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Fragrances

1997, Clinics in Dermatology

AI-generated Abstract

This paper explores the significant role of fragrances in allergic contact dermatitis (ACD), highlighting that a substantial portion of ACD cases are linked to cosmetic use, particularly involving fragrance ingredients. Historical context is provided, tracing the characterization and recognition of fragrance-related dermatitis since World War II. Evidence indicates a noteworthy prevalence of fragrance allergy among the general population, warranting further attention and exploration into the complex composition of fragrance materials and their potential allergenic properties.

C

osmetics account for a significant proportion of those patients patch tested for suspect allergic contact dermatitis (ACD) accounting for 6% of those tested by the North American Contact Dermatitis Group (NACDG) between 1977 and 198O.l Thirty percent of the identified cases with ACD due to cosmetics in a later study reported by the NACDG were due to fragrance ingredients.2 A Belgian study evaluated 5,202 patients in the 1980s and found that 11.7% had experienced reactions to their cosmetics.3 Of the Belgian patients who proved to have ACD, cosmetics were implicated as one of the causal agents in 16.4% of the cases, while irritation was caused by cosmetics in only 1.5%. Contact dermatitis due to fragrance ingredients was the principal cause of ACD in these patients, accounting for more than one third of the reactions. A group of investigators has estimated that about 18% of the general female population may have fragrance allergy.4 Despite this information contact allergy due to fragrance is a relatively recent concern.

Past

Contact dermatitis due to perfume and fragrance materials has been recognized and characterized largely since World War II. At the beginning of the 20th century, it was known that patients treated for scabies with topical balsams occasionally experienced dermatitis venenata, which we now recognize was ACD due to fragrance materials in these medicaments. The use of perfume as a medicament dates back to ancient times, when Egyptians used lotus oil topically. Avencinna, the great Persian physician, used perfume materials to treat epidemics of disease a millennium ago. Bonnevie began testing patients with suspect allergic contact dermatitis, what was then referred to as dermatitis venenata, in the late 1930s.5 He used balsam of Peru (Peruvian balsam) as one of his "standard" test substances, because this vegetable product was used medicinally at that time. This Danish dermatologist ably evaluated patients with morphologically positive responses to Peru balsam and found that, for many, he was unable to establish that they had relevant previous or present topical exposure to a medicament containing the balsam. Bonnevie reported in 1948 that cinnamic aldehyde, a component of Peru balsam, was a potent contact allergen.6 When contact dermatitis became a matter of greater interest in the 195Os, the role of contactants (eg, chromium, nickel) was more clearly established.7 In 1961, Nels Hjorth published his extensive, seminal investigations into the response elicited by Peruvian balsam. His detailed, elegant work established that the balsam was made up of many components that were potential allergens.8 Hjorth was the principal innovator who, through his incisive study, established fragrance allergy as a matter for detailed study and evaluation. Hjorth related some exposure to such sensitizers to the ingestion of flavors in foodstuffs. Cinnamic aldehyde, known to cause occupational allergic contact dermatitis (ACD) in bakers and candy makers, was established to be a cause of ACD due to toothpaste by a group of investigators. Other investigators reviewed the chemistry of "aroma chemicals" in 1975 and pointed out the complexity of such materials and the sources of information available to assist the dermatologist wishing to pursue the composition of a given commercial product.11 What was clear was that a given fragrance may have hundreds of components and that the nomenclature was complicated by virtue of the natural plant sources of the scents. Single chemicals often have many different names; and essential oils, like cinnamon oil, may vary dramatically in composition depending on the source of the oil. An example is Chinese cinnamon bark oil, which is 70%-90% cinnamic aldehyde, while Ceylon cinnamon leaf oil has less than 7% cinnamic aldehyde content. There are 15 essential oils derived from cinnamomum species alone.12

