AZINPHOS-METHYL JMPR 1973
This pesticide was evaluated for acceptable daily intake by the
Joint Meetings of the FAO Committee on Pesticides in Agriculture and
the WHO Expert Committee on Pesticide Residues (FAO/WHO, 1965;
FAO/WHO, 1968). At the latter meeting it was considered desirable for
studies to be made available on cholinesterase inhibition of plasma
and erythrocytes in man, on the metabolism of the pesticide by man and
on the identification and toxicology of metabolites. The present
monograph addendum summarizes further relevant studies that have
EVALUATION FOR ACCEPTABLE DAILY INTAKE
Absorption, distribution and excretion
A preliminary study showed that, following oral or
intraperitoneal administration of 0.1-0.2 mg/kg bw of 14C-labelled
azinphos-methyl to rats, about two-thirds of the activity was excreted
in urine and one-quarter in faeces within 48 hours. Over 90% of orally
administered compound is absorbed and activity is eliminated from the
body with a halflife of eight to nine hours. Following intravenous
administration, biliary excretion accounts for about one-third of
activity eliminated. Less than 0.1% of activity appeared as carbon
dioxide, indicating that the benzotriazine ring is not degraded
extensively. An equivalent of only 0.1 mg/kg azinphos-methyl tissue
remained in the tissues 48 hours after oral administration of 2 mg/kg
bw of the compound (Anon, 1973).
The in vitro metabolism of methoxy-14C- and 32P-azinphos-methyl
by subcellular fractions from mouse liver was investigated.
Degradation occurred mainly in microsomal and soluble fractions.
Dimethylphosphorothioic and dimethylphosphoric acids were formed by
microsomal dearylation. The microsomal system also caused oxidative
desulfuration, resulting in the formation of the oxygen analogue.
Examination of the degradative activity of the soluble fraction
suggested that glutathione alkyltranferase catalysed the conjugation
of azinphos-methyl and glutathione, the only products found being
S-methyl glutathione and desmethyl azinphos-methyl. The enzyme showed
little activity against the oxygen analogue of azinphos-methyl
(Motoyama and Dauterman, 1972).
Special studies on mutagenicity
Groups of 12 male mice received a single intraperitoneal
injection of 0, 0.125 or 0.25 mg/kg bw of azinphos-methyl as a
solution in corn oil. Each mouse was mated with a group of three
virgin females. At the end of one week they were replaced by a further
group and this procedure was repeated for six weeks. Female animals
were examined to determine the number of implantation and resorption
sites and the number of embryos produced. The fertility of male
animals and the number of implantation and embryos were unaffected by
treatment and the number of deciduomata were not increased (Arnold et
Observations in man
Two male subjects each received 16 mg azinphos-methyl orally
daily for 30 days. The daily urinary output of azinphos-methyl related
compounds, estimated by a method which converted them to anthranilic
acid, was determined before, during and after cessation of treatment.
The amount of anthranilic acid excreted in urine was increased on the
day following the start of treatment and remained at a high level
during treatment with azinphos-methyl; it returned to a normal level
on the day following cessation of treatment. Neither subject showed a
depression of blood cholinesterase levels during treatment (Thornton,
Groups of five male subjects received 10, 12, 14 or 16 mg
azinphos-methyl by mouth daily for 30 days. Plasma and erythrocyte
cholinesterase levels were measured before and during treatment. No
significant inhibition of enzyme activity was found (Rider et al.,
Further groups of five male subjects received daily doses of 18
or 20 mg for an unspecified period with depression of serum or
erythrocyte cholinesterase activity (Rider et al., 1972).
Azinphos-methyl is readily absorbed from the gastrointestinal
tract although some of it or its metabolites are returned to the gut
by biliary secretion. The benzotriazin moiety is rapidly excreted in
animals and man and concentration in particular organs does not occur.
Dimethylphosphorothioic and dimethylphosphoric acids, desmethyl
azinphos-methyl and the oxygen analogue of azinphos-methyl have been
demonstrated as metabolites in in vitro studies using mouse tissues.
The results of a dominant lethal test in mice were negative.
Plasma and erythrocyte cholinesterase activities were not
depressed in human subjects receiving up to 16 mg azinphosmethyl daily
for 30 days. Full details of the investigation, however, are not
available and the meeting was unable to use these data in estimating
the acceptable daily intake for the compound. The previous estimate
based on the results of experimental studies on animals was confirmed.
Level causing no significant toxicological effects
Rat: 2.5 ppm (0.00025%) in diet, equivalent to 0.125 mg/kg bw
Dog: about 5 ppm (0.0005%) in dry diet, equivalent to 0.125 mg/kg
Estimate of acceptable daily intake in man
0-0.0025 mg/kg bw
FURTHER WORK OR INFORMATION
1. Identification and toxicity of metabolites.
2. Residue data for other crops including grapes, for which
insufficient data were available to establish or amend tolerances
at the 1973 meeting.
Anon. Pharmacokinetic studies with 14C-labelled Gusathion A
1973 and Gusathion M (Provisional results). Unpublished
report from Isotopen-Institut submitted by
Arnold, D., Keplinger, M. L. and Faucher, O. E, Mutagenic
1971 Study with Guthion in Albino Mice. Unpublished
report from Industrial Biotest Laboratories, Inc.
submitted by Chemagro Corporation
Motoyama, N. and Dauterman, W. C. The in vitro metabolism of
1972 azinphos-methyl by mouse liver. Pesticide
Biochemistry and Physiology, 2: 170-177
Rider, J. A., Swader, J. I. and Puletti, E. J.
1971 Anticholinesterase toxicity studies with methyl
parathion, guthion and phosdrin in human subjects.
Federation Proceedings, 30: H.2
Rider, J. A., Swader, J. I. and Puletti, E. J.
1972 Anticholinesterase toxicity studies with guthion,
phosdrin, di-syston and trithion in human
Subjects. Fed. Proc,, Fed. Amer, Sec. Exp. Biol.
Thornton, J. S. Analysis of urine samples from human subjects
1971 treated orally with guthion. Unpublished report
from Chemagro Corporation, Research and