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

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The no-observed-adverse-effect level (NOAEL) was 200 ppm, equal to 34.2 mg/kg bw per day,
on the basis of clinical signs, reduced body weight and ovary weight and changes in liver weight and
histology at 2500 ppm, equal to 440 mg/kg bw per day.
Rats
Groups of 10 male and 10 female Wistar rats (outbred KFM-Han, SPF) were given diets containing
difenoconazole technical (purity, ≥ 95%) at a concentration of 0, 250, 1500 or 10 000 ppm,
equal to 0, 27, 156 and 914 mg/kg bw per day for male rats and 0, 27, 166 and 841 mg/kg bw per
day for female rats, for 33 days. The stability of difenoconazole in the diet and the homogeneity of
the dietary mixtures were verified before the start of the study. Analyses for correct concentration
were performed before the study start. Food consumption and body weight were determined once
each week. The state of health was checked twice per day. Eye examinations were carried out before
the start and at the end of the dosing period. Blood samples were taken from all rats for haematology
and blood chemistry examination at the end of the dosing period. 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. Microscopic examinations were conducted on liver and all gross lesions in
rats from all groups receiving difenoconazole.
There were no mortalities in the study and difenoconazole did not induce any remarkable clinical
signs of toxicity in any of the groups receiving difenoconazole. Body weights and body-weight
gain in the group of rats at 10 000 ppm were significantly (p < 0.01) lower than those in the control
group throughout the study. No body-weight losses were recorded, but body weights of males and
females at 10 000 ppm were 42% and 36% lower, respectively, than those of the males and females
in the control group after 26 days. Body weights of males at 250 ppm were also significantly lower
than those of males in the control group at weeks 2 and 3, but these reductions were not considered
to be treatment-related owing to the absence of effects in the males at 1500 ppm. Food consumption
by the group of rats at 10 000 ppm was also markedly reduced throughout the study, most notably
during the first study week (reductions of 75% and 71% for males and females, respectively). Food
consumption by the group of rats at 10 000 ppm increased, relative to the controls, in the following
weeks, but remained low. No statistical tests were performed on food consumption data owing to the
low number of observations (n = 2 cages per dose group).
Ophthalmoscopy revealed no treatment-related findings. Treatment-related differences in haematological
parameters were observed between the control group and the group at 10 000 ppm.
These consisted of slightly decreased concentration of haemoglobin, erythrocyte volume fraction,
mean corpuscular volume, mean corpuscular haemoglobin and slightly shorter thromboplastin times
in males and females and slightly decreased thrombocyte count and slightly increased reticulocyte
count in females only. Slightly shorter thromboplastin times in the group of males at 1500 ppm were
also considered to be related to treatment. All other statistically significant differences (primarily in
the group of females at 250 ppm) were considered to be incidental and within the normal range of
biological variation.
Treatment-related, statistically significant changes in blood chemistry parameters for rats at 10
000 ppm included moderately increased cholesterol concentrations, slightly decreased sodium concentrations,
slightly increased alkaline phosphatase and γ-glutamyl transferase activities in males and
females, slightly increased aspartate aminotransferase activity for males only, and slightly increased
phosphate concentrations for females only. The more notable changes were the increase in total cholesterol
concentration (230% and 240% in males and females, respectively) and in gamma-glutamyl
transferase activity (75% and 73% in males and females, respectively). In addition, protein electrophoresis
revealed treatment-related, statistically significant effects at all doses: slightly increased
albumin concentrations in males at all doses and in females of the group at 10 000 ppm; slightly
decreased α1-globulin fractions in males at all doses and in females of the group at 10 000 ppm;
slightly decreased β-globulin fractions in males at all doses; slightly increased albumin/globulin
DIFENOCONAZOLE 201–272 JMPR 2007