Allergens of Special Interest

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1 Chapter Allergens of Special Interest Jeanne Duus Johansen, Jean-Pierre Lepoittevin, David Basketter, John McFadden, Heidi Søsted Contents.1 Fragrances Jeanne Duus Johansen, Jean-Pierre Lepoittevin.1.1 Introduction Fragrance Ingredients The Fragrance Formula Chemistry Fragrance Contact Allergens Fragrance Chemicals Oxidation Products Fragrance Naturals Epidemiology of Fragrance Contact Allergy Clinical Aspects Exposure to Fragrance Allergens Consumer Products Occupational Exposure Diagnosis of Fragrance Contact Allergy Clinical Relevance and Patient Advice Other Skin Effects Immediate Reactions Photoallergy/Phototoxic Reactions Irritant Contact Dermatitis Airway Symptoms Case Reports References Hair Dyes David Basketter, Jeanne Duus Johansen, John McFadden, Heidi Søsted.2.1 Introduction Clinical Picture Allergic Contact Dermatitis Temporary Tattoos Diagnosis Immediate Reactions PPD The Archetype Chemistry Immunology Epidemiology Cross Reactions Occupational Allergy to PPD Substances Other than PPD Toluene-2,5-diamine Resorcinol Aminophenol Henna Bleaching Agents New Generation of Hair Dyes Pre-testing and Advising Patients Pre-testing Advising Patients Case Reports References Fragrances Jeanne Duus Johansen, Jean-Pierre Lepoittevin.1.1 Introduction The applications of fragrances are numerous and contact may be difficult to avoid, if one should wish so. Fragrances are used in all kinds of cosmetics and toiletries, in cleansing agents, air fresheners, toys and textiles, and in industrial settings. Many fragrance ingredients are also used as flavors in food and some are naturally occurring in spices. Fragrance products are used in aromatherapy, may be contained in herbal remedies, and, in some regions, natural fragrance products are used as topical medicaments for their antiseptic properties. Fragrances are capable of neutralizing unpleasant odors. They are added to products to produce a pleasant scent, add special character to the product, or as functional ingredients, e.g., providing antibacterial effects..1.2 Fragrance Ingredients The International Fragrance Association (IFRA) defines fragrance ingredients as any basic ingredient used in the manufacture of fragrance materials for its odorous, odor enhancing, or blending properties [1]. A fragrance ingredient may be a chemically defined substance or a natural product.

2 508 Jeanne Duus Johansen et al. Natural fragrance products are obtained by processing material from fragrance-producing plants. The fragrance can be present in almost any part of the plant and is obtained by pressing or steam distillation to give essential oils or by organic solvent extraction to give concretes and absolutes [2]. The content and consistency of the naturals depends on climatic and soil conditions for the plant, as well as many other factors, which makes it very difficult, if not impossible, to fully standardize the contents and quality of the end product. The volatile fragrance product obtained from plants usually contains numerous ingredients. The characteristic odor of the fragrance product may be due either to a particular ingredient, or, in the case of a complex composition, the blending of a number of ingredients [3]. Oak moss absolute contains at least 250 ingredients and has several odor-determining agents [4], while clove oil contains up to 80% eugenol, which is the determining odor agent [5]. Previously, also animal secretions, such as musk from deer and ambergris from the sperm whale, were used as the basis for the production of natural fragrance ingredients. These are now mostly replaced by blends of fragrance chemicals. Originally, all perfumes were composed of natural products, but with the scientific and technical developments in the first half of the 19th century, chemists were able to identify the odor-determining major ingredients of natural fragrance materials. Following this development, industrial production of synthetic fragrance materials began. The synthesized ingredients are often nature-identical chemicals, that is, imitations of naturally occurring substances; however, also, the production of entirely new chemicals takes place. The EU Commission has issued two inventories of fragrance ingredients, both of which are currently in use, one of the chemical substances and one of the natural products, also named botanicals. The lists are based on information from the industry and contain about 2,500 different ingredients [6]. Core Message Two thousand five hundred (2,500) fragrance ingredients are in current use for compounding perfumes. The ingredients are natural extracts of plant products, nature-identical, or entirely synthetic chemicals..1.3 The Fragrance Formula A fragrance formula consists of a mixture of or more different fragrance ingredients, naturals, and/or chemicals. The fragrance formula is incorporated into the end product, e.g., a cosmetic. Some cosmetic products are used primarily for their scent, such as perfumes, eau de cologne, and aftershaves. These products consist mainly of fragrance ingredients diluted with alcohol/water. A perfume usually contain 15 30% fragrance ingredients, a cologne about 3 5%, a deodorant 1%, a cream 0.4%, and undiluted soaps 0.5 2% [7]. The creation of a perfume, the fragrance formula, is regarded as an art. In designing a perfume, components from different odor families and of different volatilities are combined to form an esthetic whole. The most volatile ingredients are called top notes, usually fruity and spicy, which is followed by the heart note, built up by floral accords, forming the most essential part of the perfume; the long-lasting materials are known as the bottom notes. These include woody, moss-like, and sweet vanilla-like ingredients [8]. The basic pattern and principal structure of perfumes has not changed dramatically throughout the history of perfumery. The difference lies in the quality and availability of the raw materials and a different way of compounding [8]..1.4 Chemistry Fragrance ingredients are organic compounds and must be volatile to be perceived. Therefore, in addition to the nature of the functional groups and the molecular structure of a substance, the molecular mass is an important factor. Molecular masses of about 200 occur relatively frequently [5]; further, many of the fragrance ingredients are lipophilic in nature and, thus, have good penetration abilities, even of intact skin [9]. A fragrance formula is a mixture of molecules with very different physico-chemical properties; allergens may be formed in the mixture, e.g., by oxidization [10] or in the skin by metabolism [11]. The mixture of molecules may result in interactions during skin penetration, skin metabolism, and epitope formation [9]. These interactions may lead to a change in sensitization and elicitation potential [12 15], effects, which, as yet, have only been seldom investigated [9].

