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Alergia a los perfumes

5. How is the general public exposed to fragrance allergens?

    The SCCS opinion states:

    10. Exposure

    Exposure to fragrance chemicals and other potential allergens is most commonly by direct skin contact. Exposures to fragrance chemicals occur from:

    • Personal cosmetic use;
    • Detergents and other household products;
    • Medicaments;
    • Occupation, i.e. personal hygiene, manufacturing ingredient(s), product in work process, plant materials;
    • Secondary exposure from another individual (e.g. spouse, child);
    • Toys;
    • Oral intake;
    • Airborne exposure.

    Factors that are important for both the induction and elicitation of contact allergy are:

    • Dose per unit area;
    • Vehicle effects including penetration enhancers;
    • Presence of skin irritants;
    • Presence of other allergens (combination effects);
    • Duration of skin exposure;
    • Frequency of applications;
    • Anatomical sites of exposure;
    • Condition of the skin (barrier function impairment, pre-existing inflammation);
    • Occlusion (e.g. in flexures, under clothing and personal protective equipment).

    Fragrance mix ingredients are commonly present in cosmetic formulations (71, 222-224). Cosmetics based on natural ingredients may contain fragrance allergens at a higher concentration than other cosmetic products (225). The clinical significance of exposure to natural extracts is difficult to determine as there is often “hidden and variable” exposure to important and potent allergens in natural products.

    10.1. Concentrations and quantities used

    Consumers are exposed in daily life to fragrance chemicals from a large variety of products, such as cosmetics, toys, detergents and other cleaning products, etc. The fragrance exposure may be via dermal and/or inhalation route. With respect to “Terms of Reference” to the SCCS, only dermal exposure from cosmetics is addressed in this opinion. As cosmetics are the perfumed products most commonly used in daily life, potential fragrance allergens identified by the use of cosmetics also represent the exposures of these chemicals from other product categories. In recent years, it has become a trend to add fragrance chemicals to many other types of consumer products, such as children’s toys, toilet paper and nappies, which may contribute significantly to the fragrance exposure of the consumer by the dermal route. Factors for the fragrance exposure assessment by the dermal route require knowledge on:

    • Product types (categorisation of scented products) used by the consumer.
    • Market survey (impression of the qualitative and quantitative contents of different allergens in consumer products).
    • Hydrolysis, metabolism or oxidation of a fragrance material, which may generate a potential skin allergen.
    • Chemicals in the product matrix, which may significantly enhance or reduce dermal absorption of a fragrance material.

    Fragrance materials, both defined chemical substances and natural mixtures of chemicals (essential oils), are used in all types of cosmetic products: perfumes, eau de cologne, eau de perfume (EDP), and eau de toilette (EDT), aftershave lotion, deodorants, skin care products, skin cleansers, make-up cosmetics, hair care products, and oral care products, etc. However, some unscented cosmetic products have also reached the market in the last decade. Products containing the highest concentration of fragrance chemicals are perfumes, followed by eau de cologne, eau de perfume (EDP) and eau de toilette (EDT). Concentrations of fragrance chemicals in deodorant products are lower than those in EDT/EDP products, but still significant. Aftershave products also contain relatively high amounts of fragrance chemicals. Other cosmetic products contain relatively low amounts, 0.1-1% of fragrance compound, compared to up to 30% fragrance compound in EDT/EDP (226). The fragrance compound are mixtures of 20 to over 200 synthetic fragrance chemicals or natural fragrance materials (essential oils), selected from over 3,000 fragrance materials (226). For the exposure assessment, levels of fragrance chemicals in cosmetics containing significant amounts of fragrance materials (i.e. EDP/EDT/aftershave/deodorant) should be selected. It may not be possible to detect/measure the amounts of all fragrance chemicals when present in highly diluted form in a cosmetic product such as skin care products, make-up cosmetics etc. On the other hand, if a fragrance is evaluated safe for use when present in significant amounts in a product, it will also be safe for use in other products. Also the analysis of trend of the use of individual fragrance materials should be based on monitoring their contents in fine perfumes and deodorants.

    Ninety of the 100 fragrance materials used in annual volumes > 175 tons in perfume formulations are fragrances and the remaining ten are used for other functions such as solvents or antioxidants (IFRA, personal communication 2010). Among the 26 fragrances currently requiring individual labelling, amyl cinnamal, benzyl benzoate, benzyl salicylate, butyl phenyl methyl propional, citral, citronellol, coumarin, eugenol, geraniol, hexyl cinnamal, hydroxyisohexyl 3-cyclohexene carboxyaldehyde (HICC), alpha-isomethyl ionone, and linalool are used in volumes greater than 175 ton. α- Amylcinnamyl alcohol, anisyl alcohol, benzyl alcohol, benzyl cinnamate, cinnamal, cinnamyl alcohol, farnesol, hydroxycitronellal, isoeugenol, d-limonene, methyl-2-octynoate, oak moss (Evernia prunastri), tree moss (Evernia furfuracea) are used in volumes less than 175 ton.

    According to the information from the fragrance industry, 80% of the total fragrance chemical volume is used in cosmetics and 20% in household products. Since the implementation of the regulation of labelling of 26 fragrance substances in cosmetic products, qualitative information on fragrance exposure from cosmetics is provided in some market surveys performed on cosmetics (Table 10-1, (227)) and (Table 10-2, (228)) and on consumer products including cosmetics (Table 10-3, (229);

    Table 10-4, (115); and Figure 10-1, (105)). Thus, the implementation of the regulation of fragrance allergens in detergents (Directive 648/2004/EC), similar to that for cosmetics, has also added to the knowledge of fragrance exposure to the consumer. These market surveys revealed that fragrance ingredients which are potent allergens and frequently cause allergies in consumers are used as ingredients in consumer products including cosmetics. The results of these surveys further revealed that limonene and linalool were the most commonly used fragrance chemicals in cosmetics, while anisyl alcohol, cinnamal, α- amylcinnamyl alcohol, oak moss and tree moss were the least used fragrance ingredients in cosmetics and other consumer products. In general, the most potent allergens were also the most infrequently used ingredients. Prior to the regulation of the 26 allergens, analysis of 21 selected fragrance chemicals in deodorants also revealed additional 66 potential allergens in these products on the basis of structure activity relationship (230).

