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

Abstract

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 developed, validated, and adopted in OECD test guidelines. However, work is ongoing to develop NAMs for predicting skin sensitization potency on a quantitative scale for use as a point of departure (POD) in next-generation risk assessment (NGRA). GARDskin Dose-Response (DR) is an adaptation of the validated GARDskin assay (OECD TG 442E), and the readout of the assay is a quantitative potency prediction similar to the No Expected Sensitization Induction Level (NESIL) value (µg/cm2). The goal of this study was to evaluate the performance of the GARDskin DR assay for potency prediction of fragrance ingredients. One hundred (100) fragrance ingredients from a reference database covering varied structural reactivity domains and potency were tested in GARDskin DR. Materials tested had varied 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 1 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- 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.