University of Groningen Formaldehyde-releasers de Groot, Anton C.

24 Pages·2009·0.7 MB·English

University of Groningen

Formaldehyde-releasers
de Groot, Anton C.; Flyvholm, Mari-ann; Lensen, Gerda; Menne, Torkil; Coenraads, Pieter-
Jan
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CONTACT DERMATITIS
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de Groot, A. C., Flyvholm, M., Lensen, G., Menne, T., & Coenraads, P-J. (2009). Formaldehyde-releasers:
relationship to formaldehyde contact allergy. Contact allergy to formaldehyde and inventory of
formaldehyde-releasers. CONTACT DERMATITIS, 61(2), 63-85.
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ContactDermatitis2009:61:63–85 ©2009JohnWiley&SonsA/S
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CONTACTDERMATITIS
Review Article
Formaldehyde-releasers: relationship
to formaldehyde contact allergy. Contact allergy
to formaldehyde and inventory
of formaldehyde-releasers
AntonC deGroot1, Mari-ann Flyvholm2, Gerda Lensen1, Torkil Menne´3 AND Pieter-Jan Coenraads1
1Department of Dermatology, University Medical Center Groningen, University of Groningen,
9700 RB Groningen, The Netherlands,
2National Research Centre for the Working Environment, Lerso Parkalle´ 105, DK-2100 Copenhagen, and
3Gentofte Hospital, Dermato-Allergology Department K, Niels Andersens Vej 65, 2900 Hellerup, Denmark
Thisisoneofseriesofreviewarticlesonformaldehydeandformaldehyde-releasers(others:formaldehyde
in cosmetics, in clothes and in metalworking fluids and miscellaneous). Thirty-five chemicals were
identified as being formaldehyde-releasers. Although a further seven are listed in the literature
as formaldehyde-releasers, data are inadequate to consider them as such beyond doubt. Several
(nomenclature) mistakes and outdated information are discussed. Formaldehyde and formaldehyde
allergy are reviewed: applications, exposure scenarios, legislation, patch testing problems, frequency
of sensitization, relevance of positive patch test reactions, clinical pattern of allergic contact dermatitis
from formaldehyde, prognosis, threshold for elicitation of allergic contact dermatitis, analytical tests
to determine formaldehyde in products and frequency of exposure to formaldehyde and releasers. The
frequency of contact allergy to formaldehyde is consistently higher in the USA (8–9%) than in Europe
(2–3%). Patch testing with formaldehyde is problematic; the currently used 1% solution may result in
both false-positive and false-negative (up to 40%) reactions. Determining the relevance of patch test
reactionsisoftenchallenging.Whatconcentrationofformaldehydeissafeforsensitivepatientsremains
unknown.Levelsof200–300p.p.m.freeformaldehydeincosmeticproductshavebeenshowntoinduce
dermatitis from short-term use on normal skin.
Key words: contact allergy; formaldehyde; formaldehyde releaser; patch testing; review article;
threshold. © John Wiley & Sons A/S, 2009.
Acceptedforpublication1April2009
Formaldehydeisacommoncauseofcontactallergy. under usageconditions, theso-calledformaldehyde-
In Europe, 2–3% of patients suspected of con- releasers (or formaldehyde donors). Well-known
tact dermatitis have positive patch test reactions, examples are quaternium-15, imidazolidinyl urea,
and in the USA prevalence rates of sensitization of diazolidinyl urea, DMDM hydantoin and 2-bromo-
8–9%arereportedinthisselectedgroupofpatients.
2-nitropropane-1,3-diol, preservatives frequently
Allergic contact dermatitis caused by formalde-
used in cosmetic products. Industrial products such
hyde is often chronic, presumably because it is
as metalworking fluids frequently contain formalde-
difficult to avoid exposure to the allergen com- ®
hyde donors, such as the Bioban product range
pletely. Indeed, formaldehyde may be found in
of biocides and tris(N-hydroxyethyl) hexahydrotri-
many cosmetics, toiletries, household products such
®
azine(betterknownbyitstradenameGrotan BK).
