Formaldehyde-releasers in cosmetics: relationshipto 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
1Department of Dermatology, University Medical Center Groningen, University of Groningen,The Netherlands,
2Department of Cutaneous Allergy, St John’s Institute of Dermatology, St. Thomas’ Hospital, London, UK, and3National Research Centre for the Working Environment, Copenhagen, Denmark
This is the second part of an article on formaldehyde-releasers in cosmetics. The patch test relationshipbetween the releasers in cosmetics to formaldehyde contact allergy is reviewed and it is assessedwhether products preserved with formaldehyde-releasers may contain enough free formaldehyde to posea threat to individuals with contact allergy to formaldehyde. There is a clear relationship betweenpositive patch test reactions to formaldehyde-releasers and formaldehyde contact allergy: 15% ofall reactions to 2-bromo-2-nitropropane-1,3-diol and 40–60% of the reactions to the other releasersare caused by a reaction to the formaldehyde in the test material. There is only fragmented dataon 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 arelacking) 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 inany particular product cannot be determined from the ingredient labelling. Therefore, we recommendadvising patients allergic to formaldehyde to avoid leave-on cosmetics preserved with quaternium-15,diazolidinyl urea, DMDM hydantoin, or imidazolidinyl urea, acknowledging that many would toleratesome products.
In the first part of this article (1), key data onformaldehyde-releasers used in cosmetics (benzyl-hemiformal, 5-bromo-5-nitro-1,3-dioxane, 2-bromo-2-nitropropane-1,3-diol, diazolidinyl urea, DMDMhydantoin, imidazolidinyl urea, quaternium-15 andsodium hydroxymethylglycinate) were presented,including applications, frequency of sensitization,
relevance of patch test reactions, and their frequencyof use in cosmetics. In this second part, the patchtest relationship of these chemicals to formalde-hyde are reviewed and assessed whether productspreserved with formaldehyde-releasers may con-tain enough free formaldehyde to pose a threat toindividuals who are contact allergic to formaldehyde.
Contact Dermatitis 2010: 62: 18–31 FORMALDEHYDE-RELEASERS IN COSMETICS: PART 2 19
Relationship between Formaldehyde-Releasersand Contact Allergy to Formaldehyde
When patients are tested with formaldehyde andone or more formaldehyde-releasers, concomitantpositive reactions may be observed to formalde-hyde and (one or more) donors. It is often assumedthat 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 morethan one releaser reacts in formaldehyde-sensitivepatients, even when the preservatives are not struc-turally related (cross-reactions unlikely). In a recentstudy, for example, among 219 patients aller-gic to formaldehyde and/or formaldehyde-releasers(quaternium-15, diazolidinyl urea, imidazolidinylurea, 2-bromo-2-nitropropane-1,3-diol, DMDMhydantoin, and ethylene urea/melamine-formaldehy-de resin), 76 (35%) were positive to only one ofthese 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 thetested formaldehyde(releasing) materials (2). Of 59patients, patch test positive to quaternium-15 1%petrolatum (pet.), 31 (53%) were also allergic toformaldehyde (tested 2% aqua). However, of sevenpatients 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 454patients allergic to formaldehyde, 38 patients (8.4%)reacted to both formaldehyde and two releasersand 4 reacted to all three donors tested (2-bromo-2-nitropropane-1,3-diol, imidazolidinyl urea, andquaternium-15). Of these patients reacting to twoor three releasers (suggesting formaldehyde to bethe cause), quaternium-15 (which probably releasesthe 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 withthe formaldehyde-releasers urea formaldehyde (8%aqua), glyoxal urea (10% aqua), and quaternium-15(1% pet.). All six patients reacting to diazolidinylurea AND to formaldehyde also reacted to theother releasers, whereas of those patients not aller-gic to formaldehyde, NONE had a positive reactionto any of the formaldehyde-releasers. It was con-cluded that in the six patients allergic to diazolidinyland formaldehyde, the reactions to diazolidinyl ureawere probably caused by formaldehyde in the patchtest (5). Such studies, of which there are many,
indicate that at least in a number of patients co-reactions between formaldehyde and releasers aredue to formaldehyde sensitivity. On the other hand,the investigation of Perret and Happle also indi-cates that sensitivity to diazolidinyl urea can existindependent of formaldehyde release, as none of theseven patients allergic to diazolidinyl urea but notto formaldehyde reacted to any of other releasers.
