Allergy and Hypoallergenic products

A. Goossens

Department of Dermatology

University Hospital

Katholieke Universiteit Leuven

Leuven, Belgium

I. Introduction

The assessment and detection of the number of contact allergic reactions to cosmetics is not simple. Generally, a consumer who has a problem with cosmetics will consult a doctor (not to say a dermatologist) only if he or she does not recognize the cause to be a particular cosmetic product or if the dermatitis persists when the suspected product as been replaced by another, determined by trial and error. Consequently, only a small proportion of the population with cosmetic intolerance problems is ever seen by a dermatologist. Moreover, cosmetic reactions may present in unusual clinical forms, which may evoke an erroneous diagnosis (e.g., 1.2.3).

In general, adverse effects are under reported (4), certainly to the cosmetics industry, which obtains its most reliable information in this regard mainly from the relatively few dermatologists who concentrate especially on cosmetic-intolerance problems and from reports in the literature, which are, almost by definition, out of date. Sometimes beauticians and consumers report adverse reactions, but, in most cases, this kind of information is difficult to objectify, unless it is verified by a dermatologist.

Application to the skin of cosmetic products may cause irritant, phototoxic, contact and photocontact allergic reactions, as well as contact urticaria. It is generally agreed that most skin adverse reactions to cosmetic products are irritant in nature and that people with "sensitive skin" such as atopic dermatitis, rosacea, or seborrheic dermatitis are particularly liable to develop such reactions. Contact allergic reactions though often get much more attention and thus have the tendency to be overestimated (4). However, the identification of the cosmetic allergen is by no means a simple task. First, it demands special skills and interest on the part of the dermatologist , -although cosmetic ingredient labeling, now also in Europe,- is facilitating his task. Moreover, there are many factors involved in the sensitization to a specific cosmetic product, all of which have to be taken into account when one seeks an allergen (1,2)( cfr. below).

II. Factors contributing to the frequency of contact allergic reactions to a cosmetic product

A. Its popularity

One may expect frequently used products to cause more skin reactions than exclusive products, simply because more people are exposed to them. Of itself, this does not imply anything about the quality of these products (the same phenomenon applies to cosmetic ingredients).

B. Its composition

The complexity of a formula can be either positive or negative as far as its allergenicity is concerned. One of the principles of creating "hypoallergenic" cosmetics and perfumes is simplicity of formula. The fewer the constituents, the easier it is to identify the offending substance should difficulties arise and the less danger their is of synergism, and, indeed, the more ingredients there are, the more chance there is of being sensitized by one of them. However, some authors recommend placing upper limits on concentrations rather than advising against the use of any particular ingredient or suggest more complex formulas (see 5 for a review).

Preservatives are needed in water-based or other easily contaminated products and are common cosmetic allergens. Apparently, it is very difficult to combine potent antimicrobial and antifungal properties with low allergenicity. It seems to be very difficult to restrict the biological activity of a substance to a single domain.

C. The concentration of its ingredients

Although the use of low concentrations does not assure complete safety, the incidence of sensitization induction is, indeed, a function of the concentration of the allergen, at least to some extent. Cases of allergy to the preservative agent (chloro)methylisothiazolinone illustrate this problem very well. At first, when a 50 ppm concentration of this agent was allowed for use in cosmetic products by EC law and when this concentration was actually used in some products, "epidemics" of contact-allergic reactions to it occurred (e.g., 6). Lately, the frequency of positive reactions to it has been diminishing considerably, not only because its use is declining and primarily limited to "rinse-off "products (3), but also because its usage concentration has been reduced to 15 to 7.5 ppm (as its manufacturers advised). Of course, once a patient has become sensitized, even low concentrations can trigger a reaction.

D. The purity of the ingredients

It is impossible to refine raw materials to absolute purity. More or less strict control of raw materials and finished products has long been a general practice in modern cosmetic manufacturing. However, one can never rule out the sensitizing potential of impurities in these materials (e.g., 5).

E. The common use of cosmetic ingredients also in other products, mainly pharmaceuticals Patients easily become sensitized to topical pharmaceutical products which are most often used on diseased skin, in contrast to cosmetics. Once sensitization has occurred, however, they may also react to cosmetics containing the same ingredients (e.g., 5).

