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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

    DEMETON

    Chemical name

         Demeton consists of a mixture of two isomers;

         (X) Demeton-O and (II) Demeton-S.

    (I)  diethyl 2-(ethylthio)ethyl phosphorothionate; O,O-diethyl
         O-[2-(ethylthio)ethyl]phosphorothioate.

    (II)  diethyl S-[2-(ethylthio)ethyl]phosphorothiolate;
          O,O-diethyl S[2-(ethylthio)ethyl]-phosphorothioate.

    Synonyms

    (I)   P=S systox; thiono systox; mercaptofos; systox.

    (II)  P=O systox; isosystox; thiol systox; mercaptofos tiolovy.

    Empirical formula

         C8H19O3PS2

    Structural formula

    CHEMICAL STRUCTURE 

    BIOLOGICAL DATA

    Biochemical aspects

         The thiono and thiol isomers of demeton are metabolized by plants
    and animals, degraded to a number of derivatives. In the mouse, 50-70%
    of an orally-administered dose is eliminated in the urine within 24
    hours. The principal pathway of metabolism for both isomers is the
    oxidation of the mercapto sulfur of the ethyl mecapto ethyl moiety to
    the sulfoxide and sulfone.

         A secondary pathway involves the oxidation of the thiono sulfur
    to produce the phosphate and its sulfoxide and sulfone. Finally, both
    isomers and their metabolites are degraded by hydrolysis of the
    P-O- or P-S- bond to form the alcohol and acid, with the exception of
    the sulfone of demeton-S which gives ethyl vinyl sulfone and diethyl
    phosphorothioate (Fukuto et al., 1955; March et al., 1955).

         The demeton isomers and a number of derivatives are highly active
    in vivo and in vitro as cholinesterase inhibitors.

         In vitro: molar concentrations necessary to produce 50%
    cholinesterase inhibition expressed as I50 are as follows (Barnes &
    Denz, 1954; DuBois et al., 1956; Wirth, 1958).

         The sulfoxide and the sulfone of Demeton-O are less toxic than
    the parent compound (LD50 respectively for the rat, oral, 100 mg/kg
    and 90 mg/kg body-weight) (Wirth, 1958). The sulfoxide and the sulfone
    of Demeton-S have about the same toxicity as technical demeton, the
    oral LD50 for the rat being approximately 2.0 for both derivatives
    (DuBois et al., 1956; Wirth, 1958).

    Short-term studies

         Rat. Fifty ppm of demeton in the diet for 112 days produced the
    typical symptoms of depressed cholinesterase activity, especially in
    the first week. No histological changes were observed. Three ppm for
    77 days caused only a small inhibition of cholinesterase (Schrader,
    1957).

         Groups of 12 to 18 female rats fed 50 ppm (48% Demeton-S) for 16
    weeks showed signs of poisoning and the growth-rate was affected. No
    histological changes were observed. Groups receiving 10 and 20 ppm
    showed severe inhibition of the brain and blood cholinesterase
    activity, while 3 ppm still gave 30% inhibition of blood
    cholinesterase activity. One ppm did not cause significant inhibition
    (Barnes & Denz, 1954).

         The daily administration of 0.75 mg/kg of Demeton-S for 3 days
    caused a progressive decrease in the cholinesterase activity of the
    brain, serum and submaxillary glands (DuBois et al., 1956).

         Groups of 5 rats were given 65 oral doses of 0.4, 0.66 and 1.89
    mg/kg body-weight of technical demeton over a period of 90 days. One
    animal at the highest dose level died. No other signs of intoxication
    were seen (Deichmann & Rakoczy, 1955).

         Guinea-pig. With daily doses of 2.5 mg of demeton (30%
    Demeton-S per kg body-weight) for 48 days, no toxic changes were
    observed (10 animals), but there was an inhibition of blood
    cholinesterase activity (Bär, 1954).

         Dog. Groups of 2 dogs (one female and one male) were given
    technical demeton for 24 weeks. No significant depression of plasma
    cholinesterase activity was found with 0.025 mg/kg body-weight per
    day. With 0.047 mg/kg body-weight per day significant plasma
    inhibition was found after 16 weeks (Frawley & Fuyat, 1957).


                                                                                                                       
                                         I50 × 10-6 M in 30 minutes at 37°C

                             Rat              Human             Human             Rat         References
                            brain             serum          erythrocyte         plasma
                       cholinesterase    cholinesterase    cholinesterase    cholinesterase
                                                                                                                   

    Demeton-S (48%)         4.0                                                    2.4        Mühlmann & Tietz, 1956

    Demeton-O               4.26*             1.9*              4.65*                         DuBois et al., 1956

    Sulfoxide               4.75*             3.1*              6.2*                                   "
    Sulfone                48.30*            17.2*             51.0*                                   "

    Demeton-S               0.078*            0.078*            0.31*                                  "
                            0.21                                                              Barnes & Denz, 1954

    Sulfoxide               3.58*             1.5*              2.56*                         DuBois et al., 1956
                            2.2                                                               Barnes & Denz, 1954

    Sulfone                 2.86*             0.52*             1.69*                         DuBois et al., 1956
                            2.0                                                               Barnes & Denz, 1954
                                                                                                                   

