7. Conclusion : are the current European regulations on fragrance allergens adequate?
- 7.1 Is the current list of possible allergens adequate ?
- 7.2 Is there a threshold of safe use for these allergens?
- 7.3 Are there other substances that are relevant for consumers regarding perfume allergies?
7.1 Is the current list of possible allergens adequate ?
The SCCS opinion states:
Contact allergy to fragrances is a common, significant and relevant problem in Europe. The studies since the SCCNFP opinion on fragrance allergy in consumers in 1999 (SCCNFP/0017/98) (SCCNFP 1999) have confirmed that the 26 fragrance allergens, identified by the SCCNFP, are still relevant fragrance allergens for consumers because of their exposure from cosmetic products. Additional exposure to many of these 26 fragrance allergens also occurs from the use of other consumer products, such as detergents, toys, etc. Some of these fragrance substances are also used as preservatives.
The overall trend of fragrance contact allergy appears to have been stable for the last 10 years, as some causes of fragrance allergy have decreased and others increased. From the few population-based studies, it can be estimated that the frequency of contact allergy to fragrance ingredients in the general population in Europe is 1-3%. This is based on the limited testing with eight common fragrance allergens (FM I) out of the approximately 2500 fragrance ingredients listed in CosIng and indicative of the substances that may be present in fragrance compounds. However, the real prevalence of contact allergy to fragrance substances may be higher if the testing were to be performed with the full spectrum of fragrance allergens, including oxidised substances, where relevant.
Among eczema patients in the European population, around 16% are sensitised to fragrance ingredients. The disease can be severe and generalised, with a significant impairment of quality of life and potential consequences for fitness for work. Contact sensitisation, and its clinical manifestation, allergic contact dermatitis, can be prevented if the exposure to known contact allergens is reduced or abolished (primary prevention). Experiences so far, have indicated that not all substances that later turned out to be significant contact allergens after human exposure, were predicted by experimental studies, e.g. the preservative methyldibromo glutaronitrile and the fragrance chemical HICC. Thus, a significant exposure of the population may occur before a substance is established as an important contact allergen in man.
Elicitation of allergic contact dermatitis occurs when a consumer sensitised to a certain substance is re-exposed to the substance in question. Prevention at this stage, termed secondary prevention, can be achieved if use of the allergen in products is eliminated or reduced to a tolerable level (general prevention), or if the patients succeed in avoiding all sources of exposure (individual prevention). Ingredient listing of individual fragrance allergens has been shown to be an important tool to enable consumers with an identified allergy to reduce/avoid relevant exposures. Moreover, ingredient listing is also of great importance to ensure that an adequate diagnosis of fragrance contact allergy can be made without undue delay. If the information given on the presence of fragrance allergens is incomplete, diagnosis of fragrance contact allergy may be missed. The SCCNFP, in its 1999 opinion, identified 26 fragrance allergens for which information should be provided to consumers concerning their presence in cosmetic products. This was implemented in the European Cosmetics legislation (298) as ingredient labelling of these 26 fragrance substances (Annex III, entries 67-92). However, safe use concentrations for these substances in cosmetic products have not yet been determined and much new evidence concerning fragrance allergy has been published since 1999. The present opinion updates the SCCNFP opinion with a systematic and critical review of the scientific literature up to October 2010. This review addresses the issue of contact allergy to fragrance substances, including natural extracts and updates the list of fragrance allergens relevant to consumers. Clinical, epidemiological and experimental studies were evaluated, as well as modelling studies performed, to establish lists of: (i) established fragrance allergens; (ii) likely fragrance allergens; and (iii) possible fragrance allergens. The review also includes fragrances, which on modification by oxidation or by enzyme mediated processes, can produce allergens. Available dose-response data have been examined to answer whether safe thresholds can be established for the most frequent fragrance allergens.
13.1. Question 1
Does the SCCS still consider that the fragrance allergens currently listed in Annex III, entries 67-92, for labelling purposes represent those fragrance ingredients that the consumer needs to be made aware of when present in cosmetic products? In order to answer this question, the SCCS has used clinical and epidemiological data to identify known fragrance allergens. These were categorised as established contact allergens in humans (see Table 13-1).
Where sufficient animal evidence was present, these substances were categorised as established contact allergens in animals (Table 13-2). For a number of other fragrance substances, combinations of limited clinical data together with SAR considerations have been applied to indicate likely fragrance allergens in man (Table 13-3
). Finally, SAR has also been applied to substances that lack human data to identify fragrance chemicals that have the structural potential to be contact allergens. Substances with insufficient human data were also considered as possible fragrance allergens. For these further tests (experimental/clinical data) are required (Table 13-4).
