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    METHIDATION

    IDENTITY

    Chemical name

         O,O-dimethyl-S-(2-methoxy-1,3,4-thiadiazol-5
    (4H)-onyl-(4)-methyl)-dithiophosphate

    Synonyms

         SUPRACIDE(R)/ULTRACIDE(R) Ciba-Geigy (GS 13005)

    Structural formula

    CHEMICAL STRUCTURE 1


    Other information on properties

         Physical state:     white crystalline powder

         Melting Point:      39-40°C

         Vapour Pressure:    1.0 × 10-6 mm Hg at 20°C

         Density:            1.495 g/cm3 at 20°C

         Solubility:         in water 240 ppm = 0.024% at 20°C; slightly
                             soluble in methanol, acetone and benzene.

         Stability:          relatively stable in neutral and slightly
                             acid media; does not change its content
                             during three days in a phosphate buffer or in
                             a 0.01 N HCl solution. Stability in alkaline
                             media is low.

         Purity of
         technical
         material:           minimum 95%

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Absorption, distribution and excretion

    Methidathion is well absorbed when administered orally to rats (Esser
    et al., 1967) and other mammals but no accumulation occurs in
    particular tissues. The activity in all tissues except muscle was
    below the detectable level 48 hours after a single oral dose to rats
    of about 4 mg/kg of 14C-methidathion (labelled in heterocyclic ring)
    (Esser and Müller, 1966). No activity was detected in tissues of rats
    eight days after completion of ten consecutive daily oral doses of
    about 0.8 mg/kg/day (Dupuis et al., 1971). A total of 34% of
    administered activity was recovered from faeces and 24% from urine
    after oral administration of 1 mg/kg 14C-methidathion/day for five
    days to a lactating cow. The highest tissue level was 0.11 ppm
    methidathion equivalents in the liver (Cassidy et al., 1969b).
    Traces of methidathion could be detected in the tissues of bull calves
    receiving 2.0 mg but not 1.0 mg/kg/day for ten weeks (Polan et al.,
    1969a). Rats administered orally about 4 mg/kg of 14C-methidathion
    labelled in heterocyclic moiety excreted 80% of the activity in 96
    hours, 42.8% in urine, 1.3% in faeces and 36.4% in expired air (Esser
    and Müller, 1966). Essentially similar results were found by Dupuis
    et al. (1971). One cow excreted 16% of the activity from a 1.7 mg/kg
    body-weight oral dose of 14C-methidathion in expired air, 37.9% in
    urine, 5.5% in faeces and 1.2% in milk. The animal had received
    pre-treatment for 30 days with 1 mg/kg/day of non-labelled
    methidathion. Another cow excreted 50.8%, 43.2%, 4.3% and 0.8% by
    these routes when given the same dose but without pre-treatment (Polan
    and Chandler, 1971).

    Biotransformation

    In animals

    According to Esser et al., (1969), metabolism in the rat commences
    by splitting the P-S bond, the thiol group on the heterocyclic
    compound being methylated and then oxidized to the polar sulphoxide.
    The greater part of the sulphoxide is oxidized to CO2 after ring
    cleavage, excreted directly or oxidized to sulphone, which may itself

    be excreted or oxidized to CO2. Three samples of methidathion, each
    labelled with 14C in a different position in the molecule, were
    administered orally to rats. An identical pattern of excretion was
    found with all, up to 36% of the dose being excreted as 14CO2 and up
    to 43% as urinary metabolites (Esser and Müller, 1966; Esser et al.,
    1967). In experiments in which 90% of administered 14C activity was
    recovered, 22-26% of intraperitoneally administered 14C-labelled
    methidathion was eliminated as CO2 and 52-58% as urinary metabolites;
    71% of 14C-labelled 2-methoxy-delta2-1,3,4-thiadiazolin-5-one,
    administered intraperitoneally, was excreted by rats as 14CO2,
    showing the heterocyclic moiety is readily cleaved (Bull, 1968). The
    same behaviour of 2-methoxy-delta2-1,3,4-thiadiazolin-5-one was
    observed in rats after oral administration of carbonyl 14C-labelled
    compound with 45% of the label being expired as 14CO2 (Dupuis
    et al., 1971). Analysis of urine from rats administered 6 mg/kg
    32P-labelled methidathion intraperitoneally showed the presence of
    desmethyl methidathion, dimethyl phosphate, dimethyl phosphorothioate,
    methyl phosphate and phosphoric acid (Bull, 1968). Of an oral dose of
    methidathion 20-25% was excreted in urine by rats as the sulphoxide
    and 5-7% as the sulphone derivate of methidathion (Esser et al.,
    1967); Dupuis et al., 1971). Traces of sulphoxide and sulphone, but
    not of methidathion or its oxygen analogue, were detected in the
    tissues of chicken (Kahrs and Mattson, 1969) and in milk from cows
    (Polan and Chandler, 1971) administered methidathion. The studies of
    Dupuis et al. (1971) on the metabolism of the sulphone and
    sulphoxide derivatives confirm the metabolic pathway described by
    Esser et al. (1967).

    In plants

    In addition to methidathion, several metabolites have been
    demonstrated to occur in treated plants. Dupuis et al. (1971) found
    that, in beans and alfalfa, one-third of metabolites liberated
    2-methoxy-delta2-1,3,4-thiadiazolin-5-one on hydrolysis. Only trace
    amounts of O-[(2-methoxy-5-oxo-delta2-1,3,4-thiadiazolin-4-yl)-methyl],
    O,O-dimethyl phosphorothioate and free
    2-methoxy-delta2-1,3,4-thiadiazolin-5-one were detected.
    Methidathion, its oxygen analogue, phosphate, methyl phosphate,
    dimethyl phosphate, dimethylphosphorothioate and desmethyl-methidathion
    were demonstrated in treated cotton plants (Bull, 1968).

    TOXICOLOGICAL STUDIES

    Special studies on the metabolites

    Acute toxicity of metabolites

    The acute toxicity of methidathion metabolites have been studied in
    the rat and results are summarized in Table 1 (Dupuis et al., 1971).


        TABLE 1  Acute toxicity of methidathion metabolites

                                                                                                        

    Substance                                                         Cholinesterase       Rat LD50
                                                                      inhibition (AChE)    (mg/kg
                                                                      IC50 - molar         body-weight)
                                                                      concentration
                                                                                                        

    Methidathion                                                      > 10-4                35

    2-methoxy-1,3,4-thiadiazol-5(4H)-one                              6 × 10-3              750

    Methidathion-oxygen analogue                                      5.4 × 10-7            10

    2-methoxy-4-methylthiomethyl-1,3,4-thiadiazol-5(4H)-One           > 10-2                1 110


    2-methoxy-4-methylsulphinyl methyl-1,3,4-thiadiazol-5(4H)-one     > 10-2                535


    2-methoxy-4-methylsulphinyl methyl-1,3,4-thiadiazol-5(4H)-one     > 10-2                1 750

                                                                                                        
    
    Short-term studies on the metabolites

    Groups of five male and five female rats were administered by gavage
    25, 50, 100, 200 or 400 mg/kg of 2-methoxy-1,3,4-thiadiazolin-5(4H)-
    one each day for four weeks. A group of ten male and ten female rats
    were fed a control diet for the same period. Three rats died at the
    top dosage level and this dose consistently caused convulsions and
    hyperirritability. At 200 and 400 mg/kg/day levels, the gain in
    body-weight was inhibited. Histological examination indicated
    dose-related occurrence of extra medullary haematopoiesis in the
    spleen which began to show in the 50 mg/kg group. The no-effect level
    was 25 mg/kg/day in this study (Stenger and Roulet, 1965 b).

    Two groups of five male and five female rats were fed 0 or 16.2 ppm of
    methidathion oxygen analogue in the diet for three weeks. Growth and
    behaviour were unaffected but brain and erythrocyte cholinesterase
    were inhibited in the test group (Coulston, 1968).

    Groups of 25 male and 25 female rats were fed on 0, 2, 6 and 12 ppm of
    methidathion-oxygen analogue for three months. Brain cholinesterase
    was inhibited above the 2 ppm dietary level; the inhibition of
    erythrocyte cholinesterase at this level was of questionable
    significance. The behaviour, body-weights, food consumption,
    haematological indices, serum chemistry and gross and microscopic
    pathology were similar in controls and all test groups (Serrone and
    Fabian, 1969).

    Special studies on neurotoxicity

    Four adult hens received four subcutaneous injections of 50 mg
    methidathion/kg body-weight (the maximum tolerated dose) at weekly
    intervals and they were observed for a further four weeks. The signs
    of acute poisoning lasted two to three days each time, but birds
    remained in good condition and no paralysis developed.
    Neuropathological examinations were not performed (Noakes, 1964).

    Five groups of ten adult hens were fed diets containing 0, 16, 52 or
    160 ppm methidathion or 316 ppm tri-orthocresylphosphate for 45-47
    days. No abnormal neurological signs were found in birds fed
    methidathion, but those on tri-ortho-cresylphosphate showed leg
    weakness, lack of balance and ataxia during the final week of
    treatment. Unequivocal evidence of demyelination of neural tissue was
    not found in methidathion or tri-orthocresylphosphate treated animals
    (Johnston, 1965).

