Declining frequency of sensitization to fragrance mixes I and II: IVDK-data of the years 2012-2021.

BACKGROUND: EU Commission Regulation 2017/1410 prohibits using atranol and chloroatranol, the main allergens in Evernia prunastri (oakmoss), and hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC) in cosmetic products. Oakmoss absolute is contained in fragrance mix (FM) I and HICC in FM II which are patch tested as screening mixtures in the baseline series. OBJECTIVE: To describe the time trends of reaction frequencies to both FMs as well as to their components in FM-positive patients. METHODS: Retrospective analysis of data from the Information Network of Departments of Dermatology (IVDK), 2012-2021. RESULTS: Positive reactions to FM I (FM II) declined from 9.1% (4.7%) in 2012 to 4.6% (3.0%) in 2021. Full breakdown tests were performed in 24% (FM I) and 31% (FM II), respectively, of the mix-positive patients. From this data, frequencies of sensitization to the 14 single fragrances of FM I and FM II were calculated. For the majority, a decline was noted from 2012/2013 to 2020/2021, for oakmoss absolute 1.9%-0.8% and for HICC 1.8%-0.9%. CONCLUSION: EU Commission Regulation 2017/1410 was an effective measure. However, our data have some limitations, possibly causing underestimation of sensitization frequencies to fragrances.

Fragrance allergens in cosmetic products marketed for children in Denmark.

BACKGROUND: Fragrances are among the most common contact allergens in children. Cosmetic products are the most frequent source of skin exposure. OBJECTIVE: To investigate exposure to fragrance allergens among Danish children, based on a sample of 1179 cosmetic products marketed for children. METHODS: Information regarding cosmetic products marketed to children was obtained using a non-profit smartphone application registry, with data from December 2015 to November 2022. RESULTS: The number of validated products was 26 537, of which 1349 marketed for children. After elimination of duplicates, 1179 (4.4%) individual products remained. The majority 53.8% (634/1179) of the products were fragranced. The highest frequency of declared fragrances was found in 'Facial care'-products: 93.0% (80/86), of which 97.7% were lip balms. The highest number of labelled fragrances in one single product (n = 16) was found in a baby perfume. Fragrance mix I (FMI) or II (FMII) allergens were found in 25.3% (298/1179) of the products. Limonene and linalool were the two most frequently labelled fragrance allergens. CONCLUSION: Children can be exposed to a vast number of fragrance allergens from scented cosmetic products. Allergens from FM I and FMII are widely used in cosmetic products marketed to children. Patch testing with FMI and FMII remains relevant in children.

Contact allergy to hydroxyisohexyl 3-cyclohexene carboxaldehyde in Italy: Prevalence, trend, and concordance with fragrance mix II.

BACKGROUND: Hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC), contained in fragrance mix II (FM II), has been recognized as a contact sensitizer since the mid-1990s. After several attempts to reduce its use during the last two decades, HICC was permanently banned from the European market in August 2021. OBJECTIVES: To assess the prevalence and the time trend of contact allergy to HICC and to investigate the concordance of HICC allergy compared to FM II allergy in an unselected Italian patch test population. METHODS/PATIENTS: Retrospective analysis on demographics and patch test results of HICC-sensitized and/or FM II-sensitized patients was performed over a 6-year period (2016-2021) at 6 patch test Clinics in Italy. RESULTS: Among 7266 patients (4942 females, 68.0%, mean age 45.4 ± 20.6 years), 1% (70) resulted positive to HICC and 2.1% (153) to FM II. Clinical relevance was documented in 72.9% (51/70) of HICC positive patients. Among the 169 HICC and/or FM II positive patients, 9.5% had a positive reaction to HICC only, 31.9% to both HICC and FM II, and 58.6% to FM II only. The prevalence trend line of HICC positive reactions showed a decrease from 1.15% (2016) to 0.96% (2021). CONCLUSIONS: We documented a decreasing trend of HICC allergy in Italy, in line with the data recently reported in literature. Nevertheless, HICC should be maintained in the baseline series to monitor the benefits of its ban from the European market.

Use of sorbitan sesquioleate in patch test preparations and patch testing with the substance-What do our results mean?

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.

Simultaneous patch testing with fragrance markers in the baseline series and the ingredients of fragrance mixes: An update from southern Sweden.

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.

Myroxylon pereirae (balsam of Peru): Still worth testing?

