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

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necropsy. The uterus and ovaries were exposed and the number of corpora lutea on each ovary was
recorded. Gravid uteri were weighed, opened, and the location and number of viable and nonviable
fetuses, early and late resorptions, and the total number of implantations were recorded. Uteri from
females that appeared nongravid were opened and placed in 10% ammonium sulfide to detect any
early implantation loss. All fetuses were weighed, sexed, and examined for external malformations/
variations. Each fetus was examined viscerally by fresh dissection and the sex verified. Visceral examination
was performed on fetuses preserved in Bouin fixative using a modified Wilson technique.
For skeletal examination, fetuses were preserved in methanol and stained with Alizarin Red.
Analysis of preparations for the lowest, intermediate and highest dose were within 114.0–138.6%,
94.7–96.9% and 96.2–106.8% of the target doses, respectively. All rats survived to terminal sacrifice
except one in the control group and one at the lowest dose that died on days 13 and 18 of gestation,
respectively. The cause of death of the female at the lowest dose was gavage error. At the highest dose,
treatment-related clinical signs of toxicity included hair loss, slight to moderate emaciation and hunched
posture. No clinical signs of toxicity were observed at 7 or 85 mg/kg bw per day. Treatment-related,
statistically significant decreases (9.8% on day 16 of gestation) in body weights and body-weight gains
(42.3%) were observed in rats at the highest dose. These decreases were accompanied by 16.7–18.2%
decreases in food consumption from day 6 to 15 of gestation. No effects on body weights, body-weight
gains and food consumption were observed at 7 or 85 mg/kg bw per day. At necropsy, no treatmentrelated
gross pathological findings were observed except hair loss in rats at the highest dose.
No treatment-related effects were seen in the mean number of corpora lutea, implantation sites,
pre- and post-implantation loss, or early and late resorptions. There were no statistically significant
differences in litter size, number of fetuses, number of implantations or fetal sex ratio. Statistically
significant decreases in mean litter weight (14%) and mean fetal weight (7%) was observed in rats at
the highest dose. Data provided for historical controls indicated that the mean litter and fetal weights
were essentially similar. No treatment-related external, visceral, or skeletal malformations/variations
were observed in any fetuses.
The NOAEL for maternal toxicity was 85 mg/kg bw per day. The LOAEL for maternal toxicity
was 1000 mg/kg bw per day on the basis of abnormal clinical signs, reduced body weights and
body-weight gains and reduced food consumption. The NOAEL for developmental toxicity was
1000 mg/kg bw per day. The LOAEL for developmental toxicity was not identified (Jackson &
B ennett, 1991; Reader, 2003c).
Rabbit
In a study of developmental toxicity, groups of 18 or 19 pregnant New Zealand White rabbits
were given pyrimethanil (purity, 97.1%) at a dose of 0, 7, 45, or 300 mg/kg bw per day by gavage
in 1% methylcellulose in sterile water on days 7–19 of gestation, inclusive. Stability, homogeneity
and dose concentrations were confirmed analytically. All rabbits were observed twice per day for
mortality and moribundity and once daily for clinical signs of toxicity. Rats were also observed for
signs of toxicity at approximately 1 h after dosing. Maternal body weights were recorded on days 0,
3 and daily from days 7–20 of gestation, and on days 22, 25 and 28 of gestation. Food consumption
was measured every 2 days from day 3 to day 27 of gestation and daily from day 27 and day 28 of
gestation. A gross postmortem examination was done on all females aborting during the study. On
day 28 of gestation, all surviving does were killed and subjected to gross necropsy. The uterus and
ovaries were excised and the number of corpora lutea on each ovary was recorded. Gravid uteri were
weighed, opened, and the location and number of viable and nonviable fetuses, early and late resorptions,
and the total number of implantations were recorded. All fetuses were weighed and examined
for external malformations/variations. Crown–rump measurements were recorded for late resorptions
and the tissues were discarded. Each fetus was examined viscerally by fresh dissection and the
sex was determined. The brain from each fetus was examined by mid-coronal slice. All carcasses
were eviscerated and processed for skeletal examination.
PYRIMETHANIL 445–486 JMPR 2007