Cosmetics rarely are the cause of contact urticaria; however, many cases of “subjective irritation” might actually represent very mild nonimmunological contact reactions, caused especial
Trang 1Fatal Attractiveness: The Shady Side
ANTON C DE GROOT, MD, PhD
C osmetics (which include skin-care products and
decorative cosmetics) and toiletries (which in-
clude soap, shampoo, bath-foam, and tooth-
paste) 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 cosmet-
ics are infrequent; however, mild unwanted effects are
experienced by over 10% of the population.1,2 Diagnos-
ing and treating patients with such reactions are part of
the daily routine of dermatologists In this contribution
cosmetic-related irritation, photosensitivity, and imme-
diate contact reactions will be discussed briefly; contact
allergy as a side effect of cosmetics is presented in more
detail, highlighting recently emerged important cos-
metic allergens.‘-”
Irritation
There are two forms of irritation: subjective and objec-
tive Subjective irritation may be defined as chemically
induced burning, stinging, itching, or other skin dis-
comfort without visible, objective signs of inflamma-
tion It is estimated that between 1 and 10% of all
(women) cosmetic users note this discomfort, primarily
on the face Objective irritation is defined as nonimmu-
nologically mediated inflammation of the skin Its signs
are usually mild erythema and scaling, but frank der-
matitis 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 re-
sponses to deodorants and antiperspirants Surfactants
and emulsifiers present in moisturizing or emollient
creams may also cause irritation, especially when ap-
plied 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, ‘s-
Hertogerlbosch, The Netherlands
Address correspondence to Anton C De Groot, M.D., Carolus-Liduina
Hospital, P.0 Box 3 102, 5200 BD’s-Hertogenbosch, The Netherlands
0 1998 by Elseuier Science Inc
Photosensitivity
With the exception of the epidemic caused by the halo- genated salicylanilides in the 196Os, photosensitivity has accounted for only a small proportion of cosmetic- related side effects In a study from the United States, photoallergy and phototoxicity were responsible for only 9 reactions in 713 patients investigated for cos- metic 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) recom- mended that musk ambrette not be utilized in products
in contact with skin; since then, the numbers of relevant photocontact allergic reactions have decreased consid- erably Nowadays, paradoxically as this may seem, ul- traviolet (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 aller- gic reactions to UV filters Patients with photosensitive diseases, such as chronic polymorphic light eruption (CPLE) and chronic actinic dermatitis, who use sun- screens habitually are particularly sensitive to develop- ing photocontact allergy Most cases are caused by the benzophenones (notably oxybenzone) and the UVA- filtering dibenzoylmethanes (notably isopropyl diben- zoylmethane, butyl methoxydibenzoylmethane).lOJi Other less frequent photosensitizers are p-aminoben- zoic acid @‘ABA), octyl dimethyl PABA, and ethyl- hexyl-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, result- ing in missed cases of photocontact allergy
0738-081X/98/$19.00
Trang 2Clinics izz Dermatology l 1998;16:167-179
Immediate Contact Reactions
(Contact Urticaria)
The contact urticaria syndrome may comprise cutane-
ous reactions (localized urticaria, generalized urticaria)
as well as extracutaneous reactions (bronchial asthma,
rhinoconjunctivitis, otolaryngeal symptoms, gastroin-
testinal symptoms, anaphylactic shock) Immediate
contact reactions are either nonimmunological (caused
by nonimmunological release of histamine and other
vasoactive substances) or immunological (IgE-mediat-
ed) 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 ad-
dition, immediate contact reactions to fragrance mate-
rials 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 cos-
metic 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 unrec-
ognized for several reasons.7 (1) Frequently patients
have used the causative cosmetics for many years; the
development of skin problems from such products con-
flicts 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 man-
ifested 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 exac-
erbated by cosmetic dermatitis; dermatitis caused by
emollient creams interpreted as worsening of dry skin
or atopic dermatitis for which it was applied; and con-
tact 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 pa-
tients patch tested for suspected allergic contact derma-
titis, some 10% are allergic to cosmetic products.12 Six to
11% of routinely tested individuals react to the fra-
grance mix, a mixture of 8 commonly used fragrance
materials to detect sensitization to perfumes In the list
of frequent allergens, the fragrance mix usually is num-
ber 2 after nickel sulfate.6 An estimated 1% of the gen-
eral population is allergic to fragrances, and 2-3% are
allergic to substances that may be present in cosmetics
and toiletries 12,13
Clinical 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 conse- quently, the sites of application) and the degree of the patient’s sensitivity Usually, cosmetics and their ingre- dients are weak allergens, and the dermatitis resulting from cosmetic allergy is mild: erythema, mild edema, desquamation, and papules Weeping vesicular derma- titis 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 unpub- lished observations)
