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

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Deaths occurred in all groups, including controls (one rabbit in the control group, two at
1.5 mg/kg bw per day, one at 4.75 mg/kg bw per day, and three at 15 mg/kg bw per day). Death in
the control group and in the group at the lowest and intermediate dose was attributed to intercurrent
infections, while at the highest dose it was attributed to accidental lung dosing. No treatment-related
clinical signs or changes in body-weight gain were observed. After 11 days of dosing, erythrocyte
acetylcholinesterase activity was significantly reduced (p < 0.05) by 27% at 15 mg/kg bw per day.
Significant reductions in plasma cholinesterase activity were seen at all doses after 11 days of
treatment. However, there was no consistent dose–response relationship and the magnitude of the
inhibition was 22%, 29%, and 26%, at 1.5, 4.75 and 15 mg/kg bw per day, respectively. Erythrocyte
acetylcholinesterase activity was only significantly reduced (27%) at 15 mg/kg bw per day.
No treatment-related effects were observed in gravid uterine weight, number of live fetuses,
number of resorptions, placental weight or crown–rump length. However, the number of fetuses
with a bodyweight of less than 30 g was significantly increased at 15 mg/kg bw per day. Skeletal examination
revealed a statistically-significant increase in the incidence of reduced ossification of long
bone epiphyses in fetuses at 4.75 and 15 mg/kg bw per day. The incidence of reduced ossification
(42.4% and 44.3%, respectively) was also outside the range of mean values for historical controls
(10.7–35.9%). The NOAEL for developmental effects was 1.5 mg/kg bw per day on the basis of retarded
ossification of the long bones at 4.75 and 15 mg/kg bw per day and reduced fetal body weight
at 15 mg/kg bw per day. The NOAEL for maternal toxicity was 4.75 mg/kg bw per day on the basis
of significant i nhibition of erythrocyte acetylcholinesterase activity at 15 mg/kg bw per day (Gal
et al., 1988).
2.5 Special studies: neurotoxicity
Hens
In a published report of experiments designed to investigate the potential relationship between
delayed neurotoxicity and copper concentration in the serum of hens, it was reported that azinphosmethyl
failed to produce symptoms of neurotoxicity after either single or repeated doses (Kimmerle
& Loser, 1974; Annex 1, reference 64).
In a test for acute delayed neurotoxicity, a group of 30 white Leghorn hens was given two doses
of azinphos-methyl (purity, 85%) at a dose of 330 mg/kg bw, with an interval of 21 days between doses.
Hens in the untreated-control, vehicle-control and positive-control (triorthocresyl phosphate, TOCP
at 600 mg/kg bw) groups, each comprising 10 animals, were also included. To protect against sudden
death, atropine (15 mg/kg bw) was administered intramuscularly 15 min before dosing hens with
TOCP or azinphos-methyl. A total of 11 hens treated with azinphos-methyl survived until sacrifice.
These animals appeared normal during the last 12 or 13 days of the study, but exhibited varying degrees
of impaired locomotor activity soon after dosing. Histopathological examinations indicated that
azinphos-methyl did not increase the incidence or severity of lesions in the nerve tissue compared with
untreated and vehicle controls. Investigations of neuropathy target esterase activity were not included
in the study (Glaza, 1988; Annex 1, reference 64, modified with reference to the original data).
Groups of eight HNL hens (age 18–20 months) were given diets containing azinphos-methyl
(purity not stated; prepared as an 80% premix in Silkasil S) at a dose of 0, 75, 150, 300 or 600 ppm
(equivalent to approximately 0, 9.4, 18.7, 37.5 and 75.0 mg/kg bw per day) for 30 days. This was followed
by a post-treatment recovery period of 4 weeks during which the birds were examined for signs
of neurotoxicity (leg weakness, limping and inability to walk). Blood (site or method of blood collection
was not specified) cholinesterase activity was determined before the commencement of the study,
AZINPHOS-METHYL 139–172 JMPR 2007