Pesticide residues in food — 2007: Toxicological ... - ipcs inchem

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for c onsideration by the present Meeting. Several new studies, including two double-blind clinical
studies in human volunteers, were also considered by the present Meeting.
Most studies, excluding some described in previous JMPR monographs, were certified as having
been performed in compliance with good laboratory practice (GLP) and in accordance with the
relevant Organization for Economic Co-operation and Development (OECD) test guidelines. The
studies in humans were conducted in accordance with the principles of good clinical practice and the
Declaration of Helsinki, or equivalent statements prepared for use by national and/or multinational
authorities. As these guidelines specify the tissues normally examined and the clinical pathology
tests normally performed, only significant exceptions to these guidelines are reported here, to avoid
repetitive listing of study parameters.
Evaluation for acceptable daily intake
1. Biochemical aspects
1.1 Absorption, distribution and excretion
The pharmacokinetic behaviour of carbonyl- 14 C-labelled azinphos-methyl was investigated
in male Sprague-Dawley rats. The material was almost completely absorbed from the digestive
tract, and irrespective of dose and route of administration, 60–70% was eliminated in the urine and
25–35% in the faeces within 48 h. Less than 0.1% of the administered radiolabel was eliminated
with the respiratory air within 24 h after dosing, and in rats with biliary fistulas about 30% of the
intravenously administered radiolabel was eliminated in the bile within 24 h after dosing. Two days
after dosing, the total amount of radioactivity in the animal (excluding digestive tract) was less than
5% of the administered dose; by 4 days this had declined to 2% and by 16 days to 1%. Six hours
after dosing, the highest concentrations of radioactivity were found in the organs of elimination
(liver and kidney) with relatively high concentrations found in blood. The activity concentrations
decayed rapidly in all organs up to 2 days after dosing, but thereafter the activity was more slowly
eliminated. At 16 days after dosing, the highest concentration was found in the erythrocytes. In
studies in vitro, in which whole blood was incubated with labelled parent compound, there was
no evidence for accumulation of radioactivity in the blood constituents (Patzschke et al., 1976;
A nnex 1, reference 64).
The pharmacokinetic behaviour of benzazimide was investigated in rats using the 14 C-ringlabelled
compound. After oral administration, the 14 C was almost completely absorbed from the gastrointestinal
tract. Elimination of the radiolabel took place quickly, 24 h after administration only
1.3% of the amount administered was present in the animal not including the gastrointestinal tract.
More than 99% of the amount administered was eliminated within 48 h (54–66% in the urine and
33–45% via the faeces) (Weber et al., 1980; Annex 1, reference 64).
1.2 Biotransformation
The metabolism of azinphos-methyl was investigated by administration of ring-UL- 14 C-labelled
azinphos-methyl to male and female Sprague-Dawley rats. The proposed metabolic pathway
of azinphos-methyl in rats is given in Figure 1. Upon absorption, azinphos-methyl is rapidly
metabolized by mixed function oxidases and glutathione transferases in the liver and other tissues,
which results in the formation of azinphos-methyl oxygen analogue, mercaptomethylbenzazimide,
glutathionyl methylbenzazimide and desmethyl isoazinphos-methyl. Further hydrolysis,
AZINPHOS-METHYL 139–172 JMPR 2007