2. What kind of skin problems are known to be caused by fragrance ingredients?
- 2.1 What is contact allergy?
- 2.2 What ‘other’ non-allergic reactions to fragrance ingredients are observed?
- 2.3 How can contact allergies be diagnosed?
- 2.4 How common is perfume allergy and can it be avoided?
2.1 What is contact allergy?
The SCCS opinion states:
4. Clinical aspects of contact allergy to fragrance ingredients
4.1. Spectrum of reactions
Adverse reactions to fragrances in perfumes and in fragranced cosmetic products include allergic contact dermatitis, irritant contact dermatitis, photosensitivity, immediate contact reactions (contact urticaria), and pigmented contact dermatitis. Airborne and connubial contact dermatitis occur.
4.1.1. Allergic contact dermatitis
Allergic contact dermatitis (ACD) depends primarily on the activation of allergen-specific T- cells. In allergic contact dermatitis, a distinction is made between induction (sensitisation) and elicitation phases. A useful review is available (2). The induction phase includes the events following initial contact with the allergen and is complete when the individual is sensitised and capable of giving a positive allergic contact dermatitis reaction.
The elicitation phase begins upon re-exposure to the allergen (challenge) and results in clinical manifestation of allergic contact dermatitis. The entire process of the induction phase requires ca. 10 days to several weeks, whereas an elicitation phase reaction develops within 1–2 days.
Most contact allergens are small, chemically reactive compounds. As these compounds are too small to be directly immunogenic, they act as haptens; i.e. they react with higher molecular weight epidermal and/or dermal biomolecules to form immunogenic adducts. It is usually considered that the biomolecules involved are free or membrane bound proteins, which react via nucleophilic thiol, amino, and hydroxyl groups.
Dendritic cells (DCs) and the local tissue microenvironment are crucial factors in the development of ACD. Langerhans cells (LCs), as epidermal DCs, and dermal DCs are pivotal for the sensitisation and the elicitation phases of ACD. During sensitisation, DCs react with the immunogenic complexes by interaction with neighbouring keratinocytes, migration to the local draining lymph nodes and the priming of naïve T-cells. These reactions are mediated by inflammatory cytokines, chemokines and adhesion molecules. Antigen specific effector T-cells are then recruited into the skin upon contact with the same hapten (elicitation). Following their recruitment these T-cells are activated by antigen-presenting skin cells, including LCs, dermal DCs and keratinocytes, and macrophages.
Although most allergens can form hapten–carrier complexes directly, some need activation, e.g. by enzyme-induced metabolic conversion or abiotic oxidation. Such compounds are termed prohaptens and prehaptens, respectively, and are discussed in more detail in chapter 5. Well known examples of prehaptens and prohaptens are limonene and eugenol. Reduced enzyme activity in certain individuals, related to genetic enzyme polymorphisms, may give an increased or reduced risk of sensitisation to prohaptens (that need enzymatic activation) in certain individuals or populations. Once sensitised, individuals can develop allergic contact dermatitis upon re-exposure to the contact allergen. Positive patch test reactions mimic this process of allergen-specific skin hyper-sensitivity. Skin contact induces an inflammatory reaction that is maximal within 2–3 days and, without further allergen supply, then declines.
Overview of clinical features
Perfumes and deodorants are the most frequent sources of sensitisation to fragrance ingredients in women, while aftershave products and deodorants are most often responsible in men (3). Thereafter, eczema may appear or be worsened by contact with other fragranced products such as cosmetics, toiletries, household products, industrial contacts and flavourings.
Contact allergy to a particular product or chemical is established by means of diagnostic patch testing. When patients with suspected allergic cosmetic dermatitis are investigated, fragrances are identified as the most frequent allergens, not only in perfumes, after-shaves and deodorants, but also in other cosmetic products. Evaluation of perfume allergy may be difficult; a perfume compound may consist of ten to > 300 basic components selected from about 2500 materials.
Between 6 and 14% of patients routinely tested for suspected allergic contact dermatitis react to a standard indicator of fragrance allergy, the Fragrance Mix I (4), see also chapter 4.3.2. When tested with ten popular perfumes, 6.9% of female eczema patients proved to be allergic to them (5) and 3.2–4.2% were allergic to fragrances from perfumes present in various cosmetic products (6). The finding of a positive reaction to the Fragrance Mix I should be followed by a search for its relevance, i.e. is fragrance allergy the cause of the patient’s current or previous complaints, or does it at least contribute to it? Between 50 and 65% of all positive patch test reactions to the mix are relevant. Sometimes, correlation with the clinical picture is lacking and many patients appear to tolerate perfumes and fragranced products without problems (7). This may be explained by: a) irritant (false-positive) patch test reactions to the mix; b) the absence of relevant allergens in those products; and c) the concentration being too low to elicit clinically visible allergic contact reactions. Contact allergy to fragrances often causes dermatitis of the hands (and aggravation of), face and neck, axillae and patches in areas where perfumes are dabbed on such as behind the ears, upper chest, elbow flexures and wrists. Depending on the degree of sensitivity and exposure, the severity of dermatitis may range from mild to severe with dissemination (8) [pp 158–170].
