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2.5 Reproductive toxicity
(a)
Multigeneration studies
Rats
Groups of 30 male and 30 female sexually immature albino rats were fed diets containing
difenoconazole technical (purity, 97.4%) at a concentrations of 0, 25, 250 or 2500 ppm in a twogeneration
study of reproduction. These diets delivered difenoconazole at the doses given in Table 9.
The grand mean daily consumption of difenoconazole (mean of all calculated means) was 0, 1.75,
17.3 and 178.0 mg/kg bw per day at 0 25, 250 and 2500 ppm, respectively.
After 11 weeks, the rats were mated and allowed to rear the ensuing F 1
litters to weaning. Litters
were culled to four males and four females on postnatal day 4. F 0
parental males and females were killed
and autopsied after weaning of the last litter. Paired testes and ovaries of the parental rats were weighed.
Microscopic examinations were performed on specified sex organs and the pituitary from the rats at 0
ppm and 2500 ppm, as well as any gross lesions found in any rat. After weaning (age, 31–48 days), 30
males and 30 females per group were selected as the F 1
generation; pups not selected for mating were
killed and autopsies performed. Feeding and mating of the F 1
generation followed the same procedures as
the F 0
generation, except that the period before mating was 14 weeks. Clinical signs, body weights, food
consumption, mating, gestation and delivery parameters, pup survival and development were recorded. F 1
parental males and females were killed and autopsies and microscopic examinations performed as for the
F 0
generation. Analysis of the diet for difenoconazole content was performed on seven of the diet mixes
prepared throughout the study. The concentrations ranged from −10% to +7% of the target concentrations.
The grand means of the analytical concentrations were 24.0, 246 and 2524 ppm. Pre-test mixes at
25 and 2500 ppm were also analysed for stability and found to be stable at room temperature for at least
30 days. Two sets of mixes were analysed for homogeneity and the concentrations were found to vary between
−2% and +2% of the mean concentrations, demonstrating homogeneous distribution in the diet.
F 0
females received difenoconazole at the same dietary concentrations during gestation and
lactation. The breeding programme was repeated with the F 1
parents (selected from the F 1
offspring)
Table 9. Mean consumption of difenoconazole by parental animals given diets containing
d ifenoconazole
Generation
Mean consumption (mg/kg bw per day)
25 ppm 250 ppm 2500 ppm
Start End Start End Start End
F 0
generation
Males:
Before mating 2.75 1.31 27.4 13.3 247.5 132.1
Females:
Before mating 2.65 1.65 26.3 16.2 227.6 166.3
Gestation 1.82 1.52 17.5 15.5 173.2 168.2
F 1
generation
Males:
Before mating 2.56 1.15 27.6 11.5 300.9 122.7
Females:
Before mating 2.54 1.41 25.6 13.7 269.7 149.3
Gestation 1.62 1.56 15.2 14.1 164.5 158.0
From Giknis (1988)
DIFENOCONAZOLE 201–272 JMPR 2007