Comparison of Cramer classification between Toxtree, the OECD QSAR Toolbox and expert judgment.

The Threshold of Toxicological Concern (TTC) is a pragmatic approach in risk assessment. In the absence of data, it sets up levels of human exposure that are considered to have no appreciable risk to human health. The Cramer decision tree is used extensively to determine these exposure thresholds by categorizing non-carcinogenic chemicals into three different structural classes. Therefore, assigning an accurate Cramer class to a material is a crucial step to preserve the integrity of the risk assessment. In this study the Cramer class of over 1000 fragrance materials across diverse chemical classes were determined by using Toxtree (TT), the OECD QSAR Toolbox (TB), and expert judgment. Disconcordance was observed between TT and the TB. A total of 165 materials (16%) showed different results from the two programs. The overall concordance for Cramer classification between TT and expert judgment is 83%, while the concordance between the TB and expert judgment is 77%. Amines, lactones and heterocycles have the lowest percent agreement with expert judgment for TT and the TB. For amines, the expert judgment agreement is 45% for TT and 55% for the TB. For heterocycles, the expert judgment agreement is 55% for TT and the TB. For lactones, the expert judgment agreement is 56% for TT and 50% for the TB. Additional analyses were conducted to determine the concordance within various chemical classes. Critical checkpoints in the decision tree are identified. Strategies and guidance on determining the Cramer class for various chemical classes are discussed.

A practical guidance for Cramer class determination.

Expanded use of the Threshold of Toxicological Concern (TTC) methodology has brought into discussion the intent of the original questions used in the Cramer scheme or Cramer decision tree. We have analysed, both manually and by Toxtree software, a large dataset of fragrance ingredients and identified several issues with the original Cramer questions. Some relate to definitions and wording of questions; others relate to in silico interpretation of the questions. We have endeavoured to address all of these inconsistencies and misinterpretations without changing the basic structure and principles of the original decision tree. Based on the analysis of a large data set of over 2500 fragrance ingredients, we found that most of the 33 questions in the original Cramer scheme are straightforward. Through repeated examination each of the 33 questions, we found 14 where the logic underlying the development of the rule is unclear. These questions are well served by minor wording changes and/or further explanation designed to capture what we perceive to be the intent of the original decision tree. The findings reported here could be used as a guidance for conducting Cramer classification and provide advices for the improvement of the in silico tools.

Categorization of fragrance contact allergens for prioritization of preventive measures: clinical and experimental data and consideration of structure-activity relationships.

Contact allergy to fragrances is still relatively common, affecting ∼ 16% of patients patch tested for suspected allergic contact dermatitis, considering all current screening allergens. The objective of the review is to systematically retrieve, evaluate and classify evidence on contact allergy to fragrances, in order to arrive at recommendations for targeting of primary and secondary prevention. Besides published evidence on contact allergy in humans, animal data (local lymph node assay), annual use volumes and structure-activity relationships (SARs) were considered for an algorithmic categorization of substances as contact allergens. A total of 54 individual chemicals and 28 natural extracts (essential oils) can be categorized as established contact allergens in humans, including all 26 substances previously identified as contact allergens (SCCNFP/0017/98). Twelve of the 54 individual chemicals are considered to be of special concern, owing to the high absolute number of reported cases of contact allergy (>100). Additionally, 18 single substances and one natural mixture are categorized as established contact allergens in animals. SARs, combined with limited human evidence, contributed to the categorization of a further 26 substances as likely contact allergens. In conclusion, the presence of 127 single fragrance substances and natural mixtures should, owing to their skin sensitizing properties, be disclosed, for example on the label. As an additional preventive measure, the maximum use concentration of 11 substances of special concern should be limited to 100 ppm. The substance hydroxyisohexyl 3-cyclohexene carboxaldehyde and the two ingredients chloroatranol and atranol in the natural extracts Evernia prunastri and Evernia furfuracea should not be present in cosmetic products.

Inhalation exposure of children to fragrances present in scented toys.

