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

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hypospadias, testicular atrophy, distended preputial grand, inflammatory changes in the accessory sex
organs (seminal vesicles, prostate and coagulating glands), and lower organ weights of testes and
prostate. At 500 mg/kg bw per day, there was a significant increase in the incidence of bifid thoracic
vertebral centra in fetuses and prostate lesions in male offspring. Male offspring at 12.5 and 3.5 mg/
kg bw per day were not affected by treatment. No treatment-related influence on sexual differentiation
and development of female offspring was observed at any dose.
The NOAEL for maternal toxicity was 12.5 mg/kg bw per day, on the basis of reduced weight
gain and food intakes at 125 mg/kg bw per day and above. The NOAEL for developmental toxicity
was 12.5 mg/kg bw per day, on the basis of the reduction of anogenital distance at 125 mg/kg bw per
day and above in males. These studies contained GLP compliance statements (Hoberman, 1992a,
1992b, 1992c).
A study was performed to determine the minimum toxic dose of procymidone required to produce
the external effects on male genitalia of rats. Groups of 20 pregnant Crj:Sprague-Dawley rats
were given procymidone (purity, 99.6%) at a dose of 37.5 or 62.5 mg/kg bw per day during the critical
period of development of fetal external genitalia (between days 6 and 19 of gestation). Dams were
allowed to deliver and, together with female pups, were euthanized on postnatal day 21. Male pups
were weaned and euthanized on postnatal day 56. Maternal rats and offspring were observed daily
for clinical signs of toxicity and body weights were recorded at intervals. Maternal rats and offspring
were given a gross necropsy at euthanasia. Observations on the offspring included macroscopic
examination of the external genitalia for all males, organ weights were also measured. In maternal
rats, samples of blood were taken for analysis of procymidone concentrations. Blood samples were
collected from additional groups of rats on days 6 and 19 of gestation, at 2, 4, 8 and 24 h after dosing
and analysed for procymidone.
There were no treatment-related effects on clinical or gross necropsy observations in the
maternal rats. Maternal body-weight gains were suppressed in both groups. The blood concentration
of procymidone was at a maximum (C max
) between 2 h and 4 h after dosing and higher C max
values were found at the end of the dosing period (day 19 of gestation) than at the beginning (day 6
of gestation), but the rate of elimination of procymidone from plasma appeared to be more rapid on
day 19 of gestation than on day 6 of gestation. The kinetic data showed only slightly higher systemic
exposures at the higher dose (Table 23). There were no effects on pregnancy outcome or pup viability.
One pup in the group at 62.5 mg/kg bw per day died, but there were no effects on clinical signs
or body weight in the surviving offspring. Gross necropsy observations on the offspring included
a dose-related increase in misshapen penis (hypospadias, unseparated prepuce) and undescended
and abnormal testes size. There were no statistically significant effects on organ weights in the male
pups, although prostate and seminal vesicle weights were approximately 10% lower in the group at
the highest dose. No abnormalities were detected in female offspring.
Table 22. Anogenital distances in male rats exposed to procymidone in utero
Time-point
Anogenital distance (mm)
Dose (mg/kg bw per day)
0 3.5 12.5 125 500
Postnatal day 1 2.6 ± 0.2 2.6 ± 0.2 2.6 ± 0.4 1.8 ± 0.2* 1.3 ± 0.1*
Postnatal day 21 12.3 ± 1.1 11.9 ± 0.7 11.8 ± 1.3 9.7 ± 1.4* 8.3 ± 1.1*
Termination (postnatal day 45) 33.0 ± 1.1 32.8 ± 1.6 32.3 ± 1.7 27.2 ± 2.2* 23.1 ± 2.2*
From Hoberman (1992a, 1992b, 1992c)
* p < 0.05.
PROCYMIDONE 349–401 JMPR 2007