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

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control group. This was observed from the first week of treatment and was considered to be suggestive
of very slight unpalatability at the highest dose. It was noted that this did not affect the achievement
of target doses. Body-weight gain was affected and the body weights of males and females at the
highest dose were lower than those of controls throughout the study. The mean terminal body weights
were reduced in males (14.5%) and females (9.25%) at 200 mg/kg bw per day compared with those
of dogs in the control group.
Haematological tests at 3, 4, 6, 7, 8 and 12 months showed marked reductions in haemoglobin
concentration, erythrocyte volume fraction, erythrocyte and leukocyte counts in one male dog at
200 mg/kg bw per day at 3 and 4 months compared with pre-study and inter/intra-group values.
Peripheral blood smears from this dog, which was killed and necropsied on day 119, showed marked
polychromasia and moderate hypochromasia after 3 months and additionally slight anisocytosis
on day 119. A female dog at 200 mg/kg bw per day also showed reductions in haemoglobin
concentration, erythrocyte volume fraction and erythrocyte counts from 3 months onwards.
Microscopic examination of peripheral blood smears revealed slight hypochromasia. However,
there was apparent compensation of anaemia in the female dog and the unscheduled haematological
assays were discontinued after 8 months. Extramedullary haematopoiesis was seen in most dogs at
200 mg/kg bw per day.
Clinical chemistry showed an increase (greater than twofold) in serum ALP activity in male
and female dogs at 200 mg/kg bw per day compared with controls. The magnitude of the increase
in ALP exhibited a clear relationship with duration of dosing. Increased serum ALP activity might
be indicative of cholestasis (impaired hepatobiliary function), enzyme induction or hepatocellular
damage. Transient or non dose-related changes in bilirubin and cholesterol were considered to be not
treatment-related. Urine analysis at 6 months and at necropsy did not reveal any significant treatmentrelated
changes.
The absolute (27.5% in males and 9.4% in females) and relative liver weights of male and
female dogs at 200 mg/kg bw per day were increased compared with controls and were considered to
be treatment-related (Table 8). The remaining changes in relative organ weights of the brain, kidney
and pituitary in dogs at 200 mg/kg bw per day were considered to be related to the lower body weight
of this group and, in the absence of any supporting histopathological or functional evidence in these
organs, not treatment-related.
Histopathology of the liver showed an increase in the incidence of diffuse hepatocyte
hypertrophy (three out of four males and three out of four females) and increased bile in bile
canaliculi (one out of four males and one out of four females) in both sexes at 200 mg/kg bw per
day. No treatment-related changes were observed in the kidneys and testes.
The NOAEL was 20 mg/kg bw per day on the basis of reduced food consumption and bodyweight
gain, haematological changes consistent with haemolytic anaemia and a compensatory
response, increased serum activity of ALP, increased liver weight and histopathological changes in
the liver at 200 mg/kg bw per day (Cosse et al., 1995).
Table 8. Hepatic findings in dogs a fed diets containing quinoxyfen for 52 weeks
Finding
Dose (mg/kg bw per day)
Male
Female
0 5 20 200 b 0 5 20 200
Body weight (g) 12923 12735 13274 11171 9924 9187 9688 8249
Liver weight (g) 296 372 369 407 269 271 279 297
Liver (% bw) 2.3 2.9 2.8 3.6 2.7 2.9 2.9 3.7
QUINOXYFEN X-X JMPR 2006