The existence of allergy to the releaser 2-bromo-2-nitropropane-1,3-diol per se (independentof formaldehyde contact allergy) was demonstrated25 years ago by Storrs and Bell (6). These inves-tigators described seven patients reacting to patchtests with 2-bromo-2-nitropropane-1,3-diol 0.25%and/or 0.5% and/or 1% aqua or pet. They hadall been sensitized by Eucerin® cream, which waswidely used in their geographic area as an emollientfor dry and damaged skin, containing 0.05% 2-bromo-2-nitropropane-1,3-diol. The Eucerin® creamwas also patch test positive in all patients. None ofthem were allergic to formaldehyde and they did notreact to either quaternium-15 or imidazolidinyl urea.All patients performing a ROAT for a maximumof 2 weeks on normal skin with Eucerin® creamdeveloped dermatitis. This indicated that 2-bromo-2-nitropropane-1,3-diol allergy per se exists and that0.05% 2-bromo-2-nitropropane-1,3-diol in a creamis sufficient to give a positive patch test and apositive ROAT in 2-bromo-2-nitropropane-1,3-diolallergic patients who are not sensitive to formalde-hyde. In addition, the investigators had seen anotherfour patients reacting to 2-bromo-2-nitropropane-1,3-diol but NOT to Eucerin® cream. These patientsDID co-react to formaldehyde and to quaternium-15and/or imidazolidinyl urea. They concluded that theamount of formaldehyde in the cream containing0.05% 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 alsoallergic to formaldehyde?
In many studies, patients have been patch tested withformaldehyde and one or more releasers, especiallywith quaternium-15, which is included in the base-line series in both Europe and the USA. This givesan opportunity to study the possible relationshipbetween formaldehyde and the donors, at least inthis diagnostic setting. In Table 1, data are presentedon the frequency of co-reactions to formaldehyde inpatients allergic to formaldehyde-releasers.
There is a consistent picture for 2-bromo-2-nitropropane-1,3-diol. Less than 25% (and usuallyfar less) of 2-bromo-2-nitropropane-1,3-diol-sen-sitive patients co-react to formaldehyde. Thissuggests that most patch test reactions to 2-bromo-2-nitropropane-1,3-diol indicate sensitivity to this
20 DE GROOT ET AL. Contact Dermatitis 2010: 62: 18–31
Tabl
e1.
Perc
enta
ges
posi
tive
tofo
rmal
dehy
dein
pati
ents
reac
ting
tofo
rmal
dehy
de-r
elea
sers
a
2-B
rom
o-2-
nitr
o-pr
opan
e-1,
3-di
olD
iazo
lidi
nyl
urea
DM
DM
hyda
ntoi
nIm
idaz
olid
inyl
urea
Qua
tern
ium
-15
Ref
eren
ce
Cou
ntry
and
peri
odof
stud
yN
umbe
rof
patie
nts
%+
form
alde
hyde
Num
ber
ofpa
tient
s%
+fo
rmal
dehy
deN
umbe
rof
patie
nts
%+
form
alde
hyde
Num
ber
ofpa
tient
s%
+fo
rmal
dehy
deN
umbe
rof
patie
nts
%+
form
alde
hyde
Finl
and
2001
–20
0715
83%
(7)
UK
2004
–20
0587
17%
7855
%64
53%
129
59%
(8)
USA
1992
–20
0478
8b69
%b
515b
83%
b75
6b63
%b
(9)
Ger
man
y19
94–
2004
180
37%
(?)
(10)
IVD
K19
92–
1995
160
5%12
912
%85
15%
6447
%(1
1)A
ustr
ia19
92–
1993
432%
3611
%70
27%
(12)
UK
1982
–19
9389
25%
9125
%15
624
%29
955
%(1
3)U
SA19
89–
1991
5881
%(1
4)U
SA19
82–
1989
244
20%
8746
%18
165
%(1
5)T
heN
ethe
rlan
ds19
84–
1988
1346
%(5
)U
K19
8516
38%
(3)
UK
1983
–19
8459
53%
(3)
USA
1983
–19
8789
55%
(15)
USA
<19
8024
83%
(16)
a Onl
yst
udie
sw
ithat
leas
t10
posi
tive
reac
tions
toth
ere
leas
ers
are
incl
uded
.D
ata
on<
10pa
tien
tsar
epr
esen
ted
inR
efs
(2,
6,7,
17–
21).
bM
ean
num
bers
/per
cent
ages
intw
opa
tien
tgr
oups
reac
ting
toth
ere
leas
erin
wat
eran
dto
the
rele
aser
inpe
t.ve
hicl
e.
