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    METHAMIDOPHOS           JMPR 1976

    IDENTITY

    Chemical name

         OS-dimethyl phosphoramidothioate

    Synonyms

         Tamaron R, Monitor R, SRA 5172, Bayer 71 628, RE 9006

    Structural formula

    CHEMICAL STRUCTURE 1


    Other information on identity and properties

    Molecular weight:             141.1

    State:                        yellowish to colourless crystals
                                  (technical)
                                  colourless crystals (pure)

    Melting point:                37 - 39°C (technical)
                                  44.5°C (pure)

    Vapour pressure:              3 x 10-4 mm Hg at 30°C (pure)

    Density:                      1.31

    Solubility:                   Readily soluble in water, alcohols
                                  ketones, aliphatic chlorinated
                                  hydrocarbons; sparingly soluble
                                  in ether; practically insoluble
                                  in petroleum ether.

    Stability (alkaline           Half-life of 120 hours at pH 9
    and acidic conditions         and 37°C  Half-life of 140 hours at
    pH 2
                                  and 40°C

    Impurities in the technical product

                                                 Maximum level, %

    Total impurities                             27

    OO-Dimethyl phosphoramidothioate             12

    Other methyl esters of phosphoramido
    and phosphoro-N-methylamidothioates          12

    Methyl esters of phosphoric and
    phosphorothioic acids                        8

    Phosphate, sulphate, sulphonium ion,
    water                                        8

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Absorption, distribution and excretion

         Male and female rats were orally administered methamidophos
    (32p-labelled) following a two-week preconditioning period where
    a daily dose of 0.5 mg/kg was orally administered. Male rats only
    were administered 14C-methamidophos with no preconditioning at the
    same dose level. In the 14C study (label = S-CH3) absorption and
    a distribution was rapid. Elimination of 14C02 within the first
    6 hours accounted for 32% of the recovered radioactivity with 9% of
    the dose in the urine. Over a 5-day period only 50% of the
    administered dose was recovered (39% as 14C02 and the rest
    predominantly in urine). The remainder of the 14C was probably
    present as residual radioactivity in the body, distributed
    randomly. The major tissue residue was found in the polar lipid
    fraction with lesser amounts as phospholipids and proteins
    (probably incorporated as natural products). Studies with 32p
    confirm the rapid absorption and distribution of radioactivity in
    rats. The major amount of material recovered following 32p labelled
    methamidophos dosing was observed in urine within 1 day. Feces
    contained small quantities that were continually excreted (<20% of
    the dose was excreted in feces over a 28-day test interval). Thus,
    methamidophos is rapidly absorbed and distributed in the body.
    Methamidophos and metabolites are excreted predominantly as urinary
    products (Crossley and Tutass, 1969).

         The metabolic fate of methamidophos in a lactating ruminant
    (goat) was essentially the same as reported for the rat. Small
    amounts of radioactivity were observed in milk, predominantly as
    the parent molecule shortly after dosing. About 1% of the
    radioactivity (<0.003 mg/kg) in the milk was methamidophos, which
    disappeared rapidly. Distribution of the applied radioactivity in
    the goat was rapid, predominantly as exhaled 14C02, in urine

    and as radioactivity incorporated into some tissues (muscle, liver,
    fat). 24% of the administered radioactivity was excreted within the
    dosing period. In tissues, the predominant residue was not the
    parent compound as evidenced by solvent partition characteristics
    (Lee and Crossley, 1972).

         Further details of the fate of metamidophos in the rat and
    lactating goat are given in the section "Fate of residues".

    Biotransformation

         Methamidophos is rapidly degraded primarily by cleavage of the
    P-N bond yielding dimethyl phosphoric acid derivatives. Microsomal
    preparations in vitro accelerated the hydrolysis of the
    phosphoramidate bond (Tutass, 1968a). A qualitative sequence of
    metabolism is as follows:

    CHEMICAL STRUCTURE 2


    (Crossley and Tutass, 1969)

         A list of the identified metabolites of methamidophos is given
    in Figure 1.

    Effects on enzymes and other biochemical parameters

         Methamidophos is an active, direct cholinesterase inhibitor.
    In blood, cholinesterase depression was observed to be maximum
    within 3 hours following oral acute intoxication of male rats.
    Cholinesterase activity was maintained at a low level for at least
    24 hours following acute poisoning. Three days after treatment, the
    enzyme activity of whole blood returned to a level that was almost
    normal (Lorke and Kimmerle, 1967).

    FIGURE 1

         RBC cholinesterase appears to be more sensitive than plasma
    cholinesterase to inhibition as noted by the differing I50 values.

                                   I50(M)

              Bovine RBC           3.1 x 10-5

              Human Plasma         1.6 x 10-4

                                   (Tucker, 1972)

         The sensitivity of RBC relative to plasma cholinesterase to
    inhibition by methamidophos was noted in a 3-week dietary study
    where methamidophos was fed at 0 and 10 ppm. No cumulative enzyme
    depression was observed and RBC was affected slightly more than
    plasma (Cavalli and Spence, 1970;) [see acephate - Cavalli and
    Spence, 1970f, summary of the data in addendum]. 

    TOXICOLOGICAL STUDIES

    Special studies on delayed neurotoxicity

         Groups of hens (10 mature laying hens - 1-2 years old/group)
    were fed methamidophos in the diet (dosage levels were said to be
    0, 0.3, and 3.0 mg/kg body weight) for four weeks. There was a
    control of TOCP fed at a dose of 50 mg/kg body weight. No mortality
    or severe weight loss was observed and clinical signs of ataxia
    were not noted. The TOCP-treated hens developed clinical signs of
    ataxia. Histological examination of nervous tissue showed no
    abnormalities, even in the TOCP control group (Fletcher et al.,
    1971).

         In two trials, groups of adult hens (varying in number from 2
    to 10/group) were administered methamidophos once orally or by
    intraperitoneal injection in the presence or absence of 2-PAM and
    atropine. The test protocol used doses equal to and exceeding the
    LD50 values in an attempt to establish the neurotoxic potential for
    methamidophos. Although mortality was observed, no clinical signs
    of delayed neurotoxicity were evident. Histopathological
    examinations were not performed (Lorke and Kimmerle, 1967).

         A group of six hens each were administered methamidophos
    orally at an LD50 dose level of 27.5 mg/kg, observed for 21 days,
    re-treated with the same dose and maintained for an additional 21
    days. Two separate control groups were used - an untreated control
    and a TOCP (500 mg/kg, oral dose) positive control. While some of
    the hens (2/6) died from acute toxicity, the survivors of the
    methamidophos treatment did not lose weight or show signs of
    delayed ataxia. The TOCP treatment group lost weight and showed
    positive signs of ataxia within 14 days of poisoning.
    Histopathology examination was not performed (Wolvin, et al.,
    1968).

    Special studies on reproduction

    Rat

         Groups of rats (8 male and 16 female/group) were fed
    methamidophos in the diet at dose levels of 0, 3, 10, and 30 ppm
    for 100 days and mated to begin a standard 3 generation, 2
    litter/generation reproduction study. Body weights of parental
    males (but not females) were reduced but the reduction was slight
    and not dose-related. Cholinesterase activity values of the female

    animals were measured after the mating trials were concluded. RBC
    and plasma cholinesterase depression was evident at 30 ppm in males
    and females (male plasma was also depressed at 10 ppm). There were
    no significant effects noted on gross or microscopic examinations
    of tissues and organs.

         Reproductive indices were generally affected at the 30 ppm
    dose level. The incidence of pregnancy (fertility index) incidence
    of parturition (gestation index) and viability and lactation
    indices were reduced at 30 ppm. Numbers of stillborn and
    cannibalized pups were increased at the 30 ppm dose but no
    suggestions of terata were presented. Histopathologic examination
    of the progeny did not reveal any abnormalities. No effects on
    reproduction were observed at 10 ppm (Arnold et al., 1970).

