Utilizing Threshold of Toxicological Concern (TTC) with high throughput exposure predictions (HTE) as a risk-based prioritization approach for thousands of chemicals

•An approach of using TTC and HTE to facilitate risk-based prioritization is presented.•Used the Kroes et al. (2004) workflow to identify the number of chemicals within respective TTC classes.•Compared the predicted exposures with the relevant TTC values.•The appropriate TTC value was found to be protective for most TTC categories.•Possible refinements to the approach are outlined. Regulatory agencies across the world are facing the challenge of performing risk-based prioritization of thousands of chemicals in commerce. Here, we present an approach using the Threshold of Toxicological Concern (TTC) combined with heuristic high-throughput exposure (HTE) modelling to rank order chemicals for further evaluation. Accordingly, for risk-based prioritization, chemicals with exposures > TTC would be ranked as higher priority for further evaluation whereas substances with exposures the Cramer Class III TTC (1.5 μg/kg-day). We extended the analysis by profiling the same dataset through the TTC workflow published by Kroes et al. (2004) which accounts for known exclusions to the TTC as well as structural alerts. UCI exposures were then compared to the appropriate class-specific TTC. None of the substances categorized as Cramer Class I or Cramer Class II exceeded their respective TTC values and no more than 2% of substances categorized as Cramer Class III or acetylcholinesterase inhibitors exceeded their respective TTC values. The modeled UCI exposures for the majority of the 1853 chemicals with genotoxicity structural alerts did exceed the TTC of 0.0025 μg/kg-day, but only 79 substances exceeded this TTC if median exposure values were used. For substances for which UCI exposures exceeded relevant TTC values, we highlight possible approaches for consideration to refine the HTE: TTC approach. Overall, coupling TTC with HTE offers promise as a pragmatic first step in ranking substances as part of a risk-based prioritization approach.