Contact allergy to fragrances may resemble nummu- lar eczema, seborrheic dermatitis, sycosis barbae, or lupus erythematosus 6 Lesions in the skin folds may be mistaken for atopic dermatitis Dermatitis due to per- fumes or toilet water tends to be “streaky” Allergy to toluenesulfonamide/formaldehyde resin in nail polish may affect the fingers, 14 but 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 fre- quently 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 previ- ously healthy skin (especially the face), nails or hair Allergic cosmetic dermatitis may also be caused by products used on previously damaged skin, for exam- ple 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), de- odorants 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
Trang 3Clinics in Dermatology l 1998;16:167-179 THE SHADY SIDE OF COSMETICS 169
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 con-
sumers 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 al-
lergy to cosmetics and toiletries,>5 only 2 studies have
systematically investigated the allergens in such prod-
ucts.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 toluene-
sulfonamide/formaldehyde resin, UV-filters (more often
photocontact allergy), and various emulsifiers More re-
cently, the surfactant cocamidopropyl betaine and the
preservative methyldibromo glutaronitrile have emerged
as important cosmetic allergens.16-20
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 Formaldehyde is a frequent sensitizer and ubiquitous allergen Routine testing in patients with suspected allergic contact dermatitis yields prev- alence rates of sensitization of 3% or more, but most cases are from non-cosmetic sources The cosmetic in- dustry 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 DONORS Formaldehyde donors are pre- servatives that, in the presence of water, release form- aldehyde 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 Form- aldehyde donors used in cosmetics and toiletries in- clude quaternium-15, imidazolidinyl urea, diazolidinyl urea, 2-bromo-2-nitropropane-1,3-diol, and DMDM hy- dantoin Quaternium-15 releases the most, imidazolidi- nyl urea the least free formaldehyde.2” Contact allergy
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 Approx-
imately 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 materi-
als, of which it may contain from a few to over 300
Perfumes contain approximately 12-20% of the per-
fume 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 8 commonly used fra-
grance ingredients: cw-amylcinnamic aldehyde, cin-
namic alcohol, cinnamic aldehyde, eugenol, geraniol,
hydroxycitronellal, isoeugenol, and oak moss absolute
It is estimated that 70-80% of fragrance-allergic pa-
tients will react positively to the mix Twenty to 30%
will remain undetected, and the mix causes both false-
positive and false-negative reactions Approximately
100 fragrance materials have been identified as contact
allergens.”
to formaldehyde donors may be due either to the pre- servative itself or to formaldehyde sensitivity.21,22 Whereas the formaldehyde donors appear to be gaining
in popularity as preservatives in cosmetics, formalde- hyde itself has largely been replaced by other chemi- cals, because it is suspected (when inhaled as a gas), of being a possible human carcinogen.25
QUATERNIUM-15 (DOWICIL 2OO@) Quaternium-15 is the most frequent preservative sensitizer in cosmetic prod- ucts.’ Routine testing by the NACDG yielded a preva- lence rate of 9.6% in patients suspected of allergic con- tact 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 formalde- hyde-sensitive patients is sufficient to cause allergic cosmetic dermatitis In Europe, sensitization to quater- nium-15 is less frequent.28
IMIDAZOLIDINYL 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%.26 Cross reactions to and from the related preservative diazolidinyl urea may be observed.28
Trang 4170 DE GROOT Clitlics in Dermnfology l 1998;16:167-179
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 dermati-
tis.z6 Diazolidinyl urea appears to be a stronger sensi-
tizer than imidazolidinyl urea Patients allergic to this
preservative may or may not react to formaldehyde.2*
2-BROMO-2-NITROPROPANE-1,3-DIOL (BRONOPOL) Bro-
nopol has been responsible for so many cases of 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
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 32 In addition, provocation tests with a cream
containing 0.25% w/w DMDM hydantoin in formalde-
hyde-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
PARABENS 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 con-
centrations as used in cosmetics In Europe, routine
testing with the parabens yields low rates of sensitiza-
tion (less than 1%),33 and in the United States, 2.3%.26
Most cases of sensitization to parabens are caused from
the use of topical pharmaceutical preparations on ec-
zematous skin or leg ulcers A review of paraben sen-
sitivity has been published.23
METH~(CHLORO)ISOTHIAOUNONE MI/MCI(KathonCG@,
Euxyl K loo@) is a preservative system containing, as
active ingredients, a mixture of methylchloroisothiazolin-
one 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 be-
come a major cause of cosmetic allergy in most European
countries The subject has been reviewed.34,35 In the
United States, prevalence rates of 1.7%-1.9% (NACDG) and 3.6% (Mayo Clinic) have been observed.%,37 The 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 pa- tients 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, prev- alence rates in Europe are decreasing
