4.12 Malathion (049)(T,R)

T- toxicological evaluation; R-residue and analytical aspects

TOXICOLOGY

Malathion was evaluated by JMPR in 1963, 1965 and 1966. An ADI of 0-0.02 mg/kg bw was assigned at each Meeting. Malathion was re-evaluated by the JMPR in 1997, when an ADI of 0-0.3 mg/kg bw was assigned. Malathion was re-evaluated at the present Meeting in order to establish an acute reference dose (RfD), at the request of the Codex Committee on Pesticide Residues. The Meeting reviewed a study in humans and some studies of toxicity in animals and studies of genotoxicity which were produced since the last evaluation by the JMPR. The FAO and WHO are in the process of revising the specifications for malathion technical material.

As a supplement to a study of developmental neurotoxicity, a study was undertaken on the effects of orally administered malathion on the activity of cholinesterase. In this study, single or repeated doses of malathion of up to 450 mg/kg bw were administered orally to pregnant rats, pre-weaning offspring at various stages of development, and young adults. The NOAEL for the study was 50 mg/kg bw. Inhibition of brain cholinesterase activity was observed in offspring of untreated females who were given a single direct dose of 150 mg/kg bw on post-natal day 11.

A study of developmental toxicity in rabbits was evaluated at the 1997 JMPR. This study was re-evaluated in 2002. Malathion was administered by gavage at doses of 25, 50 and 100 mg/kg bw per day to groups of mated female rabbits from day 6 to day 18 of gestation. The NOAEL for maternal toxicity was 25 mg/kg bw per day, on the basis of decreased maternal bodyweight gain during dosing. There was no difference in fertility, number of corpora lutea, implantation sites, litter size or fetal weight and length. The NOAEL was 100 mg/kg bw per day for fetal toxicity, on the basis of the absence of developmental toxicity at any dose.

A study of developmental neurotoxicity in which malathion was administered orally to rats was undertaken. Malathion was administered to groups of mated females from day 6 of gestation to post-natal day 10 and to their offspring from post-natal day 11 to post-natal day 21 at doses of 5, 50 or 150 mg/kg bw per day. Behavioural assessments were performed on both dams and pups, in the latter at intervals up to postnatal day 60. The NOAEL for the study was 50 mg/kg bw per day for developmental neurotoxicity (slower surface righting reflex at the highest dose of 150 mg/kg bw per day on post-natal day 11, but not subsequently) and 150 mg/kg bw per day for maternal toxicity. It was considered that the effects observed were likely to have been caused by current treatment rather than any permanent developmental neurotoxic effect because neurotoxicity was not observed in the offspring at later time points in the study.

The results of tests for chromosomal aberrations in human lymphocytes and gene mutation in mouse lymphoma cells were positive at cytotoxic concentrations. A test for unscheduled DNA synthesis in vivo in male rats gave negative results. This is consistent with the conclusions of the 1997 JMPR, which recorded that although the results of some tests in vitro on malathion were positive, malathion was not genotoxic in vivo.

An acceptable^[16] randomized double-blind placebo-controlled ascending single oral dose study was carried out in healthy men and women aged 18-50 years, using malathion in gelatine capsules. Doses of malathion used were 0.5, 1.5, 5, 10 or 15 mg/kg bw. No test-material-related clinical changes were seen, nor were electrocardiograms (ECGs), haematology and clinical chemistry parameters affected by treatment with malathion. No significant changes in plasma or erythrocyte cholinesterase activity were observed when compared to pre-dosing activity or placebo controls at any dose. As no test-material-related effects were observed during the study, the NOAEL was considered to be 15 mg/kg bw.

After considering the new data made available to the Meeting and also the previous monograph, the Meeting established an acute RfD of 2 mg/kg bw on the basis of the study in humans and a safety factor of 10. It should be noted that this acute RfD is likely to be conservative as erythrocyte cholinesterase was more sensitive to inhibition by malathion than brain cholinesterase in the studies available to the Meeting. The Meeting considered that the use of data from studies in which pre-weaning pups received bolus doses of pesticides by direct dosing, particularly when they were also receiving the pesticide in unknown amounts from the dams via their milk, was inappropriate for the establishment of an acute RfD.

An addendum to the toxicological monograph was prepared.

Estimate of acute RfD

2 mg/kg bw

Further studies that would provide information useful for continued evaluation of the compound

Further observations in humans