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    CHINOMETHIONAT     JMPR 1977

    Explanation

    Chinomethionat was last reviewed by the 1974 Meeting (FAO/WHO 1975)
    and the following further information was required by 1977.

    1. Studies to identify and evaluate the toxicity of metabolites.

    2. A method of analysis that determines the
    2,3-dithiolo-6-methylquinoxaline metabolite.

    The 1974 Meeting also considered the following information desirable:

    1. Studies on the relationships between observed liver enlargements
    and reduced microsomal enzyme activity.

    2. Studies of metabolism in non-rodent species of animal.

    3. Observation in humans.

    4. Information on the lower limit of determination of chinomethionat
    in various crops with the use of Vogeler's method.

    The Codex Committee on Pesticide Residues at the ninth session (1977,
    Alinorm 78/24) requested governments to make residue data available to
    the 1977 Joint Meeting and also requested the Joint Meeting to
    reconsider the basis for the data on which its recommendation for a
    temporary maximum residue limit of 0.5 mg/kg in apples was set. This
    was because some delegations believed that a limit of 0.2 mg/kg would
    suffice.

    No information was received from governments but the principal
    manufacturer provided data on residues and analytical methods in
    response to the request of the Joint Meeting. These and some data on
    evaluation for ADI are reviewed below.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Biotransformation

    Chinomethionat was given to rats orally as a suspension or an an
    emulsion, labelled with 14C either at the carbonyl carbon or in the
    ring, the dose being 10 mg/kg (Gaines, 1969; Carlson and duBois,
    1970). The animals were immediately placed in all-glass Roth
    metabolism cages. It was found that 97% of the dose of the
    carbonyl-labelled compound was recovered as CO2, and the conversion
    was so rapid (75% in 7 hr) to suggest that some was lost before the
    animals were placed securely in their cages. This method of labelling,
    therefore, was of no value in the further study of chinomethionat
    metabolism. However, when the compound was given in the ring-labelled

    form, 75% of the radioactivity was recovered from the excreta in 72
    hr, and 83% in 382 hr (partition between urine and faeces not given).
    Residues of 14C were found mainly in the lower G.I. tract, liver,
    kidney and stomach at 12 and 24 hr. in the kidneys and lower G.I.
    tract at 72 hr. Chinomethionat was not detected as such in urine or
    faeces; therefore, all of the radio-activity present therein (as
    suggested by the experience with the carbonyl-labelled compound) had
    to be present in the form of degradation products. One of these
    products, 2,3-dithiol-6 methylquinoxaline (QDSH) was found in both
    urine and faeces. It was believed by the authors that the hydrolysis
    ChQDSH occurs in the G.I. tract. Two metabolites, identified only as
    "unconjugated compounds", accounted for 48% of the radioactivity in
    the urine. Glucuronides accounted for 8% and other water-soluble
    compounds for 44%. At least 6 metabolites were found in the urine, of
    which one was QDSH, free and/or bound.

    The metabolism of chinomethionat (35S-labelled) following single oral
    doses of 40 mg/kg dissolved in olive oil, to male rats, has been
    studied. These doses were very rapidly absorbed, with 35S appearing
    in the plasma within 20 minutes and peaking at about 90 minutes. This
    peak concentration was followed by a very slow decline, at a
    regression rate indicating a half-life of about 26. The radioactive
    compound in the plasma was very firmly bound to proteins, in the
    approximate ratio albumin-globulin = 4/1. In animals sacrificed 24
    after dosage the distribution of radioactivity was as follows: stomach
    and contents, 3.5%; intestine and contents, 8.65%; caecum and
    contents, 1.1%; liver, 1.05% (0.095% of dose/g); kidneys, 0.21%
    (0.082% of dose/g); epididymal fat 12.4% (4.14% of dose/g); urine,
    20.1%; faeces, 7.7%. On i.v. administration as a previously prepared
    plasma protein complex, the 35S of chinomethionat was excreted
    rapidly in the bile, peaking at about 50 minutes and then decreasing
    rather rapidly to 1/6 the rate 180 minutes. The plasma regression rate
    following i.v. administration of the protein complex suggested a
    two-compartment model of volumes 10.4 (central) and 12.9 (peripheral),
    and a plasma half-life for the comples of 7.9 hr. The peripheral
    compartment as so conceived would include the adipose tissue (Carrera
    et al., 1976).

