Kirsten Olson

ETX 101
TEMEPHOS PART 1
NAMES:
Common: Temephos, Temefos (1,2) Trade: Abaphos, Abate, Abathion, Biothion, Difenthos,
Difos, Nephis1G, Procida, Swebate (2) IUPAC: O,O,O',O'-tetramethyl O,O'-thiodi-p phenylene
bis(phosphorothioate); O,O,O',O'-tetramethyl O,O'-thiodi-p-phenylene diphosphorothioate; O-4-
({4-[(dimethoxyphosphorothioyl)oxy]phenyl}thio)phenyl] O,O-dimethyl thiophosphate (3)

CHEMICAL STRUCTURE:

Temephos (1) Iso-Temephos (3)

USES AND ENVIRONMENTAL OCCURENCE:

Uses: Temephos kills insects (esp. larvae); it has been used in plant and animal agriculture, for
flea collars, and human body lice (1,3-11). Use has declined as legal applications were rescinded
(1,8,12). The most important current use is to control disease-vector mosquitos: in drinking water
overseas, or in tire piles and non-potable water (salt marshes, lake edges, temporary or polluted
waters) in the US (1,3,4). EU has banned it; US is phasing it out (8,12). Occurrence: Temephos
has low persistence and does not naturally occur (1,3-5,7,9,13-15). Due to minimal use, US
residents do not encounter appreciable amounts unless they enter recently sprayed areas or work
with it (1,2). There is more exposure where used in agriculture and in drinking water, but this is
limited (3-7). Transformation products: Iso-temephos, temephos oxon, its isomer, temephos
sulfoxide, its isomer, temephos sulfone, temephos sulfide and potential others (dioxins, phenols)
are likely more to far more toxic than temephos, but have not really been studied (1,3,4,9,11,16).

PHYSICAL PROPERTIES:
MW: 466.3 g/mol (15) MP: Technical Grade (TC): 25-30C Analytical Grade (AG): 30-30.5C
(15) BP: TC decomposes at 120-125C (15) Vapor Pressure: 7.17x10-8 mmHg at 25C (15)
Std. State: AG: white crystals TG: thick, light brown fluid (2,15). Specific Gravity: 1.32 (2)

CHEMICAL PROPERTIES:
Sol. in water: 9.0x10-6 g/L at 10C; 2.7x10-4 g/L at 20C; 7.0x10-4 g/L at 30 C (17) Sol. in
hexane: 9.6g/L (18) Soluble in: acetonitrile, carbon tetrachloride, diethyl ether, ethylene
dichloride, lower alkyl ketones, and toluene (15) Log Kow: 4.91 at 25 C (1) Koc: 16,250 (1)

ROUTES OF EXPOSURE:
Target species: Dermal, oral - Temephos is usually applied in liquid formulations, and/or to
water, to form a thin surface layer (1,3,7,19). Nontarget species: Dermal, oral, inhalation - It
can be absorbed from treated surfaces/water, ingested with treated water/food, or inhaled (less
inhalation risk, due to large droplets) (1,3-7,11,15). Temephos bioaccumulates (1,11). Human
specific: Main acute or chronic risk is occupational exposure (dermal, inhalation); where legal in
agriculture/potable water, there is also chronic risk from oral exposure in food/water (1,3-7,15).

