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    METHAMIDOPHOS

    EXPLANATION

         Methamidophos was evaluated by the Joint Meeting in 1976, when an
    ADI was allocated (Annex 1, FAO/WHO, 1977a). A toxicological monograph
    was prepared (Annex 1, FAO/WHO, 1977b). Some relevant toxicological
    studies from Industrial Bio-test Laboratories (IBT), supporting the
    1976 evaluation, have been found to be invalid.

         The compound was re-evaluated in 1982, when some substitute
    studies were made available (Annex 1, FAO/WHO, 1983a). A monograph
    addendum was prepared (Annex 1, FAO/WHO, 1983b). The 1982 JMPR
    allocated a temporary ADI and requested long-term studies, a
    carcinogenicity study, and a reproduction study.

         The required studies, along with other toxicological studies,
    have been submitted and are summarized in this monograph addendum.
    Those sections of the 1976 evaluation summarizing invalid IBT studies
    have been superseded by the 1982 and 1985 re-evaluations.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution, excretion, and metabolism

    Rat

         Male and female albino rats were each given orally a single dose
    of 32p_ labelled methamidophos at a level of 15 mg/kg b.w. After 24
    hours, 77% of the administered radioactive dose was recovered in the
    urine.

         Identified urinary metabolites were; phosphoric acid, S-methyl
    thiophosphoric acid, O,S-dimethyl thiophosphoric acid, O-methyl
    phosphoric acid amide, and S-methyl phosphoramidothioic acid.
    Unchanged methamidophos and a highly non-polar unidentified metabolite
    were detected in the urine (Fakhr et al., 1982).

         The tissue distribution and excretion of 14CH3S-methamidophos
    was followed in female Sprague-Dawley rats after i.v. injection at a
    toxic, but non-lethal, dose (8 mg/kg). Radiolabel was rapidly
    distributed to all tissues at approximately equal concentrations. Peak
    tissue levels were achieved within 1-10 minutes except in the central
    and peripheral nervous system, where peak levels (40 nmol/g) were

    found between 20 and 60 minutes, corresponding to peak signs of
    toxicity. Within 24 hours of dosing, 47% of the radioactivity was
    recovered in the urine and 34% as 14CO2, with < 5% in the faeces
    over 7 days (Gray et al., 1982).

    Effects on enzymes and other biochemical parameters

         Acetylcholinesterase (AChE) inhibition was measured in
    erythrocytes, plasma, and various regions of the central nervous
    system (CNS) at selected times after i.v. administration of
    methamidophos at 8 mg/kg to rats. The degree of Ache inhibition in 3
    CNS regions was similar, reaching a minimum activity of 15-20% of
    control values at 30-60 minutes, when toxicity was most severe. The
    degree of erythrocyte AChE inhibition was less that that of the CNS,
    although the time course was similar. Plasma AChE inhibition was more
    rapid than that of the CNS or erythrocytes, and reactivation was
    slower. When similar concentrations of methamidophos to those found
    in vivo were incubated with CNS homogenates, plasma, or erythrocytes
    in vitro (3  10-3), a similar degree of inhibition occurred over
    the same time course. Therefore, the authors concluded that
    cholinergic toxicity produced by methamidophos is a result of the
    in vivo stability of this compound, which permits its entry into the
    nervous system in sufficiently-high concentrations to inhibit AChE
    (Gray et al., 1982).

         The methylthiophosphorous linkage of methamidophos is cleaved in
    the reaction, leading to the inhibition of acethylcholinesterase
    (Thompson & Fukuto, 1982).

    Special studies on embryotoxicity and teratogenicity

    Rat

         Groups of 22-26 pregnant female CD rats were administered once
    daily, by gavage, methamidophos (technical grade, 70.5% a.i.) at dose
    levels of 0, 0.3, 1.0, or 3.0 mg/kg b.w. on days 6 through 15 of
    gestation, inclusive.

