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    CHINOMETHIONAT       JMPR 1974

    Explanation

         Chinomethionat was reviewed by The 1968 Meeting (FAO/ WHO,1969)
    under the name of oxythioquinox. An ADI was not allocated because of
    the occurrence of liver hypertrophy at 10 mg/kg, the lowest dose
    studied, in a long-term rat study. Further information was required on
    metabolism and excretion, anti-spermatogenic effects, use patterns and
    resultant residues, the nature of terminal residues, the levels of
    residues in raw agricultural products moving in commerce and residue
    levels in the total diet. Two year studies on rats at lower dosage and
    a comparative evaluation of methods of analysis for regulatory
    purposes were also required. Further studies on cutaneous toxicity,
    including studies on photo sensitization, were regarded as desirable.

         Further information has become available and is summarized and
    discussed in the following monograph addendum.

    IDENTITY

         The common name originally recommended by B.S.I., oxythioquinox,
    was withdrawn because it was not acceptable internationally. The
    B.S.I. common name is now quinomethionate, the English equivalent of
    the German chinomethionat.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Effects on enzymes and other biochemical parameters

         Various enzymes found in intermediary metabolism of carbohydrates
    were studied with regard to the inhibitory properties of
    chinomethionat and its dithiol metabolite. Inhibition of sulfhydryl
    enzymes including pyruvic dehydrogenase, succinic dehydrogenase,
    malate dehydrogenase and alphaketoglutarate oxidase was observed.
    Reduction of nitroreductase and reduced glutathione in the liver was
    also observed. In vivo, its dithiol metabolite inhibited the same
    systems. These observations indicated that inhibition of sulfhydryl
    enzymes might be responsible for the toxicity in mammals (Carlson and
    DuBois, 1970).

    TOXICOLOGICAL STUDIES

    Special studies on carcinogenicity

    Rat

         Groups of rats (25 males and 25 females per group) were fed
    chinomethionat in the diet at a level equivalent to 100 mg/kg. The
    animals were dosed 5 days per week for the first year, and 7 days per

    week for the next 250 days. After 660 test days, it was calculated
    that the animals had consumed a total of 16.7 mg/kg body weight. A
    control group was administered saline solution subcutaneously at
    weekly intervals. There was no effect on behaviour. The average
    survival time was somewhat longer in the treated rats. In the treated
    group, 11 animals died of malignant tumours with 13 deaths recorded
    for controls. There was no apparent difference in the control and
    treated group with regard to tumours in the survivors. There was a
    high percentage of malignant and benign tumours in all groups
    attributable to the long survival time observed in this study. There
    was a suggestion of possible cirrhosis of the liver induced by
    chinomethionat, possibly as a result of the high dose exhibiting a
    certain degree of liver toxicity. Three adenomas of the thyroid were
    observed (Steinhoff, 1970).

    Special studies on mutagenicity

    Mouse

         Groups of male mice (12 mice per group) were administered
    chinomethionat by single intraperitoneal injection at doses of 0, 50
    and 100 mg/kg and mated with 3 virgin females at weekly intervals in a
    standard dominant lethal test (Arnold, 1970). A reference material,
    methyl methanesulfonate, was included in the study as a positive
    control. The mating indices were slightly lower in the high dosed
    group. In this study, chinomethionat was not mutagenic.

    Special studies on spermatogenesis

    Dog

         Groups of dogs (2 males per group) were fed chinomethionat in the
    diet for 90 days at levels of 0, 60, 150 and 500 mg/kg. There were no
    effects at any dose on sperm count, sperm viability or number and
    survival of progeny. At 500 mg/kg histological examination revealed a
    mild reduction of germinal epithelium (Mastalski, 1971).

    Special studies on teratogenicity

    Rat

         Groups of female rats were fed chinomethionat in the diet during
    gestation from insemination to day 20 at dosage levels of 0 (11 rats),
    100 (9 rats), 250 (11 rats) and 750 mg/kg (9 rats). At 750 mg/kg
    embryo toxicity was observed with 8 of 9 litters. Although the dose
    reduced growth of dams, no effect was noted on fetuses. No
    malformations were noted in this experiment (Lorke, 1970).

    Acute Toxicity

    TABLE 1.  Acute toxicity of chinomethionat

                                                                          

                                      LD50
    Species   Sex            Route    (mg/kg)    References
                                                                          

    Rat       M (adult)      ip       95         Carlson and DuBois, 1970

              M (weanling)   ip       320        Carlson and DuBois, 1970

              F (adult)      ip       192        Carlson and DuBois, 1970

              F (weanling)   ip       325        Carlson and DuBois, 1970

              F (oil)        oral     1800       Steinhoff, 1970

              F (saline)     oral     4800       Steinhoff, 1970

              F (oil)        sc       3200       Steinhoff, 1970

              F (saline)     sc       >6000      Steinhoff, 1970

    Mouse     Male           ip       473        Carlson and DuBois, 1970

              Female         ip       458        Carlson and DuBois, 1970
                                                                          


    TABLE 2.  Acute toxicity of metabolite (6 methyl-2,3
              quino-oxalinedithiol

                                                                          

                                      LD50
    Species   Sex            Route    (mg/kg)    References
                                                                          

    Rat       M (adult       ip       38         Carlson and DuBois, 1970

              M (weanling)   ip       115        Carlson and DuBois, 1970

              F (adult)      ip       86         Carlson and DuBois, 1970

              F (weanling)   ip       124        Carlson and DuBois, 1970

    Mouse     M (adult)      ip       249        Carlson and DuBois, 1970

              F (adult)      ip       263        Carlson and DuBois, 1970
                                                                          

         In rats, marked diarrhoea and decreased activity were prominent
    following acute poisoning. In addition, decreased blood pressure and
    urine output were noted, perhaps as a result of water loss from
    diarrhoea.

