo consiste en la aplicacin de antiparasitarios sistmicos
como Ivermectina que con dosis de 200 mcg/Kg de peso por va subcutnea, presenta alta
efectividad y gran poder residual (Guerrero et al., 1986).

2.2 Garrapatas

Las garrapatas son parsitos hematfagos en un gran

nmero de vertebrados terrestres, incluidos reptiles,
aves, perros y humanos (Strickland et al., 1976).
Pertenecen a la clase Arachnida, orden Acarina,
suborden Ixodides que est formado por ms de 800
especies (Casanueva, 1995), agrupadas en la
superfamilia Ixodoidea (Krantz, 1978), que rene a tres
familias: Argasidae, Ixodidae y Nuttalliellidae
(Casanueva, op. cit.).

La familia Ixodidae incluye 13 gneros, de los cuales los

de mayor importancia son: Amblyomma, Hyalomma,
Dermacentor, Boophilus, Ixodes, Rhipicephalus y Amblyomma parvitarsum
Haemaphysalis.

Segn Dale y Venero (1977) la especie que parasita a la vicua es Amblyomma parvitarsum y
se localiza de preferencia en la regin perianal; ello ha sido confirmado para las poblaciones del
altiplano chileno (SAG, 2002).

Cabe sealar el hallazgo de una larva de esta especie de garrapata en una lagartija de la
especie Liolaemus jamesi. Esta fue capturada en marzo de 2003 en el Parque Nacional Surire,
cerca del Salar de Surire, en el altiplano de la Provincia de Parinacota, a 4.250 m.s.n.m. Este es
el primer registro confirmado de una larva de A. parvitarsum en una lagartija y, adems, en un
ambiente compartido con camlidos sudamericanos, hospedadores del estado adulto del
parsito (Gonzlez et al., 2004)

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Ciclo biolgico

El ciclo completo de A. parvitarsum se conoce por analoga con estudios en A. habreum, que
son garrapatas de 3 hospederos, es decir, que los diferentes estadios del desarrollo requieren
de un mismo o distintos hospederos para completar su desarrollo, siendo estos roedores, aves
y camlidos.

La teologina o garrapata hembra realiza la ovoposicin en los pastizales, eliminando mas de

20.000 huevos, que eclosionan liberando la neolarva. Esta trepa en un primer hospedero,
donde se alimenta y trasforma en metalarva, para luego desprenderse y mudar en el medio
ambiente a ninfa, que infecta a un segundo hospedero. Aqu se alimenta y evoluciona a
metaninfa, que abandona al hospedero y muda en el medio ambiente, diferencindose en
adultos, machos y hembras, que finalmente infestan un tercer hospedero donde copulan. La
teologina repleta de huevos se desprende y cae al pasto. El ciclo completo puede durar entre
74 a 242 das (Soulsby, 1988).

Epidemiologa

Las garrapatas se ubican preferentemente en las zonas del cuerpo con piel delgada y sin fibra,
como la regin perianal, donde se fijan firmemente al husped succionando la sangre y linfa de
ste. Por el hecho de ser hematfagos y pasar por distintos hospederos, adquieren gran
importancia desde el punto de vista mdico veterinario y de salud pblica, ya que pueden ser
vectores de enfermedades bacterianas, virales, protozoarias y rickettsiales (Barriga, 1994).

Habitan zonas de la pradera alto andina, con entorno climtico de temperaturas entre -10 y 18
C, y humedad relativa entre 45 y 65%; que corresponde al hbitat de los camlidos
sudamericanos. Las Ninfas y Adultos se observan muy activos en los estercoleros o letrinas que
habitualmente forman los camlidos (Rojas 2004).

Sintomatologa

En general las garrapatas producen intranquilidad, prurito, hiperqueratosis, inflamaciones

cutneas con ulceracin y trastornos del desarrollo, adelgazamiento y anemia en caso de fuerte
infestacin (Mehlhom et al., 1993).

Diagnstico

Se realiza mediante el hallazgo del parsito en la piel del animal.

Tratamiento

Se pueden realizar los mismos tratamientos usados para combatir la sarna; es decir, un bao
acaricida o un antiparasitario sistmico.

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2.3 Pediculosis

La pediculosis es una enfermedad parasitaria de la piel,

producida por insectos hematfagos, denominados
comnmente piojos. Estos pertenecen al orden Pthiraptera
y se agrupan en 2 subordenes: Mallophaga (que comen
lana) y Anoplura (de cola inerme). Los del suborden
Mallophaga son masticadores, pequeos (0.5 a 1 mm), de
cuerpo aplastado, despigmentado y peludo; La cabeza es
gruesa y ancha, con ojos pequeos y sin ocelos. Las
antenas son cortas, de 3 5 segmentos, al igual que las Microthoracius sp.
patas, con tarsos de 1 a 2 segmentos El aparato bucal de
tipo masticador es muy desarrollado.

Las especies del suborden Anoplura poseen un cuerpo

aplastado, de 1 a 3 mm de longitud, con los tres segmentos
del trax fusionados. La cabeza es cnica con antenas
cortas de 3 a 5 segmentos y las patas anteriores son
transformadas en pinzas. El aparato bucal es de tipo
chupador, con prosboscis corta.

En vicuas se han descrito anopluras de las especies

Microthoracius poelonguiceps y M. Minor. y mallofagas
como Damalina aucheniae (Legua, 1991).
Damalina aucheniae
Ciclo biolgico

Las hembras depositan huevos o liendres ovales y translcidos, cubiertos de una sustancia
pegajosa que les permite adherirse fuertemente a la fibra. All se desarrollan dando lugar a 3
estados ninfales, para finalmente transformarse en adultos, entre 3 a 5 semanas (Legua,
1999).

Epidemiologa

La enfermedad es de alta contagiosidad, que ocurre, esencialmente, por contacto directo y en

menor grado a travs de fomites (lana desprendida con piojos, utensilios de esquila) y
revolcaderos, entre otros.

Los piojos no sobreviven ms de una semana fuera del husped y los huevos no eclosionan a
temperaturas menores que la corporal de las alpacas.

Estos parsitos afectan con ms frecuencia a animales jvenes as como a aquellos sometidos
a condiciones de manejo deficientes (sobrepoblacin y mala alimentacin, entre otros) o a
condiciones estresantes y debilitantes (Legua, op.cit.).

Sintomatologa

La sintomatologa producida por los piojos masticadores se caracteriza por intranquilidad a

causa del prurito; sensibilizacin de la piel e intensa produccin de escamas; los piojos
chupadores producen irritacin local y prurito, frecuentemente en la zona del lomo, cuello y
cabeza (Mehlhorn, 1994).

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Diagnstico

Se realiza mediante la observacin de signos clnicos y se confirma mediante la deteccin de

los parsitos o sus huevos adheridos a las fibras del animal.

Tratamiento

El control de piojos chupadores en animales, se puede realizar con productos de accin

sistmica como ivermectina con dosis de 200 mcg/kg de peso por va subcutnea.

El control de los piojos masticadores, como en el caso de la sarna, implica el tratamiento del
animal infestado con baos antiparasitarios. Los insecticidas menos txicos utilizados son los
piretroides, entre los que se encuentran la permetrina, cipermetrina, d-fenotrin y tetrametrina.
Estos productos actan alterando la transmisin nerviosa del parsito interfiriendo en los
canales de sodio y causando la parlisis del insecto, teniendo adems accin repelente,
otorgando una accin residual post-tratamiento.

3. Enfermedades endoparasitarias

3.1 Gastroenteritis verminosa

Esta enfermedad es producida por distintas especies de nemtodos que actan generalmente
asociados. Los nemtodos constituyen una clase dentro del grupo Asquelmintos, la que est
conformada por unas 12.000 especies. Son organismos fusiformes, cilndricos y no
segmentados. Su cutcula no es elstica motivo por el cual, como sucede con muchos
artrpodos, necesitan mudar peridicamente para crecer en longitud y espesor.
Existen especies de nemtodos especficos de los camlidos como son: Graphinema
aucheniae, Spiculopteragia peruviana, camelostrongylus, Nematodirus lamae, y lamanema.
En las vicuas presentes en altiplano chileno se han encontrado huevos de Nematodirus,
Trichuris, Capilaria y Lamanema (SAG, 2002).

Estudios realizados en vicuas del departamento de Arequipa, Per han determinado como
nemtodos ms frecuentes en vicuas a Moniezia, Nematodirus, Trichuris, Ostertagia,
Lamanema y Trichostrongilus (Cartagena et al., 2004).

Ciclo biolgico

El ciclo es directo, con variaciones entre las distintas especies, lo que permite agruparlas en dos
tipos.

a) Especies con larvas que se desarrollan fuera del huevo: los huevos son eliminados al
medio ambiente por las fecas del hospedador, desde donde emergen larvas L1, que se
tranforman en L2, ambos estadios son larvas desnudas poco resistentes a la sequedad y a
temperaturas bajas, las que sobreviven alimentandose de bacterias y otros
microorganismos. La larva de tercer estado (L3) infectante, est cubierta por una doble
cutcula que la hace resistente a las bajas temperaturas. Esta es ingerida con el pasto,
llegando a las diferentes reas del tracto digestivo dependiendo de la especie, donde se
transforman en L4 y posteriormente L5, las que maduraran y producen huevos que son
eliminados a travs de las fecas; con ello se cierra el ciclo. Con este ciclo se encuentran los
nemtodos que producen huevos tipo Strongylus: Trichostrongylus, Ostertagia,
Spiculopteragia, Graphinema, Cooperia y Oesophagostomum

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Manejo sanitario de la vicua
b) Especies con larvas que se desarrollan dentro del huevo: los huevos son eliminados al
ambiente con las fecas del hospedador, sin embargo, los estados L1 a L3 ocurren dentro
del huevo, desde donde emerge la larva infestante. Esta caracterstica le confiere una alta
resistencia al fro y a la sequedad. Segn Rojas et al. (1981) Nematodirus sp.y Lamanema
sp. cumplen este tipo de ciclo. En el caso de Lamanema chavezi se produce un dao mayor
que en el resto de los nemtodos, ya que las larvas que han llegado hasta el Intestino
Delgado (L3), migran al hgado va linftica o sangunea, donde se transforman en L4; stas
regresan al intestino por el coldoco para alcanzar el estado adulto (Guerrero et al., 1973).

CICLO BIOLGICO DE NEMTODOS

GASTROINTESTINALES

L3

L4-L5
L3
L4-L5

Huevos
Huevos

SUELO L1 L1-L2-L3
L3
L2

Epidemiologa

En la presentacin de las gastroenteritis nematdicas intervienen factores del animal, del

parsito y el medio ambiente. La presentacin es mas frecuente en individuos jvenes y con
deficiencias nutricionales, lo que est dado principalmente por la ausencia de una inmunidad
adecuada. La relacin del medio ambiente con la supervivencia del parsito es muy estrecha,
existiendo una mayor sobrevida de las larvas en condiciones climticas favorables encontradas
en las pocas de lluvia. En el caso de los nemtodos donde el desarrollo de L1 a L3 ocurre
dentro del huevo, como es el caso de Lamanema, se han encontrado larvas viables en
pastizales hasta por 2 aos (Rojas et al., 1981).

Sintomatologa

En los animales afectados por nemtodos gastrointestinales es frecuente la presencia de

diarreas, principalmente en animales jvenes, la que puede llevar a una perdida de condicin
corporal, predisponiendo a la presentacin de otras patologas de tipo infeccioso. En casos
severos es posible encontrar animales deshidratados y anmicos.

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Diagnstico

Se realiza mediante la observacin de la sintomatologa asociada a la edad de los animales y

se confirma mediante exmenes coprolgicos y necropsia.

Tratamiento

El tratamiento consiste en la aplicacin de vermicidas de uso interno o sistmico. En el primer

caso, se utilizan los derivados de la pirimidina como el pirantel, y los benzimidaslicos como el
thiabendazol, albendazole y fenbendazole (dosis de 7,5 mg/kg de peso) El tratamiento
sistmico con productos como ivermectina (ver tratamiento de la sarna) es mas recomendable,
ya que, adems permite el control de ectoparsitos.

3.2 Coccidiosis

Es una enfermedad producida por protozoos del gnero Eimeria; en vicuas de Per se han
reportado 4 especies: E. alpacae, E. lamae, E. mucusaniensis y E. punoensis, todas parasitan
las clulas del Intestino Delgado. (Legua, 1991).

Ciclo biolgico

El ciclo es directo, donde el animal se infecta al ingerir pasto o agua contaminados con
ooquistes microscpicos esporulados (esporozoitos) que han sido eliminados por las heces
desde el intestino de los hospedadores (Guerrero et al., 1970). Dichas estructuras contienen en
su interior 8 esporozoitos que se liberan en el estmago del nuevo hospedador, desde donde
invaden las clulas epiteliales o glndulas crpticas del intestino, all inician la reproduccin
asexual transformndose en esquizontes que se reproducen internamente hasta romper las
clulas, liberando cientos de merozoitos que ingresan a nuevas clulas intestinales, dando lugar
a la segunda y siguientes generaciones de esquizontes. Posteriormente, se inicia la
reproduccin sexual o gametogonia, aqu algunos merozoitos se diferencian en clulas
femeninas, macrogamontes que originaran macrogametos y otros en clulas masculinas,
microgamontes, que originarn microgametos. La unin de ambos forma un ooquiste inmaduro
que es eliminado con las heces al ambiente, donde, en presencia de humedad y temperatura
adecuada esporula, originando 4 esporocistos con dos esporozoitos cada uno. (Guerrero et al.,
1970, 1971).

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 CICLO BIOLGICO DE EIMERIA

Invasin de Ruptura celular

Nuevas clulas con liberacin de
Merozoitos Esquizonte maduro
Formacin de con Merozoitos
Microgamontes
Inmaduros

Microgamonte Formacin del

Maduro Esquizonte

Liberacin de Formacin
Microgametos de
LUMEN Trofozoito
INTESTINAL
Penetracin de
Microgametos
en Macrogamonte Invasin de nueva
clula Intestinal

Macrogamonte
fecundado (Cigoto)
Formacin y maduracin del
Formacin Esquizonte y posterior salida
del Ooquiste de Merozoitos
Formacin
Ooquiste Esporozoito de
Inmaduro Ingresa por Trofozoito
saliendo al lumen Alimento o
intestinal Bebida

FASE SEXUADA FASE ASEXUADA

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Epidemiologa

Las cuatro especies de Eimeria encontradas en vicua (sealadas anteriormente) tambin

afectan a alpacas y llamas, presentndose la enfermedad de preferencia en animales jvenes
criados en confinamiento, notificndose tasas de prevalencia del 30 al 100%( Chavez y Col.,
1982).

Aunque en vicuas no se han descrito los periodos de mayor susceptibilidad a contraer la

enfermedad, se ha demostrado que las cras de alpacas pueden infectarse a partir de la
segunda semana de edad, incrementndose la eliminacin de ooquistes en las 8 semanas
siguientes. (Melo y Hurtado, 1985).

Sintomatologa

Esta enfermedad generalmente se presenta en forma subclnica. En los casos clnicos existe
presencia de diarrea ligeramente sanguinolenta y maloliente, acompaada de deshidratacin,
sed, perdida de peso, debilidad, postracin y en casos graves, la muerte.

Diagnstico

Se basa en la observacin de los signos clnicos, confirmado por un examen coprolgico para
determinar la presencia de ooquistes esporulados.

Tratamiento

No se ha descrito un tratamiento en camlidos; sin embargo, en ovinos se ha utilizado

Monenzina, con dosis de 1,6 mg/kg durante 7 das (Legua, 1999).

3.3 Hidatidosis

Es una zoonosis producida por el gusano plano (platelminto) Echinococcus granulosus, un

cestodo de la familia Taeniidae, que incluye a las tenias. Su tamao flucta entre los 3 6 mm.
y su extremo anterior presenta un rgano de fijacin o escolex con dos filas de ganchos y
cuatro ventosas. Este se contina en un cuello que da origen a la estrbila, conformada por
progltidas, que corresponden a segmentos, cada uno con un aparato reproductor completo. El
parsito adulto posee 3 a 4 progltidas, la ltima cargada de huevos, se desprende de la
estrbila, llega al ambiente y los libera. (Danovaro, 1980).

Ciclo biolgico

El Echinococcus granulosus presenta un ciclo biolgico caracterizado como una ciclozoonosis,

es decir, se requiere la presencia de dos o mas huspedes vertebrados para mantener el
agente infeccioso (Thompson, 1979). La poblacin del parsito comprende tres sub
poblaciones: tenias adultas en el husped definitivo, larvas en el husped intermediario y
huevos en el medio ambiente, siendo cada una de estas sub poblaciones dependientes una de
la otra (Gemmell, 1990).

En el intestino delgado de los cnidos (hospederos finales) se desarrolla el hidtide

(Lombardero, 1990). El parsito adulto elimina una progltida cada 14 das a travs de las fecas
del perro infectado (Basso et al., 1992). Esta progltida se desintegra en el medio ambiente,
liberando los huevos y contaminando as las los pastos y aguas (Lawson, 1980). Cada huevo

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Manejo sanitario de la vicua
contiene una oncsfera que debe ser ingerida por un hospedador intermediario (herbvoro) para
continuar el ciclo biolgico del parsito. (Tagle, 1970).

CICLO BIOLGICO E. GRANULOSUS

Epidemiologa

En esta enfermedad es fundamental la coexistencia de las vicuas con carnvoros,

principalmente perros, donde la tenia puede vivir y producir progltidas grvidas durante varios
aos, liberando huevos muy resistentes a la desecacin y bajas temperaturas.

Otro factor importante en la persistencia del parsito en el medio es la alimentacin de los

perros con vsceras de animales domsticos contaminadas, los que seguirn diseminando
huevos en los pastos e infectando nuevos herbvoros o reinfestndolos.

Sintomatologa

Se relaciona con el rgano afectado, desde problemas hepticos, hasta neurolgicos si el

quiste es de ubicacin cerebral. En caso de ruptura de los quistes se producir la muerte por
shock anafilctico.

Diagnstico

Se realiza mediante la necropsia del animal, encontrando los quistes en distintos rganos del
animal.

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Tratamiento

No existe tratamiento para eliminar las formas parasitarias dentro de los quistes, por lo que la
prevencin mediante el tratamiento antiparasitario de los perros pastores y la educacin
sanitaria, enfocada a la destruccin de las vsceras de animales domsticos que son faenados
en el campo, son fundamentales para cortar el ciclo y evitar el contagio de las vicuas y
animales herbvoros domsticos.

3.4 Sarcocistiosis

Es una enfermedad zoontica, parasitaria producida por protozoos. En vicuas se han

identificado dos especies de Sarcocystis: S. aucheniae y S. lamacanis. (Guerrero et al., 1967).

Ciclo biolgico

Es un ciclo indirecto, donde la vicua acta como husped intermediario. El animal se infecta al
ingerir pasto o agua contaminados con ooquistes esporulados que han sido eliminados por las
heces de los perros. Los ooquistes en su interior contienen esporozoitos, los cuales luego de
liberados en el estmago, atraviesan la pared intestinal y se dirigen al endotelio vascular de los
distintos rganos. Aqu darn origen a 2 generaciones de esquizontes mediante reproduccin
asexual (esquizogonia). La tercera generacin de esquizontes se realiza en el msculo cardiaco
(Legua et al., 1988).

Los esquizontes se reproducen internamente hasta romper las clulas, liberando cientos de
merozoitos que son transportados por el torrente sanguneo hacia la musculatura esqueltica y
cardiaca, donde se transforman en metrozoitos, que se multiplican, originando una cubierta
qustica, que proteger a los bradizoitos que son las formas infectantes. El ciclo contina
cuando un carnvoro ingiere msculo con quistes, liberndose en el intestino los bradizoitos
que ingresan a las clulas, dando origen a la fase sexual o gametogonia. Con produccin de
clulas femeninas, macrogamontes que originaran macrogametos y otros en clulas
masculinas, microgamontes que originarn microgametos, de la unin de estos con los
magrogametos se formar el ooquiste inmaduro que esporula o madura en el intestino delgado,
siendo eliminado con las heces al medio ambiente, donde ser ingerido por los camlidos que
reiniciarn el ciclo. (Legua et al., op cit.)

Epidemiologa

Esta enfermedad se presenta generalmente en forma subclnica en animales adultos, donde las
vicuas actan como husped intermediario, siendo los carnvoros los huspedes definitivos,
habindose demostrado en perros la participacin en el ciclo biolgico (Alva et al., 1981). La
supervivencia de las formas infectantes del parsito es mayor en periodos de lluvias y en zonas
hmedas.

Esta enfermedad puede adquirir importancia en sistemas de confinamiento, donde exista

convivencia de vicuas con perros pastores que no estn bajo control parasitario.

En caso de consumo por parte del ser humano de carne que contengan quistes, se puede
producir un cuadro de gastroenteritis generada por la accin de sustancias txicas presentes en
estos.

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Sintomatologa

No se ha detectado sintomatologa clnica relacionada con esta enfermedad; sin embargo, se

reconoce dada la notoriedad de los quistes que pueden encontrarse al realizar una necropsia.

Diagnstico

Se realiza mediante la observacin de los quistes macroscpicos en la musculatura del animal.

Tratamiento

No se ha descrito un tratamiento efectivo, ya que no existen productos que tengan accin sobre
las formas qusticas del parsito. Lo mas efectivo es realizar tratamiento antiparasitario a los
perros pastores que pudieran estar eliminando formas infectantes al medio, para lo cual se han
utilizado con xito las sulfonamidas como Sulfametoxazol mas Trimetropin (Yujra et al.,2004)

4. Enfermedades infecciosas

La ocurrencia de estas enfermedades en camlidos sudamericanos (causadas por bacterias y

virus) tiene trascendental importancia tanto para las especies domsticas, (alpaca y llama),
como para las especies silvestres, (vicua y guanaco). En las primeras se produce una
repercusin negativa en la produccin, lo que se traduce en un impacto socio-econmico para
el criador y para la economa local, como resultado de su efecto en comercializacin y
exportacin de sus productos. En el caso de camlidos silvestres, la ocurrencia de problemas
sanitarios atenta contra la conservacin de la especie, adems de influir tambin en forma
negativa, en la produccin de explotaciones autorizadas.

4.1 Leptospirosis

La Leptospirosis es una enfermedad de gran importancia en la salud animal, especialmente en

bovinos, porcinos y ovinos. Sin embargo, en camlidos sudamericanos no se ha estudiado con
profundidad, aunque existen algunos datos relativos a vicuas del altiplano de Chile, que
sealan la presencia de anticuerpos contra Leptospira pomona, L. grippot y L. copenahenn, sin
evidencia de sintomatologa clnica (SAG, 2002). Estos serotipos son coincidentes con los
encontrados en casos asociados a mortalidades de adultos y cras de alpacas, en el estudio
sealado.

Etiologa

Todos los mamferos domsticos son susceptibles a leptospirosis, condicin que tambin se ha
descrito en numerosas especies de animales silvestres. La enfermedad si bien es enzotica en
varias regiones, se presenta frecuentemente como brotes, provocando abortos, disminucin de
la produccin lechera en hembras, y muerte en animales jvenes, pudiendo tambin afectar al
hombre donde produce una afeccin renal.

Al producirse la infeccin del animal se produce primero una leptospiremia, luego estas
bacterias colonizan el rin y son eliminadas por la orina produciendo la contaminacin del
ambiente. Existen animales que tienen una leptospiruria prolongada y no manifiestan sntomas
aparentes, siendo estos los que juegan un papel crtico en la diseminacin de la infeccin. Otro

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Manejo sanitario de la vicua
papel muy importante lo juegan los animales silvestres en la epidemiologa de la enfermedad,
siendo los roedores el reservorio principal.

R e la c i n a n im a le s p o s itiv o s v s n e g a t iv o s a L e p to s p ir o s is
s e g n m u e s t r e o . C c u lic c u lin e N o v 2 0 0 2 -E n e 2 0 0 3

P o s itiv o s
35 N e g a tiv o s

30 12

25
20

15 5
24
10
5 13
5
4
0
P ilo to M u e s tre o 1 M u e s tre o 2

Diagnstico

Se realiza mediante un examen serolgico, siendo el mtodo de micro aglutinacin (M.A.T.) el

ms utilizado en la actualidad.

Tratamiento

Se recomienda el uso de dihidroestreptomicina en dosis de 25 mg. por Kg. de peso corporal va

intramuscular, (Fowler, 1993) repitiendo a los 14 das. Cabe sealar, que este tratamiento fue
adoptado por el SAG como parte del protocolo de exportaciones de camlidos sudamericanos
domsticos.

Profilaxis

No se recomienda la vacunacin por tratarse de una enfermedad espordica.

4.2 Queratoconjuntivitis

Es una inflamacin que afecta el tejido ocular externo de los camlidos sudamericanos de
cualquier edad y ha sido diagnosticada solo en las especies domsticas. Algunos factores
predisponentes son el polvo y partculas de pastos que pueden causar la irritacin de los ojos,
permitindose de este modo la accin de algunos microorganismos oportunistas.

La enfermedad puede afectar un ojo o ambos, presentando una secrecin que al avanzar la
afeccin va adquiriendo caractersticas purulentas, las que pueden llegar a impedir la apertura
palpebral.

La mortalidad por dichas afecciones es reducida y en la literatura slo se informan casos

aislados de muertes a causa de cuadros complicados (Ramirez, 1980).

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Etiologa

Este proceso infeccioso de los ojos, est relacionado con pocas de sequas, cuando hay
mucho polvo y pasto seco que actan como agentes predisponentes, irritando los ojos;
actuando diversas bacterias pigenas oportunistas como agentes principales, entre las cuales
se encuentran Staphylococcus aureus, Streptococcus sp., Corynebacterium pyogenes y
Moraxella liquefaciens (Brightman y Col., 1981).

Diagnstico

Es posible realizarlo mediante la observacin del los sntomas, que incluyen: secrecin ocular,
fotofobia, congestin de la conjuntiva y gran sensibilidad del rgano visual, pudiendo
encontrarse opacidad corneal y lceras.

Tratamiento

Es importante practicar la limpieza de los ojos afectados con una solucin desinfectante y
posteriormente la aplicacin de antibiticos en ungento o spray, lo que ha producido
resultados satisfactorios con aplicaciones locales 2 veces al da hasta la remisin de los
sntomas. En otros casos, infecciones mixtas han sido tratadas con administracin sistmica de
antibiticos y atropina (Fowler, 1993).

4.3 Enterotoxemia

Es una eenfermedad aguda que afecta a las cras bien nutridas, dentro de su primer mes de
vida. Se caracteriza por presentar un cuadro de toxemia generalizado en el animal, debido a la
accin de toxinas de C. perfringes tipo A. La presentacin de la enfermedad se relaciona con
los aos que hay abundantes lluvias, cuando hay ms pasto, relacionado con la mayor
produccin de leche, favorable para la multiplicacin del clostridium.

Etiologa

Es producida por el Clostridium perfringes tipo A, anteriormente conocido como Clostridium

welchi, (Moro, 1967; Huaman et al., 1977; Ramirez et al., 1981). Este clostridium es una
bacteria anaerbica, en forma de bacilo, capaz de formar esporas y de producir potentes
toxinas, las cuales rpidamente causan dao severo a nivel intestinal y en rganos vitales del
animal afectado.

Sntomas

En los pios afectados las cras permanecen echadas y lejos de sus madres, con los miembros
estirados y apoyando la cabeza en el suelo. Existe muerte repentina de cras, generalmente las
ms robustas, las que muestran un abdomen prominente con notable presencia de gases en los
intestinos y fluidos en la cavidad torcica y abdominal. Tambin se presentan pequeas
hemorragias en el timo, corazn y tejido subcutneo. La mortalidad es elevada, pudiendo
afectar a todas las cras.

Diagnstico

Es necesario identificar la magnitud del problema tomando en cuenta la edad de los animales
afectados, nmero de animales enfermos y mortalidad de cras. Todo esto relacionado con los

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Manejo sanitario de la vicua
signos clnicos y alteraciones anatomopatolgicas encontradas nos pueden acercar al
diagnstico.
La confirmacin se realiza mediante examen de laboratorio. La mejor muestra para identificar la
toxina, es un trozo de intestino delgado (ileon) de unos 20 cms., amarrado en ambos extremos,
con su contenido. Este trozo se pone en un frasco de boca ancha que contenga glicerina
tamponada y se enva al laboratorio.

Profilaxis

Como medidas preventivas se recomienda el uso de medidas higinicas bsicas en el manejo

de las vicuas, tales como mantener limpia las aguadas y contar con reas secas para
dormideros.

El uso de vacunas est siendo evaluado en camlidos sudamericanos, no reportndose

resultados lo suficientemente satisfactorios que permitan recomendar su utilizacin.

Tratamiento
Se recomienda el uso de antibiticos como la Oxitetraciclina en dosis de 20 mg. por Kg. de
peso, para controlar la multiplicacin del clostridium y combatir la flora bacteriana secundaria.

4.4 Neumona

Es una afeccin respiratoria aguda, que se observa con mayor frecuencia en cras. En el
complejo neumnico participan comnmente Pasteurella multocida (Ameghino y Calle, 1989) y
Pateurella haemolytica (Remirez, 1991), las que proliferan al existir algn tipo de estrs en el
animal.

Sntomas

Se observan animales decados que rehsan comer, se puede observar exudado

mucopurulento en las fosas nasales, disnea y temperatura corporal de 40 - 41C. Los cuadros
neumnicos agudos, se presentan en camlidos de pocos das o semanas de edad,
producindose la muerte de algunas cras sin manifestaciones clnicas. Segn Garmendia el al.
(1987) lo factores predisponentes en animales de 3 semanas, son una insuficiente ingestin de
calostro y la exposicin a temperaturas bajas o su brusca fluctuacin diaria.

Diagnstico

Se realiza mediante la observacin de los sntomas clnicos descritos.

Profilaxis

Una medida de gran utilidad en neonatos es asegurarles la provisin de calostro. De no ser

posible contar con la madre, podra suplementarse con el de otra especie.
Para el caso de animales sometidos a esquila, se recomienda una antibioterapia con
Enrofloxacino al 5% en dosis de 1ml/50 kg de peso vivo.

Tratamiento

Se recomienda la administracin de antibiticos de amplio espectro como el Enrofloxacino al

5% en dosis de 1ml/50 kg de peso vivo, en dosis nica.

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4.5 Fiebre aftosa y estomatitis vesicular

Ambas enfermedades virales estn ausentes de Chile. En la literatura internacional, existe el

reporte de 16 llamas, 16 alpacas y 1 caso en vicuas reproducido a travs de la inoculacin va
venosa (Mancini, 1952).

Debido a que los camlidos sudamericanos tienen una baja susceptibilidad a contraer la
enfermedad, stos slo presentaran sntomas si estn expuestos a grandes cantidades del
virus, sin embargo, es importante sealar que los camlidos podran actuar como vectores
mecnicos si estn en contacto con bovinos infectados. (Fowler, 1993)

Como parte del programa de vigilancia epidemiolgica del SAG, desde el ao 1999, se han
realizado exmenes de laboratorio peridicos en muestras de vicuas para descartar la
presencia de serologa positiva a Fiebre Aftosa y Estomatitis Vesicular, encontrndose
resultados negativos en todas las muestras procesadas.(SAG, 2002)

4.6 Brucelosis

Enfermedad reproductiva de alto impacto en la produccin. Afecta la fertilidad, produciendo en

las hembras, abortos en el ltimo tercio de gestacin o muerte de la cra inmediatamente
despus del nacimiento (Acosta et al., 1972). En los machos de alpacas la incidencia es muy
baja y no se observan casos de epididimitis u orquitis, como ocurre en otras especies. (Fowler,
1993)

Para el caso de las vicuas en cautiverio en el altiplano chileno, se analiz muestras de sangre
de 58 animales arrojando resultados negativos a las prueba de Rosa de Bengala. (SAG, 2002).

Diagnstico

La ocurrencia de abortos en el ltimo tercio de gestacin y muerte de cras despus del parto,
constituyen las manifestaciones clnicas ms evidente de la enfermedad en alpacas (Acosta et
al., 1972). La prueba de aglutinacin en placa es de utilidad en el diagnstico.

Profilaxis

La recomendacin es evitar la crianza mixta de ovinos o caprinos con camlidos por el riesgo
de enfermar a estos ltimos, ya que en los casos descritos en Per en alpacas, donde se aisl
Brucella mellitensis, se atribuy un brote de la enfermedad al contacto de los camlidos con
ovinos enfermos (Acosta et al., op cit.).

Tratamiento

No existe tratamiento efectivo para la Brucelosis. En caso de prevalencias bajas la

recomendacin es realizar pruebas de laboratorio y posterior eliminacin de los reaccionantes
positivos.

BOLETN VETERINARIO OFICIAL, BVO N9, II SEMESTRE 2007 18/21

Manejo sanitario de la vicua
5. Acciones profilcticas propuestas para un criadero

A continuacin se sealan las acciones de manejo para el control de la carga parasitaria de los
animales, junto a un aporte vitamnico mnimo para etapas crticas.

ESQUEMA DE TRATAMIENTO SANITARIO PREVENTIVO

MAYO NOVIEMBRE

ENERO 1 DIC 2

1) Se realiza un tratamiento con Ivermectina (200 mcg/Kg de peso corporal, por va subcutnea)
y vitaminas ADE a todos los animales (1 ml. por animal va intramuscular, con preparados
comerciales que contienen Vitamina A: 500.000 UI, Vitamina D: 75.000 UI y Vitamina E: 50
UI por cada ml. de solucin). Esta poca es crtica, ya que las cras nacidas en enero estn
susceptibles a desarrollar los parsitos ingeridos por las pasturas, sumado al estrs
provocado por las sequas del periodo. Con este tratamiento se controlan ectoparsitos y
endoparsitos, aportando adems vitaminas para este periodo crtico del ao.

2) Se efecta un segundo tratamiento con Ivermectina y vitaminas ADE a todos los animales.
Este tratamiento se realiza para controlar los parsitos que se puedan haber desarrollado en
los periodos de primavera y bajar la carga parasitaria de las praderas en los meses de lluvia
prximos. Adems se aportan vitaminas para suplir las deficiencias del periodo anterior de
sequa.

Fotografa: R. Denegri

BOLETN VETERINARIO OFICIAL, BVO N9, II SEMESTRE 2007 19/21

Manejo sanitario de la vicua
6. Bibliografa

Acosta M, Ludea H, Barrueto D, Moro M, 1972. Brucelosis en alpacas. Rev Inv Pec IVITA
(Per)
Alva, J., Bazalar, H., Guerrero, C. y Nuez, A, 1981. Observaciones del ciclo de vida del
Sarcocystis aucheniae de alpacas (Lama pacos) Res. Proy. Inv. Univ. Nac. S. Marcos.
3: 4
Ameghino, E. y Calle, S. 1989. Aislamiento de Pasteurella multocida de procesos neumnicos
en cras de alpacas. XII Reunin cientfica Anual. Asoc. Peruana de produccin animal.
Lima, Per. Memo 1989 99 pp
Barriga, O.O. 1994. Veterinary Parasitology. The Ohio State University. 297 pp.
Becklund, W., 1963. Lamanema chavexi gen. N; sp.n. and Nematodirus lamaesp. N.
(Nematoda trichostrongylidae) from the alpaca, lama pacos, and vicua, Vicugna
vicugna in per. J. Parasit 49: 1203: 1037.
Brigthtman, A. H; MacLaugthling, S. A. y Brumley, V. 1981. Keratoconjuntivitis in a llama. Vet.
Med. Samll. Anim. Clin.
Casanueva, M.E.C. 1995. Apuntes de Acaraloga general. Universidad de Concepcin. Facultad
de Ciencias Biolgicas y Oceanogrficas. 139 pp.
Chvez, C. y Guerrero, C. 1960. Ecto y endoparsitos identificados en el Departamento de
Parasitologa de la facultad de medicina Veterinaria (1947 1960). Rev. Fac. Med. Vet.
Lima 15: 48:68.
Dale, E. y Venero, L. 1977. Insectos y Acaros. Ectoparsitos de la vicua en Pampa Galeras.
Rev. Ent. Lima. 20 (1) 193-99 pp.
Fowler, M. E. 1989. Medicine and Surgery of South American Camelids. 1st Ed. Iowa Sate Univ.
Press Ames, USA.
Garmendia, A. Palmer, G. De Martn, J. y mcGuire, T. 1987. Failure of pasive inmunoglobulin
transfer. Amajor determi8nant of mortality in newborn alpacas (Lama pacos). Am. J. Vet.
Res. 48 (10): 1472 - 1476
Guerrero, C. Alva, J. 1986. Gastroenteritis nematdica y sarna de Alpacas. Bol. IVITA. Univ.
San Marcos. Lima, Per. 21:25-33
Guerrero, C. Alva, J. Vega, I. Hernndez, J. y Rojas M. 1973. Algunos aspectos biolgicos y
parasicolgicos de Lamanema chavezi en alpacas. Rev Inv Pec (IVITA). Univ. Nac.
Mayor de San Marcos. 2: 29 42
Guerrero, C. Alva, J. Bazalar, H y Tibacchi. L. 1970. Infeccin experimental de alpacas con
Eimeria lamae. Bol. Ext. IVITA. 4: 79-83

Guerrero, D.; Hernndez, J.; Bazalar, H. y Alva, J. 1971. Eimeria macusaniensis of the alpaca.
J. Protozool. 18:162 pp.
Guerrero, C.; Hernndez, J. y Alva, J. 1967. Sarcocystis en alpacas. Rev. Fac. Med. Vet. Lima.
69-76 pp
Huaman, D. Y Ludena, H. 1977. Clostridia Aislados en Cras de Alpacas. Veterinaria y
Zootecnia. Vol XXIX, Nos. 82,83,84
Krantz, W. 1978. A manual of acarology. Second edition. Oregon State Univ. Bookstore,
Corvallis. 509 pp.
Legua, G. 1999. Enfermedades Parasitarias y Atlas Parasitolgico de Camlidos
Sudamericanos. Editorial de Mar, Per. 100 pp.
Legua, G. 1991. Avances y perspectivas del conocimiento de los Camlidos Sudamericanos.
FAO. 327-356 pp.
Legua, G., Guerrero, C. Sam, R y Rosadio, R. 1988. Patolog{ia de sarcocystis aucheniae en
alpacas infectadas experimentalmente X Cong. Pan . Cienc,. Vet. Lima. Per.
Manzini, A. 1952. Ensayos sobre la receptividad de los Auqunidos a la fiebre Aftosa. Bol. Inst.
Nac. Antiaftoso. Lima 1 (3): 127 - 146

BOLETN VETERINARIO OFICIAL, BVO N9, II SEMESTRE 2007 20/21

Manejo sanitario de la vicua
Melo, A. y Hurtado, E. 1985. Infestacin parasitaria en alpacas desde el nacimiento al destete.
ALLPAKA. Rev. Inv. Camlidos sudamericanos. Univ. Nac. Del Altiplano. Puno. 1(2): 78-
86.
Moro, M. 1967 Enfermedades Infecciosas de la Alpaca. 5. Enterotoxemia. Diarrea bacilar
producida por Clostridium welchii tipo A. Rev. Fac. Medicina Veterinaria. UNMSM. Lima,
Per.
Ramrez, A. 1991. EnfermedadesInfecciosas en Alpacas y Llamas. Produccin de Rumiantes
menores: Alpacas. 201 247 pp
Ramrez, A; Huaman, D. y Ellis, R.P. 1985. Enterotoxemia de la Alpaca. Colorado State
University. USA y Centro de Investigacin IVITA. Univ. Nac. Mayor de San Marcos.
Lima. Per. Convenio SR-CRSP/USAID e INIA.
Ramrez, A. 1980. Aspectos Sanitarios en la Alpaca. En: Curso Sistemas de Produccin
Pecuaria en los Altos Andes. Asociacin Peruana de Produccin Animal. Lima. Per.
Rojas, M., Nez, A. Y Alva, J. 1981.Observaciones del desarrollo y sobrevivencia de
Lamanema chavezi en condiciones naturales. Res. Proy. Inv. Univ. San Marcos, Lima,
Per, p.179.
SAG, 2002 Oficio Ordinario N 1251 del 14 de Agosto del 2002. Resultados exmenes
serolgicos y parasitarios en vicuas silvestres y en cautiverio.
Sanchez, C.J. Bustinza y E. Avila. 1985. Biologa de los caros de la Sarna. Res. V Con. Int.
Camlidos sudamericanos. Cusco, Per.
Soulsby, E. 1988. Parasitologia y enfermedades parasitarias en los animales domsticos. 7 Ed.
Interamericana, Mxico. 823 pp.
Strickland, R.K.; R.R. Gerrish, J.L. Hourrigan y G.O. Schubert. 1976. Ticks of veterinary
importance. Agriculture Handbook N 485. United States Departament of Agriculture,
Washington D.C., 122 pp.

BOLETN VETERINARIO OFICIAL, BVO N9, II SEMESTRE 2007 21/21

Manejo sanitario de la vicua
ANEXO 2
 W H O Te c h n i c a l R e p o r t S e r i e s

997

Evaluation of certain
veterinary drug residues in food

Eighty-first report of the Joint

FAO/WHO Expert Committee on
Food Additives
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 W H O Te c h n i c a l R e p o r t S e r i e s
9 9 7

Evaluation of certain
veterinary drug residues in food

Eighty-first report of the Joint

FAO/WHO Expert Committee on
Food Additives

This report contains the collective views of an international group of experts and
does not necessarily represent the decisions or the stated policy of the World Health Organization
WHO Library Cataloguing-in-Publication Data
Evaluation of certain veterinary drug residues in food: eighty-first report of the Joint FAO/WHO
Expert Committee on Food Additives.
(WHO technical report series ; no. 997)
1.Food Contamination. 2.Drug Residues - analysis. 3.Drug Residues - toxicity. 4.Veterinary Drugs -
toxicity. 5.Veterinary Drugs - pharmacology. 6.Risk Assessment. 7.Maximum Allowable Concentrations
- standards. 8.No-Observed-Adverse-Effect Level. I.World Health Organization. II.Food and Agriculture
Organization of the United Nations. III.Joint FAO/WHO Expert Committee on Food Additives. IV.Series.

