ELSEVIER Fatal Attractiveness: of Cosmetics ANTON C DE GROOT, MD, The Shady Side PhD osmetics (which include skin-care products and decorative cosmetics) and toiletries (which include soap, shampoo, bath-foam, and toothpaste) are used by nearly everyone Not surprisingly and inevitably, these products will cause side effects in some consumers Contrary to what the title of this article suggests, serious adverse reactions from cosmetics are infrequent; however, mild unwanted effects are experienced by over 10% of the population.1,2 Diagnosing and treating patients with such reactions are part of the daily routine of dermatologists In this contribution cosmetic-related irritation, photosensitivity, and immediate contact reactions will be discussed briefly; contact allergy as a side effect of cosmetics is presented in more detail, highlighting recently emerged important cosmetic allergens.‘-” C Irritation There are two forms of irritation: subjective and objective Subjective irritation may be defined as chemically induced burning, stinging, itching, or other skin discomfort without visible, objective signs of inflammation It is estimated that between and 10% of all (women) cosmetic users note this discomfort, primarily on the face Objective irritation is defined as nonimmunologically mediated inflammation of the skin Its signs are usually mild erythema and scaling, but frank dermatitis may occur Irritation may be observed with cosmetic products containing detergents such as soap, shampoo, and bath/shower foam Atopics and elderly people with good/excessive hygiene are particularly susceptible to developing this side effect, mainly during the winter when humidity is low Itching usually starts on the legs, arms and hips The humid climate in, and anatomical occlusion of, the axillae favor irritant responses to deodorants and antiperspirants Surfactants and emulsifiers present in moisturizing or emollient creams may also cause irritation, especially when applied to facial skin Daily application of eye makeup cosmetics and removal with cleansing products often irritate the sensitive skin of the eyelids -~ -~~- From the Department of DematoIogy, Carolus-Liduina Hospital, ‘sHertogerlbosch, The Netherlands Address correspondence to Anton C De Groot, M.D., Carolus-Liduina Hospital, P.0 Box 102, 5200 BD’s-Hertogenbosch, The Netherlands 1998 by Elseuier Science Inc 655 Azfetzue of tlw Americas, New York, NY 10010 Photosensitivity With the exception of the epidemic caused by the halogenated salicylanilides in the 196Os, photosensitivity has accounted for only a small proportion of cosmeticrelated side effects In a study from the United States, photoallergy and phototoxicity were responsible for only reactions in 713 patients investigated for cosmetic dermatitis.7 Musk ambrette, a fragrance fixative formerly used in many aftershaves, until recently was a major cause of photocontact allergy, often leading to persistent light reactions;8 an association with chronic actinic dermatitis has also been suggested.9 In 1985, the International Fragrance Association (IFRA) recommended that musk ambrette not be utilized in products in contact with skin; since then, the numbers of relevant photocontact allergic reactions have decreased considerably Nowadays, paradoxically as this may seem, ultraviolet (UV) filters have become important causes of photocontact allergy The increased public awareness of the risks of premature skin aging and cancer caused by exposure to sunlight has led to more extensive use of UV filters, not only in sunscreen preparations but also in skin-care products (notably facial creams); this is the major cause of the recent increase of photocontact allergic reactions to UV filters Patients with photosensitive diseases, such as chronic polymorphic light eruption (CPLE) and chronic actinic dermatitis, who use sunscreens habitually are particularly sensitive to developing photocontact allergy Most cases are caused by the benzophenones (notably oxybenzone) and the UVAfiltering dibenzoylmethanes (notably isopropyl dibenzoylmethane, butyl methoxydibenzoylmethane).lOJi Other less frequent photosensitizers are p-aminobenzoic acid @‘ABA), octyl dimethyl PABA, and ethylhexyl-p-methoxycinnamate Possibly, the frequency of photocontact allergy to cosmetics is underestimated When such reactions occur to sunscreens, the resulting photoallergic reaction may be interpreted by the patient as the failure of the product to adequately protect against the sun’s rays rather than as an adverse reaction to the product; medical consultation is then not sought In addition, probably only a minority of dermatologists in private practice perform photopatch testing, resulting in missed cases of photocontact allergy 0738-081X/98/$19.00 I’ZI SO738-081X(97)00179-X 168 DE GROOT Immediate Contact Reactions (Contact Urticaria) The contact urticaria syndrome may comprise cutaneous reactions (localized urticaria, generalized urticaria) as well as extracutaneous reactions (bronchial asthma, rhinoconjunctivitis, otolaryngeal symptoms, gastrointestinal symptoms, anaphylactic shock) Immediate contact reactions are either nonimmunological (caused by nonimmunological release of histamine and other vasoactive substances) or immunological (IgE-mediated) Cosmetics rarely are the cause of contact urticaria; however, many cases of “subjective irritation” might actually represent very mild nonimmunological contact reactions, caused especially by ingredients in cosmetic products known to induce such symptoms, such as sorbic acid, benzoates, and cinnamic aldehyde In addition, immediate contact reactions to fragrance materials in perfumes may induce or worsen respiratory problems such as shortness of breath, asthma, and sneezing People with respiratory allergy commonly experience aggravation of their complaints around cosmetic counters, candle shops, and from perfumes worn by other people, for example, in church.‘j Contact Allergy Epidemiology Allergic contact reactions to cosmetics often go unrecognized for several reasons.7 (1) Frequently patients have used the causative cosmetics for many years; the development of skin problems from such products conflicts with the consumer’s perception of allergy, which is based on the assumption that a new cosmetic has to be introduced (2) Cosmetic allergy is sometimes manifested by mild reactions only, for example, itching, faint erythema, and mild scaling of the eyelids (3) Cosmetic dermatitis may sometimes be noticed, but wrongly interpreted Psoriasis of the face may be exacerbated by cosmetic dermatitis; dermatitis caused by emollient creams interpreted as worsening of dry skin or atopic dermatitis for which it was applied; and contact allergy to sunscreens as failure of the product to adequately protect the skin against the sun’s rays Nevertheless, allergic contact dermatitis to cosmetic products is frequently observed Of dermatological patients patch tested for suspected allergic contact dermatitis, some 10% are allergic to cosmetic products.12 Six to 11% of routinely tested individuals react to the fragrance mix, a mixture of commonly used fragrance materials to detect sensitization to perfumes In the list of frequent allergens, the fragrance mix usually is number after nickel sulfate.6 An estimated 1% of the general population is allergic to fragrances, and 2-3% are allergic to substances that may be present in cosmetics and toiletries 12,13 Clinics izz Dermatology Clinical l 1998;16:167-179 Picture Sometimes, contact allergic dermatitis from cosmetic products can be easily recognized Examples include reactions to deodorant, eye shadow, perfume dabbed behind the ears or on the wrist, and lipstick In more than half of all cases,the diagnosis of cosmetic allergy is suspected neither by the patient nor by the doctor.7 The clinical picture of allergic cosmetic dermatitis depends on the type of products used (and consequently, the sites of application) and the degree of the patient’s sensitivity Usually, cosmetics and their ingredients are weak allergens, and the dermatitis resulting from cosmetic allergy is mild: erythema, mild edema, desquamation, and