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    FAO/PL:1967/M/11/1
    WHO/Food Add./68.30

    1967 EVALUATIONS OF SOME PESTICIDE RESIDUES IN FOOD

    THE MONOGRAPHS

    The content of this document is the result of the deliberations of the
    Joint Meeting of the FAO Working Party of Experts and the WHO Expert
    Committee on Pesticide Residues, which met in Rome, 4 - 11 December,
    1967. (FAO/WHO, 1968)

    FOOD AND AGRICULTURE ORGANIZATION OF THE UNITED NATIONS
    WORLD HEALTH ORGANIZATION
    Rome, 1968

    DEMETON

    This pesticide was evaluated toxicologically by the 1965 Joint meeting
    of the FAO Committee on Pesticides in Agriculture and the WHO Expert
    Committee on Pesticide Residues (FAO/WHO, 1965). Since no additional
    information on the toxicology of this compound has become available,
    the following monograph addendum in confined to the evaluation for
    tolerances and a review of methods of analysis.

    EVALUATION FOR TOLERANCES

    USE PATTERN

    Pre-harvest treatments

    Demeton is a widely used insecticide on over 30 different fruit,
    vegetable, nut and forage crops applied primarily as a foliar spray to
    combat against aphids, thrips, mites, leafhoppers and leafminers. See
    Table I for typical dosages being recommended and pre-harvest
    intervals for the various crop classes.

        TABLE I
                                                                                

                                  Recommended dosage
    Crop                              lb/100 gal           Pre-harvest
                                       or lbs/A              period
                                                                                

    apples, pears                0.25 "full coverage"          21

    peaches, apricots, plums     0.25 "full coverage"          30

    citrus                       0.25 "full coverage"          21

    grapes, strawberries,           0.4         lbs/A          21
    melons

    nuts                            0.25        "              21

    leafy vegetables                0.25-0.5    "       21 (28 for celery)

    legumes and root veg.           0.25-0.5    "              21

    tomatoes and peppers            0.25-0.4    "               3

    grains                          0.25        "              45

    alfalfa and clover              0.25        "       21 day pre-grazing
                                                        and cutting interval
                                                                                
    
    Post-harvest treatments

    No use is known for application on stored products. Demeton is
    recommended for use on some fruit trees after the harvesting of the
    fruits.

    Other uses

    Demeton is used on several ornamental flowers, shrubs, and trees for
    garden pests such as various scales, mites, aphids, etc.

    RESIDUES RESULTING FROM SUPERVISED TRIALS

    A large number of supervised field trials have been conducted. These
    data (mostly unpublished) are incorporated in pesticide petitions
    submitted to the U.S. Food and Drug Administration, 1955-1962. The
    trials were made in various geographical locations throughout the
    U.S.A. and represent differing weather conditions, amounts of
    application, stage of crop growth, pre-harvest intervals, etc.

    A summary of the results of those trials reflecting the recommended
    usage given in Table I is shown in Table II.

    The actual active residue resulting from treatment with demeton is a
    variety of isomers and oxidative alteration products, therefore values
    for the residues shown in this table represent a measure of the total
    anticholinesterase compounds expressed as equivalents of a mixture of
    65 parts of the thiono and 35 parts of the thiol isomers of demeton.

        TABLE II
                                                                                           

                            Typical initial   Pre-harvest    Residue at end    Estimated
    Crop                    residues, ppm     period, days   of pre-harvest    half-life
                                                             period, ppm       days
                                                                                           

    Tree fruits

    Apples                  0.6-1.5               21            0.2-0.5           12

    Pears                   -                     21             < 0.75           15

    Peaches                 0.3-5.0               30            0.2-0.7            7

    Apricots                1.0-2.0               30            0.3-0.6           20

    Plums                   0.7-3.0               30              < 0.2            8

    Oranges                 -                     21              < 0.1            -

    TABLE II (cont'd)
                                                                                           

