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Fragrance materials are widely used in various types of products in daily life and many of them can be contact sensitizers. Contact allergy to fragrances has been reported to be common worldwide. Unlike other groups of contact allergens such as metals and preservatives, fragrance materials in consumer products can be present as single fragrance chemicals or in the form of mixtures known as natural complex substances. Due to the complexity of the fragrance materials and the high number of fragrance substances known to cause contact sensitization, selecting suitable materials for patch testing is challenging. Emerging fragrance markers have been additionally introduced in different baseline series for screening to enhance the rate of fragrance contact allergy detection. Moreover, there have been continual updates on basic knowledge, clinical perspectives, sources of exposure, and regulations on the use of fragrance materials. Avoiding pitfalls while performing patch testing with fragrance test materials is also crucial and should not be overlooked. Therefore, this review aims to update knowledge to provide a high-quality holistic approach to fragrance contact allergy diagnosis and management.

Background: Quantitative risk assessment (QRA) for skin sensitization is used to derive safe use levels of sensitising fragrance ingredients in products. Post-marketing surveillance of the prevalence of contact allergy to these ingredients provides relevant data to help evaluate the performance of these measures., Objectives: To determine a suitable patch test concentration for five fragrance materials that had hitherto not been tested on a regular basis. These concentrations are then to be used in a surveillance study with patch testing consecutive patients over an extended monitoring period., Materials and Methods: Furaneol, CAS.3658-77-3; trans-2-hexenal, CAS.6728-26-3; 4,8-dimethyl-4,9-decadienal, CAS.71077-31-1; longifolene, CAS.475-20-7; benzaldehyde, CAS.10052-7, were patch tested with other fragrance allergens in four clinics. Patch testing was conducted in three rounds, starting with the lowest concentrations of the five ingredients. The doses were increased in the subsequent rounds if no late-appearing positive reactions and virtually no irritant reactions were reported., Results: Overall, 373 patients were tested. No positive allergic reaction was reported to the five ingredients. Patch test results of other fragrance allergens are reported., Conclusions: The highest test concentrations are each considered safe for patch testing consecutive patients. Further surveillance based on these preparations will evaluate the hypothesis that QRA-driven consumer product levels of these fragrances can prevent sensitization., (© 2024 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd.)

Background: Contact allergy rates of linalool and limonene hydroperoxides (HPs) have increased., Objectives: To demonstrate the patterns of simultaneous positive patch test (PT) reactions and prevalences of multiple contact allergies (MCAs) in patients with contact allergy to linalool and/or limonene HPs., Methods: A retrospective analysis of consecutive dermatitis patients in 2015-2020 was performed., Results: Of all 4192 patients, 1851 had at least one positive PT reaction. Of these, 410 (22.2%) had MCAs, significantly related to a higher age (p-value = 0.003). Patients with an exclusively positive reaction to linalool HPs but not limonene HPs were shown to have MCAs (p-value <0.001, odds ratio (95% confidence interval) = 4.15 (3.01-5.73)). Patients with simultaneous contact allergies to both linalool and limonene HPs had contact allergies to many other screening and fragrance allergens., Conclusions: Simultaneous positive PT reactions to allergens in baseline series and fragrances are common in patients with the HPs contact allergy, especially linalool HPs. The pattern of simultaneous PT reactions principally suggested the co-sensitization of the cosmetic allergens., (© 2023 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd.)

Background: Eugenol is a known contact sensitiser included in fragrance mix I., Objective: To assess the allergic reactivity to eugenol in different concentrations using patch test as well as repeated open application test (ROAT)., Methods: Overall 67 subjects from 6 European dermatology clinics participated in the study. The ROAT was performed for 21 days twice a day, applying 3 dilutions of eugenol (2.7%-0.5%) and a control. Before and after the ROAT, patch testing with 17 dilutions of eugenol (2.0%-0.00006%) and controls was performed., Results: Out of the 34 subjects with contact allergy to eugenol, 21 (61.8%) showed a positive patch test before ROAT was performed, the lowest positive concentration was 0.031%. The ROAT was positive in 19 (55.9%) of the 34 subjects, the time until a positive reaction occurred was negatively associated with the concentration of the ROAT solution, as well as with the allergic reactivity of the subjects as defined by patch testing. In the patch test after ROAT, 20 of the 34 test subjects (58.8%) showed a positive reaction. In 13 (38.2%) of the 34 test subjects, the patch test result was not reproduceable, still 4 (31.0%) of these 13 subjects developed a positive ROAT., Conclusion: Eugenol can provoke a positive patch test reaction in a very low dose; besides, this hypersensitivity may persist even if a former positive patch test is not reproduceable., (© 2023 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd.)