F. The role of cross-sensitivity

Chemically related substances are likely to induce cross reactions and contact eczematous lesions may be maintained in this way. This is especially the case with perfume ingredients which often cross react with each other, but applies to all other cosmetic ingredients as well.

G. The use of penetration-enhancing substances

The chemical environment can substantially affect the sensitizing potential of individual chemicals. For example, emulsifiers and solvents enhance skin penetration and, thereby, contact sensitization. Penetration-enhancing agents can also be the root of false-negative patch-test reactions: the cosmetic product itself may be clearly allergenic (or irritant) while the individual ingredients, abstracted from the environment of the product and tested separately, may not cause a reaction.

H. Its application site

Some areas of the skin, like the eyelids, are particularly prone to contact dermatitis reactions. A cream applied to the entire face, as is the case with face-care products, but also hair products may cause an allergic reaction only on the eyelids. Moreover, "ectopic dermatitis" (caused by the transfer of the allergen by the hand, as often occurs with tosylamide/formaldehyde (= para-toluenesulfonamideformaldehyde) resin, the allergen in nail polish), "airborne" contact dermatitis (e.g., due to perfumes -7), as well as "connubial" dermatitis (caused by products used by the partner,8) often occur only on "sensitive" skin areas such as the eyelids, the lips, and the neck.

Moreover, the penetration potential of cosmetics is heightened in certain "occluded" areas, such as the body folds (axillary, inguinal), and the anogenital region, which also increases the risk of contact sensitization. In the former cases, the allergenic reactions tend to persist for weeks after the contact with the allergen had ceased. This may be partly due to residual contamination of clothing but also to the increased penetration of the allergen which is certainly assisted by occlusion and friction (e.g., 9): a reservoir may be formed from which the allergen is subsequently released.

I. The condition of the skin

Application, for example, on damaged skin, that is, where the skin barrier is impaired, enhances the penetration of substances and thus increases the risk of an allergic reaction. This is, for example, the case with body-care products intended to be used to alleviate dry, atopic skin and with barrier creams for protecting the hands, which themselves often give rise to irritancy problems (dryness, cracking, etc). In some cases, the allergic reaction may be limited to certain areas of the skin (areas already affected react more readily to another application of the same allergen) and may even present an unusual clinical picture that does not immediately suggest contact dermatitis. Indeed, a number of cases of contact-allergic reactions to preservative agents on the face may present as a lymphocytic infiltrate or even a lupus erythematous-like picture (3,10).

J. The contact time

In the world of cosmetics, a distinction is now being made between leave-on products, which are intended to remain on the skin for several hours like face- and body-care products and make-up, and rinse-off products, which are intended to be removed immediately.

The division between these two kinds of products, however, is not always relevant to the sensitization process because a thin film can remain on the skin and be sufficient to allow penetration of certain ingredients. This is the case with, for example, moist toilet paper (with mainly preservatives as the allergens) and make-up removers.

K. The frequency of application and cumulative effects

Daily use or use several times a day of cosmetics may cause ingredients to accumulate in the skin, thus increasing the risk of adverse reactions. In fact, the concentration of an ingredient may be too low to induce sensitivity in a single product but may reach critical levels in the skin if several products containing it are used consecutively. This may be the case for people who tend to be loyal to the same brand of, for example, day and night creams, foundations, and cleansing products, since a manufacturer will often use only one preservative system for all of its products. This should be taken into consideration by companies that use biologically active ingredients such as preservative agents, emulsifiers, anti-oxidants, and perfumes, since it might well account for many of the adverse reactions to these particular substances. In our experience, intense users of cosmetics are more prone to cosmetic dermatitis than others.

III. Correlations between the nature of allergenic cosmetic products and the location of the lesions

Like many other contact allergens, cosmetics can reach the skin in several different ways (1,2): by direct application; by airborne exposure to vapors, droplets, or particles that are released into the atmosphere and then settle on the skin ‘e.g., 7); by contact with people (partners, friends, co-workers) who transmit allergens to cause “connubial” or “consort” dermatitis(e.g., 8); by transfer from other sites on the body, often the hands, to more sensitive areas such as the mouth or the eyelids (“ectopic” dermatitis); and in association with exposure to the sun with photoallergens.

