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

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and 357. This reduced food consumption corresponded to reduced body-weight gains among the
group of females at 1500 ppm. Food consumption was not affected in females at 20, 100 and 500 ppm
or in any of the groups of males.
Physical examinations, including heart rate, rectal temperature, hearing tests and ophthalmoscopic
examinations, revealed no treatment-related findings. A single incidence of ocular change
(corneal opacity) was seen in one female in the control group.
There were no treatment-related differences among the groups in haematology parameters. A statistically
significant reduction in reticulocyte count from 0.8% to 0.3% in females at 1500 ppm was observed
at week 52, but this difference was considered to be spurious, there being no accompanying reductions in
erythrocyte parameters that could indicate a response to toxicity; furthermore, the results showed little consistency
in that the reticulocyte count in females at 1500 ppm at 25 weeks increased to 0.8% from a control
mean of 0.5%. Differentials were also unremarkable; the only apparent difference among the groups was
a statistically significant decrease in relative eosinophils among females at 100 ppm at week 13, which
was not considered to be related to treatment. Blood chemistry analysis showed significantly higher alkaline
phosphatase activity in the groups of males at 1500 ppm at all measurement times and in males at
500 ppm at week 52. All other statistical differences (reduced BUN in the groups of males receiving 100
and 1500 ppm, increased total bilirubin concentration in males at 100 ppm, increased sodium concentration
in females at 1500 ppm) were considered to be incidental and within the range for normal biological
variation. Measurements at weeks 13 and 26 were not noticeably different from those at week 52.
No significant or remarkable changes in urine analysis were observed.
There were no treatment-related differences in organ weights among the groups. The few differences
noted were not considered to be toxicologically relevant. Decreased adrenal weights in males at
20 and 500 ppm and increased thyroid weights in females at 20 ppm were statistically different from
the respective control animals but not meaningful due to the absence of a dose–response relationship
and corresponding histopathology. No treatment-related observations were recorded at autopsy or
upon microscopic examination of the organs and tissues.
The NOAEL in dogs given diets containing difenoconazole for 52 weeks was 100 ppm, equal
to 3.7 mg/kg bw per day, on the basis of reduced body-weight gain in females at 500 ppm, equal to
19.4 mg/kg bw per day (Rudzki et al., 1988).
2.3 Long-term studies of toxicity and carcinogenicity
Mice
Groups of 60 male and 60 female CD-1®(ICR) mice were given diets containing difenoconazole
technical—first batch, of 94.5% purity, was given during weeks 1–20 and the second batch, of 95%
purity, was given in weeks 21–80—at a concentration of of 0, 10, 30, 300, 3000 or 4500 ppm for 18
months. The diet containing difenoconazole at 3000 ppm was exchanged after the first 3 weeks for
one containing difenoconazole at 2500 ppm and the group of females at 4500 ppm was discontinued
because of excessive toxicity very early in the study. The doses had been selected on the basis of the
results of a 3-month study (Cox, 1987a). These dietary exposures were equal to 0, 1.5, 4.7, 46.3, 423
and 819 mg/kg bw per day for males and 0, 1.9, 5.6, 57.8 and 513 mg/kg bw per day for females in the
groups at 0, 10, 30, 300, 2500 ppm (and 4500 ppm in males), respectively. Additional groups of 10 male
and 10 female mice were fed diets containing difenoconazole at 0, 3000 or 4500 ppm then allowed a
recovery phase after 12 months of treatment. However, all of the females at 4500 ppm and 16 of the
females at 3000 ppm died or were killed because of their moribund condition within the first 2 weeks.
Food consumption and body weights were recorded weekly for weeks 1–16 and every 4 weeks
thereafter. Mortality was checked twice per day, clinical signs were recorded once per day and detailed
physical examinations (including palpation) were performed weekly. Eye examinations were
DIFENOCONAZOLE 201–272 JMPR 2007