Evaluations of Sex Differences in Dosimetry in Rats Following Perfluorohexanesulfonamide (PFHxSA) Oral Exposure

Perfluorohexanesulfonamide (PFHxSA) is used as a replacement for legacy PFAS. Non-targeted analysis identified perfluorohexane sulfonic acid (PFHxS) as the primary metabolite of PFHxSA in plasma and liver in a short-term (5-day) repeat dose study with male and female Sprague Dawley rats (Crl:CD(SD)). This evaluation sought to quantitate PFHxSA and PFHxS concentrations by targeted liquid chromatography/mass spectrometry (LC/MS/MS) to further evaluate metabolism and dosimetry following in vivo PFHxSA exposure. In males, quantified plasma and liver PFHxS concentrations were higher than those of its parent, PFHxSA. PFHxS was detected in female plasma and liver at on average 5.3- and 2.9-fold lower, respectively, than PFHxSA. In both sexes, plasma and liver PFHxSA dose concentrations decreased with increasing doses, suggesting hepatic enzyme induction. Liver-to-plasma partitioning favored plasma across all doses in both sexes. In vitro-in vivo extrapolation (IVIVE) suggests higher steady-state plasma concentrations in humans vs. rats for PFHxSA and PFHxS. The in vivo concentrations aligned reasonably (i.e., within 6- to 12.1-fold) with the IVIVE-derived rat plasma estimates. Identifying when PFAS co-exposures may result due to metabolic biotransformation of the parent PFAS to a stable and potentially bioactive metabolite is important to better inform the interpretation of in vivo and in vitro findings.