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

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To investigate the contribution of the E and Z isomers to the toxicity of dimethomorph, two
4-week studies in rats treated by oral gavage were performed with both isomers. Gavage administration
was chosen to reduce exposure of the test compounds to light, since photoisomerization is
known to occur between the E- and Z-isomers of dimethomorph.
In the first 4-week study, groups of seven male and seven female Fischer 344 rats received
dimethomorph E-isomer (purity, 99.5%) at a dose of 0, 10, 100, or 750 mg/kg bw per day. During the
4 weeks of the study, no changes in the composition of the test compound were observed. Clinical
examinations were performed twice per day, feed consumption and body-weight development were
recorded weekly. At the end of the study, haematology and clinical chemistry parameters were investigated
and organ weights (brain, heart, liver, kidneys, spleen, adrenals, testes) were recorded and
gross pathology performed. Histopathology was performed for rats in the control group and at the
highest dose for adrenals, heart, intestines, liver (also for rats at the lowest and intermediate dose),
kidneys, pituitary, spleen and stomach. The study complied with GLP.
There were no mortalities in the study. A minimal increase in body-weight gain was observed in
males at the highest dose coinciding with a minimal increase in feed intake. In rats at the highest dose
there were some statistical significant haematological changes, including reduced leukocyte counts in
males, and mildly reduced haemoglobin and increased platelet counts and some changes in plateletassociated
parameters in males and females. Statistical significant changes in clinical chemistry for
males and females at the highest dose included increased concentrations of protein, urea, bilirubin,
cholesterol, calcium, creatinine, and phosphate. In males at the intermediate and highest dose, there
was also an increase in urea concentration, while females at the intermediate and at the highest dose
showed an increased albumin concentration and increased activity of gamma-glutamyltransferase.
Significant decreases in spleen weight were observed in males at the highest dose, and in males
at the intermediate and the highest dose liver and adrenal weights were also increased. In females at
the highest dose, liver weights were increased, as were adrenal weights, although this was not statistically
significant (Table 15). Macroscopic and histological changes found were caecal enlargements,
liver enlargements, liver dark discolorations and liver fatty vacuolations in both sexes. In males, most
findings were present in groups at the intermediate dose and the highest dose, but in females mostly
only at the highest dose ( Table 16).
Table 14. Body weight and body-weight gain in rats fed diets containing dimethomorph for
4 weeks
Dietary concentration (ppm) Body weight (g) Body-weight gain
Week 0 Week 1 Week 2 Week 3 Week 4 (g) % of
control
Males
0 194 253 303 345 380 186 —
2000 194 242 285 324 357 163 88
3000 196 241* 286 323 353 157 84
4000 193 224*** 264*** 292*** 312*** 119 64
Females
0 135 160 183 202 219 84 —
2000 133 150* 165** 179** 190** 57 68
3000 137 151 164** 170*** 172*** 35 42
4000 130 140*** 151*** 154*** 155*** 25 30
From Scott (1986)
* p < 0.05; ** p < 0.01; *** p < 0.001.
DIMETHOMORPH 273–315 JMPR 2007