The composition of the essential oil jasmin that is derived from the jasmin flower (jasminum oficinal) comprises d-and dl-linalool, benzyl alcohol, geraniol, nerol, 1-cx-terpinol, benzyl acetate, linalyl acetate, benzyl benzoate, methylanthracate, jasmin, jasmin lactone, methyl-jasmin, benzoic acid, as well as other ingredients'3 In 1974, a study of 183 Japanese patients found that Peruvian balsam accounted for only a single case, while patch tests with 8 essential oils resulted in a significant number of responses (Table l).la There were cross-reactions between the test substances, suggesting that 0738-081X/97/$32.00 PI1 SO738-081X(97)00053-9

Table

NETHERCOTT AND LARSEN

Uitrics irz Demafology * /997;J5:&3--5iG4 of the essential oils contained certain of the pure chemicals (Table 2)."& In contrast to Europe, in Japan, Peruvian balsam and its components were apparently not common sensitizers, while essential oils and their ingredients, especially jasmin, cananga, ylang ylang, and sandalwood oils, were common causes of positive patch-test responses? Canaga and ylang ylang oils are both derived from the canartgu odor&z plant by different extraction methods.

Table 2

Concordant Responses iu japanese Patie&+

In 1974, a study on the use of cikamic aldehyde as a screening test substance for perfume allergy in 89 patients reported positive responses in 5 patients.15 Citing earlier work ,16-18 the investigator pointed out that jasmin was a very common fragrance ingredient that might be synthetic or absolute. The incorporation of jasmin into fragrances was so common that the investigator noted that the earlier report contained the comment "No perfume without jasmin". a-Amyl-cinnamic aldehyde is often used as an additive to pure jasmin absolute to enhance its potency, because the latter is very expensive. The prevalence of positive responses to jasmin oil in the Japanese study was consistent with the earlier findings.lX

In 1975, a case was reported in which 94 perfume ingredients that had been supplied by a fragrance manufacturer as the components in a perfume in a cosmetic were tested.19 The investigator established that hydroxycitronellal was the responsible allergen. In the same year, another investigator published a long list of fragrance ingredients and suggested concentrations for epicutaneous tests;20 he indieated that establishing the precise contactant in a fragrance accounting for ACD in a given patient might be a "formidable task".""

In 1977, one of the present authors reported a study of 20 patients with suspect perfume allergy, and from the results he developed the fragrance mixture (FM) a~ a screening patch-test substance for fragrance allergy." The mixture consisted of 8 fragrance ingredients at 2% concentration in petrolatum. Five of the FM components are found in Peruvian balsam (ie, cinnamic alcohol, cinnamic aldehyde, alpha-amyl cinnamic alcohol, eugenol, and isoeugenol), geraniol (an essential oil ingredient found in both jasmin and geranium oil), oak moss absolute, and hydroxycitronella. Hydroxy-citronella1 had been established by a group of investigators to be a cause of fragrance allergy in 9.4% of Japanese patients that were tested, geraniol 13.7X, VUgenol 4.4%, a n d cinnamic alcohol 2.7% (Table 1). j i Peruvian balsam was known to contain cinnamon deriv-atives. This mix was expected to produce positive responses in many fragrance-sensitive patients, affd it did. The study did not address those patients sensiti\ic to essential oils other than jasmin and geranium, and it would not be expected to have elicited a response in all of those sensitive to the latter two oils either. Cinnamic aldehyde is found in patchouli oil and Bulgarian rose oil and would be expected to pick LOP some of those with ACD due to these essential oils.'" All of the pure chemicals in the FM are phenolic in structure, except geraniol and hydroxycitronellal, which are terpenes. While by 1975 the Japanese study had been using essential oils as components in a panel of 18 test substances in the Japanese fragrance screening series,' i 111 that time, the latter materials were not used in Europe or North America for screening patients for suspect allergic contact dermatitis due to perfume. Essential oits are still not generally used as screening tests substances in routine patch testing, although they are used in aimed testing in patients with suspect ACD due to perfume.