    Special studies on pharmacology

    The effects of atropine and the oxime reactivator, pralidoxime, on the
    acute toxic effects of methidathion were investigated in male rats.
    Repeated atropine or pralidoxime administration was effective against
    one to two times the rat median lethal dose of methidathion, and the
    two substances were more effective when given together (Sanderson,
    1964).

    Groups of 20 female rats were administered half the LD50 dose of one
    of 15 other organo-phosphorus or carbamate compounds, respectively. If
    a potentiating effect was found, decreasing amounts of the combined
    insecticidal compounds were given to further groups. Azinphos-methyl,
    mevinphos and parathion-methyl had a potentiating effect with ´LD50
    doses and carbaryl and fenchlorvos with ¨LD50 doses (Johnston and
    Scott, 1965).

    Special studies on reproduction

    In a three-generation study, three groups of 10 male and 20 female
    rats were fed on a diet containing 0, 2 or 16 ppm methidathion for
    three weeks, and thereafter on a diet containing 0, 4 or 32 ppm
    methidathion. Litters from the second matings were used to provide the
    new generations. The F1b litters did not receive test diets until 26
    days and the F2b until 22 days after weaning. Fo, F1b and F2b
    generations received diets for 27-28 weeks during which they produced
    two litters. The number of young surviving at weaning was reduced in
    all generations of litters from animals fed 32 ppm methidathion and
    the mean liver weight of F3b weanlings of this group was slightly
    raised. The body-weight, reproductive capacity and mortality of
    parents and the number of litters, litter size, mean birth and weaning
    weights of test groups were comparable to controls. The number of
    stillbirths and incidence of congenital abnormalities were unaltered
    by treatment. No histological damage was found in the organs of the
    F3b animals examined. The no-effect level in this study was 4 ppm
    methidathion (Lobdell and Johnston, 1966).

    Groups of four male and eight female rats were fed for 12 weeks on
    diets containing 0 or 50 ppm methidathion and mated, one male being
    left with two females for two weeks. No differences from controls were
    found with regard to gestation period, fertility, number of young,
    survival at weaning or average weight at 25 days of age. No congenital
    abnormalities were found in either group (Noakes and Watson, 1964a).

    Acute toxicity

    The acute toxicity of methidathion has been studied in several animal
    species, and the results are summarized in Table 2.

    Short-term studies

    Rat

    Three groups of ten male rats received by gavage 8.3, 16.6 or 33.2 mg
    methidathion/kg/day on five days a week. None, six and ten animals,
    respectively, died within the two-week treatment period (Noakes and
    Watson, 1964b).

    Five groups of ten male rats received by gavage 0, 0.25, 0.83, 2.5 or
    8.3 mg methidathion/kg body-weight/day on five days a week for four
    weeks. Signs of cholinesterase inhibition occurred during the first
    week at the 8.3 mg/kg/day level, but not after in this or other
    groups. Dose-related cholinesterase inhibition occurred in RBC and
    plasma, the no-effect level being 0.25 mg/kg/day. Plasma
    cholinesterase had returned to normal three days after treatment was
    stopped but RBC enzyme had not reached normal figures after 21 days
    (Noakes and Watson, 1964b).

    TABLE 2  Summary of acute oral toxicity of methidathion 1/
                                                                      
    Animal       Sex       LD50             References
                           (mg/kg
                           body-weight)
                                                                      
    Mouse        F         17               Noakes and Sanderson, 1964b

    Hamster      F         30               Ibid.

    Rat          M & F     20 - 81          Stenger, 1964a, 1964b, 1966a,
                                            1966b; Aeppli, 1969a, 1969b,
                                            1970a, 1970b; Noakes and
                                            Sanderson, 1964b

    Rat          M         26 - 65          Ibid., 1964a
                                            Mastri and Keplinger, 1969

    Guinea pig   F         25               Noakes and Sanderson, 1964b

    Rabbit       M         80               Ibid.

    Dog          M & F     200              Sachsse, 1971

    Chicken      F         80               Noakes and Sanderson, 1964b
                                                                      
    1  Formulations calculated as a.i.


    Five groups of five male and five female rats received by gavage 0,
    2.5, 5.0, 10 and 20 mg methidathion/kg body-weight/day on six days a
    week for four weeks. In the 10 and 20 mg/kg groups, four and nine
    animals died respectively. Body-weight gain was depressed in all
    groups but no relation to dosage was apparent. There was a slight
    increase in fat deposition in the liver at 5 mg/kg and at the higher
    levels this was more marked (Stenger and Roulet, 1963).

    Groups of 24 male and 24 female rats were fed for 22 weeks on diets
    containing 0, 1, 4, 16 and 64 ppm methidathion. In a similar study in
    the same laboratories groups of 24 male and 24 female rats were fed
    for 26 weeks on diets supplying 0, 128 and 256 ppm methidathion. The
    rate of body-weight gain was reduced at 64 ppm and above in females

    but not in males. Histopathological examination of liver, spleen and
    kidneys showed a dose-related increase in fat deposition in the liver
    at doses above 64 ppm in both sexes. No abnormalities in
    haematological indices or in results of urine analysis were found
    (Stenger and Roulet, 1965a).

    Groups of 20 male and 20 female rats were fed for six months on diets
    containing 0, 0.5, 2, 10, 50 and 250 ppm methidathion. At the 250 ppm
    level weight gain was slightly depressed and clinical signs of
    cholinesterase inhibition were seen, particularly in females. Plasma
    cholinesterase was inhibited in the 250 ppm group and erythrocyte
    cholinesterase in groups receiving 10 ppm and above. Experimental
    groups were similar to controls with regard to survival, food intake,
    weights and microscopic appearance of liver, kidneys, spleen and
    testes and the macroscopic appearance of other organs (Noakes and
    Watson, 1964a).

    Dog

    Four groups of three male and three female beagle dogs received diet
    containing 0, 4, 16 and 65 ppm methidathion for two years. The animals
    were starved of diet one day each week and received a double ration on
    the next day. Administration of methidathion was discontinued from
    week 16 to 19.

    Erythrocyte cholinesterase was inhibited in the 64 ppm group but brain
    cholinesterase was unaffected by treatment. SGPT was markedly elevated
    in the 64 and 16 ppm groups and slightly raised in males of the 4 ppm
    group. During weeks 16 to 19 these levels fell, but only the 4 ppm
    group returned to normal. SGOT levels were not different from controls
    at all treatment levels but serum alkaline phosphatase was elevated
    and sulphobromophthalein retention increased in the 16 and 64 ppm
    groups. The livers of dogs receiving 16 and 64 ppm were pigmented on
    macroscopic examination. Microscopically, pigmentation could be seen
    in macrophages and hepatic cells (principally centrilobular) in 16 and
    64 ppm groups, the intensity of deposit being dose related. The Perl's
    reaction showed that the pigment did not contain appreciable
    quantities of iron. The kidneys of the 64 ppm group also showed
    pigmentation. It was questionable whether the livers of the 4 ppm
    group contained excess pigment. Control and test groups were
    indistinguishable regarding behaviour, results of clinical tests
    including neurological examination, haematological findings, organ
    weights and macroscopic and microscopic appearance of organs other
    than those mentioned. In addition, two dogs received 64 ppm
    methidathion in the diet for four weeks. The SGOT was elevated at two
    and four weeks and at autopsy the livers were dark in colour. Moderate
    diffuse pigmentation was seen microscopically in the liver of one
    animal. The 4 ppm dietary level was considered to be without toxic
    effect (Johnston, 1967).

    Monkey

    Three Rhesus monkeys were administered by stomach tube individual
    doses of methidathion on six days per week. One animal received a
    constant dose of 2.56 mg/kg during the entire experimental period (91
    days), another monkey received 0.64 mg/kg for 39 days, 5.12 mg/kg for
    25 days and 15.26 mg/kg for additional 25 days, the third animal was
    given 1.28 mg/kg for 39 days, 3.84 mg/kg for ten days and 7.68 for 40
    days. No definite effects were detected using a wide range of toxicity
    criteria (Woodward et al., 1965).

    Four Rhesus monkeys were administered orally 1 mg methidathion/kg
    body-weight/day on six days a week for six months. No changes in
    appearance or behaviour were observed, and weight gain, the results of
    haematological and serum chemical examinations, the plasma and RBC
    cholinesterase activities, brain cholinesterase and gross and
    microscopic examination of tissues showed no untoward effect
    (Coulston, 1969).

    Three groups of Rhesus monkeys (approximately equal numbers of each
    sex) were administered 0, 0.25 and 1.0 mg methidathion/kg
    body-weight/day by stomach tube, six days a week for 23 months. Two of
    each group were autopsied after 12 months. Plasma and erythrocyte
    cholinesterase were inhibited in the 1 mg/kg group but not at the
    lower level. Brain cholinesterase was un altered by treatment. Growth,
    results of haematological tests, results of chemical analyses of serum
    (including for SPGT and alkaline phosphatase) and macro- and
    microscopic examination of tissues were similar in control and test
    groups (Fabian et al., 1971).

