Abstract
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 μg/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.
Highlights
The Threshold of Toxicological Concern (TTC) is a pragmatic approach for risk assessment and management of chemicals of known structure with low human exposure and little or no compound-specific toxicological data
In cases where multiple study data were available for one substance, only one study was selected in the order of which had more reliability, TABLE 1 | Data sources of the Hazard Evaluation Support System (HESS) threshold of toxicological concern (TTC) dataset
The newly compiled HESS TTC dataset is a high-quality dataset that consists of the reliable subacute or subchronic toxicity data of industrial chemical substances according or equivalent to standard test guidelines
Summary
The Threshold of Toxicological Concern (TTC) is a pragmatic approach for risk assessment and management of chemicals of known structure with low human exposure and little or no compound-specific toxicological data. TTC uses exposure thresholds for humans derived from oral toxicity test results for cancer and non-cancer endpoints. If the exposure is lower than the TTC value, it suggests a very low potential for safety concerns, and if it exceeds the TTC value, additional data is needed to assess the risk of concern. For non-cancer endpoints, Munro et al (1996) proposed a comprehensive human exposure threshold based on the relationship between chemical structure and toxicity. The 5th percentile value was calculated from the distribution of Point of Departure (POD) values for each class, and the human exposure value for each class was derived
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