1-[5-(2,6-difluorophenyl)-4,5-dihydro-1,2-oxazol-3-yl]ethanone

Endpoint summary

Description of key information

The test substance is metabolized rapidly and extensively and is not likely to accumulate following multiple dosing.

Additional information

The toxicokinetics of the test item was studied in male Sprague-Dawley rats. Experiments were performed to understand plasma kinetics following single oral gavage, intravenous, or 14-day repeated oral gavage administration. Four male rats were administered the test item at 100 or 1000 mg/kg bw by single oral gavage. Another four male rats were administered the test item at 100 mg/kg bw daily by gavage for 14 days. Following the last administered dose, blood was collected via the tail vein at 15 and 30 min, as well as at 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours. Pharmacokinetics of the test item in plasma following single oral gavage administration showed both rapid absorption and elimination. Mean peak plasma concentrations (Cmax) at the low and high dose were 59.3 (±4.1) and 205 (±42) ng/mL, respectively. Mean Tmax values were 1.2 (±0.8) and 0.63 (±0.25) hours at the low and high dose respectively. Concentrations of the test item were (above the LOQ) in plasma for up to 2 hours after dose administration in the low-dose group and 24 hours in the high-dose group. In some, but not all of the rats in the high dose group, plasma concentrations of the test item fell below the LOQ at the 8- and/or 12-hour time point before increasing to above the LOQ at 24 hours. The mean plasma terminal elimination half-life value and area-under-the-curve (AUC) for the single oral gavage high dose group was 2.0 (±0.4) hours and 942 (±466) hr x ng/mL, respectively. The half-life and AUC could not be determined for the single oral gavage low dose group because it lacked enough time points with quantifiable concentrations of the test item in plasma. Plasma concentrations of the test item were not quantifiable at any of the measured time points after the intravenous administration and after the repeated dose 14-day oral gavage administration experiments. Therefore, the pharmacokinetic parameters terminal half-life, AUC, Cmax, Tmax, volume of distribution, oral bioavailability, and clearance were not determined for these groups. However, in order to determine the fate of the test item, plasma samples at the 1-hour time point from each dose group were submitted for high resolution/high mass accuracy mass spectrometry to tentatively determine structures of the metabolites. The test item metabolized readily to 23 tentatively identified components. Qualitatively, metabolism in the rat was similar among the different dose groups. In summary, the pharmacokinetics of the test item showed both rapid absorption and elimination. Metabolism of the absorbed dose was extensive and characterized by 23 tentatively identified components in plasma. The results from these experiments (single oral gavage, intravenous, and 14-day repeated oral gavage administration) indicate that the test item metabolized rapidly and extensively and is not likely to accumulate following multiple dosing.