         These dosages were based on preliminary work using dams dosed at
    0.5, 1.5, or 4.5 mg/kg b.w. Dams in the 4.5 mg/kg b.w. group aborted
    their litters at approximately day 15 of gestation; dams treated at
    1.5 mg/kg b.w. carried their litters to day 21. The positive control
    group received 350 mg/kg b.w. hydroxyurea on days 9, 10, and 11 of
    gestation. Body weights and feed consumption were measured on days 6,
    13, and 21 of gestation. On day 21 of gestation, rats were sacrificed
    and Caesarean sections were performed. Foetuses were inspected grossly
    and were preserved for internal or skeletal examination.

         Signs of intoxication typical of cholinesterase-inhibiting
    compounds were observed only in the rats at 3.0 mg/kg b.w. on days 6-8
    to day 20 of gestation. No mortality occurred in any of the groups.
    Body weights and feed consumption for rats at 3.0 mg/kg b.w. were
    significantly lower than those of the controls from days 13 to 21 of
    gestation; body-weight gain (absolute and corrected) was also
    significantly reduced.

         There were no statistically-significant differences between
    control and treated groups with respect to mean values per litter of
    implantations, early resorptions (no late resorptions occurred in any
    group), or live foetuses.

         The mean weights of live foetuses from dams at 3.0 mg/kg b.w.
    were significantly lower than those of the controls.

         There were no differences between control and treated groups with
    respect to the incidence of foetuses with gross internal or skeletal
    abnormalities. Increased incidences of abnormal foetuses were observed
    in the positive control group.

         The no-effect level for maternal and foetal toxicity was
    1.0 mg/kg b.w.; that for embryotoxicity and teratogenicity was
    3.0 mg/kg b.w. (Hixson, 1984a).

    Special studies on reproduction

         Groups of CD rats (26/sex/dietary level) were fed diets
    containing methamidophos (technical grade, 70.5% purity) at levels of
    0, 3, 10, or 33 ppm. After at least 100 days of dosing, the F0 rats
    were mated to start a two-generation reproduction study with one set
    of F1 litters and 2 sets of F2 litters (F2a and F2b). Because
    mating was done on a 2-females-to-l-male basis, only half of the males
    in each group were used for mating. The remaining 13 males per group
    were continued on treated feed for possible use as replacement
    breeders.

         Necropsy was performed on F0 and F1 parents and F1a, F2a, and
    F2b weaned pups. Tissues processed for histopathology included
    reproductive organs from F0 males and females (when available),
    reproductive organs from F1 male and female adults, and gross
    lesions.

         The percent of F0 dams delivering was reduced in all treated
    groups, but not in a dose-related pattern. During gestation of F0
    dams, feed consumption was comparable among groups, whereas body-
    weight gain of the 33-ppm dams was lower than in the controls.
    Although there was a trend toward decreased live births in F1 litters
    with increasing dose, the differences were not statistically
    significant. There was also a trend toward decreased viability

    compared with controls during the course of lactation; the difference
    was not statistically significant. For F1 pups in the 33-ppm dietary
    groups, mean pup weights from lactation day 4 onward and mean litter
    weights from lactation day 7 onward were significantly lower than in
    controls.

         Among F1 parents, rats in the 33-ppm dietary level had body
    weights significantly lower than controls throughout the growth
    period.

         The number of F1 dams delivering litters (as percent of sperm-
    positive females) were reduced in the 10-ppm and 33-ppm groups during
    production of F2a litters and in all treated groups during production
    of F2b litters; in both cases no clear dose-related pattern was
    evident. During gestation of F2a and F2b litters, body-weight gains
    of dams in the 33-ppm group were lower than in controls and in the
    other 2 treated groups, but not statistically-significantly different
    from controls.

         As with F1 litters, F2a and F2b litters showed a trend toward
    decreased live births, decreased lactation indices and decreased
    viability indices with increasing dose during lactation; however, the
    differences were statistically-significantly different from controls
    only on lactation day 14 for the mean number of pups per litter and
    the viability index of the 33-ppm F2a group and for the mean number
    of pups per litter of the 33-ppm F2b group.

         In the 33-ppm group, the F2a mean litter weight was
    significantly reduced compared to controls from day 1 onward, and the
    mean pup weight was significantly reduced throughout lactation. In the
    33-ppm group, the F2b mean litter weight was significantly reduced
    compared to controls throughout lactation, but the mean pup weight was
    reduced only on lactation day 7.

