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

160
in males at 120 ppm and in females at 45 and 90 ppm. Body weight (reduced by 9–10%) and food
consumption were affected by treatment at the highest dose for males (120 ppm) and females
(90 ppm). The results from FOB revealed treatment-related effects in males at the highest dose
(perianal stain), in females at the intermediate dose (urine stain) and in females at the highest dose
(urine and perianal stains, increased reactivity, abnormal righting reflex, tremor, and decreased
forelimb-grip strength).
Signs of toxicity persisted with continued exposure, but there was no evidence of cumulative
toxicity beyond week 4. Treatment-related decreases in motor and locomotor activity were
observed in males at the highest dose during weeks 4, 8, and 13 of exposure, with no evidence
of cumulative toxicity beyond week 4, and in females at the highest dose during week 4 only.
Greater than 20% inhibition of erythrocyte and plasma cholinesterase activity was observed at all
doses, as was the inhibition of brain cholinesterase activity at the intermediate and highest doses
(Table 16).
Gross lesions were not evident at terminal sacrifice. Brain weight was not affected by treatment
in either sex. There were no treatment-related ophthalmic findings or microscopic lesions
within neural tissues or skeletal muscle. The NOAEL for inhibition of brain cholinesterase activity
was 15 ppm (equal to 1 mg/kg bw per day), while a NOAEL for inhibition of acetylcholinesterase
activity in erythrocytes could not be identified in this study. The statistically significant inhibition of
brain cholinesterase activity at 15 ppm in both sexes was discounted because it was less than 20%
and other studies of a similar duration in which more rats per group were tested, inhibition of cholinesterase
activity was not shown to be statistically significant (Sheets & Hamilton, 1995; Sheets
et al., 1997).
3. Observations in humans
A randomized double-blind study with ascending single oral doses was reported in which a
formal statement was provided to indicate that it complied with the principles of good clinical practice
(CPMP/ICH/135/95) and the OECD principles of GLP. The study was conducted in accordance
with the guidelines established in the Declaration of Helsinki 1964, as amended by the 29th World
Medical Assembly in Tokyo 1975, the 35th World Medical Assembly in Venice 1983, the 41st World
Medical Assembly in Hong Kong 1989 and the 48th General Assembly, Somerset West, Republic
of South Africa October 1996. The study sought to determine the safety of azinphos-methyl (purity,
89.2%) and to establish a NOAEL for inhibition of cholinesterase activity in humans and compare
Table 16. Cholinesterase activity in ratsa given diets containing azinphos-methyl
Tissue
Cholinesterase activity (% inhibition relative to values for controls)
Dietary concentration (ppm)
15/15 (males/females) 45/45 (males/females) 120/90 (males/females)
Week 4
Plasma 7/14* 42*/59* 75*/83*
Erythrocyte 37*/41* 88*/88* 98*/91*
Week 13
Plasma 15*/13 44*/60* 69*/81*
Erythrocyte 37*/38* 84*/78* 95*/95*
Brain 8*/16* 46*/72* 82*/85*
From Sheets & Hamilton (1995) and Sheets et al. (1997)
a
n = 6.
* p < 0.05
AZINPHOS-METHYL 139–172 JMPR 2007