Patch testing with aluminium Finn Chambers could give false-positive reactions in patients with contact allergy to aluminium.

BACKGROUND: Earlier laboratory studies have shown that sodium tetrachloropalladate, Myroxylon pereirae, caine mix II, and palladium chloride trigger the release of aluminium (Al) from Finn Chambers (FC). OBJECTIVES: To investigate whether aluminium realease from FC could influence the diagnostic outcome of patch testing with FC. METHOD: A retrospective analysis of patch test results from 2010 to 2019 was performed. A two-sided Fisher's exact test was used to calculate any overrepresentation of contact allergy to Al among patients with positive reactions to sodium tetrachloropalladate, Myroxylon pereirae, caine mix II, and palladium chloride. RESULTS: A total of 5446 patients had been tested with FC during the study period. There was a significant overrepresentation of contact allergy to Al among patients with positive reactions to sodium tetrachloropalladate, Myroxylon pereirae, caine mix II, and palladium chloride. Patients with a strong Al allergy had significantly higher amounts of concomitant reactions to sodium tetrachloropalladate, Myroxylon pereirae, caine mix II, and palladium chloride compared to patients with weak Al allergy. These results were not seen for patients tested with Finn Chambers AQUA. CONCLUSION: In patients with contact allergy to Al, patch testing with Finn chambers could give false-positive reactions to sodium tetrachloropalladate, Myroxylon pereirae, caine mix II, and palladium chloride.

Allergen fragrance molecules: a potential relief for COVID-19.

BACKGROUND: The latest coronavirus SARS-CoV-2, discovered in China and rapidly spread Worldwide. COVID-19 affected millions of people and killed hundreds of thousands worldwide. There are many ongoing studies investigating drug(s) suitable for preventing and/or treating this pandemic; however, there are no specific drugs or vaccines available to treat or prevent SARS-CoV-2 as of today. METHODS: Fifty-eight fragrance materials, which are classified as allergen fragrance molecules, were selected and used in this study. Docking simulations were carried out using four functional proteins; the Covid19 Main Protase (MPro), Receptor binding domain (RBD) of spike protein, Nucleocapsid, and host Bromodomain protein (BRD2), as target macromolecules. Three different software, AutoDock, AutoDock Vina (Vina), and Molegro Virtual Docker (MVD), running a total of four different docking protocol with optimized energy functions were used. Results were compared with the five molecules reported in the literature as potential drugs against COVID-19. Virtual screening was carried out using Vina, molecules satisfying our cut-off (- 6.5 kcal/mol) binding affinity was confirmed by MVD. Selected molecules were analyzed using the flexible docking protocol of Vina and AutoDock default settings. RESULTS: Ten out of 58 allergen fragrance molecules were selected for further docking studies. MPro and BRD2 are potential targets for the tested allergen fragrance molecules, while RBD and Nucleocapsid showed weak binding energies. According to AutoDock results, three molecules, Benzyl Cinnamate, Dihydroambrettolide, and Galaxolide, had good binding affinities to BRD2. While Dihydroambrettolide and Galaxolide showed the potential to bind to MPro, Sclareol and Vertofix had the best calculated binding affinities to this target. When the flexible docking results analyzed, all the molecules tested had better calculated binding affinities as expected. Benzyl Benzoate and Benzyl Salicylate showed good binding affinities to BRD2. In the case of MPro, Sclareol had the lowest binding affinity among all the tested allergen fragrance molecules. CONCLUSION: Allergen fragrance molecules are readily available, cost-efficient, and shown to be safe for human use. Results showed that several of these molecules had comparable binding affinities as the potential drug molecules reported in the literature to target proteins. Thus, these allergen molecules at correct doses could have significant health benefits.

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.

Fragrance inhalation and adverse health effects: The question of causation.

The toxicology of fragrance materials is largely well understood. Although most are benign, a minority have the potential to cause adverse health effects, notably allergic contact dermatitis resulting from skin sensitization. As a consequence, industry guidelines have banned certain materials and strictly limited the use of others. Recently, data have been published that have been interpreted to suggest that inhalation of fragrances is associated with the occurrence of a variety of health effects, ranging from headaches to asthma attacks. In this review, the evidence basis for these assertions is examined critically and the biological basis and mechanistic plausibility for causation by fragranced products of these health effects is explored. This review concludes that respiratory effects, including irritation and allergy appear highly unlikely to occur by this route. While some sensory/psychosomatic effects are possible, this does not explain the very high rates of adverse effects reported in the recently published questionnaire studies, which this review concludes are more likely to be attributed to methodological weaknesses. Ultimately, it is concluded that adverse health effects arising from fragrance inhalation are uncommon and remain to be identified and confirmed by methodologically rigorous epidemiological investigations supported by a convincing biological and mechanistic basis.

