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

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Hydroxyatrazine was not carcinogenic in rats. The NOAEL was 25 ppm, equal to 0.96 and
1.2 mg/kg bw per day in males and females, respectively, on the basis of kidney toxicity at 200 ppm
and greater (Chow & Hart, 1995).
In an assay for reverse mutation in bacteria, hydroxyatrazine (purity, 99%) did not induce gene
mutations at the histidine locus of S. typhimurium when tested at concentrations of up to 5000 µg/
plate (Deparade, 1988).
In two tests for DNA repair in vitro, hydroxyatrazine (purity, 96–99%) did not induce unscheduled
DNA synthesis in primary rat hepatocytes exposed at concentrations of up to 1500 µg/ml
(Hertner, 1988a) and in human fibroblasts exposed at concentrations of up to 1500 µg/ml (Meyer,
1988).
In an assay for micronucleus formation in mouse bone marrow, hydroxyatrazine (purity, 99%)
did not induce micronucleus formation in the PCE of Tif:MAGF mice treated once orally at doses
ranging from 1250 to 5000 mg/kg bw (Ceresa, 1988a).
In a study of prenatal developmental toxicity, which complied with GLP and US EPA test
guidelines, groups of 26 pregnant female Crl:COBS CD(SD)BR rats were given hydroxyatrazine
(purity, 96.7%; suspended in 3% corn starch with 0.5% Tween 80) at a dose of 0, 5, 25 or 125 mg/kg
bw per day by oral gavage on days 6 to 15 of gestation.
No mortalities or treatment-related clinical observations were noted. Food consumption was
significantly decreased at 125 mg/kg bw per day during days 8–12 of gestation (−12.1%) and during
the entire dosing period (−8.4%). Body-weight gain at 125 mg/kg bw per day was decreased by about
24% during days 8–12 of gestation, while corrected body-weight gain was decreased by about 11%.
There were no treatment-related effects on any reproductive parameter examined. Fetal body
weights were slightly, but significantly lower at 125 mg/kg bw per day (males, −3.9%; females, −5.0%).
There were no treatment-related external, visceral or skeletal malformations. At 125 mg/kg bw per
day, there were significantly increased fetal and litter incidences of not completely ossified hyoids,
not completely ossified interparietals, and not ossified forepaw metacarpals and proximal phalanges
(Table 20).
There was no evidence of teratogenicity.
The NOAEL for maternal toxicity was 25 mg/kg bw per day on the basis of decreased food
consumption and body-weight gain at 125 mg/kg bw per day. The NOAEL for developmental toxicity
was 25 mg/kg bw per day on the basis of increased incidences of incompletely ossified hyoid and
interparietal bones and not ossified forepaw metacarpals and proximal phalanges at 125 mg/kg bw
per day (Lindsay et al., 1989).
(b)
Studies on site and mechanism of action in the central nervous system
In a in-vitro study on the mechanism by which chlorotriazines interfere with hypothalamic control
of the gonadotrophin releasing hormone (GnRH) release and luteinizing hormone (LH) surge,
the ability of atrazine and its metabolites DIA, DEA and DACT to interact with gamma-aminobutyric
acid A-type (GABA A
) receptors in rat cortical membranes was examined by measuring their effects
on binding of the following prototypical ligands to their recognition sites on GABA A
receptors: [ 3 H]
muscimol, which binds to the GABA binding site; [ 3 H]Ro15-4513, which binds to the benzodiazepine
site on the GABA A
receptor; and [ 35 S]tert-butylbicyclophosphorothionate (TBPS), which binds
to the picrotoxin binding site in the chloride channel of GABA A
receptors.
Atrazine significantly inhibited the binding of [ 3 H]Ro15-4513 at concentrations of 30 μmol/l
and greater, and the half-maximal inhibitory concentration (IC 50
) was calculated to be 305 μmol/l.
The chlorotriazine metabolites, however, were without significant effect on Ro15-4513-binding when
ATRAZINE 37–138 JMPR 2007