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    THIOMETON      JMPR 1973

         Thiometon was considered at the 1969 Joint Meeting (FAO/WHO,
    1970b). At that time it was not possible to establish an acceptable
    daily intake so no tolerances were recommended. Information was
    provided on the nature and level of residues following the use of
    thiometon.

         Further information was required by the 1969 Joint Meeting before
    tolerance could be established. Information was received on most of
    these issues and the following monograph addendum summarizes its
    evaluation by the Meeting.

    IDENTITY

    Chemical name - Thiometon

         O,O-dimethyl-S-[2-(ethylthio)-ethyl phosphorodithioate
         (C6H15O2PS3)
         (MeO)2 P(S)-S-ET-S-ET (MW-246)

    Appearance and solubility

         Colourless oil with characteristic odour - slightly soluble in
         water (0.2 mg/ml); and soluble in organic solvents

         B.P. - 110°C at 0.1 mm Hg
         V.P. 3 x 10-4 mm Hg at 20°C

    Composition of technical Thiometon

         Thiometon                                         ca 95%

         O-S-dimethyl S-((2-ethylthio)
         ethyl) - phosphorodithioate                       ca 0.5 - 1.0%

         2-6-dithia-octane                                 ca 0.6 - 1.8%

         3,6,7,10-tetrathia-dodecane                       ca 0.8%

         3,6,9-trithia-undecane                            ca 1.6%

         O-methyl S, S-di ((2-ethylthio)
         - ethyl) -phosphorodithioate                      ca 1.6%

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    Biochemical aspects

    Effects on enzymes and other biochemical parameters

         Data are available on the cholinesterase inhibiting properties of
    thiometon as reviewed in 1968 (FAO/WHO, 1969). Based upon analogous
    work with dissolution, thiometon is a poor inhibitor of cholinesterase
    activity and when it is converted to the phosphorothiolate, activity
    of cholinesterase is rapidly depressed. Oxidation of demeton-S-methyl
    to the sulfoxide and sulfone did not significantly increase the
    inhibitory power. The I50 values for sheep erythrocyte
    cholinesterase were 6.5 X 10-5, 4.1 x 10-5, and 2.3 x 10-5 M. for the
    sulfide, sulfoxide and sulfone respectively (Health and Vandekar,
    1957).

    TOXICOLOGICAL STUDIES

    Special studies on reproduction

    Rat. Groups of 10 male and 10 female rats were fed thiometon in the
    diet at 1 mg/kg/day to examine the effect of thiometon on reproduction
    and fertility. After feeding for six months, animals were mated to
    produce an F-1 generation and young from this F-1 generation were
    chosen at weeks 10 and 17 for mating to produce an F-2A and F-2B
    generation respectively. Reproduction indices recorded for the F-2A
    and F-2B generation receiving 1 mg/kg/day were comparable with those
    of the control animals. On the basis of what can be determined from
    this unusually designed study, a dose of 1 mg/kg/day in the diet would
    not have a substantial effect on reproduction (Klotzsche, 1972).

    Acute toxicity

                                                                            

    Substance   Animal       Sex    Route       LD50 (mg/kg)   References
                                                                            

    Thiometon   Mouse        M      oral        66             Anon., 1969
                             F      oral        62             Anon., 1969

                Rat          M      oral        100-120        Anon., 1969;
                                                               Ben-Dyke,
                                                               Sanderson and
                                                               Noakes, 1970

                             F      oral        120-125        Anon., 1969

                Guinea-pig   M      oral        261            Anon., 1969

    (cont'd)
                                                                            

    Substance   Animal       Sex    Route       LD50 (mg/kg)   References
                                                                            


                Rabbit       M      oral        95             Anon., 1969

                Rat          M      i.v.        27.5           Anon., 1969
                             F      i.v.        35.5           Anon., 1969

                Rat          M      i.p.        45.0           Anon., 1972
                             F      i.p.        47.0           Anon., 1972

                Rabbit       M      i.v.        22.0           Anon., 1969

                Rat          M      dermal      >1100          Klotzsche, 1964

                Rat          M      oral pure   225            Klotzsche, 1958
                                    compound

                Rat          M&F    inhalation  >60 mg/l       Klotzsche, 1958
                                    1h
                                                                            


    Short-term studies

    Rat. Groups of rats (15 male and 15 female WISTAR-strain rats per
    group) were fed thiometon in the diet at concentrations of 0, 0.5, 2
    and 5 ppm for four weeks. Cholinesterase activity in plasma and red
    blood cell was examined at 1, 3, 7, 14, 21 and 28 days and brain
    cholinesterase was examined on animals sacrificed at 14 and 28 days.
    There was no effect in this study on growth or behaviour. There was no
    apparent effect on plasma cholinesterase in both males and females.
    There was a slight effect observed in red blood cell cholinesterase in
    both males and females at 5 ppm which was carried over to the
    observations on brain cholinesterase at the two intervals examined. On
    the basis of cholinesterase inhibition, the no-effect level in this
    study would be 2 ppm in the diet although the 5 ppm effect was
    marginal (Carpy, 1972).