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
Number ofpatients allergicto formaldehyde
Percentage of patients allergic to formaldehyde with positive reactions to:
aOnly 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 hydantoinConcomitant allergy to DMDM hydantoin
Patients allergic to formaldehyde 3.0% (only) 1% (also) 0.3% (also) Negative1% only = 7 3 41% and 0.3% = 4 2 21% 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) Negative1% only = 12 1 111% and 0.3% = 4 1 1 21% 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 alsofairly consistent. In all but two studies, half thenumber of patients or more reacted to formalde-hyde, indicating that formaldehyde is in >50% ofthe cases responsible for the quaternium-15 patchtests. Less consistent are the figures for diazo-lidinyl urea (12–81% formaldehyde co-reactions),DMDM hydantoin (37–83%), and imidazolidinylurea (11–63% co-reactions to formaldehyde).
How often are patients reacting to formaldehydealso allergic to one or moreformaldehyde-releasers?
The reverse situation, i.e. what percentage ofpatients allergic to formaldehyde reacts to thereleasers, 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 areconsistent: less than 10% of patients allergic toformaldehyde react to 2-bromo-2-nitropropane-1,3-diol. On the other side of the spectrum, in all buttwo studies at least 30% of the patients reacting toformaldehyde also reacted to quaternium-15. Lesspatients (<30%) will react to diazolidinyl urea, andstill fewer (<23%) to imidazolidinyl urea. One study
showed that about one out of five formaldehyde-sensitive individuals was also patch test positive toDMDM hydantoin. The relationship between posi-tive patch tests to formaldehyde allergy and patchtest reactions to DMDM hydantoin was investigatedin detail by De Groot et al (22). Thirty-five patientsallergic to formaldehyde were patch tested withformaldehyde and dimethylhydantoin (DM hydan-toin; the parent compound). Twenty-one of theseformaldehyde-sensitive subjects were also testedwith MDM hydantoin (DM hydantoin +1 moleculeformaldehyde), the other 14 also with DMDMhydantoin (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 patientreacted to the parent compound DM hydantoin. Ofthe 14 patients in Group I, 8 (57%) reacted toDMDM hydantoin. Of the 21 patients in Group II, 7(33%) reacted to MDM hydantoin. In both groups,most negative reactions to (D)MDM hydantoin wereobserved in patients reacting only to the 1% solutionof formaldehyde. Patients with ‘stronger’ allergies toformaldehyde (reacting to 0.1% and/or 0.3% also)tended to show more positive reactions even to thelower 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
Number ofpatients allergicto formaldehyde
Percentage of patients allergic to releaser with positive reactions to:
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% solution0.02% (200 p.p.m.) free formaldehyde. Thus, 3 of14 patients reacted to 200 p.p.m. upon patch testing.This may be comfounded somewhat by the fact thatthe patients were also concurrently tested with thehigher concentrations and with formaldehyde (addi-tive effect). These data demonstrate that aqueouspreparations of DMDM hydantoin, in concentrationscomparable to those used in cosmetic products, con-tain enough free formaldehyde to cause dermatitis insome patients allergic to formaldehyde when patchtested (22).
How often are patients reacting to a formaldehydedonor also allergic to one or more otherformaldehyde-releasers?
In four large studies, the dynamics of patch test reac-tivity between the various formaldehyde-releaserswas 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 otherformaldehyde-releasers, formaldehyde plays a minorrole. There is in two of three studies a very highco-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 toquaternium-15, indicating a role for formaldehydebecause these chemicals are structurally unrelated.Conversely, however, of the patients reacting toquaternium-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 toformaldehyde, but the amount of formaldehyde inthe diazolidinyl urea and imidazolidinyl urea testsubstances is not enough to cause a positive patchtest reaction.
The recent experience of the British ContactDermatitis 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))
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 FORMALDEHYDE-RELEASERS IN COSMETICS: PART 2 23
may be read as follows: horizontal row, 52% ofpatients allergic to formaldehyde are also allergicto quaternium-15 and 23% are also allergic toimidazolidinyl urea. Conversely, vertical row, 59%of patients allergic to quaternium-15 are allergic toformaldehyde, and 53% of the patients allergic toimidazolidinyl urea (55% for diazolidinyl urea) arealso allergic to formaldehyde.
The associations between formaldehyde and thereleasers were highly significant (Kendall’s τ -b correlation score [P < 0.001]); this was alsothe case for the associations between the vari-ous releasers (8). As the chemical structures ofthese 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 becalled ‘pseudo-cross-reactions’ to formaldehyde).Indeed, the strongest association is seen betweenformaldehyde and quaternium-15, known to releasethe 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 toformaldehyde and the parent molecule may alsocontribute to these associations in a number ofcases (11, 24).