                            Typical initial   Pre-harvest    Residue at end    Estimated
    Crop                    residues, ppm     period, days   of pre-harvest    half-life
                                                             period, ppm       days
                                                                                           

    Lemons                  -                     21            0.3-0.5            -

    Grapefruit              -                     21              0-0.5            -

    Other Fruits

    Grapes                  -                     21            0.2-1.0            -

    Strawberries            -                     21              < 0.1            -

    Melons                  0.2-0.5               21              < 0.1            -

    Nuts

    Walnut, almond          -                     21              0-0.3            -
    and pecan (meats)

    Pecan Hulls             -                     21              0-0.4            -

    Almond Hulls            -                     21            1.9-3.4            -

    Vegetables

    Broccoli                1.5-2.5               21              0-0.7           14

    Brussels Sprouts        -                     21              0-0.5            -

    Cabbage                 9-35                  21              0-0.7            4

    Cauliflower             -                     21              0-0.5            -

    Celery                  9-21                  28            0.2-0.4            6

    Lettuce                 -                     21              < 0.7            8

    Green beans             0.2-0.3               21              < 0.1            -

    Lima beans              0-0.2                 21              0-0.3            -

    Peas                    -                     21              0-0.6            -

    Potatoes                0-0.2                 21              0-0.2            -

    Peppers                 0.2-0.6                3              0-0.5            7

    TABLE II (cont'd)
                                                                                           

                            Typical initial   Pre-harvest    Residue at end    Estimated
    Crop                    residues, ppm     period, days   of pre-harvest    half-life
                                                             period, ppm       days
                                                                                           

    Tomatoes                0.1-0.3                3            0.2-0.3            -

    Sugar beets (roots)     -                     30              0-0.3            -

    Hops                    -                     21              < 1.0            -

    Grains

    Barley                  -                     45              < 0.1            -

    Oats                    -                     45              < 0.3            -

    Wheat                   -                     45              < 0.1            -

    Forage, and Hays

    Fresh alfalfa           20-90                 21                1-3            3

    Fresh clover            -                     21                1-2            8

    Sugar beets             1-2.5                 30              0-3.4            -

    Pea                     8-21                  21                0.3            5

    Bean                    5-7                   21            0.3-0.7            5

    Alfalfa hay             -                     21              < 12             -

    Barley straw            -                     45              0-1.0            -

    Oats and wheat          -                     45              0-0.5            - 
    straw
                                                                                           
    
    FATE OF RESIDUES

    General considerations

    Cook (1954, 1955a, 1955b) reported that the two demeton isomers were
    very susceptible to ultraviolet light. It was shown that short
    exposure to ultraviolet light produced powerful anticholinesterase
    products more hydrophilic than the parents. This could have a very

    significant bearing on the "metabolism" of these compounds because of
    the similarity of the light-produced and metabolism-produced
    compounds.

    In plants and animals

    The metabolism of demeton involves a complexity of oxidation and
    hydrolytic reactions resulting in a number of intermediates. Metcalf
    and associates (1954, 1955) demonstrated that the compounds
    0,0-diethyl-0-ethyl-2-ethylthio phosphorothionate (demeton
    thiono isomer) and
    0,0-diethyl-S-ethyl-2-ethylthio-phosphorothiolate (demeton thiol
    isomer) are metabolized in plant and animal tissues to the
    corresponding sulfoxide and sulfone derivatives, some of which are the
    ultimate systemic toxicants. In a series of papers, Fukuto et al.
    (1955) and March et al. (1955) described the chemical behavior of the
    demeton isomers in biological systems. Comparison of cholinesterase
    inhibiting activity, systemic activity, mammalian and insect
    toxicities, and relative behavior on paper chromatograms of the
    metabolic and synthetic oxidation products showed that each isomer was
    first converted to the corresponding sulfoxide by oxidation of the
    ethyl-thioethyl moiety and subsequently converted to the sulfones.
    Metcalf et al. (1955) concluded that the thiolphosphate sulfoxide
    (demeton thiolsulfoxide) and the thiolphosphate sulfone (demeton
    thiolsulfone) are probably the principal toxic plant metabolites
    resulting from the pesticidal application of Systox. Additional
    studies by Metcalf (1956) and Fukuto et al. (1956) have shown that the
    thiolisomer metabolites accumulate in plants from 5 to 10 times as
    rapidly as the thiono isomer metabolites and are considerably more
    persistent. Muhlmann and Tietz (1956) corroborated the finding of the
    previous workers utilizing methylisosystox and its sulfoxide and
    sulfone. This work further showed that the sulfoxide and sulfone were
    the toxic metabolites formed when applied to peas, potted sugar beets,
    cucumbers, potatoes and cabbages.