Clinical studies have shown a highly significant association between reporting a history of visible skin symptoms from using scented products and a positive patch test to the Fragrance Mix I (9). Provocation studies with perfumes and deodorants have also shown that fragrance-mix-positive eczema patients often react to use-tests with the products. Subsequent chemical analysis of such products has detected significant amounts of one or more Fragrance Mix I ingredients, confirming the relevance of positive patch tests to the Fragrance Mix I in these patients (5, 10).
Contact sensitisation may be the primary cause of hand eczema, or may be a complication of irritant or atopic hand eczema. The number of positive patch tests has been reported to correlate with the duration of hand eczema, indicating that long-standing hand eczema may often be complicated by sensitisation (11). The most common contact allergies in patients with hand eczema are metals, the Fragrance Mix, Myroxylon pereirae, and colophonium (12).
Fragrance allergy may be a relevant problem in patients with hand eczema; perfumes are present in consumer products to which their hands are exposed (13). A significant relationship between hand eczema and fragrance contact allergy has been found in some studies based on patients investigated for contact allergy (14). However, hand eczema is a multi-factorial disease and the clinical significance of fragrance contact allergy in (severe) chronic hand eczema may not be clear. A review on the subject has been published (15).
Bilateral axillary dermatitis may be caused by perfume in deodorants and, if the reaction is severe, it may spread down the arms and to other areas of the body (8) [pp 158–170]. In individuals who consulted a dermatologist, a history of such first-time symptoms was significantly related to the later diagnosis of perfume allergy (9).
Facial eczema is an important manifestation of fragrance allergy from the use of cosmetic products (16). In men, aftershave products can cause an eczematous eruption of the beard area and the adjacent part of the neck (8) [pp 158–170], and men using wet shaving as opposed to dry have been shown to have an increased risk of 2.9 of being fragrance allergic (17).
Source & ©: SCCS,
26-27 June 2012, 4.1.1 Allergic contact dermatitis. p. 12-14
2.2 What ‘other’ non-allergic reactions to fragrance ingredients are observed?
The SCCS opinion states:
4.1.2. Irritant reactions (including contact urticaria)
Irritant effects of some individual fragrance ingredients, e.g. citral (18, 19), are known. Irritant contact dermatitis from perfumes is believed to be common, but there are no existing investigations to substantiate this (7). Many more people complain about intolerance or rashes to perfumes/perfumed products than are shown to be allergic by testing (9). This may be due to irritant effects or inadequate diagnostic procedures. Fragrances may cause a dose-related contact urticaria of the non-immunological type (irritant contact urticaria). Cinnamal, cinnamic alcohol, and Myroxylon pereirae are well recognised causes of contact urticaria, but others, including menthol, vanillin and benzaldehyde have also been reported (20). The reactions to Myroxylon pereirae may be due to cinnamates (21).
A relationship to delayed contact hypersensitivity was suggested (22), but no significant difference was found between a fragrance-allergic group and a control group in the frequency of immediate reactions to fragrance ingredients (20), in keeping with a non- immunological basis for the reactions seen.
4.1.3. Pigmentary anomalies
The term “pigmented cosmetic dermatitis” was introduced in 1973 for what had previously been known as melanosis faciei feminae when the mechanism (type IV allergy) and causative allergens were clarified (23). It refers to increased pigmentation, usually on the face/neck, often following sub-clinical contact dermatitis. Many cosmetic ingredients were patch tested at non-irritant concentrations and statistical evaluation showed that a number of fragrance ingredients were associated: jasmine absolute, ylang-ylang oil, cananga oil, benzyl salicylate, hydroxycitronellal, sandalwood oil, geraniol, geranium oil (24).
Musk ambrette produced a considerable number of allergic photocontact reactions (in which UV-light is required) in the 1970s (25) and was later banned from use in the EU. Nowadays, photoallergic contact dermatitis is uncommon (26). Furocoumarins (psoralens) in some plant-derived fragrance ingredients caused phototoxic reactions with erythema followed by hyperpigmentation resulting in Berloque dermatitis (8) [pp 417–432]. There are now limits for the amount of furoumarins in fragrance products. Phototoxic reactions still occur but are rare (27).
Fragrances are volatile and therefore, in addition to skin exposure, a perfume also exposes the eyes and naso-respiratory tract. It is estimated that 2–4% of the adult population is affected by respiratory or eye symptoms by such an exposure (28). It is known that exposure to fragrances may exacerbate pre-existing asthma (29). Asthma-like symptoms can be provoked by sensory mechanisms (30). In an epidemiological investigation, a significant association was found between respiratory complaints related to fragrances and contact allergy to fragrance ingredients, in addition to hand eczema, which were independent risk factors in a multivariate analysis (31).
Source & ©: SCCS,
26-27 June 2012, 4.1.2, 4.1.3, 4.1.4, 4.1.5. p. 14
2.3 How can contact allergies be diagnosed?
The SCCS opinion states:
4.2. Patch testing
The diagnosis of contact sensitisation (or contact allergy – regarded here as synonymous) as the immunological alteration underlying allergic contact dermatitis is made by patch testing. This diagnostic tool involves the standardised application of small doses of a set of potential or individually suspected allergens for a period of 1 day or, mostly, 2 days. In the following days, exposed skin sites are checked for the occurrence of allergic reactions, which morphologically mimick allergic contact dermatitis occurring elsewhere, after exposure to culprit products. International guidelines for the application, reading and interpretation of the patch test exist (32). The present brief section does not intend to reiterate all technical and scientific aspects, but to outline some aspects of diagnostic patch testing which are often misunderstood (for a recent comment see also (33)).
