16000536, 2022, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cod.14089 by Cochrane Mexico, Wiley Online Library on [17/03/2023].

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Received: 9 November 2021 Revised: 22 February 2022 Accepted: 24 February 2022
DOI: 10.1111/cod.14089

REVIEW

Contact allergy to and allergic contact dermatitis from

formaldehyde and formaldehyde releasers: A clinical review
and update

An Goossens1 | Olivier Aerts2

1
Department of Dermatology, University
Hospitals KU Leuven, Leuven, Belgium
2
Department of Dermatology, University
Hospital Antwerp (UZA) and Research group
Immunology, INFLA-MED Centre of
Excellence, University of Antwerp, Antwerp,
Belgium
Correspondence
Professor Dr Olivier Aerts, Contact Allergy
Unit, Department of Dermatology, University
Hospital Antwerp (UZA), Drie Eikenstraat
655, B-2560 Antwerp, Belgium.
Email: olivier.aerts@uza.be
Abstract
This review aims to provide a clinically useful update regarding the role of formaldehyde
(FA) and its five main releasers (FRs) quaternium-15, diazolidinyl urea, DMDM
hydantoin, imidazolidinyl urea, and 2-bromo-2-nitropropane-1,3-diol (bronopol) in con-
tact allergy and allergic contact dermatitis. These ubiquitous preservatives are still often
present, and sometimes undeclared, in cosmetics, pharmaceuticals, medical devices,
household detergents, and chemical (industrial) products. In Europe, the use of free FA
and quaternium-15 in cosmetics is forbidden and contact allergy rates have been found
to be stable to decreasing. However, FA/FRs still readily provoke localized (eg, facial/
hand), airborne, and generalized dermatitis, and may also complicate atopic and stasis
dermatitis, or result in nummular dermatitis. Seborrheic-, rosacea- and impetigo-like der-
matitis have recently been reported. For a correct diagnosis, FA 2% aq. (0.60 mg/cm2)
should be used, and particularly the FRs bronopol 0.5% pet. and diazolidinyl urea 2%
pet. should be patch tested separately in a baseline series. If sensitization to FA occurs,
both FA and FRs should preferably be avoided, except perhaps for bronopol in case it
tests negatively. If a patient reacts to one or more FRs (such as bronopol or diazolidinyl/
imidazolidinyl urea), but not to FA, then the specific FR(s) should be avoided.

KEYWORDS
allergic contact dermatitis, bronopol, cosmetics, diazolidinyl urea, DMDM hydantoin,
formaldehyde, formaldehyde releasers, imidazolidinyl urea, preservatives, quaternium-15

1 | I N T RO DU CT I O N 2 | U S E S A N D EX P O S U RE

Formaldehyde (FA) and formaldehyde releasers (FRs) are still widely
present in our environment and continue to be important causes of
contact allergy and allergic contact dermatitis (ACD). An excellent
review on the subject has been published previously by de Groot and
1,2
co-workers in 2010, and the current article is a clinical update of a
more recent review.3 Herein we describe the use and exposure
sources of FA/FRs, their prevalence of sensitization, frequent and
less-common clinical pictures of ACD attributed to these preserva-
tives, their skin test conditions and coupled reactivity, as well as their
legal regulations in cosmetics.
FA is commonly present in food, cosmetics, pharmaceuticals, house-
hold detergents, and many other consumer products, as well as in
chemical (industrial) products (Table 1).
Although in Europe, contrary to the United States, the use of free
FA in cosmetics is nowadays forbidden, mainly due to its carcinogenic
properties, it can still be found as a hidden impurity in them (see
Section 8).
Moreover, FA can also occasionally be formed de novo from
auto-oxidation of ethoxylated alcohols in cosmetics and detergents.4-6
The potential presence of FA in medical devices such as facial masks

20 © 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd wileyonlinelibrary.com/journal/cod Contact Dermatitis. 2022;87:20–27.