papules Weeping vesicular dermatitis rarely occurs, although some products, especially the permanent hair dyes, may cause fierce reactions, notably on the face and ears and less on the scalp Allergic reactions on the scalp tend to be seborrheic dermatitis-like with temporary hair loss, (HB van der Walle, personal communication, 1997; personal unpublished observations) Contact allergy to fragrances may resemble nummular eczema, seborrheic dermatitis, sycosis barbae, or lupus erythematosus Lesions in the skin folds may be mistaken for atopic dermatitis Dermatitis due to perfumes or toilet water tends to be “streaky” Allergy to toluenesulfonamide/formaldehyde resin in nail polish may affect the fingers, 14but most allergic reactions are located on the eyelids, in and behind the ears, in the neck, and sometimes around the anus or perivulval The typical patient suffering from allergic cosmetic dermatitis is a woman aged 20-45 years with mild dermatitis of the eyelids The face itself is also frequently involved, and often the dermatitis is limited to the face and/or eyelids Other predilection sites for cosmetic dermatitis are the neck, the arms and the hands; however, all parts of the body may be involved Most often, the cosmetics have been applied to previously healthy skin (especially the face), nails or hair Allergic cosmetic dermatitis may also be caused by products used on previously damaged skin, for example to treat or prevent dry skin of the arms and legs or irritant or atopic hand dermatitis.6 The Products Causing Cosmetic Allergy Most allergic reactions are caused by cosmetics that remain on the skin: “stay-on” or “leave-on” products: skin care products (moisturizing and cleansing creams, lotions, milks, tonics), hair cosmetics (notably hair dyes), nail cosmetics (nail polish, nail hardener), deodorants and other perfumes, and facial and eye make-up products.3,6,7,15 “Rinse-off” or “wash-off” products such as soap, shampoo, bath foam, and shower foam rarely elicit or induce contact allergic reactions This may be explained by the dilution of the Clinics in Dermatology l 1998;16:167-179 product (and, consequently, of the [potential] allergen) under normal circumstances of use, and the fact that the product is removed from the skin by washing after a short period of time One exception to this general rule is allergy to the surfactant cocamidopropyl betaine, which has caused many reactions to shampoo in consumers and occupational dermatitis in hairdressers, and to shower gels (see later).16J7J8 Of course, trends in cosmetic usage, e.g the growing cosmetic market for men and the development of new products (“kiddy cosmetics”, hair gel), may influence the situation The Allergens Although there are many publications on contact allergy to cosmetics and toiletries,>5 only studies have systematically investigated the allergens in such products.7J5 In both studies, fragrances and preservatives were the most common causative ingredients in allergic cosmetic dermatitis Other important allergens are the hair color y-phenylenediamine (and related permanent dyes), lanolin and its derivatives, the nail lacquer resin toluenesulfonamide/formaldehyde resin, UV-filters (more often photocontact allergy), and various emulsifiers More recently, the surfactant cocamidopropyl betaine and the preservative methyldibromo glutaronitrile have emerged as important cosmetic allergens.16-20 Fragrances Fragrances are the most frequent cause of cosmetic allergy, both from products primarily used for their scent (perfumes, colognes, eaux de toilette, aftershave, deodorants) and from other scented products.6 Approximately 3000 chemical substances (of which 300-400 are of natural origin) are used in the fragrance industry A perfume is a creative composition of fragrance materials, of which it may contain from a few to over 300 Perfumes contain approximately 12-20% of the perfume compound, toilet water 5-8%, colognes 2-5%, and cosmetics 0.5% Most fragrance-sensitive patients are identified by positive patch tests to personal products, the “fragrance-mix”, or the North American Contact Dermatitis Group (NACDG) perfume-screening series The “fragrance mix” contains commonly used fragrance ingredients: cw-amylcinnamic aldehyde, cinnamic alcohol, cinnamic aldehyde, eugenol, geraniol, hydroxycitronellal, isoeugenol, and oak moss absolute It is estimated that 70-80% of fragrance-allergic patients will react positively to the mix Twenty to 30% will remain undetected, and the mix causes both falsepositive and false-negative reactions Approximately 100 fragrance materials have been identified as contact allergens.” THE SHADY SIDE OF COSMETICS 169 Preservatives are added to water-containing cosmetics to inhibit the growth of nonpathogenic and pathogenic microorganisms, which may cause degradation of the product or endanger the health of the consumer.21-23 Formaldehyde and Formaldehyde Donors Formaldehyde is a frequent sensitizer and ubiquitous allergen Routine testing in patients with suspected allergic contact dermatitis yields prevalence rates of sensitization of 3% or more, but most cases are from non-cosmetic sources The cosmetic industry uses free formaldehyde almost exclusively in rinse-off products, which rarely gives rise to cosmetic allergy The literature on formaldehyde allergy has been reviewed.21,22 FORMALDEHYDE Formaldehyde donors are preservatives that, in the presence of water, release formaldehyde Therefore, cosmetics preserved with such chemicals will contain free formaldehyde, the amount depending on the preservative used, its concentration, and the amount of water present in the product Formaldehyde donors used in cosmetics and toiletries include quaternium-15, imidazolidinyl urea, diazolidinyl urea, 2-bromo-2-nitropropane-1,3-diol, and DMDM hydantoin Quaternium-15 releases the most, imidazolidinyl urea the least free formaldehyde.2” Contact allergy to formaldehyde donors may be due either to the preservative itself or to formaldehyde sensitivity.21,22 Whereas the formaldehyde donors appear to be gaining in popularity as preservatives in cosmetics, formaldehyde itself has largely been replaced by other chemicals, because it is suspected (when inhaled as a gas), of being a possible human carcinogen.25 FORMALDEHYDE DONORS 2OO@) Quaternium-15 is the most frequent preservative sensitizer in cosmetic products.’ Routine testing by the NACDG yielded a prevalence rate of 9.6% in patients suspected of allergic contact dermatitis.26 Half of these reactions may be caused by formaldehyde sensitivity.27 At the commonly used concentration of O.l%, quaternium-15 releases about 100 ppm free formaldehyde, which in some formaldehyde-sensitive patients is sufficient to cause allergic cosmetic dermatitis In Europe, sensitization to quaternium-15 is less frequent.28 QUATERNIUM-15 (DOWICIL UREA (GERMALL 1159 Imidazolidinyl urea releases little formaldehyde, and consequently poses little threat to formaldehyde-sensitive subjects In the United States, the prevalence rate of contact allergy to imidazolidinyl urea is 2.3%.26Cross reactions to and from the related preservative diazolidinyl urea may be observed.28 IMIDAZOLIDINYL 170 Clitlics in Dermnfology DE GROOT DIAZOLIDINYL UREA (GERMALL II@) Diazolidinyl urea is chemically related to imidazolidinyl urea It has been in use only since 1982, and is the most active preservative of the imidazolidinyl urea group Routine testing by the NACDG resulted in a prevalence rate of sensitization of 3.0% in patients suspected of allergic contact dermatitis.z6 Diazolidinyl urea appears to be a stronger sensitizer than imidazolidinyl urea Patients allergic to this preservative may or may not react to formaldehyde.2* (BRONOPOL) Bronopol has been responsible for so many casesof allergic cosmetic dermatitis from Eucerin@ cream in the United States, that the manufacturer decided to replace it.29,30 Currently, its prevalence rate of sensitization in the United States is 2.2%.26 Another concern is that its interaction with amines and amides can result in the formation of nitrosamines and nitrosamides, which are suspected to be carcinogens In