Background: Carvone (l-carvone) is a mint-tasting flavour additive that most of us is exposed to and can cause allergic contact reactions., Objectives: To analyse the frequency and the relevance of positive carvone reactions in a dermatitis population., Method: A retrospective analysis of dermatitis patients consecutively tested with carvone from 2017 to 2021. Data were retrieved from the department's patch-test database., Results: Of 3554 patients tested with carvone, 28 (0.79%) had a positive reaction. Carvone-positive patients had higher mean age, were significantly more likely female (p < 0.001) and had often an intraoral/lip involvement (p < 0.001). In the carvone-positive group, 50% (n = 14) had a relevant reaction, and in 4 of 14, the relevance was first revealed after test reading. Of the carvone-positive patients, 18 of 28 did not have a coexisting allergy to a fragrance/flavour allergen and of these 44% had a relevant allergy., Conclusions: The study suggests that a significant fraction of relevant carvone contact allergies may be overlooked if the allergen is not tested. Furthermore, as the exposure is widespread, inclusion of carvone in the Swedish baseline series may be justified even if the contact allergy prevalence is below 1%., (© 2022 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd.)

Background: Sorbitan sesquioleate (SSO) is a sorbitan fatty acid ester, an emulsifier used in topical products and certain patch test preparations. SSO may affect the patch test results. It has been debated whether to include the substance in the baseline series to avoid misinterpretation of the results., Objectives: To report the prevalence and simultaneous reactions of SSO with other patch test preparations containing SSO as an emulsifier., Materials and Methods: A retrospective analysis of 3539 dermatitis patients who underwent patch testing from 2016 to 2020 was performed., Results: The 5-year SSO contact allergy prevalence was 0.48%, and 1.3% had a doubtful reaction. Patients with a stronger positive reaction (2+, 3+) were more likely to react simultaneously to other allergen preparations containing SSO (p value = 0.018). One patient with a strong reaction to SSO reacted positively to all SSO-containing patch test preparations. Definite fragrance allergens could not be identified in the patients who had simultaneous reactions to SSO and fragrance mix (FM) I., Conclusions: Patch testing with allergen preparations containing SSO affected the patch test interpretation. Fragrance contact allergy could not be ruled out when a patient simultaneously reacted to SSO and FM I. Changing emulsifiers in patch test preparations would be advantageous., (© 2022 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd.)

Background: Contact allergy can manifest in a variety of ways clinically. Systemic contact allergy may occasionally present with pain in muscles and joints. Fibromyalgia is a chronic rheumatic disease characterized by pain and with virtually unknown aetiology., Objectives: The aim of this study was to investigate the contact allergy rates to the sensitizers in a baseline series and compare with corresponding rates in dermatitis patients and the general population., Methods: Patch testing with the Swedish baseline series was performed in 120 individuals with fibromyalgia. Fisher's exact test was used for pair-wise comparisons of contact allergy rates between the fibromyalgia group and two control groups, dermatitis patients and individuals in the general population., Results: Contact allergy was significantly more common in the fibromyalgia group compared to the general population concerning nickel and the fragrance markers Myroxolon pereirae and fragrance mix I. There were fewer allergic reactions to preservatives in the fibromyalgia group compared with the dermatitis group., Conclusions: Myroxolon pereirae and fragrance mix I represent besides fragrance allergy also allergy to flavouring substances which indicate that oral exposure to flavouring substances and hygiene products might be important for sensitization and possibly elicitation of systemic contact allergy symptoms in fibromyalgia individuals., (© 2022 European Academy of Dermatology and Venereology.)