TYPICAL LEVELS:
Food: US: Temephos tolerances voided 1998 (1). EU: Illegal since 2002; default MRL (Max.
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Residue Level) is 0.01 mg/kg (8,20). Australia: Temephos + its sulfoxide total MRLs in cattle: 2-
5 mg/kg (temp.); in sheep: 0.5-3mg/kg (6). FAO/WHO: NOAEL (2006) 2.3 mg/kg body mass/d
(day) (5). Potable water: Per WHO, 1 mg/L (4). Non-potable water: Less negative effects on
wetland life with 0.0313lbs/active ingredient/acre (1). Air/occupational: ACGIH recommended
Threshold Limit Value, 8 hr Time Weighted Average: 1 mg/m3 (inhalable fraction, vapor, skin)
(21). Soil: >90% gone 40 days post application (13). Plants: Not deemed phytotoxic. Recent
EPA, WHO, Australian assessments did not include (1,4,5,7, 11). Animals: Fish exposed to
avg. 0.65 g/L for 28 days gained 1500 mcg/kg residues; with 14 days depuration, residue was
380 g (7). EPA estimated residues would be lower than avian subacute dietary LC50 so did
not require bioaccumulation study in fish-eating birds (1). Chickens fed 920 ppm for 30 days had
diarrhea for 2 wks and lost weight, but had no demyelinated nerves (5). Rabbit oral NOAELs: 10
mg/kg body mass/d or 30 mg/kg body mass/d (reproductive); dermal exposure: cholinesterase
was inhibited at all doses (9-100/75 mg/kg) (5). Daphnia magna NOEC: 0.0025 g/L (7). EPA
never received a proper bee study, then waived it when temephos uses were rescinded (11).

ENVIRONMENTAL FATE:
Soil T1/2: Field conditions: 18.14-20.44 days; leached to 7.5cm (sandy loam) (13). Water T1/2:
Lab conditions, hydrolysis: min. change in 30 days at pHs of 5-9. Extrapolated or calculated
values: pH 4, 79.3 days; pH 5, 1030 days, pH 7, 28.7-460 days, pH 9, 49.1-86 days (3,11). Lab
conditions, photolysis: 15 days (11). Field conditions: 6 hrs to 17.2 days (7,9). Air T1/2: 0.117
days (2.808 hrs) (22). Wide variations in aqueous T1/2s are not just odd data; they reflect many
processes working simultaneously in a natural setting (11). Temephos is hydrophobic; it adsorbs
to soil or organic matter, or forms a surface layer that is 20-30 times the concentration of bulk
water (1,3,7,14). It is mostly degraded by oxidation by sun and/or microbes. This major pathway
converts temephos into its oxon or sulfide, which are found just after spraying (3,4,7,9, 11,13-
16,23). Also, in chlorinated water, temephos sulfoxide and temephos oxon sulfoxide formed
immediately. Within 24 hours they were gone, but some had converted to temephos dioxon
sulfoxide and temephos dioxon sulfone. These remained at the end of the 72 hour experiment
(23). Microbial metabolism causes oxidation of the thioether and thiophosphate groups, then
phosphate hydrolysis to other products, eventually leading to carbon dioxide. This pathway
occurred under both aerobic and anaerobic conditions, except that in anaerobic conditions, no
CO2 was produced. In lake water/sediment, temephos converted into at least 5 different chemi-
cals: temephos sulfoxide, temephos sulphone, a bis(phenol) derivative, and 2 others (7). Based
on similar chemicals, most of these transformation products are probably 1 or 2 orders of
magnitude more acutely toxic than temephos itself (3,4,16).They are more water soluble and
therefore can move into the water more easily (1,7). Volatilization would seem unlikely, given
its low vapor pressure and high Koc (1,15). But it does seem to dissipate, in part, by volatilizing,
especially from warm water (7,9). In a mangrove forest, temephos stayed longest on the leaves
over 7 days (14). In bluegill, the bioaccumulation factor was 2,300, and depuration T1/2 was 8
days (7). So, when Temephos is applied, some dissipates into air, some is on plants, some is in
the water surface, and some sticks to soil. Right away, sun and microbes begin degrading it into
much more toxic and more soluble substances (7,9,11,13-16). Animals take in temephos and its
products from the water and from surfaces; it leaves their bodies slowly. Other animals eat them
and bioaccumulate even more temephos. The most risk is for animals that are in contact with the
top layer of water, who drink it, and who eat other contaminated organisms (11,14-16). Sunny
warm weather will enhance volatilization, oxidation, and somewhat increase solubility (9,17).
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References Part 1

(1) U.S. Environmental Protection Agency (2000) Temephos Reregistration Eligibility Decision.
EPA 738-F-00-018. Office of Pesticide Programs Public Regulatory Docket (7502C), U.S. EPA.