Table 1

In 1977, an investigator reported 18 cases of ACD due to lichen extract in fragrance materials.'" In 1982 there was a further report concerning 7 such cases.2' The latter seven cases, drawn from a population c)f 2,000 test subjects, exhibited a positive response to oak moss absolute. A number of these seven also reacted to aromatic chemicals found in the lichen materials [cg, atranorin (4), usnic acid (51, evernic acid (4), physodic acid/physodalic acid (3), and diffractaic acid (l)]. In 1980, a group of investigators reported their data from the evaluation of 2461 patients tested with FM and the individual ingredients in the mix (Table 3).24 Most of the responses to FM were considered to be relevant to the patient's complaints, and so the author's recommended that FM be incorporated as a standard test material in routine patch-test screening series. The same authors reported five cases of perioral and lip ACD due to phenyl salicylate and one due to geraniol in 1981.25 Between 1983 and 1985, a group of investigators patch tested 2,700 patients with suspect ACD with fragrance ingredients. 26 In 1,200 patients they tested with FM with the individual ingredients at 2% (ie, 16% fragrance mix) and in 1,500 with FM. The proportion of positive responses with FM was less (5.3% vs 3.6%, x2 = 4.39, p = 0.04). In 1,200 patients they also tested with 15 other perfume ingredients not in FM. Of these latter materials, only jasmin synthetic and jasmin absolute produced a comparable number of responses to the ingredients in the FM (ie, 1.1% and l%, respectively). The latter prevalence approximates that of 6 of the 8 components in FM in the 1,200 patients they tested, namely: oak moss absolute (1.4%), isoeugenol (1.2%), hydroxycitronellal (l.l%), cinnamic alcohol (0.8%), cinnamic aldehyde (0.8%), and eugenol (0.7%). Table 4. Eugenol, cinnamic alcohol, hydroxycitronellal, coumarin, and abitol accounted for many positive responses. Predictive assays using the guinea pig and humans were clearly not able to predict the practical risk of inducing allergy in use situations as documented in human maximization tests result). The following year the Dutch group reported a study of 179 patients tested with the FM components and other fragrance materials (Table 5).2x Isoeugenol, oak moss and geraniol accounted for most of the positive responses elicited to FM in this group of patients. In 1987, a group of investigators reported a patch test study of 606 Belgian patients with suspect intolerance to cosmetics." Fragrance ingredients were the most common causes of ACD in these patients. Of those with ACD, the proportions due to various test materials was as follows:

Table 3

Table 4

Fragrance Materials (RIFM) and on annual use data from the United States reported by RIFM. In this selected sample for aimed testing, 21.3% of the patients reacted to Peruvian balsam and 28% to FM. The results of the tests with pure chemicals is summarized in

Table 5

Response to Fragrance Materials in the Netherlands* Responses to Fragrance Ingredients in London, England*

Peruvian balsam (33.3%), FM (31.4%), isoeugenol (10.3%), eugenol (7.1%), cinnamic aldehyde (5.1%), cinnamic alcohol (3.8%)' jasmin (2.6%), cw-amyl cinnamic aldehyde (1.3%), and geraniol (1.3%). Jasmin proved to be an important allergen. Notably, jasmin is not one of the components in FM.

In 1987, a group of investigators reported a patient with depigmentation from exposure to an incense containing musk ambrette and santanol, the principal ingredient of sandalwood oil, and they established that the patient exhibited a positive epicutaneous response to both materials.'"