The most common sources of cosmetic allergens applied directly to the body are listed in Table 1.

IV. The nature of cosmetic allergens

-Fragrance ingredients are the most frequent culprits in cosmetic allergies, which is in agreement with the literature(11-15). Katsarar et al., who investigated the results of patch testing over a 12-year period, found an increasing trend in sensitivity to fragrance compounds, which reflects the effectiveness of the advertising of fragranced products (16). Common features of a fragrance contact dermatitis are:

- axillary dermatitis

- dermatitis of the face (including the eyelids) and neck

- well-circumscribed patches in areas of dabbing-on perfumes( wrists, behind the ears) and (aggravation of) hand eczema.

Airborne or connubial contact dermatitis should be considered as well.

Other less frequent adverse reactions to fragrances are: photocontact dermatitis, contact urticaria, irritation, and pigmentation disorders (17).

Sensitization is, in most cases, induced by highly perfumed products, such as toilet waters, after-shave lotions, and deodorants, the latter of which have recently been shown to contain well-known allergens, such as cinnamic aldehyde and iso-eugenol (18).

As reported in the literature, the fragrance mix remains the best screening agent for contact allergy to perfumes for it detects some 70 to 80% of all perfume allergies (19, 20), however, it depicts also the need for additional perfume allergy markers.

-Preservatives follow in the second place; they are important allergens in cleansers, skin-care products and make-up (12,21). Within this class important shifts have occurred over the years, however.

The methyl(chloro)isothiazolinone mixture was commonly used in the 1980s and was then a frequent cause of contact allergies; this frequency has declined considerably in recent years (3,12). Since then, formaldehyde and its releasers, and particularly methyldibromoglutaronitrile (=dibromodicyanobutane)-as used in the mixture with phenoxyethanol, better known as EUXYL K400- did gain in importance in this regard (e.g., 12,21-25), although the frequency of positive reactions observed seems to be influenced by the patch test concentration (24,25).

The spectrum of the allergenic preservatives also differs from country to country. For example, in contrast to continental Europe where reactions to methyl(chloro)isothiazolinone and later on methyldibromoglutaronitrile have been the most frequent in the past (e.g. 12,13,21,26), in the U.K. formaldehyde and its releasers have always been much more important, particularly as concerns quaternium-15 (21), although its incidence seems to have slightly decreased recently (27). Parabens are rare but potential causes of cosmetic dermatitis; in most cases, topical pharmaceutical (or other products, e.g., 28) are the primary sensitization sources. Recently, we could observe another example in this regard (data in file): a young lady who, after having previously been sensitized to mefenesin in a rubefacient, presented with an acute contact dermatitis on the face at the first application of a new cosmetic cream containing chlorphenesin, used as a preservative agent. Apparently it is a potential sensitizing agent (29), and probably cross reacts to the pharmaceutically used mefenesin.

-Antioxidants only repesent a minor group of cosmetic allergens. Examples are propyl gallate (may cross react with other gallates, also used as food additives), and t-butyl hydroquinone, a well-known allergen in the U.K., in contrast to continental Europe (e.g., 21).

-With regard to "active" or category-specific ingredients, in contrast to de Groot (3), we found an increase of the number of reactions to oxidative type hair dyes (PPD and related compounds) during the period 1991-1996, compared to the period 1985-1990 (12,13). According to one cosmetic manufacturer (personal communication), the use of such hair

dyes has more than doubled in recent years. However, the replacement since 1987 of PPD-hydrochloride by PPD-base - a more appropriate screening agent for PPD-allergy -might also have influenced it (30). They are important causes of professional dermatitis in hairdressers , who also often react to allergens in bleaches (persulfates, also causes of contact urticaria), permanent-wave solutions ( primarily glycerylmonothioglycolate which may provoke cross-sensitivity to ammoniumthioglycolate), and sometimes shampoos e.g., cocamidopropylbetaine and formaldehyde (31-32). Sodium pyrosulfite (or metabisulfite) was recently also found to be a professional allergen due to its presence in oxidative hair dyes (data on file).