(2) National Institute for Occupational Safety and Health, Education and Information Division
(2016) NIOSH Pocket Guide to Chemical Hazards, online version. NIOSH Publications, Centers
for Disease Control and Prevention, U.S. Department of Health and Human Services. Print
Version: DHHS (NIOSH) Publication No. 2005-149, Cincinnati, Ohio, 454 total pages.

(3) World Health Organization (2010) WHO Specifications and Evaluations for Public Health
Pesticides: Temephos. Comprised of the following reports, with supporting information:
Specifications (2008): 340/TC, 340/GR, 340EC & Evaluations: 340/2010, 340/2008, 340/2005.

(4) World Health Organization (2009) Temephos in Drinking-water: Use for Vector Control in
Drinking-water Sources and Containers (Draft). WHO/HSE/WSH/09.01/1.

(5) Food and Agricultural Organization of the United Nations/World Health Organization (2006)
Pesticide Residues in Food: 2006, Toxicological Evaluations, WHO Press, Geneva Switzerland.

(6) Australian Pesticides and Veterinary Medicines Authority (2016) Australia New Zealand
Food Standards Code Schedule 20 Maximum residue limits. F2016C00886. Federal Register
of Legislation, Australian Government.

(7) Australia Department of Environment, Heritage, Water and the Arts, Environment Protection
Branch, Chemical Assessment Section (2003) Environmental Assessment Report: For the review
of Temephos in the product Coopers Assassin Sheep Dip. Publication 1553. Australian
Pesticides and Veterinary Medicines Authority.

(8) European Commission (2002) Commission Regulation (EC) No. 2076/2002 of 20 November
2002 extending the time period referred to in Article 8(2) of Council Directive 91/414/EEC and
concerning the non-inclusion of certain active substances in Annex I to that Directive and the
withdrawal of authorizations for plant protection products containing these substances.
32002R2076. Official Journal of the European Communities.

(9) Lacorte, S., Ehresmann, N. and Barcel, D. (1996) Persistence of Temephos and Its
Transformation Products in Rice Crop Field Waters, Environmental Science & Technology
volume 30, pages 917-923.

(10) Office of Pesticides and Toxic Substances, U.S. EPA (1981) Temephos: O, O'-(Thiodi-4,1-
Phenylene)Bis(O, O-Dimethyl Phosphorothioate) Pesticide Registration Standard. 540RS81018.
National Service Center for Environmental Publications (NSCEP), U.S. EPA.

(11) Environmental Fate and Effects Division, U.S. EPA (1999) Memorandum: Reregistration
Eligibility Document for Temephos, with revised E.F.E.D. chapter attached. D240786; Case No.
818974/Chem. No. 059001. Office of Prevention, Pesticides and Toxic Substances, U.S. EPA
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Archive Document.

(12) U.S. EPA (2011) Temephos Registration Review Final Decision. Docket Number: EPA-
HQ-OPP-2008-0444. Office of Pesticide Programs, U.S. EPA.

(13) Verm, G., Kumar, A., Tomar, A., and Singh, K.K. (2004) Studies on persistence of
temephos in sandy loam soil under field and laboratory conditions, Journal of Environmental
Science and Engineering volume 46, pages 108-115.

(14) Pierce, R., Henry, M., Kelly, D., Sherblom, P., Kozlowsky, W., Wichterman, G., and Miller,
T.W. (1996) Temephos distribution and persistence in a southwest Florida salt marsh
community, Journal of the American Mosquito Control Association volume 12, pages 637-646.

(15) American Cyanamid Company (1998) ABATE Larvicide Brochure. FHT-D394-10M-9801.

American Cyanamid Company, Agricultural Products Research Division.

(16) U.S. EPA U.S. Environmental Protection Agency (2010) Memorandum: Clarification of
Degradates in Temephos Environmental Fate Studies. PC Code: 059001 DP Barcode: 373143.