         A slight protection against acute effects of chinomethionat was
    noted with glutathione and cysteine but not with BAL (Carlson and
    DuBois, 1970). The interaction with these agents provides some support
    for the hypothesis that chinomethionat and its metabolite react with
    sulfhydryl groups of cell constituents.

    Short-term studies

    Rat

         Groups of 5 female rats were administered chinomethionat by
    intraperitoneal injection of various daily dose levels. A daily dose
    of 25 mg/kg was tolerated over the 60 day period suggesting a high
    cumulative toxicity (Carlson and DuBois, 1970).

         Groups of male rats (5 rats/group) were fed chinomethionat in the
    diet at levels of 0, 10, 25, 60, 150, and 500 mg/kg for 90 days. At
    500 mg/kg, a decreased growth rate was observed accompanied by an
    enlarged liver, decreased microsomal enzyme activity and decreased
    acetoacetate synthesis. This latter biochemical alteration was also
    noted at 150 mg/kg. The enlarged liver was normal in histological
    examination. Lipid content, DNA, protein and water content were not
    affected. Analysis of the liver for chinomethionat indicated no
    significant build-up or storage (Carlson and DuBois, 1970).

    Long-term studies

    Rat

         Groups of rats (30 male and 30 female rats/group, the control
    group contained 60 males and 60 females) were fed chinomethionat in
    the diet at concentrations of 0, 3, 6 and 12 mg/kg for two years
    (Loser, 1971). No effects were noted on growth, behaviour, food
    consumption, clinical chemistry values, haematology, serum enzymes,
    parameters related to liver functions, urine analyses, blood sugar and
    cholesterol or on gross and microscopic analysis of tissues and organs
    (Cherry et al., 1972). The incidence and distribution of tumours did
    not indicate a potential carcinogenic action. A no-effect level in
    this study was 12 mg/kg.

    COMMENTS

         Biochemical studies in 90-day feeding experiments with
    chinomethionat in rats indicated relatively specific inhibition of
    sulfhydryl enzymes, probably after its metabolic conversion to
    6-methyl-2,3-quino-oxalinedithiol. At high dosages microsomal enzyme
    activities were reduced and the livers were enlarged but no
    histopathological changes were observed. No effects were noted on

    parameters related to spermatogenesis in 90-day feeding studies in
    dogs at 150 ppm or less, and only at the dietary level of 500 ppm was
    there a small reduction of germinal epithelium. The results of
    dominant lethal test for mutagenesis in mice and tests for teratogenic
    action in rats were negative. The results of a long-term study
    conducted over the life-time of rats indicated a similar incidence of
    tumours in chinomethionat-fed rats and concurrent controls, however, a
    severe hepatic cirrhosis was observed in an unspecified number of
    treated animals. This study was conducted on SPF Wistar rats that have
    a relatively high incidence of tumours which appeared late in the
    life-span (1 000 days) of both treated and controls. The Meeting felt
    that the report of these experiments was deficient, thus making
    difficult a proper evaluation. However, a two-year feeding study in
    rats showed that 12 ppm was a no-effect level as indicated by
    extensive haematological, clinical chemistry and histopathology
    examinations. No evidence of tumourigenesis was observed in this
    study.

         On the basis of the additional information available, the Meeting
    allocated a temporary ADI.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

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

    ESTIMATE OF TEMPORARY ACCEPTABLE DAILY INTAKE FOR MAN

         0 - 0.003 mg/kg bw.

    RESIDUES IN FOOD AND THEIR EVALUATION

    USE PATTERN

         Chinomethionat is generally used as a wettable powder at a
    concentration of 0.03 - 0.1%.

         The uses for additional crops proposed since the previous
    evaluation (FAO/WHO, 1969) are summarized in Table 3. All applications
    are foliar sprays before or during bloom for almonds and post-bloom
    for avocados, macadamia nuts, citrus and papayas in sufficient
    quantity to give full coverage.

    TABLE 3.  Summary of uses of chinomethionat proposed for
              additional crops since 1968

                                                                         

                    Spray                Volume
                    concentration,       of spray,         Number of
    Crop            % a.i.               l/ha              applications
                                                                         

    Almonds         0.06                 935-3740          1

    Avocados        0.03                 8100-8530         1

    Macadamia       0.03-0.06            935-3740          3
    nuts

    Papayas         0.03-0.06            935               1

    Citrus          0.045                935-9350          2

                                                                         

         Data were provided on registered uses from Hungary, the
    Netherlands and New Zealand. They are summarized in Table 4.

    RESIDUES RESULTING FROM SUPERVISED TRIALS

         Supervised trials were carried out on almonds (California, USA),
    apples (Federal Republic of Germany, the Netherlands), avocados
    (Florida, USA), barley (F.R.G.), cucumbers (the Netherlands, New
    Zealand), currants, gooseberries (F.R.G.), grapes (New Zealand,
    Missouri USA), grapefruit, oranges (Florida USA), limes (California,
    USA), macadamia nuts, papayas (Hawaii, USA), rye (F.R.G.), tangerines
    (Arizona, USA), tea (India), wheat (F.R.G.). The results of these
    trials are summarized in Table 5. The data are from reports by Buyer
    (1968-1972), Bevenue (1968a), Chemagro (1964-1968; 1969a, b; 1970) and
    Post (1969).

