SARA-ICE model for identification of skin sensitizers
Assessing the potential of chemicals to cause skin sensitization (allergic reaction) is essential for protecting public health. While nonanimal methods have been developed, single tests alone are not sufficient to fully determine a chemical’s sensitization risk or potency. Defined approaches (DAs) such as those described in OECD TG 497 (OECD 2025) combine multiple data sources for more reliable evaluations. However, existing DAs lack the ability to calculate a specific dose threshold, known as a point-of-departure (POD), for use in risk assessments.
The Skin Allergy Risk Assessment–Integrated Chemical Environment (SARA-ICE) DA for skin sensitization (Reinke et al. 2025) was developed by NICEATM and the consumer products company Unilever specifically to address this challenge. SARA-ICE employs statistical modeling to estimate a human-relevant metric called the ED01. The ED01 is the probability distribution for the dermal dosage at which there is a 1% chance of inducing sensitization, making it directly applicable to risk assessment. SARA-ICE integrates data from various in vitro tests as well as data from the local lymph node assay and HPPT, drawing upon historical data from 434 chemicals, and accounts for variability and uncertainty in input data. In addition to the ED01, SARA-ICE provides probabilities for GHS skin sensitization classifications. Specifically, the model calculates the probability that a chemical would be placed into a GHS subcategory: severe sensitizers (1A), moderate sensitizers (1B), or Not Classified (NC). In a case study focused on isothiazolinones, SARA-ICE demonstrated its ability to integrate diverse data inputs and calculate ED01 values for six isothiazolinone compounds that compared favorably with results based on historical datasets (Reinke et al. 2025).
In 2025, OECD revised TG 497 to include a more limited guideline-specific version of the SARA-ICE model, which provides a POD as the geometric mean of the ED01 and does not provide hazard or GHS classification predictions. It also assumes that any chemical evaluated is presumed to be a skin sensitizer due to model restrictions.
To broaden the accessibility of the SARA-ICE model, in 2025 NICEATM developed the SARA-ICE app. The app provides access to the two SARA-ICE models: the "OECD TG 497 DA”, which aligns with TG 497 criteria, and the “Extended Model”, which allows the user to make a hazard determination and predict GHS subcategorization and alternative “EDx” outputs (e.g. ED05, the dose at which 5% of a population would be sensitized). The Extended Model does not assume a chemical is a skin sensitizer and allows the user to adjust the GHS decision threshold depending on desired stringency. The OECD TG 497 DA is static because it is based on the guideline; however, the Extended Model could be modified in the future to add in more test methods or outputs. Current outputs include a graphic representation of the uncertainty distribution and a tabular report of the probability distributions for various classifications. Future development may add methods to the Extended Model, in silico reactivity structural alerts, extrapolation of population-level effects, a user input feature, and a downloadable local version.