3 Allergens of Special Interest Chapter Fragrance Contact Allergens Table 1.1. Ingredients of fragrance mix I (FM I) Fragrance ingredients, Concentration INCI name (chemical name) in FM I (%) α-amyl cinnamal (α-amylcinnamic 1 aldehyde) Cinnamal (cinnamic aldehyde) 1 Eugenol (eugenol) 1 Geraniol (geraniol) 1 Hydroxycitronellal (hydroxycitronellal) 1 Isoeugenol (iso-eugenol) 1 Evernia prunastri (oak moss absolute) 1 Emulsifier Sorbitan sesquioleate 5 Each ingredient is tested at the same concentration in FM I as individually, except sorbitan sesquioleate, which is individually tested at 20% in petrolatum Allergenic fragrance ingredients have been identified by predictive assays in humans [16], in guinea pigs [17], and in mice [18]. A number of these studies are produced by the fragrance industry itself. In the past, most of such studies have remained unpublished, inhouse data. Recently, the industry has changed this policy and has published data in review form. Due to the high number of fragrance ingredients in use, structure activity relationship (SAR) analysis has been employed to identify potential allergens, e.g., in deodorants [19]. Testing a series of individual aldehydes in the animal assay, local lymph node assay (LLNA), and combining these results with reactivity and lipophilicity parameters has developed further quantitative SARs (QSARs). Equations derived from these QSARs allow improvement of the predictions made based on chemical structure alone of new aldehydes [18, 20]. However, most clinically relevant knowledge comes from patch testing eczema patients with fragrance ingredients suspected of causing allergic reactions. In this way, the first screening test for fragrance contact allergy was designed [21], an approach followed by others [22 33]. This first true screening test for fragrance allergy, called the fragrance mix (FM I), was composed in the late 1970s by Larsen [21]. It consists of a mixture of eight ingredients: seven chemicals and a natural extract with the addition of an emulsifier (Table 1.1). Among the ingredients of FM I, the natural oak moss absolute has, for some years, been the top ranking, usually followed by isoeugenol, cinnamal, and/or hydroxycitronellal (Fig. 1.1). In recent multinational studies, additional important allergens have been identified [26 30]. Among these are both chemicals, such as hydroxyisohexyl 3-cyclohexene carboxaldehyde (Lyral) [34], farnesol, citral, α-hexylcinnamic aldehyde [26], as well as natural extracts, such as ylang ylang oil, lemongrass oil, narcissus absolute, sandalwood oil, and jasmine absolute [27]. The following sections are comments on selected fragrance chemicals and naturals of special interest Fragrance Chemicals Cinnamal (chemical name cinnamic aldehyde) is a strong allergen [16] and has, for many years, been a Fig Time trend of reactions to ingredients of fragrance mix (FM I). Data collected by the Information Network of Departments of Dermatology (IVDK), University of Göttingen, Germany. Testing performed in selected patient numbers of between 1,083 and 1,924 yearly, adapted from Schnuch et al. [61]

4 510 Jeanne Duus Johansen et al. top ranking fragrance allergen [35], though recently a decline in reactions has been seen [36]. Cinnamal is the main component of cinnamon oil. It is also used as a flavoring and is described as an occupational allergen in bakers on a case basis [37, 38]. In newer investigations, cinnamal was found only rarely in cosmetic products [39 42]; however, the chemically related substance, cinnamic alcohol, seems to be converted in the skin to cinnamal [11, 43]. Cinnamal is restricted to 0.1% in the Cosmetic Directive [44]. Isoeugenol is a strong allergen [16]. It caused contact allergy in 1.7% of 2,261 consecutively tested eczema patients in a European multi-center study [45]. It is found in many cosmetic products and may be present in relatively high concentrations, especially in colognes and similar products [42]. There seems to be no relation between the metabolism of eugenol, which is also a constituent of fragrance mix, and isoeugenol [46, 47]. Isoeugenol is restricted to 0.02% in cosmetic products in the Cosmetic Directive [44]. Recent studies have shown that patients with isoeugenol contact allergy react to esters, but not ether derivatives of isoeugenol [45], providing a basis for allergen substitution. Hydroxycitronellal is classified as a relatively weak allergen based on its inherent properties [48]; even so, it is one of the top ranking causes of fragrance contact allergy. It is widely used in cosmetic products, both perfumes and deodorants, and often in relatively high concentrations. It is restricted to 1% in cosmetic products [44]. Hydroxyisohexyl 3-cyclohexene carboxaldehyde (Lyral) has been used for many years without restrictions. It is related to hydroxycitronellal and has probably been used as a substitute in many cases as hydroxycitronellal was restricted [49]. The use concentrations have generally been very high; more than 3.0% in perfumes have been reported [49].A series of systematic investigations under the leadership of Frosch has shown that Lyral is one of the most frequent allergens, giving positive reactions in 