GOOSSENS AND AERTS
TABLE 1 Formaldehyde (FA): Examples of common exposure
sourcesa
Foodstuffs (eg, coffee, caviar, smoked ham, cod)
Cosmetics
Pharmaceuticals (eg, corticosteroid creams, vaccines)
Household detergents
Textiles (eg, including nowadays rather low-formaldehyde containing
textile resins for permanent-press fabrics, leather goods, and re-
usable [even “hypoallergenic”] gloves)
Chemical (industrial) products (eg, metalworking fluids, glues and
adhesives, inks, paints, disinfectants in fumigations, and dairy
equipment)
Health care sector products (eg, embalming fluid [mostly as formalin,
an aqueous solution containing 37% w/v of FA], tissue fixative,
disinfection and sterilization agents for renal dialysis and root canal
treatments; medical devices [personal protective equipment,
including gloves, surgical masks, and protective clothing])
Energy sources (eg, the incomplete combustion of wood, tobacco,
coal, and gasoline)
Other: (electronic) cigarettes; tattoo inks; FA-based resins used in
paper sizing; plastics, coatings, (medium density) fiberboards,
contact cement, and neoprene
a
Nonexhaustive list, for more examples see Ref.1
has been highlighted,7-8 and a case of allergic contact dermatitis from
FA/FR due to their presence in polypropylene (“plastic”) surgical
masks was reported recently, although no confirmatory chemical ana-
9
lyses were performed in the latter case. In addition, other personal
protective equipment (PPE), such as clothing,10 to protect health care
workers from coronavirus disease 2019 (COVID-19) (see Ref.11 for a
review on the subject), and even tattoo inks, may contain FA.12
FRs constitute a group of
40, chemically different preserva-
tives/biocides, all containing a detachable FA moiety and introduced
to replace the more carcinogenic free FA. Indeed, in cosmetic, medi-
cal, household, as well as several industrial applications, FA has been
replaced by FRs, exerting the same broad-spectrum activity against
bacteria, notably gram-negative bacteria, such as Pseudomonas
aeruginosa, yeasts, and fungi. Certain releasers, that is, imidazolidinyl
urea and diazolidinyl urea have less antifungal activity and are, there-
fore, often combined with other preservatives. The five most relevant
FRs used in cosmetics (in declining order of their potential to release
FA) are: quaternium-15 (although in the EU forbidden since 2019, see
9. Legislation) > diazolidinyl urea > DMDM hydantoin > imidazolidinyl
urea > 2-bromo-2-nitropropane-1,3-diol (bronopol)13-15; other FRs
potentially present in cosmetics include 5-bromo-5-nitro-1,3-dioxane,
sodium hydroxymethylglycinate, and benzylhemiformal, the latter,
0
together with 3,3 -methylene-bis(5-methyloxazolidine), is also often
present in metalworking fluids (Bioban P-1487 and CS-1135 seem to
16
be no longer used).
The different FRs have applications similar to those of FA, but
their use in each domain varies. Quaternium-15 can, in contrast to the
European market, still be found as a preservative in US cosmetics.
Diazolidinyl urea and imidazolidinyl urea can also be frequently found
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21
in cosmetics, both in Europe and in the United States, and can be par-
ticularly present in topical corticosteroids,17 and only to a lesser
extent in occupational products.13,18 For example, a recent Canadian
survey showed that these two FRs as well as DMDM hydantoin may
be present in up to 7% of commercialized topical corticosteroid for-
mulations.19 The latter can also be found in herbicides and cutting oils,
and notwithstanding it is a common cosmetic preservative in the
United States, in Europe its use appears to be more limited, except
perhaps for hair care products. Bronopol has mostly FA-independent
sensitizing properties, and the potential formation of nitrosamines (ie,
carcinogens) make it a less-attractive preservative, although the addi-
tion of antioxidants (eg, tocopherol or BHT [butylated hydro-
xytoluene]) might reduce the latter.13,20 Nowadays, only a few
products contain this FR, although it has been recently identified,
together with FA, in a facial surgical mask.9
Given the widespread presence of free formaldehyde (FA) and
formaldehyde releasers (FRs) in many sectors (see Section 2), both
consumers and various professionals can get sensitized and become
affected by ACD from them.
3 | PREVALENCE OF SENSITIZATION
In Europe, the prevalence of contact allergy to FA and FRs has been
found to be stable to decreasing in recent years,15,21-23 that is,
between 1.5% and 2.5%, yet occasionally somewhat higher figures
were reported (eg,
4%),24 the latter attributed to a higher pick-up
rate by using the nowadays recommended FA 2% aq. test preparation
(see Section 5). In the United States, where cosmetic regulations are
less stringent and exposure to these chemicals is thus more pro-
nounced, contact allergy rates are overall still very high, that
is,
8%.25
Nevertheless, some US centers (albeit only patch testing FA 1%
aq.) have recently reported a relative decline in FA sensitization, possi-
bly attributed to the lower use of FA/FRs in the products of some
companies.26
Like adults, sensitization rates to FA and FRs are also higher
among US children (
3%) as compared to the EU (<1%).27 Formalde-
hyde is indeed a top allergen in the pediatric population,27 and both
FA and FRs can be found in personal care products for babies and
children, including disposable diapers, wipes, and topical (diaper)
preparations.28,29
Exposure to free FA may occur from its presence in chemical
(industrial) products, but also in US cosmetics, and, occasionally, in
cosmetics on the European market, where FA can be hidden as an
impurity (see Section 8). FA contact allergy may also be the result of
exposure to FRs that are widely used, not only in cosmetics, but also
in occupational products, such as metalworking fluids,16,30 cleaning
agents, and disinfectants. Occupations at risk for occupational ACD
from FA/FRs comprise, among others, metalworkers, health care
workers (eg, hemodialysis nurses, laboratory technicians, embalmers),
hairdressers and beauticians, painters, veterinary and dental students,
and laborers in the food-processing industry.3,24,30-33