         Sporadic differences from controls in absolute and relative gonad
    weights of adults and pups gave no evidence of a dose-related effect.

         Gross and microscopic changes were observed in control and test
    groups of each generation and were considered unrelated to treatment.

         Statistically-significant effects of methamidophos on
    reproduction occurred only at the 33-ppm dietary level; thus the no-
    effect level in this study was 10 ppm (Hixson, 1984b).

    Special studies on carcinogenicity

    Mouse

         Groups of CD1 albino mice (50 males and 50 females/sex/dietary
    level; 10 males and 10 females in the satellite groups) were fed diets
    containing methamidophos (70% purity) at levels of 0, 1, 5, or 25 ppm
    for 106 weeks.

         Mice in the satellite groups were used for haematology
    determinations at 6 months and 1 year. Ten mice were randomly selected
    among surviving mice for haematology at termination. All mice found
    dead or moribund-sacrificed during the study, interim sacrificed at 1
    year, and terminal sacrificed were subjected to gross necropsy. The
    adrenals, brain with entire brainstem, gonads, heart, kidneys, liver,
    lungs, and spleen were weighed. A number of tissues and organs from
    all animals were subjected to histopathological examination.

         The administration of the test compound had no toxocological
    effect on behaviour, occurence of masses, or mortality. Feed
    consumption of the controls and those in the 1-ppm and 5-ppm groups
    were generally comparable. The 25-ppm females had a fairly consistent
    significant decrease in feed consumption after one year. Mean body
    weights of male and female mice in the 25-ppm group were significantly
    lower than controls in the second half of the study. Haematological
    values gave no indication of a treatment-related effect.

         Average absolute organ weights were generally comparable between
    the control and treated groups, except for lung weights of the 25-ppm
    female mice, which were higher than those of the controls, possibly
    due to the increased incidence of interstitial pneumonia present in
    that group. Relative average weights of adrenals, brain, heart,
    kidneys, and lungs of the 25-ppm females and of the brain of the
    25-ppm males were significantly higher than those of the controls,
    possibly due to significantly-decreased body weights at the 25-ppm
    dietary level.

         Other than an increase in interstitial pneumonia in the 25-ppm
    females and males, the non-neoplastic histopathologic observations
    were those of spontaneous lesions of aging mice and were comparable
    between dietary levels.

         The neoplastic histopathologic observations were naturally-
    occurring neoplasms of aging mice. There were no unusual or rare
    tumours observed. On the basis of type, site, frequency distribution
    by sex, and dietary level, there was no indication of a dose-related
    effect. Moreover, there were no dose-related increases in animals with
    tumours (either single or multiple), with total tumours, with total
    benign tumours, with only single or multiple benign tumours, with at
    least one benign tumour, or with both benign and malignant tumours.

    There was an increase, interpreted as random, in total malignant
    tumours found in female mice fed 1 and 5 ppm, but not 25 ppm,
    methamidophos when compared to controls. There was also an increase in
    the number of animals with only malignant tumours in female mice fed 5
    and 25 ppm methamidophos. These increases in malignant tumours were
    interpreted by the author as random, due to: 1) multiple tabulation of
    metastatic tumours and malignant lymphomas in 1 animal; 2) the lack of
    dose-relationship trends in animals with at least 1 malignant tumour
    and animals with both benign and malignant tumours; and 3) there was
    no dose-response relationship in the above-mentioned increases. In
    summary, there was no evidence of induced oncogenicity for mice
    consuming up to and including 25 ppm methamidophos in the diet for 106
    weeks.

         The no-effect level in this study was 5-ppm, equal to 0.67 mg/kg
    b.w./day and 0.78 mg/kg b.w./day for males and females, respectively
    (Hayes, 1984a).

    Special studies on mutagenicity

    See Table 1.

    Acute toxicity

    See table 2.

         When administered to male rats, a combination of 53% cyfluthrin
    and 47% methamidophos had a lesser toxic effect (LD50 = 26.0 mg/kg
    b.w.) than expected (LD50=17.0 mg/kg b.w., assuming an additive
    effect) (Heinmann, 1983),

    Short-term studies

    Dog

         Groups of Beagle dogs (6/sex/dietary level) were fed diets
    containing methamidophos (70% purity) at levels of 0, 2, 8, or 32 ppm
    for 52 weeks.

