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    PESTICIDE RESIDUES IN FOOD - 1979


    Sponsored jointly by FAO and WHO






    EVALUATIONS 1979





    Joint meeting of the
    FAO Panel of Experts on Pesticide Residues
    in Food and the Environment
    and the
    WHO Expert Group on Pesticide Residues
    Geneva, 3-12 December 1979



    THIOMETON

    Explanation

    Thiometon was previously evaluated in 1969, 1973 and 1976.  In 1973 a
    temporary ADI and some temporary MRLs were proposed.  Further
    information from (1) a long-term chronic toxicity study; (2)
    metabolism studies in plants and animals; (3) supervised trials, was
    required.  In 1976 some further information on metabolism in plants
    and animals, and some further data from supervised trials were
    considered.  In the absence of a long-term chronic toxicity study, the
    temporary ADI was extended to 1979.  Further information on the level
    and fate of residues in livestock feed containing residues was also
    listed as desirable.

    At the present meeting reports of additional toxicological studies and
    of supervised trials on some 30 commodities, apparently intended to
    confirm temporary MRLs previously recommended and to support a few
    additional figures, were considered.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Absorption, Distribution and Excretion

    About 15 mg/kg body weight of radioactive thiometon, labelled in the
    OCH3-groups, was administered orally to rats.  Most of the activity
    was excreted in urine (83% after 24 hours, 91% after 96 hours).  In
    the faeces, 5.5% was excreted, and 4% remained in the carcass after 96
    hours.  In the blood, the maximum level (6.1 g equivalents/ml) was
    reached after three hours.

    In bile-canulated rats, 4 percent of the dose was excreted in the bile
    and about 76% in urine after 72 hours.  In another experiment where
    the expired air was measured, about 5% was excreted as 14CO2, about
    90% in urine, and about 4% in faeces.  Absorption, distribution and
    elimination in the rat occurred rapidly (Tanner, et al., 1978).

    Biotransformation

    In the urine, no unchanged thiometon was found.  TLC analyses of 0-24
    hours urine samples revealed the presence of three major radioactive
    components two of which were characterized as O-thiometon sulfoxide
    (26 percent of the dose) and O-thiometon sulfone (5 percent).  The
    main metabolite (52%) was a very polar compound which was
    characterized as O,O-dimethylphosphoric acid.  From the excretion of
    small amounts of the radioactivity in expired air, it was concluded
    that O-demethylation took place, but only to a limited extent (Tanner,
    et al., 1978).

    FIGURE 1

    TOXICOLOGICAL STUDIES

    Special Study on Reproduction

    In a standard 3-generation, 2 litter/generation reproduction study,
    groups of 30 female and 30 male animals were fed diets containing 0,
    1, 2.5 and 6.25 ppm thiometon.  From the F1b, F2b, and F3b
    generations, five pregnant females per group were killed for
    teratological investigation.  From 10 animals per sex in each dosage
    group of the F3b generation, about 30 organs or tissues were studied
    histopathologically.

    In the 6.25 ppm group, the lactation index was lower in the F1b, F3b
    and F3c litters, the viability index in the F2b and F3b litters, and
    pup weight in the F2a and P3b litters.  The number of stillborns was
    somewhat higher in the F3a.  There was no influence on the fertility
    or the gestation indices, and no histopathological or teratogenic
    abnormalities were found.  It was concluded that 6.25 ppm had a
    marginal effect on reproduction (Carpy and Klotzsche, 1978).

    Short-term studies

    Dog

    Groups of 4 male and 4 female animals were fed for two years on diets
    containing 0, 6, 12 or 48 ppm thiometon.  Treatment of the test
    animals did not affect general condition, behaviour, mortality,
    ophthalmoscopic findings and organ weights.  Growth, food consumption,
    hematology, clinical chemistry, and urinalysis showed occasionally
    abnormal values, but there was no dose-response relationship.  The
    main effect was noted as cholinesterase inhibition.  At 48 ppm, a
    statistically significant cholinesterase inhibition in plasma and RBC
    was found in males and females at all times (after 1, 2, 3, 4, 8, 13,
    20 and 26 weeks and thereafter each 3 months).  At 12 ppm, only the
    male animals showed a significant cholinesterase inhibition in RBC.
    Plasma cholinesterase in the 12 ppm group was slightly inhibited in
    males and females, especially toward the end of the experiment.  Brain
    cholinesterase activity was reduced slightly at 48 ppm.
    Histopathologically no dose-related effects were found.  The dosage
    level of 6 ppm was considered to be the no-effect level (Hamburger,
    et al., 1978).

