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    METHIDATHION

    First draft prepared by M. Caris,
    Bureau of Chemical Safety
    Health and Welfare Canada, Ottawa, Canada

    EXPLANATION

         Methidathion is a broad-spectrum organophosphate insecticide,
    whose mode of action is by inhibition of acetylcholinesterase.
    Methidathion has been previously evaluated by the Joint Meeting in
    1972 (Annex I, reference 18) when a Temporary ADI of 0.005 mg/kg bw
    was allocated and in 1975 (Annex I, reference 24), when an ADI of
    0.005 mg/kg bw was allocated.

         The purpose of the present evaluation was to review additional
    toxicity data which had been generated in an effort to compliment
    and update the existing data base on methidathion. The first
    comprehensive review of methidathion (Annex I, reference 19)
    indicated that the technical material contained a minimum of 95%
    pure active ingredient. The purity of the technical material
    reported in the presently reviewed studies ranged from 92.6-99.95%.

         In order to facilitate a comprehensive review of the toxicology
    data on methidathion, relevant summaries from previously published
    monographs and monograph addenda (Annex I, references 19 and 25)
    have been included herein.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution, and excretion

    Mice

         Male and female CFI mice were treated dermally with 14C-
    radiolabelled methidathion in the carbonyl carbon of the thiadiazole
    ring in acetone solution or formulated in petroleum hydrocarbon with
    emulsifier (the ratio of active ingredient to petroleum hydrocarbon
    to emulsifier was 6:10:1). The actual dermal dose was stated to be
    12 mg/kg bw. The test solutions for both sexes were well absorbed
    through the skin as measured over a 72-h period, with residual
    radioactivity on the skin in the acetone group of 0.47-0.67% and in
    the formulated product of 0.35-1.27% of the dose. The highest
    concentrations of radioactivity were recovered in the expired CO2
    (50.85-64.1%) and urine (14.48-23.47%). Radioactivity found in
    tissues (0.3-0.7%) and blood (0.03-0.21%) was minimal. Total
    recovery represented 83-94% of the administered dose. The half-lives
    for the testing solutions on the skin were calculated for the
    acetone group to be 9.1 and 10.5 h for males and females, and for
    the formulated group to be 10.4 and 10.9 h for males and females,
    respectively. Blood and tissue levels appeared to plateau
    approximately 4 h post-dosing, with tissue levels rarely exceeding 4
    ppm (Simoneaux & Marco, 1984).

    Rats

         Methidathion, 14C-radiolabelled in the carbonyl carbon of the
    thiadiazole ring was administered by gavage to groups of 5 male and
    5 female Charles River CD rats as a single oral nominal dose of 0.25
    or 2.5 mg/kg bw. A third test group was pretreated with unlabelled
    methidathion for 14 days at the low dose of 0.25 mg/kg bw/day
    followed by a single oral 14C-radiolabelled dose of methidathion
    at 0.25 mg/kg bw. Two rats/sex served as vehicle (3% cornstarch
    suspension with 0.5% polysorbate-80) controls. The total recovered
    radioactivity accounted for 75.1-92.9% of the administered dose. The
    data generated from the present study indicate that the principal
    route of elimination was via the urine, with 30.3-37.1% of the
    radioactivity excreted at the low dose and from 41.8-57% excreted at
    the high dose. Residual tissue levels determined 7 days post-dosing,
    generally accounted for less than 1% of the dose with highest
    concentrations of radioactivity found in the liver, carcass and
    bone. Faeces contained only 2.2-2.6% of the administered
    radioactivity. Radioactivity in respired CO2 was not measured. The
    half-lives of elimination in the urine of 14C-labelled
    methidathion ranged from 7.4 to 9.7 h. There were no obvious

    differences in the distribution patterns when consideration was
    given to dose levels administered, pretreatment or sex (Szolics &
    Simoneaux, 1987a).