Regarding the above categorisation of fragrance substances, the following aspects need to be considered when interpreting an outcome other than established contact allergen in humans:
- If human evidence is negative, there is still a potential sensitisation risk, as in this set of substances the number of (consecutive) patients tested was low, i.e. up to a few hundred.
- If EC3 values are given as higher (>) than a certain value (see 8.3), an exact EC3 could not be established, as the substance had been tested in too low concentration(s). In these cases, the substances have not been categorised as ‘established contact allergen in animals’.
- For SAR, the categories of prediction are: non-sensitiser (0); possible-sensitiser (+); predicted sensitiser (++); and not predictable (n.p.). (For details see Table 9-3 and Table 9-4). SAR predictions are only considered when human and animal data are limited or missing.
- Several substances are currently banned from the use in cosmetic products by Annex II of the Cosmetics Directive, based on concerns regarding one or more toxicological endpoints. While available clinical evidence regarding this set of substances is listed in Annex I to this opinion, these substances have not further been evaluated.
Fragrance ingredients listed in Table 13-1 clearly have caused disease in man, and based on the clinical experience alone, these 82 substances were classified as established contact allergens in humans, 54 individual chemicals and 28 natural extracts (mixtures of chemicals), including all 26 fragrance allergens identified by SCCNFP in 1999. For a number of other substances, no patch test data were available, but positive animal data, obtained by a validated guideline method (LLNA) addressing hazard, indicate that a – yet not quantified – risk for humans is very likely to exist, given sufficient exposure. In other cases only in a relatively small number of patients has been tested positively (‘limited human evidence’). Here, combination with SAR analyses corroborates the conclusion that these substances, too, are sufficiently qualified to be regarded as ‘likely fragrance allergens’.
Of those 82 substances identified as established contact allergens in humans, 12 chemicals (listed in Table 13-5) and eight natural extracts are considered of special concern as they have given rise to at least 100 reported cases. These substances pose a particularly high risk of sensitisation to the consumer and are further considered in the answer of question 2. One substance, hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC), was shown to be the cause of allergic contact dermatitis in more than 1500 reported cases since 1999. The number of cases is only those reported in scientific publications, and therefore the actual number of cases is severely under-estimated.
The established contact allergens in animals (Table 13-2) and the likely contact allergens, identified based on a combination of limited evidence from man together with positive SAR predictions (Table 13-3), are predicted to cause disease in man given sufficient exposure.
Information on the presence of all the substances given in Table 13-1, Table 13-2 and Table 13-3 in cosmetic products is important in order to enable aimed testing of patients with contact dermatitis and to diagnose fragrance allergy without delay. Further, this information is important to the sensitised consumer as it will enable them to avoid cosmetic products, which they may not tolerate. Substances given in Table 13-4 are possible contact allergens and further data are required to judge if these are contact allergens in humans and give rise to contact allergy in consumers.
Conclusions - Question 1
The studies since the SCCNFP Opinion on fragrance allergy in consumers (1) have confirmed that the fragrance allergens currently listed in Annex III, entries 67-92 are still relevant fragrance allergens for the consumers from their exposure to cosmetic products.
The review of the clinical and experimental data shows that many more fragrance substances than those identified in the SCCNFP opinion of 1999 have been shown to be sensitisers in humans. A comprehensive list of established contact allergens in humans is given in Table 13-1.
Moreover, animal experiments indicate that additional fragrance substances can be expected to be contact allergens in humans, although human evidence is currently lacking.
Additionally, limited human and/or animal evidence together with structure activity relationship analysis suggests that other fragrance ingredients may be a cause of concern with regard to their potential of causing contact allergy in humans. Ingredient listing is important in clinical practice for the management of patients who are allergic to one or more of the listed fragrance chemicals. It is also important for the patients in order to avoid future exposure to fragrance contact allergens which they may not tolerate.
The SCCS considers that those substances itemised in Table 13-1, Table 13-2 and Table 13-3 represent those fragrance ingredients that the consumer should be made aware of when present in cosmetic products.
Substances known to be transformed (e.g. hydrolysis of esters) to known contact allergens should be treated as equivalent to these known contact allergens. The combined concentration of the alcohol and its ester must be considered regarding exposure. Important indicative, but not exhaustive, examples include isoeugenol and its esters, geraniol and its esters, eugenol and its esters, and linalool and its esters.