22
In the United States, quaternium-15 is by far the most common
sensitizer among the FRs, with a reported sensitization rate of 7.7%,25
in general, and 3.6% in the pediatric population,13,34 as compared to
the other releasers, which have sensitization rates in the range of
1.5%–2%. In Europe, quaternium-15 sensitization rates are much
lower: between 0.7% and 1.7%.21,35,36
Although its counterpart imidazolidinyl urea is more widely used,
diazolidinyl urea is a more-potent sensitizer, accounting for higher
overall rates of sensitization, being more pronounced in the
United States (2%–4%) as compared to Europe (0.5%–1.5%).13,23,35-36
Because diazolidinyl urea is less frequently used in occupational prod-
ucts, data on its importance as an occupational allergen are lacking.
Sensitization rates to the widely used releaser imidazolidinyl urea
have ranged between 2% and 3% (up to 3.8% in hand dermatitis
patients) in the United States, and between 0.4 % and 1% in
Europe.13,30,35-36,37-38
Regarding DMDM hydantoin, in the United States and Europe,
sensitization rates of up to 4.7% and 0.4%,13,35,38 respectively, have
been reported, the latter reflecting its limited use in EU cosmetics.
Although used in occupational products, virtually no data on sensitiza-
tion from these products are currently available. As regards bronopol,
in the United States, ≥1.0% of patch-tested patients have been found
to be sensitized to this FR, albeit showing a decreasing trend, whereas
in Europe the sensitization rate is only
0.5%.13,23,35
4 | CLINICAL PICTURE
In addition to localized forms also widespread (nummular, patchy) der-
matitis, airborne dermatitis, and even erythroderma, due to FA and
FRs contact allergy, have been published (Table 2).3 Moreover, FA is a
commonly identified contact allergen in adults and children with
atopic dermatitis,39 and in subjects with hand dermatitis,40 nummular
(discoid) dermatitis,41 and stasis dermatitis.42 (Occupational) hand der-
3
matitis and sensitization to FA might signify a worse prognosis. With
regard to contact allergy and ACD from FA/FRs in cosmetics, mainly
middle-aged women are affected, who present primarily with facial
and/or hand dermatitis, elicited by leave-on and/or rinse-off cos-
metics containing these preservatives. Shampoos may contribute to a
head and neck dermatitis, whereas deodorants may provoke axillary
dermatitis, and, occasionally, more atypical localizations of ACD from
FA/FRs (eg, leg dermatitis related to bronopol sensitization) have been
13,24
reported. Several cases of airborne ACD from FA, often pre-
senting as severe facial edema, have been published due to its pres-
ence in hair-straightening products (“Brazilian keratin
treatments”),43-45 which may also lead to the release of FA into the
air, and thus provoke mucosal and respiratory symptoms in both cli-
ents and hairdressers (eg, rhinoconjunctivitis and/or asthma ). 46
Among many other contact allergens, FA has also been associated
with frontal fibrosing alopecia (FFA), especially due to its presence in
47
hair-straightening products.
FA-containing nail hardeners may result in peri-ungual dermatitis,