         Groups of 2 SD rats/sex were treated orally by gavage with a
    single dose of 14C-methidathion radiolabelled on the carbonyl
    group at a dose of 0.295 or 2.949 mg/kg bw (as suspensions in 3%
    cornstarch suspension containing 0.5% polysorbate-80). Overall
    radioactive recovery accounted for 99.6-102.5% of the administered
    dose. The primary route of elimination was via the urine with 54.2-
    56.9% of the dose excreted after 96 h. The second highest source of
    radioactivity was recovered from expired CO2, representing 32.2-
    34.4% of the radioactivity at the low dose and from 41.2-43.5% of
    the administered dose at the higher dose level. Radiolabelled CO2
    was detected within 4 h post-dosing at both dose levels ranging from
    3.3-7.5% of the dose, suggesting early fragmentation of the
    thiadiazole ring. Radioactivity in the faeces accounted for 2.9-4.5%
    and from 8.2-11.6% of the dose for the low- and high dose level,
    respectively. There were no major differences in elimination
    patterns with respect to sex (Szolics & Simoneaux, 1987b).

         Methidathion, 14C-labelled in the methoxy group was
    administered as a single oral dose to 2 SD rats/sex at a dose of
    2.597 mg/kg bw (in a 3% cornstarch suspension containing 0.5%
    polysorbate-80). Total radioactive recovery represented 93% of the
    administered dose. The major route of elimination was via the urine,
    which in males comprised 39.8% and in females, 48.3% of the
    administered radiolabel. The level of radioactivity in expired
    volatiles was 33-39.3% of the dose, with recovery as early as 4 h
    post-dosing. The radioactivity in the faeces (7.6% and 8.3% for M
    and F, respectively) and carcass (6.3% and 3.9% for M and F,
    respectively) contributed minimally to the total recovery (Szolics &
    Simoneaux, 1987c).

         Methidathion, 14C-radiolabelled in the ring carbon adjacent
    to the methoxy group was given to SD rats (2/sex/group) by gavage at
    a single oral dose of 0.25 or 2.52 mg/kg bw (in a 3% cornstarch
    suspension containing 0.5% polysorbate-80). The principal route of
    elimination was via the urine, which represented 52.4-69% of the
    recovered radioactivity. Radioactivity recovered from the faeces
    ranged from 5.5-7.6% of the dose and from 3.6-6.7% in the carcass.
    The majority of the excreted urinary and faecal radiolabel was
    recovered within 24 h of dosing. Expired CO2 accounted for
    approximately 10% of the administered dose, with maximum recovery at
    24 h and detection as early as 4 h post-dosing. The distribution of
    radioactivity was not significantly affected by dose or sex. Overall
    recovery of radioactive label was 77.6-91.5% of the administered
    dose (Szolics & Simoneaux, 1987d).

         Male and female SD rats were treated dermally with methidathion
    14C-labelled in the carbonyl carbon of the thiadiazole ring in

    acetone solution or formulated in petroleum hydrocarbon with
    emulsifier (the ratio of active ingredient to petroleum hydrocarbon
    to emulsifier was 6:10:1). The dermal dose was stated to be
    equivalent to 12 mg/kg bw. Methidathion was well absorbed through
    the skin as measured over a 72-h period. Higher percentages of
    residual radioactivity were found in the skin of both sexes treated
    with the formulated product (4.5-9.8%) when compared to the acetone
    group (0.3-1.9%), suggesting slower absorption of the formulated
    material over the 72-h period. There were no other differences with
    respect to sex or testing solution. The highest concentrations of
    radioactivity, in order of magnitude, were recovered in the expired
    CO2, urine and carcass. Total recovery represented 86-95% of the
    administered dose. The half-lives for the testing solutions on the
    skin were calculated for the acetone group to be 16.9 and 15.9 h for
    males and females, and for the formulated group to be 17.2 and 17.4
    h for males and females, respectively. Plasma and tissue levels
    generally attained plateau levels 48-h post-dosing, with tissue
    levels rarely exceeding 2 ppm (Marco & Simoneaux, 1982).