Hair Colors
Hair colors may be temporary, semipermanent, or per- manent 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) ap- pears to have decreased This is attributed to the pro- vision 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 appli- cation 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 hair- dresser.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 cos- metics, 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 pro- pylene glycol has been suggested:41 (1) irritant contact dermatitis; (2) allergic contact dermatitis; (3) nonimmu- nologic contact urticaria, and (4) subjective or sensory
Trang 5Clinics in Dermatology l 1998;16:167-179 THE SHADY SIDE OF COSMETICS 171
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 ear-
lier 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 di-
agnosis 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% pro-
pylene glycol help in dividing irritant responses from
true allergic ones A negative reaction strongly suggests
a previously irritant response; a positive reaction sug-
gests 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~~ic cmtact urticaria can also occur after
topical application of propylene glycol The mechanism
entails microinjury to skin Although this does not rep-
resent a contact urticaria in the strictest sense, it is
usually categorized as such
tional Nomenclature of Cosmetic Ingredients (INCI) name: tosylamide/formaldehyde resin] The exact aller- genic ingredients of this resin are still unknown.46 Other allergens have rarely been reported: formaldehyde, ni- trocellulose (dubious), guanine, polyester resin, phtha- lates, amyl and butyl acetate, dye, ethylene dichloride, Betonite@, and o-toluenesulfonamide.45r4h
Contact allergy to toluenesulfonamide/formalde- hyde 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%.26 The resin (10% petrolatum) should always be tested on subjects using nail cosmetics, be- cause neither the history nor the clinical features are sufficient criteria for excluding or suggesting the diag- nosis.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 loss14 Allergic 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 do so.49 Also, such nail lacquers may contain other sensi- tizers, such as methyl acrylate and epoxy resin.50 Useful review articles on adverse reactions to nail cosmetics and sculptured nails have recently been published.51-53
Lanolin (Derivatives)
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 derma-
tologists It is a phenomenon that also occurs in volun-
teers 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 pro-
tect 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 cases have 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”) der-
matitis has been observed The main allergen is the
resin toluenesulfonamide/formaldehyde resin [Interna-
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 reac- tions in eczema patients.26 Most cases are caused by topical pharmaceutical preparations containing it, espe- cially 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 con- tact with lanolin or its derivatives often leads to disap- pearance 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 pho- todegradation The main classes of sunscreens are PABA and its esters (amyl dimethyl, glyceryl, octyl dimethyl), the cinnamates, the salicylates, the anthrani- lates, the benzophenones, and the dibenzoylmeth- anes.s5 The latter category is gaining popularity, be- cause it absorbs mainly in the UVA region (315-400
Trang 6172 DE GROOT Clinics in Dermatology l 2998;16:167-179
nm) UV filters have been identified with increasing
frequency as allergens and photoallergens, but reac-
tions to them remain uncommon Photoallergic reac-
tions 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 sun-
screen was used PABA is a common cause of photoal-
lergic reactions Recently, most such reactions have
been caused by benzophenones and the dibenzoyl-
methanes, isopropyl dibenzoylmethane and butyl me-
thoxydibenzoylmethane 55 The literature on adverse re-
actions 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.58 Both
allergic and photoallergic reactions are reported to the
main classes of UVA filters: benzophenones and diben-
zoylmethanes 10~9-63 Oxybenzone (benzophenone 3) es-
pecially causes many cases of photoallergic contact der-
matitis, and to a lesser extent allergic contact
dermatitis.10,59-61,63 Patients who regularly use sun-
screens 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 cases of suspected adverse reactions
to sunscreens, both patch and photopatch tests should
be performed.‘O
New Important Cosmetic Allergens
New important contact allergens do not appear every
day; however, in recent years two chemicals, the sur-
factant cocamidopropyl betaine and the preservative
methyldibromo glutaronitrile (in Euxyl@ K 400), have
emerged as important causes of allergic cosmetic der-
matitis 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 hast-
ily 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 co-
conut fatty acids (obtained from coconut oil) with di-
methylaminopropylamine, yielding cocamidopropyl di-
methylamine, which is subsequently allowed to react
with sodium monochloroacetate to give the end prod-
uct cocamidopropyl betaine The lipophilic tail is
formed by coconut fatty acids, a mixture of fatty acids
with chain lengths varying between C, and C,, Coca- midopropyl betaine is therefore a mixture of several compounds with the same basic structure, but with differing lipophilic tails Depending on the source, co- camidopropyl betaine can still contain varying amounts