1 2.7% of consecutively patch tested patients [25, 26, 29, 34] (Table 1.2). Farnesol is both used as a fragrance ingredient and as a biocide, e.g., in deodorants [50]. It is has been shown to cause allergy in 1.1% of patients consecutively patch tested by the German Information Network of Departments of Dermatology (IDVK) [51]. Those positive to farnesol were characterized by being young females and having hands and face more often affected than patients negative to farnesol [51]. Probably, many cases of deodorant contact allergy due to farnesol have been missed in the past, as most of the patients reacting to farnesol are negative to the fragrance mix [29, 51]. Citral is a relatively weak allergen, which also has irritant properties. It has a steep dose response curve [52] and has been shown to be of possible significance in patients with long-term chronic hand eczema, which may be due to its combined allergenic and irritant effects [52, 53]. The irritant properties of citral have been shown to be temperature dependent [54]. In European multi-center studies, % of consecutively tested eczema patients gave a positive reaction to citral 2% [26, 29]. Coumarin is the subject of several studies and case investigations [26, 55]. It has been reported to cause reactions in 0.4% of consecutively tested patients [56] and also gave rise to positive reactions in 0.3% of patients in a European multi-center study [26]. However, in the most recent European investigation, it gave no reactions among 1,701 patients [29]. The reason for this is unknown, but may be related to the use of a better quality of coumarin containing fewer sensitizing impurities. Table 1.2. Ingredients of fragrance mix II (FM II) and reactivity Ingredient Patch test concentration Patch test concentration Frequency of reac- Frequency of reac- (INCI name) in FM II (14% in at individual ingredient tions to individual tions to individual petrolatum) [28] testing in petrolatum ingredients [26] ingredients [29] (N=1,855) (N=1,701) Lyral a 2.5% 5.0% 50 (2.7%) 28 (1.6%) Citral 1.0% 2.0% 21 (1.1%) 12 (0.7%) Farnesol 2.5% 5.0% 10 (0.5%) 6 (0.4%) Citronellol 0.5% 1.0% 7 (0.4%) 4 (0.2%) α-hexyl cinnamal 5.0% 10% 6 (0.3%) 1 (0.06%) Coumarin 2.5% 5.0% 5 (0.3%) 0 a INCI name: hydroxyisohexyl 3-cyclohexene carboxaldehyde

5 Allergens of Special Interest Chapter 511 Core Message Hydroxyisohexyl 3-cyclohexene carboxaldehyde (Lyral) has, in recent years, been identified as a frequent cause of contact allergy Oxidation Products d-limonene is obtained as a by-product from the citrus juice industry. Peal oil from the skins of citrus fruits contains normally more than 95% d-limonene. It is used as a fragrance ingredient, but also has many other applications. In itself, it is not a sensitizer, but it rapidly oxidizes when in contact with air [10]. Antioxidants such as butylated hydroxytoluene (BHT) are, therefore, often added to commercial products. However, once the antioxidant is consumed, the oxidation starts immediately. The allergens formed are mainly hydroperoxides [57], with strong sensitizing potential. Testing consecutive patients in different clinics with oxidized d-limonene gave positive results in % of cases [58]. Recently, similar findings have been obtained for linalool, another terpene [59, 60]. This emphasizes the need for testing with the chemicals that are in the products and not just what was originally added. Patch test material of the oxidized forms of linalool and limonene are not commercially available yet. In terms of prevention, expiry dates taking auto-oxidation into consideration will help solve the problem. the single ingredients are tested [36, 61] (Fig. 1.1). A systematic search of the allergens in the extract has recently been performed. A bio-guided fractionation procedure was used based on the testing of patients sensitized to oak moss absolute with fractions of the natural in question. This was combined with chemical analysis and SAR analysis to ultimately identify the allergens in oak moss absolute [4]. Several allergens were identified, and among these chloroatranol, atranol, and methyl-β-orcinol carboxylate gave the most reactions. These allergens are formed during the processing of the lichen (Fig. 1.2). Chloroatranol and atranol have been further studied and are shown to be strong allergens and potent elicitors, giving reactions at extremely low levels [62]. An explanation of the high rates of sensitization to oak moss absolute was found by assessing exposure. Chloroatranol and/or atranol were found in 87% of investigated products, mostly perfumes [63]. Core Message Strong allergens are formed by autooxidation of d-limonene and linalool. This can probably be extended to other terpenes. If patch testing is done with nonoxidized material, false-negative results may be expected Fragrance Naturals Oak moss absolute is derived from the lichen Evernia prunastri. It has been used as a basic ingredient and a fixative in many perfumes. It is a constituent of the fragrance mix and it is a top ranking allergen when Fig Degradation products of atranorin and chloroatranorin formed during oak moss processing. R=H: atranorin, R=Cl: chloroatranorin. Adopted from Bernard et al. [4].