        Table 1.  Special studies on mutagenicity with methamidophos
                                                                                                           

    Test                          Test                Range of doses      Result              Reference
    organism                      substance           or concentration
                                                      tested
                                                                                                           

    S. typhimurium                Methamidophos       0.1-10.0 mg/        No significant      Machadao
    TA1535, TA1537,               technical           plate               differences of      et al.,
    TA1538, TA98,                 (% a.i. not                             revertants          1982
    TAlO0                         given)                                  compared to
                                                                          negative
                                                                          control.*

    Mouse:

    Dominant lethal               Methamidophos       0, 5, 50, 150       No significant      Eisenlord,
    assay - 12                    technical           ppm (not            differences         et al.,
    males/group;                  (74.3% a.i.)        corrected for %     indicative of a     1984
    8 week mating                                     a.i.), 5-day        dominant lethal
    cycle, 2 females                                  feeding             effect between
    to 1 male                                                             control and
                                                                          treated groups.

    Mouse in vivo:

    Chromosomal                   Methamidophos       0.6, 2.0, 6.0,      No significant      Esber, 1983
    aberrations                   technical           9.0, 12.0 mg/       differences in
    in bone marrow                (74.4% a.i.)        kg b.w. by          chromosomal
    cells (4 M +                                      gavage (as          aberrations at 6,
    4 F/dose level/                                   methamidophos)      24, or 48 hrs.
    test time)                                                            between control and
                                                                          treated groups.
                                                                                                           

    Table 1.  (Con't)
                                                                                                           

    Test                          Test                Range of doses      Result              Reference
    organism                      substance           or concentration
                                                      tested
                                                                                                           

    DNA damage:

    E. coli (K12)                 Methamidophos       0.625-10,000        No differences in   Herbold,
     p3478, DNA                   (71.2% a.i.)        g/plate            the zones of        1983
     repair -                                         (not corrected      growth inhibition
    E. coli W3110                                     for % a.i.)         indicative of DNA
     DNA repair +                                                         damage.*
                                                                                                           

    *    Both with and without S-9 mix

    Table 2.  Acute toxicity of methamidophos in the rat
                                                                                                     

              Test                                  LD50*            LC50*
    Sex       comp.               Route             (mg/kg b.w.)     (mg/m3)        Reference
                                                                                                     

    M         Methamidophos       Oral              21.0                            Duke et al., 1982
              (73.1% a.i.)

    F         Methamidophos       Oral              16.2                            Duke et al., 1982
              (73.1% a.i.)

    M         Methamidophos       inhalation                         377            Sangha, 1983
              technical           1 hr. exp.
              (75.1% a.i.)

    F         Methamidophos       inhalation                         241            Sangha, 1983
              technical           1 hr. exp.
              (75.1% a.i.)

    M         Methamidophos       inhalation                         63.2           Sangha, 1984
              technical           4 hrs. exp.
              (70.5% a.i.)

    F         Methamidophos       inhalation                         76.5           Sangha, 1984
              technical           4 hrs. exp.
              (70.5% a.i.)
                                                                                                     

    *    Not corrected for the % of a.i.
    

         Cholinesterase (ChE) activity of plasma and erythrocytes was
    determined on all dogs 3 times at weekly intervals prior to initiation
    of the study. After initiation, determinations were made twice monthly
    for 3 months, then every month and at termination of the study. Brain
    cholinesterase activity was determined at termination.

         Haematology, blood chemistry, and urinalysis were performed on
    all dogs prior to initiation, monthly for 3 months, then every other
    month and prior to termination of the study. Gross anatomical
    examination was performed on all the dogs sacrificed at termination. A
    number of tissues and organs from all animals were subjected to
    histopathological examination.

         No mortality occurred during the study. Daily observations for
    toxicological effects did not reveal treatment-related effects. The
    administration of the test compound did not affect feed comsumption or
    body weight.

         Plasma, erythrocyte, and brain cholinesterase activity of male
    and female dogs in the 2-ppm group were not significantly (< 20%)
    different from control values at each test period. At 8 and 32 ppm, a
    strong dose-related inhibition in cholinesterase activity, that
    remained constant throughout the study, was observed, except for the
    plasma cholinesterase in the 8-ppm females.