(17) Yalkowsky, S.H., He, Y. (2003) Handbook of Aqueous Solubility Data: An Extensive
Compilation of Aqueous Solubility Data for Organic Compounds Extracted from the AQUASOL
dATAbASE, CRC Press LLC, Boca Raton, FL, 1512 total pages.

(18) Tomlin, C.D.S. (ed.) (2004-05) The e-Pesticide Manual, 13th Edition Version 3.1 electronic
version, British Crop Protection Council, Surrey, UK,. Print version: The Pesticide Manual, 13th
ed., British Crop Protection Council, Surrey, UK, 1344 total pages.

(19) BASF (undated) ABATE Larvicide Leaflet. BASF SA (Pty)Ltd, Gauteng, South Africa.

(20) European Parliament, Council of the European Union (2005) Regulation (EC) No. 396/2005
of the European Parliament and of the Council of 23 February 2005 on maximum residue levels
of pesticides in or on food and feed of plant and animal origin and amending Council Directive
91/414/EEC. 32005R0396. Official Journal of the European Communities.

(21) American Conference of Governmental Industrial Hygienists (2009) Threshold Limit

Values of Chemical Substances and Biological Exposure Indices, ACGIH, Cincinnati, OH, 256
total pages.

(22) International Resources Group, for United States Agency for International Development
(2012) Integrated Vector Management Programs for Malaria Vector Control (2012 Update) -
Programmatic Environmental Assessment, Volume 2: Annexes, USAID, Washington, DC, 496
total pages.

(23) Kamela, A., Byrneb, C., Vigob, C., Ferrariob, J., Stafforda, C., Verdina, G., Siegelmana, F.,
Kniznerc, S., Hetrickd, J. (2009) Oxidation of selected organophosphate pesticides during
chlorination of simulated drinking water, Water Research, Volume 43, Issue 2, Pages 522534.
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TEMEPHOS PART 2
Toxic Effects:
A. Target Organ/Systems:
Temephos is toxic due to its capacity to inhibit acetylcholinesterase (AChE) (1). This affects the
respiratory, cardiovascular, and gastrointestinal systems, CNS, eyes, and muscles, because
unhydrolyzed acetylcholine builds up in the synapses (1-3). This constantly stimulates receptors,
so muscles continually contract and glands excessively secrete. This is particularly bad for the
respiratory system, as it simultaneously makes it hard to breathe in or breathe out: It constricts
bronchioles, clogs the lungs with secretions, and wont allow the diaphragm to relax (1,3,4).
B. Mechanism of Action:
Temephos becomes more toxic during phase I metabolic reactions: Oxidative desulfuration by
cytochrome P450 or FMO enzymes exchange a sulfur for an oxygen, which makes organophos-
phorus pesticides like temephos into their far more toxic oxon analogs (1). The oxon phosphory-
lates the serine in the active site of AChE, which causes essentially irreversible inhibition (1,4).
With AChE inhibited, acetylcholine (ACh) does not break down and then continually acts on
muscarinic and nicotinic receptors until it degrades or new enzyme is created (1,3,4). In a high
enough dose, this results in the wide-ranging set of toxic effects called a cholinergic crisis (4).
C. Symptoms and/or Clinical Signs:
ACh has functions at all levels of the nervous system; inhibiting AChE has significant and varied
effects (1,4). A mnemonic for cholinergic crisis symptoms is SLUDGE and the killer Bs, for:
salivation, lacrimation, urination, defecation, GI upset, emesis, bradycardia, bronchospasm, and
bronchorrhea. These symptoms come from excess stimulation of muscarinic receptors (1,4).
Excess ACh at nicotinic receptors causes neuromuscular blockade, with weak, spasming muscles
and paralysis (1). Hyperstimulation of both kinds of receptors in the CNS causes the victim to be
nervous, dizzy, dazed, have blurry eyes, lack muscular control, and suffer convulsions (1-4).
D. Other Important Toxic Effects:
1. Mutagenicity:
Temephos was found to be genotoxic and mutagenic in both bacterial tests and a Comet assay
using rat blood cells (3). It was also found to be genotoxic in a study using human cells (5).
2. Carcinogenicity:
Based on limited evidence, temephos is not designated a carcinogen (6-11). The WHO, EPA, and
California DPH all referred to the same rat study, considered unacceptable by the CDPH (7-11).
3. Teratogenicity:
Insufficient evidence to evaluate. EPA, WHO and CDPH all referred to the same rat and/or
rabbit studies, which were inadequate according to either the EPA (rat) or the CDPH (rabbit) (7-
10).