    Special studies on teratogenesis

         Groups of pregnant rabbits (from 17-23 does/group) were
    administered methamidophos by gelatin capsule from day 6 through
    day 18 of gestation at dosage levels of 0, 0.1, and 0.3 mg/kg. A
    positive control (thalidomide, 37.5 mg/kg) was administered to a
    group of 27 pregnant does. All animals were sacrificed on day 29 of
    gestation. Positive teratogenic signs were observed as expected
    with thalidomide. No effects were noted as a result of
    administration of methamidophos on growth of does or on fetal
    mortality. Fetus weight was normal and skeletal development was
    unaffected. One of 63 pups at the 0.3 mg/kg dose level displayed
    talipomanus, club hand. This malformation was not observed in 75-79
    pups at the low dose or in the controls, but it occurred in 8 of 85
    in the positive controls (Ladd et al., 1971). There were no other
    obvious defects noted in the study with methamidophos. A larger
    number of defects were noted with thalidomide (umbilical hernia,
    harelip, cervical elongation, frontal fontanel) that were not seen
    with methamidophos. Skeletal examinations of the pups from
    methamidophos-treated does were normal.

    Special studies on mutagenicity

         Groups of mice (12 males/group) were administered
    methamidophos by intraperitoneal injection at dosage levels of 0,
    1, and 2 mg/kg and mated to virgin females for 6 consecutive weeks
    in a dominant lethal test. A positive control group administered
    ethylmethane sulfonate (EMS, 400 mg/kg) was included in the study.
    Females sacrificed one week after breeding with the treated males
    were examined for pregnancy and resorption of fetuses.
    Mutagenicity, measured by comparing viable embryos in the test and
    control groups, was not evident with methamidophos treatment. A
    mutagenic response to EMS was indicated in the first two weeks of
    the test (Arnold et al., 1971).

         Results of in vitro tests using Salmonella and
    Escherichia Spp tester strains were negative when methamidophos was
    examined (Hanna and Dyer, 1975).

    Special studies on antidotes

         Antidotal effects were noted with atropine and atropine +
    2-PAM combination administered following intoxication. BH6 and
    2-PAM alone were not effective antidotes. Atropine + PAM was more
    effective than atropine alone but less effective than atropine +
    BH6 (Lorke and Kimmerle, 1967).

         The acute oral toxicity of methamidophos in male rats was
    reduced 3-fold when animals were administered atropine alone or in
    combination with 2-PAM. While 2-PAM alone was not as therapeutic as
    atropine it reduced the toxicity by more than two-fold (Schoenig et
    al., 1968).

    Special studies on potentiation

         Simultaneous administration of methamidophos to rats either by
    oral gavage or intraperitoneal injection in combination with
    malathion showed a significant potentiation (acute interaction in
    the toxicity as measured by reduction of the LD50 value). Graduated
    doses of malathion and methamidophos by oral administration
    resulted in a greater than two-fold potentiation with malathion.
    (Gröning, 1975). A slightly less than two-fold increase was
    observed when ip injection was the route of administration used
    (Crawford and Anderson, 1973). Oral administration of methamidophos
    in combination with parathion or EPN did not result in potentiation
    of the acute toxicity (Gröning, 1975).

    Acute toxicity

    TABLE 1. Acute toxicity of methamidophos

                                                                        

    Species      Sex    Route         LD50          Reference
                                      (mg/kg)
                                                                        

    Rat          M      Oral          15.6-32.3     Lorke & Kimmerle,
                                                    1967; Cavalli
                                                    et al., 1968a;
                                                    1968b; 1968g.

                 F      Oral          13.0-29.6

                 M      ip            21.3          Lorke & Kimmerle.
                                                    1967

                 F      ip            26.4          Lorke & Kimmerle,
                                                    1967

    TABLE 1. (Cont'd.)

                                                                        

    Species      Sex    Route         LD50          Reference
                                      (mg/kg)
                                                                        

    Rat             M      Dermal
                        4-hr exp.     110           Lorke & Kimmerle,
                        7-day exp.    50            1967

                        Inhalation
                        1-hr exp.     0.525 mg/L    Lorke & Kimmerle,
                        4-hr exp.     0.162 mg/L    1967

    Guinea Pig          Oral          30-50         Lorke & Kimmerle,
                                                    1967

    Mice                Oral          16.2          Cavalli et al.,
                        (Technical)                 1968c

                        Oral (75%     18.0          Cavalli et al.,
                        Technical)                  1968d

    Rabbit              Oral          10-30         Lorke & Kimmerle,
                                                    1967

                        Dermal        118-125       Cavalli et al.,
                                                    1968e; 1968f

    Cat                 Oral          10-30         Lorke & Kimmerle,
                                                    1967

    Dog                 Oral          10-30         Lorke & Kimmerle,
                                                    1967



    Chicken      F      Oral          25            Lorke & Kimmerle,
                                                    1967

                 F      ip            10            Lorke & Kimmerle,
                                                    1967
                                                                        

         The observed signs of poisoning were typical of
    anticholinesterase agents. The signs appeared rapidly following
    poisoning (5-20 minutes) and disappeared in 4-6 days. Typical
    parasympathomimetic signs of poisoning would be expected.

    
    TABLE 2. Acute toxicity of impurities

                                                                                   
                                                LD50
    Compound        Species    Sex     Route    (mg/kg)      Reference
                                                                                   

    (CH3O)2P(S)     Rat        M       Oral     633          Cavalli et al., 1968h

    NH2 (RE9169)               F       Oral     549          Cavalli et al., 1968h

    Signs of poisoning were typical of CNS depression
    - paresis, hyporeflexia and anesthesia.

                    Rabbit             Dermal   2,500-       Cavalli et al., 1969
                                                5,000
                                                (intact
                                                skin)

                                                1,570        Cavalli et al., 1969
                                                (abraded
                                                skin)

                                                                                   
    
    See the monograph on acephate for the toxicity of other products.

    Short-term studies

    Rat

         Groups of rats (15 females/group) were administered methamidophos
    orally or by intraperitoneal injection, 5 days/week for 60 days to
    examine possible cumulative effects. Oral application consisted of
    daily doses of 0, 1.5, 3.0, 6.0, 10.0, and 15.0 mg/kg while ip
    application consisted of doses of 0, 1.3, 2.6, 5.3, 8.8, and 13.2
    mg/kg. While slight mortality was observed (oral = 3/15, ip = 6/15)
    there was no evidence of cumulative action. The cumulative LD50 by
    either oral or ip administration was estimated to be > 15 mg/kg body
    weight (Lorke & Kimmerle, 1967).

         Groups of rats (30 females/treatment group - 90 females were used
    as controls) were fed methamidophos in the diet at dosage levels of 0,
    0.25, 0.50, 1.00, 2.00 and 4.00 ppm for 13 weeks (a further 4-week
    recovery period using a control diet followed this test interval).

         There were no deaths or adverse behavioral reactions. Growth, as
    evidenced by body weight gain, was normal at all treatment levels.
    Cholinesterase depression of plasma, RBC and brain was reported only
    in the high dose group.

         At 4.0 ppm depression of enzyme activity was obvious in plasma
    and RBC, less so in brain. A comparison of the total depression of
    cholinesterase activity and recovery during the 4-week control diet
    period suggests a no-effect level of 2.0 ppm (Reyna et al., 1973).

         Groups of rats (35 males and 35 females/group) were fed
    methamidophos in the diet for 13 weeks at dietary levels of 0, 0.3,
    1.0, 3.0 and 10.0 ppm. Cholinesterase activity was examined at
    periodic intervals using plasma, RBC, and brain tissue. Significant
    dose-related depression of plasma cholinesterase activity was noted in
    male rats at 3 and 10 ppm and in females at 10 ppm. Decreases in
    cholinesterase activity of RBC and brain were noted at 3 and 10 ppm in
    both sexes. RBC activity was depressed in both sexes at 10 ppm and in
    males only, marginally depressed at 1 and 3 ppm. Recovery of enzyme
    activity was noted after one week of control diets following 3 ppm and
    at 4 weeks of control diets following 10 ppm (Plank et al., 1969).