    Sheep

    Three groups of two male and two female sheep were fed 0, 15 and 30
    ppm methidathion in their diet for 45 days. No abnormalities which
    could be attributed to treatment were found when growth, faecal
    consistency and gross appearance at autopsy were observed (Murchison,
    1969).

    Horse

    Four groups of two horses received 0, 10, 20 and 30 ppm of
    methidathion in their diet for two weeks. No differences were observed
    between control and test animals with respect to appearance, appetite
    and results of urine analysis, haematology and serum analysis and
    physical and neurological examinations (Watson and Polan, 1967).

    Cattle

    Five groups of two male and two female calves aged about seven days
    were fed for 87 days on a diet containing 0, 5, 15, 25 and 35 ppm
    methidathion. Blood cholinesterase was inhibited after 45 days in the
    35 ppm group and after 49 days in the 25 ppm group. Brain
    cholinesterase was slightly inhibited in the 35 ppm group. There was
    no adverse effect on food intake, body-weight, haematological indices
    or the gross and microscopic appearance of tissues (Polan and Libke,
    1967).

    Groups of five ruminating bull calves were administered daily by
    capsule 0, 0.5, 1.0 to 2.0 mg methidathion/kg body-weight for ten
    weeks. Three animals receiving 2 mg/kg died before the end of the
    test. Food intake and body-weight were reduced and blood
    cholinesterase inhibited in the 2 and 1 mg/kg groups. The results of
    haematological and gross and microscopic tissue examinations were
    unremarkable (Polan, 1968).

    Long-term studies

    Rat

    In order to investigate the long-term toxic effects and possible
    carcinogenic action of methidathion, four groups of 25 male and 25
    female rats each were fed for three weeks on diets containing 0, 2, 8
    or 32 ppm and for a further 101 weeks on diets containing 0, 4, 16 and
    64 ppm methidathion. The rate of gain in body-weight was reduced from
    week 8 in male animals of the 64 ppm group. After the first year the
    rates of gain became erratic in all groups making interpretation of
    findings difficult. Female rats on test diets grew at a rate
    comparable to controls. Erythrocyte cholinesterase was inhibited in
    the 16 and 64 ppm groups while plasma enzyme showed minimal inhibition
    at 100 weeks in the 64 ppm group only. Brain cholinesterase was
    inhibited in the 64 ppm group with marginal and no reduction in the 16
    and 4 ppm groups, respectively. Decreased relative adrenal weights
    were found in females of the 16 ppm and 64 ppm groups, and decreased
    ovary weights in the 64 ppm groups. The relative kidney weights of
    males was increased in the 16 and 64 ppm groups. A greater frequency
    of hepatic degenerative changes was noted in rats fed methidathion in
    the diet; the high incidence of pulmonary infections in the rats
    renders this finding of doubtful toxicological significance. The food
    intake, results of haematological investigations and chemical analysis
    of serum (including SPGT) and the survival rate were similar in the
    test groups and in the control. The incidence of tumours was variable
    between groups but was low and not dose-related, and no unusual
    tumours were found. The no-effect level in this study was a 4 ppm
    methidathion in the diet (Johnston, 1967).

    OBSERVATIONS IN MAN

    One male subject took 4 mg/day (0.04 mg/kg/day) for 17 days and 8
    mg/day (0.08 mg/kg/day) of methidathion for 27 days. No effect was
    found on RBC and plasma cholinesterase, the thrombocyte count and
    stability or on the clinical condition of the subject (Payot, 1965).

    Two groups of eight men received 0.04 and 0.11 mg/kg each day of
    methidathion orally in capsules for six weeks. Four men received
    placebo capsules. The treatment with methidathion was without effect
    on plasma and RBC cholinesterase, SGPT and SGOT, the results of urine
    analysis or on the EEG pattern or clinical condition of the subjects
    (Coulston, 1970).

    COMMENT

    Methidathion is absorbed from the gastrointestinal tract and rapidly
    excreted, mainly as CO2 or as low toxicity urinary metabolites. No
    tissue accumulation occurs. The oxygen analogue of methidathion is a
    transient metabolite in plants but has not been identified in animals;
    it is more acutely toxic than methidathion.

    Methidathion, a cholinesterase inhibitor, is potentiated with several
    other organo-phosphorus compounds, does not cause delayed neurotoxic
    effects, is not teratogenic and affects reproductive function only at
    a level which is toxic to the adult.

    In short-term studies in rats, an increase in the hepatic fat was
    observed histologically at high levels. In a two-year feeding study in
    dogs, signs of hepatic injury were found at all dietary levels. At the
    higher levels evaluated, SGPT, serum alkaline phosphatase and
    sulphobromophthalein occurred and pigment deposition was observed
    histologically in macrophages and hepatocytes. The nature of the
    pigment is not known. Deposition of pigment and signs of liver damage
    were not seen in monkeys or rats.

    In a long-term study in rats, a greater frequency of hepatic
    degenerative changes was noted. There was no evidence of
    carcinogenicity. The no-effect level in this study was 4 ppm, based
    upon cholinesterase depression. No untoward effects were seen in human
    subjects even at 0.11 mg/kg/day taken for six weeks. A no-effect level
    was not observed in dogs at 0.1 mg/kg - a lower level than the
    no-effect level in other species. However, it was felt that a
    temporary ADI could be established on the basis of the data in human
    beings.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Rats:               4 ppm in diet, equivalent to 0.2 mg/kg
                             body-weight/day

         Monkeys:            0.25 mg/kg body-weight/day

         Human subjects:     0.11 mg/kg body-weight/day

    ESTIMATE OF TEMPORARY ACCEPTABLE DAILY INTAKE FOR MAN

         0 - 0.005 mg/kg body-weight

    RESIDUES IN FOOD AND THEIR EVALUATION

    USE PATTERN

    Methidathion was first introduced on a large scale for control of
    insects in 1964. It is officially registered and/or approved for use
    in the following countries:

    Algeria                  England                  Netherlands

    Angola                   France                   Nicaragua

    Argentina                Greece                   Pakistan

    Australia                Germany,Fed.Rep.of       Panama

    Austria                  Guatemala                Poland

    Belgium                  Iran                     Senegal

    Brazil                   Israel                   Somalia Dem.Rep.

    Bulgaria                 Italy                    South Africa

    Chile                    Jamaica                  Spain

    Costa Rica               Japan                    Switzerland

    Cyprus                   Lebanon                  Syria

    Czechoslovakia           Mexico                   Tunisia

    Denmark                  Morocco                  Turkey

    Dominican Republic       Mozambique               U.S.A.

                                                      Yugoslavia

    Pre-harvest treatments

    Use recommendations

    Methidathion can be applied against pests in a variety of different
    crops, including pome and stone fruits, grapes, citrus, cotton,
    potatoes, beet crops, hops, cereals, vegetables, olives and
    sugar-cane. The main fields of application are in stone and pome
    fruits, citrus and cotton.

    The recommended application rates in various crops are given in Table
    3.

    Post-harvest treatments

    Methidathion is only recommended for application to growing crops.

    RESIDUES RESULTING FROM SUPERVISED TRIALS

    Pome fruits, stone fruits, grapes, citrus fruits, vegetables, field
    crops and other food plants were treated in field trials with
    methidathion 40% ES or WP formulation in concentrations of 20 to 60 g
    a.i./100 l spray mixture and in high level dosage trials of up to 300
    g a.i./100 l and investigated for residues.

    In the residue investigations methidathion was determined by gas
    chromatography with a thermionic phosphorus, an electrolytic
    conductivity detector or with a microcoulometer, and the two
    metabolites GS 13007 and GS 12956 by thin-layer chromatography by
    means of fly head-cholinesterase inhibition or silver nitrate.

    The limit of detection of the methods is 0.01 ppm. The extraction and
    cleanup techniques as well as analytical methods are described in
    detail by Eberle and Hörmann. (1971).

    Data from residue trials conducted in Australia, France, Germany,
    Greece, Indonesia, Israel, Italy, Mexico, Morocco, New Zealand, South
    Africa, Spain, Switzerland, United Kingdom and United States of
    America were available for evaluation. Copies of the reports of these
    trials were filed with FAO.

    Eberle and Hörmann (1971) applied statistical tests to show the
    possible relationship between the disappearance rate of methidathion
    residues and the following parameters: type of formulation,
    concentration of a.i. applied, kind and variety of crop.

    Using the principles established by these authors it has been possible
    to apply the calculations to the extensive data available from many
    countries.

