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

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in the control group and in the groups at 1 and 25 mg/kg bw per day tended to decrease after the end
of dosing, while the rabbits at 75 mg/kg bw per day continued to increase their food consumption.
Fifteen does that were inseminated were not pregnant at caesarean section on day 29: three in the
control group, five at 1 mg/kg bw per day, three at 25 mg/kg bw per day and four at 75 mg/kg bw per day.
Three does died (one each in the control group and the groups at 1 mg/kg bw per day and 75 mg/kg bw
per day) and two does at 75 mg/kg bw per day aborted, so there were 15, 13, 16 and 12 litters for evaluation
in the control group and the groups receiving 1, 25 and 75 mg/kg bw per day, respectively. Data from
caesarean sections indicated that the mean numbers of corpora lutea, implantation sites and live fetuses
were comparable between the groups. There were no dead fetuses. The numbers of resorptions per pregnancy
were only slightly and not significantly higher among the rabbits at 75 mg/kg bw per day.
The weights of male and female fetuses were not significantly different between the groups,
although some statistical differences were described in the original report. It was subsequently determined
that the statistical routine used for generating the report tables ran incorrectly, i.e., post hoc
comparisons were inappropriately performed although the overall F statistics were not significant
(p = 0.072 for males; p = 0.104 for females). It was also suggested in the original report that variations
in litter size could account for apparent differences in fetal weights. To this end, the data were
subsequently analysed by analysis of covariance with litter size as the covariate. These analyses were
also not significant at the p ≤ 0.05 level for males and females. Moreover, it was stated in the original
report that the weights for fetuses from the control group (males, 47.3 ± 1.6 g; females, 45.6 ± 1.5 g)
were exceptionally high in comparison with the mean values for historical controls of 43.4 g for male
fetuses and 42.2 g for female fetuses. The weights for the fetuses in the treated groups were closer to
these values than were those for the control group in this study. Fetal sex ratios were not affected by
treatment. Maternal autopsy examinations did not reveal any treatment-related findings
Fetal examinations did not reveal any treatment-related effects on the incidences of external,
visceral or skeletal variations or malformations. One fetus in the group at 25 mg/kg bw per day was
found during external examination to have a raised, discoloured area on the ventral thoracic region
that may have resulted from technical manipulation and was considered to be incidental. The only
visceral findings were a horseshoe kidney in one fetus at 75 mg/kg bw per day, microencephaly in
one fetus at 25 mg/kg bw per day and partial cryptophthalmos in one fetus at 75 mg/kg bw per day.
Skeletal alterations were seen in approximately 80–90% of the fetuses and all of the litters. There
were no statistically significant or biologically meaningful differences among the groups (by fetus or
by litter) in the incidence of any finding.
The NOAEL for maternal toxicity was 25 mg/kg bw per day on the basis of reduced bodyweight
gain at 75 mg/kg bw per day. The NOAEL for fetal toxicity was 75 mg/kg bw per day, the
highest dose tested. There were no indications of embryotoxicity, fetotoxicity or teratogenicity at a
dose up to 75 mg/kg bw per day (Hummel et al., 1987).
2.6 Special studies
(a)
Studies on neurotoxic potential
In a study of neurotoxicity, groups of 10 male and 10 female Alpk:AP f
SD (Wistar-derived) rats
were given single doses of difenoconazole technical (purity, 94.3 %) at a dose of 0, 25, 200 or 2000
mg/kg bw in 1% carboxymethyl cellulose andthen observed for 14 days.
All rats were observed before the study start and daily throughout the study for any changes in
clinical condition. In addition, a functional observation battery (FOB), including quantitative assessments
of landing foot splay, sensory perception and muscle weakness, was performed in week −1,
and on days 1 (at the time of anticipated maximum effect), 8 and 15. Locomotor activity was also
monitored in week −1, and on days 1, 8 and 15. Body weights and food consumption were measured
DIFENOCONAZOLE 201–272 JMPR 2007