- The patch test identifies whether the patient has contact allergy to a substance, but cannot contribute information on the clinical relevance of that contact allergy for the eczema that led to consultation and to patch testing (see 4.4.1).
- Exposure conditions of the patch test (one-time, prolonged occlusive application, usually in petrolatum or water, of a single substance) have been optimised to achieve above diagnostic aim, and thereby have nothing in common with exposures which lead to sensitisation and elicitation of allergic contact dermatitis. These are normally repetitive, often over weeks, months or years, non-occlusive, and to much lower concentrations and doses/area, respectively, but possibly on damaged or inflamed skin. In fact, the repeated open application test (ROAT), which is sometimes used after a positive patch test of uncertain validity to verify that contact allergy indeed exists mimics these day-to-day exposure conditions, and typically involves single dosing which are a small fraction of the one-time patch test dose (see 11).
- It is self-evident that such (repeated, low-level) exposures must have occurred and have culminated in an adaptive immune response – therefore it is axiomatic that the substance involved is a skin sensitiser in humans (33).
- Repeated patch testing, which is a relatively rare event, does not contribute significantly to contact allergy (to fragrance allergens).
- Most allergen test preparations, and certainly those that are included in international baseline series, have evolved from studies critically (re-) appraising their diagnostic validity, i.e., sensitivity and specificity. Notwithstanding this, false-positive and false-negative reactions do occur (as with any diagnostic tool). While in the individual case such diagnostic misclassification may have unfortunate consequences, it will hardly impair epidemiological estimates of contact allergy frequency – at least as long as a reasonable balance between false-positive and false-negative reactions is achieved.
Source & ©: SCCS,
26-27 June 2012, 4.2 Patch testing. p. 15
2.4 How common is perfume allergy and can it be avoided?
The SCCS opinion states:
4.3. Epidemiology of fragrance allergy
4.3.1. Substances used for screening of contact allergy to fragrance ingredients
A fragrance formula may consist of ten to 300 or more different ingredients. The Cosmetic Ingredients (CosIng) database established by the European Commission lists 2587 ingredients used for perfuming1, as well as several other materials classified as odour “masking” agents, which is equivalent with regard to allergy. A mixture of seven fragrance chemicals and one natural extract, which have been identified as major fragrance allergens in the past (34), are used for diagnosing contact allergy to fragrance ingredients (Table 4-1). This mixture is called the Fragrance Mix (FM I) and is included in the standard patch test tray containing the most common allergens in Europe.
However, due to the introduction of new fragrance ingredients (with allergenic potential), the above Fragrance Mix I was deemed not to be sufficient for the diagnosis of fragrance allergy. Thus, Fragrance Mix II was devised to supplement Fragrance Mix I in a European multicentre study (35, 36). Since then, FM II has been included in the European baseline series. Table 4-2 lists the ingredients of FM II. In addition to being tested in FM II, hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC) is also tested separately at 5% test concentration in the baseline series (37).
Patch test results in patients and in population samples with these two screening mixes, and single allergens, will be presented and discussed in the following two sections.
4.3.2. Clinical epidemiology
For a number of reasons the bulk of the evidence regarding the frequency of contact allergy to fragrance ingredients relies on clinical data, i.e. the history, clinical presentation and test results of patients patch tested for suspected allergic contact dermatitis – in general, and not specifically due to fragrance ingredients. The frequency of contact allergy to fragrance ingredients (or other contact allergies, for that matter) cannot be related to the population directly, as it is derived from a subgroup (of patients) selected for specific morbidity. Nevertheless, these data can be examined epidemiologically assuming a largely similar selection process: (i) across time in a given department; and (ii) between departments at any point of time. If the notion of similarity, and thus direct comparability, does not appear valid, adjustment or standardisation techniques can be employed to account for differences, e.g. the average age of patients in a time series on a (fragrance) allergen with age- associated risk of sensitisation. In this situation, changes in the age composition of the patients tested may confound a time trend. A distinction must be made between patch testing “consecutive” patients, i.e. all patients who are patch tested for suspected contact sensitisation, and “aimed” patch testing, i.e. application of allergens only in the subset of patients in whom exposure to the particular allergens of the applied “special series” is suspected. For any given allergen, the latter “aimed” approach will usually yield higher sensitisation prevalence than the testing of not-further-selected “consecutive” patients. Thus, information on the inclusion of an allergen either in a baseline series (tested in virtually all patients) or in a special series (applied in an aimed fashion) must be considered and is given in the following tables, where available in the cited references. Notwithstanding the potential pitfalls of clinical data, they have proven useful in identifying emerging trends or persisting problems, and also in evaluating the effect of preventive action – either regarding the entire population, or subgroups thereof, such as certain occupations. Regarding the fragrance mixes (FM I and FM II) mentioned above, evidence regarding sensitisation frequencies published since 1999 will be outlined below, thus supplementing the data presented in the SCCNFP opinion on Fragrance Allergy in 1999 (1).
Fragrance Mix I (“Larsen Mix”)
Table 4-3: Results with screening agents for contact allergy to fragrance ingredients reported since 1999 in patients patch tested for suspected allergic contact dermatitis in Europe: Fragrance Mix “I” (see Table 4-1). If not given in the publication, the confidence interval (CI) was calculated from the absolute numbers by the SCCS (§).
