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

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Analyses of the sites of fetal ossification revealed a significant increase in the average number
of ribs in the fetuses from the dams at 200 mg/kg bw, with a related significant increase in the number
of thoracic vertebrae and decrease in the average number of lumbar vertebrae. Increases in the average
number of ossified hyoid and caudal vertebrae and decreases in the average number of sternal
centres and hind-paw phalanges also occurred for fetuses at 200 mg/kg bw. All other incidences were
within the expected range for fetuses of this strain and age and were not significantly different among
the groups. The differences in skeletal observations that were recorded as statistically significant are
summarized in Table 14. As may be seen, the changes were extremely small and unlikely to have
produced any deleterious effects.
TheNOAEL for maternal toxicity was 20 mg/kg bw per day on the basis of reduced body-weight
gain at 100 mg/kg bw per day. The NOAEL for fetal toxicity was 100 mg/kg bw per day on the basis of
a low incidence of minor deviations in skeletal ossification found at 200 mg/kg bw per day. There were
no indications of embryotoxicity or teratogenicity at any dose up to 200 mg/kg bw (Lochry, 1987).
Rabbit
In a study of developmental toxicity, groups of 20 artificially inseminated New Zealand White
rabbits were given difenoconazole technical (purity, 95.7%) at a dose of 0, 1, 25 or 75 mg/kg bw
per day in an aqueous vehicle (3% aqueous corn starch containing 1.0% Tween 80) administered by
stomach tube on days 7–19 after insemination. A standard dose volume of 5 ml/kg bw was used. The
control group was dosed with the vehicle only. Food consumption and body weights were recorded
regularly throughout the study period. The state of health of the rabbits was checked each day. Eye
examinations were performed before dosing and at the end of the dosing period on all rabbits. On day
29 after insemination, all surviving females were killed and assessed by gross pathology (including
weights of the unopened uterus and the placentae). For each dam, corpora lutea were counted and
number and distribution of implantation sites (differentiated as resorptions, live and dead fetuses)
were determined. The fetuses were removed from the uterus, sexed, weighed and further investigated
for any external, soft tissue and skeletal findings. The stability of the test substance was proven by
reanalysis. The stability and homogeneity of the test substance preparation was analytically verified
over at least a 21-day period. The correctness of the concentrations was analytically demonstrated to
be 96%, 96% and 97% of the target concentrations of 1, 25 and 75 mg/kg bw.
Premature mortality occurred in three study groups: one control doe and one doe at 1 mg/kg
bw per day were found dead on days 15 and 16, respectively, apparently due to dosing accidents and
one doe at 75 mg/kg bw per day was found dead on day 18, after a period of apparently treatmentrelated
anorexia. Clinical observations possibly related to treatment included stool variations in 7 out
of 19 and 12 out of 19 of the groups of does at 25 and 75 mg/kg bw per day, respectively, compared
with two or three in the groups at 0 and 1 mg/kg bw per day, although this was thought to be secondary
to variations in food consumption. There were two abortions in the group at 75 mg/kg bw per
day, which were attributed to treatment. Other signs, including alopecia, anogenital stains and blood
in pan were considered incidental. All does at 75 mg/kg bw per day lost body weight during the first
few days of treatment and body-weight gains of the does at 75 mg/kg bw per day were significantly
lower than rabbits in the control group for most of the dosing period. This effect of treatment was
consistent with reduced food consumption and indicative of toxicity. Body-weight gains of the does
at 25 mg/kg bw per day were also somewhat lower than those of the controls, but not significantly so.
Body-weight gains of the does at 1 mg/kg bw per day were not affected by treatment. Body-weight
changes over the full duration of the study (and including uterus and its contents) were 0.61, 0.54,
0.48 and 0.40 kg in the groups at 0, 1, 25 and 75 mg/kg bw per day, respectively. Relative to the control
group, food consumption was significantly reduced in the group at 75 mg/kg bw per day during
the treatment period (days 7–19), with mean values being about 50% lower than those for the controls
during the first week of dosing. Food consumption increased in all groups during the second week of
dosing, most prominently among the rabbits at 75 mg/kg bw per day. Food consumption by the does
DIFENOCONAZOLE 201–272 JMPR 2007