ArticlePDF Available

Cosmetic Reactions

February 2004

DOI:10.1201/9780203426272.ch51

Authors:

Jorge R Toro

National Cancer Institute (USA)

Patricia Engasser Md

Stanford Medicine

Howard I Maibach

UCSF University of California, San Francisco

…

Patch and photopatch testing

…

Figures - uploaded by Howard I Maibach

Content may be subject to copyright.

Content uploaded by Howard I Maibach

Content may be subject to copyright.

Cosmetic Reactions

SARA P MODJTAHEDI, JORGE R TORO,

PATRICIA ENGASSER, AND HOWARD I MAIBACH

Contents

51.1 Introduction

51.2 Cutaneous reactions

51.3 Ingredient patch testing

51.4 Cosmetic products

51.5 Cosmetic intolerance syndrome

51.6 Occupational dermatitis: hairdressers

CHAPTER

51.1 INTRODUCTION

The term “cosmetic” is familiar, and its meaning has been expanded by an

increase in the variety and complexity of substances used for cosmetic purposes.

There are numerous ways to deﬁne and describe cosmetics. The Food, Drug and

Cosmetic Act, which the Food and Drug Administration (FDA) administers,

deﬁnes cosmetics in the following manner:

The term “cosmetic” means articles intended to be rubbed, poured,

sprinkled, or sprayed on, introduced into, or otherwise applied to the

human body or any part thereof for cleansing, beautifying, promoting

attractiveness, or altering the appearance, and (Jackson, 1991) articles

intended for use as a component of any such articles: except the term shall

not include soap.

(Code of Federal Regulations, 1986: 20201(I), paragraph 40)

Definitions pertaining to Europe and Japan are found in Barel et al. (2001),

Elsner and Maibach (2000), Elsner et al. (1999), Baran and Maibach (1998). Note

two important aspects of this legal deﬁnition of cosmetics. First, in the United

States, cosmetics in theory do not contain “active drug” entities of any

type nor can they be promoted as altering any physiological state either in

disease or health. Many countries do not recognize this legal distinction. The

US FDA classiﬁes products into cosmetics, OTC (over-the-counter) drugs, and

prescription drugs. By the US deﬁnition, antiperspirants are OTC drugs regulated

by the FDA through the OTC drug monograph system, while deodorants are

cosmetics. The second aspect of the US deﬁnition of cosmetics is the so-called

soap exemption. Soap in the classic sense, as made of natural ingredients, is the

type of soap that is excepted by the definition above. However, if the soap

product is made of detergent chemicals (synthetic surfactants) the product is

regulated by the Consumer Product Safety Commission under the Federal

Hazardous Substances Act, as a household product. If the soap contains a

therapeutic ingredient for a medical condition it is regulated as a prescription

drug (Jackson, 1991). Likewise the classiﬁcation of cosmetics is equally complex.

The cosmetic industry itself divides the products into more general categories

oriented as to their purpose as described in the deﬁnition.

Reactions to cosmetics constitute a small but signiﬁcant portion of the cases

of contact dermatitis seen by dermatologist in the United States. In a ﬁve-year

study, the North American Contact Dermatitis Group found that 5.4 percent

511

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of 13,216 patients tested were identiﬁed as having reactions caused by cosmetics

(Adams and Maibach, 1985. This is an under-representation of the true inci-

dence because most patients who experience reactions to newly purchase

cosmetics seldom consult a physician and just stop using the suspected

cosmetic. In addition, they reported that 59 percent of the reactions caused by

cosmetics occurred on the face including the periorbital area and 79 percent

were females. Half of the cases later proven to evoke reactions to cosmetics were

initially unsuspected. Reactions to cosmetics can have a variety of presentations.

including subjective and objective irritation, allergic contact dermatitis, contact

uriticaria, photosensitive reactions, pigmentation and, hair and nail changes.

51.2 CUTANEOUS REACTIONS

51.2.1 Irritant dermatitis

Objective irritation

Skin irritation has been described by exclusion as localized inﬂammation not

mediated by either sensitized lymphocytes or by antibodies, e.g., that which

develops by a process not involving the immune system. Skin irritation depends

on endogenous and exogenous factors (Lammintausta and Maibach, 1988).

Predictive testing in human beings and rabbits can reliably detect strong or

moderate irritants as ingredients in cosmetics or the products themselves.

This allows manufacturers to test thoroughly to eliminate these potential

hazards before marketing. There is recent evidence that no signiﬁcant difference

across skin types exists (McFadden et al., 1998). Because the stratum corneum

of the facial skin is penetrated easily, more irritant reactions occur but always

recognized clinically because of the complex biology of the human face. Many

supposedly non irritating moisturizers or emollient creams contain surfactants

and emulsiﬁers that are mild irritants. These cosmetics are applied frequently

to facial or inﬂamed skin resulting in irritant reactions. In product use testing,

reproducing an irritant reaction may be difﬁcult because penetrability of the

stratum corneum varies with environmental conditions; and small panel testing

may not account for the complexity and variance of the human genome.

Provocative use testing may be performed at the original site of the reactions.

Application of some chemicals may directly destroy tissue, producing skin

necrosis at the application site. Chemicals producing necrosis that results in

formation of scar tissue are described as corrosive. Chemicals may disrupt cell

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functions and/or trigger the release, formation, or activation of autocoids that

produce local increases in blood ﬂow, increase vascular permeability, attract

white blood cells in the area, or directly damage cells. The additive effects of the

mediators result in local skin inﬂammation. A number of as yet poorly deﬁned

pathways involving different processes of mediator generation appear to exist.

Although no agent has yet met all the criteria to establish it as a mediator of skin

irritation, histamine, 5-hydrotryptamine, prostaglandins, leukotrienes, kinins

(Effendy and Maibach, 2001), complement, reactive oxygen species, and

products of white blood cells have been implicated as mediators of some irritant

reactions (Protty, 1978). Chemicals that produce inﬂammation as a result of a

single exposure are termed acute or primary irritants.

Some chemicals do not produce acute irritation from a single exposure

but may produce inﬂammation following repeated application, i.e., cumulative

irritation, to the same area of skin. Because of the possibility of skin contact

during transport and use of many chemicals, regulatory agencies have mandated

screening chemicals for the ability to produce skin corrosion and acute irrita-

tion. These studies are conducted in animals, using standardized protocols.

However, the protocols speciﬁed by some agencies vary somewhat. It is not

routinely appropriate to conduct screening studies for corrosion in humans,

but acute irritation is sometimes evaluated in humans after animal studies have

been completed. Tests for predicting irritation in both animals and humans

have been widely utilized. Predictive irritation assay in animals includes

modiﬁed Draize test repeated application patch tests, the guinea pig immersion

test and mouse ear test. Predictive human irritation assay includes many forms

of the single application patch test, cumulative irritation assays, chamber

scrariﬁcation test and exaggerated exposure test. These predictive assays have

been reviewed (Marzulli and Maibach, 1991). Currently in vitro skin corrosion

test methods are being developed that avoid using animal models (Robinson

and Perkins, 2002). Sensitive bioengineering equipment used to evaluate patho-

physiology of skin irritation includes transepidermal water loss (Effendy et al.,

1995), dielectric characteristics, skin impedance, conductance, resistance, blood

ﬂow velocity skin pH, 02resistance and C02effusion rate (Fluhr et al., 2001).

Several textbooks describe these methods in detail (Berardesca et al., 1994;

1995a, b; 2002; Wilhelm et al., 1997). Also, irritant contact dermatitis can be

avoided by prevention methods (Lofﬂer and Effendy, 2002).

COSMETIC REACTIONS

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Sensory or subjective irritation

Application of a cosmetic causing burning, stinging, or itching without

detectable visible or microscopic changes, is designated as subjective irritation.

This reaction is common in certain susceptible individuals occurring most

frequently on the face. Some of the ingredients that cause this reaction are not

generally considered irritants and will not cause abnormal responses in non-

susceptible individuals. Materials that produce subjective irritation include

dimethyl sulfoxide, some benzoyl peroxide preparations, and the chemicals

salicylic acid, propylene glycol, amyl-dimethyl-amino benzoic acid, and 2-

ethoxy ethyl-methoxy cinnamate, which are ingredients of cosmetics and over-

the-counter (OTC) drugs. Pyrethroids, a group of broad-spectrum insecticides,

produce a similar condition that may lead to paraesthesia (Cagen et al., 1984)

at the nasolabial folds, cheeks, periorbital areas, and ears.

Only a portion of the human population seems to develop nonpyrethroid

subjective irritation, and ethnic variations in self-perceived sensitive skin has

been noted (Jourdain et al., 2002). Frosch and Kligman (1977a) found that they

needed to prescreen subjects to identify “stingers” for conducting predictive

assays. Only 20 percent of subjects exposed to 5 percent aqueous lactic acid in

a hot, humid environment developed stinging response. All stingers in their

series reported a history of adverse reactions to facial cosmetics, soaps, etc.

A similar screening procedure by Lammintausta et al. (1988) identiﬁed 18 percent

of their subjects as stingers. Prior skin damage, e.g., sunburn, pretreatment with

surfactants, and tape stripping, increase the intensity of responses in stingers,

and persons not normally experiencing a response report pain on exposure to

lactic acid or other agents that produce subjective irritation (Fosch and Kligman,

1977b). Attempts to identify reactive subjects by association with other skin

descriptors, e.g., atopy, skin type, or skin dryness, have not yet been fruitful.

However, Lammintausta et al. (1988) showed that stingers develop stronger

reactions to materials causing nonimmunologic contact urticaria and some

increase in transepidermal water loss and blood ﬂow following application of

irritants via patches than those of non-stingers.

The mechanisms by which materials produce subjective irritation have

not been extensively investigated. Pyrethroids directly act on the axon by

interfering with the channel gating mechanism and impulse ﬁring (Vivjeberg

and VandenBercken, 1979). It has been suggested that agents causing subjective

irritation act via a similar mechanism because no visible inflammation is

present. An animal model was developed to rate paraesthesia to pyrethroids

DERMATOTOXICOLOGY

1026 ■

and may be useful for other agents (Cagen et al., 1984). Using this technique,

it was possible to rank pyrethroids for their ability to produce paraesthesia.

Lammintausta et al. (1988) and Berardesca et al. (1991) suggested that patients

with subjective irritation have more responsive blood vessels. Assays and tests

have been developed to quantify subjective irritation (Herbst, 2001; Pelosi

et al., 2001).

As originally published, in human subjective irritation assay volunteers were

seated in the chamber (110°F (65°C) and 80 percent relative humidity) until a

profuse facial sweating was observed (Frosch and Kligman, 1977a). Sweat was

removed from the nasolabial fold and cheek; then a 5 percent aqueous solution

of lactic acid was briskly rubbed over the area. Those who reported stinging for

3 to 5 minutes within the ﬁrst 15 minutes were designated as stingers and were

used for subsequent tests. Lammintausta et al. (1988) used a 15-min treatment

with a commercial facial sauna to produce facial sweating. The facial sauna

technique is less stressful to both subjects and investigators and produces similar

results.

51.2.2 Allergic contact dermatitis

Although allergic contact dermatitis is the most frequently diagnosed reaction

to cosmetics and its incidence is rising (Kohl et al., 2002), it is clinically suspected

initially in less than half the proven cases. Most cosmetics are a complex mixture

containing perfumes, preservatives, stabilizers, lipids, alcohols, pigments, etc.

Frequently, these components are responsible for cosmetic allergy (Ale and

Maibach, 2001). The clinical relevance of allergic contact dermatitis has been

described (Ale and Maibach, 1995).

Allergic contact dermatitis is cell-mediated. This type of skin response is

often referred to as delayed type contact hypersensitivity because of the

relatively long period (–24 h) required for the development of the inﬂammation

following exposure. Lymphocytes are responsible for producing delayed-type

hypersensitivity (DTH) and for regulation of the immune system. Lymphocytes

leaving the lymphoid organs are “programmed” to recognize a speciﬁc chemical

structure via a receptor molecule(s). If, during circulation through body tissues,

a cell encounters the structure it is programmed to recognize, an immune

response may be induced. To stimulate an immune response, a chemical must

be presented to lymphocytes in an appropriate form (Landsteiner and Jacobs,

1935). Chemicals are usually haptens, which must conjugate with proteins

in the skin or in other tissues in order to be recognized by the immune

COSMETIC REACTIONS

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system. Haptens conjugate with proteins to form a number of different antigens

that may stimulate an allergic response (Polak et al., 1974). Hapten protein

conjugates are processed by macrophages or other cells expressing proteins on

their surface. Although the exact nature of this process is not completely

understood, it is known that physical contact between macrophage and T cells

is required (Unanue, 1984). In the skin, keratinocytes produce interleukin

(Cunningham-Rundles, 1981), an important regulatory protein for induction

of DTH. Langerhans cells express Ia antigen and may act as antigen presenting

cells (Lever and Schaumberg-Lever, 1983). Histologically, the DTH response has

been described as a hyperproliferative epidermis with intracellular edema,

spongiosis, intraepidermal vesiculation, and mononuclear cell inﬁltrate by 24

h. The dermis shows perivenous accumulation of lymphocytes, monocytes, and

edema. No reaction occurs if the local vascular supply is interrupted and the

appearance of epidermal changes follows the invasion of monocytes. The

histology of the response varies somewhat by species.

Many factors modulate development of DTH in experimental animals and

humans. The method of skin exposure and rate of penetration inﬂuence the rate

of sensitization, The effects of vehicle and occlusion are well documented

(Magnussun and Kligman, 1970; Franklin, 2001). Vehicle choice determines in

part the absorption of the test material and can inﬂuence sensitization rate, ability

to elicit response at challenge, and the irritation threshold. Application of haptens

to irritated or tape stripped skin, the dose per unit area, repeated applications to

the same site (Magnussun and Kligman, 1969), increased numbers of exposures

(this applies through 10–15 exposures only), an interval of 2–6 days between

exposures (Magnussun and Kligman, 1969) and treatment with adjutant increase

sensitization rates (Maguire, 1974). The development of DTH is under genetic

control; all individuals do not have the capability to respond to a given hapten.