Toxicity:
A. Acute Toxicity:
An LD50 of 183 mg/kg was calculated from four deaths in a neurotoxicology study of female
chickens (9). A rabbit study found an acute dermal LD50 of 1850 mg/kg (m), and 970 mg/kg (f),
but EPA notes that rabbits are a poor choice for dermal studies of organophosphates with sulfur
because they have high amounts of detoxifying arylesterases, leading to underestimates of
toxicity (8,12). A 1967 rat study found an acute dermal LD50 of >4,000 mg/kg (m,f) (10).
Reported values for acute oral rat LD50 vary from 444 mg/kg (sex not specified) to 86,000
mg/kg (m) and 13,000 mg/kg (f) (8,10,12). Rat inhalation LC50 is listed as >4.79 mg/l (m,f) (8).
B. Chronic Toxicity:
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Subchronic, 90 day oral studies were done in 1965 on rats and dogs (9). NOAELs found were:
Rats, 0.3 mg/kg bw/day (m,f) and dogs, 0.45 mg/kg bw/day (m,f); adverse effect was inhibition
of cholinesterase in the brain (8,9). These studies were also deemed unacceptable by the CDPH
for various reasons (9). A human oral total dose of 256 mg/day for 5 days or 64 mg/day for four
weeks did not result in any observable symptoms or effects on cholinesterase in the blood (3).

Overview of Latest Research:

The few past tests of genotoxicity gave mixed results (3,5,10). Genotoxicity and mutagenicity
was investigated in a 2002 study using bacteria and also rat blood cells. All tests indicated geno-
toxicity or mutagenicity at some dose, and two of them in doses comparable to that used in
Brazilian drinking water. In the Comet rat blood assay, 1.34 mM temephos caused severe DNA
damage to 22% of the samples, while 48% of the samples had such damage at 21.75 mM. In the
bacterial SOS assay, mutagenicity was indicated at 1.66 M and above. Addition of proteins to
metabolize the chemical decreased the response, and different bacterial strains had differing
responses. The authors concluded that biotransformation may make temephos less toxic or less
mutagenic, possibly because the damage can be repaired. In the Ames assay, temephos was
mutagenic above 3.33 M. This test also suggested that nitroreductase can make temephos less
toxic, although the mechanism is unclear since temephos does not contain nitrogen (3). In a 2015
study, genotoxicity was investigated using human cells. They used lymphocytes to test temephos
itself, because they dont biotransform as fully as other cells, and they used hepatoma cells to
simulate possible metabolic activation. There was DNA damage in both types of cells. Lympho-
cytes had damage at as low as 1 M, but results indicated this may be repairable. Hepatoma cells
had damage at 10 M, but this seemed permanent. The authors concluded that biotransformation
probably has a significant effect on the genotoxicity of temephos. The mechanism may be
through the production of reactive oxygen species or interference with DNA repair genes by
metabolism products (5). These two studies show that temephos can cause irreparable DNA
damage at some doses and also indicate how little is known about temephos metabolism (3,5).

Conclusions:
Temephos is used in drinking water to combat mosquitos that spread diseases like dengue,
malaria, and yellow fever (3,5,14). This is a crucial use, but people must know if temephos is
going to cause serious effects on humans or the environment. Temephos has not been sufficiently
tested. It has been used routinely for decades, and may not be a serious threat in small enough
doses. However, more information is needed to determine if its use should be continued, if it
should be limited to breeding season and the water avoided then, if certain populations are more
at risk, or what else can be done to balance vector control with toxic risk. Temephos is also very
toxic to bees (13). Killing bees threatens the food supply, so they must be protected as well.