ISBN 978 92 4 120997 7 (print)
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Printed in Malta
Contents
List of participants v
List of abbreviations viii
1. Introduction 1
1.1 Declarations of interests 2
1.2 Modification of the agenda 2
2. General considerations 3
2.1 Matters of interest arising from previous sessions of the Codex Committee on Residues
of Veterinary Drugs in Foods (CCRVDF) 3
2.2 MRLs for generic fish species 4
2.3 Acute reference dose (ARfD) for veterinary drugs 7
2.4 Chronic dietary exposure assessment 9
2.4.1 Approach for dietary exposure assessment of compounds used for multiple
purposes (i.e. veterinary drugs and pesticides) 9
2.4.2 Dietary exposure assessment for less-than-lifetime exposure 10
2.4.3 Recommendations 11
2.5 Update and revision of Principles and methods for the risk assessment of chemicals
in food (EHC 240) 11
2.6 Guidance for the evaluation of veterinary drug residues in food by JECFA 12
2.7 Update on FAO and WHO databases related to the work of the Committee 12
2.8 Processing of food containing residues of veterinary drugs 13
2.9 Reporting of original data in JECFA monographs 14
2.10 Assessment of short-term (90-day and 12-month) studies in dogs 14
2.11 Coordination of the agendas of JECFA and JMPR 15
3. Response to concern forms from CCRVDF 17
3.1 Lasalocid sodium 17
4. Comments on residues of specific veterinary drugs 25
4.1 Diflubenzuron 25
4.2 Ivermectin 39
4.3 Sisapronil 49
4.4 Teflubenzuron 59
4.5 Zilpaterol hydrochloride 73
5. Future work and recommendations 85

Acknowledgements 87

References 89

Annex 1
Reports and other documents resulting from previous meetings of the Joint FAO/WHO
Expert Committee on Food Additives 93

iii
 Annex 2
Recommendations on compounds on the agenda 105
Annex 3
Meeting agenda 109

iv
List of participants

Eighty-first meeting of the Joint FAO/WHO Expert Committee on

Food Additives
Rome, 1726 November 2015

Members
Professor A. Anadn, Department of Toxicology and Pharmacology, Faculty of Veterinary
Medicine, Universidad Complutense de Madrid, Madrid, Spain
Dr J.O. Boison, Centre for Veterinary Drug Residues, Canadian Food Inspection Agency,
Saskatoon, Saskatchewan, Canada (Joint Rapporteur)
Professor A.R. Boobis, Centre for Pharmacology & Therapeutics, Department of
Experimental Medicine, Division of Medicine, Faculty of Medicine, Imperial College
London, London, England, United Kingdom (Vice-Chair)
Dr L.G. Friedlander, Residue Chemistry Team, Division of Human Food Safety, Center
for Veterinary Medicine, Food and Drug Administration, Department of Health and
Human Services, Rockville, Maryland, United States of America (USA) (Chair)
Dr K.J. Greenlees, Office of New Animal Drug Evaluation, Center for Veterinary Medicine,
Food and Drug Administration, Department of Health and Human Services, Rockville,
Maryland, USA (Joint Rapporteur)
Professor S.H. Jeong, Department of Biomedical Science, College of Life and Health
Science, Hoseo University, Asan City, Chungnam, Republic of Korea
Professor B. Le Bizec, Laboratoire dtude des Rsidus et des contaminants dans les
aliments (LABERCA), cole Nationale Vtrinaire, Agroalimentaire et de lAlimentation
Nantes Atlantique (ONIRIS), Nantes, France
Professor J. Palermo-Neto, Department of Pathology, Faculty of Veterinary Medicine,
University of So Paulo, So Paulo, Brazil
Professor Emeritus L. Ritter, University of Guelph, Guelph, Ontario, Canada
Dr P. Sanders, National Reference Laboratory for Veterinary Drug Residues and
Antimicrobial Resistance, Agence nationale de scurit sanitaire de lalimentation, de
lenvironnement et du travail (ANSES), Fougres, France

Secretariat
Ms G. Brisco, Joint FAO/WHO Food Standards Programme, Food and Agriculture
Organization of the United Nations, Rome, Italy (Codex Secretariat)

v
 Dr A. Bruno, Joint FAO/WHO Food Standards Programme, Food and Agriculture
Organization of the United Nations, Rome, Italy (Codex Secretariat)
Dr C.E. Cerniglia, Division of Microbiology, National Center for Toxicological Research,
Food and Drug Administration, Department of Health and Human Services, Jefferson,
Arkansas, USA (WHO Expert)
Dr A. Chicoine, Veterinary Drugs Directorate, Health Canada, Saskatoon, Saskatchewan,
Canada (FAO Expert)
Dr H. Erdely, Residue Chemistry Team, Division of Human Food Safety, Center for Veterinary
Medicine, Food and Drug Administration, Department of Health and Human Services,
Rockville, Maryland, USA (FAO Expert)
Dr V. Fattori, Food and Agriculture Organization of the United Nations, Rome, Italy (FAO
Secretariat)
Dr S. Ghimire, Veterinary Drugs Directorate, Health Canada, Ottawa, Ontario, Canada
(WHO Expert)
Dr J.C. Leblanc, Food and Agriculture Organization of the United Nations, Rome, Italy (FAO
Secretariat)
Dr M. Lipp, Food and Agriculture Organization of the United Nations, Rome, Italy (FAO
Joint Secretary)
Dr J. MacNeil, Consultant, Food and Agriculture Organization of the United Nations, Rome,
Italy (FAO Technical Editor)
Dr K. Ogawa, Division of Pathology, Biological Safety Research Center, National Institute of
Health Sciences, Tokyo, Japan (WHO Expert)
Professor S. Rath, Department of Analytical Chemistry, University of Campinas, Campinas,
So Paulo, Brazil (FAO Expert)
Dr R. Reuss, Food Standards Australia New Zealand, Canberra, Australian Capital Territory,
Australia (FAO Expert)
Dr G.J. Schefferlie, Veterinary Medicinal Products Unit, Medicines Evaluation Board
Agency, Utrecht, the Netherlands (WHO Expert)
Dr S. Scheid, Department of Veterinary Medicines, Federal Office of Consumer Protection
and Food Safety, Berlin, Germany (FAO Expert)
Dr C. Schyvens, Scientific Assessment and Chemical Review, Australian Pesticides and
Veterinary Medicines Authority, Kingston, Australian Capital Territory, Australia (WHO
Expert)
Ms M. Sheffer, Orleans, Ontario, Canada (WHO Editor)
Dr A. Tritscher, Risk Assessment and Management, Department of Food Safety and
Zoonoses, World Health Organization, Geneva, Switzerland (WHO Secretariat)

vi
Dr S. Vaughn, Chair, Codex Committee on Residues of Veterinary Drugs in Foods (CCRVDF),
Office of New Animal Drug Evaluation, Center for Veterinary Medicine, Food and Drug
Administration, Department of Health and Human Services, Rockville, Maryland, USA
(CCRVDF)
Dr P. Verger, Risk Assessment and Management, Department of Food Safety and Zoonoses,
World Health Organization, Geneva, Switzerland (WHO Joint Secretary)
Ms Yong Zhen Yang,1 Food and Agriculture Organization of the United Nations, Rome,
Italy (FAO JMPR Secretariat)
Dr T. Zhou, Office of New Animal Drug Evaluation, Center for Veterinary Medicine, Food
and Drug Administration, Department of Health and Human Services, Rockville,
Maryland, USA (WHO Expert)

Attended session on dietary exposure assessment only.

1

vii
 List of abbreviations
95/95 UTL 95/95 upper tolerance limit; upper limit of the one-sided 95%
confidence interval over the 95th percentile of residue concentrations
ADI acceptable daily intake
ARfD acute reference dose
AUC area under the concentrationtime curve
AUC(072) area under the concentrationtime curve from 0 to 72 hours
BMD benchmark dose
BMD10 benchmark dose for a 10% response over the controls
BMDL lower 95% confidence limit on the benchmark dose
BMDL10 lower 95% confidence limit on the benchmark dose for a 10%
response over the controls
BMR benchmark response
bw body weight
CAS Chemical Abstracts Service
CCPR Codex Committee on Pesticide Residues
CCRVDF Codex Committee on Residues of Veterinary Drugs in Foods
CI confidence interval
CIFOCOss Chronic Individual Food Consumption Database Summary statistics
CL clearance
Cmax maximum concentration
CPU 4-chlorophenylurea
EDI estimated daily intake
EHC Environmental Health Criteria monograph
eq equivalent
EU European Union
F0 parental generation
F1 first filial generation
F2 second filial generation
FAO Food and Agriculture Organization of the United Nations
GABA gamma-aminobutyric acid
GDWQ Guidelines for Drinking-water Quality (WHO)
GEADE global estimate of acute dietary exposure
GECDE global estimate of chronic dietary exposure
GL36 Guideline 36 (VICH)
GLP good laboratory practice
GVP good practice in the use of veterinary drugs
H2B1a 22,23-dihydroavermectin B1a; ivermectin B1a
H2B1b 22,23-dihydroavermectin B1b; ivermectin B1b
HPLC high-performance liquid chromatography

viii
HPT hypothalamicpituitarythyroid
INN International Non-proprietary Name
IUPAC International Union of Pure and Applied Chemistry
JECFA Joint FAO/WHO Expert Committee on Food Additives
JMPR Joint FAO/WHO Meeting on Pesticide Residues
LC50 median lethal concentration
LC-MS liquid chromatography with mass spectrometry
LC-MS/MS liquid chromatography with tandem mass spectrometry
LD50 median lethal dose
LOAEL lowest-observed-adverse-effect level
LOD limit of detection
LOQ limit of quantification
MIC minimum inhibitory concentration
MIC50 minimum concentration required to inhibit the growth of 50% of
organisms
MRL maximum residue limit
MRT mean residence time
MR:TR marker residue to total residue ratio
MR:TRR marker residue to total radioactive residue ratio
NOAEL no-observed-adverse-effect level
NOEL no-observed-effect level
OECD Organisation for Economic Co-operation and Development
PCA 4-chloroaniline; p-chloroaniline
ppb parts per billion
QuEChERS Quick, Easy, Cheap, Effective, Rugged and Safe
rbSTs recombinant bovine somatotropins
SD standard deviation
t half-life
T3 triiodothyronine
T4 thyroxine
Tmax time to reach the maximum concentration (Cmax)
TMDI theoretical maximum daily intake
TRR total radioactive residue
TRS Technical Report Series
TSH thyroid stimulating hormone
U uniformly labelled
UGT uridine diphosphate-glucuronosyltransferase
USA United States of America
UTL upper tolerance limit
UV ultraviolet

ix
 VICH International Cooperation on Harmonisation of Technical
Requirements for Registration of Veterinary Medicinal Products
v/v volume per volume
WHO World Health Organization
WHOPES WHO Pesticide Evaluation Scheme
WP withdrawal period
w/v weight per volume

x
Monographs containing summaries of relevant data and toxicological evaluations are
available from WHO under the title:

Toxicological evaluation of certain veterinary drug residues in food. WHO Food Additives
Series, No. 72, 2016.

Residue monographs are issued separately by FAO under the title:

Residue evaluation of certain veterinary drugs. FAO JECFA Monographs 18, 2016.

Use of JECFA reports and evaluations by registration authorities

Most of the evaluations and summaries contained in this publication are based on
unpublished proprietary data submitted to JECFA for use when making its assess-
ment. A registration authority should not consider granting a registration based on
an evaluation published herein unless it has first received authorization for such use
from the owner of the data or any second party that has received permission from the
owner for using the data.

xi
1. Introduction
The Joint FAO/WHO Expert Committee on Food Additives (JECFA) met in Rome
from 17 to 26 November 2015. The meeting was opened by Mr Ren Wang, Assistant
Director-General of the Agriculture and Consumer Protection Department of the
Food and Agriculture Organization of the United Nations (FAO), on behalf of the
directors-general of FAO and the World Health Organization (WHO). Mr Wang
noted that the Thirty-eighth Session of the Codex Alimentarius Commission has
reconfirmed the fundamental role of JECFA in providing independent scientific
advice on which Codex can base its deliberations. Furthermore, given the
importance of the joint FAO/WHO activities on scientific advice related to food
safety, both FAO and WHO have confirmed their continuing commitment and
work in this area and are actively involved in discussions with Codex that will
provide sustainable resources for the work of JECFA.
Mr Wang explained that the scientific advice that JECFA provides is a
cornerstone in the process of providing guidance on food safety and ultimately
ensures that food safety and quality measures and standards are based on sound
scientific principles and ensure the protection of the health of consumers.
Therefore, JECFAs work remains a high priority for both FAO and WHO.
Mr Wang reminded the Committee that participants have been invited
to this meeting in their individual capacities as international experts and not as
representatives of their organizations. He also reminded the Committee of the
confidential nature of the meeting and stressed that the meeting report, which will
need to be approved by the end of the meeting, will remain a restricted document
until its publication is authorized by both FAO and WHO. Finally, Mr Wang
expressed his sincere gratitude to participants for placing their valuable time
and, most importantly, their expertise at the disposal of the two organizations
and for the work that participants have already done in preparing to address the
challenging agenda of the meeting.
Twenty meetings of the Committee had been held to consider veterinary
drug residues in food (Annex 1, references 80, 85, 91, 97, 104, 110, 113, 119,
125, 128, 134, 140, 146, 157, 163, 169, 181, 193, 208 and 217) in response to
the recommendations of a Joint FAO/WHO Expert Consultation held in 1984
(1). The present meeting2 was convened to provide guidance to FAO and WHO
Member States and to the Codex Alimentarius Commission on public health
issues pertaining to residues of veterinary drugs in foods of animal origin. The
specific tasks before the Committee were:

As a result of the recommendations of the first Joint FAO/WHO Conference on Food Additives held in
2

1955 (FAO Nutrition Meeting Report Series, No. 11, 1956; WHO Technical Report Series, No. 107, 1956),
there have been eighty previous meetings of JECFA (Annex 1).
1
 Joint FAO/WHO Expert Committee on Food Additives Eighty-first report

to elaborate further on principles for evaluating the safety of residues

of veterinary drugs in food, for establishing acceptable daily intakes
(ADIs) and acute reference doses (ARfDs) and for recommending
maximum residue limits (MRLs) for such residues when the drugs
under consideration are administered to food-producing animals in
accordance with good practice in the use of veterinary drugs (GVP)
(see section 2);
to evaluate the safety of residues of certain veterinary drugs (see
section 4 and Annex 2); and
to respond to specific concerns raised by the Codex Committee on
Residues of Veterinary Drugs in Foods (CCRVDF) (see sections 3
and 4 and Annex 2).

1.1 Declarations of interests

The Secretariat informed the Committee that all experts participating in the
eighty-first meeting had completed declaration of interest forms. Professor Alan
Boobis, Dr Kevin Greenlees and Dr Tong Zhou declared interests. As these
interests were not related to topics on the agenda, they were not considered to be
a conflict.

1.2 Modification of the agenda

The agenda (see Annex 3) was modified to exclude ethoxyquin, as no data were
submitted by the sponsor.
WHO Technical Report Series No. 997, 2016

2
2. General considerations

2.1 Matters of interest arising from previous sessions of the Codex

Committee on Residues of Veterinary Drugs in Foods (CCRVDF)
The Codex Secretariat informed the Committee about relevant decisions of the
Codex Alimentarius Commission and the principal outcomes and discussions
of the Twenty-second Session of CCRVDF (2), which was held after the seventy-
eighth meeting of the Committee in 2013 (Annex 1, reference 217).
The Twenty-second Session of CCRVDF finalized work on the MRLs
for derquantel, emamectin benzoate and monepantel that were recommended
by the seventy-eighth meeting of the Committee; these MRLs were subsequently
adopted by the Codex Alimentarius Commission at its Thirty-eighth Session
(3). The Twenty-second Session of CCRVDF agreed to hold the MRLs for (1)
ivermectin, because the recommended MRLs did not reflect approved GVP and
in view of the request for re-evaluation that was put forward; and (2) lasalocid
sodium, for which concern forms were submitted on the approach used to
estimate short-term exposure of consumers and the possibility that the MRLs
might expose consumers to residues higher than the ADI. The Committee noted
that CCRVDF will consider the MRLs for lasalocid sodium at its next session (in
October 2016) based on the Committees recommendations. With regard to the
MRL for lasalocid sodium in egg, CCRVDF established an electronic working
group to prepare a discussion paper addressing the unintended presence of
residues of veterinary drugs in food commodities resulting from carry-over of
veterinary drugs into feed and to consider the establishment of MRLs at its next
session as guided by the agreed policy.
The Twenty-second Session of CCRVDF finalized work on risk
management recommendations for dimetridazole, ipronidazole, metronidazole
and ronidazole, which were subsequently adopted by the Codex Alimentarius
Commission at its Thirty-eighth Session. On the basis of the outcome of the
evaluation of the seventy-eighth meeting of the Committee, CCRVDF had also
formulated a risk management recommendation for gentian violet, which will be
considered by the next session of CCRVDF.
The Codex Secretariat informed the Committee that the Twenty-second
Session of CCRVDF had considered the outcome of the discussion by the seventy-
eighth meeting of the Committee on the issue of MRLs in honey, including the
key issues to be considered for recommending MRLs in honey. CCRVDF agreed
to leave unaltered the current text of Risk analysis principles applied by the Codex
Committee on Residues of Veterinary Drugs in Foods (4), noting that CCRVDF

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can make requests to JECFA for MRLs for honey (and other commodities) using
alternative approaches.
With regard to recombinant bovine somatotropins (rbSTs), the Twenty-
second Session of CCRVDF considered the outcome of the JECFA re-evaluation,
taking note of the report of the seventy-eighth meeting of the Committee.
Although CCRVDF agreed that the Committee had addressed all of the questions
posed to it by the Codex Alimentarius Commission, there were differing opinions
regarding the Committees replies. The Committee was informed that the Thirty-
eighth Session of the Codex Alimentarius Commission recognized the validity
of JECFAs risk assessments as the sound scientific basis for its deliberations on
rbSTs. However, consensus was not reached on the adoption of the draft MRLs
for rbSTs, and the Codex Alimentarius Commission agreed to hold the draft
MRLs at Step 8 to provide further time to facilitate a consensus.
The Twenty-second Session of CCRVDF agreed on a priority list of
veterinary drugs for evaluation (or re-evaluation) by JECFA and noted the
importance of the commitment to submit the necessary data within the indicated
time frame to ensure an efficient planning process for JECFA work.
The Twenty-second Session of CCRVDF requested the Committee to
provide advice on the establishment of generic MRLs for fish species.

2.2 MRLs for generic fish species

The following two questions were forwarded to the eighty-first meeting of JECFA
by the Twenty-second Session of CCRVDF (2).

While recognising the ongoing activities of VICH [International Cooperation

on Harmonisation of Technical Requirements for Registration of Veterinary
Medicinal Products] in this area, the Committee agreed to forward the following
requests to JECFA:
WHO Technical Report Series No. 997, 2016

1. To provide an assessment on whether on the basis of data from one or more

fish species, it is possible to establish an MRL for finfish, crustaceans or molluscs
in general, or for multiple similar groups.

Response from JECFA: In 2012, the following question was posed to the seventy-
eighth meeting of JECFA (Annex 1, reference 217) by the Twentieth Session of
CCRVDF (5):

Possibility of extending extrapolation by JECFA similar to that allowed under the current
EU [European Union] guidelines. EHC [Environmental Health Criteria] 240 does not
allow for the extrapolation of MRLs from muscle of Salmonidae to other finfish, but this

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 General considerations

is allowable based on European Union guidelines. JECFA should consider extrapolation

of MRLs between fish species. If the data required to support such MRL extrapolation is
not available, what further work may be required?

The seventy-eighth meeting of JECFA responded:

JECFA must first receive information to confirm that there is an existing approval in
a member state for use of the drug in the species of fish for which extrapolation of
MRLs is requested, including a label or a statement of the approved conditions of use
(GVP). The conditions of approved use (GVP) may differ depending on species of fish
and region. However, the water temperature at which a product is used for treatment of
fish and at which residue studies have been conducted are major considerations in the
recommendation of MRLs for fish. This may result in different MRLs being recommended
for different species, based on the GVP established for the use of the drug in one or more
fish species in a member state or member states.

These concerns remain and are key factors in the JECFA evaluation of any
substance for which data are provided for evaluation.
As of the seventy-eighth meeting of JECFA, only 10 substances had
been evaluated by JECFA for the establishment of MRLs for finfish, and three
of these substances were also evaluated for use in the treatment of crustaceans
(shrimp). In most of these evaluations, the residue information reviewed by
JECFA was primarily from the peer-reviewed scientific literature and reports
from government laboratories and agencies.
No MRLs were recommended for four of these 10 substances
(chloramphenicol, Annex 1, reference 110; gentian violet, Annex 1, reference 217;
malachite green, Annex 1, reference 193; and oxolinic acid, Annex 1, reference
113) because an ADI could not be established by JECFA. Of the five substances
for which JECFA has made recommendations of MRLs for finfish, two have
been for fish and three for salmon and/or trout, based on the information
provided. For the substances for which recommendations have been for fish,
data have been provided for three or more diverse species of finfish.
Three substances have been evaluated by JECFA for use in the production
of crustaceans; in all three cases, residue data provided were only for Giant prawn,
also known as Black tiger shrimp (Penaeus monodon).
JECFA has not been requested by CCRVDF to recommend MRLs for
any veterinary drug in any species of mollusc to date and also has not received
any data regarding such use. Any comment on the feasibility of extrapolation of
MRLs for mollusc species would therefore be speculative.
In conclusion, in order to properly address the issue of extrapolation of
MRLs to fish species, JECFA requires, in addition to the information identified
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by the seventy-eighth JECFA, further information on adequate groupings of fish

species so that representative species can be identified from which MRLs may be
extrapolated to other similar species. The Committee notes that several principles
for grouping of fish species may be applied for example, based on criteria such
as a common aquaculture environment (salinity and temperature), phylogeny or
common physiology (high lipid or low lipid) and common behaviour (demersal
or not, type of diets). In any case, it would be necessary to develop clear boundaries
around each group and define the inclusion and exclusion criteria for each group.
JECFA is aware of work on this issue being conducted by VICH and will review
the applicability of the guidance that results from that activity.

2. For emamectin benzoate, to provide an assessment as to whether there are any

identified toxicological, dietary exposure modelling, or analytical methodology
issues preventing extrapolation of the proposed MRLs to a general finfish MRLs
or a more appropriate sub-grouping.

Response from JECFA: Although JECFA is not aware of any toxicological issues
that would prevent extrapolation of MRLs to additional species of fish, the
Committee has also noted, in response to a previous question on this issue from
the Twenty-first Session of CCRVDF (6), that, in the absence of information, it
is difficult to assure that there are no novel unknown metabolites of potential
toxicological concern in tissues of the species for which no data have been
available for evaluation.
The exposure modelling for emamectin benzoate was done by JECFA
using data from depletion studies in Atlantic salmon. Median residues used in the
exposure assessment could differ in other fish species, depending on the depletion
profile, leading to higher or lower estimates of exposure. No information has
been provided to JECFA to conduct such an assessment.
A primary issue in the consideration of the extension or extrapolation
WHO Technical Report Series No. 997, 2016

of the MRLs for emamectin benzoate residues in salmon and trout to additional
species of fish is that the product containing emamectin benzoate intended for
use in aquaculture for which information was provided to JECFA is intended
only for treatment of sea lice in salmonids inhabiting cold water. Information is
therefore required to demonstrate additional approved uses, and residue data are
required to demonstrate the depletion profile in species other than salmonids;
a suitably validated analytical method for any additional non-salmonid species
would also be necessary.
In conclusion, in order to consider a request to extrapolate the MRLs
recommended for salmon and trout to additional fish species, JECFA would require
information on such approved uses, data to demonstrate pharmacokinetic and
depletion behaviour of emamectin in a non-salmonid species and information to
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 General considerations

demonstrate that the method validated for the analysis of the high lipid content
tissue of salmon and trout is applicable to non-salmonid species, preferably a
species with low lipid content.

2.3 Acute reference dose (ARfD) for veterinary drugs

Following a recommendation of the Committee at its seventy-fifth meeting
(Annex 1, reference 208), a working group to elaborate guidance on the
establishment of ARfDs for veterinary drugs was formed. The working group
developed a discussion paper, and key principles from this paper were discussed
at the current meeting. The Committee agreed on the following principles, which
will allow the working group to develop guidance on when and how to establish
ARfDs for veterinary drugs:
The main driver for the need to consider establishing an ARfD is the
toxicological profile of the compound. For a veterinary drug, high
exposure can also be a consideration.
There are currently insufficient data to determine a generic
toxicological cut-off value for acute effects based on exposure
considerations; hence, the decision on whether to establish an ARfD
is taken after consideration, case by case, of different (realistic)
acute exposure scenarios, thereby allowing practical exposure
considerations. As experience is gained, it may be possible to establish
such a cut-off value, as has been done for pesticides.
An appropriate acute dietary exposure assessment method needs to
be used. The principles for a suitable method were described in EHC
240 (7), and details of the method were proposed in the report of
the FAO/WHO workshop on dietary exposure to veterinary drugs
(global estimate of acute dietary exposure, or GEADE) (8).
The Committee clarified that the theoretical maximum daily intake
(TMDI) calculation is a tool used as a proxy in dietary exposure
assessment, in which a standard amount of food is combined with
a selected highest residue level. The standard amounts of food used
in the TMDI can be lower than the 97.5th percentile, as stated in
EHC 240. Therefore, the TMDI is not appropriate for acute dietary
exposure assessment.
For establishing an ARfD for veterinary drugs, basic concepts as
established for pesticide residues can be used. The key differences
between veterinary drugs and pesticides relate to microbiological
effects and to specific exposure scenarios. Regarding pharmacological
effects i.e. interaction with molecular targets (e.g. receptors) it was
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noted that this is not unique to veterinary drugs and that such effects
do not automatically raise an acute health concern. Such effects need
to be considered for acute and chronic health effects, in the same way
as for toxic effects. In practice, this may lead to the same numeric
value for the ADI and ARfD.
Misuse (e.g. off-label use) of compounds is not within the scope of
these considerations, just as they are not for chronic risk assessments.
Regarding considerations for a microbiological ARfD, the Committee
recognized that an acute exposure of the gut microbiota is different
from the chronic daily exposure that JECFA evaluates to establish
the microbiological ADI and that the most relevant microbiological
end-point for acute exposure would most likely be disruption of the
colonization barrier.
It was noted that in extrapolating in vitro minimum concentration
required to inhibit the growth of 50% of organisms (MIC50) values
(and other microbiological data) to an effect dose in vivo, the
factors to be considered differ from those used in establishing
a microbiological ADI from such data. This could result in the
incorporation of a different value for the correction factor used
in the formula to calculate the microbiological ADI. The specific
factor to be used would be compound specific, and guidance needs
to be developed on the type of information necessary to enable the
Committee to estimate such a factor. Consideration will also need
to be given as to what would be an appropriate default factor in the
absence of compound-specific information.
When discussing the implications for MRL recommendations, the
Committee suggested to continue with MRL derivations that are
compatible with chronic exposure (i.e. the ADI) and the respective
withdrawal times. If an ARfD is established for the compound as
WHO Technical Report Series No. 997, 2016

well, an acute exposure assessment will then be performed based

on tissue concentrations at the estimated withdrawal times, and the
consequences will be described in detail. If the ARfD is exceeded, this
will be reported, and possible refinements of the assessment will be
described, including options such as the selection of a later time point
for the recommendation of MRLs.
The working group will continue its work on a draft guidance, which
will be made available for public comments before further discussion at the next
JECFA meeting dealing with veterinary drug residues in food.
The Committee recommended that a subgroup be established to review
available information on acute exposure to residues of veterinary drugs and

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 General considerations

to identify an upper-bound exposure value with sufficient confidence that will

enable, if possible, the derivation of a cut-off value for acute toxicity.

2.4 Chronic dietary exposure assessment

During its previous meetings, JECFA agreed to develop an approach to assess
more accurately the chronic dietary exposure to veterinary drug residues (global
estimate of chronic dietary exposure, or GECDE). At the present meeting, the
Committee decided to continue using this approach in parallel with the estimated
daily intake (EDI) model in order to gain experience and to continue improving
the methodology. Moreover, the Committee identified two additional important
issues concerned with the methodologies applied by JECFA and the Joint FAO/
WHO Meeting on Pesticide Residues (JMPR) to estimate chronic dietary
exposures that merit general consideration.

2.4.1 Approach for dietary exposure assessment of compounds used for

multiple purposes (i.e. veterinary drugs and pesticides)
As a consequence of its consideration of two veterinary drugs (teflubenzuron,
see section 4.4; and diflubenzuron, see section 4.1) at the present meeting, the
Committee identified the issue of how to estimate chronic dietary exposure
to residues of substances used as both veterinary drugs and pesticides. The
Committee noted that it has been common practice to assess the chronic exposure
of pesticide and veterinary drug residues using different approaches that have
been developed after consideration of the types of substances of interest, duration
of exposure, exposure in different subgroups and the type of estimate needed,
based on the information available. However, the Committee expressed the view
that it may be necessary to estimate the total chronic exposure from both sources.
The Committee noted a number of compounds that have been evaluated
by JECFA as well as by JMPR: abamectin, cypermethrin and alpha-cypermethrin,
cyfluthrin, cyhalothrin, deltamethrin, diflubenzuron, emamectin benzoate,
thiabendazole and teflubenzuron.
The Committee identified some possible approaches to estimating the
total chronic exposure to residues from these compounds. The easiest approach
would be to sum up the chronic exposure estimates derived by the two expert
committees to arrive at an estimate of total chronic exposure. Alternatively, the
JMPR or JECFA methodologies could be extended to estimate chronic exposure
from all sources. Finally, the most comprehensive approach would be to develop
a specific chronic exposure model that would fit both JMPR and JECFA risk
assessment purposes.
The Committee noted that simply combining chronic exposure
estimates or hybridizing methodologies would mix estimates underpinned by

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different assumptions about chronic consumption, one using average per capita
consumption (JMPR) and the other using model diets that aim to cover high-
percentile consumption in any population group (JECFA). The Committee was
of the opinion that such an approach may be used in the interim, but might not
be rigorous enough in the longer term.
The Committee saw merit in developing a comprehensive solution to
the challenge of chronic exposure assessment of residues of substances used as
veterinary drugs and pesticides by developing a new methodology for estimating
exposure that would suit JMPR and JECFA risk assessment purposes. However,
the Committee noted that it would take some time to develop, implement and
validate such a method.
In conclusion, the development of chronic dietary exposure assessment
methods that take into account combined chronic exposure from pesticide and
veterinary drug residues should be investigated. These methods should be robust
and fit both JMPR and JECFA risk assessment purposes.

2.4.2 Dietary exposure assessment for less-than-lifetime exposure

Based on the consideration raised by JMPR, the Committee noted that the
current long-term chronic dietary risk assessment of pesticides is based on
multi-annual consumption data averaged over the whole population to capture
the per capita dietary pattern over a lifetime. However, no-observed-adverse-
effect levels (NOAELs) for pesticides derived from animal studies with exposure
ranging from 4 weeks to 104 weeks are often similar. This suggests that over wide
exposure duration ranges, adverse effects generally are not related to duration of
exposure. JMPR considered that in consequence, short-term (weeks to months)
or consumer-only exposures may not be adequately described to determine
whether an ADI is exceeded in these situations and whether this would result in
health concerns. The present Committee noted that its chronic dietary exposure
model (GECDE) is addressing the exposure of consumers over times shorter
WHO Technical Report Series No. 997, 2016

than a lifetime.
However, the Committee noted that there are examples of veterinary
drugs where the duration of exposure was an important consideration in the
toxicological evaluation (e.g. sisapronil, this meeting; see section 4.3). The
frequency with which the toxicity of veterinary drugs progresses after exposures
of 4 weeks is unknown and should be evaluated. Based on the outcome of this
exercise, it may be necessary to align the choice of the dietary exposure model
with duration of exposure at which the adverse effects occur.

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2.4.3 Recommendations
The Committee recommends that the FAO and WHO Secretariats convene an
expert meeting on two important issues concerned with the methodologies
applied by JECFA and JMPR to estimate chronic dietary exposures.

In regards to dietary exposure assessment of compounds used for multiple purposes

(i.e. veterinary drugs and pesticides):
1. Develop chronic dietary exposure assessment methods that take
into account combined exposure from pesticide and veterinary drug
residues.
2. Investigate the applicability of these methods using compounds that
have been evaluated as both pesticides and veterinary drugs.

In regards to dietary exposure assessment for less-than-lifetime exposure:

1. Investigate the effects of duration of exposure in toxicity studies
on veterinary drugs on toxicological end-points and the points of
departure (e.g. NOAELs).
2. Based on the outcome of #1, identify those toxicological situations
requiring less-than-lifetime exposure assessment.

In regards to dietary exposure assessment

1. Apply the methodologies developed above to some key examples
of veterinary drugs and pesticides that are unlikely to accumulate
(including compounds that have been evaluated as both pesticides
and veterinary drugs) and report the outcome to JECFA and JMPR.

2.5 Update and revision of Principles and methods for the risk
assessment of chemicals in food (EHC 240)
The Committee discussed ways in which exposure from the dual use of a substance
as both a pesticide and a veterinary drug might be assessed. It was recommended
that a joint JECFA (veterinary drug residues)/JMPR multidisciplinary working
group be established to develop suitable methodology (see section 2.4.1). In
addition, this group should consider the recommendations of the 2015 JMPR (9)
regarding shorter-than-lifetime exposure (see section 2.4.2). Depending on the
outcome of this exercise, the relevant section(s) of EHC 240 should be updated.

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The Committee was updated on and discussed the key issues in the
development of guidance for the establishment of ARfDs for residues of
veterinary drugs. This poses some unique challenges, such as the possibility of
acute antimicrobial effects. The working group developing this guidance will
complete its draft guidance and submit it for public comment before placing it on
the agenda for the next JECFA (veterinary drug residues) meeting (see section
2.3). Once finalized, this will necessitate suitable addition to EHC 240.
The Committee discussed whether processing data should be sought for
all residues of veterinary drugs. It was agreed that this would not be practical, but
that the issue should be dealt with on a case-by-case basis, where there was some
reason for possible concern (see section 2.8). Some minor amendment of EHC
240 might be necessary to reflect this.
The Committee agreed to adopt the practice of JMPR to consider
identifying an overall NOAEL for studies in dogs of 90 days and 12 months
duration (see section 2.10). EHC 240 should be updated to reflect this procedure,
now in use by both JMPR and JECFA (veterinary drug residues).

2.6 Guidance for the evaluation of veterinary drug residues in

food by JECFA
The Committee was provided with drafts of the revised guidance documents
for JECFA monographers and reviewers evaluating residues of veterinary drugs.
While these guidance documents are intended primarily for JECFA Experts
who prepare residue and toxicological monographs for JECFA and for Members
(reviewers) who have been assigned to peer review them and propose evaluations,
they will also be useful to manufacturers who submit dossiers to JECFA and
other parties interested in understanding the process followed in the evaluation
of residues of veterinary drugs in food by JECFA.
The Committee was asked to provide written comments to the respective
WHO Technical Report Series No. 997, 2016

Secretariat by the end of 2015 so that the documents can be finalized early in
2016.

2.7 Update on FAO and WHO databases related to the work of the
Committee
The current FAO JECFA databases (one for food additives, one for flavouring
agents and one for residues of veterinary drugs) were developed in early 2000 and
are based on outdated underlying software. The FAO Secretariat has therefore
started a project to modernize the three databases.
Although the major features and output will not differ significantly from
the current version, the project aims to develop an online platform that allows

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the Secretariat to manage the process from adding records to or updating records
in the database to publishing the adopted JECFA evaluations. The new databases
will also allow for improved interconnectivity with other databases, such as the
Codex database of adopted MRLs of residues of veterinary drugs and the WHO
summaries of JECFA evaluations.
The new databases are currently being finalized and should be operational
in the next months.
To improve the data used for dietary exposure assessment, FAO and
WHO continue to collect and compile national individual food consumption
data. Summary statistics from (currently) 37 surveys (only those with a duration
of 2 days or more) from 26 countries are published in the FAO/WHO Chronic
Individual Food Consumption Database Summary statistics (CIFOCOss).

2.8 Processing of food containing residues of veterinary drugs

During the evaluation of diflubenzuron by the present Committee (see section
4.1), the issue of its thermal degradation to 4-chloroaniline (p-chloroaniline or PCA),
a metabolite of substantial toxicological concern, was discussed. As this reaction can
occur at temperatures readily achieved during home cooking (>100 C), this had to
be taken into account in the risk assessment of the residues of diflubenzuron.
In the evaluation of residues of pesticides by JMPR, the effect of processing,
including cooking in the home, on the amount and nature of the residues
ingested by consumers is routinely considered. The present Committee therefore
considered whether this should also be undertaken routinely in its assessment of
residues of veterinary drugs.
The Committee noted that whereas for many pesticides, residue levels may
be reduced or eliminated prior to cooking (e.g. residues in skin would be removed
by peeling), this would rarely, if ever, be the situation for residues of veterinary
drugs. In addition, the variation in cooking conditions and temperatures of food
containing residues of veterinary drugs is appreciably greater than that for food
containing pesticide residues, as would be the impact on the bioavailability of
non-extractable residues. Also, more foods containing pesticide residues are
eaten raw (without cooking) than are foods containing residues of veterinary
drugs. These factors would make the task of routinely assessing the effects of
processing of foods on residues of veterinary drugs much more complex and
onerous than when assessing pesticide residues. Reflecting this, such information
is not routinely requested by regulatory authorities (e.g. European Medicines
Agency, United States Food and Drug Administration) involved in the assessment
of veterinary drugs for use in food-producing animals.
The Committee therefore concluded that it would not routinely assess,
or seek to address, the effects of processing foods on residues of veterinary drugs.

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However, if there is evidence, or some other reason to suspect, that processing of

foods containing residues of specific veterinary drugs could have toxicological
implications, such as for diflubenzuron, the effect of processing should be taken
into consideration in the assessment of that compound.

2.9 Reporting of original data in JECFA monographs

JECFA publishes its assessments of residues of veterinary drugs in food in the
form of monographs (toxicological evaluations in the WHO Food Additives
Series and residue evaluations in FAO JECFA Monographs) and summaries in the
form of reports in the WHO Technical Report Series. Although the Committee
seeks to be as transparent as possible in these publications, JECFA, like other
organizations involved in the evaluation of veterinary drugs, is sometimes
constrained, by requirements for confidentiality, in the information that it can
make available publicly. However, subject to this restriction, in reporting its
findings, the Committee will seek to publish such information as necessary to
enable the basis of its conclusions to be clearly understood and independently
verified.

2.10 Assessment of short-term (90-day and 12-month) studies in

dogs
Following analysis of a number of databases comprising information from several
hundred compounds, including many pesticides, many authorities (including
the United States Environmental Protection Agency, European Commission
and JMPR) concluded that the nature and potency of effects observed after oral
administration to dogs for 90 days rarely showed any change after a further 9
months of administration; in other words, the effects and the NOAELs at 12
months were the same as at 90 days. As a consequence, it was recommended that
there was need for only a 90-day study in dogs, and this has since been reflected
WHO Technical Report Series No. 997, 2016

in the Organisation for Economic Co-operation and Development (OECD) test

guideline for short-term studies in dogs.
JMPR noted that in light of this, it would be possible to consider most
90-day and 12-month studies in dogs to be short-term repeated-dose studies
providing the same information. Hence, following the same considerations as for
two studies of the same duration (see JECFA guidance (10)), it would be possible
to identify an overall NOAEL (and lowest-observed-adverse-effect level, or
LOAEL) for the studies. It was agreed that JECFA would adopt the same practice
and that the guidance should be amended accordingly.

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2.11 Coordination of the agendas of JECFA and JMPR

JMPR evaluates residues of pesticides in food, whereas JECFA (veterinary drug
residues) evaluates residues of veterinary drugs in food. In general, although there
are many assessment principles in common and these are being harmonized to
the extent possible the groups tend to operate largely independently.
There are some substances that are used both as pesticides and as
veterinary drugs for example, teflubenzuron at the present meeting (see section
4.4). Because of differences in their residue profiles and exposures when used,
respectively, as a pesticide and a veterinary drug, both JMPR and JECFA will
be asked to assess such compounds for both their toxicology and their residues.
In general, different experts are involved in the assessment of the compounds
by JECFA and JMPR, and hence it is quite possible that there will be some
differences in the interpretation of data and the conclusions reached. It is also
possible that there are different sponsors for the substance when used as a
pesticide and when used as a veterinary drug, which could lead to differences
in the data made available to the respective experts. Indeed, this might even
happen when the sponsor is the same, but different departments are responsible
for pesticide and veterinary use. In the event that this leads to different outcomes
or recommendations for example, the ADI established this would lead to
confusion among those relying on such assessments.
Hence, the present Committee strongly recommends that where dual-use
substances are to be evaluated by both JMPR and JECFA, the Codex Committee
on Pesticide Residues (CCPR) and CCRVDF coordinate the prioritization of
such substances for evaluation by the respective experts. The Committee also
recommends that the Joint Secretariats of JMPR and JECFA ensure that there is
suitable interaction between experts in the evaluation of such compounds.

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3. Response to concern forms from CCRVDF

3.1 Lasalocid sodium

Background
The seventy-eighth meeting of JECFA (Annex 1, reference 217) evaluated lasalocid
sodium and established a microbiological ADI with an upper bound of 8.4 g/
kg body weight (bw) or 504 g/person, applying the standard approach of VICH
Guideline 36 (GL36), for chronic exposure to lasalocid residues. The toxicological
ADI, with an upper bound of 5 g/kg bw or 300 g/person, based on effects
observed in developmental and reproductive toxicity studies in experimental
animals, was lower than the microbiological ADI and thus was considered to
be more relevant in the assessment of lasalocid sodium. The seventy-eighth
Committee recommended MRLs that are compatible with this ADI, using the
EDI approach for chronic exposure assessment. At the Twenty-second Session of
CCRVDF (2), the Delegation of the EU expressed concern regarding a potential
for acute health risk from intake of lasalocid residues and submitted a concern
form. No new data were provided with the concern form.

