2-[4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl]-3-pyridine carboxylate; imazapyr (ISO)

Endpoint summary

Description of key information

A metabolism study in rats revealed that a majority of the administered dose was quickly excreted unchanged (American Cyanamid Company, IZ-440-004, 1994). This was further supported by another metabolism study in rats (American Cyanamid Company, IZ-401-010, 1983)

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Key study (American Cyanamid Company, IZ-440-004, 1994)

In a metabolism study in rats (according to EPA OPP 85-1), the test item was orally administered to Sprague-Dawley rats (5 animals per dose and sex) per gavage at single dose levels of 9.5 mg/kg bw and 924 mg/kg bw, 10 mg/kg bw daily for 14 days and intravenously administered at 9.94 mg/kg bw.

The radiolabelled test substance was dissolved in corn oil for all oral dosing solutions. The intravenous dosing solution was prepared in normal saline solution. The study was conducted using both male and female Spraque-Dawley rats (circa 6-10 weeks old). The experiment comprised five groups of male and five groups of female rats. A group of five rats for each sex was treated with carbon-14 test substance and two for each sex served as control (Group E, control) which were dosed with carrier corn oil only (no test substance). One group of treated rats was each given a single oral low dose of 9.50 mg/kg of carbon-14 test substance (Group A: low dose). Another group of rats was each given a single oral dose of 924 mg/kg of carbon-14 test substance (Group B, high dose). In addition, male and female rats were also administered orally with non-radiolabelled test substance at approx.10 mg/kg once daily for 14 days followed by a single oral low dose of carbon-14 test substance at 9.26 mg/kg (Group C, multiple low dose). Finally, five male and five female rats were administered a single intravenous dose of carbon-14 test substance in saline solution at a rate of 9.94 mg/kg (Group D, IV low dose). The animals were given daily ration of food and water for seven days ad libitum. Urine and feces were collected over 7-day intervals. Animals were sacrificed at seven days after administration of radiolabeled dose. Blood, selected tissue samples and the residual carcass were collected.

Total radioactive residues (TRR) in excreta and tissues were determined by either direct liquid scintillation counting (LSC) or combustion of aliquots to yield carbon-14 CO2. LSC was used to analyze trapped carbon-14 CO2. The identity of the residue component was determined by chromatography with known reference compounds using high performance liquid chromatography (HPLC) and thin layer chromatography (TLC).

Regardless of the treatment regimen, carbon-14 test substance was rapidly eliminated by the rats, primarily through urine (67.8 % - 94.6 % of the dose). Most of the elimination in urine occurred within the first 24 hours after dosing (56.9 % - 90.6 % of dose). The TRR in feces ranged from 5.5 % to 33.2 % of dose, with a majority also eliminated within the first 24 hours (3.0 % - 23.8 % of dose). The percent of carbon-14 test substance-derived radioactivity absorbed in the single oral dose group and multiple oral low dose groups was calculated by comparing the percent dose excreted in urine by these groups with the percent dose excreted in urine by the intravenous low dose group. The calculated percent of absorption in the oral dose groups was 80.6 % and 80.0 % for Group A males and females, respectively, and 75.6 % and 71.4 % for Group C males and females, respectively. Analysis of rat tissues and organs (blood, bone-femur, brain, fat-reproductive area, skin-shaved, testes, ovaries, heart, kidneys, liver, lungs, muscle-thigh, spleen and residual carcass) showed that TRR levels were below detection limits except in carcass (< 0.01 - 0.87 ppm) and high dose liver (0.45 ppm in female rats) and kidney (0.36 ppm for male rats and 0.52 ppm for female rats) and multiple dose ovaries (0.03 ppm). TRR levels in control (untreated) animal samples were all less than the validated minimum quantifiable limit of detection. In all treatment groups, total radioactive residue in tissues and organs accounted for < 9.01 % of the administered dose while the residual carcass accounted for < 0.2 % of the dose.

Since the majority of the administered dose appeared in the day-1 and day-2 excreta of all the groups, the day-1 and day-2 urine were pooled according to sex for Groups A, B and C; and 0.8 hours and 8 - 48 hours urine were pooled according to sex for Group D and used to analyze and quantify the respective metabolites. Day-1 feces from Group A male rats and from Group D male and female rats, and 12-24 hours feces from Group A female rats and from Group B and C male and female rats were pooled according to sex and group and analyzed for metabolite distribution. Filtered urine samples were used for analysis. Results showed that the parent compound was the major product (94.4 % - 100.0 % of urine TRR) in the early urine samples of both male and female rats from all the dose groups. Two metabolites (the substituted and nonsubstituted 2-carbamoyl derivatives) accounted for 0.24 % and 0.15 % of urine, respectively. Low, but detectable, levels of several unknown metabolites (0.21 to 5.65 % of urine) were also found in urine samples; however none of the individual unknown metabolites exceeded 0.11 % of urinary radiocarbon.

