Contact Dermatitis 2010: 62: 18–31 © 2010 John Wiley & Sons A/S

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CONTACT DERMATITIS

Review Article

Formaldehyde-releasers in cosmetics: relationship

to formaldehyde contact allergy
Part 2. Patch test relationship to formaldehyde contact allergy,
experimental provocation tests, amount of formaldehyde released,
and assessment of risk to consumers allergic to formaldehyde

Anton de Groot1 , Ian R. White2 , Mari-Ann Flyvholm3 , Gerda Lensen1 AND Pieter-Jan Coenraads1
1 Department of Dermatology, University Medical Center Groningen, University of Groningen,

The Netherlands,
2
Department of Cutaneous Allergy, St John’s Institute of Dermatology, St. Thomas’ Hospital, London, UK, and
3
National Research Centre for the Working Environment, Copenhagen, Denmark

This is the second part of an article on formaldehyde-releasers in cosmetics. The patch test relationship
between the releasers in cosmetics to formaldehyde contact allergy is reviewed and it is assessed
whether products preserved with formaldehyde-releasers may contain enough free formaldehyde to pose
a threat to individuals with contact allergy to formaldehyde. There is a clear relationship between
positive patch test reactions to formaldehyde-releasers and formaldehyde contact allergy: 15% of
all reactions to 2-bromo-2-nitropropane-1,3-diol and 40–60% of the reactions to the other releasers
are caused by a reaction to the formaldehyde in the test material. There is only fragmented data
on the amount of free formaldehyde in cosmetics preserved with formaldehyde donors. However,
all releasers (with the exception of 2-bromo-2-nitropropane-1,3-diol, for which adequate data are
lacking) can, in the right circumstances of concentration and product composition, release >200 p.p.m.
formaldehyde, which may result in allergic contact dermatitis. Whether this is actually the case in
any particular product cannot be determined from the ingredient labelling. Therefore, we recommend
advising patients allergic to formaldehyde to avoid leave-on cosmetics preserved with quaternium-15,
diazolidinyl urea, DMDM hydantoin, or imidazolidinyl urea, acknowledging that many would tolerate
some products.

Key words: benzylhemiformal; 5-bromo-5-nitro-1,3-dioxane; 2-bromo-2-nitropropane-1,3-diol;

cosmetics; diazolidinyl urea; DMDM hydantoin; formaldehyde; imidazolidinyl urea; preservative;
quaternium-15; sodium hydroxymethylglycinate. © John Wiley & Sons A/S, 2010.
Accepted for publication 22 July 2009

In the first part of this article (1), key data on
formaldehyde-releasers used in cosmetics (benzyl-
hemiformal, 5-bromo-5-nitro-1,3-dioxane, 2-bromo-
2-nitropropane-1,3-diol, diazolidinyl urea, DMDM
hydantoin, imidazolidinyl urea, quaternium-15 and
sodium hydroxymethylglycinate) were presented,
including applications, frequency of sensitization,
relevance of patch test reactions, and their frequency
of use in cosmetics. In this second part, the patch
test relationship of these chemicals to formalde-
hyde are reviewed and assessed whether products
preserved with formaldehyde-releasers may con-
tain enough free formaldehyde to pose a threat to
individuals who are contact allergic to formaldehyde.
Contact Dermatitis 2010: 62: 18–31
Relationship between Formaldehyde-Releasers
and Contact Allergy to Formaldehyde
When patients are tested with formaldehyde and
one or more formaldehyde-releasers, concomitant
positive reactions may be observed to formalde-
hyde and (one or more) donors. It is often assumed
that this is due to ‘cross-allergy’ to formalde-
hyde (more correctly termed ‘pseudo-cross-allergy’
in our opinion), i.e. that the patch test reac-
tion to the donor is caused by the formalde-
hyde present in the test material of the releaser.
In favour of this assumption is that often more
than one releaser reacts in formaldehyde-sensitive
patients, even when the preservatives are not struc-
turally related (cross-reactions unlikely). In a recent
study, for example, among 219 patients aller-
gic to formaldehyde and/or formaldehyde-releasers
(quaternium-15, diazolidinyl urea, imidazolidinyl
urea, 2-bromo-2-nitropropane-1,3-diol, DMDM
hydantoin, and ethylene urea/melamine-formaldehy-
de resin), 76 (35%) were positive to only one of
these compounds, 53 (24%) reacted to two, 27
(12%) reacted to three, 31 (14%) to four, 25 (11%)
to five, and 7 (3%) patients reacted to six of the
tested formaldehyde(releasing) materials (2). Of 59
patients, patch test positive to quaternium-15 1%
petrolatum (pet.), 31 (53%) were also allergic to
formaldehyde (tested 2% aqua). However, of seven
patients allergic to quaternium AND to 2-bromo-2-
nitropropane-1,3-diol, imidazolidinyl urea, or both,
ALL were also allergic to formaldehyde, attest-
ing to the role of formaldehyde in multiple reac-
tions to releasers (3). In a USA study with 454
patients allergic to formaldehyde, 38 patients (8.4%)
reacted to both formaldehyde and two releasers
and 4 reacted to all three donors tested (2-bromo-
2-nitropropane-1,3-diol, imidazolidinyl urea, and
quaternium-15). Of these patients reacting to two
or three releasers (suggesting formaldehyde to be
the cause), quaternium-15 (which probably releases
the most formaldehyde) was positive in ALL (4).
Perret and Happle investigated 13 patients with pos-
itive patch test reactions to diazolidinyl urea 2%
aqua. Six of them were also allergic to formalde-
hyde. All 13 patients were additionally tested with
the formaldehyde-releasers urea formaldehyde (8%
aqua), glyoxal urea (10% aqua), and quaternium-15
(1% pet.). All six patients reacting to diazolidinyl
urea AND to formaldehyde also reacted to the
other releasers, whereas of those patients not aller-
gic to formaldehyde, NONE had a positive reaction
to any of the formaldehyde-releasers. It was con-
cluded that in the six patients allergic to diazolidinyl
and formaldehyde, the reactions to diazolidinyl urea
were probably caused by formaldehyde in the patch
test (5). Such studies, of which there are many,
FORMALDEHYDE-RELEASERS IN COSMETICS: PART 2 19
indicate that at least in a number of patients co-
reactions between formaldehyde and releasers are
due to formaldehyde sensitivity. On the other hand,
the investigation of Perret and Happle also indi-
cates that sensitivity to diazolidinyl urea can exist
independent of formaldehyde release, as none of the
seven patients allergic to diazolidinyl urea but not
to formaldehyde reacted to any of other releasers.
The existence of allergy to the releaser 2-
bromo-2-nitropropane-1,3-diol per se (independent
of formaldehyde contact allergy) was demonstrated
25 years ago by Storrs and Bell (6). These inves-
tigators described seven patients reacting to patch
tests with 2-bromo-2-nitropropane-1,3-diol 0.25%
and/or 0.5% and/or 1% aqua or pet. They had
all been sensitized by Eucerin® cream, which was
widely used in their geographic area as an emollient
for dry and damaged skin, containing 0.05% 2-
bromo-2-nitropropane-1,3-diol. The Eucerin® cream
was also patch test positive in all patients. None of
them were allergic to formaldehyde and they did not
react to either quaternium-15 or imidazolidinyl urea.
All patients performing a ROAT for a maximum
of 2 weeks on normal skin with Eucerin® cream
developed dermatitis. This indicated that 2-bromo-
2-nitropropane-1,3-diol allergy per se exists and that
0.05% 2-bromo-2-nitropropane-1,3-diol in a cream
is sufficient to give a positive patch test and a
positive ROAT in 2-bromo-2-nitropropane-1,3-diol
allergic patients who are not sensitive to formalde-
hyde. In addition, the investigators had seen another
four patients reacting to 2-bromo-2-nitropropane-
1,3-diol but NOT to Eucerin® cream. These patients
DID co-react to formaldehyde and to quaternium-15
and/or imidazolidinyl urea. They concluded that the
amount of formaldehyde in the cream containing
0.05% 2-bromo-2-nitropropane-1,3-diol was insuffi-
cient to cause a positive patch test (6).
How often are patients reacting to a releaser also
allergic to formaldehyde?
In many studies, patients have been patch tested with
formaldehyde and one or more releasers, especially
with quaternium-15, which is included in the base-
line series in both Europe and the USA. This gives
an opportunity to study the possible relationship
between formaldehyde and the donors, at least in
this diagnostic setting. In Table 1, data are presented
on the frequency of co-reactions to formaldehyde in
patients allergic to formaldehyde-releasers.
There is a consistent picture for 2-bromo-2-
nitropropane-1,3-diol. Less than 25% (and usually
far less) of 2-bromo-2-nitropropane-1,3-diol-sen-
sitive patients co-react to formaldehyde. This
suggests that most patch test reactions to 2-bromo-
2-nitropropane-1,3-diol indicate sensitivity to this
 20
DE GROOT ET AL.