Other investigators then reported that furocoumarin in fragrance materials caused photoallergic reactions."" Subsequently, a research group established that another aromatic, though not phenolic, artificial perfume ingredient, musk ambrette, caused photoallergic reactions as well.R1 Musk ambrette is referred to in the cosmetic industry as a nitro musk, because it has a nitro addition to the aromatic ring of its chemical structure. It was widely used in 1974, with 100,000 pounds of musk ambrette being manufactured for use in cosmetics and food.32 An investigator reported a standard protocol for photopatch testing patients with musk ambrette, and she reported a low prevalence of such responses (ie, ~1%) in the 495 patients she tested."" While musk ambrette is a contact allergen, photoallergen, and phototoxin, the other nitro musk compounds that have been derived and studied for use in cosmetics (eg, musk ketone, musk moskene, musk tibetene, and musk xylol) do not pose a significant risk of inducing such responses.34 Musk ambrette has been removed from commerce voluntarily by the cosmetic industry in recognition of its potential to induce such responses, even though few instances of health effects were identified relative to the volume of the material that had been placed in commerce.

Benzyl salicylate, used in perfume products as a preservative, is also a sensitizer. This was first reported in 1968,"" and later by other investigators.13 Recently, the allergenicity of benzyl salicylate in perfume-sensitive patients, especially in Japanese patients, has been :onfirmed."h A study reported in 1985 examined the ability of common fragrance ingredients to cause nonimmuno-Logical contact urticaria, and the investigators estabished that many common fragrance ingredients would elicit such responses .37 They emphasized the need for :hose evaluating such patients to be aware that such Ionspecific, nonallergic reactions might be misleading.

In a report published in 1994, there is an account of a aatient allergic to underarm deodorant where the respon-sible fragrance ingredients, lyral [3and 4(4hydrmy4methylpenty)-3-cyclohexane1-aldehyde]

and acetyl cedrane, were not recognized fragrance materials known to cause ACD.38

Present

The concentration of the ingredients in FM has been reduced to half of the original concentrations because of concern regarding false positive responses; on the other hand, investigators have questioned whether false negative responses may be occurring with the revised EM concentration with certain of the ingredients.3" Recently, a report was published on 14 years of use of EM, and the investigators noted a 5.5% positive response rate.40 Another report cited an 8.3% prevalence in 1,072 patients tested recently in Europe with FM."' Sorbitan sesquioleate added to the FM to keep the ingredients in solution may augment its potency for certain components and cause false positive responses.42

The European Environmental and Contact Dermatitis Research Group carried out a multicenter study of 48 fragrance materials, which they reported in 1995.4" Their findings with FM and the individual ingredients in FM were similar to previous studies in 1,072 patients tested. Few responses were elicited to additional fragrance materials evaluated; but due to the study design, the number of subjects evaluated with each was limited to 100 patients or slightly more. Thus, the statistical power of the investigation was such that definite conclusions with respect to the allergenicity of the materials is not possible. A few of the new fragrance components did produce notable responses; these were lyral and citronellol, which were associated with a 2.8% and 1% response prevalence in Barcelona, where they were used to test 106 subjects. Lilial [2-methyl-3(4-trrt-butyiphenyl)-propionaldehyde], which has been reported to cause ACD in a single case of a user of underarm deodorant,43 resulted in no positive responses in 106 patients tested.

When a group of investigators evaluated the use ot FM and Peruvian balsam as screening test substances to detect fragrance allergy in perfume-sensitive patients, they found that one or another of the two test materials yielded a positive response in almost all of this selected sample of patients. 3h Asians were more likely to react to benzyl salicylate, while western patients exhibited more reactions to isoeugenol and oak moss absolute. The authors found that three other essential oils (sandalwood, nard.ssus, and ylang ylang) and benzyl salicylate accounted for many of the positive responses missed by FM and Peruvian balsam. The addition of these materials, [three of the four of which have been part of the Japanese fragrance screening tray (Table 2)] as additional screening-test substances in addition to FM and Peruvian balsam would be expected to improve the sensitivity of screening materials used to detect fragrance allergy. As jasmin is widely used and accounts for a significant number of positive responses when tested,aJ3 its use as an additional screening test material has been recently investigated by the World Fragrance Research Team (WFRT) as a follow up to their recent study. 44 In 754 patients tested with jasmin combined with 7 of the 8 ingredients present in FM and with other fragrance components (jasmin/FM mix), these investigators identified 19 perfume-allergic patients who would not have been identified by testing with FM alone. While testing with jasmin/FM mix and FM simultaneously increased the total number of patients identified, testing with the jasmin/FM mix would have identified only 63 perfume-sensitive patients, whereas testing with FM would have identified 67. There was concordance of response for both test substances in only 44 instances; thus, adding further ingredients to the FM apparently eliminated some of the positive responses that were evident with FM alone. The latter results serve to emphasize the problems in developing new test substances for patch testing for fragrance allergy. In the same investigations, the WFRT established that testing with Peruvian balsam, FM, and either jasmin/FM mix or a mixture of 6 natural fragrance ingredients, the yield of positive patients increased to 95, though choosing one or another of the additional mixes failed to identify 5 of the total of 100 fragrance allergic patients identified by testing with all 4 fragrance test materials. Certainly, the addition of jasmin synthetic or a mixture of natural fragrance materials such as was used in the WFRT study to the present screening panel of Peruvian balsam 25% and FM 8% would appear to be indicated in order to avoid missing a significant number of patients allergic to fragrance materials.