    TABLE 3  Recommended application rates of methidathion

                                                                      

    Crop                          g ai/100 litres          g ai/ha
                                                                      

    pome fruit                    30 - 60

    stone fruit                   30 - 60

    citrus fruit                  30 - 60

    grapes                        30 - 60

    hops                          40

    potatoes                                               250 - 800

    beets                                                  300 - 600

    alfalfa1                                               600 - 1 200

    cereals, millet1                                       250 - 800

    vegetables                                             250 - 1 000

    soya1                                                  250 - 800

    groundnuts1                                            250 - 800

    sunflower                                              400 - 800

    maize (corn)1                                          250 - 800

    tobacco, cotton1                                       250 - 800

    sugarcane                     50 - 60                  300 - 1 500

    pineapple                     50

    tea, coffee                   30 - 60                  250 - 800

    palm                          40 - 60

    banana                        50 - 60                  250 - 600
                                                                      

    1  In these crops it is necessary to adjust the dosage within the
       given range to the height and density of the plant.

    The degradation of methidathion in apples, grapes, plums, cherries,
    oranges and alfalfa is presented using a semi-logarithmic plot (Fig.
    1, 2, 3 and 4). The dissipation curves (regression lines) indicate
    that methidathion in a rapidly degrading insecticide, the residues of
    which decrease exponentially with time. Based on a statistical
    analysis of the many residue data obtained in field trials, it is
    possible to present the dissipation curves of methidathion on various
    crops as regression lines according to the equation log y = a + bx
    (Eberle and Hörmann, 1971). These lines are determined by the initial
    residue a and the slop b 1; the logarithms of these values are given
    in Table 4.

    According to Table 4 the initial residue in cherries is log 0.43 = 2.7
    ppm. By means of the slope value b = log 0.86 - 1 and an assumed value
    for x (time interval), any point on the dissipation curve can be
    calculated from the equation log y = a + bx.

    On the basis of statistical analysis of the residue results from pome
    and stone fruits and grapes (Eberle and Hörmann, 1971), and from
    oranges and alfalfa (Hörmann, 1971) the rate of dissipation is not
    significantly dependent on the dose or the formulation of the product,
    i.e. the rate of dissipation of methidathion in a particular crop does
    not change whether the applications are made with 20 or 60 g a.i. per
    100 l or whether the EC or the WP formulation is applied.

    Pome and stone fruits and grapes

    Pome and stone fruits and grapes were treated according to good
    agricultural practice in the respective country with 30-60 g a.i./100
    l one to five times during a season. In orchards, a spray volume of
    2 000 - 2 500 l/ha was applied, in vineyards 1 000 - 1 500 l/ha.

    The residues immediately after the final treatment were 1.5 to 3 ppm;
    they fell by a half after six to seven days in apples, plums and
    grapes and were below 0.15 ppm after 28 days (Fig. 1 and 2).

    The methidathion residue in cherries was different from that in the
    other fruit types; the initial residues are high (2.5 - 5 ppm) but
    these are rapidly reduced by a rapid fruit growth and enzymatic
    processes in the cherries; the half-life is only two days, and only 10
    to 12 days after the application the residue values were already below
    0.3 and 0.15 ppm.

    In contrast to stone fruit and grapes the level of residues in apple
    can be variety-specific. Thus the residues in the apple variety Golden
    Delicious were higher than in other apples, as a result of the high
    wax content in the peel of this variety. In Delicious apples the
    residue was 0.25 ppm three weeks after the final application; in other
    apple varieties a level of 0.12 ppm methidathion was determined at
    this stage (Fig. 1).

              
    1 Example of a dissipation curve is shown in Fig. 3.
    FIGURE 1

    FIGURE 2

    TABLE 4  Logarithmic values for the initial residue a and the slope b,
             calculated from the given number of residue determinations in
             different crops

                                                                             

    Crop                    a = initial     b = slope        number of data
                            residue         of the curve     evaluated for
                                                             the calculation
                                                                             

    apple                   0.29            0.95 -1          68
    (Golden Delicious)

    apple                   0.79 -1         0.96 -1          130
    (other varieties)

    grapes                  0.14            0.94 -1          85

    plums                   0.33            0.95 -1          20

    cherries                0.43            0.86 -1          26

    oranges                 0.10            0.99 -1          92

    alfalfa (fresh)         1.10            0.96 -1          90

    alfalfa (dried)         1.19            0.98 -1          39
                                                                             


    The two metabolites GS 13007 and GS 12956 are only found in traces in
    plant material. The GS 13007 content was determined in apples (in 12
    experiments) and in grapes (in three experiments). After the treatment
    average levels of 0.04 ppm GS 13007 were found in apples (all
    varieties) and 0.15 ppm in grapes (Fig. 1 and 2). Four weeks later the
    metabolite GS 13007 had been degraded to lees than 0.02 ppm in both
    crops, and after six weeks it was no longer detectable in any of the
    samples (limit of detection: 0.01 ppm). The metabolite GS 12956 may
    also occur at the same time as GS 13007. As was determined in apples,
    grapes and plums, GS 12956 residues after treatment with methidathion
    were at no time higher than 0.04 ppm.

    In apples residues of 0.02 ppm GS 12956 were found 4 days after
    treatment with methidathion. This content was reduced to below 0.01
    ppm 10 days after application in all trials.

    In apples the residues of methidathion remaining for several weeks
    after a treatment are not only in the peel but also penetrate into
    the most lipophilic part of the fruit, i.e. the core. This could be
    determined in freshly picked apples and apples stored for one year,
    dipped for one minute in an emulsion containing 40 g a.i./100 l and

        

    analysed in layers (sample from peel, fruit and core). The active
    ingredient content decreases from the peel in the pulp and then
    increases in the core. The peel and core contain higher residue
    levels compared with the pulp as a result of their higher lipid
    content. This analytical result was confirmed by an autoradiogram,
    which showed the concentration of methidathion in the peel and core
    of a ripe Delicious apple treated 14 days previously with
    14C-labelled methidathion (Eberle and Hörmann, 1971).

    Citrus fruit

    For scale control in citrus crops it is usually sufficient to apply 60
    g methidathion per 100 l; if several applications have to be carried
    out the dosage is reduced to 40 g a.i./100 l for each. Trees are
    sprayed to runoff at a rate of 20 to 60 l/tree. Addition of oil to the
    spray mixture, which is not necessary for a successful application in
    citrus crops, leads to an increase of methidathion residues.

    In citrus fruits methidathion residues are found exclusively in the
    peel. The active ingredient does not penetrate into the fruit pulp.
    Analytical data for the whole fruit are calculated by multiplying the
    peel value by a factor of 0.28 (= proportion of peel to the whole
    fruit).

    In small citrus fruits such as lemons, higher residues are recorded
    than in larger fruits, as a result of the difference in surface/weight
    ratio. For example, two months after one of two treatments with 60 g
    methidathion per 100 l, residues in lemons and limes average 0.70 and
    0.61 ppm, in oranges and grapefruits, however, residues are only 0.33
    or 0.16 ppm.

    The dissipation curve for methidathion in oranges, illustrated in Fig.
    31 is a regression line determined from 92 residue values. According
    to this, immediately after treatment residues of 1 - 1.5 ppm
    methidathion are found in oranges. Reduction of residues is slow;
    two-thirds of the initial residues are still present after four weeks
    and one-third (0.40 ppm) after 12 weeks (Fig. 3).

    Special investigations to determine the oxo-compound GS 13007 and
    other metabolites during the breakdown of methidathion in citrus
    fruits gave the results shown in Table 5.

    TABLE 5  Methidathion metabolites in citrus fruit

    metabolite                            residue in ppm              
                                  whole fruit         dried fruit pulp

    GS 13007                      <0.01              <0.01
    sulphoxide                    <0.05              <0.05
    sulphone                      <0.05              <0.05

    None of the metabolites listed was detected; the analysis values were
    below the limit of detection (Kahrs et al., 1969).

    FIGURE 3

    Vegetables

    In these crops spray treatments are applied at a rate of 0.3 - 1 kg
    methidathion/ha.

    Because of the structure of leaf vegetables (lettuce, leek, artichoke,
    cabbage), higher residues are found in these than in vegetables with
    smooth surfaces (tomatoes or legumes). The residues immediately after
    treatment were high (in some cases > 10 ppm), however they fell
    rapidly and 14 days later were <1 ppm in leeks, <0.5 ppm in
    cabbage and artichokes. In beans and peas the residues were below 0.1
    ppm after seven days. In tomatoes even less methidathion was found at
    this stage after treatment. Methidathion has a half-life of one day on
    tomatoes.

    Field and forage crops

    For control of resistant potato beetles in potatoes, rates of
    0.4 - 0.6 kg methidathion/ha are recommended. According to Swiss and
    Australian analyses, methidathion residues are found in the foliage
    but never in the potato tubers.

    In sugar beets no methidathion is detected in the beets.

    Maize is free from residues four weeks after two treatments with 1 kg
    methidathion per ha or one treatment with 0.8 kg a.i. per ha.

    In cotton, rates of 0.3-0.8 kg methidathion per ha are recommended for
    the control of various insects and spider mites. Methidathion residues
    could be detected in the seeds and in cotton seed oil obtained from
    them. Ten and 57 days after five or six applications with 0.5 kg
    a.i./ha, residues in the seeds were 0.34 and 0.06 ppm, in crude oil
    0.44 and <0.05 ppm, and in refined oil 0.41 and 0.05 ppm.