In addition, the status of the immune system determines if an immune response

can be induced. For example, young animals may become tolerant to a hapten,

and pregnancy may suppress expression of allergy (Magnussun and Kligman,

1969). The intrinsic biological variables controlling sensitization can be inﬂu-

enced only by selection of animals likely to be capable of mounting an immune

response to the hapten. Thresholds in contact sensitization using immunolog-

ical models and experimental evidence have been described (Boukhman and

Maibach, 2001). The extrinsic variables of dose, vehicle, route of exposure,

adjuvant, etc., can be manipulated to develop sensitive predictive assays.

Appropriate execution of predictive sensitization assays is critical. All too

often techniques are discredited when, in fact, the performance of the tests was

DERMATOTOXICOLOGY

1028 ■

inferior or study design, e.g., choice of dose, was inappropriate. A common error

in choosing an animal assay is using Freund’s complete adjuvant (FCA) when

setting dose response relationships. The adjuvant provides such sensitivity that

dose effect relationships are muted. Although the dose must be high enough to

ensure penetration, it must be below the irritation threshold at challenge

to avoid misinterpretation of irritant inﬂammation as allergic. For instance,

the quaternary ammonium compounds, e.g., benzalkonium chloride, rarely

sensitize but have been identified as allergens in some guinea pig assays.

Knowing the irritation potential of compounds and choosing an appropriate

experimental design will allow the investigator to design and execute these

studies appropriately. John Draize developed the ﬁrst practical animal assay to

predict the proclivity of a chemical or a ﬁnal product to produce allergic contact

dermatitis. This test is widely used and forms the basis for current testing.

Modifications to this test include the Buhler method, Freud’s adjuvant, the

Freud’s complete adjuvant test and the open epicutaneous test. An extensive

review of this assay is found in Maibach and Marzulli (1991). If done properly,

these tests will identify most of the contact allergens. Human testing supple-

ments animal testing but most sensitization studies have been done in animals

The Draize repeated insult patch test is the standard human assay to identify

the propensity of a chemical to induce ACD Modiﬁcations to this test have been

developed. A complete review of assays is found in Maibach and Marzulli (1991).

Patch testing of patients with suspected cosmetic contact dermatitis is discussed

later in this chapter, and the scientiﬁc basis of patch testing can be found in

Ale and Maibach (2002). Recent Prevention and treatment of allergic contact

dermatitis has been discussed (Wille and Kyclonieus, 2001).

51.2.3 Contact urticaria syndrome

Contact urticaria has been deﬁned as a wheel-and-ﬂare response that develops

within 30 to 60 min after exposure of the skin to certain agents (von Krogh and

Maibach, 1982). Symptoms of immediate contact reactions can be classiﬁed

according to their morphology and severity. Itching, tingling, and burning with

erythema is the weakest type of immediate contact reaction. Local wheel-and-

flare with tingling and itching represents the prototype reaction of contact

urticaria. Generalized urticaria after local contact is rare but can occur. Signs and

symptoms in other organs can appear with the skin symptoms in cases of

immunologic contact urticaria syndrome. This includes asthma, angioedema

and anaphylaxis.

COSMETIC REACTIONS

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The strength of the reactions may greatly vary, and often the whole range of

local symptoms—from slight erythema to strong edema and erythema—can be

seen from the same substance if different concentrations are used in skin tests

(Lahti and Maibach, 1980). Not only the concentration but also the site of the

skin contact affects the reaction. A certain concentration of contact urticant

may produce strong edema and erythema reactions on the skin of the back

and face but only erythema on the volar surfaces of the lower arms or legs.

In some cases, contact urticaria can be demonstrated only on damaged or

previously eczematous skin. Some agents, such as formaldehyde, produce

urticaria on healthy skin following repeated but not single applications to the

skin. Differentiation between nonspeciﬁc irritant reactions and contact urticaria

may be difficult. Strong irritants, e.g., hydrochloric acid, lactic acid, cobalt

chloride, formaldehyde, and phenol, can cause clear-cut immediate whealing

if the concentration is high enough, but the reactions do not usually fade away

within a few hours. Instead, they are followed by signs of irritation; erythema,

scaling, or crusting are seen 24 h later. Some substances have only urticant

properties (e.g., benzoic acid, nicotinic acid esters). Diagnosis of immediate

contact urticaria is based on a thorough history and skin testing with suspected

substances. Skin tests for human diagnostic testing are summarized by Von

Krogh and Maibach (1982), and patch testing and photopatch testing for

contact urticaria has been described (Amin and Maibach, 2001). Because of the

risk of systemic reactions, e.g., anaphylaxis, human diagnostic tests should only

be performed by experienced personnel with facilities for resuscitation on hand.

Contact urticaria has been divided into two main types on the basis of proposed

pathophysiological mechanisms, nonimmunologic and immunologic (Maibach

and Johnson, 1975). Recent reviews list agents suspected to cause each type of

urticarial response (Lahti and Maibach, 1985; Harvel et al., 1994). Some

common urticants are listed in Table 51.1. A ﬂow sheet designed by von Krogh

and Maibach (1982) (46) can be used to approach testing in suspected cases

(Table 51.2).

Nonimmunologic contact urticaria

Nonimmunologic contact urticaria is the most common form and occurs

without previous exposure in most individuals. The reaction remains localized

and does not cause systemic symptoms or spread to become generalized

urticaria. Typically, the strength of this type of contact urticaria reaction varies

from sensory complaints of sting, itch or burn to an urticarial response,

DERMATOTOXICOLOGY

1030 ■

COSMETIC REACTIONS

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Table 51.1:

Some agents reported to cause urticaria in humans

Immunologic mechanisms

•Bacitracin

•Ethyl and methyl parabens

•Seafood (high molecular weight protein extracts)

Nonimmunologic mechanisms

•Cinnamic aldehyde

•Balsam of Peru

•Benzoic acid

•Ethyl aminobenzoate

•Dimethyl sulfoxide

Unknown mechanisms

•Epoxy resin

•Lettuce/endive

•Cassia oil

•Formaldehyde

•Ammonium persulfate

•Neomycin

Table 51.2:

Test procedures for evaluation of immediate-type reactions in recommended

order

1. Open application

•Nonaffected normal skin:

Negative

•Slightly affected (or previously affected) skin:

Negative Positive →positive diagnosis

2. Occlusive application (infrequently needed)

•Nonaffected normal skin:

Negative

•Slightly affected (or previously affected) skin:

Negative

3. Invasive (inhalant, prick, scratch, or intradermal injection)*

*When invasive methods are employed (especially scratch and inhalant testing) adequate controls

are required.

depending on the concentration, skin site and substance. The mechanism

of nonimmunologic contact urticaria has not been delineated, but a direct

influence on dermal vessel walls or a non-antibody-mediated release of

histamine prostaglandins, leukotrienes, substance P, or other inflammatory

mediators represents possible mechanisms. Lahti and Maibach (1985) suggested

that nonimmunologic urticaria produced by different agents may involve

different combinations of mediators. Common non-immunological urticans

can be inhibited by oral acetylsalicylic acid and indomethacin (Lahti et al., 1983;

1986) and by topical dicloferac and naproxene gel, but not hydroxyzine or

terfenadine (Lahti, 1987) and capsaicin. This suggests that prostaglandins and

leukotrienes may play a role in the inﬂammatory response.

The most potent and best studied substances producing nonimmunologic

contact urticaria are benzoic acid, cinnamic acid, cinnamic aldehyde, and

nicotinic esters. Under optimal conditions, more than half of a random sample

of individuals show local edema and erythema reactions within 45 min of

application of these substances if the concentration is high enough. Benzoic

acid and sodium benzoate are used as preservatives for cosmetics and other

topical preparations at concentrations from 0.1 percent to 0.2 percent and are

capable of producing immediate contact reactions at the same concentrations

(Marzulli and Maibach, 1974). Cinnamic aldehyde at a concentration of 0.01

percent may elicit an erythematous response associated with a burning

or stinging feeling in the skin. Mouthwashes and chewing gums contain

cinnamic aldehyde at concentrations high enough to produce a pleasant

tingling sensation in the mouth and enhance the sale of the product. Higher

concentrations produce lip swelling or typical contact urticaria in normal skin.

Eugenol in the mixture may inhibits contact sensitization to cinnamic aldehyde

and inhibits nonimmunologic contact urticaria from this same substance, The

mechanism of the putative quenching effect is not certain, but a competitive

inhibition at the receptor level may be an explanation (Guin et al., 1984).

Provocative testing patients suspected of non-immunologic urticaria with

individual ingredients such as benzoic acid, sorbic acid and sodium benzoate,

commmon preservatives found in cosmetics, frequently will reproduce patients

symptoms.

Immunologic contact urticaria

Immunologic contact unicaria is an immediate Type I allergic reaction in people

previously sensitized to the causative agent (von Krogh and Maibach, 1982).

DERMATOTOXICOLOGY

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It is more prevalent in atopic patients than in non-atopic patients (Fisher, 1990).

The molecules of a contact urticant react with speciﬁc IgE molecules attached

to mast cell membranes. The cutaneous symptoms are elicited by vasoactive

substances, i.e, histamine and others, released from mast cells. The role of hista-

mine is conspicuous, but other mediators of inﬂammation, e.g., prostaglandins,

leukotrienes, and kinins, may inﬂuence the degree of response. Immunologic

contact urticaria reaction can extend beyond the contact site, and generalized

urticaria may be accompanied by other symptoms, e.g., rhinitis, conjunctivitis,

asthma, and even anaphylactic shock. The term “contact urticaria syndrome”

was therefore suggested by Maibach and Johnson (1975). The name generally

has been accepted for a symptom complex in which local urticaria occurs at

the contact site with symptoms in other parts of the skin or in target organs

such as the nose and throat, lung, and gastrointestinal and cardiovascular

systems. Anaphylactic reactions may result from substances that induce a strong

hypersensitivity response or easily absorbed from the skin (Lahti and Maibach,

1987). Fortunately, the appearance of systemic symptoms is less common than

the localized form, but it may be seen in cases of strong hypersensitivity or in

a widespread exposure and abundant percutaneous absorption of an allergen.

Foods are common causes of immunologic contact urticaria (Table 51.1). The

orolaryngeal area is a site where immediate contact reactions are frequently

provoked by food allergens, most often among atopic individuals. The

actual antigens are proteins or protein complexes. As a proof of immediate

hypersensitivity, speciﬁc IgE antibodies against the causative agent can typically

be found in the patient’s serum using the RAST technique and skin test for

immediate allergy. In addition, the prick test can demonstrate immediate

allergy. The passive transfer test (Prausnitz-Kustner test) also often gives a

positive result. This is now performed in the monkey rather than man.

51.2.4 Acne and comedones

Acnegenesis and comedogenesis are distinct but often related types of adverse

skin reactions to facial, hair and other products. Acnegenesis refers to the

chemical irritation and inﬂammation of the follicular epithelium with resultant

loose hyperkeratotic material within the follicle and inflammatory pustules

and papules. Comedogenesis refers to the noninﬂammatory follicular response

that leads to dense compact hyperkeratosis of the follicle. Mills and Berger

(1991) indicated that the time courses for the development of facial acne

and comedones are different. While facial acne will appear in a matter of

COSMETIC REACTIONS

■1033

days, comedone formation in the human back and rabbit model takes longer

to occur.

Classes of ingredients such as the lubricants isopropyl myristate and some

analogs, lanolin and its derivatives, detergents, and D&C red dyes have been

incriminated by the rabbit ear test (Fulton et al., 1984). Fulton (1989) published

a report about the comedogenicity and irritancy of commonly used cosmetics.

Lists of comedogenic agents are not necessarily meaningful. Although they are

important for pharmaceutical research and for the formulation of nonacnegenic

products, they cannot alone predict the defects of the final product. The

concentrations used in testing are often much greater than those in the ﬁnal

product. Thus it is possible to use concentrations that are lower that the minimal

acnegenic level. In addition, the vehicles in ﬁnished products can increase or

decrease the acnegenic potential of individual compounds. In the ﬁnal analysis,

what is important is the testing of the ﬁnished product for its acnegenic and

irritancy potential. When only inadequate data are available, elimination

regimen remains the only constructive approach to treat patients with suspected

acne or comedones secondary to cosmetic use.

The rabbit ear assay is the mayor predictive animal model available. Kligman

and Mills (1972) developed the value of testing cosmetics and its ingredients by

the rabbit ear assay. However, several improvements in the model have been

proposed (Tucker et al., 1986). The test is not standardized. The AAD Invitational

Symposium on Comedogeninity Panel (1989) suggested some guidelines for

maximizing the usefulness of the rabbit ear model.

In 1972, Kligman and Mills showed production of microcomedones in

the backs of black men after testing cosmetics with occlusion. One test for

evaluating comedogenicity in humans is the occlusive-patch application to the

back followed by a cyanoacrylate follicular biopsy as described by Mills and

Kligman (1982). The test material previously positive in the rabbit ear assay is

applied for 4 weeks under occlusion to the upper portion of the back of people

with large follicles. This test needs reﬁnement. However, if this occlusive patch

test is negative, it provides additional assurance that the test material may be

nonacnegenic.

Bronaugh and Maibach (1982) reported that results of the rabbit ear test

correlate well with pustule formation noted in use tests of cosmetics performed

on women’s faces. They noted that some cosmetics may produce papulopustules

after 3 to 7 days of use. The products were strongly positive in the rabbit ear

model. This may represent a manifestation of primary irritancy. Correlative

studies with rabbit pustulogenicity assay should be performed. The acute onset

DERMATOTOXICOLOGY

1034 ■

papulopustules are often described by the patient as a “breakout.” The cause

and effect relationship to cosmetics is strong but is often missed by the

dermatologist. Jackson and Robillard (1982) proposed the ordinary clinical-

usage test. This test, conducted for 4–6 weeks, may not provide reliable

information on comedogenesis. However, follicular inﬂammation may be noted

within 1 to 2 weeks of applications done twice a day to the face of people with

acne-prone oily skin.