         Groups of rats (25 male and 25 female per group) were fed
    thiometon in the diet at dose levels of 0, 5, 15 and 45 ppm for 90
    days. Blood chemistry including plasma and erythrocyte cholinesterase
    were examined at 4, 8, and 13 weeks. At the conclusion of the study
    the animals were sacrificed and gross pathology performed on the
    following tissues: heart, kidney, spleen, adrenal, testes, and liver.
    Mortality was apparently observed in this study at 45 ppm in the diet
    after the fourth week. Clinical chemistry values were unaffected at
    any level in both males and females and the gross pathological

    examination of tissues showed no differences from controls. Plasma
    cholinesterase in males and females was significantly reduced at
    15 ppm in the diet. Red blood cell cholinesterase activity was
    significantly depressed at 15 ppm in the diet and was slightly
    affected at 5 ppm. An apparent no-effect level in this study based
    upon cholinesterase depression would be 5 ppm in the diet (Klotzsche,
    1971).

    Dog. Groups of beagle dogs (four male and four female dogs per
    group) were fed thiometon in a standard diet (NAFAG - 164) for 90
    days. The dietary concentrations of 0, 10, 20 and 40 ppm in the diet
    corresponded to an actual intake of 0.35, 0.65 and 1.40 mg
    thiometon/kg/day.

         There were no effects noted in food consumption, growth or
    behaviour of the animals over the 90-day period. Results of the
    haematology, clinical chemistry and urinalysis wore normal. Gross and
    histological examinations showed no differences from the controls.
    Plasma cholinesterase depression was evident in the study with a
    slight effect being noted at 40 ppm in both males and females
    primarily at the end of the 90 day feeding interval. Brain
    cholinesterase was unaffected at dose levels up to and including 40
    ppm in the diet while red blood cell cholinesterase was inhibited
    significantly at 20 ppm and above. A no-effect level of 10 ppm based
    upon red blood cell cholinesterase depression is considered to be the
    most sensitive parameter examined (Klotzsche and Carpyl 1973).

    Comments

         Thiometon, like the diethyl ester, disulfoton, is an alkyl
    thioether dimethyl organophosphorus ester of moderately acute
    toxicity. No information from metabolic studies in animals or from
    observations in man are available. In a previous evaluation (FAO/WHO,
    1970b) an ADI was not established. Short term studies in rats and dogs
    have indicated no-effect levels, based on cholinesterase depression,
    at 5 ppm and 10 ppm in the diet, respectively. A reproduction study in
    rats was negative at a dosage level of 1 mg/kg. The results of
    long-term studies are not available. The analogy with cliaulfoton
    suggests that thiometon should be metabolized to the sulfoxide and
    sulfone of the dithioate ester and to demeton-S-methyl, but evidence
    that this is so is not available. On the basis of the short-term
    studies with thiometon a temporary ADI for man was established.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effects

         Rat:  5 ppm in the diet, equivalent to 0.25 mg/kg bw

         Dog:  0.35 mg/kg bw/day

    Estimate of temporary acceptable daily intake for man

         0-0.005 mg/kg bw.

    RESIDUES IN FOODS AND THEIR EVALUATION

         Data is available on supervised trials from Czechoslovakia, the
    Netherlands, United Kingdom and South Africa.

         The dosages applied and the residues found in the various
    commodities are listed in Table 1.

    
    TABLE 1.  RESIDUE DATA PROM SUPERVISED TRIALS
              (Thiometon expressed as the sum of thiometon, thiometon-sulfoxide and
               thiometon-sulfone)

                                                                                                

    Crop or                Rate of               Pre-harvest and    Residue     Country
    product                application           interval/day.      in ppm.*
                                                                                                

    Apples                 1.25 g/tree           0                  0.71        Czechoslovakia
                                                 2                  0.63
                                                 6                  0.70
                                                 9                  0.06
                                                 13                 0.13

                           (multi-treatment)
                           2.5 g/tree            0                  0.84        Czechoslovakia
                           4                                        0.38
                           7                                        0.71
                           13                                       0.30
                           21                                       0.22
                           0.5 kg/ha             0                  0.62        United Kingdom
                                                 1                  0.52
                                                 3                  0.4
                                                 21                 <0.01