    Alfalfa was investigated after spraying at rates of 0.6-2.8 kg
    methidathion per ha. The recommended dose is 0.6 kg a.i. In alfalfa
    and pasture crops the residues detected were of the same order. The
    level and rate of dissipation of methidathion residues were not
    affected by the method of application, so that both aerial and ground
    applications, each with 0.6 kg a.i./ha, produced similar initial
    residues of 21 and 24 ppm (Mattson and Kahrs, 1969a).

    Residue determinations in alfalfa from seven different areas in the
    U.S.A. gave the results shown in Table 6 (Mattson and Kahrs, 1969b).

    TABLE 6  Methidathion residues in alfalfa

                                                                   

    Dose             Interval       Methidathion residues (ppm)
    (kg a.i./ha      (days)         range                  average
                                                                   

    0.6              0              7.0 - 41.0             24.0

                     7              0.27 - 5.20            2.3

                     14             0.08 - 1.10            0.53

                     21             0.08 - 0.36            0.24

    1.1              0              13.0 - 74.0            41.0

                     7              1.5 - 9.10             6.3

                     14             0.44 - 3.40            1.5

                     21             0.19 - 0.64            0.42
                                                                   


    The results show that the level of the residues is dependent on the
    level of the applied dose; it is independent of the formulation and
    the number of applications. Thus similar residues could be detected
    after one or after three applications carried out at monthly
    intervals. The initial residues on alfalfa and pasture plants are high
    (>10 ppm) but fall rapidly even the first day after application (Fig.
    4).

    Residues of 8.8 ppm found one day after application of 0.6 kg a.i./ha
    fell to 1.6 ppm by the seventh day (Nelson, 1967). The half-life for
    methidathion on alfalfa was found to be 3´ days (Mattson et al.,
    1969). Fahey and co-workers (1970) also confirmed the rapid breakdown
    of methidathion, and further determined that the chemical in fresh
    alfalfa was considerably reduced by drying. With the help of a
    conventional farm drier, the methidathion residues in green alfalfa
    were reduced by 8 to 57%.

    The following residues of GS 13007, the oxo-analogue of methidathion,
    were found in alfalfa and clover (Table 7).

    FIGURE 4

    TABLE 7  Residues of the methidathion metabolite GS 13007 in field crops

                                                                             

    Dose                     Interval           GS 13007 residues (ppm)
    (kg methidathion/ha,     (days)          alfalfa            clover
    3 applications)                      fresh    dried     fresh    dried
                                                                             

    0.6                      0           0.40     0.08      0.40     0.10

                             7           0.06     0.04      0.05     0.04

                             14          <0.01    0.01      0.015    0.03

                             21          <0.01    0.01      <0.01    0.02

    1.1                      0           0.40     0.20      0.10     0.40

                             7           0.10     0.20      0.05     0.26

                             14          0.02     0.08      0.025    0.05

                             21          0.01     0.02      0.01     0.07
                                                                             


    The proportion of GS 13007 in the total spray residue was about 1% of
    the unchanged insecticide. The metabolite was continually degraded
    after treatment: its half-life was two to four days on alfalfa and
    four to six days on clover (Mattson et al., 1969). This result was
    confirmed by Cassidy and co-workers (1969a) by investigations with
    14C-labelled methidathion on alfalfa.

    The two metabolites GS 28370 and GS 28369, the sulphomide and the
    sulphone of methidathion, were not detected during the degradation of
    methidathion in alfalfa (Kahrs et al., 1969).

    Hops

    Three weeks after four applications, each with 40 g methidathion per
    100 l, residues of 1-2 ppm were found in fresh green hops and 2.3-2.5
    ppm on dried hops.

    In beer brewed from hops containing 2.4 ppm methidathion, no
    methidathion could be detected, with a limit of detection of 0.0001
    ppm, which indicates that methidathion residues are completely broken
    down during the brewing process.

    Tea

    Tea treated with the recommended level of methidathion (40-60 g
    a.i./100 l), contained less than 0.1 ppm a.i. after seven days. After
    nine days the values were below the limit of detection of 0.01 ppm.
    These analytical results, together with the fact that in the
    preparation of tea considerable dilution takes place and only some of
    the active ingredient is extracted from the tea leaves, indicated that
    methidathion residues are unlikely to be present in brewed tea.

    FATE OF RESIDUES

    In animals

    In feeding studies in bull calves using 14C-labelled methidathion it
    was shown that a daily dose of 1 mg methidathion per kg body-weight,
    administered over ten weeks, left no insecticide residues in the
    skeletal musculature or in various organs (heart, kidneys, spleen,
    liver, brain). The oxo-compound, GS 13007, did not occur either (Polan
    et al., 1969a). It was also shown in studies in milk cows that after
    administration of 30, 15 or 7.5 ppm methidathion (corresponding to a
    dose of 0.17, 0.35 or 0.18 mg/kg body-weight) for a period of 55 days
    neither methidathion (limit of detection 0.005 ppm) nor GS 13007
    (limit of detection 0.025 ppm) could be detected in fatty tissue or in
    milk (Polan et al., 1969b).

    Feeding with alfalfa which has been treated with a normal dose of
    methidathion does not lead to active ingredient residues in the milk.
    After administration of 1 mg 14C labelled methidathion/kg body-weight
    to milk cows for one or five days, only about 1% of the radioactivity
    of the administered dose was found in the milk within 4 or 15 days.
    This radioactivity was attributable to a small extent only to the
    metabolites GS 28370 (sulphoxide) and GS 28369 (sulphone), but mainly
    to polar substances which probably originated from the intermediary
    metabolism. This is an indication that the thiadiazole ring of the
    methidathion molecule is split, and that the resulting C-1 fragments
    are utilized for the synthesis of genuine organic substances. No
    unchanged methidathion and no GS 13007 (limit of detection 0.01 ppm)
    were present in the milk (Cassidy et al., 1969b; Polan and Chandler,
    1971).

    A dose of 1 mg methidathion/kg body-weight which was chosen in most of
    the feeding studies is high in comparison with possible insecticide
    uptake with treated feed. In order to ingest this dose, a cow for
    example must be fed with alfalfa containing residues of 50 ppm
    methidathion (Polan et al., 1969a).

    These high residues are only occasionally found on alfalfa or grass
    after insecticide application, and after one week they are already
    dissipated to an average of 3 ppm. In summary, it can be stated with
    certainty that no methidathion residues occur in meat or milk products
    if the animal has been fed with alfalfa treated with a normal dose of
    insecticide under the usual practical conditions.

    Since alfalfa is fed to poultry, it was important to clarify whether
    methidathion residues remaining for a short time on the feed plants
    after an insecticide application affect the poultry in any way or lead
    to residues in eggs. Wisman and Young (1969) fed white Leghorn hens
    for 30 days with feed containing 10, 50, 100 or 500 ppm methidathion.
    Only feed containing 500 ppm impaired feed uptake and laying rate of
    the hens. Feed containing 100 ppm had no visible effect. Insecticide
    residues were found in the egg yolk after the three higher doses;
    after feeding with 100 or 50 ppm the residues were however less than
    0.01 ppm methidathion, and six days after the application were below
    the limit of detection of 0.002 ppm (for analytical method see Young,
    1970). No residues occurred in eggs after ingestion of feed containing
    10 ppm.

    The doses in feed chosen for this trial are - when compared with
    residues actually occurring in green feed - again very high. When it
    is further taken into consideration that alfalfa forms only about 15%
    of chicken feed, the contamination of the eggs with methidathion via
    the feed is unlikely.

    In plants

    In plants treated with 14C-labelled methidathion only slight
    translocation of the insecticide could be detected. The radioactivity
    measured in untreated parts of the plants was generally low and in
    most experiments was present in the form of polar metabolites. Traces
    of methidathion were only found in alfalfa stems and bean plants one
    and two weeks after treatment (about 0.2-0.5% of the applied
    radioactivity). Bull (1968), who investigated the translocation of
    32P-labelled methidathion after injection into the cotyledons of
    cotton plants, also confirmed that methidathion is found in
    non-treated parts of the plants in very small proportions only.

    Investigations of the metabolism of methidathion in alfalfa and beans
    are described in detail and summarized in a paper by Dupuis and
    co-workers (1971). The following therefore largely refers to this
    paper and is completed by results from investigations described in
    other publications.

    As early as 1966 Esser and Müller demonstrated in bean plants and
    freshly harvested apples that plants possess the ability to split off
    the heterocyclic moiety of the insecticide methidathion and to
    metabolize it to CO2.

    Dupuis et al. (1971) carried out studies in beans (Phaseous
    vulgaris) and alfalfa (Medicago sativa) with 14C-labelled
    methidathion to demonstrate CO2 excretion. The product was labelled
    as for the metabolic studies on animals, either on the methoxy, the
    carbonyl or the methylene group of the molecule. As Fig. 5 shows,
    methidathion is degraded to CO2 in both plant species. The lower
    percentage proportion of 14CO2 in alfalfa is attributed to the
    greater rate of application of methidathion on the leaves of these
    plants and not to the difference in plant species.