Allergic contact dermatitis caused by hydroperoxides of limonene and dose-response relationship-A repeated open application test (ROAT) study.

BACKGROUND: Contact allergy to oxidized limonene, with hydroperoxides of limonene (Lim-OOHs) as the main allergens, is common. However, high proportions of weak positive and doubtful patch test reactions have been reported. OBJECTIVES: To determine the clinical relevance, elicitation threshold and dose-response relationship of Lim-OOHs in individuals with a positive or doubtful patch test reaction to standard Lim-OOHs 0.3% pet. METHODS: A multicentre 3-week double-blind vehicle-controlled repeated open application test (ROAT) study with a simulated fine fragrance containing Lim-OOHs at 1260, 420 and 140 ppm, equal to a dose/area per application of Lim-OOHs of 3.0, 0.99 and 0.33 µg/cm2 , was performed. RESULTS: Among 11 subjects allergic to Lim-OOHs, 11 (100%), 7 (64%), and 3 (27%), respectively, reacted to the applied doses. No reactions were seen in 17 healthy controls exposed to the highest dose. This difference in reactivity was statistically significant (P < 0.0001). Among 13 subjects with doubtful patch test reactions to Lim-OOHs, two (15%) had positive ROAT reactions to the highest Lim-OOH dose applied (P = 0.36 as compared with controls). CONCLUSIONS: Contact allergy to Lim-OOHs is of clinical relevance in patients with positive patch test reactions. A doubtful patch test reaction to Lim-OOHs 0.3% pet. can be of clinical relevance.

Skin Sensitization Induction Potential From Daily Exposure to Fragrances in Personal Care Products.

BACKGROUND: Many chemicals used for fragrance purposes in a diversity of products have allergenic potential. Based on such concerns, industry groups developed concentration limits for use of fragrance chemicals in personal care and cosmetic products. OBJECTIVE: The aim of this study was to use a quantitative risk assessment to evaluate the potential for skin sensitization induction resulting from daily exposure to fragrance chemicals present in personal care and cosmetic products. METHODS: Product-specific dermal consumer exposure levels were calculated based on product use data in US adult females and benchmarked against acceptable exposure levels based on reported no expected sensitization induction levels to determine a margin of safety for each fragrance under evaluation. CONCLUSIONS: The results demonstrate an increased risk of skin sensitization induction for several leave-on products (lipstick, solid antiperspirant, eye shadow, face cream) for most of the evaluated fragrance chemicals, particularly under high-use exposure scenarios. In contrast, rinse-off products (shampoo, conditioner, facial cleanser) were not associated with risk of skin sensitization induction. Because the approach was based on maximum use limits for fragrance chemicals with skin sensitization concerns, the results suggest these limits may not be protective, particularly in the United States.

RIFM fragrance ingredient safety assessment, 1,1-diethoxyheptane, CAS Registry Number 688-82-4.

The use of this material under current conditions is supported by existing information. 1,1-Diethoxyheptane was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from the read-across analog octanal dimethyl acetal (CAS # 10022-28-3) show that 1,1-diethoxyheptane is not expected to be genotoxic. Based on the application of the non-reactive DST, 1,1-diethoxyheptane does not present a concern for skin sensitization. The repeated dose, developmental and reproductive, and local respiratory toxicity endpoints were completed using the TTC for a Cramer Class I material (0.03 mg/kg/day, 0.03 mg/kg/day, and 1.4 mg/day, respectively). The phototoxicity/photoallergenicity endpoint was completed based on UV spectra. The environmental endpoints were evaluated; 1,1-diethoxyheptane was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.

RIFM fragrance ingredient safety assessment, ethyl 2-methyl-1,3-dioxolane-2-acetate, CAS Registry Number 6413-10-1.

