Contact Dermatitis 2009: 61: 63–85 © 2009 John Wiley & Sons A/S Printed in Singapore. All rights reserved CONTACT DERMATITIS Review Article Formaldehyde-releasers: relationship to formaldehyde contact allergy. Contact allergy to formaldehyde and inventory of formaldehyde-releasers 1 2 1 3 1 Anton C de Groot , Mari-ann Flyvholm , Gerda Lensen , Torkil Menne´ AND Pieter-Jan Coenraads 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 This is one of series of review articles on formaldehyde and formaldehyde-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 Several (nomenclature) mistakes and outdated information are discussed.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 reactions is often challenging. What concentration of formaldehyde is safe for sensitive patients remains unknown. Levels of 200–300 p.p.m. free formaldehyde in cosmetic products have been shown to induce 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. Accepted for publication 1 April 2009 Formaldehyde is a common cause of contact allergy. under usage conditions, the so-called formaldehyde- 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% are reported in this selected group of patients. 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- ® pletely. Indeed, formaldehyde may be found in hyde donors, such as the Bioban product range of biocides and tris(N-hydroxyethyl) hexahydrotri- many cosmetics, toiletries, household products such ® as washing and cleaning agents and in a great num- azine (better known by its trade name Grotan BK). 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 DE GROOT ET AL. Contact Dermatitis 2009: 61: 63–85 Table 1. Data in the literature about formaldehyde-releasers that appear to be wrong or outdated (1–8) Presented as formaldehyde releaser (chemical name and/or trade name) Comments Bakzid® P (mixture of cyclic amino-acetals and organic amine salts) The trade name Bakzid® P is probably not used currently. However, some Bakzid® products contain the formaldehyde releaser tris(N-hydroxyethyl) hexahydrotriazine (triazinetriethanol) Biocide® DS 5249 (1,2-benzisothiazolin-3-one + a formaldehyde Trade name currently not used releaser) Dantoin MDMH (methylaldimethoxy-methan formal) Neither name can be identified Forcide® 78 (mixture of triethylhexahydro s-triazine and Forcide® 78 is the current trade name for trihydroxyethylhexahydro s-triazine) 2-hydroxymethylaminoethanol-tri-N-ethylhydroxy-2- aminomethylene Glutaraldehyde Glutaraldehyde occasionally cross-reacts with formaldehyde, but in the literature it is not found to be a formaldehyde releaser Grotan® HD (N-methylol-chloracetamide) Grotan® HD is a current trade name for tris(N-hydroxyethyl) hexahydrotriazine (triazinetriethanol) Hexamidine Hexamidine in the literature is not a found to be a formaldehyde releaser Imidazolidinyl urea (Euxyl® K 200) Trade name Euxyl® K 200 is probably currently not used KM 103 This name is probably currently not in use. There are, however, various chemicals named KM followed by a number, of which KM 200 (alcohol) contains the formaldehyde releaser tris(N-hydroxyethyl) hexahydrotriazine (triazinetriethanol) MDM hydantoin (Dantoin®, Dantoin® 685) Dantoin® is used as synonym for 1,3-dichloro-5,5-dimethylhydantoin and for phenytoin sodium. The trade name Dantoin® 685 is probably currently not used Parmetol®lK50(N-methylol-chloracetamid, O-formal of benzyl The name Parmetol® K 50 was only found as being a registered alcohol) trade name in Canada for a mixture of 13% chloroacetamide and 7.3% paraformaldehyde (under the company Gray Products) Preventol® D1 (1-(3-chloroallyl)-3,5, Chemical name is incorrect, benzyl formal must be deleted. The 7-triaza-1-azoniaadamantanechloride benzyl formal) trade name Preventol® D1 is probably currently not in use Preventol® D2 (benzylhemiformal) Preventol® D2 is in chemical databases used as a trade name for 1,1’-(methylenebis(oxymethylene)) bis-benzene, but also used for benzylhemiformal Preventol® D3 (chlormethylacylamino methanol) The trade name Preventol® D3 is probably currently not in use. Chemical name chlormethylacylamino methanol cannot be identified in chemical databases Preventol® D3/D5 (N-methylol-chloracetamide) The trade names Preventol® D3 and D5 are probably currently not in use finishes and caused dermatitis from clothing in often lacking (9–11). Whether it is really necessary formaldehyde-sensitive individuals due to 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), have experimental use test exposure 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 Table 2. Formaldehyde and reported formaldehyde-releasersa (adapted from Andersen et al. (1), Timmer (2), Flyvholm (3), Fiedler (4), Flyvholm and Andersen (5), Dahlquist and Fregert (6), Contact Dermatitis 2009: 61: 63–85 Geier (7) and Geier et al. (8)) Commonly used name IUPAC name Other synonyms Current trade namesb CAS number (A) Chemicals for which adequate clinical data are available to identify them as formaldehyde-releasers beyond doubt Benzylhemiformal (INCI) Phenylmethoxymethanol (Benzyloxy)methanol Akyposept®B [Preventol® D2; 14548-60-8 See there] Bioban CS 1135® 4,4-Dimethyloxazolidine; Bioban CS 1135® 81099-36-7 (ingred. 3,4,4-trimethyloxazolidine 75673-43-7 and 51200-87-4) Bioban CS 1246® 5-Ethyl-3,7-dioxa-1-azabicyclo[3.3.0] 7-Ethylbicyclo-oxazolidine Bioban CS-1246®; 7747-35-5 octane Chemtan A60®; Oxazolidine-E®; Zoldine ZE®; Bioban P-1487® 4-[2-(Morpholin-4-ylmethyl)-2-nitro- Mixture of nitrobutylmorpholine and Bioban P-1487® 37304-88-4 (ingred. 1854-23-5 butyl]morpholine; ethylnitrotrimethylenedi morpholine and 2224-44-4) 4-(2-nitrobutyl) morpholine 2-Bromo-2-nitropropane As in column 1 Bromonitropropanediol; Bronopol®; Chemynol BP®; 52-51-7 -1,3-diol (INCI) Bronopol Myacide Pharma BP®; Onyxide 500® FORMALDEHYDE AND