Extraction of feces homogenates showed that almost all (> 98 %) of the radioactivity in the feces was extractable by acidified aqueous methanol. The unextractable radiocarbon in the post-extraction solid (PES) of low dose animals accounted for 0.61 % - 1.89 % of feces TRR. The PES accounted for 0.74 % - 0.82 % of feces TRR in high dose animals. The major metabolite found in feces was the methyl ester of the parent compound (11.6 % - 16.7 % of feces extract) in addition to parent (75.4 % - 92.3 % of feces extract). The substituted 2-carbomoyl derivative was detected only in feces of intravenous group female rats (3.6 % of extract), the non substituted metabolite was found in all female groups (1.1 % - 2.1 % of extract) and in high dose group male rats (1.6 % of extract). Two or more very minor unknown metabolites were found in the feces and none of the individual unknowns exceeded 0.9 % of dose. Reextraction of the male feces with acidified aqueous acetone followed by TLC analysis did not show any trace of the methyl ester of the parent compound, which suggested that this metabolite is an extraction artifact from methylation of the parent compound. Therefore, the percent distribution of this metabolite in the feces was assigned to parent. After correction, the percent distribution of the test substance ranged from 85.7 % to 97.8 % of feces residues.

In all of the analyzed urine and feces, 78.3 % - 96.0 % of the administered dose was excreted unchanged, 0.1 % - 0.2 % was changed to the substituted 2-carbomoyl derivative and up to 0.5 % was changed to the non substituted 2-carbomoyl derivative. The total of unknown metabolites ranged from 1.3 % - 2.3 % of the administered dose and none of the individual unknowns exceeded 0.9 % of the administered dose. PES of feces contained 0.1 % - 0.2 % of the dose.

In summary, the test substance was mostly excreted unchanged (78.3 % - 96.0 %). Two metabolites (the substituted and nonsubstituted 2-carbamoyl derivatives) were found in both urine and feces, but only trace amounts were detected (< 0.1 % - 0.5 %). The number of unknown metabolites varied from 3 to 12 and none of the individual unknowns exceeded 0.9 % of the dose.

The test item was quickly absorbed and excreted following administration to rats. There were no substantial sex differences in the absorption, elimination, and distribution of radioactivity for the rats that received an oral dose of 14C-test item. The majority of the administered dose was excreted in the urine and, to a lesser degree, in the faeces (78.3 % to 96.0 % was excreted in the first 24 hours). The test chemical was mostly excreted as intact test item, indicating a low level of biochemical alteration of the parent chemical. Trace levels of polar and nonpolar metabolites were formed and excreted in the urine and faeces. Finally, only trace amounts of tissue residues were detected in the liver and kidneys of the high dose group. On the basis of the urine and faeces analyses, it appears that only a small amount of the administered test item was transformed via hydrolysis to the substituted and not-substituted 2-carbamoyl derivative.

 

Supporting study (American Cyanamid Company, IZ-401-010, 1983)

12 male Sprague Dawley rats were administered a single oral dose of 14C-carboxyl-labelled test substance at a rate of 4.4 mg/kg bw. 3 rats served as control animals. Approximately 87.2, 93.3 and 94.9 % of the total administered dose was rapidly excreted in the urine and faeces at 1, 2, and 4 days postdosing, respectively. Elimination of the administered dose was essentially complete by day 6 and accounted for 95.1 % of the total 14C-activity. After one day, about 55 % of the dose was excreted in the urine and about 32 % was excreted in the faeces. The half life of the test substance in the rat was less than one day. 14C-activity in the urine and in organosoluble extracts of faeces was characterized as parent compound.

Remaining 14C-residues, expressed as ppm equivalents of the test substance were 0.03 and 0.02 ppm in the liver and kidney, respectively, on day 1 and below 0.01 ppm on day 8. 14C-residues in muscle, fat, and blood were below 0.01 ppm at both 1 and 8 days post-treatment.

 

CONCLUSION

Both metabolism studies in rats revealed that the majority of the administered dose was excreted mainly as parent compound in faeces and urine (78.3 % to 96.0 %) in the first 24 hours. This indicates a low level of biochemical alteration.