         Groups of rats (15 males and 15 females/group; 30 of each sex
    were used as controls) were fed methamidophos in the diet at dosage
    levels of 0, 2, 6, 20, and 60 ppm for 3 months. No mortality or
    behavior changes were observed although growth was depressed
    significantly at 60 ppm in both sexes. Blood chemistry, hematology,
    and urine analysis parameters were normal (bilirubin content of males
    only at 20 and 60 ppm was depressed at 90 days, and OCT
    (Ornithinecarbamoyl transferase) activity was depressed in females fed
    60 ppm at 90 days. These unusual effects were reported to be within
    physiological limits). Cholinesterase activity was depressed at 6 ppm
    and above in both plasma and RBC (RBC was slightly more sensitive). No
    effects were noted at 2 ppm over the 13 week feeding interval. Gross,
    macroscopic examination of tissues and organs showed a reduction in
    both males and females in the size of several organs; thymus, liver,
    spleen, adrenals, and gonads only at 60 ppm. There were no effects
    noted at 20 ppm. Microscopic examination of the tissues did not show
    any adverse effects related to the presence of methamidophos in the
    diet. A no-effect level based on cholinesterase depression is 2 ppm in
    the diet (Löser and Lorke, 1970b; Gröning, 1976).

    Rabbit

         Groups of rabbits (5 males and 5 females/group) were administered
    methamidophos dermally to intact or abraded skin at dose levels of 0,
    5, or 10 mg/kg (a 75% technical product). The application was made 6-7
    hours/day, 5 days/ week for 3 weeks. Application was to a new site
    each day. Mortality occurred in the 10 mg/kg abraded skin group
    accompanied by signs of cholinergic stimulation. Hematologic studies,
    blood chemistry and urinalysis parameters were unaffected by dermal
    application of methamidophos. Gross and microscopic analyses of
    tissues and organs were uneventful. Dermatologic reactions, such as
    erythema, were minor. The affected skin returned to normal within 1-2
    days. Growth was slightly retarded at the 10 mg/kg dose group but was
    not accompanied by other adverse signs of poisoning (Mastri et al.,
    1968).

    Dog

         Groups of dogs (3 male and 3 female/group) were administered
    methamidophos orally by capsule daily, seven days per week, for 90
    days at dosage levels of 0, 0.025, 0.075, and 0.25 mg/kg body weight.
    There was no mortality. Growth and food consumption were unaffected.
    Red blood cell and plasma cholinesterase activity, examined at several
    intervals both before and during treatment, was normal. There was no
    depression of cholinesterase noted in this study (Carlson et al.,
    1969).

         Groups of dogs (3 male and 3 female/group) were used in a repeat
    of the above test to examine the 90-day subacute anticholinesterase
    effects of methamidophos. Growth was reduced in males at the highest
    dose level. In females, a reduced weight gain was observed at all dose
    levels. Food consumption was reduced at the highest dose level in both
    sexes. Depressed erythrocyte cholinesterase was observed at 0.25 mg/kg
    in both males and females. No effects were noted on plasma enzymes. A
    no-effect level based on RBC cholinesterase is 0.075 mg/kg (Lindberg
    et al., 1970).

         Groups of dogs (2 male and 2 female/group) were administered
    methamidophos by capsule for periods varying from 21-28 days, at doses
    ranging from 0 to 0.6 mg/kg/day. In this study each dog was examined
    for 34 weeks to determine a pre-treatment baseline for cholinesterase
    activity. Animals were then administered a dose of 0.025 mg/kg for 28
    days after which the dose was increased to 0.05 mg/kg. The total
    treatment sequence was as follows: 0.025, 0.05, 0.075, and 0.10 mg/kg
    each administered for 28 days, followed by 0.125, 0.20, 0.30, 0.40,
    0.50, and 0.60 mg/kg each administered for 21 days, after which a
    control diet was administered for 28 days. Cholinesterase activity was
    measured several times (generally at weekly intervals) during the
    course of treatment. In both males and females a dose level was
    reached where plasma and RBC cholinesterase activity was depressed. In
    males, plasma and RBC cholinesterase was depressed when the dose
    regimen reached 0.125 mg/kg. In females, plasma was depressed at a
    dose of 0.3 mg/kg while RBC was affected at approximately 0.2 mg/kg.
    Based on these data, no effects on cholinesterase would be expected to
    occur at levels around 0.1 mg/kg/day. In this study, depression was
    considered positive when the average value for cholinesterase activity
    declined below the lowest range of the pre-treatment mean (Greco et
    al., 1971). 

         Groups of dogs (2 male and 2 female beagles/group), 3 of each sex
    were used as controls) were fed diets containing methamidophos at
    dosage levels of 0, 1.5, 5, and 15 ppm for 90 days. There was no
    mortality or behavioral change noted over the course of treatment.
    Growth and food consumption were normal. There were no effects noted
    in blood chemistry, hematology or urinalysis parameters.
    Cholinesterase depression (RBC and plasma) was noted at 5 ppm and
    above in both sexes (within the first week of dietary administration
    at the high dose and after 2 months at the intermediate dose). Gross

    macroscopic examination of tissues and calculation of relative organ
    weights did not indicate any effects at the highest treatment level. A
    dietary no-effect level in this study is 1.5 ppm (Löser and Lorke,
    1970a)

         Histopathological examination of tissues and organs showed no
    effects of methamidophos (Gröning and Lorke, 1976).

         Groups of dogs (3 male and 3 female beagles/group) were
    administered methamidophos by capsule, orally, for two years at dosage
    levels of 0, 0.075, 0.25 and 0.75 mg/kg. There were no deaths or
    observable differences in behavior over the two-year study. Growth was
    unaffected by methamidophos. There were no effects noted on clinical
    chemistry, hematology, or urinalysis parameters recorded.
    Cholinesterase activity was not reported. Gross and microscopic
    examination of tissues and organs showed no abnormalities (Lindberg et
    al., 1969).

    Long-term studies

    Rat

         Groups of rats (45 males and 45 females/group) were fed
    methamidophos in the diet at dosage levels of 0, 3, 10, and 30 ppm for
    two years. Growth was reduced at the high dose level in males. Growth
    in females was unaffected in this study. A separate paired feeding
    study (21-day) was conducted where it was noted that growth was
    unaffected at 30 ppm. Examination of food consumption data suggested
    this effect to be due to diet rejection rather than a direct effect of
    methamidophos in the diet. (Plank et al., 1968). In the long-term
    study, there were no effects reported on behavior, hematologic blood
    chemistry or urinalysis parameters. Gross and microscopic examination
    of tissues and organs at 12 or 24 months showed no abnormalities
    attributed to methamidophos in the diet. The tumor incidence was
    unaffected and a definitive, no-effect level based on somatic changes
    would be greater than 30 ppm. Cholinesterase activity was not measured
    in the study (Plank et al., 1970).