Concern from EU
The EU concern read as follows:

In the case of lasalocid sodium, JECFA identified a hazard that may occur following short
term exposure to residues: a disruption of the colonisation barrier. The level of consumer
exposure that JECFA considered not leading to a disruption of the colonisation [barrier]
was expressed as a microbiological ADI (8.4 g/kg bw or 504 g/person). Because this
hazard may occur following a short term residue exposure, there must be assurance
that even occasional, high residue intake will not exceed the microbiological ADI. The
EDI cannot provide this assurance. JECFA is developing a complementary approach
for addressing short term exposure scenarios based on high residue intake. However,
this work has not yet been finalised. Therefore JECFA was unable to assess this kind of
exposure. If the TMDI approach is used for this purpose which is the approach that
JECFA has used in other cases where short term exposure may lead to a consumer safety
concern the proposed draft Codex MRLs for poultry tissues would be estimated to
lead to a consumer exposure of 882.11 g/person, which represents 175% of the JECFA
microbiological ADI thus representing a risk to consumer health.

Response from JECFA: The EU has raised a concern with respect to short-
term exposure, interpreted by the present Committee to mean acute exposure,
to lasalocid residues and the potential disruption of the colonization barrier

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in the gastrointestinal tract. In the concern raised, it is assumed that the upper
bound of the microbiological ADI is the appropriate reference point for acute
microbiological effects. The conclusion is provided that the estimated exposure,
using the TMDI approach as a proxy for acute exposure, would lead to an
exceedance of the microbiological ADI and therefore represents a health concern.
The Committee recognizes that when antimicrobials are used at high
doses in humans, this might acutely affect the intestinal microbiota. However,
the Committee concludes that the upper-bound microbiological ADI of 8.4 g/
kg bw or 504 g/person for lasalocid sodium established at the seventy-eighth
meeting of JECFA is protective of the health of the consumer and that significant
disruption of the colonization barrier would not occur even at acute exposure
levels.
The microbiological ADI established by the seventy-eighth meeting
of JECFA was derived in part from MIC50 data on relevant human intestinal
microbiota. The Committee does not consider that the microbiological ADI
derived from such data represents an appropriate health-based guidance value
with which to assess the risks of effects on the intestinal microbiota from acute
exposure to residues of lasalocid. The reasons for this are outlined below.
There are differences in exposure of the intestinal microbiota in the colon
following acute and chronic oral doses of the veterinary drug residue in food.
The concentration of a lasalocid residue following a single dose would
initially enter the oesophageal/gastrointestinal tract as a one-time bolus in a
meal and then be subjected to dilution, binding and gastric emptying processes
while traversing the intestinal tract to the colon, which has not previously been
exposed to lasalocid. In contrast, chronic daily ingestion of the same amount of
lasalocid residue each day for a lifetime, as assumed in the microbiological ADI
calculation, would result in drug residues continuously transiting through the
gastrointestinal tract, with the potential for lasalocid to accumulate, resulting in
an increased concentration in the colon, and impact the intestinal microbiota
WHO Technical Report Series No. 997, 2016

on a daily basis. Thus, the residue concentrations to which intestinal bacteria are
exposed following an acute dose will be lower than those occurring following
chronic ingestion at the upper-bound microbiological ADI; unlike the situation
with chronic exposure, there would be no possibility of an additive effect over
time. From the above considerations, it is reasonable to assume that the fraction of
the oral dose of lasalocid available to intestinal bacteria would be lower following
acute exposure than following chronic daily exposure to the same amount of
drug residue each day for a lifetime.
It is important to note that an observed minimum inhibitory concentration
(MIC) value (i.e. bacterial growth inhibition) is an in vitro measure of effect, but
one cannot translate this directly to an acute in vivo level of bacterial exposure
to the drug in the intestinal tract. The MIC standard test methodology, while
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 Response to concern forms from CCRVDF

a well-accepted in vitro measure of bacterial susceptibility to an antibacterial

drug, does not take into account the interactions of the intact gastrointestinal
environment such as the complexity of the intestinal microbial community,
drug binding with food components or intestinal contents, metabolism by the
host and the resilience of the intestinal microbiota to a single versus repeated
exposure and thus overestimates the drug potency in vivo. Therefore, the MIC
test itself does not provide a measure of the concentration that would produce an
acute effect in vivo. The result is a conservative estimate of the microbiological
ADI when applied to chronic effects and an overly conservative estimate when
applied to acute effects on the human intestinal microbiome. It should also be
noted that the formula given in EHC 240 (also presented in VICH GL36) that is
used in the assessment of lasalocid results in a conservatively low estimate of the
upper-bound microbiological ADI, as the MIC calculation utilizes the lower 90%
confidence limit of the MIC50 of those groups of bacteria against which lasalocid
is active and does not take into account the MICs of those groups of intestinal
microbiota that are not sensitive.
Based on the data that the Committee reviewed at the seventy-eighth
meeting, faecal binding of lasalocid was greater than 90%, a value that was used in
deriving the microbiological ADI. When considering acute exposure, drug binding
may be even higher than following chronic exposure because of the greater number
of luminal binding sites available to the drug, and hence the fraction of a single
dose of lasalocid available to microorganisms might be lower under conditions of
acute exposure to the veterinary drug residues compared with chronic exposure
to those residues. It should also be noted that the use of a mass of colon content of
220 g in the formula is a conservatively low estimate, as recent data indicate that the
colon volume is, in fact, much higher than this (561 mL).
The Committee is continuing to work on the implementation of its global
approach to assessing the acute risk from ingestion of residues of veterinary drugs,
including microbiological risk, when relevant. However, it should be emphasized
that with respect to the assessment of acute dietary exposure (to be compared
with an ARfD), the methodology is already fully described in the report of the
FAO/WHO workshop on dietary exposure to veterinary drugs (8).
The Committee wishes to clarify that JECFA does not use the TMDI
approach for assessing acute dietary exposure for risk assessment and that the
TMDI is not appropriate for this purpose. The TMDI calculation is a tool used
as a proxy in dietary exposure assessment, in which a standard amount of food
is combined with a selected highest residue level. The standard amounts used
in the TMDI can be lower than the 97.5th percentile, as stated in EHC 240. The
Committee does not consider the microbiological ADI to be an appropriate
health-based guidance value for conducting an acute risk assessment. Although
the Committee has not finalized its methodology for establishing a microbiological
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ARfD, as a conservative surrogate, it used the upper-bound microbiological ADI

after taking into account some factors that will impact on this value. As discussed
above, recent data support a colon volume of 561 mL (g), rather than 220 g (mL).
In addition, whereas a value of 90% was used for faecal binding of lasalocid by
the seventy-eighth JECFA, this was a very conservative estimate, and a more
realistic estimate, based on information provided to the seventy-eighth JECFA,
would be 9599%, which might be further increased with an acute exposure.
Assuming binding of 95%, together these factors would result in an increase in
the upper-bound microbiological ADI by 5.0-fold. The extent of dilution of the
microbiologically active residues following an acute exposure and the resilience
of the gut microbiota to an acute exposure will further increase this value, but the
Committee did not have sufficient information to quantify the impact of these
factors at this time.
The Committee estimated acute exposure to lasalocid residues using the
methodology developed for this purpose (GEADE) and concluded that it would
be approximately 3.5-fold higher than the upper bound of the microbiological
ADI established by the seventy-eighth JECFA. Taking into consideration the
possible acute microbiological effect (>5-fold higher than the upper bound of
the microbiological ADI) and acute exposure to lasalocid residues (not greater
than 3.5-fold higher than the upper bound of the microbiological ADI), the
Committee concluded that there would be no concern for colonization barrier
disruption in the colon from acute exposure to residues of lasalocid.
The Committee recognizes the need to develop an approach for
establishing a microbiological ARfD, as it is possible that the acute ingestion of an
antimicrobial veterinary drug could affect the colonic microbiota, but there are a
number of important differences in how an acute exposure to microbiologically
active residues should be evaluated compared with those ingested chronically.
Consideration also needs to be given to the data that would be necessary to enable
the establishment of a microbiological ARfD. These issues are currently under
WHO Technical Report Series No. 997, 2016

discussion by the working group that is developing guidance on establishing an

ARfD for veterinary drugs (see section 2.3).

Concerns from Canada

The concerns raised by Canada were presented in RVDF/22 CRD 27, Agenda
Item 6(c), at the Twenty-second Session of CCRVDF (2), with the subsequent
submission of a concern form:

Canada would like to raise the following scientific points for further consideration by
JECFA:

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 Response to concern forms from CCRVDF

1. The MRLs proposed for this compound were calculated based on the estimated daily
intake (EDI) approach. Canada had earlier expressed the concern that there would
be limitations with using the EDI approach when residue depletion data are highly
variable. In the case for lasalocid residues in chicken tissues (see Table 7.5 of the
monograph) the standard deviations of residues in each tissue on 1-day withdrawal
period (WP) (time for which exposure estimates were evaluated) were much higher
than the mean of the residues (i.e., the coefficient of variation was > 100%). Mean
and standard deviations of lasalocid A residues at 1-day WP were respectively, 65
ppb [parts per billion] and 103 ppb in muscle, 244 ppb and 329 ppb in liver, 128 ppb
and 194 ppb in kidney, and 106 ppb and 165 ppb in skin/fat of chickens. Given the
highly variable nature of the data used to derive the MRLs, Canada considers that
this approach may not be robust enough for the establishment of lasalocid MRLs in
order to ensure safety to consumers.

Response from JECFA: The Committee has considered the concern expressed
by the Member State. In developing the EDI procedure, the sixty-sixth meeting
of the Committee (Annex 1, reference 181) concluded that the TMDI was no
longer the most suitable estimate of chronic intake, because the MRL was a single
concentration representing the estimated upper limit of a high percentile of the
distribution of marker residue present in a given tissue of the treated animals.
The sixty-sixth meeting of the Committee concluded that

it was not realistic to use an extreme value of the distribution in a scenario describing
chronic intakes. In such a scenario, all concentrations of the distribution of residues
should be considered. The median concentration represents the best point estimate of a
central tendency over a prolonged period of time, because the concentration of residues
in a given tissue consumed varies from day to day, as reflected in the distribution.
Therefore, the Committee decided to use the median of the residue distribution to
substitute for the MRL in the intake estimate.

While acknowledging that the lasalocid data are variable, the current
Committee noted that the EDI approach has been applied in other assessments
where residue data were variable. Additionally, the Committee noted that the
median is not unduly affected by outliers. Finally, the Committee noted that
variability in residue values is not uncommon in studies involving poultry or
when dosing via feed. The observed variability associated with lasalocid residue
values does not appear to be the result of a systematic bias. The current Committee
concluded that the lasalocid residue depletion data are robust, were collected in
a good laboratory practice (GLP)compliant study and can be used with the EDI
approach.

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2. JECFA monograph indicates that the residue data from 1-day WP was used to derive
the proposed MRLs. However, marker to total residue (MR:TR) ratios based on data
for 0-day WP were used instead. There is significant reduction in MR:TR between
the 0-day and 1-day WP (see Appendix below). After 1-day WP, the MR:TR remains
fairly stable. Hence, the MR:TR ratio at 0-day would likely under-estimate the total
exposure. Canada therefore considers that MR:TR based on 1-day WP of <25% for
muscle, 8.8% for liver, 14.2% for kidney and 29.2% for skin/fat (see Table 7.2 of the
monograph) should perhaps be used along with the residue depletion data in the
exposure assessment.

Response from JECFA: As noted in the monograph prepared for the seventy-
eighth JECFA (Table 7.2, footnote; Annex 1, reference 218), the withdrawal times
for the radiolabelled residue depletion study are actually 16 hours post last dose
relative to their designation (i.e. 0 withdrawal is actually 16 hours post last
dose). For the current assessment, all the withdrawal times are restated to clearly
indicate the elapsed time from the final dosing. Following this re-presentation of
the withdrawal times in the radiolabelled residue depletion study, it is clear that
the withdrawal times in that study align more closely with the withdrawal times
in the residue depletion study using non-radiolabelled drug than was apparent
from Table 7.2. The marker residue to total radioactive residue (MR:TRR) ratios
at 16 hours post last dose are 55% (muscle), 52% (skin/fat), 22% (liver) and 41%
(kidney).
Using a different approach, interpolated MR:TRR values were developed.
For muscle, where there was no MR:TRR at 40 hours post last dose (formerly
designated 24 hours withdrawal), the hypothetical 25% MR:TRR for muscle
proposed by the requestor was used. The formula (MR:TRR16 MR:TRR40)/3
was used to calculate the change-over-time in the MR:TRR ratio between 16 and
40 hours post last dose in 8-hour increments, and this value was then subtracted
from MR:TRR16 to give MR:TRR24. The interpolated MR:TRR ratios at 24 hours
WHO Technical Report Series No. 997, 2016

post last dose are 45% (muscle), 44% (skin/fat), 18% (liver) and 32% (kidney).
Using either the experimentally derived MR:TRR ratios or those
MR:TRR ratios developed through the interpolation, both the EDI and the
GECDE remain below the ADI for adults, children and infants. However, because
the re-presented sample collection times in the radiolabelled residue depletion
study align well with the sampling times in the depletion study using unlabelled
drug, the experimentally derived MR:TRR ratios at 16 hours post last dose are
used in conjunction with MRLs derived from the 1-day withdrawal residues in
the residue depletion study using unlabelled drug in the exposure assessment for
lasalocid in chicken tissues.

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 Response to concern forms from CCRVDF

3. When the data are insufficient or of quality not suitable for the EDI approach,
the JECFA has historically used the theoretical maximum daily intake (TMDI)
approach to establish MRLs. Based on our calculation using the same data but using
the TMDI approach, if the exposure was estimated using the proposed MRLs and
the marker to total residue ratios at 1-day WP, the daily human exposure to lasalocid
residues would be 2157.6 g per person which is 7 times higher than the ADI value
of 300 g per person (see Table 6 of Appendix for detailed calculation).

Response from JECFA: The Committee has concluded that when data are
sufficiently robust to support the use of the EDI approach, that approach will be
used, because it is more representative of actual exposure from the consumption
of tissues derived from treated animals. The lasalocid residue depletion data are
robust, were collected in a GLP-compliant study and can be used with the EDI
approach (see also the response to #4).

4. While Canada understands that the new dietary exposure assessment approach
piloted by the JECFA in its 78th meeting is still being verified, the global estimate
of chronic dietary exposure (GECDE) using the MR:TR on 1-day WP for lasalocid
would have exceeded the ADI. The GECDE represents 92% of ADI for adults, 168%
of ADI for children and 149% of ADI for infants (see Appendix for calculations).
JECFAs conclusion that the GECDE is below the ADI was because of considering
the MR:TR for 0-day WP which we believe underestimates the exposure. Given that
1-day WP residue data does not support the safety to consumers based on GECDE
approach, perhaps the residue data from 2-day WP would have been ideal to
establish MRLs for this compound. The 95th percentile (upper 95% CI [confidence
interval]) of residue data at 2-day WP would have yielded the MRLs of 100 ppb
in muscle, 500 ppb in liver, 250 ppb in kidney and 200 ppb in skin and fat (see
Appendix, Table 7).

Response from JECFA: Following re-presentation of the sampling times in the

radiolabelled residue depletion study to clearly reflect the actual time post last
dose at which the samples were collected, it is clear that the sampling times in
that study and the sampling times in the residue depletion study using non-
radiolabelled drug align well and can be used to derive MRLs for the use of
lasalocid in chickens. Using the MR:TRR at 16 hours post last dose, both the EDI
and the GECDE remain below the upper bound of the ADI for adults, children
and infants.
An EDI of 80 g/person per day was calculated, based on median residues
for a 1-day withdrawal in chicken, which represents 27% of the upper bound of
the ADI, based on a 60 kg individual.

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The GECDE for the general population is 1.85 g/kg bw per day, which
represents 37% of the upper bound of the ADI. The GECDE for children is 3.38
g/kg bw per day, which represents 67% of the upper bound of the ADI. The
GECDE for infants is 2.99 g/kg bw per day, which represents 60% of the upper
bound of the ADI.

In addition to the numbered questions, the Member State raised the

additional concern that they were not able to reproduce the results contained in
Table 7.2 of the JECFA monograph.

Response from JECFA: The values in Table 7.2 of the JECFA monograph are
correctly calculated. For complete transparency, the individual residue values for
each animal and each tissue assayed in both the radiolabelled residue depletion
study and the residue depletion study using unlabelled drug are presented in the
current addendum to the residue monograph.

Conclusions
Following consideration of the issues raised in the concern forms, the ADI
established and MRLs recommended at the seventy-eighth meeting of JECFA
remain unchanged.
WHO Technical Report Series No. 997, 2016

24
4. Comments on residues of specific veterinary drugs
The Committee evaluated or re-evaluated five veterinary drugs. Information on
the safety evaluations is summarized in Annex 2.

4.1 Diflubenzuron

Explanation
Diflubenzuron (International Union of Pure and Applied Chemistry [IUPAC]
name: 1-(4-chlorophenyl)-3-(2,6-difluorobenzoyl)urea; Chemical Abstracts
Service [CAS] no. 35367-38-5) is an acyl urea derivative (halogenated
benzoylphenylurea). Diflubenzuron is approved for use as a veterinary drug
in Norway and Chile in the treatment of sea lice (Lepeophtheirus salmonis and
Caligus rogercresseyi) infestations in Atlantic salmon (Salmo salar) as an oral
dosage of 36 mg/kg bw in feed for 14 consecutive days, with a withdrawal period
in the range of 105300 degree-days. It is also used as an insecticide/acaricide
in agriculture and forestry against larvae of Lepidoptera, Coleoptera, Diptera
and Hymenoptera and as a vector control agent in drinking-water sources and
drinking-water storage containers.
The mechanism of action of diflubenzuron is to inhibit the formation
of new chitin in the insect cuticle during the moulting process by inducing both
chitinase and phenoloxidase.
Diflubenzuron has not previously been evaluated by the Committee. The
Committee evaluated diflubenzuron at the current meeting at the request of the
Twenty-second Session of CCRVDF (2). The Committee was asked to establish
an ADI and recommend MRLs for diflubenzuron in salmon muscle and skin in
natural proportion.
The Committee noted that the toxicity of diflubenzuron has been
previously evaluated by JMPR in 1981, 1985 and 2001 (1113) and by a
number of other scientific or regulatory bodies, including the WHO Task
Group on Environmental Health Criteria for Diflubenzuron, which prepared
Environmental Health Criteria 184 (14). In 2001, JMPR established an ADI of
00.02 mg/kg bw for diflubenzuron, based on the NOAEL of 2 mg/kg bw per
day for haematological effects observed in 2-year toxicity studies in rats and a
52-week toxicity study in dogs (13).
The metabolism of diflubenzuron is known to lead to the formation of
PCA in some species, but not the rat, and it is not known whether PCA is formed
in salmon or humans. PCA might also occur as an impurity in the product
formulation or as a degradation product generated during food processing.
PCA is considered by many scientific and regulatory bodies (e.g. International

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Agency for Research on Cancer) as genotoxic and carcinogenic. The Committee

therefore evaluated the toxicity of PCA, focusing particularly on its genotoxicity
and carcinogenicity as well as on its possible carcinogenic mode of action, based
on studies retrieved from a search of published literature.

Toxicological and microbiological evaluation

Because the sponsor did not provide any toxicological data on diflubenzuron,
the Committee relied mainly on the summary evaluation prepared by JMPR in
2001. The Committee considered JMPRs summary evaluation of studies on the
short-term and long-term toxicity, reproductive and developmental toxicity, and
genotoxicity and carcinogenicity of diflubenzuron. It also considered information
obtained from literature searches on diflubenzuron and PCA.
The original studies provided to the 2001 JMPR were performed over a
period of approximately 40 years, and all the studies were considered adequate
for their intended purpose unless otherwise specified in the JMPR monograph.
Some of the critical studies did not comply with GLP regulations, as the data
were generated before the implementation of GLP regulations. Overall, however,
the Committee considered that the database was adequate to assess the risk of
diflubenzuron.

Biochemical data
Diflubenzuron is rapidly absorbed to a moderate extent from the gastrointestinal
tract. In a single-dose oral study with 14C-labelled diflubenzuron in rats, about
30% of the administered dose was absorbed at 5 mg/kg bw, and less was absorbed
at 100 mg/kg bw. Once absorbed, diflubenzuron is extensively metabolized and
rapidly excreted, mostly in the urine, although some enterohepatic circulation
occurs. In the radiolabel study, more than 90% of the administered dose (5 and
100 mg/kg bw) was excreted within 24 hours. When mice were given a single
oral dose of diflubenzuron at 12, 64, 200 or 920 mg/kg bw, excretion was almost
WHO Technical Report Series No. 997, 2016

complete within 48 hours.

The primary metabolic pathways are hydroxylation of the aniline ring,
cleavage of the ureido bridge and conjugation, mainly with sulfate. In rats, about
80% of the metabolites were identified as involving hydroxylation of the phenyl
moieties of diflubenzuron, and approximately 20% underwent scission at the
ureido bridge.
PCA was not detected in bile or urine using a method with a limit of
quantification (LOQ) of 7.5 ng/mL in rats. A radiolabel study with rats given a
single dose of [U-14C-anilino]diflubenzuron at 104 mg/kg bw also did not identify
PCA in urine. PCA was not detected (limits of detection [LODs] not given) in
urine or faeces of sheep or cow following administration of a single oral dose of

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 Comments on residues of specific veterinary drugs

diflubenzuron at 10 mg/kg bw or in rat urine following administration of a single

oral dose of diflubenzuron at 5 mg/kg bw. However, when diflubenzuron was
given as a single oral dose of 5 mg/kg bw, PCA was detected in small quantities in
swine urine (1.03% of the oral dose) and chicken excreta (0.44% of the dose).
When diflubenzuron was given as a single oral dose, 4-chlorophenylurea
(CPU), a metabolite that may be reduced to PCA, was detected in small quantities
in the urine of swine (0.82% of a 5 mg/kg bw dose), in the urine of cows (0.6% of
a 10 mg/kg bw dose) and in chicken excreta (3.14% of a dose of 5 mg/kg bw).

Toxicological data
Diflubenzuron was of low acute toxicity when given to mice and rats by the oral,
inhalation or dermal route. The oral median lethal dose (LD50) was greater than
4600 mg/kg bw in mice and rats, the dermal LD50 was greater than 10 000 mg/
kg bw in rats and the inhalation median lethal concentration (LC50) was greater
than 2.9 mg/L in rats.
Diflubenzuron was not irritating to the skin of rabbits and was slightly
irritating to the eyes of rabbits. Diflubenzuron was not a skin sensitizer in a study
in guinea-pigs.
The primary target for toxicity is the erythrocytes, with secondary effects
on liver and spleen. Dose-related methaemoglobinaemia has been consistently
demonstrated in both sexes of various species (mice, rats and dogs) after short-
term or long-term oral exposure to diflubenzuron.
In a 13-week study, rats were fed diets containing diflubenzuron at a
concentration of 0, 160, 400, 2000, 10 000 or 50 000 mg/kg feed (equivalent to
0, 8, 20, 100, 500 and 2500 mg/kg bw per day, respectively). A range of dose-
related changes in erythrocyte parameters (erythrocyte counts, haemoglobin,
reticulocytes, methaemoglobin and sulfhaemoglobin) were noted in both sexes at
400 mg/kg feed and above, with minimal effects at 160 mg/kg feed. The absolute
and relative weights of the spleen were increased in males at 160 mg/kg feed
and above and in females at 400 mg/kg feed and above for 7 weeks. Pathological
findings included chronic hepatitis, haemosiderosis and congestion of the
spleen, and erythroid hyperplasia of the bone marrow in all treated groups; and
haemosiderosis in the liver at 400 mg/kg feed and above. A NOAEL could not
be identified, because there were small, but statistically significant, increases in
methaemoglobin concentration and associated changes in the spleen and bone
marrow at the lowest dose tested (160 mg/kg feed, equivalent to 8 mg/kg bw per
day).
In a 13-week non-GLP-compliant study in dogs, animals received diets
containing diflubenzuron at a concentration of 0, 10, 20, 40 or 160 mg/kg feed (equal
to 0, 0.4, 0.8, 1.6 and 6.4 mg/kg bw per day, respectively). At week 6, haemoglobin

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concentration and erythrocyte count were reduced and methaemoglobin and

free haemoglobin concentrations were increased at 160 mg/kg feed. There was an
increase in the myeloid:erythroid ratio in bone marrow at 160 mg/kg feed at week
12. A NOAEL of 40 mg/kg feed (equal to 1.6 mg/kg bw per day) was identified,
based on changes in haematological end-points and bone marrow at 160 mg/kg
feed (equal to 6.4 mg/kg bw per day).
In a 52-week non-GLP-compliant study, dogs received gelatine capsules
containing diflubenzuron at a dose of 0, 2, 10, 50 or 250 mg/kg bw per day. A
range of effects related to impaired erythrocytes was seen at the two highest
doses from week 13 onwards. Increases in methaemoglobin and sulfhaemoglobin
concentrations and in platelet counts were seen at 10 mg/kg bw per day and above.
The only histopathological findings were in the liver (increased pigmentation of
Kupffer cells and macrophages) at 10 mg/kg bw per day and above. A NOAEL
of 2 mg/kg bw per day was identified, based on effects on methaemoglobin and
sulfhaemoglobin concentrations, platelet counts and hepatic pigmentation at 10
mg/kg bw per day.
In a chronic toxicity and carcinogenicity study, diflubenzuron was given
to mice in the diet at a concentration of 0, 16, 80, 400, 2000 or 10 000 mg/kg
feed (equal to 0, 1.2, 6.4, 32, 160 and 840 mg/kg bw per day for males and 0, 1.4,
7.3, 35, 190 and 960 mg/kg bw per day for females, respectively) for 91 weeks.
Significant, dose-related changes were seen in a number of haematological
parameters from week 26 onwards (methaemoglobin and sulfhaemoglobin at 80
mg/kg feed and above; haemoglobin at 2000 mg/kg feed and above; leukocyte and
erythrocyte counts at 10 000 mg/kg feed). On week 26, absolute spleen weights
were significantly increased at 2000 mg/kg feed and above. Increased incidences
of splenic siderocytes at 400 mg/kg feed and above and of pigmented Kupffer cells
at 10 000 mg/kg feed were noted. A NOAEL of 16 mg/kg feed (equal to 1.2 mg/
kg bw per day) was identified, based on methaemoglobin formation at 80 mg/kg
feed (equal to 6.4 mg/kg bw per day). There was no evidence of carcinogenicity
WHO Technical Report Series No. 997, 2016

in this study.
In a non-GLP-compliant chronic toxicity and carcinogenicity study
in rats, animals received diflubenzuron in the diet at a concentration of 0, 10,
20, 40 or 160 mg/kg feed (equivalent to 0, 0.5, 1, 2 and 8 mg/kg bw per day,
respectively) for 2 years. The achieved dietary concentrations and homogeneity
of diflubenzuron in the feed were not confirmed. The NOAEL was 40 mg/kg
feed (equivalent to 2 mg/kg bw per day), based on increases in methaemoglobin
concentration and reduced free haemoglobin concentration at 160 mg/kg feed
(equivalent to 8 mg/kg bw per day). There was no increase in the incidence of
tumours in treated animals. However, the poor survival (<30% in all groups at
termination) and limited range of tissues examined limited the power of this
study to detect any carcinogenicity of diflubenzuron.
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 Comments on residues of specific veterinary drugs

In a GLP-compliant combined 2-year toxicity and carcinogenicity study,

rats received diflubenzuron in the diet at a concentration of 0, 160, 620, 2500 or
10 000 mg/kg feed (equal to 0, 7.1, 28, 112 and 472 mg/kg bw per day for males and
0, 9.3, 37, 128 and 612 mg/kg bw per day for females, respectively). Erythrocyte
parameters (e.g. methaemoglobin and sulfhaemoglobin concentrations) were
altered, with no marked progression with duration and dosing. The main
treatment-related histopathological findings were pigmented macrophages in the
spleen and liver and erythroid hyperplasia of the bone marrow at 620 mg/kg feed
and above. A NOAEL for toxicity could not be identified, owing to increases in
methaemoglobin and sulfhaemoglobin concentrations noted at 160 mg/kg feed
(equal to 7.1 mg/kg bw per day), the lowest dose tested. The overall incidences of
tumours were low, with no treatment- or dose-related findings.
The overall NOAEL for toxicity in the 2-year studies in rats was 2 mg/kg
bw per day, and the overall LOAEL was 7.1 mg/kg bw per day.
The Committee concluded that diflubenzuron is not carcinogenic in
mice or rats.
The genotoxicity of diflubenzuron was evaluated in an adequate range
of assays, both in vitro and in vivo. No evidence of genotoxicity was found,
other than two recent in vivo studies in which positive findings in micronucleus
induction and comet formation in the peripheral blood (the target of toxicity)
were reported in mice given diflubenzuron at a dose of 0.3, 1 or 3 mg/kg bw.
The genotoxicity potency reported in this study was inconsistent with what
was reported in other studies and has not been replicated. The Committee
concluded that diflubenzuron is not genotoxic based on the weight of evidence of
genotoxicity information available.
In view of the lack of genotoxicity and the absence of carcinogenicity in
mice and rats, the Committee concluded that diflubenzuron is unlikely to pose a
carcinogenic risk to humans from the diet.
In a two-generation reproductive toxicity study, rats received diets
containing diflubenzuron at a concentration of 0, 500, 5000 or 50 000 mg/kg
feed (equal to 0, 42, 430 and 4300 mg/kg bw per day for males and 0, 36, 360 and
3800 mg/kg bw per day for females, respectively). Haematological parameters
and the spleen were not examined in young animals. Reproductive parameters
were not affected. Pup weights were reduced in a dose-related manner in the F1
generation, but not in the F2 generation. Alterations in erythrocyte parameters
and increases in lymphocyte counts and platelet numbers were seen in all parental
groups. The spleen was the primary target organ, showing increases in weight,
congestion and haemosiderosis at all doses and an increase in the incidence of
congested red pulp in F0 animals at the middle and high doses. Effects on liver
included increased incidences of centrilobular hepatocyte hypertrophy at the
middle and high doses and brown pigmentation of Kupffer cells in all treated
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 Joint FAO/WHO Expert Committee on Food Additives Eighty-first report

groups. The NOAEL for reproductive effects was 50 000 mg/kg feed (equal to
3800 mg/kg bw per day), the highest dose tested. The NOAEL for offspring toxicity
was 5000 mg/kg feed (equal to 360 mg/kg bw per day), based on reductions in
pup body weight at 50 000 mg/kg feed (equal to 3800 mg/kg bw per day) in the F1
generation. A NOAEL for parental toxicity could not be identified because of the
haematological effects observed at all doses tested.
In a developmental toxicity study, rats were dosed orally by gavage with
diflubenzuron at 0 or 1000 mg/kg bw per day (the limit dose) from days 6 to 15
of gestation. The dams were killed on day 20 of gestation. No treatment-related
effects on the dams or fetuses were noted. The NOAEL for both maternal and
embryo/fetal toxicity was 1000 mg/kg bw per day, the only dose tested.
In another developmental toxicity study, rabbits were dosed orally
by gavage with diflubenzuron at 0 or 1000 mg/kg bw per day (the limit dose)
from days 7 to 19 of gestation. The does were killed on day 28 of gestation. No
treatment-related effects on the does or fetuses were noted. There was no evidence
of developmental toxicity in rabbits. The NOAEL for both maternal and embryo/
fetal toxicity was 1000 mg/kg bw per day, the only dose tested.

Observations in humans
No reports of adverse effects or poisoning incidences associated with
diflubenzuron were found.

Toxicological data on PCA (a metabolite of diflubenzuron)

Repeated exposure to PCA leads to cyanosis and methaemoglobinaemia,
followed by effects in blood, liver, spleen and kidneys, as evidenced by changes in
haematological parameters, splenomegaly and haemosiderosis (from moderate
to heavy) in spleen, liver and kidney, partially accompanied by extramedullary
haematopoiesis. The LOAELs for a significant increase in methaemoglobin levels
WHO Technical Report Series No. 997, 2016

in rats and mice were 5 and 7.5 mg/kg bw per day, respectively, for a 13-week
oral gavage administration of PCA. The LOAEL for a 103-week oral gavage study
in rats (with administration 5 days/week) was 2 mg/kg bw per day, based on a
significant increase in methaemoglobin levels and fibrotic changes of the spleen
in male rats; hyperplasia of bone marrow was observed in female rats at and
above 6 mg/kg bw per day. This information demonstrated that PCA exhibits
toxicity end-points similar to those of diflubenzuron, but is more potent than
diflubenzuron.
PCA was tested for carcinogenicity in mice and rats by administration in
the diet and by oral gavage.
In a dietary carcinogenicity study in mice, animals received PCA
at a concentration of 0, 2500 or 5000 mg/kg feed (equivalent to 0, 375 and

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 Comments on residues of specific veterinary drugs

750 mg/kg bw per day, respectively) for 78 weeks, followed by a 13-week

observation period. Decreased body weight gain was observed in treated animals.
Non-neoplastic proliferative and chronic inflammatory lesions were found in the
spleens of treated mice. There was an increased incidence of haemangiosarcomas
in the spleen, liver, kidney and subcutaneous tissue (combined) for both sexes.
It was concluded that there was insufficient evidence to conclude that PCA was
carcinogenic in mice.
In a second carcinogenicity study in mice, animals were administered
PCA by oral gavage in aqueous hydrochloric acid at 0, 3, 10 or 30 mg/kg bw per
day, 5 days/week, for 103 weeks. Incidences of proliferation of haematopoietic
cells in the liver were increased in dosed females. Multifocal renal tubular
pigmentation (haemosiderin) was observed in high-dose females. There were
increases in the incidences of hepatocellular carcinomas in males dosed at 10 and
30 mg/kg bw per day (3/50, 7/49, 11/50, 17/50), incidences of combined
hepatocellular adenomas and carcinomas in all treated males (11/50, 21/49,
20/50, 21/50) and incidences of haemangiosarcomas of the liver and spleen
(combined) in males at 30 mg/kg bw per day (4/50, 4/49, 1/50, 10/50). It was
concluded that there was some evidence of carcinogenicity in male mice and no
evidence in female mice.
In a dietary carcinogenicity study in rats, animals received PCA
at a concentration of 0, 250 or 500 mg/kg feed (equivalent to 0, 12.5 and
25 mg/kg bw per day, respectively) for 78 weeks, followed by a 24-week observation
period. Mesenchymal tumours (fibroma, fibrosarcoma, haemangiosarcoma,
osteosarcoma and sarcoma not otherwise specified) in the spleen were observed
in males at the high dose and in females at both doses; no tumours were found
in the controls. It was concluded that there was insufficient evidence to conclude
that PCA was carcinogenic in rats.
In a second carcinogenicity study in rats, animals were administered PCA
by oral gavage in aqueous hydrochloric acid at 0, 2, 6 or 18 mg/kg bw per day,
5 days/week, for 103 weeks. Changes in haematological parameters (e.g. decreases
in haemoglobin concentration, erythrocyte count and haematocrit) were noted at
various time points. Non-neoplastic findings included bone marrow hyperplasia,
hepatic haemosiderosis and splenic fibrosis. The incidence of uncommon
sarcomas of the spleen in high-dose male rats was significantly higher than that
in the vehicle controls (fibrosarcomas, osteosarcomas or haemangiosarcomas,
combined: 0/49, 1/50, 3/50, 38/50); some of these tumours metastasized to one
or more sites. One mid-dose female developed fibrosarcoma, and one high-dose
female developed osteosarcoma; the controls showed zero incidence of either
of these tumours. The incidence of adrenal phaeochromocytomas or malignant
phaeochromocytomas combined was significantly higher in the high-dose males.
There was a non-significant increase in the incidence of phaeochromocytomas in
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high-dose females (2/50, 3/50, 1/50, 6/50). It was concluded that there was clear
evidence of carcinogenicity in male rats and equivocal evidence in female rats.
The oral gavage carcinogenicity study is considered to be more appropriate
than the dietary admixture feeding study for determining carcinogenicity
because (1) PCA is unstable in feed and (2) mice and rats in the feeding studies
were dosed for 78 weeks and killed and examined for histopathology following a
further 13-week (mice) or 24-week (rats) observation period. Nonetheless, both
studies showed some similar effects: splenic toxicity in male and female rats, a
treatment-related increase in uncommon splenic sarcomas in male rats and a
treatment-related increase in haemangiosarcomas in male mice.
The Committee concluded that PCA is carcinogenic in mice and rats.
PCA has been tested for genotoxicity in various in vitro and in vivo
systems. PCA is genotoxic in vitro and in vivo. The Committee is aware of the
existence of additional in vivo genotoxicity studies; however, these were not
available to the Committee.
The Committee concluded that PCA is genotoxic.
There is no established mode of action for PCA carcinogenesis;
it is not known whether it is mediated through a genotoxic and/or non-
genotoxic mechanism. Several hypotheses regarding the mechanism of splenic
carcinogenicity have been proposed. However, because PCA is genotoxic
and carcinogenic, the Committee could not exclude the possibility that the
carcinogenesis of PCA occurs by a genotoxic mode of action.

Microbiological data
Considering the chemical structure and mode of action of diflubenzuron, the
Committee did not anticipate any adverse effects of diflubenzuron residues on
human gastrointestinal microbiota.

Evaluation
WHO Technical Report Series No. 997, 2016

In the absence of adequate information on exposure to PCA, a genotoxic and

carcinogenic metabolite and/or degradate of diflubenzuron, and on whether
diflubenzuron can be metabolized to PCA in humans, the present Committee
was unable to establish an ADI for diflubenzuron because it was not possible to
assure itself that there would be an adequate margin of safety from its use as a
veterinary drug. The Committee also noted that it was not possible to calculate a
margin of exposure for PCA in the absence of adequate information on exposure
to PCA.

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 Comments on residues of specific veterinary drugs

Additional information that would assist in the further evaluation of the compound

A comparative metabolism study of diflubenzuron in humans and

rats (e.g. in hepatocytes)
Information on PCA exposure associated with the consumption of
treated fish
Information on the amount of PCA present (if any) as an impurity in
the product formulation
Information on the amount of PCA generated during food processing.

Recommendation
The Committee recommended that JMPR consider the re-evaluation of
diflubenzuron at a future meeting and that the WHO Pesticide Evaluation
Scheme (WHOPES) and the WHO Guidelines for Drinking-water Quality
(GDWQ) Chemical Working Group reconsider their recommendations for the
use of diflubenzuron as a vector control agent in drinking-water.

A toxicological monograph was prepared.

Residue evaluation
The Committee reviewed studies on the pharmacokinetics and metabolism of
diflubenzuron in food-producing animals, including Atlantic salmon. Also, a
number of radiolabelled and non-radiolabelled diflubenzuron residue depletion
studies in Atlantic salmon and Atlantic cod were reviewed. The analytical method
submitted by the sponsor to support the residue monitoring has been assessed.
All studies were GLP compliant unless otherwise stated.

Data on pharmacokinetics and metabolism

In two studies conducted at a water temperature of 15 C, Atlantic salmon
received a single dose of [14C]diflubenzuron or multiple doses (13 days of feeding
of non-radiolabelled diflubenzuron followed by a single dose of radiolabelled
[14C]diflubenzuron) at a concentration of 3 mg/kg bw. Diflubenzuron was the
main component of the total radioactive residue (TRR) both in fillet and in liver,
corresponding to 94.8% and 72.2%, respectively, at day 1 after the repeated-dosing
regimen. For the single-dose regimen, diflubenzuron represented 88.6% and
69.3% of the TRR for fillet and liver, respectively. Diflubenzuron was metabolized
and rapidly excreted, mainly via the bile. Six hours after administration, 39%
of the radioactivity in bile was identified as diflubenzuron. One and 4 days
after administration, most of the radioactivity in bile was attributable to polar

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 Joint FAO/WHO Expert Committee on Food Additives Eighty-first report

metabolites. Chromatographic analysis with radiohigh-performance liquid

chromatography (HPLC) of fillet revealed three components. The major
component was identified as diflubenzuron at concentrations of 389 g/kg, 99.6
g/kg and 21.4 g/kg at 1, 4 and 7 days following repeat administration and 410
g/kg at 1 day following a single administration. Furthermore, one metabolite
was identified as CPU with a maximum concentration of 0.23 g/kg at 4 days
following repeat administration of diflubenzuron. The third component was not
identified, but the retention time was in the same range as for PCA. Base hydrolysis
of solid residues in liver revealed at least five components at concentrations lower
than 9 g/kg. Three of the components were identified as diflubenzuron, PCA
(<3 g/kg) and CPU (<9 g/kg). The two unidentified metabolites were probably
monohydroxylated products of diflubenzuron.
In a non-GLP-compliant study, Atlantic salmon smolts (weighing
approximately 60 g), maintained at a water temperature of 8 C, received a single
dose of 75 mg/kg bw of [14C]diflubenzuron via gavage. After 2 hours, 12 hours, 2
days, 6 days, 10 days, 13 days, 20 days and 27 days, fish were slaughtered, and 12
fish were sampled for autoradiography. Samples were taken from blood, brain,
muscle, abdominal fat, kidney, liver, bile, cartilage and cutaneous mucus. The
concentration of radioactivity in brain and cartilage was highest 12 hours after
administration, with concentrations of 13.8 g/g and 10.9 g/g, respectively. In
bile, the concentration of radioactivity varied between 275 and 1066 g/g in the
first 10 days after administration, then dropped to less than 4 g/g for the rest of
the period.

Residue data
The Committee reviewed residue depletion studies for Atlantic salmon and
Atlantic cod.