Experimental Provocation Tests with CosmeticsContaining Formaldehyde-Releasers in
Formaldehyde-Sensitive Subjects
Fifteen patients with contact allergy to formalde-hyde (n = 7) and/or the formaldehyde-releasersquaternium-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 negativeto diazolidinyl urea underwent a ROAT (twice dailyapplication to the antecubital fossa for 2 weeks)with a moisturizer preserved with 0.2% diazolidinylurea. In only one patient, the ROAT was clearlypositive. Afterwards, this patient was retested withdiazolidinyl 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 thatin patients allergic to formaldehyde and/or oneor more formaldehyde-releasers, complete avoid-ance of other formaldehyde-releasers to which thepatient is patch test negative is not always necessary,‘notably if the amount of formaldehyde released bythat compound is below the threshold of reactivityfor 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 bepositive in the absence of a positive reaction to the
ROAT on the arm (25), so false-negative reactionsmay have occurred.
Twelve patients allergic to formaldehyde per-formed a ROAT with a cream containing 1%DMDM hydantoin (twice daily for a week in theflexor aspect of the lower arm) and in four patients(33%), dermatitis was observed after 3–6 days.These four subsequently tested the same cream butnow containing 0.25% of the preservative (estimatedto 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: only1 week) (22). It was concluded that cosmetics pre-served with 0.25% DMDM hydantoin may pose athreat 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 allergicto formaldehyde. They developed a dose-escalatingdesign, including four diazolidinyl urea concen-trations, and exposure to three different anatomi-cal regions (upper arm, neck, and face) each of2-week duration. The test population consisted of30 patients allergic to formaldehyde, 10 patientsallergic to diazolidinyl urea (of which 7 had alsoreacted to formaldehyde) and 10 non-allergic con-trols. The four versions of the test cream werepreserved 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, 730and 1500 p.p.m. formaldehyde, respectively. Theywere applied twice daily for 2 weeks on a 5 × 5 cmarea of the flexor aspect of the upper arm (ROAT). Ifno 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 further2 weeks. If a positive reaction was observed at anytime before the end of the 6-week period, the patientwas 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 positivereaction. The cream preserved with 0.15% diazo-lidinyl urea elicited two reactions in 10 patients,0.3% induced seven positive reactions and theROAT 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 of370–1500 p.p.m., respectively), a dose dependentincrease in patients’ reactivity was seen, not onlyin the number of reactors but also in the strengthof the reaction. On the basis of this investigation,the amount of formaldehyde that does not elicit der-matitis in formaldehyde-sensitive subjects should bebetween 130 and 370 p.p.m.
24 DE GROOT ET AL. Contact Dermatitis 2010: 62: 18–31
Of the 10 patients allergic to diazolidinyl urea (7of which also reacted to formaldehyde), 9 had a pos-itive ROAT to the cream with 0.15% diazolidinylurea, 6 on the arm, and 3 in the neck (comparedwith 2 of 10 in patients reacting to formaldehydebut patch test negative to diazolidinyl urea) (25).There are several possible explanations for this:(i) Patients were not only allergic to formaldehydebut also to another compound in diazolidinyl urea(see also under chemical structure). The thresholdfor 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 diazolidinylurea) than those allergic to formaldehyde, for whomthe amount of formaldehyde in the diazolidinyl ureatest preparation was insufficient to elicit a positivereaction. (iii) In at least two patients with a posi-tive ROAT, formaldehyde was negative. This mayhave been false negative. But if they were trulynon-allergic, the allergy to the (other) compound indiazolidinyl urea that caused the reaction was strongenough to induce a positive ROAT. From thesedata, it may (tentatively) be concluded that levelsof 370 p.p.m. formaldehyde (0.03–0.04%) releasedby a formaldehyde-releaser may–under certain con-ditions of use–induce allergic contact dermatitison normal skin in a number of patients sensitiveto formaldehyde. Some patients may react to evenlower formaldehyde concentrations. When patientsreact to both formaldehyde and the releaser itself,the risk of developing allergic contact dermatitisincreases.