    OBSERVATIONS IN MAN

         A study was conducted where controlled doses of combinations of
    acephate and methamidophos were orally administered to people for
    periods up to 21 days. A cohort of 14 people were divided into 3
    groups containing either 4 or 6 people. The groups received either a
    combination mixture of 1:4 (methamidophos:acephate), 1:9 or a control
    dose, daily (divided into 3 equal doses), for periods of 21 days. Each
    group was administered the combination at a dose of 0.1 mg/kg/day for
    21 days after which the dose was increased (to 0.2 mg/kg/day) and
    continued for another 21 days. The protocol called for a total of 4
    dose levels (up to 0.4 mg/kg/day) each to be administered for 21 days.
    Blood cholinesterase (plasma and RBC) was examined periodically. No
    effects were noted on RBC cholinesterase at any treatment level. There

    was no substantial depression noted in the female group receiving the
    1:9 combination tested at the highest dose (0.4 mg/kg/day). The male
    cohort was substantially affected at the 0.3 mg/kg dose and was not
    retested at the higher dose level. The group (both males and females)
    receiving the higher methamidophos:acephate ratio (1:4) showed
    reduction of plasma cholinesterase after two weeks of receiving a dose
    of 0.2 mg/kg/day. The 0.3 mg/kg regimen was not used in the 1:4 dose
    group. This study indicated the minimal dose necessary to decrease
    plasma cholinesterase for the combination of acephate and
    methamidophos was 0.2 mg/kg/day of a 1:4 combination of the two
    toxicants. No effects with this combination were noted at 0.1 mg/kg
    (Garofalo et al., 1973). See the monograph on acephate for a further
    amplification of these data.

    COMMENTS

         Methamidophos, an anticholinesterase organophosphorus ester, is
    also a metabolite of acephate. Methamidophos is rapidly absorbed,
    distributed, metabolised and excreted in mammals. Bioaccumulation,
    based on data on solubility properties, would not be expected to
    occur. Biotransformation in mammals results in metabolites of
    insignificant toxicological properties. Methamidophos is an acutely
    toxic pesticide. The acute signs of poisoning can be relieved with the
    aid of atropine (and reactivators, such as 2-PAM). In contrast to the
    innocuous metabolites, methamidophos is an active cholinesterase
    inhibitor, primarily affecting RBC (and presumably brain)
    cholinesterase in animal models. In humans, plasma cholinesterase
    appears to be the more sensitive enzyme parameter.

         Methamidophos does not induce delayed neurotoxicity although
    potentiation of the acute toxicity of malathion has been noted. In
    reproduction studies, several parameters were affected at relatively
    low levels (the levels were however sufficient to impart
    cholinesterase depression in the parents). No terata were induced in
    the reproduction study or in special teratological studies in rabbits,
    although the dose levels used in this latter study were extremely low.
    Mutagenicity tests were negative.

         In short and long term studies no significant somatic effects
    were noted. Cholinesterase depression was manifested in short term
    studies. In 90 day dog studies, cholinesterase depression was observed
    at 5 ppm while a dietary level of 1.5 ppm (equivalent to 0.04
    mg/kg/day) caused no observable effects. In a 2 year dog study,
    somatic effects were not noted at levels of 0.75 mg/kg/day but
    cholinesterase activity was not determined. Depression of
    cholinesterase activity in rat feeding studies was observed at dietary
    levels of 3 ppm and above while 2 ppm was found to induce no
    depression of cholinesterase activity. In a controlled study where a
    combination dose of methamidophos and acephate was administered to a
    group of male and female volunteers, cholinesterase depression was
    observed predominantly when a higher methamidophos:acephate ratio was
    used (1:4 rather than 1:9). Based on the results of this study a

    no-effect level of 0.02 mg/kg was suggested. A higher total
    concentration (0.2 mg/kg), administered in a lower ratio (1:9) also
    gave no depression of enzyme activity. Based on the no-effect level of
    0.04 mg/kg bw in dog an ADI was allocated. The no-effect level in
    human studies was further assurance of the adequacy of the numerical
    value of the ADI.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Rat: 2 ppm in the diet equivalent to 0.1 mg/kg bw

         Dog: 1.5 ppm in the diet equivalent to 0.04 mg/kg bw

         Man: 0.02 mg/kg bw/day

    ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN

         0 - 0.002 mg/kg bw

    RESIDUES IN FOOD AND THEIR EVALUATION

    USE PATTERN

         Methamidophos is an organophosphorus insecticide with systemic
    properties. It is a good stomach poison with further contact poison
    action and has good residual activity. It is claimed to be effective
    for the control of sucking pests such as aphids, whitefly and spider
    mites as well as biting pests such as Laphygma, Prodenia, Trichoplusia
    and others.

         Methamidophos is used world-wide, chiefly in regions with a
    subtropical climate. Formulations based on methamidophos are
    registered and sold in more than 40 different countries of the world,
    including Egypt, many countries of Latin America, Turkey, U.S.A.,
    Canada and several countries of Europe. Methamidophos is marketed in
    different emulsifiable concentrate formulations.

         The major uses of methamidophos are pre-harvest treatments on
    cotton, vegetables, potatoes, maize, sugar beet, stone fruit, tobacco,
    hops and ornamentals. Further details on its uses and recommendations
    are given in Table 3.

    RESIDUES RESULTING FROM SUPERVISED TRIALS

    In vegetables

         Residue data are presented in Table 4 on a number of vegetable
    crops, namely broccoli, Brussels sprouts, cabbage, cauliflower,
    celery, cucumber, eggplant, lettuce, peaches, pepper, potatoes and

    tomatoes. Most of the data have been received in detailed as well as
    in summarised form from the manufacturers (Chevron Chemagro and
    Bayer-reports in file), although with some supplementary material from
    other sources (Davis et al., 1974).

         Generally vegetable crops are treated with 0.5 - 1 kg/ha of
    methamidophos, which leaves residues of a non-persistent nature and
    with a well-known distribution pattern, viz. the outer leaves,
    especially of leafy vegetables, carry considerably higher residues
    than the internal parts of the plants. Some of these outer leaves may
    or may not be discarded as "trimmings" when marketed.

         With only occasional high values, the data in Table 4 indicate
    that residues of methamidophos will rapidly dissipate to low levels.
    With appropriate pre-harvest intervals, from 1-3 weeks, the average
    residues in all vegetables are usually well below 1 mg/kg.

    TABLE 3. Recommended use patterns of methamidophos
                                                                    

    Crop                Dose,          Number          Recommended
                        kg a.i./ha     of              pre-harvest
                                       treatments      interval, days
                                                                    

    Cotton              0.05-1.5       3-5             21
    Cucumbers           0.4 -0.75      3-4             3
    Tomatoes            0.4 -0.75      3-4             3
    Cauliflower         0.4 -1.12      3-5             7
                                             (U.S.A.  14)
    Brussels sprouts    0.56-1.12      3-5             7
    Broccoli            0.56-1.12      3-5             7

    Other brassicas     0.4 -1.12      3-5             7
    Celery              0.56-1.12      5               21
    Lettuce             0.56-1.12      3-4             21
    Potatoes            0.5 -1.12      3               7
    Maize               0.9 -1.5       3               21
    Sugar beet          0.5 -0.6       3-5             28
    Stone fruit         0.5 -1.0       2-3             21
      (peach)
    Tobacco             0.3 -0.6       3-4             14
    Hops                0.3 -2.0       4               21
    Rape                0.28-0.56      2               10
                                                                    



        TABLE 4. Residues of methamidophos in vegetable crops (supervised trials)
                                                                                                                      

    Crop          Dose,          Number        Time after         Residues (mg/kg)            Number       Country
                  kg/ha          of            final              range           average     of
                                 treatments    application                                    values
                                               (w=weeks-d=days)
                                                                                                                      

    Broccoli

    heads         0.56-1.12      3-6           2 w                n.d. - 2.84     0.45        21           U.S.A.
                                               3 w                n.d. - 0.14     0.03        9
                                               4 w                n.d. - 0.09     0.02        7

    leaves        1.12           3-6           2 w                0.22 - 7.62     2.50        7            U.S.A.
                                               3 w                n.d. - 0.88     0.28        7
                                               4 w                n.d. - 0.54     0.16        7

    total         1.12           3-6           2 w                0.16 - 3.74     1.41        7            U.S.A.
                                               3 w                n.d. - 0.57     0.18        7
                                               4 w                n.d. - 0.44     0.13        6

    Brussels sprouts

    heads         1.12           3-5           2 w                0.07 - 0.47     0.26        6            U.S.A.
                                               3 w                0.08 - 0.64     0.27        6
                                               4 w                0.05 - 0.22     0.12        6

    leaves        1.12           3-5           2 w                0.16 - 0.17     0.17        2            U.S.A.
                                               3 w                0.06 - 0.21     0.14        2
                                               4 w                n.d. - 0.10     0.05        2

    total         1.12           3.5           2 w                0.10 - 0.11     0.11        2            U.S.A.
                                               3 w                0.12            0.12        2
                                               4 w                0.05 - 0.08     0.07        2
    Cabbage

    heads         0.56 - 1.12    2-9           1 w                n.d. - 0.7      0.11        11           U.S.A.
                                               2 w                n.d. - 0.35     0.04        11           GFR

    TABLE 4. (Cont'd.)