Europe, bronopol in an infrequent sensitizer.31 2-BROMO-2-NITROPROPANE-1,3-DIOL DMDM HYDANTOIN Dimethylol dimethyl hydantoin (Glydantm) has so far not been implicated as causing cosmetic allergy, although routine testing in the United States yielded a prevalence of 1.6% positive reactions.26 It has been demonstrated that some patients allergic to formaldehyde may react upon patch testing to DMDM hydantoin 32In addition, provocation tests with a cream containing 0.25% w/w DMDM hydantoin in formaldehyde-sensitive subjects elicited a positive response in some of them, indicating that patients who are allergic to formaldehyde may be at risk of developing allergic cosmetic dermatitis from products preserved with DMDM hydantoin.s2 Other Preservatives The paraben esters (benzyl, butyl, ethyl, methyl, propyl) are the most widely used preservatives in cosmetic products, and may be considered very safe in terms of causing allergy, especially in the low concentrations as used in cosmetics In Europe, routine testing with the parabens yields low rates of sensitization (less than 1%),33and in the United States, 2.3%.26 Most cases of sensitization to parabens are caused from the use of topical pharmaceutical preparations on eczematous skin or leg ulcers A review of paraben sensitivity has been published.23 PARABENS MI/MCI(KathonCG@, Euxyl K loo@) is a preservative system containing, as active ingredients, a mixture of methylchloroisothiazolinone and methylisothiazoli The most widely used commercial product is Kathon CG (where CG denotes cosmetic grade), which contains 1.5% active ingredients In recent years, this highly effective preservative has become a major cause of cosmetic allergy in most European countries The subject has been reviewed.34,35 In the METH~(CHLORO)ISOTHIAOUNONE l 1998;16:167-179 United States, prevalence rates of 1.7%-1.9% (NACDG) and 3.6% (Mayo Clinic) have been observed.%,37The use concentration of MCI/MI is mostly between 3-15 ppm, which is usually far below the threshold for detection of allergy with patch tests, indicating that most allergic patients will not react to the product upon patch testing Therefore, MCI/MI always has to be tested separately (100 ppm water) whenever cosmetic allergy is suspected It is present in the European Environmental and Contact Dermatitis Research Group (EECDRG) standard series Currently, MCI/MI is mainly used in rinse-off products at low concentrations, which infrequently leads to induction or elicitation of contact allergy.38 As a consequence, prevalence rates in Europe are decreasing Hair Colors Hair colors may be temporary, semipermanent, or permanent Most cases of cosmetic allergy from hair dyes are caused by the (permanent) oxidation dyes of the PARA-type (p-phenylenediamine and related dyes) In recent years, the incidence of dermatitis due to hair dyes containing p-phenylenediamine (derivatives) appears to have decreased This is attributed to the provision of cautionary notices on the product, awareness of the risk, patch testing of the product by future users, improvements in the technical quality of the cosmetic product, and improvements in the technique of application of these dyes Nevertheless, p-phenylenediamine remains an important cause of cosmetic allergy,7 6.3% of all patients routinely tested by the NACDG reacting to it.26 These oxidation dyes are also an occupational hazard for hairdressers and beauticians.39 Glyceyl Thioglycolate Glyceryl thioglycolate, a waving agent used in acid permanent waving products, may sensitize consumers, but it is usually an occupational hazard for the hairdresser.7,26,39,40 Patients allergic to glyceryl thioglycolate infrequently react to ammonium thioglycolate, used in “hot” permanent wave procedures Propylene Glycol Propylene glycol is widely used in dermatologic and nondermatologic topical formulations, including cosmetics, as well as in numerous oral and parenteral medication, hygiene products, and food products.41-43 It was reported to be a common cause of cosmetic dermatitis;7 however, irritant reactions are observed regularly, and a test concentration low enough to cause no irritation but high enough to detect all cases of sensitization is lacking The following classification for skin reactions to propylene glycol has been suggested:41 (1) irritant contact dermatitis; (2) allergic contact dermatitis; (3) nonimmunologic contact urticaria, and (4) subjective or sensory Clinics in Dermatology l 1998;16:167-179 irritation There has been no evidence of photoallergy or phototoxicity Irritant reactions are common reactions, and they should be a diagnosis of exclusion from clinical history, physical examination, and a negative patch test Allergic contact dermatitis is probably uncommon, and the clinical significance has been overestimated In earlier studies, higher concentrations of propylene glycol may have induced many irritant patch test reactions Currently, a concentration of l%-10% is advised to avoid such irritation, but cases of contact allergy are probably then missed (false-negative reactions).*3 A diagnosis of allergic contact dermatitis should never be made on the basis of one positive patch test alone Retesting should always be done after several weeks Next, retests with serial dilutions down to 1% propylene glycol help in dividing irritant responses from true allergic ones A negative reaction strongly suggests a previously irritant response; a positive reaction suggests contact allergy Repeated open application tests (ROAT) and/or provocative use tests (PUT) can be conducted to verify the allergic basis of a positive patch-test result In subjects with a negative patch test, the ROAT/PUT may also be useful as a simulation of normal application procedures Nonimmunolo~~iccmtact urticaria can also occur after topical application of propylene glycol The mechanism entails microinjury to skin Although this does not represent a contact urticaria in the strictest sense, it is usually categorized as such Subjectivebr sensory irritation, with itching, burning, or stinging sensations but no signs of inflammation, is a commonly noticed reaction among users of cosmetic products and does not usually result in visits to dermatologists It is a phenomenon that also occurs in volunteers after application of propylene glycol in different concentrations81 Toluenesulfonamidelformaldehyde Allergens) in Nail Lacquer Resin (and Other Several recent articles have discussed the allergens in nail varnish, the features of allergic contact dermatitis, and its frequency ~44-48 Nail polish is intended to protect the nails and make them beautiful This cosmetic product was introduced to the market in 1919; the first reports of contact allergy date from 1925 Since then, more than 6700 caseshave been reported in the medical literature Every second case manifests as an eyelid dermatitis Eighty percent of all reactions are observed as a dermatitis of the face and neck Occasionally other parts of the body are involved, including the thighs, the genitals, and the trunk; generalized dermatitis is rare Periungual dermatitis may be far more common (60%) than previously thought 14 Partner (“connubial”) dermatitis has been observed The main allergen is the resin toluenesulfonamide/formaldehyde resin [Interna- THE SHADY SIDE OF COSMETICS 171 tional Nomenclature of Cosmetic Ingredients (INCI) name: tosylamide/formaldehyde resin] The exact allergenic ingredients of this resin are still unknown.46 Other allergens have rarely been reported: formaldehyde, nitrocellulose (dubious), guanine, polyester resin, phthalates, amyl and butyl acetate, dye, ethylene dichloride, Betonite@, and o-toluenesulfonamide.45r4h Contact allergy to toluenesulfonamide/formaldehyde resin in nail varnish is far from rare Up to 6.6% of women habitually or occasionally using nail cosmetics and presenting with dermatitis are allergic to it,44 and the prevalence in patients routinely tested in the United States was 1.9%.26The resin (10% petrolatum) should always be tested on subjects using nail cosmetics, because neither the history nor the clinical features are sufficient criteria for excluding or suggesting