Pesticide residues in food — 2006: Toxicological ... - ipcs inchem

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inspected twice daily for morbidity or mortality and clinical signs. Detailed clinical examinations
were performed weekly. A complete physical examination was performed on each dog before study
initiation and during months 3, 6, 9, and 12. Body weight and food consumption were measured
weekly. An ophthalmoscopic examination was done before dosing and at 6 and 12 months. Blood was
collected from all animals before dosing, and at 3, 6, and 12 months of dosing, for measurement of
haematological and clinical parameters. Urine analysis was performed on all animals before dosing,
and at 3, 6, and 12 months. At the end of the study, a complete postmortem was carried out. The
adrenals, brain, kidneys, liver, pituitary, thyroid and parathyroid, heart, salivary gland and testes/
ovaries were weighed. The organs specified were examined microscopically. This study complied
with GLP.
The test article was evenly distributed in the diet and was stable in the diet for at least
2 weeks at room temperature. Measured test concentrations ranged between 97% and 101% of the
target concentrations. No deaths occurred during the study. No treatment-related clinical signs,
ophthalmoscopic findings, or abnormalities on the physical examination were observed. Body weights
were comparable between treated and control animals throughout the study. Overall (weeks 0–52),
body-weight gains were slightly decreased in the animals at 400 ppm (males, 14%; females, 19%) and
1000 ppm (males, 14%; females, 23%) animals. These differences were not statistically significant
and reflected large, erratic changes in body-weight gains in all treated groups at various times during
the study which were considered unrelated to treatment. Mean food consumption was decreased in
males at 400 and 1000 ppm (17% and 12%, respectively). Decreased food consumption in males was
not observed to occur in a dose-related manner and food consumption was not affected in females.
Overall, food conversion efficiency values [100 × body-weight change (g) / food consumed (g)] were
generally comparable, allowing for the observed erratic changes in body weight and food intake.
Test article-related alterations in haematology parameters were observed at 400 and 1000 ppm at all
analysis time-points (Table 16). The following increases in haematology parameters were observed
at 1000 ppm at months 3, 6, and 12: (i) leukocytes in males; (ii) platelets in males and females;
(iii) reticulocyte counts in females; (iv) segmented neutrophils in males; and (v) increased mean cell
volume in females. The following decreases in haematology parameters were observed in the animals
at the highest dose at months 3, 6, and 12: (i) erythrocytes in males and females; (ii) haemoglobin
in males and females; and (iii) erythrocyte volume fraction in males and females. At 400 ppm, the
following differences in haematological parameters were noted: (i) platelets were increased in males
and females (months 3, 6, and 12); (ii) leukocytes were increased in males at months 3, 6 and 12;
(iii) erythrocytes were decreased in males and females at months 3, 6, and 12; (iv) segmented
neutrophils were increased in males (months 3, 6 and 12) and in females (months 3 and 6);
(v) haemoglobin was decreased in females at month 3; (vi) mean cell volume was increased in males
and females at months 3, 6, and 12; (vii) reticulocyte counts were increased in males and females at
months 3, 6, and 12; and (viii) erythrocyte volume fraction was decreased in females at month 3.
Table 16. Haematological findings in beagle dogs fed diets containing bifenazate for 1 year
Finding
Erythrocyte count (10 6 /mm 3 ):
Before treatment
3 months
6 months
12 months
Dietary concentration (ppm)
Males
Females
0 40 400 1000 0 40 400 1000
5.36 5.55 5.40 5.52 5.37 5.63 5.64 5.95**
7.19 7.09 6.12* 5.33** 7.54 7.40 5.84** 5.56**
6.79 6.96 6.23 5.46* 6.47 6.89 5.76 5.43**
7.35 7.43 6.38 5.50** 6.46 7.00 5.96 5.04**
BIFENAZATE X-X JMPR 2006