Source & ©: SCCS,
26-27 June 2012, 13. Opinion. p. 105-115.
7.2 Is there a threshold of safe use for these allergens?
The SCCS opinion states:
13.2. Question 2
Can the SCCS establish any threshold for their safe use based on the available scientific data?
Dose-response relationships exist between exposure to contact allergens and the proportion of consumers who will become sensitised to an allergen (i.e. induction), as well as the proportion who will suffer from allergic contact dermatitis (elicitation). For a number of recognised contact allergens in man, dose-elicitation studies on sensitised individuals are available. These studies indicate that it is in principle possible to derive exposure levels that the majority of sensitised individuals will tolerate. The SCCS considers that thresholds based on elicitation levels in sensitised individuals will be sufficiently low to protect both the majority of sensitised individuals as well as most of the non-sensitised consumers from developing contact allergy and limit the risk of induction.
Among the established chemical fragrance allergens, 12 were identified as posing a high risk of sensitisation to the consumer (Table 13-5), i.e. more than 100 reported cases. For these substances, limitation of exposure would help to protect sensitised consumers from developing allergic contact dermatitis. In cases where specific data of sufficient quality on threshold levels for a particular allergen are available, these data should be used to set an individual safe threshold. However, when such quality data are not available and a substance has been identified to pose a high risk of sensitisation to the consumer, a general threshold limit can be applied.
Dose-response studies have been performed with only four of these fragrance substances (HICC, isoeugenol, cinnamal and hydroxycitronellal). In addition, such a study has also been performed on chloroatranol, a potent allergen in Evernia prunastri and Evernia furfuracea. These studies, however, are not adequate to derive safe thresholds for the individual substances directly from the data. If no adequate data are available, for substances posing a high risk to the consumer (like the 12 listed in Table 13-5), the use of a general threshold may be considered. A threshold of 0.8 μg/cm2 has been derived based on a statistical analysis of the available data in the scientific literature, including two fragrance allergens. This corresponds to 0.01% (100 ppm) limit in cosmetic products indicative for safe use. This approximation may hold for weak to strong allergens. However, some strong and extreme sensitisers may require lower individual thresholds. As an example, chloroatranol, present in the natural product Evernia prunastri and in Evernia furfuracea, has been shown to have an elicitation threshold of 0.0004 μg/cm2 under experimental conditions similar to those yielding above results. On the other hand, for very weak sensitisers, this generic threshold may be too conservative.
The model providing the general threshold of 100 ppm has been based on single substances only and no general safe level for the natural extracts of concern can be Hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC) has been the most frequently reported chemical causing fragrance allergy since the 1999 opinion on fragrance allergy.
In total, reports of more than 1500 cases have been published in the scientific literature (see chapter 7.1 and Annex I), which will severely underestimate the actual prevalence in the population. 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. The SCCP concluded in 2003 that 200 ppm of HICC would be tolerated by the majority of sensitised individuals and this level of exposure would have a low potential to induce sensitisation (241). 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. Chloroatranol and atranol are the main allergenic components of Evernia prunastri and Evernia furfuracea. The SCCS concluded in 2004 (239) that these should not be present in cosmetic products, due to their exceptionally high sensitisation potential. Attempts to effectively reduce the content of these compounds in “oak moss abs.” (300) have largely failed to reduce contact allergy to Evernia prunastri and Evernia furfuracea and the data presented in this opinion show that the number of cases remains high.
Conclusions - Question 2
There are two components to the safety of fragrance ingredients in terms of contact allergy. First, the need to eliminate or reduce induction of contact allergy (primary prevention), which, when it occurs, is life long. Secondly, the need to eliminate or reduce elicitation reactions (secondary prevention) on the skin of those individuals who are already sensitised. Human dose elicitation experiments have hithereto been performed only for a very small number of substances. It is unlikely that more of these studies will be performed due to experimental and subject recruitment difficulties. For individual substances, no levels that could be considered safe for the majority of consumers could be established from the available data.
The dose elicitation studies available indicate that a general level of exposure of up to 0.8 μg/cm2 (0.01%) may be tolerated by most consumers with contact allergy to fragrance allergens. The SCCS considers that this level of exposure could be efficient in limiting elicitation unless there is substance specific data, either experimental or clinical, to the contrary.