    Long-Term Studies

    Rat

    Groups of 50 male and 50 female animals were fed for two years on
    diets containing 0, 1, 2.5, 6.25, or 300 ppm thiometon.  During the
    first six weeks of the study, the diets contained 0, 0.2, 1,2 or 20
    ppm, respectively.  After 60 weeks, five rats of each sex per dose
    group (with the exception of the 300 ppm group) were sacrificed.

    Soon after increasing the dosage level to 300 ppm, the animals lost
    weight and showed signs of acute poisoning (11 males and 14 females
    died).  Thereafter, mortality did not differ from other dosage groups.
    At 300 ppm, the body weight remained low during the study.  In this
    group, a decreased food consumption and water intake was observed and
    a number of hematological and clinical chemical parameters were
    affected.  In females, hemoglobin, MCV, and MCH were generally lower
    during the study.  Glucose, protein, and cholesterol levels were also
    decreased while urea in blood was increased.  The activities of SGPT
    and alkaline phosphatase were increased.  Cholinesterase activity in
    plasma, RBC, brain and liver was strongly inhibited with 300 ppm.  At
    6.5 ppm, lower values for cholinesterase in plasma and RBC were
    observed on some occasions.  In the brain, a slight inhibition of
    cholinesterase was noted in females.  At 2.5 ppm, RBC cholinesterase
    activity was reduced in both sexes on most occasions.  This reduction
    was always less than 20% and of marginal significance.  The urine had
    a higher specific gravity at 300 ppm, but the volume produced in 24
    hours was low.  In the urine, red and white blood cells and amorphous
    uric acid crystals were found more frequently in this group during the
    last half year of the experiment.  At the conclusion of the study, the
    relative weight of spleen was decreased, while weights of adrenals,
    lungs, brain pituitary and gonads were increased at 300 ppm in both
    sexes.  The relative weight of the liver was decreased in males only.
    Histopathologically, the number of tumors at 300 ppm was decreased,
    especially the mammary tumors.  Thiometon was not carcinogenic and did
    not induce any specific lesions in any organ at any dose level.  A
    no-effect level in this study is 2.5 ppm (Hamburger, et al., 1978).

    COMMENTS

    In 1973, a temporary acceptable daily intake of 0.005 mg/kg body
    weight was established.  The long-term study in rats, required by the
    1977 Meeting and additional studies on metabolism in animals, a 2-year
    study in dogs, and a 3-generation study in rats were reviewed.

    Thiometon is almost completely absorbed in the rat and is excreted
    rapidly, mainly in the urine.

    In a 2-year dog study, a no-effect level was found to be 6 ppm in the
    diet.  In the long-term rat study, a no-effect level of 2.5 ppm was
    observed.  In both studies, the no-effect level was based on
    cholinesterase inhibition.  In a 3-generation reproduction study, it
    was found that thiometon was not teratogenic and that 6.25 ppm in the
    diet had a marginal effect on reproduction.

    After evaluation of the available toxicological information, an ADI
    was allocated.

    TOXICOLOGICAL EVALUATION

    Level Causing No Toxicological Effect

    Rat: 2.5 ppm in the diet, equivalent to 0.12 mg/kg body weight
    Dog: 6 ppm in the diet, equivalent to 0.15 mg/kg body weight

    ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN

    0 - 0.003 mg/kg body weight

    RESIDUES IN FOOD AND THEIR EVALUATION

    USE PATTERNS

    No additional information was received.

    RESIDUES RESULTING FROM SUPERVISED TRIALS

    Reports of additional supervised trials on 19 crops in five countries
    were available (Sandoz, 1979).  Most of the residue trials were
    carried out in India, while some other were carried out in Italy,
    Australia, France and Switzerland.  Of the crops studies the data
    relative to 12 did not indicate a need for a change in any of the
    previously recommended MRLs.

