This study provides the first in vivo pharmacokinetic data for chlorinated perfluorooctanesulfonate (Cl-PFOS), 6:2 and 8:2 chlorinated polyfluoroalkyl ether sulfonates (Cl-PFESAs), upon a 30 day dietary exposure and 34 day depuration phase in rainbow trout (Oncorhynchus mykiss). Biological handling of these three novel molecules and legacy PFOS were investigated via cross-comparison. PFOS and Cl-PFOS displayed comparable bioaccumulative potencies and similar distribution tendencies in tissues (blood > liver > kidneys), despite the presence of a terminal chlorine atom in Cl-PFOS molecule. The Cl-PFESAs, especially 8:2 Cl-PFESA, were predominantly assimilated from the bloodstream by liver and kidneys and resisted elimination, leading to higher bioaccumulation factors in liver than in blood (0.576 and 0.254, respectively, for 8:2 Cl-PFESA) and longer half-lives in liver and kidneys than PFOS, suggesting these alternatives may pose greater risks in terms of the great accumulation potentials in fish tissues. The present study provides the first report of the in vivo transformation of 6:2 and 8:2 Cl-PFESAs and identifies 6:2 and 8:2 H-PFESAs as their respective sole metabolites. This provides the first line of evidence suggesting that the transformation susceptibility of Cl-PFESAs in organisms is distinct from their environmental persistence.

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6:2 chlorinated polyfluorooctane ether sulfonate (6:2 Cl-PFESA) was previously shown to undergo limited dechlorination in rainbow trout to yield 6:2 hydrogen-substituted polyfluorooctane ether sulfonate (6:2 H-PFESA) as the sole metabolite. However, the biotransformation susceptibility of 6:2 Cl-PFESA has not been investigated in mammals and the biological behavior of 6:2 H-PFESA has not been defined in any species. We investigated the respective transformation products of 6:2 Cl-PFESA and 6:2 H-PFESA and their toxicokinetic properties in male Sprague–Dawley rats as a mammalian model. 6:2 H-PFESA was the sole detectable metabolite of 6:2 Cl-PFESA, with a transformation percentage of 13.6% in rat liver, but it resisted further degradation. 6:2 Cl-PFESA also transformed to 6:2 H-PFESA in reductive rat liver S9 incubations but remained stable under oxidative conditions, suggesting a reductive enzyme-dependent transformation pathway. 6:2 Cl-PFESA was more enriched in lipid-rich tissues, while 6:2 H-PFESA was more prone to cumulative urinary excretion. From this perspective, it may suggest a detoxification mechanism for organisms to form the less hydrophobic 6:2 H-PFESA to alleviate total burdens. To date, 6:2 Cl-PFESA was the second perfluoroalkyl acid reported to undergo biotransformation in mammals. The toxicokinetic properties determined for 6:2 Cl-PFESA and 6:2 H-PFESA in blood and urine were found to be structure and dose dependent.