as washing and cleaning agents and in a great num-
ber of industrial applications including adhesives, Other products containing and releasing formalde-
paints, lacquers and metalworking fluids. Often, hyde are the formaldehyde resins including urea
the products are not preserved with formaldehyde formaldehyde and melamine formaldehyde resins.
itself, but with agents that release formaldehyde These were formerly used extensively as textile
64 DEGROOTETAL. ContactDermatitis2009:61:63–85
Table1. Dataintheliteratureaboutformaldehyde-releasersthatappeartobewrongoroutdated(1–8)
Presentedasformaldehydereleaser
(chemicalnameand/ortradename) Comments
® ®
Bakzid P(mixtureofcyclicamino-acetalsandorganicaminesalts) ThetradenameBakzid Pisprobablynotusedcurrently.
®
However,someBakzid productscontaintheformaldehyde
releasertris(N-hydroxyethyl)hexahydrotriazine
(triazinetriethanol)
Biocide®DS5249(1,2-benzisothiazolin-3-one+aformaldehyde Tradenamecurrentlynotused
releaser)
DantoinMDMH(methylaldimethoxy-methanformal) Neithernamecanbeidentified
® ®
Forcide 78(mixtureoftriethylhexahydros-triazineand Forcide 78isthecurrenttradenamefor
trihydroxyethylhexahydros-triazine) 2-hydroxymethylaminoethanol-tri-N-ethylhydroxy-2-
aminomethylene
Glutaraldehyde Glutaraldehydeoccasionallycross-reactswithformaldehyde,but
intheliteratureitisnotfoundtobeaformaldehydereleaser
® ®
Grotan HD(N-methylol-chloracetamide) Grotan HDisacurrenttradenamefortris(N-hydroxyethyl)
hexahydrotriazine(triazinetriethanol)
Hexamidine Hexamidineintheliteratureisnotafoundtobeaformaldehyde
releaser
® ®
Imidazolidinylurea(Euxyl K200) TradenameEuxyl K200isprobablycurrentlynotused
KM103 Thisnameisprobablycurrentlynotinuse.Thereare,however,
variouschemicalsnamedKMfollowedbyanumber,ofwhich
KM200(alcohol)containstheformaldehydereleaser
tris(N-hydroxyethyl)hexahydrotriazine(triazinetriethanol)
® ® ®
MDMhydantoin(Dantoin ,Dantoin 685) Dantoin isusedassynonymfor
1,3-dichloro-5,5-dimethylhydantoinandforphenytoinsodium.
®
ThetradenameDantoin 685isprobablycurrentlynotused
® ®
Parmetol lK50(N-methylol-chloracetamid,O-formalofbenzyl ThenameParmetol K50wasonlyfoundasbeingaregistered
alcohol) tradenameinCanadaforamixtureof13%chloroacetamide
and7.3%paraformaldehyde(underthecompanyGray
Products)
®
Preventol D1(1-(3-chloroallyl)-3,5, Chemicalnameisincorrect,benzylformalmustbedeleted.The
®
7-triaza-1-azoniaadamantanechloridebenzylformal) tradenamePreventol D1isprobablycurrentlynotinuse
® ®
Preventol D2(benzylhemiformal) Preventol D2isinchemicaldatabasesusedasatradenamefor
1,1’-(methylenebis(oxymethylene))bis-benzene,butalsoused
forbenzylhemiformal
® ®
Preventol D3(chlormethylacylaminomethanol) ThetradenamePreventol D3isprobablycurrentlynotinuse.
Chemicalnamechlormethylacylaminomethanolcannotbe
identifiedinchemicaldatabases
® ®
Preventol D3/D5(N-methylol-chloracetamide) ThetradenamesPreventol D3andD5areprobablycurrently
notinuse
finishes and caused dermatitis from clothing in often lacking (9–11). Whether it is really necessary
formaldehyde-sensitive individuals dueto their high to avoid all formaldehyde-releasing preservatives
content of free formaldehyde. The finishes used in patients allergic to formaldehyde is largely
currently by the clothing manufacturers release far unknown. Indeed, only with a few compounds
less free formaldehyde, but are even today reported such as diazolidinyl urea (12) and imidazolidinyl
as causes of clothing allergic contact dermatitis. urea (13),haveexperimental usetestexposure stud-
Lists of formaldehyde-releasers have been pub- ies have been performed in patients allergic to
lished in articles and recent textbooks (1–8). Such formaldehyde. Some authors have suggested that
lists are commonly handed out to patients allergic for formaldehyde-sensitive patients, it is sufficient
to formaldehyde with the instruction to avoid con- to avoid only those formaldehyde-releasers that, in
tact with these chemicals and products containing addition to formaldehyde, also elicited a positive
them. However, for most formaldehyde-releasers, patch test reaction (14). Others, however, think that
the current understanding of their relationship to it is prudent for formaldehyde-sensitive subjects to
formaldehyde allergy appears to be limited and recommend avoidance of products containing any
mainly based on patch test studies. Thus, it is releaser (15–17).
