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

Hexafluoropropylene oxide trimer acid (HFPO-TA, C2F5(CF2OCF(CF3))2COOH) 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.