Limonene and linalool are among the most common fragrance terpenes used in everyday products. They are pre-haptens, forming hydroperoxides (Lim-OOHs, Lin-OOHs) upon oxidation and inducing frequent positive patch test reactions in patients with dermatitis, and yet they are not routinely tested in Europe. This review evaluates current patch testing with Lim-OOHs and Lin-OOHs by asking whether hydroperoxide patch testing is warranted, examining the difficulties or challenges related to reading and interpreting hydroperoxide patch test results with currently available material, and assessing their relevance. Studies are increasingly pointing to high percentages of positive reactions in patients consecutively patch tested with these oxidized products. An association between a positive clinical history and a strong patch test reaction has been described, but problems with doubtful/irritant reactions have also been reported. Considering the high frequency of relevant positive reactions, the incorporation of Lim-OOHs 0.3% and Lin-OOHs 1% in the baseline series may be justified. Since exposure, sensitization, and elicitation limits of Lim-OOHs and Lin-OOHs in the products still need to be better determined, an assessment of previous exposure, possible sensitizations, and reactions may help to improve the clinical assessment., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Regularly updating the prevalence of fragrance contact allergy (CA) is important. Patch testing with fragrance markers in the baseline series and the ingredients of fragrance mixes (FMs) is still debated., Objectives: To update the prevalence and clinical characteristics of patients with fragrance CA. To establish the results of patch testing with individual allergens of FMs., Methods: A retrospective analysis of 3539 patients with dermatitis who were patch tested with the baseline series and FMs ingredients during 2016 to 2020 was performed., Results: The prevalence of fragrance CA was 13%. About 10% of these patients with fragrance CA would be missed if the individual ingredients were not tested. Unlike hydroxyisohexyl 3-cyclohexene carboxaldehyde, there was no decreasing trend of CA to Evernia prunastri (oakmoss) extract after the EU regulation came into force. Patients with CA from only one ingredient of the mixes or having a weak positive reaction to the ingredients were significantly missed when tested with only the fragrance markers in the baseline series., Conclusions: Patch testing with individual fragrance allergens is crucial for experts to expand knowledge in the fragrance CA field. The concentrations of the allergens in FMs may need to be adjusted to detect patients with fragrance CA, since some were significantly overlooked., (© 2022 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd.)