Such a threshold based on elicitation levels in sensitised individuals will be sufficiently low to protect both sensitised individuals as well as most of the non-sensitised consumers from developing contact allergy. The SCCS is of the opinion that for substances idendified as posing a high risk to the consumer and for which no individual thresholds could be derived (Table 13-5), the general threshold of 0.01% would limit the problem of fragrance allergy in the consumer significantly.
Opinion on fragrance allergens in cosmetic products identified, but the maximum use concentration applies to the identified fragrance allergens also when present in the natural extract.
It was 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 SCCS considers that the maximum use concentration applies to the above identified fragrance allergens also when present in the natural extract. This will also reduce the risk of sensitisation and elicitation from natural extracts.
It is important to stress that this general threshold, although limiting the problem, does not preclude that the most sensitive segment of the population may react upon exposure to these levels. Hence, this threshold does not remove the necessity for providing information to the consumer concerning the presence of the fragrance substance in cosmetics.
In the case of hydroxyisohexyl 3-cyclohexene carboxaldehyde, in 2003 the SCCP suggested that levels of up to 200 ppm would be tolerated by the majority of sensitised individuals. 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 products for the consumer. 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 allergenic constituents, despite efforts to reduce the allergen content (296). The SCCS is of the opinion that the presence of the two constituents, chloroatranol and atranol, in cosmetic products are not safe.
Source & ©: SCCS,
26-27 June 2012, 13. Opinion. p. 115-117.
7.3 Are there other substances that are relevant for consumers regarding perfume allergies?
The SCCS opinion states:
13.3. Question 3
Many fragrance substances can act as prehaptens or prohaptens, forming allergens which are more potent than the parent substance by abiotic and/or metabolic activation, and thus increasing the risk of sensitisation.
Experimental and clinical studies have shown that there are fragrance substances that act as prehaptens, i.e. their sensisitation potency is markedly increased by air exposure due to oxidation (autoxidation). Non/low-sensitising compounds are thereby transformed into more potent sensitisers. Limonene, linalool, linalyl acetate, alpha-terpinene and geraniol have all been identified as prehaptens. These fragrance substances are common in scented cosmetics as well as in household products. The clinical studies show that the exposure to allergens formed due to autoxidation causes significant contact allergy in consumers. Patch testing with oxidised limonene and oxidised linalool shows that these substances rank among the most common contact allergens.
In the SAR analyses performed in this work by the SCCS, fragrance compounds with structural alerts that indicate that they are possible prehaptens have been identified (Table 9-1, Table 9-2). In such cases further thorough investigations are needed. It is also important to investigate the stability of the primary oxidation products (the hydroperoxides) formed from various structures of fragrance compounds. The stability of these compounds can have great impact on the sensitisation potency of the oxidised compound as they are strong sensitisers. However, the secondary oxidation products (aldehydes and epoxides) can also be important sensitisers depending on the overall structure of the compound as was demonstrated for oxidised geraniol. Air oxidation of prehaptens can be prevented to a certain extent by measures during handling and storage of the ingredients and final products to avoid air exposure, and/or by addition of suitable antioxidants. The autoxidation rate depends not only on the compound itself, but also on its purity. The prevention of autoxidation using antioxidants needs thorough investigation because antioxidants can exert their function by being oxidised instead of the compound that they protect and might thereby be activated to skin sensitising derivatives after oxidation. As antioxidants are now frequently used at elevated concentrations in scented products due to a growing awareness of the problem of autoxidation, there is a risk that sensitisation caused by the antioxidants will rise. One of the most used antioxidants is butylated hydroxytoluene (BHT) which is considered a minimal risk for sensitisation in the concentrations used but nevertheless, with increased concentrations and usage, the risk of sensitisation could increase. It should be noted that, to decrease the risk for sensitisation in the population, the possibility to reduce the sensitisation potency by preventing autoxidation is important also for a direct acting hapten or prohapten, if a further activation by air oxidation to more allergenic compounds has been shown. Based on the clinical data, oxidised limonene and oxidised linalool are allergens of high concern (Table 13-5) which pose a high risk of sensitisation to the consumer. For these substances the presence of the oxidised fraction represented by the peroxide content should not be higher than 10 ppm. Alternatively, the suggested general threshold dose/area of 0.8 μg/cm2 (100 ppm in cosmetic products) could be applicable to the total oxidised fraction, i.e. not only peroxides but also secondary oxidation products such as aldehydes and epoxides.