    Barley                 (grain) 0.250 kg/ha   28                 <0.01
                           (straw)               42                 <0.01       Netherlands

    Bean                   0.125 kg/ha           7                  0.13        South Africa
                                                 14                 0.1

    Brussels sprouts       0.5 kg/ha             1                  2.0
                                                 0                  2.5         United Kingdom
                                                 3                  0.21
                                                 21                 <0.01

    (cont'd)
                                                                                                

    Crop or                Rate of               Pre-harvest and    Residue     Country
    product                application           interval/day.      in ppm.*
                                                                                                

    Cabbage                0.4 kg/ha             1                  1.6         Czechoslovakia
                                                 1                  0.13
                                                 15                 <0.01

                           0.4 kg/ha             1                  1.78        Czechoslovakia
                                                 8                  <0.01
                                                 15                 <0.01
                           2 x 0.4 kg/ha         1                  4.08        Czechoslovakia
                                                 8                  0.19
                                                 15                 0.02
                           0.5 kg/ha             0                  2.1
                                                 3                  0.32
                                                 7                  0.06
                                                 10                 0.09

    Carrots                0.5 kg/ha             21                 0.03        United Kingdom


    Corn                   0.125 kg/ha           28                 0.05        South Africa

    Hops                   0.5 kg/ha             17                 0.15        United Kingdom

    Lettuce                0.33 kg/ha            0                  1.3         United Kingdom
                                                 1                  0.3
                                                 3                  0.11
                                                 21                 <0.01
                           0.5 kg/ha             0                  2.52
                                                 3                  0.36
                                                 7                  0.09
                                                 10                 0.02
                                                 16                 <0.01

    Lettuce (glasshouse)   0.5 kg/ha             0                  3.02
                                                 7                  2.25
                                                 11                 1.62
                                                 18                 0.69
                                                 22                 0.43
                                                 25                 0.11

    Peas (including pod)   0.5 kg/ha             21                 <0.01       United Kingdom

    Potatoes               0.5 kg/ha             21                 <0.01       United Kingdom
                           0.25 ka/ha            27                 <0.05       South Africa

    (cont'd)
                                                                                                
    Crop or                Rate of               Pre-harvest and    Residue     Country
    product                application           interval/day.      in ppm.*
                                                                                                

    Red peppers            2 kg/ha               0                  0.56
    (glasshouse)                                 2                  0.38
                                                 4                  0.29
                                                 7                  0.31
                                                 9                  0.18


    Strawberries           0.5 kg/h.             0                  0.43        United Kingdom
                                                                    (GLC)
                                                 1                  0.23
                                                 3                  0.08
                                                 21                 <0.01

    Sweet cherries         0.06 kg/tree          7                  0.83
                                                 12                 0.09
                                                 16                 0.125
                                                 20                 0.16

    Tomatoes               0.025% spray          7                  <0.05       South Africa

    Wheat (grain)          0.25 kg/h.            56                 <0.01
          (straw)                                56                 <0.01       Netherlands

    Sugar beet             0.5 kg/ha             0                  2.2         United Kingdom
    (leaves)                                     1                  2.7
                                                 3                  0.26
                                                 7                  0.02
                                                 14                 <0.01
                                                 21                 <0.01

                           0.5 kg/ha             0                  2.6         United Kingdom
                                                 1                  1.9
                                                 3                  1.3
                                                 7                  0.08
                                                 14                 <0.01
                                                 21                 <0.01
                                                                                                
    
         Information on national tolerances available to the Meeting is
    set out in Table 2.

    TABLE 2.  NATIONAL TOLERANCES

                                                                  

    Country                 Product                     Tolerance
                                                                  

    Belgium                 Fruits, vegetables          0.5
                            Potatoes                    0.05

    Hungary                 General                     0.5

    Netherlands             Fruit, vegetables           0.5
                            Potatoes                    0.05

    New Zealand                                         0.00

    Poland                  Vegetables, fruits          0.5

    South Africa            General                     2

    Switzerland             Fruits                      0.3
                            Potatoes                    0.05

    USSR                    Fruits                      0.5
                                                                  

    Methods of residue analysis

         For the analysis of the parent compound and its oxidative
    metabolites TLC and GLC methods and available (Huntington, 1969) and
    (Sandoz, 1972). The limits of determination of the methods are 0.02
    ppm and 0.01 ppm respectively.

         The sample is extracted with acetonitrile. The extract is treated
    with potassium permangamate and subjected to clean-up by partition
    between water and methylene chloride/petroleum ether (1/9).