Salmon. Two residue depletion studies using radiolabelled diflubenzuron and

WHO Technical Report Series No. 997, 2016

three residue depletion studies using non-radiolabelled diflubenzuron were

provided for Atlantic salmon, using a single oral dose or repeated dose. Whereas
the residue depletion studies with radiolabelled diflubenzuron were conducted at
a water temperature of 15 C, the studies with the non-radiolabelled drug were
carried out at two water temperatures: 15 C and 6 C.
In the first study, Atlantic salmon (440851 g) held at a water temperature
of 15 C received a dose of 3 mg/kg bw of [14C]diflubenzuron by gavage. Liver,
fillet (muscle and skin), gallbladder (including bile) and residual carcass were
collected from 10 fish each at 1 and 7 days post final dose administration.
Samples of tissues were collected for TRR determination using liquid scintillation
counting. The LODs were 2 g equivalent (eq)/kg for liver and 0.6 g eq/kg for

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 Comments on residues of specific veterinary drugs

fillet and carcass. Acetonitrile and ethyl acetate tissue sample extracts were also
analysed using reversed-phase HPLC with an ultraviolet (UV) detector operating
at 254 nm. Fish fillet extracts were analysed by liquid chromatography with mass
spectrometry (LC-MS). Diflubenzuron was found as the main TRR both in fillet
and in liver, corresponding to 88.6% and 69.3% of the TRR for fillet and liver,
respectively.
In a second study, Atlantic salmon weighing 514863 g received a non-
radiolabelled diflubenzuron dose of 3 mg/kg bw per day for 13 consecutive
days followed by a single dose of 3 mg/kg bw radiolabelled [14C]diflubenzuron
by gavage. Liver, fillet (muscle and skin), gallbladder (including bile) and
residual carcass were collected from 10 fish each at 1, 4 and 7 days post final
dose administration. The analyses were carried out as described in the first study.
Diflubenzuron was found as the main TRR component both in fillet and in liver,
corresponding to 94.8% and 72.2%, respectively, at day 1 post-treatment. The
highest concentration of radioactivity (mean standard deviation [SD]) in liver
(811 100 g eq/kg), fillet (466 66 g eq/kg) and carcass (734 118 g eq/kg)
occurred 1 day after administration of the drug.
In both studies with radiolabelled diflubenzuron, the highest
concentrations of [14C]diflubenzuron equivalents occurred at 1 day post-
treatment. Less than 20% of the radiochemical dose remained in the liver, fillet
and carcass 1 day following repeated administration, and less than 33% remained
following a single dose administration. The concentrations decreased to less than
1.5% by 7 days following both dosing regimens. The major metabolic pathway is
excretion of the parent compound.
At a water temperature of 15 C, the MR:TRR ratio at day 1 post-dose was
0.91 in muscle in the single-dose regimen. For the repeated dose, the MR:TRR
ratios were 0.96, 0.88 and 0.94 for 1, 4 and 7 days post last dose.
In a study using non-radiolabelled diflubenzuron in feed, Atlantic salmon
(600987 g), maintained at a water temperature of 6 C, received a dose of 3 mg/
kg bw for 14 consecutive days. Tissues (liver, muscle and skin) were collected
and analysed after 1, 7, 14 and 21 days post-treatment. Diflubenzuron was
extracted from the tissues by solidliquid extraction with acetonitrile. Samples
were analysed using a validated HPLC-UV method. The average concentrations
of diflubenzuron in fillet were 2240 g/kg, 400 g/kg, 100 g/kg and <LOQ
(50 g/kg) on days 1, 7, 14 and 21 post-treatment, respectively. The average
concentrations of diflubenzuron in liver were 3190 g/kg, 730 g/kg, 120 g/kg
and <LOQ on days 1, 7, 14 and 21 post-treatment, respectively.
The same protocol as described previously was used for another
study at 15 C, where Atlantic salmon (600987 g) received non-radiolabelled
diflubenzuron in feed daily at a dose of 3 mg/kg bw for 14 consecutive days.
Diflubenzuron was quantified in muscle and liver by the same HPLC-UV method
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 Joint FAO/WHO Expert Committee on Food Additives Eighty-first report

described in the previous study. The average concentrations of diflubenzuron

determined in fillet were 1550 g/kg and 200 g/kg on days 1 and 7, respectively,
and <LOQ on days 14 and 21 post-treatment. The average concentrations of
diflubenzuron in liver were 2170 g/kg and 260 g/kg on days 1 and 7 post-
treatment, respectively, and <50 g/kg (LOQ) after 14 days post-treatment.
In another depletion study carried out at 15 C, Atlantic salmon (weighing
4.65.6 kg) received non-radiolabelled diflubenzuron at 3 mg/kg bw for 14
consecutive days. Liver, muscle and skin samples were collected during the
treatment with the medicated feed (days 3, 7 and 14) and days 5, 14, 21 and
28 post-treatment and then analysed. Results for samples taken post-treatment
are as follows: In liver, the average diflubenzuron concentrations (10 fish) were
520 g/kg and 70 g/kg on days 5 and 14, respectively. In muscle, the average
concentrations were 900 g/kg and 100 g/kg on days 5 and 14, respectively. In
skin, the average concentrations were 320 g/kg and <50 g/kg on days 5 and 14,
respectively. At 21 days post-treatment, all samples analysed had diflubenzuron
concentrations lower than 50 g/kg (LOQ). In samples taken during the treatment,
the highest average diflubenzuron concentration was determined at day 14 in
liver (1820 g/kg) and muscle (2130 g/kg). For skin, the highest diflubenzuron
concentration of 1320 g/kg was reached on day 7. The maximum diflubenzuron
concentration of 3700 g/kg was found in one muscle sample on day 14.

Atlantic cod. In a non-GLP-compliant residue depletion study, Atlantic cod

(Gadus morhua) (81122 g), maintained at a water temperature of 7.7 0.2 C,
received a dose of 3 mg/kg bw of diflubenzuron in feed for 14 consecutive days.
The highest concentration of diflubenzuron in liver (181 21 ng/g) was observed
1 day after the end of the treatment (day 15).
In another non-GLP-compliant study conducted at a water temperature
of 7.7 C, Atlantic cod (65165 g) received diflubenzuron in feed at a dose of 3 mg/
kg bw for 14 consecutive days. Samples of fillet and skin in natural proportion,
WHO Technical Report Series No. 997, 2016

liver and terminal colon were taken on days 4, 8 and 12 during the treatment and
days 1, 4, 8, 15, 22 and 30 post-treatment. At each time point, 10 fish were collected
and analysed individually, with the exception of the bile samples, which were
combined into one or two group samples for each sampling day. Diflubenzuron
was quantified by LC-MS using teflubenzuron as the internal standard. The LOQ
of the validated method was 20 g/kg. The calculated tissue concentrations in the
samples showed high variability, probably due to individual differences in feed
consumption and, to a lesser extent, in absorption. The median concentration
determined in fillet and skin throughout the treatment period was 36.1 g/kg,
only 1.5% of the mean concentration determined in Atlantic salmon fillet after the
same treatment, which suggests that diflubenzuron has a lower gastrointestinal
uptake in Atlantic cod compared with Atlantic salmon. The depletion half-lives
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 Comments on residues of specific veterinary drugs

for diflubenzuron in fillet and liver ranged from 0.8 to 0.9 day. PCA was not
detected (LOD 2 g/kg) in any samples analysed by liquid chromatography with
tandem mass spectrometry (LC-MS/MS).

Analytical methods
The Committee assessed the validation data against the requirements for
analytical methods as published in CAC/GL 71-2009 (15).
The validated HPLC-UV method used in the depletion studies is based
on solidliquid extraction, followed by several clean-up steps using liquidliquid
extraction and solid-phase extraction on a Florisil sorbent. Quantification was
performed at 254 nm using an external calibration curve. Average recoveries of
88% for liver, 91% for muscle (values corrected for blank) and 103% for skin
were determined. The LOD and LOQ were 20 g/kg and 50 g/kg, respectively.
The Committee concluded that the HPLC-UV method provided by the sponsor
lacks in selectivity because of possible interferences from other components in
the extract at a wavelength of 254 nm and cannot be recommended for regulatory
monitoring of salmon tissues for diflubenzuron.
Several multi-residue analytical methods are reported in the peer-
reviewed scientific literature. These methods are based on solvent extraction
(acetone, acetonitrile or methanol) with or without hexane liquidliquid
extraction to remove fat, followed by clean-up over C18 or silica gel solid-phase
extraction cartridges and determination by LC-MS/MS or using the QuEChERS
(Quick, Easy, Cheap, Effective, Rugged and Safe) approach for the sample
preparation. However, the Committee noted that the methods reported in the
peer-reviewed scientific literature did not meet the analytical method validation
requirements as published in CAC/GL 71-2009 (15).

Maximum residue limits

The Committee noted that PCA is a potential hydrolysis product of
4-chlorophenyl isocyanate, which is one of the starting materials for the
synthesis of diflubenzuron, and that PCA could be formed through degradation
of diflubenzuron at high temperatures during processing of feed or food. The
data available to the Committee at the time of the assessment were inadequate
regarding the formation or presence of PCA in fish, as well as in processed food.
MRLs for diflubenzuron could not be recommended by the Committee,
as the Committee was unable to establish an ADI for diflubenzuron.
The Committee also noted that there is no analytical method suitable for
regulatory monitoring purposes.

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Additional information that would assist in the further evaluation of the compound

A method suitable for monitoring diflubenzuron residues in fish

muscle and fillet (muscle plus skin in natural proportion).

A residue monograph was prepared.

Summary and conclusions

Studies relevant to risk assessment

Species / study type Doses (mg/kg bw NOAEL (mg/kg LOAEL (mg/kg
(route of administration) per day) Critical end-point bw per day) bw per day)
Diflubenzuron
Mouse
Ninety-one-week toxicity Males: 0, 1.2, 6.4, 32, Toxicity: Increased methaemoglobin 1.2 6.4
and carcinogenicity study 160, 840 concentration
(diet) Females: 0, 1.4, 7.3, 35,
190, 960 Carcinogenicity: None 840a
Rat
Two-year toxicity and car- Study 1: 0, 0.5, 1, 2, 8 Toxicity: Increased methaemoglobin and 2c 7.1d
cinogenicity studiesb (diet) Study 2: sulfhaemoglobin concentrations
Males: 0, 7.1, 28, 112, Carcinogenicity: None 472a
472
Females: 0, 9.3, 37,
128, 612
Two-generation reproductive Males: 0, 42, 430, 4 300 Reproductive toxicity: None 3 800a
toxicity study (diet) Females: 0, 36, 360, Parental toxicity: Changes in haematologi- 36e
3 800 cal parameters
Offspring toxicity: Decreased F1 pup weights 360 3 800
Developmental toxicity study 0, 1 000 Maternal: None 1 000f
WHO Technical Report Series No. 997, 2016

(gavage) Embryo/fetal toxicity: None 1 000f

Rabbit
Developmental toxicity study 0, 1 000 Maternal toxicity: None 1 000f
(gavage) Embryo/fetal toxicity: None 1 000f
Dog
One-year toxicity study 0, 2, 10, 50, 250 Increased methaemoglobin and sulfhaemo- 2 10
(capsule) globin concentrations, platelet counts and
hepatic pigmentation
4-Chloroaniline (PCA)
Mouse
Two-year carcinogenicity 0, 3, 10, 30 Increased incidence of hepatocellular 3e
study (gavage) adenomas and carcinomas in male mice

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Species / study type Doses (mg/kg bw NOAEL (mg/kg LOAEL (mg/kg

(route of administration) per day) Critical end-point bw per day) bw per day)
Rat
Two-year carcinogenicity 0, 2, 6, 18 Increased incidence of spleen sarcoma in 6 18
study (gavage) male rats
a
Highest dose tested.
b
Two or more studies combined.
c
Overall NOAEL.
d
Overall LOAEL.
e
Lowest dose tested.
f
Limit dose.

ADI
In the absence of adequate information on exposure to PCA, a genotoxic and
carcinogenic metabolite and/or degradate of diflubenzuron, and on whether
diflubenzuron can be metabolized to PCA in humans, the present Committee
was unable to establish an ADI for diflubenzuron because it was not possible to
assure itself that there would be an adequate margin of safety from its use as a
veterinary drug.

MRLs
MRLs for diflubenzuron could not be recommended by the Committee, as no
ADI was established and there is a lack of data about the metabolite/degradation
product PCA.

4.2 Ivermectin
Explanation
Ivermectin (CAS no. 70288-86-7) is a macrocyclic lactone that is a member
of the avermectin series and is widely used as a broad-spectrum antiparasitic
endectocide against nematode and arthropod parasites in food-producing
animals. In human medicine, ivermectin is used to treat onchocerciasis,
lymphatic filariasis, strongiloidiasis and scabies. Ivermectin consists of two
homologous compounds, 22,23-dihydroavermectin B1a (H2B1a or ivermectin B1a)
and 22,23-dihydroavermectin B1b (H2B1b or ivermectin B1b), in the H2B1a:H2B1b
ratio of 80:20. Ivermectin is used in cattle, sheep, goats, pigs, horses, reindeer and
American bison at doses of 0.10.5 mg/kg bw given subcutaneously, topically or
orally as a single-dose treatment only. Withdrawal periods range from 14 to 122
days where ivermectin is approved for use.
Ivermectin was previously considered by the Committee at its thirty-
sixth, fortieth, fifty-eighth, seventy-fifth and seventy-eighth meetings (Annex 1,
references 91, 104, 157, 208 and 217). At its fortieth meeting, the Committee

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established an ADI of 01 g/kg bw based on developmental toxicity of ivermectin

in CF-1 mice and recommended MRLs of 40 g/kg for fat, 100 g/kg for liver and
10 g/kg for milk as ivermectin in cattle (using the marker ivermectin B1a). At its
seventy-eighth meeting, the Committee recommended an MRL of 4 g/kg for
cattle muscle based on 2 LOQ of the analytical method.
At its seventy-fifth meeting, the Committee concluded that there was
a need to evaluate the toxicological information on ivermectin with a view to
identifying a critical effect other than in the CF-1 mouse for the establishment of
an ADI. CCRVDF at its Twenty-second Session requested that JECFA re-evaluate
the ADI and the MRLs in all cattle tissues (2). CCRVDF noted that the draft MRL
for ivermectin in bovine muscle recommended at the seventy-eighth meeting
was in some cases 2.5 times lower than the MRL established in other countries
where ivermectin was used. This did not reflect GVP. Furthermore, JECFA had
not recommended an MRL for bovine kidney.

Toxicological and microbiological evaluation

The Committee considered data from a safety, tolerability and pharmacokinetics
study in humans and information on various repeated-dose ivermectin treatment
regimens in patients, which were provided by a sponsor. The Committee also
considered previous evaluations by JECFA on ivermectin in various animal
species and the pharmacokinetics of ivermectin in dogs in particular, so that a
more appropriate animal model could be used to establish an ADI. In light of
the possibility for acute exposure to high concentrations of ivermectin from the
injection site, the Committee also considered the acute toxicity of ivermectin
with a view to establishing an ARfD.
The critical animal studies were not performed to GLP because the
data were generated prior to the implementation of GLP. The human study
was conducted according to the principles of the Declaration of Helsinki. The
Committee considered that the database was adequate for the evaluation.
WHO Technical Report Series No. 997, 2016

Biochemical data
Pharmacokinetics data were obtained from the submitted safety, tolerability and
pharmacokinetics study in humans (16). Twelve fasted subjects per dosing group
were given a single oral dose of 30, 60, 90 or 120 mg ivermectin or multiple doses
of either 30 or 60 mg ivermectin over 7 days. Pharmacokinetic analysis revealed
that ivermectin concentrations in plasma were generally proportional up to a
single oral dose of 120 mg in fasted subjects. Dose linearity of the maximum
concentration in plasma (Cmax) and the area under the plasma concentrationtime
curve (AUC) was confirmed after dose normalization. There were no differences
in pharmacokinetic variables between men and women. Minimal accumulation

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 Comments on residues of specific veterinary drugs

was observed with repeated dosing, and the elimination half-life ranged from
18.8 to 20.1 hours in fasted subjects. The ivermectin AUC was 2.57-fold greater
in fed versus fasted subjects receiving a single dose of 30 mg, but the elimination
half-life was shorter, at 15.0 hours.
A literature search identified a number of oral dosing studies in dogs that
had relevant pharmacokinetics data from a test group treated with ivermectin.
The data indicate that for a 3-fold increase in ivermectin dose (81.5250 g/kg
bw per day), there was approximately a 5.5-fold increase in the ivermectin Cmax
(24132.6 ng/mL) and a 6-fold increase in the plasma ivermectin AUC (38.9237
ng.d/mL). Dose normalization of the pharmacokinetics data from the oral dosing
studies in dogs confirmed non-linear plasma pharmacokinetics of ivermectin in
dogs. Furthermore, for this dose range, the elimination half-life ranged from 3.3
to 4.4 days.

Toxicological data
Repeated-dose studies with ivermectin in laboratory animals have previously
been evaluated by JECFA (Annex 1, reference 91). The findings from the most
relevant of these non-GLP-compliant studies are summarized below.
In a 14-week study, ivermectin was given orally to rat pups 34 weeks of
age, obtained from dams treated with ivermectin, at a dose of 0, 0.4, 0.8 or 1.6
mg/kg bw per day. Spleen enlargement and reactive bone marrow hyperplasia
were observed in one animal at 0.8 mg/kg bw per day and in three animals at 1.6
mg/kg bw per day. Based on these observations, a LOAEL of 0.8 mg/kg bw per
day was identified, and the NOAEL was 0.4 mg/kg bw per day. The Committee
noted that the study design was not clearly explained and the findings were
difficult to interpret.
In a 14-week study, ivermectin was given to dogs (four of each sex per
group) by oral gastric intubation at a dose of 0, 0.5, 1.0 or 2.0 mg/kg bw per
day. Controls received water or vehicle (sesame oil). At 2.0 mg/kg bw per day,
mydriasis was observed in all animals; three males and one female developed
tremors, ataxia, anorexia and dehydration, lost body weight (1.01.6 kg), were
frequently found laterally recumbent and were ataxic when standing. Based on
occasional mydriases and a retardation of weight gain in animals, the LOAEL was
1.0 mg/kg bw per day, and the NOAEL was 0.5 mg/kg bw per day (17).
In a 16-day oral toxicity study, ivermectin was given to immature
rhesus monkeys (1321 months old) at a dose of 0, 0.3, 0.6 or 1.2 mg/kg bw
by nasogastric intubation. Controls received vehicle (sesame oil). There were no
treatment-related effects noted in any of the treated animals. A NOAEL of 1.2
mg/kg bw per day, the highest dose tested, was identified.

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 Joint FAO/WHO Expert Committee on Food Additives Eighty-first report

Long-term oral toxicity or carcinogenicity studies with ivermectin were

not available, but the Committee at its thirty-sixth meeting (Annex 1, reference
91) concluded that given the structural similarities and comparative toxicological
profiles of ivermectin and abamectin, such studies were not required. In a 94-
week dietary carcinogenicity study in mice using abamectin doses of 0, 2, 4 and 8
mg/kg bw per day, a no-observed-effect level (NOEL) (NOAEL) of 4.0 mg/kg bw
per day was identified. Furthermore, in a 105-week dietary carcinogenicity study
in rats with abamectin doses of 0, 0.75, 1.5 and 2.0 mg/kg bw per day, a NOEL
(NOAEL) of 1.5 mg/kg bw per day was identified. The present Committee agrees
with these conclusions.
In a reproductive toxicity study, ivermectin was given orally to female
rats at a dose of 0, 0.4, 0.8 or 1.6 mg/kg bw per day from 15 days prior to mating
until 20 days postpartum. Two control groups received the vehicle (sesame oil).
Based on no adverse findings in the dams, a maternal toxicity NOAEL of 1.6 mg/
kg bw per day, the highest dose tested, was identified. A statistically significant,
treatment-related increase in pup mortality in the 1.6 mg/kg bw per day group
was observed on day 1 and days 714 postpartum. An offspring toxicity LOAEL
of 1.6 mg/kg bw per day was identified, and the offspring toxicity NOAEL was 0.8
mg/kg bw per day.
Three multigeneration reproductive toxicity studies were undertaken
in rats. The first two studies failed to establish a NOAEL for ivermectin when
given orally to rats at 0.4, 1.2 and 3.6 mg/kg bw per day or 2.0 mg/kg bw per day,
respectively. In a third multigeneration study, rats were given ivermectin orally
at 0.05, 0.1, 0.2 or 0.4 mg/kg bw per day. A vehicle control group received sesame
oil. Treatment-related effects were limited to a slight, but statistically significant,
decrease in body weight gain during the post-weaning period in the F1b females
in the 0.4 mg/kg bw per day group and the F2b males in the 0.2 and 0.4 mg/kg
bw per day groups. There were no treatment-related effects on the reproductive
performance of male or female rats in any dose group. There was no evidence of
WHO Technical Report Series No. 997, 2016

teratogenicity in the F3 offspring. A parental and offspring toxicity NOAEL of 0.4

mg/kg bw per day, the highest dose tested, was identified.

Observations in humans
In a double-blind, randomized, placebo-controlled, multiple-rising-dose
study (0, 30, 60, 90 and 120 mg, equivalent to 0, 0.4, 0.8, 1.2 and 1.5 mg/kg bw,
respectively, based on median body weight) to investigate the safety, tolerability
and pharmacokinetics of multiple doses of ivermectin, 12 healthy human
subjects per dose group were administered oral doses of ivermectin of 30 or 60
mg on days 1, 4 and 7 or single doses of 90 or 120 mg. An additional four healthy
human subjects per dose group were administered a placebo. All subjects were

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fasted prior to dosing. A group of the subjects who received 30 mg were allowed
a 1-week washout and then fed prior to administration of a single oral dose of
30 mg ivermectin. All doses of ivermectin were well tolerated. No adverse effects
on human health, in particular upon the neurological system, were identified.
The NOAEL for acute oral toxicity of ivermectin was determined to be 120 mg,
equivalent to 1.5 mg/kg bw, the highest dose tested, based on a median body
weight of 77.9 kg (16).
Ivermectin has been administered to several million human patients for
the treatment of onchocerciasis at a recommended oral dose level of 150 g/kg
bw administered once every 12 months. No signs of acute central nervous system
toxicity have been reported. The adverse reactions that have been observed in
treated patients have been described as allergic or inflammatory responses
resulting from the killing of microfilariae, referred to as the Mazotti reaction.
No significant adverse effects on fetuses have been reported when pregnant
women were inadvertently treated with ivermectin.
Ivermectin may also be used in the treatment of lymphatic filariasis,
strongiloidiasis and scabies. The treatment of scabies generally requires a single
oral dose of 200 g/kg bw, but two or three repeated doses may be needed,
separated by an interval of 1 or 2 weeks, to be fully effective. The sponsor identified
a number of reported studies where parasitized patients received up to 13 oral
doses of ivermectin (800 g/kg bw) during the course of treatment. These studies
reported that ivermectin was well tolerated and noted no serious adverse health
effects. A recent review of the acute toxicity of macrocyclic lactones reported that
adverse health effects of ivermectin treatment in patients with onchocerciasis
were related not to the dosage of ivermectin, but to the skin microfilarial load.

Microbiological data
Considering the chemical structure and mode of action, the Committee did not
anticipate any adverse effects of ivermectin residues on human gastrointestinal
microbiota.

Evaluation

Acceptable daily intake. The Committee established an ADI of 010 g/kg bw on

the basis of a NOAEL of 0.5 mg/kg bw per day for neurological effects (mydriasis)
and retardation of weight gain in a 14-week dog study (17), with application of an
uncertainty factor of 50. The previous ADI of 01 g/kg bw is withdrawn.
The Committee did not consider the human clinical data sufficient to
assess the possible long-term effects of repeated exposure to ivermectin, such
as would occur from its use as a veterinary drug. Therefore, the Committee

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identified the 14-week dog study as the most appropriate for use in establishing
an ADI, given the non-relevance of effects in the CF-1 mouse and the neonatal
rat due to their low expression of P-glycoprotein.
As the interspecies differences in pharmacokinetics between dogs and
humans are such that humans would be exposed to less ivermectin at a given
dose compared with dogs, a reduction in the interspecies uncertainty factor
for pharmacokinetics would be appropriate. The quality of the information on
pharmacokinetics in dogs was not sufficient to enable the Committee to calculate
accurately a chemical-specific adjustment factor for interspecies differences in
pharmacokinetics. A reduction by 50% was used as a conservative estimate. An
uncertainty factor of 50, comprising a factor of 5 for interspecies differences and
a factor of 10 for intraspecies differences, was therefore adopted.

Acute reference dose. As ivermectin may be administered to cattle in an

injectable form, there is the possibility that humans may be exposed to animal
tissue containing high concentrations of ivermectin from the injection site. For
this scenario, the Committee evaluated the acute toxicity of the compound to
determine the need for establishing an ARfD.
The Committee established an ARfD of 200 g/kg bw, based on a
NOAEL of 1.5 mg/kg bw, the highest dose tested in a safety, tolerability and
pharmacokinetics study in healthy human subjects (16), with application of an
uncertainty factor of 10 for intraspecies variability. The Committee identified the
human study as the most appropriate study for use in establishing an ARfD, given
the non-relevance of the embryo/fetal toxicity findings in juvenile rats due to
their low expression of P-glycoprotein. The Committee noted that the ARfD was
conservative, as an acute oral LOAEL for ivermectin has not been identified in
humans.

An addendum to the toxicological monograph was prepared.

WHO Technical Report Series No. 997, 2016

Residue evaluation
The current Committee received seven residue depletion studies from two sources.
Six had not been previously reviewed by JECFA, and one was resubmitted from
the original sponsor.
All studies in this report are GLP compliant unless otherwise indicated.

Resubmitted study
In a study using non-radiolabelled drug, 36 castrated male and 36 female
crossbred beef cattle weighing 297401 kg were used. A 1% weight per volume
(w/v) ivermectin injectable formulation was administered subcutaneously at

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1 mL/50 kg. Animals were killed in groups of 12 at 21, 28, 35, 42, 49 and 56
days post-dose, and edible tissues, including injection site, were collected from
each animal. The samples were analysed by a validated HPLC method with
fluorescence detection. The LOD and limit of reliable measurement, assumed
to be the LOQ, were 12 g/kg and 10 g/kg, respectively. Residues were highest
in liver, followed by fat. Residues had depleted to below the LOQ of the method
in liver by 49 days post-dose. In muscle and kidney, residue concentrations had
depleted to below the LOQ by 21 days post-dose.

New studies submitted for consideration by current JECFA

A non-GLP-compliant radiolabelled residue depletion study was conducted
using [3H]ivermectin pour-on formulation. Twelve steers were dosed at 0.5 mg/
kg bw with a topical formulation of 0.5% w/v ivermectin at a specific activity of
11.1 MBq/mg and a 93:7 ratio of H2B1a:H2B1b. Three animals in each group were
slaughtered at 7, 14, 28 or 42 days post-dose to collect edible tissues and excreta.
The TRR concentrations were determined by combustion analysis. The drug was
excreted mainly in faeces, with a much lower percentage excreted in urine. The
residue concentrations were highest in liver, followed by fat, muscle adjacent to
the dose site, kidney and, lastly, regular muscle.
In a non-radiolabelled residue depletion study, 40 cattle (20 females, 20
males) weighing 255382 kg were administered a single subcutaneous injection
of a combination product at a dose of 0.2 mg ivermectin/kg bw plus 2 mg
clorsulon/kg bw. Tissue samples (entire liver, both kidneys, perirenal fat, skeletal
muscle, core injection site and concentric ring around the core injection site) were
collected on days 3, 10, 17, 28, 45, 52, 60, 70, 79 and 80 post-dose. Tissue samples
were assayed for determination of ivermectin marker residue (ivermectin B1a)
using a validated analytical method utilizing HPLC with fluorescence detection.
The validated LOQ for the marker residue was 5 g/kg, and the LOD was 1 g/
kg. The injection site core muscle had the highest residues among all analysed
tissues, followed by the liver, fat, kidney and regular muscle, consistent with the
distribution pattern observed in the previously described studies. At 60 days post-
dose, residues were still found in some liver and fat samples. Although sampling
continued through 80 days post-dose, no samples were analysed beyond 60 days
post-dose.
An additional three studies of unknown GLP status and one GLP-
compliant study conducted in cattle were also submitted. Although lacking
sufficient information to be considered suitable in the development of MRL
recommendations, these studies provided supporting information consistent
with more well-documented studies.

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On the basis of the deficiencies identified by the Committee in four of

the new depletion studies submitted for consideration by the eighty-first JECFA,
only one new depletion study with non-radiolabelled drug together with the new
radiolabel study and the depletion study with non-radiolabelled drug previously
submitted to JECFA were used in the development of MRL recommendations.
The Committee confirmed that ivermectin B1a is the marker residue and
that liver and fat are the target tissues for the use of ivermectin in cattle.

Analytical methods
A reversed-phase HPLC method with fluorescence detection was used to
determine the marker residue (ivermectin B1a) in bovine edible tissues. After
tissue homogenization in acetone/water, the marker residue is extracted with
isooctane. After evaporation, fat is removed from the sample with acetonitrile/
hexane binary mixture. The solvent is removed by evaporation, and a fluorescent
derivative is formed by on-line derivatization with trifluoroacetic anhydride/N-
methylimidazole. The derivatized residue is assayed using HPLC/fluorescence
with an excitation wavelength of 365 nm and an emission wavelength of 470
nm. No internal standard is used. The method quantitatively measures the B1a
component of ivermectin by comparison with a series of derivatized ivermectin
external standards.
The Committee assessed the validation data against the analytical
requirements as published in CAC/GL 71-2009 (15). The method has been
validated for selectivity, precision and accuracy, LOD and LOQ. No interfering
peaks were observed at the retention time of ivermectin B1a in any of the non-
fortified tissue samples, attesting to the selectivity of the method. The response of
the method was linear over the range 51000 g/kg. Calculated LODs were 0.10
g/kg for fat, 0.10 g/kg for kidney, 0.10 g/kg for liver and 0.05 g/kg for muscle.
The LOD of the method was set at 1 g/kg (lowest analysed concentration). The
LOQ was set at 5 g/kg for all tissues, the lowest concentration validated for
WHO Technical Report Series No. 997, 2016

ivermectin B1a with an acceptable precision and accuracy.

The Committee considered the quantitative HPLC/fluorescence
method submitted by the sponsor to be suitably validated to support the MRLs
recommended by the present meeting of the Committee. In addition, the
Committee noted the availability of LC-MS/MS methods, such as the method
reviewed by the seventy-eighth meeting of the Committee (Annex 1, reference
217), which meet both quantitative and confirmatory requirements for the
determination of ivermectin B1a residues in bovine muscle.

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Maximum residue limits

In recommending MRLs for ivermectin in cattle, the Committee considered the
following factors:
The ADI established by the Committee was 010 g/kg bw.
An ARfD of 200 g/kg bw was established by the Committee.
Ivermectin B1a (synonym for 22,23-dihydroavermectin B1a) is
confirmed as the marker residue.
The ratios of the marker residue to total residues of 0.18 in fat, 0.54 in
kidney, 0.37 in liver and 0.67 in muscle defined by the fortieth JECFA
were confirmed.
Two studies were used for deriving the MRLs and represent different
formulations and routes of administration of ivermectin to cattle.
The analysis of all data in cattle shows comparable residue depletion
profiles.
A validated quantitative analytical method for all edible tissues is
available and is suitable for regulatory monitoring.
The MRLs recommended for cattle tissues are based on the upper
limit of the one-sided 95% confidence interval over the 95th percentile
of residue concentrations (95/95 upper tolerance limit, or UTL) for
the day 14 post-treatment data from the non-radiolabelled residue
depletion studies. The time point chosen is consistent with approved
uses (GVP).
Based on the new assessment, the Committee recommended the
following revised MRLs in cattle tissues: 400 g/kg for fat, 100 g/kg for kidney,
800 g/kg for liver and 30 g/kg for muscle.3

Chronic dietary exposure assessment

The EDI is 38 g/person per day, based on a 60 kg individual, which represents
6% of the upper bound of the ADI.
The GECDE for the general population is 0.9 g/kg bw per day, which
represents 9% of the upper bound of the ADI. The GECDE for children is 1.5 g/
kg bw per day, which represents 15% of the upper bound of the ADI. The GECDE
for infants is 1.3 g/kg bw per day, which represents 13% of the upper bound of
the ADI.

No new data were provided for use of ivermectin in dairy cattle; therefore, the Committee did not
3

recommend any revision to the MRL of 10 g/kg for ivermectin in milk.

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 Joint FAO/WHO Expert Committee on Food Additives Eighty-first report

Acute dietary exposure assessment: injection site residues

A combined analysis of all studies submitted showed that after 14 days, the
maximum values of residues found at injection sites led to acute exposures
(GEADE) of 52 g/kg bw for the general population and 87 g/kg bw for children,
corresponding, respectively, to 27% and 43% of the ARfD.
The Committee considers that the presence of high concentrations
of ivermectin residues at the injection site is product dependent and must be
assessed on a case-by-case basis during marketing authorization by comparison
of suitable acute dietary exposure estimates with the ARfD.

A residue monograph was prepared.

Summary and conclusions

Studies relevant to risk assessment

Species / study type Doses (mg/kg bw NOAEL (mg/kg LOAEL (mg/kg
(route of administration) per day) Critical end-point bw per day) bw per day)
Rat
Reproductive toxicity study 0, 0.4, 0.8, 1.6 Increase in pup mortality 0.8 1.6
(oral)
Multigeneration reproduc- 0, 0.05, 0.1, 0.2, 0.4 No adverse findings 0.4a
tive toxicity study (oral)
Dog
Fourteen-week toxicity study 0, 0.5, 1.0, 2.0 Mydriasis, retarded body weight gain 0.5* 1.0
(gastric intubation)
Rhesus monkey
Sixteen-day toxicity study 0, 0.3, 0.6, 1.2 No adverse findings 1.2a
(nasogastric intubation)
Human
Safety, tolerability and 0, 0.4, 0.8, 1.2, 1.5 No adverse findings 1.5a,**
pharmacokinetics study in
WHO Technical Report Series No. 997, 2016

healthy subjects (oral)

* Pivotal study value for the derivation of the ADI (17)
** Pivotal study value for the derivation of the ARfD (16)
a
Highest dose tested.

Uncertainty factor
ADI: 50 (5 for interspecies variability and 10 for intraspecies variability)
ARfD: 10 (10 for intraspecies variability)

ADI (based on toxicological effects)

010 g/kg bw

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ARfD (based on toxicological effects)

200 g/kg bw

Residue definition
Ivermectin B1a (22,23-dihydroavermectin B1a)

MRLs
400 g/kg for fat, 100 g/kg for kidney, 800 g/kg for liver and 30 g/kg for
muscle in cattle

Estimated chronic dietary exposure

The EDI is 38 g/person per day, based on a 60 kg individual, which represents 6%
of the upper bound of the ADI. The GECDE for the general population is 0.9 g/
kg bw per day, which represents 9% of the upper bound of the ADI. The GECDE
for children is 1.5 g/kg bw per day, which represents 15% of the upper bound of
the ADI. The GECDE for infants is 1.3 g/kg bw per day, which represents 13%
of the upper bound of the ADI.

Estimated acute dietary exposure

After 14 days, the maximum values of residues found at injection sites led to
acute exposures (GEADE) of 52 g/kg bw for the general population and 87 g/
kg bw for children, corresponding, respectively, to 27% and 43% of the ARfD.

4.3 Sisapronil
Explanation
Sisapronil, formerly known as phenylpyrazole, is the proposed
International Non-proprietary Name (INN) for 5-amino-1-[2,6-dichloro-4-
(trifluoromethyl)phenyl]-4-[2,2-difluoro-1-(trifluoromethyl) cyclopropyl]-1H-
pyrazole-3-carbonitrile (IUPAC), with CAS no. 856225-89-3. It is a new member
of the phenylpyrazole class of compounds. It is a long-acting subcutaneous
injectable ectoparasiticide for control of cattle ticks. It also aids in the control of
bot fly larvae, hornfly and screwworm. It is approved for use in cattle as a single
subcutaneous injection of 2 mg/kg bw, with a withdrawal time of 120 days.
Sisapronil binds to ligand-gated chloride channels, in particular those
gated by the neurotransmitter gamma-aminobutyric acid (GABA), thereby non-
competitively blocking pre-synaptic and post-synaptic transfer of chloride ions
across cell membranes in insects or acari. This mechanism of action results in
uncontrolled activity of the central nervous system and death of the parasites.

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Sisapronil has not previously been evaluated by the Committee. The

Committee evaluated sisapronil at the present meeting at the request of the
Twenty-second Session of CCRVDF (2), with a view to establishing an ADI and
recommending MRLs in cattle tissues.

Toxicological and microbiological evaluation

Information submitted to the Committee included studies on acute, repeated-
dose, reproductive and developmental toxicity, genotoxicity and neurotoxicity.
Pivotal studies were conducted according to GLP standards and in accordance
with OECD and/or VICH guidelines. A literature search provided no additional
information.

Biochemical data
The pharmacokinetics of sisapronil were studied in rats, dogs and cynomolgus
monkeys. Most of the investigations were done as part of the toxicological studies.
Twenty-four hours after administration of 14C-labelled sisapronil by
oral gavage to rats at a dose of 50 mg/kg bw, the radioactivity in faeces was
approximately 98% of the total recovery from excreta, and the remainder was
found in urine, suggesting limited absorption.
An oral bioavailability of 6.8% was determined in cynomolgus monkeys
by comparing the pharmacokinetics data in plasma following a single oral
administration with those following a single intravenous administration.
There was little information on the distribution and metabolism of
sisapronil in laboratory animals. In a radiolabel study in rats, the parent sisapronil
accounted for more than 91% of the radioactivity in faeces at 24 hours after oral
administration. In addition, sisapronil was identified as the primary residue in
the liver. A metabolite was detected in the liver of rats, but could not be identified.
It had the same retention time as the main metabolite found in cattle liver, which
WHO Technical Report Series No. 997, 2016

could not be identified because of the low quantities present. These data suggest
that sisapronil undergoes minimal metabolism and that the metabolite found in
cattle is also present in the rat and therefore is inherently tested in the toxicity
studies on rats.
In rats, the elimination half-life of sisapronil in plasma was approximately
14 days. This half-life was determined in a 28-day repeated-dose toxicity study in
which blood samples were taken at 4, 8 and 24 hours post-dosing on several study
days, including day 1. The Committee considered that this estimated half-life
in rats should be viewed with great caution, because it was based on only three
time points and involved a large time extrapolation. The sponsor cited a half-life
of 2039 days, derived from an exploratory oral study in rats with a sampling
period of 14 days; however, that study was not provided. The Committee noted

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that a time to steady state of approximately 100150 days could be estimated

from the timeconcentration profile in plasma in rats from the 1-year repeated-
dose toxicity study. In the 1-year rat study, the mean concentrations of sisapronil
in plasma at the last time point were approximately 325, 567, 1172 and 3424 ng/
mL for the 0.1, 0.3, 1.0 and 10 mg/kg bw per day dose groups, respectively. The
increase in sisapronil concentration in plasma was dose dependent, but less than
dose proportional. Across the repeated-dose toxicity studies in rats, substantial
differences in sisapronil concentrations in plasma were noted, but the cause of
this could not be determined.
In a non-GLP-compliant study, dogs were given a single intravenous
sisapronil dose of 0.5, 1.5 or 5 mg/kg bw. Blood samples were taken over a period
of 268 days. The plasma elimination half-life for all three doses was approximately
100 days.
The concentration of sisapronil in plasma was studied in cynomolgus
monkeys over a period of 70 days after a single intravenous administration of
0.5 mg/kg bw. From this study, a plasma elimination half-life of 12.4 days was
calculated.