of the reactants and intermediates involved in its syn- thesis A major impurity is dimethylaminopropylamine Case Reports 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 prod- uct Thus, cocamidopropyl betaine is the exception to the rule that allergic reactions are usually caused by
“stay-on” (“leave-on”) cosmetic products Other cos- metic products that have caused cosmetic allergy from the presence therein of cocamidopropyl betaine include skin-care products (moisturizing and cleansing prod- ucts), 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 hair- dressers Prevalence rates of sensitization to cocamido- propyl 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-re- lated allergic contact dermatitis and/or dermatitis of the head and neck area.64 Seven of these were consid- ered 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 be- taine.66 The products causing allergic contact dermatitis were shampoos, face cleansing lotions, gynecological antiseptic syndets, liquid shower soaps, and anal hy- gienic detergents 66 In 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 con- tams varying amounts of the reactants and intermedi- ates involved in its synthesis To determine the actual allergenic ingredient in cocamidopropyl betaine, a
Trang 7Clinics in Dernzatolqpy l 1998;16:167-179 THE SHADY SIDE OF COSMETICS 173
group of investigators tested 30 patients allergic to co-
camidopropyl 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 dim-
ethylaminopropylamine is the major allergen in coc-
amidopropyl 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 reac-
tions 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 cocamido-
propyl betaine be tested separately It is therefore
suggested to include cocamidopropyl betaine in the
hairdresser’s series and in the cosmetic series Coca-
midopropyl betaine in the usual and commercially
available concentration of 1% in water is a marginal
irritant, and not all “positive” patch test reactions indi-
cate (relevant) contact allergy to it Relevance can be
established only when allergic patients are actually ex-
posed to products containing cocamidopropyl betaine,
and avoidance results in clearing or obvious improve-
ment of dermatitis
Mefhyldibromoglutaronitrile (EuxyP K 400)
Euxyl K 400 (Schiilke & Mayr, Norderstedt, Germany)
is a preservative system for cosmetics and toiletries,
containing 2 active ingredients: methyldibromoglut-
aronitrile (MDG; synonym: 1,2-dibromo-2,4-dicyanobu-
tane) and phenoxyethanol in a 1:4 ratio.ls-20 Typical use
concentrations are 0.05%-0.20% Euxyl@ K 400 was in-
troduced in Europe in the mid 198Os, and it has been
used in the United States for approximately 6 years In
the Netherlands in 1995,25%-35% of all cosmetic prod-
ucts 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 7 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 methyl-
dibromoglutaronitrile The first cases of contact allergy
to Euxyl K 400 were reported from Germany in 1989
Later case reports include sensitization to moistened
toilet tissues (especially in the Netherlands), skin-care products, cucumber eye gel, barrier cream gel, cleans- ing cream, ultrasonic gel, and makeup.19 In the Nether- lands, the prevalence of contact allergy to methyldibro- moglutaronitrile 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 1991- 1994.71~7z In Germany, approximately 2.3% of suspected contact dermatitis patients are currently allergic to Eu- xyl K 400 and the members of the North American Contact Dermatitis Group in 1992-1994 found a preva- lence of 1.5%.26,73 Between 23% and 75% of positive patch-test reactions are considered to be relevant Usu- ally, cosmetics, both of the stay-on and of the rinse-off variety, and, in the Netherlands, moistened toilet tis- sues, 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 estab- lished, but it may be 0.5% in petrolatum In our expe- rience, it is necessary to add an emulsifier, such as soy lecithin, to obtain homogeneous dispersions With the currently available commercial allergens, methyldibro- moglutaronitrile 0.1% pet (Trolab) and Euxyl K 400 0.5% pet (Chemotechnique), false-negative reactions may occur.74
Folliculav Reactions fo Tocopheryl Linoleafe
in Cosmef its
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 dermatolo- gists 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 Epi- demiological and clinical data incriminated a new line
Trang 8Clinics in Dermatology 1998;16:167-179
of cosmetics containing vitamin E linoleatem, a mixture allergy from nail lacquers or hardeners A thorough
of fatty acid esters of DL-a-tocopherol composed not history of cosmetic usage should always be obtained It only of tocopheryl linoleate but also of tocopheryl must be stressed that most women think of “cosmetics” oleate, palmitate, and myristate The lesions appeared in terms of decorative cosmetics such as eye shadow, after l-160 days (mean 14 days) following the initial rouge, lipsticks, hair colors, and nail lacquers There- application of the tocopheryl linoleate-containing cos- fore, it is necessary to specifically inquire about prod- metics In many cases, the rash extended and the pru- ucts such as day and night cream, cleansers, makeup ritus increased several days after the application had removing pads, perfume, eye cream, and so forth The been stopped In l/5 of the cases, a secondary extension “classic” cosmetic dermatitis of periorbital dermatitis