    Hens

         Methidathion, 14C-radiolabelled at the second carbon adjacent
    to the methoxy group was administered to a white leghorn chicken in
    gelatin capsules equivalent to 45.3 ppm for a period of 16 days.
    Total radiolabel recovered was 92.7%, of which 89.96% was found in
    the excreta. Expired CO2 comprised 1.7% of the dose, whereas the
    remainder of the radioactivity was divided among the egg yolk
    (0.21%), egg white (0.21%), tissues (0.49%) and blood (0.06%).
    Radioactive levels in the egg were observed to plateau between days
    9 and 14 of treatment. Total residual radioactivity accounted for
    0.49% of the administered dose. The highest residue levels in the
    individual tissues were found in the liver (3.85 ppm) and kidney
    (2.02 ppm) (Szolics & Simoneaux, 1985).

    Goats

         A single lactating goat was treated daily with a capsule of
    methidathion, 14C-labelled in the ring carbonyl group at a level
    equivalent to 5 ppm in the diet for a period of 10 consecutive days.
    Total radioactive recovery from all sources was 91.5% of the
    administered dose. The principal route of elimination was by expired
    CO2, representing 65.8% of the dose. Urinary and faecal radiolabel
    accounted for 20.4% and 3.4% of the dose, respectively. The
    remaining radioactivity was dispersed among the various fractions,
    rarely exceeding 1% of the total admin-istered dose. Residual levels
    in body tissues were less than 0.35% of the dose and ranged from
    0.02 to 0.15 ppm. Highest levels were found in the liver. Recovery
    of radioactivity from milk reached plateau levels at 0.11 ppm after
    5 days of treatment (Staley  et al. 1987).

         A single lactating goat was treated daily with a capsule of
    methidathion, 14C-labelled in the ring carbon adjacent to the
    methoxy group at a level equivalent to 5 ppm in the diet for a
    period of 10 consecutive days. The majority of the radioactive label
    was eliminated via the urine, accounting for 18.1% of the
    administered dose. Expiration by CO2 and elimination via the
    faeces represented 9.6% and 6.4% of the dose, respectively. Recovery
    of the remaining radioactivity was distributed in the blood (2.9%),
    liver (1.2%) and generally less than 1% of the dose was found in
    each of the samples from milk, perirenal and omental fat, kidney,
    leg muscle and tenderloin. Total recovery of radioactivity was only
    40.1% of the administered dose. It has been postulated that this may
    be due to a neutral volatile e.g., methane, which could not be
    trapped in the standard volatile or CO2 trap (Staley & Simoneaux,
    1987).

    Biotransformation

    Rats

         The proposed metabolic pathway in animals is depicted in Figure
    1 (Szolics & Simoneaux, 1987h).

         Partitioning of urine collected from rats treated orally with
    14C-carbonyl labelled methidathion at 0.295 or 2.949 mg/kg bw
    (Szolics & Simoneaux, 1987b) indicated that the urine consisted of
    mainly organic soluble metabolites, which accounted for 79% in male
    and 66% in female of the total urinary radioactivity. The major
    metabolite was the sulfide derivative accounting for 44-45% of the
    radioactivity. The other principal metabolites were the sulfone
    (14.2 and 8% for males and females, respectively) and the sulfoxide
    (11.1 and 3.3% for males and females, respectively). The RH compound
    represented only 2.4% of the urinary radioactivity whereas the
    parent, methidathion, was present as only 0.7%. The oxygen analog
    was not identified. The remainder of the total urinary radioactivity
    (21-34%) was aqueous soluble metabolites. Two of the three
    chromatographed peaks, displayed elution patterns similar to the
    cysteine conjugate (2.1%) and desmonomethyl derivative (15.3%) of
    methidathion (Szolics & Simoneaux, 1987e).