         The residues were generally low in flesh, kernels and pulps
    (<0.1 mg/kg) and concentrated mainly in the hulls, peels and skins of
    the various commodities. In apples, residues up to 0.5 mg/kg were
    found in occasional individual samples 11 days after treatment. The
    highest residue found in citrus fruit after 7-10 weeks was 0.9 mg/kg,
    but this would presumably be largely in the peel (see "Fate of
    residues in processing"). Residues in whole Papayas up to 3 mg/kg were
    found after 7 days, but again most of the residue was in the peel.
    Residues in the pulp one day after treatment were below 0.1 mg/kg.



        TABLE 4a. Residues of chinomethionat resulting from supervised trials (at intervals up to 7 days)
                                                                                                                                

                             Application
                                Rate                   Number        Residues, mg/kg range, of chinomethionat at interval,
                       a.i., %                           of          days, after last treatment*
    Crop               or g/ha    l/ha        No.      Samples       0-1             2-4             5-6            7
                                                                                                                                

    Apples1            0.01%      1300        13       2-4           0.004-0.02      0.07-0.08       0.04-0.06      0.02-0.05
                                                                     (0.01)          (0.08)          (0.05)         (0.04)

    Apples2            0.075%     200         1        -             0.07-0.3        0.09-0.2        0.05-0.2       -

    Apples2            0.075%     200         4        -             0.1-0.3         0.02-0.13       -              0.05-0.13

    Apples2            0.075%     200         4        -             0.05-0.08       0.02-0.04       0.07-0.23      -

    Apples2            0.013%     1200        3        -             n.d.-0.06       n.d.-0.05       -              n.d.-0.05

    Apples2            0.125%     200         1        -             0.3-0.9         0.06-0.3        0.04-0.06      -

    Citrus3            0.045%     -           -        20            -               -               -              0.1-2
    fruits

    Cucumbers2         0.0075%    -           Each     -             0.01-0.03       -               -              -
                                              Week

    Cucumbers2         0.0075%    -           Each 2   -             0.02-0.03       -               -              -
                                              Weeks

    Cucumbers2         0.0075%    -           5        -             n.d.            -               -              -

    Cucumbers4         8g/1000
    skin               plants     -           -        -             (0.12)          (0.08)-(0.12)   -              (0.10)
    pulp                          -           -        -             (0.05)          (0.05)          -              (0.05)

    Currants (black,   0.0075%    1000        3        -             0.1-0.25        -               -              0.02 (0.02)
    red or white)                                                    (0.13)

    Gherkins           0.0075%    -           3        -             0.02            -               0.02           -

    TABLE 4a. (Cont'd.)
                                                                                                                                
                            Application
                               Rate                    Number        Residues, mg/kg range, of chinomethionat at interval,
                       a.i., %                           of          days, after last treatment*
    Crop               or g/ha    l/ha        No.      Samples       0-1             2-4             5-6            7
                                                                                                                                

    Gooseberries       0.0075%    1000        3        2             (0.05)          -               -              (0.02)

    Grapes4            0.012%     900         2        1             0.4             -               -              0.07

    Macadamia          0.22%      935-3740    3
      nuts5
      kernels                                          20            0.02 (0.02)     -               -              -
      shell                                            20            0.02 (0.02)     -               -              -
      husk                                             20            7-12 (9.5)      -               -              -

    Papayas6           0.06%      935         3
      peel                                             21            6-23 (15)       -               -              4-14 (8)
      pulp                                             21            0.05-0.08       -               -              -
      whole fruit                                      21            0.8-3.2         0.8-3.1         0.7-2.8        0.5-2.3
                                                                        (2.1)           (1.6)           (1.3)          (1.2)

    Papayas6           0.09%      935         3
      peel                                             21            5-29 (17)       -               -              2.5-22 (9.2)
      pulp                                             21            0.05-0.08       -               -              -
      whole fruit                                      21            0-7-4.3         0.9-3.0         0.6-2.9        0-4-3.1
                                                                        (2.6)           (2.0)           (1.7)          (1.5)

    Tea7               185-370    224-675     1-2      12            20-90           -               0.1-0.4        0.1-0.4
                       g/ha
                                                                                                                                

    *  Mean value in brackets
    1 Bayer, 1969
    2 Netherlands, 1974
    3 Chemagro, 1964-1968
    4 New Zealand, 1974
    5 Chemagro, 1970
    6 Bevenue, 1968a
    7 Bayer, 1970

    TABLE 4b. Residues of chinomethionat resulting from supervised trials (at intervals up to 75 days)

                                                                                                                                          

                            Application
                               Rate                    Number     Residues, mg/kg range, of chinomethionat at interval,
                       a.i., %                           of       days, after last treatment*
    Crop               or g/ha      l/ha        No.    Samples    9-11          14              20-21           29-35            49-75
                                                                                                                                          

    Almonds1           0.06%      3700-4600     2
      kernels                                          8          -             -               -               0.02-0.07        -
                                                                                                                    (0.04)
      hulls                                            8          -             -               -               3.5-14           -
                                                                                                                   (7.7)