    Table 10-1: Presence in children's cosmetics of the 26 fragrance substances that are required to be labelled in cosmetics (227).

    Table 10-2: Usage trends in deodorants of fragrance chemicals that are required to be labelled in cosmetics.

    Table 10-3: Frequency of occurrence in consumer products of the 26 fragrance allergens that are required to be labelled in cosmetics and detergents (229).

    Table 10-4: Frequency in 516 consumer products of the 26 fragrance substances that are required to be labelled in cosmetics* (115).

    Figure 10-1: Frequency of occurrence in 3,000 consumer products of the 26 fragrance allergens that are required to be labelled in cosmetics and detergents (CVUA Karlsruhe, Germany, 2006/2007), according to (105).

    Contents of fragrance substances determined in cosmetic products have been described in several studies, both before and after the regulation of the 26 fragrance allergens. The studies prior to the regulation of the 26 fragrance allergens included many, but not all of these 26 allergens. On the other hand, these studies included some other possible fragrance allergens. The quantitative analysis of fragrance substances has been performed in prestige perfumes (5, 157, 232-234), deodorants (228, 231), children’s cosmetics and cosmetic toys (115, 227, 235), products marketed as natural cosmetics (225) and in cosmetics used by patients with contact allergy to fragranced products (35, 71). Quantitative analyses have revealed that the consumer is exposed to most, but not all of the 26 fragrance allergens from the use of cosmetics. However, when fragrance exposure from other consumer products, for example detergents and other household products is also taken into consideration (Table 10-3, Table 10-4, Figure 10-1), (105, 115, 229, 236), exposure to all of the 26 allergens is foreseeable in daily life. Although from the data available, the exposure to α-amylcinnamyl alcohol, cinnamal, methyl-2- octynoate, Evernia prunastri (oak moss) and tree moss may appear to be low, these are very strong allergens.

    The changes in the use of fragrance chemicals in cosmetic formulations, during last 12 years, i.e. before and after the regulation of the 26 fragrance allergens, is reflected in the studies concerning contents of fragrances substances in popular perfumes (5, 232). As described in Table 10-5, the content of FM I allergens in prestige perfumes was significantly reduced from 1996 to 2003. Whether this is also the case for the perfumes sold as natural cosmetics (Table 10-6) has not yet been investigated.

    Table 10-5: Concentration of Fragrance Mix I ingredients in five prestige perfumes before and after the regulation of the 26 fragrance allergens.

    Table 10-6: Concentrations of Fragrance Mix I ingredients, hexyl cinnamal and coumarin in 22 perfumes marketed as natural cosmetics investigated in 1996.

    The trend in the use of most of the fragrance allergens in deodorants before and after their regulation is reflected by the two studies performed by Rastogi et al. (228, 231). The results of these studies cannot be directly compared, because the study from 1998 included randomly selected deodorants, while selection of the deodorants for the 2007 study was based on the labelling of the presence of known strong fragrance allergens in these products. The number of products analysed in the 1998 study were three times more than those analysed in 2007, but not all of the 26 fragrance allergens were analysed in the 1997 study. However, an indication of the change in the use of the fragrance allergens during 1998-2007 may be obtained by reviewing the results of these two studies. Among the 17 common fragrance substances studied in the two studies, the frequency of use of 16 of these substances in deodorants was reduced in 2007 compared to that in 1998 (Table 10-2). The frequency of use of butyl phenyl methyl propional in deodorants appeared to be unchanged. The contents of benzyl alcohol, benzyl salicylate, cinnamal, cinnamyl alcohol, eugenol, geraniol, isoeugenol and linalool were found to be lower in the deodorants analysed in 2007 compared to those in 1998. Citronellol, coumarin and alpha-isomethylionone contents in the deodorants were similar in both studies, but concentrations of benzyl benzoate, butyl phenyl methyl propional, hexyl cinnamal, hydroxyisohexyl-3-cyclohexene carboxyaldehyde and linalool were much higher in deodorants in 2007 compared to those in 1998. This analysis of trend of use of fragrance allergens in cosmetic products indicates that the regulated fragrance allergens are used less frequently, but exposures from some of the regulated fragrance allergens may be much higher compared to those before regulation.

    Table 10-7: Atranol and chloroatranol content in eau de toilette/eau de perfume, investigated in 2004 and in 2007.

    Atranol (CAS no. 526-37-4) and chloroatranol (CAS no. 57074-21-2), constituents of oak moss and tree moss have been shown to be very potent fragrance allergens (237, 238). The EC Scientific Committee on Consumer Products (SCCP) recommended that atranol and chloroatranol should not be present in cosmetic products (239). Two other commonly used fragrance chemicals, isoeugenol (240) and hydroxyisohexyl-3-cyclohexene carboxyaldehyde (HICC) (71), have also been shown to be important contact allergens. The contents of atranol, chloroatranol, isoeugenol and hydroxyisohexyl-3-cyclohexene carboxyaldehyde in fine fragrances was determined for the exposure assessment of these fragrances (233). The results revealed that isoeugenol was present in 56%, HICC in 72%, atranol in 59%, and chloroatranol in 36% of the 22 eau de toilette/eau de parfum products. The concentrations of isoeugenol were, in all products, below 0.02% which is the maximum concentration recommended by the fragrance industry. HICC reached a maximum concentration of 0.2%, which is 10-fold higher than the maximum tolerable concentration considered safe by the EC Scientific Committee (241). The concentrations of atranol and chloroatranol in the products investigated in 2007 were comparable to those found in similar products in 2004 (Table 10-7, (233, 234). A significant decrease in the frequency of the presence of chloroatranol in the products was found in 2007 (Table 10-7).

    10.2. Global exposure (household and occupational exposures)

    Fragrances are used in cosmetics that the consumer applies to themself, as described in the previous section. In addition, exposure to fragrance substances is possible by a number of other exposure routes briefly outlined in this section.

