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    THIOMETON       JMPR 1976

    Explanation

         In 1969 the Joint Meeting (FAO/WHO, 1970b) evaluated thiometon
    in the light of information then available. No ADI could be
    established and no maximum residue limits were recommended.
    Thiometon was reviewed by the Joint Meeting in 1973 (FAO/WHO,
    1974b) and a temporary ADI and some temporary maximum residue
    limits were recommended. The 1973 Meeting listed three items on
    which further work or information was required in order that the
    temporary limits could be confirmed and additional maximum residue
    limits recommended. Information has become available on the fate of
    thiometon in plants, animals and soil. Further data on residues
    from supervised trials and a GLC method of residue analysis have
    also been reported. The new information is evaluated in this
    monograph addendum.

         The present Meeting was informed of a long-term study in rats
    and a 2-year study in dogs which are in progress. The temporary ADI
    has therefore been extended until 1979, when the compound will be
    re-evaluated.

    RESIDUES IN FOOD AND THEIR EVALUATION

    RESIDUES RESULTING FROM SUPERVISED TRIALS

         Additional data on residues resulting from supervised trials
    which have become available since the 1973 Meeting are summarized
    in Table 1.

    FATE OF RESIDUES

    In plants

         Thiometon in plants (apples, Brussels sprouts, lettuce,
    strawberries and sugar beets) persists for only a few hours after
    application, being rapidly converted to the sulphoxide which occurs
    as the main metabolite within the first 3 days after application.
    The sulphoxide is further oxidised to the sulphone. Oxidation of
    the P=S group with the formation of the phosphorothiolates
    demeton-S-methyl, oxydemetonmethyl and demeton-S-methyl sulphone
    was also observed, but the amounts detected in various plants were
    small. These compounds, especially demeton-S-methyl, are usually
    rapidly degraded and do not accumulate in plants.

         The further degradation of thiometon and its metabolites takes
    place by hydrolytic processes which are catalyzed by enzymic
    systems. The predominant pathway can be O-dealkylation of the
    CH3-O-P group producing methanol and the corresponding diesters or
    disruption of the acid-anhydride bond with the formation of
    OO-dimethyl phosphorothionate or phosphate and the corresponding
    side chain thiols (2-(ethylthio)-ethanethiol and its oxidation

    
    TABLE 1. Thiometon residues resulting from supervised trials

                                                                                                                                               

                         Application (as spray)                                  Residues, mg/kg
                         Rate,                       Time after last                                                                  References
    Commodity            kg ai./ha             No    application                 Thiometon                   Total as
                         or concentration            days                        sulphoxide      Thiometon   Thiometon      No. of
                                                                      Thiometon                  sulphone                   trials
                                                                                                                                               

    apples               0.15-0.25             3         28                                                  0.10-0.16         3      a

    beans                0.15-0.25             3         21                                                  <0.02-0.06        3      a

                         500ml 25%E.C.         -         1-7                     0.55-0.13(2)                                         b
                                                         14                      <0.1

    cabbage              500ml 25%E.C.         -         7-14                    0.15-0.05(2)                                         b

    cottonseed           11 25% E.C.           -         160                     <0.1                                                 b
    oil

    grain crops

    barley               0.24-0.5              3         0                                                   1.8-2.6           3      a
    (whole plant)                                        28                                                  <0.02-0.09        3

    barley (grain)                                       42-59                                               <0.02             11     a,c
    barley (straw)                                       42-73                                               <0.02             7

    maize (leaves)       500ml 25%E.C.         -         28                      <0.1                                                 b
    stalks, cobs)

    wheat (Spring        0.25                  1         0            0.02       0.1             0.1         0.2                      c
    wheat, seed)                                         7-28         0.02       <0.02           <0.02       0.02

    wheat (whole         0.15-0.5              3         0                                                   0.7-3.4           3      a
    plant)                                               28                                                  0.02              6

    TABLE 1. (Cont'd.)