    EFFECTS ON ENZYMES AND OTHER BIOCHEMICAL PARAMETERS

    The LD50 of chinomethionat in adult male rats is increased by the
    prior administration of phenobarbital but not by the administration of
    estradiol or by castration. In contrast, the LD50 in adult female
    rats is decreased by the prior administration of phenobarbital, but
    is not affected by the administration of testosterone (Carlson and
    duBois, 1970).

    TOXICOLOGICAL STUDIES

    ACUTE TOXICITY

        TABLE 1. Acute toxicity of chinomethionat
                                                                             

                        Route of
    Animal         Sex  Administration   LD50, mg/kg       Reference
                                                                             

    Rat                 Oral             1100 - 3000       Jones,   1968

    Rat                 Dermal           >1000             "        "

    Rat            M    Oral             1800(1513-2142)   Gaines,  1969

    Rat            F    Oral             1100(917-1320)    "        "

    Rat            M    Dermal           >2000             "        "

    Rat            F    Dermal           >2000             "        "

    Rat (adult)    M    I.P.             192  4.5         Carlson, 1970

    Rat (adult)    F    I.P.             95  14           "        "

    Rat (weanling) M    I.P.             325  16          "        "

    Rat (weanling) F    I.P.             320  19          "        "

    Rat (adult)    M    I.P.             458  14          "        "

    Rat (adult)    F    I.P.             473  6.6         "        "
                                                                             
    
    Acutely toxic doses cause diarrhoea, increased haematocrits, decreased
    urine volume and lower blood pressure.

    Relative toxicities of chinomethionat and its primary metabolite.
    Carlson and duBois (1970) had available for test authentic samples of
    chinomethionat and of its primary metabolite
    (2,3-dithiol-6-methoxyquinoxaline). Both were evaluated for toxicity
    in rats and mice, with these results (as i.p. LD50, mg/kg):

                                                                       

    Test                                              QDSH
    Animal              Sex       Chinomethionat    Metabolite
                                                                   
    Adult rat           M         192  4.5         38  5

    Adult rat           F         95  14           86  9

    Weanling Rat        M         325  16          115  12

    Weanling Rat        F         320  19          124  6

    Adult Mouse         M         458  14          249  43

    Adult Mouse         F         473  6.6         263  40
                                                                   
    

    These data indicate that the metabolite was in all cases more toxic
    than the parent compound although in the adult female rat the
    difference found was not significant. By and large the LD50 of
    chinomethionat appears to be higher than that of the QDSH metabolite.

    SHORT TERM STUDIES

    Rat

    In female rats the MTD without mortality in a 2-month test was 25
    mg/kg. Dietary levels of 500 ppm were fed to male rats in both 3- and
    6-month experiments without producing excessive mortality in the
    treated animals. Rather minor effects were observed, namely lower body
    weights, some hepatomegaly and minor hepatic histopathology. The no-
    effect level, therefore, would be somewhat less than 500 ppm. Rather
    similar effects on body weight and hepatic morphology were obtained by
    applying an aqueous suspension of chinomethionat to the clipped backs
    of the animals 5 days/week for 3 weeks, at dose levels of 125
    mg/kg/day. At lower doses no effects were seen (Carlson and duBois,
    1970).

    COMMENTS

    A temporary ADI for humans was previously established.

    A request was made for further metabolic studies in a non-rodent
    species, explanation of the liver cell hyperplasia, loss of liver
    microsomal enzyme activity, and, where possible, observation in
    humans. Although some new metabolic data have been supplied, in
    general no other information was provided. Therefore, it was decided
    to extend the temporary ADI for humans.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

    Rat: 12 mg/kg in the diet, equivalent to 0.6 mg/kg bw.