Table 1. Percentages positive to formaldehyde in patients reacting to formaldehyde-releasersa

2-Bromo-2-nitro-propane-1,3-diol Diazolidinyl urea DMDM hydantoin Imidazolidinyl urea Quaternium-15 Reference
Country and Number of %+ Number of %+ Number of %+ Number of %+ Number of %+
period of study patients formaldehyde patients formaldehyde patients formaldehyde patients formaldehyde patients formaldehyde
Finland 2001–2007 15 83% (7)
UK 2004–2005 87 17% 78 55% 64 53% 129 59% (8)
USA 1992–2004 788b 69%b 515b 83%b 756b 63%b (9)
Germany 1994–2004 180 37% (?) (10)
IVDK 1992–1995 160 5% 129 12% 85 15% 64 47% (11)
Austria 1992–1993 43 2% 36 11% 70 27% (12)
UK 1982–1993 89 25% 91 25% 156 24% 299 55% (13)
USA 1989–1991 58 81% (14)
USA 1982–1989 244 20% 87 46% 181 65% (15)
The Netherlands 1984–1988 13 46% (5)
UK 1985 16 38% (3)
UK 1983–1984 59 53% (3)
USA 1983–1987 89 55% (15)
USA <1980 24 83% (16)
a Only studies with at least 10 positive reactions to the releasers are included. Data on <10 patients are presented in Refs (2, 6, 7, 17–21).
b Mean numbers/percentages in two patient groups reacting to the releaser in water and to the releaser in pet. vehicle.
Contact Dermatitis 2010: 62: 18–31
Contact Dermatitis 2010: 62: 18–31 FORMALDEHYDE-RELEASERS IN COSMETICS: PART 2 21

Table 2. Percentages positive to formaldehyde-releasers in patients allergic to formaldehydea

Percentage of patients allergic to formaldehyde with positive reactions to:
Number of 2-Bromo-2- DMDM
Country and patients allergic nitropropane- Diazolidinyl hydantoin Imidazolidinyl Quaternium-15
period of study to formaldehyde 1,3-diol (%) urea (%) (%) urea (%) (%) Reference
Finland 2001–2007 73–79 4 11 5 21 (7)
UK 2004–2005 142 10 30 23 52 (8)
USA 1992–2004 2225 24.50 19 17 (9)
UK 1992–1993 629 4 4 6 47 (13)
Austria 1992–1993 105 1 4 18 (12)
USA 1982–1989 454 10 10 31 (4)
USA <1980 30 30 (16)

a
Only studies with at least 20 positive reactions to formaldehyde are included. Data on <20 patients are presented in Refs (2) and (6).

Table 3. Testing with DMDM hydantoin and its parent compound in patients allergic to formaldehyde (22)
Group I. 14 patients tested with DMDM hydantoin
Concomitant allergy to DMDM hydantoin
Patients allergic to formaldehyde 3.0% (only) 1% (also) 0.3% (also) Negative
1% only =7 3 4
1% and 0.3% =4 2 2
1% and 0.3% and 0.1% =3 2 1
Group II. 21 patients tested with MDM hydantoin
Concomitant allergy to MDM hydantoin
Patients allergic to formaldehyde 3.0% (only) 1% (also) 0.3% (also) Negative
1% only = 12 1 11
1% and 0.3% =4 1 1 2
1% and 0.3% and 0.1% =5 2 2 1

preservative per se and are not related to formalde-
hyde allergy. The picture for quaternium-15 is also
fairly consistent. In all but two studies, half the
number of patients or more reacted to formalde-
hyde, indicating that formaldehyde is in >50% of
the cases responsible for the quaternium-15 patch
tests. Less consistent are the figures for diazo-
lidinyl urea (12–81% formaldehyde co-reactions),
DMDM hydantoin (37–83%), and imidazolidinyl
urea (11–63% co-reactions to formaldehyde).
How often are patients reacting to formaldehyde
also allergic to one or more
formaldehyde-releasers?
The reverse situation, i.e. what percentage of
patients allergic to formaldehyde reacts to the
releasers, can also be deducted from many studies.
The available data are shown in Table 2.
For 2-bromo-2-nitropropane-1,3-diol, the data are
consistent: less than 10% of patients allergic to
formaldehyde react to 2-bromo-2-nitropropane-1,3-
diol. On the other side of the spectrum, in all but
two studies at least 30% of the patients reacting to
formaldehyde also reacted to quaternium-15. Less
patients (<30%) will react to diazolidinyl urea, and
still fewer (<23%) to imidazolidinyl urea. One study
showed that about one out of five formaldehyde-
sensitive individuals was also patch test positive to
DMDM hydantoin. The relationship between posi-
tive patch tests to formaldehyde allergy and patch
test reactions to DMDM hydantoin was investigated
in detail by De Groot et al (22). Thirty-five patients
allergic to formaldehyde were patch tested with
formaldehyde and dimethylhydantoin (DM hydan-
toin; the parent compound). Twenty-one of these
formaldehyde-sensitive subjects were also tested
with MDM hydantoin (DM hydantoin +1 molecule
formaldehyde), the other 14 also with DMDM
hydantoin (two molecules formaldehyde). Test con-
centrations were 0.1–0.3–1% for formaldehyde,
0.3–1–3% for DMDM hydantoin and MDM hydan-
toin, and 1–3–10% for DM hydantoin, all in water
(w/w). Control tests in 97 patients had excluded irri-
tancy. The results are shown in Table 3. No patient
reacted to the parent compound DM hydantoin. Of
the 14 patients in Group I, 8 (57%) reacted to
DMDM hydantoin. Of the 21 patients in Group II, 7
(33%) reacted to MDM hydantoin. In both groups,
most negative reactions to (D)MDM hydantoin were
observed in patients reacting only to the 1% solution
of formaldehyde. Patients with ‘stronger’ allergies to
formaldehyde (reacting to 0.1% and/or 0.3% also)
tended to show more positive reactions even to the
lower concentrations of (D)MDM hydantoin.
22 DE GROOT ET AL. Contact Dermatitis 2010: 62: 18–31

