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

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the control group were terminated at week 13, the remaining mice at the highest dose at week 52 of
dosing. In both the main and the satellite study, mice were daily observed for mortalities and clinical
signs; body weights, feed and water consumption and palpable masses were recorded weekly.
Haematology data in the main study were collected at weeks 52, 78 and 104 of dosing and gross
necropsy with extensive histopathology examination of tissues was done after terminal sacrifice. In
the satellite study, blood samples were taken in week 14 and 52 for clinical chemistry analysis and at
study termination a full necropsy, as in the main study, was performed with additional recording of
liver weight and liver histology. The study complied with GLP.
The survival rate in males at 10 and 1000 mg/kg bw per day was higher than in the control
group and no clinical signs of toxicity were seen throughout the study in any group nor were
changes in feed and water consumption or in differential blood counts detectable. Absolute terminal
body weight and body-weight gain was reduced significantly in males at 1000 mg/kg bw per day
(Table 23). In the satellite group, males and females at the highest dose at week 13 showed slight
increases in alkaline phosphatase activity (32% and 26%, respectively) were observed and at week
52 no obvious changes in clinical chemistry were evident, although no concurrent control was available.
Liver weights in males were increased by 15% (relative, body-weight adjusted) in week 14
and 17% in week 52 (absolute, compared with laboratory historical controls); in females, 28% (relative,
body-weight adjusted) in week 14 and 32% in week 52 (absolute, compared with laboratory
historical controls). Histologically, there were no correlates to the liver weight increases at week 13
and 52 in both sexes but at week 13 moderate dilations of and villous atrophy in the ileums of one
male and some females at 1000 mg/kg bw per day. At week 52, no treatment-related histological
findings were recorded.
In the main study, an increase in the incidence of enlarged spleen was observed in both sexes
at 1000 mg/kg bw per day (Table 24), but no histological changes were reported and organ weights
not recorded. In females at the highest dose, the incidence of mammary adenocarcinoma of 6% was
higher than in all other groups and at the upper bound of the range for historical controls (range,
Table 22. Absolute body and organ weights of dogs fed diets containing dimethomorph for
52 weeks
Body or
organ
Absolute body or organ weight (body-weight adjusted group mean, ± SD ) a
Dietary concentration (ppm)
0 150 450 1350
Males
Body 13.1 ± 1.1 12.1 ± 1.0 11.4 ± 1.5 12.1 ± 1.1
weight (kg)
Liver (g) 371.65 ± 33.52 (368.14) 327.71 ± 31.93 (328.01) 345.36 ± 23.96 (349.20) 433.44 ± 30.87* (433.82*)
Prostate (g) 8.25 ± 2.4 (7.4) 8.97 ± 2.52 (9.04) 5.55 ± 1.35 (6.23) 4.27 ± 1.86* (4.36)
Testes (g) 27.25 ± 2.52 (25.44) 27.41 ± 4.56 (27.56) 30.04 ± 3.12 (31.49*) 32.53 ± 4.37 (32.73*)
Females
Body 10.7 ± 0.8 11.5 ± 0.6 10.1 ± 1.1 10.3 ± 1.0
weight (kg)
Liver (g) 281.83 ± 17.56 (280.25) 297.15 ± 11.55 (264.79) 328.97 ± 105.06 (350.02) 399.36 ± 49.13** (412.26**)
From Greenough & Goburdhun (1988)
a
In parentheses: body-weight adjusted group means determined by covariance analysis.
* p < 0.05; ** p < 0.01.
SD, standard deviation.
DIMETHOMORPH 273–315 JMPR 2007