Pesticide residues in food — 2006: Toxicological ... - ipcs inchem

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for premature deaths, 10 male and 25 female F 1
parents, 5 pups of each sex per group in the F 1b
and
F 2b
, and 10 pups of each sex per group in the F 3b
.
Several parental deaths occurred in all groups, but aside from one male at 1000 ppm that was killed
in extremis on day 9 after showing signs of severe neurological disturbance, they were not attributed
to treatment. Clinical signs observed in most F 0
parental animals during the first 3 weeks of exposure
at 1000 ppm were high-stepping gait, ataxia/uncoordinated movement, increased sensitivity to sound,
piloerection, increased or decreased activity and unsteady gait, with a low incidence of trembling,
weak, hunched, salivation, and increased sensitivity to touch. Toxicity in the F 0
and F 2
parental groups
was indicated by significant reductions in body-weight gain in the periods before mating of 10–40%
for both sexes at ≥ 750 ppm, and at 150 ppm for F 0
females and F 2
males and females (approximately
10%). Relative to controls, food consumption (g per rat) was reduced at 1000/750 ppm in parental
males of all generations, in parental females in the F 0
and F 2
, and in 150 ppm F 0
females. During
pregnancy, body-weight gain in F 1b
and F 2b
females at 750 ppm was 10% less than that of controls up
to day 14 of gestation and weight gain in the F 1b
, F 2b
and F 3b
litters at 750 ppm was also less, relative
to that of controls (approximately 12%). There were no treatment-related effects on fertility, gestation
length, live births, litter size or pup survival index. At 750 ppm, a mammary gland adenocarcinoma
was observed in one F 1
parental female, but as this is a common neoplasm in this strain of rat, this
isolated finding was not attributed to treatment. One abnormal pup was reportedly observed at 750 ppm
in both the F 2b
and F 3a
, but no details were provided. Three weanlings died or were killed in extremis.
The cause of death of a F 2a
female pup at 750 ppm could not be determined due to cannibalization.
One F 3a
male pup at 750 ppm had severe internal hydrocephalies, but this abnormality was also seen
in a control pup and a pup at 150 ppm in the F 1b
, so was not attributed to treatment. Clinical signs of
ataxia were noted for one male F 1a
pup at 150 ppm, but histopathology indicated congenital lymphoid
hypoplasia, and as there were no similar findings at the highest dose, this was not considered treatmentrelated.
Microphthalmia was observed in three pups in the F 1b
(0, 150, and 750 ppm), and was not seen
in subsequent generations, so was not ascribed to treatment. Overall, there were no treatment-related
macroscopic or microscopic findings in the parental animals or the F 2b
pups.
The NOAEL for parental toxicity was 50 ppm, equal to 3.8 mg/kg bw per day, on the basis of
reduced body-weight gain at the higher doses. The NOAEL for pup development was 150 ppm, equal
to 11 mg/kg bw per day, due to reduced body-weight gain during lactation. There were no r eproductive
effects at the highest dose of 750 ppm, equal to 56 mg/kg bw per day (Milburn, 1982b).
(b)
Dominant lethal studies
Mice
Groups of 12 male mice (36 mice were used as controls) were given cypermethrin (dissolved
in dimethyl sulfoxide) as a single dose at f 0, 6.25, 12.5 or 25 mg/kg bw or as five successive daily
oral doses at 0, 2.5 and 5.0 mg/kg bw. After dosing, each male was caged with three virgin females
for 7 days. The mating procedure was repeated weekly over an interval of 8 weeks in a standard
dominant-lethal test. Females mated to males treated with five daily oral doses at 2.5 mg/kg bw and
those mated to males receiving a single dose of 12.5 mg/kg bw showed a significant reduction in
the incidence of pregnancy during the second and third week respectively of the onset of treatment.
This did not occur with other groups receiving higher or lower doses or at other intervals. In females
mated to males treated daily with doses of cypermethrin, a significant reduction in fetal implants was
observed during the second week of mating. Early fetal deaths were increased in the second week at
5 mg/kg bw. No such increases occurred in any other weekly interval or any other dosed group. Thus,
multiple administration of cypermethrin on five successive days induced a significant reduction in
fetal implants during the second week of mating and a marginal increase in early fetal deaths at the
same time interval.
CYPERMETHRINS X-X JMPR 2006