Future

As we approach the end of the 20th century, it can be stated that significant progress has been made in identifying fragrance materials as causal agents in the induction of ACD in those in contact with cosmetics, food, and other environmental materials that contain fragrances. Hjorth's work identified the need to understand the chemistry of scented materials. Other workers emphasized the botanical sources, the complexity of the task and provided the first mixture of such materials that allowed the identification of many perfume sensitive patients. The challenge facing us is to better characterize the chemicals used to produce scents in the manner that has been suggested and to document their potential hazard of inducing ACD in usage situations. The 8 fragrance materials in FM produce a test substance that is an effective screening test for the detection of ACD due to fragrances; however, false negative patch-test responses continue to occur because the 8 components are each present at only 1% concentration in petrolatum in the mix. The further challenge then is to increase the validity of the mixture as a screening test (ie, reduce the number of false negative responses and not increase the number of false positives). By identifying additional allergens supplemental to the 8 in the present FM, this should be possible. New fragrance allergens could be incorporated in a second FM or added to a second generation FM.

If a patient is clinically fragrance allergic but patchtest negative to the FM, it is essential to carry out epicutaneous tests with the individual components in the perfume to which they are known to react. This allows the investigator to determine the precise offending allergen(s). Only by pursuing such detailed testing is it possible to identify new fragrance contact allergens. When asked for assistance, perfume manufacturers are usually very cooperative in supplying fractions of their perfume products to allow such tests to be performed.

A further approach to discovering new fragrance allergens is to screen suspect fragrance-allergic patients with a relatively wide array of uncommon and new fragrance materials in order to ferret out instances of allergic response to further fragrance materials.36f41

Predictive tests in humans and animals are helpful, but not infallible (Table 4). Information about the chemistry of fragrance materials is sparse and not easily available to the medical community. New materials continue to enter commerce in cosmetics, toiletries, and other applications without dermatologists becoming aware of their existence. Better communication between the fragrance industry, the Cosmetic Toiletry and Fragrance Association, the International Fragrance Research Association, and international groups involved in the prospective evaluation of patients with suspect ACD would allow better surveillance of the potential risk associated with these chemicals. Such cooperation would benefit both industry and the medical community, while reducing the risk of fragrance-induced ACD to consumers. Our present ability to engage in secondary prevention is limited because of the complexity of the chemistry of fragrance materials."* Patients at present can be given only very general advice about product labelling (ie, perfume free, fragrance free, unscented, sensitive skin formula) and advised on the use of use tests as a way to avoid problems.45 Hopefully, primary prevention should be possible with the identification of allergenic materials and their elimination and the substitution of alternative materials as was undertaken for musk ambrette. Such intervention may allow the avoidance of the induction of allergy and the simplification of the problems for consumers through prevention. This outcome can only come through better cooperation between industry and dermatologists, which is clearly now feasible.

Table 4