Updating the Dermal Sensitisation Thresholds using an expanded dataset and an in silico expert system.

The Dermal Sensitisation Thresholds (DST) are Thresholds of Toxicological Concern, which can be used to justify exposure-based waiving when conducting a skin sensitisation risk assessment. This study aimed to update the published DST values by expanding the size of the Local Lymph Node Assay dataset upon which they are based, whilst assigning chemical reactivity using an in silico expert system (Derek Nexus). The potency values within the expanded dataset fitted a similar gamma distribution to that observed for the original dataset. Derek Nexus was used to classify the sensitisation activity of the 1152 chemicals in the expanded dataset and to predict which chemicals belonged to a High Potency Category (HPC). This two-step classification led to three updated thresholds: a non-reactive DST of 710 µg/cm2 (based on 79 sensitisers), a reactive (non-HPC) DST of 73 µg/cm2 (based on 331 sensitisers) and an HPC DST of 1.0 µg/cm2 (based on 146 sensitisers). Despite the dataset containing twice as many sensitisers, these values are similar to the previously published thresholds, highlighting their robustness and increasing confidence in their use. By classifying reactivity in silico the updated DSTs can be applied within a skin sensitisation risk assessment in a reproducible, scalable and accessible manner.

Application of the dermal sensitization threshold concept to chemicals classified as high potency category for skin sensitization assessment of ingredients for consumer products.

Skin sensitization evaluation is a key part of the safety assessment of ingredients in consumer products, which may have skin sensitizing potential. The dermal sensitization threshold (DST) concept, which is based on the concept of the thresholds of toxicological concern, has been proposed for the risk assessment of chemicals to which skin exposure is very low level. There is negligible risk of skin sensitization if a skin exposure level for the substance of interest was below the reactive DST which would protect against 95% of protein-reactive chemicals. For the remaining 5%, the substance with the defined knowledge of chemical structure (i.e., High Potency Category (HPC) rules) needs to be excluded from the application. However, the DST value for HPC chemicals has not yet been proposed. In this study, we calculated the 95th percentile probabilities estimate from distributions of skin sensitization potency data and derived a novel DST for HPC chemicals (HPC DST) of 1.5 µg/cm2. This value presents a useful default approach for unidentified substances in ingredients considering, as a worst-case scenario, that the unidentified compound may be a potent skin sensitizer. Finally, we developed a novel risk assessment workflow incorporating the HPC DST along with the previously published DSTs.

Extension of the Dermal Sensitisation Threshold (DST) approach to incorporate chemicals classified as reactive.

The evaluation of chemicals for their skin sensitising potential is an essential step in ensuring the safety of ingredients in consumer products. Similar to the Threshold of Toxicological Concern, the Dermal Sensitisation Threshold (DST) has been demonstrated to provide effective risk assessments for skin sensitisation in cases where human exposure is low. The DST was originally developed based on a Local Lymph Node Assay (LLNA) dataset and applied to chemicals that were not considered to be directly reactive to skin proteins, and unlikely to initiate the first mechanistic steps leading to the induction of sensitisation. Here we have extended the DST concept to protein reactive chemicals. A probabilistic assessment of the original DST dataset was conducted and a threshold of 64 µg/cm(2) was derived. In our accompanying publication, a set of structural chemistry based rules was developed to proactively identify highly reactive and potentially highly potent materials which should be excluded from the DST approach. The DST and rule set were benchmarked against a test set of chemicals with LLNA/human data. It is concluded that by combining the reactive DST with knowledge of chemistry a threshold can be established below which there is no appreciable risk of sensitisation for protein-reactive chemicals.

Principles for identification of High Potency Category Chemicals for which the Dermal Sensitisation Threshold (DST) approach should not be applied.

An essential step in ensuring the toxicological safety of chemicals used in consumer products is the evaluation of their skin sensitising potential. The sensitising potency, coupled with information on exposure levels, can be used in a Quantitative Risk Assessment (QRA) to determine an acceptable level of a given chemical in a given product. Where consumer skin exposure is low, a risk assessment can be conducted using the Dermal Sensitisation Threshold (DST) approach, avoiding the need to determine potency experimentally. Since skin sensitisation involves chemical reaction with skin proteins, the first step in the DST approach is to assess, on the basis of the chemical structure, whether the chemical is expected to be reactive or not. Our accompanying publication describes the probabilistic derivation of a DST of 64 µg/cm(2) for chemicals assessed as reactive. This would protect against 95% of chemicals assessed as reactive, but the remaining 5% would include chemicals with very high potency. Here we discuss the chemical properties and structural features of high potency sensitisers, and derive an approach whereby they can be identified and consequently excluded from application of the DST.