the diagnosis.44 Testing the patients’ own nail varnishes may also be helpful 14 The sociomedical consequences of nail-varnish allergy may be severe and include sick leave, hospitalization, and work loss14Allergic patients should stop using nail varnishes or purchase varnishes free of toluenesulfonamidelformaldehyde resin (eg Shiseido, Rot, Clinique); however, apparently some products claiming not to contain the resin in fact so.49Also, such nail lacquers may contain other sensitizers, such as methyl acrylate and epoxy resin.50Useful review articles on adverse reactions to nail cosmetics and sculptured nails have recently been published.51-53 Lanolin (Derivatives) Lanolin and lanolin derivatives are used extensively in cosmetic products as emollients and emulsifiers The allergens are the wool alcohols In the United States, the NACDG found a prevalence rate of 1.5% positive reactions in eczema patients.26 Most cases are caused by topical pharmaceutical preparations containing it, especially for treating varicose ulcers and stasis dermatitis The-presence of-lanolin or its derivatives in cosmetics rarely sensitizes patients, but patients presensitized may experience cosmetic allergy from using cosmetics containing lanolin or its derivatives Avoidance of contact with lanolin or its derivatives often leads to disappearance of sensitivity.% Stlnscreens As drugs, sunscreens are used to prevent sunburn and to prevent photosensitive dermatoses, such as herpes labialis and chronic polymorphic light eruption (CPLE) In cosmetics, they are added not only to protect the skin of the user but also to prevent the product from photodegradation The main classes of sunscreens are PABA and its esters (amyl dimethyl, glyceryl, octyl dimethyl), the cinnamates, the salicylates, the anthranilates, the benzophenones, and the dibenzoylmethanes.s5 The latter category is gaining popularity, because it absorbs mainly in the UVA region (315-400 172 Clinics in Dermatology DE GROOT nm) UV filters have been identified with increasing frequency as allergens and photoallergens, but reactions to them remain uncommon Photoallergic reactions can easily be overlooked, because the resulting dermatitis may be interpreted by the patient/consumer as failure of the product to protect against sunburn or as worsening of the photodermatosis for which the sunscreen was used PABA is a common cause of photoallergic reactions Recently, most such reactions have been caused by benzophenones and the dibenzoylmethanes, isopropyl dibenzoylmethane and butyl methoxydibenzoylmethane 55The literature on adverse reactions to sunscreens has been reviewed.55-57 The most frequent adverse reaction to sunscreen preparations is irritation, which may occur in over 15% of users.58Both allergic and photoallergic reactions are reported to the main classesof UVA filters: benzophenones and dibenzoylmethanes 10~9-63Oxybenzone (benzophenone 3) especially causes many casesof photoallergic contact dermatitis, and to a lesser extent allergic contact dermatitis.10,59-61,63Patients who regularly use sunscreens because they suffer from the photosensitivity dermatitis/actinic reticuloid syndrome may have an increased risk for developing allergic side effects of sunscreens.6:’In all casesof suspected adverse reactions to sunscreens, both patch and photopatch tests should be performed.‘O New Important Cosmetic Allergens New important contact allergens not appear every day; however, in recent years two chemicals, the surfactant cocamidopropyl betaine and the preservative methyldibromo glutaronitrile (in Euxyl@ K 400), have emerged as important causes of allergic cosmetic dermatitis Tocopheryl linoleate, a vitamin E derivative present in a new line of cosmetics, was the cause of an epidemic of contact dermatitis; the products were hastily withdrawn from the market Cocamidopropyl Befaine Cocamidopropyl betaine is an amphoteric surfactant that enjoys increasing popularity among cosmetic chemists because of its low potential for irritation of the skin.‘b-18 In the United States, the surfactant in 1980 was present in only 47 of 19,000 products on file with Food and Drug Administration (FDA), in 1992 this number had risen to 521.3 Most of the products are shampoos and bath products, such as bath and shower gels Cocamidopropyl betaine is prepared by reacting coconut fatty acids (obtained from coconut oil) with dimethylaminopropylamine, yielding cocamidopropyl dimethylamine, which is subsequently allowed to react with sodium monochloroacetate to give the end product cocamidopropyl betaine The lipophilic tail is formed by coconut fatty acids, a mixture of fatty acids l 2998;16:167-179 with chain lengths varying between C, and C,, Cocamidopropyl betaine is therefore a mixture of several compounds with the same basic structure, but with differing lipophilic tails Depending on the source, cocamidopropyl betaine can still contain varying amounts of the reactants and intermediates involved in its synthesis A major impurity is dimethylaminopropylamine CaseReports of Contact Allergy to Cocamidopropyl Betaine The first case of cosmetic allergy to cocamidopropyl betaine was reported in 1983 In many cases published since then, shampoo was the causative cosmetic product Thus, cocamidopropyl betaine is the exception to the rule that allergic reactions are usually caused by “stay-on” (“leave-on”) cosmetic products Other cosmetic products that have caused cosmetic allergy from the presence therein of cocamidopropyl betaine include skin-care products (moisturizing and cleansing products), deodorant, shower gel, bath foam, and liquid soap; in addition, several cases of contact allergy to cocamidopropopyl betaine in contact lens fluids have been described Epidemiology of Contact Dermatitis to Cocamidopropyl Betaine By its presence in shampoos, cocamidopropyl betaine appears to be an important occupational hazard to hairdressers Prevalence rates of sensitization to cocamidopropyl betaine range from 3.7% to 5% One investigator obtained 12 positive patch test reactions among 210 (5.7%) patients suspected to suffer from cosmetic-related allergic contact dermatitis and/or dermatitis of the head and neck area.64Seven of these were considered definitely relevant All of these were allergic to shampoos containing cocamidopropyl betaine.@ A group of investigators tested 1200 consecutive patients with dermatitis of various types with cocamidopropyl betaine and found allergic reactions in 46 (3.8%).65 Patch tests were relevant in all, the causative products being mostly shampoos and bath foam.65 In another Italian study, 17 of 1190 unselected eczema patients (1.4%) proved to be allergic to cocamidopropyl betaine.66 The products causing allergic contact dermatitis were shampoos, face cleansing lotions, gynecological antiseptic syndets, liquid shower soaps, and anal hygienic detergents 66In Arnhem, the Netherlands, 56 out of a population of 781 dermatitis patients (7.2%) reacted to cocamidopropyl betaine; however, in only 17 of these 56 (30%, ie 2.2% of the population tested), were the reactions scored as relevant.17 The Allergen(s) in Cocanzidopropyl Betaine Depending on its source, cocamidopropyl betaine contams varying amounts of the reactants and intermediates involved in its synthesis To determine the actual allergenic ingredient in cocamidopropyl betaine, a Clinics in Dernzatolqpy l 1998;16:167-179 THE group of investigators tested 30 patients allergic to cocamidopropyl betaine with the chemicals used for its synthesis 65 All reacted to dimethylaminopropylamine 1% aqua, whereas only 16 patients (53%) reacted to cocamidopropyl betaine of purer grade.65 The authors suggest that dimethylaminopropylamine is the (only) allergen in cocamidopropyl betaine.65 These results were later confirmed.66 Thus, it would appear that dimethylaminopropylamine is the major allergen in cocamidopropyl betaine and other alkylamidobetaines.66,67 As the amounts of dimethylaminopropylamine found in commercial preparations containing cocamidopropyl betaine is far lower than the eliciting concentration, this concept may be challenged.68 Patch Testing With Cocamidopropyl