UNLABELLED: When utilized in the perfuming of children's toys, fragrances capable of inducing contact allergy in human skin may also become bioavailable to children via the inhalation route. The aim of this study was to determine the area-specific emission rates of 24 fragrances from a plasticized PVC reference material that was meant to mimic a real plastic toy. This material was introduced into an emission chamber for 28 days at handling conditions or at worst-case conditions. As a result, fragrances can be separated into three categories according to their emission rates ranging from 0.0041 to 16.2 mg/m² × h, i.e., highly volatile, semivolatile, and low-volatile compounds. Compounds of the first and second categories were monitored with decreasing emission rates. Substances of the third category were detected with increasing emission rates over time. Further, higher temperatures led to higher emission rates. The emission concentration of fragrances from four real scented toys varied between 1.10 and 107 µg/m³ at day 1 in the test chamber. Therefore, short-term inhalation exposure to fragrances originating from toys was in the range of 0.53-2700 ng/kg BW/d for the children of age 1 and older. Long-term exposure to these fragrances was calculated in the range of 2.2-220 ng/kg BW/d. PRACTICAL IMPLICATIONS: Besides household products and cosmetics, fragrances can be found in toys for children. Some fragrances are known contact allergens in the skin, but there is a lack of information on their effects in the human respiratory tract. Here, we analyzed and categorized fragrances present in a plasticized PVC reference material according to their emission profiles and volatility. We also demonstrate that volatile fragrances are being emitted from real toys and thus may get inhaled under consumer conditions to different extents.

Allergic contact dermatitis caused by farnesol: clinical relevance.

CONTEXT: The fragrance material farnesol is cited as an infrequent but important cause of allergic contact dermatitis (ACD). It is included in the fragrance mix II patch series and requires labeling in the European Union if it is used in a consumer product. OBJECTIVE: To review the existing literature to determine the causative role of farnesol in clinical contact allergy. MATERIALS AND METHODS: Survey of the literature on farnesol studies; predictive and clinical elicitation tests in case reports, reviews, and abstracts. RESULTS: Predictive animal studies demonstrated in most cases that farnesol was a nonsensitizer. However, 2 local lymph node assays (LLNAs) indicated strong sensitization potential. Predictive human test data indicated a low potential, if any, for sensitization in human tests with farnesol at 10% or 12%. A few clinical reports indicated low-level allergy or questionable reactions to farnesol, with 5% being the most commonly used. There were also reports in which no reactions were seen. DISCUSSION: Predictive testing on farnesol in animals shows conflicting results depending on the study methodology used. Human predictive patch-test data also had gaps that prevented it from being definitive in pointing to a causative relationship between farnesol and contact dermatitis. The real sensitizing potential of a material can best be determined by evaluating the clinical and epidemiological data so as to help resolve the conflicting animal and human predictive test data. CONCLUSIONS: This literature and scoring exercise showed that predictive and clinical elicitation data do not document a clear causative determination that farnesol is a frequent contact allergen. Detailed clinical relevance and patient studies should clarify the clinical problem farnesol represents.

Fragrance material review on cinnamyl cinnamate.

A toxicologic and dermatologic review of Cinnamyl cinnamate when used as a fragrance ingredient is presented.

Fragrance material review on isodamascone (isomer unspecified).

A toxicologic and dermatologic review of isodamascone when used as a fragrance ingredient is presented.

Fragrance material review on cinnamyl tiglate.

A toxicologic and dermatologic review of cinnamyl tiglate when used as a fragrance ingredient is presented.

Fragrance material review on butyl salicylate.

A toxicologic and dermatologic review of butyl salicylate when used as a fragrance ingredient is presented.

Fragrance material review on isobutyl cinnamate.

A toxicologic and dermatologic review of isobutyl cinnamate when used as a fragrance ingredient is presented.

Fragrance material review on isopropyl cinnamate.

A toxicologic and dermatologic review of isopropyl cinnamate when used as a fragrance ingredient is presented.

Fragrance material review on cinnamyl isovalerate.

A toxicologic and dermatologic review of cinnamyl isovalerate when used as a fragrance ingredient is presented.

Fragrance material review on cinnamyl formate.

A toxicologic and dermatologic review of cinnamyl formate when used as a fragrance ingredient is presented.

Fragrance material review on cinnamyl propionate.

A toxicologic and dermatologic review of cinnamyl propionate when used as a fragrance ingredient is presented.

Fragrance material review on cinnamyl butyrate.

A toxicologic and dermatologic review of cinnamyl butyrate when used as a fragrance ingredient is presented.

Fragrance material review on methyl-alpha-ionone.

A toxicologic and dermatologic review of methyl-alpha-ionone when used as a fragrance ingredient is presented.

Fragrance material review on trans,trans-delta-damascone.

A toxicologic and dermatologic review of trans,trans-delta-damascone when used as a fragrance ingredient is presented.

Fragrance material review on 1,3-dimethyl-3-butenyl salicylate.

A toxicologic and dermatologic review of 1,3-dimethyl-3-butenyl salicylate when used as a fragrance ingredient is presented.

Fragrance material review on ethyl salicylate.

A toxicological and dermatological review of ethyl salicylate when used as a fragrance ingredient is presented.

Fragrance material review on pentyl salicylate.

A toxicologic and dermatologic review of pentyl salicylate when used as a fragrance ingredient is presented.