It is not known how long the applications need to be continue to observe

true comedogenesis. Clinical observations should be done at least weekly for

the ﬁrst 2 weeks of using the product to detect folliculitis. The acute papulo-

pustular form will be identiﬁed in short term testing (days, in contradistinction

to months). However, to conclusively incriminate cosmetics as a cause

of comedonal acne, long-term testing using a single cosmetic on the faces of

women will have to be conducted and the disease produced. Lines of cosmetics

will ideally be manufactured which are screened with an appropriate rabbit ear

test and then tested deﬁnitively in panels of acne-prone women for long term.

Wahlberg and Maibach (1981) attempted to brige the gap between comedo

identiﬁed in the rabbit ear assay and the more common acute papulo-pustule

by developing an animal model. The rabbit’s back is pierced with a needle

and dosed topically. The resulting lesion closely resembles that seen in man.

Unfortunately, for several reasons including reluctance to performed animal

testing, identiﬁcation of acnegenicity premarketing remains a weak link in the

of dermatotoxicology. The lesion occurs not only from cosmetics ingredients

but also from topical and systemic drugs.

51.2.5 Pigmentation

Hyperpigmentation of the face caused by contact dermatitis to ingredients in

cosmetics occurs more frequently in dark complexioned individuals (Rorsman,

1982). An epidemic of facial pigmentation reported in Japanese women was

attributed to “coal tar” dyes principally Sudan I, a contaminant of D&C Red

No. 31 (Kozuka et al., 1980). The following fragrance ingredients have also

been implicated-benzyl salicylate, ylang-ylang oil, cananga oil, jasmin abso-

lute, hydroxycitronellal, methoxycitronellal, sandalwood oil, benzyl alcohol,

cinnanuc alcohol, lavender oil, geraniol, and geranium oil (Nakayama et al.,

1976). Histologic examination shows hydropic degeneration of the basal layer,

pigment incontinence and little evidence of inﬂammation (Lahti and Maibach,

1987). Mathias (1982) reported pigmented cosmetic contact dermatitis due to

COSMETIC REACTIONS

■1035

contact allergy to chromium hydroxide used as a dye in toilet soap, and Maibach

(1978) reported hyperpigmentation in a black man sensitive to petrolatum.

Dermatologists should search scrupulously for a causative agent in patients with

hyperpigmentation. Eliminating the product results frequently in gradual

fading of the pigment. Unfortunatly, until a predictive assay is 14 identiﬁed,

most patients will be incorrectly indentiﬁed as idiopathic.

Cosmetic chemicals have infrequently been associated with leukoderma.

Nater and de Groot (1985) and de Groot (1988) listed chemicals associated

with leukoderma. Recently, Taylor and colleagues (1993) added seven more

chemicals. Although Riley (1971) reported that low concentrations of butylated

hydroxyanisole were toxic in culture guinea pig melanocytes, Gellin et al. (1979)

could not induce depigmentation in guinea pigs or black mice by appying

butylated hydroxyanisole. In addition, Maibach and colleagues (1975) were

unable to produce depigmentation after a 60-day occlusive application of

hydroxytoluene to darkly pigmented men. The Cosmetic Ingredient Review

panel (1984) concluded that is safe to use BHA in the present practices of use.

Hydroquinone has produced depigmentation in humans. Although it is a

weak depigmenter at 2 percent concentration, it is a stronger depigmenter at

higher concentrations and with different vehicles. Hydroquinone, used as a

bleaching agent, has caused postinflammatory hyperpigmentation in South

African Blacks. Findlay et al. (1975) from South Africa reported a long-

term complication of the use of hydroquinone-deposits of ochronotic pigment

in the skin along with colloid milia. The melanocyte, despite intense hydro-

quinone use, escaped destruction and the site of the injury shifted to the dermis

and the ﬁbroblast. Polymeric pigment adhered to thickened, abnormal collagen

bundles. In 1983, Cullison et al. reported that an American black woman

developed this complication after intense use of a 2 percent hydroquinone

cream. Prolonged use of hydroquinone followed by sun exposure may lead to

exogenous ochronosis with colloid milium production. In addition, a few cases

of persistent hypopigmentation have incriminated topical hydroquinone

(Fisher, 1983). Pyrocatechol has similar structure and effects to hydroquinone.

The most frequent use of hydroquinone and pyrocatechols is in rinse-off

type hair dyes and colors in which the use concentration is 1 percent concen-

tration or less. The Cosmetic Ingredient Review panel declared hydroquinone

and pyrocatechol safe for cosmetic use at 1 percent concentration or less.

Monobenzyl ether of hydroquinone is a potent depigmenting agent and is not

approved for cosmetic use in the United States. The only approved use for

monobenzyl ether of hydroquinone is as a therapeutic agent for patients with

DERMATOTOXICOLOGY

1036 ■

vitiligo. P-hydroxyanisole is a potent depigmenting agent in black guinea pigs

at concentrations near ones used in cosmetics. It may cause depigmentation at

distant sites from application in humans.

Angenilli and co-worker (1993) reported depigmentation of the lip margins

from p-tertiary butyl phenol in a lip liner. The p-tertiary butyl phenol patch test

site also depigmented and the presence of p-tertiary butyl phenol was conﬁrmed

by gas chromatography with mass spectroscopy. Most recently, Taylor and

co-workers (1993) reported four cases of chemical leukoderma associated with

the application of semipermanent and permanent hair colors and rinses. They

identiﬁed benzyl alcohol and paraphenylenediamine in three of the four cases.

Depigmentation occurred at the hair color patch test sites in three of the

four cases.

Mathias et al. (1980) reported perioral leukoderma in a patient who used

a cinnamic aldehyde-containing toothpaste. Wilkenson and Wilkin (1990)

reported that azelaic acid is a weak depigmenter and its esters do not depigment

pigmented guinea pig skin.

51.2.6 Photosensitivity

Contact photosensitivity results from UV-induced excitation of a chemical

applied to the skin. Contact photosensitivity is divided into phototoxic

and photoallergic reactions. Phototoxic reactions may be experienced by any

individual, provided that ultraviolet light contains the appropriate wave lengths

to activate the compound and that the UV dose and the concentration of the

photoreactive chemical are high enough. Clinically, it consists of erythema

followed by hyperpigmentation and desquamation. Sunburn is the most

common phototoxic reaction. However, photoallergic reactions require a period

of sensitization. The reactions are usually delayed, manifesting days to weeks

or years after the UV exposure. The major problem with photoallergic reactions

is that the patient may develop persistent light reaction for many years after the

chemical has been removed. These patients tend to be exquisitely sensitive to

the sun and usually have very low UV-B and UVA minimal erythema doses.

With the exception of the epidemic caused by halogenated salicylanides in soap

in the 1960s, photosensitivity accounts for a small number of cosmetic adverse

reactions. Maibach and colleagues (1988) reported only nine of 713 patients

with photoallergic and photosensitive reactions. Musk ambrette, a fragrance

in some aftershaves, has been reported as a major cause of cosmetic photo-

sensitivity reactions.

COSMETIC REACTIONS

■1037

Predictive testing in human skin is not always definitive. In the 1960s,

identiﬁcation of TCSA and related phenolic compounds was accomplished by

photopatch testing clinically involved patients. Subsequently, Willis and

Kligman (1968) induced contact photoallergy to certain agents in normal

human subjects using a modification of the maximization test which was

developed for evaluating the potential of chemicals to produce contact dermatitis

(Kligman, 1966).

Kaidbey and Kligman (1980) and Kaidbey (1983) modified the photo-

maximization procedure. They were able to sensitize normal human volunteers

readily to certain methylated coumarins derivatives, e.g., TCSA, 3,5-DBS,

chlorpromazine and sodium omadine. A smaller number of positive induction

responses was noted with TBS contaminated with 47 percent DBS, 4,5-DBS,

Jadit and bithionol. Negative results were obtained with para-aminobenzoic

(PABA) and musk ambrette, which have produced photoallergic contact

dermatitis clinically. To date there is no proven effective predictive testing

model for photoallergic contact dermatitis in that most of the known photo-

allergens have been identified clinically and not in toxicologic assays.

Furthermore, the reﬁnement of risk assessment (not hazard identiﬁcation) may

be difﬁcult, e.g., sodium omadine is positive in the assay but not yet clinically

in spite of extensive use.

Photopatch testing

The criteria for separating allergic contact and allergic photocontact dermatitis

utilizing patch-testing techniques are imprecise. General criteria and their

interpretation are listed in Table 51.3. Often, the results are not all-or-none,

as implied in the table. Frequently, there is a difference in response intensity,

with either the contact or photocontact response being greater. All too

infrequently serial dilutions are performed with either the putative antigen or

the amount of ultraviolet light employed. Until a signiﬁcant number of patients

are so studied, it will be unclear how many of them represent contact versus

photocontact sensitization.

Wennersten et al. (1986) recommended that patients with suspected

photocontact allergy be phototested prior to implementation of patch testing.

The aim of this preliminary light testing is to detect any abnormal sensitivity

to UVA and UVB wavebands. It is generally agreed that UVA sources are

adequate and sufﬁcient to elicit responses, an important convenience as UVA

does not produce erythema in normal fair-skinned subjects until a dose of

DERMATOTOXICOLOGY

1038 ■

20–30 J/cm2is delivered. High doses of UVA such as 10–15J/cm2for photopatch

testing are unnecessary. Such doses increase the possibility of adverse reactions

and increase the incidence of phototoxic reactions. Despite widespread use,

there is little standardization in the UVA dosage used in photopatch testing.

Doses may range from 1J/cm2–15J/cm2at various centers (Holzle et al., 1988).

The Scandinavian Photodermatitis Group was the ﬁrst to formulate a protocol

using 5 J/cm2of UVA in photosensitive patients, half their UVA MED for the

prodedure. Most photoallergies will be defined with a far smaller dose (e.g.

1 J/cm2). Duguid et al. (1993) showed that positive responses occur at 1.0, 1.0

and 0.7 J/cm2for Eusolex 8020, benzophenone-10 and benzophenone-3

respectively. In addition Duguid and coworkers (1993) conﬁrmed the adequacy

of 5 J/cm2or less as a photoelicitation dose. Although some data on the dose of

light required to elicit a response exists, this remains incomplete and must be

studied in context with the dose of antigen and the vehicle. Until the light and

antigenic intensities are more fully deﬁned, most physicians utilize a PUVA

unit, a bank of UVA bulbs in a diagnostic unit or a hot quartz (Kromayer) unit,

with an appropriate ﬁlter to remove any light with wavelengths below 320 nm

(UVB). The effect of UV irradiation on photopatch test substances in vitro has

been reported by Bruze et al. (1985). It appears that 5 J of UVA is almost always

adequate. All thirteen photoactive compounds formed photoproducts after

UVA irradiation; eight substances were decomposed by both UVA and UVB

radiation; ﬁve by UVA alone. It is also possible that some patients may require

UVB to elicit photoallergic dermatitis. However, since UVB testing is not done

routinely, it may be some time before this is clariﬁed. Epstein (1963) observed

that many patients are so sensitive to light that the dose delivered under

an ordinary patch will elicit reactions. He provided details of testing the

nonexposed site, utilizing a large light-impermeable black patch applied in a

dimly lit room.

COSMETIC REACTIONS

■1039

Table 51.3:

Patch and photopatch testing

Contact test site Photocontact test site Interpretation

response response

Positive Positive Allergic contact dermatitis

Negative Positive Photoallergic dermatitis

Negative Negative Non sensitized

Commercial sources of appropriately diluted sunscreen antigens are

not presently available in the United States. On request, many thoughtful

manufacturers provide patch-test kits of individual ingredients for their

products. A “standard” series of sunscreen antigens has been proposed by the

International Contact Dermatitis Research Group (ICDRG). In Europe, these

test kits are commercially available. These sunscreen antigens are available

in 2 percent concentrations, although the maximum nonirritating doses of

putative antigens in a given vehicle have not been deﬁned. Maibach et al. (1980)

and de Groot (1994) reported the test concentrations and vehicles for the

dermatological testing of many cosmetic ingredients that may be in sun-

screen formulations. We currently lack adequate virgin controls for the high

concentrations used in contemporary formulations. When high concentrations

are required to elicit allergic contact dermatitis, an impurity or a photoproduct

may be the actual allergen.

The specific vehicle in which the allergens are dissolved or suspended is

important (Fisher and Maibach, 1986; Tanglersampan and Maibach, 1993).

The ICDRG list employs petrolatum as diluent. This vehicle appears to be

adequate to elicit reactions in many patients. It is clear, however, that the

bioavailability of the antigen may be too limited in some cases. Thus Mathias

et al. (1978) required ethanol to demonstrate PABA sensitivity, and Schauder

and Ippen (1988) noted more pronounced test reactions to avobenzone in

isopropylmyristate than petrolatum. This topic remains an area of investigation.

Presumably each ingredient may require an optimal vehicle and concentration

for eliciting a reaction.

Some patients develop dermatitis that appears allergic or photoallergic in a

morphologic and historic sense, yet fails to demonstrate a positive patch or

photopatch test, in spite of seemingly appropriate testing. Such false-negative

reactions are more difﬁcult to identify than false positive reactions (Rycroft,

1986). Table 51.4 provides the basic strategy employed in attempting to help

these patients. Unfortunately, in some patients, even these extensive work-ups

fail to elicit the etiology of their reactions.

Many of the reported positives test to date, and especially the cross-reaction

studies, may well represent false-positives due to the Excited Skin Syndrome.