    Topical pharmaceutical products

    In a study from Belgium, 370 of the 3,280 topical products marketed in Belgium have been found to contain one or more of 66 fragrance substances (242). This publication also contains a description of causative fragrance allergens in 127 patients reacting to 48 specific topical products. In a broader sense, exposure of the patient by extracts used in aromatherapy falls in this category as well.

    Childrens products and toys

    Children’s products may contain fragrance allergens and high levels may be present (235). It has been stated that children may become sensitised to fragrance chemicals used by their mothers (243).


    Washed fabrics have been reported to contain fragrances (244). Odour-neutralising agents are sometimes used for shoe insoles. In one case, an insole containing cinnamon, has been reported to lead to plantar vesicular contact dermatitis due to contact sensitisation to FM I and, in the breakdown, to cinnamal and cinnamyl alcohol (245).

    Cleaning agents and other household products

    Contact dermatitis from geraniol in washing-up liquid has been reported (246). Terpenes are used as solvents and cleansing agents (e.g. limonene) (247) and have been reported as cause of hand dermatitits (248, 249). In an analysis of 59 household products the most common fragrance allergens were limonene (78%), linalool (61%) and citronellol (47%) (250). In a review of 301 cosmetic and detergent consumer products in Sweden, in half of the cosmetics and one-third of the detergents, one or more of the 26 fragrances requiring labelling were identified (251). In the UK, a review of 300 consumer products showed that linalool and limonene were present in 63% of products. Dental products contained on average 1.1 fragrance substances that are presently required to be labelled and women’s perfumes contained 12 of these fragrance substances (Table 4-1 and Table 4-3) (229).


    The dermal hand transfer of three fragrance materials (cinnamic aldehyde, d-limonene and eugenol) from scented candles was determined in ten subjects (i.e. 20 hands) after grasping scented candles for five consecutive 20 second exposures/grasps. The total mean residues of cinnamal and eugenol transferred per grasp from the candles to the hands were 0.255 μg/cm(2) and 0.279 μg/cm(2), respectively (252).


    Food causing cheilitis or bullous stomatitis (e.g. due to cinnamal (253)) or lichen planus- like lesions (e.g. due to cinnamal (254)) or contact gingivitis (e.g. due to eugenol (255)) has been reported. Moreover, food containing fragrance allergens, e.g. citrus oil terpenes (256) may cause allergic contact dermatitis by handling this food.

    Occupational exposure

    In a number of occupations, contact allergy to fragrances is more common than in others, including geriatric nurses, masseurs and physiotherapists, metal furnace operators and potters/glass makers, according to a multifactorial analysis (90).

    Moreover, hairdressers, beauty therapists and aroma therapists are examples of occupations where there is occupational exposure to fragrance-containing cosmetic and other products. Cleaners are exposed to fragrance-containing household products (e.g. detergents). Cooks and bakers are exposed to flavour chemicals and spices. Healthcare workers are also at risk of acquiring fragrance contact allergy. “Odour maskers” may contain important fragrance allergens (89, 90, 257-259). Occupational exposure and occupational ACD to fragrances have been described in perfume bottlers (260).

    Industrial use of a powder masking the vinyl smell of car seats, containing cinnamal, causing occupational ACD has been reported (259). A number of fragrance chemicals are also used as biocides (see Commission Regulation (EC) No 1451/2007 of 4 December 2007 on the second phase of the 10-year work programme referred to in Article 16(2) of Directive 98/8/EC of the European Parliament and of the Council concerning the placing of biocidal products on the market, published 11.12.2007 EN Official Journal of the European Union L 325/3 –L325/65), see Table 10-8 below.

    Table 10-8: Parts of Annex I to (EC) No 1451/2007 (see above): “Active substances identified as existing”, if use is ‘perfuming’ or ‘masking’ according to CosIng. The above illustrates that the consumer is exposed to fragrance substances from a wide variety of cosmetic products, other consumer products, pharmaceuticals and occupational exposures.

    All these exposures are of importance in the context of contact allergy as it is not the source of exposure that is critical for both induction and elicitation, but the cumulative dose per unit area.

    10.3. Exposures related to particular anatomical sites

    Contact allergy to fragrances most often causes dermatitis of the hands, face and axillae. Axillary involvement has been shown to be statistically related to fragrance allergy (9). It is recognised that the axillary skin is a problematic area as it is moist, occluded and is easily irritated. Moreover, facial eczema is a common manifestation of fragrance allergy (3, 47). There is an association between fragrance allergy and hand eczema or aggravation of hand eczema (13-15). Vehicles may influence elicitation capacity of an allergen and the presence of detergents (surfactants) as in hand cleaning products may increase the clinical response by a factor of 4-6 (261). Men using wet shaving as opposed to electric razors have an increased risk of being fragrance allergic (17), most likely due to microtraumata and to the presence of surface active substances in shaving foam.

    In use tests, the upper arm has been shown to be more sensitive than the forehead and lower arm (262). The axillae, neck and face are more sensitive than the upper arms (10). The threshold of elicitation may vary depending on the volatility of the substance (263). A cumulative effect of exposures occurs so that repeating exposures cause elicitation in more individuals (264).

    Patients appear to become sensitised to fragrances primarily from deodorants and perfumes and to a lesser extent from other cosmetic types (74). Allergic contact dermatitis may develop where a perfume has been applied (behind ears, neck, upper chest, antecubital fossae, wrists and the axillae bilaterally (265). Following this, eczema may appear, or be worsened by, the use of a variety of product types including other cosmetics, household products, industrial products and flavours.

    The association between contact allergy to fragrance ingredients and certain anatomical sites, which mirrors exposure to fragrance-containing products on these anatomical sites, has been described in several publications (266, 267), see above. However, due to the potential confounding effect of other factors, at least on some anatomical sites, an adjusted analysis will provide a more valid impression of the association between certain anatomical sites and contact allergy to fragrance ingredients. As an adjusted, multifactorial analysis relies on: (i) a substantial number of observations (patients tested); and (ii) an outcome prevalence not too close to 0%, such an approach has, hitherto, been limited to FM I.