6 512 Jeanne Duus Johansen et al. Table 1.3. Patch test reactions to selected natural ingredients [27, 30, 33]. (NT Not tested) Ingredient Ylang ylang oil I Ylang ylang oil II Ylang ylang oil (unspecified) d Lemongrass oil Narcissus abs. d Jasmine abs. d Sandalwood oil d Patchouli oil Spearmint oil d Dwarf pine needle oil Cedarwood oil Peppermint oil Clove bud oil Lavender oil Eucalyptus oil Geranium oil bourbon N=1,606 [27] a N=218 [30] b N=178 [] c 2.6% a 2.5% a NT 1.6% a 1.3% a 1.2% a, 16.9% c 0.9% a 0.8% a 0.8% a, 5.0% c 0.7% a 0.6% a 0.6% a 19.3% b 2.8% b 1.8% b 8.4% c a Consecutively tested patients b, c Selected patients with fragrance sensitivity d Tested as a natural mix in 752 fragrance-sensitive subjects, gave a response in 47% of cases [33] Based on these investigations, the Scientific Committee on Consumer Products (SCCP) advisory to the EU Commission has expressed an opinion that neither chloroatranol nor atranol should be present in consumer products [64]. Ylang ylang oil is produced by steam distillation of the flowers of Cananga odorata. Four grades are produced, which differ in odor, price, and composition. Ylang ylang oil is a major cause of allergic contact dermatitis in Asian countries, where it is frequently followed by hyper-pigmentation [65]. In a European multi-center study including 1,606 patients, ylang ylang oils of grades I and II were tested and gave a positive patch test reaction in 2.6% and 2.5% of patients, respectively, with the highest frequency in London, possibly due to the city s large Asian population; detailed information can be found in a paper by Frosch et al. [27]. Lemongrass oil, narcissus absolute, jasmine absolute, geranium oil bourbon, spearmint oil, sandalwood oil, lavender oil, and others have also been reported as frequent sensitizers [27, 30 32, 65] (Table 1.3). Myroxylon pereirae (balsam of Peru) is derived from the sap of a tree, Myroxylon pereirae (MP) and is composed of 250 constituents, of which 189 are known structurally [66]. MP has been used in topical medicaments, such as wound treatment, for its antibacterial properties [67], but also as a flavor and perfume ingredient. In many countries, the use of MP in topical medicaments has been discontinued due to its sensitizing properties; however, it may still occur in herbal and natural products [68]. The crude form of MP has been banned from use in perfumes by the fragrance industry since 1974 [69]; however, the extent of the use of modified MP in perfumes is unknown. MP has been in the standard series since its first edition and is still causing many reactions [61]. Colophony (rosin) is a resin obtained from different species of coniferous trees. It is a complex mixture of resin acids and natural substances. Its composition varies with the species from which it is obtained and also depends on the recovery processes and storage conditions [70]. Unmodified colophony is known to cause contact allergy. The main allergenic components are oxidized resin acids formed on exposure to air. The allergenicity can be changed by chemical modification, e.g., it can be decreased by hydrogenation, while other kinds of modifications may enhance the allergenicity [70]. Colophony has many applications and has also been used as a fragrance ingredient. The use of unmodified colophony in perfumes was banned in 1992 by the industry [71]; however, it is unknown to what extent modified forms of colophony are used in perfumes. An extensive review has been published listing fragrance ingredients, chemicals, and natural products identified in the available literature as allergens in clinical studies of groups of patients or single cases [72]; about 100 chemicals and a similar number of natural products are in these lists. Core Message The main allergens in the natural extract oak moss absolute have been identified as chloroatranol and atranol, which elicit contact allergy at very low levels. A ban on those ingredients in cosmetics has been proposed..1.6 Epidemiology of Fragrance Contact Allergy Frequencies of sensitization to perfume ingredients were previously difficult to estimate due to the lack of a reliable test substance to screen for this allergy, but it was regarded as a common condition [73]. MP was shown by Hjorth to be a marker of contact allergy to fragrances in the 1960s [67], and later the fragrance

7 Allergens of Special Interest Chapter 513 mix (FM I) was developed, which enabled assessment of the problem [21]. Contact allergy to fragrance ingredients as identified with FM I is seen in all geographical regions of the industrialized world [28, 74 77]. Studies of the general population show that about 2% of adolescents and 1 4% of adults have fragrance contact allergy in Denmark [78 80], depending on the age group of investigation. One-third of 12- to 16- year-old children had, at the time of diagnosis, symptoms of their allergy, as did half of the adult population [78, 79]. An estimation based on the sales of patch test materials in Germany and patient data gave similar results. It showed that % of the German population is sensitized to fragrance mix, amounting to million people in the German population of 82 million inhabitants [81]. In adults with contact eczema undergoing patch testing contact allergy, FM is one of the most frequent causes of contact allergy, often next to nickel. In the most recent multi-center investigations in Europe, 6.5% of adult eczema patients reacted to the fragrance mix and 10.9% in North America [28, 82], which was a decrease compared to previous findings [26, 82]. The frequency of fragrance allergy in patch-tested patients increases with age [83, 84]; nevertheless, FM I is also among the top-ranking allergens in children with eczema [85, 86], and cases down to 2 years of age have been reported, even though it is rare [83]. In eczema patients, the female : male ratio of FM I allergy is usually 2 : 1 [36, 61, 87], while in the general population, especially in the younger years, a more equal sex distribution is seen [78]. While an increase in FM I allergy was described in the 1990s, at least in some geographical regions [61, 87, 88], the most recent investigations from the German surveillance system (IVDK) shows a statistically significant decrease in the frequency of FM I allergy among eczema patients in recent years from 13.1% in 1999 to 7.8% in 2002 [61]. This is in accordance with a chemical analysis of ten prestige perfumes, showing that fewer FM allergens were present in newly launched perfumes in comparison with perfumes manufactured more than 10 years ago [89]. MP showed a similar trend, but to a lesser extent and surpassed the FM I in frequency in 2002 [61]. This may be a reminder that the use of other allergenic fragrance compounds, structurally similar to ingredients in MP, may have increased [61]. Certainly, high