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

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Rabbits
In a dose-range finding study, groups of eight time-mated female New Zealand White rabbits
received dimethomorph (purity, 96.6%) at a dose of 0, 300, 600, or 1000 mg/kg bw per day by oral
gavage as a suspension in a volume of 10 ml/kg, on day 6 until day 18 of gestation. In the group at
the highest dose, nine animals were used. Dams were examined twice per day for clinical and behavioural
signs of toxicity and body weights were recorded regularly. On day 28, dams were terminated
and the fetuses removed and ovaries and uteri examined. The numbers of corpora lutea, implantation
sites, viable fetuses and resorptions were recorded. Fetuses were sexed and body weights measured
and fetuses were subjected to external examinations. The study complied with GLP.
One dam at 1000 mg/kg bw per day was killed on day 7 post coitum because of an injury to a
hindlimb. Another six aborted and were terminated pre-term; for three of these, there were findings in
the liver and/or spleen. After dosing, all rabbits at thee highest dose showed reduced feed/water consumption
and two of them were severely emaciated at abortion. At 300 mg/kg bw per day, one dam
aborted, but none did so at 600 mg/kg bw per day. In all dosed groups, body-weight gain was reduced
during days 6–12 of gestation when compared with controls, an analysis of the group at the highest
dose was not possible due to the abortions (Table 37). Of the two remaining dams at 1000 mg/kg
bw per day, one had total postimplantation losses at necropsy. A slight increase of postimplantation
losses was also evident at 600 mg/kg bw per day, but not at 300 mg/kg bw per day, numbers and sex
of fetuses were not affected. At 600 mg/kg bw per day, mean fetal body weight was slightly reduced.
No increased incidences in malformations were observed.
The NOAEL for maternal toxicity was 300 mg/kg bw on the basis of reduced maternal bodyweight
gain at 600 mg/kg bw. The NOAEL for developmental toxicity was 300 mg/kg bw per day
on the basis of reduced fetal body weight and increased postimplantation losses at 600 mg/kg bw per
day (Müller, 1987a).
In the definitive study, groups of 22 time-mated female New Zealand White rabbits received
dimethomorph (purity, 96.6%) at a dose of 0, 135, 300, or 650 mg/kg bw per day by oral gavage as
a suspension in a volume of 10 ml/kg, from day 6 until day 18 of gestation. Dams were examined
twice per day for clinical and behavioural signs of toxicity and body weights and feed consumption
were recorded regularly. On day 28, dams were terminated and the fetuses removed and ovaries and
uteri examined. The numbers of corpora lutea, implantation sites, viable fetuses and resorptions were
recorded. Fetuses were sexed and body weights measured and fetuses were subjected to external,
visceral and skeletal examinations. The study complied with GLP.
In the control group and in the group at the lowest dose, one dam died and one was terminated
because they aborted. In the group at the intermediate dose, three dams died for different not treatment-related
reasons, no abortions occurred. In the group at the highest dose, four rabbits died, three
Table 37. Body-weight gain in a study of developmental toxicity studying rabbits given
dimethomorph by gavage
Days of gestation
Body-weight gain (kg)
Dose (mg/kg bw per day)
0 300 600 1000
0–6 0.2 0.2 0.2 —
6–12 0.2 0.1 −0.1 —
12–18 0.1 0.2 0.2 —
18–24 0.1 0.1 0.2 —
0–28 0.7 0.7 0.7 —
From Müller (1987a)
DIMETHOMORPH 273–315 JMPR 2007