Toxicokinetics of Bisphenol S in male and female Harlan Sprague Dawley rats and B6C3F1/N mice following oral gavage administration

Abstract

Bisphenol S (BPS), a bisphenol analogue, is a component of polyether sulfones. As part of the toxicity testing of BPS, toxicokinetic studies were conducted following single gavage (34, 110 or 340 mg/kg) or intravenous (iv) administration of BPS to male and female Harlan Sprague Dawley rats and B6C3F1/N mice. Blood was collected at time points up to 72 h after dosing and plasma was analyzed for both total BPS (unconjugated and conjugated) and free BPS (unconjugated) by liquid chromatograph-tandem mass spectrometry. The concentration vs time plots suggest enterohepatic recirculation which is more pronounced in mice than rats with a mono-exponential elimination in rats after oral administration but a bi-exponential elimination in mice (oral and iv) and after iv in rats. Mean plasma concentrations vs. time were analyzed using compartmental models. BPS was rapidly absorbed in rats with free BPS Tmax ≤ 2h in male, 5.5 h in female. Elimination half-lives of free BPS in rats increased from ~ 6 to ~ 12 h and AUC0-∞ increased disproportionally with dose, indicating a saturation of kinetics. Total BPS Tmax was 1-3 h in rats with AUC0-∞ 15-28-fold higher than corresponding free BPAF AUC0-∞

indicating rapid and extensive conjugation of BPS in rats. A similar doubling of elimination half-life (9 to 19 h) was observed for total BPS with increasing dose, but AUC was linear with dose. In mice, highest concentrations were measured at first time point (15 min) following oral administration. In male mice, the elimination half-lives of free BPS and total BPS were shorter (ca. 2-3 h) than rats after 34 and 340 mg/kg oral doses. AUC for total BPS and free BPS in mice increased non-linearly with increasing dose. AUC0-∞ for rats and mice was generally similar at each dose level. Similar to rats, extensive metabolism in mice is indicated by AUC0-∞of total BPS ~ 11x that of free BPS. No sex differences were observed in either species. Oral bioavailability of free BPS in mice (12-37%) was slightly higher than rats (7-14%). The data indicate that BPS is rapidly absorbed and rapidly and extensively metabolized to conjugates after oral administration in rats and mice.