         Although statistically-significant differences in haematological,
    clinical chemistry, and urinalysis values between control and treated
    groups occurred sporadically, there was no evidence of treatment- or
    dose-related trends.

         Ophthalmological examination did not reveal any effect of
    treatment. Absolute and relative organ weights were not affected by
    the treatment. Gross necropsy and histopathological examination gave
    no indication of a treatment-related effect.

         The no-effect level in this study for ChE inhibition was 2 ppm,
    equal to 0.06 mg/kg b.w./day for both male and female dogs (Hayes,
    1984b).

    Long-term studies

    Rat

         Groups of Fischer 344 rats (50/sex/dietary level, plus 10 reserve
    rats and 10 replacement rats/sex/dietary level) were fed diets
    containing methamidophos (70% purity) at levels of 0, 2, 6, 18, or
    54 ppm for 2 years.

         Animals were observed for toxicological effects, abnormalities,
    masses (by palpation), and mortality. Feed consumption and body
    weights were determined weekly.

         Haematology and blood chemistry parameters (including
    cholinesterase) were determined at initiation, 6, 12, 18, and 24
    months. Reserve rats were used for testing at 6 and 12 months, and 10
    randomly-selected animals from the experimental groups were used for
    testing at 18 and 24 months. Also, plasma, erythrocyte, and brain
    cholinesterase inhibition were determined on control and 2-ppm
    replacement rats at 1 month. Due to a slight decrease in plasma
    cholinesterase activity at 12 months in 2-ppm female reserve rats,
    plasma and erythrocyte cholinesterase determinations were made on 10
    male and 10 female rats from all dietary levels of chronic-study
    animals at 12 and 15 months.

         All moribund rats (which were sacrificed), all rats found dead
    during the study, and all rats interim-sacrificed at 1 year and at
    termination were subjected to gross necropsy. A number of tissues and
    organs from all animals were subjected to histopathological
    examination.

         The animals of the 2- and 6-ppm groups did not differ from the
    control animals in behaviour or appearance. Most animals of the 18-
    and 54-ppm groups showed, after about 20 weeks from the start of the
    study, loose stools, urine staining, rough coats, and skin lesions
    (predominantly tail rash) as the most frequently-seen signs. The
    number of masses, time of their first observation, and mortality were
    not affected by treatment. Mortality in all groups was in the range
    2-6% and 18-30% at 78 and 105 weeks, respectively. Feed consumption at
    all dietary levels, including the controls, was erratic and no clear
    trend was apparent. Decreased body weights were observed in male rats
    at 18 and 54 ppm and in female rats at the 54-ppm dietary level.

         Although some statistically-significant differences occurred in
    haematology and blood chemistry values, there was no evidence of a
    dose-related effect.

         A strong, dose-related inhibition of plasma, erythrocyte, and
    brain cholinesterase activities was observed at each test period in
    the 6-, 18-, and 54-ppm groups, compared to the controls. The degree
    of inhibition was comparable for both sexes and remained almost
    constant throughout the study. The 2-ppm dietary level was the no-
    effect level for cholinesterase activity.

         Statistically-significant differences were observed in absolute
    and relative organ weights for males at 18 and 54 ppm and for females
    at 2, 6, 18, and 54 ppm, but they were within the normal range of
    untreated mature Fischer 344 rats (historical data for the laboratory
    were provided) and no dose-related effect was apparent.

         Gross and histopathological findings were comparable between
    control and treated groups. The type, site, time of onset, and
    incidence of neoplastic changes gave no indication of an oncogenic
    effect of methamidophos.

         The no-effect level in this study was 2 ppm, based on ChE
    inhibition (Hayes, 1984c).

    Observations in man

         "In workers engaged in the manufacture of methamidophos-
    formulated products an occasional temporary inhibition to a minor
    degree of cholinesterase activity was observed" (No determinations
    presented) (Kollert, 1981).

         There have been "no damaging effects on the well-being of the
    people engaged with the formulation of methamidophos" (Miksche, 1981).