often assumed that concomitant positive patch test The purpose of this study is to review the liter-
reactions to formaldehyde and a releaser or to ature on the formaldehyde-releasers and their rela-
two or more releasers are caused by allergy to tionship to formaldehyde sensitivity with emphasis
formaldehyde, though definite proof of this is on (i) frequency of sensitization, (ii) patch test
ContactDermatitis2009:61:63–85 FORMALDEHYDEANDFORMALDEHYDE-RELEASERS 65
egert(6), 1200-87-4) 1854-23-5
Fr d.5 d.
5),Dahlquistand CASnumber 14548-60-8 81099-36-7(ingre75673-43-7and 7747-35-5 37304-88-4(ingreand2224-44-4) 52-51-7 78491-02-8 68411-81-4 3923-79-3 26811-08-5 1854-26-8 136-84-5
(
n
e
s
der 2; e
ndAn ®olD ®BP; ®II;Biopur ®LE;
Fiedler(4),Flyvholma bCurrenttradenames ®AkyposeptB[PreventSeethere] ®BiobanCS1135 ®BiobanCS-1246;®ChemtanA60;®Oxazolidine-E;®ZoldineZE; ®BiobanP-1487 ®Bronopol;Chemynol®MyacidePharmaBP;®Onyxide500 ®AbiolForte;Germall®LiposerveDU;Nipa®200 ®Fixapret(various);®FreerezPKF;Knittex®Permafresh(various);®Sumitex(various) ®FixapretNF ®Fixapret(various);®Permafresh(various) ®FixapretAH
3),
(
Andersenetal.(1),Timmer(2),Flyvholm Othersynonyms asformaldehyde-releasersbeyonddoubt (Benzyloxy)methanol 7-Ethylbicyclo-oxazolidine Mixtureofnitrobutylmorpholineandethylnitrotrimethylenedimorpholine Bromonitropropanediol;Bronopol N,N’-bis(hydroxymethyl)urea Dimethylolglyoxalurea,methylated Formaldehyde,polymerwith5,5-dimethyl-2,4-imidazolidinedione;DMHF 1,3-Bis(hydroxymethyl)-4,5-dihydroxy-2-imidazolidinone
m
m e
aedformaldehyde-releasers(adaptedfro IUPACname clinicaldataareavailabletoidentifyth Phenylmethoxymethanol 4,4-Dimethyloxazolidine;3,4,4-trimethyloxazolidine 5-Ethyl-3,7-dioxa-1-azabicyclo[3.3.0]octane 4-[2-(Morpholin-4-ylmethyl)-2-nitro-butyl]morpholine;4-(2-nitrobutyl)morpholine Asincolumn1 1-[1,3-bis(hydroxymethyl)-2,5-dioxo-imidazolidin-4-yl]-1,3-bis(hydroxymethyl)urea 4,5-Dihydroxy-1,3-bis(hydroxymethyl)-imidazolidin-2-one,methylated 4,5-Dihydroxy-1,3-dimethylimidazo-lidin-2-one 5,5-Dimethylimidazolidine-2,4-dione,formaldehyde 4,5-Dihydroxy-1,3-bis(hydroxymethyl)-imidazolidin-2-one 1,3-Bis(hydroxymethyl)imidazolidin-2-one
Table2.FormaldehydeandreportGeier(7)andGeieretal.(8)) Commonlyusedname (A)Chemicalsforwhichadequate Benzylhemiformal(INCI) ®BiobanCS1135 ®BiobanCS1246 ®BiobanP-1487 2-Bromo-2-nitropropane-1,3-diol(INCI) Diazolidinylurea(INCI) Dihydroxydimethylolethyleneurea,methylated 1,3-Dimethyl-4,5-dihydroxyethyleneurea Dimethylhydantoinformaldehyderesin Dimethyloldihydroxyethyleneurea Dimethylolethyleneurea
66 DEGROOTETAL. ContactDermatitis2009:61:63–85
ber 1 (b) 9
CASnum 3270-74-4 140-95-4 6440-58-0 120-93-4 77044-78- 7779-27-3 50-00-0 3720-97-6 39236-46-
®;