Betaine Cocamidopropyl betaine usually causes allergic reactions in rinse-off products As patch testing with these products is likely to result in both false-positive and false-negative reactions, and such procedures therefore are often unreliable, it is imperative that cocamidopropyl betaine be tested separately It is therefore suggested to include cocamidopropyl betaine in the hairdresser’s series and in the cosmetic series Cocamidopropyl betaine in the usual and commercially available concentration of 1% in water is a marginal irritant, and not all “positive” patch test reactions indicate (relevant) contact allergy to it Relevance can be established only when allergic patients are actually exposed to products containing cocamidopropyl betaine, and avoidance results in clearing or obvious improvement of dermatitis Mefhyldibromoglutaronitrile (EuxyP K 400) Euxyl K 400 (Schiilke & Mayr, Norderstedt, Germany) is a preservative system for cosmetics and toiletries, containing active ingredients: methyldibromoglutaronitrile (MDG; synonym: 1,2-dibromo-2,4-dicyanobutane) and phenoxyethanol in a 1:4 ratio.ls-20 Typical use concentrations are 0.05%-0.20% Euxyl@ K 400 was introduced in Europe in the mid 198Os, and it has been used in the United States for approximately years In the Netherlands in 1995,25%-35% of all cosmetic products and two-thirds of all moistened toilet tissues used for anal hygiene were preserved with Euxyl K 400 In the United States in 1992, methyldibromoglutaronitrile was present in only out of 20,000 products on file with the FDA.” In 1995, this number had risen to 56 of 22,287 products Methyldibromoglutaronitrile is also available for a variety of noncosmetic (industrial) applications.69 Contact Alleugj to Euxyl K 400 and its Ingredient Methyldibromoglutavollitrile The sensitizer in Euxyl K 400 is nearly always methyldibromoglutaronitrile The first cases of contact allergy to Euxyl K 400 were reported from Germany in 1989 Later case reports include sensitization to moistened SHADY SIDE OF COSMETICS 173 toilet tissues (especially in the Netherlands), skin-care products, cucumber eye gel, barrier cream gel, cleansing cream, ultrasonic gel, and makeup.19 In the Netherlands, the prevalence of contact allergy to methyldibromoglutaronitrile rose from 0.5% in 1991 to 4.0% in 1994.20,70 It is now the most frequent cosmetic allergen In Bologna, Italy, the prevalence of allergy to Euxyl K 400 rose from 1.2% in 1988-1990 to 2.3-2.9% in 19911994.71~7zIn Germany, approximately 2.3% of suspected contact dermatitis patients are currently allergic to Euxyl K 400 and the members of the North American Contact Dermatitis Group in 1992-1994 found a prevalence of 1.5%.26,73 Between 23% and 75% of positive patch-test reactions are considered to be relevant Usually, cosmetics, both of the stay-on and of the rinse-off variety, and, in the Netherlands, moistened toilet tissues, were the cause of the reaction.2” The Profile of Patients Sensitized to Euxyl K 400 Allergic patients have either cosmetic dermatitis or perianal eczema The former category are usually women, the latter mainly men Cosmetic dermatitis is often localized on the face and/or periorbital and on the neck Skin-care products used for prevention and/or treatment of dry skin may also be the cause of cosmetic dermatitis, which may thus be localized, especially on the hands, but also on the arms, the neck; widespread; or even generalized Occupational hand dermatitis may be observed in hairdressers and masseurs The Appropriate Test Concentration Most investigators have used Euxyl K 400 “per se” as test allergen As the allergen in Euxyl K 400 is nearly always its ingredient methyldibromoglutaronitrile, MDG can thus be conveniently utilized as a single allergen indicator for allergy to Euxyl K 400.74 The optimal test concentration (and vehicle, MDG has thus far been tested only in petrolatum) has yet to be established, but it may be 0.5% in petrolatum In our experience, it is necessary to add an emulsifier, such as soy lecithin, to obtain homogeneous dispersions With the currently available commercial allergens, methyldibromoglutaronitrile 0.1% pet (Trolab) and Euxyl K 400 0.5% pet (Chemotechnique), false-negative reactions may occur.74 Folliculav Reactions in Cosmef its fo Tocopheryl Linoleafe In spring 1992, an epidemic outbreak of skin eruption caused by a new line of cosmetics occurred throughout Switzerland.75,76 Within a 3-month period, this outbreak affected at least 263 people who consulted dermatologists and at least 642 people who did not The lesions were mainly papular and follicular, widely distributed, with pronounced pruritus, which was aggravated by sweating or heat exposure, and were long lasting Epidemiological and clinical data incriminated a new line 174 DE GROOT of cosmetics containing vitamin E linoleatem, a mixture of fatty acid esters of DL-a-tocopherol composed not only of tocopheryl linoleate but also of tocopheryl oleate, palmitate, and myristate The lesions appeared after l-160 days (mean 14 days) following the initial application of the tocopheryl linoleate-containing cosmetics In many cases, the rash extended and the pruritus increased several days after the application had been stopped In l/5 of the cases, a secondary extension to the face was seen, though the cosmetics had not been applied to these sites Patch testing showed positive patch tests with the undiluted final cosmetic products, ranging from 21% to 64%, depending on the individual product None of the control subjects showed a positive test reaction In addition, 60% of patients had positive or doubtful reactions to undiluted vitamin E linoleate, while none of controls had Thirteen out of 45 (29%) tested patients presented a positive or doubtful reaction to tocopheryl linoleate 10% in petrolatum Patch tests with other vitamin E derivatives induced only a few positive reactions Twelve of 15 (80%) patients who performed repeated open-application tests reacted to the body lotion containing tocopheryl linoleate; however, several also reacted to the lotion without tocopheryl linoleate Skin biopsies performed on lesional skin showed spongiosis of the follicular epidermis with a perifollicular and perivascular infiltrate containing a predominantly mononuclear clear cell infiltrate with some neutrophils An in vitro time-dependent formation of oxidative products under storage or oxidation-stimulating conditions was observed The authors conclude that oxidized vitamin E derivatives could act in vivo as haptens and/or irritants, possibly with synergistic effects.75 An allergic mechanism was later favored by the authors.76 This is a unique study of a very curious cosmetic reaction The mechanism remains unknown Several factors favor an allergic etiology, others suggest irritation rather than contact allergy Probably more than one mechanism was involved However, there can be no doubt that tocopheryl linoleate was the cause of this outbreak of cosmetic contact dermatitis Diagnostic Procedures The diagnosis of cosmetic allergy should strongly be suspected in any patient presenting with dermatitis of the face, eyelids, lips, and neck.7L78 Cosmetic allergic dermatitis may develop on previously healthy skin of the face or on already damaged skin (irritant contact dermatitis, atopic dermatitis, seborrheic dermatitis,, allergic contact dermatitis from other sources) Also, dermatitis of the arms and hands may be caused or worsened by skin-care products to treat or prevent dry skin and irritant or atopic dermatitis Patchy dermatitis in the neck and around the eyes is suggestive of cosmetic Clinics in Dermatology l 1998;16:167-179 allergy from nail lacquers or hardeners A thorough history of cosmetic usage should always be obtained It must be stressed that most women think of “cosmetics” in terms of decorative cosmetics such as eye shadow, rouge, lipsticks, hair colors, and nail lacquers Therefore, it is necessary to specifically inquire about products such as day and night cream, cleansers, makeup removing pads, perfume, eye cream, and so forth The “classic” cosmetic dermatitis of periorbital dermatitis may be