                                                                                                                                               

                         Application (as spray)                                  Residues, mg/kg
                         Rate,                       Time after last                                                                  References
    Commodity            kg ai./ha             No    application                 Thiometon                   Total as
                         or concentration            days                        sulphoxide      Thiometon   Thiometon      No. of
                                                                      Thiometon                  sulphone                   trials
                                                                                                                                               

    wheat                                                0                                                   0.3-5.8           6      a
    (seed)                                               14                                                  <0.02-0.25        4
                                                         28-56                                               0.02              4      a

    wheat (seed)         0.25                  1         33           0.06       <0.02           <0.02       approx. 0.06                    c

    wheat (seed)         375ml 25%E.C.         -         7                       4                                                    b
                                                         14                      0.2
                                                         21                      0.05

    wheat (straw)        0.15-0.5              3         0                                                   0.9-6.3           5      a
                                                         14                                                  0.02-0.3          6
                                                         28                                                  0.02-0.04         3
                                                         42-56                                               0.02              3

    groundnuts           375-500ml 25% E.C.    -         7                       0.14-0.19                                            b
    (leaves)
    (roots)                                                           <0.1-0.14

    hops (green, fresh)  0.15-0.25             3         28                                                  0.3-0.9           3      a

    lettuce              0.15-0.25             3         21                                                  <0.02-0.4         3      a

    peaches              0.15-0.25             3         28           0.03-0.14  3               a

                         500ml 25%E.C.         -         7                       0.15                                                 c
                                                         14                      <0.1

    peas (green          0.15-0.25             3         21                                                  <0.02                    a
    in pods)

    TABLE 1. (Cont'd.)

                                                                                                                                               

                         Application (as spray)                                  Residues, mg/kg
                         Rate,                       Time after last                                                                  References
    Commodity            kg ai./ha             No    application                 Thiometon                   Total as
                         or concentration            days                        sulphoxide      Thiometon   Thiometon      No. of
                                                                      Thiometon                  sulphone                   trials
                                                                                                                                               

    potatoes             11 25% E.C.           -         27                      <0.1                                                 b

    potatoes (fineke,    0.25                            30-34                                               <0.01             14     d
    Biutige)

    sugar beets          0.15-0.25             3         0                                                   <0.02-0.07        3      a
                                                         7                                                   <0.02-0.11        2
                                                         14-118                                              <0.02             7

    sugar beet leaves    0.15-0.25             3         0                                                   1.4-4.8           9      a
                                                         7                                                   0.1-0.3           6
                                                         14-118                                              <0.02             7

    tomatoes             0.15-0.25             3         7                                                   0.12-0.22         3      a

                         500ml 25%E.C.         -         1                       0.05                                                 b
                                                         7                       <0.05

                                                                                                                                               

    a = Sandoz, 1976c; trials carried out in the Netherlands and/or Switzerland
    b = Anon., 1976a; trials in South Africa
    c = Anon., 1976b; trials in the Netherlands
    d = TNO, 1973; trials in the Netherlands

    

    products). These side chains are either conjugated within the plant or
    cleaved by desalkylation with the formation of acetic acid, mercaptoacetic
    acid and ethanethiol and its derivatives. Intermediate metabolites
    containing a free hydroxyl function conjugate to form glycosides.

         Results of many field trials on sugar beets (roots and leaves),
    wheat plants, apples, lettuce and potato tubers show that residues
    consist mainly of thiometon sulphoxide and sulphone. Residues of the
    P=0 analogues, demeton-S-methyl and its sulphoxide and sulphone,
    amount to less than 25% of the total residue recovered just after
    treatment.

         The other metabolites mentioned above decrease very rapidly; no
    residues above 0.05 mg/kg can be detected 28 days after application.
    The half-life period for the degradation of the total residue is
    calculated to be 4 days or less (Sandoz, 1976a, where references to
    the original authors are given).

    In animals

         It has been shown in many investigations of disulfoton, phorate
    and demeton that the metabolism of these compounds in animals is
    similar to that in plants. Several studies including in vitro and
    in vivo experiments with boll weevil, bollworm, rat liver and the
    mouse confirmed the finding. It is therefore reasonable to conclude
    that thiometon is metabolised in animals in the same way as in the
    plant.

         Metabolites containing a free hydroxyl or a thiol group (e.g.
    desmethylated thiometon or 2-(ethylthioethanethiol) are able to
    conjugate, forming mainly glucoronides, sulphates and glutathione
    conjugates which are readily excreted (Sandoz, 1976a).

    In soil

         The fate of thiometon in soil has been reviewed (Sandoz 1976b).
    It is degraded rapidly. The half-life periods for degradation in the
    soils tested (containing 1.7 and 4.5% organic matter) were found to be
    less than 2 days. Thiometon sulphoxide was the main metabolite,
    recovered in about 70% yield 3 days after incorporation. This compound
    was further oxidised to thiometon sulphone yielding up to 65% of the
    applied thiometon 14 days after treatment. Oxidation to
    demeton-S-methyl and its sulphoxide and sulphone occurred to a limited
    extent. The final yield calculated as the sum of these compounds
    amounted to less than 18%.

