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

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at the highest dose. In both species, body-weight gain for treated males and in females at the highest
dose was lower than in animals in the control groups. In rats there was some evidence of decreased
survival at the highest dose compared with controls, but this was not seen in mice. In both sexes at
all doses, survival to termination was adequate for assessment of effects on late-appearance tumours.
The report concluded that the incidence of tumours of the pancreatic islets, and of follicular cells in
the thyroid in males suggested, but did not clearly implicate, azinphos-methyl as a carcinogen in rats.
There was no similar evidence in female rats, and in male and female mice sex there was no increased
incidence of tumours that could be related to the administration of azinphos-methyl (N ational Cancer
Institute, 1978; Annex 1, reference 64, amended with reference to original data).
In a study of carcinogenicity in mice, groups of 50 male and 50 female CD-1 mice received
azinphos-methyl (purity, 88.6%) at a dietary concentration of 0 (control), 5, 20, or 40/80 ppm (equal
to 0.79, 3.49, or 11.33 mg/kg bw per day in males and 0.98, 4.12, or 14.30 mg/kg bw per day in
females) for 2 years. The study was initially used 80 ppm as the highest dietary concentration, but
this was reduced to 40 ppm after 1 week, owing to severe reaction (including mortality) to treatment
at 80 ppm. After the reduction in the highest dietary concentration, there were no clinical signs and
mortality remained unaffected by treatment. Weight gain and food intake remained unaffected by
treatment at dietary concentrations up to and including 40 ppm. Haematological investigations revealed
no indication of any reaction to treatment. Measurement of cholinesterase activity revealed
that at 5 ppm, plasma, erythrocyte and brain cholinesterase activities remained comparable with control
values. At 20 and 40 ppm there was a dose-related inhibition of cholinesterase activity in plasma
and erythrocytes. A similar effect was noted in brain, except that males were only affected at 40 ppm,
while females exhibited a depression of brain cholinesterase activity at 20 and 40 ppm (Table 5).
Pathological investigations revealed no evidence of any reaction to treatment, in particular
there was no evidence of any carcinogenic effect of azinphos-methyl at any dose. The NOAEL was
5 ppm (equal to 0.79 and 0.98 mg/kg bw per day in males and females, respectively) on the basis
of inhibition of cholinesterase activity in plasma, erythrocytes and brain at 20 ppm (Hayes, 1985;
A nnex 1, reference 64, amended with reference to original data).
Rats
In a combined long-term study of toxicity and carcinogenicity in rats, groups of 60 male and
60 female Wistar rats received diets containing azinphos-methyl (purity, 87.2%) at a concentration of
0 (control), 5, 15 or 45 ppm (equal to 0.25, 0.75, or 2.33 mg/kg bw per day for males and 0.31, 0.96,
or 3.11 mg/kg bw per day for females, respectively). From each group, 10 males and 10 females were
killed after 1 year, while all survivors were killed after 2 years of continuous treatment. There were
no clinical signs of reaction to treatment and survival was unaffected by azinphos-methyl. Bodyweight
gain of males at the highest dose was slightly less than that of the controls (7%), but growth
in other groups was not affected by treatment. Clinical biochemistry (apart from investigations of
acetylcholinesterase activity), haematology and urine analysis revealed no indication of any reaction
to treatment.
Determinations of cholinesterase activity in erythrocytes, plasma and brain revealed a marked
inhibition, relative to controls, in males and females from the group at the highest dose (erythrocytes,
plasma and brain) and a less marked effect at 15 ppm (males, erythrocytes; females, erythrocytes and
plasma). Cholinesterase activity in brain from rats at 15 ppm and in erythrocytes, plasma and brain
from rats at 5 ppm remained unaffected by treatment with azinphos-methyl (Table 6). Pathological
examinations (including gross examination, organ-weight analysis and histological examination of
tissues) revealed no evidence of any reaction to treatment; in particular, there was no evidence of any
carcinogenic effect. The NOAEL was 15 ppm, equal to 0.75 and 0.96 mg/kg bw per day in males
and females, respectively, on the basis of effects on body-weight gain and brain acetylcholinesterase
activity (Schmidt, 1987; Annex 1, reference 64, modified with reference to the original data).
AZINPHOS-METHYL 139–172 JMPR 2007