frequencies of contact allergy to natural extracts such as ylang ylang oil and jasmine absolute have been demonstrated [27, 30, ] and, in addition, a number of chemicals not included in FM I have been shown to be important allergens [26, 30 32]. Thus, the epidemiology of fragrance contact allergy is only partly displayed by the results from testing with FM I, which should be borne in mind both in assessing the size of the problem on a community level and in the diagnostic workup of the individual patient..1.7 Clinical Aspects Allergic contact dermatitis may develop as itchy eczematous patches where perfume has been applied, usually behind the ears, on the neck, the upper chest, and sometimes the elbow flexures and wrists [73]. Another typically presenting feature is a bilateral axillary dermatitis caused by perfume in deodorants; if the reaction is severe, it may spread down the arms and to other areas of the body [73] (Fig. 1.3). It is not always that such patients will consult a dermatologist, but a history of such first-time symptoms have been shown to be statistically significantly related to the diagnosis of perfume allergy by FM I in eczema patients [90]. Facial eczema is a classical manifestation of fragrance allergy from the use of different fragranced cosmetic products [33, 91, 92]. In men, aftershave lotion may cause a eczematous eruption of the beard area and adjacent part of the neck [73] (Fig. 1.4) and Fig Allergic contact dermatitis from perfume in deodorant (courtesy of N. Veien)

8 514 Jeanne Duus Johansen et al. men using wet shaving opposed to dry have been shown to have an increased risk of 2.9 of being fragrance allergic [93]. Data from St Johns in London in 1980s showed that perfumes and deodorants were the most frequent sources of sensitization in women and aftershave lotions and deodorants were usually the most responsible in men [73]. More recent investigations have confirmed that this is still the case [42, 94 98]. Primary hand eczema or aggravation of hand eczema can be caused by contact to fragranced products, as seen in occupational settings [99].Also, a significant relationship between hand eczema and fragrance contact allergy has been found in some studies based on patients investigated for contact allergy [ ]. However, hand eczema is a multi-factorial disease and the clinical significance of fragrance contact allergy in (severe) chronic hand eczema is controversial. A review on the subject has been published by Heydorn et al. [99]. Pigmented contact dermatitis has been described in Japan as a manifestation of contact allergic reaction to a range of contact allergens, e.g., ylang ylang oil and jasmine absolute [65]. The pigmentation disappears or improves upon avoidance. Systemic contact dermatitis may occur in selected cases. The phenomenon that patients, sensitized by skin contact, react with a rash to oral intake of flavored food has especially been described in conjunction with MP sensitivity [68, ]. In general, the problem is to quantify exposure and determine the relevance to chronic eczema. Systemic contact dermatitis is the subject of a separate chapter in this book, Chap. 16. Core Message Deodorants and perfumes/aftershaves are frequent sources of perfume allergy. Fig Allergic contact dermatitis from perfume in aftershave (courtesy of N. Veien).1.8 Exposure to Fragrance Allergens Consumer Products Exposure may be by direct skin contact, and, the longer time of contact, the higher the risk of sensitization and elicitation, even though the frequency of applications also plays a role. The most significant nonoccupational exposure is from cosmetics products. Chemical analysis of more than 150 different cosmetic products has shown that the fragrance mix ingredients occur widely and, in some products, in high concentrations (Table 1.4). Isoeugenol was found in 24% of products in a concentration of between <0.001% and 0.34% [7]. Also, an important allergen, Lyral, has been shown to be widely distributed in cosmetic products and, in particular, in high concentrations of 3% or more in fine fragrances [34, 49, 106]. Natural-ingredient-based cosmetic perfumes have been shown to contain fragrance allergens to the same degree or more than ordinary products [39], which perhaps is not so surprising, since most fragrance ingredients and, thus, allergens are nature-identical. Children s products may also contain fragrance allergens; however, in an investigation of 25 children s products, the fragrance mix ingredients were either not present or present in fairly low concentrations [41]. The highest levels of fragrance mix allergens were found in perfumes and extreme levels were seen in a toy perfume [41]. Chemical analysis of 59 household products showed that the most commonly detected fragrance allergen was limonene, which was found in 78% of products, followed by linalool in 61%, and citronellol in 47% [107], while the ingredients of the fragrance mix were found less frequently than expected from the analysis of cosmetic products. Some of the investigated household products were also for occupational use. The exposure to naturals extracts, which may have a signifi-

9 Allergens of Special Interest Chapter 515 Table 1.4. Exposure assessment of fragrance allergens in cosmetics and household products by chemical analysis and information from the industry. [ND Not done. NQ not quantified, NG not given, PPM µg/ml (10,000 ppm=1%)] Ingredient Prestige perfumes, Natural-ingredient- Deodorants Household products N=10 a ; N=NG b ; based perfumes N=73 [40] N=59 [107] N= c ; [42] a ; [49 b ; [62] c N=22 [39] In % of Concentration In % of Concentration In % of Concentration In % of Concentration analyzed range (ppm) analyzed range (ppm) analyzed range (ppm) analyzed range (ppm) products products products products α-amyl cinnamal 30 a 300 6, ,940 30, NQ Cinnamal 0 a NQ Cinnamyl alcohol 60 a 300 7, , ,169 2 NQ Eugenol 90 a 400 8, , , Geraniol 90 a 800 4, NQ , ,758 Hydroxycitronellal 90 a 2,500 11, ,350 60, , Isoeugenol 70 a 500 3, , NQ Lyral 46 b 32,000 (mean) ND , Farnesol ND ND ND ND Citral ND ND ND ,088 Limonene ND ND ND ,443 Linalool 90 b 47,000 (mean) ND , Chloroatranol d 87 c ND ND ND Atranol d 77 c ND ND ND a Consecutively tested patients b, c Selected patients with fragrance sensitivity d Allergens in oak moss absolute cant allergenic potential, is virtually unknown, as it is only possible to quantify the exposure to identified chemicals. The demonstration of the main allergens in the extract oak moss absolute and their presence in almost all investigated perfumes/aftershaves is an example of a hidden exposure to important allergens in naturals [4, 63]. Core Message Fragrance allergens are widespread in consumer products Occupational Exposure There are a number of occupations where fragrance exposure may occur from cosmetic or domestic