Table 4-4: Results with screening agents for contact allergy to fragrance ingredients reported since 1999 in patients patch tested for suspected allergic contact dermatitis in non-European countries: Fragrance Mix “I” (see Table 4-1). If not given in the publication, the confidence interval (CI) was calculated from the absolute numbers by the SCCS (§).
Beyond the studies discussed above, regarding a time trend of sensitisation to FM I, a significant increase of positive results to FM I until 1998, and a significant drop thereafter has been noted in the IVDK study covering 1996 to 2002 (42). A similar drop from 1999 to 2007 has been observed in female, but not male patients from Copenhagen (52). In accordance with these findings, the prevalence of positive reactions to FM I doubled, or thereabouts, from 1989-1993 to 1994-1998 in Ljubljana, Slovenia (41).
Within Europe, a comparison between different countries and clinical departments is possible. An EECDRG study covering 1996-2000 found 9.7% positives to FM I (range: 5.0– 12.6% in ten departments from seven European countries (66). A different European study, covering 10/1997-10/1998, found 11.3% (95% CI: 9.9–12.9%) positive reactions to FM 1 in 1,855 patients; the variation between centres was marked: Gentofte 8.2% vs. Leuven 23.0% as extremes (67). In the first study of the European Surveillance System on Contact Allergies (ESSCA), covering 2002 and 2003, 9663 patients were patch tested with FM I, overall yielding 7.1% positive reactions with marked variation between participating departments. In Dortmund, Germany, the minimum frequency of 3.7% was noted, while in Lahti, Finland, the highest prevalence, namely 10.4%, was found (53). Subsequently, in the year 2004, the overall prevalence was 7.6%, i.e. largely unchanged (54). In the most recent study by ESSCA, based on 2005/2006 PT data across Europe, significant differences were again noted, this time on the aggregated level of European regions, with FM I sensitisation being the least frequent in the Southern countries (4.8% [95% CI: 3.9–5.5%] age- and sex-standardised prevalence) vs. 7.7% (95% CI: 7.0–8.4%) in the central European departments, with the Finnish, Polish and Lithuanian departments (5.7% [95% CI: 4.6 – 6.8%]) and the UK network (6.8% [95% CI: 6.3 – 7.3%]) in an intermediate position (55).
Fragrance Mix II
Table 4-5: Results with screening agents for contact allergy to fragrance ingredients reported since 1999 in patients patch tested for suspected allergic contact dermatitis: Fragrance Mix “II” (see Table 4-2). The FM II was only conceived in 2005, so results are still sparse). If not given in the publication, the confidence interval (CI) was calculated from the absolute numbers by the SCCS (§).
Hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC)
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 about 1500 cases have been published in the scientific literature (see section 7.1).
HICC was recognised as an allergen in 1995 (70) and later included in the new perfume mixture, Fragrance Mix II (71), which is routinely used for the diagnosis of perfume allergy, see above. Furthermore, it is recommended to test separately with HICC, because it is a very frequent allergen (37) and detects relevant fragrance sensitisation which would otherwise have been missed (49). In the studies performed in European dermatology clinics, 0.5-2.7% of eczema patients have been found to be allergic to HICC with the highest frequency in central Europe (55). For further details see Table 4-6.
Table 4-6: Results with fragrance contact allergy screening agents reported since 1999 in patients patch tested for suspected allergic contact dermatitis: HICC (5% pet. if not stated otherwise). If not given in the publication, the confidence interval (CI) was calculated from the absolute numbers by the SCCS (§).
Myroxylon pereirae (Balsam of Peru)
Myroxylon pereirae is a balm obtained from a Central American tree. It is used as a screening substance for fragrance allergy in Europe and other geographical areas. Although the crude balm is not used in Europe in cosmetics, extracts and distillates are used (75). This natural mixture has been employed as screening agent in the baseline series for many decades. Hence, a wealth of data is available; Table 4-7 summarises results of the past 10 years.
Table 4-7: Results with fragrance contact allergy screening agents reported since 1999 in patients patch tested for suspected allergic contact dermatitis: Myroxylon pereirae resin (Balsam of Peru) (25% pet.). If not given in the publication, the confidence interval (CI) was calculated from the absolute numbers by the SCCS (§).
Oil of turpentine
This natural extract is not tested in all baseline series. It is considered as a minor screening allergen for fragrance contact allergy. Moreover, oil of turpentine is used as a raw material in perfumery (see Annex I). Table 4-8 summarises results of the past 10 years with patch testing of consecutive patients.
Table 4-8: Results with fragrance contact allergy screening agents reported since 1999 in patients patch tested for suspected allergic contact dermatitis: Oil of turpentine (10% pet.) patients patch tested for suspected allergic contact dermatitis. If not given in the publication, the confidence interval (CI) was calculated from the absolute numbers by the SCCS (§).
An “overall burden” of fragrance contact allergy, in terms of the prevalence of contact allergy to at least one of the up-to-five screening allergens present in the baseline series (FM I, FM II, HICC, Myroxylon pereirae, oil of turpentine) has not been given in the published studies. A re-analysis of data from the two published studies of the IVDK (43, 68), covering central Europe from 2005 to 2008 (Germany, Austria and Switzerland), yielded an estimate of such overall prevalence of 16.2% (95% CI: 15.8-16.6%) (IVDK technical report, 2011-11-18).
