Determination of acceptable margins of exposure (MoE) for NAM-based skin sensitisation risk assessment.

Abstract

Skin sensitisation safety decisions for consumer goods predominantly use approaches such as Quantitative Risk Assessment (QRA) to judge whether a dermal exposure is low risk by comparing a point of departure (PoD) against an expected consumer exposure. Traditionally, the no-expected-sensitisation-induction level (NESIL), derived from human or murine studies, has provided this PoD. Safety Assessment Factors (SAFs) are used to adjust the NESIL to derive an Acceptable Exposure Level (AEL). Exposures are considered low risk when the AEL exceeds the Consumer Exposure Level (AEL:CEL > 1). An equivalent approach evaluates the Margin of Exposure (MoE), defined as the PoD/CEL, and deems exposure low risk when the MoE exceeds a predetermined threshold. As new approach methodologies (NAMs) increasingly supply PoDs, a key question is whether MoE and SAFs, established for human and murine NESILs, are appropriate for NAM-based PoDs, or whether recalibration is required to maintain protectiveness. We propose a statistical framework that converts precedent MoE and SAFs used with traditional NESILs into statistically equivalent thresholds for NAM-derived PoDs. The framework uses benchmark consumer exposure scenarios for skin-sensitising ingredients and proposes a risk-matching approach that enables conversion of traditional acceptable MoEs/SAFs to NAM PoD-appropriate equivalents. Assuming a risk assessor can specify the desired MoE or SAF for a traditional NESIL, the output is a simple conversion table for NAM PoD-appropriate equivalent values. We provide a conversion table for PoDs from SARA-ICE, the GARDskin dose-response assay, and the multiple-regression approach and illustrate application with a simple, illustrative case study.