J P Lepoittevin

Further important sensitizers in patients sensitive to fragrances - II. Reactivity to essential oils

The aim of this study was to determine the frequency of responses to selected fragrance materials in consecutive patients patch tested in 6 dermatological centres in Europe. 1855 patients were evaluated with the 8% fragrance mix (FM) and 14 other frequently used well‐defined fragrance chemicals (series I). Each patient was classified regarding a history of adverse reactions to fragrances: certain, probable, questionable, none. Reactions to FM occurred in 11.3% of the subjects. The 6 substances with the highest reactivity following FM were Lyral® (2.7%), citral (1.1%), farnesol P (0.5%), citronellol (0.4%), hexyl cinnamic aldehyde (0.3%), and coumarin (0.3%). 41 (2.2%) of the patients reacted only to materials of series I and not to FM. 6.6% of 1855 patients gave a history of adverse reactions to fragrances which was classified as certain. This group reacted to FM only in 41.1%, to series I and FM in 12.0% and to series I only in 7.2%. 74.3% of the 39 patients reacting to both FM and 1 of the materials of series I had any type of positive fragrance history, which was significantly higher in comparison to those with isolated reactions to series I (53.6% of 41), p = 0.04. The study identified further sensitizers relevant for patch testing of patients with contact dermatitis, of which Lyral® is the most important single chemical.

Deodorants on the European market: quantitative chemical analysis of 21 fragrances

Deodorants are one of the most frequently used types of cosmetics and side‐effects from them are common. Recent studies relate perfume allergy to this type of product. 73 deodorants were analyzed by gas chromatography ‐ mass spectrometry for the determination of the contents of 7 well‐known fragrance allergens from the fragrance mix and 14 other commonly used fragrance materials. The deodorants were purchased at retail outlets in 5 European countries. It was found that in general, fragrance mix ingredients were more frequently present in vapo‐ and aerosol sprays than in roll‐on products. The levels of the fragrance mix substances ranged from 0.0001–0.2355%. The products investigated contained cinnamic aldehyde and isoeugenol less frequently (17% and 29% respectively), and eugenol and geraniol most frequently (57% and 76% respectively). The 14 other fragrance materials were found in 40–97% of the deodorants, with hedione and benzyl acetate the most frequently found substances. The concentration of these 14 substances ranged from 0.0001–2.7%. It is concluded that the levels of cinnamic aldehyde and isoeugenol found in the deodorants could prove to be relevant for elicitation of contact dermatitis. No conclusions could be drawn about the other fragrance mix constituents, as threshold levels in sensitized individuals have not been investigated. Furthermore, all of the fragrance materials investigated were frequently found in deodorants and, apart from the fragrance mix ingredients, the extent of problems with sensitization to these fragrance materials is largely unknown.

Further important sensitizers in patients sensitive to fragrances

In order to find sensitizers additional to the current fragrance mix (FM) a series of fragrance materials (series II) was evaluated in 6 dermatological centres in Europe. 11 of the test materials were essential oils, the remaining 7 being either mixtures of isomers or simple chemicals of frequent usage in the perfume industry. 1606 patients were consecutively tested with series II and 8% FM. Each patient was classified regarding a history of adverse reactions to scented products: certain, probable, questionable, none. Reactions to FM occurred most frequently in 11.4% of the subjects. The 6 materials with the highest reactivity after the FM were ylang‐ylang oil (YY) I (2.6%), YY II (2.5%), lemongrass oil (1.6%), narcissus absolute (1.3%), jasmine absolute (1.2%) and sandalwood oil (0.9%). 48 (3.0%) of the patients reacted only to materials of series II and not to FM. 6.0% of 1606 patients gave a history of adverse reactions to fragrances which was classified as certain. This group reacted to FM only in 22.9%, to series II and FM in 15.6% and to series II only in 5.2%. 63.5% of the patients reacting to both FM and 1 of the materials of series II had some type of positive fragrance history, which was higher in comparison to those with isolated reactions to FM (46.2% of 121) or to series II, respectively, (45.8% of 48). However, this difference was not statistically significant. In conclusion, the materials of series II identified a further subset of patients with a fragrance problem, which would have been missed by the current FM as the single screening tool for patch testing.