    In a paper published 2001, data from the IVDK in terms of patch test reactions to FM I and relevant clinical and demographic information of the patients tested (n=57,779) was studied by Poisson regression analysis (90). Risk was quantified by the prevalence ratio, which can be interpreted as an estimate of relative risk, i.e. the factor by which the risk of being sensitised to FM I (in this example) is to be multiplied (RR > 1: elevated risk; or RR < 1: reduced risk) if a certain “risk factor” is present, compared to those patients in whom this risk factor is not present (the reference category) (general aspects of such analyses are discussed in (268)). In the analysis, potential risk factors and confounders, respectively, including occupation, year of patch testing (to address a possible time trend), sex, age, past or current atopic dermatitis, in addition to anatomical site. The relevant part of Table 3 of (90) is reproduced below.

    Table 10-9: Result of a Poisson regression analysis of patients tested with the Fragrance Mix between January 1992 and December 1998, considering two alternative outcomes – part I: non- occupational factors.

    Compared to the trunk, which was arbitrarily chosen as the reference category, all other anatomical sites are associated with an increased risk of being sensitised to FM I (significantly if the lower limit of 95% CI is > 1). Most evidently, dermatitis of the axilla(e) is strongly associated with contact allergy to FM I, presumably due to the application of deodorants. Furthermore, the part of the table shown above illustrates a strong, positive age gradient, i.e. the older patients are, the more likely they are to be sensitised to FM I, the risk being almost double when comparing the oldest with the youngest age group. This observation is in concordance with a bivariate (unadjusted) association between age and contact allergy to FM I found in another study (89). This association is presumably the result of life long exposures and cumulative risk. In a similar analysis of Myroxylon pereirae resin, published in 2002 (269): (i) an even stronger age gradient; and (ii) no particular association to axillary dermatitis (included in the “other” category) was found (Table 10-10).

    Table 10-10: Association between selected risk factors and positive patch test to Myroxylon pereirae resin. For full model see (269). Risk quantified with the prevalence ratio (PR) with accompanying 95% confidence interval (CI).

    10.4. Conclusion

    There are various modes of exposure to fragrances, including not only products used for their scent, such as perfumes and eau de toilette, after shaves, and deodorants, but also types of products where scent is an added feature, such as other cosmetic categories (including wipes), topical pharmaceuticals, household products, and products encountered in the occupational setting. Consumer exposure can change over time, both qualitatively and quantitatively. Different routes of exposure are reflected by certain anatomical sites affected: deodorants are associated with axillary dermatitis, the axillary skin being particularly vulnerable to sensitisation due to occlusion, maceration and irritation. However, while sensitisation and initial disease may follow a distinct pattern, later less specific exposures, e.g. via hand creams, cleaning lotions etc. may be sufficient to cause allergic contact dermatitis.

    11. Dose-response relationships and thresholds

    The dose-response relationship between exposure to contact allergens and induction of allergy, i.e. sensitisation, is well established in animal models and by experiments in healthy volunteers (270). It seems that not only the dose per unit area of allergen (271), but also the number of exposures, i.e. the accumulated dose, is of importance for the risk of induction of contact allergy (272). The induction of contact allergy is an immunological process (type IV-allergy), which is without any clinical symptoms. In the case of continued exposure or re-exposure with a sufficient dose of allergen, elicitation will occur. Elicitation is an inflammatory response (eczema) with clinical symptoms of erythema, induration and in some cases vesicles. Studies of the elicitation response are normally done in patients with an allergy to the substance in question. Different provocation models exist (see chapter 11.2.1). Elicitation experiments in healthy human volunteers following the induction have only rarely been performed (273) and may be considered a less valid model than patient studies. The reason is that following experimental induction, the level of sensitivity may not be at the same level as in a real life situation and that individuals who have actually acquired the disease are a more relevant endpoint to study.

    Knowledge of the dose-response relationship provides an opportunity to establish levels of exposure which are safe for the majority of individuals. In the following chapter, the use of different data and models for the establishment of such safe levels in relation to fragrance ingredients are explored. The focus will be on those chemicals, which have been identified in chapter 7.1 as established contact allergens in humans and which have already given rise to a significant number of published cases (category 3 or more): cinnamal, cinnamyl alcohol, citral, coumarin, eugenol, farnesol, geraniol, hydroxycitronellal, isoeugenol. Limonene and linalool are considered in chapter 5 as their ability to cause sensitisation depends on air oxidation, and hydroxyisohexyl 3- cyclohexene carboxaldehyde is considered in chapter 4.3.2 and 11.4.

    11.1. Induction

    A model for dermal sensitisation quantitative risk assessment (QRA) has been developed and implemented by the fragrance industry. This model relies on thresholds, no effect or low-effect levels, established in healthy human volunteers and/or in animal experiments, mainly the local lymph node assay (LLNA) (see chapter 8.1). A set of safety factors are applied for inter-individual differences, for vehicle effects and for use considerations, stated to give rise to a safety margin from 10 to 1000 (274). In this way, a so-called “acceptable exposure level” is derived. The exposure to an allergen in different types of products should be below this level. The restrictions, which have been introduced by the fragrance industry based on the QRA model, are given in Table 11-1 for some important product categories.

    The IFRA guidelines give concentration limits for 11 product categories (, last accessed 2011-11-02), three of which are mentioned in Table 11-1. These three products have the lowest concentrations except for lip products, which give a slightly lower concentration limit.

    Table 11-1: Current IFRA restrictions based on induction experiments.

    The SCCP evaluated this methodology (275) as well as its application to three model fragrance substances.

    It was, among other things, concluded that: “The data provided show that the application of the dermal sensitisation QRA approach would allow increased exposures to allergens already known to cause allergic contact dermatitis in consumers. The model has not been validated and no strategy of validation has been suggested. There is no confidence that the levels of skin sensitisers identified by the dermal sensitisation QRA are safe for the consumer.” and that:

    “Identification of safe levels of exposure to existing substances known to cause allergic contact dermatitis in the consumer should be based on clinical data and/or elicitation low-effect levels. Currently, these are the only methods which have proven efficient in reducing/preventing existing problems of sensitisation/allergic contact dermatitis in the consumer.”