caused by any product used on the hair, the scalp, the face, the hands, and the nails When the diagnosis of cosmetic allergy is suspected, patch tests should be performed to confirm the diagnosis and identify the sensitizer Only in this manner can the patient be counseled about future use of cosmetic (and other) products and the prevention of recurrences of dermatitis from cosmetic or noncosmetic sources Patch tests should be performed with the NACDG or EECDRG routine series, a “cosmetic series” containing known cosmetic allergens, and, of course, all products used by the patient The NACDG routine series contains a number of allergens that may cause allergic cosmetic dermatitis: rosin (colophony, an indicator for perfume allergy, and a possible allergen in eyeshadow); the preservatives diazolidinyl urea, imidazolidinyl urea, formaldehyde and quaternium-15; the fragrances cinnamic aldehyde and cinnamic alcohol and balsam of Peru (indicator for perfume sensitivity); the hair color p-phenylenediamine; and lanolin alcoho1.26The EECDRG routine series contains colophony, balsam of Peru, the fragrance mix, formaldehyde, quaternium-15, methyl(chloro)isothiazolinone, wool alcohols, and p-phenylenediamine A suggested “cosmetic series” is shown in Table Most of these allergens are available from Chemotechnique (Malmo, Sweden) or from Hermal Chemie (Reinbek/Hamburg, Germany) Although the patient’s products should always be tested (for test concentrations, see Table 2), patch testing with cosmetics has some important drawbacks Patients often use many cosmetic products, which makes the investigation very laborious More importantly, both false-negative and false-positive reactions occur frequently False-negative means that the patient is allergic to a certain cosmetic, but the patch test reaction to the product itself remains negative This is due to the low concentration of some allergens and the usually weak sensitivity of the patient The product does cause allergic cosmetic dermatitis when applied repeatedly (eg daily), when applied to damaged (dry or eczematous) skin, or when applied to very sensitive skin, for example, the eyelids One application on the thick and intact skin of the back, even under occlusion (as is the case with patch testing) is insufficient to cause a positive patch test reaction Classic examples of false-negative reactions are with methyl(chloro)isothiazolinone and paraben sensitivity.34,“6 Therefore, such allergens have to be routinely Clinics in Dermatology l 1998;16:167-2 Table 79 THE SHADY SIDE OF COSMETICS 175 Suggested Allergens for a “Cosmetic Screening Series” Allergen Test Concentration and Vehicle Function Amerchol L lOl* Benzophenone-3 (oxybenzone) Benzophenone-10 (mexenone) BHA (butylated hydroxyanisole) BHT (butylated hydroxytoluene) 2-Bromo-2-nitropropane-1,3-diol Cetearyl alcoholt Cocamidopropyl betaine Diazolidinyl meaS Fragrance mix§ Glyceryl thioglycolate Imidazolidinyl urea$ Isopropyl dibenzoylmethane Methyl(chloro)isothiazolinone§ Methyldibromo glutaronitrile Octyl dimethyl PABA PABA Parabenss Propolis Propylene glycol Toluenesulfonamide/formaldehyde resinq[ Emulsifier Sunscreen Sunscreen Antioxidant Antioxidant Preservative Emulsifier Surfactant Preservative Fragrance Permanent waving Preservative Sunscreen Preservative Preservative Sunscreen Sunscreen Preservatives Natural ingredient Humectant Nail lacquer resin agent 50% pet 2% pet 2% pet 2% pet 2% pet 0.5% pet 30% pet 1% water 2% water or pet 8X1% pet 1% pet 2”%i pet 2% pet 100 ppm in water 0.5% pet 2% pet 2% pet 5X3% pet 10% pet 10% water 10% pet pet= petrolatum * INCl name: innolin alcohol and paraffinurn liquidurn f 1NCl nnme: cetyl alcohol, stearyl alcohol #Present in the NACDG series Present in the EECDRG series y TNCJ name: tosylamide/formaldehyde resin tested in the appropriate concentration in a cosmetic screening series False-positive reactions may occur with any cosmetic product, but especially with products containing detergents/surfactants such as shampoo, soap, bath, and shower foam As a consequence, these products are usually diluted to 1% in water before testing Even then, mild irritant reactions are observed frequently; and, of course, the (necessary) dilution of Table Products Recommended Test Concentrations for Cosmetic Cosmetic Product Test Concentration Bleach Depilatory Foaming bath product Foaming cleanser Hair dyes Mascara Nail cuticle remover Nail glue Nail polish Nail polish remover Permanent wave solution Shampoo Shaving lather or cream Skin lightener Soap or detergent Straightener Toothpaste Ammonium persulfate 1% pet Thioglycolate 1% pet 1% Water 1% Water 2% Water Pure (allow to dry) Individual ingredients Individual ingredients Pure (allow to dry) Individual ingredients Glyceryl thioglycolate 1% pet 1% Water 1% Water Hydroquinone 1% pet 1% Water Individual ingredients 2% Water Adapted from De Groat, Weijlmd and N&r.” Most cosmetics not mentioned in this table cm be tested undiluted and Vehicle these products may result in false-negative results in patients who are actually allergic to them Testing these products, therefore, is highly unreliable In many cases, testing with the NACDG/EECDRG routine series, the suspected products, and a cosmetic screening series will establish the diagnosis of cosmetic allergy and identify one or more contact allergens On the incriminated product or the label can be found whether or not the product actually contains the allergen(s) If not, the possibility of a false-positive reaction to the product should be suspected The test should be repeated and/ or control tests on nonexposed individuals should be performed If allergy is confirmed, an ingredient of the product that was not tested in the NACDG/EECDRG series and the cosmetic screening series may have been responsible In such cases, the manufacturer should be asked for samples of the ingredients, and these can be tested on the patient after proper dilution.79 In certain cases, allergy to cosmetics is strongly suspected, but patch testing remains negative In such patients, ROAT and/or usage tests can be performed In the ROAT, the product is applied twice daily for a maximum of 14 days to the antecubital fossa A negative reaction after weeks makes sensitivity highly unlikely This procedure should be performed with all suspected products In the usage test, all cosmetic products are stopped until the dermatitis has disappeared Then, cosmetics are reintroduced as normally used, one at a time, with an interval of days for each product, 176 DE GROOT until a reaction develops Diagnostic problems with propylene glycol were discussed in a previous section Photopatch testing should be performed whenever photoallergic cosmetic dermatitis is suspected When all tests have remained negative, the possibility of seborrheic dermatitis (scalp, eyelids, face, axillae, trunk), atopic dermatitis (all locations), irritant contact dermatitis (also from cosmetic products), and allergic contact dermatitis from other sources should first be considered Therapy and &even tion The therapy of allergic cosmetic dermatitis consists of discontinuation of the (suspected) allergenic product(s) and, if necessary, topical (and rarely systemic) steroids To prevent recurrences, the patient should receive the Cosmetic, Toiletry and Fragrance Association (CTFA) names (United States) or INCI names (European Union) of the allergen(s) identified, and be instructed to avoid cosmetic and non-cosmetic products containing them and possible cross-reacting (chemically-related) substances Cosmetic ingredient labelling enables the patient to choose products not containing these In the case of contact allergy to fragrances, balsam of Peru and possibly colophony, unfragranced products should be used In some patients a fragrance may sometimes be applied to clothing or hair without eliciting an allergic response “Connubial contact” (ie from the partner) with fragrances should be avoided.6 Many allergens in cosmetics are relatively easy to avoid, because they are used only or mainly in cosmetics Others have many applications (eg methyl(chloro)isothiazolinone), and some are impossible to avoid (eg formaldehyde) Finally! Ingredient Labelling in the European Union New Opportunities but Also New Problems Cosmetic ingredient labelling (introduced in the United States already 20 years ago!) has been a constant demand of European dermatologists and allergists for years 12,80,8* The benefits are obvious: dermatologists have a better chance to identify allergens in products used by their patients; and, if a patient is allergic to one or more cosmetic ingredients, he or she can avoid products containing this ingredient On January lst, 1997, the 6th Amendment to the European Union Cosmetics Directive (76/768) came into force This directive requires, among others, that all cosmetic products marketed in the European Union display their ingredients on the outer package or, in certain cases, on an accompanying leaflet, label, tape, or tag.82 The primary purpose of ingredient labelling is to allow dermatologists to identify specific ingredients that cause allergic responses in their patients and enable such patients to avoid cosmetic products containing the Clinics in Dermatology l 1998;16:167-179 substances to which they are allergic by checking their labels.l* The nomenclature used throughout the European Union for labelling is the INCI (International Nomenclature Cosmetic Ingredient), based on the (American) CTFA (Cosmetic, Toiletry and Fragrance Association) nomenclature Most CTFA terms have been retained unchanged All colorants are listed as color index (CI) numbers, except hair dyes, which have INCI names Plant ingredients are declared as genus/ species using the Linnaean system The source of information on ingredients is the European Inventory published in all official European Union languages Provided are the INCI names (in alphabetical order), CAS-number, EINECS-ELINCS numbers, chemical/IUPAC names, and functions EINECS = European inventory of existing commercial chemical substances and ELINCS = European list of notified chemical substances We have found that the inventory has several disadvantages The major problem is the “translation” of plant products and colors from the CTFA nomenclature to the INCI Lists of synonyms are not provided Only those who have access to botanical literature and specific literature on colors can find relevant names Apart from the fact that we will have to get used to some very exotic names, who would be able to find “Myroxylon Pereirae” for balsam of Peru, “Eugenia caryophyllus” for clove oil or “CI 77000” for aluminum? The order of listing is sometimes rather illogical: for p-aminophenol, look under “pa .” instead of “Am .“ Benzophenone-11 comes before benzophenone-2 (because 11 begins with 1, thus lower than 2) It is stated that fragrances have not been included in the INCI, because they need not to be declared; however, we found many fragrance names (eg geraniol, hydroxycitronellal, cinnamal, cinnamyl alcohol) Their function is described as “additives” Additives are defined as “Substances which, often in fairly small amounts, are added to cosmetic products to create or improve desired properties or minimize or suppress undesired properties” In this context one may think of “masking perfumes”, the classic example of which is ethylene brassylate (indeed mentioned in the inventory) We not know whether producers of cosmetics will actually declare such fragrances on the label In addition, dermatologists will have to check the inventory as to whether or not a specific fragrance is included before advising patients allergic to these individual fragrance compounds In spite of the fact that fragrances not need to be declared, part II of the inventory lists some 2500 fragrances (including plant extracts) and aroma chemicals In itself this could be very useful; however, the chemicals are not listed in alphabetical order, but in order of ascending EINECS/ELINCS numbers, and thus impossible to trace for almost all dermatologists Clinics in Dermatolq~y l 1998;16:167-2 79 Evidently, patients allergic to certain ingredients of cosmetics should be supplied with the INCI names of their allergens They will fruitlessly seek for names such as Kathon CG, oxybenzone, balsam of Peru, Amerchol L 101, dibromodicyanobutane, or orange oil Therefore, dermatologists should be familiar with INCI names From the above it is clear that the relevant names are sometimes very hard or impossible to find To overcome this problem, a list of substances that can be present in cosmetics and have been described as allergens was made, and their names (CTFA, Merck Index, names provided by the producers of commercially available allergens [Chemotechnique, Trolab], “common names”, commonly used trade names) were compared with INCI 3,h All allergens for which the INCI names were different were tabulated alphabetically.83 In spite of these shortcomings, ingredient labelling will be extremely useful to dermatologists, allergic patients, and interested consumers References De Groot AC, Nater JP, van der Lende R, et al Adverse effects of cosmetics: A retrospective study in the general population Int J Cosm Sci 1987;9:255-9 Berne B, Lundin A, Enander Malmros I Side effects of cosmetics and toiletries in relation to use A retrospective study in a Swedish population Eur J Dermatol 1994;4: 189-93 De Groot AC, Weijland JW, Nater JP Unwanted effects of cosmetics and drugs used in dermatology 3rd ed Amsterdam: Elsevier, 1994:422-724 De Groot AC, White IR Cosmetics and skin care products In: Rycroft RJG, Menne T, Frosch PJ, editors Textbook of contact dermatitis 2nd ed Berlin: Springer-Verlag, 1995: 461-76 De Groot AC Cosmetics In: JD Guin, editor Practical contact dermatitis New York: McGraw-Hill, 1995:333-54 De Groot AC, Frosch PJ Adverse reactions to fragrances A clinical review Contact Dermatitis 1997;36:57-86 Adams RM, Maibach HI A five-year study of cosmetic reactions J Am Acad Dermatol 1985;13:1062-9 Lan LR, Lee JYY, Kao HF, et al Persistent light reaction with erythroderma caused by musk ambrette Cutis 1994; 54~167-70 Du Menage H, Ross JS, Norris PG, et al Contact and photocontact sensitization in chronic actinic dermatitis; Sesquiterpene lactone mix is an important allergen Br J Dermatol 1995;132:543-7 10 Szczurko C, Dompmartin A, Michel M, et al Photocontact allergy to oxybenzone: Ten years of experience Photodermatol Photoimmunol Photomed 1994;10:144-7 11 Jeanmougin M, Manciet JR, Pons-Guiraud A, et al Contact and photocontact allergies to sunscreens A six-year experience Nouv Dermatol 1994;13:372-8 12 De Groot AC Labelling cosmetics with their ingredients Br Med J 1990;300:1636-8 13 Nielsen NH, Menne T Allergic contact sensitization in an THE SHADY SIDE OF COSMETICS 177 unselectedDanish population Acta Derm Venereol 1992; 72:456-60 14 Liden C, Berg M, F;irm G, et al Nail varnish allergy with far-reaching consequences.Br J Dermatol 1993;128:57-62 15 De Groot AC, Bruynzeel DP, BosJD, et al The allergensin cosmetics.Arch Dermatol 1988;124:525-9 16 De Groot AC Cocamidopropyl betaine: A “new” impor- tant cosmeticallergen Dermatosen 1997;45:60-3 17 De Groot AC, van der Walle HB, Weijland JW Contact allergy to cocamidopropyl betaine Contact Dermatitis 1995;33:419-22 18 De Groot AC Contact allergens-What’s new? Cosmetic dermatitis Clin Dermatol 1997;15:485-91 19 De Groot AC, van Ginkel CJW, Weijland JW Methyldibromoglutaronitrile (Euxyl K 400): An important “new“ allergen in cosmetics J Am Acad Dermatol 1996;35:743-7 20 De Groot AC, de Cock PAJJM, Coenraads PJ, et al Methyldibromoglutaronitrile is an important contact allergen in the Netherlands Contact Dermatitis 1996;34:118-20 21 Fransway AF The problem of preservation in the 1990s.I Statement of the problem, solution(s) of the industry and the current use of formaldehyde and formaldehyde releasing biocides Am J Contact Dermat 1991;2:6-23 22 Fransway AF, Schmitz NA The problem of preservation in the 1990s II Formaldehyde and formaldehyde-releasing biocides: Incidences of cross-reactivity and the significance of the positive response to formaldehyde Am J Contact Dermat 1991;2:78-88 23 Fransway AF The problem of preservation in the 1990s III Agents with preservative function independent of