    Of the remaining crops, the information supported additional MRLs for
    mustard seed, rape seed and eggplant (See Recommendations).  These
    recommendations are based partly on similarities with other crops.  No
    information was available on "normal" or registered use patterns in
    the countries where the trials were conducted.  However, the
    pre-harvest interval on these crops was not a factor in that residues
    at no time exceeded the MRL level in the similar crops.  On certain
    other crops, substantial waiting periods would be required before
    residues declined to MRL levels.

    Table 1 contains a summary of the residues found in the supervised
    trials for various crops.  The residue values as reported by the
    analyst are apparently the simple arithmetic sum of ppm thiometon
    sulfone and P=O thiometon sulfone which were determined separately.
    In comparing these values to the recommended MRLs it should be noted
    that the MRLs are based on measurement of the thiometon sulfone but
    expressed as thiometon and excluding the P=O analogues.



        Table 1.  Thiometon residues in crops from supervised trials (formulated
              product Ekatin 25 EC used in each trial)

                                                                                      
                         Rate
    Crop               (No. of         Interval     Residue               Country
                     applications)      (days)
                                                                                      

    Cabbage          0.375 kg/ha       3            n.d. - 0.06           India
                     (1)               5            n.d
                                       20           n.d.

    Cauliflower      0.375 kg/ha       3            0.13-0.25             India
                     (1)               5            n.d - 0.03
                                       10           n.d.
                                       20           n.d.

    Eggplant         0.375%            2            0.08 - 0.11           India
                     (1)               6            trace - 0.05
                                       11           n.d.
                                       20           n.d.

    Okra             0.375%            3            trace - n.d.          India
                     (1)               10           n.d. - 0.02
                                       20           n.d.
                     0.375%            3            0.02 - 0.04           India
                     (1)               5            n.d.
                                       20           n.d.

    Tomatoes         0.375 kg/ha       3            0.02 - 0.08           India
                     (1)               10           n.d.
                     0.375 kg/ha       3            0.02 - 0.03           India
                     (1)               5            n.d.

    Peach            0.03%             7            0.26 - 0.38           Italy
                     1                 14           0.08 - 0.1
                                       21           n.d. - 0.02
                                       35           n.d.
                                                                                      

    Table 1.  Continued...

                                                                                      
                     Rate
    Crop             (No. of           Interval     Residue               Country
                     applications)     (days)
                                                                                      

    Grape            0.03%             13           0.8                   Italy
                     (1)               28           0.2
                                       40           0.11 - 0.16
                                       63           0.08

    Potatoes         0.25 kg/ha        22           n.d.                  India
                     (2)
                     0.25 kg/ha        22           n.d.
                     (2)
                     0.375 kg/ha       22           n.d.                  India
                     (2)
                     0.375 kg/ha       22           n.d.
                     (2)

    Sugarbeet        0.025%            0            Root: 0.22 - 0.12     Switzerland
                     (1)                            Leaf: 4.95
                                       28           Root: n.d.
                                                    Leaf: n.d.
                     0.025%            0            Root: n.d. - 0.05     Switzerland
                     (1)                            Leaf: 0.23 - 0.7
                                       28           Root. n.d.            Switzerland
                                                    Leaf: n.d.
                     0.025%            0            Root: n.d.            Switzerland
                     (1)                            Leaf: 1.4 - 2.6
                                       28           Root: n.d.            Switzerland
                                                    Leaf: n.d.

    Lucerne          98 g/ha           3            1.15                  Australia
                     (1)               7            n.d.
                                       14           n.d. - 0.02
                                       24           n.d. - 0.02
                                                                                      

    Table 1.  Continued...

                                                                                      
                     Rate
    Crop             (No. of           Interval     Residue               Country
                     applications)     (days)
                                                                                      

    Lucerne          147 g/ha          7            trace - 0.02          Australia
                     (1)               14           n.d.
                                       24           n.d.
                     220 g/ha          7            n.d. - 0.03           Australia
                     (1)               14           n.d.
                                       24           n.d.
                     294 g/ha          7            0.09                  Australia
                     (1)               14           0.03
                                       24           0.09

    Lupine           0.025%            7            0.24                  Australia
                     (1)               28           0.03
                     0.05%             7            0.52                  Australia
                     (1)               28           0.1

    Rape             0.025%            1            n.d.                  Australia
                     (1)               8            n.d.
                                       15           n.d.
                                       25           n.d.
                     0.05%             1            n.d.                  Australia
                     (1)               8            n.d.
                                       15           n.d.
                                       25           n.d.

