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    METHIDATHION        JMPR 1975

    Explanation

         Methidathion was evaluated by the Joint Meeting in 1972 (FAO/WHO,
    1973). Further work was required to elucidate the formation of pigment
    and the nature of the liver lesion which leads to increased serum
    transaminase levels in dogs. It was considered desirable to have
    metabolic studies in man to determine comparative degradation between
    man and other species, a study to determine dose levels causing no
    carboxylesterase (aliesterase) activity depression, and further
    information on the fate of residues in storage and processing.

         Since the 1972 Meeting, some additional residue information has
    become available.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

         A re-evaluation of the histological slides of the liver tissue
    from the original study in which dogs were treated for 104 weeks with
    2, 4, 16 and 64 ppm methidathion (Johnston, 1967; Ferrell, 1973) has
    been submitted by Ciba-Geigy Limited. Intrahepatic cholestasis was
    observed in dogs fed 16 and 64 ppm methidathion. Neither degenerative
    nor inflammatory changes were associated with this lesion.
    Pigmentation occurred as bile-plugs in biliary ductules, or as
    amorphous deposits in Kupffer cells or as lipofuscin in both hepatic
    and Kupffer cells. Haemolysis was not detected. A minimal degree
    lipofuscin pigmentation was also observed at 4 ppm and in the control
    group. Mild irregular fatty changes of the hepatocytes with occasional
    periportal histiolymphocytic infiltration of the liver were observed
    in both treated and control animals (Hess, 1975).

         In the two-year dog study at 64 ppm (1.6 mg/kg/day) it is
    significant that the plasma enzyme and liver histology changes at 30
    days of treatment were not increased after two years' treatment at
    this dose. Furthermore, the serum enzyme changes at 16-19 weeks'
    treatment at 64 ppm were reversible and returned to normal after three
    weeks with no dosage.

         It is well-known that a variety of drugs and chemicals produce
    increases in plasma transaminases due to enzyme induction or increased
    permeability of hepatocyte plasma membrane. Also many chemicals,
    especially those which are highly lipophilic and are biliary excreted,
    may compete with bilirubin and alkaline phosphatase for biliary
    excretion, causing reversible elevations of plasma alkaline
    phosphatase and bilirubin. The moderate hepatic accumulation of bile
    pigment and lipid at the higher doses (16 and 64 ppm) would be in
    keeping with these other observations.

    COMMENTS

         Concern was expressed by the 1972 Joint Meeting with respect to
    the hepatic lesions observed in a previously evaluated dog study.
    Although no new data were provided, a re-evaluation and interpretation
    was made of the liver damage previously noted in the original dog
    study. Since no-effect levels were previously established for
    cholinesterase inhibition in the rat, monkey and man, an acceptable
    daily intake was established on the basis of the data in man.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Rat:      4 ppm in diet equivalent to 0.2 mg/kg bw.

         Dog:      4 ppm in diet equivalent to 0.1 mg/kg bw.

         Monkey:   0.25 mg/kg bw.

         Man:      0.11 mg/kg bw.

    ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN

         0-0.005 mg/kg bw.

    RESIDUES IN FOOD AND THEIR EVALUATION

         The use patterns of methidathion in some countries were reported
    to the Meeting and are summarized in Table 1.

        TABLE 1.  Use patterns of methidathion in some countries

                                                                                                 
                                                                                     Preharvest
                                                Rate                                 interval
    Country             Crops,                  (kg/ha)            Insects           (days)
                                                                                                 

    Canada              Potatoes                0.2            Colorado potato          14
                                                               beetle, potato
                                                               flea, beetle

    Hungary             Apples, apricots,       45-60g/        Mites, aphids,           28
                        peaches, pears,         100            moths, Colorado
                        potatoes                litres         potato beetle

    The Netherlands*    Apples, pears           0.6            Mites, aphids,           21
                                                               moths
                                                                                                 

    * Also used in tree nurseries.
        RESIDUES RESULTING FROM SUPERVISED TRIALS

         Residue levels of methidathion from supervised trials on apples
    were reported from the Netherlands (Rijksinstituut, 1966). The data
    are summarized in Table 2.

    FATE OF RESIDUES

    General

         Dejonckheere and Kips (1974) studied the photodecomposition of
    methidathion. Irradiation of methidathion was carried out with
    ultraviolet light at a wavelength of 254 nm. The following products
    were identified: amorphous sulfur, the oxygen analogue, 
    O,O,S-trimethyl phosphorodithioate, O,O,S-trimethyl phosphorothioate,
    5,5-methylenebis-(O,O-dimethyl phosphorodithioate),
    2-methoxy-4-methylthiomethyl-delta2-1,3,4,-thiadiazolin-5-one,
    2-methoxy-delta2- 1,3,4-thiadiazolin-5-one,
    2-methoxy-4-methyldithiomethyl-delta2-1,3,4-thiadiazolin-5-one,
    bis(2-methoxy-delta2-1,3,4-thiadiazolin-5-one-4yl) disulfide, and
    1,3,4-oxadiazolidine-2,5-dione and S,S-methylenebis(O,O-dimethyl
    phosphorodithioate).