Isaksson et al. (26) have investigated whetherthe presence of 175 p.p.m. formaldehyde releasedfrom the preservative imidazolidinyl urea in a cor-ticosteroid cream influences (i.e. diminishes) thecream’s therapeutic efficiency in treating experimen-tally induced allergic contact dermatitis. In sevenpatients allergic to nickel and formaldehyde, patchesof 8 × 9 cm of allergic contact dermatitis were pro-voked on the outer part of both upper arms. Ina double-blind fashion, these were treated with acorticosteroid cream containing approximately 175p.p.m. formaldehyde and (the other arm) with a cor-ticosteroid cream of similar strength not containingformaldehyde. As controls served 17 patients aller-gic to nickel but not to formaldehyde. In two ofseven patients allergic to formaldehyde (29%), theeczema treated with the formaldehyde-containingcream healed completely within 4 weeks, comparedwith 12 of 17 (71%) in the control group; the dif-ference was statistically significant. There was nocorrelation between the formaldehyde reactivity, asmeasured by serial dilution testing, and the ten-dency to healing in the group allergic to formalde-hyde and treated with the formaldehyde-containing
corticosteroid cream. From this study, it may beconcluded that the presence of 175 p.p.m. formalde-hyde in a corticosteroid cream has a negative effecton the therapeutic efficacy of the corticosteroid onexperimentally induced allergic contact dermatitis inpatients allergic to formaldehyde and such creamsshould therefore not be used by formaldehyde aller-gic individuals (26).
Flyvholm et al. (27) saw a positive reaction toa stay-on cosmetic preserved with 0.3% imidazo-lidinyl urea (containing approximately 300 p.p.m.free formaldehyde) in a ROAT lasting 1 week inone of three patients allergic to both formaldehydeand imidazolidinyl urea. In 20 patients with allergyto formaldehyde but negative reactions to imida-zolidinyl urea, the ROAT produced some follicularpapules in 5 of 20. These were considered to be amild allergic reaction, as none of the controls sub-jects had any reaction at all (27).
The Amount of Formaldehyde Released byFormaldehyde-Releasers
There is only fragmented data available on theamounts of formaldehyde that will be released byformaldehyde donors. These amounts depend on thenature of the releaser, its concentration, the pH ofthe product, the temperature (the higher the temper-ature the more formaldehyde is present in solutionafter constant time) (28), the age of the product(upon storage increased levels of formaldehyde willbe released), the level of microbial contamination,and the other constituents of the products containingthe releaser (11, 28–30).
The pH may greatly influence the release offormaldehyde. 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 ina low pH (acidic) environment, but with increas-ing pH the amount of free formaldehyde alsoincreases (32, 33). The same holds true for DMDMhydantoin, whereas sodium hydroxymethylglycinatetends 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. atpH 3 (34).
Other ingredients, i.e. the nature and composi-tion of a product, may also influence the amount offree 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 releasedformaldehyde (23). In mascara preserved with 0.4%imidazolidinyl urea, the levels of formaldehyde were
Contact Dermatitis 2010: 62: 18–31 FORMALDEHYDE-RELEASERS IN COSMETICS: PART 2 25
<10 p.p.m., but in creams or milks containing0.3–0.5% the concentration of formaldehyde variedbetween 100 and 130 p.p.m. (28).
Several methods for determining formaldehydehave been used (28, 32–38) which make compar-isons difficult. None of the methods is absolutelyreliable or does always give reproducible results,which may in part account for (sometimes greatly)varying results. With some methods (including theofficial EU adopted method), the releasers deliver inthe presence of the reagent free formaldehyde con-tinuously during its determination, which may resultin too high and non-reproducible values (11, 28).Several tests are now available to overcome thisproblem (28, 32, 34, 36). It should be realizedthat free formaldehyde present in products preservedwith a formaldehyde-releaser may not only originatefrom the releaser itself but may also comprise excessformaldehyde used to synthesize the preservative,formaldehyde from other formaldehyde-based rawmaterials used to prepare the cosmetic product,formaldehyde used as a preservative for the rawmaterials 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 incosmetic products. It degrades rapidly in an aqueoussolution, and at pH 5 the maximum possible amountof 300 p.p.m. formaldehyde of an 0.1% benzylhemi-formal solution can be demonstrated (36). Emeiset al. (32) found that benzylhemiformal at 2% w/waqueous solution mixes spontaneously, with decom-position of 97% of the benzylhemiformal. Higherdilution leads to instantaneous, complete decompo-sition of the releaser into formaldehyde and benzylalcohol. At the maximum permissible concentrationof 0.15% benzylhemiformal in cosmetic rinse-offproducts, the concentration of free formaldehydeshould according to these authors be just under 0.05wt% (500 p.p.m.) (32).
