Biotransformation of 2,3,3,3-tetrafluoropropene (HFO-1234yf) in rabbits

2,3,3,3-Tetrafluoropropene (HFO-1234yf) is a non-ozone-depleting fluorocarbon replacement with a low global warming potential and is developed as refrigerant. Due to lethality observed after high concentration inhalation exposures of HFO-1234yf in a developmental toxicity study with rabbits, the biotransformation of HFO-1234yf was investigated in this species. Female New Zealand White rabbits were exposed to air containing 2000; 10,000; or 50,000 ppm (n=3/concentration) HFO234yf. All inhalation exposures were conducted for 6 h in a dynamic exposure chamber. Animals were individually housed in metabolic cages after the end of the exposures and urines were collected at 12 h intervals for 60 h. For metabolite identification, urine samples were analyzed by (1)H-coupled and (1)H-decoupled (19)F-NMR and by LC/MS-MS or GC/MS. Metabolites were identified by (19)F-NMR chemical shifts, signal multiplicity, (1)H-(19)F coupling constants and by comparison with synthetic reference compounds. In urine samples of rabbits exposed to 2000; 10,000; or 50,000 ppm HFO-1234yf, the predominant metabolite was N-acetyl-S-(3,3,3-trifluoro-2-hydroxypropanyl)-l-cysteine and accounted for app. 48% of total (19)F-NMR signal intensities. S-(3,3,3-Trifluoro-2-hydroxypropanyl)mercaptolactic acid, 3,3,3-trifluoro-1,2-dihydroxypropane, 3,3,3-trifluoro-2-propanol and inorganic fluoride were also present as urinary metabolites. In incubations of rabbit liver S9 fractions containing glutathione, NADPH and HFO-1234yf, 3,3,3-trifluoro-1,2-dihydroxypropane, S-(3,3,3-trifluoro-2-hydroxypropanyl)glutathione, 3,3,3-trifluoro-2-propanol and inorganic fluoride were identified as metabolites of HFO-1234yf by (19)F-NMR. The quantity of recovered metabolites in urine suggest a low extent (<0.1% of dose received) of biotransformation of HFO-1234yf in rabbits, and 95% of all metabolites were excreted within 12 h after the end of the exposures (t(1/2) app. 9.5 h). The obtained results indicate that HFO-1234yf is metabolized in rabbits by a CYP450-mediated epoxidation at low rates and glutathione conjugation of the epoxide. The differences in urinary metabolite patterns between rats and rabbits seen with HFO-1234yf are likely due to species-specific processing of glutathione S-conjugates. Rabbits also show a larger extent of biotransformation of HFO-1234yf.