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

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2.5 Reproductive toxicity
(a)
Multigeneration studies
Rats
In a two-generation study of reproductive toxicity, groups of 30 male and 30 female (parental
generation, P) or 25 male and 25 female (F 1
) Sprague-Dawley Crl:CD(SD)BR rats were given diets
containing pyrimethanil (purity, 96.2–97.3%) at a concentration of 0, 32, 400, or 5000 ppm (equal to
0/0, 1.9/2.2, 23.1/27.4, and 293.3/342.8 mg/kg bw per day in the P rats and 0/0, 2.3/2.7, 29.1/34.0,
and 389.0/449.6 mg/kg bw per day in the F 1
for males/females, respectively). Exposure of the P generation
began at age approximately 8 weeks and continued for 14 weeks, and throughout the pairing
(mating) period, gestation and lactation to necropsy. The groups of 25 male and 25 female F 1
pups
selected to produce the F 2
generation were exposed to the same doses as their parents, beginning on
postnatal day 21. F 1
rats were dosed with pyrimethanil for 14 weeks before mating produce the F 2
litters,
and throughout pairing (mating) period, gestation and lactation to necropsy. Mating to produce
a second F 2
b generation was not performed.
Diets were prepared weekly and stored at −20 °C. Stability, homogeneity and dietary concentrations
were confirmed analytically. Analysis of homogeneity, stability and achieved concentrations
were not reported in the study report. The sponsor reported that “results were within limits c onsidered
acceptable for administration to the study animal”.
Rats were inspected twice per day for mortality and morbidity and daily for clinical observations.
Body weights of males were recorded weekly. Females were weighed weekly during premating
and on days 0, 6, 12, 15 and 20 of gestation, and days 1, 4, 7, 14, and 21 of lactation.
Food consumption was measured weekly for males and females during the pre-mating period and
daily during gestation and lactation for the females, but was reported at body-weight intervals; food
consumption for males was recorded on a weekly basis after mating and until scheduled necropsy.
Estrous cycles were monitored, with vaginal smears taken during the mating and until mating was
confirmed. Gestation duration was calculated. Females were allowed to deliver normally and rear
young to weaning on day 21. Litters were examined after delivery and pups were sexed, examined for
gross abnormalities and the number of stillborn and live pups recorded. Litters were then examined
twice per day for survival. Number, sex and weight of pups were recorded on postnatal days 1, 4, 7,
14 and 21. All surviving pups were assessed for the age at which pinnae unfolding, incisor eruption
and eye opening took place, and on day 1 for surface-righting reflex, day 17 for air-righting reflex,
and day 21 for grip reflex, pupilliary reflex and auditory startle response. All P and F 1
rats and those
found dead and killed in extremis were necropsied and examined macroscopically. Selected tissues
(ovaries, testes, uterus, epididymides, cervix, seminal vesicles, vagina, prostate pituitary gland, and
coagulating glands lesions) were examined histopathologically in untreated rats and those treated at
5000 ppm. Organ weights were not recorded in this study.
There were no treatment-related clinical signs or mortalities observed in the P or F 1
. Rats killed
in a moribund condition included two parental females (one at the intermediate dose on day 15 of
gestation and one at the highest dose on day 1 of lactation), as well as two F 1
females (one at the
intermediate dose on day 1 of lactation and one at the highest dose on day 24 of gestation). One F 1
male from the group at the lowest dose was found dead on week 11 of the pre-mating period. One F 1
female from the group at the lowest dose died as a result of accidents. None of the deaths in either
generation were attributed to treatment. Clinical signs, consisting of increased incidence of fur staining,
were limited to females at the highest dose (F 0
, and F 1
) during gestation and lactation. A high
incidence of food scattering was also observed in females at the highest dose (F 0
, and F 1
). Treatmentrelated
decreases in mean body weights were limited to parental rats at the highest dose and their
offspring. During weeks 0–7 of the pre-mating period, F 0
males and females had significantly lower
PYRIMETHANIL 445–486 JMPR 2007