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

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Corpora lutea in each ovary were identified and counted. Each uterus was examined for pregnancy,
number and placement of implantations, early and late resorptions and live and dead fetuses. After removal
from the uterus, fetuses were weighed, numbered, examined externally and sexed. Live fetuses
were killed. Approximately 50% of the fetuses in each litter were examined for visceral alterations
using a modification of the Wilson sectioning technique. The remaining fetuses in each litter were
eviscerated, cleared, stained with alizarin red S and examined for skeletal alterations.
There were no premature deaths in the study. Clinical observations possibly related to treatment
included excess salivation in 14 out of 23 and 19 out of 25 of the dams at 100 and 200 mg/kg
bw, respectively, compared with none in the groups at 0, 2, or 20 mg/kg bw and red vaginal exudate in
3 out of 23 dams at 100 mg/kg bw and 3 out of 25 dams at 200 mg/kg bw, compared with 0 out of 25
rats in the control group, 1 out of 25 dams at 2 mg/kg bw and 1 out of 25 dams at 20 mg/kg bw. The
excess salivation was first observed in most rats on days 7 or 8. Nearly all dams at 100 and 200 mg/kg
bw lost body weight during the first few days of treatment. Also, the body-weight gains of the dams at
100 and 200 mg/kg bw were significantly lower than those of rats in the control group throughout the
dosing period. Mean body-weight gains in the rats at 100 and 200 mg/kg bw after cessation of dosing
were greater than in controls. Body weights of the dams at 2 and 20 mg/kg bw were not affected by
treatment. Relative to the control group, food consumption was significantly reduced in the groups at
100 and 200 mg/kg bw during the treatment period (days 6–15) by about 10% and 22%, respectively.
Food consumption by the dams in these groups was greater than that of rats in the control group after
the end of dosing. Food consumption was not affected in the groups at 2 and 20 mg/kg bw.
One dam at 20 mg/kg bw and two at 100 mg/kg bw showed signs of having mated, but were
not pregnant. Except for one dam at 200 mg/kg bw, all the pregnant rats were killed as scheduled
and all were found to have viable fetuses, so there were 25, 25, 24, 23 and 24 litters for evaluation in
the groups at 0, 2, 20, 100 and 200 mg/kg bw, respectively. Data from caesarean sections indicated
that the mean numbers of corpora lutea and implantation sites were comparable between the groups.
There were no dead fetuses and there was only one dam (at 200 mg/kg bw) with total implant loss.
The number of resorptions per litter (mainly early) was slightly higher and litter size was slightly
lower among the rats at 200 mg/kg bw, but these variations were not statistically significant.
The weights of male and female fetuses were not significantly different between the groups,
although the means of the fetuses at 200 mg/kg bw were slightly less than those for fetuses in the
control group. Fetal sex ratios were not affected by treatment. Maternal autopsy examinations did not
reveal any treatment-related findings.
Data derived from fetal examinations were classified as either malformations (irreversible
changes) or developmental changes (reversible accelerations or delays of development). Examinations
did not reveal any treatment-related effects on the incidences of external or visceral findings.
One fetus at 100 mg/kg bw was found during external examination to have a depressed left-eye bulge
and one fetus at 200 mg/kg bw had an umbilical hernia. These irreversible changes were considered to
be incidental. The only irreversible visceral finding was agenesis of the diaphragmatic lobe of the lung
in one fetus at 100 mg/kg bw. Delays in visceral development were seen in renal pelvic dilation in 0, 1,
4, 1, and 1 fetuses from the control litters and litters at, 2, 20, 100 and 200 mg/kg bw, respectively, and
slight dilation of the lateral and/or third ventricle of the brain in two fetuses in the control group (two
litters) and one fetus at 200 mg/kg bw. These findings were not considered to be treatment related.
Skeletal alterations were seen in approximately 7% of the fetuses and 30% of the litters. Overall,
more alterations were found in fetuses in the control group and litters than in any of the treated
groups. Wavy and/or incompletely ossified ribs, incompletely ossified or non-ossified sternebra(e)
and incompletely ossified pelvis (ischia or pubis) were seen in significantly more control fetuses than
in the fetuses from the treated dams. Fetal incidence of bifid and unilaterally ossified thoracic vertebral
centres was significantly higher in the fetuses at 200 mg/kg bw than in the controls, but the litter
incidence was not statistically different.
DIFENOCONAZOLE 201–272 JMPR 2007