4.3.3. Population-based epidemiology
In principle, the examination of a representative sample of the population is the most valid approach for estimating disease frequency, as there is no systematic selection process. However, in practice, participation of much less than 70% of those approached introduces the possibility of self-selection and thus of biased morbidity (or risk) estimates. Moreover, the resources needed prohibit regular, e.g. yearly, patch test studies in a sample of several thousand persons. For these reasons few studies exist (see Table 4-9).
A Swedish study of hand eczema in an industrial city showed that among 1,087 individuals recruited from the general population with symptoms of present or previous hand eczema, 5.8% were positive to the Fragrance Mix (81). In Denmark, Fragrance Mix sensitivity was found in 1.1% (0.3-2.1%) of 567 persons drawn as a sample from the general Danish population; only nickel sensitivity was more prevalent (82). In Italy, female patients with hand eczema caused by contact with detergents were patch tested. Of 1100 women, 3.1% reacted to Fragrance Mix I (83). A control group of 619 female patients with no eczema disease were also patch tested; 1.3% were positive to the Fragrance Mix (83). On the other hand, in a sample of 593 healthy Italian recruits, only three positive reactions (0.50%) to FM I were observed (84). Among Danish school children, 14-15 years of age, fragrance contact allergy was detected in 1.8% by patch testing with Fragrance Mix I (85). A study of 85 American student nurses showed that 15 (17.6%) had a positive reaction to Fragrance Mix I; 12 of the individuals also had a positive history of contact dermatitis (86). In this study the concentration of Fragrance Mix I was 16% as opposed to the currently recommended concentration of 8% and the study included only young females. Both of these factors may have contributed to the high prevalence of fragrance sensitivity found.
In 1990, 1998 and 2006, samples of the Danish adult population living in the Copenhagen area were patch tested with the European baseline series. In total 4299 individuals aged 18-69 years (18-41 years only in 1998) completed a pre-mailed questionnaire and were patch tested with FM I and Myroxylon pereirae (82, 87, 88). In 1990, 1.1% were found positive to FM I and in 2006, 1.6% were positive, which means no general change. However, when the age group of 18-41 years was analysed, the prevalence of FM I sensitisation followed an inverted V-pattern among women, i.e. an increase from 0.7% in 1990 to 3.9% in 1998, followed by a decrease to 2.3% in 2006. The participation rate varied in the three samples from 71.5% in 1990 to 52.4% in 1998, and to 43.7% in 2006 (82, 87, 88).
Contact sensitisation to FM I is strongly age related, with the relative risk more than doubling in the older age groups, compared to younger PT patients. This has been found in both bivariate (89) and adjusted multifactorial analyses (90). Hence, in older samples of the population, the prevalence of contact allergy to fragrance ingredients in general, and to FM I in particular, can be expected to be higher than in younger samples. From this background, the strikingly high prevalence observed in the MONICA/KORA allergy study in Augsburg, Germany (see Table 4-9) (80), may be explained, together with some residual confounding from the rather complex sampling process.
Table 4-10: Results from patch testing with other fragrance allergens in different population based groups. If not given in the publication, the confidence interval (CI) was calculated from the absolute numbers by the SCCS (§).
4.4.1. Clinical relevance
Clinical relevance is a concept used to describe the significance of a positive (allergic) patch test reaction for an individual patient: a reaction is deemed relevant if contact allergy to the substance is associated with previous or current episodes of allergic contact dermatitis. Thereby, the evaluation of clincial relevance links past exposure to morbidity. For the evaluation of relevance, past or recent exposure(s) to the allergen need to be identified in the patient's history. The success of this process generally depends on:
- The patient's understanding and awareness;
- The dermatologist's knowledge concerning exposures;
- Ingredient labelling; and
- Information about the actual chemical composition of the implicated product.
As these requirements may be met to a varying extent, the validity of relevance information as reported in clinical studies may also be variable. However, information on clinical relevance is important, in principle, because the proportion of currently relevant sensitisations reflects the amount of current exposure and resulting disease state, which may increase or decrease with time. In this way, current relevance also reflects the direct burden of a fragrance contact allergy to the individual and indirectly to society. Further important aspects of the evaluation of clinical relevance as a final step of patch testing have been discussed (32, 94-96).
Generally, clinical relevance is categorised as “current”, “previous” or “unknown”. Further differentiation has been introduced by adding information on:
- Occupational versus non-occupational causation; and
- The level of certainty of the relevance statement, e.g. as “certain”, “probable”, “possible”.
In some cases, clinical relevance may not be established due to:
- Immunological cross-reactivity with an individual allergen, diagnosed or not;
- Active sensitisation by the patch testing;
- Contact sensitisation not caused by the substance, but by a contaminating constituent; or
- Failure to test with a true hapten (e.g. haptens formed from prehaptens on exposure to air, see chapter 5).
It should be noted that this statement on clinical relevance refers to the past history of a patient. This implies that a lack of, or unknown, clinical relevance does not make future allergen avoidance unnecessary. In the context of contact allergy to fragrance ingredients, a number of alternative concepts of relevance have been used, for example:
- A history of intolerance to perfume or to perfumed products;
- A history of intolerance to perfume actually containing the allergen diagnosed;
- Detection of the culprit allergen in a perfume previously used.