2-Bromo-2-nitropropane-1,3-diol only releasesformaldehyde at higher pH values. Breakdown of 2-bromo-2-nitropropane-1,3-diol results in formationof formaldehyde and bromonitroethanol, a processwhich is accelerated by increased pH and/or tem-perature. The half life is more than 5 years at pH 4but drops to 2 months at pH 8 (40, 41).
Diazolidinyl urea is produced from 4 mol offormaldehyde and 1 mol of allantoin (compare:imidazolidinyl urea from 3 mol of formaldehydeand 2 mol of allantoin). From each molecule ofdiazolidinyl urea, four formaldehyde molecules canbe released (4 mol formaldehyde/mole diazolidinylurea). However, only about 50% of the theoreticalamount of formaldehyde in diazolidinyl urea can be
released upon complete hydrolysis (see diazolidinylurea, chemical structure (1)).
DMDM hydantoin is produced by reactingformaldehyde with DM hydantoin (5,5-dimethyl-hydantoin). The composition of DMDM hydantoinas determined by gas chromatography is as fol-lows: 94–98% DMDM hydantoin, 2.5–3% MDMhydantoin (monomethyloldimethylhydantoin), otherdimethylhydantoin formaldehyde products comprisethe balance. One mole of DMDM hydantoin canrelease a total of 2 mol of formaldehyde. The con-centrations of free formaldehyde depend on thepH; in alkaline environment more formaldehydeis released. DMDM hydantoin is said to contain0.5–2% free formaldehyde and concentrations incosmetics range from 0.1% to 0.6% (42, 43). Ithas been suggested that most formulations will,therefore, contain between 20 and 120 p.p.m. freeformaldehyde (31, 44). However, these estimatesmay be too low, as a cream preserved with 0.15wt% DMDM hydantoin contained 0.013 wt% (130p.p.m.) free formaldehyde (32).
Imidazolidinyl urea is prepared from 3 mol offormaldehyde and 2 mol of allantoin (compare: dia-zolidinyl urea from 4 mol of formaldehyde and1 mol of allantoin). From each molecule of imida-zolidinyl urea, two formaldehyde molecules can bereleased (2 mol formaldehyde/mole imidazolidinylurea) (44). Release is hastened by increased tem-perature and pH. Only about 75% of this theoreticalamount of formaldehyde in imidazolidinyl urea willbe released upon complete hydrolysis (44).
Sodium hydroxymethylglycinate. Emeis et al.investigated the release of formaldehyde fromsodium hydroxymethylglycinate with 13C NMRspectroscopy (32). At a concentration of 1% and apH of 5.5, sodium hydroxymethylglycinate decom-poses completely into formaldehyde and sodiumglycinate. In a basic environment, decomposition isincomplete. It is not until further dilution to 0.5%w/w–the maximum concentration allowed in cos-metic products–that it decomposes completely at apH of 8.5. The concentration of free formaldehydethen is 0.12% w/w (1200 p.p.m.) (32).
Rosen and McFarland (23) investigated proteinand non-protein shampoos with the preservativesDMDM hydantoin, imidazolidinyl urea, diazolidinylurea, and quaternium-15 added in concentrationsof 0.1%, 0.2%, 0.4%, and 0.8%, and determinedthe amounts of free formaldehyde in the sham-poos. In the first experiment, the shampoos wereheated to steambath temperatures. It was found thatDMDM hydantoin had released all its formalde-hyde (2 mol/mole DMDM hydantoin) after 15 min,quaternium-15 had released its total of 6 mol/moleafter 3 min and imidazolidinyl urea its 2 molafter 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)
aPercentage 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 atsteam bath temperatures.
In the second experiment, free formaldehyde wasdetermined in the protein and non-protein shampoosat 23◦C by a microdiffusion method. The resultsare shown in Tables 6 (non-protein shampoo) and 7(protein-containing shampoo).
As the concentration of each preservative isincreased in the shampoo, the amount of freeformaldehyde generated by hydrolysis increases.With increasing concentrations, the percentage of(theoretical) total formaldehyde released, however,decreases. The amount of free formaldehydereleased changes when protein is incorporated intothe shampoo, which is now depressed for all fourpreservatives when compared with the non-proteinshampoos. This indicates that free formaldehyde hasbeen 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 eachcontain two methylol groups while diazolidinyl ureahas four. The molar percentages of free formalde-hyde found for these three materials are about thesame over the concentration range studied. An aver-age of 1.3 mol of free formaldehyde per mole ofpreservative was found at 0.1%. This represents65% of the formaldehyde in DMDM hydantoin andimidazolidinyl urea, but only 33% for diazolidinylurea. This means that–under the condition of theinvestigation–only two of the four methylol groupsare formaldehyde donors. The relationship of freemolecular formaldehyde versus concentration for
quaternium-15 is analogous to DMDM hydantoinand imidazolidinyl urea, even though quaternium-15has six bound formaldehyde moieties. At 0.1% con-centration, four of the six formaldehyde moieties arereleased, 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). Theyused this method to determine the amount offormaldehyde in cream and lotion preserved withformaldehyde-releasers by adding formaldehyde-releasers in concentrations ranging from 200 to 2400μg/g (0.02–0.24%) to diluted Essex® cream andEssex® lotion. Diazolidinyl urea and imidazolidinylurea 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 formaldehydedonor and the amount of formaldehyde detectedwas found. The amounts (approximate, read froma graphic in the publication) results are shown inTable 8.