         The urine of rats treated with 14C-labelled methidathion in
    the methoxy group at 2.597 mg/kg bw (Szolics & Simoneaux, 1987c)
    comprised both organic (67-72%) and aqueous (28-33%) soluble
    metabolites. The major organic metabolites were the sulfoxide
    (40.5%) and sulfone (23%). The remainder were identified as the RH
    compound (1%), unchanged parent (0.8% - female only), the sulfide
    (0.3% - male only) and oxygen analog (0.2% - male only). The aqueous
    soluble metabolites were characterized as the cysteine conjugate
    (2.1%) and desmonomethyl derivative (10.5%) of methidathion (Szolics
    & Simoneaux, 1987f).

    FIGURE 1

         Metabolites from the urine of rats administered single oral
    doses of 14C-labelled methidathion in the ring carbon adjacent to
    the methoxy group at 0.25 or 2.52 mg/kg bw (Szolics & Simoneaux,
    1987d) were identified. Organic soluble metabolites represented 61-
    63%, whereas aqueous soluble metabolites accounted for 37-39% of the
    urinary radioactivity. The major organic metabolite was the sulfide
    (35.4%). Similar amounts of the sulfoxide (8.6%) and the sulfone
    (8.2%) were detected. The RH compound represented 2.1% of the
    radioactivity, and the oxygen analog represented 0.6%. No unchanged
    parent was identified. With respect to the aqueous soluble
    metabolites, the desmonomethyl derivative of methidathion accounted
    for 20% (Szolics & Simoneaux, 1987g).

    Goats

         The urine of a single lactating goat treated daily by capsule
    equivalent to a dietary intake level of 5 ppm for 10 days (Staley
     et al. 1987) was selected for characterization of metabolites.
    Partitioning data revealed that 84.5% of the urinary radioactivity
    were aqueous soluble and 5.5% were organic soluble metabolites. The
    principal aqueous soluble metabolites were the desmonomethyl
    derivative (59.7%) and cysteine conjugate (10.4%) of methidathion.
    Chromatography of the organic soluble components reportedly showed
    that the metabolites in the goat were qualitatively the same as
    those found in rat urine. The proposed predominant metabolic pathway
    of methidathion in the goat was 0-demethylation (Szolics &
    Simoneaux, 1987h).

    Toxicological studies

    Acute toxicity studies

         Acute toxicity studies conducted in both the male and female
    Tif.RAIf rat (Table 1), reveal that technical methidathion, upon
    oral administration is highly toxic with LD50 values of 26 to 43.8
    mg/kg bw. The acute dermal studies indicate that methidathion is
    slightly to moderately toxic. Clinical signs of toxicity, upon oral
    and dermal dosing were generally manifest as curved or ventral body
    position, dacryorrhea/chromodacryorrhea, diarrhoea, dyspnea,
    exophthalmus, ruffled fur, sedation, tonic/clonic muscle spasms and
    trismus. The symptoms were reversible in surviving animals.

         The acute oral toxicity of methidathion has been investigated
    in several animal species (Table 2). The results indicate that
    methidathion is moderately to highly toxic in all species tested
    with LD50 values ranging from 17 to 200 mg/kg bw.

        Table 1.  Acute toxicity of technical methidathion
                                                                                 
    Species      Sex  Route   Vehicle         LD50        Purity  Reference
    (strain)                                  (mg/kg bw)
                                                                                 

    Rat          M&F  oral    CMC, 2%         43.8        ?       Bathe (1973a)
    (Tif. RAIf)

    Rat          M&F  oral    PEG, 400        26          96.9%   Bathe & Sachsse 
    (Tif. RAIf)                                                   (1980a)

    Rat          M&F  oral    PEG, 400        26          92.7%   Bathe & Sachsse 
    (Tif. RAIf)                                                   (1980b)

    Rat          M&F  dermal  CMC, 2%         1546        ?       Bathe, (1973b)
    (Tif. RAIf)

    Rat          M&F  dermal  CMC, 2%         1663        ?       Bathe & Sachsse
    (Tif. RAIf)                                                   (1975)

    Rat          M&F  dermal  CMC, 2% +       297         92.6%   Sarasin (1980)
    (Tif. RAIf)               Tween 80, 0.1%
                                                                                 
