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

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24 h. Clearance of radioactivity from the blood was best described by a two-compartment model with
half-lives of 1.5 and 17.7 h, respectively; the half-life for renal clearance was 20.8 h. By the end of
the 7-day collection period, about 85% of the administered dose was found in the urine and 12% in
the faeces (Hui et al., 1996a).
In a study on absorption, distribution, metabolism and elimination, three groups of four female
Rhesus monkeys (aged 6–25 years) received capsules containing [ 14 C]atrazine ([U 14 C]-triazine
labelled; radiochemical purity, 96.8%; purity of unlabeled atrazine, 98.7%) as a single dose at 1, 10
or 100 mg per monkey. Samples of urine, faeces and blood were collected for 168 h after treatment.
Maximum blood concentrations were achieved after 2, 8 and 24 h at the lowest, intermediate and
highest dose, respectively. On the basis of the comparison of AUCs after oral and intravenous administration
(Hui et al., 1996a), the bioavailabilities were estimated at 92%, 75% and 78% for the lowest,
intermediate and highest dose, respectively. The terminal half-lives for elimination from plasma were
31.9 h, 21.6 h and 19.7 h for the lowest, intermediate and highest dose, respectively. By the end of
the 7-day collection period, excretion of radioactivity in the urine was about 57%, 58% or 53% for
the lowest, intermediate and highest dose, respectively, and in faeces about 21%, 25% or 35% for the
lowest, intermediate and highest dose, respectively (Hui et al., 1996b).
1.2 Biotransformation
The metabolic pathway of atrazine in the rat is illustrated in Figure 1. The experimental evidence
supports a metabolic pathway dominated by oxidative removal of the alkyl side-chains with
2-chloro-4, 6-diamino-s-triazine (G 28273) being the major metabolite. The 2 carbon-chlorine
bond is stable to enzymatic hydrolysis, but is subject to conjugation via the action of glutathione-
S-transferase. Action on sulfur-containing metabolites gives 2-sulfhydryl-s-triazines which in turn
are subject to methylation followed by oxidation to the corresponding S-oxides. Oxidation of primary
positions of the alkyl side-chains to carboxyl functions is a minor alternative metabolic
route.
The different species including humans appear to share this common pathway (Figure 2); however,
differences in the kinetics of each step may be inferred. No difference in metabolism was found
in those cases where the sexes were compared. Although in-vitro data suggest that metabolism to
the bi-dealkylated metabolite by cultured hepatocytes from women is minimal, this data were not
confirmed by analysis of urine in vivo in two studies in men in which the bi-dealkylated form was
a major component, as in the rat. The possibility of significant post-hepatic modification in humans
cannot therefore be excluded.
Rats
From a study in Sprague-Dawley rats described previously (section 1.1; Paul et al., 1993), the
excreta from male rats treated with atrazine as a single dose at 100 mg/kg bw, and from bile-duct
cannulated male rats treated with a single dose at 1 mg/kg bw were used for the separation and identification
of the metabolites. Urine and faeces were collected for up to 168 h, and bile for up to 48 h.
Metabolites were analysed by two-dimensional thin-layer chromatography (TLC). The pattern of
metabolites was complex, with 26, 12 and 9 different metabolites identified in the urine, faeces and
bile, respectively. The major metabolite DACT (G 28273) accounted for approximately 26% of the
administered dose in the urine, 1.6% in bile and 1.3% in faeces. Approximately 1% of the administered
dose was the mercapturic derivative of the DACT (CGA 10582) in the urine. Lesser amounts
of the mono-dealkylated metabolites G 28279 and G 30033 were found in the urine, bile or faeces. A
trace amount of parent atrazine was found in the faeces (Paul et al., 1993).
ATRAZINE 37–138 JMPR 2007