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

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There were also no treatment-related microscopic changes of the reproductive organs from F 1
rats of the groups at 0 ppm and 2500 ppm or in the few rats with macroscopic findings. A mammary
mass in a female at 0 ppm was diagnosed as a fibroadenoma. The few other findings that were noted
were considered to be of no toxicological relevance.
There were no treatment-related effects on the number of rats mating (0 ppm, 25 out of 30;
2500 ppm, 30 out of 30) the number of females becoming pregnant (0 ppm, 20 out of 25; 2500 ppm,
24 out of 30), or the mean number of days until evidence of mating (0 ppm, 3.4 days; 2500 ppm, 2.4
days). The mean duration of gestation was approximately 23 days in all groups. A total of 19, 25,
21 and 23 females in the groups at 0, 25, 250 and 2500 ppm, respectively, were pregnant and gave
birth to live young. One female in the control group and two at 250 ppm did not deliver but were
s ubsequently found to be pregnant; one female at 2500 ppm delivered a litter with all pups stillborn.
The mean litter size, the number of live pups at birth and the sex ratios were similar in all
groups (Table 13). Survival of pups from days 0 to 4 and days 4 to 21 was not different among the
groups. Similar to the parental animals, body weights of the F 2
pups at 2500 ppm were significantly
different from those of pups in the control group from birth onwards, but body weights of the pups at
25 and 250 ppm were not affected by treatment.
There were no treatment-related clinical signs for the F 2
pups during lactation and no treatmentrelated
macroscopic findings were noted at necropsy of the F 2
pups. Histopathological examination
of five male and five females pups per group did not reveal any treatment-related findings.
The NOAEL for toxicity in adult rats was 250 ppm, equal to 11.5 mg/kg bw per day in males
and 13.3 mg/kg bw per day in females, on the basis of reduced body-weight gain during the premating
period in F0 and F1 generations at 2500 ppm, equal to 122.7 mg/kg bw per day in males and
149.3 mg/kg bw per day in females. The NOAEL for offspring toxicity was 250 ppm, equal to 14.1
mg/kg bw per day in females, on the basis of reduced pup weight at birth and pup-weight gain at 2500
ppm in F 1
and F 2
generations, equal to 158.0 mg/kg bw per day in females. There were no effects
on reproductive indices at doses up to and including 2500 ppm, equal to 132.1 mg/kg bw per day in
males and 158.0 mg/kg bw per day in females, the highest dose tested. The Meeting concluded that
difenoconazole is not a reproductive toxicant in rats (Giknis, 1988).
(b)
Developmental toxicity
Rats
In a study of developmental toxicity, groups of 30 female Crl:COBS®CD®(SD)BR rats were
paired with males of the same strain for a maximum of 5 days. The day that successful mating
was established (presence of a vaginal plug or sperm in a vaginal smear) was designated as day 0.
Difenoconazole technical (purity, 95.7%) was prepared for dosing by first combining it with HiSil
using acetone as a solvent to reduce to a powder and then mixing it in the vehicle consisting of 0.5%
carboxymethyl cellulose in purified water. This preparation was administered at a dose of 0, 2, 20,
100 or 200 mg/kg bw per day by gavage on days 6–15 of presumed gestation. The control group of
rats received vehicle only. A standard dose volume of 10 ml/kg bw was used. Analysis of the dosing
suspensions used in the study (two sets of preparations, each sampled on the first and last days
of use) indicated that the concentrations of suspensions were consistently lower than the nominal
concentrations and somewhat variable under the conditions of the test. Actual concentrations were
71%, 78%, 85% and 86% of the target concentrations for the doses of 2, 20, 100 and 200 mg/kg bw,
respectively. Concentrations of the samples taken on the last day of use were within −11% to +20%
of the c omparable samples taken on the first day of use.
Clinical signs were recorded daily before and after dosing and several times daily during days
6–15. Body weights were recorded five times before mating, on day 0 and daily on days 6–20. Food
consumption was recorded on days 0–6 and then daily on days 6–20. The dams were killed on day 20.
DIFENOCONAZOLE 201–272 JMPR 2007