Determining a point of departure for skin sensitization potency and quantitative risk assessment of fragrance ingredients using the GARDskin dose-response assay.

Potency and quantitative risk assessment are essential for determining safe concentrations for the for­mulation of potential skin sensitizers into consumer products. Several new approach methodologies (NAMs) for skin sensitization hazard assessment have been adopted in OECD test guidelines. Work is ongoing to develop NAMs for predicting skin sensitization potency on a quantitative scale for use as a point of departure in next generation risk assessment (NGRA). GARDskin Dose-Response (DR) is an adaptation of the GARDskin assay (OECD TG 442E); its readout is a quantitative potency pre­diction similar to the No Expected Sensitization Induction Level (NESIL) value (μg/cm2). Our goal was to evaluate the performance of the GARDskin DR for potency prediction of fragrance ingre­dients. One hundred fragrance ingredients from a reference database were tested in GARDskin DR. Materials tested had various protein-binding reactivity alerts, including Schiff base, Michael addition, SN2, and acylation. Potency categories were predicted with a total accuracy of 37% and an approximate accuracy (exact match or off by one category) of 81%. Combining predicted weak and very weak categories increased total accuracy to 53% and approximate accuracy to 98%. The mean prediction error for the NESIL and local lymph node assay (LLNA) EC3 was 3.15-fold and 3.36-fold, respectively. Based on the results of this study, GARDskin DR is a promising pre­dictor of skin sensitization potency with an applicability domain covering a wide range of fragrance ingredient reaction mechanisms, increasing the confidence in using the assay to conduct NGRA, ultimately reducing the need for animal testing.