1-(allyloxy)-2-methyl-1-oxopropan-2-yl 2-chloro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl]benzoate

Endpoint summary

Description of key information

Seven studies have been provided on a weight of evidence basis to address the metabolism and distribution of the test material. The overall consensus of the studies is that the test material is rapidly absorbed and then eliminated via urine, faeces and biliary excretion. Additionally very low levels are found in edible portions of the animals. Several major and minor metabolites have consistently been identified. The predominant metabolic pathway for the test material has been proposed and involves initial hydrolysis of the test material. All effects were most entirely independent of sex and dose level. Based on the weight of evidence the bioaccumulation potential is considered to be low.
WoE: Rapid elimination, mostly within 24 hours, predominant route bile. Main metabolites identified. EPA OPP 85-1, Emrani 1997.
WoE: Rapid elimination, mostly within 24 hours. EPA OPP 85-1, Cheng 1996.
WoE:  Rapid absorption and rapid elimination, independent of sex and dose level. EPA OPP 85-1, OECD 471, EU Method B.36, Stampf 1998.
WoE: Rapid elimination mainly in the faeces and nearly complete within 48 hours. EPA OPP 85-1, Sved 1996.
WoE: Three main metabolites identified and the proposed metabolic pathway. EPA OPP 85-1, Emrani 1997.
WoE: Excretion mainly in the faeces, two metabolites identified and description of the proposed metabolic pathway. EPA OPP 171-4, Kennedy 1997a.
WoE: Most radioactivity was recovered in the faeces, low levels in the milk and edible tissue. Three major metabolites identified, where the predominant metabolic pathway involves hydrolysis. EPA OPP 171-4, Kennedy 1997b.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

The study Emrani, Carlin (1997) was conducted to determine the absorption and excretion behaviour of the test material administered in a single oral dose to both male and female rats at 0.5 mg/kg bw. Bile, urine and faecal matter were collected for 48 hours post dosing. The bile samples were also characterised for metabolites. Under the conditions of the test approximately 80% of the 14C was absorbed, being comparable for males (80.25%) and females (81.53%). For both genders, the majority of excreted radioactivity was eliminated in the 0-24 hour interval, where biliary excretion was the predominant route of elimination. There was a slight sex related difference in the elimination patterns, with biliary excretion favoured in males (78.7%) slightly more than in females (74.3%) and urinary excretion being exactly the opposite (1.55% for male, and 7.23% for female). Profiling of selected male and female bile samples and composites showed that the major metabolites (95%) in the bile are the same as the major metabolites in the excreta. The 4-6 minor metabolites (a total of 5%) in the bile appear to be conjugates of the major metabolites. No parent compound was present in the bile of either the male or female rat. The profiles indicated that male and female bile contained common metabolites that differed in both relative abundance and percent of dose.

The study Cheng (1996) was conducted to determine the absorption and excretion behaviour of the test material administered in a single oral dose to both male and female rats at 0.5 mg/kg bw. Bile, urine and faecal matter were collected for 48 hours post dosing. The test material was well absorbed from the intestinal tract and the majority of radioactivity was eliminated within 24 hours post-dose. There were no major sex-related differences regarding the absorption or elimination of radioactivity by rats, where biliary excretion was the predominant route of elimination.

The study Stampf (1998) is and in vivo ADME study where male and female rats were administered the test material a single oral dose via gavage. Animals were treated at nominal concentrations of 0.5 or 100 mg/kg. Absorption was determined to be rapid, with at least 80% absorption, independent of sex and dose. Rapid and almost complete excretion occurred resulting in low tissue residues. Route of excretion were slightly dependant on sex, with higher amounts renally excreted by females. Then metabolite pattern in excreta were qualitatively independent on sex, dose and pre-treatment.

The study Sved (1996) is an in vivo metabolism study in male and female rats. This portion of the study investigates the distribution, absorption and excretion of the test material. Rats received a single oral dose at 0.5 or 100 mg/kg via gavage. Elimination of the administered radioactivity was nearly complete within 48 hours of dose administration, independent of animal gender or dose level. Most elimination occurred via the faeces. Female rats eliminated more of the radioactivity in their urine than male rats; the difference was less pronounced at the 100 mg/kg dose level. The presence of radioactivity in the urine indicates that some absorption did occur; however, the extent of absorption could not be determined because elimination was predominantly in the faeces. Residues in all tissues were low.