Lyral® is an important sensitizer in patients sensitive to fragrances

Contact allergy to fragrances is a common problem world‐wide. The currently used fragrance mix (FM) for patch testing has only eight constituents and does not identify all fragrance‐allergic patients. As perfumes may contain 100 or more substances, the search for markers for allergy continues. The synthetic fragrance 4‐(4‐hydroxy‐4‐methylpentyl)‐3‐cyclohexene carboxaldehyde (Lyral®) was tested together with the FM and 11 other fragrance substances on consecutive patients in six European departments of dermatology. All patients were carefully questioned regarding a history of reactions to scented products in the past and were grouped into four categories: ‘certain’, ‘probable’, ‘questionable’ and ‘none’. Lyral® (5% in petrolatum) gave a positive reaction in 2·7% of 1855 patients (range 1·2–17%) and ranked next to 11·3% with FM allergy. Twenty‐four patients reacted to both Lyral® and FM, but 21 (1·1%) reacted positively only to Lyral®. Of 124 patients with a ‘certain’ history, 53·2% reacted to the FM and a further 7·2% to Lyral® only. If any kind of history of fragrance intolerance was given, 80% (40 of 50) of Lyral® positive patients had a ‘positive’ history while only 58·6% (123 of 210) of FM positive patients had such a history; this difference was significant at P < 0·01. Lyral® was identified by gas chromatography–mass spectrometry in some products which had caused an allergic contact dermatitis in four typical patients who showed a patch test positive to Lyral® and negative or doubtful to FM. In conclusion, we recommend the testing of 5% Lyral® (in petrolatum) in patients suspected of contact dermatitis.

The repeated open application test: suggestions for a scale of evaluation

J. D. J1, M. B2, K. E. A3, P. J. F4, B. D4, I. R. W5, S. R6, J. P. L7  T. M́1 1Department of Dermatology, Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark; 2Department of Occupational and Environmental Dermatology, University Hospital, Malmö, Sweden; 3Department of Dermatology, Odense University Hospital, Denmark; 4Hautklink, Städtische Kliniken, Dortmund and University of Witten/Herdecke, Germany; 5St. John’s Institute of Dermatology, London, England; 6Department of Environmental Chemistry, National Environmental Research Institute, Roskilde, Denmark; 7Laboratorie de Dermatochimie, Université Louis Pasteur, Strasbourg

Contents of fragrance allergens in children's cosmetics and cosmetic-toys

Fragrances are one of the major causes of allergic contact dermatitis from use of cosmetics. The aim of the current study was to assess the possible exposure of infants and children to fragrance allergens from cosmetic products and “toy‐cosmetics”. 25 childrens cosmetics or toy‐cosmetic products were analysed by gas chromatography ‐ mass spectrometry. Target substances were the fragrance allergens from the fragrance mix and 14 other fragrance substances, most of which have been described as contact allergens. The fragrance mix ingredients were either not present in childrens shampoos/shower gels and cream/lotions, or they were present in fairly low concentrations. In hydro‐alcoholic products, such as eau de parfum, eau de toilette, several ingredients of the fragrance mix were found: geraniol was present in 7/7 products, hydroxycitronellal in 6/7 and isoeugenol in 2/7 products. Isoeugenol was present in a maximum concentration of 0.07%. In one cosmetic‐toy, cinnamic alcohol was present at 3.7% which exceeds the current industry guideline for safe products by a factor of 5. In all types of products other fragrance allergens were frequently found. In conclusion, children are already exposed at an early age to well‐known allergens, sometimes at concentrations which are considered to be unsafe. As contact allergy usually persists for life, manufacturers of childrens cosmetics should be aware of their special responsibility and apply the highest possible safety standards.

Structure-activity relationships for selected fragrance allergens.

Fragrance substances represent a very diverse group of chemicals, a proportion of them providing not only desirable aroma characteristics, but also being associated with adverse effects, notably the ability to cause allergic reactions in the skin. However, efforts to find substitute materials are hampered by the need to undertake animal testing to evaluate both the presence and the degree of skin sensitization hazard. One potential route to avoid such testing is to understand the relationships between chemical structure and skin sensitization. In the present work we have evaluated two groups of fragrance chemicals, saturated aldehydes (aryl substituted and aliphatic aldehydes) and α,β‐unsaturated aldehydes. Data on their skin sensitization potency defined using the local lymph node assay has been evaluated in relation to their physicochemical properties. The initial outcome has been consistent with the concept that α,β‐unsaturated aldehydes react largely via Michael addition, whilst the group of saturated aldehydes form Schiff bases with proteins. Simple models of chemical reactivity based on these mechanisms suggest that it may be possible to predict allergenic potency. Accordingly, the evaluation of an additional group of similar aldehydes is now underway to assess the robustness of these models, with some emphasis being based on ensuring a wider spread of chemical reactivity.