Table 4. Percentages positive to other formaldehyde-releasers in patients allergic to a particular formaldehyde-releaser

Percentage of patients allergic to releaser with positive reactions to:
Number of 2-Bromo-2-
Country and patients allergic nitropropane- Diazolidinyl Imidazolidinyl
period of study to formaldehyde 1,3-diol (%) urea (%) urea (%) Quaternium-15 (%) Reference
2-Bromo-2-nitropropane-1,3-diol
UK 2004–2005 87 (100) 10 8 13 (8)
UK 1982–1993 89 (100) 2 2 13 (13)
USA 1982–1989 244 (100) NT 5 14 (4)
Diazolidinyl urea
UK 2004–2005 78 11 (100) 60 49 (8)
UK 1982–1993 91 2 (100) 75 21 (13)
USA 1981–1991 58 5 (100) 29 41 (14)
Imidazolidinyl urea
UK 2004–2005 64 12 75 (100) 47 (8)
UK 1982–1993 156 1 44 (100) 22 (13)
USA 1982–1989 87 10 NT (100) 40 (4)
Quaternium-15
UK 2004–2005 129 9 30 23 (100) (8)
UK 1982–1993 154 2 5 6 (100) (13)
USA 1982–1989 181 15 NT 17 (100) (4)
NT, not tested.

Using the data from Rosen and McFarland (23),
it was estimated that 3% DMDM hydantoin con-
tains 0.3% (3000 p.p.m.) and the 0.3% solution
0.02% (200 p.p.m.) free formaldehyde. Thus, 3 of
14 patients reacted to 200 p.p.m. upon patch testing.
This may be comfounded somewhat by the fact that
the patients were also concurrently tested with the
higher concentrations and with formaldehyde (addi-
tive effect). These data demonstrate that aqueous
preparations of DMDM hydantoin, in concentrations
comparable to those used in cosmetic products, con-
tain enough free formaldehyde to cause dermatitis in
some patients allergic to formaldehyde when patch
tested (22).
How often are patients reacting to a formaldehyde
donor also allergic to one or more other
formaldehyde-releasers?
In four large studies, the dynamics of patch test reac-
tivity between the various formaldehyde-releasers
was studied. The results are shown in Table 4.
Again, for 2-bromo-2-nitropropane-1,3-diol, there is
a consistent pattern: few reactions to and from other
formaldehyde-releasers, formaldehyde plays a minor
role. There is in two of three studies a very high
co-reactivity between imidazolidinyl urea and dia-
zolidinyl urea, higher than with formaldehyde, indi-
cating (true) cross-allergy or a reaction to a common
(non-formaldehyde) constituent (see under imidazo-
lidinyl urea and under diazolidinyl urea, Ref. (1)).
Of the patients reactive to diazolidinyl urea or imi-
dazolidinyl urea, up to nearly half have reactions to
quaternium-15, indicating a role for formaldehyde
because these chemicals are structurally unrelated.
Conversely, however, of the patients reacting to
quaternium-15, only up to 23% react to imidazo-
lidinyl urea and up to 30% to diazolidinyl urea.
In such cases, the patient may well be allergic to
formaldehyde, but the amount of formaldehyde in
the diazolidinyl urea and imidazolidinyl urea test
substances is not enough to cause a positive patch
test reaction.
The recent experience of the British Contact
Dermatitis Society with formaldehyde and formal-
dehyde-releasers is shown in Table 5 (8). This table

Table 5. Relationship between formaldehyde and formaldehyde-releasers: UK experience 2004–2005 (8))

