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

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b
Each test was conducted in triplicate.
c
Two separate experiments were conducted.
d
S9 was prepared from livers of Sprague Dawley rats pre-treated with polychlorinatedbiphenyl mixture..
e
S9 was prepared from livers of Sprague Dawley rats pre-treated with phenobarbital and β-naphthoflavone.
f
The study was performed in compliance with good laboratory practice and according to United States Environmental
Protection Agency (EPA) study guideline 84-2.
g
One hundred cells from duplicate cultures were analysed at 10 and 18 h after treatment.
h
Fifty metaphases were analysed at each concentration.
i
Three replicates of 50 cells were analysed in each experiment.
j
Hepatocytes were prepared from Sprague-Dawley rats; at each concentration, six replicates of 50 cells were analysed.
k
Six mice were treated for 6, 24 and 48 h after intraperitoneal administration; 50 metaphases in bone-marrow cells were
analysed for each mouse.
l
Six mice were treated at each concentration.
were based on a preliminary study that showed decreased litter size and feminization of male pups
at ≥ 1000 ppm. After 12 weeks, the rats were mated and allowed to rear the F 1a
litters to weaning and
then paired again to produce the F 1b
litters. F 1
parents selected from the F 1a
litters were mated to produce
two further litters (F 2a
and F 2b
). Body weight, food intake and clinical condition were recorded
weekly. Reproductive parameters (fertility, length of gestation, precoital interval, litter size, viability
and number of live and dead pups) were recorded for each generation and litter. The parental rats
were given a postmortem, the liver and reproductive organs were weighed and tissues were examined
histopathologically. Clinical observations, body weights, organ weights and pathology findings were
also recorded for the offspring. Additional pathological examinations were performed subsequently
and were reported in addenda.
Achieved intakes of procymidone throughout the study were not tabulated; data for premating
periods only were presented in Wickramaratne & Milburn (1990), but actual concentrations, stability
and homogeneity in diet were confirmed as acceptable. All parental rats at the highest dose showed
reductions in body-weight gain from the start of compound administration; statistically significant
for F o
rats of both sexes and F 1
and F 2
females. There were no consistent effects on body weight or
body-weight gain at 250 ppm. Precoital interval was generally reduced in pairings at 750 ppm. In F 1
males at the highest dose (but not F o
), there was a significant reduction in fertility (Table 20), associated
with hypospadias (Table 20). Relative liver and relative testes weights were increased at 250 and
750 ppm (Table 20). The duration of gestation was similar in all groups. Litter size was reduced in the
F 1b
mating at 750 ppm, but not in any other matings. Penile abnormalities were noted at both gross
and microscopic examinations in rats at 750 ppm. No effects were observed on sperm parameters.
Sexing pups at birth was made difficult by reductions in anogenital distance (qualitative assessment)
in male offspring at 750 ppm. Liver weight and testes-weight findings in parents were repeated in
offspring; the increase in testes weights at 50 ppm in the F 1b
pups was < 10%, and not statistically
significant in the F 2b
pups and was not considered to be adverse. Reductions in weights of the prostate
and epididymis were seen at 250 ppm (F 1b
) and 750 ppm (Table 20). There were no adverse effects
on the sex organs of female pups.
The NOAEL for pup development was 50 ppm, equivalent to 3 mg/kg bw per day, on the basis
of alterations in testes, prostate and epididymis weights at 250 ppm. The NOAEL for reproductive
effects was 250 ppm, equivalent to 17 mg/kg bw per day, on the basis of reduced male fertility at
750 ppm. The NOAEL for parental toxicity was 250 ppm on the basis of reduced body weights at
750 ppm. The study was inspected by a quality assurance unit and complied with OECD test guideline
416 (1983) (Wickramaratne et al., 1988a; Milburn & Moreland, 1991).
A modified study of reproduction in rats was performed to provide information on the development
of reproductive organs of F 1
males aged 5 weeks and at sexual maturity (aged 10 weeks). Groups
of 26 male and 26 female Alpk:APfSD (Wistar-derived) rats received diets containing procymidone
(purity, 98.7–99.1%) at a constant dose equal to 0, 2.5, 12.5 or 37 mg/kg bw per day throughout the
PROCYMIDONE 349–401 JMPR 2007