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

291
health, moribundity and mortality, and weekly detailed clinical examinations were performed. Feed
consumption and body-weight development were recorded regularly. Before treatment, at week 26
and in the final week of treatment, detailed ophthalmic examinations were performed. At the beginning,
at weeks 13 and 26 and at the end of the study, haematological and clinical chemistry and urine
analysis parameters were analysed. At the end of the study, organ weights were recorded and gross
pathology and histopathology examinations were performed. The study complied with GLP.
There were no mortalities in the study and no dose-related changes in body-weight gain and
feed consumption were recorded. In haematology and urine analysis, no significant changes were
found at any dose. Alkaline phoshatase activity was increased slightly but statistically significantly in
week 13 and then nearly doubled at week 26 and 51 in males at 1350 ppm; the same effect was somewhat
more pronounced in females at 1350 ppm. There were no other treatment-related changes in
biochemical parameters. Organ-weight analysis (Table 22) showed significant liver-weight increases
in males and females at the highest dose and testes-weight increases in all groups receiving dimethomorph,
these effects becoming statistically significant at the intermediate and the highest dose. In the
testes, no histological changes were observed. Although statistically not significant, prostate weights
were decreased in dogs at 1350 ppm. Histopathologically, three out of four males at 1350 ppm had
mildly increased hepatic lipid while none did in the other groups; two out of four females at 1350 and
450 ppm showed this effect as well as one out of four in the control group and none in the group at
150 ppm. A very slight increase in severity of prostate interstitial fibrosis was observed at the highest
dose. All other organs investigated histologically were not different from controls.
The NOAEL was 450 ppm, equal to 15.2 mg/kg bw per day, on the basis of changes in the
weights of the liver, prostate and testes and prostate fibrosis at 1350 ppm (Greenough & Goburdhun,
1988).
2.3 Long-term studies of toxicity and carcinogenicity
Mouse
In a 24-month study of toxicity and carcinogenicity, groups of 50 male and 50 female CD-1
mice were fed diets containing dimethomorph (purity, 96.6%) adjusted to provide doses of 0, 10, 100
and 1000 mg/kg bw per day. Adjustment of dietary concentrations was weekly for the first 13 weeks
and every 4 weeks thereafter. In a satellite study, four males and six females served as a control group
and 15 males and 15 females were fed diets adjusted to provide dimethomorph at doses of 1000 mg/kg
bw per day. In this satellite study, eight males and eight females at the highest dose and all mice in
Table 21. Mean relative organ weights of dogs fed diets containing dimethomorph for 13 weeks
Organ
Males
Mean relative weight (% of body weight, ± SD)
Dietary concentration (ppm)
0 150 450 1350
Thymus 0.0692 ± 0.0192 0.0511 ± 0.0286 0.083 ± 0.0223 0.1215 ± 0.0485*
Prostate 0.0701 ± 0.0264 0.0598 ± 0.0079 0.057 ± 0.029 0.0271 ± 0.0104**
Females
Liver 2.821 ± 0.209 3.297 ± 0.091 3.208 ± 0.247 3.585 ± 0.510**
From Greenough & Goburdhun (1986b)
* p < 0.05; ** p < 0.01
SD, standard deviation.
DIMETHOMORPH 273–315 JMPR 2007