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

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(b)
Developmental toxicity
Rats
Groups of 25 (presumed) pregnant female Sprague-Dawley rats received procymidone technical
(purity, 99.6%) at a dose of 0, 30, 100 or 300 mg/kg bw per day in corn oil by oral gavage on days
6–15 of gestation. Doses were based on the results of a range-finding study (Pence et al., 1980a).
Rats were observed twice per day and weighed at intervals during the study. Dams were terminated
on day 20 of gestation, fetuses were delivered by caesarean section and a uterine examination was
performed. The number, sex and weights of fetuses were recorded; visceral examinations (Wilson
technique) were performed on 33% of the fetuses and skeletal examinations (alizarin staining) conducted
on the remainder.
All dams survived the study, pregnancy rates were acceptable and there were no treatmentrelated
clinical signs. Body-weight gains were reduced (60%) during days 6–11 of gestation at
300 mg/kg bw per day, although parity with the controls was regained by the end of the dosing
period; food consumption was not measured. The proportion of males was reduced relative to controls
(57.5%) at the intermediate (50%) and highest (46%) doses, but the values were within the
normal ranges for studies of developmental toxicity in rats. There was no effect of treatment on
litter values or the incidence of fetal abnormalities at any dose. The NOAEL for maternal toxicity
was 100 mg/kg bw per day on the basis of reduced body-weight gain on days 6–11 of gestation.
The NOAEL for developmental toxicity was 300 mg/kg bw per day, the highest dose tested, on the
basis of the absence of a treatment-related effect on embryo-fetal development. The study claimed
compliance with GLP and complies with the essential elements of OECD test guideline 414 of 1981
(Pence et al., 1980b).
To more fully evaluate the incidence and significance of the genital abnormalities observed
in the multigeneration study of reproduction (Wickramaratne et al., 1988a), an additional study of
developmental toxicity was conducted. For dose-range finding, groups of eight (presumed) pregnant
female Sprague-Dawley rats received procymidone (purity, 99.4%) at a dose of 0, 12.5, 300, 500,
750 or 1000 mg/kg bw per day in corn oil by oral gavage on days 6–19 of gestation. The NOAEL for
maternal toxicity was 12.5 mg/kg bw per day on the basis of clinical signs at 300 mg/kg bw per day,
and the NOAEL for developmental toxicity was 12.5 mg/kg bw per day on the basis of hypospadias
(71% vs 0% in controls), and reduced anogenital distance at 300 mg/kg bw per day (Hobermann,
1992a).
In the main study, groups of 45 (presumed) pregnant female Sprague-Dawley rats received
procymidone (purity, 99.4%) at a dose of 0, 3.5, 12.5, 125 or 500 mg/kg bw per day in corn oil by
oral gavage on days 6–19 of gestation. Approximately half the females in each group were terminated
on day 20 of gestation. Uterine examinations were performed and litter parameters were evaluated
for fetuses on day 20 of gestation. The fetuses were weighed and examined for visceral and skeletal
abnormalities. The remaining females were allowed to deliver and rear their pups to weaning. Male
offspring were retained until postnatal day 45 and females until postnatal days 51 to 53. Rats were
observed daily for clinical signs of toxicity, body weights and food consumption were recorded daily
in the periods during and after dosing. Pups delivered normally were weighed and anogenital distance
measured on postnatal days 1, 21 and 45. At necropsy, these pups were given a detailed examination
and reproductive organs were weighed and examined histopathologically.
There were no deaths during the study. Maternal toxicity was apparent at 125 and 500 mg/kg bw
per day as clinical signs (ungroomed coat, urine-stained fur), initial body-weight loss and reduced food
intake. Developmental toxicity was apparent at 125 and 500 mg/kg bw per day as lower fetal weights,
reduced anogenital distance (Table 22), higher incidences of male offspring with undescended testes,
PROCYMIDONE 349–401 JMPR 2007