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EC number: 942-380-9 | CAS number: 131796-64-0
The objective of the current study was to investigate potential hydrolysis and metabolic degradation of pyranyl acetate pure in plasma, liver and skin of rats as well as in gastric and intestinal fluids (BASF SE, 2015). To determine hydrolysis in either compartment, the test substance was incubated with liver and skin S9 fractions from rats as well as in rat plasma and in gastric and intestinal fluid simulants in duplicates at a target concentration of 250μM for defined incubation periods at 37 °C. Incubation periods were 0.5, 1 and 2 hours for liver S9 fraction and gastric fluid simulant or 2 hours for skin S9 fraction, plasma and intestinal fluid simulant. After incubation, the amounts of remaining substrate were analyzed in the appropriate incubates by GC/MS. Depending on the test system, heat deactivated controls (HDC) and controls, directly stopped after addition of test substance (t=0 controls) served as control samples. A buffer control (BC, test substance in the incubation buffer) was used to calculate consequent recoveries. Defined incubates were additionally analyzed for the potential hydrolysis product pyranol. Positive controls were performed with benzyl benzoate at a concentration of 250μM for liver S9 fraction, rat plasma and intestinal fluid simulant and with fluorescein diacetate at a concentration of 250μM for skin S9 fraction. No positive control was applied for the investigation of the abiotic hydrolytic stability of pyranyl acetate pure in hydrochloric acid (gastric fluid simulant).
It could be demonstrated that after 2 hours of incubation, benzyl benzoate was hydrolyzed extensively in liver S9 fraction (99.9 %), plasma (91.6 %) and in intestinal fluid simulant (70.4 %). In skin S9 fraction, fluorescein diacetate was metabolized extensively and 86.1 % were degraded after an incubation period of 2 hours. These data proofed the enzymatic activity of the test systems and the validity of the incubation conditions used.
For pyranyl actetate pure, the following results were obtained:
In liver S9 fraction of rats, recoveries of pyranyl acetate pure (peak areas in t = 0 control versus BC) ranged between 101 % - 103 %. Recoveries related to heat deactivated controls were 65 %. In the active incubate, pyranyl acetate pure was almost completely metabolized under the applied incubation conditions after two hours and the mean metabolic turn over was 79 % (related to HDC). The assumed hydrolysis product pyranol could be detected in the active incubates qualitatively, but not in performed controls. However, analyzed concentrations of pyranol in active incubates did not correspond stoichiometrically to the amounts of degraded test substance. This demonstrated that beside pyranol further metabolites may occur when pyranyl acetate pure is metabolized in rat liver in vitro systems. In skin S9 fraction of rats, plasma or gastrointestinal fluids, the amounts of pyranyl acetate pure measured in the active incubates of the test systems were generally between the amounts detected in the t = 0 control and the HDC. Therefore, a degradation of the test substance under the used test conditions cannot be demonstrated. In gastric fluid simulant, amounts of analyzed pyranyl acetate pure were 9 – 21 % less than in t = 0 controls. Compared to relative amounts of the test substance in HDC of other matrices (HDC are not possible for this matrix) compared to t = 0 controls, it can be assumed that these findings are not based on hydrolytic degradation of pyranyl acetate pure in gastric fluid simulant. This assumption is confirmed by the analysis of pyranol that was not detectable in any of the samples measured.
Taken together, the current in vitro experiments demonstrated that under the test conditions used, pyranyl acetate pure degrades in liver S9 fraction of rats and the degradation after 2 hours of incubation is virtually complete in this test system. Based on the obtained results, it was not possible to show a degradation of pyranyl acetate pure in skin S9 fraction, plasma or gastrointestinal fluids.
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