5-Isothiazolecarboxamide, 3,4-dichloro-N-(2-cyanophenyl)-

Endpoint summary

Additional information

Absorption:

The maximum plasma concentration (Cmax) of 0.2 - 0.36 µg of test substance equivalents/g administered dose following the 4 mg/kg treatment was reached at 0.3 to 1.7 hours. Following the 200 mg/kg treatment the highest plasma concentration of 2.57 - 4.17 µg test substance equivalents/g administered dose was reached at 0.9-10.6 hours. Elimination half-lives (t1/2) were marginally longer at the 200 mg/kg dose level (17.9-20.5 hours) than at the 4 mg/kg dose level (13.9-17.8 hours). There were slight differences in the genders at both dose levels. For the female rats values were greater than the corresponding values for male rats. The absorption for the two dose levels, as determined by comparison of plasma Cmax and AUC values, was dose-dependent (nonlinear). Approximately of the administered dose was absorbed within 168 hours (calculated from the % of the administered dose recovered in urine and tissues).

Distribution:

After a 168-h exposure period, total residues in tissues were below 0.2 % of the administered dose and total residues in the residual carcass were 0.4% of the administered dose or less. Within the 4 mg/kg dose group, the highest residue levels were found in liver (0.134 ppm) and kidney (0.068 ppm). Residue levels for all other tissues were less than 0.03 ppm or were not detectable for the 4 mg/kg dose level. No sex-related differences in tissue residue levels were observed.

Within the 200 mg/kg dose group, the highest residue were found in stomach (8.95 ppm), intestine (1.29 ppm), kidney (1.29 ppm), liver (4.92 ppm) and packed cells (0.98 ppm). Residue levels for all other tissues were less than 0.6 ppm or not detectable for the 200 mg/kg dose level. No sex-related differences in tissue residue levels were observed.

Excretion:

In the 4 mg/kg group, up to 65% of the administered dose was found in faeces and 31% in urine after 48 hours. In the 200 mg/kg group, up to 86% of the administered dose was found in faeces and 12% in urine after 48 hours. The 168 hour values for total excretion were only ≤2% higher than the 48 hour values for all groups.

Metabolism:

Metabolites were identified in the urine and in faeces. In urine the metabolites were: 3,4 -dichloro-5 -isothiazolecarboxylic acid, sulfate of 2 -amino-5 -hydroxybenzonitril, and 4’-OH- and 4’,5’-OH-metabolites of test substance and glucuronide of 4’-OH-metabolite of test substance, respectively. In the faeces unmetabolised test substance was the main ¹⁴C component, while 4’-OH-, 3’,4’-OH- and 4’,5’-OH- metabolites of the test substance were also detected to a lesser degree.

Absorption, excretion and metabolism of Isotianil were also investigated in bile-duct cannulated rats after single oral administration of the test substance using two different labelling positions. The test substance was labelled with ¹⁴C at the phenyl ring (Phenyl-14C-S-2310 label) or with ¹⁴C on the 3 position at the isothiazole ring and the carboxamide (Isothiazole-14C-S-2310 label). A dose level of 4 mg/kg bw was administered to groups of 4 animals/sex. Bile, urine, and faeces were collected in intervals between dosing and sacrifice 48 h after dosing. The total radioactivity, representing the sum of the parent compound and metabolites, was determined in urine, faeces, cage washes, bile and carcass.

After oral administration of either Phenyl-14C-S-2310 or Isothiazole-14C-S-2310, 14C was excreted mainly into the bile. Within 48 h after dosing, 46.2% - 63.8%, 14.7% - 24.6% and 4.6% - 13.1% were excreted into bile, urine and faeces, respectively. Remaining 14C in the body except for the stomach content was 1.7% - 3.0%. From the sum of 14C excreted into urine and bile and remaining 14C in the body, the absorption rate of orally administered 14C was estimated to be 72.5% - 85.9%, indicating that the test substance was rapidly absorbed.

Furthermore, it is reported that 14C was rapidly excreted from the body and more than 90% of orally administered 14C was excreted into urine and faeces within 48 h after dosing. As a total of 87.1% - 97.2% of 14C was excreted into urine, bile and faeces, it was considered that the reabsorption rate (enterohepatic circulation) of 14C excreted into the gastrointestinal tract via bile excretion was low. 14C excreted into the gastrointestinal tract is rapidly eliminated into faeces.

Analyses of the metabolites in urine, faeces and bile showed that the major metabolites in urine were DCIT-acid produced by the cleavage of the amide bond of the test substance, and sulfate of 2-amino-5-hydroxybenzonitrile formed from the conjugation with sulfuric acid of the hydroxylated metabolite at 5-position of 2-aminobenzonitrile produced by the cleavage of the amide bond. In bile, some metabolites hydroxylated at the phenyl group and glucuronides of these metabolites were observed. The major metabolites were glucuronide of monohydroxylated metabolite, 4'-OH-S-2310, trihydroxylated metabolite, Tri-OH-S-2310 (putative structure), and glucuronide of dihydroxylated metabolite, 4',5'-OH-S-2310. The unmetabolised test substance was not detected in urine or bile. In contrast, no metabolite was observed in faeces and only the parent compound was detected. Based on the results, most of the test substance orally administered was absorbed into the body and metabolized rapidly. Hydroxylated metabolites and conjugates were mainly excreted into bile. Amide bond cleaved metabolites were eliminated into urine, while unabsorbed test substance was excreted into faeces as unmetabolised compound.

Overall conclusion:The result of this study clearly shows that male and female rats exhibited a very similar absorption and excretion behaviour. Any accumulation or retention of radioactivity administered with the test substance can be excluded for male and female rats.