Background: In a European study on contact allergy in the general population, it has been hypothesized that the combination of contact allergy to a fragrance together with a history indicating dermatitis at exposure and thereafter subsequent avoidance of scented products implied a diagnosis of allergic contact dermatitis., Objectives: The primary aim of this study was to validate this hypothesis/algorithm. The secondary aim was to investigate whether there was any association between the outcome of the recent repeated open application test (ROAT) and the patch test reactivity., Methods: One hundred nine subjects with and without contact allergy to fragrance mix II (FM II) were recruited. Volunteers from six European dermatology clinics participated in the study including a patch test and a ROAT., Results: Twenty-four positive ROAT reactions were noted in total including 20 of those 32 with contact allergy to FM II. None of the volunteers reacted to the vehicle (P < 0.001). More individuals with a positive algorithm had positive ROATs when compared with those with a negative algorithm. However, the difference was not statistically significant (P = 0.12). The lower the patch test concentration eliciting a positive test reaction, the more likely was a positive ROAT and the more likely that the positive ROAT appeared early during the investigative period., Conclusions: The algorithm used in this study was not validated but it was indicated in this ROAT setup. The stronger the patch test reactivity the more likely was a positive ROAT and the more likely it was that the positive ROAT appeared early during the application period., (© 2021 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: Geraniol is a widely used fragrance terpene, and is included in fragrance mix I. Geraniol is prone to autoxidation, forming the skin sensitizers geranial, neral, and geraniol-7-hydroperoxide. Oxidized geraniol has previously been patch tested in 1 clinic, giving 1% to 4.6% positive reactions in consecutive patients when tested at 2% to 11%., Aim: To compare test reactions to pure and oxidized geraniol, to compare 2 different test concentrations of oxidized geraniol and to investigate the pattern of concomitant reactions to fragrance markers of the baseline series in a multicentre setting., Methods: One thousand four hundred and seventy-six consecutive patients referred for patch testing were patch tested with geraniol 6% pet. and oxidized geraniol 6% and 11% pet., Results: Pure geraniol 6% pet., oxidized geraniol 6% pet. and oxidized geraniol 11% pet. gave 1%, 3% and 8% positive patch test reactions and 0.7%, 3% and 5% doubtful reactions, respectively. Approximately 50% of the patients with doubtful reactions to oxidized geraniol 6% pet. had positive reactions to oxidized geraniol 11% pet., Conclusions: Oxidized geraniol 11% pet. provides better detection than oxidized geraniol 6% pet. As most patients reacted only to oxidized geraniol, it is important to explore further whether oxidized geraniol should be included in a baseline patch test series., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Fragrance mix I (FM I) and fragrance mix II (FM II) are included in the European baseline series as screening substances for fragrance contact allergy., Objectives: To investigate the frequency of allergic reactions to FM I, FM II and their ingredients in consecutively patch tested patients., Materials and Methods: A retrospective analysis of data from 4430 patients patch tested between 2009 and 2015 was performed., Results: Of the patients, 6.5% were FM I-positive and 3.2% were FM II-positive. Forty-five per cent of FM I-positive patients did not have positive reactions to FM I ingredients. Thirty-five per cent of those who were FM II-positive did not have positive reactions to FM II ingredients. Twenty-seven per cent of those with positive reactions to one or more of the FM I ingredients were FM I-negative, and 36% of those who had positive reactions to one or more of the FM II ingredients were FM II-negative. The allergens with the highest pick-up rates were Evernia prunastri (1.8%), cinnamal (1.3%), citral (1.2%), and hydroxyisohexyl 3-cyclohexene carboxaldehyde (1.2%). Significant differences were observed in the proportions of positive reactions to FM I, FM II, eugenol, isoeugenol, and farnesol when results from patch testing with materials from different suppliers were compared., Conclusions: There is a risk of missing fragrance contact allergy when testing with only the fragrance mixes is performed. The use of preparations from different suppliers may affect the patch test results., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: In 2014, the fragrance hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC) was excluded from the Swedish baseline series., Objectives: To study (i) whether fragrance mix (FM) II with 5% HICC detects more positive reactions than usual FM II with 2.5% HICC, and (ii) the reproducibility of patch testing with HICC., Methods: Two thousand one hundred and eighteen dermatitis patients at five Swedish dermatology departments were consecutively tested with FM II 14% pet., FM II 16.5% pet., and duplicate preparations of HICC 5% pet., Results: Of the patients, 3.2% reacted to FM II 14%, and 1.5% reacted to HICC. Separate testing with HICC detected 0.3% reactions without concomitant reactivity to FM II. FM II with 5% HICC did not give rise to more irritant reactions or signs of active sensitization than FM II with 2.5% HICC. Patch testing with duplicate applications of HICC increased the overall prevalence of HICC contact allergy to 1.9%., Conclusion: FM II with 5% HICC does not detect more positive reactions than FM II with 2.5% HICC. Separate testing with HICC does not detect a sufficient proportion of patients who react only to HICC, without concomitant reactions to FM II, to warrant its inclusion in a baseline series., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Several of the ingredients in fragrance mix I (FM I) have been shown to evaporate from petrolatum preparations applied in test chambers to an extent that can be suspected to affect the patch test result., Objectives: To compare the reactivity towards FM I and fragrance mix II (FM II) when they are applied in test chambers in advance and immediately prior to the patch test occasion., Methods: Seven hundred and ninety-five consecutive patients were simultaneously patch tested with duplicate samples of FM I and FM II. One sample was applied in the test chamber 6 days in advance (6D sample), and the other sample was applied immediately before the patients were patch tested (fresh sample)., Results: Twenty-two (2.8%) patients reacted exclusively to the fresh sample of FM I, 6 (0.7%) reacted exclusively to the 6D sample, and 22 (2.8%) reacted to both samples. The corresponding numbers for FM II were 9 (1.1%) for the fresh sample, 6 (0.7%) for the 6D sample and 12 (1.5%) for both samples., Conclusions: There was a statistically significant difference between the numbers of patients reacting to the fresh and 6D samples of FM I. No corresponding difference was observed for FM II. This can probably be explained by differences in volatilities between the ingredients of FM I and FM II., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Petrolatum patch test preparations are for practical reasons often applied in test chambers in advance, several hours or even days before the patient is tested. As many fragrance compounds are volatile it may be suspected that petrolatum preparations applied in test chambers are not stable over time., Objectives: To investigate the stability of petrolatum preparations of the seven chemically defined components in the fragrance mix (FM I) when stored in test chambers., Methods: Samples of petrolatum preparations applied in test chambers stored at room temperature and in a refrigerator for between 4 and 144 h were analysed using liquid chromatographic methods., Results: The concentration decreased by ≥ 20% within 8 h in four of seven preparations stored in Finn chambers at room temperature. When stored in a refrigerator only the preparation of cinnamal had decreased by ≥ 20% within 24 h. The stability of preparations of cinnamal stored in IQ chambers with a plastic cover was slightly better, but like the preparations applied in Finn chambers, the concentration decreased by ≥ 20% within 4 h at room temperature and within 24 h in a refrigerator. Cinnamal and cinnamyl alcohol were found to be more stable when analysed as ingredients in FM I compared with when analysed in individual preparations., Conclusions: Within a couple of hours several fragrance allergens evaporate from test chambers to an extent that may affect the outcome of the patch test. Application to the test chambers should be performed as close to the patch test occasion as possible and storage in a refrigerator is recommended., (© 2012 The Authors. BJD © 2012 British Association of Dermatologists.)