         Oxidation in soil may be catalysed by heavy metal ions bound to
    the soil and/or by soil micro-organisms (Getzin and Chapman, 1960).
    Micro-organisms and acidic and basic sites in clay minerals are able
    to accelerate hydrolysis of thiometon and its primary metabolites.

    In water

         The fate of thiometon in water (50 mg/kg aqueous buffer solutions
    of pH 3, 6 and 9) was investigated. Half-lives during hydrolysis at
    5°C were 90, 83 and 43 days at pH3, 6 and 9. The corresponding periods
    at 25°C were 25, 27 and 17 days. No oxidation products of thiometon
    (Sulphoxide, sulphone and P=O analygues) were detected. It is assumed
    that thiometon is hydrolyzed in the same way as similar
    phosphorodithioates and thioates (Eto, 1974), yielding 2-(ethylthio)
    ethanethiol in acidic solution, ethylthioethylene as an additional
    product under alkaline conditions. Comparison with related compounds
    (Muhlmann and Schrader, 1957) shows the following order of decreasing
    stability: disulfoton demeton-S thiometon phorate (Sandoz, 1976d).

    METHODS OF RESIDUE ANALYSIS

         The method for determining thiometon residues in plant materials
    and soil is based an extraction with acetonitrile containing acetic
    anhydride, followed by oxidation with potassium permanganate in
    aqueous buffer solution at pH 7.0 (Titrisol/phosphate). By this
    treatment, thiometon and its sulphoxide are converted to thiometon
    sulphone, and the P=O metabolite (demeton-S-methyl) and its sulphoxide
    are oxidised to the P=O sulphone. Many tests have shown that oxidation
    of the P=S group is less than 10%. The extract is cleaned up by
    partition between water and methylene chloride/petroleum ether (9:1).
    Quantitative and separate determination of the two sulphones dissolved
    in toluene is achieved by GLC using the phosphorus-sensitive
    thermionic detector with a column of 10% Dexsil 300 on Gas chrom Q.
    The calibration curve is linear from 0.2 to 3.0 ng. the lower limit of
    determination is about 0.02 to 0.1 mg/kg. In spiked samples at 0.1 to
    1 mg/kg levels the overall recoveries in general ranged between 70 and
    90% (Sandoz, 1975).

         This method of analysis has been applied successfully to apples,
    potatoes, wheat and soil. It should be mentioned that the sulphones
    are more stable to the GLC conditions than the corresponding
    sulphoxides which are determined by other GLC methods. The method
    cannot at present be recommended for regulatory analysis because the
    extent of interference by other organophosphorus compounds is not
    known.

         A similar GLC method was reported for the determination of
    thiometon, its sulphoxide and sulphone and similar compounds as
    sulphones in potatoes, where the lower limit of determination was
    0.01 mg/kg (TNO, 1973).

         Thin layer chromatography has also been used for the estimation
    of thiometon, its sulphoxide and sulphone in samples of spring wheat
    and wheat grain. A lower limit of detection of 0.02 mg/kg has been
    reported. However as the final result is obtained by visual assessment
    of a coloured spot of each of the compounds, the method can only be
    described as semi-quantitative (Huntingdon Research Centre, 1971).

    APPRAISAL

         Since the 1973 Joint Meeting information has become available on
    the metabolism of thiometon in plants, animals and soil. Further data
    on residues from supervised trials and a sensitive GLC method of
    residue analysis have also been reported.

         In plants thiometon persists for only a few hours after
    application, being rapidly converted to the sulphoxide which occurs as
    the main metabolite during the first three days.The sulphone is also
    formed. Oxidation of the P=S group leads to the formation of
    demeton-S-methyl, its sulphoxide and its sulphone, but in only very
    small quantities. Further degradation is by 0-dealkylation to methanol
    and the corresponding demethylated compounds, and cleavage to 00-
    dimethyl phosphorothioate or phosphate and 2-ethylthio-ethanethiol and
    its oxidation products. Intermediate metabolites containing a free
    hydroxyl group conjugate to form glycosides.

         Metabolism in insects, mice and rats is similar to that in
    plants. Metabolites containing a free hydroxyl or thiol group form
    glucuronides, sulphates and gluthathione conjugates which are readily
    excreted.

