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

212
and 0, 4.6, 45.2 and 639 mg/kg bw per day in females, for 13 weeks. Because of mortalities occurring
at a very early stage in this study, the intake of difenoconazole was not calculated for the two groups
at the highest dose. An additional five males and five females were included in the control group.
Mortality was checked twice per day, clinical signs were recorded once per day and detailed physical
examinations were performed each week. Food consumption and body weight were determined once
per week. Eye examinations were conducted on all mice before treatment and at the end of treatment
in week 13. Haematology investigations were conducted on 10 males and 10 females per group at the
end of the treatment period.
Ten males and ten females per group were killed in week 13. All these mice were subjected
to complete gross examinations, and weights of selected organs were determined. Autopsies were
also carried out on mice that were found dead or killed in extremis. Microscopic examinations were
conducted on all organs from mice in the control group and the group at the highest dose and on
lung, liver, kidneys and all gross lesions from mice from all dose groups. Specified organs of mice
scheduled to be killed were weighed and all specified tissues were collected, fixed and examined
microscopically. The stability of difenoconazole in the diet was verified and the homogeneity of the
dietary mixtures was verified before the start of the study.
Dietary administration of difenoconazole at doses of 7500 and 15 000 ppm for up to 3 months
resulted in very high mortality by week 3. All female mice receiving difenoconazole at 7500 or
15 000 ppm died or were found in a moribund condition and were killed on study days 3–7. Males
survived a few days longer, but all males at 15 000 ppm were dead by day 11 and 13 out of 15 males at
7500 ppm were dead by day 18. The remaining two males at 7500 ppm were removed from the study
by day 21. One female at 2500 ppm was also found dead during week 3. In addition, one male in the
control group, one male at 20 ppm and one female at 200 ppm died on day 16. A female at 200 ppm
was considered to have died accidentally after blood collection during week 13.
Clinical signs in the groups at 2500 ppm or less were noted at low frequencies and there was
no dose–response pattern, although polypnoea was seen in most females at 2500 ppm during the first
study week. Ophthalmoscopy revealed no treatment-related findings. Unilateral diffuse retinochoroidal
degeneration was seen in one male at 2500 ppm and in one female at 2500 ppm, but owing
to the low incidence these findings were considered to be incidental to treatment. Body weights of
the group of mice at 2500 ppm were somewhat lower than those of the mice in the control group
throughout the study, but food consumption was not affected by treatment. Dark areas in the stomach
were noted at necrospy in 5 out of 13 males at 7500 ppm, 14 out of 15 males at 15 000 ppm, 15 out
of 15 females at 7500 ppm and 14 out of 15 females at 15 000 ppm. These findings corresponded
to microscopic findings of erosion/ulceration of the glandular stomach and/or hyperkeratosis in the
non-glandular stomach in most of these mice. Haematology parameters were not different among
the groups. There was a statistically significant positive trend in platelet counts in males, but there
was no trend in the females and no other findings that would indicate this was a meaningful effect.
None of the other parameters measured were remarkable. Absolute and relative liver weights were increased
in mice at 2500 ppm and relative liver weights were increased in males at 200 ppm. The only
other statistically significant organ-weight changes were a 25% reduction in absolute ovary weight
and a 7.7% reduction in absolute heart weight in females in the group at 2500 ppm. Liver enlargement
and prominent reticular patterns were seen at an increased frequency in the group of mice at
2500 ppm. There was an increased incidence of diffuse hepatocellular enlargement in all male and
female mice of this same group and some minimal centrilobular hepatocellular enlargement in males
at 200 ppm. Hepatic vacuolization also occurred with greater frequency and severity in the group of
mice at 2500 ppm. Since minimal centrilobular hepatocellular enlargement only occurred in males
of the group at 200 ppm it probably represented a less severe manifestation of the diffuse response to
difenoconazole at higher doses seen in this organ. This can be considered to be an adaptive change
at this dose (Cox, 1987a).
DIFENOCONAZOLE 201–272 JMPR 2007