TOXICOLOGY
Methidathion was last evaluated toxicologically by the 1992 JMPR when an ADI of 0-0.001 mg/kg bw was established on the basis of an NOAEL of 0.14 mg/kg bw per day in three-month, one-year, and two-year studies in dogs. The ADI was based on a study in which effects on the liver were observed. The CCPR requested the JMPR to establish an acute RfD for methidathion in view of its high acute toxicity. New studies submitted for review were evaluated by the present Meeting.
The NOAEL for behavioural changes in rats after a single oral dose was 3 mg/kg bw. The NOAEL for the inhibition of brain acetylcholinesterase activity measured 4 h after treatment was 1 mg/kg bw in males and 2.5 mg/kg bw in females.
In another study of acute neurotoxicity in rats, changes in clinical signs, the results of a battery of functional observational tests, and maze activity were observed at the time of peak effect (about 2 h after treatment) at 8 mg/kg bw and above in males and at 4 mg/kg bw and above in females. Inhibition of acetylcholinesterase activity in various regions of the brain was found at doses of 4 mg/kg bw and above. Reduced acetylcholinesterase activity in the cortex and hyppocampus of a male treated with 1 mg/kg bw was not considered to be relevant. The overall NOAEL in this study was 1 mg/kg bw.
In a case of methidathion poisoning, the estimated dose was more than 10 times the LD50 in rats. The patient recovered from the cholinergic toxicity and developed a mild neuropathy; however, no details were given.
The hepatic changes observed in short-term studies in dogs were not considered relevant for establishing an acute reference dose for humans, as no such changes were observed in the volunteer studies after repeated dosing for up to six weeks. Furthermore, no indication of hepatic toxicity (except slight, transient jaundice in one case) was seen in three cases of massive oral overdose which required atropine and oxime administration and assisted ventilation.
The Meeting established an acute RfD of 0.01 mg/kg bw on the basis of a study reviewed by the 1992 JMPR in which the NOAEL in humans for inhibition of erythrocyte acetylcholinesterase activity was 0.11 mg/kg bw (highest dose tested) and a safety factor of 10. This value is supported by the NOAEL of 1 mg/kg bw in rats for the inhibition of brain acetylcholinesterase activity.
An addendum to the toxicological monograph was prepared.
TOXICOLOGICAL EVALUATION RELEVANT FOR ESTABLISHING AN ACUTE RfD
Levels that cause no toxic effect
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Rat: |
1 mg/kg bw (single oral administration, inhibition of brain acetylcholinesterase activity) |
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Human: |
0.11 mg/kg bw per day (six-week study in volunteers, highest dose tested) |
Estimate of acute reference dose for humans
0.01 mg/kg bw
