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

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Dealkylation reactions at the 4 and 6 positions resulting in the formation of either of the monodealkylated
metabolites (desethyl-atrazine, desisopropyl-atrazine), which in turn can be further dealkylated
to DACT, may occur in animals, plants and bacteria. Hydroxyatrazine is the major metabolite
in plants, but is only a minor metabolite in animals in which the varying forms of the delkylated
chlorometabolites dominate instead. The metabolism of atrazine to hydroxyatrazine in plants is a
detoxification reaction as the phytotoxicity of hydroxyatrazine is greatly reduced compared with the
parent compound.
A limited toxicology database is available for these four metabolites and the studies are summarized
below.
(i) Deethyl-atrazine, DEA (G 30033)
DEA was of moderate acute oral toxicity in rats (LD 50
, 1110 mg/kg bw). In short-term studies
in rats given DEA at dietary concentrations of up to 1500 ppm, effects included reduced body-weight
gain and food consumption, decreased erythrocyte parameters and lymphoid atrophy of the thymus.
The overall NOAEL was 50 ppm, equal to 3.2 mg/kg bw per day. In a 13-week study in dogs given
DEA at dietary concentrations of up to 1000 ppm, effects included reduced body weight and food
consumption, decreased erythrocyte parameters and renal tubular epithelial hyperplasia/basophilia.
The NOAEL was 100 ppm, equal to 3.7 mg/kg bw per day. DEA was not genotoxic in a battery of
tests including assays for point mutation and DNA repair in vitro and testing for clastogenicity in
vivo. In a study of prenatal developmental toxicity in rats, the NOAEL for maternal toxicity was
5 mg/kg bw per day on the basis of decreased body-weight gain and food intake at 25 mg/kg bw
per day and greater. The NOAEL for developmental toxicity was 25 mg/kg bw per day on the basis
of increased incidences of fused sternebrae and incomplete ossification of the proximal phalanx of
posterior digit 5 at 100 mg/kg bw per day. There was no evidence of teratogenicity. In a special study
on the effects of DEA on pubertal development in male rats, atrazine equimolar doses of ≥ 25 mg/kg
bw per day delayed preputial separation, with a NOAEL of 12.5 mg/kg bw per day.
In a study of acute oral toxicity, which complied with GLP and the US EPA test guidelines,
groups of HSD:(SD) rats received DEA (purity, 95.7%; suspended in 2% carboxymethyl-cellulose)
as a single dose at 250, 500, 2000, 3500 or 5050 mg/kg bw by gavage. Each group consisted of five
males and five females with the exception of the group at the lowest dose, which consisted of five
females. The rats were observed for clinical signs and mortality for 14 days. The LD 50
s for males,
females and both sexes combined were 1890, 669 and 1110 mg/kg bw, respectively (Kuhn, 1991c).
In a short-term study of oral toxicity, which complied with GLP and the test guidelines of
OECD and US EPA, groups of 10 male and 10 female KFM-WIST rats were fed diets containing DEA
(purity, 99.3%) at a concentration of 0, 50, 500 or 1500 ppm, equal to 0, 4.5, 49.3 and 145.9 mg/kg bw
per day in males and 0, 4.6, 49.0 and 132.8 mg/kg bw per day in females, for 4 weeks.
Clinical signs of excitement were observed in the rats at the highest dose during the fourth week
of treatment. There was a decrease in food consumption that was apparent at 1500 ppm with an average
reduction over the 4-week treatment period of 24% in males and 19% in females. A dose-related
reduction of body weight with statistically significant differences from the second week of treatment
was observed for the males and females at the highest dose and for the males at the intermediate
dose. At the end of the 4-week treatment, body weights were significantly decreased in both sexes
at 500 ppm (17% in males, 9% in females) and at 1500 ppm (30% in males, 19% in females) when
compared with rats in the control group. Slight changes in haematological and clinical biochemistry
parameters were observed in the groups at the intermediate and highest dose. Thymus : body weight
ratios were decreased in females at the lowest, intermediate and highest dose (15%, 19% and 26%,
ATRAZINE 37–138 JMPR 2007