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

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The ileums from all mice in the 6-week dose range-finding study (Perry, 1986) and all rats in
the 4-week dose range-finding study (Scott, 1986) were examined histologically, this organ seemed
to be a target of toxicity of dimethomorph in the rat. The study complied with GLP.
Table 20 presents histological findings in the ileum of rats and mice. For both species, the ileum
is a target of toxicity attributable to dimethomorph. Rats were more sensitive to changes in the ileum
than were mice, and female rats were more sensitive than male rats. This difference between the sexes
was not evident in mice (Perry, 1987).
Dog
In the first part of a two-part study to determine the maximum tolerated dose in beagle dogs,
one male and one female were fed diets containing dimethomorph (purity, 96.6%) at a concentration
of 1000 ppm for the first 7 days, then at 750 ppm for 7 days, then at 900 ppm for 7 days and finally
at 1200 ppm for 7 days. In the second part, one male and one female received diet containing dimethomorph
at a concentration of 1200 ppm for 14 consecutive days. The study complied with GLP.
In the first part, clinical signs in the male were emesis, subdued behaviour and increased
micturition on a few occasions. No signs of toxicity were seen in the female.
In the second part, the male showed occasionally body tremors.
In both parts of the study, no marked effects on body-weight gain were recorded and there wre
no evident changes in clinical chemistry, urine analysis and macroscopic lesions in organs.
The maximum tolerated dose was greater than 1200 ppm (Greenough & Goburdhun, 1986a).
In a 13-week feeding study, groups of four male and four female beagle dogs were fed 400 g of
diet containing dimethomorph (purity, 96.6%) at a concentration of 0, 150, 450, or 1350 ppm (equal
to 0, 6, 15, 43 mg/kg bw per day) each day. The dogs were examined daily for general health, moribundity
and mortality, and weekly detailed clinical examinations were performed. Feed consumption
and body-weight development were recorded regularly. Before treatment and in the final week of
treatment, detailed ophthalmic examinations were performed. At the beginning, at week 6 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 were
performed. The study complied with GLP.
There were no mortalities in the study and the only treatment-related clinical signs were
increased incidences of lip-licking and subdued behaviour in males and females at 1350 ppm most
frequently observed from week 4 on and usually within 2 h after feeding. A very slight body-weight
reduction in females at 1350 ppm coincided with a minor decrease in feed intake in these dogs; bodyweight
development and feed intake in all other groups were not affected. There were no significant
haematological changes in any group. In all dogs receiving dimethomorph, an increase in alkaline
phosphatase activity was observed at 6 and 13 weeks and this became statistically significant for
males at the highest dose only at 6 and 13 weeks. Alkaline phosphatase activity in these dogs was
nearly doubled. No other biochemistry parameters were changed. In males at 1350 ppm, body-weight
adjusted thymus weights were increased and prostate weights were decreased, and in females a significant
increase in liver weights was recorded (Table 21). Histopathologically, only in the prostate
were treatment-related findings recorded. All males at 1350 ppm had increased fibrosis in the prostate
and prostatitis was found in two males. Prostatitis was also diagnosed in one male at 150 ppm.
The NOAEL was 450 ppm, equal to 15 mg/kg bw per day, on the basis of weight and histological
changes in organs and behavioural findings at 1350 ppm (Greenough & Goburdhun, 1986b).
In a 52-week feeding study, groups of four male and four female beagle dogs were fed 400 g
of diet containing dimethomorph (purity, 96.6%) at a concentration of 0, 150, 450, or 1350 ppm
(equal to 0, 5, 15.2, and 44.8 mg/kg bw per day) each day. The dogs were examined daily for general
DIMETHOMORPH 273–315 JMPR 2007