Biotransformation of 2,3,3,3-tetrafluoropropene (HFO-1234yf) in male, pregnant and non-pregnant female rabbits after single high dose inhalation exposure.
2,3,3,3-Tetrafluoropropene (HFO-1234yf) is a novel refrigerant intended for use in mobile air conditioning. It showed a low potential for toxicity in rodents studies with most NOAELs well above 10,000 ppm in guideline compliant toxicity studies. However, a developmental toxicity study in rabbits showed mortality at exposure levels of 5,500 ppm and above. No lethality was observed at exposure levels of 2,500 and 4,000 ppm. Nevertheless, increased subacute inflammatory heart lesions were observed in rabbits at all exposure levels. Since the lethality in pregnant animals may be due to altered biotransformation of HFO-1234yf and to evaluate the potential risk to pregnant women facing a car crash, this study compared the acute toxicity and biotransformation of HFO-1234yf in male, female and pregnant female rabbits. Animals were exposed to 50,000 ppm and 100,000 ppm for 1h. For metabolite identification by (19)F NMR and LC/MS-MS, urine was collected for 48 h after inhalation exposure. In all samples, the predominant metabolites were S-(3,3,3-trifluoro-2-hydroxypropanyl)-mercaptolactic acid and N-acetyl-S-(3,3,3-trifluoro-2-hydroxypropanyl)-L-cysteine. Since no major differences in urinary metabolite pattern were observed between the groups, only N-acetyl-S-(3,3,3-trifluoro-2-hydroxypropanyl)-L-cysteine excretion was quantified. No significant differences in recovery between non-pregnant (43.10 ± 22.35 μmol) and pregnant female (50.47 ± 19.72 μmol) rabbits were observed, male rabbits exposed to 100,000 ppm for one hour excreted 86.40 ± 38.87 μmol. Lethality and clinical signs of toxicity were not observed in any group. The results suggest that the lethality of HFO-1234yf in pregnant rabbits unlikely is due to changes in biotransformation patterns or capacity in pregnant rabbits.
Institut für Toxikologie, Universität Würzburg, Versbacher Str. 9, 97078 Würzburg, Germany.
Tobias
T
Schmidt
Rüdiger
R
Bertermann
George M
GM
Rusch
Gary M
GM
Hoffman
Wolfgang
W
Dekant
D000818:Animals; D001711:Biotransformation; D005260:Female; D005466:Fluorocarbons / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019570:Inhalation Exposure; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011247:Pregnancy; D011817:Rabbits; D012737:Sex Factors; D006845:Hydrocarbons, Fluorinated
D005466:Fluorocarbons; C528198:2,3,3,3-tetrafluoropropene; D006845:Hydrocarbons, Fluorinated