products, e.g., in hairdressers, beauticians, aromatherapists, masseurs, and cleaners. Chefs and bakers are exposed to spices and flavors, which may contain fragrance allergens, e.g., cinnamal from cinnamon. Eugenol is used for dental fillings and is a rare cause of contact allergy in dentists [108]. Multivariate analysis of associations between occupation and contact allergy to the fragrance mix showed that the highest occupational risk of fragrance contact allergy was associated with work as a masseur, physiotherapist, metal furnace operator, potter or glass marker, or geriatric nurse, when using data on 57,779 patients from the German surveillance system (IVDK) [109]. In an English investigation, healthcare worker (medicine, dentistry, nursing, veterinary) was also the occupation with the highest overall prevalence of sensitization to FM I [83]. Metalworkers exposed to metalworking fluids and with occupational skin diseases were found to have an increased risk of sensitization to fragrances in terms of a positive patch test to FM I and MP, when compared to metalworkers with occupational disease, but not exposed to metalworking fluids [110]; this could not be explained by the use of skin care and protecting creams. According to recent information from the lubricants-producing industry, fragrances are no longer usually added to metalworking fluid concentrate. However, it may be that masking fragrances are added during usage [110]. It is recommended that cases of fragrance allergy in metal workers should be thoroughly investigated for a causal relationship [111]. Another association to fragrance allergy was found in workers producing rotor blades for wind turbines with an epoxy-based tech-

10 516 Jeanne Duus Johansen et al. nology [112]. A significant relationship between contact allergy to epoxy resins and FM I was found, and the same association was found among male eczema patients undergoing patch testing, possibly caused by cross-reactivity [112]..1.9 Diagnosis of Fragrance Contact Allergy The basic investigation of suspected fragrance contact allergy is made by patch testing with the standard patch test series, which currently entail three potential indicators of fragrance contact allergy: FM I, MP, and colophony. FM I has been used as an indicator of fragrance contact allergy since the late 1970s. The ingredients of the mix have remained unchanged since, while the test concentration of the mix was lowered from 16% originally to 8% in 1984, as data suggested that the higher concentration gave irritant reactions [113]. Thus, the individual ingredients were lowered from 2% to 1%, which may give rise to false-negative results when testing the ingredients separately [114]. The emulsifier sorbitan sesquioleate was later added to the individual ingredients, as it was shown to improve the positive rate [115]. FM I is a heterogeneous mix, which means that it contains molecules that differ widely in size and reactivity [9]. In this way, it is a realistic imitation of perfumes. Further, its composition has been shown to be a relevant reflection of exposure [116]. It has been assessed that FM I detects 50 80% of eczema patients with reactions to perfumes in cosmetics [42, 74, 117]. The same applies if individual fragrance allergens are tested [23, 26, 27, 30 32]. However, the developments in the fragrance industry, changing fashion, and regulatory interventions mean that the exposure pattern is constantly changing and fragrance ingredients other than FM I are relevant to test [22, 25 27, 30 32, 74, 102, 118]. An EU-funded research program was aimed at designing an additional screening test for fragrance allergy, fragrance mix II (FM II) [28, 29]. Based on previous investigations [22, 23, 25, 30 32, 49], published information in general and the IFRA guidelines, a selection of candidates for testing was made, chemicals [26] and naturals [27]. Fourteen chemical were tested in 1,855 patients; the six chemicals with the highest reactivity following FM were Lyral (2.7%), citral (1.1%), farnesol (0.5%), citronellol (0.4%), α-hexylcinnamal (0.3%), and coumarin (0.3%) [26]. These six chemicals were further tested as a mixture in three different concentrations, and with the corresponding individual ingredients in 1,701 consecutive patients [28]. Positive reactions to the FM II were dose-dependent and 2.9% reacted to the FM II in a test concentration of 14%, which was recommended as an additional diagnostic screening tool [28]. About one-third of those reacting to FM II 14% were negative at testing with FM I. In breakdown testing of the single ingredients, 74% gave a response, if doubtful reactions were included [29], and the rank order of the ingredients was as in the first study [26], except that no unequivocal positive reaction to coumarin was observed. Lyral was the dominant single constituent, with positive reactions in 36% of patients reacting to 14% FM II. Assessments made of clinical relevance by different methods showed that FM II detects additional relevant cases of contact allergy to fragrances [28, 29]. It is recommended to supplement the standard patch test series with FM II 14%, when available, and Lyral 5% pet., as a fragrance ingredient of special importance. Lyral is already included in the standard series in Germany [119] and many other clinics. The allergens present in FM I and II also cover the most frequent fragrance allergens detected in patients with hand eczema: citral, hydroxycitronellal, Lyral, and eugenol [53], though oxidized limonene, which gave positive patch tests in 0.9% of chronic hand eczema patients [53], is not commercially available. The function of MP as an indicator of fragrance contact allergy is more complex and heterogeneous than FM and may vary in different parts of the world due to local habits. MP contains ingredients also present in FM I, such as cinnamates, which comprise more than 35% of the MP constituents and isoeugenol/eugenol [68]. Hausen has hypothesized that the pattern of reactions may indicate sources of exposure, so that contact allergy to MP and isoeugenol/eugenol can be traced back to fragrances, especially if the reaction to FM I is moderate or strong, while reactions to cinnamal/cinnamates can be traced to essential oils and possible sunscreens [68]. A statistically significant relationship between reactions to FM I and MP was seen in a study covering several countries [29]. This may be explained by the contents of mutual allergens, while only a weak association was seen with FM II, the ingredients of which are not in MP, except for farnesol in trace amounts [68]. Some advances in the diagnostics of contact allergy to natural fragrance ingredients have also been attempted [27, 30 32]. Larsen tested a natural mix consisting of jasmine absolute, ylang ylang oil, narcissus absolute, sandalwood oil, and spearmint oil, and found that it identified 84% of perfume-allergic patients [33]. Natural extracts, such as ylang ylang oil, narcissus oil, sandalwood oil, and jasmine absolute, were identified as frequent sensitizers by Frosch [27],