    In animals

         Methidathion was fed to a Holstein cow at the 5 mg/kg level in
    the ration for four days (St John and Lisk, 1974). Residues of intact
    methidathion were not detected in milk, urine or faeces samples
    collected throughout the feeding period and for six days thereafter.
    In in vitro studies, methidathion was stable in rumen fluids for
    periods up to eight hours. Analysis of urine showed the presence of
    dimethyl phosphorodithioate and dimethyl phosphorothioate
    representing, respectively, 2.74 and 3.58% of the total methidathion
    dose. After 30 minutes' incubation with beef liver 10 000  g
    supernatant fraction, degradation of methidathion in three replicated
    samples was 82, 86 and 74%.

         In in vitro studies with rumen contents, Polan et al. (1969)
    concluded that breakdown of methidathion was due to microbial activity
    because neither boiled nor clarified rumen contents degraded the
    compound. Methidathion disappeared rapidly from the intact rumen and
    more than 80% of the original dose had disappeared within two hours.
    It was concluded that microbial degradation of methidathion in the
    rumen was of relatively little importance since absorption into the
    bloodstream was so rapid.


        TABLE 2.  Residues of methidathion in apples, resulting from supervised trials

                                                                                                             

                                            Mean residue, mg/kg (range in parenthesis), at interval, days,
                 Rate        No. of                       after application
    Crop         (kg/ha)     treatments      0             2            10-11         20-21         30-31
                                                                                                             

    Apples       0.8          1             0.4           0.4            0.2           0.06         <0.05
                                            (0.11-        (0.21-        (0.09-        (<0.05-
                                             0.63)         0.64)         0.28)         0.07)

                              1              0.9           0.3           0.15          0.1           0.07
                                            (0.79-        (0.28-        (0.12-        (0.08-        (<0.05-
                                             1.0)          0.37)         0.20)         0.15)         0.08)
                                                                                                             
    

    In plants

         Silage and hay were made from alfalfa and timothy that were
    treated with methidathion at the rate of 1.12 kg/ha (Polan et al.,
    1969). A logarithmic rate of degradation of methidathion occurred in
    the silage and hay for 200 and 120 days, respectively.

         Methidathion residues were not detected in either cured or
    noncured tobacco grown on soils treated at rates of 0.28 to 2.24 kg/ha
    (Townsend and Specht, 1975).

    In soil

         Methidathion residues ranged from 0.01 to 0.70 mg/kg in soils
    from tobacco fields one month after treatment at rates of 0.28 to 2.24
    kg/ha (Townsend and Specht, 1975). Residue levels ranged from about
    0.01 to 0.15 mg/kg three months later. In another experiment it was
    determined that three months after treatment (1.12 kg/ha)
    approximately 2% of the applied methidathion remained in the soil.

    RESIDUES IN FOOD IN COMMERCE OR AT CONSUMPTION

         Hungary and France submitted to the Meeting analytical data on
    residue levels of methidathion detected in food samples. The data are
    summarized in Tables 3 and 4.

         In Hungary 1974, 282 samples were analysed of which 16 contained
    residues above the limit of determination of 0.02 mg/kg. Three potato
    samples and one tomato sample had residues in excess of the temporary
    tolerances of 0.02 and 0.1 mg/kg respectively, established at the 1972
    Meeting (FAO/WHO, 1973).

         In France during 1973-75, 74 food samples were analysed. Six
    samples contained residues and all were within the temporary tolerance
    established in 1972.

    NATIONAL TOLERANCES REPORTED TO THE MEETING

         Some further examples of national tolerances were reported to the
    Meeting and are listed in Table 5.

    APPRAISAL

         Some additional information on methidathion was presented to the
    Meeting on the following: use patterns in some countries; a supervised
    trial on apples in the Netherlands; identification of
    photodecomposition products; fate in a cow; degradation in hay, silage
    and rumen; residues in tobacco and in soil from a tobacco field; data
    from food samples in Hungary and France. Of the 282 food samples
    analysed in Hungary, methidathion residues in three potato samples and
    in one tomato sample exceeded the temporary tolerances recommended at
    the 1972 Meeting. Further examples of national tolerances were
    reported.