and even nail damage with onycholysis, sometimes mimicking
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GOOSSENS AND AERTS
T A B L E 2 Examples of clinical manifestations of contact allergy to
formaldehyde (FA) and releasers (FRs)
Localized allergic contact dermatitis
eg, (1) foot, leg, face and/or (occupational) hand dermatitis, sometimes
with a nummular (discoid) morphology; (2) “low-grade” facial
dermatitis,a ie, demonstrating only mild erythema and/or scaling,
resembling seborrheic dermatitis, impetigo and/or rosacea, mostly
from cosmetics; (3) head and neck dermatitis (from hair care
products); and (4) axillary dermatitis (from deodorants)
Aggravation of a preexisting dermatosis with predominantly clinical
signs of the underlying skin condition
eg, flares of atopic dermatitis, stasis dermatitis, and rosacea
eg, FA in hair-straightening products complicating frontal fibrosing
alopecia (FFA)
Airborne allergic contact dermatitis and related symptoms
eg, pronounced facial dermatitis or edema, mucosal and/or respiratory
symptoms (rhino-conjunctivitis and/or asthma)
Peri-ungual dermatitis
eg, nail damage and onycholysis, sometimes mimicking psoriasis (from
nail hardeners)
Peri-ulcer dermatitis
eg, from FA in medical devices such as self-adherent bandages and
wound dressings
Generalized allergic contact dermatitis
eg, nummular or patchy dermatitis, or presenting as erythroderma
Generalized and localized presentations of systemic allergic
dermatitis (SAD)
eg, from FA in vaccines, or aspartame (degraded to FA) in medication
and food.
Immediate-type allergy
eg, contact urticaria, asthma, or anaphylaxis from dental root
treatments or hemodialysis
a
The skin irritation potential of FA, imidazolidinyl urea, and DMDM
hydantoin may also provoke mild irritant facial dermatitis.
psoriasis.48 In this regard, it is also important to realize that FA can still
be present (>2 ppm) in nail polishes marketed as “FA-free”
(“nontoxic”).49
Facial cosmetics may sometimes also cause “low-grade” facial
dermatitis, showing only mild, but persistent, erythema and/or scaling,
sometimes resembling seborrheic dermatitis. In addition, impetigo and
rosacea(-like dermatitis) have been highlighted. The latter has been
reported as a predominant clinical feature of FA contact allergy,50-51
and some studies have shown that it is a primary culprit allergen in
patients with rosacea and co-existent facial ACD.52 The skin irritation
potential of FA, and FRs such as imidazolidinyl urea and particularly
DMDM hydantoin may also provoke mild (facial) erythema.53
FA-containing household detergents, including all-purpose
cleaners and dishwashing liquids, but also industrially used cleaning
agents, and even reusable gloves,54 even if the latter are labeled as
“hypoallergenic,”55 may all be relevant sources of (occupational) hand
dermatitis. Peculiar cases of hand dermatitis due to the presence of
FA in cigarettes have occasionally been published56; it is noteworthy
that FA can also be present in electronic cigarettes.57 Medical devices,
such as self-adherent bandages and wound dressings, may also con-
tain traces of FA, and provoke ACD in previously sensitized subjects