Compounds that are bioactivated by metabolising enzymes to haptens are referred to as prohaptens. Established prohaptens of clinical importance are cinnamyl alcohol, geranial, geraniol, eugenol, isoeugenol and alpha-terpinene.
When bioactivation occurs, the risk of cross-reactivity should be considered. An increased complexity in the cross-reactivity pattern is obtained when a compound could act both as a prehapten and a prophapten. For instance, it is known that cinnamyl alcohol and cinnamal can cross-react due to the formation of common sensitising substances. The same applies to geraniol and citral. In case derivatives of a fragrance substance are used, it must be taken into account that the derivative could be transformed into the parent or a cross-reacting compound. For such derivatives the same rules as for the corresponding parents should apply, unless the stability of the derivative has been demonstrated. In particular, hydrolysis of esters to the corresponding alcohols can cause cross-reactions. Acetate esters of eugenol, isoeugenol and geraniol are frequently used in cosmetics. To be able to predict the sensitisation potency of prohaptens, steps of bioactivation have to be included in the predictive tests. Activation of individual compounds to various haptens increases the risks of cross- reactivity between chemicals and also causes difficulties in prediction of these risks. Prediction of risks requires sound application of theoretical principles in combination with well designed experimental studies. Based on the acquired knowledge, qualified suggestions using structure activity relationship (SAR) regarding many fragrance substances have been made (Table 9-1 to Table 9-3). However, as the stability of formed oxidation products (mainly hydroperoxides) is important for the sensitisation potency, the SAR hypotheses must be followed by experimental investigations for the actual compounds.
Conclusions - Question 3
Many fragrance substances can act as prehaptens or prohaptens, forming allergens which are more potent than the parent substance by abiotic and/or metabolic activation. Activation can thus increase the risk of sensitisation. Fragrances with published data showing the formation of sensitising compounds by autoxidation, bioactivation or both include the following (see also Table 13-6). Fragrance substances of clinical importance known to be prehaptens and to form sensitising compounds by air oxidation are limonene, linalool, and linalyl acetate. Fragrance substances of clinical importance known to be prohaptens and to form sensitising compounds by metabolic transformation are cinnamyl alcohol, eugenol, isoeugenol and isoeugenyl acetate. Fragrance substances of clinical importance with published data known to be both prehaptens and prohaptens and to form sensitising compounds by air oxidation (prehaptens) and by metabolic transformation are geraniol and alpha -terpinene. A fragrance substance that sensitises without activation but forms more potent sensitising compounds by air oxidation and also by metabolic transformation is geranial (one isomer of citral).
In the case of prehaptens, it is possible to prevent activation outside the body to a certain extent by different measures, e.g. prevention of air exposure during handling and storage of the ingredients and the final product and by the addition of suitable antioxidants. When antioxidants are used, care should be taken that they will not be activated themselves and thereby form new sensitisers. The possibility to reduce the sensitisation potency by preventing air oxidation is important also for a direct acting hapten or prohapten, if a further activation by air oxidation to more allergenic compounds has been shown. In the case of prohaptens, the possibility to become activated is inherent to the molecule and activation cannot be avoided by extrinsic measures. Activation processes increase the risk for cross-reactivity between fragrance substances. Cross-reactivity has been shown for certain alcohols and their corresponding aldehydes, i.e. between geraniol and geranial (citral) and between cinnamyl alcohol and cinnamal. Cross-reactivity is also expected between ester derivatives and their parent alcohols, as the esters will be hydrolysed by esterases in the skin. Esters of important contact allergens that can be activated by hydrolysis in the skin are isoeugenyl acetate, eugenyl acetate and geranyl acetate which all are known to be used as fragrance ingredients. The substances presented above are based on current knowledge and should be seen as indicative and illustrative of the general problem. As substances with structural alerts for acting as pro- and/or prehaptens are quite common among the fragrance substances listed (see Tables 9-1 and 9-2), the possibility for activation to generate new potent allergens should be considered. The SCCS is of the opinion that substances known to be transformed (e.g. by oxidation either via air oxidation or via bioactivation) to known contact allergens should be treated as equivalent to these contact allergens, i.e the same restrictions and other regulatory requirements should apply, unless specific data exist that allow for an individual assessment. Important indicative examples include limonene, linalool, linalyl acetate, geraniol, geranial, alpha-terpinene, eugenol, isoeugenol and cinnamyl alcohol.
Source & ©: SCCS,
26-27 June 2012, 13. Opinion. p. 117-120.