Animal Metabolism

The metabolism of methoxyfenozide is well understood for regulatory purposes, with the parent compound and a glucuronide metabolite being the primary residues in animals. Animal feeding studies with diets manufactured with methoxyfenozide-treated commodities have demonstrated that residues are low in tissues, milk and eggs.

The metabolism, distribution and elimination of 14C-methoxyfenozide (labeled in each ring or in the t-butyl position) were studied in lactating goats (E50ppm dietary equivalents for seven consecutive days) and laying hens (E60ppm in the diet for seven consecutive days).38

In goats, the majority of the residue was excreted in the feces (74-84% of the dose) with an additional 5-7% of the dose recovered in the urine. In the edible tissues, total radioactive residues were highest in the liver (0.26-1.2 mg kg-1), followed by kidney (0.045-0.2 mg kg-1) and fat (0.018-0.053 mg kg-1). Muscle contained <0.025 mg kg-1. Residues in milk were low (<0.018 ppm) and reached a plateau within 24-36 hours of dosing. Methoxyfenozide was the major residue in fat, muscle and milk. Liver and kidney showed a large percentage of RH-141518 and trace amounts of other glucuronides.

In hens, the majority of the dose was recovered in the excreta. Less than 0.03% of the dose was recovered in the eggs and tissues where metabolite RH-141518 represented a major component of the residue in addition to methoxyfenozide.

In rats,39,40 methoxyfenozide (labeled in each ring or in the t-butyl position) was rapidly and moderately well absorbed following a single oral administration, with peak blood or plasma levels achieved within 15-30 min and 62-70% of the dose systemically absorbed. Methoxyfenozide is extensively metabolized by rats and eliminated in the bile, feces and urine. Very little radioactivity was released as volatile components such as carbon dioxide (CO2). Metabolism involves demethylation, hydroxylation and glucuronidation. A total of

Figure 6.5 Proposed metabolic pathway for methoxyfenozide showing metabolites identified in animals, plants and soil (g = goat, h = hen and r = rat).

31 metabolites were isolated from rat urine and feces (25 of which were identified), and 24 metabolites were characterized in bile (12 of which were identified and 4 of which were only found in bile). There were seven major metabolites present at >5% of the administered dose in feces plus urine, including those shown in the metabolic pathway in Figure 6.5. Parent meth-oxyfenozide was found in feces, but was not present in urine or bile.

The metabolism of methoxyfenozide is similar in poultry and ruminants, and qualitatively the same in rats. The residues were concentrated in the fat relative to the muscle by factors of e2-5, which is consistent with the log Pow for methoxyfenozide of 3.7. The proposed metabolic pathway in animals is presented in Figure 6.5.

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