    Almonds1           0.12%      3700-4600     1
      kernels                                          8          -             -               0.02-0.07       -                -
                                                                                                    (0.04)
      hulls                                            8          -             -               9-19 (13)       -                -

    Apples2            0.01%      1300          13     2-4        0.008-0.02    0.003-0.007     -               -                -
                                                                       (0.01)        (0.004)

    Apples3            0.075%     200           1      -          0.04-0.06     -               0.02-0.07       -                -

    Apples3            0.075%     200           4      -          0.01-0.1      -               0.01-0.06       0.02-0.03        -

    Apples3            0.075%     200           4      -          n.d.-0.13     -               -               -                -

    Apples3            0.013%     1200          3      -          0.01-0.07     -               n.d.-0.02       -                -

    Apples3            0.125%     200           1      -          0.2-0.5       -               0.03-0.1        0.01-0.03        -

    Avocados4          0.045%     8100          3      3          -             -               -               0.03-0.09        0.01
      whole fruit                                                                                                   (0.06)       (0.01)

    Avocados4          0.09%      8530          3      3          -             -               -               0.06             0.05
      whole fruit                                                                                               (0.06)           (0.05)

    Barley             100-125    -             -      6          -             -               -               -                (0.1)
                       g/ha

    TABLE 4b. (Cont'd.)

                                                                                                                                          

                       Application
                          Rate                         Number     Residues, mg/kg range, of chinomethionat at interval,
                       a.i., %                           of       days, after last treatment*
    Crop               or g/ha      l/ha        No.    Samples    9-11          14              20-21           29-35            49-75
                                                                                                                                          

    Citrus             0.045%     -             -      20         -             0.1-2           0.1-2           0.1-0.7          0.1-0.9
      fruit6

    Currants (black,   0.0075%    1000          3      -          -             n.d.-0.03       (0.02)          -                -
    red or white)                                                                   (0.02)

    Gooseberries       0.0075%    1000          3      2          -                 (0.02)      (0.02)          -                -

    Grapes7            0.012%     900           2      1          -             0.02            0.004           -                -

    Rye8               100 g/ha   -             1      1          -             -               -               -                n.d.10

    Tea9               185-370    224-675       1-2    12         0.1-0.2       0.1             -               -                -
                       g/ha

    Wheat8             100 g/ha   -             1      1          -             -               -               -                0.1
                                                                                                                                          

    *  Mean value in brackets
    1  Chemagro, 1969a
    2  Bayer, 1969
    3  Netherlands, 1974
    4  Chemagro, 1969b
    5  Bayer, 1968
    6  Chemagro, 1964-1968
    7  New Zealand, 1974
    8  Bayer, 1969
    9  Bayer, 1970
    10 101 days after treatment
    
    
    TABLE 5.  Effect of processing on chinomethionat resiclues in fruits
                                                                                             

                Application                                 Days after      Chinomethionat,
    Fruit       rate, % a.i.   Process                      application     mg/kg
                                                                                             

    Grapes      0.045          Fresh fruit (89% water)          0                7.1

                               Sun-dried 27 days (17%
                               water)                           27               40

    Grapes      0.045          Fresh fruit                      0                2.0

                               Dried 150F, 22 hours
                               (32% water). surface             1                1.3

                               Dried 150F, 22 hours
                               (32% water). Internal            1                0.52

    Grapes      0.045          Fresh fruit                      0                0.55

                               80C water dip, 5-20 sec.
                               Surface                          1                0.31

                               80C water dip, 5-20 sec.
                               Internal                         1                0.16

    Papayas1    0.06           Fresh whole fruit                0                3.6
                                                                1                7.7
                                                                3                4.0
                                                                5                3.5
                                                                7                3.7

                               Whole fruit puree                0                1.5
                                                                1                1.5
                                                                3                1.5
                                                                5                1.5
                                                                7                1.9

    TABLE 5.  (cont'd)
                                                                                             

                Application                                 Days after      Chinomethionat,
    Fruit       rate, % a.i.   Process                      application     mg/kg
                                                                                             

                               Peeled fruit puree               0                0.2
                                                                1                0.24
                                                                3                0.25

    Plums       0.03           Fresh fruit                      40               0.14

                               Sun-dried 10 days, then
                               frozen (i.e. dried plums
                               or "prunes")                     50               0.23
                                                                                             

    1 All residue values for papayas are means from two experiments.
    
    FATE OF RESIDUES

    In animals

         To determine the total residue to be expected in animal tissues
    and milk, dairy cattle were fed a diet containing 0.21 ppm
    chinomethionat-2,3-14C for 25 days. Total carbon-14 residues were
    <0.0006 mg/kg in milk and <0.01 mg/kg in meat, fat, liver, kidney,
    heart and brain (Flint and Gronberg, 1970).

         It was reported in the previous evaluation FAO/WHO, 1969 that
    unidentified insoluble residues were found in apples and oranges.
    Excretion studies have now been conducted to determine the biological
    availability of the insoluble and soluble residues to animals. Apples
    and oranges were treated on the tree with 14C-chinomethionat. The
    fruit was picked and unchanged chinomethionat was extracted from the
    surface. Peel from the fruit was fed to rabbits and dogs, either
    directly or after extraction of the soluble residues. Measurement of
    the radioactivity in the faeces showed that about 90% or more of the
    insoluble residue had not been absorbed,(Everett and Shaw, 1968; Flint
    and Gronberg, 1970). The biological availability of the soluble
    activity was higher: soluble residues obtained from apple and orange
    samples harvested 36 days after treatment contained available
    radioactivity to the extent of about 40% and 25% respectively.

