(2RS,3RS)-3-(2-chlorophenyl)-2-(4-fluorophenyl)-[(1H-1,2,4-triazol-1-yl)methyl]oxirane

Endpoint summary

Description of key information

Absorption, excretion and bioavailability

Excretion of 14C-epoxiconazole (BAS 480 F) after oral administration to male and female rats at nominal dose levels of 3 and 100 mg/kg bw was almost complete at 168 h post-dosing, with 90-95% of the administered dose being excreted within 72 h. It occurred mostly via feces (76%-82%) and urine (12%-21%), while in expired air, no significant amounts of radioactivity were detected. Quantitatively, there were no significant differences between sexes, between the low- (ca. 3 mg/kg bw) and high-dose (ca. 100 mg/kg bw) groups, or after repeated oral administration (14x unlabeled and 1x labelled epoxiconazole at the low dose). However, on the whole, excretion occurred later with female animals than with the males. Based on urinary and biliary elimination, oral bioavailability was about 80 % in male and 50 % in female animals.

 

Pharmacokinetics

Peak plasma concentrations were observed no later than 2 h after administration in both dose groups and with male as well as female animals. Both Cmax and AUCs of the females were about 50% higher at the low, and 10-20% higher at the high-dose, if compared to those of the males. For both sexes, Cmax increased slightly less than proportionally with dose, whereas the AUC was linear over the tested dose range, indicating that the absorption process was not saturated at the high dose level. Terminal half-lives of 5-6 and 32-34 h were observed for the low and high dose, respectively.

 

Distribution

Epoxiconazole was widely distributed in the organism, with highest residues found in blood, liver, kidneys, spleen, lung, and adrenals. Overall, at 168 h post-dosing, only small amounts of radioactivity were detected in these organs, while only whole blood (but not plasma) and spleen levels were declining more slowly. Taking together the results of both the tissue distribution and pharmacokinetics experiments, it was concluded that epoxiconazole is unlikely to accumulate in tissues.

 

Metabolism

After oral administration to male and female rats, epoxiconazole was rapidly and intensively metabolized to a large number of biotransformation products. Phase I biotransformation is characterized by the opening of the oxirane ring, hydroxylation of the chlorophenyl ring and also of the fluorinated aromatic ring. In addition, cleavage of the carbon bridge between the two aromatic nuclei is observed. Quantitatively the most important phase II reactions consist of the formation of glutathione adducts and conjugation of glucuronides. Degradation of these glutathione adducts further enlarges the number of metabolites. No major differences were observed with regard to sex and dose level.

 

Dermal absorption

The dermal absorption of epoxiconazole in vivo was determined by applying test solutions of 1 and 10 g/L, respectively, to the skin of male and female Fisher rats, resulting in applied concentrations of 0.06 and 0.6 mg/cm2 (equivalent to doses of about 3.7 and 37 mg/kg bw). After an exposure duration of 10 h, absorbed amounts were ca. 8% of dose for the lower and ca. 16% of dose for the higher concentration. Dermal penetration through rat skin in vitro was found to be about 2-3 times higher than observed in human skin at 0.0125 and 0.1 mg/cm2, and about 5-7.5 times higher at 0.8 mg/cm2, respectively. 

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100