    ESTIMATE OF TEMPORARY ACCEPTABLE DAILY INTAKE FOR HUMANS

    0-0.003 mg/kg bw

    RESIDUES IN FOOD AND THEIR EVALUATION

    USE PATTERN

    Use of the compound have been summarized in the previous evaluations
    (FAO/WHO 1969, 1975). Additional use patterns are summarized in Table
    2.

    RESIDUES RESULTING FROM SUPERVISED TRIALS

    Supervised trials were carried out on oranges and apples (United
    States), strawberries (Japan), cucurbits and grapes. The results are
    summarized in Table 3. It is seen that low residue levels were
    observed, and in most fruits covered with peel penetration into the
    pulp appears to be negligible.

    FATE OF RESIDUES

    In Animals

    To determine whether or not chinomethionat residues in cattle feed
    prepared from citrus peel could be transferred to milk or meat, a
    dairy cow was given doses of 14C-labelled chinomethionat, twice daily
    for 24 days, equivalent to a rate of 0.0675 mg/kg body weight/day, the
    dosage expected to be normally consumed by the cow when feeding on dry
    citrus peel prepared from fresh orange peel containing a residue of
    1.5 mg/kg. The only tissue residue detected after the 25th day was
    0.05 mg/kg in liver and the highest milk residue was 0.002 mg/kg.
    Minimum limits of detection were 0.001 mg/kg for milk and 0.02 mg/kg
    for meat. The experiment showed that residues of chinomethionat in
    cattle feed at the level used were not likely to result in residues in
    meat or milk, especially when one considers the data in Table 3 as
    well as the 93% destruction of chinomethionat when fresh citrus peel
    is converted to dry cattle feed (Everett and Olson, 1968).

    Almond hulls are also used for cattle feed and a study was conducted
    to determine whether or not residues would be detected in the tissues
    and milk of two dairy cows. Almond hulls containing approximately 0.08
    mg/kg chinomethionat, 14C-labelled, and 1.14 mg/kg equivalent of
    total radioactive residue comprised about 20% of the ration.
    Radioactive residues in milk are shown in Table 4 while Table 5 shows
    the residue levels in meat. Tissue residues could be detected only in

    liver and kidney and residues in milk never exceeded 0.008 mg/kg with
    maximum residues being reached about 10 days after the start of
    feeding. The highest level in plasma was about 0.007 mg/kg at about 14
    days, declining to about 0.005 mg/kg at day 21 (Murphy et al., 1977).

    In Plants

    When 14C-chinomethionat was applied to apples and oranges, slow
    hydrolysis to 2,3-dithiol-6-methylquinoxaline (QDSH) was observed,
    reaching a maximum at 7-14 days after application. QDSH was reported
    as the total of free and bound QDSH and the residue levels in the
    peels are shown in Table 6. One or more unidentified bound metabolites
    were also reported; their residue levels are also summarized in Table
    6.

    In pre-bloom application to apple trees, only chinomethionat was
    detected in fruits, possibly owing to the low residues observed.
    Residues in fruits were 0.002 mg/kg or less.

        TABLE 2. Summary of additional uses of chinomethionat

                                                                             

    Crop            Pest             Application rate         Pre-harvest
                                     (% a.i.)                 interval
                                                              (days)
                                                                             

    Apples    )     Mites            0.0125                   21
    Peaches   )     Powdery mildew   0.0125                   21
    Cucurbits )                                               7
                                                              (3 under glass)

    Citrus    )     Mites            0.0125                   21
    Grapes    )

    Cereals         Powdery mildew   0.13 kg a.i./            ----
                                     100-200 liters/ha.
                                                                             

    

        TABLE 3. Summary of additional residues data from supervised trials with chinomethionat

                                                                                               

    Fruit               Application rate                        Days after          Residues,
                   % a.i.              No. of applications      application         mg/kg
                                                                                               