         Goats were maintained for 30 days on a diet containing 50% of
    dried orange pulp (Gronberg et al., 1973). The pulp was prepared
    (Flint and Gronberg, 1973) by commercial procedures from oranges
    treated on the tree with 14C-chinomethionat: it contained 3.8 mg/kg
    total 14C residues of which 7% was unchanged chinomethionat. Total
    14C residues in the tissues of the goats were 0.05 mg/kg in liver,
    0.04 mg/kg in kidney, 0.004 mg/kg in milk, and less than 0.02 mg/kg in
    meat, fat, skin, blood and brain.


    In plants

         The fate of chinomethionat-2,3-14C was investigated in
    cucumbers, cucumber leaves and strawberries by Khasawinah (1970) and
    in oranges by Flint and Gronberg (1973). A negligible amount of
    radioactivity penetrated the fruit pulp of the cucumbers and oranges.
    Most of the radioactivity in the treated leaves and peel was not
    organo-extractable. The metabolic pattern was similar to that in
    oranges and apples previously reported (FAO/WHO, 1969). The metabolite
    2,3-dithiol-6-methyl-quinoxaline was identified. It was bound to
    solids in cucumbers and was combined as three different water-soluble
    conjugates with molecular weights of about 350 in cucumbers, cucumber
    leaves and strawberries. The conjugates were not identified but were
    probably sugars. Organo-soluble radioactivity accounted for only 9-10%
    of the total recovered residue. The organo-soluble part of the
    residues decreased while the insoluble part increased with time.

    In soils

         Laboratory studies using soil columns showed that chinomethionat
    was strongly adsorbed by soils, particularly those with a high organic
    matter content, and virtually none was leached with ten column void
    volumes of water.

         Residues in run-off water after application to soil plots or to
    apple trees were not more than 1% of the applied material when
    rainfall and irrigation amounted to a total of 2-6 inches during a
    period of 2-4 weeks after the first treatment (Flint and Shaw, 1970).

         Sandy and silt loam soils were treated with chinomethionat-14C
    under laboratory conditions. The half-life of chinomethionat was 1-3
    days. Loss of residue by volatilization was negligible (1.6% in silt
    loam soil) during a 3-week period (Robinson and Flint, 1970).
    Degradation was faster in non-sterile than in sterile soil, showing
    the importance of microbial activity.

         About half of the radioactivity was acetone-extractable after one
    week and the organo-soluble metabolites appeared to be a mixture of
    6-methyl-2,3-dithiolquinoxaline monomeric units, probably bound
    together through disulphide linkages. The remaining radioactivity was
    bound to the soil and could only be completely extracted by blending
    with 0.1 N sodium hydroxide. Reduction of this alkali-extractable
    residue followed by reaction with phosgene produced chinomethionat in
    35-75% yield, indicating that at least part of the residue contained
    the intact quinoxaline nucleus (Khasawinah, 1971).

         Chinomethionat at a concentration of 24.3 kg/ha was incubated in
    sandy and silt loam soils for 1 and 21 days prior to adding
    glucose-14C. Microbial activity as measured by CO2 evolution was
    unaffected in sandy or silt loam containing 1.4-1.8% organic matter,
    but in a silt loam containing 4.6% organic matter, the rate of CO2
    evolution was decreased to 42% and 65% of that in untreated soil for
    1- and 21-day incubation periods respectively (Robinson and Flint
    1970).

    In water and under UV radiation

         Breakdown in buffer solutions increased at higher pH values. At
    30C, the half-life decreased from 4 days at pH 5 to 1 day at pH7,
    while the increase of the temperature to 50C decreased the stability
    at pH 5 by four- and at pH 7 by six-fold. In pond water outdoors at pH
    7 and 32C, the half-life was less than 4 hours (Flint and Shaw,
    1970). Sunlight probably had an important effect since degradation of
    chinomethionat in the presence of UV irradiation has been reported
    (Gray et al., 1972). After 7.5 hours of radiation of oxythioquinox by
    UV light at wavelengths above 280 nm at 25C in benzene,
    dimethylthieno [2,3-b : 4,5-b] diquinoxaline, dimethyl-p-dithiino
    [2,3-b : 5,6-b] diquinoxaline, elemental sulphur and some minor
    unidentified products were found in the reaction mixture.

    In processing

         Residues in dried fruit were determined after drying fresh grapes
    and plums (Post, 1969; Olsen, 1970. See Table 6). When grapes were
    washed in hot water for 5-10 seconds the residues decreased by 15%.
    Residues in fresh grapes decreased by 10% after drying at 150F for 22
    hours: when allowance was made for the decreased water content, there
    was a net loss of residue of 77% (Olson, 1970). Raisins prepared by
    sun drying for 27 days contained residues at a level of about six
    times that in the fresh grapes. There was a net loss of 25% of the
    residue during the drying process however.

         Sun drying for 10 days produced a residue level in dried plums
    1.6 times that in the fresh fruit (Post, 1969).

