What determines skin sensitization potency: Myths, maybes and realities. The 500 molecular weight cut-off: An updated analysis.

It is widely accepted that substances must have a molecular weight (MW) < 500 to penetrate effectively through the skin to induce sensitization. Roberts et al. (2012. Contact Dermatitis 68: 32-41) evaluated a data set of 699 substances taken from the TIMES-SS expert system and identified that of the 13 substances with a MW > 500, five were sensitizers. This provided good evidence to refute such a MW 500 threshold. While Roberts et al. (2012) made a convincing case that the MW > 500 cut-off was not a true requirement for sensitization, the number of counter examples identified were too few to draw any statistical conclusions. This updated analysis systematically interrogated a large repository of sensitization information collected under the EU REACH regulation. A data set of 2904 substances that had been tested for skin sensitization, using guinea pigs and/or mice were collected. The data set contained 197 substances with a MW > 500; 33 of these were skin sensitizers. Metal containing complexes, reaction products and mixtures were excluded from further consideration. The final set of 14 sensitizers substantiated the original findings. The study also assessed whether the same reaction chemistry principles established for low MW sensitizers applied to chemicals with a MW > 500. The existing reaction chemistry considerations were found appropriate to rationalize the sensitization behaviour of the 14 sensitizers with a MW > 500. The existence of the MW 500 threshold, based on the widespread misconception that the ability to penetrate efficiently the stratum corneum is a key determinant of skin sensitization potential and potency, was refuted. Copyright © 2016 John Wiley & Sons, Ltd.

An assessment of the ECETOC TRA Consumer tool performance as a screening level tool.

BACKGROUND: The European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) Targeted Risk Assessment (TRA) Consumer tool was developed to fill in a methodology gap for a high throughput, screening level tool to support industry compliance with the European Union's Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) regulation. OBJECTIVE: To evaluate if the TRA Consumer tool has met its design of being a screening level tool (i.e., one which does not under-predict potential exposures). METHODS: The TRA Consumer tool algorithms and defaults were reviewed and performance benchmarked vs. other consumer models and/or empirical data. Findings from existing reviews of the TRA consumer tool were also considered and addressed. RESULTS: TRA predictions based on its default inputs exceeded measured exposures when available, typically by orders of magnitude, and were generally greater than or similar to those of other consumer exposure tools. For dermal exposure from articles, there was no evidence that a diffusivity approach would provide more appropriate exposure estimates than those of the TRA. When default values are refined using more specific data, the refined values must be considered holistically to reflect the situation being modeled as some parameters may be correlated. SIGNIFICANCE: This is the first evaluation of the ECETOC TRA consumer tool in its entirety, considering algorithms, input defaults, and associated predictions for consumer products and articles. The evaluation confirmed its design as a screening level tool. IMPACT STATEMENT: The ECETOC TRA Consumer tool has been widely applied to generate exposure estimates to support chemical registrations under the EU REACH regulation. This evaluation supports the appropriateness of the TRA as a screening level exposure assessment tool. It also warrants additional measurements of consumer exposure, especially for article use scenarios, to aid the development of consumer exposure tools and chemical risk assessment.