bCurrenttradenames ®®FixapretPH;KnittexPRS ®®KauritS;Methural;®Permafresh477;®Urofix ®®CoseptDM;Dekafald;®Glydant(2000,XL-1000);®LanodantDM;MackstatDM®MicrocareDH ®dForcide78 ®(b)Vancide-TH;®dForcide78 ®®Germall115;LiposerveIU;®NipaBiopure100;Protacide®®U-13;UnicideU-13
ed
Othersynonyms DMPU;Tetrahydro-1,3-bis(hydroxymethyl)-1H-pyrimidin-2-one N,N’-Bis(hydroxymethyl)urea;Carbamol;Dihydroxymethylurea;N,N’-dimethylolurea;Dimethylurea;Oxymethurea(MI);Ureaformaldehyde Dimethyloldimethyl-hydantoin;1,3-dimethylol-5,5-dimethyl-hydantoin;DMDMH 2-Imidazolidinone(MI);2-Oxoimidazolidine N2-Hydroxymethylamino-ethanol-tri--ethylhydroxy-2-amino-methylene s(b)Hexahydro-1,3,5-triethyl--triazine;(b)Triethyl-trimethylenetriaminemixturof(a)triazinetriethanol(seethere)an(b)hexahydro-1,3,5-triethyl-1,3,5-triazine Formalin;Methanal;Methylaldehyde;Oxymethylene Dihydroxyethyleneurea;Glyoxalmonoureine Bis(methylolhydantoinurea)methane;Imidurea(MI)
e
IUPACname 1,3-Bis(hydroxymethyl)-1,3-diazinan-2-one 1,3-Bis(hydroxymethyl)urea 1,3-Bis(hydroxymethyl)-5,5-dimethyl-imidazolidine-2,4-dion Imidazolidin-2-one (Z)-3-(Bis(2-hydroxyethyl)amino)-2-(2-hydroxyethyl-(hydroxymethyl)amino)prop-2-en-1-ol 1,3,5-Triethyl-1,3,5-triazinane(b) Formaldehyde 4,5-Dihydroxyimidazolidin-2-one 3-[3-(Hydroxymethyl)-2,5-dioxo-imidazolidin-4-yl]-1-[[[3-(hydroxymethyl)-2,5-dioxo-imidazolidin-4-yl]carbamoylamino]methyl]urea
MI)
Table2.Continued() Commonlyusedname Dimethylolpropyleneurea Dimethylolurea(INCI) DMDMhydantoin(INCI) Ethyleneurea ®cForcide78I ®eForcide78II Formaldehyde(INCI,MI) Glyoxalurea Imidazolidinylurea(INCI,
ContactDermatitis2009:61:63–85 FORMALDEHYDEANDFORMALDEHYDE-RELEASERS 67
ber 2 4
ASnum 6-25-6 0-97-0 204-44- 25-90-1 32-19-1 00-82-4 525-89- 03-08-1 11-05-6 49-70-4 80-31-3
C 11 10 66 56 28 10 30 90 90 27 40
e
m
na ®;
®; e Q
bCurrenttradenames ®Glycoserve ®Cystamine;Urotropine®VulkacitH30 ®GrotanOX ®GrotanDF-35 ®®Aldacide;Formagene ®Karbamol(B/M);®Kaurit(285FL,240);®Uformite ®PreventolD2.Thistradisalsooftenusedforbenzylhemiformal ®Cosept200;Dowicide®Dowicil(75,200)
Othersynonyms 1-Hydroxymethyl-5,5-dimethylhydantoin(MI);MDMH;Methyloldimethylhydantoin;Monomethyloldimethylhydantoin Aminoform;Formamine;Hexamethylenetetramine;Hexamine;Methenamide Bismorpholinomethane;Dimorpholinomethane;4,4’-methylenebis-morpholine NChloroacetamide--methylol N-(hydroxymethyl)urea;Methylhydroxyurea;Mono(hydroxymethyl)urea;Monomethylolurea; Paraform;Poly(oxymethylene) Melamine,polymerwithformaldehyde;Melamine/formaldehyderesin;Nanoplast Polynoxylin;Urea–formaldehyderesin;Urea,polymerwithformaldehyde Bis(benzyloxy)methane;Mixtureofhydroxymethyleneandpolyhydroxymethylenemonobenzylether;1,1’-(Methylenebis(oxymethylene))bis-benzene N-(3-Chloroallyl)hexaminiumchloride;Chloroallylhexaminiumchloride;1-(3-Chloroallyl)-3,5,7-triaza-1-azonia-adamantanechloride;Hexamethylenetetraminechloroallylchloride