2-Bromo-2-nitro- Imidazolidinyl
Formaldehyde (%) Quaternium-15 (%) propane-1,3,diol (%) urea (%) Diazolidinyl urea (%)
Formaldehyde (100) 52 10 23 30
Quaternium-15 59 (100) 9 23 30
2-Bromo-2-nitropropane- 17 13 (100) 8 10
1,3-diol
Imidazolidinyl urea 53 47 12 (100) 75
Diazolidinyl urea 55 49 11 60 (100)
This table may be read as follows: horizontal row, 52% of patients allergic to formaldehyde are also allergic to quaternium-15 and 23%
are also allergic to imidazolidinyl urea. Conversely, vertical row, 59% of patients allergic to quaternium-15 are allergic to formaldehyde,
and 53% of the patients allergic to imidazolidinyl urea (55% for diazolidinyl urea) are also allergic to formaldehyde.
Contact Dermatitis 2010: 62: 18–31
may be read as follows: horizontal row, 52% of
patients allergic to formaldehyde are also allergic
to quaternium-15 and 23% are also allergic to
imidazolidinyl urea. Conversely, vertical row, 59%
of patients allergic to quaternium-15 are allergic to
formaldehyde, and 53% of the patients allergic to
imidazolidinyl urea (55% for diazolidinyl urea) are
also allergic to formaldehyde.
The associations between formaldehyde and the
releasers were highly significant (Kendall’s τ -
b correlation score [P < 0.001]); this was also
the case for the associations between the vari-
ous releasers (8). As the chemical structures of
these compounds–with the exception of diazo-
lidinyl urea and imidazolidinyl urea–are dissimi-
lar, there is probably a major role for formalde-
hyde in these co-reactivities (which may then be
called ‘pseudo-cross-reactions’ to formaldehyde).
Indeed, the strongest association is seen between
formaldehyde and quaternium-15, known to release
the most formaldehyde of the releasers. 2-Bromo-2-
nitropropane-1,3-diol, on the other hand, releases lit-
tle formaldehyde, and the association with formalde-
hyde, though statistically significant, is far weaker.
Of course, concomitant (‘dual’) sensitization to
formaldehyde and the parent molecule may also
contribute to these associations in a number of
cases (11, 24).
Experimental Provocation Tests with Cosmetics
Containing Formaldehyde-Releasers in
Formaldehyde-Sensitive Subjects
Fifteen patients with contact allergy to formalde-
hyde (n = 7) and/or the formaldehyde-releasers
quaternium-15 (n = 8), DMDM hydantoin (n =
1), imidazolidinyl urea (n = 2), and/or 2-bromo-2-
nitropropane-1,3-diol (n = 6) but patch test negative
to diazolidinyl urea underwent a ROAT (twice daily
application to the antecubital fossa for 2 weeks)
with a moisturizer preserved with 0.2% diazolidinyl
urea. In only one patient, the ROAT was clearly
positive. Afterwards, this patient was retested with
diazolidinyl urea 1% pet. and 1% aqua and (now)
had a positive reaction to 1% aqua but not to diazo-
lidinyl urea 1% pet. The amount of free formalde-
hyde was not investigated. It was concluded that
in patients allergic to formaldehyde and/or one
or more formaldehyde-releasers, complete avoid-
ance of other formaldehyde-releasers to which the
patient is patch test negative is not always necessary,
‘notably if the amount of formaldehyde released by
that compound is below the threshold of reactivity
for virtually all formaldehyde-sensitive individuals
(around 250 p.p.m.)’ (2). It should be realized, how-
ever, that a ROAT on the neck or on the face may be
positive in the absence of a positive reaction to the
FORMALDEHYDE-RELEASERS IN COSMETICS: PART 2 23
ROAT on the arm (25), so false-negative reactions
may have occurred.
Twelve patients allergic to formaldehyde per-
formed a ROAT with a cream containing 1%
DMDM hydantoin (twice daily for a week in the
flexor aspect of the lower arm) and in four patients
(33%), dermatitis was observed after 3–6 days.
These four subsequently tested the same cream but
now containing 0.25% of the preservative (estimated
to contain approximately 200 p.p.m. free formalde-
hyde) in a ROAT; the test was negative in two,
produced only itching but no visible changes in one,
and provoked mild dermatitis in one (cave at: only
1 week) (22). It was concluded that cosmetics pre-
served with 0.25% DMDM hydantoin may pose a
threat to certain patients allergic to formaldehyde.
Zachariae et al. (25) performed an experimen-
tal use test exposure study with a cream pre-
served with diazolidinyl urea in patients allergic
to formaldehyde. They developed a dose-escalating
design, including four diazolidinyl urea concen-
trations, and exposure to three different anatomi-
cal regions (upper arm, neck, and face) each of
2-week duration. The test population consisted of
30 patients allergic to formaldehyde, 10 patients
allergic to diazolidinyl urea (of which 7 had also
reacted to formaldehyde) and 10 non-allergic con-
trols. The four versions of the test cream were
preserved with 0.05%, 0.15%, 0.30%, and 0.60%
diazolidinyl urea (maximum allowed in the EU:
0.5%), which were found to contain 130, 370, 730
and 1500 p.p.m. formaldehyde, respectively. They
were applied twice daily for 2 weeks on a 5 × 5 cm
area of the flexor aspect of the upper arm (ROAT). If
no reaction occurred after 2 weeks, the cream appli-
cation continued on the neck for another 2 weeks,
and on the face, in a similar fashion, for further
2 weeks. If a positive reaction was observed at any
time before the end of the 6-week period, the patient
was examined and withdrawn from the study.
The results were as follows: of the 10 formalde-
hyde allergic patients tested with the cream contain-
ing 0.05% diazolidinyl urea, none had a positive
reaction. The cream preserved with 0.15% diazo-
lidinyl urea elicited two reactions in 10 patients,
0.3% induced seven positive reactions and the
ROAT with 0.6% resulted in seven positive reac-
tions in 10 patients. Thus, with an increasing con-
centration of diazolidinyl urea from 0.15% to 0.6%
(corresponding to formaldehyde concentrations of
370–1500 p.p.m., respectively), a dose dependent
increase in patients’ reactivity was seen, not only
in the number of reactors but also in the strength
of the reaction. On the basis of this investigation,
the amount of formaldehyde that does not elicit der-
matitis in formaldehyde-sensitive subjects should be
between 130 and 370 p.p.m.
24 DE GROOT ET AL.
Of the 10 patients allergic to diazolidinyl urea (7
of which also reacted to formaldehyde), 9 had a pos-
itive ROAT to the cream with 0.15% diazolidinyl
urea, 6 on the arm, and 3 in the neck (compared
with 2 of 10 in patients reacting to formaldehyde
but patch test negative to diazolidinyl urea) (25).
There are several possible explanations for this:
(i) Patients were not only allergic to formaldehyde
but also to another compound in diazolidinyl urea
(see also under chemical structure). The threshold
for a patch test response is lowered by simultane-
ous presence of more than one allergen (25). (ii)
These patients were more sensitive to formaldehyde
(and thus reacted to formaldehyde and diazolidinyl
urea) than those allergic to formaldehyde, for whom
the amount of formaldehyde in the diazolidinyl urea
test preparation was insufficient to elicit a positive
reaction. (iii) In at least two patients with a posi-
tive ROAT, formaldehyde was negative. This may
have been false negative. But if they were truly
non-allergic, the allergy to the (other) compound in
diazolidinyl urea that caused the reaction was strong
enough to induce a positive ROAT. From these
data, it may (tentatively) be concluded that levels
of 370 p.p.m. formaldehyde (0.03–0.04%) released
by a formaldehyde-releaser may–under certain con-
ditions of use–induce allergic contact dermatitis
on normal skin in a number of patients sensitive
to formaldehyde. Some patients may react to even
lower formaldehyde concentrations. When patients
react to both formaldehyde and the releaser itself,
the risk of developing allergic contact dermatitis
increases.
Isaksson et al. (26) have investigated whether
the presence of 175 p.p.m. formaldehyde released
from the preservative imidazolidinyl urea in a cor-
ticosteroid cream influences (i.e. diminishes) the
cream’s therapeutic efficiency in treating experimen-
tally induced allergic contact dermatitis. In seven
patients allergic to nickel and formaldehyde, patches
of 8 × 9 cm of allergic contact dermatitis were pro-
voked on the outer part of both upper arms. In
a double-blind fashion, these were treated with a
corticosteroid cream containing approximately 175
p.p.m. formaldehyde and (the other arm) with a cor-
ticosteroid cream of similar strength not containing
formaldehyde. As controls served 17 patients aller-
gic to nickel but not to formaldehyde. In two of