     * In 40 minutes at 37° celsius
                                                                                                    
    Animal              Route          Substance               LD50 mg/kg     References
                                                               body-weight
                                                                                                    

    Mouse          Intraperitoneal     Demeton (Demeton-S)     5.6-7          DuBois et al., 1956
                                                                              Mühlmann & Tietz, 1956

                        Oral           Demeton (technical)     2.5-14         Barnes & Denz, 1954
                                       (diverse mixtures)                     Borgmann & Hunold, 1954
                                                                              Gaines, 1960
                                                                              Metcalf, 1955
                                                                              Schrader, 1957

                        Oral           Demeton (Demeton-O)     7.5-30         Metcalf, 1955
                                                                              Schrader, 1957
                                                                              Wirth, 1958

                        Oral           Demeton (Demeton-O)     1.5-16.2       Borgmann & Hunold, 1954
                                                                              DuBois et al., 1956
                                                                              Metcalf, 1955
                                                                              Schrader, 1957
                                                                              Wirth, 1958

                   Intraperitoneal     Demeton                 3              DuBois & Coon, 1955

                   Intraperitoneal     Demeton (Demeton-S)     1.5            DuBois et al., 1956

    Guinea-pig     Intraperitoneal     Demeton (Demeton-S)     5.5            DuBois et al., 1956
                                                                                                    
    

    Acute toxicity

         Cattle. Technical demeton (0.1 mg/kg body-weight) fed in
    capsules to a cow for 3 consecutive days caused severe symptom of
    poisoning. After feeding demeton-treated hay containing an average
    concentration of 41 ppm to 3 cows for 56 days, no adverse effects on
    weight changes and milk production were observed, but during the last
    6 days of feeding them was a decrease in erythrocyte cholinesterase
    activity (Dahm & Jacobson, 1956).

         Man. Groups of 5 subjects were given demeton for 30 days, in
    the following amounts: 4.125 mg, 4.5 mg, 4.875 mg per day. Each period
    was followed by a second control period of 30 days. The plasma and
    erythrocyte cholinesterase activity remained within 20% of the control
    values during the administration of demeton (Moeller & Rider, 1965).

    Long-term studies

         No data available.

    Comments on experimental studies reported

         Long-term toxicity tests on rats using demeton have not been
    carried out. The toxicity of technical demeton is dependent upon the
    proportion of each isomer in the mixture. The toxic effect of demeton
    results from the action of the unchanged isomers and, moreover, of
    different metabolic products. Demeton-S and its metabolic products are
    more toxic than Demeton-O.

    EVALUATION

    Level causing no significant toxicological effect in animals

         Rat. The estimated maximum no-effect level is 1 ppm, equivalent
    to 0.05 mg/kg body-weight.

         Dog. 0.025 mg/kg body-weight seems to be the no-effect level.

         Man. In man a dose equivalent to approximately 0.07 mg/kg
    body-weight per day showed no effect.

    Estimate of acceptable daily intake for man

         0-0.0025 mg/kg body-weight per day.

         This value is based on experiments carried out with specimens of
    technical demeton and does not therefore take account of the chemical
    changes in the crop.

    Further work desirable

         Chemical composition and toxicity of the residues. Reproduction
    studies in the rat.

    REFERENCES

    Bär, F. (1954) Arzneimittel-Forsch., 4. 668

    Barnes, J. M. & Denz, F. A. (1954) Brit. J. Industr. Med., 11, 11

    Borgmann, W. & Hanold, G. A. (1954) Report from Max von Pettenkofer
    Institute

    Dahm, P. A. & Jacobson, N. L. (1956) J. Agric. Food Chem., 4, 150

    Deichmann, W. B. & Rakoczy, R. (1955) Arch. industr. Hlth, 11, 324

    DuBois, K. P. & Coon, M. J. (1955) Arch. industr. Hyg., 6, 9

    DuBois, K. P., Murphy, S. D. & Thursh, D. R. (1956) Arch. industr.
    Hlth., 13, 606

    Frawley, J. P. & Fuyat, H. N. (1957) J. Agric. Food Chem., 5, 346

    Fukuto, T. R., Metcalf, R. L., March, R. B. & Maxon, M. G. (1955)
    J. econ. Ent., 48, 347

    Gaines, Th. B. (1960) Toxicol. Appl. Pharmacol., 2, 88-99

    March, R. B., Metcalf, R. L., Fukuto, T. R. & Maxon, M. G. (1955)
    J. econ. Ent., 48, 355

    Metcalf, R. L. (1955) Organic Insecticides, Interscience, New York

    Moeller, H. C. & Rider, J. A. (1963) Fed. Proc., 22 (171), 187

    Mühlmann, R. & Tietz, H. (1956) Höfchen-Briefe, 9, 116

    Schrader, G. (1957) Communication to Farbenfabriken Bayer AG,
    Leverkusen, Agnew. Chemie, 69, 86

    Wirth, W. (1958) Arch. exp. Path. Pharmacol., 234, 352
    


    See Also:
       Toxicological Abbreviations
       Demeton (FAO/PL:1967/M/11/1)
       Demeton (WHO Pesticide Residues Series 5)