Fluoroethylene

Endpoint summary

Additional information

Rats were exposed to the test substance and also to the analogous chemical, vinyl chloride, in a closed all-glass system. The equilibration constant of the atmospheric test substance with the rat was 0.91. Clearance values were 4200 (k₁₂V₁(mL/h)) and 4600 (k₂₁V₂(mL/h)). The saturation point in air was extrapolated to be 75 ppm for the test substance. In comparison, the saturation point for vinyl chloride was 250 ppm, thereby demonstrating that vinyl chloride has a significantly greater capacity to produce metabolites. First order metabolic clearance rate for the test substance was 2.5 L/h kg body wt. Zero orderV_max was 7 μmol/ h kg body wt. Upon further analysis, the concentration of the test substance in tissues of rats exposed to a constant concentration of 100 ppm in air was calculated and would reach equilibrium very rapidly, within 30 minutes after beginning of exposure.

 

In a separate study, groups of 3 rats or 5 mice were exposed to the test substance in a closed-chamber gas uptake system at starting concentrations ranging from 50 to 250 ppm. Partition coefficients were determined and used as parameters for a physiologically based pharmacokinetic (PBPK) model. Mice showed a higher whole-body metabolic capacity compared to rats (Vmaxc = 0.3 vs. 0.1 mg/hr-kg). The optimized estimated Km was approximately 0.02 mg/L for mice and approximately 0.001 mg/L for rats. The specificity for the oxidation of the test substance in vivo was determined by selective inhibition or induction of CYP 2E1. Inhibition with 4-methylpyrazole completely impaired the test substance uptake in rats and mice, whereas induction with ethanol (rats only) increased the metabolic capacity by two- to threefold. These results indicate that CYP 2E1 is most likely the only isozyme involved in the oxidation of the test substance in rodents at low airborne concentrations. In rats pretreated with L-buthionine-(R,S)-sulfoximine, a glutathione depletory, no difference could be observed in the uptake behaviour of the test substance. This however, does not conclusively rule out a possible involvement of glutathione in metabolism of the test substance. The pharmacokinetics of the test substance was also investigated in vitro. Microsomes from rat and mouse liver were incubated in a sealed vial with the test substance and an NADPH-regenerating system. Headspace concentrations were 10–300 ppm. The test substance was metabolized faster by mouse microsomes than by rat microsomes. Vmax was 1.1 nmol/hr-mg protein for rats and 3.5 nmol/hr-mg protein for mice. Km was essentially the same in both species (0.5 μM). In human samples, Vmax for 9 of 10 samples ranged between 0.57 and 1.27 nmol/hr-mg protein and was 3.3 nmol/hr-mg protein for one sample. Km in humans was the same as that found in rodents (0.5 μM). Metabolic rates in human microsomes were found to correlate with the amount of CYP 2E1 as determined by Western blotting and by chlorzoxazone 6-hydroxylation.