    Degradation to CO2 is independent of labelling, which indicates that
    not only the ester compound but also the heterocyclic ring of the
    methidathion molecule is split. The quantitative difference in CO2
    excretion in bean plants related to the position of labelling is
    explained by the number of oxidation processes on the C atom
    concerned. By control experiments, in which the stability of
    methidathion was tested on glass plates under the same conditions as
    in plant experiments, it could be shown that the 14CO2 determined
    originated exclusively from metabolic processes in the plant.

    After CO2 excretion of treated bean and alfalfa plants was measured
    for two weeks, the plants were extracted for further investigation in
    an acetone-water mixture; after evaporation of the acetone the extract
    was separated by partition into a chloroform and an aqueous phase. The
    radioactivity of the non-extracted parts was determined by combustion.
    Table 8 (Dupuis et al., 1971) shows the distribution of
    radioactivity in the different extraction phases of bean and alfalfa
    plants. The high radioactivity in the aqueous phase indicates a
    considerable degradation of the insecticide. Unchanged methidathion is
    only present in the chloroform phase; the relatively larger proportion
    in alfalfa plants two weeks after the treatment is attributed to the
    relatively high dose of methidathion applied to these plants.

    The metabolite fractions of the chloroform phase can be separated into
    a polar and a non-polar fraction by thin-layer chromatography. The
    substances in the polar fraction were not analysed further.

    The non-polar fraction was rechromatographed using various solvent
    systems whereby Rf values corresponding to GS 13007 and GS 12956 were
    obtained. Methidathion was found to be the main constituent of the
    chloroform phase. Confirmation of the identity of methidathion, GS
    13007, and GS 12956 was achieved by co-chromatography with reference
    substances in various solvent systems, and by electrophoresis in the
    case of GS 12956.

    The presence of GS 13007 could also be confirmed by hydrolytic
    conversion to GS 12956.

    FIGURE 5


        TABLE 8  Distribution of radioactivity in plants after foliar application

                                                                                                                                               

    plant     type of        dose          days after                   chloroform phase
              labelling      (µCi/µl)      treatment     methidathion   GS 13007   GS 12956   polar       equeous     non-           14CO2
                                                                                              fraction    phase       extractable
                                                                                                                                               

              methidathion                               .............................. percentage of applied dose ........................

    beans     C = 0          8.3/1 500     71            6.03           0.22       0.66       1.95        20.2        1.55           20.4
                             15 plants

    beans     C = 0          1.39/300      141           <------------------ 6.9 (total) -------->        14.9        12.4           27.4
                             3 plants

    beans     OCH3           1.35/300      161           1.34           0.23       0.55       1.81        47.0        10.65          8.0
                             3 plants

    beans     OH2            6.53/600      131           3.33           0.15       traces     0.15        25.7        10.9           23.3
                             3 plants

    alfalfa   C = 0          7.89/200      141           39.35          0.86       1.00       1.80        32.0        6.4            13.7
                             75 leaves

    alfalfa   C = 0          17.1/400      72            53.23          0.33       1.74       0.33        14.5        2.9            -
                             153 leaves

    alfalfa   C = 0          17.1/400      132           31.94          0.57       0.48       0.39        17.25       4.9            -
                             153 leaves

              GS 12956

    beans     C = 0          7.43/400      151           -              -          5.4        1.8         55.3        6.7            2.3
                             3 plants
                                                                                                                                               
    1  plants cultivated under laboratory conditions
    2  plants cultivated outdoors
    3  including 21.5% from yellowed leaves
    4  including 9.3% from yellowed leaves
    
    The pattern of metabolites occurring in the chloroform phase is
    unrelated to the labelling of the methidathion molecule. The
    quantitative distribution of the radioactivity is the result of
    different experimental conditions (see Table 8).

    The presence of unchanged methidathion, the oxo-analogue GS 13007 and
    a further radioactive substance (according to Dupuis et al., 1971,
    it is GS 12956) in the chloroform phase was also confirmed by Bull
    (1968), and Cassidy and co-workers (1969a). Occurrence of the
    metabolite GS 13007 was only transitory during the degradation of the
    insecticide and in small quantities, according to Bull (1968) to a
    maximum of 1.3% of the applied radioactivity; it is in no way a main
    metabolite and is not stored in the plant (Cassidy et al., 1969a).
    These laboratory experiments were confirmed by residue determinations
    for GS 13007 in alfalfa and clover crops grown under practical
    conditions outdoors and treated with methidathion. These trials showed
    that residues of the oxo-compound represented 1% of the total amount
    of methidathion on the plants (see section on residues in field and
    forage crops). Residue determinations were made by thin-layer
    chromatography by means of fly head cholinesterase inhibition (Mattson
    et al., 1969).

    In the aqueous phase at least four metabolic fractions occurred which,
    however, could not be satisfactorily separated by thin-layer
    chromatography in neutral solution systems. Using solvent systems
    containing formic acid or ammonium hydroxide a separation into
    distinct zones can be obtained, although this leads to decomposition
    of the metabolites. One substance can be determined as the final
    product of degradation in the aqueous phase. It can also be liberated
    from one-third of the water-soluble radioactivity by acid hydrolysis
    of the entire aqueous phase. This substance is GS 12956, whose
    identity can be confirmed by co-chromatography with the reference
    substance in various solvent systems and by electrophoretic
    determination. In addition, it can be converted to GS 26703
    (1,3,4-thiadiazolidin-2,5-dione) by acidic cleavage of the methyl
    group, a process which Rüfenacht (1968) has described for GS 12956.

    To determine whether the metabolic pattern of the aqueous phase is
    dependent on the labelling of the methidathion molecule, bean leaves
    were treated with differently 14C-labelled samples of the product and
    analysed one week later.

    The Rf values of the radioactive metabolite fractions of the aqueous
    phase, listed in Table 9, indicate that the position of the label has
    no significant influence on the metabolite pattern (Dupuis et al.,
    1971).

    As already mentioned, GS 12956 can only be determined in the aqueous
    phase after acid hydrolysis (7 N HCl for 24 hours at 23°C) : after
    O14CH3-labelling 29.5% of the measured radioactivity is obtained as
    14C-GS 12956 and after 14C = 0-labelling 25%. As is to be expected,
    after labelling of the methylene group no radioactive GS 12956 is
    obtained. If the radioactive fractions of the aqueous phase from zone
    1 and zone 2 (see Table 9) are separately hydrolysed with acid, GS
    12956 is obtained both from zone 2 and zone 1. This finding indicates
    the presence of several metabolites in the aqueous phase; they have
    the general structure 


    CHEMICAL STRUCTURE 2

    and differ from one another only by the radical R.


    TABLE 9  Distribution of radioactivity in bean plant after treatment
             of leaves with 14C-labelled methidathion

                                                                         

                        Rf values of radioactive fractions of the
                        aqueous phase
                                                                         
    label               0.05      0.351     0.5            0.8
                                  zone 1                   zone 2
                                                                         

    14CH2                         81.5%                    18.5%

    14C = 0                       85.3%                    14.7%

    O14CH3                        83.4%                    16.6%
                                                                         

    1  main fraction

    The instability of zone 2 is an indication of the presence of the
    desmethyl conjugate of methidathion, namely  O-H-O-methyl-S[2-methoxy-
    1,3,4-thiadiazol -5(4H)-onyl-(4)-methyl]-dithio-conjugate is a labile,
    rapidly decomposing substance, which contributes some 20% of the
    radioactivity of the aqueous phase. The conjugate is metabolized to
    water-soluble desmethyl methidathion. From metabolic studies with
    14CO-labelled desmethyl methidathion, which was injected into alfalfa
    plants, it is known that the conjugate and the desmethyl methidathion,
    which arises in the alfalfa plants, are not stable but are converted
    to more polar metabolites. As in methidathion the thiadiazole ring is
    oxidized to CO2. Desmethyl methidathion does not inhibit
    cholinesterase (Simoneaux and Cassidy, 1969).

    In soil

    Contamination of the soil with insecticides may occur either during
    the process of application (drainage of the product from the plants,
    direct spraying of the soil) or because the treated plants excrete the
    insecticide or its metabolites into the soil.

    In the soil residues of methidathion were detected after direct
    application and also after spraying of apple trees. The active
    ingredient content of the upper 5 cm of soil was up to 1.9 ppm, lower
    layers from 5-25 cm remained mainly residue-free or contained slight
    levels of active ingredient. Initial residues of 1.6-1.9 ppm were
    reduced to about 0.25 ppm after two weeks. Methidathion could not be
    detected in the soil four weeks after application.