Tosylamide/formaldehyde (= toluenesulfonamide formaldehyde) resin is considered to be an important allergen (e.g., 4) and is the cause of "ectopic" dermatitis due to nail lacquer, which also may contain epoxy and (meth)acrylate compounds, 3); it often gives rise to confusing clinical pictures, even mimicking professional dermatitis (33).

(Meth)acrylates are also causes of reactions to artificial nails preparations, more recently to gelformulations being the newest development in this regard, both in clients but particularly in manicurists (34).

Moreover, also some more recently introduced "natural" ingredients may induce contact allergic reactions; examples are: butcherbroom (=ruscus aculateus), also a potential allergen in topical pharmaceutical products (35), hydrocotyl (=asiaticoside)(36), and dexpanthenol (37). Farnesol, a well-known perfume ingredient and cross reacting agent to balsam of Peru, has become a potential allergen in deodorants, in which it is used for its bacteriostatic properties(38).

Certain sunscreen agents such as benzophenone-3 (may also cause contact urticaria) and dibenzoylmethane derivatives have been recognised in the past as being important allergens (3,21,39-41), -with isopropyldibenzoylmethane even having been withdrawn for this reason (3). On the other hand, methylbenzylidene camphor, cinnamates, and phenylbenzimidazole sulfonic acid are only occasional, sometimes even rare, causes of cosmetic reactions. The use of PABA and its derivatives has decreased considerably; Contact allergic reactions to them were generally related to their chemical relationship to para-aminocompounds (e.g. 42). They were also important photosensitizers though (39).

In our experience (12,13,21), the share of sunscreens in cosmetic allergy is relatively limited, in spite of the increase in their use due to more media attention being given to the carcinogenic effects of sunlight and accelerated aging of the skin by the sun. The low percentage of allergic reactions observed may well be because a contact allergy or a photoallergy to sunscreen products is often not recognized since a differential diagnosis with a primary sun intolerance is not always obvious. Furthermore, also the patch test concentrations might be too low (43), although irritancy has to be avoided.

-Many excipients and emulsifiers are common ingredients to topical pharmaceutical and cosmetic products, the former being likely to induce sensitization; typical examples are wool alcohols, fatty alcohols (e.g., cetylalcohol), and propyleneglycol (13). They may also be sensitizing in cosmetics though, such as for example maleated soy bean oil (e.g., 44). Emulsifiers, in particular, have mainly been regarded as irritants in the past, but their sensitization capacities should not be overlooked. However, one must conduct the patch testing properly to avoid irritancy, and determine the relevance of the positive reactions found. This is certainly the case for cocamidopropylbetaine, an amphoteric tenside mainly present in hair-and skin-cleansing products. Whether the compound itself or cocamidopropyl dimethylamine, an amido-amine, or dimethylaminopropylamine (both intermediates from the synthesis) are the actual sensitizers, is still a matter of debate (e.g., 45,46). It is also not clear whether cocamidopropyl-PG-dimonium chloride phosphate (phospholipid PTC)(47), a new allergen in skin-care products, can cross react with cocamidopropylbetaine.

Coloring agents- besides hairdyes- have been rarely reported as cosmetic allergens. With the increased use of cosmetic tattoos (e.g., eye and lip make-up), however, more treatment resistant skin lesions might develop in the future(48).

V. Diagnosing cosmetic allergy

The history of the patient and the inspection of the clinical symptoms and localisation of the lesions are crucial. Allergen identification for a patient with a possible contact allergy to cosmetics is done by means of patch testing with the standard series, specific cosmetic test series, the product itself, and all its ingredients. (We only find where we are looking for in allergy!). With regard to skin tests with cosmetic products the patients supply themselves, there are several guidelines (e.g., 49). Not only patch and photopatch tests, but also semi-open tests, usage tests or repeated open application tests (ROAT's) may need to be performed to diagnose a contact allergy.

