Hexafluoropropylene Oxide Trimer Acid Is an Unsafe Substitute to Perfluorooctanoic Acid Due to Its Remarkable Liver Accumulation in Mice Disclosed by Comprehensive Toxicokinetic Models

COOH) is widely used as an alternative to perfluorooctanoic acid (PFOA), but whether it is a safe alternative requires further evaluation. In this study, male mice were exposed to three dosages (0.56, 2.8, and 14 mg/kg) of HFPO-TA via single oral gavage or intravenous injection for 28 days. HFPO-TA was rapidly absorbed into the blood and tissues within 15 min postexposure, with a volume of distribution approximately 3 times higher than PFOA, indicating a greater propensity for tissue distribution. Notably, HFPO-TA was distinctly more accumulated in liver compared to plasma and other tissues and very poorly excreted, with only 2.23% in urine and 7.26% in feces on the 21st day after oral exposure. A physiologically based toxicokinetic model, extrapolated to long-term low-dose exposure, revealed a lower bile clearance rate (8-fold) and higher liver partition coefficient (7-fold) than PFOA, and a higher hepatic first-pass effect of HFPO-TA (5-fold) than PFOA, contributing to its remarkable liver accumulation (5-fold). Molecular docking analysis reveals strong binding affinity of HFPO-TA with typical enterohepatic circulation transport proteins due to its strong hydrophobicity, flexible chain structure, and formation of additional hydrogen bonds, favoring HFPO-TA accumulation in the liver. The results suggest that HFPO-TA may not be a safe substitute for legacy PFAS, and further human exposure risk assessments are warranted.