    As determined by residue analyses of soil samples, methidathion could
    no longer be determined three to five weeks after spray applications
    on apple trees or direct application on the soil (Eberle and Hörmann,
    1971). The possibility of contamination from treated plants is however
    unlikely. According to investigations by Dupuis and co-workers (1971)
    bean plants and young apple trees treated with 14C-labelled
    methidathion and grown in a nutrient solution excreted only little or
    no radioactivity. The radioactivity measured in the nutrient solution
    of the bean plants four weeks after treatment was no more than 1-1.5%
    of the applied dose. As demonstrated by thin-layer chromatography,
    polar substances are involved here. With apple trees no radio-labelled
    substances were detected in the nutrient solution (investigation
    period: four months; limit of detection: 0.1% of the applied dose). In
    two pots, in which young trees were grown in soil, again no
    radio-labelled substance was excreted into the soil. These findings
    are in accordance with the results of investigation of the
    translocation of methidathion in the plant organism. These showed that
    radio-labelled methidathion applied on the leaves is translocated in
    only very slight quantities to untreated parts of the plants.

    As in animal and plant organisms methidathion is metabolized to CO2
    in the soil. This is the result of laboratory trials in which Dupuis
    and co-workers (1961) treated samples of different soil types with
    14CO-labelled methidathion and measured the 14CO2 release at
    different times after treatment. The values are summarized in Table
    10.

    The important role of microorganisms in the breakdown of methidathion
    can be seen from the very low release of CO2 from sterilized loam
    (2%) and the high level of radioactivity that can be extracted with
    acetone from the soil in the form of the unchanged insecticide. In
    contrast, the extracted radioactivity (8% from non-sterilized soils)
    consists of only one-third of unchanged methidathion. The two
    metabolites GS 13007 and GS 12956 do not occur in soil (Eberle and
    Hörmann, 1971).

    As for other insecticides, microorganisms are largely responsible for
    the degradation of methidathion in soil. According to the
    investigations of Getzin and Rosefield (1968) 50% of applied
    methidathion is metabolized in a non-sterile loam while only 17 or 29%
    is degraded in a loam sterilized by irradiation or heating.

    The question of how far methidathion can be washed into the soil has
    been tested in the laboratory. Metal columns were filled with
    air-dried samples of a sandy loam, a marly loam and a sand containing
    5.6%, 3.6% and 2.2% organic components, respectively, treated with
    radioactive methidathion (corresponding to a rate of application of 5
    kg a.i./ha and artificially watered at a rate of 200 mm during 48
    hours). Radioactivity measurements showed that in sandy loam, with the
    highest content of organic matter, methidathion can be detected only
    in the upper 4 cm, in marly loam and in sandy soil in 8- and 16-cm
    deep soil layers. The insecticide content in the 16-cm layer is very
    small (1.3% of the applied level). A contamination of underground
    water with methidathion is not very likely, since the insecticide,
    even in weakly absorbing sand, only penetrated 16 cm into the soil
    after 200 mm artificial rain. This assumption has also been confirmed
    by the analysis of the rain water, in which methidathion could not be
    detected (limit of detection: 0.5% of the applied dose).

    TABLE 10  Degradation of 14CO-labelled methidathion
              to 14CO2 in soils
                                                                             
    Soil type           Days after     14CO2 release       Radioactivity
                        treatment      (% of applied       extracted with
                                       dose)               acetone (%)
                                                                             

    humus               8              9.6
    loam                8              27.9
                        21             45.0                8
    sterilized loam     26             2.0                 63
                                                                             

    Summary of the metabolism of methidathion

    Metabolic studies with radio-labelled material in animals, plants and
    soil have shown that the dithiophosphoric ester methidathion
    (O,O-dimethyl-S-[2-methoxy-1,3,4-thiadiazol-5(4H)-onyl-(4)-methyl]
    dithiophosphate) is metabolized in all the systems investigated and
    largely broken down to C-1 fragments (CO2).

    The degradation pathways and the intermediary compounds occurring
    during the metabolism in the different systems investigated are shown
    in Figure 6. The continuous arrows indicate identified metabolites.
    The broken lines indicate the probable but unproven sequence of
    metabolites found. The dotted arrow symbolizes a metabolic pathway of
    minor importance. The mercaptomethyl compound GS 32978 is placed in
    brackets since, although its presence as a primary degradation product
    must be assumed, it has not been demonstrated.

    In storage and processing

    Residue determinations in cooked apples and vegetables

    To determine how far methidathion residues would be influenced by the
    cooking process, untreated samples of apples, spinach and tomatoes
    were fortified with 0.2, 1.0 and 5.0 mg methidathion/kg and cooked for
    15, 30 or 45 minutes. Results are shown in Table 11. Residue
    determinations were carried out by gas chromatography with a
    thermionic phosphorus detector. The limit of detection of this method
    is about 0.04 ppm (Blass, 1972).

    As can be seen from Table 11 the cooking process leads to a
    considerable degradation of the insecticide. After a cooking time of
    15 minutes, the added methidathion, which corresponds approximately to
    an insecticide residue resulting from an outdoor spray application,
    was reduced by at least 90%. After 30 minutes the residue levels, with
    the exception of two samples, were below the limit of detection.

    In view of the persistence of methidathion residues in the peel of
    citrus fruits it was necessary to determine the fate of the residue
    when citrus peel is used in the preparation of marmalade. One such
    study (Geigy Australasia, 1970) showed that there were no detectable
    residues (less than 0.01 ppm) in marmalade prepared from oranges
    containing 2 ppm of methidathion in the peel.

    Studies show that beer, brewed from treated hops containing 2.4 ppm
    methidathion, does not contain methidathion or metabolites at or above
    0.0001 ppm. Likewise tea treated with methidathion is unlikely to give
    rise to residues in brewed tea.

    FIGURE 6

    TABLE 11  Residues of methidathion in apples, spinach and tomatoes
              after cooking

                                                                             

    Sample         Methidation added        Cooking time        residues
                   (ppm)                    (minutes)           (ppm)
                                                                             

                                            15                  <0.04
                   0.2                      30                  <0.04
                                            45                  <0.04
    apples
                                            15                  0.08
                   1.0                      30                  <0.04
                                            45                  <0.04

                                            15                  <0.04
                   0.2                      30                  <0.04
                                            45                  <0.04
    spinach
                                            15                  0.09
                   1.0                      30                  0.06
                                            45                  <0.04

                                            15                  <0.04
                   0.2                      30                  <0.04
                                            45                  <0.04
    tomatoes
                                            15                  0.10
                   1.0                      30                  <0.04
                                            45                  <0.04

                                            15                  0.28
                   5.0                      30                  0.21
                                            45                  <0.04
                                                                             


    METHODS OF RESIDUE ANALYSIS

    Residues of methidathion can be determined by specific methods
    including gas-liquid chromatography, which are described by Eberle and
    Hörmann (1971).

    The parent compound methidathion is determined in various agricultural
    crops and soil by gas chromatography using both sodium thermionic and
    electrolytic conductivity detectors with a limit of determination of
    0.01 ppm. This gas chromatographic procedure is simple, versatile and
    very useful for routine analysis.

    The oxo-analogue GS 13007 is detected on thin layer chromatographic
    plates by fly head cholinesterase inhibition, and GS 12956, the
    heterocyclic moiety of methidathion, by silver nitrate with a
    detection limit of 0.01 ppm each.

    NATIONAL TOLERANCES

    The various tolerance values established for methidathion in different
    countries are shown in Table 12.


    TABLE 12  Examples of National Tolerances Reported to the Meeting

                                                                             

    Country                  Tolerance   Crop
                             (ppm)
                                                                             

    Australia                2.0         citrus fruit (whole)
                             0.75        seed oil crops
                             0.2         pome, fruits (apples, peers)
                             0.1         vegetables (cauliflower, broccoli
                                         seed vegetables, legumes, tomatoes)

                             0.01        root vegetables
                             0.01        cereals, sorghum (grain)

    Germany, (Fed. Rep. of)  2.0         citrus fruit
                             0.3         pome fruits, cabbage
                             0.2         all other fruits and vegetables
                             0.21        citrus fruit (without peel)
                             0.1         other plant products
                             0.02        potatoes

    Belgium                  0.2         all fruit and vegetables

    Holland                  0.2         all fruit and vegetables

    Switzerland              0.15        pome fruits, grapes

    South Africa             0.5         citrus fruit (whole)

    U.S.A.                   6.0         alfalfa, clover, grass (fresh and
                                         dried)

                             0.2         cotton seeds
                                                                             

    1  provisional tolerance

    The withholding periods established for methidathion (see Table 13)
    vary considerably from country to country for the same crop, as a
    result of different meteorological conditions and differences in
    agricultural practices - both factors which can influence the rate of
    breakdown of a pesticide.