         Fresh papayas were processed to whole fruit puree which contained
    about 40% of the residue found in unprocessed whole papayas (Bevenue,
    1968). Peeled fruit puree contained less than 10% of the level in
    whole unprocessed fruit.

         Oranges treated on the tree with chinomethionat 2,3-14C (0.043%
    a.i.) were harvested after 60 days and processed using procedures
    similar to commercial operations. Residues of the parent compound were
    found on the fruit surface and, to a slight extent, in the peel. The
    total radioactivity in the peel was equivalent to about 6 mg/kg of
    chinomethionat, and practically no residue was detected in the juice
    from the peeled oranges. 67% of the total radioactive residue in the
    peel was carried over into citrus pulp cattle feed. Only about 7% of
    this was chinomethionat (Flint and Gronberg, 1973; see also previous
    section).

    RESIDUES IN FOOD MOVING IN COMMERCE

         Chinomethionat was found in 10 apple samples during food
    inspection in the Netherlands in 1973. Six of these contained less
    than 0.1 mg/kg, two contained 0.1-0.2, and two 0.2-0.3 mg/kg.

         In New Zealand 6 apple samples known to have been treated with
    chinomethionat were analysed in 1971 and 4 in 1972. Of these, two in
    1971 contained 0.02 mg/kg and one in 1972 contained 0.01 mg/kg.
    Chinomethionat was not detectable in the other samples.

    METHODS OF RESIDUE ANALYSIS

         An additional gas-chromatographic method for plants has been
    reported (Tjan and Konter, 1971), which required minimal clean-up of
    the acetonitrile or benzene extracts. The recovery from apples, pears,
    cucumbers and gherkins was 92-99%, the limit of determination being
    0.1 mg/kg for these products.

         A gas-chromatographic method has recently been developed for
    chinomethionat in animal tissues and milk (Thornton, 1974). Samples
    are extracted with acetone and chloroform and the extract is
    evaporated to remove solvent. The solid residue is partitioned with
    acetonitrile/hexane to remove the oil and purified by Florisil column
    chromatography prior to gas chromatography. A second
    gas-chromatographic column is used for confirmation of identity.
    Detection is by electron capture with sensitivities of 0.1 and 0.01
    mg/kg for tissues and milk respectively, and recoveries are generally
    greater than 75%.

         Residues of chinomethionat in oranges were determined by five
    different analytical methods: GLC with both electron capture and
    microcoulometric detection, colorimetry, polarography and
    fluorescence. All five methods gave similar results. Since they
    determine overlapping parts of the chinomethionat molecule each was
    evidently measuring unchanged chinomethionat (Gaston et al., 1974).

         The gas-chromatographic methods of Vogeler and Niessen (1967; see
    1968 evaluation, FAO/WHO, 1969) and Thornton (1974) are suitable for
    regulatory purposes.

    NATIONAL TOLERANCES REPORTED TO THE MEETING

         Tolerances have been established in several countries. Those
    reported to the Meeting are listed in Table 6.

    TABLE 6.  National tolerances reported to the Meeting
                                                                              
                                                   Pre-harvest
                                                   interval        Tolerance
    Country             Crop                       days            mg/kg
                                                                              
    Australia           fruit and
                        vegetables                                 0.5

    Canada              cucumbers, water
                        melons, winter
                        squash                                     0.75

    TABLE 6.  (Cont'd.)

                                                                              

                                                   Pre-harvest
                                                   interval        Tolerance
    Country             Crop                       days            mg/kg
                                                                              

                        plums                                      1

                        cherries                                   3

                        apricots                                   4

                        strawberries                               6

    Denmark             cucumbers                  4

    Finland             cucumbers                  4

    Federal             cucumbers, melons
    Republic of         (field grown and
    Germany             under glass), squash       4

                        fruit, vegetables          14              0.3

    Hungary             fruit                      14              0.1

                        vegetables                 7               0.1

    Italy                                          21

    Israel              tomatoes, green
                        peppers, aubergines,
                        cucurbitaceae              2

                        leafy vegetables           7

                        fruits                     10

                        grapes                     14

                        strawberries               14

    Japan               cucumbers, strawberries,
                        aubergines                 1

                        citrus                     7

    TABLE 6.  (Cont'd.)

                                                                              

                                                   Pre-harvest
                                                   interval        Tolerance
    Country             Crop                       days            mg/kg
                                                                              

                        watermelons, melons,
                        sweet melons, pumpkins,
                        green peppers              3

    Netherlands         fruit                      14              0.3

                        vegetables                 3               0.3

    New Zealand         fruit                      21

                        cucumbers, cucurbits       7

    Norway              general                    7

                        cucumber (under glass)     4

    Poland              fruit                      21

                        vegetables                 21              0.3a

                        cucumbers                  4

    South Africa        apples                     14              0.5
                        pears, cucurbitaceae,
                        peaches, citrus fruit,

                        tomatoes                   3               0.5

                        cotton                     14              0.5

    Spain               general                    15

                        cucumbers                  10

                        melons                     10

    Sweden              general                    7

                        cucumbers                  4

    Switzerland         cucumbers                  3               0.1

                        fruit                      21              0.1

    TABLE 6.  (Cont'd.)