mi- ne
hyl-i din- pholi
IUPACname 1-(Hydroxymethyl)-5,5-dimetdazolidine-2,4-dione Notavailable 5-Methyl-3-[(5-methyloxazoli3-yl)methyl]oxazolidine 4-(Morpholin-4-ylmethyl)mor N2-Chloro--(hydroxymethyl)acetamide Hydroxymethylurea Formaldehyde Notavailable Formaldehyde;urea Phenylmethoxymethoxy-methylbenzene Notavailable
Table2.Continued() Commonlyusedname MDMhydantoin(INCI) Methenamine(INCI,MI) N,N’-Methylenebis(5-methyloxazolidine) 4,4’-Methylenedimorpholine N-Methylol-chloracetamide Methylolurea Paraformaldehyde Polyoxymethylenemelamine(INCI) Polyoxymethyleneurea(INCI) ®fPreventolD2 Propyleneglycolhemiformal Quaternium-15(INCI,MI)
68 DEGROOTETAL. ContactDermatitis2009:61:63–85
3 7
161-44- 95-50-6 19-04-4 6-11-4 007-47- 86-55-8
0 3 7 2 0 5
7 5 4 1 3 3
®
Grotan®200; &10
here);nyxide ®ol5
®SuttocideA ®Fixapret140 ®Forcide78(seet(B,BK,HD);O®RoksolT1–7 ®TrisNitro ®Bronidox;Dekas ®Dascocide9;®NipacideFC
salt m
m u
NGlycine,-(hydroxymethyl)-,sodiu(1:1);N-hydroxymethylglycine(mono)sodisalt;NSodium-(hydroxymethyl)glycinate Tetrakis(hydroxymethyl)glycoluril;Tetramethylolglycoluril Hexahydro-1,3,5-tris(hydroxyethyl)triazine;Triazinetriethanol;Trihydroxyethylhexahydros-triazine;1,3,5-Trihydroxyethylhexa-hydrotriazine Nitromethylidynemethanol;Trimethylolnitromethane;Trisnitro maldehyde-releasersbeyonddoubt Bromonitrodioxane Dimethylolglycol;2,5-Dioxahexane-1,6-diol;(Ethylenedioxy)dimethanol;Ethyleneglycoldiformal
r
o
f
s
a
m ol
Notavailable 2,4,6,8-Tetrakis(hydroxymethyl)-2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-dione 2-[4,6-Bis(2-hydroxyethyl)1,3,5-triazinan-2-yl]ethanol 2-(Hydroxymethyl)-2-nitropropane-1,3-diol nicaldataarelackingtoidentifythe 5-Bromo-5-nitro-1,3-dioxane 2-(Hydroxymethoxy)ethoxymethan
cli
e
at e
u n
Table2.Continued() Sodiumhydroxymethyl-glycinate(INCI) Tetramethylolacetylenediurea NTris(-hydroxyethyl)hexahydrotriazine Tris(hydroxymethyl)-nitromethane(INCI,MI) (B)Chemicalsforwhichadeq 5-Bromo-5-nitro-1,3-dioxane(INCI) 1,6-Dihydroxy-2,5-dioxahexa
ContactDermatitis2009:61:63–85 FORMALDEHYDEANDFORMALDEHYDE-RELEASERS 69
at: de
a
Table2.Continued() bCommonlyusednameIUPACnameOthersynonymsCurrenttradenamesCASnumber HydantoinImidazolidine-2,4-dioneGlycolylurea;461-72-32-Hydroxy-2-imidazolin-4(or5)-one (Hydroxymethyl)-5,5-dimethyl-Notavailable27636-82-42-4-imidazolidinedione Asincolumn14,4-Dimethyl-2,5-dioxo-1-16228-00-53-(Hydroxymethyl)-5,5-imidazolidenemethanoldimethylimidazolidine-2,4-dione ®Methylal(INCI,MI)Dimethoxymethane2,4-dioxapentane;Formal;Anesthenyl109-87-5Formaldehydedimethylacetal ®N-Methylolethanolamine2-(Hydroxymethylamino)ethanolTroysan17434375-28-5 CTFACosmeticIngredientDictionaryandHandbookINCI,INCIname(,11thedition.Washington,DC,USA,TheCosmetic,ToiletryandFragranceAssociation,Inc.,2006.AvailableTheMerckIndexwww.personalcarecouncil.org);MI,MerckIndexname(,14thedition.WhitehouseStation,NJ,USA,Merck&Co.,Inc.,2006.Availableat:www.merck.com).aThedatainthistableare–inadditiontothereferencesmentionedinthetable’sheading–retrievedfromand/orverifiedinthefollowingsources:TheCTFACosmeticIngredientDictionaryandHandbook(1),11thedition.Washington,DC,USA,TheCosmetic,ToiletryandFragranceAssociation,Inc.,2006.TheMerckIndex(2),14thedition.WhitehouseStation,NJ,USA,Merck&Co.,Inc.,2006.(3)Thefollowingdatabases:(a)ChemicalNameSynonymFinder(www.chemindustry.com);(b)ComparativeToxicogenomicsDatabase(http://ctd.mdibl.org/voc.go?type=chem);(c)UnitedStatesNationalLibraryofMedicine:ChemIDplusAdvanced(http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp);(d)Chemfinder.com(http://chemfinder.cambridgesoft.com/);(e)Thepubchemproject(http://pubchem.ncbi.nlm.nih.gov/).(4)Otherrelevantinternetsources,notablythewebsitesofthemanufacturersofthevariouschemicals.bTradenamesmentionedbyvarioussourcesareincludedinthistableonlywhentheirexistencecouldbeverifiedbyinternetsearchingformanufacturerssellingtheproductsunderthesetrnames.®cDescriptionofForcide78asinHamann(19)andtheabove-mentionedchemicaldatabases.®dForcide78isalsousedasatradenamebyRedoxPtyLtd(www.redox.com/msds/data/TRIAZI80.html)forapreservativecontaining75–80%triazinetriethanol.®eDescriptionofForcide78asinAndersenetal.(20).®fPreventolD2isalsousedasatradenameforbenzylhemiformalbyLanxessEnergizingChemistry(www.protectedbypreventol.com).
70 DEGROOTETAL. ContactDermatitis2009:61:63–85
relationship to formaldehyde and other formalde- list cannot be expected to be complete. Moreover,
hyde-releasers, (iii) the relevance of positive patch 7 of the 42 chemicals have been mentioned as
test reactions, (iv) the amount of formaldehyde formaldehyde-releasers in one or more publications,
releasedbythevariouschemicalsand,consequently, butdataareinadequatetolabelthemassuchbeyond
(v) the risk they pose for individuals allergic to doubt (Table 2B). Over half of the formaldehyde-
formaldehyde. Do we have adequate knowledge to releasers are commercially available for patch test-
giveformaldehydeallergicpatientsproperadviceon ing (Table 3).
avoidance of formaldehyde-releasers? Not included in this review are:
This review is presented as a series. In this
(1) Compounds that may (possibly) cross-react to
article, formaldehyde sensitivity is reviewed, an
formaldehyde, such as glutaraldehyde (21) and
inventoryoftheformaldehyde-releasersispresented
glyoxal (22, 23).
