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

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and DACT (G 28273) using a gas chromatography method with stated detection limit of 0.005 ppm.
Atrazine and G 28279 were detected in whole blood but were below the limit of quantification. The
metabolite G 30033 appeared rapidly in the plasma reaching a peak after 2 h to decline rapidly thereafter
with a half-life of 2.8 h. The disappearance of G 30033 corresponded with an increased plasma
concentration of the metabolite G 28273 which reached a peak at 5 h after dosing and was eliminated
with a half-life of 17.8 h. This suggests a step-wise dealkylation of atrazine to DEA and then to DACT.
The elimination of both metabolites from the blood was consistent with one-compartment first-order
kinetics at least up to 32 h after dosing. Analysis of urine identified only approximately 14.5% of the
administered dose, with consistent results for all six men. The chloro-metabolites G 30033, G 28279
and G 28273 accounted for 5.4%, 1.4% and 7.7% of the administered dose, respectively. For metabolite
G 28273, urinary kinetics suggested a single-compartment first-order model with a half-life of
11.5 h. For the metabolites G 30033 and G 28279, a two-compartment first-order model suggested a
fast and slow phase of 2.3 h or 8.4 h and 2.4 h or 36.2 h, respectively (Davidson, 1988).
In a biological monitoring study on a group of six manufacturing workers exposed to atrazine
(10–700 µmol per workshift), total urinary excretion of atrazine plus three metabolites accounted for
1–2% of the external dose, with 50% of the amount excreted in the first 8 h following the workshift.
About 80% of the excreted metabolites accounted for DACT (G 28273), 10% for DIA (G 28279), 8%
for DEA (G 30033), and only 1–2% was atrazine (Catenacci et al., 1993).
In a study on comparative metabolism of atrazine in vitro, cultures of hepatocytes from
CD1 mice, Sprague-Dawley rats, Fischer 344 rats, guinea-pigs, goats and Rhesus monkeys, and
two women were used. The isolated cells were assayed for viability and cultured with [ 14 C]atrazine
(purity, 97%) at a concentration of 1, 5, 10, 25 or 100 ppm for up to 24 h. Analysis of the metabolites
was by thin-layer and cation-exchange chromatography. The different species appeared to share
common pathways for the metabolism of atrazine, dealkylation of the ethyl- and isopropyl moities
but displayed significant differences in the kinetics of phase I and phase II metabolism of atrazine.
Human and CD1 mice hepatocytes showed a marked preference for rapid N-deethylation, while in
rats and Rhesus monkeys N-deisopropylation predominanted over N-deethylation. Sprague-Dawley
rat, Fischer rat, CD1 mouse and Rhesus monkey hepatocytes rapidly metabolized atrazine to the
di-dealkylated metabolite DACT (G 28273) and then further metabolized this intermediate to different
conjugates. For guinea-pig, goat and human hepatocytes, the primary products were the monodealkylated
metabolites DEA (G 30033) and DIA (G 28279) with only traces of the bis-dealkylated
metabolite DACT. The bis-dealkylated metabolite DACT accounted for 50–70% of total radiolabel in
24-h incubations with hepatocytes from CD1 mice, rats (both strains) and Rhesus monkeys, but only
3–10% in incubations with guinea-pig, goat and human hepatocyte cultures. The percentages of the
different metabolic products of atrazine produced by hepatocytes from different species are presented
in Table 1 (Thede, 1988).
2. Toxicological studies
2.1 Acute toxicity
(a)
Lethal doses
In a study of acute oral toxicity, groups of five male and five female Tif:RAI rats received atrazine
as a single dose at 600–6000 mg/kg bw suspended in 2% carboxymethyl cellulose Clinical symptoms
occurred within 2 h after treatment in all groups and included sedation, dyspnoea, exophthalmus,
curved body position and ruffled fur. The surviving animals recovered between days 7 and 8 after
treatment. The median lethal dose (LD 50
) was 1869 mg/kg bw (Sachsse & Bathe, 1975b).
ATRAZINE 37–138 JMPR 2007