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Fragrance contact dermatitis - a worldwide multicenter investigation (Part III).

The purpose of this study was to determine the frequency of responses to selected fragrance materials in patients who were fragrance sensitive. 218 fragrance sensitive subjects were evaluated in eight centres worldwide with a fragrance mixture (FM) and 17 less well-studied fragrance materials. Reaction to the fragrance mixture (FM) occurred in 76% of the subjects. The (FM) detected all reactions to nerol and hydroxycitronellol and 93% of the reactions to clove bud oil. Ten fragrance materials were not detected by the FM and deserve further study: benzenepropanol, beta, beta, 3-trimethyl, hexyl-salicylate, dl-citronellol, synthetic ylang ylang oil, benzyl mixture, cyclohexyl-acetate, eugenyl methyl ether, isoeugenyl methyl ether, 3-phenyl-1-propanol, and 3, 7-dimethyl-7-methoxyoctan-2-ol.

Adult↗

Studies on the autoxidation and sensitizing capacity of the fragrance chemical linalool, identifying a linalool hydroperoxide.

Fragrances are among the most common causes of allergic contact dermatitis. The two monoterpenes linalool and d-limonene are the most frequently incorporated fragrance chemicals in scented products. Previous studies on d-limonene show that this monoterpene oxidizes on air exposure (autoxidation) and that allergenic oxidation products are formed. Due to structural similarities, linalool might also form allergenic oxidation products on air exposure. The aim of the present study was to study the autoxidation of linalool and to investigate the sensitizing potential of linalool before and after air exposure. Linalool was oxidized for 10 weeks and gas chromatographic analyses showed that the content of linalool decreased to about 80%. The chromatograms revealed the formation of other compounds during oxidation. One of the major oxidation products was isolated and identified as 7-hydroperoxy-3,7-dimethyl-octa-1,5-diene-3-ol. This substance is, to the best of our knowledge, described for the first time. In sensitization studies in guinea pigs, linalool of high purity gave no reactions, while linalool that had been oxidized for 10 weeks sensitized the animals. It is concluded that autoxidation of linalool is essential for its sensitizing potential.

Acyclic Monoterpenes↗

Lyral has been included in the patch test standard series in Germany.

Lyral 5% pet. was tested in 3245 consecutive patch test patients in 20 departments of dermatology in order (i) to check the diagnostic quality of this patch test preparation, (ii) to examine concomitant reactions to Lyral and fragrance mix (FM), and (iii) to assess the frequency of contact allergy to Lyral in an unselected patch test population of German dermatological clinics. 62 patients reacted to Lyral, i.e. 1.9%. One third of the positive reactions were + + and + + +. The reaction index was 0.27. Thus, the test preparation can be regarded a good diagnostic tool. Lyral and fragrance mix (FM) were tested in parallel in 3185 patients. Of these, 300 (9.4%) reacted to FM, and 59 (1.9%) to Lyral. In 40 patients, positive reactions to both occurred, which is 13.3% of those reacting to FM, and 67.8% of those reacting to Lyral. So the concordance of positive test reactions to Lyral and FM was only slight. Based on these results, the German Contact Dermatitis Research Group (DKG) decided to add Lyral 5% pet. to the standard series.

Aldehydes↗

Multicentre study of fragrance allergy in Hungary. Immediate and late type reactions.

The authors followed the frequency of fragrance contact sensitization in Hungary in a multicentre study in the years 1998 and 1999. A total of 3,604 patients were tested with fragrance mix (FM), and positive reactions were observed in 294 (8.2%). In 160 FM hypersensitive patients, the study was continued with patch testing of the mix constituents (cinnamic alcohol, cinnamic aldehyde, eugenol, amyl cinnamic aldehyde, hydroxycitronellal, geraniol, isoeugenol, oak moss absolute). Of the patients tested, 70.6% produced positive reactions to the constituents. FM contact sensitization was mainly observed in female patients (74.4%). The incidence of contact urticaria in FM hypersensitive patients was 6.1%. Simultaneous patch test trials of other environmental contact allergens, in both early and late evaluations, mainly confirmed hypersensitivity reactions to balsams. Female dominance of hypersensitivity reactions observed during testing the individual components of the mix was striking (82.4%). In positive skin reactions, cinnamic alcohol, isoeugenol and oak moss provoked skin symptoms most frequently. We also tested the 104 patients who produced negative reactions to FM with the constituent individual allergens, with 11.9% positive incidence. The clinical symptoms of the patients were above all manifest in the form of contact eczema, located on the hands, face, eyelids and axillae. With this study, the authors, members of the Hungarian Contact Dermatitis Research Group, call attention to one of the most frequent allergens in the environment.

