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

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2. Toxicological studies
2.1 Acute toxicity
(a)
Oral administration
The acute oral toxicity of difenoconazole was evaluated in groups of five male and female
Sprague-Dawley rats given difenoconazole technical (purity not specified) as a single dose at 0, 1000,
2000 or 3000 mg/kg bw in 3% cornstarch and 1% Tween 80 in water in a dose volume of 50 ml/kg bw
administered orally by gavage. The rats were then observed frequently after dosing on test day 1 and
then twice per day on days 2−14. Body weights were recorded twice during the period before testing
and on test days 1, 8 and 15. Necropsy was performed on all rats.
Signs of toxicity in male and female rats in all treatment groups were observed from 0.5 h after
dosing with no clear differences between the groups at 1000, 2000 and 3000 mg/kg bw. These signs
included hypoactivity, stains around the mouth, perineal staining, ataxia, lacrimation, soft faeces,
hypothermia, prostration, chromodacryorrhoea, chromorhinorrhoea, spasms, salivation, unkempt appearance,
rhinorrhoea, hypopnoea, or ptosis. Mortality of 40%, 40%, and 100% occurred at doses of
1000, 2000, and 3000 mg/kg bw, respectively. The oral median lethal dose (LD 50
) was calculated to
be approximately 1453 mg/kg bw for both sexes. In rats that were found dead on test days 3−5 after
receiving a dose of 2000 mg/kg bw, pronounced stomach lesions were observed. No other significant
findings on necropsy were noted for rats at other doses (Argus et al., 1987).
The acute oral toxicity of difenoconazole was evaluated in groups of five male and female
Tif:MAG f (SPF) mice given difenoconazole technical (purity not specified) as a single dose at 1000
(females only) or 2000 mg/kg bw in arachis oil and administered orally by gavage in a dose volume of
10 ml/kg bw. Mortality and clinical symptoms were recorded 1, 3 and 5 h after treatment and at daily
intervals thereafter for a total of 14 days. Body weights were recorded immediately before treatment
and on test days 7 and 14 or at death. Autopsy was performed on all mice.
Piloerection, abnormal body positions, and dyspnoea were observed, these being common
symptoms in tests for acute toxicity. Additionally, reduced locomotor activity and ataxia was observed
in the mice of both dose groups from 5 h after dosing. The group of mice at 2000 mg/kg bw
experienced tonic spasms. At autopsy, no deviations from normal morphology were found. On the
basis of limited mortality, the acute oral LD 50
was estimated to be > 2000 mg/kg bw in male and
female mice (Hartmann, 1990).
(b)
Dermal administration
The acute percutaneous (dermal) toxicity of difenoconazole technical (purity not specified)
was investigated after administering the test material at a dose of 2010 mg/kg bw as a 50% ethanol
preparation to the shaved flank skin of groups of five New Zealand White rabbits. The treated area
represented about 10% of the body surface. The treated area was covered with a gauze dressing attached
by tape. Exposure lasted 24 h; the gauze was then removed and the skin was washed with
ethanol and dried with paper towels. Rabbits were observed regularly after dosing on test day 1 and
at least daily thereafter until day 14. Body weights were recorded before treatment on day 1 and on
days 8 and 15. Autopsy was performed on all rabbits.
No mortality occurred after dermal application of difenoconazole at a dose of 2010 mg/kg bw
for 24 h. Clinical observations that were performed over 14 days after treatment were unremarkable for
all rabbits; however, slight erythema (Draize grade 1) at the treatment site of three rabbits was observed
at the end of the dosing period and fissuring or desquamation of the skin was noted in rabbits of both
sexes, probably as a result of exposure to the ethanol vehicle. Body-weight data indicated that all rabbits
gained weight during the study and gross visceral evaluations performed on all rabbits at the termination
DIFENOCONAZOLE 201–272 JMPR 2007