    Other related compounds have been studied including the P(S)S analog
    Di-Syston, and the dithiomethylene analog, Thimet. The metabolism of
    these thioethers has a bearing on the consideration of demeton because
    they are so similar chemically and it has been shown that metabolism
    results in a number of metabolites, some of which are identical and
    some similar to those from demeton. Bull (1965) studied the metabolism
    of Di-Syston by insects, plant leaves and rats. He reported that
    insects excreted the toxic oxidative derivatives as well as the
    hydrolytic products of Di-Syston metabolism, but rats slowly excreted
    only the hydrolytic products. As many as four oxidative and nine
    hydrolytic metabolites of Di-Syston were found in the biological
    systems used. When Di-Syston was supplied to cotton plants, it was
    rapidly metabolized. By 24 hours, four metabolites were present,
    representing the sulfoxides and sulfones of Di-Syston and its
    phosphorothiolate oxidation product. The proportion of these changed
    with time. Metcalf's group (1959) studied the effects of temperature
    and plant species upon the rates of metabolism of applied Di-Syston.

    The metabolism of Di-Syston sulfoxide and the hydrolytic decomposition
    of the toxic products occurred from 2-3 times as fast in tomato leaves
    at 70F as in cotton leaves under identical conditions.

    Thimet metabolism (Bowman and Casida, 1958a, 1958b) followed a
    substantially similar pattern except that the parent-compound
    persisted longer, and the rates of oxidation of two sulfoxides to
    sulfones were measurably slower. For example, the half-life of the
    phosphordithicate sulfoxide was 200 hours as compared to 100 hours for
    the corresponding Di-Syston metabolite.

    O'Brien (1960) indicates that the thioether pesticides show
    selectivity with respect to toxicity. It was tentatively concluded
    that the phosphatases responsible for the degradation of the selective
    compounds are more effective in mammals than in insects.

    In storage and processing

    Since the residues of demeton are within the plants, the fate after
    harvest probably depends on the metabolic rate in the product in
    storage. Thus it is anticipated that residues in food products from
    treating growing plants would not diminish appreciably in storage
    because storage conditions are generally designed to retard plant
    metabolism processes. The reduction of residues during the milling of
    grain may be less marked than with other chemicals which are found on
    the outside surfaces of grain being milled; although cooking may lead
    to destruction of some residues, little work has been done to confirm
    this supposition. The only information available indicates stability
    during cooking. Apples from trees treated with demeton were used for a
    collaborative methods study. Some observations were made on the
    stability of the metabolites (Cook, 1955c). Boiling apple juice
    prepared from treated apples did not detectably reduce the
    anticholinesterase activity; nor did the activity of the boiled juice
    diminish over a short storage period. Painter et al. (1963) have shown
    that demeton in grape musts were still present in the finished wine
    with only a small loss.