    Curcurbits     0.0125%             1                        1                   0.12
                                                                2                   0.08
                                                                4                   0.12
                                                                7                   0.10
    Grapes         0.0125%             2                        1                   0.38
                                                                7                   0.06
                                                                14                  0.02
                                                                21                  ND1
    Oranges (peel) 0.22                1                        7                   0.38
                   (controlled                                  14                  0.37
                   application)                                 28                  0.16
                                                                36                  0.08
    Oranges (pulp)                                                                  <0.01
    Apples (peel)  0.145               1                        0                   1.8
                   (controlled
                   application)                                 7                   0.58
                                                                14                  0.32
                                                                28                  0.05
                                                                36                  0.03
    Apples (pulp)                                                                   <0.01
    Apples        prebloom application                          35
                                                                79                  <0.01
                                                                157                 ND1-0.002
    Strawberry     0.01                6                        1                   0.5
                                                                3                   0.35
                                                                7                   0.2
                                                                14                  0.05
                                                                                               
    1 Not detectable.
    

        TABLE 4. Residues of 14C-chinomethionat in milk from dairy cows fed daily
    with almond hull ration containing chinomethionat residues
                                                                                   
    Days after first feeding      Residues, mg/kg chinomethionat equivalents
                                  Cow A                         Cow B
                                                                                   
    0                             0.0002                        -

    1                             -                             0.0002

    2                             0.002                         0.001

    5                             0.0035                        0.0018

    8                             0.0036                        0.0025

    10                            0.007                         0.005

    11                            0.0054                        0.0039

    14                            0.005                         0.0033

    16                            0.0042                        -

    17                            -                             0.0032

    21                            0.0026                        0.0022
                                                                                   


    TABLE 5. Residues of C14-chinomethionat in tissues taken
    from dairy cows fed an almond hull ration for 21 days
                                                                         

    Tissue              Residue, mg/kg chinomethionat equivalents

                        Cow A               Cow B
                                                                         
    Liver               0.02                0.03

    Kidney              0.03                0.02

    Heart               <0.02               <0.02

    Brain               <0.02               <0.02

    Muscle              <0.02               <0.02

    Fat                 <0.02               <0.02
                                                                         

    TABLE 6. Summary of reported residue levels of QDSH and unidentified bound
    metabolites in orange and apple peels from chinomethionat application.
                                                                                           

                  Application rate
    Crop          chinomethionat              Days after        Residues, mg/kg
                  % a.i.            Number    Application       QDSH      unidentified
                                                                                           
    Oranges       0.22              1         7                 0.2       0.09

                  (C14labelled cpd.,          14                0.2       0.09
                  controlled appln.)          28                0.13      0.14
                                              36                0.14      0.18

    Apples        0.145             1         0                 0.6       0.01
                                              7                 0.25      0.64
                                              14                0.11      0.55
                                              21                0.1       0.62
                                              28                0.03      0.5
                                              36                0.01      0.4
                                                                                           

    
    METHODS OF RESIDUE ANALYSIS

    A method suitable for the analysis of QDSH was submitted by the
    manufacturer. It is based on chelation with an ammoniacal nickel
    reagent to give a red colour which can be measured at 540 nm (Havens
    et al., 1964). The method can detect about 0.1 mg/kg chinomethionat or
    QDSH.

    NATIONAL TOLERANCES REPORTED TO MEETING

    Additional national tolerances and safety intervals reported to the
    Meeting are listed in Table 7.

    APPRAISAL

    Chinomethionat is a widely used fungicide/acaricide used mainly in
    fruits with some uses in vegetable production. In apples, if
    recommended application rates (e.g. 0.0125%) and application intervals
    of 7-21 days are observed, residue levels under field conditions
    appear to be less than 0.2 mg/kg. Thus the proposed temporary maximum
    residue limit can be lowered from 0.5 mg/kg to 0.2 mg/kg.

    Chinomethionat residues are generally low 14 days after application
    (about 0.37 mg/kg in orange peel and 0.32 mg/kg in apple peel) and
    penetration into the flesh of fruits covered with peel appears
    negligible (< 0.01 mg/kg). Residues of 2,3-dithio-6-methyl
    quinoxaline (QDSH) and unidentified metabolites arising from
    chinomethionat application are confined to the peel.


        TABLE 7. Additional national tolerances and safety intervals for chinomethionat.