Background: According to EU legislation, 26 fragrance substance allergens must be labelled on cosmetic products. For 12 of them, the optimal patch test concentration/dose has not been evaluated., Objectives: To establish the optimal patch test doses in mg/cm2 for the 12 fragrance substances that are not included in fragrance mix I or II in the European baseline patch test series., Materials and Methods: Patch testing with the 12 fragrance substances was performed in a stepwise manner encompassing up to five rounds in at least 100 dermatitis patients for each round. Before patch testing, an individual maximum concentration/dose was determined for each fragrance substance., Results: The predetermined maximum patch test concentrations/doses could be tested for all 12 fragrance substances, with no observable adverse reactions being noted., Conclusions: For each fragrance substance investigated, it is recommended that half of the maximum patch test dose (mg/cm2) be used for aimed and screening patch testing., (© 2012 John Wiley & Sons A/S.)

Background: Potential fragrance allergens used in daily products should have a concentration limited to levels that are at, or below, acceptable exposure levels based on the quantitative risk assessment for the induction of dermal sensitization. To date, there are insufficient data to discern any quantitative relationship between induction and elicitation concentrations for fragrance ingredients that have a potential for dermal sensitization. When available, these data should be used to confirm the effectiveness of quantitative risk assessment-based risk management procedures., Objective: In this study, the relationship between the allergen concentration and the time to elicit allergic contact dermatitis in eugenol-sensitized patients was studied. The products used to elicit allergic contact dermatitis had a concentration of eugenol that was equal to, or below, the International Fragrance Association standard., Methods: Volunteers with and without known sensitization to eugenol were patch tested with various concentrations of eugenol (dilution series) and also underwent repeated open application tests (ROATs). This study model has previously been successfully used with stronger sensitizers., Results: In this study, allergic contact dermatitis, as evidenced by a positive ROAT, could not be elicited by any of the concentrations studied, including in those patients where the patch tests were positive., Conclusions: When tested in a 3-week ROAT at, or below, its current International Fragrance Association Standard, eugenol did not induce reactions even in those known to be sensitized. Whether this represents a false-negative result for a weak allergen is unknown.