4.4.2. Elicitation with clinical symptoms/signs, current and past
In case reports or small series, the clinical relevance of positive patch test reactions is usually well established and presented in detail. Moreover, a few large-scale clinical studies on contact allergy to fragrance ingredients have reported results on clinical relevance, which will be presented and discussed in this section. The studies can be subdivided into those which focus on medical history, patch testing with consumer products or detection of specific allergens in consumer products used by patients.
A series of studies conducted in the 1990s showed that most individuals with contact allergy to fragrance ingredients were aware that they could not tolerate fragranced products on their skin and were able to specifically name product categories that initiated their disease (9). In this context, colognes, deodorants and lotions were named significantly more often by fragrance allergic dermatitis patients than by patients without fragrance contact allergy (3). These studies are described in the SCCNFP opinion on fragrance allergy of 1999 (1). Newer studies are outlined below. NACDG 2009 study (65) The definition of “present” clinical relevance in this North American network study was strict, requiring:
- A positive use or patch test with the suspected item(s) for “definite” relevance; and
- Verification of the presence of the allergen in known skin contactants, and consistent clinical presentation for “probable”.
If these conditions were not met, but skin contact to items generally containing the item was likely, “possible” was used. Regarding fragrance allergens, the proportions were as described in Table 4-11.
Frosch 2002 (a) study (67)
In this study, 1,855 consecutive patients were patch tested with FM I and a series of a further 14 fragrance chemicals. Prior to the test, the history of adverse reactions to fragrances was classified as “certain” (6.6%), “probable” (8.0%), “questionable” (9.2%) or “none” (76.1%) (see (71)).
Frosch 2002 (b) study (97)
A series of 18 essential oils or components thereof, together with FM I, was assessed in 1,606 consecutive patients. Similar to the above study, the proportions of patients with a “certain” or “probable” history (or otherwise) and positive reactions to either FM I or the special series, or both, were cross-tabulated. Of note, 53.7% of patients with positive reactions to FM I only, had no history. Similarly 54.2% of patients with positive reactions only to one of the essential oils had no history. However, in cases of reactivity to both FM I and one of the essential oils, the proportion of patients with no history was only 36.5%.
Frosch 2005 study (35)
The diagnostic properties of FM I and the new FM II were evaluated in 1,701 consecutive patients patch tested in six European centres. Contrasting a “certain” (found in 8.7% of patients) with “no history” (75.3% of patients), the sensitivity of FM I was 25.2%, and the positive predictive value (PPV) 45.1%. In comparison, the sensitivity of FM II at 14% concentration was 13.5% and the PPV was 55.6%. The combination of the two mixes was important, as more patients with a “certain” history, but also independently from history, reacted to just one of the mixes rather than to both. Danish Contact Dermatitis Group 2005-2008 (69)
In 12302 consecutive patients patch tested in seven dermatology clinics and three university hospitals, 10.6% were positive to one or more of the fragrance allergy markers (FM I, FM II, Myroxylon pereirae or hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC)). Clinical relevance covered current and/or past relevance based on: 1) medical history; 2) results of patch and/or use tests; 3) ingredient labelling: or 4) chemical analysis. Clinical relevance was found in 71.0% of cases positive to FM I, 72.2% of those positive to FM II and 76.7% of those positive to HICC. These proportions were higher than the average for other cosmetic allergens such as preservatives and hair dyes, which gave relevant reactions in about 50% of those positive, as did Myroxylon pereirae. Myroxylon pereirae itself is not used in cosmetics as it is banned, but sensitisation may be caused by exposures to related substances and thus relevance may be difficult to determine.
Fragrance formulae from cosmetic products
Popular fine fragrances (5), as well as toilet soaps, shampoos, lotions, deodorants, and aftershaves have been shown to provoke allergic contact dermatitis in patients when used for patch testing (5, 6, 98, 99). Moreover, commercially available fragrance formulae and dilutions of individual fragrance allergens were potent elicitors of allergic contact dermatitis under simulated use conditions (10, 100, 101).
More recently, deodorants spiked with the fragrance allergens cinnamal, hydroxycitronellal and HICC, respectively, in realistic in-use concentrations were shown to elicit allergic contact dermatitis in 89-100% of the fragrance allergic individuals tested (102-104). In 87.5% of HICC sensitised individuals the use of a cream (and in 82.8% the use of an ethanol solution) spiked with HICC provoked dermatitis (105). These studies are discussed in more detail in chapter 11 on quantitative aspects. Other new studies are mentioned below:
IVDK “own perfumes” study (106)
A different perspective on clinical relevance is provided by assessing the proportion of positive reactions to the FM I or single fragrance allergens in patients who had not tolerated certain perfumed products, such as deodorants and aftershaves and who were patch test positive to these cosmetics. The following two tables are taken from this publication.
Of the 66 patients with a positive patch test reaction to their own deodorant, most had positive reactions to one or more fragrance allergens. This was much more prevalent than those patients in whom no positive reaction to their deodorant was observed. This observation supports the notion that the respective fragrance allergens are important in contact allergy to fragrance ingredients caused by deodorants, supporting data regarding exposure (chapter 10.1).
Table 4-13: Extract from ((106) Table 2) on the frequency of positive reactions to fragrance allergens in patients with vs. without positive patch test reaction to their own aftershave, eau de toilette or perfume.
