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

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There was very high mortality at the beginning of the study, with 52 out of 70 of the group
of female mice at 4500 ppm dying or being killed in a moribund condition within the first 9 days
(Table 5). The remaining 18 females in the group at 4500 ppm were killed in a moribund condition
on day 10, and 10 of the females at 0 ppm were transferred to the 3000/2500 ppm diet on the same
day. Four of the males at 4500 ppm died or were killed in a moribund condition during the same time
period and an additional seven died during week 3. Primarily due to these early deaths, survival to
termination was significantly reduced among the males at 4500 ppm.
The early deaths were accompanied by clinical signs of thinness, hunched posture and rough
hair coat. The female mice at 4500 ppm that survived to the first measurement of body weight had
lost approximately 25% of their initial weight. At autopsy, findings were recorded for: liver, males
at 4500 ppm, 7 out of 11, females at 4500 ppm, 22 out of 70 and females at 2500 ppm, 2 out of 9;
and, stomach, males at 4500 ppm, 5 out of 11, females at 4500 ppm, 31 out of 70 and females at
2500 ppm, 3 out of 9. Tissues of females in the group at 4500 ppm were not examined microscopically,
but the liver findings in the group of males at 4500 ppm and females at 2500 ppm that died early
tended to be correlated with individual cell necrosis and hepatocellular hypertrophy. For the most
part, the stomach findings were not confirmed microscopically.
Thinness, hunched posture and rough hair coat were also observed at a higher incidence in the
group of females at 2500 ppm and males at 4500 ppm that survived the first three study weeks than
in the other treated and control groups. In addition, reduced motor activity was noted for the males
at 4500 ppm. No other clinical signs that were noted showed dose-related incidences and all were
common for studies of this duration.
Body weights of the groups of males at 4500 ppm and 2500 ppm and group of females at
2500 ppm were lower than those in mice at 0 ppm throughout the study. Nearly all of the males at
2500 ppm and all of the females at 2500 ppm and males at 4500 ppm lost weight during the first study
week. These weight losses were approximately 18% of initial weight in the latter two groups. Bodyweight
gains then began to recover and approach values in the group at 0 ppm, but body weights in
these groups remained lower through to the end of the study. Body-weight gains of the male mice at
300 ppm were also somewhat reduced relative to those of the controls in the first 36 weeks of the study,
but recovered thereafter. Body weights of the mice at 10 and 30 ppm were not affected by treatment.
There were no clear differences in weekly food consumption among the groups.
Ophthalmoscopy at weeks 27, 53 and 78 revealed no treatment-related findings. Corneal calcification
(corneal dystrophy) was observed in about 20% of the mice examined after 53 weeks, but
the incidence was similar among mice in the control group and mice treated with difenoconazole.
Posterior subcapsular or complete cataracts were observed in about 50% of the mice at 0 ppm and
25% of the males at 4500 ppm and females at 2500 ppm at the 78-week examination. These findings
were considered to be incidental to treatment.
Haematology revealed no treatment-related effects. The percentage segmented neutrophil count
was increased and percentage of lymphocytes was decreased in females at 2500 ppm at week 79, but the
biological significance of this change was unclear. Decreases in the percentage of eosinophils in males
at 4500 ppm and females at 2500 ppm at week 79 relative to the group of mice at 0 ppm were too small
to be meaningful. No treatment-related changes were seen in the differential counts on blood from mice
that were killed while moribund. Blood chemistry analysis at 53 weeks revealed significant increases in
ALT activity in the group of males at 2500 and 4500 ppm and sorbitol dehydrogenase activity in males
at 300, 2500 and 4500 ppm; but these values decreased towards values for the control group after the
4-week recovery period (week 57). At the end of the study, ALT activities were elevated in males at
4500 ppm and females at 2500 ppm; sorbitol dehydrogenase activities were elevated in groups of males
at 4500 ppm and 2500 ppm and females at 2500 ppm and alkaline phosphatase activities were increased
in males at 4500 ppm. The significantly lower values for sorbitol dehydrogenase activity in group of
females at 10 and 30 ppm at week 53 were considered not to be toxicologically meaningful.
DIFENOCONAZOLE 201–272 JMPR 2007