BACKGROUND: Because Myroxylon pereirae (MP), or balsam of Peru, is nowadays almost not used "as such," and fragrance mix 1 (FM1) apparently is more sensitive in detecting fragrance allergy, the usefulness of testing MP in baseline series was recently questioned. OBJECTIVES: Identification of the number of clinically relevant patch test reactions to MP not detected by FM1. METHODS: Retrospective analysis of 12 030 patients patch tested with MP and FM1 for contact dermatitis between January 2018 and December 2019 in 13 Italian dermatology clinics. RESULTS: Four hundred thirty-nine patients (3.6%) had a positive patch test reaction to MP; 437 (3.6%) had a positive patch test reaction to FM1. Positive reactions to both MP and FM1 were observed in 119 subjects (1.0%), 310 (2.6%) reacted to MP only, 304 (2.5%) to FM1 only, 5 to MP and sorbitan sesquioleate (SSO), 9 to FM1 and SSO, and 5 to MP, FM1, and SSO. Single sensitizations were clinically relevant in 75.2% of cases for MP (62.9% current, 12.3% past) and 76.3% for FM1 (70.1% current, 6.2% past). CONCLUSIONS: Based on our results, MP appears to be still worth testing along with FM1 in baseline series, because it allows detection of a remarkable number of fragrance allergies, often relevant, which would be otherwise missed.

A negative breakdown test in a fragrance mix I-positive patient does not rule out contact allergy to its fragrance constituents.

BACKGROUND: In about half of the patients reacting positive to fragrance mix I (FM I), breakdown testing remains negative. This raises the question of whether the reaction to FM I is false-positive, or the breakdown test is false-negative. OBJECTIVES: To identify characteristics and sensitization patterns of patients positive to FM I, but not to its fragrance constituents. PATIENTS AND METHODS: Retrospective analysis of data from the Information Network of Departments of Dermatology (IVDK) between 2005 and 2019. Three patient groups were defined according to their reaction pattern: Group I, FM I positive and ≥1 single fragrance positive in the breakdown test (n = 1912); Group II, FM I positive and breakdown test negative (n = 1318); Group III, FM I negative (n = 19 790). RESULTS: Regarding the pattern of concomitant reactions to other fragrances, Group II had an intermediate position between Group I and Group III. In other respects (age and sex distribution, frequency of sensitization to non-fragrance baseline series allergens), Group II rather resembled Group I. CONCLUSIONS: Not every positive reaction to FM I in patients with negative breakdown tests is false-positive. There may be false-negative reactions to the single fragrance components when patch tested at 1% pet. Raising patch concentrations of some single fragrances is recommended.

Prevalence, concomitant reactions, and factors associated with fragrance allergy in Thailand.

BACKGROUND: Fragrances are the most common cause of cosmetic contact allergy. Up-to-date information on contact allergy frequencies and relevance aids primary and secondary preventive measures. OBJECTIVES: To determine the prevalence, associated factors, and concomitant reactions in fragrance allergy among Thais. METHODS: This retrospective study collected data from 2012 to 2019. The patient characteristics of fragrance and nonfragrance allergy groups were compared. Concurrent positive reactions to fragrance allergens (fragrance mix [FM] I, FM II, Myroxylon pereirae resin and hydroxyisohexyl 3-cyclohexene carboxaldehyde) and other baseline-series allergens were analysed. RESULTS: Of 1032 patients, 175 (17.0%) had fragrance allergy, with 57.7% of clinical relevance. FM I showed the highest prevalence (9.4%). The associated factors were being elderly, lesions on the extremities, metal allergy history, and long dermatitis duration. Contact allergies to epoxy resin and Compositae plants were significantly associated with fragrance allergy with an odds ratio of 5.95 (95% confidence interval [CI]: 5.21-6.80) and an odds ratio of 4.42 (95% CI: 1.58-12.36), respectively. No significant associations between colophonium (previously proposed as a fragrance marker) and fragrance allergens were found. CONCLUSIONS: The prevalence of fragrance contact allergy remains high and should be considered in old patients presenting with long-standing eczema on the extremities. Unlike reports from other countries, varied, significant, concomitant reactions were observed.

Patch testing with purified and oxidized citronellol.