Similar results were obtained from the subgroup of patients with a positive reaction to their eau de toilette, aftershave (hydroalcohol solutions) or perfumes (Table 4-13). However, notable differences were: (i) the greater relative importance of Evernia prunastri (Oak moss absolute); and (ii) generally an extremely high proportion of positive reactions to various other fragrance ingredients.
4.4.3. Elicitation in diagnostic patch tests without clinical history
In a variable proportion of patients, a positive patch test reaction does not correlate with recent or past episodes of presumptive allergic contact dermatitis. Apart from particular circumstances, such as cross-reactivity or reactivity to contaminants outlined above, there are several possible explanations for this:
- The patch test reaction was a false-positive (irritant).
- There was erroneous recall/interpretation of the patient's history (false-negative).
- Lack of knowledge concerning exposures.
- If the patient is weakly sensitised (e.g. by a low induction dose), the occlusive exposure during patch testing may have been the only exposure above the individual elicitation threshold capable of eliciting an unequivocal allergic contact reaction. In this situation, clinical relevance would be classified as “unknown”. Nevertheless, there is an alteration of the immune status of the individual.
4.5. Socio-economic impact of contact allergy
4.5.1. Health related quality of life
Skin diseases in general are known to affect quality of life significantly (107); this also applies to eczema, where most studies concern atopic dermatitis and hand eczema patients (108, 109). Hand eczema has a poor prognosis and may affect the self-image, limit social activities and lead to occupational restrictions (109, 110). The quality of life in hand eczema patients with fragrance contact allergy is affected in a similar degree as patients with other contact allergies (111).
In a questionnaire study of 117 patients recently diagnosed with contact allergy to fragrance ingredients, most presented with hand or facial eczema. In response to the question if and how fragrance allergy had affected their life situation, 67.5% replied that they often had to take special precautions, 47.0% replied that they were often bothered by eczema and itch, 17.1% said that they had had to take sick leave due to their fragrance contact allergy and 45.3% felt that fragrance contact allergy had significantly influenced their daily living (112).
4.5.2. Occupational restrictions
Contact allergy is known to influence severity and prognosis of hand eczema (113, 114) including risk of sick leave (111). Fragrance contact allergy is mostly of a non-occupational origin (90) related to the personal use of scented cosmetics, but may have secondary occupational consequences. This may be due to exposure to fragrance ingredients also in the work place or because hand eczema has developed. Hand eczema itself may make it impossible to remain in the trade even if protective equipment is used. In young people, fragrance allergy may limit the choice of occupations, as it will be difficult to work as a hairdresser, cosmetologist or in other occupations with a significant skin exposure to fragranced products.
4.5.3. Costs to health care/health economics
In a population based study of 3,460 individuals, contact allergy to FM I was found in 1.6%; logistic regression analyses showed that medical consultation due to cosmetic dermatitis (OR 3.37, 95% CI 1.83-6.20) and cosmetic dermatitis within the past 12 months (OR 3.53, CI 2.02-6.17) were significantly associated with sensitisation to FM I (88). Further, as mentioned above, fragrance allergy may lead to sick leave (112). No specific cost estimates for fragrance allergy exist, but the yearly total costs of contact dermatitis in Western Europe was estimated to be 5.2 billion Euro in 1997. Prices were based on the Allergy White Paper (1997) and on results of investigations and extrapolations of known data for Western Europe (115). Fragrance allergy is the second most frequent cause of contact allergy after nickel allergy and is seen in every 10th patient investigated for contact allergy. Even a modest reduction in nickel allergy has been estimated to have the value of 12 million Euro/year/million people in Denmark (Environmental Project Nr. 929, 2004; https://www2.mst.dk/Udgiv/publications/2004/87-7614-295-7/pdf/87-7614-296-5.pdf, last accessed 2011-11-13). The costs are likely to differ in other countries, some with higher expenses and some with lower costs. These estimates show that the cost of contact allergy in the population may be considerable.
4.6. Allergen avoidance
Generally, “allergen avoidance” can be regarded as having two aspects: (i) primary prevention of the acquisition of contact allergy achieved by avoiding or limiting exposure of the general population, or certain parts of it, to allergens; and (ii) secondary prevention in terms of avoiding (re-)elicitation of allergic contact dermatitis in sensitised individuals.
4.6.1. Primary prevention: limiting or eliminating exposure to allergens in the population
The main aim of public health is the primary prevention of disease in populations. Allergic contact dermatitis (to fragrances) has the potential to have a significant impact on quality of life, including effects on fitness for work (chapter 4.5). Moreover, it is a common phenomenon and therefore a reduction of exposure to (fragrance) allergens must be an objective of effective Public Health measures. Means of limiting or eliminating exposure to fragrance allergens include the following:
- Prohibition by regulatory measures or other means.
- Restriction by regulatory measures or other means of the maximum permissible concentration of a substance, or a critical component of natural mixtures, possibly according to different uses and product types, respectively.
- Substitution with suitable, but less or non-allergenic compounds. Substitution by a component which is chemically different, but effectively not different in terms of allergenicity or cross-reactivity, is not adequate (e.g. an ester) (chapter 5).
- Formulating the fragrance with the aim of limiting or eliminating those substances for which a sensitising potential has been shown. One difficulty with this approach is that sometimes no sensitisation data exist for those components of a fragrance formula which are used to replace a “known sensitiser”.