seven patients allergic to formaldehyde (29%), the
eczema treated with the formaldehyde-containing
cream healed completely within 4 weeks, compared
with 12 of 17 (71%) in the control group; the dif-
ference was statistically significant. There was no
correlation between the formaldehyde reactivity, as
measured by serial dilution testing, and the ten-
dency to healing in the group allergic to formalde-
hyde and treated with the formaldehyde-containing
Contact Dermatitis 2010: 62: 18–31
corticosteroid cream. From this study, it may be
concluded that the presence of 175 p.p.m. formalde-
hyde in a corticosteroid cream has a negative effect
on the therapeutic efficacy of the corticosteroid on
experimentally induced allergic contact dermatitis in
patients allergic to formaldehyde and such creams
should therefore not be used by formaldehyde aller-
gic individuals (26).
Flyvholm et al. (27) saw a positive reaction to
a stay-on cosmetic preserved with 0.3% imidazo-
lidinyl urea (containing approximately 300 p.p.m.
free formaldehyde) in a ROAT lasting 1 week in
one of three patients allergic to both formaldehyde
and imidazolidinyl urea. In 20 patients with allergy
to formaldehyde but negative reactions to imida-
zolidinyl urea, the ROAT produced some follicular
papules in 5 of 20. These were considered to be a
mild allergic reaction, as none of the controls sub-
jects had any reaction at all (27).
The Amount of Formaldehyde Released by
Formaldehyde-Releasers
There is only fragmented data available on the
amounts of formaldehyde that will be released by
formaldehyde donors. These amounts depend on the
nature of the releaser, its concentration, the pH of
the product, the temperature (the higher the temper-
ature the more formaldehyde is present in solution
after constant time) (28), the age of the product
(upon storage increased levels of formaldehyde will
be released), the level of microbial contamination,
and the other constituents of the products containing
the releaser (11, 28–30).
The pH may greatly influence the release of
formaldehyde. Diazolidinyl urea, for example,
releases formaldehyde foremost in an alkaline prod-
uct, i.e. with high pH value (31, 32). Imidazo-
lidinyl urea in lower concentrations is stable in
a low pH (acidic) environment, but with increas-
ing pH the amount of free formaldehyde also
increases (32, 33). The same holds true for DMDM
hydantoin, whereas sodium hydroxymethylglycinate
tends to release formaldehyde more in acidic solu-
tions (32). In a 0.1% quaternium-15 solution,
the amount of formaldehyde is strongly depen-
dent on the pH: <200 p.p.m. formaldehyde at pH
>9, 250–300 p.p.m. at pH 7 and 600 p.p.m. at
pH 3 (34).
Other ingredients, i.e. the nature and composi-
tion of a product, may also influence the amount of
free formaldehyde. In a protein-free shampoo, 0.1%
quaternium-15 released 482 p.p.m. formaldehyde,
but in a shampoo with protein only 122 p.p.m. Pre-
sumably, the protein forms complexes with released
formaldehyde (23). In mascara preserved with 0.4%
imidazolidinyl urea, the levels of formaldehyde were
Contact Dermatitis 2010: 62: 18–31
<10 p.p.m., but in creams or milks containing
0.3–0.5% the concentration of formaldehyde varied
between 100 and 130 p.p.m. (28).
Several methods for determining formaldehyde
have been used (28, 32–38) which make compar-
isons difficult. None of the methods is absolutely
reliable or does always give reproducible results,
which may in part account for (sometimes greatly)
varying results. With some methods (including the
official EU adopted method), the releasers deliver in
the presence of the reagent free formaldehyde con-
tinuously during its determination, which may result
in too high and non-reproducible values (11, 28).
Several tests are now available to overcome this
problem (28, 32, 34, 36). It should be realized
that free formaldehyde present in products preserved
with a formaldehyde-releaser may not only originate
from the releaser itself but may also comprise excess
formaldehyde used to synthesize the preservative,
formaldehyde from other formaldehyde-based raw
materials used to prepare the cosmetic product,
formaldehyde used as a preservative for the raw
materials themselves, and from degradation of non-
formaldehyde ingredients such as polyethylenegly-
col ethers (39).
Benzylhemiformal is the reaction product of ben-
zyl alcohol and formaldehyde, and is rarely used in
cosmetic products. It degrades rapidly in an aqueous
solution, and at pH 5 the maximum possible amount
of 300 p.p.m. formaldehyde of an 0.1% benzylhemi-
formal solution can be demonstrated (36). Emeis
et al. (32) found that benzylhemiformal at 2% w/w
aqueous solution mixes spontaneously, with decom-
position of 97% of the benzylhemiformal. Higher
dilution leads to instantaneous, complete decompo-
sition of the releaser into formaldehyde and benzyl
alcohol. At the maximum permissible concentration
of 0.15% benzylhemiformal in cosmetic rinse-off
products, the concentration of free formaldehyde
should according to these authors be just under 0.05
wt% (500 p.p.m.) (32).
2-Bromo-2-nitropropane-1,3-diol only releases
formaldehyde at higher pH values. Breakdown of 2-
bromo-2-nitropropane-1,3-diol results in formation
of formaldehyde and bromonitroethanol, a process
which is accelerated by increased pH and/or tem-
perature. The half life is more than 5 years at pH 4
but drops to 2 months at pH 8 (40, 41).
Diazolidinyl urea is produced from 4 mol of
formaldehyde and 1 mol of allantoin (compare:
imidazolidinyl urea from 3 mol of formaldehyde
and 2 mol of allantoin). From each molecule of
diazolidinyl urea, four formaldehyde molecules can
be released (4 mol formaldehyde/mole diazolidinyl
urea). However, only about 50% of the theoretical
amount of formaldehyde in diazolidinyl urea can be
FORMALDEHYDE-RELEASERS IN COSMETICS: PART 2 25
released upon complete hydrolysis (see diazolidinyl
urea, chemical structure (1)).
DMDM hydantoin is produced by reacting
formaldehyde with DM hydantoin (5,5-dimethyl-
hydantoin). The composition of DMDM hydantoin
as determined by gas chromatography is as fol-
lows: 94–98% DMDM hydantoin, 2.5–3% MDM
hydantoin (monomethyloldimethylhydantoin), other
dimethylhydantoin formaldehyde products comprise
the balance. One mole of DMDM hydantoin can
release a total of 2 mol of formaldehyde. The con-
centrations of free formaldehyde depend on the
pH; in alkaline environment more formaldehyde
is released. DMDM hydantoin is said to contain
0.5–2% free formaldehyde and concentrations in
cosmetics range from 0.1% to 0.6% (42, 43). It
has been suggested that most formulations will,
therefore, contain between 20 and 120 p.p.m. free
formaldehyde (31, 44). However, these estimates
may be too low, as a cream preserved with 0.15
wt% DMDM hydantoin contained 0.013 wt% (130
p.p.m.) free formaldehyde (32).
Imidazolidinyl urea is prepared from 3 mol of
formaldehyde and 2 mol of allantoin (compare: dia-
zolidinyl urea from 4 mol of formaldehyde and
1 mol of allantoin). From each molecule of imida-
zolidinyl urea, two formaldehyde molecules can be
released (2 mol formaldehyde/mole imidazolidinyl
urea) (44). Release is hastened by increased tem-
perature and pH. Only about 75% of this theoretical
amount of formaldehyde in imidazolidinyl urea will
be released upon complete hydrolysis (44).
Sodium hydroxymethylglycinate. Emeis et al.
investigated the release of formaldehyde from
sodium hydroxymethylglycinate with 13 C NMR
spectroscopy (32). At a concentration of 1% and a
pH of 5.5, sodium hydroxymethylglycinate decom-
poses completely into formaldehyde and sodium
glycinate. In a basic environment, decomposition is
incomplete. It is not until further dilution to 0.5%
w/w–the maximum concentration allowed in cos-
metic products–that it decomposes completely at a
pH of 8.5. The concentration of free formaldehyde
then is 0.12% w/w (1200 p.p.m.) (32).
Rosen and McFarland (23) investigated protein
and non-protein shampoos with the preservatives
DMDM hydantoin, imidazolidinyl urea, diazolidinyl
urea, and quaternium-15 added in concentrations
of 0.1%, 0.2%, 0.4%, and 0.8%, and determined
the amounts of free formaldehyde in the sham-
poos. In the first experiment, the shampoos were
heated to steambath temperatures. It was found that
DMDM hydantoin had released all its formalde-
hyde (2 mol/mole DMDM hydantoin) after 15 min,
quaternium-15 had released its total of 6 mol/mole
after 3 min and imidazolidinyl urea its 2 mol
after 5 min. Diazolidinyl urea, theoretically able to
26 DE GROOT ET AL. Contact Dermatitis 2010: 62: 18–31