BACKGROUND: Citronellol is a commonly used fragrance terpene included in fragrance mix II. As with many other fragrance terpenes, citronellol is susceptible to autoxidation. Citronellol hydroperoxides are formed in large amounts and are the only oxidation products identified as sensitizers in oxidized citronellol. AIM: To compare frequencies of contact allergy to purified and oxidized citronellol and to investigate the pattern of concomitant reactions to fragrance markers of the baseline series, oxidized linalool, and oxidized limonene. METHODS: A total of 658 dermatitis patients were patch tested with purified and oxidized citronellol at 2.0%, 4.0%, 6.0%, and 1.0%, 2.0%, 4.0%, 6.0% petrolatum, respectively. The irritant properties of purified and oxidized citronellol were studied before patch testing. RESULTS: Few irritant reactions were observed in the pretest. Purified citronellol detected positive reactions in 0.15%-0.31% of patients, while oxidized citronellol detected positive reactions in 0.61%-4.5%. Among patients reacting to oxidized citronellol, 34%-50% showed concomitant reactions to fragrance markers of the baseline series and 75%-91% to oxidized linalool or oxidized limonene. CONCLUSION: Oxidized citronellol detects more cases of contact allergy than purified citronellol, and these cases are not all detected using fragrance mix II. Patch testing with oxidized citronellol will add to the tools in the diagnosis of fragrance allergy.

[How common is fragrance allergy really?] / Wie häufig ist die Duftstoffallergie wirklich?

BACKGROUND: Fragrances are regarded as the most common contact allergens after nickel. In this context, the frequency of positive patch test reactions to fragrance mix is often presented as proof. According to EU regulation No. 1223/2009, 26 fragrances that are regarded as significant allergens have to be declared on cosmetic products. OBJECTIVES: The frequency of patch test reactions to fragrances and differentiation between frequently and rarely sensitizing fragrances were evaluated. MATERIALS AND METHODS: Data from the Information Network of Departments of Dermatology (IVDK), mostly of the years 2016-2018, were retrospectively analyzed. RESULTS: Frequency of positive reactions to fragrance mix I in the departments of dermatology joining the IVDK reached a historical low of 5.4% in 2018. Since 2013, positive reactions to fragrance mix II have been declining, yielding 3.2% in 2018. Of fragrance mix I, the allergen with the most positive test reactions is no longer oakmoss absolute, but isoeugenol. In fragrance mix II, hydroxyisohexyl 3­cyclohexene carboxaldehyde (HICC) is still leading. Only 11 of the 26 fragrances subject to mandatory declaration elicited allergic test reactions in more than 1% of the patients tested. DISCUSSION: The decline of positive test reactions to the fragrance mixes is mainly due to the reduced use of oakmoss containing atranol and chloroatranol, and HICC. Use of these substances in cosmetic products was prohibited within the EU starting in August 2019. Therefore, a further decline of the sensitization frequencies can be expected. A differentiated consideration of the individual fragrances under allergological aspects is urgently required.

Contact allergy to citral and its constituents geranial and neral, coupled with reactions to the prehapten and prohapten geraniol.

BACKGROUND: Citral is commonly used as a fragrance and flavor material and consists of the aldehydes geranial and neral. Citral is included in fragrance mix (FM) II. Geranial and neral have also been identified in autoxidation of geraniol, a fragrance compound present in FM I. OBJECTIVES: To study contact allergy to citral, geranial, and neral, and concomitant reactivity to oxidized geraniol and fragrance markers of the baseline series. METHODS: A total of 1476 dermatitis patients with suspected allergic contact dermatitis were patch tested using geranial, neral, and citral, all 3.5% petrolatum (pet.) as well as geraniol 6.0% and oxidized geraniol 11% pet. in addition to the Swedish baseline series. RESULTS: Frequencies of positive reactions to citral, geranial, and neral were 2.9%, 3.4% and 1.9%, respectively. Together, citral and geranial gave 4.2% positive patch test reactions in consecutive dermatitis patients. In patients with positive reactions to citral or its components, 25% to 34% reacted to FM II and 61% reacted to oxidized geraniol. CONCLUSIONS: Patch testing with citral, its components, or oxidized geraniol detects contact allergic reactions not detected using the baseline series. Patch testing with pure geraniol was shown to be of little value. Geranial and neral, although closely chemically related, are concluded to be separate haptens.

Adding sorbitan sesquioleate to the European baseline series: Necessary, reasonable, or unavoidable?

Positive reactions to fragrance mix I (FM I) are frequent in consecutively patch tested patients suspected of having allergic contact dermatitis. However, the FM I test preparations contain 5% of the emulsifier sorbitan sesquioleate (SSO), and it is well known that SSO can cause contact allergic reactions in its own right. Indeed, the available data show that some patients with contact allergy to SSO react to FM I but are not allergic to fragrances. When SSO is not tested, this situation may go unnoticed, a wrong diagnosis of fragrance allergy may be given to the patient, and unjustified advice to avoid fragrances and fragranced products will be given in such cases. To avoid such suboptimal patient care, we postulate that testing with SSO in all patch tested individuals is mandatory. As it is well known that only a minority of FM I-reactive patients will undergo a breakdown test with the ingredients and SSO, testing with SSO in all patients can only be achieved by adding it to the European baseline series. Not testing with SSO may also result in misinterpretation of patch test reactions to Myroxylon pereirae resin and 2-hydroxyethyl methacrylate in the baseline series, as both (may) contain SSO, and, for the same reason, of reactions to several other hapten test materials.