GOOSSENS AND AERTS
in a wound care context.58 Cyanoacrylate-containing surgical glues,
another frequently used medical device, also contain traces of FA as
an impurity, but patients with ACD due to these products are always
contact allergic to the cyanoacrylate component, and never to the FA
residue.59
A few peculiar cases of generalized systemic allergic dermatitis
60
(SAD) have been attributed to the presence of FA in vaccines, and
both generalized and localized cases of SAD (eg, eyelid dermatitis)
have been attributed to the oral intake of aspartame (which is
degraded to FA) due to its presence in medication and food.61-63
Finally, not only delayed but also immediate-type allergy, that is, con-
64
tact urticaria, asthma, and even anaphylaxis may occur, for example,
due to dental root treatments (eg, see Refs.65-70), or in the context of
hemodialysis patients (eg, see Ref.71).
5 | PATCH AND PRICK TESTING
The patch-test concentrations of aqueous solutions of FA have been
debated frequently in the past,3 but 2% aq. (0.60 mg/cm2) is now rec-
ommended for the baseline series instead of 1.0% aq. (0.30 mg/cm2),
since the former detects significantly more contact allergy.72
In a recent Swedish study, the number of positive reactions to FA
increased significantly following the use of the 2.0% test concentra-
tion instead of the 1.0%, that is, almost doubled from a mean of 2.2%
(2010–2013) to a mean of 4.1% (2014–2017).73
Hence, in the past, clinically relevant patch-test reactions have
been potentially missed and contributed to the lower sensitization
rates observed. This may also depend on the patch-test system used,
as was shown recently in a study74 comparing the use of a 2%
aq. solution in Finn chambers, resulting in 4.57% positive reactions,
with the TRUE Test system, for which only a positivity rate of 1.14%
in the patients tested was observed (all reacting to the 2% aq.). The
TRUE Test system was thus shown to have a 100% specificity, yet
only a 33% sensitivity to detect FA sensitization. According to another
recent study,75 comparing two patch-test systems and different
patch-test concentrations of FA, that is, 0.32 mg/cm2 in the Finn
Chamber Aqua (chambers mounted on a moisture-resistant adhesive
2
patch with pre-mounted filter papers), vs 0.60 mg/cm in the regular
Finn Chambers, no significant differences regarding the detection of
positive reactions could be observed. This was attributed to a better
occlusion by the former, but which also elicited significantly more irri-
tant reactions, justifying further research on optimization of the dose.
23
Of interest, according to a recent Spanish study, in which the use of
Finn chambers was compared to the TRUE Test system for testing
FRs (although not in the same population), the latter produced more
often positive reactions to them than the Finn chambers, particularly
to bronopol (although only tested in a 0.25% concentration in pet.)
and less so to quaternium-15 and imidazolidinyl urea, whereas the
test results to diazolidinyl urea were quite comparable in both
systems.
Although it has been demonstrated36 that stronger patch-test
reactions to FA were associated with positive reactions to FRs,
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23
favoring its important causative role in them, according also to a more
recent article, even its 2% aq. test concentration cannot be considered
an adequate screen to pick up contact allergy to all FRs35 (see also
Section 6). Hence, the addition of some of the FRs was proposed for
inclusion in the European baseline series,23,76-77 and recently this has
been recommended for bronopol 0.5% pet. and diazolidinyl urea 2%
pet., both crossing the 0.5% threshold. Meanwhile, quaternium-15 1%
pet. could be omitted from the baseline series because reactions to it
are often associated with FA (see Section 6), and it could be moved,
together with imidazolidinyl urea 2% pet. and DMDM hydantoin 2%
pet., to more specialized series.78 As regards the workup of
immediate-type hypersensitivity from FA, a specific IgE is available
(eg, ImmunoCAP allergen k80 formaldehyde/formalin, from Thermo
Fisher Scientific, Waltham, MA), and skin prick tests can be performed
using FA 1% and 0.1% aq.71
6 | C O U P LE D R E A C T I V I T Y BE T W EE N
FO R M A LD E H Y D E A N D I T S RE L E A S E R S
The degree of co-reactivity with FA varies substantially between the
FRs, from virtually nonexistent in the case of bronopol 0.5%
pet.23,35-36 to a weaker concordance observed for the other FRs.
According to the results of a recent large multicenter study from the
ESSCA network, regarding 15 067 subjects tested to both FA and
FRs,35 those not reacting simultaneously were in descending order:
bronopol (96.3%) > DMDM hydantoin (83.3%) > imidazolidinyl urea
(67.4%) > diazolidinyl urea (64%) > quaternium-15 (46.8%), which is
related to their FA-releasing capacity (see Section 2).
Whether patients sensitized to FA should avoid using products
containing FRs has been often discussed in the literature.2,3 Formalde-
hyde has an important causative role in positive reactions to FRs,
except for bronopol,36 and it was shown that exposure to low levels
of free FA, within the range of 2.5–40 ppm, as measured by the chro-
motropic acid (CA) method (which can detect as little as 2.5 ppm of
free FA), may worsen dermatitis in FA-sensitized subjects; therefore,
this argues for avoidance of all FRs in such patients.79 Even bronopol-
containing cutting fluids that have an elevated pH may contain
enough free FA to elicit dermatitis in patients who are allergic to this
biocide.13
Sensitization to FRs may be independent from FA though and caused
by breakdown products that show reactivity toward amino acids, as
shown for bronopol.80 This compound releases small amounts of FA at
physiological conditions but produces multiple degradation products,
among which 2-bromoethanol and bromonitromethane are potential aller-
genic culprits.81 The concomitant reactions observed between diazolidinyl
urea and/or imidazolidinyl urea have been explained by reactivity toward
common degradation products, that is, 4-hydroxymethyl-2,5-dioxo-
imidazolidin-4-yl (HU) and 3,4-hydroxymethyl-2,5-dioxo-imidazolidin-4-yl
(3,4-BHU).82-83 Furthermore, also methenamine (hexamethylenetetra-
mine), a compound with pharmaceutical, chemical, and industrial
applications, was found to degrade to the reactive compound
diaminomethane.80 DMDM hydantoin was shown to be reactive toward