Toxicological data
Single-dose oral toxicity studies with sisapronil were conducted in mice and rats.
The oral LD50 in rats was 552 mg/kg bw. In mice, no mortality was observed at 30
mg/kg bw, the highest dose tested.
Studies in rabbits showed that sisapronil was not irritating to the skin
or the eyes. Sisapronil was not a skin sensitizer in the murine local lymph node
assay.
Repeated-dose oral toxicity studies were conducted with sisapronil in
rats (gavage) and dogs (capsules). The main studies in rats included a 90-day
study and a 1-year study. Studies in dogs included a range-finding 28-day study
and a 90-day study.
The main target organs for toxicity in rats and dogs were the liver and
thyroid.
In rats given an oral gavage sisapronil dose of 0, 0.1, 0.3, 1.0 or 10 mg/
kg bw per day for 90 days, increased levels of thyroid stimulating hormone
(TSH) and decreased levels of thyroxine (T4) in plasma were observed at the
highest dose. Animals of this group also showed increased absolute and relative
liver and thyroid weights, hepatocellular hypertrophy and thyroid follicular cell
hypertrophy. The NOAEL in this study was 1.0 mg/kg bw per day, based on effects
on the liver and thyroid at 10 mg/kg bw per day.
In rats given an oral gavage sisapronil dose of 0, 0.1, 0.3, 1.0 or 10 mg/
kg bw per day for 1 year, decreases in levels of triiodothyronine (T3) and T4 in

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plasma were observed at the highest dose. Increased absolute and relative liver
weights were observed in both sexes at 1.0 and 10 mg/kg bw per day. Increased
relative thyroid weights were observed at 1.0 mg/kg bw per day in males only,
and absolute and relative thyroid weights were seen at 10 mg/kg bw per day in
both sexes. The livers of the animals at 1.0 and 10 mg/kg bw per day showed
centrilobular hepatocellular hypertrophy and vacuolation. Thyroid follicular cell
hypertrophy, hyperplasia and adenomas were statistically significantly increased
at doses of 1.0 and 10 mg/kg bw per day. The NOAEL in this study was 0.3 mg/kg
bw per day, based on changes in the liver and thyroid at 1.0 mg/kg bw per day.
In a range-finding 28-day oral toxicity study, dogs were given sisapronil
in capsules at a dose of 0, 1, 5 or 25 mg/kg bw per day. Relative liver weights were
increased in high-dose males and females, accompanied by increased glycogen
in hepatocytes. Absolute and relative thymus weights were decreased in females
of the 5 and 25 mg/kg bw per day groups. These decreases were statistically
significant in females of the 5 mg/kg bw per day group only. Microscopically, the
decreased thymus weights correlated with an increased incidence of minimal to
mild decreased cellularity of the lymphoid tissue. The NOAEL in this study was
1 mg/kg bw per day, based on changes in the thymus at 5 mg/kg bw per day.
In a 90-day repeated-dose oral toxicity study, dogs were given sisapronil in
capsules at a dose of 0, 0.3, 1 or 10 mg/kg bw per day. Dogs had increased absolute
and relative liver weights and vacuolar degeneration of individual hepatocytes
at the highest dose. At 1 and 10 mg/kg bw per day, an increase in glycogen in
hepatocytes was observed. Minimal thyroid follicular cell hypertrophy was
observed at 1 and 10 mg/kg bw per day. Thyroid follicular cell hypertrophy was
characterized by cuboidal to tall cuboidal follicular cells, frequently associated
with increased vacuolation in the apical cytoplasm. This hypertrophy occurred
without increased thyroid weight or changes in thyroid hormone levels in blood.
A NOAEL of 0.3 mg/kg bw per day was identified, based on minimal thyroid
follicular cell hypertrophy and increased glycogen in hepatocytes at 1 mg/kg bw
WHO Technical Report Series No. 997, 2016

per day.
The genotoxicity of sisapronil was investigated in an adequate array of in
vitro and in vivo tests. No evidence of genotoxicity was found. In silico analysis
revealed no structural alerts for genotoxicity. The Committee concluded that
sisapronil is not genotoxic.
No specific 2-year toxicity studies or carcinogenicity studies were
provided. The study with the longest duration was the 1-year repeated-dose oral
toxicity study in rats.
The only test articlerelated proliferative lesions in the 1-year oral toxicity
study in rats described above were thyroid hyperplasia and thyroid tumours
(adenomas). The NOAEL for these thyroid effects was 0.3 mg/kg bw per day. A
study was conducted to determine a possible mode of action for thyroid hormone
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changes and to evaluate the microscopic liver and thyroid changes observed
in rats. This study supported a mode of action for sisapronil-induced thyroid
tumour formation involving the disruption of homeostasis of the hypothalamic
pituitarythyroid (HPT) axis by an extrathyroidal mechanism. Specifically,
sisapronil induces uridine diphosphate-glucuronosyltransferase (UGT), which
increases the conjugation of thyroid hormones (T3 and T4) in the liver. In
response to the hypothyroid state, TSH synthesis and release are stimulated, and
this is the key event that leads to thyroid follicular cell growth and hyperplasia.
In response to the hypothyroid state and increased TSH levels, the thyroid
gland is stimulated to produce more T4, and, over time, there is compensatory
thyroid gland enlargement. For sisapronil, the available data provide compelling
evidence that increased hepatic clearance of T3 and T4 causes chronic stimulation
of the HPT axis, seen acutely as an increase in TSH secretion, with long-term
stimulation of the thyroid gland as a chronic consequence leading to follicular
cell adenoma development.
The data from the 1-year rat study were used for benchmark dose (BMD)
modelling to assist in the analysis of the proposed mode of action. A number of
variables were used for the BMD analysis: TSH, total T4, free T3, relative (to body
and brain weights) liver and thyroid weights as well as the occurrence of bilateral
thyroid adenoma and hypertrophy. A benchmark response (BMR) of 10% extra
risk above the background was selected as the basis for estimating BMDs. Among
the variables analysed, the lower 95% confidence limit on the benchmark dose
(BMDL) values ranged from 0.26 to 0.79 mg/kg bw per day, which are supportive
of the 0.3 mg/kg bw per day NOAEL identified in this study.
Although the Committee recognized that a specific carcinogenicity study
had not been conducted, it concluded that sisapronil is not genotoxic and that the
thyroid tumours in rats are a result of an indirect perturbation of the HPT axis by
a mode of action not considered relevant to humans. Therefore, the Committee
concluded that sisapronil does not pose a risk of carcinogenicity to humans at
doses relevant to residues of veterinary drugs.
A two-generation reproductive toxicity study was conducted in rats
given sisapronil by oral gavage at a dose of 0, 0.3, 2.0 or 15 mg/kg bw per day.
The 15 mg/kg bw per day dose group was discontinued for the F1 generation
because of the high pup mortality in that group. Systemic toxicity was evidenced
by significant effects on the liver (increased absolute and relative liver weights)
and thyroid (follicular cell hypertrophy and hyperplasia) at 2.0 mg/kg bw per
day and higher. Although the reproductive performance of the F0 generation was
not affected at any dose level, low fertility in males and females, decreased male
copulation, decreased female conception indices and decreased ovarian follicle
counts were noted in the F1 generation at 2.0 mg/kg bw per day. The NOAEL for
reproductive toxicity was 0.3 mg/kg bw per day, the NOAEL for offspring toxicity
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was 2.0 mg/kg bw per day and the NOAEL for parental toxicity was 0.3 mg/kg bw
per day.
Developmental toxicity studies were conducted in rats and rabbits. The
rat study used oral gavage doses of 0, 0.3, 2.0 and 20 mg/kg bw per day. The only
effects seen in this study were reduced body weight gain and feed consumption
in dams at the high dose, which resulted in lower pup weights in that group. The
NOAEL for both maternal toxicity and embryo/fetal toxicity was 2.0 mg/kg bw
per day.
The developmental toxicity study in rabbits used oral gavage doses of
0, 0.3, 2.0 and 12.5 mg/kg bw per day. The dams of the high-dose group showed
reduced feed intake and severe body weight loss, resulting in moribundity,
abortion and premature delivery in several dams. The fetuses of this dose group
had lower mean body weights. The NOAEL for both maternal and embryo/fetal
toxicity was 2.0 mg/kg bw per day.
The Committee concluded that sisapronil is not teratogenic.
The acute neurotoxicity of sisapronil was investigated in rats given an oral
gavage dose of 0, 100, 500 or 1000 mg/kg bw. There was mortality at the highest
dose, and animals of the 500 and 1000 mg/kg bw per day groups showed reduced
gait, tremors, convulsions (high dose), hyperactivity, vocalization, laboured
breathing, reduced foot splay, reduced grip strength and altered reflex responses.
Motor activity parameters were also affected in these groups. The NOAEL in this
study was 100 mg/kg bw per day.

Microbiological data
Considering the chemical structure and the mode of action of sisapronil, the
Committee did not anticipate any adverse effects of sisapronil residues on the
human gastrointestinal microbiota.

Evaluation
WHO Technical Report Series No. 997, 2016

The main findings in the livers of rats and dogs treated with sisapronil included
increased liver weights, centrilobular hepatocellular hypertrophy, vacuolation
and increased glycogen in hepatocytes. Hepatocellular hypertrophy and increased
liver weights in rats are considered to be related to hepatic drug metabolizing
enzyme induction, an adaptive response. It is well known that rats are particularly
sensitive to developing thyroid tumours according to a mode of action, described
above, that is considered not to be relevant to humans.
The Committee noted that the lowest relevant NOAEL was 0.3 mg/kg
bw per day in both the 90-day oral toxicity study in dogs and the two-generation
reproductive toxicity study in rats. However, the Committee considered this 90-
day study in dogs to be unsuitable to address long-term toxicity, in view of the very

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long elimination half-life of sisapronil in dogs (i.e. 100 days). Longer-term oral
toxicity studies with sisapronil in dogs were not available. It remains uncertain
how the toxic effects in dogs might progress and whether or not other effects
might be triggered upon longer-term exposure. The Committee also concluded
that the NOAEL from the reproductive toxicity study in rats may not be sufficient
to protect against long-term effects of sisapronil.
The Committee concluded that a toxicological ADI could not be
established because the Committee had no basis upon which to determine a
suitable uncertainty factor to accommodate the lack of a long-term toxicity study.

Additional information that would assist in the further evaluation of the compound

Data to address long-term toxicity relevant to humans (e.g. 1-year

dog study)
Comparative pharmacokinetics studies and an explanation of
interspecies differences in the pharmacokinetic profiles.

A toxicological monograph was prepared.

Residue evaluation
The Committee reviewed studies on the pharmacokinetics and metabolism
of sisapronil in cattle, a radiolabelled residue depletion study in cattle, a non-
radiolabelled residue depletion study in cattle and information on an analytical
method submitted by the sponsor. All studies are compliant with GLP unless
otherwise specified.

Data on pharmacokinetics and metabolism

Cattle. Two non-GLP-compliant studies were conducted examining the
pharmacokinetics of non-radiolabelled sisapronil. In one study, cattle were
administered a single subcutaneous injection of sisapronil at a dose of 2 mg/kg
bw, and sisapronil concentrations were measured in plasma. Sisapronil reached a
mean peak concentration of 0.075 g/mL 15 days post-dose. The pharmacokinetic
parameters are a mean observed plasma elimination half-life of 23 days, a mean
residence time (MRT) of 48 days and an AUC of 39.5 d.g/mL.
In the second non-GLP-compliant study, cattle were treated with a single
injection of sisapronil at a dose of 2.0 mg/kg bw intravenously or subcutaneously.
Following a single intravenous dose, mean clearance of sisapronil was 0.87 L/
kg per day, or 0.6 mL/kg per minute, the mean volume of distribution was 24 L/
kg and the mean observed plasma elimination half-life was 19 days. Following a
single subcutaneous dose, the mean Cmax was 0.072 g/mL at a mean time to reach
Cmax (Tmax) of 12 days. Based upon comparison of mean AUCs for subcutaneous
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and intravenous treatments, the bioavailability after subcutaneous administration

was near 100%. The mean observed plasma elimination half-life was 19 days, and
the MRT was 32 days.
In a GLP-compliant study, nine groups of three beef cattle each were
treated with a single subcutaneous injection of [14C]sisapronil at a dose of 2.0
mg/kg bw, and groups were slaughtered at 10-day intervals from day 10 to day
90 post-dose for tissue residue analysis. Plasma samples were collected from the
final two sacrifice groups at study days 1, 5, 10, 20, 30, 40, 50, 60, 70, 80 and
90 (final group only) post-dose. Urine and faeces were collected on study days
1012, 3032 and 6062 and analysed for TRR. Parent sisapronil was identified
as the primary residue present in fat, liver, kidney and muscle. One significant
metabolite accounting for 1945% of the TRR was observed in liver. Only about
16% of the total dose administered was excreted. Most of the material was
excreted via faeces (97%). Radioactivity in plasma peaked at 5 days post-dose,
reaching a mean of 343 g eq/kg (80 days post-dose group) and 300 g eq/kg (90
days post-dose group). Total radioactivity in plasma declined to a mean of 42 g
eq/kg at 80 days post-dose and 26 g eq/kg at 90 days post-dose.

Residue data
Cattle. One study using [14C]sisapronil was performed. Cattle were treated with
a single subcutaneous dose of [14C]sisapronil of 2.0 mg/kg bw, and groups of four
animals (two of each sex) were slaughtered at 10-day intervals from day 10 to
day 90 post-dose. Total radioactivity was analysed, and sisapronil residues were
determined. In edible tissues, TRR were highest in fat, followed by liver, kidney
and then loin muscle. Mean TRR in fat were 10 195 g eq/kg at 30 days, declining
to 891 g eq/kg at 90 days. Mean TRR in liver were 2793 g eq/kg at 10 days,
declining to 299 g eq/kg at 90 days. Mean TRR in kidney were 1552 g eq/kg at
10 days, declining to 133 g eq/kg at 90 days. Mean TRR in hindquarter muscle
were 183 g eq/kg at 10 days, declining to below the LOD at 90 days.
WHO Technical Report Series No. 997, 2016

Based on the data from this study, the Committee took a conservative
approach and chose the lowest value reported over all time points analysed. The
following MR:TRR ratios were established for the following tissues: 0.90 for
muscle, 0.50 for liver, 0.86 for kidney and 0.94 for fat.
In another study, the depletion of non-radiolabelled sisapronil was
studied using cattle that received a single subcutaneous injection of sisapronil
of 2.0 mg/kg bw. Groups of four animals (two of each sex) were slaughtered at
30-day intervals from 30 to 240 days post-dose, and sisapronil concentrations
were determined using an LC-MS/MS method with an LOQ of 5 g/kg. In edible
tissues, at all time points, the highest residue concentrations were observed in
fat, followed by liver, kidney and then hindquarter muscle, with results above the

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LOQ observed at all time points. Mean residues in fat were 7520 g/kg at 30 days,
declining to 564 g/kg at 240 days. Mean residues in liver were 759 g/kg at 30
days, declining to 60 g/kg at 240 days. Mean residues in kidney were 465 g/kg at
30 days, declining to 43 g/kg at 240 days. Mean residues in hindquarter muscle
were 172 g/kg at 30 days, declining to 32 g/kg at 240 days. Mean residues in
core injection site muscle were 29 650 g/kg at 30 days, declining to 76 g/kg at
240 days. Mean residues in surrounding injection site were 4007 g/kg at 30 days,
declining to 119 g/kg at 240 days.
The Committee noted that the residue depletion data suggested that the
terminal elimination phase was appreciably longer than the reported plasma
elimination half-life.

Analytical methods
An LC-MS/MS method was used to determine the marker residue (parent
sisapronil) in bovine edible tissues. The marker residue is extracted by solidliquid
extraction. After agitation and centrifugation, the supernatant is transferred to
an HPLC vial. The stationary phase was a C18 column, and the mobile phase was
0.027% formic acid in 2 mM ammonium acetate (volume per volume [v/v]) (A)
and acetonitrile (B). Sisapronil residues are ionized in an electrospray interface
(negative polarity) before acquisition of the signal in the selected reaction
monitoring mode in a triple quadrupole mass spectrometer. Sisapronil labelled
at three positions (13C2-15N) was used as an internal standard. Standard curves
were generated using simple linear regression.
The Committee assessed the validation data against the requirements
for analytical methods as published in CAC/GL 71-2009 (15). The method has
been validated for selectivity, precision, accuracy, LOD and LOQ. No interfering
peaks were observed at the retention time of sisapronil in any of the non-fortified
samples, attesting to the selectivity of the method. The intra-day and inter-day
mean accuracies were in the range 85110% and 94105%, respectively, for all
tissues. The intra-day and inter-day precisions were in the range 1.117.5% and
3.412.4%, respectively, for all tissues. The calculated LODs were 0.2 g/kg for
muscle, 0.6 g/kg for liver, 0.6 g/kg for kidney and 0.3 g/kg for fat. The calculated
LOQs were approximately 0.6 g/kg for muscle, 1.6 g/kg for liver, 1.7 g/kg for
kidney and 0.8 g/kg for fat; the method validation established 5 g/kg as the
LOQ for sisapronil in bovine edible tissues. The analytical method proposed for
routine residue surveillance is a gradient LC-MS/MS method applicable in the
range of 51000 g/kg for all tissues. Accordingly, the method is expected to be
practicable and applicable in normal routine laboratory use.

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Maximum residue limits

MRLs could not be recommended by the Committee, as an ADI could not be
established.

A residue monograph was prepared.

Summary and conclusions

Studies relevant to risk assessment

Species / study type Doses (mg/kg bw NOAEL (mg/kg LOAEL (mg/kg
(route of administration) per day) Critical end-point bw per day) bw per day)
Rat
Three-month study of 0, 0.1, 0.3, 1.0, 10 Hepatocellular hypertrophy; thyroid 1.0 10
toxicity (gavage) follicular cell hypertrophy
One-year study of toxicity 0, 0.1, 0.3, 1.0, 10 Centrilobular hepatocellular hypertrophy; 0.3 1.0
(gavage) thyroid follicular cell hypertrophy,
hyperplasia and adenoma
Two-generation reproductive 0, 0.3, 2.0, 15 Parental toxicity: Follicular cell hypertrophy 0.3 2.0
toxicity study (gavage) and hyperplasia; increased liver weights
Reproductive toxicity: Low fertility in males 0.3 2.0
and females, decreased male copulation,
decreased female conception indices and
decreased ovarian follicle counts in F1
generation
Offspring toxicity: Decreased survival 2.0 15
Developmental toxicity study 0, 0.3, 2.0, 20 Embryo/fetal toxicity: Lower pup weight 2.0 20
(gavage) due to lower body weight gain and lower
feed consumption in dams
Rabbit
Developmental toxicity study 0, 0.3, 2.0, 12.5 Maternal toxicity: Severe body weight loss, 2.0 12.5
(gavage) reduced feed intake, moribundity, abortion
and premature delivery
Embryo/fetal toxicity: Reduced pup weight 2.0 12.5
WHO Technical Report Series No. 997, 2016

Dog
Three-month study of 0, 0.3, 1, 10 Increased glycogen in hepatocytes; thyroid 0.3 1
toxicitya (capsule) follicular cell hypertrophy
a
A plasma half-life of approximately 100 days was found in a non-GLP-compliant study in dogs.

ADI
No ADI was established because the Committee had no basis upon which to
determine a suitable uncertainty factor to accommodate the lack of a long-term
toxicity study.

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MRLs
MRLs could not be recommended by the Committee, as an ADI could not be
established.

4.4 Teflubenzuron
Explanation
Teflubenzuron (IUPAC name: 1-(3,5-dichloro-2,4-difluorophenyl)-3-(2,6-difluoro-
benzoyl)urea; CAS no. 83121-18-0) is an insecticide belonging to the benzoylurea
group of compounds. Its mode of action is through inhibition of the synthesis of
chitin, and hence it is most effective on the developmental stages of insects. Insects
are killed as a result of the disruption of their moulting. Teflubenzuron is approved
in many countries as an insecticide for use in plant production as well as for control
of sea lice (Lepeophtheirus salmonis and Caligus rogercresseyi) in aquaculture.
Teflubenzuron is used as a premix coated onto non-medicated fish feed pellets
to achieve an intended dose of 10 mg/kg bw per day for 7 consecutive days. The
withdrawal periods range from 7 to 11 days and from 45 to 96 degree-days.
Teflubenzuron has not been previously evaluated by the Committee,
although it was evaluated by JMPR as a pesticide in 1994 and 1996 (18, 19) and is
scheduled for periodic re-evaluation at JMPRs September 2016 meeting. JMPR
established an ADI of 00.01 mg/kg bw on the basis of a LOAEL of 2.1 mg/kg bw
per day in a mouse carcinogenicity study with the application of an uncertainty
factor of 200, including an additional factor of 2 to account for the use of a LOAEL
instead of a NOAEL.
The Committee evaluated teflubenzuron at the present meeting at the
request of the Twenty-second Session of the Codex Committee on Residues
of Veterinary Drugs in Foods (2), with a view to establishing an ADI and
recommending MRLs in finfish tissues.

Toxicological and microbiological evaluation

The Committee considered data on the pharmacokinetics, short- and long-
term toxicity, reproductive and developmental toxicity, genotoxicity and
carcinogenicity of teflubenzuron. In addition to a sponsors submission, relevant
studies retrieved from the published literature were evaluated. Most studies
submitted by the sponsor were conducted under GLP-compliant conditions.
Those that were not conducted under GLP-compliant conditions are identified
in this report.

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Biochemical data
Orally administered teflubenzuron was only partially, but relatively quickly,
absorbed. Following a single oral dose of radiolabelled teflubenzuron at 25 mg/kg
bw, approximately 20% of the radioactivity was absorbed; only 4% was absorbed
when rats were dosed at 750 mg/kg bw, suggesting a dose-dependent absorption.
Peak plasma concentrations were reached within 12 hours post-dosing and
were maintained at similar levels for up to 8 hours (low dose) or 24 hours (high
dose). In repeatedly dosed animals, there was some evidence of a dose-dependent
plateau in plasma concentration.
Most (9095%) radiolabelled teflubenzuron administered by gavage to
rats (single dose at 25 or 750 mg/kg bw or 14 daily doses of 25 mg/kg bw of
unlabelled drug followed by a single dose of 25 mg/kg bw radiolabelled drug)
was excreted in faeces, primarily as the parent compound. More than 85% of the
drug was excreted within the first 24 hours of the dosing. Only a small fraction
(0.153%) of the total oral dose of teflubenzuron was excreted in the urine. There
was no difference in excretion pattern between sexes or between animals dosed
with a single or multiple doses of the drug. Absorbed teflubenzuron was mostly
excreted through bile, predominantly as polar materials. Only negligible residues
of teflubenzuron were detected in tissues and organs (<2% of the dose), with no
evidence of accumulation.
Metabolites identified in bile and urine were benzoyl or aniline ring
hydroxylated teflubenzuron and conjugates of (3,5-dichloro-2,4-difluorophenyl)-
urea and 3,5-dichloro-2,4-difluoroaniline. Several polar metabolites were
detected in faeces, but the only metabolite characterized was (3,5-dichloro-
2,4-difluorophenyl)urea. Hydrolytic cleavage of the phenylurea bridge was
identified as the predominant pathway of teflubenzuron metabolism in a non-
GLP-compliant study in which rats were gavaged once with approximately 55
mg/kg bw of the drug. The scission products thus produced were either excreted
unmodified or further metabolized and excreted.
WHO Technical Report Series No. 997, 2016

Toxicological data
Teflubenzuron was shown to have low acute toxicity in laboratory animals. The
oral LD50 in mice and rats was greater than 5000 mg/kg bw. The dermal LD50 in
rats was greater than 2000 mg/kg bw, and the inhalation LC50 in rats was greater
than 5000 mg/m3 air. Teflubenzuron was not irritating to the skin or eyes of
rabbits, and it did not cause skin sensitization in the guinea-pig maximization
test.
Short-term toxicity studies of teflubenzuron in which the drug was
administered in diet were conducted in mice (one 13-week study), rats (one 13-
week study) and dogs (two 13-week studies and one 52-week study). In all three

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species, liver was identified as the target organ for toxic effects, as evidenced by
elevated enzyme activities and/or adaptive cellular changes.
In a study whose GLP-compliant status could not be verified, mice were
administered teflubenzuron at a concentration of 0, 100, 1000 or 10 000 mg/kg
diet (equal to 0, 12, 115 and 1213 mg/kg bw per day for males and 0, 14, 142
and 1450 mg/kg bw per day for females, respectively) for 13 weeks. In the high-
dose group, activities of liver enzymes (alkaline phosphatase in males, alanine
transaminase in females) and total cholesterol levels (females) were elevated,
and blood glucose levels (both sexes) were altered. In the mid- and high-dose
groups, absolute and relative liver weights were increased, with centrilobular
hepatocellular swelling (both sexes) and microscopic fatty changes (in males).
The NOAEL was identified as 100 mg/kg feed (equal to 12 mg/kg bw per day),
based on liver changes at 1000 mg/kg feed (equal to 115 mg/kg bw per day).
Rats were administered teflubenzuron at a concentration of 0, 100, 1000
or 10 000 mg/kg feed (equal to 0, 8, 82 and 809 mg/kg bw per day for males
and 0, 9, 94 and 942 mg/kg bw per day for females, respectively) for 13 weeks.
Some animals from the control and high-dose groups were observed for an
additional 4 weeks without treatment. Increased activities of several enzymes,
notably aspartate transaminase (middle and high doses, both sexes), ornithine
transcarbamylase (high dose, both sexes), alanine transaminase (mid- and high-
dose males), lactate dehydrogenase (high-dose males) and alkaline phosphatase
(all treated males), were observed, which returned to normal levels after 4 weeks
of drug withdrawal. At necropsy, increased absolute and relative weights of liver
in females and of testes in males were observed at the high dose. The statistically
significant change in alkaline phosphatase activity in male rats of the low-dose
group was not considered to be biologically relevant, being less than 1.5-fold
above the control value and within the normal physiological range. Based on
effects on liver enzymes at 1000 mg/kg feed (equal to 82 mg/kg bw per day), a
NOAEL of 100 mg/kg feed (equal to 8 mg/kg bw per day) was identified.
In a non-GLP-compliant study, the potential of teflubenzuron to form
methaemoglobin and exert other effects on haematological parameters in rats
was investigated in a comparative study that investigated five benzoylurea
insecticides. Although reticulocyte count was increased in rats treated with
teflubenzuron (100 mg/kg bw per day for 28 days), it was not associated with
anaemia or the formation of methaemoglobin.
In dogs administered teflubenzuron at a concentration of 0, 100, 1000 or
10 000 mg/kg feed (equal to 0, 3.5, 33.7 and 318.2 mg/kg bw per day for males and
0, 4.0, 42.8 and 417.1 mg/kg bw per day for females, respectively) for 13 weeks,
activities of alanine transaminase, aspartate transaminase, alkaline phosphatase
and ornithine transcarbamylase were increased in both sexes at the high dose. At
necropsy, absolute and relative liver weights were elevated and the incidence of
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nodular foci in the pyloric or fundic region of the stomach was increased at the
high dose. Isolated dark red foci were noted in the pyloric region of the stomach at
the middle and high doses. Focal gastritis was observed in females at the middle
and high doses, and follicular hyperplasia of the pyloric mucosa was noted in most
animals at the high dose. Mild hepatitis in one male and centrilobular hepatic
necrosis in another male were observed at the low dose. Also, moderate chronic
active hepatitis was diagnosed in one animal of each sex at the high dose. Given
the lack of a clear doseresponse relationship for hepatitis, the mild microscopic
hepatic changes noted in two dogs in the low-dose group were not considered to
be a treatment-related adverse effect. The NOAEL was 100 mg/kg feed (equal to
3.5 mg/kg bw per day), based on stomach lesions at 1000 mg/kg feed (equal to
33.7 mg/kg bw per day).
In a supplementary study to clarify the effects on liver, dogs were
administered teflubenzuron at a concentration of 0, 30 or 100 mg/kg feed (equal
to 0, 1.2 and 4.4 mg/kg bw per day for males and 0, 1.5 and 5.1 mg/kg bw per day
for females, respectively) for 13 weeks. There were no treatment-related adverse
effects identified in clinical examination, laboratory testing, and macroscopic or
microscopic examination of organs. The NOAEL was 100 mg/kg feed (equal to
4.4 mg/kg bw per day), the highest dose tested.
In a 52-week study, dogs were administered teflubenzuron at a
concentration of 0, 30, 100 or 500 mg/kg feed (equal to 0, 1.0, 3.2 and 17.3 mg/
kg bw per day for males and 0, 1.2, 4.0 and 18.0 mg/kg bw per day for females,
respectively). At necropsy, the absolute liver weight in males was increased at the
high dose, but no treatment-related changes were noted in gross pathological or
histopathological examinations. The NOAEL was 100 mg/kg feed (equal to 3.2
mg/kg bw per day), based on the liver weight change at 500 mg/kg feed (equal to
17.3 mg/kg bw per day).
The Committee identified an overall NOAEL of 100 mg/kg feed (equal
to 4.4 mg/kg bw per day) from three short-term studies in dogs, based on the
WHO Technical Report Series No. 997, 2016

findings of adverse effects in liver at a dose of 500 mg/kg feed (equal to 17.3 mg/
kg bw per day).
In a carcinogenicity study in mice (20), teflubenzuron was administered
at a concentration of 0, 15, 75 or 375 mg/kg feed (equal to 0, 2.1, 10.5 and
53.6 mg/kg bw per day for males and 0, 3.1, 15.4 and 71.7 mg/kg bw per
day for females, respectively) for 78 weeks, with an interim kill at week 52.
Aspartate transaminase, alanine transaminase, ornithine transcarbamylase,
lactate dehydrogenase and alkaline phosphatase activities were elevated in
high-dose males, but only alanine transaminase activity was elevated in high-
dose females. Absolute and relative liver weights were higher in both sexes at
the high dose, and relative liver weight was slightly increased in the mid-dose
males. The incidence of macroscopic hepatic nodules was increased in the high-
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dose males. Histopathology indicated an increased incidence of hepatocellular

adenomas and nodular hepatic hyperplasia in males treated at the middle and
high doses compared with both concurrent and historical controls, but there was
no difference in the incidence of hepatic carcinoma. Several treatment-related,
dose-dependent, non-neoplastic hepatic changes were also observed, which were
more pronounced in males than in females. In particular, males in the control,
low-dose, mid-dose and high-dose groups, respectively, had dose-dependent
incidences of hepatocellular hypertrophy (12/60, 29/60, 46/60 and 56/60), single-
cell necrosis (13/60, 26/60, 42/60 and 56/60), phagocytic cell foci (17/60, 21/60,
43/60 and 54/60) and lipofuscin accumulation (8/60, 11/60, 20/60 and 27/60). In
the low-dose group, the incidence, but not the severity, of these non-neoplastic
hepatic changes was significantly higher when compared with the controls.
Histopathological sections of liver from male mice in this study were re-
evaluated by an independent pathologist, with a focus on nodular liver lesions. The
pathologist concluded that there was a dose-related increase in the incidence of
hepatocellular hyperplastic nodules and a slight, but statistically non-significant,
increase in hepatocellular adenoma.
Given that only hepatic adenomas were observed and that the
genotoxicity test results were negative (see below), the Committee considered
that teflubenzuron was not carcinogenic in mice. However, the Committee
concluded that teflubenzuron induced hyperplastic proliferation in liver of mice
by an unknown mechanism. Based on the increased incidence of non-neoplastic
hepatic changes observed in liver (e.g. hepatocellular hypertrophy, single-cell
necrosis, phagocytic cell foci, lipofuscin accumulation) at all doses, no NOAEL
could be identified. The lowest dietary concentration, 15 mg/kg feed (equal to 2.1
mg/kg bw per day), was identified as the LOAEL.
In the absence of a NOAEL, to better characterize the point of departure,
the Committee conducted a doseresponse analysis of these data using the BMD
approach. Of several non-neoplastic hepatic changes identified, hepatocellular
hypertrophy was considered to be the most toxicologically relevant effect for dose
response modelling. The BMD and BMDL for a 10% response over the controls
(BMD10 and BMDL10) were determined using nine different dichotomous models.
Three models (LogLogistic, LogProbit and Multistage) provided acceptable fits
based on statistical considerations. However, the BMD10 and BMDL10 estimated
by the LogLogistic and LogProbit models were much lower than the lowest dose
used in the study. Furthermore, the Multistage model provided a better fit of the
BMDL value for the benchmark response at the low end of the observed range of
the data. Therefore, the Committee considered the BMDL10 of 0.54 mg/kg bw per
day for the BMD10 of 0.73 mg/kg bw per day estimated by the Multistage model
as the most appropriate point of departure for this study.

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 Joint FAO/WHO Expert Committee on Food Additives Eighty-first report

In a carcinogenicity study, rats were administered teflubenzuron at a

concentration of 0, 20, 100 or 500 mg/kg feed (equal to 0, 1.0, 4.8 and 24.8 mg/
kg bw per day for males and 0, 1.2, 5.9 and 29.9 mg/kg bw per day for females,
respectively) for 120 weeks, with an interim kill at weeks 53 and 107. Mortality
ranged from 40% to 50% at week 120, which was not influenced by treatment.
Increased (approximately 1.5- to 3-fold) activities of alanine transaminase,
aspartate transaminase and ornithine transcarbamylase were noted in males in
the high-dose group. Absolute and relative liver weights were increased in high-
dose males. Several non-neoplastic microscopic changes were noted in different
organs, but were not treatment related. Trend analysis identified increased
incidences of haemangiomas in mesenteric lymph nodes and pancreatic exocrine
carcinoma in the high-dose males. However, they were not significantly different
when compared with historical controls. Also, the occurrence of pancreatic
exocrine carcinoma was too infrequent (2/47 versus 0/50) to allow a meaningful
comparison to be drawn. Based on the effect on liver enzymes and liver weight
at 500 mg/kg feed (equal to 24.8 mg/kg bw per day), the NOAEL was 100 mg/kg
feed (equal to 4.8 mg/kg bw per day).
In a supplemental carcinogenicity study, rats were administered
teflubenzuron at a concentration of 0, 2500 or 10 000 mg/kg feed (equal to 0,
123 and 487 mg/kg bw per day for males and 0, 154 and 615 mg/kg bw per
day for females, respectively) for 111 weeks, with an interim kill at week 104.
Clinical biochemistry revealed increased activities of alanine transaminase and
aspartate transaminase in males at both doses and of aspartate transaminase in
females at the high dose. The absolute and relative liver (interim and terminal
kill) and kidney (interim kill) weights were increased in males at the high dose
compared with controls. Dose-dependent increases in the incidence of diffuse,
clay-coloured discoloration and focal and multifocal discoloration of livers were
observed in treated males (both doses). Also, treatment-related non-neoplastic
microscopic changes (e.g. fatty changes, mixed cell and basophilic cell foci, focal
WHO Technical Report Series No. 997, 2016

hepatocellular hyperplasia, spongiosis hepatis) were noted in the liver of both sexes
at both doses tested, lesions being more severe in males than in females. There
was no compound-related increase in the incidence of any tumours observed
in this study, including mesenteric lymph node haemangioma and pancreatic
exocrine carcinoma in male rats, thus confirming the lack of association between
substance administration and the occurrence of these tumours suggested from
the previous study.
Although no NOAEL could be identified in the second study owing to
non-neoplastic microscopic hepatic changes and elevated liver enzyme activities
in both treatment groups, the Committee was able to identify an overall NOAEL
of 100 mg/kg feed (equal to 4.8 mg/kg bw per day) from the two chronic toxicity
and carcinogenicity studies in rats.
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 Comments on residues of specific veterinary drugs

The Committee concluded that teflubenzuron is not carcinogenic in

mice or rats.
The genotoxic potential of teflubenzuron was investigated in an adequate
range of in vitro and in vivo assays. No evidence of genotoxicity was detected, and
teflubenzuron was considered unlikely to be genotoxic.
In view of the lack of genotoxicity and the absence of carcinogenicity in
mice and rats, the Committee concluded that teflubenzuron is unlikely to pose a
carcinogenic risk to humans.
In a multigeneration reproductive toxicity study, teflubenzuron was
administered to rats at a concentration of 0, 20, 100 or 500 mg/kg feed (equal to
0, 1.5, 7.4 and 36.9 mg/kg bw per day for males and 0, 1.6, 7.9 and 39.5 mg/kg bw
per day for females, respectively). The only treatment-related adverse effect noted
was a significant increase in the incidence of unilateral and bilateral dilatation of
the renal pelvis in F1 pups in the high-dose group (6.8%) when compared with
the controls (0.9%). No such effect was seen in the F2 generation. The NOAEL for
offspring toxicity was 100 mg/kg feed (equal to 7.4 mg/kg bw per day), and the
NOAEL for both parental and reproductive toxicity was 500 mg/kg feed (equal to
36.9 mg/kg bw per day), the highest dose tested.
The developmental toxicity of teflubenzuron was investigated in pregnant
rats by gavage administration at 0, 10, 50 or 250 mg/kg bw per day from days 6 to
15 of gestation. The number of live pups per dam was significantly reduced at the
high dose when compared with the controls. The NOAEL for maternal toxicity
was 250 mg/kg bw per day, the highest dose tested, and the NOAEL for embryo/
fetal toxicity was 50 mg/kg bw per day, based on a reduction in the number of live
pups per dam at 250 mg/kg bw per day.
In a second developmental toxicity study, teflubenzuron was administered
by gavage to pregnant rats at 0, 100, 300 or 1000 mg/kg bw per day during days
717 of gestation. No treatment-related toxicity was observed in dams, for both
general health and reproductive parameters. No external, visceral or skeletal
abnormalities were observed in pups. The NOAEL for both maternal and embryo/
fetal toxicity was 1000 mg/kg bw per day, the highest dose tested.
An overall NOAEL of 1000 mg/kg bw per day for maternal toxicity was
identified. No overall NOAEL for embryo/fetal toxicity could be identified, as
the reason for the difference in NOAELs for embryo/fetal toxicity in these two
developmental toxicity studies in rats was unknown.
Pregnant rabbits were dosed with teflubenzuron by gavage at 0, 10, 50
or 250 mg/kg bw per day from days 6 to 18 of gestation and killed on day 29 of
gestation. No maternal or reproductive toxicity was observed, and there were no
developmental abnormalities. The only significant effect noted in the offspring
was decreased survival during the first 24 hours in the high-dose group (88.5%)
compared with the controls (100%). The NOAEL for embryo/fetal toxicity was
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 Joint FAO/WHO Expert Committee on Food Additives Eighty-first report

50 mg/kg bw per day, based on decreased survival at 250 mg/kg bw per day, and
the NOAEL for maternal toxicity was 250 mg/kg bw per day, the highest dose
tested.
To further elucidate the embryotoxic effect in rabbits, a small
supplementary study (five per group) was conducted by administering
teflubenzuron by gavage at 0, 250, 500 (killed on day 19) or 500 mg/kg bw per day
(killed at day 29) on days 618 of gestation. There was evidence of embryotoxicity
in all treated animals, although no maternal toxicity was identified.
In another developmental toxicity study in rabbits, pregnant animals were
dosed with teflubenzuron by gavage at 0 or 1000 mg/kg bw per day during days
618 of pregnancy and killed on gestation day 28. Treated rabbits had a higher
incidence of liver lesions compared with controls, but there were no treatment-
related reproductive or developmental abnormalities. No NOAEL was identified
for maternal toxicity, as effects were noted at the only dose tested. The NOAEL for
embryo/fetal toxicity was 1000 mg/kg bw per day, the only dose tested. However,
this study did not evaluate offspring survival during the first 24 hours, and hence
the Committee cannot discount the effects seen in the previous study.
An overall NOAEL of 500 mg/kg bw per day was identified for maternal
toxicity, and an overall NOAEL of 50 mg/kg bw per day was identified for embryo/
fetal toxicity.

Microbiological data
Considering the chemical structure and mode of action of teflubenzuron, the
Committee did not anticipate any adverse effects of teflubenzuron residues on
human gastrointestinal microbiota.

Evaluation
An ADI of 05 g/kg bw was established on the basis of a BMDL10 of 0.54 mg/
WHO Technical Report Series No. 997, 2016

kg bw per day for hepatocellular hypertrophy in male mice observed in the

carcinogenicity study, with application of an uncertainty factor of 100 to account
for interspecies and intraspecies variability, and rounded to one significant figure.
The use profile of teflubenzuron as a veterinary drug is such that dietary
exposure to teflubenzuron from a large portion is unlikely to be markedly greater
than that from chronic consumption. The toxicological profile of teflubenzuron
is such that it is unlikely to present an acute hazard. The Committee therefore
concluded that it was not necessary to assess the acute risk from exposure to
teflubenzuron when used as a veterinary drug.
A toxicological monograph was prepared.

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 Comments on residues of specific veterinary drugs

Residue evaluation
The Committee reviewed studies on the pharmacokinetics and metabolism of
teflubenzuron in Atlantic salmon. Also, a number of radiolabelled and non-
radiolabelled teflubenzuron residue depletion studies in Atlantic salmon were
reviewed. The analytical method submitted by the sponsor to support the residue
monitoring has been assessed.
All studies were GLP compliant unless otherwise stated.

Data on pharmacokinetics and metabolism

Two studies evaluated the pharmacokinetics of teflubenzuron in Atlantic salmon
held at a water temperature of 1314 C. Plasma samples were taken at 15 minutes
and 3, 6, 9, 12, 24, 48, 72, 120 and 168 hours post-treatment.
In the first study, Atlantic salmon weighing 173395 g received a single
dose of 2 mg/kg bw teflubenzuron by intravenous injection. At 15 minutes after
dosing, teflubenzuron was detected in plasma at a concentration of 5.2 4.9 g/
mL (mean SD; 10 fish). The pharmacokinetic parameters were: AUC(072) of 23.4
g.h/mL, half-life (t) of 15.3 hours and clearance (CL) of 1.4 mL/kg per minute.
In the second study, Atlantic salmon weighing 100425 g received a
single dose of teflubenzuron by gavage at a dose of 10 mg/kg bw. The maximum
concentration of teflubenzuron in plasma was 0.5 0.1 g/mL (mean SD; 10
fish) at 9 hours post-dose. The pharmacokinetic parameters were: Tmax of 9.0
hours, AUC(072) of 10.9 g.h/mL and t of 14.2 hours.
In another study, Atlantic salmon weighing 626918 g were held at a
water temperature of 78 C and received teflubenzuron medicated feed at a
daily dose of 10 mg/kg bw for 7 consecutive days. Plasma samples were collected
during the feeding period (6 hours post-feeding on days 17) and after 30 and
48 hours following administration of the last medicated feed. The maximum
teflubenzuron concentration in plasma was 0.250 0.074 g/mL on day 6 during
the administration of the medicated feed. Thirty hours after the last dose, the
concentration of teflubenzuron had depleted to 0.10 0.065 g/mL.
Two metabolism studies were conducted with Atlantic salmon at a water
temperature of 10 C. In the first study, Atlantic salmon weighing 537999 g
received [14C]teflubenzuron at a single dose of 10 mg/kg bw by intra-oesophageal
intubation. Tissue samples were collected at 9 hours and 1, 3, 4, 6, 8, 13 and 18 days
post-dose. TRR was determined at 1 and 8 days post-dose. The marker residue,
teflubenzuron, was the major residue in muscle on day 1 (MR:TRR ratio 0.99)
and day 8 (MR:TRR ratio 0.84) post-dosing. In skin, the MR:TRR ratio was 1.04
and 0.77 at day 1 and day 8, respectively. In liver, 3,5-dichloro-2,4-difluoroaniline
(3.1% of TRR) and 3-hydroxy-teflubenzuron (3.3% of TRR) were detected at
1 day post-dosing. One metabolite (6.4% of TRR) remained unidentified in liver.

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 Joint FAO/WHO Expert Committee on Food Additives Eighty-first report

In the second study, Atlantic salmon (5081297 g) received medicated

feed at a teflubenzuron dose of 10 mg/kg bw for 6 consecutive days. On the
seventh day, the fish received [14C]teflubenzuron at a dose of 10 mg/kg bw by
intra-oesophageal intubation. On day 1 post-dose, the major residue in salmon
tissues (muscle, skin, liver and kidney) was the parent compound, determined by
radio-HPLC. In liver, as in the first study, 3,5-dichloro-2,4-difluoroaniline and
3-hydroxy-teflubenzuron were identified. The MR:TRR ratio at day 8 post-dose
was 1.28 in muscle and 0.82 in skin.
Based on the results of these two studies, the Committee determined that
a value of 0.8 was appropriate for the MR:TRR ratio. This value was the mean
value of the MR:TRR ratio of muscle and skin determined 8 days post last dose of
teflubenzuron at a water temperature of 10 C, excluding the value of 1.28, which
was considered an outlier.