                                                                                                                      

    Crop          Dose,          Number        Time after         Residues (mg/kg)            Number       Country
                  kg/ha          of            final              range           average     of
                                 treatments    application                                    values
                                               (w=weeks-d=days)
                                                                                                                      

    Cabbage

    savoy         0.3            3             1 w                                0.09        1            GFR
                                               2 w                                0.07        1

    Cauliflower

    heads         0.56 - 1.12    3-12          2 w                n.d. - 0.45     0.11        16           U.S.A.
                                               3 w                n.d. - 0.23     0.06        7            GFR
                                               4 w                n.d. - 0.12     0.03        7

    leaves        0.56 - 1.12    3-12          2 w                0.1 - 6.28      1.85        8
                                               3 w                n.d. - 1.11     0.46        7
                                               4 w                n.d. - 0.62     0.24        7

    Celery

    stalks        1.12           5-7           3 w                0 - 1.55        0.33        6            U.S.A.
    tops          1.12           5-7           3 w                0.08 - 6.0      2.59        6
    whole plant   1.12           5-7           3 w                0.02 - 2.0      0.74        6

    Cucumber      0.6            4-6           0 d                0.19 - 0.45     0.35        3            Mexico
                  (dust treatment)             1 d                0.13 - 0.44     0.32        3
                                               3 d                0.05 . 0.41     0.24        3
                                               5 d                0.06 - 0.2      0.15        3
                                               7 d                0.03 - 0.31     0.16        3

    Eggplant      0.45 - 0.6     7-9           0 d                0.03 - 0.10     0.07        2            Mexico
                                               1 d                0.02 - 0.05     0.04        2
                                               3 d                0.05 - 0.06     0.06        2
                                               5 d                0.03 - 0.04     0.04        2

    TABLE 4. (Cont'd.)

                                                                                                                      

    Crop          Dose,          Number        Time after         Residues (mg/kg)            Number       Country
                  kg/ha          of            final              range           average     of
                                 treatments    application                                    values
                                               (w=weeks-d=days)
                                                                                                                      

    Lettuce                                    7 d                0.05 - 0.06     0.06        2

    head (1)      0.56 - 1.12    3-8           2 w                0.01 - 0.68     0.24        12           U.S.A.
                                               3 w                n.d. - 0.02     n.d.        5
    wrapper
    leaves (2)    1.12           3-4           3 w                0.1 - 0.77      0.19        5            U.S.A.
    (1) + (2)     1.12           3-4           3 w                n.d. - 0.25     0.07        5            U.S.A.

    head          1.12           5             2 w                n.d. - 1.40     0.21        9            U.S.A.

    wrapper                                    3 w                n.d.            n.d.        6
    leaves (2)    1.12           5             2 w                0.01 - 2.42     0.78        5            U.S.A.
                                               3 w                0.02 - 0.15     0.07        6
    (1) + (2)     1.12           5             2 w                0.05 - 0.93     0.31        5            U.S.A.
                                               3 w                n.d. - 0.39     0.09        6

    Peppers       0.34 - 1.12    4-20          1 w                0.04 - 2.3      1.00        7            U.S.A.
                                               2 w                0.08 - 1.09     0.38        8            Mexico
                                               3 w                n.d. - 0.58     0.16        8 )          Australia
                                               4 w                n.d.            n.d.        4 )

    Potatoes      1.12           6-8           1 w                n.d. - 0.11     0.04        12           U.S.A.
                                               2 w                n.d.            n.d.        5            U.S.A.
                                                                                                           Canada

    Tomatoes      0.5            4             1 d                -               0.50        1            Venezuela
                                               3 d                -               0.28        1
                                               7 d                -               0.22        1
                                               10 d               -               0.23        1
                                               14 d               -               0.20        1

    TABLE 4. (Cont'd.)

                                                                                                                      

    Crop          Dose,          Number        Time after         Residues (mg/kg)            Number       Country
                  kg/ha          of            final              range           average     of
                                 treatments    application                                    values
                                               (w=weeks-d=days)
                                                                                                                      

                                               18 d               -               0.19        1
    Tomatoes      0.6 - 1.33     4-10          0 w                0.10 - 5.07     1.05        17           Australia
                                               1 W                0.08 - 1.83     0.55        18           U.S.A.
                                               2 w                0.03 - 1.62     0.30        18           Venezuela
                                               3 w                0.03 - 0.18     0.09        6

                                                                                                                      

    

    In oil seeds, hops and sugar beets

         Rape and cotton plants have been treated with varying amounts of
    methamidophos, ranging from 0.28 kg/ha up to an overdose of 2.24 kg/ha
    and with up to 4 applications. In these experiments residues in the
    harvested seeds ranged from undetectable to 0.06 mg/kg 21-26 days
    after the last treatment, and no residues could be detected at 32-72
    days after application.

         Limited residue data for methamidophos in hops are available.
    After six applications with 0.66 kg/ha dried hops contained 3.0 mg/kg
    at 17 days. After 3 spray applications with 1.8 kg/ha, the residue
    levels of methamidophos amounted to 1.4-2.8 mg/kg at 20 days.

         Sugar beets were sprayed on the foliage 4 times with 0.48 kg/ha.
    The residue levels 23 days after the last application were 0.01 mg/kg
    of methamidophos in the roots and 0.6 mg/kg in the leaves. After 28
    days the roots were free of residues, while the tops contained 0.9
    mg/kg methamidophos.

    In peaches

         Peaches were sprayed with 1 kg/ha of methamidophos under German
    climatic conditions. 1 week after the second of 2 applications
    residues varied from 0.50-1.05 mg/kg (average, 0.73 mg/kg), and 1 week
    later they were 0.28-0.75 mg/kg (average 0.45 mg/kg).

    FATE OF RESIDUES

         The identified metabolites formed from methamidophos are shown in
    Figure 1.

    In animals

         Studies of the absorption, distribution and excretion of
    methamidophos in the rat (Crossley and Tutass, 1969), and lactating
    goat (Lee and Crossley, 1972) are described in the section
    "Biochemical aspects," p. ). Some features of these studies,
    particularly the distribution in tissues, are amplified below.

         Female and male rats each received a single dose of radiolabelled
    methamidophos, administered intragastrically as an aqueous solution
    (Crossley and Tutass, 1969). The doses received by each rat were
    0.16-0.19 mg of 14C methylthio-labelled methamidophos and 0.21 mg of
    32P-labelled methamidophos. In both experiments, the majority of the
    applied dose was excreted within 24 hours. This period of fast
    elimination in which over 50% of the activity was excreted was
    followed by a second phase during which only 1-2% of the applied dose
    was eliminated daily.

         In the experiments with 14C-labelled methamidophos, the major
    excretion route was via the breath (approx. 39% of the applied dose);

    urine and faeces contained 11.1% and 1.5% respectively. In the
    experiments with 32P-labelled methamidophos, on the other hand, the
    majority of radioactivity was eliminated in the urine (until day 14),
    and up to about 20% was eliminated in the faeces. There was no
    accumulation in tissues or organs (see Table 5).

