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

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lower than those of rats in the control group throughout the study. In addition to occasional bodyweight
losses, body weights of the groups of males and females at 1500 ppm were 13% and 10%
lower, respectively, than their controls after 13 weeks on test. During the 4-week recovery period,
body-weight gains of the rats at 1500 ppm were slightly greater than those among rats in the control
group, resulting in differences of only −9% for males and −4% for females by week 17. Body
weights of the groups of rats at 40 and 250 ppm were not affected by treatment. Hearing tests and
ophthalmoscopy revealed no treatment-related findings. There were no treatment-related differences
between the control and treated rats in the haematology parameters and there were no clearly treatment-related
changes in blood chemistry parameters. At the end of the treatment period, there was
a slight increase in alkaline phosphatase activity for males and females at 1500 ppm and a slight
decrease in total protein concentrations among males at 1500 ppm, but these values returned to the
normal range by the end of recovery. All other statistically significant differences were considered
to be incidental and within normal biological variation. Decreased glucose concentrations in males
at 250 ppm and increased chloride values in males at 40, 250 and 1500 ppm did not follow dose–
response patterns. Increased values for urea, gamma-glutamyl transferase activity and phosphate
concentration in males at 1500 ppm and potassium and phosphate in females at 1500 ppm, as well
as decreased sodium in females at 1500 ppm, were well within the range for historical controls. The
increased gamme-glutamyl transferase activity noted in males at 1500 ppm at 13 weeks was lower
than the control value at the end of the 4-week recovery period. A similar result was obtained for
cholesterol concentrations in female rats, suggesting that variations in these parameters, although statistically
significant, were most probably random variations. Also, significant reductions from control
values in lactate dehydrogenase (LDH) activity in males at 1500 ppm were less than the reductions
in LDH in control groups at the end of the recovery period compared with the control group value at
13 weeks. The lower creatinine values for females at 1500 ppm at 13 weeks were due to a few exceptionally
low values and the means were not different from the control animals after recovery. Slight
variations in albumin and globulin fractions were not of sufficient magnitude to be meaningful. The
quantitative and qualitative analyses of urine revealed no toxicologically significant effects. The few
statistically significant differences were considered to be incidental and within the range for normal
biological variation. Increased urobilinogen scores in males of the groups at 250 and 1500 ppm did
not follow a dose-related pattern.
Increased absolute liver weights (18% in male and 22% in female rats) and liver-to-body weight
ratios were observed in male and female rats at 1500 ppm. Liver-to-body weight ratios were also increased
among males and females at 250 ppm. These differences were not apparent among the rats
killed at the end of the recovery period. The few other statistically significant differences were not
considered to be toxicologically relevant and could, at least for the group at 1500 ppm, be attributed
to the significantly reduced carcass weights in this group and to random variation (female kidney
weights) in the group at 250 ppm. No differences were seen between the group of rats at 40 ppm
and their controls. No treatment-related observations were recorded at autopsy or upon microscopic
evaluation of tissues. Observations that were made were consistent with those expected in rats of this
strain and age.
The NOAEL in rats fed diets containing difenoconazole for 13 weeks was 250 ppm, equal to
20 mg/kg bw per day, on the basis of increased liver weight at 1500 ppm, equal to 121 mg/kg bw per
day (Suter, 1986b).
Groups of 15 male and 15 female CRL:CD(SD)® rats were given diets containing difenoconazole
(purity, 94.5%) at a concentration of 0, 20, 200, 750, 1500 or 3000 ppm, equal to 0, 1.3, 13, 51,
105 and 214 mg/kg bw per day in males and 0, 1.7, 17, 66, 131 and 275 mg/kg bw per day in females,
for 3 months. An additional five males and five females were included in the control group. Analyses
for correct concentrations were performed on all batches of diet, which were prepared every 2 weeks.
DIFENOCONAZOLE 201–272 JMPR 2007