Deriving a point-of-departure for skin sensitization risk assessments, application of the SARA-ICE tool to a diverse set of chemicals

The Skin Allergy Risk Assessment - Integrated Chemical Environment (SARA-ICE) is a Bayesian framework for quantitative skin sensitization hazard and potency assessment and estimates an ED₀₁, the dermal dose associated with a 1% sensitization probability in humans. SARA-ICE has two implementations: (i) SARA-ICE DA, a fixed defined approach (DA) for point-of-departure derivation (PoD), accepted by the Organisation for Economic Co-operation and Development and usable under Mutual Acceptance of Data; and (ii) SARA-ICE Extended, which returns ED₀₁ distributions, a prediction uncertainty ratio, and probabilities for assignments to Globally Harmonized System of Classification and Labeling of Chemicals (GHS) categories. Using in chemico and in vitro skin sensitization data on 180 substances of interest to U.S. federal agencies, we evaluated the performance of both SARA-ICE versions against human and murine data and OECD Guideline 497 DAs. SARA-ICE Extended showed high sensitivity for identifying sensitizers (up to 100% vs. human data), with balanced accuracy spanning 64-97%; its specificity for non-sensitizers was lower but consistent with comparator methods. For GHS subcategorization, accuracy ranged from 33-77% with low underprediction (8-21%), with concordance highest with the Guideline 497 DAs. We demonstrate application of the SARA-ICE DA using PoDs defined from the ED₀₁ in a quantitative risk assessment across a range of exposures. PoD -based risk calls from SARA-ICE were broadly comparable to HPPT-derived metrics and generally more protective than LLNA-derived PoDs. Collectively, these results support SARA-ICE as an approach for hazard identification and exposure-led safety assessment within next-generation risk assessment frameworks.