Reaction mass of (R)-cyano(3-phenoxyphenyl)methyl rel-(1R,3R)-3-((1Z)-2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropanecarboxylate and (R)-cyano(3-phenoxyphenyl)methyl rel-(1S,3S)-3-((1Z)-2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropanecarboxylate

Endpoint summary

Additional information

Single oral doses of [¹⁴C]-labelled cyhalothrinto rats (1 or 25 mg/kg) using two different [¹⁴C]-labelsare incompletely absorbed following oral administration, and the absorbed dose is extensively metabolised and rapidly excreted. Most of the radioactive dose was rapidly eliminated in the first 24 hours after dosing, but a small proportion of an oral dose (2 – 3%) was still retained in the animals after seven days. Radiolabelled components were distributed to most tissues and were detectable seven days after dosing. Residues in fat were many-fold higher than in any other tissue and were very similar with both [¹⁴C]-forms of cyhalothrin indicating that the fat residue may be due to unchanged cyhalothrin. The highest concentration was in brown fat.The concentration of radioactivity in brown fat and other tissues, with the exception of white fat, declined relatively quickly. The peak concentration of radioactivity in white fat increased in proportion to the administered dose. Apart from in the gonads, where levels in ovaries were higher than in testes, no marked sex differences were noted in the tissue distribution of [¹⁴C]-benzyl labelled cyhalothrin.

Two repeat dose oral studies were performed in the rat. In the first rats were given 14 consecutive daily oral doses of 1 mg/kg [¹⁴C]-benzyl or [¹⁴C]-cyclopropyl labelled cyhalothrin. Approximately 90% of the cumulated dose was recovered in urine and faeces by 7 days after the last dose. The carcass residue at 7 days was due almost entirely to residues in the fat. These fat residues were shown to be principally unchanged cyhalothrin present at a concentration of 3.3mg equivalents/g. In the second study groups of male rats were each given up to 119 consecutive daily oral doses of 1 mg/kg [¹⁴C]-cyclopropyl labelled cyhalothrin. The concentration of cyhalothrin in fat increased throughout the dosing period to a maximum of approximately 10mg equivalents/g, whereas those in blood, liver and kidneys appeared to plateau and were significantly lower. On cessation of dosing the radioactive residues in tissues other than fat declined rapidly indicating rapid elimination.

It is established that cyhalothrin, in common with other synthetic pyrethroids, can accumulate in abdominal fat with repeated dosing, but the amount accumulated is low. Assuming that fat constitutes 15% of the bodyweight, the total amount of cyhalothrin retained after repeated administration would be equivalent to approximately 1.5 times the daily dose. The total amount of retained cyhalothrin is therefore unlikely to present a greater hazard than a single dose of the same magnitude.

Cyhalothrin was variably absorbed after oral administration to dogs. The degree of absorption was difficult to assess but seems to cover at least the range 48 - 80%, this being attributable to inter-animal variation. Excretion of radioactivity after both oral and intravenous dosing was initially rapid, with most of the dosed radioactivity excreted in the first 48 hours after dosing. However, excretion remained incomplete after 7 days with a mean of between 82 and 93% recovered in this time. The absorbed material was extensively metabolised and eliminated via the kidney and in bile.

Apart from the fat residue, any absorbed cyhalothrin was extensively metabolised. The major pathway of metabolism in both rat and dog was ester cleavage followed by conjugation of the cleaved metabolites with either glucuronic acid or sulphate. 

The major radioactive component in urine of rats dosed with [¹⁴C]-benzyl labelled cyhalothrin was the sulphate conjugate of 3-(4'-hydroxyphenoxy) benzoic acid (compound XXIII). Un-conjugated compound XXIII and 3-phenoxybenzoic were minor metabolites. The major radioactive component in urine of rats dosed with [¹⁴C]-cyclopropyl labelled cyhalothrin was the glucuronide conjugate of (1RS)-cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropane carboxylic acid. One of the minor metabolites also appeared to be a glucuronide conjugate, which was tentatively identified as a hydroxylated analogue of cyclopropane acid. 

Metabolites identified in the dog were 3-phenoxybenzoic acid mainly as its glucuronide conjugate, but also as a glycine conjugate; 3-(4'-hydroxyphenoxy)benzoic acid mainly as the sulphate conjugate and (1RS)-cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropane carboxylic acid and the corresponding glucuronide.