This state of skin hyperirritability often induced by a concomitant dermatitis

is responsible for many nonreproducible patch tests. Bruynzeel and Maibach

(1986) detail strategies for minimizing such false-positives.

DERMATOTOXICOLOGY

1040 ■

51.2.7 Nail changes

Paronychia, onycholysis (Draelos, 2001), nail destruction and discoloration

are some of the most common cosmetic adverse reactions found in the nails.

The physician should obtain a detailed description of the nail grooming

habits in patients who have paronychia, onycholysis, nail destruction, or nail

discoloration because any of these problems may be caused by nail cosmetic

usage. Nail discoloration has been reported with the use of hydroquinone

bleaching creams and hair dyes containing henna (Fitzpatrick et al., 1966;

Samman, 1977).

51.2.8 Hair changes

Permanents and hair straighteners are intended to break the disulﬁde bonds

that give hair keratin its strength. Improper usage or incomplete neutralization

of these cosmetics causes hair breakage. Hair that has been damaged by previous

applications of permanent waves, straighteners, oxidation type dyes, bleaches,

or excessive exposure to sunlight and chlorine is more susceptible to this

damage. The dermatologist should always take a complete history in these cases,

including a detailed account of the use of drugs, to detect any causes of telogen

or anagen efﬂuvium. Careful examination of the hair shafts is essential to detect

any pre-existing abnormalities. Saving a sample of these hairs in the patient

COSMETIC REACTIONS

■1041

Table 51.4:

Strategy for identifying the cause when routine patch testing is negative

Intervention Comment

Increase UVA dose Avoid UVA erythema

Use UVA control

Increase concentration of sunscreen Upper limit of nonirritating dose not

completely deﬁned

Alter vehicle Ethanol has been found to be effective

Test other components Sunscreen manufactures often helpful in

providing test kits

Add suberythemogenic doses of UVB

Perform provocative-use test on ﬁnal

formulation

Consider “compound” allergy

record may be invaluable should litigation against the beautician or supplier

occur (Whitmore and Maibach, 1984).

51.3 INGREDIENT PATCH TESTING

The diagnosis and treatment of reactions to cosmetics has been facilitated by

the Food and Drug Administration’s (FDA) regulation (1975) requiring the

ingredient labeling of all retailed cosmetics.

The European Community has also endorsed such labeling. The ingredients

are listed in order of descending concentration. Because of the complexity of

the composition of fragrances, their compositions are not given but are listed

simply as “fragrance.” The regulation was designed to aid the consumer in

identifying ingredients at the time of purchase; therefore, the list is often placed

on the outer package, which may be discarded, rather than the container.

Correspondence with the manufacturer or a trip to the cosmetic counter,

however, can bring the needed information. This regulation, besides identifying

ingredients, is helpful to dermatologists because it mandated a uniform

nomenclature for cosmetic ingredients. The CTFA Ingredient Dictionary

published by the Cosmetic Toiletries and Fragrance Association (1993) is the

source for the official names This dictionary provides a brief description of

the chemical, alternative names, and names of suppliers: Without this key

reference book the dermatologist is at a distinct disadvantage in advising

patients in this area.

The standard screening patch test tray includes some ingredients that are

allergens found in cosmetics (De Groot, 2000). Imidazolidinyl urea, diazalidinyl

urea, thimerosal, formaldehyde, and quaternium 15 are preservatives. Patch

testing balsam of Peru screens for approximately 50 percent of the known

allergic reactions to fragrance in the United States. Colophony and its

constituents are used in the manufacture of eye cosmetics, transparent soap, and

dentifrice (Rapaport, 1980). If a patient has a positive patch-test reaction to one

of these chemicals, clinicians should consider allergic contact dermatitis to

cosmetics a possible diagnosis. We emphasize that cosmetic contact dermatitis

can often be unsuspected. Any positive patch tests should be interpreted

cautiously because many cosmetics are mild irritants and Excited Skin State

may cause false positive results. Ideally, a positive patch test should should be

conﬁrmed with a repeat test several weeks later or with a provocative-use test.

Reassessment of the patient’s history and presenting ﬁndings and patch testing

with the patient’s cosmetics may establish the diagnosis.

DERMATOTOXICOLOGY

1042 ■

Once a product or products has been implicated with patch testing, pin

pointing the offending ingredient is an important part of the work-up so that

the patient may spare recurring reactions. Cosmetic ingredient patch testing is

complicated because the proper concentration for closed patch testing is known

only for a small percentage of these ingredients. Patch test concentrations

and vehicles has been proposed for less than 450 of the nearly 2000 cosmetic

ingredients listed (Bruze et al., 1985). The texts by Nater and de Groot (1993)

and by Cronin (1980) are important sources for clinicians seeking information

on cosmetic ingredient patch testing.

Screening fragrance trays provides the most common fragrance allergens in

the United States. Further information for patch testing fragrance ingredients

is reviewed in several articles (Larsen, 2000; Launder and Kansky, 2000). When

the clinical history, appearance of the reaction, or patch test results lead the

clinician to conclude that a cosmetic has caused an adverse reaction, it is

important to obtain the ingredients for patch testing. The Cosmetic, Toiletry,

and Fragrance Association publishes a pamphlet called “Cosmetic Industry On

Call.” This pamphlet lists the names of members of the industry who are willing

to answer questions about their products. Physicians can contact these persons

requesting speciﬁc ingredients for patch testing and information about patch-

test concentrations. If the patient does or does not prove to have a reaction

due to the cosmetics, the manufacturer should be notified of your results.

Manufacturers will not always send materials for patch testing, and the patient

cannot be treated successfully and counseled on how to avoid recurrences. On

occasion “fractionated” samples will be sent for patch testing. Because irritant

concentrations of ingredients may be present in these samples, they are often

not suitable to use for closed patch testing. Some manufacturers will supply

individual ingredients in the concentration that they appear in the product.

These are often unsatisfactory for patch testing because the nonstandardized

concentrations may be too low to provoke an allergic response or may be high

enough to elicit irritation under occlusion.

51.4 COSMETIC PRODUCTS

51.4.1 Preservatives

After fragrances, preservatives are the next most common cause of cosmetic

reactions (Adams and Maibach, 1985). The ten most frequently used preser-

vatives are listed in Table 51.5 (FDA, 1993). A large number of speciﬁc studies

COSMETIC REACTIONS

■1043

have focused on individual preservatives as being identified as potential

sensitizers and directly responsible for a number of adverse reactions.

Paraben Esters (Methyl, Propyl, Butyl, and Ethyl) are nontoxic and nonirri-

tating, preservatives that protect well against gram-positive bacteria and fungi,

but poorly against several gram-negative bacteria including pseudomonads

(White et al., 1982). Parabens, the most widely used preservatives in topical

products, have long been known to be contact allergens, when at relatively high

concentrations and at a low frequency (Schubert et al., 1990). However, their

potential for being the causative agents in cosmetic adverse reactions has not

diminished their use, and in fact, it is on the increase. Fortunately, parabens

compared to total use (tons ×years) have a remarkable safety record. Although

parabens may be sensitizers occasionally when applied to eczematous skin,

cosmetics containing parabens infrequently cause clinical difﬁculties when they

are applied to normal skin. Fisher (1980a) called this phenomenon the “paraben

paradox.” It is not known how often this phenomenon represents the Excited

Skin State (due to high concentration of paraben in the patch-test mixture)

rather than the paraben paradox.

Imidazolidinyl Urea (Germall 115) has low toxicity and is nonirritating.

It has a broad antimicrobial activity especially when used in combination with

parabens. Although formaldehyde is released on hydrolysis, the levels are too

low to cause reactions in many formaldehyde-sensitive patients clinically or

during patch testing. Diazolidinyl urea is a related preservative, whose use is

increasing.

DERMATOTOXICOLOGY

1044 ■

Table 51.5:

Preservative frequency of use (FDA data)*

Chemical Name No. of products using chemical

Methylparaben 6738

Propylparaben 5400

Propylene glycol 3922

Citric acid 2317

Imidazolidinyl urea 2312

Butylparaben 1669

Butylated hydroxyanisole (BHA) 1669

Butylated hydroxytoluene (BHT) 1610

Ethylparaben 1213

5-Choro-2-methyl-4-isothiazolin-

3-one (methylchloroisothiazoline) 1042

*Adapted from preservative frequency of use. Cosmetic and Toiletries (1993) 108: 97–98

Quaternium-15 is active against bacteria but less active against yeast and

molds. It is a formaldehyde releaser. A patient who has simultaneous positive

patch test readings to quaternium-15 and formaldehyde should be studied

carefully, as this may require special instructions.The patient may be allergic to

both ingredients or sensitive only to formaldehyde reacting to its release by this

preservative in the occlusive patch test. In the latter situation, quaternium-15

may or may not be tolerated by the patient when present in cosmetics at a 0.02

to 0.3 percent concentration. A product use test should clarify the situation.

A negative test relates to the product tested and not to all products due to

differences in bioavailability.

Formaldehyde as a preservative is used almost exclusively in wash-off

products such as shampoos. Used in this manner, formaldehyde is seldom a

cause of sensitization in the consumer and is only infrequently problematic for

the beautician (Lynde and Mitchell, 1982; Bruynzeel et al., 1984).

Bronopol (2-Bromo-2-nitropropane-1,3-diol) has a broad spectrum of

activity, most effective against bacteria. It is a formaldehyde releaser and may

pose a problem for the formaldehyde-sensitive patient. In addition, this

preservative may interact with amines or amides to produce nitrosamines or

nitroamides: suspected carcinogens. Patch testing with standard concentrations

may produce marginal irritations responses. Positives are best retested and if

positive followed by a provocative use test.

Benzoisothiazides have developed great popularity as preservatives. Kathon

CG (5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one)

has been a preservative of choice by many formulators because of its broad

application and ease of formulation it is incorporated in many popular rinse

off products, and some leave on cosmetics under concentration restrictions.

In spite of inducing sensitivity in guinea pigs at levels down to 25 ppm

and elicitation levels down to 100 ppm and less, this preservative has

infrequently produced sensitization from shampoo usage (Chan et al., 1983).

Methylchoroisothiazolinone and methylisothiazolinone has been the subject

of several adverse reaction investigations. It has shown significant rates of

sensitization at concentrations from 2 to 5 percent (Shuster and Shapiro, 1976;

Hjorth and Roed-Peterson, 1986; Patcher and Hunziker, 1989). Diagnostic

testing should be performed at 100 ppm in water bacause 300 ppm in water

induces active sensitization (Bjorker and Fregert, personal communication).

Possibly 150–200 ppm might be more appropiate, but this requires additional

study.

COSMETIC REACTIONS

■1045

51.4.2 Preservation of the future

The cosmetic industry experiences two major challenges: the elimination of all

animal testing and the development of preservative-free cosmetics. In recent

years, a strong socio-economic pressure has focused interest and research on

developing preservative free products and preservation based upon natural

extracts. Both of these approaches while seemingly sound scientifically and

from a marketing position, are fraught with problems. Natural preservatives are

often complex mixtures with many unknown chemicals. It is likely that some

of these active materials may present with sensitization rates equal or greater

than synthetic materials. The Sixth Amendment of the EC Cosmetic Directive

has called for the elimination of all animal testing of personal care products and

ingredients by 2002, unless alternative methods cannot be developed by then.

While most new raw materials will be able to use new, alternative safety testing

methods, preservatives will experience difficulty complying with existing

requirements for chronic safety studies such as mutagenicity and teratogenicity,

without relying on animals. Almost all regulatory agencies currently require

the use of in vivo methods to conﬁrm the safely of biocidal ingredients. In vitro

tests will most likely be used ﬁrst as prescreening test. At the present time, this

may reduce the need for some animal testing. However, it is unlikely that all

in vivo methods of biocide safety will be replaced in the short term. Before in vitro

assays can replace animal testing they should be validated against the known

in vivo testing. This is an unfortunate drawback of increasing the safety testing

cost since the cost of acute in vitro testing is as high as acute in vivo.

51.4.3 Emulsiﬁers

Creams and lotions require the presence of an emulsifier to allow the

combination of water and oil. Emulsiﬁers may act as mild irritants especially if

applied to slightly damaged skin. Pugliese (1983) suggested that increased

epidermal cell renewal or “plumping” of the skin may be due to mild irritant

effects of nonionic surfactants. Hannuksela et al. (1976) patch tested over 1200

eczematous patients with common emulsiﬁers.

Another emulsifier, stearamidoethyl diethylamine phosphate, has been

implicated in four cases of cosmetic contact dermatitis (Taylor et al., 1984).

Irritant reactions are seen at the same concentration as allergic responses. When

5 percent triethanolamine stearate in petrolatum was tested, 9.5 percent of

the patch tests showed irritant reactions. Even positive reactions to 1 percent

DERMATOTOXICOLOGY

1046 ■

triethanolamine in petrolatum should be confirmed by retesting and the

provocative-use testing.

51.4.4 Lanolin

Lanolin is a mixture of esters and polyesters of high molecular weight alcohols

and fatty acids. This naturally occurring wax varies in its composition

depending on its source. Adams and Maibach (1985) reported in the NACDG

study that lanolin and its derivatives remains among the ingredients that most

commonly cause allergic contact dermatitis in cosmetics. Because of its superior

emollient properties, lanolin is a popular ingredient for cosmetics.

Sulzberger et al. (1953) patch tested over 1000 patients suspected of having

contact dermatitis, 1 percent reacted to anhydrous lanolin. The allergen or

allergens which have not been identiﬁed are found in the alcoholic fraction of

lanolin. Patch testing is done most accurately using 30 percent wool alcohols

in petrolatum. Kligman ( 1983) tested 943 healthy young women with hydrous

lanolin and 30 percent wool wax alcohol. The results were interpreted as follows:

no positive allergic patch tests were read, but irritant reactions to wool alcohols

were common. Clark et al. (1981) estimated that the incidence of lanolin allergy

in the general population is 5.5 per million. Lanolin is an important sensitizer

when it is applied to eczematous skin eruptions, especially stasis dermatitis.

