8:2 fluorotelomer alcohol: A one-day nose-only inhalation toxicokinetic study in the Sprague-Dawley rat with application to risk assessment

Abstract

8:2 fluorotelomer alcohol (8:2 FTOH) inhalation exposure was investigated to (1) compare plasma metabolites to oral data, (2) conduct a route-to-route extrapolation (oral to inhalation), (3) develop a human equivalent air concentration (HEC) from a 90-day oral sub-chronic study in rats using BMD analysis, and (4) calculate a margin of exposure (MOE) between the HEC and measured air concentrations. Male and female rats were exposed nose-only for 6h at 3 or 30mg/m3. Blood was collected at 1, 3 and 6h during exposure and 6 and 18h post exposure. Alcohol, perfluorocarboxylic acid and polyfluorinated acid metabolites were determined in plasma by LC–MS/MS. 8:2 FTOH was <LOQ (32nM) at the low exposure and quantifiable (37–69nM) at the high exposure. The quantifiable metabolites in plasma were dose proportional and comprised mainly of 8:2 FTCA, 7:3 Acid, and PFOA. By kinetic modeling, the yields of the terminal products 7:3 Acid (1.6–2.1 and 0.9mol%) and PFOA (1.0–1.2 and 0.3mol%) of the inhaled dose were low for male and female rats, respectively. The kinetic yield of PFOA after oral dosing was similar (1.1–1.7-fold) for male rats and greater (8–9-fold) for female rats relative to inhalation exposure, an observation confirmed by non-compartmental analysis. A BMDL10% (3.7mg/kg/day) was derived for mild hepatic necrosis observed in male rats following a 90-day oral dose study with 8:2 FTOH. The corresponding HECs were 1.8 and 3.7mg/m3, which gave MOE values ranging from 1.8×104 to 6.1×106 based on reported ambient air concentrations of 0.3–209ng/m3. These findings demonstrate rapid 8:2 FTOH uptake and clearance by the inhalation route and a consistent metabolite profile between inhalation and oral exposures in rats. No toxicity is expected in humans from typical ambient 8:2 FTOH air exposures.