Contact sensitization to ingredients of dental materials and cosmetics in dental students: a pilot study.

OBJECTIVE: The aim of this study was to evaluate the rate of contact sensitization to selected cosmetic allergens, i.e. ingredients of dental materials, in students of dental medicine and dental patients. METHODS: A total of 50 participants were included in the study: 40 students of dental medicine exposed to the studied allergens during the course of practical education; and 10 randomly selected dental patients without occupational exposure to the investigated substances served as a control group. All of them were patch-tested with colophonium, myroxylon pereirae resin, paraben mix, fragrance mix I, isopropyl myristate, triclosan, polysorbate 80, compositae mix II, and hydroperoxides of limonene. RESULTS: The sensitization rates for colophonium and polysorbate 80 were the highest. For the group of dental students, we established significantly higher sensitization rate for colophonium compared to the ones for myroxylon pereirae resin and hydroperoxides of limonene (χ2 = 4.93; p = 0.026), paraben mix (χ2 = 3.6; p = 0.05), isopropyl myristate (χ2 = 6.56; p = 0.01), and triclosan (χ2 = 8.5; p < 0.001); and to polysorbate 80 compared to the ones for myroxylon pereirae resin and hydroperoxides of limonene (χ2 = 3.97; p = 0.046), isopropyl myristate (χ2 = 5.47; p = 0.02) and triclosan (χ2 = 7.34; p = 0.007). Significantly increased concomitant sensitization rate to compositae mix and to hydroperoxides of limonene was established (χ2 = 12.55; p < 0.001). Generally, the incidence of concomitant sensitization to the studied allergens in the whole studied population was high. CONCLUSIONS: Colophonium and polysorbate 80 could be outlined as sensitizers of paramount importance for both dental students and dental patients. We consider the major importance of exposure to colophonium during the course of practical education in dentistry for the onset of the sensitization. Sensitization to compositae mix was observed only among dental students. We consider the leading role of consumer exposure for the onset of the sensitization to triclosan and to hydroperoxides of limonene. Unexpected and unreported reactions of concomitant sensitization were observed.

Contact allergy to oxidized geraniol among Swedish dermatitis patients-A multicentre study by the Swedish Contact Dermatitis Research Group.

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.

Simultaneous patch testing with fragrance mix I, fragrance mix II and their ingredients in southern Sweden between 2009 and 2015.

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.

Non-mix fragrances are top sensitizers in consecutive dermatitis patients - a cross-sectional study of the 26 EU-labelled fragrance allergens.

BACKGROUND: For cosmetics, it is mandatory to label 26 fragrance substances, including all constituents of fragrance mix I (FM I) and fragrance mix II (FM II). Earlier reports have not included oxidized R-limonene [hydroperoxides of R-limonene (Lim-OOH)] and oxidized linalool [hydroperoxides of linalool (Lin-OOH)], and breakdown testing of FM I and FM II has mainly been performed in selected, mix-positive patients. OBJECTIVES: To report the prevalence of sensitization to the 26 fragrances, and to assess concomitant reactivity to FM I and/or FM II. METHODS: A cross-sectional study on consecutive dermatitis patients patch tested with the 26 fragrances and the European baseline series from 2010 to 2015 at a single university clinic was performed. RESULTS: Of 6004 patients, 940 (15.7%, 95%CI: 14.7-16.6%) were fragrance-sensitized. Regarding the single fragrances, most patients were sensitized to Lin-OOH (3.9%), Evernia furfuracea (3.0%), Lim-OOH (2.5%), and hydroxyisohexyl 3-cyclohexene carboxaldehyde (2.1%). Significantly fewer patients were 'FM I-positive and constituent-positive' than 'FM II-positive and constituent-positive' (32.7% versus 57.0%, p < 0.0001). Additionally, significantly more patients were 'FM II-negative but constituent-positive' than 'FM I-negative but constituent-positive' (12.4% versus 3.2%, p = 0.0008). CONCLUSIONS: Non-mix fragrances are the most important single fragrance allergens among consecutive patients. The test concentration of the single FM I constituents should be increased when possible.

Patch testing with hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC) - a multicentre study of the Swedish Contact Dermatitis Research Group.

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.