However, cosmetics containing lanolin applied to normal skin are generally

harmless. Cronin (1980) reported only 26 cases of lanolin-cosmetic dermatitis

seen between 1966 to 1976 in women.

In all of these cases, the lanolin-cosmetic dermatitis affected the face at some

time during its course; almost half showed eyelid involvement. The history was

of intermittent eruptions often with swelling and edema.

51.4.5 Eye makeup preparations

Mascara, eyeliner, eye shadow, and eyebrow pencil or powders are the most

commonly used eye-area makeups. The upper eyelid dermatitis syndrome is

complex and often frustrating to the patient and dermatologist, because of

chronicity and failure to respond to our well-intentioned assistance. Causes

that we have documented included in Table 51.6.

Although patients often consider this a reaction to eye makeup, the

association is seldom proven. In the North American Contact Dermatitis Group

study 12 percent of the cosmetic reactions occurred on the eyelid but only 4

COSMETIC REACTIONS

■1047

percent of the reactions were attributed to eye makeup (Adams and Maibach,

1985). A workup of patients with eyelid dermatitis includes a careful history of

all cosmetic usage, because facial, hair, and nail cosmetic reactions appear

frequently on the eyelids (Sher, 1979). Reactions to cosmetics on the eyelid are

often the irritant type; and to further complicate their diagnosis, they may be

due to cumulative irritancy—the summation of several, mild irritants (climatic,

mechanical, or chemical).

When the history does not clearly incriminate certain cosmetics, test with

the screening patch-test trays as well as all cosmetics that may reach the eye area

directly or indirectly. Occlusive patch tests with eyeliner or mascara may give

an irritant reaction, thus weakly positive results are interpreted cautiously.

Waterproof mascaras must be dried thoroughly for 20 minutes to volatilize

hydrocarbon solvents before occluding, and even with this precaution. Epstein

(1965) noted some irritant reactions. Positive patch tests are repeated for

conﬁrmation, and individual ingredient patch testing should be carried out

whenever possible. Patch testing cosmetics used in the eye area may occasionally

give false-negative results when testing is done on the back or extremities (Sher,

1979). A provocative use test performed in the antecubital fossa or the eyelid

itself may ultimately prove the diagnosis.

In the United States, the pigments used in eye area cosmetics are restricted.

No coal-tar derivatives may be incorporated; only purified natural colors or

inorganic pigment or lakes of low allergic potential are used. Nickel contami-

nation of iron oxide pigments has been implicated as a cause of allergic reaction

to these cosmetics in the nickel-sensitive user (Van Ketel and Liem, 1981). Eye

cosmetics are seldom fragranced, but other known allergens are used in these

DERMATOTOXICOLOGY

1048 ■

Table 51.6:

Some causes of upper-eyelid dermatitis syndrome

•Irritant dermatitis

•Allergic contact dermatitis

•Photoallergic contact dermatitis

•Phototoxic dermatitis

•Contact urticaria

•Seborrheic dermatitis

•Rosacea diathesis

•Psoriasis

•Collagen vascular diseases

•Conjunctivitis

•Blepharitis

•Dysmorphobia

cosmetics. Almost all eye area cosmetics are preserved with parabens combined

with a second preservative such as phenyl mercuric acetate, imidazolidinyl urea,

quaternium-15, or potassium sorbate. The following antioxidants are sensitizers

found in eye cosmetics: butylated hydroxytoluene, butylated hydroxyanisole

(Turner, 1977), propyl gallate (Cronin, 1980), ditert-butyl hydroquinone

(Calnan, 1973), resins: colophony (Cronin, 1980) and dihydroabietyl alcohol

(Doons-Gossens et al., 1979), bismuth oxychloride (Eierman et al., 1982), and

lanolin (Schorr, 1973). Propylene glycol may act as an irritant or sensitizer. Soap

emulsifiers, surfactants, and solvents are all potential irritants used in these

cosmetics. Allergic contact dermatitis from shellac (Le Coz et al., 2002), prime

yellow carnauba wax and coathylene (Chowdhury, 2002), and black iron oxide

(Saxena et al., 2001) found in mascara has been reported.

Infected corneal ulcers due to abrasions from mascara resulted when the

mascaras were not properly preserved (Wilson et al., 1979). These preservation

problems appear to be solved and reports of infected corneal ulcers have

decreased. Patients should be urged to use their eye cosmetics hygienically and

advised not to use eye cosmetics inside the lash line.

51.4.6 Hair preparations (non-coloring)

Permanents

Permanent waves are cosmetics that alter the disulﬁde bonds of hair keratin so

that hair ﬁber conﬁguration can be changed. The disulﬁde bonds of cystine are

broken in the ﬁrst step when the waving solution is applied to the hair wound

around mandrels. In the second step, with neutralization, new disulﬁde bonds

are formed by locking in the curl conﬁguration of the hair.

The waving solutions contain reducing agents that can cause irritant

reactions when allowed to run incautiously on the skin surrounding the scalp.

Irritant reactions range from erythema to bullous dermatitis. Hair breakage

and loss may result when permanent waves are used improperly—in too

concentrated a form, for too long a time, or on hair previously damaged by

dyes, straighteners, or permanent waves. Old-fashioned hot waves occasionally

caused chemical burns, which scarred the scalp producing permanent alopecia,

but modern permanents can cause breakage, which results in temporary loss.

In 1973, “acid permanents” were introduced for beauty salon use (Brauer,

1984). Acid permanents are the most widely used perm preparation today. These

waving lotions, which contain anhydrous glyceryl monothioglycolate in acid

COSMETIC REACTIONS

■1049

form, are mixed at the time of application with a water-based ammonium

hydroxide solution to produce a neutral solution. The hair is covered with a

plastic cap and placed under a hair dryer. Since the introduction of “acid perms,”

irritant and allergic reactions have been noted to occur on the hands of

hairdressers and the face, neck, scalp, and hair line of their customers from use

of these permanents (Storrs, 1984). Patch testing can be carried out with 1.0

percent glyceryl thioglycolate (glyceryl monothioglycolate) in petrolatum or

water (freshly prepared).

When clients are suspected of contact sensitization, glyceryl mono-

thioglycolate (GMT) is one of the most likely sensitizers. Frosch et al. (1993)

stated that sensitization seems to be much less frequent in clients than in

hairdressers due to less exposure.; this was evident with ammonium persulfate

(APS) (0 percent in clients versus 8 percent in hairdressers) Guerra et al. (1992)

studied 261 hairdresser’s clients and reported similar results. They reported

the mean frequencies of sensitization as follows: p-phenylenediamine (PPD)

7 percent, O-nitro-p-phenylenediamine (ONPPD) 5 percent, GMT 3 percent

ammonium thioglycolate (AMT) 1 percent and APS 3 percent. Morrison and

Storrs (1988) indicated that the identiﬁcation of GMT sensitization in a patient

is of particular importance, as the clinical symptoms may continue for months

even if the use of acid permanents waves is stopped. The allergen clings to the

hair and during shampooing, it is liberated in sufﬁcient amounts to maintain

the dermatitis. This may elicit dermatitis on the face and neck, which may be

confused with allergy or irritancy to shampoo. The operational deﬁnition for

allergic contact dermatitis has not been fulﬁlled. It is likely that most if not all

patch test reactions are irritant rather than allergic.

The “cold waves” contain thioglycolic acid combined with ammonia or

another alkali to raise the pH. The concentration of the thioglycolic acid and

alkali can be varied to change the products’ speed of action or to suit the type

of hair to be waved, i.e., hard to wave, normal, or easy to wave. The neutralizer

contains hydrogen peroxide or sodium bromate. These permanents have been

alleged to rarely cause allergic reactions. Ammonium thioglycolate can be patch

tested as 1 or 2.5 percent in petrolatum (FDA, 1975). Positives should be

confirmed with serial dilution patch testing and provocative use testing.

Another type of permanent used primarily at home is the sulﬁte wave. Although

the sulfite wave produces less strong curls and is slower, the odor is more

pleasant. Neutralization is done usually with bromates. Occasional allergic

reactions have been alleged with these permanents. It is recommened to use 1

percent sodium bisulﬁte in water for patch testing (Schorr, 1983).

DERMATOTOXICOLOGY

1050 ■

Straighteners

Straightening hair involves using a heated comb with petrolatum or a mixture

of petrolatum, oils, and waxes. The petrolatum or “pressing oils” act as a heat

modifying conductor, which reduces friction when the comb travels down the

hair ﬁbers. Mechanical and heat damage can cause hair breakage. Over the years,

the heated oils can injure the hair follicles leading to scarring alopecia.

Chemical straighteners containing sodium hydroxide, “lye,” cleave the disul-

ﬁde bonds of keratin thoroughly and straighten hair permanently. Experience

and caution in applying these straighteners are important to avoid hair breakage

and chemical burns. Similar products that contain guanidine carbonate mixed

with calcium hydroxide are reputed to be milder. It is necessary to straighten

new growth every several months. Care is taken not to “double process” the

distal hair, which is already straightened. Some manufacturers advise against

using permanent hair colors that require peroxide on chemically straightened

hair to avoid damage. Sulfite straighteners, chemically similar to sulfite

permanents, are best suited to relaxing curly Caucasian hair. “Soft Curls” have

become a fashionable way of styling black hair. Ammonium thioglycolate and

a bromate or peroxide neutralizer are used to achieve restructuring of the hair.

Shampoos

When shampoos are used, they have generally a short contact time with the

scalp and are diluted and rinsed off quickly. These factors reduce their sensitizing

potential. Consumers’ complaints are commonly directed at their eye stinging

and irritating qualities (Nater and de Groot, 1993). The importance of eye safety

testing for these products became apparent 35 years ago when shampoos based

on blends of cationic and nonionic detergents caused blindness in some users.

Modern shampoos are detergent-based with a few containing small amounts

of soap for conditioning. Anionic detergents and amphoteric detergents are

occasional sensitizers (Sylvest et al., 1975; Van-Hoote and Dooms-Goosens,

1983). Fatty acid amides used in shampoos as thickeners and foam stabilizers

have caused allergic contact dermatitis in other products (Hindson and Lawler,

1983). Formaldehyde or formaldehyde releasers may be used as a preservative

in shampoos but formaldehyde rarely causes contact dermatitis in hairdressers

or consumers related to use of shampoos (Lynde and Mitchell, 1982; Bruynzeel

et al., 1984). Other new preservatives used in shampoos include 5-cloro-2-

methyl-4-isothozoline-3-one and 2-methyl-4-isothiazoline-3-one. Individual

COSMETIC REACTIONS

■1051

ingredient patch testing is necessary to incriminate allergens in shampoos. They

produce false negative results because they are diluted in the ﬁnal product.

51.4.7 Hair coloring preparations

Over 30 million Americans color their hair using five different types of

dye: Permanent hair dyes (Type I) are mixtures of colorless aromatic compounds

that act as primary intermediates and couplers. The primary intermediates,

phenylenediamine (PPD), toluene-2,5 diamine (p-toluenediamine), and p-

ami-nophenol are oxidized by couplers to form a variety of colors that blend

to give the desired shade. These reactions take place inside the hair shaft

accounting for the fastness of these dyes. Permanent dyes are the most popular

in the United States because of the variety of natural colors they can achieve.

Semipermanent hair dyes (Type II) contain low molecular weight nitro-

phenylenediamine and anthroquinone dyes which penetrate the hair cortex to

some extent. Their color lasts-through approximately ﬁve shampoos. Temporary

rinses (Type III) are mixtures of mild, organic acids and certiﬁed dyes that coat

the hair shaft. These rub and shampoo off easily Vegetable dyes (Type IV) in the

United States contain henna, which only colors hair red. Metallic dyes (Type

V) contain lead acetate and sulfur. When they are combed through the hair

daily they deposit insoluble lead oxides and sulﬁdes that impart colors that

range from yellow-brown to dark gray.

Types I and II contain “coal tar” hair dyes, and in the United States they

must bear a label warning about adverse reactions. Instructions for open patch

testing are given. The law requires patch testing be performed before each

application of dye; in practice, this is seldom carried out in homes or salons.

“Coal tar” dyes are added occasionally to temporary rinses; these rinses must

also bear a warning label and patch-test instructions.

A persistent and significant number of reactions to hair dyes are seen by

dermatologists each year. Seven percent of the reactions to cosmetics diagnosed

by the North American Contact Dermatitis Group were caused by hair dyes

(Adams and Maibach, 1985). Their severity ranges from mild erythema at the

hair line, ears to swelling of the eyelids and face, to an acute vesicular eruption

in the scalp that requires prompt medical attention.

Most reactions to “coal tar” dyes are reactions to PPD. Independent

sensitization to toluene-2,5diamine or 2-nitro-p-phenylenediamine dyes or

resorcinol occurs rarely, but positive patch tests to toluene-2,5-diamine or 2-

nitro-p-phenylenediamine dyes result generally from cross-sensitization to PPD.

DERMATOTOXICOLOGY

1052 ■

One percent PPD in petrolatum is used in the standard closed patch test

Occasionally patients 32 who have a +1 reaction to PPD do not have a signiﬁcant

reaction when they dye their hair, but stronger patch-test results should

warn patients not to use these hair dyes. P-phenylenediamine is a colorless

compound. Patch-test material gradually darkens as PPD oxidizes, and it should

be stored in dark containers and should be made fresh at least yearly.

The products of PPD’s oxidation are not allergenic. Reiss and Fisher (1974)

studied the allergenicity of dyed hair. Twenty patients sensitive to PPD were

tested to freshly dyed hair in closed patch tests and all were negative.

The ﬁndings of this study are important particularly to hairdressers, sensitive

to PPD, who may work with dyed hair all day. Occasional case reports have

appeared that suggested contact reactions occurred to another person’s dyed

hair (Cronin, 1973; Hindson, 1975; Warin, 1976; Foussereau et al., 1980). We

assume that the dyeing process must not have been carried out properly and that

the unoxidized products remained on the hair.