    TABLE 5. Distribution of radioactivity in tissues and organs of
             rats after dosing with labelled methamidophos (Crossley
             and Tutass, 1969)
                                                                       
                  Radioactivity, % of applied dose
                                                                        
    Organ/        14C                                 32P           
    tissue        female rats    male rats            female rats
                  Day 5 - 9      Day 1    Day 28      Day 1     Day 28
                                                                       

    Carcass       21.9           9.9      6.7         11.3      4.4

    Liver         0.4            6.9      0.1         5.6       0.1

    Kidney        0.1            0.5      0.0         0.4       0.0

    Heart         0.3            0.1      0.0         0.1       0.0

    Lung          0.1            -        -           -         -

    Fat           -              0.1      0.0         0.2       0.0

    Muscle        -              0.2      0.1         0.3       0.1

    Total         22.6           17.4     6.9         17.4      4.6
                                                                       

         The degradation of methamidophos in the animal body is hydrolytic
    in nature (Crossley & Tutass, 1969; Tutass, 1968). The degradation
    sequence (Crossley & Tutass, 1969), is shown above
    ("Biotransformation"). Data on the quantitative distribution of
    residues 32P residues in the urine are presented in Table 6.

         In the faeces, the majority of radioactivity was not extractable
    with either water or acetone. That which was extractable showed the
    same degradation profile as in the urine. The non-extractable
    radioactivity was in all probability incorporated into natural
    biochemical constituents.

    TABLE 6. Distribution of 32P in urine of rats dosed with
             32P-methamidophos (Crossley and Tutass, 1969)
                                                                  
                             32P, % of total in sample
                                                                   
    Metabolite*              Male rats              Female rats
                             Day 1    Day 2         Day 1    Day 2
                                                                  

    methamidophos (I)        40       10            40       trace

    OS-dimethyl
    phosphorothioate (II)    5        -             5        -

    methylphosphoric
    acid (III)               40       25            40       30

    phosphoric acid (IV)     15       65            15       70
                                                                  

    * Numbers in parenthesis refer to Figure 1.

         S-methyl-14C-methamidophos was given orally to a goat in order
    to assess its fate in a lactating ruminant (Lee and Crossley, 1972).
    The goat received 3.75 mg. of 14C methamidophos daily after the
    morning milking for 7 consecutive days. Methamidophos was rapidly
    metabolized and about half of the radioactivity rapidly excreted. This
    excreted radioactivity was distributed mainly between the breath and
    urine and, to a lesser extent, the faeces and milk. The activity that
    remained in the animal after the initial rapid excretion was
    eliminated at a slower but constant rate. None of the radioactivity
    remaining in the body was concentrated in any one organ, although
    slightly higher levels were found in the liver than elsewhere. The
    distribution of radioactivity in the goat is summarized in Table 7.
    The results are essentially the same as those found in the rat study
    (Table 5), although a somewhat higher proportion was excreted in the
    breath of the rats.


    
    TABLE 7. Distribution of radioactivity in goat dosed with 14C-methamidophos expressed as
             percentage of applied dose or mg/kg methamidophos equivalents (Lee and Crossley, 1972)

                                                                                                  

    Sample        Dosing Period   Recovery Period    Total           Blood and Tissues
                  (days 0 - 8)    (days 9 - 17)      Excreted
                  %               %                  %                             %          mg/kg
                                                                                                  

    Urine         17.24           0.63               17.87           Bloodx        5.87       -

    Faeces        4.00            0.98               4.98            Liver         3.93       0.22

    Milk          2.49            0.74               3.23            Kidney        0.61       0.16

    Total         23.73           2.35               26.08           Heart         0.61       0.16

                                                                     Mammary       0.82       0.10

                                                                     Brain         0.21       0.08

                                                                     Fatxx         4.13       0.16

                                                                     Musclexxx     33.10      0.16

                  Total recovered = 75%                              Total         49.28      1.04

                                                                                                  

      x Assuming blood to be 10% of the body weight
     xx Assuming fat to be 5% of the body weight
    xxx Assuming muscle to be 40% of the body weight

    

         TLC of urinary samples revealed the presence of methamidophos and
    the first metabolite OS-dimethyl phosphorothioate (II in Figure 1). In
    the sample taken 12 hours after the third dose, 7% of the activity in
    the urine was found to be parent compound and 16% metabolite II.
    Extraction procedures applied to the samples of tissues, blood, milk,
    urine and faeces extracted only small proportions of their activity,
    indicating that the main source of activity was not methamidophos. The
    maximum possible level of methamidophos in milk estimated on this
    basis was 0.008 mg/kg. The maximum content in the milk found by direct
    analysis was 0.003 mg/kg (about 1% of the total activity in the milk).
    Since the data obtained from the goat are similar to those from the
    rats; it is believed that the non-extractable activity in the goat
    tissues, milk, etc. is due to the incorporation of 14C into the
    natural constituents of the body, as in rats.

    In plants

         Methamidophos is an insecticide with systemic activity (Werner,
    1972). The physical and chemical basis of systemic movement in the
    cotton plant was investigated by Hussain et al. (1974).

         Root and leaf treatment of tomato, cabbage and bean plants
    demonstrated that 14C-methamidophos is readily taken up by roots and
    leaves and transported with the transpiration water towards the
    margins of leaves, while little is retained in the stem and petioles.
    The labelled compound accumulating at the margins of leaves is
    essentially only methamidophos, while in the centre of the leaf some
    more polar compounds are present, apparently as the result of
    metabolic degradation. The uptake of methamidophos by roots appears to
    be independent of pH within the physiological range of 3.5-7.5
    (Tutass, 1968b).

         Horler et al., (1975) showed that in tomato plants there is only
    slight movement of the intact insecticide from treated leaves to the
    fruit. After rapid penetration of 14C-methamidophos or/and
    32P-methamidophos into tomato leaves, the residue in leaves and fruit
    in the initial phase has a biological half-life of 7-10 days. However,
    especially in the fruit, after this initial period the rate slows to
    give a half-life of about 6 weeks (Horler et al., 1975). The authors
    assume that intact insecticide is lost from fruits and leaves by a
    mechanism associated with transpiration, rather than by metabolism and
    translocation.

         Werner (1973) also reports rapid absorption of
    methylthio-14C-methamidophos by the roots of Loblolly pine seedlings.
    After 96 hours exposure, an accumulation of radioactivity was evident
    in the needle tips. Besides unchanged methamidophos, 3 compounds were
    isolated from the seedlings. One was identified as the major
    metabolite, OS-dimethyl phosphorothioate (II, Figure 1), and in
    addition two unidentified compounds were detected, of which one

    (Unknown 1) was probably phosphoric acid (VI, Figure 1).
    Methamidophos, II and Unknown 1 were detected in the roots, stems and
    needles, but Unknown 2 only in the needles, of seedlings treated for
    72 and 96 hours (see Table 8).

    
    TABLE 8. Percentage distribution of radioactive methamidophos
             and 14C-compounds from TLC and GLC of pine seedling
             extracts (Werner, 1973)

                                                                                   
                                      Seedling exposure period (h)
                                                                                    

    Compound*            Plant part   6       12      24      48      72      96
                                                                                   

    I (methamidophos)    Roots        80.0    46.0    40.0    35.7    3.3     0.9

                         Stem         0       0       1.6     1.0     1.1     1.7

                         Needles      0       31.0    27.9    26.3    22.0    30.5

    II (OS-dimethyl      Roots        20.0    3.8     1.6     1.0     3.3     3.5
    phosphorothioate)
                         Stem         0       3.8     13.1    6.1     11.0    10.4

                         Needles      0       46.0    26.2    18.4    16.5    17.4

    Unknown 1            Roots        0       0       1.6     1.0     2.2     1.7

                         Stem         0       3.8     4.9     3.1     4.4     2.6

                         Needles      0       19.2    18.1    17.4    19.7    10.4

    Unknown 2            Roots        0       0       0       0       0       0

                         Stem         0       0       0       0       0       0

                         Needles      0       0       0       0       16.5    20.9
                                                                                   

    * Roman numerals refer to Figure 1.
    