VI. Hypoallergenic products

Most of the cosmetic industry-in part because of pressure from the outside ( consumers association, ecological groups, toxicologists, and law)-make great efforts to commercialise products that are the safest possible. Some manufacturers bring on the market cosmetics containing raw materials having a "low" sensitization index, of a high degree of purity, or from which certain components have been eliminated (e.g., 5,50). The latter mostly concern perfume ingredients, but sometimes also "active" preservative agents are omitted; the same trend is emerging in sun products, a number of which are based on the more immunologically inert physical sunscreens. Statements such as "recommended by dermatologists","allergy-tested", or "hypo-allergenic" have been put on the packaging by manufacturers trying to distinguish themselves from each other. Although there do exist several measures to reduce allergenicity (e.g., 3), there are no federally mandated standards or industry requirements (51).

The latest trends is to target marketing to people with hypersensitive skin-, an often used term for the shadowy zone between normal and pathological skin-, i.e. for people with increased neurosensitivity (e.g., atopics) or immuneresponsiveness(e.g., atopic and contact allergic individuals), or a defective skin barrier, i.e. people with irritable skin such as atopics or those suffering from seborrheic dermatitis (52) or rosacea. This means that part of the cosmetic industry is moving more into the area of pathological skin, which means that certain products become, in fact, drugs, often called cosmeceuticals. This has already has caused a great deal of regulatory concern (53-54) both in the US and the EU, because it suggests some middle category between cosmetics and drugs that does not yet legally exist, except for Japan, where regulations term this category quasi-drugs.

The meaning of most claims used nowadays is unclear both for the dermatologist (50-52) and the consumer, the latter being often convinced that all relates to allergy. It is obvious that it is the dermatologists task to diagnose the skin condition concerned and to provide specific advice about the products to be used. All problems must be approched individually , not at least the contact allergic types since people sensitive to specific ingredients must avoid products containing them.

Therefore ingredient labeling, now also in Europe, is of tremendous help, and providing the allergic patients with a limited list of cosmetics that can be used is extremely practical (e.g., 55).

VII. Conclusion

The identification of cosmetic allergens is challenging because of the extreme complexity of the problem not only for the dermatologist who tries to identify the culprit and advise his patient but certainly also for cosmetic manufacturers, who are extremely concerned about the innocuousness of their products. The precise, current, and rapid information about adverse reactions to cosmetic products is critical in product design. Apparently, pre-marketing studies are unable to identify all the pitfalls. Therefore, the fruitful communication that is developing between interested dermatologists and cosmetic manufacturers must be encouraged. Sensitivity to cosmetics will always occur, but its incidence can be substantially reduced.

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Table 1

Cosmetic and cosmetic-related dermatitis caused by direct application of the allergen

Area of Dermatitis	Cosmetics That May Contain Allergens
Face in general	Facial skin–care products (creams, lotions, masks), sunscreen products, makeup (foundations, blushes, powders), cleansers (lotions, emulsions), and cosmetic appliances (sponges), perfumed products (after–shave lotion).
Forehead	Hair–care products (dyes, shampoos
Eyebrows	Eyebrow pencil, depilatory tweezers
Upper eyelids	Eye makeup (eye shadow, eye pencils, mascara), eyelash curlers
Lower eyelids	Eye makeup
Nostrils	Perfumed handkerchiefs
Lips, mouth, and perioral area	Lipstick, lip pencils, dental products (toothpaste, mouthwash), depilatories
Neck and retroauricular area	Perfumes, toilet waters, hair–care products
Head	Hair–care products (hair dyes, permanent–wave solutions, bleaches, shampoo ingredients), cosmetic appliances (metal combs, hairpins)
Ears	Hair–care products, perfume
Trunk/upper chest, arms, wrists (elbow flexures)	Body–care products, sunscreens and self-tanning products, cleansers, depilatories
Axillae	Deodorants, antipersperants, depilatories
Anogenital area	Deodorants, moist toilet paper, perfumed pads, depilatories
Hands	Hand–care products, barrier creams, all cosmetic products that come in contact with the hands
Feet	Foot–care products, antiperspirants