Patients sensitive to PPD should be warned about possible cross-reactions

with local anesthetics (procaine and benzocaine), sulfonamides, and para-

aminobenzoic acid sunscreens. It is estimated that 25 percent of patients who

are PPD-sensitive will react to semipermanent hair dyes. Patients who wish to

try these as a substitute, should do an open patch test with the dye ﬁrst.

Several patients have been reported who experienced immediate hyper-

sensitivity reactions to PPD, and this spectrum of reactions to hair dyes should

now be considered as a diagnostic possibility in appropriate patients (Engrasser

and Maibach, 1985). Some patients complain of scalp irritation after dyeing

their hair, but we are unware of published data that study the potential of these

dyes for irritation. Some hair-dye reactions occur most prominently in light-

exposed areas, but the phototoxic and photoallergic potential of “coal tar” dyes

has not been investigated. Severe reactions to hair dyes are uncommon, but not

impossible, as even fatal anaphylactic reactions to hair dyes have been reported

(Belton and Chira, 1997).

Henna has not been reported to cause allergic contact dermatitis when

used as a hair dye, but a case has been reported from coloring the skin with

henna (Pasricha et al., 1980). Cronin (1979) described a hairdresser who noted

wheezing and coryza when she handled henna; this patient had a positive prick

test to henna. Edwards (1982) reported a case of contact dermatitis due to lead

acetate in the metallic dyes.

When hair is bleached ammonium persulfate is added to hydrogen peroxide

to obtain the lightest shades. Ammonium persulfate has several industrial uses

COSMETIC REACTIONS

■1053

and it is known commonly to cause irritant reactions and allergic contact

dermatitis occasionally. Methods of testing for immediate hypersensitivity

include rubbing a saturated solution of ammonium persulfate on intact

skin; scratch tests or intracutaneous tests using 1 percent aqueous solution of

ammonium persulfate; and inhalation of 0.1 µg of ammonium persulfate

powder. All of these methods can cause immediate hypersensitivity reactions

including urticaria, facial edema, asthma, and syncope so they should be

performed only when emergency treatment for anaphylaxis is available.

These reactions are histamine mediated, but it is not clear whether or not

immunologic mechanisms are involved (Fisher and Dooms-Goosens, 1976).

Hairdressers should be instructed that clients who develop hives, generalized

itching, facial swelling, or asthma when the hair is bleached should not have

the process repeated using persulfate. Clients experiencing such reactions

should receive immediate medical attention.

51.4.8 Facial makeup preparations

Eleven percent of the reactions to cosmetics in the NACDG Study were

attributed facial make-up products, which includes lipstick, rouge, makeup

bases, and facial powder (Adams and Maibach, 1985). Prior to 1960, allergic

reactions to lipsticks were common: most were caused by D&C Red 21 (eosin),

an indelible dye used in longlasting deeply colored lipsticks. The sensitizer in

eosin proved to be a contaminant; improved methods of purification have

reduced its sensitizing potential. Because eosin is strongly bound to keratin,

patch tests are performed with 50 percent eosin in petrolatum.

Other dyes have occasionally been reported as sensitizers. Cronin (1980)

reported reactions to D&C Red 36, D&C Red 31, D&C Red 19, D&C Red 17, and

D&C Yellow 11. The latter is a potent sensitizer seldom used in lipsticks, but

reported also as a sensitizing agent in eye Cream (Calnan et al., 1976) and rouge

as well as lipstick (Calnan, 1976a). D&C Red 17 not permitted in lipstick in US

D&C Yellow 10, produced by the sulfonation of D&C Yellow 11, is not a potent

sensitizer (Sato et al., 1984). Other sensitizers reported in lipsticks include castor

oil acting as a pigment solvent (Sai, 1983) antioxidants propyl gallate and

monotertiarybutylhydroquinone (van Joost et al., 1984), sunscreens phenyl

salicylate and amyldimethyl aminobenzoic acid (Calnan, 1981; Calnan et al.,

1981), lanolin (Schorr, 1973), and fragrance.

Although reactions to lipstick are uncommon, dermatologists should

consider this diagnosis even when the eruption has spread beyond the lips,

DERMATOTOXICOLOGY

1054 ■

because the sensitizing chemical may be present in cosmetics other than the

lipstick. Do not neglect to test each lipstick that the patient uses closed as well

as performing photopatch tests, because some of the dyes used may be

photoallergens.

Rouge or “blush” is manufactured in various forms—powder, cream, liquid,

stick, or gel. It is designed to highlight the cheeks with color. The composition

is not unique: powders are similar to face powder, and creams and liquids are

similar to foundation. To achieve bright shades, organic colors are added to

rouges as they are to lipsticks. D&C Yellow 11 caused allergic reactions to rouges

as well as lipsticks (Chowdhury, 2002). Some women may use lipstick to color

their cheeks in place of rouge, or rouge may be used all over the face to achieve

a healthy glow. These practices need to be taken into account when evaluating

patterns of contact dermatitis on the face.

Facial makeups or foundations are applied to the skin to give an appearance

of uniform color and texture and to disguise blemishes or imperfections. They

are produced in a variety of forms—emulsions of water and oil, oil-free lotions,

anhydrous sticks, poured powders, and pancake makeups and the amount of

coverage given is determined by the titanium dioxide (TiO2) content. Because

TiO2 reflects light, some ordinary makeups achieve sun protection factor

(SPF) values of 2 or even 4 (Laznet, 1982). In recent years, sunscreening agents

have been added to some foundations to increase these SPF values. When

sunscreening claims are made for these cosmetics, the US government will

consider these products as OTC drugs also. PABA derivatives, fragrances,

emulsifiers, preservatives, propylene glycol, and lanolin are chemicals with

signiﬁcant sensitizing potential used in these makeups. Synthetic esters, such

as isopropyl myristate and lanolin derivatives added to these makeups, have

been implicated as causes of acne by the rabbit’s ear test (Kligman and Mills,

1972). However, most cosmetic reactions, such as contact allergy, are due to

fragrance mixtures and formaldehyde (Held et al., 1999).

Calnan (1975) described a woman who had a positive patch test to her

foundation on two occasions, and her facial eruption flared when she used

this foundation. However, patch testing the individual ingredients of this

foundation was negative. Calnan raised the possibility of compound allergy—

the allergen is produced by a combination of more than one ingredient. Despite

some noted advers reactions to cosmetics, facial cosmetics are considered safe

consumer products (Scheman, 2000).

COSMETIC REACTIONS

■1055

51.4.9 Sunscreen

Sunscreens can be classiﬁed into two major types: chemical and physical (Food

and Drug Administration, 1978). Physical sunscreens such as titanium dioxide

and zinc oxide reduce the amount of light penetrating the skin by creating a

physical barrier that reﬂects, scatters, or physically blocks the ultraviolet light

reaching the skin surface. Chemical sunscreens, on the other hand, reduce the

amount of light reaching the stratum corneum by absorbing the radiation.

Examples of chemical sunscreens include para-amino benzoic acid (PABA) and

PABA derivatives such as Padimate 0, cinnamates, benzophenones, salicylate

derivatives, and dibenzoylmethane derivatives.

Because chemical sunscreens are applied topically to the skin in relatively

high concentrations (up to 26 percent), contact sensitization can occur (Cook

and Freeman, 2001; Nixon et al., n.d.). Similarly, because these chemicals absorb

radiation, they have the potential to cause photosensitization. Both types

of sensitization can occur with not only the various sunscreening agents but

also with excipients such as emulsiﬁers, antioxidants, and preservatives that

are included in the various hydroalcoholic lotions, ointments, oil-in-water or

water-in-oil emulsions. Despite extensive sunscreen use, there have been

infrequent published reports of sunscreen-induced side effects, including

allergic/ photoallergic reactions, but we have inadequate data to accurately

predict the degree of hypersensitivity to sunscreening agents due to the lack of

a well-developed adverse reaction reporting system.

Numerous sunscreening preparations are currently sold in the United States.

Table 51.7 lists examples of the sunscreen formulations sold in the United

States together with the active ingredients and their sun protection factors

(SPF), a measure of sunscreen protection against sunburn. Most of the formu-

lations that are combination sunscreens contain one or more UVB absorbers and

a UVA absorber to provide much needed protection against the damaging effects

of UVA. Several sunscreens also include physical blockers such as titanium

dioxide.

In general, as the SPF of the sunscreen formulation increases, the number of

active ingredients increases to three or four, and in some cases the total amount

of active sunscreens increases up to 26 percent. Not all formulations list the

speciﬁc concentrations of the active ingredients, and it is possible that some may

contain higher concentrations. As with many chemicals, increasing the concen-

trations of the active ingredients may increase the likelihood of sensitization

(Thompson, 1977). The majority of sunscreens contain octyl dimethyl PABA

DERMATOTOXICOLOGY

1056 ■

(Padimate 0) as the main UVB absorber. The cinnamate derivative, octyl

methoxycinnamate (Parsol MCX), is also used as a UVB absorber.

Most sunscreens with more than one ingredient contain oxybenzone as the

additional ingredient. The absorption peak of this compound lies in the UVB

region and extends partially into the UVA. Other agents that absorb in the

COSMETIC REACTIONS

■1057

Table 51.7:

Selected sunscreen formulations available the United States

Trade name SPF Active ingredients

Four sunscreening ingredients

Coppertone (Plough) 30 Padimate 0, Parsol MCX, octyl salicylate,

oxybenzone

Sundown (Johnson & Johnson) 30 Parsol MCX, octyl salicylate, oxybenzone,

titanium dioxide

20 Padimate 0, Parsol MCX, octyl salicylate,

oxybenzone

Cancer Garde (Eclipse Labs) 30 Padimate 0, Parsol MCX, oxybenzone,

titanium dioxide

T/I Screen (T/I Pharmaceuticals) 30+ Parsol MCX, octocrylene, octyl salicylate,

oxybenzone

Block Out (Carter Products) 30 Parsol MCX, padimate 0, octyl salicylate,

oxybenzone

Supershade (Plough) 44 Parsol MCX, padimate 0, homosalate,

oxybenzone

Three sunscreening ingredients

Solbar (Person and Covey) 50 Parsol MCX, octocrylene, oxybenzone

PreSun for Kids (Westwood) 39 Parsol MCX, octyl salicylate, oxybenzone

PreSun 29 29 Parsol MCX, octyl salicylate, oxybenzone

Bain de Soleil (Bain de Soleil) 30 Padimate 0, Parsol MCX, oxybenzone

Ultrashade (Plough) 23 Padimate 0, Parsol MCX, oxybenzone

Total Eclipse (Eclipse Labs) 15 Padimate 0, octyl salicylate, oxybenzone

Sundown (Johnson & Johnson) 15 Padimate 0, Parsol MCX, oxybenzone

Two sunscreening ingredients

Supershade (Plough) 8, 15 Parsol MCX, oxybenzone

Coppertone (Plough) 4, 6, 8, 15 Padimate 0, oxybenzone

Shade (Plough) 4, 6 Padimate 0, oxybenzone

PreSun (Westwood) 8, 15 Padimate 0, oxybenzone

Water Babies (Plough) 15 Parsol MCX, oxybenzone

Sundown (Johnson & Johnson) 4, 6, 8 Padimate 0, oxybenzone

Block Out (Carter Products) 15 Padimate 0, oxybenzone

Photoplex (Herbert Labs) 15 Padimate 0, avobenzone

One sunscreening ingredient

Coppertone (Plough) 2 Octyl salicylate

Bain de Soleil (Bain de Soleil) 2, 4 Padimate 0

Eclipse (Eclipse Labs) 5 Padimate 0

10 Glyceryl PABA

UVA region include sulisobenzone, dioxybenzone, menthyl anthranilate and

avobenzone. The latter chemical, which has an absorption maximum in the

middle of the UVA region (358 nm), has been approved in the United States in

two sunscreen formulations (Photoplex, Herbert Laboratories, Santa Ana, CA

and Coppertone, Sun and Shade) (Table 51.7).

Published reports of contact and photocontact sensitization and contact

urticaria induced by sunscreening agents are listed in Table 51.1. Representatives

of all major sunscreen categories including PABA derivatives, anthranilates,

salicylates, cinnamates, and benzophenones have caused allergic reactions are

described as follows:

Para Amino Benzoic Acid (PABA) In 1975, Willis (1975) suggested that the

sensitization potential of p-amino benzoic acid was minimal. Wennersten

(1984) reported that a total of 73/1883 (3.9 percent) subjects tested with 5

percent PABA in alcohol in the Scandinavian Standard Photopatch Tray had

either allergic or photoallergic responses to PABA. These subjects represent

73 percent of the total number of subjects with contact and photocontact

sensitization to PABA (Table 51.1). The use of PABA as a sunscreening agent in

Europe and the United States has decreased signiﬁcantly in recent years. PABA

has been replaced by ester derivatives such as Padimate 0 that, unlike PABA, are

not water soluble and tend to remain on the surface layer with less than 10

percent penetrating the corneum even after 24 hours (Weller and Eireman,

1984). These PABA esters appear to be less sensitizing than PABA; however,

there is no data to substantiate this impression.

PABA derivatives

Sensitization to glyceryl PABA have been reported for the last 30 years

(Marmalzat and Rapaport, 1976; Caro, 1978). Many of the cases of glyceryl PABA

sensitization showed uniform strong reactions to benzocaine, suggesting that

the sensitization may be due to the presence of impurities in the glyceryl PABA.