    TABLE 3.  Residue levels of methidathion in food inspection samples
              in Hungary, 1974

                                                                             

                                       No. of samples containing
                                       residues in range (mg/kg)
                      No. of
                      samples
    Crop              analysed     <0.02*       0.02-0.1       0.1-0.2
                                                                             

    Apples              129         124              4              1

    Apricot             3             2              -              1

    Cabbage             9             8              1              -

    Carrot              2             2              -              -

    Cauliflower         2             2              -              -

    Cherry              4             4              -              -

    Sour cherry         2             -              -              2

    Cucumber            1             1              -              -

    Grape               4             4              -              -

    Onion               41           41              -              -

    Parsley             9             9              -              -

    Peach               28           28              -              -

    Pear                6             6              -              -

    Plum                3             -              1              2

    Potato              33           30              -              3

    Tomato              6             5              -              1
                                                                             

    * Limit of determination of the method.

    TABLE 4.  Residue levels of methidathion in food samples in France,
              1973-1975

                                                                             

                         No. of       No. of samples
                         samples        containing
    Crop                 analysed     detectable residues      Residue, mg/kg
                                                                             

    Apple                  27                 1                    0.03
    Pear                   38                 1                    0.07
    Brussels sprouts        5                 1                    0.011
    Cherry                  1                 -                    -
    Orange                  1                 1                    0.018
    Lemon                   1                 1                    1.9
    Mandarin orange         1                 1                    0.25
                                                                             


    TABLE 5.  National tolerances reported to the Meeting

                                                                             

    Country             Commodity                               Tolerance
                                                                (mg/kg)
                                                                             

    Hungary             General                                    0.2

    South Africa        Citrus fruits (whole)                      2
                        All food products                          0.5
                        Apples, pears                              0.3
                        Apricots, grapes, peaches, plums           0.2

    USA                 Alfalfa, alfalfa hay, clover,              6
                        clover hay, grass, grass hay
                        Grapefruit, oranges, lemons,               2
                        sorghum fodder and forage
                        Sunflower seeds                            0.5
                        Cottonseed, potatoes, sorghum, grain       0.2
                        Peaches, pecans, walnuts                   0.05*

    Yugoslavia          General                                    0.1
                                                                             

    * Negligible residues.

         The additional data confirm the original evaluation and as an ADI
    has been allocated, the temporary tolerances recommended at the 1972
    Meeting are confirmed as maximum residue limits.

    RECOMMENDATIONS

         The temporary tolerances recommended at the 1972 Joint Meeting
    (FAO/WHO, 1973) are confirmed as maximum residue limits.

    FURTHER WORK OR INFORMATION

    DESIRABLE

         As FAO/WHO, 1973a, p. 45, excluding item 1.

    REFERENCES

    Dejonckheere, W. P. and Kips, R. H. (1974) Photodecomposition of
    methidathion. J. Agr. Food Chem, 22:959-968.

    Ferrell, J. F. (1973) Experimental Pathology Laboratories Inc.,
    Herndon, Virginia, USA. Report to Dr G. L. Rolofson, Agricultural
    Division, Ciba-Geigy Corporation, Ardsley, NY. April 25, 1973.

    Hess, R. (1975) Nature of the liver changes observed in a two year
    feeding study in dogs. Unpublished report from the
    Toxicology/Pathology Dept., Ciba-Geigy, submitted to the World Health
    Organization by Ciba-Geigy Ltd., Basle, Switzerland.

    Johnston, C. D. (1967) G.S. 13 005. Safety evaluation by two year
    feeding studies in rats and dogs. Unpublished report from the Woodard
    Research Corporation, submitted to the World Health Organization by
    Ciba-Geigy Ltd., Basle, Switzerland.

    Polan, C.E., Sandy, R. A. and Huber, J. T. (1969) Degradation of
    Supracide in hay silage, and the rumen. J. Dairy Sci., 52:1296-1299.

    Rijksinstituut voor de Volksgezonheid, (1966) Bilthoven, The
    Netherlands (unpublished data).

    St John, L. E. and Lisk, D. J. (1974) Feeding studies with Supracide
    in the dairy cow. Bull. Environ. Contamin. Toxicol., 12:594-598.

    Townsend, L. R. and Specht, H. B. (1975) Organophosphorus and
    organochlorine pesticide residues in soils and uptake by tobacco
    plants. Can. J. Plant Sci., 55:835-842.
    


    See Also:
       Toxicological Abbreviations
       Methidathion (ICSC)
       Methidathion (WHO Pesticide Residues Series 2)
       Methidathion (Pesticide residues in food: 1979 evaluations)
       Methidathion (Pesticide residues in food: 1992 evaluations Part II Toxicology)
       Methidathion (Pesticide residues in food: 1997 evaluations Part II Toxicological & Environmental)