    
    Short-term toxicity studies

    Rats

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

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

         Groups of 24 male and 24 female rats were fed for 22 weeks on
    diets containing 0, 1, 4, 16 or 64 ppm methidathion. In a similar
    study in the same laboratory, groups of 24 male and 24 female rats
    were fed for 26 weeks on diets supplying 0, 128 or 256 ppm
    methidathion. The rate of body-weight gain was reduced at 64 ppm and
    above in females but not in males. Histopathological examination of
    liver, spleen and kidneys showed a dose-related increase in fat
    deposition in the liver at doses above 64 ppm in both sexes. No
    abnormalities in haematological indices or in results of urinalyses
    were found (Stenger & Roulet, 1965).

    Table 2.  Acute oral toxicity of methidathion1
                                                                    
    Species       Sex     LD50           Reference
                          (mg/kg bw)
                                                                    

    Mouse         F       17             Noakes & Sanderson, 1964

    Hamster       F       30             Noakes & Sanderson, 1964

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

    Rat           M       26-65          Slenger, 1964a
                                         Noakes & Sanderson, 1964

    Guinea-pig    F       25             Slenger, 1964a
                                         Noakes & Sanderson, 1964

    Rabbit        M       80             Sachsse, 1971

    Dog           M&F     200            Noakes & Sanderson,  1964

    Chicken       F       80             Annex I, 19
                                                                    

    1 Formulations calculated as a.i.

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

    kidneys, spleen and testes and the macroscopic appearance of other
    organs (Noakes & Watson, 1964a).

    Rabbits

         A dermal study was undertaken with groups of 5 New Zeeland
    rabbits/sex administered methidathion (purity unknown) topically for
    6-h daily non-occlusive exposure periods at doses of 0 (vehicle
    control, PEG 300), 1, 5 or 20 mg/kg bw/day for a period of 22
    consecutive days. There were no significant effects of treatment on
    survival, food consumption, haematology, blood chemistry,
    cholinesterase activity, organ weights, gross morphologic or
    histopathological alterations. Based on minimal effects noted as
    hypoactivity in a single male at 20 mg/kg bw, occasional incidences
    of soft faeces or diarrhoea in treated males and a slight trend to
    decreased body-weight gain in the high dose 20 mg/kg bw/day treated
    males, a conservative NOAEL may be set at 5 mg/kg bw/day (Folinusz
     et al. 1986).

         A second dermal study was conducted with groups of New Zeeland
    HRP:SPF rabbits (4-6 per sex) topically administered methidathion
    (95% purity) daily for a 6-h occlusive exposure period at doses of 0
    (vehicle control, PEG 400), 1, 10, 40 or 80 mg/kg bw for a period of
    21 days. Treatment with methidathion resulted in mortality in males
    at all dose levels (0/5, 2/5, 2/6, 3/5 and 3/5) and in females at 40
    mg/kg bw/day and higher (0/5, 0/5, 0/4, 2/5 and 4/5). Clinical signs
    of toxicity in males treated at dose levels of 1 mg/kg bw/day and
    higher and in females treated at dose levels of 40 and 80 mg/kg
    bw/day were manifest as anorexia, ataxia, hunched posture, languid
    appearance and laboured respiration. Tremors were observed at dose
    levels of 10 mg/kg bw/day and higher, whereas convulsions were
    reported in a single high-dose (80 mg/kg bw/day) treated female.
    Cholinesterase assessments revealed significant depression in the
    mean plasma (38-86%), RBC (40-80%) and brain (37-88%) cholinesterase
    values for both sexes at dose levels of 10 mg/kg bw/day and higher.
    Treatment-related microscopic alterations were evidenced in the
    liver and gall bladder. Principal findings in the liver were denoted
    as hepatocytic clearing and congestion at dose levels as low as 1
    mg/kg bw/day. Capsular/subcapsular necrosis with acute inflammation
    was also noted in several of the treated animals. Lesions of the
    gall bladder were present in both sexes at dose levels of 10 mg/kg
    bw/day and higher and were attributed to bile reflux due to
    hyperperistalsis. Subacute inflammation of the myocardium and
    degeneration of the medial aorta occasionally with mineralization
    were observed in several of the rabbits dying during the study
    period. There were no specific effects of treatment on body-weight,
    food consumption, ophthalmoscopy, haematological and blood
    biochemical parameters or organ weights. The NOAEL was determined to
    be 1 mg/kg bw/day by the author (Osheroff, 1987).