                                                                                                                

    Country             Crop(s)                                           Tolerance        Safety intervals
                                                                          mg/kg            (days)
                                                                                                                
    Argentina           Pome and stone fruit, citrus, grapes,             -                14
                        tobacco, vegetables

    Australia           general                                           -                14
                        Pome and stone fruit                              0.5
                        Cucurbits                                         0.5

    Austria             Vegetables, fruits, cucumbers, tomatoes,          0.1              4
                        paprikas
                        All other registered crops                        -                14

    Belgium             Fruits, vegetables, except potatoes & citrus      0.3              -
                        Cucumbers                                         -                3
                        All other registered crops                        -                21

    Brazil              General                                           -                14
                        Cucurbitaceae                                     -                7

    Bulgaria            General                                           -                20

    Denmark             General                                           -                7
                        Cucumbers                                         -                4

    Finland             Cucumbers                                         -                4
                        General                                           -                14

    German Democratic   Fruit and vegetables                              -                14
    Republic            Leaf vegetables                                   -                28
                        Cucumbers (field grown and under glass)           -                4
                        Food crops, pasture                               -                14

    TABLE 7. (Continued)
                                                                                                                

    Country             Crop(s)                                           Tolerance        Safety intervals
                                                                          mg/kg            (days)
                                                                                                                

    Germany (FRG)       Vegetables, fruits                                0.3              -
                        Cucumbers, pumpkins (field grown)                 -                4
                        Cucumbers, melons (under glass)                   -                4
                        Pipfruit, currants, gooseberry (field grown)      -                14


    Hungary             General                                           0.1              -
                        Vegetables                                        -                7
                        Fruits                                            -                14

    Israel              Apples, apricots, peaches                         -                10
                        Grapes                                            -                14
                        Carrots                                           -                7
                        Tomatoes, paprikas, aubergines, cucumbers, melons -                2

    Italy               General                                           -                21

    Japan               Fruits and vegetables                             0.5              -
                        Citrus                                            -                7
                        Cucumbers, strawberries, aubergines               -                1
                        Watermelon, melon, sweet melon, pumpkin           -                3
                        green pepper

    Mexico              Fruits                                            -                14
                        Vegetables and other crops                        -                7

    New Zeland          Apples, pears, peaches, grapes, citrus            -                21
                        Cucurbits (under glass)                           -                3
                        Cucurbits (field grown)                           -                7

    Netherlands         Apples, pears                                     0.3              21
                        Cucumbers (augurk, konkommer),melons              0.3              3


    TABLE 7. (Continued)
                                                                                                                

    Country             Crop(s)                                           Tolerance        Safety intervals
                                                                          mg/kg            (days)
                                                                                                                

    Norway              As wettable powder: cucumber under glass          -                4
                        All other registered crops                        -                7
                        As fumigant: All registered crops                 -                4

    Poland              Fruit, vegetables                                 -                21
                        Cucumbers                                         -                4
                        Vegetables                                        0.3              -
                                                                       (proposed)

    Portugal            General                                           -                28

    South Africa        General                                           0.5              -
                        Apples, pears, cape gooseberries, citrus,
                        peaches, cucurbits                                -                14

                        Tomatoes                                          -                3
                        cotton (for feeding)                              -                14

    Spain               Melons, cucumbers                                 -                14
                        All other registered crops                        -                15

    Sweden              Cucumbers                                         -                4
                        All other registered crops                        -                7


    Switzerland         Fruit, cucumbers                                  0.1              -
                        Fruit                                             -                21
                        Cucumbers (field grown and under glass)           -                3

    United Kingdom      Cereals                                           -                60
                        Apples, pears                                     -                21
                        Gooseberries, black, white and red currants,
                        strawberries                                      -                14
                        Cucumbers, tomatoes                               -                2
                        Vegetables, marrows grown outdoors                -                7


    TABLE 7. (Continued)
                                                                                                                

    Country             Crop(s)                                           Tolerance        Safety intervals
                                                                          mg/kg            (days)
                                                                                                                

