Proposal for a revised TSCA carbon tetrachloride existing chemical exposure limit (ECEL) based on PBPK and benchmark dose modeling

Carbon tetrachloride (CTC) is classified by the United States Environmental Protection Agency (US EPA) as "likely to be carcinogenic to humans," based on evidence in mice. In 2021, under the Toxic Substances Control Act (TSCA), US EPA derived a CTC cancer existing chemical exposure limit (ECEL) of 0.03 parts per million (ppm) for occupational exposure, and in 2024, released its Final Risk Management Rule incorporating this ECEL. However, US EPA's CTC ECEL is considerably lower than global occupational exposure limits (OELs) (0.1-10 ppm), and arguably not consistent with the best available science, as mandated by TSCA. In its derivation of the liver cancer ECEL, US EPA applied the lowest observed adverse effect concentration (LOAEC)/no observed adverse effect concentration (NOAEC) approach, rather than benchmark dose (BMD) modeling, and did not use CTC-specific physiologically based pharmacokinetic (PBPK) models for animal-to-human extrapolation. Here we derive revised cancer and non-cancer CTC ECELs of 1.5 and 1.6 ppm, respectively, considering the most reliable and sensitive endpoints and scientifically supported methodologies, including BMD and PBPK modeling. The revised cancer ECEL is 50-fold higher than US EPA's ECEL, more consistent with global OELs, and well below the OSHA permissible exposure limit (PEL) of 10 ppm. Overall, this approach would be expected to be applicable to other chemicals with a similar mode of action.