Development of a New Threshold of Toxicological Concern Database of Non-cancer Toxicity Endpoints for Industrial Chemicals

In cases where chemical-specific toxicity data are absent or limited, the threshold of toxicological concern (TTC) offers an alternative to assess human exposure below which "there would be no appreciable risk to human health." The application of TTC to non-cancer systemic endpoints has been pursued for decades using a chemical classification and Point of Departure (POD). This study presents a new POD dataset of oral subacute/subchronic toxicity studies in rats for 656 industrial chemicals retrieved from the Hazard Evaluation Support System (HESS) Integrated Platform, which contains hundreds of reliable repeated-dose toxicity test data of industrial chemicals under the Chemical Substances of Control Law in Japan. The HESS TTC dataset was found to have less duplication with substances in other reported TTC datasets. Each chemical was classified into a Cramer Class, with 68, 3, and 29% of these 656 chemicals distributed in Classes III, II, and I, respectively. For each Cramer Class, a provisional Tolerable Daily Intake (TDI) was derived from the 5th percentile of the lognormal distribution of PODs. The TDIs were 1.9 and 30 mu g/kg bw/day for Classes III and I, respectively. The TDI for Cramer Class II could not be determined due to insufficient sample size. This work complements previous studies of the TTC approach and increases the confidence of the thresholds for non-cancer endpoints by including unique chemical structures. This new TTC dataset is publicly available and can be merged with existing databases to improve the TTC approach.