Using quantitative 13C NMR spectroscopy, theconcentration of free formaldehyde was determined,released from diazolidinyl urea and imidazolidinylurea compared with the maximum releasable con-centrations of formaldehyde as a function of dilutionand 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 maximumof 0.111% (1110 p.p.m.). Three of these productswere labelled with quaternium-15 and one withdiazolidinyl urea (46). In Switzerland, 19 of 34
Table 7. Formaldehyde recoveries from PROTEIN-CONTAINING shampoo containing various preservatives (23)
cosmetic products (56%) investigated for the pres-ence of formaldehyde using three analytical methodsincluding high-performance liquid chromatographywere found to contain free formaldehyde in amountsranging from 1 to 169 p.p.m.. Nine products con-tained more than 50 p.p.m.. In stay-on cosmetics, thehighest concentration proved to be 145 p.p.m. (35).
Other reports of free formaldehyde releasedfrom products containing formaldehyde-releasersare summarized in Table 10.
The maximum levels permitted in the EU andthe highest values of free formaldehyde foundfor these or lower concentrations are shown inTable 11. These data indicate that–with the excep-tion of 2-bromo-2-nitropropane-1,3-diol, for whichadequate data are lacking–in the right circum-stances the amount of free formaldehyde releasedby all donors may be sufficient to induce dermatitiswith regular use (48). Benzylhemiformal is per-mitted in rinse-off products only and may conse-quently pose less threat to formaldehyde-sensitivesubjects.
Discussion
Relationship between formaldehyde and releasersand between various releasers
There is ample evidence that patch test reactionsto the various releasers in patients co-reacting toformaldehyde may be caused by formaldehyde inthe patch test preparation. The mean percentages(adjusted for sample size) of patients allergic toa releaser that also react to formaldehyde in thevarious studies summarized in Table 1 were 15for 2-bromo-2-nitropropane-1,3-diol, 49 for imida-zolidinyl urea, 55 for quaternium-15, 57 for DMDMhydantoin, and 59 for diazolidinyl urea. It should
be noted that in the cases of diazolidinyl urea,DMDM hydantoin, and imidazolidinyl urea, thesepercentages are heavily influenced by one majorUSA study with by far the largest numbers ofallergic patients and high percentages co-reactingto formaldehyde (9). Nevertheless, these data doclearly 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 toformaldehyde 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-diolare seen in patients negative to formaldehyde, meansnot only that allergy to 2-bromo-2-nitropropane-1,3-diol per se (i.e. independent of formaldehyde) doesexist, but that this is the case in the great majorityfor this releaser. For the others, about half of thecases are contact allergies independent of formalde-hyde sensitivity. It should be appreciated that in anumber of these cases, the reaction to formaldehydemay have been false negative, which would makethe percentage reacting to formaldehyde in the testsubstance even greater.
Conversely, not all patients allergic to formalde-hyde react to one or more releasers, in fact it isa small minority (Table 2). The mean percentages(adjusted for sample size) of patients allergic toformaldehyde 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 diazolidinylurea, 19 for DMDM hydantoin, 14 for imidazo-lidinyl urea, and 40 for quaternium-15. Whether ornot a formaldehyde-sensitive individual will react toone or more releasers is dependent on the strength ofthe formaldehyde sensitization and on the amount offormaldehyde 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.
aApproximate values, read from a graphic.bThese releasers will be discussed in part 4.
one in about six formaldehyde allergic patients willalso react to 2-bromo-2-nitropropane-1,3-diol andimidazolidinyl urea, one in five to DMDM hydan-toin and diazolidinyl urea, and about two in fiveto quaternium-15, which indeed (Tables 6, 7, and10) releases most formaldehyde of all donors. Therelationship between strength of the reaction toformaldehyde and patch test reactions to donorswas already clearly shown by de Groot et al., whodemonstrated that patients with stronger sensitivities
to formaldehyde (reacting to 0.1% and/or 0.3%) hadpositive DMDM hydantoin patch test reactions totest preparations with lower formaldehyde content(Table 3) (22).