         By this oxidation procedure residues of thiometon, its sulfoxide
    and sulfone are determined together as thiometon sulfone. This allows
    a faster and more accurate analysis. Residues of the oxygen analogue
    and its sulfoxide add sulfone are likely to be too low to
    significantly affect the accuracy of the analysis.

    Appraisal

         Since the 1969 Joint Meeting some additional data have become
    available on residue levels in a variety of commodities after
    supervised trials.

         Taking into consideration the residue data that was available in
    1969 and additional information obtained from supervised trials
    recommendations were made for residual limits in potatoes, raw
    cereals, sugar beet and some fruits and vegetables based on a
    pre-harvest interval of 28 days.

         No information was provided on residues in commodities in
    commerce, fate in processing and cooking or residues in meat or milk.

         The information available indicates that residues of the oxygen
    analogue together with its sulfoxide and sulfone are unlikely to
    exceed 10% of the total residue.

    RECOMMENDATIONS

         Residues are to be determined as thiometon sulfone and expressed
    as thiometon.

    Temporary tolerances

         Apples, cherries (sweet),
         grapes, pears,
         peaches, plums, strawberries

         Beans, lettuce,
         peas, peppers,
         tomatoes, hops (dry)               0.5

         Carrots, potatoes,
         sugar beets,
         raw cereals (including maize)      0.05

    FURTHER WORK OR INFORMATION

    Required (before June 1976)

    1. Long-term studies to investigate chronic toxicity in at least one
    species.

    2. Metabolism studies in plants and animals.

    3. Adequate data from supervised trials, using sensitive gas-liquid
    chromatography methods, on crops (including those for which temporary
    tolerances are recommended but excluding those at or about the limit
    of determination) in order that the temporary tolerances can be
    confirmed and additional residue limits recommended.

    Desirable

    1. Data on the rate of disappearance of residues during storage.
    processing, and cooking.

    2. Information on the nature and level of residues in meat, milk, and
    eggs, following the feeding of residues of thiometon in the ration.

    3. Data on the residue level in commodities moving in commerce.

    REFERENCES

    Anon. (1969) Thiometon, toxicological investigations. Unpublished
    report from Sandoz submitted by Sandoz Ltd., Basle

    Anon. (1972) Thiometon, toxicological investigations. Unpublished
    report from Sandoz submitted by Sandoz Ltd., Basle

    Bátora, V. et al. (1968) Studies on the persistence of thiometon
    sulfoxide residues in some vegetables and fruits. Agrochemia, 8, 5

    Carpy, S. (1972) Thiometon, 28 Tage-Futterungsversuch an
    Ratten-Bestimmungen der Cholinesteraseaktivitat. Unpublished report
    Agro-Department Forschung, Sandoz Chemical Company, submitted by
    Sandoz Ltd

    Heath, D. F. and Vandekar, M. (1957) Some spontaneous reactions of
    //-dimethyl S-ethylthioethyl phosphorothiolate and related compounds
    in water and on storage, and their effects on the toxicological
    properties of the compounds.  Biochem. Journ., 67: 187-201

    Huntingdon. (1969) Huntingdon Research Centre, England, report No.
    2752

    Klotzsche, C. (1958) Thiometon, ein neuer systemischer
    Phosphorsäureester. Mitteilungen aus dam Gebiet der
    Lebensmitteluntersuchung und Hygiene, 49: 72-77

    Klotzsche, C. (1964) Zur toxikologischen prufung neuer insecticider.
    Phosphorsäureester. Int. Arch. f. Gewerbepath, u. Gewerbehyg., 21:
    92-106

    Klotzsche, C. (1971) Thiometon 90-Tage-Futterungs-Versuchmit Ratten.
    Unpublished report by Agro-Department Forschung, Sandoz Chemical
    Company, submitted by Sandoz Ltd

    Klotzsche, C. (1972) Thiometon, 3-Generationenversuch an Ratten.
    Unpublished report from Agro-Department Forschung, Sandoz Chemical
    Company, submitted by Sandoz Ltd

    Klotzsche, C. and Carpy, S. (1973) Thiometon 90-Day Feeding Study in
    Dogs. Unpublished report from Agro- Department Forschung, Sandoz
    Chemical Company, submitted by Sandoz Ltd

    Listopadova, E. and Laska, P. (1971) Thiometon residues in cabbage
    following Intration spray. Ochr. rostl. (Praha), 7(2): 113-120

    Sandoz. (1972) Report CVH 1/72

    


    See Also:
       Toxicological Abbreviations
       Thiometon (ICSC)
       Thiometon (FAO/PL:1969/M/17/1)
       Thiometon (Pesticide residues in food: 1976 evaluations)
       Thiometon (Pesticide residues in food: 1979 evaluations)