Terpenes are widely used fragrance compounds in fine fragrances, but also in domestic and occupational products. Terpenes oxidize easily due to autoxidation on air exposure. Previous studies have shown that limonene, linalool and caryophyllene are not allergenic themselves but readily form allergenic products on air-exposure. This study aimed to determine the frequency and characteristics of allergic reactions to selected oxidized fragrance terpenes other than limonene. In total 1511 consecutive dermatitis patients in 6 European dermatology centres were patch tested with oxidized fragrance terpenes and some oxidation fractions and compounds. Oxidized linalool and its hydroperoxide fraction were found to be common contact allergens. Of the patients tested, 1.3% showed a positive reaction to oxidized linalool and 1.1% to the hydroperoxide fraction. About 0.5% of the patients reacted to oxidized caryophyllene whereas 1 patient reacted to oxidized myrcene. Of the patients reacting to the oxidized terpenes, 58% had fragrance-related contact allergy and/or a positive history for adverse reaction to fragrances. Autoxidation of fragrance terpenes contributes greatly to fragrance allergy, which emphasizes the need of testing with compounds that patients are actually exposed to and not only with the ingredients originally applied in commercial formulations.

Unlabelled: A new fragrance mix (FM II), with 6 frequently used chemicals not present in the currently used fragrance mix (FM I), was evaluated in 6 dermatological centres in Europe, as previously reported. In this publication, test results with the individual constituents and after repeated open application test (ROAT) of FM II are described. Furthermore, cosmetic products which had caused a contact dermatitis in patients were analysed for the presence of the individual constituents. In 1701 patients, the individual constituents of the medium (14%) and the highest (28%) concentration of FM II were simultaneously applied with the new mix at 3 concentrations (break-down testing for the lowest concentration of FM II (2.8%) was performed only if the mix was positive). ROAT was performed with the concentration of the FM II which had produced a positive or doubtful (+ or ?+) patch test reaction. Patients' products were analysed for the 6 target compounds by gas chromatography-mass spectrometry (GC-MS)., Results: 50 patients (2.9%) showed a positive reaction to 14% FM II and 70 patients (4.1%) to 28% FM II. 24/50 (48%) produced a positive reaction to 1 or more of the individual constituents of 14% FM II and 38/70 (54.3%) to 28% FM II, respectively. If doubtful reactions to individual constituents are included, the break-down testing was positive in 74% and 70%, respectively. Patients with a positive reaction to 14% FM II showed a higher rate of reactions to the individual constituent of the 28% FM II: 36/50 (72%). Positive reactions to individual constituents in patients negative to FM II were exceedingly rare. If doubtful reactions are regarded as negative, the sensitivity, specificity, positive predictive value and negative predictive value for the medium concentration of FM II towards at least 1 individual constituent was 92.3% (exact 95% confidence interval 74.9-99.1%), 98.4% (97.7-99.0%), 48% (33.7-62.6%) and 99.9% (99.6-"100.0%), respectively. For the high concentration, the figures were very similar. The frequency of positive reactions to the individual constituents in descending order was the same for both FM II concentrations: hydroxyisohexyl 3-cyclohexene carboxaldehyde (Lyral) > citral > farnesol > citronellol > alpha-hexyl-cinnamic aldehyde (AHCA). No unequivocally positive reaction to coumarin was observed. Lyral) was the dominant individual constituent, with positive reactions in 36% of patients reacting to 14% FM II and 37.1% to 28% FM II. 5/11 patients developed a positive ROAT after a median of 7 days (range 2-10). The 5 patients with a doubtful or negative reaction to 28% FM II were all ROAT negative except 1. There were 7 patients with a certain fragrance history and a positive reaction to either 28% or 14% FM II but a negative reaction to FM I. Analysis with GC-MS in a total of 24 products obtained from 12 patients showed at least 1-5 individual constituents per product: Lyral (79.2%), citronellol (87.5%), AHCA (58.3%), citral (50%) and coumarin (50%). The patients were patch test positive to Lyral, citral and AHCA. In conclusion, patients with a certain fragrance history and a negative reaction to FM I can be identified by FM II. Testing with individual constituents is positive in about 50% of cases reacting to either 14% or 28% FM II.