and the frequency of their presence in various
(2) Chemicals in which formaldehyde may be
product categories is summarized. In other parts,
formed by air oxidation (e.g. polyoxyethylene
formaldehyde-releasers commonly used in cosmetic
dodecyl alcohols) or degradation, but for which
products are discussed, formaldehyde in textile fin-
no relevant clinical data are available (24, 25).
ishesisconsidered,andfinallyreleasersinindustrial
(3) Formaldehyde resins in which formaldehyde
products, notably metalworking fluids, and miscel-
allergy does not play an important role, such as
laneous releasers are reviewed.
phenol-3 formaldehyde resins (26) and p-tert-
butyl phenolformaldehyde resin (27).
IdentificationandSelectionof (4) Tosylamide/formaldehyde resin, a resin based
Formaldehyde-releasers on toluenesulfonamide and formaldehyde, is
the major ingredient in most nail lacquers.
Formaldehyde-releasers were defined as: (i) sub-
Free formaldehyde is present in the majority
stances that release formaldehyde as a result of
of nail lacquers, with concentrations varying
decomposition and/or (ii) chemicals synthesized
from 0.02% to 0.5% (28). Despite this, the
from formaldehyde that may still contain residues
allergen in nail lacquers appears to be the resin
of free formaldehyde (e.g. melamine/formaldehyde
itself and people do not become sensitized
and urea-formaldehyde resins).
to formaldehyde from the use of these nail
Reports on chemicals ascertained or claimed
cosmetics: the amount of free formaldehyde
to be formaldehyde-releasers were found in text-
in finished, dried nail lacquer is believed to
books (1–3), reviews (4–8), case reports and origi-
be nil (29) and nail lacquers do not seem to
nal articles. Exact identification of some substances
cause dermatitis in patients already allergic
described as formaldehyde-releasers has been prob-
to formaldehyde. This may be explained by
lematic or even impossible, as a considerable num-
application of the resin to the nail (avoiding
ber of synonyms and trade names are used in
contact with the skin), only very infrequent
the literature, without identifying active ingredi-
applicationoftheproductandswiftevaporation
ents. Several frequently used trade names (also in
of any free formaldehyde.
recent textbooks and patient information leaflets
found on the internet) currently appear to be out
of use or are applied to the wrong ingredients,
some chemical names could not be identified in
Formaldehyde
any database and some substances have incor-
rectly been identified as formaldehyde-releasers Formaldehyde (methanal) is a colourless gas with
(Table 1). a characteristic pungent odour. Formalin is a
Included in this article are only those formalde- 37–40% aqueous solution of formaldehyde, to
hyde-releasers that could unequivocally or with a which 10–15% methyl alcohol has been added to
high degree of certainty be identified, for instance, inhibit polymerization (16). This simple aldehyde
by their Chemical Abstract Service Registry Num- is ubiquitous in the environment, and is generated
bers (CAS numbers) or their chemical structure. in and released from the smoke of burning wood,
Thus, a total of 42 formaldehyde-releasers were coal, charcoal, tobacco, natural gas and kerosene.
found in the literature. These are presented alpha- Formaldehyde also occurs naturally in certain foods
betically in Table 2 with their (suggested) com- such as coffee (especially instant coffee), dried
mon name (INCI name if existing), IUPAC name, bean curd, cod fish, caviar, maple syrup, shiitake
other synonyms, (some) verified trade names and mushrooms and smoked ham. It is an irritant as
CAS numbers. Due to difficulties in identifying well as an allergen and a potential respiratory
some presumed formaldehyde-releasers in the lit- carcinogen (15). It can be formed by breaking, con-
erature data (4, 6, 18) as described above, this version and oxidization of ingested aspartame (an
ContactDermatitis2009:61:63–85 FORMALDEHYDEANDFORMALDEHYDE-RELEASERS 71
Table3. Formaldehyde-releaserscommerciallyavailableforpatchtesting
Chemical Chemotechniquea Trolabb Brialc
Benzylhemiformal 1%pet. 1%pet.
®
Bioban CS1135 1%pet. 1%pet.