    METHODS OF RESIDUE ANALYSIS

    There have been two principal methods of analysis for demeton. The
    first, an anticholinesterase method, is based on the inhibiting
    properties of the thiol isomer and its sulfoxide and sulfone. The
    thiono isomer is noninhibiting, therefore the ratio of the two isomers
    in an analytical standard is highly important. The inhibition of the
    residue products is calculated as equivalents of the standard mixture,
    see discussion in Cook, 1955c. This method was used to obtain
    essentially all of the residue data presented in this monograph. The
    method is nonspecific since any other anticholinesterase agents give
    the same response. The second method available is one in which total
    phosphorous is measured. Dry samples are extracted with chloroform and
    the residues partitioned into acetonitrile. Moist samples are
    extracted with acetone and water and the residues partitioned into
    chloroform. Naturally-occurring phosphorous compounds are removed by

    cleanup on an activated carbon-alumina column utilizing acetone as the
    eluting solvent. The column eluant is evaporated and the residues
    digested with a mixture of nitric and perchloric acids. The final
    determination is based on the phosphomolybdenum blue reaction.
    Sensitivity of the method is approximately 0.2-0.4 ppm. This method is
    also nonspecific but can be combined with a paper chromatographic
    method to provide a qualitative identification of the residue. The
    cleaned up residue is spotted on silicone treated paper. Compounds
    containing P-S form a red color on the chromatogram when treated with
    a series of reagents and 2,6-dibromo-N-chloro-p-quinoneimine (Chemagro
    Reports).

    The high polarity of the actual toxic residues causes them to behave
    very much like other polar compounds from plant materials and makes
    them difficult to clean up and gas chromatograph. These factors have
    greatly impeded the development of an adequate gas chromatographic
    method of analyses for the residues from demeton; however, many of
    these problems are fairly well solved and it is hoped that adequate
    methods of gas chromatography are nearing completion.

    NATIONAL TOLERANCES

    Country     Tolerance, ppm            Crop
                                                            

    Canada           0.75         6 fruits and 8 vegetables

                     0.5          citrus and strawberries

                     0.3          Melons, beans, tomatoes,
                     0.2          potatoes

    U.S.A.           0.75         11 fruits, 14 vegetables

                     0.75         3 nuts and 3 grains

                     0.3          beans

                     0.5          sugar beets

                     1.25         grapes, hops

                     5            almond hulls

                     5            fresh alfalfa and clover

                     5            green fodder or straw of
                                  barley, oats
                                  and wheat.

                     12           alfalfa and clover hay
                                                            

    RECOMMENDATIONS FOR TOLERANCES

    No recommendation for tolerance is made.

    When demeton is utilized to protect food products, residues as high as
    those shown below may be encountered :

              Tree fruits, including citrus           0.75

              Grapes                                  1.25

              Melons, strawberries, nuts              0.2

              Vegetables :

                   leafy, brassica, legume            0.75

                   root                               0.2

              Grains                                  0.2

    The residues from demeton appear to be fairly persistent. They do not
    disappear rapidly during storage and some data are available to show
    that residues persist during cooking.

    The meeting is of the opinion that the data derived from supervised
    trials (shown above) and other data do not give assurance that
    residues below the ADI for technical demeton will be present.

    FURTHER WORK

    Further work required before tolerances can be recommended :

    1.   Date on mount of residue appearing in total diet studies.

    2.   More data on the possible loss during processing and preparation
         for consumption.

    3.   Method of analysis adequate for use in total diet studies.

    REFERENCES PERTINENT TO EVALUATION FOR TOLERANCES

    Bowman, J.S. and Casida, J.E. (1958a) Systemic insecticides for
    THEBROMA CACAO 4, their translocation and persistence in foliage and
    residues in cacao beans. J. Econ. Ent. 51 (6): 773 - 780.

    Bowman, J.S. and Casida, J.E. (1958b) Further studies on the
    metabolism of Thimet by plants, insects and mammals. J. Econ. Ent. 51
    (6): 838 - 843.

    Bull, D.L. (1965) Metabolism of Di-Syston by insects, isolated cotton
    leaves and rats. J. Econ. Ent. 58 (2): 249 - 254.

