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

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and placed in 10% ammonium sulfide to detect any early implantation loss. Maternal tissues were
preserved for histological examination only as indicated by gross findings. All fetuses were weighed
and examined for external malformations/variations. Crown-rump measurements were recorded
for late resorptions and the tissues were discarded. Each fetus was examined viscerally by fresh
dissection and the sex determined. The brain from each fetus was examined by mid-coronal slice. All
carcasses were eviscerated and processed for skeletal examination.
One control animal died due to gavage error. One animal at 750 mg/kg bw per day died on day 17
of gestation. Two animals were found dead, one on day 11 and one on day 21 of gestation at 1000 mg/kg
bw per day. One animal at 500 mg/kg bw per day was euthanized in extremis on day 21 of gestation after
the observation of prostration, rigid body, and loss of righting reflex. On postmortem examination of this
rabbit, foci in the lungs and liver were found. Discoloured urine was observed in five out of five animals in
all treatment groups. Decreased defaecation was observed at 250 mg/kg bw per day and above. Abortions
were seen in 0, 0, 3, 2, 4 and 1 rabbit at 0, 125, 250, 500, 750 and 1000 mg/kg bw per day, respectively.
Decreased body weights and body-weight gains were seen during the treatment at 500 mg/kg bw per day
and above, with marginal effects at 250 mg/kg bw per day. The mean number of live fetuses were 3.6,
5.0, 3.0, 5.5, 0 and 3.3 at 0, 125, 250, 500, 750 and 1000 mg/kg bw per day respectively, with 5, 5, 1, 2,
1 and 3 pregnant rabbits examined in each of these groups, respectively. There were insufficient pups to
allow an evaluation of developmental toxicity in this study.
On the basis of abortions at 250 mg/kg bw per day and above, the highest dose for the definitive
study was suggested to be not more than 250 mg/kg bw per day (Denny, 1996).
In a study of developmental toxicity, groups of 20 pregnant New Zealand White rabbits
were given bifenazate (lot No. PP159981-B; purity, 92.5%) at a dose of 0, 10, 50, or 200 mg/kg bw
per day by gavage in 0.5% carboxymethylcellulose on days 7–19 of gestation, inclusive. Stability,
homogeneity and dose concentrations were confirmed analytically. All animals were observed
twice daily for mortality and moribundity and once daily for clinical signs of toxicity. Animals
were also observed for signs of toxicity at approximately 1 h after dosing. Maternal body weights
were recorded on day 0 of gestation, daily on days 7–20 of gestation, and on days 24 and 29. Food
consumption was measured daily. A postmortem examination was done on all females aborting
during the study. On day 29 of gestation, all surviving does were killed and subjected to gross
necropsy. The uterus and ovaries were excised and the number of corpora lutea on each ovary was
recorded. Gravid uteri were weighed, opened, and the location and number of viable and non-viable
fetuses, early and late resorptions, and the total number of implantations were recorded. Uteri from
females that appeared non-gravid were opened and placed in 10% ammonium sulfide to detect
any early implantation loss. Maternal tissues were preserved for histological examination only as
indicated by gross findings. All fetuses were weighed and examined for external malformations/
variations. Crown-rump measurements were recorded for late resorptions and the tissues were
discarded. Each fetus was examined viscerally by fresh dissection and the sex determined. The
brain from each fetus was examined by mid-coronal slice. All carcasses were eviscerated and
processed for skeletal examination.
There were no deaths and no treatment-related clinical signs during the study. One doe in each
of the groups at 0, 50, and 200 mg/kg bw per day aborted and was necropsied on day 21, 20, and 26 of
gestation, respectively. These abortions were not considered to be treatment-related. No statistically
or biologically significant differences in absolute body-weight changes occurred between the treated
and control groups during the study. No statistically significant differences in food consumption were
seen between the treated groups and the control group at any time during the study. No treatmentrelated
findings were observed in any animals at necropsy. No treatment-related differences were
observed between the treated and control groups for number of corpora lutea per doe, implantations
per doe, pre- or postimplantation loss, resorptions per doe, fetal body weights, or fetal sex ratios. The
slight (not significant) increase in early resorptions per doe in the group at the highest dose was due to
BIFENAZATE X-X JMPR 2006