    11.2. Elicitation

    11.2.1. General considerations

    A response in terms of elicitation of allergic contact dermatitis by application of the (suspected) allergen under standardised conditions is the outcome of interest of the routine diagnostic procedure for suspected contact allergy, the patch test. While the patch test procedure is largely standardised, it is optimised as a diagnostic tool for contact allergy. Thus exposure conditions are not comparable to actual exposures occurring in the daily life or working environment of the patient, which often involve long-term, repeated and low-dose contact with the allergen. Here, procedures such as the repeated open application test (ROAT) or provocative use test are often used, because they reflect actual exposure much better and can be used, for instance, to validate the current clinical relevance of a positive PT reaction.

    Generally, exposure of a sensitised patient to a set of graded doses (quantity/area) of the suspected allergen, i.e. threshold testing, will allow not only quantitative diagnosis of the presence or absence of specific contact sensitisation but will additionally provide evidence on the intensity (degree) of sensitisation. This may have important individual consequences in terms of everyday or occupational exposures being capable (or not) of eliciting allergic contact dermatitis. However, beyond the individual perspective, clinical dose-response data collected from sensitised individuals provide a valuable estimate of the usual doses/unit area resulting in a positive, allergic response in a certain proportion of sensitised persons, e.g. 10, 50 or 90%. Maximum concentration levels can be derived, which are safe in terms of eliciting allergic reactions in only a defined low percentage of sensitised persons. As such data will always be based on small samples, the precision of the estimate should be considered, and therefore results are preferably given with confidence intervals.

    A statistically significant relationship between threshold concentrations in the ROAT and patch test has been found, on analysing results from different allergens (see Table 11-2) (276), but the dose of allergen per unit area per application needed to elicit a reaction in the two study methods is not the same. A translation factor between the two methods has been suggested for non-volatile substances: EDxx(ROAT)=0.0296 *EDxx(patch test) based on testing nickel and methyldibromo glutaronitrile (276). Based on this the eliciting dose per application in an open test is 33 times lower than in the patch test. In practice it means that the cumulative dose in a ROAT (in μg/cm2) in two weeks with two applications per day (total 28 applications) will be almost identical to the eliciting patch test dose (in μg/cm2) for a given number of responders (see Figure 11-1). For a given cut-off point the elicitation dose determined by patch testing will be higher than determined by ROATs.

    Table 11-2: Spearman’s rank correlation between the threshold concentration in the patch test and the repeated open application test for three allergens.

    Figure 11-1: The fitted dose-response curve for patch test (solid line) is seen to be displaced to the right compared to the observed response from repeated open applications of the same allergen (HICC). It means that a smaller dose per application is needed to elicit a response than by one single occluded application as in the patch test.

    In the translation between methods, evaporation needs to be taken into consideration for volatile substances. The experience, based on a study of the fragrance ingredient HICC and using the results from the literature on isoeugenol, is that if the same equation is used as for non-volatile substances, the response in the ROAT will be overestimated by a factor 3 to 4. Thus, the translation factor would be 0.1060 instead of 0.0296, but this needs to be confirmed by other fragrance allergens. This implies that for the fragrance ingredients tested, the eliciting dose per application in a ROAT was 9.4 times lower than the patch test compared to a 33 times lower dose for non-volatile substances (276). This needs to be confirmed by studying other fragrance allergens. Thus, according to these experiments, the dose (μg/cm2) eliciting a response in threshold patch testing will be at most 33 times higher than established in the ROAT if an identical vehicle is used.

    Volatility effects in skin sensitisation

    The potency of volatile skin sensitisers can be underestimated, to an extent depending on how rapidly it evaporates, by assays such as the LLNA in which the test substance is applied topically to exposed healthy skin without occlusion. Such sensitisers present a greater sensitisation risk to consumers when the skin is occluded by clothing and/or compromised, than when healthy non-occluded skin is exposed.

    Volatility at physiological temperature, say 40 ̊C, is represented by the vapour pressure p40 at that temperature. This is related to the boiling point TB by the Clapeyron-Clausius equation, which can be written (277): Log (p40) = - (TB – 40)Tr/2.303RT Where p is in atmospheres, TB is in ̊C, R is the gas constant, Tr is the Trouton constant (also defined as the molar entropy of vaporisation, and equal to 22 cal.deg-1 for many organic compounds) and T is physiological temperature in degrees absolute (= 313 for 40 ̊C).

    It has been shown, in experiments where evaporation from a glass slide is measured under simulated LLNA conditions, that 2-hexenal (TB = 146-149 ̊C, p40 = 17 mmHg) evaporates rapidly, less than 20% remaining after 5 minutes, whereas with cinnamal (TB = 248 ̊C, p40 = 0.5 mmHg), more than 90% remains after 1 hour (278). In agreement with these findings, cinnamal fits a QSAR relating LLNA EC3 to reactivity, whereas the EC3 for 2-hexenal is higher (lower potency) than predicted from its reactivity.

    The above is only a partial rationalisation, since different solubilities in different vehicles will influence the tendency to evaporate, according to Henry's law.

    11.2.2. Studies on specific fragrance ingredients

    Studies concerning chloroatranol/atranol, cinnamal, hydroxycitronellal, hydroxyisohexyl 3-cyclohexenecarboxaldehyde and isoeugenol have been identified. These are summarised in Annex III.

    Overview of results

    In four studies dummy deodorants spiked with a single fragrance allergen in realistic use concentrations have been used to study elicitation responses, unscented deodorants were used as control products in paired designs. The deodorants were used by patients sensitised to the fragrance allergen in question as well as a healthy control group (without fragrance allergy) (102,103,104,279). Between 76 and 100% of the sensitized individuals reacted to the deodorants spiked with allergen, isoeugenol, cinnamal, hydroxycitronellal and hydroxyisohexyl 3-cyclohexene carboxaldehyde, and none of the controls (Table 11-4).