Ethyl 2-methyl-1,3-dioxolane-2-acetate (CAS # 6413-10-1) was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that ethyl 2-methyl-1,3-dioxolane-2-acetate is not genotoxic. Data from ethyl 2-methyl-1,3-dioxolane-2-acetate show that there are no safety concerns for skin sensitization under the current, declared levels of use. Data on ethyl 2-methyl-1,3-dioxolane-2-acetate provide a calculated MOE >100 for the repeated dose, developmental, and reproductive toxicity endpoints. The local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class III material, and the exposure to ethyl 2-methyl-1,3-dioxolane-2-acetate is below the TTC (0.47 mg/day). The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; ethyl 2-methyl-1,3-dioxolane-2-acetate is not expected to be phototoxic/photoallergenic. For the environmental endpoints, ethyl 2-methyl-1,3-dioxolane-2-acetate is not PBT as per the IFRA Environmental Standards, and its risk quotients (i.e., PEC/PNEC) for the aquatic environment based on its current volume of use in Europe and North America are <1.

Potential use of polymers and their complexes as media for storage and delivery of fragrances.

The use of fragrances is often essential to create an elegant, welcoming, or exhilarating environment. Through encapsulation, the release and delivery of fragrances are customized in many consumer products. For such purposes, cost-effective techniques have been developed and employed with the use of various polymers and porous organic materials to efficiently impart fragrances to foods and various other consumer products. After entrapment or uptake/storage of fragrant molecules within a polymeric complex, the properties can be investigated by automated thermal desorption (ATD) analysis. For efficient delivery, fragrances are adsorbed (or entrapped) in some media (e.g., fabric or paper). The release of such entrapped fragrances usually is achieved by spraying. Fragrances can be also loaded in a media by purging aroma gases or by adding fragrance essence directly into a liquid medium. Porous materials, such as zeolites, have been traditionally used for air purification as well as in cosmetics and similar applications. Similarly, other polymeric porous complexes have also been used in fragrance delivery as a templating agent for aromatherapy textiles. Such polymeric materials offer an advantage in terms of development of new hybrid blends via homogenous mixing of two or more matrices. Such blends may possess different desirable physical properties as encapsulants. This review article is aimed at presenting an overview of polymers and their complexes as the main media of fragrance encapsulation. This study also discusses the expansion and future application of porous materials as host matrices for fragrances.

Fragrance allergens in household detergents.

Consumers are confronted with a large number of fragrance allergens from various sources. Until now, the discussion of exposure sources has mainly addressed cosmetic products and neglected other scented products in households. For the first time, fragrance allergens were evaluated in a complete set of detergents in households. In 131 households, we investigated the prevalence of detergents and searched their lists of ingredients for 26 fragrance allergens liable to be indicated on products according to the European Detergents Regulations. On the ingredient lists of 1447 products, these 26 fragrance substances were named almost 2000 times, most often limonene, linalool and hexyl cinnamal. Benzyl salicylate was used frequently in all-purpose cleaners. Linalool and limonene, hexyl cinnamal and butylphenyl methylpropional and citronellol and linalool co-occurred most often together in products. Fragrance allergens co-occurring together most frequently within households were eugenol, coumarin and cinnamyl alcohol. The study shows that detergents could play a relevant role for the exposure of consumers towards fragrance allergens and that they should not be underestimated as an exposure source during the exposure assessment.

Deriving a No Expected Sensitization Induction Level for Fragrance Ingredients Without Animal Testing: An Integrated Approach Applied to Specific Case Studies.

Cosmetic regulations prohibit animal testing for the purpose of safety assessment and recent registration, evaluation and authorization of chemicals guidance states that the local lymph node assay (LLNA) in mice shall only be conducted if in vitro data cannot give sufficient information for classification and labeling. However, Quantitative Risk Assessment for fragrance ingredients requires an NESIL (no expected sensitization induction level), a dose not expected to cause induction of skin sensitization in humans. In absence of human data, this is derived from the LLNA and it remains a key challenge for risk assessors to derive this value from nonanimal data. Here we present a workflow using structural information, reactivity data and KeratinoSens results to predict an LLNA result as a point of departure. Specific additional tests (metabolic activation, complementary reactivity tests) are applied in selected cases depending on the chemical domain of a molecule. Finally, in vitro and in vivo data on close analogues are used to estimate uncertainty of the prediction in the specific chemical domain. This approach was applied to three molecules which were subsequently tested in the LLNA and 22 molecules with available and sometimes discordant human and LLNA data. Four additional case studies illustrate how this approach is being applied to recently developed molecules in the absence of animal data. Estimation of uncertainty and how this can be applied to determine a final NESIL for risk assessment is discussed. We conclude that, in the data-rich domain of fragrance ingredients, sensitization risk assessment without animal testing is possible in most cases by this integrated approach.