Table 6. Formaldehyde recoveries from NON-PROTEIN shampoo containing various preservatives (23)
Free formaldehyde
Preservative DMDM hydantoin Imidazolidinyl urea Diazolidinyl urea Quaternium-15
Concentration (%) mg/kg (p.p.m.) %a mg/kg (p.p.m.) %a mg/kg (p.p.m.) %a mg/kg (p.p.m.) %a
0.10 108 61 92 60 150 69 482 67
0.20 183 52 140 45 262 61 546 38
0.40 294 42 230 37 452 52 731 25
0.80 505 36 270 22 740 43 777 14
a
Percentage of theoretical total releasable formaldehyde.

release 4 mol/mole, released 2.1 mol after 5 min,
and 3.3 mol/mole formaldehyde after 60 min at
steam bath temperatures.
In the second experiment, free formaldehyde was
determined in the protein and non-protein shampoos
at 23◦ C by a microdiffusion method. The results
are shown in Tables 6 (non-protein shampoo) and 7
(protein-containing shampoo).
As the concentration of each preservative is
increased in the shampoo, the amount of free
formaldehyde generated by hydrolysis increases.
With increasing concentrations, the percentage of
(theoretical) total formaldehyde released, however,
decreases. The amount of free formaldehyde
released changes when protein is incorporated into
the shampoo, which is now depressed for all four
preservatives when compared with the non-protein
shampoos. This indicates that free formaldehyde has
been complexed by the protein introduced.
The order of formaldehyde release is imidazo-
lidinyl urea <DMDM hydantoin <diazolidinyl urea
<quaternium-15 (23).
DMDM hydantoin and imidazolidinyl urea each
contain two methylol groups while diazolidinyl urea
has four. The molar percentages of free formalde-
hyde found for these three materials are about the
same over the concentration range studied. An aver-
age of 1.3 mol of free formaldehyde per mole of
preservative was found at 0.1%. This represents
65% of the formaldehyde in DMDM hydantoin and
imidazolidinyl urea, but only 33% for diazolidinyl
urea. This means that–under the condition of the
investigation–only two of the four methylol groups
are formaldehyde donors. The relationship of free
molecular formaldehyde versus concentration for
quaternium-15 is analogous to DMDM hydantoin
and imidazolidinyl urea, even though quaternium-15
has six bound formaldehyde moieties. At 0.1% con-
centration, four of the six formaldehyde moieties are
released, which is 66% of the total available (23).
Karlberg et al. developed a method for quantifi-
cation of formaldehyde in the presence of formal-
dehyde-releasers in skin-care products (45). They
used this method to determine the amount of
formaldehyde in cream and lotion preserved with
formaldehyde-releasers by adding formaldehyde-
releasers in concentrations ranging from 200 to 2400
μg/g (0.02–0.24%) to diluted Essex® cream and
Essex® lotion. Diazolidinyl urea and imidazolidinyl
urea were added to the cream and 2-bromo-2-
nitropropane-1,3-diol to the lotion. A linear correla-
tion between the concentration of the formaldehyde
donor and the amount of formaldehyde detected
was found. The amounts (approximate, read from
a graphic in the publication) results are shown in
Table 8.
Using quantitative 13 C NMR spectroscopy, the
concentration of free formaldehyde was determined,
released from diazolidinyl urea and imidazolidinyl
urea compared with the maximum releasable con-
centrations of formaldehyde as a function of dilution
and pH (Table 9) (32).
In 8 of 161 rinse-off products and 124 leave-
on products produced in various European coun-
tries and the USA, free formaldehyde levels of
>0.05% (500 p.p.m.) were found with a maximum
of 0.111% (1110 p.p.m.). Three of these products
were labelled with quaternium-15 and one with
diazolidinyl urea (46). In Switzerland, 19 of 34

Table 7. Formaldehyde recoveries from PROTEIN-CONTAINING shampoo containing various preservatives (23)
Free formaldehyde
Preservative DMDM hydantoin Imidazolidinyl urea Diazolidinyl urea Quaternium-15
Concentration (%) mg/kg (p.p.m.) %a mg/kg (p.p.m.) %a mg/kg (p.p.m.) %a mg/kg (p.p.m.) %a
0.10 36 21 17 11 58 27 122 17
0.20 84 24 36 12 125 29 187 13
0.40 160 23 74 12 235 27 237 8
0.80 292 21 117 9 384 22 278 5
a
Percentage of theoretical total releasable formaldehyde.
Contact Dermatitis 2010: 62: 18–31 FORMALDEHYDE-RELEASERS IN COSMETICS: PART 2 27

Table 8. Amount of formaldehyde released with varying concentrations of formaldehyde-releasers (45)

Concentration of formaldehyde-releaser
0.02% 0.08% 0.16% 0.24%
Formaldehyde-releaser Free formaldehyde in the sample
Diazolidinyl urea (in dil. cream) (p.p.m.) 40 140 240 350
Imidazolidinyl urea (in dil. cream) (p.p.m.) 30 80 120 160
2-Bromo-2-nitropropane-1,3-diol (in lotion) (p.p.m.) 20 30 50 70