Future Research Needs:

We should find out how temephos is biotransformed in mammalian cells and how this impacts
its toxicity. There are a lot of gaps in the data, especially for chronic and genotoxic risks. If it
will continue to be used in drinking water, it is important to determine if there are populations at
higher genetic risk or if fetuses or children are at greater risk because they cannot metabolize it
as adults do. It is also important to learn the potentiation risks so that those too can be avoided.
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References Part 2

(1) Hodgson, E. (2004) A Textbook of Modern Toxicology, 3rd ed., John Wiley and Sons,
Hoboken, New Jersey, 557 total pages.

(2) National Institute for Occupational Safety and Health, Education and Information Division
(2016) NIOSH Pocket Guide to Chemical Hazards, online version. NIOSH Publications, Centers
for Disease Control and Prevention, U.S. Department of Health and Human Services. Print
Version: DHHS (NIOSH) Publication No. 2005-149, Cincinnati, Ohio, 454 total pages.

(3) Aiub, C., Coelho, C., Sodr, E., Pinto, L., and Felzenszwalb, I. (2002) Genotoxic evaluation
of the organophosphorus pesticide temephos, Genetics and Molecular Research volume 1 (2),
pages 159-166.

(4) Burchum, J., and Rosenthal, L. (2016) Lehne's Pharmacology for Nursing Care, 9th ed,
Elsevier Saunders, St. Louis, Missouri, 1414 total pages.

(5) Benitez-Trinidad, A., Herrera-Moreno, J., Vzquez-Estrada, G., Verdn-Betancourt, F.,

Sordo, M., Ostrosky-Wegman, P., Bernal-Hernndez, Y., Medina-Daz, I., Barrn-Vivanco, B.,
Robledo-Marenco, M., Salazar, A., Rojas-Garca, A. (2015) Cytostatic and genotoxic effect of
temephos in human lymphocytes and HepG2 cells, Toxicology in Vitro volume 29 (4), pages
779-786.

(6) American Conference of Governmental Industrial Hygienists TLVs and BEIs. (2010)
Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure
Indices, ACGIH, Cincinnati, Ohio, 246 total pages.

(7) U.S. EPA U.S. Environmental Protection Agency (1998) Report of the Hazard Identification
Assessment Review Committee. HED Doc#012620. Health Effects Division.

(8) World Health Organization (2011) WHO Specifications and Evaluations for Public Health
Pesticides: Temephos. Comprised of the following reports, with supporting information:
Specifications (2008): 340/TC, 340/GR, 340EC & Evaluations: 340/2010, 340/2008, 340/2005.

(9) California Environmental Protection Agency. (1999) Summary of toxicology data:

Temephos. Chemical Code # 1, Tolerance # 170 SB 950 # 892, File name: T991109. Department
of Pesticide Regulation, Medical Toxicology Branch.

(10) Food and Agricultural Organization of the United Nations/World Health Organization
(2006) Pesticide Residues in Food: 2006, Toxicological Evaluations, WHO Press, Geneva
Switzerland.

(11) U.S. Environmental Protection Agency. (2006) Chemicals Evaluated for Carcinogenic
Potential. Science Information Management Branch, Health Effects Division, Office of Pesticide
Programs.
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(12) U.S. Environmental Protection Agency (2000) Temephos Reregistration Eligibility

Decision. EPA 738-F-00-018. Office of Pesticide Programs Public Regulatory Docket (7502C),
U.S. EPA.

(13) Kidd, H. and James, D. R., Eds. The Agrochemicals Handbook, Third Edition. Royal
Society of Chemistry Information Services, Cambridge, UK, 1991 (as updated). 1500 total
pages.

(14) International Resources Group, for United States Agency for International Development
(2012) Integrated Vector Management Programs for Malaria Vector Control (2012 Update) -
Programmatic Environmental Assessment, Volume 2: Annexes, USAID, Washington, DC, 496
total pages.