formaldehyde release Am J Contact Dermat 1991;2: 145-74 24 Rosen M, McFarland AG Free formaldehyde in anionic shampoos J Sot Cosm Chem 1984;35:157-69 25 Council on Scientific Affairs Formaldehyde JAMA 1989; 261:1183-7 26 Marks JG, Belsito DV, DeLeo VA, et al North American Contact Dermatitis Group standard tray patch test results (1992to 1994).Am J Contact Dermat 1995;6:160-5 27 Parker LU, Taylor JS A 5-year study of contact allergy to quaternium-15 Am J Contact Dermat 1991;2:231-4 28 Jacobs M-C, White IR, Rycroft RJG, et al Patch testing with preservatives at St John’sfrom 1982to 1993.Contact Dermatitis 1995;33:247-54 29 Storrs F, Bell DE Allergic contact dermatitis to 2-bromo2-nitropropane-1,3-diol in a hydrophilic ointment J Am Acad Dermatol 1983;8:157-64 30 Peters MS, Connolly SM, Schroeter AL Bronopol allergic contact dermatitis Contact Dermatitis 1983;9:397-401 31 Frosch PJ, White IR, Rycroft RJG, et al Contact allergy to bronopol Contact Dermatitis 1990;22:24-6 32 De Groot AC, van Joost T, Bos JD, et al Patch test reactivity to DMDM hydantoin Relationship to formaldehyde Contact Dermatitis 1988;18:197-201 33 Menne T, Hjorth N Routine testing with paraben esters Contact Dermatitis 1988;19:189-91 34 De Groot AC, Weijland JW Kathon CG: A review J Am Acad Dermatol 1988;18:350-8 35 De Groot AC Methylisothiazolinone/methylchloroisothiazolinone (Kathon CG) allergy: An updated review Am J Contact Dermat 1990;1:151-6 178 Clivrics in Dermakdogy DE GROOT 36 Marks JG, Moss JN, Parno JR, et al Methylchloroisothiazolinone/methylisothiazolinone (Kathon CG) biocideUnited States multicenter study of human skin sensitization Am J Contact Dermat 1990;1:157-61 37 Fransway AF Sensitivity to Kathon CG: Findings in 365 consecutive patients Contact Dermatitis 1988;19:342-7 38 Frosch PJ, Hannuksela M, Andersen KE, et al Chloromethylisothiazolinone/methylisothiazolinone (CMI/MI) use test with a shampoo on patch-test-positive subjects Contact Dermatitis 1995;32:210-7 39 Conde-Salazar L, Baz M, Guimaraens D, et al Contact dermatitis in hairdressers: Patch test results in 379 hairdressers Am J Contact Dermat 1995;6:19-23 40 Guerra I,, Bardazzi F, Tosti A Contact dermatitis in hairdressers’ clients Contact Dermatitis 1992;26:108-11 41 Funk JO, Maibach HI Propylene glycol dermatitis: reevaluation of an old problem Contact Dermatitis 1994;31: 236-41 42 Aberer W, Fuchs Th, Peters K-P, et al Propylenglykol: Kutane Nebenwirkungen und Testmethodik Dermatosen 1993;41:25-7 43 Wahlberg JE Propylene glycol: Search for a proper and nonirritant patch test preparation Am J Contact Dermat 1994;5:156-9 44 Tosti A, Guerra L, Vincenzi C, et al Contact sensitization caused by toluene sulfonamide-formaldehyde resin in women who use nail cosmetics Am J Contact Dermat 1993;4:150-3 45 Hausen BM Nagellack-Allergie H+G Z Hautkr 1994;69: 252-62 46 Hausen BM, Milbrodt M, Koenig WA The allergens of nail polish (I) Allergenic constituents of common nail polish and toluenesulfonamide-formaldehyde resin (TSF-R) Contact Dermatitis 1995;33:157-64 47 Giorgini S, Brusi C, Francalanci S, et al Prevention of allergic contact dermatitis from nail varnishes and hardeners Contact Dermatitis 1994;31:325-6 48 Kardorff B, Fuchs M, Kunze J Kontaktallergien auf Nagellack Akt Dermatol 1995;21:349-52 49 Hausen BM A simple method of determining TS-F-R in nail polish Contact Dermatitis 1995;32:188-9 50 Kanerva L, Lauerma A, Jolanki R, et al Methyl acrylate: A new sensitizer in nail lacquer Contact Dermatitis 1995;33: 203-4 51 Rosenzweig R, Scher RK Nail cosmetics: Adverse reactions Am J Contact Dermat 1993;4:71-7 52 Bamett JM, Scher RK Nail cosmetics Int J Dermatol1992; 31:675-81 53 Kanerva L, Lauerma A, Estlander T, et al Occupational allergic contact dermatitis caused by photobonded sculptured nails and a review of (meth)acrylates in nail cosmetics Am J Contact Dermat 1996;7:109-15 54 Carmichael AJ, Foulds IS, Bradbury DS Loss of lanolin patch-test reactivity Br J Dermatol 1991;125:573-6 55 Freeman S, Frederiksen P Sunscreen allergy Am J Contact Dermat 1990;1:240-3 56 Dromgoole SH, Maibach HI Sunscreen intolerance: Contact and photocontact sensitization and contact urticaria J Am Acad Dermatol 1990;22:1068-78 57 Funk JO, Dromgoole SH, Maibach HI Sunscreen intolerance, Contact sensitization, photocontact sensitization, 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 l 1998;26:267-179 and irritancy of sunscreen agents Dermatol Clin 1995;13: 473-81 Foley P, Nixon R, Marks R, et al The frequency of reactions to sunscreens: Results of a longitudinal populationbased study on the regular use of sunscreens in Australia Br J Dermatol 1993;128:512-8 Pons-Guiraud A, Jeanmougin M Allergie et photo-allergie de contact aux cremes de photoprotection Ann Dermatol Venereol 1993;120:727-31 Trevisi I’, Vincenzi C, Chierewgato C, et al Sunscreen sensitization: A three-year study Dermatology 1994;189: 55-7 Goncalo M, Ruas E, Figueiredo A, et al Contact and photocontact sensitivity to sunscreens Contact Dermatitis 1995;33:278-80 Parry EJ, Bilsland D, Morley WN Photocontact allergy to 4-tert-butyl-4’-methoxy-dibenzoylmethane (Parsol 1789) Contact Dermatitis 1995;32:251-2 B&land D, Ferguson J Contact allergy to sunscreens chemicals in photosensitivity dermatitis/actinic reticuloid syndrome (PD/AR) and polymorphic light eruption Contact Dermatitis 1993;29:70-3 Fowler JF Cocamidopropyl betaine: The significance of positive patch test results in twelve patients Cutis 1993; 52:281-4 Angelini G, Foti C, Rigano L, et al 3-Dimethylaminopropylamine: A key substance in contact allergy to cocamidopropylbetaine? Contact Dermatitis 1995;32:96-9 Pigatto PD, Bigardi AS, Cusano F Contact dermatitis to cocamidopropylbetaine is caused by residual amines: Relevance, clinical characteristics, and review of the literature Am J Contact Dermat 1995;6:13-6 Angelini G, Rigano L, Foti C, et al Contact allergy to impurities in surfactants: Amount, chemical structure and carrier effect in reactions to 3-dimethylaminopropylamine Contact Dermatitis 1996;34:248-52 Basketter DA, Lea L, Ross JS Does DMAPA play a role in CAPB allergy? In Book of abstracts, Jadassohn Centenary Congress, London, 9-12 October 1996;44 Aalto-Korte K, Jolanki R, Estlander T, et al Occupational allergic contact dermatitis caused by Euxyl K 400 Contact Dermatitis 1996;35:193-4 De Groot AC, Bruynzeel DP, Coenraads PJ, et al Frequency of allergic reactions to methyldibromoglutaronitrile (1,2-dibromo-2,4-dicyanobutane) in The Netherlands Contact Dermatitis 1991;25:270-1 Tosti A, Guerra L, Bardazzi F, et al Euxyl K 400: A new sensitizer in cosmetics Contact Dermatitis 1991;25:89-93 Tosti A, Vincenzi C, Trevisi I’, Guerra L Euxyl K 400: Incidence of sensitization, patch test concentration and vehicle, Contact Dermatitis 1995;33:193-5 Schnuch A, Geier J, Die haufigsten Kontaktallergene im zweiten Halbjahr 1993 Dermatosen 1994;42:210-1 De Groot AC, van Ginkel CJW, Weijland JW How to detect sensitization to Euxyl K 400 Contact Dermatitis 1996;34:373 Perrenoud D, Homberger HP, Auderset PC, et al An epidemic outbreak of papular and follicular contact dermatitis to tocopheryl linoleate in cosmetics Dermatology 1994;189:225-33 Perrenoud D, and the Swiss Contact Dermatitis Research Clinics irz Dermatolqgy l 1998;16:167-179 Group Papular and follicular contact dermatitis: Irritation and/or allergy? Curr Probl Dermatol 1995;23:9-17 77 Dooms-Goossens A The red face: Contact and photocontact dermatitis Clinics in Dermatology 1993;ll: 289 -95 78 Dooms-Goossens A Cosmetics as causes of allergic contact dermatitis Cutis 1993;52:316-20 79 De Groot AC Patch testing: Test concentrations and vehicles for 3700 allergens, 2nd edition Amsterdam: Elsevier, 1994 THE SHADY SIDE OF COSMETICS 179 80 De Groot AC, White IR Cosmetic ingredient labelling in the European Community Contact Dermatitis 1991;25: 273-5 81 Elsner P What is the state of cosmetic labelling in Europe? Am J Contact Dermat 1993;4:198-200 82 Dillarstone A Letter to the Editor Contact Dermatitis 1996;35:64-5 83 De Groot AC, Weijland JW Conversion of common names of cosmetic allergens to the INCI-nomenclature Contact Dermatitis 1997;37:145-50