to the face was seen, though the cosmetics had not been may be caused by any product used on the hair, the applied to these sites scalp, the face, the hands, and the nails
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 ad-
dition, 60% of patients had positive or doubtful reac-
tions 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 vi-
tamin E derivatives induced only a few positive reac-
tions Twelve of 15 (80%) patients who performed re-
peated 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 perifollic-
ular and perivascular infiltrate containing a predomi-
nantly mononuclear clear cell infiltrate with some neu-
trophils An in vitro time-dependent formation of
oxidative products under storage or oxidation-stimulat-
ing conditions was observed The authors conclude that
oxidized vitamin E derivatives could act in vivo as
haptens and/or irritants, possibly with synergistic ef-
fects.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 irrita-
tion 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,, al-
lergic contact dermatitis from other sources) Also, der-
matitis of the arms and hands may be caused or wors-
ened 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
When the diagnosis of cosmetic allergy is suspected, patch tests should be performed to confirm the diagno- sis 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 con- tains 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 alcoho1.26 The EECDRG routine series contains colophony, balsam of Peru, the fragrance mix, formaldehyde, quaternium-15, methyl- (chloro)isothiazolinone, wool alcohols, and p-phenyl- enediamine A suggested “cosmetic series” is shown in Table 1 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 cosmet- ics 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-neg- ative 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 sensitivi- ty.34,“6 Therefore, such allergens have to be routinely
Trang 9Clinics in Dermatology l 1998;16:167-2 79 THE SHADY SIDE OF COSMETICS 175
Table 1 Suggested Allergens for a “Cosmetic Screening Series”
Allergen Function
Test Concentration and Vehicle
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 agent Preservative
Sunscreen Preservative Preservative Sunscreen Sunscreen Preservatives Natural ingredient Humectant Nail lacquer resin
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
5 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 prod-
ucts containing detergents/surfactants such as sham-
poo, 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 2 Recommended Test Concentrations for Cosmetic
Products
Cosmetic Product Test Concentration and Vehicle
Depilatory Thioglycolate 1% pet
Foaming bath product 1% Water
Foaming cleanser 1% Water
Mascara Pure (allow to dry)
Nail cuticle remover Individual ingredients
Nail glue Individual ingredients
Nail polish Pure (allow to dry)
Nail polish remover Individual ingredients
Permanent wave solution Glyceryl thioglycolate 1% pet
Shaving lather or cream 1% Water
Skin lightener Hydroquinone 1% pet
Soap or detergent 1% Water
Straightener Individual ingredients
Adapted from De Groat, Weijlmd and N&r.”
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 sus- pected, 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 nega- tive reaction after 2 weeks makes sensitivity highly unlikely This procedure should be performed with all suspected products In the usage test, all cosmetic prod- ucts are stopped until the dermatitis has disappeared Then, cosmetics are reintroduced as normally used, one
at a time, with an interval of 3 days for each product,
Trang 10Clinics in Dermatology l 1998;16:167-179
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) sub-
stances Cosmetic ingredient labelling enables the pa-
tient 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 de-
mand 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 prod-
ucts 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
substances to which they are allergic by checking their labels.l* The nomenclature used throughout the Euro- pean Union for labelling is the INCI (International No- menclature Cosmetic Ingredient), based on the (Amer- ican) 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 infor- mation on ingredients is the European Inventory pub- lished in all official European Union languages Provided are the INCI names (in alphabetical order), CAS-number, EINECS-ELINCS numbers, chemical/IU- PAC names, and functions EINECS = European inven- tory of existing commercial chemical substances and ELINCS = European list of notified chemical sub- stances
We have found that the inventory has several disad- vantages 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 spe- cific 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 (be- cause 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; how- ever, we found many fragrance names (eg geraniol, hydroxycitronellal, cinnamal, cinnamyl alcohol) Their function is described as “additives” Additives are de- fined 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 invento- ry) We do not know whether producers of cosmetics will actually declare such fragrances on the label In addition, dermatologists will have to check the inven- tory 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 do not need to be declared, part II of the inventory lists some 2500 fra- grances (including plant extracts) and aroma chemicals
In itself this could be very useful; however, the chemi- cals are not listed in alphabetical order, but in order of ascending EINECS/ELINCS numbers, and thus impos- sible to trace for almost all dermatologists