         Experiments with methylthio-14C-methamidophos on cabbages and
    tomatoes as well as on plant tissue cultures of sweet potatoes and
    tobacco have shown that degradation occurs chiefly by hydrolysis
    (Chevron, 1968). Hydrolysis first occurs at the P-N bond to yield
    OS-dimethyl phosphorothioate (II, Figure 1), which was consistently

    detected as a metabolite in all tissues investigated. Continued,
    though somewhat slower, hydrolysis of II apparently leads to cleavage
    of CH3S-P and CH3O-P bonds yielding VII and III as major products.
    Quantitative data on the residues of these metabolites are not given.
    The final fate of the radiolabel is its incorporation into plant
    constituents such as pigments, amino acids, carbohydrates and
    structural material (up to 19% of the activity in the sample of
    cabbage plants).

    In soil

         Methamidophos is degraded at a relatively fast rate in soils. In
    laboratory experiments, Leary and Tutass (1968) found half-lives of
    1.9 days in silt soil, 4.8 days in loam soil and 6.1 days in sandy
    soil. Sterilization of silt soil by autoclaving resulted in a
    considerable increase in the half-life, to about 6 weeks.

         In laboratory experiments conducted by Horler et al. (1975),
    methamidophos was also found to undergo rapid degradation. In basic
    soils (pH 7.40 and 7.75), only 3-7% of the original activity was found
    after 4 days; in an acid soil (pH 4.30), 25% was present after 9 days.
    In the basic soils, there were differences in the degradation of the
    metabolites. In clay-loam soil (pH 7.40), the metabolite degraded at a
    slower rate than in loam soil (pH 7.75). Since both soils had a
    similar pH, such differences may be connected with the fact that
    microorganisms play a role in the decomposition.

         In degradation experiments with field soils sampled from depths
    of 0-10 cm, and from depths of 0-15 cm and 15-30 cm, it was noted that
    at sampling on the day of application to the sail, only a fraction of
    the applied methamidophos was still present (Bayer, 1972; Chemagro,
    1974). Within one week, the residue dropped further to 10% of the
    level measured on the day of application. At depths of 15-30 cm, only
    very small amounts of residue (maximum of 0.04 mg/kg) were found in
    the soil, and no accumulation was noted after several applications.

         Leary and Tutass (1968) found that metabolic degradation of
    S-methyl-14-methamidophos in silt soil under aerobic conditions
    resulted after 3 days in the evolution of 70% of the applied dose as
    14CO2. On the other hand, only 7.6% was evolved as 14CO2 under
    aerobic conditions, with 84.6% of the applied activity remaining in
    the soil. Up to about 30% of the activity that remained in the soil
    was not acetone-extractable. Most of the extractable radioactivity was
    in the form of OS-dimethyl phosphorothioate (II, Figure 1), while
    minor amounts were in the form of methamidophos, amino acids and
    carbohydrates. Quantitative data on these constituents were not given.

         Horler et al (1975) also identified OS-dimethylphosphorothioate
    (II) as the major metabolite in soil. However, they also found very
    small amounts of V, VI and III in clay loam soil. In loam soil, VI was
    not found. It is stated that the loss of the methoxy group results in
    the evolution of CO2. Quantitative data are not given.

    In water

         The hydrolysis of methamidophos was examined at elevated
    temperatures in aqueous solutions as a function of pH (Leary, 1968;
    Magee, 1966). In solutions with a pH below 2, the half-life was a
    matter of hours. At pH 9, the half-life was 2.6 days at 25°C and 1.5
    days at 37°C. In mildly acidic or neutral solutions, methamidophos
    showed remarkable stability at temperatures up to 80°C (less than 5%
    hydrolysis in 25 hours). The P-NH2 bond is broken first, followed by
    hydrolysis of the CH3SP grouping.

         Leaching experiments with methamidophos and three soil types
    (muck, sandy loam and loam) (Tutass, 1968c), showed little retention
    of the compound. Soil type apparently had only a minor effect upon
    retention. The compound was least retained in loam.

         Experiments to study the leaching behaviour of methamidophos with
    a standardized soil column technique revealed that about two-thirds of
    the compound was leached out of sandy and sandy loam soils while only
    about one-fifth was leached out of a soil with an increased content of
    organic matter (Bayer, 1972).

         Flint and Shaw (1972) also studied the absorption of
    methamidophos by and its leaching from three different soil types. The
    absorption by soil was very slight, and it was further decreased by
    increasing temperature and decreasing pH. Methamidophos was not
    retarded by the soil when passed through soil columns in water. The
    chemical was found in soil run-off water only in the first two of five
    irrigations. It was degraded in a natural water system outdoors with
    half-lives of 15.9 days in water and 7.5 days in silt. It was
    concluded that although it was leached, methamidophos was degraded
    rapidly in natural water systems.

    In fish

         Bass fingerlings which had been in water containing 0.01 mg/1 of
    methamidophos for eight days, were analyzed. Less than 0.02 mg/kg of
    methamidophos was found in all samples (Stanley, 1971 b).

    In processing and storage

         The effect of simulated commercial processing on methamidophos
    residues in tomatoes was investigated by Morris and Olson (1974). The
    tomatoes were processed to juice (pressed, pasteurized), to canned
    tomatoes (sterilized), to ketchup. (sterilized, pasteurized), to dry
    tomato pomace and to dry tomato pulp. The residues in juice, canned
    tomatoes and ketchup were smaller than those found in whole tomatoes,
    amounting to 89.5, 73.0 and 68.4% respectively, of the residue levels
    prior to processing. On the other hand, the residues in dry tomato
    pomace and dry tomato pulp were 2.0 and 2.5 times the original levels
    respectively.

         The effect on residues of washing in a manner simulating
    commercial packing practice depended upon the treated crop. After
    treatment, the fruits were allowed to stand outdoors for 24 hours.
    Whereas washing green peppers and eggplants did not remove any
    significant residue, washing tomatoes removed approximately 15% and
    washing cucumbers approximately 20% of the methamidophos residue
    (Thornton, 1973).

         Dehydrated celery flakes were prepared commercially by placing
    celery leaves on trays and drying at temperatures of up to 60°C
    (Morris, 1975). Dehydration removed 80% of the weight as water, and it
    was concluded that the dehydration process did not destroy any of the
    methamidophos residue present in fresh celery leaves.

         Cottonseed was processed into delinted seed, meal, hulls. and
    oil. No residue was found in any of the seed samples or in any of the
    fractions from the processed seed. The residue found in the trash
    ranged from 0.1 to 2.7 mg/kg (Chevron, 1976).

         Rapeseed was processed into oil and meal (Chemagro, 1976). The
    following residue levels were measured: rapeseed, 0.02-0.25 mg/kg,
    rapeseed oil, n.d.-0.02 mg/kg and rapeseed meal 0.01-0.30 mg/kg.

         Leary (1968) conducted a study to determine the stability of
    weathered residues of methamidophos on chopped crop samples (broccoli,
    lettuce, cabbage, cauliflower, Brussels sprouts) stored deep frozen
    for several months. No significant evidence of decomposition was
    obtained and there was no indication of any trend towards
    decomposition with increased time of storage.

         Möllhoff (1971), however, noted that methamidophos residues
    decreased by 10-40% in cauliflower samples stored for three months at
    -20°C, and by up to 10% in tomatoes stored under the same conditions.

         In further studies conducted by Chemagro (1976), to investigate
    the effect of frozen storage at about -20°C on methamidophos residues
    in peanut meat, peanut forage, sorghum grain, rapeseed, celery and
    peppers, decomposition ranged from 0 to 22%.