         The fate of thiometon residues in soil is also similar to that in
    plants. The half-life periods for degradation in the soils tested were
    found to be less than two days.

         A method for determining residues in plant materials and soil is
    based on extraction with acetonitrile containing acetic anhydride,
    followed by oxidation with potassium permanganate. Thiometon and its
    sulphoxide as well as the P=O metabolite and its sulphoxide are
    oxidised to the corresponding sulphones. Separate quantitative
    determination of the two sulphones is achieved by GLC using a
    thermionic or flame photometric detector. The lower limit of
    determination is approximately 0.05 mg/kg (0.01-0.1 mg/kg).

    RECOMMENDATIONS

         The following recommendations for temporary maximum residue
    limits are for the sum of thiometon, its sulphoxide and its sulphone,
    expressed as thiometon. They are additional to those made in 1973,
    except the limit for hops which replaces the 1973 limit of 0.5 mg/kg.

    Commodity                                      Temporary maximum
                                                   residue limit (mg/kg)

    Hops (dried)                                             2

    Apricots, cabbage, celery, chicory,
    endives, parsley, peanuts (whole), quinces               0.5

    Commodity                                      Temporary maximum
                                                   residue limit (mg/kg)

    Cottonseed oil, maize (leaves, stalks,
    cobs), straw of grain crops                              0.1

    Fodder beets and tops, sugar beet tops                   0.05*

    * At or about the limit of determination

    FURTHER WORK OR INFORMATION

    Required (by 1979)

    1.   Submission of the long-term study in rats presently in progress.

    Desirable

    1.   Information on the level and fate of residues in live stock
         consuming feed containing thiometon residues.

    REFERENCES

    Anon. Letter from South Africa, 28 July 1976, to FAO (repeat of
    1976a               information originally sent from S. Africa in
                        1973).

    Anon. Information from the Netherlands on pesticides to be considered
    1976b               by the JMPR 1976; Thiometon. Cl 1976/10; 30 August
                        1976.

    Eto, M. Organophosphorus pesticides: organic and biological
    1974                chemistry. pp. 57 (1974) CRC Press Inc.,
                        Cleveland.

    FAO/WHO 1969 evaluations of some pesticide residues in food.
    1970                FAO/PL: 1969/M/17/1; WHO/Food Add./70.38.

    FAO/WHO 1973 evaluations of some pesticide residues in food.
    1974                FAO/AGP/1973/M/9/1; WHO Pesticide Residues Series,
                        No. 3

    Getzin, L. W. and Chapman, R. K. J. econ. Entomol., 53:47
    1960

    Huntingdon Research Centre; Determination of residues of Thiometon and
    1971                its metabolites in Spring wheat and wheat seed.,
                        4350/71/506. Huntingdon, England

    Mülhmann, R. and Schrader, G. Hydrolyse der Insektiziden
                        Phosphorsaureester., Z. Naturforschg., 126: 196

    Sandoz; Ekatin. Thiometon residues in plant materials and soil;
    1975                GLC determination method. AGRO DOK CBK 2194/76;
                        Basle, Switzerland

    Sandoz; Thiometon. Metabolism in plants and animals. A review. ACGO
    1976a               DOK 2201/76. Basle, Switzerland.

    Sandoz; Thiometon. Fate in Soil. AGRO DOK UK 2194/76; Basle,
    1976b               Switzerland

    Sandoz; Thiometon. Summary Report on Residue Data from supervised
    1976c               trials in 1974/1975, AGRO DOK CBK 1976

    Sandoz; Thiometon. Hydrolysis in aqueous buffer solution of pH3, 6
    1976d               and 9 at 5° and 25°C. AGRO DOK CBK 2202/76; Basle,
                        Switzerland

    TNO; Residuen van oxydemeton methyl, thiometon en disulfoton en
    1973                hun metaboliten in aardappelen. Centraal Instituut
                        voor Voedings=onderzoek, Utrechtsweg 48, Zeist,
                        Netherlands. Rapport Nr. R 3957, 1973.
    


    See Also:
       Toxicological Abbreviations
       Thiometon (ICSC)
       Thiometon (PDS)
       Thiometon (FAO/PL:1969/M/17/1)
       Thiometon (WHO Pesticide Residues Series 3)
       Thiometon (Pesticide residues in food: 1979 evaluations)