11 Allergens of Special Interest Chapter 517 Fig. 1.5a, b. Patch test reaction to the new fragrance mix (FM II) in dose-dependent intensity (day 3) (a). Breakdown testing revealed high sensitivity to Lyral. The repeated open application test (ROAT) with Lyral was strongly positive already on day 4 (b) (courtesy of PJ Frosch) a b and relevant cases are missed by only testing with FM I. Still, a screening series of naturals awaits development and it is not known to which extent MP and oil of turpentine are good indicators of fragrance allergy to natural extracts in general, as has been suggested previously [61]. The role of colophony in detecting fragrance contact allergy is minor compared to MP, FM I, and FM

12 518 Jeanne Duus Johansen et al. II. Colophony has many different applications and it is uncertain if it is used in fragrances; however, ingredients of colophony may be present in fragrances or cross-reactivity may occur. No relationship between reactions to FM I or FM II and colophony was found in consecutive eczema patients tested in a European multi-center study [29]. While a significant relationship between colophony and FM I, as well as colophony and MP, was found in 747 patients suspected of fragrance contact allergy [92], it was also shown that the probability of a reaction to an extended fragrances series increased with the number of positive reactions to the fragrance indicators of the standard series [92]. As none of the current diagnostic tools is perfect, it is important to test with the cosmetic products, fine fragrances, essential oils, etc. used by the patient. It should generally be confined to stay-on products, as wash-off products, due to their irritant nature, make the interpretation of patch test reactions difficult. Further investigations of reactions to commercial products can be made based on the ingredient labeling of sensitizing fragrance substances introduced for cosmetics and detergents in the EU region in 2005 [44] (Table 1.5), by obtaining information/ingredients from the manufacturer [120] or by chemical fractionation in special cases [55, 121, 122]. Core Message A new fragrance mix (FM II) has been developed, which will detect additional relevant cases of fragrance contact allergy. A validated screening agent or screening series for contact allergy to natural fragrance extracts is needed Clinical Relevance and Patient Advice Table 1.5. Fragrance ingredients to be labeled as ingredients if present in cosmetics [44] INCI name CAS no. α-isomethyl ionone Amyl cinnamal Amylcinnamyl alcohol Anisyl alcohol Benzyl alcohol Benzyl benzoate Benzyl cinnamate Benzyl salicylate Butylphenyl methylpropional Cinnamal Cinnamyl alcohol Citral Citronellol Coumarin Eugenol Evernia prunastri (oak moss) extract Evernia furfuracea (tree moss) extract Farnesol Geraniol Hexyl cinnamal Hydroxycitronellal Hydroxyisohexyl 3-cyclohexene carboxaldehyde Isoeugenol Limonene Linalool Methyl 2-octynoate The presence of the substance must be indicated in the list of ingredients when its concentration exceeds 0.001% in leave-on products and 0.01% in rinse-off products according to the Cosmetic Directive [44]. The list was complied from information in [71] regarding fragrance chemicals reported as allergens in cosmetic and toiletries and based on World Health Organization (WHO) criteria for contact allergens [142]. Oak moss/tree moss absolute were included as they were relevant for FM I Information regarding the presence of other fragrance ingredients in cosmetics may be made available by the fragrance industry on a case basis [120] Clinical relevance can be assessed based on the patient s history of rashes to perfumes/perfumes products. A significant relationship between such a history and positive patch test to FM I has been shown previously [90, 115]. Currently, a higher proportion of patients giving a positive history is found among those reacting to the newly developed FM II than those reacting to FM I [28]. Other ways of determining relevance is by exposure assessment. In a case study, all patients with a positive patch test to FM I ingredients were shown to be exposed to these allergens in cosmetic products causing eczema [116]. Similar findings exist for Lyral [34, 106] and other FM II ingredients [29]. Simulations of exposure by repeated open application tests (ROAT) with commercial products containing FM I allergens have been shown to cause eczema in 60% of exposed patients who patch tested positive to FM I [42, 95]. Dummy products spiked with a single fragrance allergen in realistic concentrations have also been tested. In a series of

13 Allergens of Special Interest Chapter 519 deodorant exposure studies with cinnamal and hydroxycitronellal, % of eczema patients sensitized to the ingredient in question reacted, while all controls were negative [96, 97]. ROAT with realistic concentrations of Lyral applied in ethanol caused reactions in 16 of 18 (89%) sensitized patients [106]. Clinical relevance can be determined by one or all of the above-mentioned methods in the individual patient. Another indicator of clinical relevance is the strength of the patch reaction. Patients with strong reactions to the standard patch test FM I are more likely to react to the individual ingredients of the mix, to a low level of allergen [123], and to give a positive ROAT with the allergen in question [124]. Further, they are more likely to have a positive history of adverse reactions to fragranced products [115]. Thus, the advice given to the patient depends on the clinical presentation and the degree of allergy. Some patients have a weak degree of allergy and no chronic eczema problem; they can usually tolerate (some) scented products on the skin. Others are more sensitive and have to abstain from stay-on products, while some cannot use any scented products at all, including wash-off products, such as shampoos. Patients with a chronic or relapsing eczema disease should be advised to use unscented emollients, regardless of whether they are allergic to fragrances or not, due to the risk of becoming sensitized and aggravation of their disease. In this context, it is important for the patient to know that the labeling fragrance-free may be misleading [125, 126]. Such products may contain fragrance ingredients, which are often various flower or plant extracts or chemicals acting as preservatives, e.g., geraniol and farnesol. A change in cosmetic legislation in Europe has been made [44] and also concerns detergents [127]. A series of 26 selected fragrance ingredients, mostly chemicals, known to cause allergic reactions in humans are mandated on the