         The effect of frozen storage at about -20°C on methamidophos
    residues in cattle tissues and milk and in poultry tissues and eggs
    has also been studied (Chemagro, 1976). It was found that
    decomposition in poultry liver amounted to 33% after 60 days and in
    cattle liver to 85% after 150 days. On the other hand, the residues
    remained completely stable in cattle steak, fat and milk, and
    decomposition amounted to a maximum of only 13% in eggs, heart and
    gizzard of poultry.

    METHODS OF RESIDUE ANALYSIS

         Methods for the gas-chromatographic determination of
    methamidophos have been developed and published in several
    modifications, but in practically all cases are based on clean-up
    procedures with silica gel columns and GLC with thermionic detection.

         Möllhoff (1971) developed a method for determination in plants,
    soil and water. Maceration with acetone or an acetone/water mixture is
    used for extraction. The limit of determination is generally about
    0.01 mg/kg, but for oil seeds only 0.05 mg/kg and for hops and tobacco
    0.1 mg/ kg. Recoveries in the 0.01-1.0 mg/kg range vary between 80%
    and 100%.

         Leary (1971) also determined methamidophos in crops, but with the
    use of ethyl acetate for extraction. The GLC instrument in this case
    was equipped with a caesium bromide thermionic detector and the method
    is claimed to have a limit of determination of 0.003-0.005 mg/kg. At
    levels of 0.5-0.1 mg/kg the majority of recovery values were from
    90-100%.

         Both these methods have been tested for specificity in
    conjunction with other organophosphorus insecticides. They were found
    to be adequately specific and without interferences from extractives
    with a number of different crops (Olson, 1973).

         Stanley and co-workers have developed methods for residues in
    different forage crops such as hay, peanut meal, sorghum grain and
    rape seed (McNamara & Stanley, 1975) and in animal tissues and milk
    (Stanley, 1971c). Extractions were with either methanol/chloroform or
    acetonitrile and Skellysolve B.

         With minor amendments these methods have been found suitable also
    for the determination of methamidophos in fish and water with limits
    of determination down to 0.02 mg/kg and 0.004 mg/kg respectively
    (Stanley 1971 a).

         These methods for the determination of methamidophos follow
    closely the general pattern for organophosphorus insecticides in
    current multi-residue procedures. Undoubtedly, therefore, they will be
    suitable for regulatory purposes.

    NATIONAL TOLERANCES REPORTED TO THE MEETING

    TABLE 9. National tolerances reported to the meeting
                                                                        
    Country          Crop                     Tolerance,     Pre-harvest
                                              mg/kg          interval
                                                                        

    Australia        Capsicums                0.25           14 days
                     Peaches                  0.25           21 days
                     Tomatoes                 0.25           21 days

    TABLE 9. (Cont'd.)
                                                                        
    Country          Crop                     Tolerance,     Pre-harvest
                                              mg/kg          interval
                                                                        

                     Potatoes                 0.05           7 days

    Canada           Broccoli, Brussels
                       sprouts, lettuce,
                       peppers                1.0
                     Cabbage, cauliflower,
                       cucumbers, eggplant,
                       tomatoes               0.5
                     Potatoes, melons         negligible
                                              residue

    Netherlands      Brassica                 0.1
                     Potatoes                 0.01x

    New Zealand      Brassicas, potatoes      0.1
                     Tomatoes                 0.1            3 days

    South Africa     Peaches                  1.0            21 days
                     Cabbage                  1.0            21 days
                     Potatoes                 1.0            14 days

    U.S.A.           Cauliflower, lettuce
                       tomatoes               2.0
                     Broccoli, Brussels
                       sprouts, cabbage,
                       peppers, cucumbers,
                       eggplant               1.0
                     Melons                   0.5
                     Cottonseed, potatoes     0.1xx
                                                                        

    x = limit of determination
    xx = negligible residues


    APPRAISAL

         Methamidophos is a chemically simple organophosphorus insecticide
    with broad spectrum effects used to control caterpillars, aphids,
    larvae etc. It is active by contact as well as systemically.

         Since 1969 methamidophos has been registered in a number of
    countries around the world, chiefly in regions with a sub-tropical
    climate. Its major uses are pre-harvest treatments of industrial
    crops, fruit and vegetables, mainly with spray solutions at rates from
    0.5-1.5 kg/ha.

         Detailed studies on the metabolic fate of methamidophos indicate
    that the compound is readily taken up by plant roots and translocated
    with the transpiration stream within the plants, i.e. towards the
    edges of the foliage. In studies with the radio-labelled compound, the
    further fate has been followed and a complete degradation pathway with
    final incorporation into plant constituents is suggested, mainly
    through steps involving hydrolytic breakdown.

         The degradation of methamidophos in the animal body is also
    hydrolytic and there are no signs of accumulation in tissues or
    organs. Most of the phosphorus-containing moiety of methamidophos (up
    to about 70%) is eliminated via the urine, while a major part of the
    carbon (about 40% in the rat) is excreted as CO2 with the breath, the
    remainder being found in the urine and faeces.

         The results of extensive residue trials on a number of vegetable
    and agricultural crops are available. The data confirm methamidophos
    as a systemic compound of relatively low persistence. Most of the data
    are from trials under practical conditions which are likely to
    represent good agricultural practice.

         Methamidophos penetrates into the flesh of the fruit in, e.g.,
    tomatoes, peppers, eggplants, etc. Washing or peeling such products
    therefore does not significantly remove residues. In the frozen
    storage of crops treated with methamidophos, residues are found to be
    stable for several months.

         Methamidophos has been found to be degraded fairly rapidly in
    soils and in natural water systems without any signs of accumulation
    or concentration in living organisms.

         Gas-chromatographic methods making use of thermionic detectors
    are available for the determination of methamidopho in various crops
    and animal products. They are combined with appropriate extraction and
    clean-up procedures and are likely to be suitable for regulatory
    purposes.

    RECOMMENDATIONS

         Maximum residue limits are recommended for methamidophos in the
    following commodities at the levels indicated. They refer to the
    parent compound.

                   Limit,                            Limit,
    Commodity      mg/kg          Commodity            mg/kg

    Hops           5              Peppers              1
    Broccoli       2              Sugar beet leaves    1
    Cauliflower    2              Cottonseed           0.1
    Celery         2              Potatoes             0.1
    Lettuce        2              Rapeseed             0.1

                   Limit,                            Limit,
    Commodity      mg/kg          Commodity            mg/kg

    Tomatoes       2              Sugar beets          0.1
    Brussels                      Meat and fat of
    sprouts        1              cattle, goats
    Cabbage        1              and sheep            0.01*
    Cucumber       1              Milk                 0.01*
    Eggplant       1
    Peaches        1

    * At or about the limit of determination

    FURTHER WORK OR INFORMATION

    DESIRABLE

    1.   Further studies an the teratogenic potential in a suitable
         species.

    2.   Further studies to elucidate the contribution of acephate and
         metamidophos alone or in combination in depressing cholinesterase
         activity.

    3.   Further information on the level and fate of residues during
         cooking and processing of fruit and vegetables.

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    See Also:
       Toxicological Abbreviations
       Methamidophos (HSG 79, 1993)
       Methamidophos (ICSC)
       Methamidophos (JMPR Evaluations 2002 Part II Toxicological)
       Methamidophos (Pesticide residues in food: 1979 evaluations)
       Methamidophos (Pesticide residues in food: 1981 evaluations)
       Methamidophos (Pesticide residues in food: 1982 evaluations)
       Methamidophos (Pesticide residues in food: 1984 evaluations)
       Methamidophos (Pesticide residues in food: 1985 evaluations Part II Toxicology)
       Methamidophos (Pesticide residues in food: 1990 evaluations Toxicology)