Residue data
Three residue depletion studies using radiolabelled teflubenzuron and two
residue depletion studies using non-radiolabelled teflubenzuron were provided
for Atlantic salmon, using a single oral dose or repeated dose at two water
temperatures (6 C and 10 C). Teflubenzuron was quantified in salmon tissues
using a validated HPLC-UV method. Average recoveries were above 70%, and
the LOQ of the method was 20 g/kg for muscle and skin in natural proportion.
In one study, Atlantic salmon (537999 g), held at a water temperature of
10 C, received a dose of 10 mg/kg bw of [14C]teflubenzuron by intra-oesophageal
intubation. Six fish were sampled at each of the following intervals: 9 hours and
1, 3, 4, 6, 8, 13 and 18 days post-dose. Tissues (mucus, liver, kidney, muscle,
skin and gallbladder) were collected, and the TRR was determined using liquid
scintillation spectrometry. The acetonitrile-extractable residue on day 8 post-dose
accounted for 84% (muscle), 77% (skin), 54% (liver) and 54% (kidney) of the TRR.
The highest concentration of radioactivity in muscle (410 89.0 g eq/kg) and skin
WHO Technical Report Series No. 997, 2016

(753 224 g eq/kg) was determined 1 day after administration of the drug.
In a similar depletion study, Atlantic salmon maintained at 10 C received
non-radiolabelled teflubenzuron in medicated feed, at a dose of 10 mg/kg bw, for
6 consecutive days; on day 7, the fish received a dose of [14C]teflubenzuron of 10
mg/kg bw by intra-oesophageal intubation. Only a small amount of radioactive
material was distributed into the tissues examined that is, the majority of
material was excreted from the fish. The highest quantity of radioactive material
was detected in the muscle (310 124 g eq/kg) and skin (554 178 g eq/kg)
1 day after administration of the last dose.
In another study, Atlantic salmon (5271403 g), held at a water
temperature of 6 C, received non-radiolabelled teflubenzuron in the diet for 13

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 Comments on residues of specific veterinary drugs

days at a dose of 10 mg/kg bw; on the 14th day, the fish received a dose equivalent
to 10 mg/kg bw of [14C]teflubenzuron by intra-oesophageal intubation. Tissues
were collected 1, 8, 16, 24, 35, 50, 75 and 97 days post-treatment. Liver contained
the highest concentration of radioactive material, with a maximum of 1170
336 g eq/kg on day 1, which decreased with an elimination half-life of 16.9 days
determined over the period of 124 days. For muscle and skin, the maximum
concentrations occurred 1 day following the final dose (153 40 g eq/kg for
muscle and 218 83 g eq/kg for skin).
The last two studies using non-radiolabelled teflubenzuron were
conducted at two water temperatures (6 C and 10 C). For the low temperature,
Atlantic salmon received teflubenzuron in the diet for 13 days; on the 14th day,
the fish were treated with the same dose of teflubenzuron by intra-oesophageal
intubation. Tissues were collected and analysed 1, 8, 16, 24, 35 days post-
treatment. The concentration of teflubenzuron in muscle with skin depleted from
407 g/kg (day 1) to 25 g/kg (day 35). For the high water temperature, Atlantic
salmon received 10 mg/kg bw teflubenzuron in the diet over a 7-day period.
One fish per group received a single oral dose of 10 mg/kg bw teflubenzuron by
intra-oesophageal intubation on feeding day 7. Samples of muscle and skin were
collected on days 1, 4, 8, 12, 18, 24, 35, 50 and 120 post-dose. The concentration
of teflubenzuron in muscle with skin depleted from 931 g/kg (day 1) to 38 g/kg
(day 35). The half-life of elimination calculated from the residue data from days
1 to 18 in the combined muscle and skin was 3.4 days.
Teflubenzuron residues depleted in muscle and skin with different half-
lives depending on the water temperature. Peak residue concentrations were higher
in the experiment performed at 10 C than in the experiment at 6 C; however,
the initial rates of depletion of tissue residues were similar. The slow terminal
phase of elimination was attributed to background levels of teflubenzuron in the
recirculated seawater in the tanks where the fish were housed. Consequently, the
data from time points 24 and 35 days were not used. Only the time points 1, 4, 8,
12 and 18 days were used to determine the MRL. The radiolabel studies indicated
that the main residue in muscle and skin is the parent compound and that the
excretion of teflubenzuron is predominantly via faeces.

Analytical methods
The Committee assessed the validation data against the requirements for
analytical methods as published in CAC/GL 71-2009 (15).
The validated HPLC-UV method with detection at 254 nm is based
on solidliquid extraction, followed by several clean-up steps using liquid
liquid extraction and solid-phase extraction on two sorbents (silica and C8).
Quantification was performed using an external calibration curve in the

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 Joint FAO/WHO Expert Committee on Food Additives Eighty-first report

concentration range of 0.021.0 g/mL (corresponding to 201000 g/kg). The

linearity was 0.9950, and recoveries were above 70%. The LOQ was 20 g/kg of
teflubenzuron in salmon muscle and skin in natural proportion. The Committee
concluded that the HPLC-UV method provided lacks in selectivity because of
possible interferences from other components in the extract at a wavelength of
254 nm and cannot be recommended for regulatory monitoring of salmon tissues
for teflubenzuron.
The Committee noted that some national authorities monitor
teflubenzuron in salmon tissues using a multi-residue pesticide monitoring
procedure that may be applicable for regulatory monitoring of salmon tissues.
The sample preparation is a modification of the QuEChERS approach without
using the dispersive sample clean-up step. Briefly, salmon tissue is shaken with
a mixture of water and acetonitrile in the presence of sodium chloride and
magnesium sulfate. The mixture is centrifuged, and a volume of the extract is
added to ammonium formate and formic acid. The filtered extract is analysed by
LC-MS/MS, using the electrospray ionization source in the negative mode. The
chromatographic separation is carried out on a reversed-phase C18 column and
a mobile phase of ammonium formate and formic acid under gradient elution.
The precursor ion at 379 m/z and two product ions at 339.1 m/z and 358.9 m/z are
used for identification and quantification. Concentrations in salmon muscle and
skin were determined by external calibration curves (standards in acetonitrile),
without using an internal standard.
The validation parameters reported were: linear range of 0.1100 ng/
mL corresponding to 0.3300 g/kg, linearity of 0.9995, intraday precision of
1.646.02% (1100 g/kg), extraction recovery in the range of 65.9101.4%
(1100 g/kg) and an estimated LOQ (signal to noise 10) of 0.3 g/kg. The
estimated LOD, which is defined as the standard concentration that can be
detected with signal to noise ratio 3, is 0.03 ng/mL (equivalent to 0.09 g/kg). The
selectivity of the method was demonstrated, and incurred samples were also used
WHO Technical Report Series No. 997, 2016

in the validation procedure. The Committee considered that the method used by
the national authorities and published in the literature could be recommended
for regulatory monitoring of salmon tissues for teflubenzuron.

Maximum residue limits

In recommending MRLs for teflubenzuron in salmon, the Committee considered
the following factors:
Teflubenzuron is authorized for use in salmon in several countries. The
maximum recommended dose is 10 mg/kg fish per day for 7 consecutive
days, administered through medicated feed. The withdrawal periods
range from 7 to 11 days and from 45 to 96 degree-days.
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 Comments on residues of specific veterinary drugs

An ADI for teflubenzuron of 05 g/kg bw was established by the

Committee.
Teflubenzuron is the marker residue in tissues.
The ratio of the concentration of marker residue to the concentration
of total residue of 0.8 was calculated in muscle and skin in natural
proportion of salmon. Residue data were provided using a validated
analytical method to quantify teflubenzuron in salmon tissues.
A validated analytical method for the determination of teflubenzuron
in edible salmon tissues is available in the literature and may be used
for monitoring purposes.
The MRLs were calculated on the basis of the upper limit of the one-sided
95% confidence interval over the 95th percentile of total residue concentrations
(95/95 UTL) in salmon muscle and skin derived from the pivotal study used for
this assessment, conducted at a water temperature of 10 C and a withdrawal
period of 96 degree-days (10 days).
The Committee recommended MRLs for teflubenzuron in salmon of 400
g/kg in fillet (muscle plus skin in natural proportion) and in muscle.
The EDI is 42.9 g/person per day, on the basis of a 60 kg individual,
which represents approximately 14% of the upper bound of the ADI.
The GECDE for the general population is 1.6 g/kg bw per day, which
represents 31% of the upper bound of the ADI; for children, 2.1 g/kg bw per day,
which represents 43% of the upper bound of the ADI; and for infants, 0.9 g/kg
bw per day, which represents 18% of the upper bound of the ADI.
A residue monograph was prepared.

Summary and conclusions

Studies relevant to risk assessment

Species / study type Doses (mg/kg bw NOAEL (mg/kg LOAEL (mg/kg
(route of administration) per day) Critical end-point bw per day) bw per day)
Mouse
Eighteen-month 0, 2.1, 10.5, 53.6 Hepatocellular adenoma 2.1 10.5
carcinogenicity study (diet) Hepatocellular hypertrophy 2.1a
BMDL10: 0.54*
Rat
Two-year toxicity and 0, 1.0, 4.8, 24.8 Increased activity of liver enzymes, and 4.8b 24.8c
carcinogenicity study (diet) increased liver weights in males
Two-generation reproductive 0, 1.5, 7.4, 36.9 Unilateral and bilateral dilatation of the Offspring 36.9
toxicity study (diet) renal pelvis in F1 pups toxicity: 7.4
Parental toxicity:
36.9d

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 Joint FAO/WHO Expert Committee on Food Additives Eighty-first report

Species / study type Doses (mg/kg bw NOAEL (mg/kg LOAEL (mg/kg

(route of administration) per day) Critical end-point bw per day) bw per day)
Reproductive
toxicity: 36.9d
Developmental toxicity Study 1: 0, 10, 50, 250 Decreased number of live pups per dam Embryo/ 250 (study 1)
studiese (gavage) Study 2: 0, 100, 300, fetal toxicity: 50
1 000 (study 1)
Maternal
toxicity: 1 000b,d
Rabbit
Developmental toxicity Study 1: 0, 10, 50, 250 Decreased survival of offspring within Embryo/fetal 250c
studiese (gavage) Study 2: 0, 250, 500 24 h of birth toxicity: 50b
Study 3: 0, 1 000 Maternal
toxicity: 500b,d
Dog
Thirteen-week studies of Study 1: 0, 3.5, 33.7, Increased liver weight 4.4b 17.3c
toxicitye (diet) 318.2
Study 2: 0, 1.2, 4.4
One-year study of toxicity 0, 1.0, 3.2, 17.3
(diet)
* Pivotal study value for the derivation of an ADI (20)
a
Lowest dose tested.
b
Overall NOAEL.
c
Overall LOAEL.
d
Highest dose tested.
e
Two or more studies combined.

Uncertainty factor
100 (10 for interspecies and 10 for intraspecies variability)

ADI (based on toxicological effects)

05 g/kg bw
WHO Technical Report Series No. 997, 2016

Residue definition
Teflubenzuron

MRLs
The recommended MRL for teflubenzuron in salmon fillet (muscle plus skin in
natural proportion) and in salmon muscle is 400 g/kg.

Estimated dietary exposure

The EDI is 42.9 g/person per day, on the basis of a 60 kg individual, which
represents approximately 14% of the upper bound of the ADI. The GECDE for
the general population is 1.6 g/kg bw per day, which represents 31% of the upper
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 Comments on residues of specific veterinary drugs

bound of the ADI; for children, 2.1 g/kg bw per day, which represents 43% of the
upper bound of the AD;I and for infants, 0.9 g/kg bw per day, which represents
18% of the upper bound of the ADI.

4.5 Zilpaterol hydrochloride

Explanation
Zilpaterol hydrochloride, ()-trans-4,5,6,7-tetrahydro-7-hydroxy-6-(isopro-
pylamino)imidazo[4,5,1-jk]-[1]benzazepin-2(1H)-one hydrochloride (zilpaterol
HCl; CAS no. 119520-06-8), is a 2-adrenoreceptor agonist repartitioning agent.
It is used to increase rate of body weight gain, improve feed efficiency and increase
carcass muscle ratio in cattle fed in confinement before slaughter. There are four
enantiomers of zilpaterol HCl. The product in use is racemic trans-zilpaterol
HCl, a mixture of the (6R,7R) and (6S,7S) enantiomers; it will be referred to as
zilpaterol HCl in this report.
Zilpaterol HCl is to be mixed into the feed at a level of 7.5 mg/kg on a
90% dry matter basis. This will result in a dose of approximately 0.15 mg/kg bw,
or 6090 mg zilpaterol HCl per animal per day. Zilpaterol HCl is administered
for a period of 2040 consecutive days before withdrawal from the feed. It is not
approved for use in lactating dairy cattle. Where information on authorized uses
was provided, withdrawal periods ranged from 2 to 4 days.
The seventy-eighth meeting of the Committee, at the request of the
Twenty-first Session of CCRVDF (6), evaluated zilpaterol HCl and established an
ADI of 00.04 g/kg bw on the basis of a LOAEL for a slight increase of tremor
in humans in a single-dose study (Annex 1, reference 217). The seventy-eighth
Committee concluded that it was not possible to recommend MRLs for zilpaterol
and that the following data were needed to establish MRLs:
results from studies investigating marker residue in liver and kidney;
results from studies determining the MR:TRR ratio in liver and
kidney;
results from depletion studies to enable the derivation of MRLs
compatible with the ADI.
Following the submission of additional information, the present
Committee evaluated the data to recommend MRLs for bovine tissues. In
addition, at the request of the Twenty-second Session of CCRVDF (2), JECFA
considered potential risks of zilpaterol residues in animal lungs and other edible
offal. In line with evolving guidance on the need to consider the establishment of
ARfDs for veterinary drugs, the Committee evaluated the acute risk of zilpaterol.

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 Joint FAO/WHO Expert Committee on Food Additives Eighty-first report

In addition, the Committee addressed a number of comments received from the

sponsor on the evaluation of zilpaterol HCl by the seventy-eighth JECFA.

Toxicological evaluation
No new toxicological data for zilpaterol HCl were submitted by the sponsor,
except for information on the structureactivity relationship of N-acetylated
deisopropyl zilpaterol.

Previous JECFA evaluation

The Committee at its seventy-eighth meeting considered the acute pharmacological
effect observed in four human studies, which was consistent with the agonistic
activity of zilpaterol HCl on the 2-adrenoceptor, to be the most sensitive adverse
effect for the establishment of an ADI for zilpaterol HCl. The LOAEL for a slight
and transitory increased incidence of tremor was 0.76 g/kg bw, the lowest dose
tested, which was found in fasted humans who ingested a single oral dose of
zilpaterol HCl as a bolus (21). The Committee established an ADI of 00.04 g/
kg bw by applying an uncertainty factor of 20, comprising a default uncertainty
factor of 10 for human individual variability and an additional uncertainty factor
of 2 to account for the use of a LOAEL for a slight effect instead of a NOAEL
(Annex 1, reference 217). Despite the fact that the ADI was based on an acute
effect, the seventy-eighth JECFA did not consider establishing an ARfD, as this
was not normal practice at the time.

Bioavailability of incurred residues

In the data submission for the current meeting, the sponsor provided comments
suggesting that the bioavailability of the incurred residues needs to be
considered in the determination of total residues of concern for zilpaterol HCl
because the design of the human studies did not reflect realistic exposure of
WHO Technical Report Series No. 997, 2016

the consumer to possible zilpaterol residues in food. The sponsor asserted that
the pharmacological effects resulting from incurred zilpaterol are reduced by a
factor of 10 in comparison with an oral bolus administration. This assertion is
based on a study in dogs showing that administration of zilpaterol HCl as an
incurred residue at a dose of 2 g/kg bw did not cause any effects, but the same
dose administered orally in a capsule induced a slight increase in heart rate; and
a pharmacokinetics study in rats in which the Cmax values were 10 times higher in
serum when zilpaterol HCl was administered via oral gavage in comparison with
a dietary admixture.
The Committee reviewed the sponsors comments and concluded as
follows:

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 Comments on residues of specific veterinary drugs

There were no changes in blood pressure or heart rate in dogs exposed

to zilpaterol HCl at approximately 2 g/kg bw per day for 5 days in
the form of incurred residues in 200 g of muscle or liver from steers.
In contrast, exposure of fasted dogs to zilpaterol HCl elicited an 11%
increase in heart rate when the zilpaterol HCl was administered via
capsule at 2 g/kg bw and an increase of 11.8% when the zilpaterol
HCl was administered via capsule at 3 g/kg bw together with
200 g of muscle or liver from untreated steers (22). These data provide
some indication that the pharmacological potency of zilpaterol HCl
is dependent on the bioavailability of incurred residues. However,
this study was inconclusive, as only small numbers of animals were
used (one male and one female per group). Additional limitations
include the absence of an oral (gavage) study in non-fasted dogs and
the absence of human fed/fasted, dietary/oral dose comparative data.
The pharmacokinetics of zilpaterol HCl were investigated in male
and female rats following administration by dietary admixture or oral
gavage for a 2-week period at a dose of 0.055 or 1.1 mg/kg bw per day
(23). The Cmax for zilpaterol HCl administered by oral admixture was
8.515.7% of that following oral gavage administration. However, the
AUC following administration by oral admixture was 38.8105.7%
of that following oral gavage administration. These data suggest
that zilpaterol administration via dietary admixture may result in
prolonged absorption and lower peak plasma concentrations, but
does not clearly lead to lower bioavailability. However, there was
considerable variation in the Tmax, Cmax and AUC values observed
in this study, making it difficult to reach clear conclusions on the
differences between the pharmacokinetics of zilpaterol residues
administered as a bolus dose or dietary admixture.

Pharmacological potency
The present Committee reviewed the pharmacological potency of metabolites
of zilpaterol HCl. The sponsor submitted a new structureactivity relationship
assessment of N-acetylated deisopropyl zilpaterol to make the case that this
metabolite has no pharmacological activity. The Committee concluded as
follows:
The affinity of zilpaterol HCl for the rat lung 2-adrenoceptor in vitro
was about 1.5-fold higher than that of its main metabolite, deisopropyl
zilpaterol (as free base or hydrochloride form) (24). However, three
in vivo rat studies demonstrated that zilpaterol HCl displays 10-fold
higher 2-adrenoceptor agonist activity compared with its main

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 Joint FAO/WHO Expert Committee on Food Additives Eighty-first report

metabolite, deisopropyl zilpaterol (2527). The Committee confirmed

its previous view that the potency of deisopropyl zilpaterol was 10%
of that of the parent.
Another metabolite, N-acetylated deisopropyl zilpaterol, found in
rat urine at up to 4% of the administered dose, is predicted to have
no pharmacological activity based on an assessment of its structure
activity relationship (28). The Committee agreed with this assessment.
Multi-step metabolism of zilpaterol is likely to lead to disruption
of the pharmacophore for 2-adrenoceptor agonist activity, and
therefore the pharmacological potency of such metabolites will be
less than that of the parent compound. A conservative estimate for
the pharmacological potency of such unidentified polar extractable
residues would be 10% of that of the parent compound (similar to the
potency of the metabolite deisopropyl zilpaterol).

Assessment of acute effects

The present Committee noted that the basis of the previously established ADI
was an acute effect in humans after a single dose of zilpaterol HCl. In line with
evolving guidance on the need to consider the establishment of ARfDs for
veterinary drugs, the Committee considered it appropriate to establish an ARfD.
The acute agonistic effect on 2-adrenoceptor in humans (21) was the most
sensitive effect observed and therefore serves as the basis for both the ADI and
the ARfD.

Evaluation
The present Committee reaffirmed the ADI of 00.04 g/kg bw that was established
at the seventy-eighth meeting of JECFA and established an ARfD of 0.04 g/kg bw
based on a LOAEL of 0.76 g/kg bw for acute pharmacological effects observed
WHO Technical Report Series No. 997, 2016

in the single-dose human study, with application of an uncertainty factor of 20,

comprising a default uncertainty factor of 10 for human individual variability
and an additional uncertainty factor of 2 to account for use of a LOAEL for a
slight effect instead of a NOAEL.
An addendum to the toxicological monograph was not prepared.

Residue evaluation
The sponsor submitted additional data that included results from two new depletion
studies in cattle, a validated analytical method for residues in bovine tissues and an
assessment of the pharmacological impact of residues in the exposure assessment.
The studies were compliant with GLP unless otherwise stated.

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 Comments on residues of specific veterinary drugs

Pharmacokinetics and residue data

The seventy-eighth Committee agreed that parent zilpaterol (free base) was
an appropriate marker residue in muscle. Only limited data were available
for tissues other than muscle, and the Committee was unable to determine a
suitable marker residue in other edible tissues. Liver and kidney contained the
highest concentrations of zilpaterol at all sampling times, followed by muscle.
The zilpaterol concentrations, and the subsequent ratios of zilpaterol to the total
residue of concern, could not be determined with confidence over the 96-hour
withdrawal period after the last drug administration due to the limited data
available and lack of analytical method sensitivity. There are no measurable
residues in fat. Pharmacokinetics, radiolabelled residue studies and the earlier
non-radiolabelled residue studies were already assessed by the seventy-eighth
JECFA. The previous evaluation by the Committee noted that zilpaterol is readily
absorbed after oral administration, although the degree of absorption may vary
depending on the specific method of oral dosing. In a rat study using the Gallo-
Torres model, the bioavailability of non-extractable radiolabelled zilpaterol
residues from cattle liver was 5% (29). Metabolism studies conducted in rats,
swine and cattle demonstrated the metabolism of zilpaterol to be qualitatively and
quantitatively comparable in these three species following oral administration.
Metabolism is mainly via deisopropylation and hydroxylation pathways. Hepatic
metabolism in cattle produces deisopropyl zilpaterol and its N-acetyl product.
Hydroxy-zilpaterol and its glucuronide conjugates are produced in rats, but have
not been detected in cattle tissues. Deisopropyl zilpaterol was the only metabolite
accounting for more than 10% of the radioactivity found in edible tissues of
cattle. Parent compound and metabolites are excreted primarily (>85%) in the
urine, with the remainder in the faeces. Unchanged parent zilpaterol is the main
compound excreted in the urine. No new pharmacokinetics data were received
for this meeting.
The previous evaluation by the Committee noted that radiolabelled
residue depletion studies were conducted in cattle after treatment at the
recommended dose of 0.15 mg/kg bw per day. The radiolabel data from a limited
number of animals provided a depletion curve for a period limited to 96 hours
post-dose. No residues were detected in fat after 12 hours, and no residues were
detected in muscle after 48 hours. Residues were detected in liver and kidney at
96 hours post-dose. Extractable residues from liver decreased from 52% to 24%
of total radioactivity between 12 and 96 hours and from 89% to 38% for kidney
over the same period. Residues in muscle were approximately 100% extractable
between 12 and 48 hours. Parent zilpaterol (free base) represented a significant
part of the extractable residue in liver, kidney and muscle. The ratio of parent
zilpaterol to total residues decreased with time for liver, kidney and muscle.

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 Joint FAO/WHO Expert Committee on Food Additives Eighty-first report

Deisopropyl zilpaterol comprised a minor fraction of the extractable residue.

Other metabolites detected in small quantities in cattle include N-acetylated
deisopropyl zilpaterol (urine only) and one unidentified metabolite. Non-
radiolabelled zilpaterol residue depletion studies were also provided, although
numerous deficiencies were noted in some studies. These included lack of kidney
residue determination in all but one study, insufficient sampling periods and
insufficiently sensitive analytical methods.

New residue data submitted to the current Committee

Data from the two new residue depletion studies provided by the sponsor were
evaluated by the present Committee, together with data from previously evaluated
residue depletion studies. The two new studies provided a more robust estimate
of residue depletion in the main target tissues, liver, kidney and muscle, due to
use of improved analytical methods and a longer sampling period (up to 240
hours post-dose). Such data provided confirmation of the marker residue in all
relevant tissues. Residue data were provided for 60 and 90 mg/head per day dose
groups, but only data from the upper limit of the approved dose range (90 mg/
head per day) were used in the subsequent exposure assessment. Furthermore,
residue depletion modelling of a pooled data set combined from multiple studies
was considered but deemed inappropriate due to significant differences in the
study methods.
From the radiolabel study, the total pharmacologically active residue
(expressed as zilpaterol HCl equivalents) was calculated using the following
formula:

Total pharmacologically active residue = Zilpaterol HCl + 0.1*[RRExt +

(0.05*RRNonExt)]

where:
WHO Technical Report Series No. 997, 2016

Zilpaterol HCl = parent zilpaterol concentration, expressed as

zilpaterol hydrochloride;
0.1 = relative pharmacological activity correction factor. The activity
attributed to zilpaterol HCl was set as 1, whereas the activity of all
other extractable and bioavailable non-extractable residues was set as
0.1 (i.e. 10% of the parent zilpaterol activity);
RRExt = sum of other extractable radioactive residue concentrations
(including the major metabolite deisopropyl zilpaterol), expressed as
zilpaterol HCl-eq;
RRNonExt = non-extractable (bound) radioactive residue concentration,
expressed as zilpaterol HCl-eq;
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 Comments on residues of specific veterinary drugs

0.05 = oral bioavailability of non-extractable residues (as per the

Gallo-Torres model).

The ratios (Rtissue(t)) between parent zilpaterol and total pharmacologically

active residue (based on the radiolabel study, as calculated above) over time were
determined. Ratios in liver decreased from 94% to 74% between 12 and 96 hours
and from 99% to 50% for kidney over the same period. For muscle, the ratio
decreased from 92% to 84% between 12 and 48 hours.
The concentrations of zilpaterol free base obtained in the pivotal non-
radiolabelled residue depletion study were converted into total pharmacologically
active residue (expressed as zilpaterol HCl-eq) using the following formula:

Total pharmacologically active residue = 1.1395* [Zilpaterol free base]/Rtissue(t)

where:
1.1395 = molecular weight conversion factor, required to convert all
zilpaterol free base residues to zilpaterol HCl for comparisons with
the ADI;
Zilpaterol free base = marker residue concentration;
Rtissue(t) = ratio between marker residue and total pharmacologically
active residue estimated at an equivalent time point (t) for each tissue
(liver, kidney, muscle) from the radioactive residue study.

Dietary exposure assessment

Both chronic and acute dietary exposures were considered for residues of zilpaterol.
As the ADI and ARfD for zilpaterol are based on an acute pharmacological end-
point, the most relevant approach was deemed the acute exposure assessment.
For acute exposure, the GEADE approach was used. Large portion size values
based on the 97.5th percentile of food consumption were used in the GEADE
assessment of zilpaterol. The consumption amounts used as inputs were based on
data from more than 70 consumers to ensure that acute exposure estimates were
statistically robust.

Analytical method
A new method was used for the analysis of free zilpaterol residues in the pivotal
studies. In brief, samples of homogenized bovine tissue were fortified with an
internal standard ([2H7]zilpaterol) and extracted with methanol. A sub-sample
of the extract was purified by cation exchange solid-phase extraction and then
analysed by a validated LC-MS/MS method using electrospray ionization in the

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 Joint FAO/WHO Expert Committee on Food Additives Eighty-first report

positive ion mode and selected reaction monitoring as the acquisition method.
Quantification was performed using a solvent calibration curve corresponding to
a range of 0.2530 g/kg tissue equivalents for all tissues. The Committee assessed
the validation data against the requirements for analytical methods as published
in CAC/GL 71-2009 (15). For all tissues, the LOQ was 0.25 g/kg. Calculated
LODs were 0.048, 0.067 and 0.045 g/kg for liver, muscle and kidney, respectively.
The average recovery of zilpaterol in the methanol extracts was determined to be
76% (liver), 85% (kidney) and 73% (muscle). The confirmatory method proposed
for routine residue surveillance is a gradient LC-MS/MS method applicable in
the range of 0.2530 g/kg for all tissues. Accordingly, the method is expected to
be practicable and applicable in normal routine laboratory use.

Maximum residue limits

In recommending MRLs for zilpaterol, the Committee considered the following
factors:
An ARfD of 0.04 g/kg bw was established. This is the same value as
the upper bound of the ADI previously established by the seventy-
eighth Committee and reaffirmed by the present Committee.
Zilpaterol HCl is registered to be mixed into feed at a level of 7.5 mg/kg
on a 90% dry matter basis. This level provides a dose of approximately
0.15 mg/kg bw or 6090 mg zilpaterol HCl per animal per day.
Where information on authorized uses was provided, withdrawal
periods ranged from 2 to 4 days.
Zilpaterol HCl is not approved for use in lactating dairy cattle.
The major metabolite in cattle tissues is deisopropyl zilpaterol.
Zilpaterol HCl administration in cattle results in non-extractable
residues that are poorly bioavailable in laboratory animals. This low
oral bioavailability (~5%) demonstrated for liver was assumed to be
WHO Technical Report Series No. 997, 2016

similar for non-extractable residues in muscle and kidney.

The most sensitive toxicological end-point is an acute pharmacological
effect. It was assumed that zilpaterol HCl has a reference activity of 1.
Deisopropyl zilpaterol was shown to have ~10% of the pharmacological
activity of parent zilpaterol, with the activity of all other extractable
and bioavailable non-extractable residues being equivalent to, or less
than, that of deisopropyl zilpaterol.
Parent zilpaterol (free base) was an appropriate marker residue in
muscle, liver and kidney. Fat was not considered relevant for residue
monitoring purposes.

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 Comments on residues of specific veterinary drugs

The ratios of zilpaterol (MR) to the total residues of concern (total

pharmacologically active residues) for muscle, liver and kidney could
be determined with sufficient confidence over a 96-hour period
after the last drug administration. The MR:total pharmacologically
active residue ratios were between 0.9 and 1.0 for liver, kidney and
muscle at 12 hours withdrawal. By 96 hours withdrawal, the MR:total
pharmacologically active residue ratios were 0.7 (liver and muscle)
and 0.5 (kidney).
A validated analytical procedure for the determination of zilpaterol
in edible bovine tissues (liver, kidney, muscle) is available and may be
used for monitoring purposes. The LOQ is 0.25 g/kg for all tissues.

The MRLs recommended for bovine tissues are based on an acute dietary
exposure scenario (GEADE). The Committee initially derived the following one-
sided 95% confidence interval over the 95th percentile of residue concentrations
(95/95 UTL) in bovine tissues at the 72-hour time point: 4.1 g/kg in kidney, 4.3
g/kg in liver and 0.6 g/kg in muscle. Using acute dietary exposure assessments
(GEADE), these 95/95 UTLs could lead to an acute dietary exposure of ~99% of
the ARfD in the general population and ~117% of the ARfD in children.
Because the exposure in children exceeded the ARfD using the 72-hour
data, the Committee considered a refined assessment with 95/95 UTLs derived at
77 hours post-dose: 3.3 g/kg in kidney, 3.5 g/kg in liver and 0.5 g/kg in muscle.
These values would result in acute dietary exposure (GEADE of 1.9 g/day for
the general population and 0.57 g/day for children) of ~94% of the ARfD in
children and ~80% of the ARfD in the general population and are recommended
as MRLs. It is noted that the time point at which the MRLs are calculated (77
hours) is consistent with currently approved withdrawal times (GVP).
The Committee recognizes that the approach used in this evaluation
differs from that of previous evaluations for similar types of veterinary
compounds. However, this was appropriate due to the acute nature of the
pharmacological end-point and the availability of an appropriate model for acute
exposure. Detailed chronic and acute dietary exposure assessments are included
in the addendum to the residue monograph to provide additional information to
risk managers.
The Committee concluded that there were insufficient zilpaterol residue
data to adequately consider exposure to residues in lungs and other edible offal
of cattle apart from liver and kidney. No non-radiolabelled residue depletion
data were provided for any cattle tissues other than liver, kidney and muscle. For
lung tissue, there were no actual residue data available in cattle, just estimates
based on ratios of plasma versus respiratory tissue radioactivity from preliminary
radiolabel studies in rats. For edible offal, the only bovine data available were

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 Joint FAO/WHO Expert Committee on Food Additives Eighty-first report

from a preliminary radiolabel study, with only two data points for tripe at each of
the 12- and 48-hour withdrawal periods.

Recommendation
The Committee noted that the definitions of the tissues comprising offal were not
consistent between countries. Therefore, JECFA requests that CCRVDF provide
a definition of edible offal.

An addendum to the residue monograph was prepared.

Summary and conclusions

Uncertainty factor (for both ADI and ARfD)

20 (10 for intraspecies variability, 2 for use of a LOAEL instead of a NOAEL)

ADI
00.04 g/kg bw

ARfD
0.04 g/kg bw

MRLs
The recommended MRLs for cattle are 3.3 g/kg in kidney, 3.5 g/kg in liver and
0.5 g/kg in muscle.

Estimated dietary exposure

GEADEs of 1.9 g/day for the general population and 0.57 g/day for children were
WHO Technical Report Series No. 997, 2016

calculated, based on 95/95 UTLs, which represent approximately 80% and 94% of
the upper bound of the ARfD for the general population and children, respectively.

Comments from the sponsor

a. The sponsor identified several errors in some of the tables in the
seventy-eighth JECFA monograph, which it believed may have had
an impact on data interpretation and conclusions.
b. The sponsor stated that data gaps identified by the seventy-eighth
JECFA were not fully justified, as available information in submitted
studies had not been used by the Committee.

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 Comments on residues of specific veterinary drugs

c. The sponsor stated that there were sufficient data sets (including the
new studies not available at the time of the seventy-eighth JECFA)
to recommend MRLs.

Response from JECFA: The corrected tables have been included where necessary
in the eighty-first JECFA addendum to the residue monograph. Assessment of
the data has been performed using an approach based on all data available.

d. The sponsor stated that only the residues of pharmacological concern

are relevant for the dietary exposure assessment, as the ADI was
based on a pharmacological end-point. In particular, the sponsor
argued that insufficient attention was paid to the 10-fold difference
in activity between zilpaterol and its main metabolite (deisopropyl
zilpaterol) with respect to 2-agonist activity on the cardiovascular
system.

Response from JECFA: The evaluation reflects this comment.

e. Regarding residues of pharmacological concern, the sponsor

proposed that the reduced bioavailability of zilpaterol residues (and
thus not pharmacologically active) should be accounted for in the
exposure assessment.

Response from JECFA: The bioavailability of the non-extractable portion of

incurred bound residues was considered in the assessment, as per the Gallo-Torres
model. A bioavailability correction factor of 0.05 was used for all non-extractable
residues. All extractable residues were assumed to be fully bioavailable, as per
current regulatory guidance in multiple jurisdictions, and the available data do
not support the sponsors proposal.

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5. Future work and recommendations
Recommendations relating to specific veterinary drugs, including ADIs, ARfDs
and proposed MRLs, are given in section 3 and Annex 2. This section includes
recommendations relating to future work by the JECFA Secretariat.

Diflubenzuron
Additional information that would assist in the further evaluation of the compound

A comparative metabolism study of diflubenzuron in humans and

rats (e.g. in hepatocytes)
Information on PCA exposure associated with the consumption of
treated fish
Information on the amount of PCA present (if any) as an impurity in
the product formulation
Information on the amount of PCA generated during food processing
A method suitable for monitoring diflubenzuron residues in fish
muscle and fillet (muscle plus skin in natural proportion).

Recommendation
The Committee recommends that JMPR consider the re-evaluation of
diflubenzuron at a future meeting and that the WHO Pesticide Evaluation
Scheme (WHOPES) and the WHO Guidelines for Drinking-water Quality
(GDWQ) Chemical Working Group reconsider their recommendations for the
use of diflubenzuron as a vector control agent in drinking-water.

Sisapronil
Additional information that would assist in the further evaluation of the compound

Data to address long-term toxicity relevant to humans (e.g. 1-year

dog study)
Comparative pharmacokinetic studies and an explanation of
interspecies differences in the pharmacokinetic profiles.

Zilpaterol hydrochloride
The Committee noted that the definitions of the tissues comprising offal were not
consistent between countries. Therefore, JECFA requests that CCRVDF provide
a definition of edible offal.

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 Joint FAO/WHO Expert Committee on Food Additives Eighty-first report

Acute reference dose (ARfD) for veterinary drugs

The Committee recommends that a subgroup be established to review available
information on acute exposure to residues of veterinary drugs and to identify
an upper-bound exposure value with sufficient confidence that will enable, if
possible, the derivation of a cut-off value for acute toxicity.

Chronic dietary exposure assessment

The Committee recommends that the FAO and WHO Secretariats convene an
expert meeting on two important issues concerned with the methodologies
applied by JECFA and JMPR to estimate chronic dietary exposures.

In regards to dietary exposure assessment of compounds used for multiple purposes

(i.e. veterinary drugs and pesticides):
1. Develop chronic dietary exposure assessment methods that take
into account combined exposure from pesticide and veterinary drug
residues.
2. Investigate the applicability of these methods using compounds that
have been evaluated as both pesticides and veterinary drugs.

In regards to dietary exposure assessment for less-than-lifetime exposure:

1. Investigate the effects of duration of exposure in toxicity studies
on veterinary drugs on toxicological end-points and the points of
departure (e.g. NOAELs).
2. Based on the outcome of #1, identify those toxicological situations
requiring less-than-lifetime exposure assessment.

In regards to dietary exposure assessment

1. Apply the methodologies developed above to some key examples
WHO Technical Report Series No. 997, 2016

of veterinary drugs and pesticides that are unlikely to accumulate

(including compounds that have been evaluated as both pesticides
and veterinary drugs) and report the outcome to JECFA and JMPR.

Coordination of the agendas of JECFA and JMPR

The Committee strongly recommends that where dual-use substances are to
be evaluated by both JMPR and JECFA, CCPR and CCRVDF coordinate the
prioritization of such substances for evaluation by the respective experts. The
Committee also recommends that the Joint Secretariats of JMPR and JECFA
ensure that there is suitable interaction between experts in the evaluation of such
compounds.

86
Acknowledgements
The Committee wishes to thank Ms M. Sheffer, Ottawa, Canada, for her assistance
in the preparation of the report.
FAO and WHO wish to acknowledge the significant contributions of the
experts, as well as their institutions (where relevant), to the work of the eighty-
first meeting of JECFA.

87
References
1. FAO/WHO. Residues of veterinary drugs in foods. Report of a Joint FAO/WHO Expert Consultation. Rome:
Food and Agriculture Organization of the United Nations; 1985 (FAO Food and Nutrition Paper, No. 32).
2. FAO/WHO. Report of the Twenty-second Session of the Codex Committee on Residues of Veterinary Drugs
in Foods. San Jos, Costa Rica, 27 April 1 May 2015. Rome: Food and Agriculture Organization of the
United Nations and World Health Organization, Joint FAO/WHO Food Standards Programme, Codex
Alimentarius Commission; 2015 ( REP15/RVDF).
3. FAO/WHO. Thirty-eighth Session of the Codex Alimentarius Commission. Geneva, Switzerland, 611 July
2015. Rome: Food and Agriculture Organization of the United Nations and World Health Organization,
Joint FAO/WHO Food Standards Programme, Codex Alimentarius Commission; 2015 (REP15/CAC).
4. FAO/WHO. Risk analysis principles applied by the Codex Committee on Residues of Veterinary Drugs
in Foods. In: Procedural manual, 17th edition. Rome: Food and Agriculture Organization of the United
Nations and World Health Organization, Joint FAO/WHO Food Standards Programme, Codex Alimentarius
Commission; 2007; 13948.
5. FAO/WHO. Report of the Twentieth Session of the Codex Committee on Residues of Veterinary Drugs in
Foods. San Juan, Puerto Rico, 711 May 2012. Rome: Food and Agriculture Organization of the United
Nations and World Health Organization, Joint FAO/WHO Food Standards Programme, Codex Alimentarius
Commission; 2012 (REP12/RVDF).
6. FAO/WHO. Report of the Twenty-first Session of the Codex Committee on Residues of Veterinary Drugs in
Foods. Minneapolis, USA, 2630 August 2013. Rome: Food and Agriculture Organization of the United
Nations and World Health Organization, Joint FAO/WHO Food Standards Programme, Codex Alimentarius
Commission; 2013 (REP14/RVDF).
7. FAO/WHO. Principles and methods for the risk assessment of chemicals in food. A joint publication of the
Food and Agriculture Organization of the United Nations and the World Health Organization. Geneva:
World Health Organization; 2009 (Environmental Health Criteria 240).
8. FAO/WHO. Joint FAO/WHO Expert Meeting on Dietary Exposure Assessment Methodologies for Residues
of Veterinary Drugs. Final report including report of stakeholder meeting. Geneva: World Health
Organization; 2012.
9. FAO/WHO. Pesticide residues in food 2015. Report of the Joint Meeting of the FAO Panel of Experts
on Pesticide Residues in Food and the Environment and the WHO Core Assessment Group on Pesticide
Residues. Rome: Food and Agriculture Organization of the United Nations and World Health Organization;
2015 (FAO Plant Production and Protection Paper, 223).
10. WHO. Guidance document for WHO monographers and reviewers evaluating veterinary drug residues in
food. Geneva: World Health Organization (in preparation).
11. FAO/WHO. Diflubenzuron. In: Pesticide residues in food 1981 evaluations. Rome: Food and Agriculture
Organization of the United Nations and World Health Organization; 1982.
12. FAO/WHO. Diflubenzuron. In: Pesticide residues in food 1985 evaluations. Rome: Food and Agriculture
Organization of the United Nations and World Health Organization; 1986.
13. FAO/WHO. Diflubenzuron. In: Pesticide residues in food 2001 evaluations. Rome: Food and Agriculture
Organization of the United Nations and World Health Organization; 2002.