The currently used 8% fragrance mix (FM I) does not identify all patients with a positive history of adverse reactions to fragrances. A new FM II with 6 frequently used chemicals was evaluated in 1701 consecutive patients patch tested in 6 dermatological centres in Europe. FM II was tested in 3 concentrations - 28% FM II contained 5% hydroxyisohexyl 3-cyclohexene carboxaldehyde (Lyral), 2% citral, 5% farnesol, 5% coumarin, 1% citronellol and 10%alpha-hexyl-cinnamic aldehyde; in 14% FM II, the single constituents' concentration was lowered to 50% and in 2.8% FM II to 10%. Each patient was classified regarding a history of adverse reactions to fragrances: certain, probable, questionable, none. Positive reactions to FM I occurred in 6.5% of the patients. Positive reactions to FM II were dose-dependent and increased from 1.3% (2.8% FM II), through 2.9% (14% FM II) to 4.1% (28% FM II). Reactions classified as doubtful or irritant varied considerably between the 6 centres, with a mean value of 7.2% for FM I and means ranging from 1.8% to 10.6% for FM II. 8.7% of the tested patients had a certain fragrance history. Of these, 25.2% were positive to FM I; reactivity to FM II was again dose-dependent and ranged from 8.1% to 17.6% in this subgroup. Comparing 2 groups of history - certain and none - values for sensitivity and specificity were calculated: sensitivity: FM I, 25.2%; 2.8% FM II, 8.1%; 14% FM II, 13.5%; 28% FM II, 17.6%; specificity: FM I, 96.5%; 2.8% FM II, 99.5%; 14% FM II, 98.8%; 28% FM II, 98.1%. 31/70 patients (44.3%) positive to 28% FM II were negative to FM I, with 14% FM II this proportion being 16/50 (32%). In the group of patients with a certain history, a total of 7 patients were found reacting to FM II only. Conversely, in the group of patients without any fragrance history, there were significantly more positive reactions to FM I than to any concentration of FM II. In conclusion, the new FM II detects additional patients sensitive to fragrances missed by FM I; the number of false-positive reactions is lower with FM II than with FM I. Considering sensitivity, specificity and the frequency of doubtful reactions, the medium concentration, 14% FM II, seems to be the most appropriate diagnostic screening tool.

Oak moss absolute is a long-known, popular natural extract widely used in perfumes. It is reported as the cause of allergic reactions in a significant number of those with perfume allergy. Oak moss absolute has been the target of recent research to identify its allergenic components. Recently, chloroatranol, a hitherto unknown fragrance allergen, was identified in oak moss absolute. The objective was to assess the clinical importance of chloroatranol as a fragrance allergen by characterizing its elicitation profile. 13 patients previously showing a positive patch test to oak moss absolute and chloroatranol were included, together with a control group of 10 patients without sensitization to either of the 2 materials. A serial dilution patch test was performed on the upper back with concentrations ranging from 200 to 0.0063 p.p.m. of chloroatranol in ethanol. Simultaneously, the participant performed an open test simulating the use of perfumes on the volar aspect of the forearms in a randomized and double-blinded design. A solution with 5 p.p.m. chloroatranol was used for 14 days, and, in case of no reaction, the applications were continued for another 14 days with a solution containing 25 p.p.m. All test subjects (13/13) developed an allergic reaction at the site of application of the solution containing chloroatranol. Among them, 12/13 (92%) gave a positive reaction to the 5 p.p.m. solution and 1 to 25 p.p.m. None of the controls reacted (P < 0.001). The use test was terminated at median day 4. The dose eliciting a reaction in 50% of the test subjects at patch testing was 0.2 p.p.m. In conclusion, the hidden exposure to a potent allergen widely used in perfumes has caused a highly sensitized cohort of individuals. Judged from the elicitation profile, chloroatranol is the most potent allergen present in consumer products today.

Citral is a well known contact allergen and a contact irritant. Routine patch testing in the past may have been restricted because of possible irritant (IR) patch test responses. 586 consecutive patients, with hand eczema, were patch tested with a selection of fragrances including citral 2% petrolatum and the European standard series. 28 of the patients showed a positive patch test reaction (+ to +++) to citral and 82 at least 1 IR patch test reaction and no positive patch test reaction to citral. A statistically significant association between a positive patch test reaction to citral and positive patch test reactions to other fragrances compared with IR reactions (n = 82) was established. The difference regarding fragrance history found between those with IR and positive reactions to citral was not significant. Citral could be an allergen and/or irritant, worthy of further more extensive studies.

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.

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.

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.

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.