    Table 11-3: Overview of results of deodorant provocation investigations with different allergens. Frequency in % of test groups, which reacted at different doses of allergen applied in a roll-on deodorant in the axilla, is given in the table.

    Table 11-4: Overview of threshold results from clinical studies.

    Summary of results for specific fragrance ingredients

    Chloroatranol (constituent of Evernia prunastri)

    In ROAT a dose of 0.025 μg/cm2 to 0.125 μg/cm2 in ethanol elicited reactions in 92% to 100% of sensitised subjects. In patch testing the ED10% was 0.0004 μg/cm2.


    In ROAT a dose of 0.26 μg/cm2 gave a response in 11% when applied as deodorant in the axilla and 82% responded to 2.63 μg/cm2. The ED50 in patch testing was 96 μg/cm2.


    In ROAT a dose of 0.0357 μg/cm2 gave no response, while the dose that elicited a reaction in 10% of the sensitised test group (in ethanol) ranged from 0.064 μg/cm2 to 1.2 μg/cm2. The dose in a cream base was 4.9 μg/cm2. In ROAT a dose of 15.3 μg/cm2 to 126.2 μg/cm2 in ethanol elicited reactions in 61% to 89% of sensitised subjects. The ED10 in patch testing ranged from 0.66-0.9 μg/cm2.


    In ROAT a dose of 0.94 μg/cm2 gave a response in 57% when applied in a deodorant in the axilla and 100% responded to 9.40 μg/cm2. The no-effect level in patch testing was below 0.036 μg/cm2.


    In ROAT a dose of 2.2 μg/cm2 a response in 42% and 9.0 μg/cm2 in 67%, when applied in ethanol on the arm. With a deodorant applied to the skin of the axillary, a dose of 0.167 μg/cm2 caused a response in 23% and 77% reacted to 1.67 μg/cm2. The ED50 in patch testing was 32 μg/cm2. The no-effect in patch testing was below 0.15 μg/cm2.

    Elicitation levels have been studied for cinnamal, isoeugenol and hydroxycitronellal which are established contact allergens in humans and which already have given rise to a significant number of cases (> 100, see chapter 7). Further HICC has been studied extensively, but is considered in a separate section (chapter 11.3) of this opinion. It is however not possible to derive a safe threshold directly from the data of cinnamal, isoeugenol and hydroxycitronellal. The main reasons are that many of the test subjects reacted to all the tested doses in ROAT, which is a simulation of every day exposures. Thus it was not possible to determine the dose only eliciting responses in a few, e.g. 10% of the subjects and that only a limited number of exposure scenarios were studied.

    The studies have covered few product types: hydro-alcoholic products, e.g. perfumes and deodorant roll-on matrix. The vehicle is one of many factors which influence the thresholds of allergic reactions. Also the presence of irritants and other allergens can influence the elicitation level. This means that the currently available studies do not cover all the relevant exposure scenarios. However, taking into account that dose- response investigations in sensitised patients are very complex to perform, it is not likely that much more data will become available in the near future. It is therefore necessary to exploit the full pool of elicitation data, also covering chemicals other than fragrance ingredients, to derive a more general threshold which could be used when no or insufficient data exist to set a specific threshold for a substance of concern.

    General thresholds

    The methodology of the different experiments has varied to some extent as different anatomical sites of exposure have been employed, different vehicles, exposure periods and cut-off points. The reason is that the studies have been performed to investigate various clinical and scientific aspects of allergic contact reactions and not for formal regulatory requirements. Some studies are small and for this reason the precision of the estimates of thresholds is limited. In spite of this, the results of the various experiments are reasonably uniform, except for chloroatranol which had very low threshold reactions, and show that low concentrations may elicit allergic reactions. The reasonably uniform data generated on the above fragrance ingredients are in agreement with a recent “meta-analysis” of dose-response data of different allergens, incorporating some of the same studies as mentioned above, but also other allergens, such as preservatives and metals. The ED10 at patch testing varied by a factor of 7 from the lowest to the highest value and the median was 0.82 μg/cm2 if the three outliers formaldehyde (1997), nickel (1999) and methyldibromo glutaronitrile (2004) were left out and 0.84 μg/cm2 if included (see Table 11-6 and Figure 11-2 below: (280)). An explanation of these results could be that thresholds in elicitation is less dependent on the antigenic properties of the individual substance (inherent potency) than thresholds of induction and more on the level of sensitivity of the individual, i.e. the level of T-cell clones able to recognise the antigen, which is not present in naïve not-sensitised, individuals. This seems plausible, based on both the recent clinical evidence (280) and guinea pig QSAR evidence (281). It provides the basis for a general approach in establishing safe thresholds for substances of concern. The consequences of a limit of 0.8 μg/cm2 for the product types most important for fragrance allergy are calculated below. The calculation is based on:

    • The generally safe exposure level, which is the median ED10 value (the dose which will elicit allergic contact dermatitis in 10% of sensitised eczema patients) under patch test conditions: 0.8 μg/cm2 (280).
    • Exposure doses and exposure areas from SCCS notes of guidance 7th revision (282) [Tables 2 and 3] and Technical dossier Quantitative Risk Assessment from RIFM (274).


    Safe concentration in product = (Generally safe exposure level (0.8 μg/cm2)/daily exposure to product (μg/cm2/day)) x 100 (for %).

    Table 11-5: Concentration limits in different product types based on 0.8 μg/cm2 allergen as a 'generally safe exposure level', if specific dose-response data are unavailable.

    The estimated daily use of the various product categories in Table 11-5 are based on the SCCS Notes of Guidance (see above), except for perfume, for which no value is given. This value is taken from the Technical Dossier on Quantitative Risk Assessment from RIFM.

    Generally the estimated use of different products is higher in the IFRA/RIFM assessments than in SCCS Notes of Guidance.

    Table 11-6: Overview of dose-response studies and thresholds for eight allergens, after (280).

    Figure 11-2: The threshold data with 95% confidence intervals from Table 11-6 presented graphically, after (280).