89
 Joint FAO/WHO Expert Committee on Food Additives Eighty-first report

14. IPCS. Diflubenzuron. Geneva: World Health Organization, International Programme on Chemical Safety;
1996 (Environmental Health Criteria 184).
15. FAO/WHO. Guidelines for the design and implementation of national regulatory food safety assurance
programme associated with the use of veterinary drugs in food producing animals. Rome: Food and
Agriculture Organization of the United Nations and World Health Organization, Joint FAO/WHO Food
Standards Programme, Codex Alimentarius Commission; adopted in 2009, revised in 2012 (CAC/GL 71-
2009).
16. Lasseter KC. A double-blind, randomized, placebo-controlled, multiple-rising-dose study to investigate
the safety, tolerability, and pharmacokinetics of multiple doses of ivermectin (MK-0933) in healthy
male and female subjects (Protocol 066). Unpublished study. Merck Research Laboratories, West Point,
Pennsylvania, USA; 2001. Submitted to WHO by Merial, Inc., Duluth, Georgia, USA.
17. Merck & Co., Inc. Fourteen week oral toxicity study in dogs. TT #78-038-00. Unpublished study; 1978.
Submitted to WHO by Merck & Co., Inc. [cited in Annex 1, reference 92].
18. FAO/WHO. Teflubenzuron. In: Pesticide residues in food 1994. Report of the Joint Meeting of the FAO
Panel of Experts on Pesticide Residues in Food and the Environment and a WHO Expert Group on Pesticide
Residues. Rome: Food and Agriculture Organization of the United Nations and World Health Organization;
1995 (FAO Plant Production and Protection Paper, 127).
19. FAO/WHO. Teflubenzuron. In: Pesticide residues in food 1996. Report of the Joint Meeting of the FAO
Panel of Experts on Pesticide Residues in Food and the Environment and the WHO Core Assessment Group
on Pesticide Residues. Rome: Food and Agriculture Organization of the United Nations and World Health
Organization; 1997 (FAO Plant Production and Protection Paper, 140).
20. Suter P, Dewert H, Luetkemeier H, Westen H, Terrier C. 18-month oncogenicity (feeding) study with CME
134 in mice. Unpublished document no. 134AB-455-003 for Project 027810 from Research and Consulting
Co. AG, Itingen, Switzerland; 1987. Submitted to WHO by Skretting AS, Stavanger, Norway.
21. Vivet P. A study of the bronchodilatating activity of 3 single oral doses of R 42173 (0.05, 0.10 and 0.25
mg) in adult asthmatics a double-blind randomized 4 way-cross-over placebo-controlled multicentric
dose-ranging study. Unpublished report of study no. FF/88/173/05 from Medical Division, Roussel Uclaf,
Romainville, France; 1989. Submitted to WHO by MSD Animal Health.
22. Vacheron F, Stecyna V, Vincent JC, Petit F. Relay pharmacology of zilpaterol in the monitored conscious dog
(pilot orientating study). Unpublished report of study no. 94/7294/PH from Central Direction of Research,
WHO Technical Report Series No. 997, 2016

Roussel UCLAF, Romainville, France; 1995. Submitted to WHO by MSD Animal Health.
23. Sauvez F. Comparative study of pharmacokinetics in plasma after repeated oral administration for 2 weeks
(dietary admixture or gavage) in rats (orientating study). Unpublished report of study no. 11557 PSR
from Centre International de Toxicologie (C.I.T.), Miserey, Evreux, France; 1995. Submitted to WHO by MSD
Animal Health.
24. Advenier C. RU 42173 antagonism by propranolol in the guinea-pig trachea. Unpublished report of
study no. AU 10 from Direction of Preclinical Development, Roussel UCLAF, Romainville, France. Document
No. V-0238-0237; 1987. Submitted to WHO by MSD Animal Health.
25. Corbier A, Petit F. Blood pressure and heart rate effects of RU 42173 in the pithed rat: study of its
mechanism of action. Unpublished report of study no. 96/8772/PH from Unit of General Pharmacology,
Hoechst Marion Roussell, Romainville, France. Document No. V-0238-0115; 1999. Submitted to WHO by
MSD Animal Health.

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 References

26. Corbier A, Petit F. Blood pressure and heart rate effects of RU 40988 in the pithed rat: study of its
mechanism of action. Unpublished report of study no. 96/8777/PH from Unit of General Pharmacology,
Hoechst Marion Roussell, Romainville, France. Document No. V-0238-0117; 1999. Submitted to WHO by
MSD Animal Health.
27. Corbier A, Petit F. Blood pressure and heart rate effects of RU 42173 in the pithed rat: study of its
mechanism of action. Unpublished report of study no. 96/8773/PH from Unit of General Pharmacology,
Hoechst Marion Roussell, Romainville, France. Document No. V-0238-0116; 1999. Submitted to WHO by
MSD Animal Health.
28. Marhfer RJ, Sekljic H. Expert opinion: Zilpaterol hydrochloride metabolite N-acetylated deisopropyl-
zilpaterol is not active in vivo. Unpublished report from MSD Animal Health Innovation GmbH,
Schwabenheim, Germany; 2015 (MSD AH Report No. V-0238-0297). Submitted to WHO by MSD Animal
Health.
29. Girkin R. 14C-Zilpaterol: Bioavailability in the rat of liver non-extractable residues from cattle. Unpublished
report of study no. HST 456/993307 from Huntingdon Research Centre Ltd, Cambridgeshire, England,
United Kingdom. Document No. V-0238-0152, 1999. Submitted to FAO by MSD Animal Health.

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Annex 1
Reports and other documents resulting from previous meetings of
the Joint FAO/WHO Expert Committee on Food Additives
1. General principles governing the use of food additives (First report of the Joint FAO/WHO Expert
Committee on Food Additives). FAO Nutrition Meetings Report Series, No. 15, 1957; WHO Technical
Report Series, No. 129, 1957 (out of print).
2. Procedures for the testing of intentional food additives to establish their safety for use (Second report
of the Joint FAO/WHO Expert Committee on Food Additives). FAO Nutrition Meetings Report Series, No.
17, 1958; WHO Technical Report Series, No. 144, 1958 (out of print).
3. Specifications for identity and purity of food additives (antimicrobial preservatives and antioxidants)
(Third report of the Joint FAO/WHO Expert Committee on Food Additives). These specifications were
subsequently revised and published as Specifications for identity and purity of food additives, Vol. I.
Antimicrobial preservatives and antioxidants, Rome, Food and Agriculture Organization of the United
Nations, 1962 (out of print).
4. Specifications for identity and purity of food additives (food colours) (Fourth report of the Joint FAO/
WHO Expert Committee on Food Additives). These specifications were subsequently revised and
published as Specifications for identity and purity of food additives, Vol. II. Food colours, Rome, Food
and Agriculture Organization of the United Nations, 1963 (out of print).
5. Evaluation of the carcinogenic hazards of food additives (Fifth report of the Joint FAO/WHO Expert
Committee on Food Additives). FAO Nutrition Meetings Report Series, No. 29, 1961; WHO Technical
Report Series, No. 220, 1961 (out of print).
6. Evaluation of the toxicity of a number of antimicrobials and antioxidants (Sixth report of the Joint FAO/
WHO Expert Committee on Food Additives). FAO Nutrition Meetings Report Series, No. 31, 1962; WHO
Technical Report Series, No. 228, 1962 (out of print).
7. Specifications for the identity and purity of food additives and their toxicological evaluation:
emulsifiers, stabilizers, bleaching and maturing agents (Seventh report of the Joint FAO/WHO Expert
Committee on Food Additives). FAO Nutrition Meetings Series, No. 35, 1964; WHO Technical Report
Series, No. 281, 1964 (out of print).
8. Specifications for the identity and purity of food additives and their toxicological evaluation: food
colours and some antimicrobials and antioxidants (Eighth report of the Joint FAO/WHO Expert
Committee on Food Additives). FAO Nutrition Meetings Series, No. 38, 1965; WHO Technical Report
Series, No. 309, 1965 (out of print).
9. Specifications for identity and purity and toxicological evaluation of some antimicrobials and
antioxidants. FAO Nutrition Meetings Report Series, No. 38A, 1965; WHO/Food Add/24.65 (out of print).
10. Specifications for identity and purity and toxicological evaluation of food colours. FAO Nutrition
Meetings Report Series, No. 38B, 1966; WHO/Food Add/66.25.
11. Specifications for the identity and purity of food additives and their toxicological evaluation: some
antimicrobials, antioxidants, emulsifiers, stabilizers, flour treatment agents, acids, and bases (Ninth
report of the Joint FAO/WHO Expert Committee on Food Additives). FAO Nutrition Meetings Series, No.
40, 1966; WHO Technical Report Series, No. 339, 1966 (out of print).

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12. Toxicological evaluation of some antimicrobials, antioxidants, emulsifiers, stabilizers, flour treatment
agents, acids, and bases. FAO Nutrition Meetings Report Series, No. 40A, B, C; WHO/Food Add/67.29.
13. Specifications for the identity and purity of food additives and their toxicological evaluation: some
emulsifiers and stabilizers and certain other substances (Tenth report of the Joint FAO/WHO Expert
Committee on Food Additives). FAO Nutrition Meetings Series, No. 43, 1967; WHO Technical Report
Series, No. 373, 1967.
14. Specifications for the identity and purity of food additives and their toxicological evaluation: some
flavouring substances and non-nutritive sweetening agents (Eleventh report of the Joint FAO/WHO
Expert Committee on Food Additives). FAO Nutrition Meetings Series, No. 44, 1968; WHO Technical
Report Series, No. 383, 1968.
15. Toxicological evaluation of some flavouring substances and non-nutritive sweetening agents. FAO
Nutrition Meetings Report Series, No. 44A, 1968; WHO/Food Add/68.33.
16. Specifications and criteria for identity and purity of some flavouring substances and non-nutritive
sweetening agents. FAO Nutrition Meetings Report Series, No. 44B, 1969; WHO/Food Add/69.31.
17. Specifications for the identity and purity of food additives and their toxicological evaluation: some
antibiotics (Twelfth report of the Joint FAO/WHO Expert Committee on Food Additives). FAO Nutrition
Meetings Series, No. 45, 1969; WHO Technical Report Series, No. 430, 1969.
18. Specifications for the identity and purity of some antibiotics. FAO Nutrition Meetings Series, No. 45A,
1969; WHO/Food Add/69.34.
19. Specifications for the identity and purity of food additives and their toxicological evaluation: some
food colours, emulsifiers, stabilizers, anticaking agents, and certain other substances (Thirteenth
report of the Joint FAO/WHO Expert Committee on Food Additives). FAO Nutrition Meetings Series, No.
46, 1970; WHO Technical Report Series, No. 445, 1970.
20. Toxicological evaluation of some food colours, emulsifiers, stabilizers, anticaking agents, and certain
other substances. FAO Nutrition Meetings Report Series, No. 46A, 1970; WHO/Food Add/70.36.
21. Specifications for the identity and purity of some food colours, emulsifiers, stabilizers, anticaking
agents, and certain other food additives. FAO Nutrition Meetings Report Series, No. 46B, 1970; WHO/
Food Add/70.37.
22. Evaluation of food additives: specifications for the identity and purity of food additives and their
WHO Technical Report Series No. 997, 2016

toxicological evaluation: some extraction solvents and certain other substances; and a review of the
technological efficacy of some antimicrobial agents (Fourteenth report of the Joint FAO/WHO Expert
Committee on Food Additives). FAO Nutrition Meetings Series, No. 48, 1971; WHO Technical Report
Series, No. 462, 1971.
23. Toxicological evaluation of some extraction solvents and certain other substances. FAO Nutrition
Meetings Report Series, No. 48A, 1971; WHO/Food Add/70.39.
24. Specifications for the identity and purity of some extraction solvents and certain other substances. FAO
Nutrition Meetings Report Series, No. 48B, 1971; WHO/Food Add/70.40.
25. A review of the technological efficacy of some antimicrobial agents. FAO Nutrition Meetings Report
Series, No. 48C, 1971; WHO/Food Add/70.41.
26. Evaluation of food additives: some enzymes, modified starches, and certain other substances:
Toxicological evaluations and specifications and a review of the technological efficacy of some

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antioxidants (Fifteenth report of the Joint FAO/WHO Expert Committee on Food Additives). FAO
Nutrition Meetings Series, No. 50, 1972; WHO Technical Report Series, No. 488, 1972.
27. Toxicological evaluation of some enzymes, modified starches, and certain other substances. FAO
Nutrition Meetings Report Series, No. 50A, 1972; WHO Food Additives Series, No. 1, 1972.
28. Specifications for the identity and purity of some enzymes and certain other substances. FAO Nutrition
Meetings Report Series, No. 50B, 1972; WHO Food Additives Series, No. 2, 1972.
29. A review of the technological efficacy of some antioxidants and synergists. FAO Nutrition Meetings
Report Series, No. 50C, 1972; WHO Food Additives Series, No. 3, 1972.
30. Evaluation of certain food additives and the contaminants mercury, lead, and cadmium (Sixteenth
report of the Joint FAO/WHO Expert Committee on Food Additives). FAO Nutrition Meetings Series, No.
51, 1972; WHO Technical Report Series, No. 505, 1972, and corrigendum.
31. Evaluation of mercury, lead, cadmium and the food additives amaranth, diethylpyrocarbamate, and
octyl gallate. FAO Nutrition Meetings Report Series, No. 51A, 1972; WHO Food Additives Series, No. 4,
1972.
32. Toxicological evaluation of certain food additives with a review of general principles and of
specifications (Seventeenth report of the Joint FAO/WHO Expert Committee on Food Additives). FAO
Nutrition Meetings Series, No. 53, 1974; WHO Technical Report Series, No. 539, 1974, and corrigendum
(out of print).
33. Toxicological evaluation of some food additives including anticaking agents, antimicrobials,
antioxidants, emulsifiers, and thickening agents. FAO Nutrition Meetings Report Series, No. 53A, 1974;
WHO Food Additives Series, No. 5, 1974.
34. Specifications for identity and purity of thickening agents, anticaking agents, antimicrobials,
antioxidants and emulsifiers. FAO Food and Nutrition Paper, No. 4, 1978.
35. Evaluation of certain food additives (Eighteenth report of the Joint FAO/WHO Expert Committee on
Food Additives). FAO Nutrition Meetings Series, No. 54, 1974; WHO Technical Report Series, No. 557,
1974, and corrigendum.
36. Toxicological evaluation of some food colours, enzymes, flavour enhancers, thickening agents, and
certain other food additives. FAO Nutrition Meetings Report Series, No. 54A, 1975; WHO Food Additives
Series, No. 6, 1975.
37. Specifications for the identity and purity of some food colours, enhancers, thickening agents, and
certain food additives. FAO Nutrition Meetings Report Series, No. 54B, 1975; WHO Food Additives
Series, No. 7, 1975.
38. Evaluation of certain food additives: some food colours, thickening agents, smoke condensates,
and certain other substances (Nineteenth report of the Joint FAO/WHO Expert Committee on Food
Additives). FAO Nutrition Meetings Series, No. 55, 1975; WHO Technical Report Series, No. 576, 1975.
39. Toxicological evaluation of some food colours, thickening agents, and certain other substances. FAO
Nutrition Meetings Report Series, No. 55A, 1975; WHO Food Additives Series, No. 8, 1975.
40. Specifications for the identity and purity of certain food additives. FAO Nutrition Meetings Report
Series, No. 55B, 1976; WHO Food Additives Series, No. 9, 1976.

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 Joint FAO/WHO Expert Committee on Food Additives Eighty-first report

41. Evaluation of certain food additives (Twentieth report of the Joint FAO/WHO Expert Committee on
Food Additives). FAO Food and Nutrition Meetings Series, No. 1, 1976; WHO Technical Report Series,
No. 599, 1976.
42. Toxicological evaluation of certain food additives. WHO Food Additives Series, No. 10, 1976.
43. Specifications for the identity and purity of some food additives. FAO Food and Nutrition Series, No. 1B,
1977; WHO Food Additives Series, No. 11, 1977.
44. Evaluation of certain food additives (Twenty-first report of the Joint FAO/WHO Expert Committee on
Food Additives). WHO Technical Report Series, No. 617, 1978.
45. Summary of toxicological data of certain food additives. WHO Food Additives Series, No. 12, 1977.
46. Specifications for identity and purity of some food additives, including antioxidants, food colours,
thickeners, and others. FAO Nutrition Meetings Report Series, No. 57, 1977.
47. Evaluation of certain food additives and contaminants (Twenty-second report of the Joint FAO/WHO
Expert Committee on Food Additives). WHO Technical Report Series, No. 631, 1978.
48. Summary of toxicological data of certain food additives and contaminants. WHO Food Additives Series,
No. 13, 1978.
49. Specifications for the identity and purity of certain food additives. FAO Food and Nutrition Paper, No.
7, 1978.
50. Evaluation of certain food additives (Twenty-third report of the Joint FAO/WHO Expert Committee on
Food Additives). WHO Technical Report Series, No. 648, 1980, and corrigenda.
51. Toxicological evaluation of certain food additives. WHO Food Additives Series, No. 14, 1980.
52. Specifications for identity and purity of food colours, flavouring agents, and other food additives. FAO
Food and Nutrition Paper, No. 12, 1979.
53. Evaluation of certain food additives (Twenty-fourth report of the Joint FAO/WHO Expert Committee on
Food Additives). WHO Technical Report Series, No. 653, 1980.
54. Toxicological evaluation of certain food additives. WHO Food Additives Series, No. 15, 1980.
55. Specifications for identity and purity of food additives (sweetening agents, emulsifying agents, and
other food additives). FAO Food and Nutrition Paper, No. 17, 1980.
WHO Technical Report Series No. 997, 2016

56. Evaluation of certain food additives (Twenty-fifth report of the Joint FAO/WHO Expert Committee on
Food Additives). WHO Technical Report Series, No. 669, 1981.
57. Toxicological evaluation of certain food additives. WHO Food Additives Series, No. 16, 1981.
58. Specifications for identity and purity of food additives (carrier solvents, emulsifiers and stabilizers,
enzyme preparations, flavouring agents, food colours, sweetening agents, and other food additives).
FAO Food and Nutrition Paper, No. 19, 1981.
59. Evaluation of certain food additives and contaminants (Twenty-sixth report of the Joint FAO/WHO
Expert Committee on Food Additives). WHO Technical Report Series, No. 683, 1982.
60. Toxicological evaluation of certain food additives. WHO Food Additives Series, No. 17, 1982.
61. Specifications for the identity and purity of certain food additives. FAO Food and Nutrition Paper, No.
25, 1982.

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62. Evaluation of certain food additives and contaminants (Twenty-seventh report of the Joint FAO/WHO
Expert Committee on Food Additives). WHO Technical Report Series, No. 696, 1983, and corrigenda.
63. Toxicological evaluation of certain food additives and contaminants. WHO Food Additives Series, No.
18, 1983.
64. Specifications for the identity and purity of certain food additives. FAO Food and Nutrition Paper, No.
28, 1983.
65. Guide to specifications General notices, general methods, identification tests, test solutions, and
other reference materials. FAO Food and Nutrition Paper, No. 5, Rev. 1, 1983.
66. Evaluation of certain food additives and contaminants (Twenty-eighth report of the Joint FAO/WHO
Expert Committee on Food Additives). WHO Technical Report Series, No. 710, 1984, and corrigendum.
67. Toxicological evaluation of certain food additives and contaminants. WHO Food Additives Series, No.
19, 1984.
68. Specifications for the identity and purity of food colours. FAO Food and Nutrition Paper, No. 31/1, 1984.
69. Specifications for the identity and purity of food additives. FAO Food and Nutrition Paper, No. 31/2,
1984.
70. Evaluation of certain food additives and contaminants (Twenty-ninth report of the Joint FAO/WHO
Expert Committee on Food Additives). WHO Technical Report Series, No. 733, 1986, and corrigendum.
71. Specifications for the identity and purity of certain food additives. FAO Food and Nutrition Paper, No.
34, 1986.
72. Toxicological evaluation of certain food additives and contaminants. WHO Food Additives Series, No.
20. Cambridge University Press, 1987.
73. Evaluation of certain food additives and contaminants (Thirtieth report of the Joint FAO/WHO Expert
Committee on Food Additives). WHO Technical Report Series, No. 751, 1987.
74. Toxicological evaluation of certain food additives and contaminants. WHO Food Additives Series, No.
21. Cambridge University Press, 1987.
75. Specifications for the identity and purity of certain food additives. FAO Food and Nutrition Paper, No.
37, 1986.
76. Principles for the safety assessment of food additives and contaminants in food. WHO Environmental
Health Criteria, No. 70. Geneva, World Health Organization, 1987 (out of print). The full text is available
electronically at www.who.int/pcs.
77. Evaluation of certain food additives and contaminants (Thirty-first report of the Joint FAO/WHO Expert
Committee on Food Additives). WHO Technical Report Series, No. 759, 1987, and corrigendum.
78. Toxicological evaluation of certain food additives. WHO Food Additives Series, No. 22. Cambridge
University Press, 1988.
79. Specifications for the identity and purity of certain food additives. FAO Food and Nutrition Paper, No.
38, 1988.
80. Evaluation of certain veterinary drug residues in food (Thirty-second report of the Joint FAO/WHO
Expert Committee on Food Additives). WHO Technical Report Series, No. 763, 1988.

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 Joint FAO/WHO Expert Committee on Food Additives Eighty-first report

81. Toxicological evaluation of certain veterinary drug residues in food. WHO Food Additives Series, No. 23.
Cambridge University Press, 1988.
82. Residues of some veterinary drugs in animals and foods. FAO Food and Nutrition Paper, No. 41, 1988.
83. Evaluation of certain food additives and contaminants (Thirty-third report of the Joint FAO/WHO
Expert Committee on Food Additives). WHO Technical Report Series, No. 776, 1989.
84. Toxicological evaluation of certain food additives and contaminants. WHO Food Additives Series, No.
24. Cambridge University Press, 1989.
85. Evaluation of certain veterinary drug residues in food (Thirty-fourth report of the Joint FAO/WHO
Expert Committee on Food Additives). WHO Technical Report Series, No. 788, 1989.
86. Toxicological evaluation of certain veterinary drug residues in food. WHO Food Additives Series, No.
25, 1990.
87. Residues of some veterinary drugs in animals and foods. FAO Food and Nutrition Paper, No. 41/2, 1990.
88. Evaluation of certain food additives and contaminants (Thirty-fifth report of the Joint FAO/WHO Expert
Committee on Food Additives). WHO Technical Report Series, No. 789, 1990, and corrigenda.
89. Toxicological evaluation of certain food additives and contaminants. WHO Food Additives Series, No.
26, 1990.
90. Specifications for identity and purity of certain food additives. FAO Food and Nutrition Paper, No. 49,
1990.
91. Evaluation of certain veterinary drug residues in food (Thirty-sixth report of the Joint FAO/WHO Expert
Committee on Food Additives). WHO Technical Report Series, No. 799, 1990.
92. Toxicological evaluation of certain veterinary drug residues in food. WHO Food Additives Series, No.
27, 1991.
93. Residues of some veterinary drugs in animals and foods. FAO Food and Nutrition Paper, No. 41/3, 1991.
94. Evaluation of certain food additives and contaminants (Thirty-seventh report of the Joint FAO/WHO
Expert Committee on Food Additives). WHO Technical Report Series, No. 806, 1991, and corrigenda.
95. Toxicological evaluation of certain food additives and contaminants. WHO Food Additives Series, No.
28, 1991.
WHO Technical Report Series No. 997, 2016

96. Compendium of food additive specifications (Joint FAO/WHO Expert Committee on Food Additives
(JECFA)). Combined specifications from 1st through the 37th meetings, 19561990. Rome, Food and
Agriculture Organization of the United Nations, 1992 (2 volumes).
97. Evaluation of certain veterinary drug residues in food (Thirty-eighth report of the Joint FAO/WHO
Expert Committee on Food Additives). WHO Technical Report Series, No. 815, 1991.
98. Toxicological evaluation of certain veterinary drug residues in food. WHO Food Additives Series, No.
29, 1991.
99. Residues of some veterinary drugs in animals and foods. FAO Food and Nutrition Paper, No. 41/4, 1991.
100. Guide to specifications General notices, general analytical techniques, identification tests, test
solutions, and other reference materials. FAO Food and Nutrition Paper, No. 5, Ref. 2, 1991.
101. Evaluation of certain food additives and naturally occurring toxicants (Thirty-ninth report of the Joint
FAO/WHO Expert Committee on Food Additives). WHO Technical Report Series No. 828, 1992.
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102. Toxicological evaluation of certain food additives and naturally occurring toxicants. WHO Food
Additives Series, No. 30, 1993.
103. Compendium of food additive specifications: addendum 1. FAO Food and Nutrition Paper, No. 52, 1992.
104. Evaluation of certain veterinary drug residues in food (Fortieth report of the Joint FAO/WHO Expert
Committee on Food Additives). WHO Technical Report Series, No. 832, 1993.
105. Toxicological evaluation of certain veterinary drug residues in food. WHO Food Additives Series, No.
31, 1993.
106. Residues of some veterinary drugs in animals and food. FAO Food and Nutrition Paper, No. 41/5, 1993.
107. Evaluation of certain food additives and contaminants (Forty-first report of the Joint FAO/WHO Expert
Committee on Food Additives). WHO Technical Report Series, No. 837, 1993.
108. Toxicological evaluation of certain food additives and contaminants. WHO Food Additives Series, No.
32, 1993.
109. Compendium of food additive specifications: addendum 2. FAO Food and Nutrition Paper, No. 52, Add.
2, 1993.
110. Evaluation of certain veterinary drug residues in food (Forty-second report of the Joint FAO/WHO
Expert Committee on Food Additives). WHO Technical Report Series, No. 851, 1995.
111. Toxicological evaluation of certain veterinary drug residues in food. WHO Food Additives Series, No.
33, 1994.
112. Residues of some veterinary drugs in animals and foods. FAO Food and Nutrition Paper, No. 41/6, 1994.
113. Evaluation of certain veterinary drug residues in food (Forty-third report of the Joint FAO/WHO Expert
Committee on Food Additives). WHO Technical Report Series, No. 855, 1995, and corrigendum.
114. Toxicological evaluation of certain veterinary drug residues in food. WHO Food Additives Series, No.
34, 1995.
115. Residues of some veterinary drugs in animals and foods. FAO Food and Nutrition Paper, No. 41/7, 1995.
116. Evaluation of certain food additives and contaminants (Forty-fourth report of the Joint FAO/WHO
Expert Committee on Food Additives). WHO Technical Report Series, No. 859, 1995.
117. Toxicological evaluation of certain food additives and contaminants. WHO Food Additives Series, No.
35, 1996.
118. Compendium of food additive specifications: addendum 3. FAO Food and Nutrition Paper, No. 52, Add.
3, 1995.
119. Evaluation of certain veterinary drug residues in food (Forty-fifth report of the Joint FAO/WHO Expert
Committee on Food Additives). WHO Technical Report Series, No. 864, 1996.
120. Toxicological evaluation of certain veterinary drug residues in food. WHO Food Additives Series, No.
36, 1996.
121. Residues of some veterinary drugs in animals and foods. FAO Food and Nutrition Paper, No. 41/8, 1996.
122. Evaluation of certain food additives and contaminants (Forty-sixth report of the Joint FAO/WHO Expert
Committee on Food Additives). WHO Technical Report Series, No. 868, 1997.
123. Toxicological evaluation of certain food additives. WHO Food Additives Series, No. 37, 1996.

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124. Compendium of food additive specifications, addendum 4. FAO Food and Nutrition Paper, No. 52, Add.
4, 1996.
125. Evaluation of certain veterinary drug residues in food (Forty-seventh report of the Joint FAO/WHO
Expert Committee on Food Additives). WHO Technical Report Series, No. 876, 1998.
126. Toxicological evaluation of certain veterinary drug residues in food. WHO Food Additives Series, No.
38, 1996.
127. Residues of some veterinary drugs in animals and foods. FAO Food and Nutrition Paper, No. 41/9, 1997.
128. Evaluation of certain veterinary drug residues in food (Forty-eighth report of the Joint FAO/WHO
Expert Committee on Food Additives). WHO Technical Report Series, No. 879, 1998.
129. Toxicological evaluation of certain veterinary drug residues in food. WHO Food Additives Series, No.
39, 1997.
130. Residues of some veterinary drugs in animals and foods. FAO Food and Nutrition Paper, No. 41/10,
1998.
131. Evaluation of certain food additives and contaminants (Forty-ninth report of the Joint FAO/WHO
Expert Committee on Food Additives). WHO Technical Report Series, No. 884, 1999.
132. Safety evaluation of certain food additives and contaminants. WHO Food Additives Series, No. 40, 1998.
133. Compendium of food additive specifications: addendum 5. FAO Food and Nutrition Paper, No. 52, Add.
5, 1997.
134. Evaluation of certain veterinary drug residues in food (Fiftieth report of the Joint FAO/WHO Expert
Committee on Food Additives). WHO Technical Report Series, No. 888, 1999.
135. Toxicological evaluation of certain veterinary drug residues in food. WHO Food Additives Series, No.
41, 1998.
136. Residues of some veterinary drugs in animals and foods. FAO Food and Nutrition Paper, No. 41/11,
1999.
137. Evaluation of certain food additives (Fifty-first report of the Joint FAO/WHO Expert Committee on Food
Additives). WHO Technical Report Series, No. 891, 2000.
138. Safety evaluation of certain food additives. WHO Food Additives Series, No. 42, 1999.
WHO Technical Report Series No. 997, 2016

139. Compendium of food additive specifications, addendum 6. FAO Food and Nutrition Paper, No. 52, Add.
6, 1998.
140. Evaluation of certain veterinary drug residues in food (Fifty-second report of the Joint FAO/WHO Expert
Committee on Food Additives). WHO Technical Report Series, No. 893, 2000.
141. Toxicological evaluation of certain veterinary drug residues in food. WHO Food Additives Series, No.
43, 2000.
142. Residues of some veterinary drugs in animals and foods. FAO Food and Nutrition Paper, No. 41/12,
2000.
143. Evaluation of certain food additives and contaminants (Fifty-third report of the Joint FAO/WHO Expert
Committee on Food Additives). WHO Technical Report Series, No. 896, 2000.
144. Safety evaluation of certain food additives and contaminants. WHO Food Additives Series, No. 44, 2000.

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145. Compendium of food additive specifications, addendum 7. FAO Food and Nutrition Paper, No. 52, Add.
7, 1999.
146. Evaluation of certain veterinary drug residues in food (Fifty-fourth report of the Joint FAO/WHO Expert
Committee on Food Additives). WHO Technical Report Series, No. 900, 2001.
147. Toxicological evaluation of certain veterinary drug residues in food. WHO Food Additives Series, No.
45, 2000.
148. Residues of some veterinary drugs in animals and foods. FAO Food and Nutrition Paper, No. 41/13,
2000.
149. Evaluation of certain food additives and contaminants (Fifty-fifth report of the Joint FAO/WHO Expert
Committee on Food Additives). WHO Technical Report Series, No. 901, 2001.
150. Safety evaluation of certain food additives and contaminants. WHO Food Additives Series, No. 46, 2001.
151. Compendium of food additive specifications: addendum 8. FAO Food and Nutrition Paper, No. 52, Add.
8, 2000.
152. Evaluation of certain mycotoxins in food (Fifty-sixth report of the Joint FAO/WHO Expert Committee on
Food Additives). WHO Technical Report Series, No. 906, 2002.
153. Safety evaluation of certain mycotoxins in food. WHO Food Additives Series, No. 47/FAO Food and
Nutrition Paper 74, 2001.
154. Evaluation of certain food additives and contaminants (Fifty-seventh report of the Joint FAO/WHO
Expert Committee on Food Additives). WHO Technical Report Series, No. 909, 2002.
155. Safety evaluation of certain food additives and contaminants. WHO Food Additives Series, No. 48, 2002.
156. Compendium of food additive specifications: addendum 9. FAO Food and Nutrition Paper, No. 52, Add.
9, 2001.
157. Evaluation of certain veterinary drug residues in food (Fifty-eighth report of the Joint FAO/WHO Expert
Committee on Food Additives). WHO Technical Report Series, No. 911, 2002.
158. Toxicological evaluation of certain veterinary drug residues in food. WHO Food Additives Series, No.
49, 2002.
159. Residues of some veterinary drugs in animals and foods. FAO Food and Nutrition Paper, No. 41/14,
2002.
160. Evaluation of certain food additives and contaminants (Fifty-ninth report of the Joint FAO/WHO Expert
Committee on Food Additives). WHO Technical Report Series, No. 913, 2002.
161. Safety evaluation of certain food additives and contaminants. WHO Food Additives Series, No. 50, 2003.
162. Compendium of food additive specifications: addendum 10. FAO Food and Nutrition Paper, No. 52,
Add. 10, 2002.
163. Evaluation of certain veterinary drug residues in food (Sixtieth report of the Joint FAO/WHO Expert
Committee on Food Additives). WHO Technical Report Series, No. 918, 2003.
164. Toxicological evaluation of certain veterinary drug residues in food. WHO Food Additives Series, No.
51, 2003.
165. Residues of some veterinary drugs in animals and foods. FAO Food and Nutrition Paper, No. 41/15,
2003.
101
 Joint FAO/WHO Expert Committee on Food Additives Eighty-first report

166. Evaluation of certain food additives and contaminants (Sixty-first report of the Joint FAO/WHO Expert
Committee on Food Additives). WHO Technical Report Series, No. 922, 2004.
167. Safety evaluation of certain food additives and contaminants. WHO Food Additives Series, No. 52, 2004.
168. Compendium of food additive specifications: addendum 11. FAO Food and Nutrition Paper, No. 52,
Add. 11, 2003.
169. Evaluation of certain veterinary drug residues in food (Sixty-second report of the Joint FAO/WHO
Expert Committee on Food Additives). WHO Technical Report Series, No. 925, 2004.
170. Residues of some veterinary drugs in animals and foods. FAO Food and Nutrition Paper, No. 41/16,
2004.
171. Toxicological evaluation of certain veterinary drug residues in food. WHO Food Additives Series, No.
53, 2005.
172. Compendium of food additive specifications: addendum 12. FAO Food and Nutrition Paper, No. 52,
Add. 12, 2004.
173. Evaluation of certain food additives (Sixty-third report of the Joint FAO/WHO Expert Committee on
Food Additives). WHO Technical Report Series, No. 928, 2005.
174. Safety evaluation of certain food additives. WHO Food Additives Series, No. 54, 2005.
175. Compendium of food additive specifications: addendum 13. FAO Food and Nutrition Paper, No. 52, Add.
13 (with Errata), 2005.
176. Evaluation of certain food contaminants (Sixty-fourth report of the Joint FAO/WHO Expert Committee
on Food Additives). WHO Technical Report Series, No. 930, 2005.
177. Safety evaluation of certain contaminants in food. WHO Food Additives Series, No. 55/FAO Food and
Nutrition Paper, No. 82, 2006.
178. Evaluation of certain food additives (Sixty-fifth report of the Joint FAO/WHO Expert Committee on
Food Additives). WHO Technical Report Series, No. 934, 2006.
179. Safety evaluation of certain food additives. WHO Food Additives Series, No. 56, 2006.
180. Combined compendium of food additive specifications. FAO JECFA Monographs 1, Volumes 14, 2005,
2006.
WHO Technical Report Series No. 997, 2016

181. Evaluation of certain veterinary drug residues in food (Sixty-sixth report of the Joint FAO/WHO Expert
Committee on Food Additives). WHO Technical Report Series, No. 939, 2006.
182. Residue evaluation of certain veterinary drugs. FAO JECFA Monographs 2, 2006.
183. Toxicological evaluation of certain veterinary drug residues in food. WHO Food Additives Series, No.
57, 2006.
184. Evaluation of certain food additives and contaminants (Sixty-seventh report of the Joint FAO/WHO
Expert Committee on Food Additives). WHO Technical Report Series, No. 940, 2007.
185. Compendium of food additive specifications. FAO JECFA Monographs 3, 2006.
186. Safety evaluation of certain food additives and contaminants. WHO Food Additives Series, No. 58, 2007.
187. Evaluation of certain food additives and contaminants (Sixty-eighth report of the Joint FAO/WHO
Expert Committee on Food Additives). WHO Technical Report Series, No. 947, 2007.

102
 Annex 1

188. Safety evaluation of certain food additives and contaminants. WHO Food Additives Series, No. 59, 2008.
189. Compendium of food additive specifications. FAO JECFA Monographs 4, 2007.
190. Evaluation of certain food additives (Sixty-ninth report of the Joint FAO/WHO Expert Committee on
Food Additives). WHO Technical Report Series, No. 952, 2009.
191. Safety evaluation of certain food additives. WHO Food Additives Series, No. 60, 2009.
192. Compendium of food additive specifications. FAO JECFA Monographs 5, 2009.
193. Evaluation of certain veterinary drug residues in food (Seventieth report of the Joint FAO/WHO Expert
Committee on Food Additives). WHO Technical Report Series, No. 954, 2009.
194. Toxicological evaluation of certain veterinary drug residues in food. WHO Food Additives Series, No.
61, 2009.
195. Residue evaluation of certain veterinary drugs. FAO JECFA Monographs 6, 2009.
196. Evaluation of certain food additives (Seventy-first report of the Joint FAO/WHO Expert Committee on
Food Additives). WHO Technical Report Series, No. 956, 2010.
197. Safety evaluation of certain food additives. WHO Food Additives Series, No. 62, 2010.
198. Compendium of food additive specifications. FAO JECFA Monographs 7, 2009.
199. Evaluation of certain contaminants in food (Seventy-second report of the Joint FAO/WHO Expert
Committee on Food Additives). WHO Technical Report Series, No. 959, 2011.
200. Safety evaluation of certain contaminants in food. WHO Food Additives Series, No. 63/FAO JECFA
Monographs 8, 2011.
201. Residue evaluation of certain veterinary drugs. FAO JECFA Monographs 9, 2010.
202. Evaluation of certain food additives and contaminants (Seventy-third report of the Joint FAO/WHO
Expert Committee on Food Additives). WHO Technical Report Series, No. 960, 2011.
203. Safety evaluation of certain food additives and contaminants. WHO Food Additives Series, No. 64, 2011.
204. Compendium of food additive specifications. FAO JECFA Monographs 10, 2010.
205. Evaluation of certain food additives and contaminants (Seventy-fourth report of the Joint FAO/WHO
Expert Committee on Food Additives). WHO Technical Report Series, No. 966, 2011.
206. Safety evaluation of certain food additives and contaminants. WHO Food Additives Series, No. 65, 2011.
207. Compendium of food additive specifications. FAO JECFA Monographs 11, 2011.
208. Evaluation of certain veterinary drug residues in food (Seventy-fifth report of the Joint FAO/WHO
Expert Committee on Food Additives). WHO Technical Report Series, No. 969, 2012.
209. Toxicological evaluation of certain veterinary drug residues in food. WHO Food Additives Series, No.
66, 2012.
210. Residue evaluation of certain veterinary drugs. FAO JECFA Monographs 12, 2012.
211. Evaluation of certain food additives (Seventy-sixth report of the Joint FAO/WHO Expert Committee on
Food Additives). WHO Technical Report Series, No. 974, 2012.
212. Safety evaluation of certain food additives. WHO Food Additives Series, No. 67, 2012.

103
 Joint FAO/WHO Expert Committee on Food Additives Eighty-first report

213. Compendium of food additive specifications. FAO JECFA Monographs 13, 2012.
214. Evaluation of certain food additives and contaminants (Seventy-seventh report of the Joint FAO/WHO
Expert Committee on Food Additives). WHO Technical Report Series, No. 983, 2013.
215. Safety evaluation of certain food additives and contaminants. WHO Food Additives Series, No. 68, 2013.
216. Compendium of food additive specifications. FAO JECFA Monographs 14, 2013.
217. Evaluation of certain veterinary drug residues in food (Seventy-eighth report of the Joint FAO/WHO
Expert Committee on Food Additives). WHO Technical Report Series, No. 988, 2014.
218. Toxicological evaluation of certain veterinary drug residues in food. WHO Food Additives Series, No.
69, 2014.
219. Residue evaluation of certain veterinary drugs. FAO JECFA Monographs 15, 2014.
220. Evaluation of certain food additives (Seventy-ninth report of the Joint FAO/WHO Expert Committee on
Food Additives). WHO Technical Report Series, No. 990, 2015.
221. Safety evaluation of certain food additives. WHO Food Additives Series, No. 70, 2015.
222. Compendium of food additive specifications. FAO JECFA Monographs 16, 2014.
223. Evaluation of certain food additives and contaminants (Eightieth report of the Joint FAO/WHO Expert
Committee on Food Additives). WHO Technical Report Series, No. 995, 2016.
224. Safety evaluation of certain food additives and contaminants. WHO Food Additives Series, No. 71, 2015.
225. Compendium of food additive specifications. FAO JECFA Monographs 17, 2015.
WHO Technical Report Series No. 997, 2016

104
Annex 2
Recommendations on compounds on the agenda

Diflubenzuron (insecticide)

Acceptable daily intakeIn the absence of adequate information on exposure

to 4-chloroaniline (PCA), a genotoxic and carcino-
genic metabolite and/or degradate of diflubenzuron,
the Committee was unable to establish an acceptable
daily intake (ADI) for diflubenzuron because it was
not possible to assure itself that there would be an
adequate margin of safety from its use as a veteri-
nary drug. The Committee also noted that it was not
possible to calculate a margin of exposure for PCA
in the absence of adequate information on exposure
to PCA.
Maximum residue limits The Committee was unable to recommend maxi-
mum residue limits (MRLs) for diflubenzuron, as an
ADI could not be established

Ivermectin (antiparasitic agent)

Acceptable daily intake The Committee established an ADI of 010 g/kg

body weight on the basis of a no-observed-
adverse-effect level (NOAEL) of 0.5 mg/kg body
weight per day for neurological effects (mydriasis)
and retardation of weight gain in a 14-week dog
study, with application of an uncertainty factor of
50 (5 for interspecies differences based on pharma-
cokinetics studies in dogs and humans and 10 for
intraspecies differences). The previous ADI of 01
g/kg body weight was withdrawn.
Acute reference dose The Committee established an acute reference dose
(ARfD) of 0.2 mg/kg body weight, based on a NOAEL
of 1.5 mg/kg body weight, the highest dose tested in
a safety, tolerability and pharmacokinetics study in
healthy human subjects, with application of an uncer-
tainty factor of 10 for intraspecies variability.
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 Joint FAO/WHO Expert Committee on Food Additives Eighty-first report

Estimated chronic The estimated daily intake (EDI) is 38 g/person per

dietary exposure day, based on a 60 kg individual, which represents
6% of the upper bound of the ADI.
The global estimate of chronic dietary exposure
(GECDE) for the general population is 0.9 g/kg
body weight per day, which represents 9% of the
upper bound of the ADI.
The GECDE for children is 1.5 g/kg body weight
per day, which represents 15% of the upper bound of
the ADI.
The GECDE for infants is 1.3 g/kg body weight per
day, which represents 13% of the upper bound of the
ADI.
Estimated acute dietary The maximum values of residues found at injection
exposure sites led to global estimates of acute dietary exposure
(GEADE) of 73 g/kg body weight for the general
population and 82 g/kg body weight for children,
corresponding, respectively, to 36% and 41% of the
ARfD.
Residue definition Ivermectin B1a

Recommended maximum residue limits (MRLs)a

Fat Kidney Liver Muscle
Species (g/kg) (g/kg) (g/kg) (g/kg)
Cattle 400 100 800 30
a
No new data were provided for use of ivermectin in dairy cattle; therefore, the Committee did not recommend any revision to the MRL of 10 g/kg for ivermectin
in milk.
WHO Technical Report Series No. 997, 2016

Lasalocid sodium (antiparasitic agent)

Following consideration of the issues raised in concern forms from the Codex
Committee on Residues of Veterinary Drugs in Foods (CCRVDF), the Committee
concluded that there would be no concern for colonization barrier disruption in
the colon from acute exposure to residues of lasalocid. The ADI established and
MRLs recommended at the seventy-eighth meeting of JECFA (WHO TRS No.
988, 2014) remain unchanged.