         The clinical and electrophysiological findings in 10 patients
    (6 males aged 14-28 years), who developed polyneuropathy after
    exposure to the organo-phosphate (OP) insecticide "Tamaron(R)"
    (marketed in Sri Lanka) were analysed. The illness is characterized by
    2 phases, an initial phase of cholinergic crisis, which responds to
    atropine or 2-PAM, and a delayed phase of paralysis of limbs, which
    develops 2-4 weeks after poisoning. Paralysis first affects the distal
    muscles of the lower limbs, and 2-4 days later the muscles of the hand
    and forearm are affected. On examination the affected muscles show
    weakness and wasting of varying severity. Four patients seen late in
    the course of the disease also had evidence of pyramidal-tract
    dysfunction. The late development of pyramidal-tract signs has also
    been reported in poisoning due to another OP compound, tricresyl
    phosphate.

         Electromyography of the distal limb muscles showed evidence of
    denervation to varying degrees. Motor nerve conduction was impaired in
    the distal segments of the nerves, while conduction in the proximal
    segments remained unaffected until the muscles were completely
    denervated. Senesory conduction was unaffected.

         An unusual feature of the polyneuropathy caused by Tamaron(R) was
    the asymmetry of neural involvement. In all patients, the right hand
    was affected more than the left hand, clinically as well as
    electrophysiologically. The observation that in all the cases the
    dominant limb was affected more severely raises the possibility that
    factors such as excessive use and fatigueability of muscles has a
    bearing on the pathogenesis of the neurophathy in OP poisoning
    (Senanayake, 1981; Senayake, 1984).

         Ten isolated cases of acute polyneuropathy seen over 3 years in
    Sri Lanka were reported. All 10 developed after poisoning by
    formulations of technical grade Tamaron(R), the main ingredient of
    which is methamidophos.

         A 22-year-old Sinhalese man was admitted to the hospital in an
    unconscious state, having ingested about 80 ml of 60% (w/v)
    Tamaron(R), in a suicide attempt, a few hours previously. The
    diagnosis of organophosphate poisoning was confirmed clinically by the
    presence of papillary constriction, muscular fasciculation, and
    profuse sweating. The patient was treated with atropine (270 mg in the
    first 24 hours), and with furosemide and penicillin. He remained
    unconscious for 24 hours, and then recovered gradually over the next 3
    days. He was discharged 5 days after admission, with no symptoms
    except blurring of vision, which lasted for several days. Ten days
    after discharge he had pain with "pins and needles" in the feet,
    lasting for 3 days. This was followed by weakness of the feet and, a
    day later, by weakness of the hands. At the height of weakness, he had
    marked difficulty in walking and using his fingers.

         On examination, 1 month after the onset of weakness, he was
    unable to move his fingers against resistance and had bilateral
    footdrop, with marked weakness of the dorsiflexor muscles and the
    evertors of the feet. The muscle power of the knee flexors and the hip
    flexors was slightly impaired, but the tone of the proximal muscles
    was increased and of a spastic type. The tendon reflexes were
    exaggerated, except that the ankle jerks were absent. The plantar
    responses were flexor. Sensory testing, including 2-point
    discrimination, revealed no abnormalities.

         The results of the following investigations were within normal
    limits: erythrocyte sedimentation rate; haemoglobin and blood picture;
    white-cell count and differential-cell count; fasting blood sugar;
    liver-function test; urinalysis for albumin, porphobilinogen, and
    urinary sediment; and cerebrospinal-fluid test for sugar, proteins and
    cells. Electromyography of the distal muscles of the limbs showed
    changes due to denervation, but the motor-conduction velocity in the
    fastest-conducting fibers of the peripheral nerves supplying those
    muscles was relatively normal. During the 1-month stay in the
    hospital, with daily physiotherapy, the patient had a considerable
    improvement in muscle power.

         The clinical and laboratory findings in the other 9 cases were
    similar. Six had ingested the poison in an attempt at suicide. In the
    other 3, the exposure had been accidental; one had ingested the poison
    while attempting to aspirate the insecticide through a tube from the
    spraying machine, another had spilled the poison on his body while
    opening the bottle, and another had become intoxicated while spraying
    the insecticide. There was good evidence that each of the 10 patients
    had used Tamaron(R).