    Figure 11-3: The fitted dose-response curves from the studies in Table 11-6, which are the basis for estimation of the ED10 value, after (280).

    The meta-analysis above has shown that the median elicitation dose by patch testing for 10% of sensitised individuals was 0.8 μg/cm2. In the model data for the fragrance substances isoeugenol and HICC was included. The two studies on isoeugenol and the three studies on HICC gave an average ED10 value of 0.85 μg/cm2 and 0.89 μg/cm2 with a range 0.23-1.48. This means that even if the model was used for these substances individually the result would be very similar to the general threshold value. The data from cinnamal and hydroxycitronellal studies was not incorporated in the model because: (i) serial dilution patch testing was done in petrolatum for cinnamal, making the dosing less exact; (ii) and only seven patients participated in the hydroxycitronellal study, while a criteria for inclusion in the model was ten participants (280).

    According to the above calculations, a limit of 0.8 μg/cm2 for the product types of most importance for fragrance allergy corresponds to concentrations of 100 to 400 ppm (0.01- 0.04%) for deodorants, perfume spray, hand and face lotions. For body lotion the general threshold was 0.16%. However, it does not seem meaningful in the context of contact allergy to distinguish between different types of creams, as a body cream would be applied with the hands and the relevant parameter in contact allergy is dose per area skin and not total dose.

    A general threshold would have to take into consideration the uncertainties in quantification of exposure and safe thresholds as well as the possibilities of aggregate exposures and exposure to chemically similar substances. Therefore in setting one general threshold the product category carrying the highest risk of sensitisation and elicitation, which is deodorants, was chosen to drive the generation of the threshold. This means that a threshold of 0.8 μg/cm2 is equal to 0.01% or 100 ppm (see Table Table 11-1 and the related text), the lowest of the threshold values derived.

    The approach taken by the SCCS is based on scientific evidence published in peer- reviewed journals (283)(284)(285)(286)(102, 224, 263)(264, 279)(287) in the past 20 years. The meta-analysis deriving the general threshold limit at 0.8 ug/cm2 limit has been published (280) in a peer-reviewed journal. The use of threshold limits based on elicitation data is a well established methodology which has been applied (with success) in EU to prevent further cases of induction and elicitation (primary and secondary prevention) in the case of nickel allergy, chromium in cement, chromium in shoes in Germany, dimetyl fumurate in consumer items and also in part in IFRA guidelines e.g. concerning HICC.

    The elicitation threshold model is based on 16 studies of 8 allergens, two of which are fragrance ingredients. It includes data from moderate to extreme allergens with a median EC3 value of 1.2.

    The 11 fragrance allergens to which the limit is suggested to apply range from extreme to moderate with median EC3 value of 4.8, although in the case of coumarin an EC3 value could not be established.

    Thus in general the potency profile of the fragrance substances of concern is not very different from those included in the model to provide the suggested general safe threshold.

    The approach is targeting the relevant end-point, namely, allergic contact dermatitis. The mere consideration of potency of the allergen, according to the LLNA (EC3), is insufficient in identifying the size of the problems of contact allergy/allergic contact dermatitis. Additional information is needed from clinical and epidemiological studies, exposure assessment and dose-elicitation studies. For instance, the elicitation thresholds of e.g. HICC (EC3: 17.1) and isoeugenol (EC3: 0.54) are very similar (0.85 μg/cm2 and 0.89 μg/cm2, respectively) despite very different potencies. Both are frequent causes of contact allergy.

    It should be noted that the general threshold is only suggested to be used for substances of concern if no specific data of sufficient quality exist to set an individual safe threshold. In cases where specific data of sufficient quality are available, these data should be used to set an individual safe threshold.

    The general threshold is indicative of a safe level for the majority of sensitised individuals, but does not preclude that the most sensitive subset of the population may react upon exposure to the allergen. These levels are based on patch tests and take no account of anatomical sites of exposure, frequency of exposure or vehicle effects. Therefore, any limitations in exposures are not substitutes for providing information to the consumer about the presence of a substance in a product as a certain fraction of sensitised individuals will still need to avoid specific exposures.

    Based on experience, limitations in exposure based on elicitation thresholds will, apart from helping the sensitised consumer, also significantly reduce the risk of induction. This is the case for nickel allergy, where the restrictions in the EU nickel directive are based on elicitation threshold, leading to a significant reduction in new cases of sensitisation in young women (288) and in a reduction in morbidity, i.e. elicitation (289). Another example is restriction of chromium VI in cement (290). It is not possible to provide a safe threshold for natural extracts of concern, as no specific investigations exist, and the model providing the general use concentration limit (0.01%) has been based on chemicals only.

    The SCCP concluded in 2004 that Chloroatranol and atranol, the main allergenic constituents of Evernia prunastri and Evernia furfuracea, should not be present in consumer products because they are extremly potent allergens (239). The persistently high frequency of contact allergy to Evernia prunastri and Evernia furfuracea noted in eczema patients does point to a persisting problem with exposure to the allergenic constituents.

    11.3. Hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC)

    Hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC) has been the most frequently reported individual fragrance chemical causing allergy since the 1999 opinion on fragrance allergy. In total, reports of about 1500 cases have been published in the scientific literature (see chapter 7.1 and Annex I to this opinion), while the second most frequently reported individual chemical was cinnamal with around 350 published cases. Only a minority of the cases seen by clinicians is published and only a (small) proportion of those with allergic contact dermatitis seeks or has the possibility to seek medical attention.

    Natural extracts such as Myroxylon pereirae and turpentine (oil) have been more frequently reported, but while HICC is a synthetic fragrance chemical, where the only source of exposure is fragrances, the natural extracts are used in many other contexts than fragrances/cosmetics.

    Of patients tested by the Danish monitoring network of dermatologists 2.4% were found to be allergic to HICC in 2005-2008 (with no decreasing trend from 2003 to 2007 (291)) (for more studies see chapter 4.3.2); in 70% of the cases the reaction was of current relevance, i.e. causing disease (69). This is in agreement with the results of a recent German study with HICC, where 48 out of 51 patients (94.1%) with a positive patch test reaction to HICC also reacted in a repeated open application test, simulating normal use conditions of cosmetics containing HICC (105). In a Danish study 69% of 14 HICC allergic individuals developed allergic contact dermatitis from use of cosmetics containing HICC in realistic amounts (102).