                                                                              

                                                   Pre-harvest
                                                   interval        Tolerance
    Country             Crop                       days            mg/kg
                                                                              

    Thailand            general                    7

    United Kingdom      apples                     21

                        black currants             14

                        cucumber (under glass)     2

                        gooseberries               14

                        strawberries               14

                        vegetable marrow           7

    Yugoslavia          general                                    0.4

                        cucumber                   7b

                        other crops                14b

                                                                              

    a Proposed tolerances

    b Proposed pre-harvest interval

    APPRAISAL

         Data available on residues in almonds, avocados, currants,
    cucumbers, gherkins, gooseberries, grapes and macadamia nuts from
    supervised trials at recommended rates indicate that the residues are
    unlikely to exceed 0.1 mg/kg after pre-harvest intervals consistent
    with good agricultural practice. The results of supervised trials on
    citrus showed that residues up to 0.5 mg/kg could still occur after 60
    days. However, other experiments showed that the residues accumulated
    virtually only in the peel, and when such peels were processed into
    cattle feed the unchanged chinomethionat was only 7% of the total
    residue remaining in the feed. The secondary residues in meat and milk
    were negligible. Residues on papayas were rather high, especially in
    the peel, and residues up to 3 mg/kg were found in the whole fruit a
    week after treatment.

         Drying of fresh grapes and plums resulted in a residue level in
    the dried fruit of about 2-6 times that in the fresh fruit. When
    allowance was made for the decreased water content, however, there was
    a net loss of residue. The residues were mainly on the surface of the
    dried fruits. Processing fresh papayas to whole fruit puree and peeled
    fruit puree removed about 60% and over 90% of the residue
    respectively.

         Laboratory studies using chinomethionat-2,3-14C indicated that
    the organo-soluble metabolites in soil are probably disulphides of
    6-methyl-2,3-dithiol quinoxaline monomeric units (about 50% of total
    residues) and that the insoluble residues contained the intact
    6-methylquinoxaline moiety.

         It was reported that chinomethionat was adsorbed strongly by soil
    and had little tendency to leach. Movement in soil was low under field
    conditions. Less than 1% of the applied active ingredient was found in
    run-off water after 2-6 inches of rainfall and/or irrigation.

         Experiments on cucumbers and strawberries indicated that their
    metabolism of chinomethionat is similar to that previously reported
    for oranges and apples. The first step in chinomethionat metabolism is
    its rapid hydrolysis to the less stable
    2,3-dithiol-6-methylquinoxaline followed by further oxidation and
    conjugation. Organo-soluble radioactivity accounted for only 9-20% of
    the total recovered residue. The organo-soluble part of the residues
    decreased while the insoluble part increased with time. Three
    water-soluble conjugates were found in cucumbers and in their leaves.
    These were probably sugar derivatives. No other metabolite has been
    identified since the previous evaluation.

         Feeding studies with lactating cows using radio-labelled
    chinomethionat-2,3-14C showed that the total residues, expressed as
    chinomethionat, were 0.0006 mg/kg in milk and 0.01 mg/kg in meat, fat,
    liver, kidney, heart and brain. Results of experiments on rabbits,
    dogs and goats confirmed that the biological availability of insoluble
    and soluble residues in apples and oranges was low.

         GLC and colorimetric analytical methods for residues are
    available, which measure only the unchanged chinomethionat. The limit
    of determination varies from 0.01-0.1 mg/kg depending on the method
    and the kind of food sampled. The GLC methods are suitable for
    regulatory purposes.

    RECOMMENDATIONS

         On the basis of the results of supervised trials, the following
    temporary tolerances can be recommended.

    TEMPORARY TOLERANCES

                                                                        

                                                    Pre-harvest
                                     Temporary      intervals on which
                                     Tolerance      recommendations
                                     mg/kg          are based (days)
                                                                        

    Papayas (whole fruit)               5.0                0

            (pulp)                      0.1

    Cucumbers, gherkins,
    gooseberries                        0.1                0

    Macademia nut (kernels)             0.02*              0

    Currants (black, red,
    white)                              0.1                7

    Apples                              0.5               14

    Grapes                              0.1               14

    Almond kernels, avocado             0.1               28

    Citrus fruits                       0.5               60

    Raw Cereals                         0.1               60

    Milk                                0.01*

    Meat                                0.05*
                                                                        

    *Limits of determination


    FURTHER WORK OR INFORMATION

    REQUIRED (by 1977)

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

    2.   A method of analysis which determines the 
         2,3-dithio-6-methylquino-oxaline metabolite.

    DESIRABLE

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

    2.   Studies of metabolism in non-rodent species.

    3.   Observations in man.

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

    REFERENCES

    Anonymous (1974). Information on chinomethionat from The Netherlands.
    (Unpublished)

    Anonymous (1974). Information from New Zealand on chinomethionat.
    (Unpublished)

    Arnold, D. (1970). Mutagenic study with Morestan technical in albino
    mice. Report of Industrial BIO-TEST Laboratories, Inc. submitted to
    WHO by Chemagro Corporation. (Unpublished)

    Bayer (1968, 1972). Morestan residues on apple, barley, currant,
    gooseberry rye, tea and wheat. Analysis reports.

    Bevenue (1968a). Morestan on/in papayas, Chemagro Division of Baychem
    Corporation, Analysis reports, Nos. 23615-23620, 23443, 23459.

    Bevenue (1968b). Morestan residues on papayas - process study.
    Chemagro Division of Baychem Corporation. Analysis reports, Nos.
    23493, 23521.