         The patients had an acute cholinergic crisis soon after exposure
    to the insecticide, with a polyneurophathy developing 2 to 3 weeks
    later. Six patients who were followed for 8 weeks or more also had
    evidence of pyramidal-tract involvement. Predominant motor paralysis

    affecting the distal muscles of the limbs, minimal sensory
    abnormalities, and calf pain preceding the onset of weakness are
    typical of polyneuropathy caused by organophosphate compounds, as are
    the electrophysiologic findings of partial denervation, with surviving
    fibres conducting at normal rates and the pyramidal-tract signs noted
    during the late stage of illness. All these features and the
    circumstantial evidence strongly suggest that the neurologic
    abnormalities in these patients were the result of delayed
    neurotoxicity caused by an organophosphate contained in the
    insecticide labeled "Tamaron(R)".

         Polyneuropathy in human beings had not been thought to be
    associated with this compound, as it has not produced neurologic
    damage in animals. It had been assumed that methamidophos is free of
    delayed neurotoxicity. However, the delayed neurotoxicity of some
    organophosphate compounds can only be demonstrated experimentally by
    using doses well above the short-term mean lethal dose, protecting the
    animal from the cholinergic crisis with atropine and oxime
    reactivators.

         The Tamaron(R) sold in Sri Lanka is formulated locally; it
    contains methamidophos as a 60% (w/v) solution in ethylene glycol
    monomethyl ether, with an added dispersing agent (5%). The trace of
    material remaining in the bottle from 1 of the above cases was
    identified as a typical formulation of Tamaron(R), which, besides
    methamidophos, normally contains small amounts of several related
    compounds as impurities (principally an isomer and the N-methyl
    analogue of methamidophos). Preliminary studies were performed on 2
    samples of Tamaron(R) purchased in Sri Lanka, and compared with
    results with a purer sample of methamidophos (95% pure). The
    formulated material, which contained impurities similar to the ones in
    the sample analysed after poisoning, was much more potent in acute
    toxicity tests than an equivalent amount of methamidophos dissolved in
    water. However, the high potency did not appear to be due to any of
    the several impurities that have been identified. It is probably due
    to alterations in the pharmacokinetics of methamidophos caused by the
    solvent. The solvent may increase absorption or it may prolong the
    circulation life of the agent. When either pure or impure
    methamidophos was administered to hens at about twice the unprotected
    median-lethal dose, 50% inhibition of the target protein involved in
    initiation of neuropathy (commonly called neurotoxic esterase) was
    found. Thus, although no neuropathic response has ever been observed
    in hens given any formulation of methamidophos, the results of the
    target-protein assays deliver a clear warning (Senanayake & Johnson,
    1982).

    COMMENTS

         Pharmacokinetic and metabolism studies indicate that
    methamidophos is rapidly absorbed, distributed, metabolized and
    excreted, mainly via urine as acid metabolites and through the expired
    air as CO2.

         In addition to the rabbit study evaluated in 1982, a no-effect
    level for embryotoxic/teratogenic effects was established in a rat
    study. A no-effect level was also found from data for reproductive
    effects.

         Methamidophos was found to be non-mutagenic in bacterial and
    in vivo assays. There were no indications of oncogenicity in a mouse
    oncogenicity study or in a rat chronic toxicity/oncogenicity study. A
    new 1-year dog study confirms the NOEL used for the derivation of the
    1982 temporary ADI.

         Methamidophos caused delayed polyneuropathy in man following
    excessive exposure. However, maximum tolerated doses in hens failed to
    cause delayed neuropathy.

         The toxicology monograph prepared by the present meeting
    supersedes the monograph prepared in 1976.

    TOXICOLOGICAL EVALUATION

    LEVEL CAUSING NO TOXICOLOGICAL EFFECT

         Rat: 2 ppm in the diet, equal to 0.1 mg/kg b.w.
         Dog: 2 ppm in the diet, equal to 0.06 mg/kg b.w.

    ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN

         0 - 0.0006 mg/kg b.w.

    FURTHER WORK OR INFORMATION DESIRED

         Observations in man

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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: 1976 evaluations)
       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: 1990 evaluations Toxicology)