Information on the fate of flumethrin in rats and cattle was provided. Because flumethrin is used only for ectoparasite control on animals the manufacturer did not consider information on the fate of residues in plants, soil, or water/sediment systems to be applicable.
Animal metabolism
Oral, i.v. and duodenally administered flumethrin is hydrolysed to the substituted cyclopropanecarboxylic acid component (flumethrin acid) and (possibly through intermediate cyanohydrin and aldehyde oxidations) 4-fluoro-3-phenoxybenzoic acid. Flumethrin acid is conjugated to form the glucuronide and the benzoic acid component is oxidized to 4-fluoro-3-(4-hydroxyphenoxy)benzoic acid; both the hydroxylated and unhydroxylated acids are conjugated with glycine. A proposed metabolic pathway is shown in Figure 1, which is based on the following studies.
Rats. Because the fate of flumethrin in rats is considered in detail in the toxicological evaluation (Evaluations Part II - Toxicology), it will be described here only to the extent needed to view the metabolism in cattle in the context of the general metabolism in mammals. Five reports were available on the fate of flumethrin in rats, all from oral, i.v. or duodenal administration (none from topical application).
In a basic study on the elimination and metabolism of unlabelled flumethrin (Rauchschwalbe, 1980) rats were given a single oral dose. The author reported the presence of flumethrin and the metabolites I and V (Figure 1) in the faeces. The two metabolites were also eliminated in the urine, although the parent compound was not detected. Theoretical intermediates from the alcoholic portion of the molecule would also include the cyanohydrin (FCR 1271) and its oxidation product 4-fluoro-3-phenoxybenzaldehyde (FCR 1260), but their instability would make their detection unlikely and they were they reported.
The elimination of flumethrin and its metabolites in faeces peaked 3 or 4 days after administration, then dropped almost to zero. Residues of the two metabolites in urine dropped below the limit of detection within 5 days. Altogether 33% of the administered dose was eliminated in the urine and faeces.
A second study investigated the pharmacokinetics of the metabolism of fluorophenyl-labelled [14C]flumethrin in rats after oral, i.v. and intraduodenal administration (Steinke et al., 1983). Approximately 50% of the 14C was reported to be absorbed from oral administration, 45% of which was eliminated in the urine (the remainder in the faeces), compared with 75% renal elimination from i.v. administration. About 95% or more of the radioactive dose administered orally or intravenously was excreted within 48 hours. After 10 days only 1% of the administered 14C was found in the animals. From duodenal administration, about 1/3 of the absorbed 14C was eliminated via the bile.
In a study of the biotransformation of [U-fluoropheny-14C]flumethrin after oral administration (Ecker, 1983) the author reported the urinary elimination of two primary metabolites, 4-fluoro-3-(4-hydroxyphenoxy)benzoic acid (not reported by Rauchschwalbe) and 4-fluoro-3-phenoxybenzoic acid (found by Rauchschwalbe), 0-24 hours and 24-48 hours after administration. The hydroxyphenoxy metabolite accounted for 50 and 80% and the phenoxy metabolite for 35 and 10% of the radioactivity at these times. The glycine conjugates of the two primary metabolites were also reported, but accounted for at most 4 and 7.4% respectively of the urinary radioactivity.
Figure 1. Proposed metabolic pathways of flumethrin in rats and cattle.
|
(I) |
4-fluoro-3-phenoxybenzoic acid |
|
(II) |
4-fluoro-3-(4-hydroxyphenoxy)benzoic acid |
|
(III) |
4-fluoro-3-phenoxybenzoylglycine (glycine conjugate of (I)) |
|
(IV) |
4-fluoro-3-(4-hydroxyphenoxy)benzoylglycine |
|
(V) |
3-(B,4-dichlorostyryl)-2,2-dimethylcyclopropanecarboxylic acid (flumethrin acid, BNF 5533A) |
|
(VI) |
flumethrin acid glucuronide |
In a fourth study whole-body autoradiography was used to study the distribution of total radioactivity during 48 hours after single oral doses of [U-chlorophenyl-14C]flumethrin (Klein, 1993a). The author reported slow or delayed absorption and only slowly decreasing residues in the organs and tissues, with the highest concentration in the liver. Towards the end of the experiment the highest residues were in the organs of excretion.
A fifth study investigated the biokinetic behaviour and metabolism of flumethrin in rats after single oral doses or after oral dosing for 7 consecutive days with flumethrin labelled with 14C in the chlorophenyl ring. In a separate experiment a single dose was also administered duodenally (Klein, 1993b). Again, radioactivity was reported to be only partially absorbed from the intestine with 77-88% slowly eliminated, (68% in the faeces, 2% in the urine). The faeces were the source of residues for identification. The highest concentrations of 14C were found in the plasma and the lowest in the brain. Nine to 20% of the dose was found in non-intestinal tissues. Multiple doses demonstrated the accumulation of residues. The only two compounds identified in the faeces were flumethrin and BNF 5533A (flumethrin acid, V in Figure 1). The ratio of flumethrin to BNF 5533A was 53:16 in males and 24:30 in females.
