Application of Defined Approaches to Assess Skin Sensitization Potency of Isothiazolinone Compounds.

Abstract

Isothiazolinones (ITs) are widely used as antimicrobial preservatives in cosmetics and as additives for preservation of consumer and industrial products to control bacteria, fungi, and algae. Although they are effective biocides, they have the potential to produce skin irritation and sensitization, which poses a human health hazard. In this project, we evaluated nonanimal defined approaches (DAs) for skin sensitization that can provide point-of-departure estimates for use in quantitative risk assessment for ITs. The skin sensitization potential of six ITs was evaluated using three internationally harmonized nonanimal test methods: the direct peptide reactivity assay, KeratinoSens™, and the human cell line activation test. Results from these test methods were then applied to two versions of the Shiseido Artificial Neural Network DA. Sensitization hazard or potency predictions were compared with those of the in vivo murine local lymph node assay (LLNA). The nonanimal methods produced skin sensitization hazard and potency classifications concordant with those of the LLNA. EC3 values (the estimated concentration needed to produce a stimulation index of three, the threshold positive response) generated by the DAs had less variability than LLNA EC3 values, and confidence limits from the DAs overlapped those of the LLNA EC3 for most substances. The application of in silico models to in chemico and in vitro skin sensitization data is a promising data integration procedure for DAs to support hazard and potency classification and quantitative risk assessment.