These findings are corroborated by the pattern ofco-reactivity between the various releasers (Tables 4and 5). 2-Bromo-2-nitropropane-1,3-diol patch testreactivity, for instance, is–as mentioned above–inonly 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
Contact Dermatitis 2010: 62: 18–31 FORMALDEHYDE-RELEASERS IN COSMETICS: PART 2 29
in a single study in more than 14% of thesepatients. The highest percentages of co-reactivitywere seen in quaternium-15, which is readilyexplained by the fact that this releaser has thehighest formaldehyde content. In patients aller-gic to imidazolidinyl urea and diazolidinyl urea,many patients co-react to quaternium-15, for thesame reason. However, the highest degree of co-reactivity is between diazolidinyl urea and imida-zolidinyl urea (up to 75% in several studies). Thisis 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 containingformaldehyde-releasers be avoided by patientsallergic to formaldehyde and/or the releasers?
When a patient reacts to formaldehyde and to, forexample, diazolidinyl urea, it would be commonsense to avoid cosmetic products containing diazo-lidinyl urea, at least the stay-on varieties. The sameholds true for a patient reacting to the releaser itselfbut not to formaldehyde: avoidance is logical. Buthow to decide when a patient has a positive patchtest to formaldehyde but not to any of the releasersor to one or two of the releasers (or when onlyformaldehyde and quaternium-15 are tested in thestandard series)? Should the ‘non-reactive’ releasersalso be avoided (50) or may this be unneces-sary (2)? Unfortunately, there are insufficient datato give firm and decisive recommendations, onlytentative advice can be given. Whether or not a cos-metic product preserved with a releaser will elicitatean allergic reaction in patients sensitive to formalde-hyde depends on: (i) the type of product; (ii) themode of usage (frequency and location of appli-cation); (iii) the skin status; (iv) the strength ofthe hypersensitivity to formaldehyde; and (v) theamount of free and releasable formaldehyde in theproduct.
Rinse-off products, in general, will have a lowrisk of causing allergic contact dermatitis. Thedaily use of stay-on products increases the risk(compared with products that are used infrequentlyor intermittently), especially when applied morethan once per day, when used on ‘sensitive’ skinsuch as the eyelids, the face, the neck, or theaxillae, and when used on damaged skin, e.g. dry(dermatitis) skin in atopic individuals.
It could be argued that, when there is a singlereaction to formaldehyde but not to any of thereleasers, the allergy to formaldehyde must be
weak and poses little threat. However, formalde-hyde being a ‘difficult’ allergen with risk of bothfalse-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 offormaldehyde in cosmetic products will dependon the releaser used for their preservation, itsconcentration, the age of the product, the pH,and other ingredients. Quaternium-15 releases thelargest amounts of formaldehyde, followed bydiazolidinyl urea, DMDM hydantoin, and imi-dazolidinyl urea. 2-Bromo-2-nitropropane-1,3-diolreleases little formaldehyde (Tables 8 and 10). AsTable 11 has shown, all releasers (with the excep-tion of 2-bromo-2-nitropropane-1,3-diol, for whichadequate data are lacking) can–in the right cir-cumstances of concentration and product compo-sition–release >200 p.p.m. formaldehyde, whichmay result in a number of patients in allergic con-tact dermatitis. Whether this is actually the casein any particular product cannot be decided on thebasis of ingredient labelling. We thus recommendto advise patients allergic to formaldehyde to avoidstay-on cosmetics preserved with quaternium-15,diazolidinyl urea, DMDM hydantoin, or imidazo-lidinyl urea, especially when to be used regularlyand/or on ‘sensitive’ or damaged skin. When thereis no alternative, products containing 2-bromo-2-nitropropane-1,3-diol may be tried. With productsthat the patient already possesses, provocation testsunder normal usage conditions may demonstratewhether they are safe (or not) in this particularpatient.
The dose–response phenomenon has sparselybeen investigated with regard to formaldehyde andits releasers, and the clinical relevance of lowvalues of formaldehyde in consumer products andcosmetics clearly needs further investigation.
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Address:Anton de GrootDepartment of DermatologyUniversity Medical Center GroningenUniversity of GroningenPO Box 30.0019700 RB Groningenthe NetherlandsTel: +31(0)521320332e-mail: [email protected]