Table 9. Free formaldehyde released from diazolidinyl urea and imidazolidinyl urea as a function of dilution and pH (32)
Diazolidinyl urea Imidazolidinyl urea
0.5% 0.2% (w%) 0.6% 0.2% (w%)
Free formaldehyde (w%)
pH 9 0.084 (840 p.p.m.) 0.047 (470 p.p.m.) 0.024 (240 p.p.m.) 0.015 (150 p.p.m.)
pH 6 0.036 (360 p.p.m.) 0.019 (190 p.p.m.) 0.012 (120 p.p.m.) 0.011 (110 p.p.m.)
pH 4 0.032 (320 p.p.m.) 0.024 (240 p.p.m.) 0.015 (150 p.p.m.) 0.010 (100 p.p.m.)
Maximum releasable (w%) 0.21 (2100 p.p.m.) 0.086 (860 p.p.m.) 0.14 (1400 p.p.m.) 0.046 (460 p.p.m.)

cosmetic products (56%) investigated for the pres-
ence of formaldehyde using three analytical methods
including high-performance liquid chromatography
were found to contain free formaldehyde in amounts
ranging from 1 to 169 p.p.m.. Nine products con-
tained more than 50 p.p.m.. In stay-on cosmetics, the
highest concentration proved to be 145 p.p.m. (35).
Other reports of free formaldehyde released
from products containing formaldehyde-releasers
are summarized in Table 10.
The maximum levels permitted in the EU and
the highest values of free formaldehyde found
for these or lower concentrations are shown in
Table 11. These data indicate that–with the excep-
tion of 2-bromo-2-nitropropane-1,3-diol, for which
adequate data are lacking–in the right circum-
stances the amount of free formaldehyde released
by all donors may be sufficient to induce dermatitis
with regular use (48). Benzylhemiformal is per-
mitted in rinse-off products only and may conse-
quently pose less threat to formaldehyde-sensitive
subjects.
Discussion
Relationship between formaldehyde and releasers
and between various releasers
There is ample evidence that patch test reactions
to the various releasers in patients co-reacting to
formaldehyde may be caused by formaldehyde in
the patch test preparation. The mean percentages
(adjusted for sample size) of patients allergic to
a releaser that also react to formaldehyde in the
various studies summarized in Table 1 were 15
for 2-bromo-2-nitropropane-1,3-diol, 49 for imida-
zolidinyl urea, 55 for quaternium-15, 57 for DMDM
hydantoin, and 59 for diazolidinyl urea. It should
be noted that in the cases of diazolidinyl urea,
DMDM hydantoin, and imidazolidinyl urea, these
percentages are heavily influenced by one major
USA study with by far the largest numbers of
allergic patients and high percentages co-reacting
to formaldehyde (9). Nevertheless, these data do
clearly show that, with the exception of 2-bromo-2-
nitropropane-1,3-diol, about half the reactions or so
(40–60%) to the releasers are caused by formalde-
hyde sensitivity. Of course, dual sensitization to
formaldehyde and a releaser per se is also possible
(11). Obviously, the fact that 85% of positive patch
test reactions to 2-bromo-2-nitropropane-1,3-diol
are seen in patients negative to formaldehyde, means
not only that allergy to 2-bromo-2-nitropropane-1,3-
diol per se (i.e. independent of formaldehyde) does
exist, but that this is the case in the great majority
for this releaser. For the others, about half of the
cases are contact allergies independent of formalde-
hyde sensitivity. It should be appreciated that in a
number of these cases, the reaction to formaldehyde
may have been false negative, which would make
the percentage reacting to formaldehyde in the test
substance even greater.
Conversely, not all patients allergic to formalde-
hyde react to one or more releasers, in fact it is
a small minority (Table 2). The mean percentages
(adjusted for sample size) of patients allergic to
formaldehyde who also react to a releaser in the var-
ious studies summarized in Table 2 were 16 for 2-
bromo-2-nitropropane-1,3-diol, 20 for diazolidinyl
urea, 19 for DMDM hydantoin, 14 for imidazo-
lidinyl urea, and 40 for quaternium-15. Whether or
not a formaldehyde-sensitive individual will react to
one or more releasers is dependent on the strength of
the formaldehyde sensitization and on the amount of
formaldehyde present in (aqueous test substances)
or releasable by the test preparation (pet.). Thus,
28 DE GROOT ET AL. Contact Dermatitis 2010: 62: 18–31

Table 10. Reports of free formaldehyde released from products containing formaldehyde-releasers
Amount of free formaldehyde Reference
Formaldehyde-releaser Present in (type of product) Concentration (%) % p.p.m.
Benzyl hemiformal Preservative solution 0.1 300 (28)
Shampoo 0.2 100 (28)
2-Bromo-2-nitropropane-1,3-diol Shampoo 0.02 10 (6)
Emulsion 0.02 15 (6)
DMDM hydantoin Preservative solution 0.25–pH 8.5–9 0.047 470 (32)
–pH 6–6.5 0.027 270 (32)
–pH 4–4.5 0.021 210 (32)
Cream 0.15 0.013 wt% 130 (32)
Preservative buffer solution 0.1 300 (33)
Imidazolidinyl urea Shampoo 0.1 8 (28)
Milky cleanser 0.3 100 (28)
Cleansing cream 0.4 92 (28)
Mascara 0.4 7 (28)
Night cream 0.5 131 (28)
Preservative saline solution 1.0 0.14 1400 (47)
Preservative buffer solution 0.1 100 (33)
Oil-in-water emulsion 0.3 300 (27)
Methenamineb Preservative solution 0.1–pH 3 480a (28)
–pH 5 220a (28)
–pH 8 10a (28)
Quaternium-15 Bath foam 0.2 398 (34)
Cleansing milk 0.2 482 (34)
Lotion 0.2 525 (34)
Shampoo 0.2 310 (34)
Sunscreen emulsion 0.2 406 (34)
product not specified 0.1 100 (31)
Shampoo 0.2 265 (28)
Eyeliner 0.2 286 (28)
Eye cream 0.2 266 (28)
Preservative solution 0.1 –pH>9 <200 (34)
–pH 7 250–300 (34)
–pH 3 600 (34)
Preservative buffer solution 0.1 700 (33)
Sodium hydroxymethylglycinate Preservative solution pH 8.5 0.5 (wt) 0.12 wt% 1200 (32)
Triazinetriethanolb Hand cleaner 0.2 344 (28)
a
Approximate values, read from a graphic.
b These releasers will be discussed in part 4.

