FAO/PL:1967/M/11/1
WHO/Food Add./68.30
1967 EVALUATIONS OF SOME PESTICIDE RESIDUES IN FOOD
THE MONOGRAPHS
The content of this document is the result of the deliberations of the
Joint Meeting of the FAO Working Party of Experts and the WHO Expert
Committee on Pesticide Residues, which met in Rome, 4 - 11 December,
1967. (FAO/WHO, 1968)
FOOD AND AGRICULTURE ORGANIZATION OF THE UNITED NATIONS
WORLD HEALTH ORGANIZATION
Rome, 1968
OXYDEMETON-METHYL
This pesticide was evaluated by the 1965 Joint Meeting of the FAO
Committee on Pesticides in Agriculture and the WHO Expert Committee on
Pesticide Residues (FAO/WHO, 1965) under the name of demeton-S-methyl
sulfoxide, a commercially produced isomer of demeton-S-methyl. Since
the previous publications, the results of additional experimental work
have been reported. This new work has been summarized, combined with
that previously published, and discussed in the following monograph.
All toxicological studies discussed in this monograph were conducted
with the commercially produced metabolite, oxydemeton-methyl (the
currently accepted ISO name of the compound).
EVALUATION FOR ACCEPTABLE DAILY INTAKES
Biochemical aspects
Demeton-S-methyl sulfoxide is produced in plants from the metabolism
of demeton-methyl. The sulfoxide is further broken down by plants and
animals. After injection into mice, 97-98 percent is rapidly
eliminated (Niessen et al., 1963).
In vitro: Molar concentrations necessary to produce 50 percent
inhibition of sheep erythrocyte cholinesterase, expressed as I50 in
30 minutes at 37°C, are as follows (Heath and Vandekar, 1957) :
demeton-S-methyl P=0 isomer 6.5 × 10-5
demeton-S-methyl sulfoxide 4.1 × 10-5
demeton-S-methyl sulfone 2.3 × 10-5
Acute toxicity
LD50 mg/kg
Animal Route body-weight References
Mouse Oral 30 DuBois and Plzak, 1962
Mouse Intraperitoneal 8-12 DuBois and Plzak, 1962
Rat Oral 30-75 Mühlmann and Tietz, 1956;
Schrader, 1963
Rat Intraperitoneal 20 DuBois and Plzak, 1962
Rat Intravenous 47 Heath and Vandekar, 1957
(cont'd)
LD50 mg/kg
Animal Route body-weight References
Guinea-pig Oral 120 DuBois and Plzak, 1962
Guinea-pig Intraperitoneal 30 DuBois and Plzak, 1962
Short-term studies
Rat. In groups of 20 rats, administration of the sulfoxide by mouth
in doses of 5 mg/kg body-weight daily for 3 months caused no signs of
intoxication or pathological changes, and 10 mg/kg body-weight for 21
days caused an inhibition of cholinesterase activity after 4-6 days
(Wirth, 1958).
Groups of 6 males and 6 females received concentrations of 20 ppm or
less in the diet for a period of 16 weeks: no significant influence on
growth-rate or food consumption was observed. Ten ppm or less caused
no significant depression of erythrocyte cholinesterase activity.
Gross and microscopic examination of the tissues of rats revealed no
indication of toxic effects except for fatty changes in the livers of
some of the rate fed 10 ppm and 20 ppm (Bär, 1963). 50 ppm for 6
months had no effect on weight gains in a group of 6 rats and showed
no pathological changes attributable to the action of the compound.
The brain and blood cholinesterase activity was strongly inhibited.
Concentrations of 100 and 200 ppm produced signs of intoxication in
the first 3 weeks of the experiment (Vandekar, 1958).
In a three-generation reproduction study at dietary levels of 0, 10,
25 and 50 ppm, groups of 10 males and 20 females of each generation,
except the third filial, were maintained through two successive
matings. Second litter animals were used for composing the succeeding
generation groups. The third filial generation was maintained only to
weaning age. At 50 ppm in all generations, the number of pregnancies
and the number of young per litter were significantly reduced.
Histological examination of the second filial generation animals
disclosed only reduced oögenesis in 3 of the 10 in the 50 ppm females,
with no apparent effect at 25 ppm. 10 ppm was without effect on the
number of pregnancies, the number of young per litter, the number of
surviving young up to 21 days and microscopic appearance of major
organs. Erythrocytic cholinesterase activity, expressed in percentage
of controls, was reduced to 83 per cent in males and 67 per cent in
females in the third filial generation, after 21 days; and in the
second generation, after 27 weeks, to 83 per cent in the males and to
61 per cent in the females. Erythrocytic cholinesterase activity was
more consistently reduced, in proportion to the test level, at the two
higher levels. No gross abnormalities nor effect on food consumption
or body-weight gain were seen at any test level (Taylor, 1967).
Dog. Diets containing 5, 10 and 20 ppm have been fed to male and
female beagle dogs for periods of 12 weeks. None of these dose levels
produced significant changes in food consumption or body-weight or
gave rise to cholinergic signs. Levels of 10 ppm or less did not cause
significant inhibition of serum or erythrocyte cholinesterase activity
(Root et al, 1963).
Long-term studies
No data available.
Comments
For the establishment of the ADI short term studies on rats and dogs
can be taken into consideration. In the rat 10 ppm, equivalent to 0.5
mg/kg/day causes no toxicologically significant inhibition of serum or
erythrocyte cholinesterase activity and no adverse effect on
reproduction in three successive generations. In the dogs 10 ppm,
equivalent to 0.25 mg/kg/day, did not show any effect.
TOXICOLOGICAL EVALUATION
Level causing no significant toxicological effect
Rat 10 ppm in the diet equivalent to 0.5 mg/kg/day
Dog 10 ppm in the diet equivalent to 0.25 mg/kg/day.
Estimate of acceptable daily intake for man
0 - 0.0025 mg/kg body weight.
Further work desirable
Observations of the effect in man.
EVALUATION FOR TOLERANCES
Not considered at the 1967 Joint Meeting.
REFERENCES PERTINENT TO EVALUATION FOR ACCEPTABLE DAILY INTAKES
Bär, F. (1963) Personal communication Unpublished report.
DuBois, K. and Plzak, G.J. (1962) Toxicol. Appl. Pharmacol., 4, 621
FAO/WHO. (1965) FAO Mtg. Rpt. PL.1965/10/1; WHO Food Add./27.65
Heath, D.F. and Vandekar, M. (1957) Biochem. J., 67, 187
Mühlmann, R. and Tietz, H. (1956) Höfchen-Briefe, 9, 116
Niessen, H., Tietz, H., Hecht, J. and Kimmerli, G. (1963) Arch.
Toxikol., 20, 44
Root, M., Gowan, J. and Doull, J. (1963) Unpublished report.
Schrader, G. (1963) Die Entwicklung neuer insectizider
Phosphorsäure-Ester, Verlag Chemie GMBH, Weinheim.
Taylor, R.E. (1967) Unpublished report submitted by Chemagro
Corporation
Vandekar, M. (1958) Brit. J. industr. Med. 15, 158
Wirth, W. (1958) Arch. exp. Path. Pharmacol., 234, 352