- Deliberate avoidance of the use of fragrances where they are not essential to the function of a finished product, but used merely to add to its appeal. Examples could include most cosmetics, topical medicaments, detergents etc., but obviously not perfumes, eau de toilette and other products used for their scent.
- Information, e.g. labelling so that the consumer may make an informed choice to avoid exposure to a particular ingredient.
4.6.2. Secondary prevention: avoiding re-exposure to (a) specific sensitiser(s) in clinically diagnosed individuals
In clinical dermatology, avoidance of re-exposure to an allergen is central to the care of sensitised patients. Contact sensitisation, as a latent condition, persists life-long, and therefore allergen avoidance is the only means of avoiding potentially severe and/or handicapping disease, which affects quality of life and may affect fitness for work, i.e. allergic contact dermatitis.
In this context, the valid diagnosis of sensitisation, by patch testing (32) with standardised materials, is a prerequisite of successful allergen avoidance. In the case of fragrances, a history clearly indicative of “fragrance dermatitis” but in which patch testing with commercially available test preparations is negative, most probably reflects a shortcoming of the patch test procedure, namely, a false-negative investigation. An important cause is inadequate information on the presence of fragrance substances present in cosmetic products (and consumer products in general). This means that patients cannot be tested for relevant substances.
A false-negative investigation can also be due to a number of other reasons: (i) non- adherence to scientific recommendations (32) or guidelines (e.g. (116)); (ii) sub-optimal patch test concentration; or (iii) use of non-oxidised material if oxidised material is the true allergen.
In an “ideal” case, from the point of view of successful patient management, the test procedure identifies all the allergen(s) to which the patient has developed contact allergy, according to the information on the culprit product(s) brought in by the patient. Such contact sensitisation is termed “clinically relevant” (65), and the need for allergen avoidance in the future is unequivocally evident in these cases. However, not infrequently, clinical relevance of an allergic patch test reaction cannot be ascertained for various reasons, which may be beyond control by the clinician (see chapter 4.4).
Nevertheless, future elicitation of allergic contact dermatitis by sufficient contact with the identified “non-relevant” allergen may be expected. Hence, the patient will need to avoid the respective substance(s).
In a less “ideal” case, only part of the fragrance allergens having caused allergic contact dermatitis are identified (and can subsequently be avoided), while another part remains unidentified, for instance because it is: (i) not labelled on the product; and/or (ii) not available for routine diagnostic patch testing (special investigations such as chemical analysis of the culprit product, and break-down patch testing of its individual components, are performed rarely). Such “residual” undetermined sensitisation will hamper the success of secondary prevention of allergic contact dermatitis due to fragrances.
The above consideration raises the question for the patient of how to identify fragrance chemicals in cosmetics and other products coming into contact with the skin, such as detergents and household products, topical medicaments, products used professionally (e.g. by hairdressers, beauticians, masseurs, aromatherapists), and in other industrially used categories of products (7) (see also chapter 9). In this regard, the labelling with “perfume” or “contains fragrances” does not provide sufficient information. Moreover, such general labelling has two main disadvantages:
- It does not aid the identification of past exposure to specific agents when planning a patch test and later, when interpreting possible positive patch test results regarding clinical relevance.
- The diagnosis of allergic contact sensitisation to unidentified fragrance allergens will lead to unnecessary avoidance of other fragrance substances to which the patient is not sensitised, which are, however, included under the label “perfume”.
Furthermore, the attribute “fragrance-free” may be misleading, as it merely states that no substance was added to the product to give it a scent, assuming it is used correctly at all. Nevertheless, fragrance substances used for other purposes, e.g. as preservatives, may expose the “fragrance allergic” patient to the allergen even in a “fragrance free” product (117). However, in terms of cosmetic ingredient labelling, such other uses are less problematic, as each ingredient not used as a fragrance component must be labelled. Also the use of natural products (essential oils) as preservatives must be considered in this context.
Ingredient labelling of 26 individual fragrance ingredients, identified as allergens in humans, was introduced for cosmetics in 2005. The intention was to provide a tool for clinicians for optimizing the investigation of patients with suspected fragrance allergy, as well as for fragrance allergic patients for avoiding products containing substances they have been shown to be allergic to. Both these aims are objectives of secondary prevention and seem to have been well accepted. In a study of fragrance allergic patients and their utilisation of ingredient labelling (112), most responded that they used the ingredient labelling (86.3%) and of those who used it, the majority (65.3%) found it helpful (112). Most allergic patients used the ingredient labelling (83.2%) to find out if the product was scented, while 35.6% also looked for specific ingredients. Many (84.9%) found that a clearer labelling, e.g. easier names and a larger font size, would increase their benefit.
Contact allergy to fragrances is relatively common, affecting 1 to 3% of the general population, based on limited testing with eight common fragrance allergens and about 16 % of patients patch tested for suspected allergic contact dermatitis. Fragrance contact allergy is mostly non-occupational and related to the personal use of cosmetic products. Allergic contact dermatitis can be severe and widespread, with a significant impairment of quality of life and potential consequences for fitness for work. Thus, prevention of contact sensitisation to fragrances, both in terms of primary prevention (avoiding sensitisation) and secondary prevention (avoiding relapses of allergic contact dermatitis in those already sensitised), is an important objective of public health risk management measures.
Source & ©: SCCS,
26-27 June 2012, 4.3, 4.4, 4.5, 4.6. p. 15-32