    Carlson, G.P. and DuBois, K.P. (1970). Studies on the toxicity and
    biochemical mechanism of action of 6-methyl-2,3-quino-oxalinedithiol
    cyclic carbonate (Morestan) J. Pharmacol. Exp. Ther., 173:60-70.

    Chemagro (1964, 1968). Morestan on/in Oranges, grapefruit, .limes and
    tangerines. Chemagro Division of Baychem Corporation. Analysis
    reports. Nos. 14371-73, 14446, 14577, 16196, 16224, 16295-97,
    19096-99, 23026, 23030, 23036, 23053.

    Chemagro (1969a). Morestan on/in almonds. Chemagro Division of Baychem
    Corporation. Analysis reports. Nos. 24892-4, 24913-4.

    Chemagro (1969b). Morestan on/in avocados. Chemagro Division of
    Baychem Corporation. Analysis reports. Nos. 25462, 25463, 25472.

    Chemagro (1970). Morestan on/in macadamia nuts. Chemagro Division of
    Baychem Corporation, Analysis reports. Nos. 28337, 28338, 28359-61.

    Cherry, C.P., Urwin, C. and Newman, A.J. (1972). Pathology report of
    BAY 36 205 rat chronic feeding study. Report from Huntingdon Research
    Centre submitted to WHO by Farben fabriken Bayer AG. (Unpublished)

    Everett, L.J. and Shaw, H.R. (1968). A study to determine the
    importance of Morestan-2,3-14C metabolites in apples and oranges.
    Chemagro Division of Baychem Corporation Research and Development.
    Report No. 23924.

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

    Flint, D.R. and Gronberg, R.R. (1970a). Biological availability in
    dogs of 2,3-14C-Morestan residues in apple-peel solids. Chemagro
    Division of Baychem Corporation Research and Development. Report No.
    28366.

    Flint, D.R. and Gronberg, R.R. (1970b). The absence of residues in
    milk and tissues from dairy cattle fed 2,3-14C Morestan. Chemagro
    Division of Baychem Corporation Research and Development. Report No.
    28363.

    Flint, D.R. and Gronberg, R.R. (1973). Residues of Morestan in orange
    fruit and processed orange products sixty days after treatment with
    Morestan-2,3-14C. Chemagro Division of Baychem Corporation Research
    and Development. Report No. 35546.

    Flint, D.R. and Shaw, H.R. (1970). Soil runoff, leaching, adsorption
    and water stability studies with Morestan. Chemagro Division of
    Baychem Corporation Research and Development. Report No. 28365.

    Gaston, L.K., Barkley, J.H., Ott, D.E., Murphy, R.T., Jeppenson, L.R.,
    and Gunther, F.A. (1974). Persistence of Morestan residues on and in
    citrus fruit. A comparison of five different analytical methods. Dept.
    of Entomology, Riverside, Calif. (Pre-publication copy available to
    Meeting).

    Gray, W.F., Pomerantz, I.H. and Ross, R.D. (1972). Ultraviolet
    irradiation of 6-methyl-2,3-quinoxalinedithiol cyclic carbonate
    (Morestan). J. Heterocyl. Chem., 9:707-711.

    Gronberg, R.R., Flint, D.R. and Simmons, C.E. (1973). Residues in
    tissues and milk from goats fed processed citrus pulp containing
    Morestan-2,3-14C residues. Chemagro Division of Baychem Corporation
    Research and Development. Report No. 37062.

    Khasawinah, A.M. (1970). Metabolism of Morestan on cucumber leaves and
    fruit and on strawberry leaves. Chemagro Division of Baychem
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    Khasawinah, A.M. (1971). Metabolism of Morestan in soil. Chemagro
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    Lorke, D. (1970). Studies on rats for embryotoxic and teratogenic
    effects. Report BAY 36 205 submitted to WHO by Farbenfabriken Bayer
    AG. (Unpublished)

    Lser, E. (1971). Chronic toxicological studies on rats (Two year
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    Mastalski, K. (1971). Spermatogenesis study with Morestan in beagle
    dogs. Report from Industrial BIO-TEST Laboratories, Inc. submitted to
    WHO by Chemagro Corporation. (Unpublished)

    Olson, T.J. (1970). Morestan residues on grapes - process study.
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    Post. (1969). Morestan residues on prunes - process study. Chemagro
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    Robinson, R.A. and Flint, D.R. (1970). Fate of 14C-labeled Morestan
    in soil. Chemagro Division of Baychem Corporation Research and
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    Steinhoff, D. (1970). Final report on carcinogenic study with Morestan
    active ingredient (BAY 36 205). Report submitted to WHO by
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    Thornton, J.S. (1974a). A gas chromatographic method for determining
    residues of Morestan in animal tissues and milk. Chemagro Division of
    Baychem Corporation Research and Development. Report No. 39354.

    Thornton, J.S. (1974b). Data for the gas chromatographic confirmatory
    method for Morestan in animal tissues and milk. Chemagro Division of
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    Tjan, G.H. and Konter, T. (1971). Gas-liquid chromatography of
    Morestan residues in plants. J. Ass. off. analyt. Chem.,
    54(5):1122-1123.

    Vogeler, K. and Niessen, H. (1967). Gas chromatographic determination
    of Morestan residues in plants. Pflanzenschutz-Nachr., Bayer,
    20:550-556.
    


    See Also:
       Toxicological Abbreviations
       Chinomethionat (Pesticide residues in food: 1977 evaluations)
       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)