Ethyl Glucuronide in Hair (hEtG) after Exposure to Alcohol-based Perfumes.

BACKGROUND: Ethyl Glucuronide in hair (hEtG) is a commonly used biomarker in the diagnosis of chronic excessive alcohol consumption. Despite high diagnostic specificity, some cosmetic treatments may influence the hEtG concentration, leading to false positive results. AIM: The aim of this study was to evaluate three cases of alleged false positive hair samples due to the exposure to perfumes. METHODS: Three subjects were monitored for up to 3 years; at least one sample collection was performed each year; all three men declared to have exposed hair to alcohol-based perfumes during the entire period, except for the last three months before last sample collection. A volunteer treated the right side of his scalp every day during a month period with alcohol-based perfumes. Collection of hair was done at both sides before the first sample treatment and at the end of the month. Hair were processed following the method routinely used in the laboratory for the determination of hEtG (double washing with methanol/dichloromethane, pulverization, overnight incubation in water, and LC-MS/MS analysis, LLOQ: 3pg/mg). RESULTS: EtG levels in hair collected from the three men during the declared exposition period ranged from < 3.0 pg/mg to 1130 pg/mg. hEtG concentrations, at the end of the three-month period without any use of perfumes, were < 3.0 pg/mg for the two men declaring an abstinence from alcoholic beverages and 26.3 pg/mg for the subject declaring an average drinking habit of about 35 g/day ethyl alcohol. Non-treated hair of the volunteer provided negative results, while hEtG levels in treated hair were 14.6 and 24.7 pg/mg. CONCLUSION: Prolonged exposition of hair to alcohol-based perfumes may increase hEtG levels, resulting in false positive results.

Aggregate exposure to common fragrance compounds: Comparison of the contribution of essential oils and cosmetics using probabilistic methods and the example of limonene.

The knowledge of aggregate exposure to different types of products is paramount in the risk assessment. The aim of this study was to compare the relative contribution of essential oils compared to cosmetics on the daily dermal exposure to limonene, an ubiquitous fragrance compound that can be an allergen depending on its degree of oxidation. Aggregate daily exposure to limonene was calculated among a panel of French volunteers using both essential oils and cosmetics, for 4 different specific zones, i.e. face and neck, chest, upper limbs and lower limbs. Calculations were made using a probabilistic Monte Carlo method and sensitivity analysis. The main strength of this work was the inclusion of essential oils in addition to cosmetics in the model. For the first time, the generated data could be used to compare the contribution of these two products in dermal exposure. Essential oils appear to be significant contributors to exposure to limonene particularly for the face. This work is a first step that will permit to determine the exposure to other fragrance compounds with sensitizing potential. These data will be useful for risk managers to consider the inclusion of essential oils in the overall burden of this pathology.

Can the epoxides of cinnamyl alcohol and cinnamal show new cases of contact allergy?

BACKGROUND: Cinnamyl alcohol is considered to be a prohapten and prehapten with cinnamal as the main metabolite. However, many individuals who are allergic to cinnamyl alcohol do not react to cinnamal. Sensitizing epoxides of cinnamyl alcohol and cinnamal have been identified as metabolites and autoxidation products of cinnamyl alcohol. OBJECTIVE: To investigate the clinical relevance of contact allergy to epoxycinnamyl alcohol and epoxycinnamal. METHODS: Irritative effects of the epoxides were investigated in 12 dermatitis patients. Epoxycinnamyl alcohol and epoxycinnamal were patch tested in 393 and 390 consecutive patients, respectively. In parallel, cinnamyl alcohol and cinnamal were patch tested in 607 and 616 patients, respectively. RESULTS: Both epoxides were irritants, but no more positive reactions were detected than when testing was performed with cinnamyl alcohol and cinnamal. Late allergic reactions to epoxycinnamyl alcohol were observed. In general, patients with late reactions showed doubtful or positive reactions to cinnamal and fragrance mix I at regular patch testing. CONCLUSION: The investigated epoxides are not important haptens in contact allergy to cinnamon fragrance. The high frequency of fragrance allergy among patients included in the irritancy study showed the difficulty of suspecting fragrance allergy on the basis of history; patch testing broadly with fragrance compounds is therefore important.