24
amino acids per se,80 although co-reactions were observed in patients
who were strongly allergic to FA, in particular.79
7 | ADVICE TO PATIENTS SENSITIZED TO
F O R M A L D E HY D E A N D/ O R T H E R E LE A S E R S
Notwithstanding that some patients who are sensitized to FA may still
tolerate products containing FRs, if sensitization to FA occurs, both
FA and FRs should preferably be avoided,79 except perhaps for
bronopol in case it tests negatively. If a patient is sensitized to a
releaser, such as bronopol, and imidazolidinyl urea or diazolidinyl urea,
or to both (in view of common degradation compounds), and not to
FA, then contact allergy was most likely induced by the releaser itself;
consequently, only this specific releaser should then be avoided.
8 | U N D E C L A R E D F O RM A LD E H Y DE I N
C O S M E T I CS A N D O T H E R CO N S U M E R
PRODUCTS
According to the EU Cosmetics Regulation, if the concentration of
free FA is above 0.05%, a cosmetic product must be labeled with
“contains formaldehyde.“ A particular problem, besides mislabeling, is
the undeclared presence of free FA in cosmetics,79,84-86 sometimes
even in high concentrations,87 the release of which is, among others,
dependent on the type of FR (if present), and also pH, time and tem-
perature, as well as the matrix (and thus type of cosmetic product)
with water-containing products potentially releasing more FA.85 FA
formation might be due to the release from FRs or other chemicals in
the formulation, such as emulsifiers and surfactants, as well as from
materials used in packaging (melamine or urea-formaldehyde resins).79
Not only cosmetics but also other consumer products are involved,
such as household products, and even personal protective equipment
(or PPE) for health care workers, including medical devices such as facial
masks,9,11 gloves,54 and other types of PPE.11 This necessitates chemi-
cal analyses of products to provide associations between causal prod-
ucts and outbreaks of ACD in FA-sensitive patients. Several analytical
methods have been used to assess free and total releasable FA within
products, among which the acetylacetone and chromotrophic acid
(CA) semi-quantitative colorimetric methods; however, both were
found to be subject to false-positive findings from potential nonspecific
79
discoloration by other aldehydes, oils, or polysorbates. Recently, the
utility of chemical-based spot test kits for identification of potential FA
exposure from personal care products has been put forward.86
9 | L E G I S LA T I O N
In Europe, a stringent yet dynamic Cosmetics Regulation exists (EC N
1223/2009, Annexes II–VI), detailing authorized, restricted, and
banned chemicals for use in cosmetics. FA and the FR quaternium-15
have, in 2019, been deleted from the list of preservatives allowed in
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GOOSSENS AND AERTS
cosmetic products in Annex V and have been added to the list of sub-
stances prohibited in cosmetic products in Annex II.88 Regarding the
other FRs, the maximum allowed concentrations for diazolidinyl urea,
DMDM hydantoin, imidazolidinyl urea, and bronopol are 0.5, 0.6, 0.6,
and 0.1, respectively. As stated above, the label must state “contains
formaldehyde” if the level of free FA exceeds (the still high level of)
0.05% (500 ppm), but the Scientific Committee on Consumer Safety
(SCCS/1632/21) considered that this threshold does not sufficiently
protect consumers who are sensitized to free FA from FRs, and that it
