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

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mean body‐weight gains. After mating, mean body weights of F 0
females at the highest dose were
significantly lower during gestation (6.4%) and lactation (3.7%). The intergroup differences in mean
body weights of the F 1
pups at birth were minimal. However, throughout lactation, F 1
pups at the
highest dose had significantly decreased (approximately 20%) body-weight gains, which resulted
in a significant decrease (16.8%) in the mean pup body weight at weaning. For the F 1
generation,
statistically and biologically significant decreases in mean body weights were observed during the
pre-mating period (males, 14–17%; females, 11–16%), gestation (14%), and lactation (9–16%) periods.
At the highest dose, F 2
pups had significantly lower mean body weights at birth (both sexes combined).
The mean body-weight gains for these rats were significantly lower (16.9%) than those of the
controls, resulting in a significant decrease in mean body weight at weaning. Mean food consumption
was decreased in rats at the highest dose (F 0
males, F 1
males and females) during the pre-mating
period; food consumption was significantly increased during gestation (F 1
females) and lactation
(F 0
and F 1
females). Food-conversion efficiency in the controls and treated groups were comparable.
Statistically significant decreases in the F 0
female fertility and fecundity indices were observed at
the highest dose; the indices were, however, within the range for historical controls. No other significant
treatment-related effects were noted in any other reproductive parameters. At the highest dose,
there was a statistically significant reduction in mean pup body weights (F 1
offspring) from day 1 of
lactation to weaning compared with controls. The combined mean body weights at birth of F 2
pups
at the highest dose were significantly lower than those of the controls. From day 1 of lactation until
day 21, the differences in the mean body weights between F 1
and F 2
pups at the highest dose and in
the control group progressively decreased. Compared with controls, the mean body weights at the
highest dose were 18% lower for F 1
pups and 16% lower for F 2
pups on day 21 of lactation. Mean
body-weight gains were also significantly reduced compared with those of the controls. There was
no treatment-related effect on total number of litters and implantation sites, pup numbers, sex ratio,
survival and clinical conditions of offspring. Developmental milestones of the F 1
generation pups did
not show any treatment-related effects. Intergroup differences in the attainment time for eye opening,
incisor eruption and pinna opening were minimal and not related to treatment; surface-righting, airrighting,
auditory response, pupillary reflex and grip strength were similarly unaffected by treatment.
No treatment-related abnormalities were observed at necropsy.
The NOAEL for parental systemic toxicity was 400 ppm, equal to 23.1 and 27.4 mg/kg bw per
day in males and females, respectively. The LOAEL parental systemic toxicity was 5000 ppm, equal
to 293.3 and 342.8 mg/kg bw per day in males and females, respectively, on the basis of decreased
body weights (11–13%) and body-weight gains (11–17%). The NOAEL for reproductive toxicity
was 5000 ppm, equal to 293.3 and 342.8 mg/kg bw per day in males and females, respectively. The
NOAEL for offspring toxicity was 400 ppm, equal to 23.1 and 27.4 mg/kg bw per day in males and
females, respectively. The LOAEL for offspring toxicity was 5000 ppm, equal to 293.3 and 342.8 mg/
kg bw per day in males and females, respectively, on the basis of decreased pup body weights (17%)
on day 21 of lactation (Clark, 1993a, 1993b, 1995).
(b)
Developmental toxicity
Rats
In a study of developmental toxicity, groups of 30 pregnant Sprague-Dawley Crl:COBS CD
(SD) rats were given pyrimethanil (purity, 96.3–97.0%) at a dose of 0, 7, 85, or 1000 mg/kg bw per
day by gavage in 0.1% methyl cellulose in distilled water on days 6–15 of gestation, inclusive. Stability,
homogeneity and dose concentrations were confirmed analytically. All rats were observed twice
per day for mortality and moribundity and daily for clinical signs of toxicity. Maternal body weights
were recorded on days 1 and 3 of gestation, daily from day 6 to day 16 of gestation, and on day 18 and
20 of gestation. Food consumption was measured between days 3–5, 6–8, 9–11, 12–15, 16–17 and
18–19 of gestation. On day 20 of gestation, all surviving dams were sacrificed and subjected to gross
PYRIMETHANIL 445–486 JMPR 2007