    On the basis of the high frequency of allergy to HICC, in 2003 the Scientific Committee on Cosmetic Products and Non-Food Products (SCCNFP) recommended 0.02% (200 ppm) as maximum amount of HICC in cosmetic products (292). This has not been implemented and no restrictions apply in the Cosmetic Directive. The fragrance industry, via the International Fragrance Association (IFRA), has its own safety guidelines. Up until 2003 HICC was used without any restriction; in 2003 a limit of 1.5% HICC in any kind of product was introduced. In 2008 this was changed according to the new risk assessment model (QRA) applied by the fragrance industry to different levels in 11 different product types derived from the QRA (see11.1). Limits from 0.11% in lip products to 1.5% in hair styling products were set. In 2009 a further lowering was made of the limits by industry with the following reasoning: “The industry firmly believes and continues to support thresholds based on induction rather than elicitation. However, given the exceptional situation in Europe, the fragrance industry elected to take further restrictive action on this material” (293). An overview of the IFRA restrictions is given in the table below.

    Table 11-7: Restriction for HICC independent of the QRA according to (293).

    As an update since the presentation of the pre-consultation version of the opinion, surveillance data on HICC from two European countries have become available, covering the period 2002-2011 (IVDK/Germany (294)) and 2003-2011 (Danish contact dermatitits group (295)), respectively. The first analysis identified a slight decrease, which was considered “not overwhelming in absolute terms”, namely, from 2.3% in 2002 to 2.1% in 2011 (crude prevalences, Figure 11-4). Thus, despite statistical significance, the decrease is too slight to be interpreted as relevant improvement. In the Danish study, some fluctuation around a mean prevalence of about 2.5% was noted, but no trend (Figure 11-5). It is reported that 74% of the positive reactions were regarded as clinically relevant.

    Figure 11-4: Time trend of hydroxyisohexyl 3-cyclohexene carboxaldehyde sensitisation prevalence [standardised prevalence of positives (%)] during 2002-2011. The decrease over time is statistically significant, after (294).

    Figure 11-5: Prevalence of positive patch test reactions to hydroxyisohexyl 3-cyclohexene carboxaldehyde over time in 37 860 subjects tested by the Danish Contact Dermatitis Group (295).

    11.4. Conclusion

    • Elicitation data can provide thresholds indicative for the safe use of those substances which have already caused significant problems in the consumer. In this context, “safe use” means that the thresholds will protect the majority of consumers from allergic contact dermatitis, but does not preclude that the most sensitive subset of the population may react upon exposure to the allergen.
    • Furthermore, based on experience from intervention studies, such thresholds will also be sufficiently low to protect (most of) the non-sensitised consumers from developing contact allergy.
    • Elicitation levels have been studied specifically for the fragrance chemicals cinnamal, hydroxycitronellal and isoeugenol. These studies, however, are not adequate to derive safe thresholds for the individual substances directly from the data.
    • In the absence of adequate substance specific data it is possible to use a general threshold. Based on a statistical analysis of the available data in the scientific literature, a threshold of 0.8 μg/cm2 was derived. This corresponds to 0.01% (100 ppm) limit in cosmetic products indicative for safe use.
    • A dose-response relationship between exposure to contact allergens and induction of allergy (sensitisation) as well as elicitation is well established. This means that in principle, thresholds can be identified which are safe for the consumer.
    • A model for dermal sensitisation quantitative risk assessment has been developed (QRA) and implemented by the fragrance industry. This model relies on thresholds, no effect or low-effect levels, established in healthy human volunteers and/or in animal experiments. The SCCP has previously reviewed this methodology and concluded that: “There is no confidence that the levels of skin sensitisers identified by the dermal sensitisation QRA are safe for the consumer.”
    • It is not possible to provide a safe threshold for natural extracts of concern, as no specific investigations exist and the model providing the general threshold (0.01%) has been based on individual chemicals only. However the maximum use concentration applies to the identified chemicals both if added as chemicals or as an identified constituent of a natural ingredient. This will also reduce the risk of sensitisation and elicitation from natural extracts.
    • For substances for which there are no clinical data of concern, models such as the dermal sensitisation QRA approach may, after refinement and validation, be used to suggest a safe level of exposure prior to incorporation into products. However, aggregated exposures must be incorporated in the dermal sensitisation QRA model.
    • HICC has for more than 10 years been recognized as an important allergen with more cases documented in the scientific literature than for any other fragrance chemical in this period. HICC has been shown to be a significant cause of disease as many of those with contact allergy to HICC had also reactions to cosmetics, which contained or were likely to contain HICC. Since 2003 attempts have been made by the fragrance industry to contain the outbreak of HICC allergy, but with no convincing success so far. Recent voluntary restrictions (recommendations to lower use concentrations, at least for some product types, to the level recommended by the SCCS in 2003) are not reflected in available evidence and are considered insufficient. The SCCS considers that the number of cases of HICC allergy documented over the last decade is exceptionally high and that continued exposure to HICC by the consumer is not considered safe, even at concentrations as low as 200 ppm. Therefore, HICC should not be used in consumer products in order to prevent further cases of contact allergy to HICC and to limit the consequences to those who already have become sensitized.
    • The SCCP concluded in 2004 that chloroatranol and atranol, the main allergenic constituents of Evernia prunastri and Evernia furfuracea, should not be present in consumer products because they are extremly potent allergens. The persistently high frequency of contact allergy to Evernia prunastri and Evernia furfuracea noted in eczema patients does point to a persisting problem with exposure to the allergenic constituents, despite efforts to reduce the allergen content (296).

    Source & ©: SCCS,   "Opinion on fragrance allergens in cosmetic products",
    26-27 June 2012, 10. Exposure, 11. Dose-response relationships and thresholds. p. 72-102.

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