Adolescent↗

Epidemiology of contact allergy: an estimation of morbidity employing the clinical epidemiology and drug-utilization research (CE-DUR) approach.

Clinical epidemiology (CE) is considered unable to estimate morbidity concerning either contact sensitization (CS) or allergic contact dermatitis (ACD) at the population level. Drug-utilization research (DUR) methods estimate the morbidity of suitable diseases based on prescription data for disease-specific drugs. Our objective was to estimate population figures for incidence and prevalence of ACD and CS based on sales data for patch test material in Germany and on patient data from the Information Network of Departments of Dermatology (IVDK). Approximately 600000 standard series are sold per year in Germany, according to the 2 main manufacturers. This raw sales figure was corrected for certain effects (discarded preparations, proportion of formerly patch-tested patients, proportion of patients with ACD seeking medical advice) to obtain an estimate of the denominator of patients eligible for patch testing annually, and combined with patch test results from the Information Network of Departments of Dermatology (IVDK). In 17.8% (of 9266 IVDK patients) ACD was established. Extrapolated to the general population, an incidence of ACD of between 1.7 and 7 per 1000 per year was estimated, depending on whether conservative or more liberal assumptions concerning the above effects were made. Of 78067 IVDK patients tested between 1992 and 2000, 46.8% had at least 1 positive reaction (+ to + + +), and 22.7% had at least 1 stronger positive reaction (+ + or + + +). The 9-year prevalence of CS was estimated to lie between 4.0% and 16.6% for the first outcome, and between 2.0% and 8.1% for the second. Concerning single allergens, 1.9-4.5 million individuals are probably sensitized to nickel, and 1.4-3.4 million to fragrance mix among the German population of 82 million inhabitants. The morbidity data found in this study are in good accordance with data from population-based epidemiological studies. In comparison to these, the CE-DUR approach seems to be an economically feasible method to estimate continuously the population impact of ACD and CS.

Allergens↗

Investigation of the skin sensitizing activity of linalool.

An increasing range of chemicals appears to be capable of causing skin sensitization as a result of their capacity to undergo air oxidation (autoxidation) with the consequent formation of reactive species such as epoxides and hydroperoxides. In this small investigation, the ability of linalool, a common fragrance ingredient, to cause such effects was quantified using the local lymph node assay before and after careful purification by vacuum distillation. The commercially available grade of linalool (97% purity) was shown to be a weak skin sensitizer. Various impurities, including linalool oxide, dihydrolinalool, epoxylinalool, 3-hexenyl butyrate and 3,7-dimethyl-1,7-octadiene-3,6-diol were identified and were completely removed (except for the dihydrolinalool remaining at 1.4%) and the re-purified linalool retested. Neither linalool or dihydrolinalool are protein-reactive compounds. The sensitization potency of the re-purified linalool sample was considerably reduced, but not entirely eliminated, suggesting either that an allergenic impurity could be very quickly reformed by mechanisms of activation or that certain potent undetectable allergens remained. Both possibilities are consistent with what is understood of the chemistry and composition of commercially available linalool.

Acyclic Monoterpenes↗

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 alpha,beta-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 alpha,beta-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.

Aldehydes↗

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.

Adolescent↗

Allergic contact dermatitis in venous leg ulcer patients.

Our aim was to determine the frequency and nature of contact sensitivity in venous leg ulcer patients in Lanarkshire. We performed patch testing with the European standard series, antimicrobials and medicaments on 200 patients referred to our leg ulcer clinics. Positive patch tests were found in 136 (68%) patients. Multiple allergies occurred in 102 (51%). The most frequent allergen groups were fragrances (30.5%), antimicrobials (19.5%), topical excipients (19.5%), rubber accelerators (13.5%) and topical corticosteroids (8%). We also found a high prevalence of positive patch tests to Intrasite gel (9.5%) and Hioxyl cream (8.5%), medicaments which are commonly used to treat leg ulcers in our area. Contact sensitivity is common in venous leg ulcer patients and has important implications for patient management. The allergens involved vary depending on local nursing practice. We suggest that all venous leg ulcer patients be patch tested with a locally relevant patch test series.

Adult↗

Hydroxyisohexyl 3-cyclohexene carboxaldehyde- known as Lyral: quantitative aspects and risk assessment of an important fragrance allergen.

