Biotransformation of trans-1,1,1,3-tetrafluoropropene (HFO-1234ze)

Abstract

trans-1,1,1,3-Tetrafluoropropene (HFO-1234ze) is a non-ozone-depleting fluorocarbon replacement with a low global warming potential and is developed as foam blowing agent. The biotransformation of HFO-1234ze was investigated after inhalation exposure. Male Sprague–Dawley rats were exposed to air containing 2000; 10,000; or 50,000 ppm ( n = 5/concentration) HFO-1234ze. Male B6C3F1 mice were only exposed to 50,000 ppm HFO-1234ze. All inhalation exposures were conducted for 6 h in a dynamic exposure chamber. After the end of the exposures, animals were individually housed in metabolic cages and urines were collected at 6 or 12 h intervals for 48 h. For metabolite identification, urine samples were analyzed by 1H-coupled and 1H-decoupled 19F-NMR and by LC/MS-MS or GC/MS. Metabolites were identified by 19F-NMR chemical shifts, signal multiplicity, 1H– 19F coupling constants and by comparison with synthetic reference compounds. In urine samples of rats exposed to 50,000 ppm HFO-1234ze, the predominant metabolite was S-(3,3,3-trifluoro- trans-propenyl)-mercaptolactic acid and accounted for 66% of all integrated 19F-NMR signals in urines. No 19F-NMR signals were found in spectra of rat urine samples collected after inhalation exposure to 2000 or 10,000 ppm HFO-1234ze likely due to insufficient sensitivity. S-(3,3,3-Trifluoro- trans-propenyl)- l-cysteine, N-acetyl- S-(3,3,3-trifluoro- trans-propenyl)- l-cysteine and 3,3,3-trifluoropropionic acid were also present as metabolites in urine samples of rats and mice. A presumed amino acid conjugate of 3,3,3-trifluoropropionic acid was the major metabolite of HFO-1234ze in urine samples of mice exposed to 50,000 ppm and related to 18% of total integrated 19F-NMR signals. Quantification of three metabolites in urines of rats and mice was performed, using LC/MS-MS and GC/MS. The quantified amounts of the metabolites excreted with urine in both mice and rats, suggest only a low extent (< 1% of dose received) of biotransformation of HFO-1234ze and 95% of all metabolites were excreted within 18 h after the end of the exposures ( t 1/2 app. 6 h). The obtained results suggest that HFO-1234ze is likely subjected to an addition–elimination reaction with glutathione and to a CYP 450 mediated epoxidation at low rates.