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

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The stability of difenoconazole in the diet for at least 16 days was verified and the homogeneity of
the dietary mixtures was also verified. The analyses were satisfactory.
Food consumption and body weight were determined once per week. Mortality was checked
twice per day, clinical signs were recorded once per day and detailed physical examinations were
performed each week. Ophthalmology was carried out on all rats before the start and at the end of
dosing. Blood samples for haematology and blood chemistry examination at the end of the dosing
period were taken from 10 males and 10 females per group. Urine was analysed at the end of the
exposure period. All rats were subjected to complete gross examinations, and weights of selected
organs were determined. Ten males and ten females per group were killed in week 13. The remaining
rats were removed from the study in week 17. Autopsies were conducted on all rats that were killed
at the scheduled times or in extremis and selected organs were weighed. Microscopic examinations
were conducted on selected organs from all rats from the scheduled kill at week 13 and on all gross
lesions.
There were no treatment-related mortalities or clinical signs. Body-weight reductions were
observed in the male group at 3000 ppm and in group of femaless receiving 200, 750, 1500 and
3000 ppm throughout the study, although no statistical analyses were performed. At the end of the
study and in comparison with the controls, the mean body weights were reduced to 90% in males at
3000 ppm and, in females of the groups receiving 200, 750, 1500 and 3000 ppm, to 94%, 93%, 89%
and 80%, respectively. Body weights of groups of males at 200, 750 and 1500 ppm and females at
20 ppm were not affected by treatment. Food consumption in the group at 3000 ppm was 3.5% lower
in males and 6.9% lower in females compared with controls; and while there was no significant trend
in males there was a significant (p < 0.05) negative trend in females.
Ophthalmoscopy revealed no treatment-related findings. Such findings that were made were
considered to be incidental. They consisted of bilateral diffuse posterior subcapsular cataract in one
male at 3000 ppm and a focal posterior subcapsular cataract in one female at 200 ppm.
Examination of blood indicated slight, statistically significant decreases in erythrocyte counts
and erythrocyte volume fraction in groups of males at 750, 1500 and 3000 ppm and females at 1500
and 3000 ppm; haemoglobin concentration was also reduced in these two groups of females. There
were no observed differences in the groups of males or females at 20 and 200 ppm. Blood chemistry
analysis showed some statistically significant changes that included a negative trend for glucose
concentration in males, a positive trend for blood urea nitrogen (BUN) in males and higher BUN
concentrations in groups of males at 1500 and 3000 ppm, lower total bilirubin values for males at
3000 ppm and for females at 1500 and 3000 ppm, a positive trend for cholesterol in females and a
negative trend in alanine aminotransferase (ALT) activity in females. The biological significance of
these differences was considered to be negligible. It is notable that there were no significant changes
in serum cholesterol concentrations in males or females of this study, although the mean value for
females of the group receiving 3000 ppm was 30% higher than the control value. It is also notable
that gamma-glutamyl transferase activity was below the level of detection in all groups, in contrast to
the findings at the much higher dose in the 33-day study described above.
Urine analyses revealed an increase in the incidence and severity of ketones in the male group
at 3000 ppm, which was attributed by the sponsor to reduced nutritional status; however, this suggestion
does not seem to be supported by the data on food consumption. Absolute liver weights were increased
in the groups of males at 750, 1500 and 3000 ppm by 25.7%, 30.9% and 30.2%, respectively
and in females by 24.5%, 26.2% and 40.2%, respectively. Liver-to-body weight ratios were increased
in these same groups and among females at 200 ppm. The few other statistically significant differences
were not considered to be toxicologically relevant and could be largely attributed to reduced
carcass weights in the higher dose groups. No organ-weight differences were seen in the group of
rats at 20 ppm. No treatment-related effects were observed at autopsy. Microscopic, treatment-related
changes were observed only in the liver and consisted of increased incidence and severity of diffuse
DIFENOCONAZOLE 201–272 JMPR 2007