should be further reduced by a factor of 50, that is, to 0.001%
(10 ppm).89 Indeed, many FA-sensitized patients react to much lower
concentrations (eg, 30 ppm).79
In the United States, the Cosmetic Ingredient Review panel (CIR)
concluded that FA is safe for use in cosmetics when formulated to
ensure use at the minimal effective concentration, but in no case
should the formalin concentration exceed 0.2% (w/w), which would
be 0.074% (w/w) calculated as FA. In addition, FA is still considered
safe in the present practices of use and concentration in nail-
hardening products on the US market, but it is unsafe in the present
practices of use and concentration in hair-smoothing (hair-straighten-
ing) products .90
10 | C O N CL U S I O N S
Both consumers and various professionals can get sensitized and
become affected by ACD from FA and FR. In Europe, the prevalence
of contact allergy has been found to be stable to decreasing in recent
years, whereas in the United States, where cosmetic regulations are
less stringent and exposure to these chemicals thus more pronounced,
contact allergy rates are still high. In Europe, because of carcinogenic
properties, free FA and more recently the FR quaternium-15 have
been prohibited in cosmetics, in contrast to other FRs, that is, dia-
zolidinyl urea and imidazolidinyl urea, DMDM hydantoin, and
bronopol. The use of a 2% aq. patch-test concentration in the baseline
series instead of 1.0% aq. detects significantly more contact allergy.
However, it cannot be considered an adequate screen to pick up con-
tact allergy to FRs, because the release of FA from them varies con-
siderably from one compound to another, quaternium-15 releasing
the most and bronopol the least FA, which renders the latter less
likely to elicit a reaction in FA-sensitized subjects. Moreover, sensiti-
zation to FR may also be caused by breakdown products, hence the
need to test the latter separately. However, if sensitization to FA
occurs, it may also be wise to avoid the releasers.
FA is not always declared on the product labels, and it has been
identified as a hidden compound in many cosmetic products, and
occasionally also in other consumer products. This underscores the
importance of chemical analyses of products and the utility of (chemi-
cal-based) spot test kits for identification of potential FA exposure. In
agreement with the literature,87 good manufacturing practices (GMPs)
by the producing companies and regulatory control to improve the
regulation and inspection of cosmetics containing FRs as preserva-
tives are highly recommended.

GOOSSENS AND AERTS
CONF LICT OF IN TE RE ST
OA is investigator, consultant, and/or speaker for Leo Pharma and
L'Oréal/La Roche Posay.
AUTHOR CONTRIBUTIONS
An Emilie Goossens: Conceptualization (equal); data curation (equal);
formal analysis (equal); writing – original draft (equal); writing – review
and editing (equal). Olivier Aerts: Conceptualization (equal); data
curation (equal); formal analysis (equal); writing – original draft (equal);
writing – review and editing (equal).
DATA AVAI LAB ILITY S TATEMENT
Data available on request.
ORCID
An Goossens https://orcid.org/0000-0002-9805-3439
Olivier Aerts https://orcid.org/0000-0002-0076-2887
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How to cite this article: Goossens A, Aerts O. Contact allergy
to and allergic contact dermatitis from formaldehyde and
formaldehyde releasers: A clinical review and update. Contact
Dermatitis. 2022;87(1):20-27. doi:10.1111/cod.14089