label, if present in more than 10 ppm in stay-on products and 100 ppm in wash-off products. These limits are administrative and decided, as, otherwise, a labeling of all perfumed cosmetics was expected due to the presence of chemical allergens in trace amounts in essential oils. This legislation is expected to be in full force in It entails all the ingredients of FM I and FM II, and will enable the fragrance-allergic patient, who wishes to use fragranced cosmetics, to make a pre-selection of products based on the ingredient information. Further, it will provide the dermatologists with a tool for improving diagnostics and assessing clinical relevance. Clinical relevance is not a static phenomenon, especially not in the area of fragrance allergy. It is a question of interaction between individual predisposition (genetics)/susceptibility and environmental exposures. Changes in general exposure to the allergens by interventions, e.g., legislation or just changes of fashion, will affect the clinical consequences of being contact allergic, defined by a positive patch test. These dynamics mean that assessment of the value of a diagnostic test such as FM I or FM II at a given time is only a snapshot. The focus, which has been on the ingredients of FM I and FM II by research programs on an EU-commission-level and by consumer organizations, means that exposure has or will be decreased [89], as actually intended by these initiatives. The consequence is that fewer individuals will become sensitized to the allergens in question, as already indicated for FM I [61], and that fewer of those already sensitized will have clinical problems, which is possibly seen in the most current assessments of clinical relevance [28]. This should not lead to the confusion that the lack of clinical relevance is a sign of false-positive patch tests. It is a consequence of changing exposures and may be different in other geographical regions or may change again with time and exposure. Core Message Twenty six fragrance ingredients with a sensitization potential are mandated on the label of cosmetics and detergents from 2005 as information to the consumer Other Skin Effects Immediate Reactions Fragrances have been reported to cause contact urticaria of the nonimmunological type. This is a highdose effect and cinnamal, cinnamic alcohol, and MP are known causes of contact urticaria, but others have been reported also [ ]. The reactions to MP may be due to its containing cinnamates [68]. A relationship to delayed contact hypersensitivity has been suggested [1], but in a recent study no significant difference was found between a fragrance-allergic group and a control group in the frequency of immediate reactions to fragrance ingredients [130]. This is in keeping with a nonimmunological basis for the reactions seen [130].

14 520 Jeanne Duus Johansen et al Photoallergy/ Phototoxic Reactions Musk ambrette produced a considerable number of photocontact allergic reactions in the 1970s [132, 133] and was later banned. Today, photoallergic contact dermatitis is uncommon [134]. Psoralens in naturally occurring fragrance ingredients were previously the cause of phototoxic reactions, giving rise to erythema, followed by hyperpigmentation in its characteristic form, called Berloque dermatitis [135]. There are now limits of the amount of psoralens in fragrance products. Phototoxic reactions still occur but are rare [136] Irritant Contact Dermatitis Irritant effects of single fragrance ingredients are well known, e.g., citral [52, 54]. Probably, irritant contact dermatitis is frequent, however no investigations exist substantiating this [72]. Many more people complain about rashes to perfumes/perfumed products than are proven allergic by testing [90]. This may be due to irritant effects or insufficient diagnostic apparatus Airway Symptoms Fragrances are intended for skin application in order to give a volatile perception. In addition to skin exposure, the wearing of perfumes exposes the eyes and airways. Many people are bothered by respiratory or eye symptoms caused by the volatile fragrance ingredients and it is estimated that 2 4% of the adult population is affected in their daily life by this exposure [137]. It is known that exposure to fragrances may exacerbate pre-existing asthma [138]; further asthmalike symptoms can be provoked possibly by sensory mechanisms [139, 140]. In an epidemiological investigation, a significant association was found between respiratory issues elicited by fragrances and contact allergy to fragrance ingredients, as well as hand eczema, which were independent risk factors in a multivariate analysis [141]. This indicates a relationship between the airways and the skin caused by fragrance ingredients [141], which opens up a new understanding of these disease entities Case Reports Case Reports A 23-year-old woman presented with a long history of axillary dermatitis. Symptoms improved on changing to a different deodorant spray and worsened again with reuse of the former deodorant. Patch testing with the deodorant as is showed a ++ reaction, no reaction was seen to FM I 8% or colophony, while a?+ was seen to Myroxylon pereirae. The perfume of the deodorant was tested in the same concentration as in the product and showed a + reaction. Farnesol was present in the deodorant and gave ++ reaction upon testing at 1% in pet. [141]. Comment: Many cases of perfume allergy due to farnesol in deodorants have probably been overlooked in the past. It is important to test with the relevant products used by the patient and to use this test as guidance for further investigation. Farnesol is a constituent of the new diagnostic test FM II and is entailed by the new ingredient labeling of selected fragrance allergens. A 50-year-old woman presented with an erythematous eruption, characterized by papules, vesicles, and crusting over the neck and chest. At patch testing, initially, the only positive reaction observed was with her own eau de toilette, named Women. FM I was negative. Chemical fractionation of the Women perfume concentrate was combined with a sequenced patch testing procedure and with SAR studies. Ingredients supplied by the manufacturer were also included in the study. Benzophenone- 2, Lyral, α-hexyl cinnamic aldehyde, and alpha-damascone were found to be responsible for the patient s contact allergy to the eau de toilette, Women [121]. Comment: It is important to test with relevant products used by the patient. Light absorbers, such as benzophenone-2, are used in perfumes to protect against degradation. These may also be the cause of contact allergy. Some patients are allergic to several fragrance ingredients. Information about the contents of fragrance ingredients can be obtained from the fragrance manufacturer [120] and for selected fragrance allergens on the label of the product.