This suggestion was ﬁrst made by Fisher (1976) and has since been conﬁrmed

(Hjorth et al., 1978). Benzocaine impurities (1–18 percent) occurred in many

commercial sources of glyceryl PABA. Thus many of the early reports of contact

allergy to glyceryl PABA may have falsely implicated glyceryl PABA as the

sensitizer. Thune (1984) reported two cases of allergic/photoallergic reactions

to glyceryl PABA in which there was no reaction to benzocaine, suggesting true

allergy to the PABA derivative. However, no allergic responses were observed

when these subjects were patched with glyceryl PABA which had been puriﬁed

DERMATOTOXICOLOGY

1058 ■

via high-pressure liquid chromatography (Bruze et al., 1988). This suggests the

presence of an, as yet, unknown impurity (or impurities) other than benzocaine

as the sensitization source. This shows the importance of utilizing puriﬁed raw

materials in the manufacture of consumer products and the need for careful

interpretation of patch test results.

Other PABA derivatives that have caused sensitization/photocontact

sensitization include octyl dimethyl PABA (Padimate 0), amyl dimethyl

PABA (Padimate A), and ethyl dihydroxy PABA. The number of case reports

of sensitization/photocontact sensitization with Padimate 0 is less than that

reported with PABA and glyceryl PABA suggesting a lower sensitization potential

with this derivative. This may be because Padimate 0 is not a true PABA ester

since it does not contain the NH2 grouping present in glyceryl PABA, PABA, and

benzocaine (Fisher, 1977a).

Although Padimate A was included (FDA, 1978) as a safe and effective

sunscreening agent, this derivative can cause phototoxicity and may have

accounted for the erythemal response observed by Katz (1970) 30 minutes after

sun exposure. This compound is no longer used in sunscreens in the United

States. In addition to benzocaine impurities in the glyceryl PABA raw materials,

some PABA esters contain 0.2 to 4.5 percent PABA (Bruze et al., 1984). It possible

that PABA impurities may account for some of the reports of sensitization to the

PABA derivatives.

Salicylates

There are two cases of contact allergy and two reports of photocontact allergy

to homomenthyl salicylate in the literature (Rietschel and Lewis, 1978) and no

reports of sensitization to octyl salicylate, the major salicylate derivative in

many sunscreens.

Cinnamates

Cinnamates are chemically related to or are found in balsam of Peru, balsam

of Tolu, coca leaves, cinnamic acid, cinnamic aldehyde and cinnamon oil, ingre-

dients used in perfumes, topical medications, cosmetics, and ﬂavoring. Thune

(1984) reported eight cases of sensitivity to cinnamates, two cases of photoallergy

to 2-ethoxyethyl-p-cinnamate, and six subjects with contact allergy to other

cinnamates such as amyl cinnamaldehyde, amyl cinnamic acid, and cinnamon

oil. Calnan (1976b) reported cross-sensitization among cinnamon derivatives.

COSMETIC REACTIONS

■1059

Benzophenones

There have been reported cases of photocontact allergy (Thune, 1984) and

contact allergy (Camarasa and Serra-Baldrich, 1986) to oxybenzone; and reports

of contact allergy (Adams and Maibach, 1985) and photocontact allergy to

sulisobenzone. Benzophenone-10 (Mexenone), a benzophenone derivative not

used in sunscreens in the United States, can also cause contact and photocontact

dermatitis (Bury, 1980; De Groot and Wegland, 1987).

Dibenzoylmethanes

Dibenzoylmethane derivatives such as isopropyldibenzoylmethane (Eusolex

8020) and butyl dibenzoylmethane (avobenzone) have been incorporated in

European sunscreens as UVA absorbers since 1980. Instances of contact allergy/

photoallergy to sunscreens and lipsticks containing dibenzoylmethanes or these

derivatives have been reported, although the majority of reports have been

associated with the isopropyl derivative (English and White, 1986; Schander

and Ippen, 1986; De Groot et al., 1987). As a result, manufacturers stopped incor-

porating Eusolex 8020 into their products (Roberts, 1988; Alomar and Cerda,

1989). Recently, the manufacturers of Eusolex 8020 withdrawn from the market.

There have been fewer reports of contact allergy/photoallergy to the butyl

dibenzoylmethane derivative, avobenzone. It is possible that some of these

reactions to avobenzone may have been cross-reactions resulting from prior

exposure to the isopropyl derivative (Held et al., 1999). Greater utilization of

these compounds with appropriate testing should help clarify their relative

sensitization potential.

Camphor derivatives

3-(4-Methyl-benzylidene) camphor (Eusolex 6300) is a sunscreening agent used

extensively in Europe, often in combination with Eusolex 8020, but it is not

approved for use in the United States. There have been several reports of allergic

and photoallergic reactions to sunscreens containing this agent (FDA, 1978).

Miscellaneous

Other chemical sunscreens that have caused allergic reactions include diagalloyl

trioleate (Sams, 1956), the glycerol ester of o-aminometa (2,3 dihydroxyproxy)

DERMATOTOXICOLOGY

1060 ■

benzoic acid (van Ketel, 1977), a dioxane derivative (Fagerlund et al., 1983);

and 2-phenyl-methyl-benzoazol (witisol) (Mork and Austad, 1984). None of

these ingredients are approved for use in sunscreens in the United States.

Titanium dioxide

Physical blockers such as titanium dioxide and zinc oxide have the advantage

of not being sensitizers, but may be so occlusive that they can cause miliaria

(Fisher, 1973). Kaminester (1981) reported that the inclusion of titanium

dioxide in a PABA sunscreen blocked the appearance of photoallergy. It is

possible that the reﬂection and scattering of light by titanium dioxide reduced

the amount of UV light that penetrated the skin and elicited photoallergy.

Excipients

Contact allergy can also be caused by excipients included in sunscreens.

These chemicals include mineral oil, petrolatum, isopropyl esters, lanolin

derivatives, aliphatic alcohols, triglycerides, fatty acids, waxes, propylene glycol,

emulsiﬁers, thickeners, preservatives, and fragrances. An extensive list of vehicle

constituents in cosmetics that can cause allergic responses has been published

(Nater and De Groot, 1993). De Groot et al. (1988) indicated that preservatives,

fragrances, and emulsiﬁers are the main classes of ingredients responsible for

cosmetic allergy, with Kathon CG producing contact allergic reactions in 27.7

percent of subjects tested. Sunscreens available in the United States provide

a complete list of ingredients including the excipients. The listing of all

ingredients in sunscreens should be encouraged so that consumers, especially

those with known sensitivities to chemicals, are fully informed about the

composition of the formulation prior to the purchase and application of

the product to the skin.

51.4.10 Manicuring preparations

In the past, adverse reactions have been reported to numerous nail cosmetics

that have been removed subsequently from the market because of reported

hazards. Nail hardeners containing formaldehyde are in this category. In the

United States, this type of hardener is permitted for use only on the free edge

of the nail when the skin is protected from contact with the hardener. Some

manufacturers sell products called hardeners but they have merely increased the

COSMETIC REACTIONS

■1061

resin content of ordinary nail enamel. Nail enamels including base coats and

top coats have a similar composition. The concentration of each of these

chemicals depends on the quality to be achieved in the ﬁnal product. The base

coat will have increased amounts of resin to improve adhesion to the nail plate,

but the top coat has increased nitrocellulose and plasticizers to enhance gloss

and abrasion resistance.

Toluene sulfonamide/formaldehyde resin (TSFR) is responsible for contact

dermatitis around the nails but also at sites distant from the ﬁngers, commonly

eyelids, around the mouth and chin, sides of the neck, on the genitalia, and

rarely a generalized eruption. In contrast free formaldehyde in nail hardeners

causes mostly local reactions. Cronin (1980) recommends 10 percent toluene

sulfonamide/formaldehyde in petrolatum to perform a closed patch test. Norton

(1991) reported that free formaldehyde (FF) hardeners are the most common

cause of nail cosmetric reaction followed by methacrylate and cyanoacrylate

resins, TSFR, acetone removers and sodium and potassium hydroxide removers.

Norton also reported onychomycosis, chromonychia, anonychia and pterigum

inversum unguis, secondary to FF nail hardeners. A small amount (0.1 to 0.5

percent) of free formaldehyde is in the resin (Calnan, 1975). Fisher (1977)

proposed that patients who are allergic to this resin may wear nail polish

without problems if they allow it to dry thoroughly with their hands quietly at

rest. Those who find this inconvenient can be advised to purchase certain

“hypoallergenic” brands of nail polish, which substitute alkyd or other resins.

Ask the patient to check the ingredient list for toluene sulfonamide/formal-

dehyde resin as a precaution. The durability and abrasion resistance of these

other resins is said to be inferior to toluene sulfonamide/formaldehyde resin.

Although onycholysis has been attributed to reactions to toluene sulfonamide/

formaldehyde resin, no published data ﬁrmly support this (Braur, 1980; Paltzik

and Enscoe, 1980). A new nail enamel compound has been introduced by Almay

and Revlon. The toluenesulfonamide/folmaldehyde resin, the principal allergic

sensitizer in nail enamels have been replaced by glyceryl tribenzoate. In

addition, these new enamels are toluene-free. The new enamel also replaces

dibutyl phthalate for glyceryl triacetate. This new plasticizer, polymer that

prevents brittleness, provides longer wearability. Another very recent innovation

is quick-drying suspensions. Two recent patents employing acetone and

halogenated hydrocarbons provide for a reduction time from 50–70 percent

over conventional nail enamel compositions without adversely affecting the

other desirable properties of the coating. Environmental safe nail enamels are

a real challenge for the cosmetic industry. Water-based nail polish with

DERMATOTOXICOLOGY

1062 ■

adhesion, gloss and drying qualities will be developed (Mitchell et al., 1992). A

water-dilutable nail polish was developed containing a mixture of poly-

urethanes, vinyl and/or acrylic ester (Yamazaki and Tanaka, 1990).

Yellow pigmentation of the nail plate, darkest at the distal end, occurs

commonly in women who wear colored nail polish. Samman (1977) reproduced

this staining with the following colors: D&C Red No. 7, D&C Red No. 34, D&C

Red No. 6, and FD&C Yellow No. 5 lake. Nail enamel removers are mixtures of

solvents such as acetone, amyl, butyl, or ethyl acetate to which fatty materials

may be added (Wilkinson and Moore, 1982). These can be irritating to the

skin and can strip the nail plate. Cuticle removers contain alkaline chemicals,

frequently sodium or potassium hydroxide to break the disulfide bonds of

keratin. They should not be left on for prolonged periods or be used by people

who are susceptible to paronychia. Cuticle removers are irritants.

“Sculptured nails” have become popular in recent years because they build

an attractive artiﬁcial nail on the nail plate. Sculpture nails are prosthetic nails

with a fresh acrylic mixture of methyl methacrylate monomer liquid and

polymer powder. They are molded within a metabolized paperboard template

on the natural nail surface to produce nails of desired thickness and length.

When hardened, the template is removed, the prosthesis ﬁled and the surface

is polished. Acrylate sculptured nails are of two varieties: methacrylate

monomers and polymers that polymerized in the presence of hydroquinone in

ordinary light, Photo-bonded acrylate sculptured nails based on acrylates that

are photobonded. Allergic reactions consist of paronychia, onychia, and severe

and prolonged paresthesia. Fisher (1980b) reported a patient developed a severe

reaction to methyl methacrylate monomers resulting in permanent loss of all

her ﬁngernails. Fisher and Baran (1991) reported that cyanoacrylates do not

cross-react with other acrylates.

Unfortunately irritant and allergic reactions to the liquid monomers as

well as secondary infections may be painful and long-lasting. Paronychia,

onycholysis, onychia, and dermatitis of the ﬁnger and distant sites may occur.

Fisher et al. (1977) reported allergic sensitization to the methyl methacrylate

monomers in sculptured nails. In 1974, the FDA banned the use of methyl

methacrylate in these cosmetics. However, analysis of 31 products sold

between 1975 and 1981 revealed this monomer was present in nine of them

(Fuller, 1982). Sensitization has also been reported to other monomers, and

cross-reactions between acrylate monomers does occur (Marks et al., 1979).

Patch testing to 1.0 to 5.0 percent monomer in petrolatum or olive oil can

help confirm the diagnosis of an allergic sensitization. Controls may be

COSMETIC REACTIONS

■1063

required if the patient responds to 5 percent and not to 1 percent of the

monomer.

Performed plastic nails may be designed to cover the nail plate or extended

tips. Their prolonged use causes mechanical damage to the nail, and those

covering the entire nail plate may cause injury by occlusion (Baran, 1982).

Sensitization to p-tertiary butylphenol formaldehyde resin in the nail adhesive

and tricresyl ethyl phthalate of the artiﬁcial nail has been reported (Burrows and

Rycroft, 1981). Nail mending and wrapping kits often help women grow the

longer nails they desire with few adverse reactions. A split nail can be repaired

with cyanoacrylate glue with a negligible risk of sensitization. The repair is

splinted with papers afﬁxed by a nitrocellulose containing glue. These papers,

or in some cases linen or silk, are wrapped over the free edge of the nail to

protect it from trauma. Use of more sensitizing glues, of course, increases the

risk of adverse reactions. The paper or cloth should not cover a large portion of

the attached nail plate to avoid complications of occlusion.

51.4.11 Oral hygiene product

Dentifrices and mouthwashes are incriminated infrequently as causing allergic

contact reactions. This may be due to the short exposure time these products

have with the skin and mucous membrane under ordinary use situations.

If sensitization occurs inside the mouth, patch testing on the skin usually shows

a positive reaction. Many of the products contain detergents and are unsuitable

for closed patch testing. To avoid irritant reactions, test open in the antecubital

fossa and conﬁrm positive results with tests in controls. To help patients avoid

further reactions, ingredient patch testing should be done. Fisher (1970)

reviewed concentrations for patch testing ingredients found in toothpastes and

mouthwashes. If the physician suspects allergic contact dermatitis and negative

patch tests on the skin do not reflect mucosal sensitivity, ingredients may

be incorporated in Orabase (Squibb). This material can be held against the

inside of the lip for 24 hours, and then examined for erythema. Reports of

allergic sensitization to toothpastes in the last decade have primarily involved

flavoring agents (Andersen, 1978). Cinnamic aldehyde has been the most

frequent offender, because it was introduced in a relatively high concentration

in toothpaste sold in several countries (Drake and Maibach, 1976). A case of

contact dermatitis to cinnamic aldehyde resulted in depigmentation about the

vermilion border (Ale and Maibach, 2001).