Hydroxyisohexyl 3-cyclohexene carboxaldehyde, also known as Lyral, is a fragrance ingredient identified as the cause of contact allergic reactions in 2-3% of eczema patients undergoing patch testing. Lyral has been included in the standard patch test series in many clinics due to its importance as an allergen. It has been used without restrictions in cosmetic products, until now. In the present study, the dose-response relationship of Lyral contact allergy was studied with doses relevant for normal exposure in cosmetic products. 18 eczema patients, who previously had given a positive patch test to Lyral 5% petrolatum, were included along with 7 control subjects. All cases were tested with a serial dilution of Lyral in ethanol 6% to 6 p.p.m and subjected to a 2-week, repeated open application test with a low dose of Lyral in ethanol. In the case of no reaction, this was followed by another 2 weeks of testing with a higher dose. The test was performed at the volar aspect of the forearm. In 16 of 18 cases (89%), a positive use test developed, 11 reacting to the low and 5 to the high concentration. None reacted to the vehicle control of ethanol applied to the contralateral arm. All controls were negative to both the test solutions of Lyral and the ethanol control. The difference between the test and the control group was statistically significant (Fisher's test, P < 0.001). It is concluded that Lyral at the current usage levels is inducing sensitization in the community. The same levels were shown to elicit allergic contact dermatitis in almost all sensitized individuals. A significant reduction in usage concentrations is recommended to prevent contact allergic reactions.

Adult↗

Fragrance allergy in patients with hand eczema - a clinical study.

Fragrance allergy and hand eczema are both common among dermatological patients. Fragrance mix (FM) and its constituents have a recognized relevance to exposure to fine fragrances and cosmetic products. Based on extensive chemical analysis and database search, a new selection of fragrances was established, including 14 known fragrance allergens present in products to which hand exposure would occur. A non-irritating patch-test concentration for some fragrances was established in 212 consecutive patients. 658 consecutive patients presenting with hand eczema were patch tested with the European standard series and the developed selection of fragrances. 67 (10.2%) of the 658 patients had a positive reaction to 1 or more of our selection of fragrance chemicals present in the new selection. The most common reactions to fragrances not included in the FM were to citral, Lyral (hydroxyisohexyl-3-cyclohexene carboxaldehyde) and oxidized l-limonene. A concomitant reaction to the FM identified potential fragrance allergy in less than (1/2) of these patients. Exposure assessment and a statistically significant association between a positive patch test to our selected fragrances and patients' history support the relevance of this selection of fragrances. Those with a positive reaction to our selected fragrances were significantly more likely to have 1 or more positive patch tests in the standard series. This observation is the basis for the hypothesis concerning cross-reactivity and the effect of simultaneous exposure. The study found that fragrance allergy could be a common problem in patients with eczema on the hands.

Acyclic Monoterpenes↗

The fragrance hand immersion study - an experimental model simulating real-life exposure for allergic contact dermatitis on the hands.

Recently, we showed that 10 x 2% of consecutively patch-tested hand eczema patients had a positive patch test to a selection of fragrances containing fragrances relevant to hand exposure. In this study, we used repeated skin exposure to a patch test-positive fragrance allergen in patients previously diagnosed with hand eczema to explore whether immersion of fingers in a solution with or without the patch-test-positive fragrance allergen would cause or exacerbate hand eczema on the exposed finger. The study was double blinded and randomized. All participants had a positive patch test to either hydroxycitronellal or Lyral (hydroxyisohexyl 3-cyclohexene carboxaldehyde). Each participant immersed a finger from each hand, once a day, in a solution containing the fragrance allergen or placebo. During the first 2 weeks, the concentration of fragrance allergen in the solution was low (approximately 10 p.p.m.), whilst during the following 2 weeks, the concentration was relatively high (approximately 250 p.p.m.), imitating real-life exposure to a household product like dishwashing liquid diluted in water and the undiluted product, respectively. Evaluation was made using a clinical scale and laser Doppler flow meter. 3 of 15 hand eczema patients developed eczema on the finger immersed in the fragrance-containing solution, 3 of 15 on the placebo finger and 3 of 15 on both fingers. Using this experimental exposure model simulating real-life exposure, we found no association between immersion of a finger in a solution containing fragrance and development of clinically visible eczema on the finger in 15 participants previously diagnosed with hand eczema and with a positive patch test to the fragrance in question.

Adult↗