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Link to relevant study record(s)

Description of key information

Rapid absorption and excretion, low potential for bioaccumulation: Basic toxicokinetics, OECD 417, Hassler 2001 (rat)
Rapid absorption and excretion, low potential for bioaccumulation: Basic toxicokinetics, OECD 417, Hassler 1998 (rat)
Rapid absorption and excretion, low potential for bioaccumulation: Basic toxicokinetics, EPA OPPTS 870.7485, OECD 417, Fleischmann 1999 (rat)
Rapid absorption and excretion, low potential for bioaccumulation: Basic toxicokinetics, EPA OPPTS 85-1, EPA OPPTS 870.7485, OECD 417, Fleischmann 2000 (rat)
Rapid absorption and excretion, low potential for bioaccumulation: Basic toxicokinetics, no guideline, Briswalter 2001 (dog)

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
84

Additional information

The test material was seen to be eliminated from the body rapidly, independent of the dose level, position of the radiolabel, sex of the animals or pretreatment. Renal elimination was found to be the major route of excretion for all dose groups. The values for urinary excretion were 76 % and 70 % of the 2 -pyridine radiolabelled test material and 58 % and 70 % of the 2 -pyrimidine radiolabelled test material in males and females, respectively. A second but smaller part of the absorbed test material was excreted with the bile fluid accounting for 11 % and 11 % of the dose of pyridine-2 radiolabelled test material and 27 % and 14 % of the dose of pyrimidine-2 radiolabelled test material in males and females, respectively. The percent of dose excreted with faeces was between 5 and 6 %. The residues remaining in the gastrointestinal tract 48 hours after administration ranged from 0.5 to 2.1 % of the dose. Based on urinary and biliary excretion and residual radioactivity in the carcass the extent of absorption was determined to be at least 84 -88 % of the dose. After 7 days, radioactivity levels were low (≤ 0.3 % of dose) in all tissues and carcass with no evidence of bioaccumulation. The biotransformation of the test material in the rat occurred mainly by three concurrent pathways: oxidative O-demethylation, hydroxylation of the pyrimidine ring and Smile's rearrangement of the sulfonylurea. Hydrolysis of the sulfonylurea and oxidative O-deethylation are minor pathways in the rat.

Based on the metabolites identified in the submitted study, the metabolism of test material in the dog proceeds by the same major pathways as in the rat.

Four in vivo studies were submitted to evaluate the metabolism, absorption, excretion and distribution of the test material in rats. All studies were performed in compliance with GLP and appropriate standardised EPA and OECD guidelines. All studies were performed in line with good scientific principles and reported to a high standard and were therefore assigned a reliability score in line with criteria as defined in Klimisch (1997). A fifth in vivo study was performed in dogs to assess the metabolism of the test material. Although not performed in line with a specific guideline, the study was performed to good scientific principles and was predominantly performed in line with GLP, the in life phase of the study was not performed under GLP, but quality assurances were provided by the performing laboratory. The study was therefore assigned a reliability score of 2 in accordance with criteria of Klimisch (1997). The conclusions of all five studies as a weight of evidence was considered a complete and accurate assessment of the test material and was carried forward for risk assessment purposes.

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