    TABLE 13  Examples of withholding periods for methidathion

                                                                             

                    Interval between
    Crop            last treatment       Country
                    and harvest
                     (days)
                                                                             

    Pome fruits        42                Switzerland
                       35                Austria, Belgium
                       30                Yugoslavia
                       28                Argentina, Germany, Fed. Rep. of
                       21                South Africa, Netherlands
                       20                Italy
                       15                France
                       14                Australia

    Stone fruits       23                South Africa
                       20                Italy
                       15                France
     cherries          14                Belgium, Yugoslavia
     peaches           30                Israel

    Grapes             56                South Africa
                       42                Switzerland
                       35                Austria
                       30                Italy, Israel

    Citrus fruit       60                Israel
                       56                South Africa
                       21                Australia
                       20                Italy

    Hops               21                England

    Vegetables         35                Austria, Belgium
                       28                Argentina
                       20                Italy
                       15                France
                        7                Australia

    TABLE 13  (Cont'd.)

                                                                             

                    Interval between
    Crop            last treatment       Country
                    and harvest
                     (days)
                                                                             


    Potatoes           35                Austria
                       30                Yugoslavia
                       21                Germany, Fed. Rep. of; Switzerland
                        6                South Africa

    Cotton             30                Israel

    Oleaginous
     plants             3                Australia

    Cereals            42                Australia

    Forage crops       21                Germany, Fed. Rep. of; Switzerland
                       14                England
                       10                U.S.A.
                        7                Australia
                        1                Australia
                                                                             

    APPRAISAL

    Methidathion is a broad spectrum organo-phosphorus insecticide/
    acaricide introduced in 1964. It is effective against a wide variety
    of pests of pome and stone fruits, grapes, citrus fruit, cotton,
    potatoes, beet, hops, cereals, vegetables, olives, sugarcane, oilseed
    crops, pastures and forage crops. The main field of application are
    pome and stone fruits, citrus fruit, cotton and forage. It has both
    contact action and stomach poison effect. The technical product
    contains a minimum of 95% methidathion.

    Methidathion is registered for use in many countries. The rate of
    application varies according to pest and ranges from 30-60 g a.i./100
    l or 250-1 000 g a.i./ha. Its action is independent of prevailing
    temperatures, though weather conditions influence the duration of
    insecticidal effect. Depending upon crop species, rate of application
    and weather, effective action ranges from one to three weeks.

    No post-harvest applications have been developed.

    Extensive residue data were available to the meeting from trials
    conducted in 15 different countries on 28 major crops comprising seven
    different crop classes. Many of the trials involved the examination of

    different crop parts, different stages of growth and analysis for
    metabolites as well as parent compound.

    Much of the residue data were subjected to statistical analysis, and
    it was possible to present the dissipation curves on various crops as
    regression lines. These curves indicate that methidathion is rapidly
    degraded, the residues decreasing exponentially with time.

    The statistical analysis of residue data from trials on pome and stone
    fruits, grapes, oranges and alfalfa showed that the rate of
    dissipation is not significantly dependent on the rate of application
    or the formulation used. In the case of cherries, the initial residue
    level was comparatively high (2.5-5 ppm), but this was rapidly reduced
    by fruit growth and enzymatic processes in the cherries. The half-life
    was only two days, in contrast to six to seven days in most other
    fruits.

    In the case of apples, the level of residues depends largely on
    variety. Varieties such as Delicious retain more residues for a longer
    time than other varieties possibly because of the higher wax content
    in the peel. The methidathion residue penetrates the peel and is to be
    found in the flesh and even the core when treated apples are stored
    for long periods. Citrus fruit, on the other hand, retain all the
    residue in the outer skin.

    Numerous studies on the metabolism of methidathion in plants and
    animals and on the fate of deposits applied to plants and soil were
    available. There is very little tendency for translocation, but a high
    proportion of the amount taken up by plants is quickly metabolized to
    CO2. The only significant metabolite found in plants is the oxygen
    analogue. The desmethyl derivative of methidathion is unstable and
    water-soluble. It does not inhibit cholinesterase. The
    methoxy-thiadiazolene moiety is only found in trace amounts in plant
    materials.

    The presence of methidathion could not be demonstrated in soil three
    to five weeks after direct application. A considerable proportion is
    converted to CO2 in that time, due apparently to the activity of
    microorganisms.

    Studies available to the meeting demonstrated the fate of methidathion
    fed to cattle and poultry at rates greatly in excess of those likely
    to be encountered in practice. Feeding treated forage, pasture or
    plant parts to ruminant animals or poultry is unlikely to give rise to
    residues of methidathion or metabolites in animal tissues, milk or
    eggs at levels above the limit of determination (0.01 ppm).

    The use of treated hops containing 2.4 ppm of methidathion did not
    give rise to residues in beer above the limit of determination of
    0.0001 ppm. Likewise, treated tea does not give rise to residues in
    brewed tea.

    A number of studies were available to show the effect of cooking on
    residues in several fruits and vegetables. Residues at the level

    resulting from approved uses are degraded by at least 90% after 15
    minutes of cooking. After 30 minutes of cooking, the residue levels
    fall below the limit of determination (0.04 ppm).

    Specific analytical methods are available, utilizing sodium thermionic
    and electrolytic conductivity detectors in gas-liquid chromatography.
    These procedures are useful for routine analysis and the method of
    Eberle and Hörmann (1971) appears satisfactory for regulatory
    purposes. The limit of determination in most plant products is 0.01
    ppm. The major metabolites have been determined by thin layer
    chromatography with a detection limit of 0.01 ppm.

    RECOMMENDATIONS

    TEMPORARY TOLERANCES

    The following temporary tolerances are based on residues likely to be
    found at harvest following currently approved use patterns. The
    temporary tolerances are expressed as methidathion as it is known that
    the oxygen analogue, if present, does not occur at concentrations
    above 0.05 ppm.

    The time interval between application and harvest which has been used
    in determining the maximum residue limits is appropriate to the
    agricultural practices in numerous countries. Residues are known to
    degrade rapidly with a half-life of six to seven days on most crops.
                                                                             
                                                           Time interval
    Crop                                    Temporary      on which
                                            tolerance      recommendation
                                            (ppm)          is based
                                                           (days)
                                                                             

    Apples and pears                        0.5            14
    Apricots, cherries, nectarines,
     peaches, plums, prunes                 0.2            14
    Grapes                                  0.2            28
    Citrus fruit                            2              21
    Leafy vegetables                        0.2            21
    Cabbage, cauliflower                    0.2            21
    Beans, peas, tomatoes                   0.1            7
    Maize, sorghum (grain)                  0.1            42
    Cottonseed                              0.2            10
    Cottonseed oil (crude)                  1              10
    Hops (dried)                            3              21
    Tea (dry manufactured)                  0.1            7
    Potatoes                                0.02 *
    Milk and milk products (fat basis)      0.02 *  (  from feeding
    Meat, fat and edible offal of cattle,           (  ontreated forage
      sheep, goats, pigs and poultry        0.02 *  (  and plant
    Eggs (shell free)                       0.02 *  (  products
                                                                             
    * at or about the limit of determination

    FURTHER WORK OR INFORMATION

    REQUIRED (by 30 June 1975)

    A study to elucidate the formation of pigment and the nature of the
    liver lesion which leads to increased serum transminase levels in
    dogs.

    DESIRABLE

    1.   Metabolic studies in man to determine comparative degradation
         between man and other species.

    2.   A study to determine dose levels causing no carboxylesterase
         (aliesterase) activity depression.

    3.   Further information on the fate of residues in storage and
         processing.

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    Stenger, E.G. and Roulet, F. (1965b) Subchronische Toxizität, Ratte
    per os, GS 12956. Unveröffentlichter Bericht der Geigy, J.R. AG.

    Stenger, E.G. (1966a) Akute Toxizität, Ratte per os, GS 13005 40 WP
    Unveröffentlichter Bericht der Geigy, J.R. AG.

    Stenger, E.G. (1966b) Akute Toxizität, Ratte per os, A 2041 C (= 40
    ES). Unveröffentlichter Bericht der Geigy, J.R. AG.

    Watson, D.F. and Polan, C.E. (1967) GS 13005: Safety evaluation by
    feeding to horses for two weeks. Report Virginia Polytechnic
    Institute. (unpublished)

    Wisman, E.L., Young, R.W. (1969) A residue and stability study of the
    insecticide Supracide in the laying hen. Poultry Science, 49(1):
    83-85.

    Woodard, M.W., Greenstein, E.T. and Woodard, G. (1965) GS 13005:
    Preliminary safety evaluation in monkeys. Report Woodard Research
    Corp. (unpublished)

    Young, R.W. (1970) Flame photometric determination, extraction, and
    cleanup procedures for GS 13005
    [O,O-dimethyl-S-2-methyloxy-1,3,4-thiodiazol-5-(4H)-onyl-(4)
    methyl-dithiophosphate(4)] and metabolite residues in egg yolk and
    poultry feed: J. Agr. Fd. Chem., 18(1): 164-167.
    


    See Also:
       Toxicological Abbreviations
       Methidathion (ICSC)
       Methidathion (WHO Pesticide Residues Series 5)
       Methidathion (Pesticide residues in food: 1979 evaluations)
       Methidathion (Pesticide residues in food: 1992 evaluations Part II Toxicology)
       Methidathion (Pesticide residues in food: 1997 evaluations Part II Toxicological & Environmental)