    Wheat            243 g/ha          43           n.d.                  France
                     (1)
                     150               43           n.d. (grain)
                     (1)
                     100               43           n.d.
                     (1)
                     240               66           n.d.                  France
                     (1)
                                                                                      

    Table 1.  Continued...

                                                                                      
                     Rate
    Crop             (No. of           Interval     Residue               Country
                     applications)     (days)
                                                                                      

    Wheat            150               66           n.d. (grain)
                     (1)
                     100               66           n.d.
                     (1)

    Rice             0.4375 kg/ha      41           grain n.d.            India
                     (1)
                     0.4375 kg/ha      22           grain n.d.
                     (1)
                     0.375 kg/ha       43           grain n.d.            India
                     (1)                            straw n.d.
                     0.375 kg/ha       26           grain (0.04 - 0.07)
                     (1)                            straw 0.02

    Mustard          0.375 kg/ha       14           seed n.d.             India
                     (2)
                     0.375 kg/ha       14           seed n.d.
                     (2)

    Sorghum          0.375 kg/ha       31           grain n.d.            India
                     (1)
                     0.375 kg/ha       26           grain n.d.
                     (1)

    Groundnuts       0.375 kg/ha       56           n.d.                  India
                     (1)
                                                                                      

    n.d. = not detectable

    "Thiometon residues" comprise thiometon, its sulfoxide and their
     corresponding P=O analogues.
    


    METHODS OF RESIDUE ANALYSIS

    The analytical method employed included a permangate oxidation
    procedure which converts thiometon and thiometon sulfoxide to
    thiometon sulfone along with P=O thiometon which is also measured as
    the sulfone.  It is probably the basic method evaluated by the 1976
    Meeting (FAO/WHO, 1977) except for minor modifications, (e.g. in
    certain trials acetone was identified as the extracting solvent rather
    than acetonitrile).  The limit of detection was 0.02 to 0.04 mg/kg for
    each component depending on substrate.  Residue values were reported
    separately for thiometon sulfone and P=O thiometon sulfone.

    The residue components of thiometon are identical or similar to
    several other pesticides including disulfoton, demeton-methyl, demeton
    and phorate.  These compounds would probably interfere with the
    determination of thiometon.  The method therefore has limited value as
    a regulatory one.

    APPRAISAL

    A series of reports on additional supervised residue trials from five
    countries tended to confirm previously recommended temporary MRLs for
    twelve commodities, and permitted recommendation for three additional
    MRLs.

    RECOMMENDATIONS

    An ADI having now been allocated, the temporary MRLs recommended by
    the 1973 and 1976 Meetings can be converted to maximum residue limits.
    The existing temporary MRL for chives was previously inserted by error
    and should be deleted.  In addition, maximum residue limits are
    recommended for three new commodities listed below.  The limits refer
    to the sum of thiometon, thiometon sulfoxide, and thiometon sulfone
    determined as thiometon sulfone and expressed as thiometon.

                                                            
           Commodity             Maximum residue limit, mg/kg
                                                            
           Mustard seed          0.05*
           Rape seed             0.05*
           Eggplants             0.5
                                                            

    (* At or about limit of determination)

    FURTHER WORK OR INFORMATION (in addition to items
    previously listed)

    Desirable

    Further information on approved use patterns.

    REFERENCES

    Carpy, S. and Klotzsche, C. - 3-Generation Study in Rats (including
    Teratogenicity). (1978) Unpublished Data submitted by Sandoz Ltd.

    Hamburger, F., Carpy, S. and Klotzsche, C. - Thiometon 2-year Feeding
    Study in Dogs. (1978) Unpublished report submitted by Sandoz Ltd.

      Thiometon 2-year Feeding Study in Rats. (1978) Unpublished report
    submitted by Sandoz Ltd.

    Tanner, P., Meier, J. and Schreier, E. - Thiometon. Pharmacokinetic
    Studies with 14C-thiometon in Rats. (1978) Unpublished report
    submitted by Sandoz Ltd.
    


    See Also:
       Toxicological Abbreviations
       Thiometon (ICSC)
       Thiometon (FAO/PL:1969/M/17/1)
       Thiometon (WHO Pesticide Residues Series 3)
       Thiometon (Pesticide residues in food: 1976 evaluations)