DERMATOTOXICOLOGY

1064 ■

51.4.12 Personal cleanliness products

The action of bacteria upon sterile apocrine secretions produces a characteristic

odor. Labows et al. (1982) reported lipophilic diptheroids as the organisms that

produce unique axillary odors. Although deodorants are considered cosmetics,

antiperspirants are regulated as over-the-counter (OTC) drugs as well as

cosmetics. Many of these products have been reformulated in the last decade

because of government regulations (Jass, 1982). Hexachlorophene was banned

because of its neurotoxicity and halogenated salicylanilides because of their

photoallergic nature. Chlorofluorocarbon propellants were removed from

aerosols because of their role in depleting the stratosphere of ozone. The

chloroﬂuorocarbons have been replaced by hydrocarbon propellants—isobutane,

butane, and propane—which are flammable. The FDA OTC Antiperspirant

Review Panel recommended the removal of zirconium-containing chemicals

from aerosol antiperspirants because of the potential for formation of granu-

loma in the lung. Sodium zirconium acetate salts had caused granulomatous

lesions in the skin of the axilla, have been removed from antiperspirants.

Simple deodorants reduce the number of bacteria in the axilla. Most deodor-

ants contain triclosan as an active ingredient. Triclosan is an antimicrobial agent

used in soaps and shampoos. Draize testing showed a low-sensitizing potential

for this chemical (Marzulli and Maibach, 1973). Allergic contact dermatitis to

this chemical have been reported, but this requires conﬁrmation (FDA, 1975).

We recommend patch testing with 1 to 2 percent triclosan in petrolatum in

suspected cases. The OTC Review Panel published a list of aluminum and

aluminum-zirconium chemicals permitted in antiperspirants. These chemicals

are not regarded us sensitizers. Irritant reactions to aluminum salts in anti-

perspirants are common because of the environmental heat, moisture, and

friction and the inflammation caused by shaving in the axilla. Dermal

penetration of calcium salts and calcinosis cutis has been studied (Soileau, 2001).

Allergic reactions are due to the other chemicals in the antiperspirants; most

frequently the fragrance ingredients. Similarly, feminine hygiene sprays are

primarily fragrance products that cause irritant reactions when sprayed at too

close a range.

51.4.13 Baby products

These products are marketed primarily to use on the skin and scalps of infants.

Some experimental data suggest that infants are less easily sensitized than adults

COSMETIC REACTIONS

■1065

are. However, Epstein (1961) reported that 44 percent of infants under 1 year

of age could be sensitized to pentadecyl catechol, but that 87 percent of children

over 3 years of age were sensitized in the same experiment. In clinical practice,

allergic contact dermatitis is diagnosed infrequently in young children (Hjorth,

1981). Patch testing with ingredients in standard concentrations may result in

a higher incidence of irritant reactions in young children (Marcussen, 1963).

Because the diaper area is a frequent site of irritant contact dermatitis, careful

attention should be paid to the products used in this area.

Generally, baby products are fragranced. Baby oil, talc, and corn starch have

simple compositions with little sensitizing potential beside the fragrances. Baby

lotions or creams may contain fragrance, preservatives, lanolin, or propylene

glycol which are common sensitizers (Eierman et al., 1982). Propylene glycol,

present in these lotions and the moistened towelettes marketed for cleansing

the diaper area, is a common irritant. In the treatment of infants with diaper

rash, it is important to examine the ingredients of the cosmetics used on the

diaper area.

51.4.14 Bath preparations

Adverse reactions to bubble bath reported to the FDA include skin eruptions,

irritation of the genitourinary tract, eye irritation, and respiratory disorders

(Simmons, 1955). The genitourinary tract reactions in children have been the

most serious; many children have been subjected to extensive urologic workups

before the cause was established. The skin eruptions are assumed usually to be

irritant reactions due to the detergent content of this cosmetic.

51.4.15 Other skin care preparations

Depilatories

Most depilatories today contain mercaptans such as calcium thioglycolate 2.5

to 4.0 percent in conjunction with an alkali to bring the pH to between 10 and

12.5 (Wilkinson and Moore, 1982). The keratin of the cortex is more vulnerable

before it emerges from the follicle, and depilatories attack it there leaving a

soft rather than sharp end For this reason, the use of depilatories in place of

shaving can prevent pseudofolliculitis barbae in some black men. Powdered

facial depilatories, produced for beard removal, contain barium or strontium

sulfide because these chemicals are quicker acting. Unfortunately, these

DERMATOTOXICOLOGY

1066 ■

chemicals cause more irritation and produce an unpleasant odor. In order to use

the less malodorous thioglycolate depilatories for coarser beard removal, hair

accelerators such as thiourea, melamine, or sodium metasilicate are added.

Depilatories cannot be patch tested directly and these thioglycolates are seldom

sensitizers.

Epilating waxes

Epilating waxes are usually warmed to soften, and they harden and enmesh the

hair after application. When the wax is pulled off, the hair is removed by the

root. Some modiﬁed waxes do not have to be warmed and can be applied with

a backing material. These cosmetics may contain beeswax, rosin (colophony),

fragrance, or rarely benzocaine as potential sensitizers (Wilkinson and Moore,

1982). The problems usually seen with these epilating cosmetics are due to

mechanical irritation.

51.5 COSMETIC INTOLERANCE SYNDROME

Fisher (1980c) coined the term “status cosmeticus” for the condition in which

a patient is no longer able to tolerate the use of many or any cosmetic on the

face. Patients complain of itching or stinging, facial burning and discomfort.

This group seriously challenges our diagnostic skills as well as our ability to be

empathetic because the severity of patients’ symptoms does not match objective

signs of disease. Most of these patients have only subjective symptoms, but

some may have mild inflammation. The Cosmetic Intolerance Syndrome is

not a single entity, but rather a symptom complex due to multiple factors,

exogenous and endogenous (Polak et al., 1974). Therefore, these patients need

a thorough history, physical examination and workup. Some patients have

occult allergic contact dermatitis, allergic photocontact dermatitis, or contact

urticarial reactions, and the causal agents are documented by careful clinical

review and patch testing.

Others who have a seborrheic or rosacea diathesis with or without inﬂam-

mation seem to have ﬂared this condition by by overusing cleansing creams and

emollients. Both of these conditions may be accompanied by facial erythema

or scaling. Some patients require anti-inflammatory therapy, as do a atopic

patients who develop this state. Fisher found that itching or stinging or both

can be produced in patients with “status cosmeticus.” He recommended that

whenever possible these chemical should be avoided by these patients.

COSMETIC REACTIONS

■1067

When the offending agent cannot be found prolonged elimination of

cosmetics seems to help some women who after 6 to 12 months or more are able

to gradually return to the use of other cosmetics (Table 51.8). Additions of skin

care products should be made one at a time and no more frequently than every

2 weeks. The ﬁnal program should be simple and limited in the number and

frequency of cosmetics used. Golbenberg and Safrin (1977) suggested that

stinging effects of cosmetics irritants may be neutralized by anti-irritants. They

proposed three possible mechanisms of action of anti-irritants: to complex the

anti-irritant, to block the reactive sites in the skin and to prevent physical

contact with the skin.

51.6 OCCUPATIONAL DERMATITIS:

HAIRDRESSERS

Cosmeticians may perform a variety of personal care tasks including hair

grooming, manicuring, and applying makeup. It is primarily the hair care tasks

that account for the high rate of occupational hand dermatitis. Cronin (1982)

noted that beauticians frequently develop a dry, scaling dermatitis over the

metacarpophalangeal joints, however individuals vary in their ability to react

to irritants (Smith et al., 2002). Novice beauticians and those in training are

required to shampoo many customers each day, and the resulting irritation is

frequently the initial cause of hand dermatitis. These hairdressers have a good

chance of improving as they learn to protect and lubricate their hands. However,

patients with atopic eczema may have a particularly difﬁcult time with hand

dermatitis as hairdressers, although we do believe they should not be barred

DERMATOTOXICOLOGY

1068 ■

Table 51.8:

Management of patients who are intolerant to cosmetic usage

1. Examine every cosmetic and skin care agent

2. Patch and photopatch test to rule out occult allergic and photoallergic contact

dermatitis, or contact urticaria

3. Limit skin care to

•Water washing without soap or detergent

•Lip cosmetics

•Eye cosmetics (if the eyelids are not symptomatic)

•Face powder

•Glycerol and rose water as moisturizer (only if needed)

•6–12 months of avoidance of other skin care agents and cosmetics

4. Watch for and test, if necessary, depression and other neuropsychiatric aspects

from this career. Young atopic patients who are contemplating career choices

should be appraised of the occupational hazards of hairdressing.

When beauticians with hand dermatitis are patch tested at different centers

the percentage of reactions varies. PPD is usually the leading offender when

allergy is present (Wahlberg, 1975). Frosch and co-workers (1993) reported that

the major contact sensitizer of hairdressers in Europe was GMT. Sensitization

is at least as frequent to PPD; in some countries (Germany, UK, Spain) sensi-

tization frequencies, were high. This has to be emphasized in comparison to the

relatively low frequencies to AMT. The recently introduced acid permanents

waves pose a higher risk of sensitization to hairdressers than the alkaline

permanent waves that have been used since the early 1940s. The low ﬁgures for

GMT sensitization in some centers may be explained by lower usage in salons

or by more careful handling. In Denmark, most hairdressers wear gloves when

dyeing and permanent waving. In Germany, most hairdressers protect their

hands only against hair dyes. There is still a strong prejudice against the use of

gloves in this occupation. Guerra et al. (1992) conﬁrmed this attitude in Italy:

only 12.5 percent of 240 hairdressers wore gloves for permanent waving,

whereas 51 percent wore them for hair dying. This group found a relatively

low sensitization to GMT, attributing this to its infrequent usage in Italy.

They demonstrated that vinyl gloves may not always suppress the reaction to

GMT in sensitized individuals. They found 3 of 8 patients patch tested with GMT

through vinyl gloves were positive after 3 days. Better plastic materials must be

looked for, if GMT continues to be used in European salons. Furthermore, it

must be kept in mind that wearing gloves over a prolonged time poses its own

risks. The primary goal in the prevention of occupational dermatitis must be

reduction of exposure to highly sensitized agents. They reported GMT was the

number one sensitizer. After the series described by Storrs (1984), the German

CDRG reported sensitization to GMT in 38 percent of 87 patients in 1989,

and in 31 percent of a second series of 178 patients (Frosch, 1989). Holness and

Nethercott (1990) found 23.5 percent of 34 patients positive to GMT. GMT

sensitization may become increasingly frequent if no further action is taken.

Hairdressers need to be instructed to handle this type of permanent wave

with caution. Direct skin contact should be avoided, Gloves and improved

handling technique may lead to a decrease in the frequency of sensitization,

which may, in comparison to hair dyes, be acceptable to this occupational

group.

Rietschel et al. (1984) and other investigators have shown that allergens can

penetrate gloves. Fisher reported that polyethylene laminate glove (4-H glove;

COSMETIC REACTIONS

■1069

Safety 4 Company, Denmark) protect allergic patients from epoxy resin and

acrylic monomers. McCain and Storrs (1992) in a placebo-controlled double-

blind patch test study reported that 4-H glove was effective in preventing allergic

contact dermatitis in GMT sensitized volunteers, protecting four of four patients

after an 8 h exposure and two of three after 48 h. Melstran et al. (1994) provides

extensive documentaion aboout protectives gloves. Frosch and co-workers

(1993) found PPD the 2nd sensitizer very closed to GMT. However, PPD

derivatives were considerably lower and ranged from 375. In the Italian study,

the figures were similar for PPD but higher for the derivatives. Frosch and

colleagues (were unable to conclude that ONPPD had the lowest sensitization

risk. They stated that pyrogallol and resorcinol are the least frequent sensitizers

in the hairdressers’ series.

Nickel, preservatives such as (cloro) methylisothiazolinone and formaldehyde,

surface active agents such as cocamidopropylbetaine and hydrolyzed animal

proteins as well as perfume ingredients, may also be responsible for dermatitis

in hairdressers. To work-up hairdressers with hand eczema, we use the standard

hairdressers screening series. This series includes resorcinol, p-toluenediamine

sulfate, glyceryl monothioglycolate, ammonium thioglycolate, ammonium

persulfate, p-aminodiphenylamine hydrochloride pyrogallol and 0-nitro-

p-phenylenediamine. At the same session, we apply 1.0 percent glyceryl

thioglycolate in petrolatum, and pieces of the hairdresser’s protective glove

applied on both sides.

Hairdressers who are nickel-sensitive also have a serious challenge. There is

evidence that permanent solutions may leach nickel out of metal objects

(Dahlquist et al., 1979). Fastidious care in the selection of stainless steel tools

and use of dimethyl glyoxide for testing pins, clips, and other paraphernalia

allows some patients to continue in this career. Hairdressers with allergic contact

dermatitis need to be told that protective gloves may not provide an absolute

barrier to allergens (Frosch et al., 1993).

Tomb and co-workers (1993) reported a young hairdresser who developed

acute periorbital eczema and marked edema of eyelids, lip erosions and eczema

of her ﬁngertips to two instant glues used to attach false hair. Patch test was

strongly positive to ethyl cyanoacrylate adhesive. Ingredient labeling of retailed

cosmetics in the United States has greatly aided dermatologists in caring for

patients with contact dermatitis. There is no regulation requiring similar

labeling for cosmetics used in beauty salons. However preventive strategies for

occupational skin diseases in hairdressers are known and can be rarely successful

(Dickel et al., 2002).

DERMATOTOXICOLOGY

1070 ■

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