    Chemagro Corporation, Kansas City, Missouri, USA. Analytical methods
    report Nos. 3424, 4638, 5339, 6684 and 8544.

    Cook, J.W. (1954) Paper chromatography of some organic phosphate
    insecticides. III. Effects of light on Systox and IsoSystox. J. Assoc.
    Offic. Agr. Chem. 37 (4): 989 - 996.

    Cook, J.W. (1955a) Paper chromatography of some organic phosphate
    insecticides. IV. Spot tests for in vitro cholinesterase inhibitors.
    J. Assoc. Offic. Agr. Chem. 38 (1): 150 - 153.

    Cook, J.W. (1955b) Paper chromatography of some organic phosphate
    insecticides. V. Conversion of organic phosphates to in vitro
    cholinesterase inhibitors by N-bromosuccinimide and ultraviolet       
    light. J.Assoc. Offic. Agr. Chem. 38 (3): 826 - 832.

    Cook, J.W. (1955c) Report on determination of insecticides by
    enzymatic methods. J. Assoc. Offic. Agr. Chem. 38 (3) : 664 - 669.

    FAO/WHO. (1965) Evaluation of the toxicity of pesticide residues in
    food. FAO Meeting Report 1965/10/1; WHO/Food Add./27.65.

    Fukuto, T.R., Metcalf, R.L., March, R.B., and Maxon, M.G. (1955)
    Chemical behavior of Systox isomers in biological systems. J. Econ.
    Ent. 48 (4): 347 - 354.

    Fukuto, T.R., Wolf, J.P., III, Metcalf, R.L. and March, R.B. (1956) 
    Identification of sulfoxide and sulfone plant metabolites of the thiol
    isomer of Systox. J. Econ. Ent. 49 (2): 147 - 151.

    March, R.B., Metcalf, R.L., Fukuto, T.R., and Maxon, M.G. (1955)
    Metabolism of Systox in the white mouse and American cockroach. J.
    Econ. Bat. 48 (4): 355 - 363.

    Metcalf, R.L. (1956) The role of systemic insecticides in world
    agriculture. Plant Protection Conference. Proc. of the 2nd Intern.
    Conf. Fernhurst Research Station, England: 129 - 142. Plant Protection
    Ltd. Butterworths Scientific Publications, London.

    Metcalf, R.L., March, R.B., Fukuto, T.R., and Maxon, M.G. (1954) The
    behavior of Systox-isomers in bean and citrus plants. J. Econ. Ent. 47
    (6): 1045 - 1055.

    Metcalf, R.L., March, R.B., Fukuto, T.R., and Maxon, M.G. (1955) The
    nature and significance of Systox residues in plant materials. J.
    Econ. Ent. 48 (4): 364 - 369.

    Metcalf, R.L., Reynolds, H.T., Winton, M., and Fukuto, T.R. (1959)
    Effects of temperature and plant species upon the rates of metabolism
    of systemically applied Di-Syston. J. Econ. Ent. 52 (3): 435 - 439.

    Muhlmann, R. and Tietz, H. (1956) The chemical behavior of
    methylisosystox in the living plant and the problem of residues.
    Off-print from Hofchen-Briefs 2/1956 Farbenfabriken Bayer, Leverkusen,
    W. Germany.

    O'Brien, R.D. (1960) Toxic phosphorus esters; Chemistry, metabolism
    and biological effects: 32 New York, N.Y. Academic Press Inc.

    Painter, R., Kilgore, W.E., and Ough, C.S. (1963) Distribution in
    fermentation products obtained from artificially fortified grape
    musts. J. Food Sci. 28 (3): 342 - 346.
    


    See Also:
       Toxicological Abbreviations
       Demeton (FAO Meeting Report PL/1965/10/1)
       Demeton (WHO Pesticide Residues Series 5)