The study Emrani (1997) is an in vivo metabolism study in male and female rats. The distribution, absorption and excretion of the test material is described in a previous study (Sved, 1996), this study concentrated on profiling the metabolism. Rats received a single oral dose at 0.5 or 100 mg/kg via gavage. Characterisation of pooled urine and faeces samples showed that the majority of the dose amount comprised of three metabolite structures. The parent compound was only observed in high dose faeces. The main differences among gender/dose subgroups were in relative abundances of the more highly metabolised structures. The identified metabolites in urine and faeces account for at least 90% - 95% of the dose. The major metabolic pathways of the test material involve (1) hydrolysis of the allyl ester; (2) reduction of the uracil ring (3) hydroxylation of the uracil ring; and (4) uracil ring opening. The phenyl and uracil rings remain connected and all major metabolites have the unchanged phenyl structure.

Kennedy (1997a) is an in vivo study to characterise the metabolism of the test material in laying hens. Female hens received a single oral dose of the test material via capsules for eight consecutive days at a nominal concentration of 100 ppm. Excreta and eggs were collected during the dosing period, 6 hours prior to sacrifice blood samples were drawn for analysis, and following necropsy the following tissue samples were taken: skin and attached fat, muscle, peritoneal fat pad and liver. Under the conditions of the study, the majority of the administered dose was recovered in the excreta which contained on average 85.98%. Radiolabelled residues in the eggs and edible tissues accounted for < 0.04% of the total dose. The major metabolite in the liver and muscle samples was identified as metabolite 2 which was also present in the excreta, egg yolks, egg whites, whole eggs and peritoneal fat samples. The major metabolite in the excreta, peritoneal fat, whole eggs, egg yolks and egg whites was identified as intact test material which was also present in liver and muscle. The predominant metabolic pathway for the test material in laying hens involves ester hydrolysis to the first acid (metabolite 2). Secondary metabolic and/or degradative processes include the addition of water across the double bond of the uracil ring to form the hydroxylated uracil analogue of Metabolite 2 (Metabolite 3a), oxidation and N-demethylation of the uracil ring to form the N-desmethyl analogue of metabolite 2 (Metabolite 3b), oxidation of the allylic ester of parent to form the glycerol ester of Metabolite 2 (Metabolite 6), as well as the glycerol ester of the N-desmethyl analogue of Metabolite 2 (Metabolite 5), oxidation and cleavage of Metabolite 6 to give the carboxymethoxy ester of Metabolite 2 (Metabolite 4b) and ester hydrolysis of Metabolite 2 to form Metabolite 4a. Phase II metabolism was not observed in the laying hens.

Kennedy (1997b) is an in vivo study to characterise the metabolism of the test material in lactating goats. Female goats received a single oral dose of the test material via capsules for four consecutive days at a nominal concentration of 100 ppm. Urine, faeces, milk, blood, bile, and tissue samples were collected for analysis. Tissue samples were collected at necropsy in the following order; hind leg muscle, omental fat, perirenal fat, kidney, liver, bile, tenderloin and gastrointestinal tract. The majority of the administered dose was recovered in the faeces (44.09%), gastrointestinal tract (23.04%), urine (12.50%) and bile (0.30%). Radiolabelled residues in the milk and edible tissues accounted for <0.60% of the total dose. Notably higher residues were present in the liver (average 4.119 ppm) and kidney (average 0.481 ppm). Radioactive residues in the bile, urine, faeces and tissue samples were comparable for both test animals. Three major metabolites were identified across all the samples collected. In addition several minor metabolites were also identified. The predominant metabolic pathway for the test material in lactating goats involves hydrolysis of intact parent to form the free acid metabolite, M1.

All studies were performed to a high standard, in line with GLP and in accordance with standardised guidelines. They have thus been assigned a reliability score of 1 in line with the principles for assessing data quality set out in Klimisch (1997). The available data are deemed to be relevant, reliable and adequate for the purposes of risk assessment.