®
Bioban CS1246 1%pet. 1%pet. 1%pet.
®
Bioban P1487 0.5%pet. 1%pet. 1%pet.
2-Bromo-2-nitropropane-1,3-diol 0.25%pet. 0.5%pet. 0.5%pet.
Diazolidinylurea 2%pet. 2%pet. 2%pet.
1,3-Dimethyl-4,5-dihydroxyethyleneurea 4.5%aqua
Dimethyloldihydroxyethyleneurea 4.5%aqua
Dimethyloldihydroxyethyleneurea,modified 5%aqua
DMDMhydantoin 2%aqua 2%aqua 2%aqua
Ethyleneurea 1%pet.
Ethyleneurea,melamineformaldehydemix 5%pet.
Formaldehyde 1%aqua 1%aqua 1%aqua
Imidazolidinylurea 2%pet. 2%pet. 2%pet.
Melamine/formaldehyderesin 7%pet.
Methenamine(hexamethylenetetramine) 2%pet. 1%pet. 1%pet.
N,N’-Methylenebis(5-methyloxazolidine) 1%pet. 1%pet.
N-Methylol-chloracetamide 0.1%pet.
Polyoxymethyleneurea(urea-formaldehyderesin) 10%pet.
Quaternium−15 1%and2%pet. 1%pet. 1%pet.
®
Tris(N-hydroxyethyl)hexahydrotriazine(triazinetriethanol,Grotan BK) 1%aqua 1%pet. 1%pet.
Tris(hydroxymethyl)nitromethane(TrisNitro) 1%pet. 1%pet.
aAvailableat:www.chemotechnique.se.
bAvailableat:www.hermal.com.
cAvailableat:www.brial.com.
artificial sweetener) and possibly causes migraines (5) formaldehydeinformaldehyde-basedrawmate-
in formaldehyde allergic individuals (30). rials used to prepare the product;
(6) formaldehyde used to sterilize vessels for the
storage of raw materials or products;
(7) formaldehyde released by package materials
Applications and exposure
such as formaldehyde resins coating cosmetic
Formaldehyde can be used as a disinfectant because and pharmaceutical tubes (39, 40);
it kills most bacteria and fungi. It was first com- (8) formaldehyde formed in situ by degradation
mercially used in embalming fluid and as a preser- ofnon-formaldehyde-containingcomponentsof
vative for laboratory specimens. Later, it was used theproduct (41).Auto-oxidationofethoxylated
to make plywood and asphalt shingles. It has also alcohols, which are widely used in cleaners,
beenaddedinbonded leather,waterproofglues,fer- toiletries and laundry products, may lead to
tilizers and photographic developers. Exposure to the formation of formaldehyde (24). Polysor-
formaldehyde is difficult to estimate because the bate 80, a non-ionic surfactant present in many
chemical, besides being used as such, is incorpo- cosmetic and pharmaceutical products, after
ratedintoalargevarietyofproductsandreactantsin air oxidization was shown to cause formalde-
many chemical processes, including formaldehyde- hyde formation in concentrations of 70–500
releasers, polymerized plastics, metalworking flu- p.p.m. (42). Lower concentrations of 2.5–6
ids (31, 32), medicaments, fabrics, cosmetics and p.p.m. have been found with polysorbate 20,
detergents (Table 4). 40 and 60 (43).
Infinishedproducts,theremaybeseveralsources
of formaldehyde, some of which are ‘hidden’ or
‘occult’ (16): Legislation in the EU
(1) formaldehyde added as an active ingredient for Exposure to formaldehyde in the EU is subject to
preservation; restrictions because of its toxicological properties.
(2) formaldehyde released from formaldehyde The maximum allowed concentration in finished
donors (usually preservatives); products is 0.2%. Annex VI of Cosmetics Directive
(3) excess formaldehyde used to synthesize the 76/768/EC further stipulates that all finished prod-
releaser; ucts containing formaldehyde or substances in this
(4) formaldehyde which is used for the preser- Annexwhichreleaseformaldehydemustbelabelled
vation of raw materials used to prepare the withthewarning‘containsformaldehyde’wherethe
product; concentration of free formaldehyde in the finished