Polyhaloalkene

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

The major metabolites of the test substance are inorganic fluoride and N-acetyl-S-(3,3,3-trifluoro-2-hydroxy-propyl)-L-cysteine in rats mice and humans. The metabolite structures are not consistent with direct conjugation reaction with glutathione which is a major metabolic pathway for a number of fluoroolefins. An in vitro study showed no direct glutathione conjugation or any signals indicative for the formation of glutathione S conjugates under oxidative conditions. Metabolites could only be identified when induced rats were used. The in vivo studies show a very low rate of oxidation (< 0.1%). The resulting epoxide may be rapidly detoxified by glutathione. The lack of significant oxidation and glutathione conjugation may explain the lack of hepatotoxicity or nephrotoxicity with the test substance.  In urine samples of rabbits exposed to the test substance, the predominant metabolite was N-acetyl-S-(3,3,3-trifluoro-2- hydroxypropanyl)-L-cysteine. Additional urinary metabolites identified were 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. In incubations of rabbit liver S9 fractions containing glutathione, NADPH and HFO-1234yf, metabolites identified included 3,3,3-trifluoro-1,2-dihydroxypropane, S-(3,3,3-trifluoro-2-hydroxypropanyl)glutathione, 3,3,3-trifluoro-2-propanol and inorganic fluoride. The quantity of recovered metabolites in urine suggests a low extent (0.1%) of biotransformation of the test substance in rabbits. Ninety five percent of all metabolites were excreted within 12 h after the end of the exposure (t1/2 app. 9.5 h). The obtained results indicate that the test substance 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 the test substance are likely due to species-specific processing of glutathione S-conjugates.

Although biotransformation is low in all species (< 0.1%), rabbits also show a larger extent of biotransformation of the test substance in vivo based on the quantity and number of urinary metabolites. This was confirmed in vitro as several metabolites were present in sufficient quantity to allow for their identification.

Based on the presented data, no quantitative conclusions can be drawn with respect to absorption, distribution, metabolism and excretion, as no mass balance was determined in any of the in vivo studies. However, since less than 0.1% of the administered dose was recovered from urine in the form of metabolites, biotransformation appears to be quite low and most of the absorbed test substance will have most likely been exhaled as parent compound. The dermal route of exposure is not relevant for this substance.