106
 Annex 2

Sisapronil (ectoparasiticide)

Acceptable daily intakeThe Committee concluded that a toxicological ADI

could not be established because the Committee had
no basis upon which to determine a suitable uncer-
tainty factor to accommodate the lack of a long-term
toxicity study.
Maximum residue limits The Committee could not recommend MRLs, as an
ADI could not be established.

Teflubenzuron (insecticide)

Acceptable daily intake The Committee established an ADI of 05 g/kg

body weight on the basis of a lower 95% confidence
limit on the benchmark dose for a 10% response
(BMDL10) of 0.54 mg/kg body weight per day for
hepatocellular hypertrophy in male mice observed
in a carcinogenicity study, with application of an
uncertainty factor of 100 to account for interspecies
and intraspecies variability.
Esimated chronic The EDI is 42.9 g/person per day, on the basis of
dietary exposure a 60 kg individual, which represents approximately
14% of the upper bound of the ADI.
The GECDE for the general population is 1.6 g/kg
body weight per day, which represents 31% of the
upper bound of the ADI.
The GECDE for children is 2.1 g/kg body weight
per day, which represents 43% of the upper bound of
the ADI.
The GECDE for infants is 0.9 g/kg body weight per
day, which represents 18% of the upper bound of the
ADI.
Residue definition Teflubenzuron

107
 Joint FAO/WHO Expert Committee on Food Additives Eighty-first report

Recommended maximum residue limits (MRLs)

Filleta Muscle
Species (g/kg) (g/kg)
Salmon 400 400
a
Muscle plus skin in natural proportion.

Zilpaterol hydrochloride (2-adrenoceptor agonist)

Acceptable daily intake The Committee reaffirmed the ADI of 00.04 g/kg
body weight established at the seventy-eighth meet-
ing (WHO TRS No. 988, 2014).
Acute reference dose The Committee established an ARfD of 0.04 g/kg
body weight based on a lowest-observed-adverse-
effect level (LOAEL) of 0.76 g/kg body weight for
acute pharmacological effects observed in a single-
dose human study, with application of an uncer-
tainty factor of 20, comprising a default uncertainty
factor of 10 for human individual variability and an
additional uncertainty factor of 2 to account for use
of a LOAEL for a slight effect instead of a NOAEL.
Residue definition Zilpaterol (free base) in muscle, liver and kidney
Estimated acute The GEADE is 1.9 g/day for the general population,
dietary exposure which represents approximately 80% of the ARfD.
The GEADE is 0.57 g/day for children, which rep-
resents approximately 94% of the ARfD.

Recommended maximum residue limits (MRLs)a

WHO Technical Report Series No. 997, 2016

Kidney Liver Muscle

Species (g/kg) (g/kg) (g/kg)
Cattle 3.3 3.5 0.5
a
There were insufficient zilpaterol residue data to adequately consider exposure to residues in lungs and other edible offal of cattle apart from liver and kidney.

108
Annex 3

Meeting agenda

81st JOINT FAO/WHO EXPERT COMMITTEE ON FOOD ADDITIVES (JECFA)

FAO Headquarters, Rome 17-26 November 2015

Opening:
Philippine Room (C 277), 17 November 2015, 9.30h

Draft Agenda

1. Opening

2. Election of Chairperson and Vice-Chairperson, appointment of Rapporteurs

3. Adoption of Agenda

4. Declarations of Interests (information by the Secretariat on any declared interests

and discussion)

5. Matters of interest arising from previous Sessions of the Codex Committee on

Residues of Veterinary Drugs in Foods (CCRVDF)
a. Concern forms on Lasalocid sodium raised by CCRVDF
b. Request from CCRVDF 22 on MRLs for generic fish species

6. Other matters of interest arising from FAO and WHO
a. Update on new FAO JECFA database on residues of veterinary drugs
b. Update on FAO/WHO CIFOCOss database

7. Critical issues and questions from Working Papers (first brief round of discussion
on all subjects to inform the full Committee)

8. Evaluations

Veterinary drug residues

- Diflubenzuron
- Ethoxyquin

109
 Joint FAO/WHO Expert Committee on Food Additives Eighty-first report

- Ivermectin
- Lasalocid sodium (response to concern forms)
- Sisapronil (formerly known as phenylpyrazole)
- Teflubenzuron
- Zilpaterol hydrochloride

9. General considerations
- JECFA response to CCRVDF 22 on MRLs for generic fish species
- New JECFA guidance on residues of veterinary drugs
- Acute Reference Dose (ARfD) for veterinary drugs
- Issues arising from JMPR for consideration by JECFA
- Approach for dietary exposure assessment of compounds used for multiple purposes
(veterinary drug, pesticide)
- Update on the revision of the Principles and Methods for the Risk Assessment of
Chemicals in Food (EHC 240)

10. Other matters as may be brought forth by the Committee during discussions at the
meeting.

11. Adoption of the report.

WHO Technical Report Series No. 997, 2016

110
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WHO Press, World Health Organization 1211 Geneva 27, Switzerland www.who.int/bookorders
tel.: +41 22 791 3264; fax: +41 22 791 4857; email: bookorders@who.int
Evaluation of certain veterinary drug residues in food
This report represents the conclusions of a Joint FAO/WHO Expert
Committee convened to evaluate the safety of residues of certain veterinary
drugs in food and to recommend maximum levels for such residues in
food.

The first part of the report considers general principles regarding the
evaluation of residues of veterinary drugs within the terms of reference
of the Joint FAO/WHO Expert Committee on Food Additives (JECFA),
including MRLs for generic fish species, acute reference doses (ARfDs)
for veterinary drugs, an approach for dietary exposure assessment
of compounds used for multiple purposes (i.e. veterinary drugs and
pesticides), dietary exposure assessment for less-than-lifetime exposure,
and the assessment of short-term (90-day and 12-month) studies in dogs.

Summaries follow of the Committees evaluations of toxicological

and residue data on a variety of veterinary drugs: two insecticides
(diflubenzuron and teflubenzuron), an antiparasitic agent (ivermectin),
an ectoparasiticide (sisapronil) and a 2-adrenoceptor agonist (zilpaterol
hydrochloride). In addition, the Committee considered issues raised in
concern forms from the Codex Committee on Residues of Veterinary
Drugs in Foods on lasalocid sodium, an antiparasitic agent. Annexed to the
report is a summary of the Committees recommendations on these drugs,
including acceptable daily intakes (ADIs), ARfDs and proposed MRLs.

ISBN 978 92 4 120997 7

ANEXO 3
20 May 2014
EMA/CVMP/294840/2014
Committee for Medicinal Products for Veterinary Use

European public MRL assessment report (EPMAR)

Ivermectin (All mammalian food producing species)

On 24 April 2014 the European Commission adopted a Regulation 1 establishing maximum residue
limits for ivermectin in all mammalian food producing species, valid throughout the European Union.
These maximum residue limits were based on the favourable opinion and the assessment report
adopted by the Committee for Medicinal Products for Veterinary Use.

In veterinary medicine ivermectin is used in cattle, sheep, goats, pigs, horses and reindeer as an
antiparasitic, administered subcutaneously, topically or orally as a single dose treatment only.

In human medicine ivermectin is used for the treatment of onchocerciasis.

Maximum residue limits were previously established for ivermectin in fat, liver and kidney for all
mammalian food producing species.

On 15 December 2010 the European Commission submitted a request for the review of the opinion on
the establishment of maximum residue limits for ivermectin to the European Medicines Agency,
focussing particularly on the possibility to establish a MRL for muscle.

Based on the available data, the Committee for Medicinal Products for Veterinary Use recommended,
on 12 September 2013, maximum residue limits for ivermectin in fat, liver, kidney and muscle in all
mammalian food producing species.

Subsequently, the Commission recommended on 19 February 2014 that maximum residue limits in all
mammalian food producing species are established. This recommendation was confirmed on 12 March
2014 by the Standing Committee on Veterinary Medicinal Products and adopted by the European
Commission on 24 April 2014.

1
Commission Implementing Regulation (EU) No 418, O.J. L124, of 25.04.2014

7 Westferry Circus Canary Wharf London E14 4HB United Kingdom

Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8416
E-mail info@ema.europa.eu Website www.ema.europa.eu An agency of the European Union

European Medicines Agency, 2014. Reproduction is authorised provided the source is acknowledged.
European public MRL assessment report (EPMAR)
Ivermectin (establishment of a maximum residue limit for muscle)

Summary of the scientific discussion for the establishment of

MRLs
Substance name: Ivermectin
Therapeutic class: Agents acting against endo- and ectoparasites
Procedure number: EU/ART11/10/184/EC
Applicant: European Commission
Target species: All mammalian food producing species
Therapeutic indication: Antiparasitic (acting against endo and ectoparasites)
Route(s) of administration: Parenteral route (subcutaneous and intramuscular), topical and
oral

1. Introduction
Ivermectin is a chemically modified fermentation product belonging to the macrocyclic lactone class of
endectocides and consisting of a mixture of two homologous compounds, 22,23-dihydroavermectin
B1a (H2B1a, not less than 80%) and 22,23-dihydroavermectin B1b (H2B1b, not more than 20%).
Ivermectin is a potent ecto- and endo-parasitic agent with broad spectrum of activity which covers
nematodes and arthropods. The substance increases the membrane permeability to chloride ions,
mediating the paralysis of the nematodes and certain classes of ectoparasites.

In veterinary medicine ivermectin is extensively used in cattle, sheep, goats, pigs, horses and reindeer
at doses of 0.1 0.5 mg/kg bw subcutaneously, topically or orally as a single dose treatment only.

In human medicine ivermectin is used for the treatment of onchocerciasis.

Ivermectin was previously assessed by the CVMP and an ADI of 10 g/kg bw/day (600 g/person/day)
was established.

European public MRL assessment report (EPMAR)

EMA/CVMP/294840/2014 Page 2/14
Currently, ivermectin is included in table 1 of the Annex to Commission Regulation (EU) No 37/2010 in
accordance with the following table:

Pharmaco- Marker Animal MRLs Target Other Therapeutic

logically active residue species tissues provisions classification
substance

Ivermectin 22,23- All 100 g/kg Fat For porcine Antiparasitic

Dihydro- mammalian 100 g/kg Liver species the fat agents/Agents
avermectin food 30 g/kg Kidney MRL relates to acting against
B1a producing skin and fat in endo- and
species natural ectoparasites
proportions

Not for use in

animals
producing milk
for human
consumption
On 15 December 2010 the European Commission submitted to the European Medicines Agency a
request under Article 11 of Regulation (EU) No 470/2009 to issue a new opinion on the substance
ivermectin including the possibility to establish a MRL for the tissue muscle. The request from the
Commission follows concerns raised with regard to the control of residues in particular when no tissues
other than muscle are available for sampling, which is frequently the case with imported meat. It has
been argued that the absence of a MRL for muscle leads to a lack of clarity over the level of residues in
muscle acceptable as not representing a concern to consumer safety.

On 9 June 2011 the CVMP adopted an opinion which recommended a muscle MRL and limits for
injection sites as shown in the table below:

Pharmaco- Marker Animal MRLs Target Other provisions Therapeutic

logically residue species tissues classification
active
substance

Ivermectin 22,23- All 30 g/kg Muscle For porcine species Antiparasitic

Dihydro- mammalian 100 g/kg Fat the fat MRL relates agents/Agents
avermectin 100 g/kg Liver to skin and fat in acting against
food
B1a natural proportions endo and
producing 30 g/kg Kidney
ectoparasites
species Not for use in
animals from which
milk is produced
for human
consumption

The MRL for

muscle does not
apply to the
injection site,
where residue
levels should not
exceed
1300 g/kg

European public MRL assessment report (EPMAR)

EMA/CVMP/294840/2014 Page 3/14
On 25 October 2011 the European Commission requested the Committee to reconsider its opinion of 9
June 2011 and to amend the part of the opinion that recommends a residue limit for the injection site
in the Other provisions of Table I of the Annex to Commission Regulation (EU) 37/2010.

2. Scientific risk assessment

2.1. Safety assessment

In 1992, the CVMP established an ADI for ivermectin of 0.2 g/kg bw/day, i.e. 12 g/person/day based
on a NOEL of 0.1 mg/kg for maternal toxicity in a mouse teratogenicity study applying a safety factor
of 500. This ADI was the same as the one established by the Joint FAO/WHO Expert Committee on
Food Additives (JECFA). In 1993, JECFA re-evaluated the ADI for ivermectin and concluded, on the
basis of new human data, that the safety factor applied to this same NOEL could be reduced to 100,
resulting in an ADI of 1 g/kg bw/day corresponding to 60 g/person/day. After reviewing this re-
evaluation the CVMP established the same revised ADI.

Subsequently, in 2003, an application was submitted for the modification of the MRLs for bovine,
porcine and ovine species, Equidae and deer and requesting revision of the toxicological ADI to take
into account data from human clinical trials in healthy volunteers and parasite-infected patients, and
reports of individuals exposed to ivermectin as a result of accidental or deliberate ingestion as the
basis for modification of the ADI.

Further to the evaluation of the new data the CVMP concluded that the dog toxicity data were the most
relevant for the establishment of the toxicological ADI. The NOEL of 0.5 mg/kg bw/day observed in the
14-week repeated-dose dog study was used as the basis for the calculation of the new ADI using a
uncertainty factor of 50 (at a dose of 1 mg/kg bw mydriasis and slight weight loss were observed). The
lower uncertainty factor compared to the standard factor of 100 was justified by the fact that the data
suggested that ivermectin may reach threshold levels for overt toxicity more readily in dogs than
humans based on comparison of pharmacokinetics and the fact that human and non-human primate
toxicological data were available. An ADI of 10 g/kg bw/day (600 g/person per day) was established
for ivermectin.

Furthermore, the Committee considered that the availability of new human safety data that accounts
for the same central nervous system neuropharmacological interactions that are present in the dog,
provides reassurance that the ADI established from the dog study is appropriate.

Therefore, no further assessment regarding the consumer safety of the substance is required for the
purpose of the evaluation of this request.

2.2. Residues assessment

Maximum residue limits for ivermectin for all mammalian food producing species were previously
established in fat, liver and kidney. The CVMP concluded at that time that as residue concentrations
were persistently low in non injection site muscle, this tissue was unsuitable for monitoring purposes
and therefore no MRL for muscle was recommended. Considering the need to ensure the control of
residues in particular when no other tissues than muscle are available for sampling, the Commission
requested the revision of the CVMP opinion including the possibility to establish a MRL for muscle. No
new residue depletion studies were submitted with the request however findings of residues of
ivermectin in imported meat that have been reported by competent authorities for residue control were
available.

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A summary of the data already available and previously evaluated in the different species is provided
below.

For the purpose of the current evaluation the previously submitted data were re-considered in
particular with regard to residues in muscle.

2.2.1. Pharmacokinetics in target species

In animal tissues ivermectin residues are essentially found as unbound residues. Similar tissue residue
distribution patterns exist in cattle, sheep, swine and rats. However, the residue depletion half-lives in
liver and fat are approximately 4 to 5 times shorter in sheep and rats than in cattle and swine,
reflecting a more rapid metabolism in sheep and rats. In cattle and rats the major liver metabolite was
24-hydroxymethyl-H2B1a and in swine the major liver metabolites were 3-O-desmethyl-H2B1a and
3-O-desmethyl-H2B1b. The parent drug accounted for at least 50% of the total residues in tissues
from cattle up to 14 days, in sheep up to 5 days, in swine up to 7 days and in rats up to 3 days after
treatment. Seven days after subcutaneous treatment 1.5% and 62% of the dose were recovered in
urine and faeces, respectively. The parent drug has been found to account for 39-78% of the faecal
radioactivity in cattle, sheep and rat.

The plasma concentration profile in deer treated subcutaneously with ivermectin showed that
maximum plasma concentration was reached approximately 28 hours after treatment with 0.2 and
0.4 mg/kg bw. The peak plasma concentrations were 15.3 g/l and 28.3 g/l, respectively. The plasma
half-lives of ivermectin in deer treated with 0.2 mg/kg or 0.4 mg/kg were approximately 4 days.

2.2.2. Residue depletion studies

Cattle

Four residue studies in cattle were presented. In three studies cattle were dosed percutaneously with
0.5 or 1.0 mg ivermectin/kg bw and in one study cattle were dosed subcutaneously with
0.2 mg/kg bw. These studies show that the highest concentrations of residues in tissues of cattle were
found in liver followed by fat, kidney and muscle except for the injection site muscle.

The Joint FAO/WHO Expert Committee on Food Additives (JECFA) has calculated the percentage of the
marker residue (22,23-dihydroavermectin B1a) of the total residues in cattle 28 days post treatment.
The marker accounted for 67% in muscle, 37% in liver, 54% in kidney and 18% in fat of total residues
and the distribution of residues between tissues was 1:2:11:27 for muscle, kidney, fat and liver,
respectively.

Pigs

In a radiometric residue depletion study, 12 pigs were given a single tritium labelled (C 22, 23 positions)
ivermectin dose of 0.4 mg/kg bw subcutaneously. Three animals in each group were killed on days 1,
7, 14 and 28 days after treatment. Fat total residue levels were the highest followed by liver. Total
residue levels in fat were 384, 152, 28 and 6 g/kg; in liver were 199, 112, 22, and 3 g/kg on 1, 7,
14 and 28 days after treatment respectively. Kidney total residue levels were 106, 55 and 10 g/kg
whereas muscle total residue levels were 43, 25 and 4 g/kg after 1, 7 and 14 days respectively. The
average marker to total residue ratios were 0.27, 0.41, 0.3 and 0.39 g/kg for liver, kidney, fat and
muscle respectively.

In another radiometric residue depletion study, 15 pigs (male and female) were given tritium labelled
(C22, 23 positions) ivermectin at a dose rate of 0.1 mg/kg bw/day for 7 days in the feed. Total

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radioactive residue levels in liver were 237.1, 43, 10.7, 4.1 and 2.7 g/kg and those in fat were 207.2,
63.6, 18, 8 and 4.5 g/kg at 4 hours, 3, 7, 14 and 21 days after treatment respectively.

In a residue depletion study where pigs were administered a single subcutaneous dose of
0.4 mg/kg bw, the highest residue levels were found at the injection site samples, followed by fat,
liver, kidney and then muscle at all time points. Mean injection site residues were 12500, 5100, 1110,
2300, 2500 and 230 g/kg at 1, 3, 5, 7, 10 and 14 days after treatment respectively. Peak residue
levels were found after 3 days in all of the other tissues. Liver residue levels were 67, 69, 53, 41, 23
and 13 g/kg and fat residue levels were 74, 110, 91, 73, 47 and 24 g/kg on days 1, 3, 5, 7, 10 and
14 days after treatment respectively.

Sheep

In a radiometric residue depletion study, 12 sheep were given a single oral (intraruminal) tritium
labelled (C22, 23 positions) ivermectin dose of 0.3 mg/kg bw. Three animals were killed on days 1, 3,
5 and 7 days after treatment. The average total concentration in liver were 238, 125, 25, 44 g/kg at
1, 3, 5 and 7 days after treatment respectively. At the same time points, average total residue
concentrations in fat were 307, 153, 63, 73 g/kg; in kidney were 72, 46, 12, 13 and in muscle were
55, 50, 9 and 10 g/kg. The ratios of marker (H2B1a) to total residues at 3 days after treatment were
0.51, 0.51, 0.44 and 0.52 g/kg for liver, fat, kidney and muscle, respectively.

In a residue depletion study, 30 sheep (male and female) were given oral doses of 0.3 mg
ivermectin/kg bw in a micellar vehicle. The highest residues (marker residue, H 2 B 1a ) were found in fat
followed by liver. Residue levels in liver were 72, 12, 11 and 8 g/kg; in fat were 145, 32, 11 and
9 g/kg; in kidney were 30, 5, 2 and 1 g/kg and in muscle were 20, 4, 2 and 2 g/kg at 1, 3, 5 and 7
days after treatment respectively.

In a residue depletion study where sheep were administered a three subcutaneous doses of
0.3 mg/kg bw at weekly intervals, the highest residue levels were found at the injection site samples,
followed by fat, liver, kidneys and then muscle at all time points. Mean injection site residues were
17000, 2900, 2300, 460 and 220 g/kg at 3, 7, 10, 14 and 28 days after last treatment respectively.
Peak residue levels were found after 7 days in all of the other tissues. Liver residue levels were 160,
190, 97, 55 and 7.2 g/kg and fat residue levels were 230, 310, 180, 99 and 13 g/kg at 3, 7, 10, 14
and 28 days after treatment, respectively.

Horses

In a radiometric residue depletion study, 3 horses were given tritium labelled (C22, 23 positions)
ivermectin doses of 0.3 mg/kg bw. Two of the animals were administered orally and the remaining one
was administered intramuscularly. The animals were then slaughtered after 28 days and the mean
total radioactivity levels in those administered orally were 2.64, 3.02, 3.1, 4.26, 4.11 and 3.52 g/kg
and in those administered intramuscularly was 43.2, 17.1, 14.4, 54.2, 47.4 and 36.1 for liver, kidneys,
muscle, perirenal fat, omental fat and subcutaneous fat respectively. Total radioactivity levels at the
injection site were 64.4 g/kg. The ratios of marker to total residues were 0.12, 0.22 and 0.36 for
liver, kidney and fat, respectively.

In a residue depletion study where horses were administered a single oral dose of 0.3 mg/kg bw, the
highest residue levels were found in fat followed by liver. Fat residues were 80 and 10.9 g/kg and
liver residues were 31 and 4 g/kg on 7 and 14 days after treatment. Residues were detected at 7
days after treatment in kidney (15 g/kg) and muscle (8.3 g/kg) but where below the limit of
detection at 14 days.

Deer

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 Following a single percutaneously administered dose of 1 mg/kg (twice the recommended dose) to red
deer, the tissue residues decreased progressively with time with highest concentrations found in fat
followed by liver, muscle and kidney. The ratios of 22,23-dihydroavermectin B1a between tissues after
28 days, were 6.8:2.5:1.3:1 for fat, liver, kidney and muscle, respectively. At 7 and 28 days after
treatment the mean concentrations of 22,23-dihydroavermectin B1a in fat were 292 g/kg and
13.2 g/kg, respectively, in liver 180 g/kg and 9.3 g/kg, in muscle were 78 g/kg and 1.4 g/kg
and in kidney were 78 g/kg and 3.6 g/kg, respectively.

A single subcutaneous dose of 0.2 mg ivermectin/kg bw was given to reindeer. The ratios of 22,23-
dihydroavermectin B1a to total residues in tissues at 17 days after treatment, were in this study
9.5:6.6:2.6:1 for fat, liver, kidney and muscle, respectively. The highest residue concentrations of
22,23-dihydroavermectin B1a 10 and 17 days after treatment, respectively, were 362 g/kg and 68
g/kg in back fat, 71 g/kg and 28 g/kg in liver, 54 g/kg and 13 g/kg in kidney, 40 g/kg and 11
g/kg in muscle, and 44 g/kg and 9 g/kg in injection site muscle, respectively. The half-lives in the
tissues after a single subcutaneous treatment were 7.1 days in the back fat, 2.9 days in the injection
site, 4.9 days in muscle, 5.8 days in liver and 5.7 days in kidney.

22,23-dihydroavermectin B 1a (H 2 B 1a ) was retained as the marker residue in all tissues and species.

The tissue distribution of residues and the overall ratios of marker to total residues were generally
similar with residue levels being the highest in fat and liver tissues. Horses and pigs had slightly
different marker/total residue ratios.

The following ratios of marker to total residues (RMT) were established from depletion studies
previously assessed by the CVMP and/or JECFA (40th JECFA report, 1993):
Species RMT
Liver Kidney Muscle Fat IS*
Cattle 0.370 0.540 0.670 0.180 0.8
Sheep 0.510 0.440 0.520 0.510 0.8
Pigs 0.270 0.300 0.390 0.500 0.8
Equidae 0.140 0.280 0.670 0.370 0.8
*IS = Injection site. Value obtained from CVMP assessment of ivermectin referral concerning injectable products for cattle

2.2.3. Monitoring or exposure data

Competent national authorities for residues control have reported findings of residues of ivermectin in
imported lean meat at levels ranging from less that 1 g/kg to higher than 500 g/kg.

2.2.4. Analytical method for monitoring of residues

A routine analytical method validated in accordance with Volume 8 of the Rules Governing Medicinal
Products in the European Union based on HPLC with fluorescence detection was presented in an
internationally recognised format for quantifying 22,23-dihydro-avermectin B1a residues in tissues
from bovine, porcine and ovine species, Equidae and deer. The limit of quantification for all tissues for
pigs, Equidae and ovine species was 5 g/kg. For bovine species the limit of quantification was 3 g/kg
for muscle, 5 g/kg for fat and kidney and 3.6 g/kg for liver. For deer the limit of quantification was
2 g/kg for all tissues. The analytical method was also validated at sufficiently high ivermectin levels to
account for residue levels that might be expected at injection sites. Although no data were available
concerning the use of the analytical method in other mammalian species this method is likely to be
applicable to other mammalian species.

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The analytical method has been reviewed by the relevant European Reference Laboratory, which noted
that the method had been in use for several years and considered that it would be applicable for
monitoring compliance with both the existing MRLs and the proposed MRL for muscle.

2.2.5. Findings of EU or international scientific bodies

Ivermectin was evaluated at the 36th, 40th, 54th and 58th JECFA meeting. Following these evaluations
and recommendations the Codex Alimentarius established MRLs for ivermectin as follows:

Liver: 100 g /kg;

Fat: 40 g/kg

Milk: 10 g /kg

The marker residue retained by JECFA is ivermectin B1a (synonym for 22,23-dihydro-avermectin B1a).

3. Risk management considerations

3.1. Potential effects on the microorganisms used for industrial food

processing

Microbiological effects are not expected for this type of substance. In addition as MRLs have not been
established for milk the assessment of potential effects on mircroorganisms used for industrial food
processing is not considered.

3.2. Other relevant risk management considerations for the establishment

of maximum residue limits

The CVMP was asked to consider setting a maximum residue limit for ivermectin in muscle in order to
allow for the monitoring of meat in particular concerning imports from third countries. As meat
imported into the EU often takes the form of lean cuts of muscle, the absence of an MRL for muscle
means that it is not possible to control residue levels in imported meat of this type.

Residue depletion data demonstrate that ivermectin residues in kidney and muscle (other than
injection site muscle) are low compared to residues in fat and liver in all animal species.

Having considered the issue at length the CVMP noted that:

it would possible to calculate a muscle MRL based on either (i) residues expected in injection site
muscle or (ii) residues expected in non-injection site muscle;

a muscle MRL based on approach (i) (residue levels expected in injection site muscle) would be of
little relevance for residue control authorities. This is because injection sites are scarce while non-
injection site muscle is abundant and consequently, except on rare, chance occasions, non-
injection site muscle will be sampled by residue control authorities. So in the vast majority of
samples residues would be far below the injection site levels used to derive the MRL, even if the
withdrawal period were not respected. So compliance with the muscle MRL would provide no
information on whether the withdrawal period had been respected or on whether residue levels in
other tissues comply with their respective MRLs;

from a residue control point of view, it would make far more sense to base the muscle MRL on
approach (ii) (residue levels that can be expected in non-injection site muscle) as this will be
representative of muscle sampled on all but very rare, chance occasions. From a consumer safety

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 perspective this is also the preferred option, as non-injection site muscle is the muscle regularly
consumed;

If the muscle MRL is based on approach (ii) (residue levels that can be expected in non-injection
site muscle), it follows that, at the withdrawal period residues in injection site muscle can be
expected to exceed the MRL;

Annex I of Regulation (EC) No 854/2004, in Section II, Chapter V, indicates that meat is to be
declared unfit for human consumption if it: (i) contains residues or contaminants in excess of the
levels laid down in community legislation (ie above the MRL);

in practice, as injection sites will not always be easily identifiable, it cannot be assumed that they
will always be removed from the food chain;

possible future need to establish an MRL in milk should be taken into account and an appropriate
portion of the ADI should be left available for this purpose.

In light of the above the CVMP concludes that the muscle MRL should be set in such a way as to
maximise both its relevance for residue control purposes and its ability to protect consumer health
i.e. it should be derived based on residue levels that can be expected in non-injection site muscle.

However, because it cannot be assumed that injection sites will always be removed from the food
chain there is also a need to ensure that residues at the injection site do not represent a risk to the
consumer. An additional value was therefore derived, which corresponds to the maximum level of
residues that would be expected in the injection site at the anticipated withdrawal period (hereafter
referred to as the Injection Site Residue Reference Value ISRRV). The ISRRV was derived as follows:
the theoretical maximum daily exposure was calculated on the basis of recommended MRLs for liver,
kidney and fat (skin+fat in the case of pig) and the resulting value was compared to the ADI. The
ISRRV was then derived in a manner that would allow for residues in 300g of muscle to correspond to
the remaining portion of the ADI (whilst leaving aside a small portion of the ADI for milk). The
withdrawal period should be derived in a manner that ensures that residues at the injection site will be
below this value and that residues in non-injection site muscle, liver, kidney and fat will be below the
MRLs for these tissues. In this way, the withdrawal period would not be longer than is necessary in
order to ensure consumer safety. Whereas, in the CVMP opinion of 9 June 2011, a value equivalent to
an ISRRV was recommended for inclusion in Regulation (EU) No. 37/2010, the current opinion does not
propose its inclusion in the regulation or its use for routine residue surveillance. This has been done to
take account of the Commissions comment that it would not be feasible for control authorities to
consider two different levels for the same tissue (muscle). Rather, the ISRRV provides a value to be
used by competent authorities when setting withdrawal periods for injectable ivermectin containing
products. The withdrawal period must ensure that residues in non-injection site muscle, as well as in
liver, kidney and fat, are below the MRLs and that residues at the injection site are below the ISRRV.
In this way the withdrawal period will ensure that, even if a consumer were to ingest an injection site,
consumer exposure to residues would not represent a health risk.

The CVMP notes that Article 1 of Directive 2001/82/EC defines the withdrawal period as the period
necessary to ensure that foodstuffs do not contain residues in excess of the MRLs. While efforts may
be made to remove injection sites, in those instances where they enter the food chain undetected,
residues may be present at levels that exceed the muscle MRL. While these residues will not represent
a consumer safety concern, the chance sampling of an injection site by a residue control authority
would lead to a non-compliant residue finding and possible punitive action against the farmer. Such
action would be unfair given that the non-compliant finding would not represent non-compliance with
the withdrawal period.

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In relation to residue monitoring, in some cases, residue control authorities will have access only to
muscle tissue, in which case only muscle tissue will be available for residue monitoring (this is
particularly the case for meat imported into Europe). However, where the entire carcass is available,
the CVMP recommends that for the purpose of monitoring residues of ivermectin, liver or fat (skin+fat
for pigs) should be sampled in preference to muscle. This is because residues in these tissues deplete
more slowly than residues in muscle and so will provide a better basis for verifying compliance with the
withdrawal period.

3.3. Elaboration of MRLs

Maximum residue limits are established for ivermectin in all mammalian food producing species as
follows:

Fat: 100 g/kg

Liver: 100 g/kg

Kidney: 30 g/kg

Residues concentrations were persistently low in non-injection site muscle in all target species. Taking
into account the residue distribution, a value of 30 g/kg for non-injectable site muscle can be
recommended.

An Injection Site Residue Reference Value (ISRRV) of 1250 g/kg 2 was calculated as follows: the
theoretical maximum daily intake was calculated on the basis of recommended MRLs for liver, kidney
and fat in horses (worst case scenario for the different species) and the resulting value compared to
the ADI. The maximum level of residues acceptable for injection site muscle was then calculated so
that residues in 300 g of muscle to correspond to 93% of the ADI (this leaves a small portion of the
ADI unused to accommodate a possible future MRL in milk). This value was then converted into the
ISSRV using a ratio of marker to total residues value of 0.8 for injection site muscle 3.

Withdrawal periods for injectable ivermectin products should ensure that residue levels present in non-
injection site muscle, liver, kidney and fat do not exceed the MRLs for muscle, liver, kidney and fat,
respectively, and that residue levels present in injection site muscle do not exceed the ISRRV.

Calculation of theoretical daily intake of residues

Detailed calculation of theoretical daily intake of residues

Tissue MRL MR:TR Total Residue Food Basket Residue

(g/kg) (g/kg) (kg) consumed (g)
Cattle Liver 100 0.37 270 0.10 27
Kidney 30 0.54 56 0.05 3
Fat 100 0.18 556 0.05 28
Muscle 30 0.67 45 0.30 13
ADI TOTAL TMDI (g): 71
(g/person): 600 %ADI: 12

2
This value is slightly different from the injection site limit recommended in the opinion of 9 June 2011 (1300 g/kg) because it was
noted that consumer intake based on horse MRLs for fat, liver, kidney and ISRRV would equate to 96% of the ADI which would not
leave sufficient room to accommodate a possible future MRL for milk.
3
Value obtained from the CVMP assessment of the ivermectin referral concerning injectable products for cattle

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 Tissue MRL MR:TR Total Residue Food Basket Residue
(g/kg) (g/kg) (kg) consumed (g)
Sheep Liver 100 0.51 196 0.10 20
Kidney 30 0.44 68 0.05 3
Fat 100 0.51 196 0.05 10
Muscle 30 0.52 58 0.3 17
ADI TOTAL TMDI (g): 50
(g/person): 600 %ADI: 8

Tissue MRL MR:TR Total Residue Food Basket Residue

(g/kg) (g/kg) (kg) consumed (g)
Pigs Liver 100 0.27 370 0.10 37
Kidney 30 0.30 100 0.05 5
Skin/Fat 100 0.50 200 0.05 10
Muscle 30 0.39 77 0.30 23
ADI TOTAL TMDI (g): 75
(g/person): 600 %ADI: 13

Tissue MRL MR:TR Total Residue Food Basket Residue

(g/kg) (g/kg) (kg) consumed (g)
Equidae Liver 100 0.14 714 0.10 71
Kidney 30 0.28 107 0.05 5
Fat 100 0.37 270 0.05 14
Muscle 30 0.67 45 0.30 13
ADI TOTAL TMDI (g): 104
(g/person): 600 %ADI: 17

Excluding intake from injection site muscle but using normal muscle, the percentage of the ADI
consumed based on the above calculations will be 12%, 8%, 13% and 17% for cattle, sheep, pigs and
Equidae respectively. The minimum portion of the ADI that can be used for residues at the injection
site was therefore calculated to be 80%. The following table shows the amount of the ADI that is used
when the theoretical maximum daily intake (TMDI) is calculated for a food basket including the ISRRV.

Species ADI TMDI ADI left Max Proposed %ADI

(g/person) (excl.muscle) for IS level limit for consumed
(g) (g/person) for IS IS
(g/kg) (g/kg)
Cattle 600 58 542 1445 1250 87.8
Sheep 33 567 1512 1250 83.6
Pigs 52 548 1461 1250 86.8
Equidae 90 510 1360 1250 93.1
RMT (ratio of marker to total) of 0.8, daily consumption of 0.3Kg of muscle were used in the calculation.

The theoretical maximum daily intake (TMDI) using residues from injection site muscle (rather than
non-injection site) and the other tissues would be 88%, 84%, 87% and 93% for cattle, sheep, pigs
and equidae, respectively.

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Codex Alimentarius set a MRL for ivermectin in milk of 10 g/kg. In the worst case scenario, using a
ratio of marker residue to total residues of 0.5, milks contribution to the ADI was 30 g/person i.e.
5% of the ADI. The proposed ISRRV of 1250 g/kg leaves room to accommodate a possible future
milk MRL for ivermectin.

3.4. Considerations on possible extrapolation of MRLs

Extrapolation of maximum residue limits to the relevant minor species have been considered by the
CVMP in the previous evaluations of ivermectin. Considering the data available and the scientific
principles for the extrapolation of MRLs described in the Volume 8 of the Rules governing medicinal
products in the European Union 4 the maximum residue limits initially established for bovine, porcine,
ovine, equidae and deer including reindeer were extrapolated in 2004 to all mammalian food producing
species.

In line with Article 5 of Regulation (EU) No 470/09, the Committee considered the possibility of further
extrapolating the existing MRLs to other species and foodstuffs with a view to ensuring availability of
veterinary medicinal products for conditions affecting food producing animals while ensuring a high
level of protection of human health. Taking into account the current scientific knowledge the
recommendations on extrapolation are justified as follows:

Animal species/ Extrapolation Justification

food possible
commodities (Yes/No)

Poultry (including No Metabolism can be significantly different in poultry compared to

eggs) mammals. Consequently species specific metabolism and residue
data are considered necessary to allow adequate evaluation of the
risk to consumer safety posed by residues in poultry-derived food
commodities.

No analytical method for monitoring of residues in poultry tissues

(or eggs) was available for evaluation.

Fin fish No Metabolism is generally less complicated in fish than in mammals.

Consequently, if the marker residue is the parent compound in
cattle and pigs it can be assumed that the parent compound would
also be a suitable marker residue in fish meat. However, no
analytical method for monitoring of residues in fish meat was
available for evaluation.

Furthermore, in view of the known toxicity of the substance to the

environment extrapolation of MRLs without specific information on
the potential use of the substance in fish would be highly
controversial.

Milk No No data are available that would allow conclusions to be drawn on

the appropriate marker residue or marker to total residues ratio to
use in milk. Data on residues in this commodity are considered
necessary in order to allow adequate evaluation of the risk to
consumer safety posed by residues in milk.

No analytical method for monitoring of residues in milk was

available for evaluation.

4
Notice to applicants and Guideline: Veterinary medicinal products - Establishment of maximum residue limits (MRLs) for
residues of veterinary medicinal products in foodstuffs of animal origin

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3.5. Conclusions and recommendation for the establishment of maximum
residue limits

Having considered that:

the a toxicological ADI of 10 g/kg bw/day (600 g/person per day) was previously established as
the overall ADI for ivermectin;

22,23-dihydroavermectin B 1a was retained as the marker residue in all tissues and target animal
species;

the tissue distribution of residues and the overall ratios of marker to total residues were generally
similar with residue levels being the highest in fat and liver tissues;

residue concentrations were persistently low in non-injection site muscle;

residues at the injection site deplete slowly and should be considered for setting withdrawal
periods;

the ratios of marker to total residues were calculated in the different animal species and tissues;

the Commission and residue control authorities consider that, in order to ensure the feasibility of
residue controls, a single residue limit for muscle must be published in Regulation (EU) No.
37/2010;

an Injection Site Residue Reference Value (ISRRV) of 1250 g/kg is established for all mammalian
food producing species this value should be taken into account when deriving withdrawal
periods;

a portion of the ADI should be reserved for a possible future need for establishing a MRL for milk,

for the purpose monitoring of residues of ivermectin it is recommended that, where the entire
carcass is available, liver or fat (skin+fat for pigs) should be sampled in preference to muscle as
residues in these tissues deplete more slowly than residues in muscle and so will provide a better
basis for verifying compliance with the withdrawal period;

a validated analytical method for the monitoring of residues of ivermectin in edible cattle, sheep,
pigs and horse tissues (liver, kidney, fat and muscle) is available;

the CVMP recommends the modification of the entry for ivermectin in table 1 of the Annex to
Commission Regulation (EU) No 37/2010 in accordance with the following table:

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Pharmaco- Marker Animal MRLs Target Other provisions Therapeutic
logically residue species tissues classification
active
substance

Ivermectin 22,23- All 30 g/kg Muscle For porcine species Antiparasitic

Dihydro-
mammalian 100 g/kg Fat the fat MRL relates agents/Agents
avermectin
B1a food 100 g/kg Liver to skin and fat in acting against
producing 30 g/kg Kidney natural proportions endo and
species ectoparasites
Not for use in
animals from which
milk is produced
for human
consumption

4. Background information on the procedure

Submission of the request 15 December 2010

Steps taken for assessment of the substance

Clock started: 16 December 2010

CVMP opinion adopted: 09 June 2011

European Commission requested revision 25 October 2011

CVMP revised opinion 12 September 2013

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ANEXO 4