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    FAO Meeting Report No. PL/1965/10/1
    WHO/Food Add./27.65

    EVALUATION OF THE TOXICITY OF PESTICIDE RESIDUES IN FOOD

    The content of this document is the result of the deliberations of the
    Joint Meeting of the FAO Committee on Pesticides in Agriculture and
    the WHO Expert Committee on Pesticide Residues, which met in Rome,
    15-22 March 19651

    Food and Agriculture Organization of the United Nations
    World Health Organization
    1965

                
    1 Report of the second joint meeting of the FAO Committee on
    Pesticides in Agriculture and the WHO Expert Committee on Pesticide
    Residues, FAO Meeting Report No. PL/1965/10; WHO/Food Add./26.65

    CHLORTHION

    Chemical name

         O,O-dimethyl-O-(3-chloro-4-nitrophenyl)-phosphorothioate;
    O,O-dimethyl-O-3-chloro-4-nitrophenyl phosphorothionate.

    Empirical formula

         C8H9O5NSCIP

    Structural formula

    CHEMICAL STRUCTURE 

    BIOLOGICAL DATA

    Biochemical aspects

         Chlorthion is activated to a potent cholinesterase inhibitor,
    chloroxon, in animals and plants. It is an active inhibitor of rat
    brain cholinesterase (DuBois et al., 1953). The molar I50 of
    chloroxon for human plasma cholinesterase (30 min. at 37) in vitro
    is 4  10-7 (Fallscheer & Cook, 1956). Its in vivo mammalian
    toxicity is high in comparison with its low in vitro activity; this
    is ascribed to slow absorption from the peritoneal cavity, the
    gastro-intestinal tract and its slow passage into the central and
    peripheral nervous systems. However, when administered
    intraperitoneally in large doses (1000 mg/kg body-weight) it can gain
    access to and inhibit the cholinesterase activity of the brain. As it
    is the 3-chloro-derivative of "methyl parathion" it will probably be
    metabolized in a similar manner to the latter compound by oxidative
    replacement of the sulfur by oxygen to produce the active form of the
    insecticide. Such a metabolite does not appear to have been described
    and there are no reports in the literature to indicate whether the
    chloronitrophenyl residue is excreted as 3-chloro-4-nitrophenol, as
    would be expected by analogy with parathion. Few hydrolytic products
    have been found in rat urine after the administration of this compound
    (Plapp & Casida, 1958). There are no details of its metabolism in
    plants.

    Acute toxicity

                                                                      
    Animal             Route       LD50 mg/kg     References
                                   body-weight
                                                                      

    Rat                Oral         625-1 500     DuBois et al., 1953
                                                  Klimmer & Pfaff, 1955

    Rat           Intraperitoneal      750        DuBois et al., 1953

    Mouse              Oral           1 250       Klimmer & Pfaff, 1955

    Guinea-pig    Intraperitoneal      525        Klimmer & Pfaff, 1955
                                                                      

         Differences in acute oral toxicity may be due to the purity of
    the material, in particular, the presence of more toxic oxidation
    products and of dimethyl-2-chloro-4-nitrophenyl thionophosphate. The
    vehicle used is also important. Combination of chlorthion with
    malathion and other phosphorothionates is said to result in a
    potentiation of its oral toxicity to mice (Rosenberg & Coon, 1958).

    Short-term studies

         Rat. Intraperitoneal injections of undiluted chlorthion to
    groups of 5 rats produced no mortality at a dose level of 50 mg/kg
    body-weight daily for 60 days; 100 mg/kg body-weight daily for 60 days
    resulted in 40% mortality. With 200 mg/kg body-weight daily all
    animals died within 5-10 days. The symptoms prior to death were
    similar to those observed for more toxic organo-phosphorus
    insecticides. Serum cholinesterase activity was decreased more than
    that of brain or submaxillary gland, probably owing to slow absorption
    into the tissues. At the lowest dose level (50 mg/kg body-weight
    daily) the serum cholinesterase activity fell to below 50% of normal
    after the first dose (DuBois et al., 1953).

         Rats (4 groups of 13 male and 4 groups of 13 female) fed for 120
    days on diets containing 10, 20 and 50 ppm of chlorthion showed no
    significant change in growth rate, food consumption, or general
    appearance and no symptoms of cholinergic stimulation. Pathological
    examination showed no difference in the gross or microscopic features
    of the tissues compared with control animals. The animals fed at the
    50 ppm level showed slight reduction in brain and submaxillary gland
    cholinesterase activity levels and a marked decrease in serum
    cholinesterase activity amounting to 76% inhibition. Reduction in
    serum cholinesterase activity was also noted at the 20 ppm level (61%
    inhibition) and at 10 ppm (27% inhibition). Reversal of the inhibition
    occurred within 2 weeks following removal of chlorthion from the diet
    (DuBois et al., 1956).

         Dog. Chlorthion fed to 4 dogs (2 male, 2 female) at dose levels
    of 0.5, 2, 5 and 15 ppm in the diet produced no depression of plasma
    and erythrocyte cholinesterase levels at 0.5, 2 and 5 ppm and gave
    only a questionable depression at 15 ppm over a period of 12 weeks
    (Williams et al., 1959).

    Long-term studies

         No data available.

    Comments on the experimental studies reported

         Although reliable acute toxicity data are available, no long-term
    toxicity tests on animals have been reported. No information is
    available about toxicity in man.

    EVALUATION

    Level causing no significant toxic effects in the rat and dog

         The data so far reported are not sufficient for an estimate to be
    made of an acceptable daily intake for man, especially as long-term
    studies are indicated because of the chemical nature of this compound.

    Further work required

         Chemical composition and toxicity of the residues. Observations
    on the effect in man. Long-term studies in rats including reproduction
    studies.

    REFERENCES

    DuBois, K. P., Doull, J., Deroin, J. & Cummings, O. K. (1953)
    Arch. industr. Hyg., 8, 350-8

    DuBois, K. P., Doull, J. & Rehfuss, P. A. (1956) Report from
    Department of Pharmacology, University of Chicago

    Fallscheer, H. O. & Cook, J. W. (1956) J. Assoc. official Agr.
    Chem., 39, 691

    Klimmer, O. R. & Pfaff, W. (1955) Arzneimitt-Forsch, 5

    Plapp, P. W. & Casida, J. E. (1958) J. econ. Ent., 51, 800

    Rosenberg, P. & Coon, J. M. (1958) Proc. Soc. exp. Biol. (N.Y.),
    97, 836-9

    Williams, M. W., Fuyat, H. N. & Fitzhugh, O. G. (1959) Toxicol.
    Appl. Pharmacol., 1, 1-7
    


    See Also:
       Toxicological Abbreviations