one in about six formaldehyde allergic patients will
also react to 2-bromo-2-nitropropane-1,3-diol and
imidazolidinyl urea, one in five to DMDM hydan-
toin and diazolidinyl urea, and about two in five
to quaternium-15, which indeed (Tables 6, 7, and
10) releases most formaldehyde of all donors. The
relationship between strength of the reaction to
formaldehyde and patch test reactions to donors
was already clearly shown by de Groot et al., who
demonstrated that patients with stronger sensitivities
to formaldehyde (reacting to 0.1% and/or 0.3%) had
positive DMDM hydantoin patch test reactions to
test preparations with lower formaldehyde content
(Table 3) (22).
These findings are corroborated by the pattern of
co-reactivity between the various releasers (Tables 4
and 5). 2-Bromo-2-nitropropane-1,3-diol patch test
reactivity, for instance, is–as mentioned above–in
only 15% attributable to formaldehyde. Indeed,
co-reactivity to the other releasers was not even

Table 11. Permitted EU use levels for formaldehyde-releasers and levels of free formaldehyde demonstrated at these levels
Formaldehyde-releasers Permitted concentration (%) Product and concentration (%) Free formaldehyde (p.p.m.) Reference
Benzylhemiformal 0.15 Preservative solution: 0.1 300 (28)
2-Bromo-2-nitropropane-1,3-diol 0.1 Lotion: 0.08 30 (45)
Diazolidinyl urea 0.5 Non-protein shampoo: 0.4 452 (23)
Preservative solution: 0.5 840 (32)
Cosmetic cream: 0.3 730 (25)
DMDM hydantoin 0.6 Non-protein shampoo: 0.4 294 (23)
Preservative solution: 0.25 470 (32)
Imidazolidinyl urea 0.6 Oil-in-water emulsion: 0.3 300 (27)
Quaternium-15 0.2 Non-protein shampoo: 0.2 546 (23)
Contact Dermatitis 2010: 62: 18–31
in a single study in more than 14% of these
patients. The highest percentages of co-reactivity
were seen in quaternium-15, which is readily
explained by the fact that this releaser has the
highest formaldehyde content. In patients aller-
gic to imidazolidinyl urea and diazolidinyl urea,
many patients co-react to quaternium-15, for the
same reason. However, the highest degree of co-
reactivity is between diazolidinyl urea and imida-
zolidinyl urea (up to 75% in several studies). This
is not due to formaldehyde but to either cross-
reactivity or contact allergy to common ingredi-
ents in the test preparation such as compound HS
[(4-hydroxymethyl-2,5-dioxo-imidazolidin-4-yl)-
urea] or allantoin-formaldehyde condensation prod-
ucts (44, 49).
Should cosmetics containing
formaldehyde-releasers be avoided by patients
allergic to formaldehyde and/or the releasers?
When a patient reacts to formaldehyde and to, for
example, diazolidinyl urea, it would be common
sense to avoid cosmetic products containing diazo-
lidinyl urea, at least the stay-on varieties. The same
holds true for a patient reacting to the releaser itself
but not to formaldehyde: avoidance is logical. But
how to decide when a patient has a positive patch
test to formaldehyde but not to any of the releasers
or to one or two of the releasers (or when only
formaldehyde and quaternium-15 are tested in the
standard series)? Should the ‘non-reactive’ releasers
also be avoided (50) or may this be unneces-
sary (2)? Unfortunately, there are insufficient data
to give firm and decisive recommendations, only
tentative advice can be given. Whether or not a cos-
metic product preserved with a releaser will elicitate
an allergic reaction in patients sensitive to formalde-
hyde depends on: (i) the type of product; (ii) the
mode of usage (frequency and location of appli-
cation); (iii) the skin status; (iv) the strength of
the hypersensitivity to formaldehyde; and (v) the
amount of free and releasable formaldehyde in the
product.
Rinse-off products, in general, will have a low
risk of causing allergic contact dermatitis. The
daily use of stay-on products increases the risk
(compared with products that are used infrequently
or intermittently), especially when applied more
than once per day, when used on ‘sensitive’ skin
such as the eyelids, the face, the neck, or the
axillae, and when used on damaged skin, e.g. dry
(dermatitis) skin in atopic individuals.
It could be argued that, when there is a single
reaction to formaldehyde but not to any of the
releasers, the allergy to formaldehyde must be
FORMALDEHYDE-RELEASERS IN COSMETICS: PART 2 29
weak and poses little threat. However, formalde-
hyde being a ‘difficult’ allergen with risk of both
false-positive and false-negative reactions, such con-
clusions may not always be valid.
Although we do not know what level of formalde-
hyde in products is safe, levels >200 p.p.m.
probably are not (at least for some formalde-
hyde allergic subjects) (22, 48). The amount of
formaldehyde in cosmetic products will depend
on the releaser used for their preservation, its
concentration, the age of the product, the pH,
and other ingredients. Quaternium-15 releases the
largest amounts of formaldehyde, followed by
diazolidinyl urea, DMDM hydantoin, and imi-
dazolidinyl urea. 2-Bromo-2-nitropropane-1,3-diol
releases little formaldehyde (Tables 8 and 10). As
Table 11 has shown, all releasers (with the excep-
tion of 2-bromo-2-nitropropane-1,3-diol, for which
adequate data are lacking) can–in the right cir-
cumstances of concentration and product compo-
sition–release >200 p.p.m. formaldehyde, which
may result in a number of patients in allergic con-
tact dermatitis. Whether this is actually the case
in any particular product cannot be decided on the
basis of ingredient labelling. We thus recommend
to advise patients allergic to formaldehyde to avoid
stay-on cosmetics preserved with quaternium-15,
diazolidinyl urea, DMDM hydantoin, or imidazo-
lidinyl urea, especially when to be used regularly
and/or on ‘sensitive’ or damaged skin. When there
is no alternative, products containing 2-bromo-2-
nitropropane-1,3-diol may be tried. With products
that the patient already possesses, provocation tests
under normal usage conditions may demonstrate
whether they are safe (or not) in this particular
patient.
The dose–response phenomenon has sparsely
been investigated with regard to formaldehyde and
its releasers, and the clinical relevance of low
values of formaldehyde in consumer products and
cosmetics clearly needs further investigation.
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Contact Dermatitis 2010: 62: 18–31 FORMALDEHYDE-RELEASERS IN COSMETICS: PART 2 31

formaldehyde contact allergy. Contact allergy to formalde- Address:

hyde and inventory of formaldehyde-releasers. Contact Der- Anton de Groot
matitis 2009: 61: 63–85. Department of Dermatology
49. Lehmann S V, Hoeck U, Breinholdt J, Olsen C E, Kreil- University Medical Center Groningen
gaard B. Characterization and chemistry of imidazolidinyl University of Groningen
urea and diazolidinyl urea. Contact Dermatitis 2006: 54: PO Box 30.001
50–58. 9700 RB Groningen
50. Flyvholm M-A, Menné T. Allergic contact dermatitis from the Netherlands
formaldehyde. A case study focussing on sources of formalde- Tel: +31(0)521320332
hyde exposure. Contact Dermatitis 1992: 27: 27–36. e-mail: antondegroot@planet.nl