    USA                 Apples, pears                                     0.05             -
                        Citrus fruits, papayas                            0.5              60
                        Macadamia nuts, walnuts                           0.6              0/30
                        Meat, fat, meat byproducts of cattle, goats,
                        hogs, horses, sheep                               0.05             -
                        Milk                                              0.01             -


    Yugoslavia          Fruit                                             0.05             -

                        Cucumbers                                         -                7
                        All other registered crops                                         14
                                                                                                                

    

    About 93% of the compound in fresh citrus peel is destroyed in the
    preparation of dry cattle feed. When dairy cows were fed with a ration
    containing 0.0675 mg/kg body weight chinomethionat in dry citrus pulp,
    no residues in meat and milk could be determined (< 0.001 mg/kg).
    Very low residues (<0.007 mg/kg) were also observed in milk when cows
    were fed almond hulls containing approximately 0.08 mg/kg
    chinomethionat; the almond hulls comprised about 20% of the ration. On
    the other hand, residues were observed in the liver and kidneys at
    0.02-0.03 mg/kg levels.

    The manufacturer submitted a colorimetric procedure for the detection
    of free QDSH at concentrations about 0.1 mg/kg.

    The information available indicated that the lower limit of
    determination of parent chinomethionat using the Vogeler method is
    0.02 mg/kg in cucumbers and pome and berry fruits.

    The Meeting agreed that the information required for the evaluation of
    residues in food by the 1974 Meeting had been provided.

    RECOMMENDATIONS

    The previously recommended temporary maximum residue limit for apples
    is amended as follows.

         Commodity      Limit, mg/kg

          Apples               0.2

    FURTHER WORK OR INFORMATION

    Require, (before July 1981)

    1. Studies on the identity and relative toxicity of metabolites.

    2. An additional carcinogenicity study in another species, in view of
    the hepatic toxicity observed in rodents.

    Desirable

    1. Observations in humans.

    REFERENCES

    Carlson, G.P. and duBois, K.P. (1970) Studies on the toxicity and
    biochemical mechanisms of action of 6-methyl-2,3-quinoxalinedithiol
    cyclic carbonate (Morestan) J. Pharmacol. Exp. Therap. 173:60-70.

    Carrera, G., Mitjavila, S., Lacombe, C. and Derache, R. (1976)
    Toxicokinetics of a pesticide of the thioquinoxaline group:
    oxythioquinox. Toxicology 5:161-171.

    Everett, L.J. and Olson, T.J. (1968) Chemagro Corp., Research Dept.,
    Report no. 23565, 18 October 1968 (unpublished).

    FAO/WHO (1969) 1968 evaluations of some pesticide residues in food.
    FAO/PL:1968/M/9/1: WHO/Food. Add./69.35.

    FAO/WHO (1975) 1974 evaluations of some pesticide residues in food.
    AGP:1974/M/11; WHO Pesticide Residues Series, No. 4.

    Gaines T.B. (1969) Acute toxicity of pesticides. Toxicol. Appl.
    Pharmacol. 14:515-534.

    Havens R., Adams J.M. and Anderson, C.A. (1964) Colorimetric
    determination of 6-methyl-2,3-quinoxalinedithion cyclic carbonate
    (Morestan) residues in apples and pears. J. Agr. Food Chem. 12(3),
    247-248.

    Jones, K.H., Sanderson, D.M. and Noakes, D.N. (1968) Acute toxicity
    data for pesticides (1968). World Rev. Pest Control 7:135.

    Murphy, J.J., Minor, R.G., Strankowski, K.J., Guerrero, F.P., Peoples,
    S.A. and Siegel, D. (1977) Chemagro Corp., Research Dept., Report No.
    53619, 27 June 1977 (unpublished).
    


    See Also:
       Toxicological Abbreviations
       Chinomethionat (WHO Pesticide Residues Series 4)
       Chinomethionat (Pesticide residues in food: 1981 evaluations)
       Chinomethionat (Pesticide residues in food: 1983 evaluations)
       Chinomethionat (Pesticide residues in food: 1984 evaluations)
       Chinomethionat (Pesticide residues in food: 1987 evaluations Part II Toxicology)