Fragrances and other materials in deodorants : search for potentially sensitizing molecules using combined GC-MS and structure activity relationship (SAR) analysis

Deodorants are one of the most frequently‐used types of cosmetics and are a source of allergic contact dermatitis. Therefore, a gas chromatography ‐ mass spectrometric analysis of 71 deodorants was performed for identification of fragrance and non‐fragrance materials present in marketed deodorants. Futhermore, the sensitizing potential of these molecules was evaluated using structure activity relationships (SARs) analysis. This was based on the presence of 1 or more chemically reactive site(s), in the chemical structure, associated with sensitizing potential. Among the many different substances used to formulate cosmetic products (over 3500), 226 chemicals were identified in a sample of 71 deodorants. 84 molecules were found to contain at least 1 structural alert, and 70 to belong to, or be susceptible to being metabolized into, the chemical group of aldehydes, ketones and α,β‐unsaturated aldehydes, ketone or esters. The combination of GC‐MS and SARs analysis could be helpful in the selection of substances for supplementary investigations regarding sensitizing properties. Thus, it may be a valuable tool in the management of contact allergy to deodorants and for producing new deodorants with decreased propensity to cause contact allergy.

Deodorants: an experimental provocation study with hydroxycitronellal

Axillary dermatitis is a common problem, particularly in individuals with contact allergy to fragrances. Many individuals suspect their deodorant to be the causal product of their fragrance allergy. It has been shown that deodorants containing cinnamic aldehyde (cinnamal) can elicit axillary dermatitis in patients sensitized to this substance. The aim of the present investigation was to evaluate the importance of hydroxycitronellal used in deodorants for the development of axillary dermatitis, when applied by individuals with and without contact allergy to this fragrance chemical. Patch tests with deodorants and ethanolic solutions containing hydroxycitronellal, as well as repeated open application tests (ROAT) with roll‐on deodorants with and without hydroxycitronellal at different concentrations, were performed in 14 dermatitis patients, 7 with and 7 without contact allergy to hydroxycitronellal. A positive ROAT was noted only in the patients hypersensitive to hydroxycitronellal (P < 0·001) and only in the axilla to which the deodorants containing hydroxycitronellal had been applied (P < 0·001). Deodorants containing hydroxycitronellal in the concentration range of 0·032–0·32% used twice daily on healthy skin in individuals hypersensitive to hydroxycitronellal can elicit axillary dermatitis in a few weeks.

Deodorants: a clinical provocation study in fragrance-sensitive individuals

Deodorants are one of the most marketed types of cosmetics and are frequently reported as a cause of dermatitis, particularly among fragrance‐sensitive persons. The aim of this study was to investigate the ability of deodorants, which had previously caused axillary dermatitis in fragrance‐mix‐sensitive eczema patients, to provoke reactions on repeated open application tests on the upper arm and in the axillae, and to relate the findings to the content of fragrance‐mix constituents in those deodorants. 14 eczema patients performed a 7‐day use test with 1 or 2 deodorants that had caused a rash within the last 12 months. 2 applications per day were made in the axilla and simultaneously on a 25 cm2 area on the upper arm. A total of 20 deodorants were tested among the 14 patients. Afterwards, the deodorants were subjected to quantitative chemical analysis identifying constituents of the fragrance mix. 12/20 (60%) deodorants elicited eczema on use testing in the axilla. 8/12 deodorants were positive in the axilla on day (D) 7 and 4 both in the axilla and on the upper arm. 2 of the 4 developed a reaction in the axilla before it developed on the upper arm. Chemical analysis revealed that 18/19 deodorants contained between 1 and 6 of the fragrance‐mix constituents, on average 3 being found. The mean concentration of fragrance‐mix constituents was generally higher in the deodorants causing a positive use test, as compared with those giving a negative reaction, indicating that the differences between the deodorants in terms of elicitation potential were more related to quantitative aspects of allergen content than of a qualitative nature. It is recommended that deodorants are tested in the axilla in the case of a negative use test on the upper arm and a strong clinical suspicion.