         The results of the present study when interpreted
    independently, have not unequivocally demonstrated 1 mg/kg bw/day to
    be a NOAEL. The author has provided valid argument that evaluation
    of primary toxicity was complicated by the additive effects of
    stress especially during clinical observations. The occlusive rubber
    binding used may not only have enhanced the absorption of the test
    material but in combination with the neck collar, may have increased
    the stress factor, thus augmenting the toxicity of the test
    material. In view of the intrinsic variables in the present study
    design, it is considered appropriate to critically assess the
    results of the present study in conjunction with those generated
    from the previously conducted rabbit dermal study, wherein dermal
    administration of methidathion under non-occlusive means failed to
    produce effects in rabbits at dose levels as high as 5 mg/kg bw/day
    (Folinusz  et al. 1986).

    Dogs

         Four groups of three male and three female beagle dogs received
    diets containing 0, 4, 16 or 65 ppm methidathion for two years. The
    animals were starved of diet one day each week and received a double
    ration on the next day. Administration of methidathion was
    discontinued from week 16 to 19. Erythrocyte cholinesterase was
    inhibited in the 64 ppm group, but brain cholinesterase was
    unaffected by treatment. SGPT was markedly elevated in the 64 and 16
    ppm groups and slightly raised in males of the 4 ppm group. During
    weeks 16 to 19 these levels fell, but only the 4 ppm group returned
    to normal. SGOT levels were not the same as controls at all
    treatment levels, but serum alkaline phosphatase was elevated and
    sulfobromophthalein retention increased in the 16 and 64 ppm groups.
    The livers of dogs receiving 16 and 64 ppm were pigmented on
    macroscopic examination. Microscopically, pigmentation could be seen
    in macrophages and hepatic cells (principally centrilobular) in the
    16 and 64 ppm groups, the intensity of deposit being dose-related.
    The Perl's reaction showed that the pigment did not contain
    appreciable quantities of iron. The kidneys of the 64 ppm group also
    showed pigmentation. It was questionable whether the livers of the 4
    ppm group contained excess pigment. Control and test groups were
    indistinguishable regarding behaviour, results of clinical tests
    including neurological examination, haematological findings, organ
    weights and macroscopic and microscopic appearance of organs other
    than those mentioned. An additional two dogs received 64 ppm
    methidathion in the diet for four weeks. The SGOT was elevated at
    two and four weeks and at autopsy the livers were dark in colour.
    Moderate diffuse pigmentation was seen microscopically in the liver
    of one animal.

         The plasma enzyme and liver histology changes at 30 days of
    treatment at 64 ppm were not increased after treatment for two years
    at this dose. Furthermore, the serum enzyme changes at 16-19 weeks
    of treatment at 64 ppm were reversible and returned to normal three

    weeks after cessation of treatment. The NOAEL was 4 ppm (Johnston,
    1967).

         The histological slides of the liver tissue from the original
    study were re-evaluated and submitted to the 1975 Joint Meeting
    Annex 1, reference 25). Intrahepatic cholestasis was observed in
    dogs fed 16 and 64 ppm methidathion. Neither degenerative nor
    inflammatory changes were associated with this lesion. Pigmentation
    occurred as bile-plugs in biliary ductules, or as amorphous deposits
    in Kupffer cells or as lipofuscin in both hepatic and Kupffer cells.
    Haemolysis was not detected. A minimal degree lipofuscin
    pigmentation was also observed at 4 ppm and in the control group.
    Mild irregular fatty changes of the hepatocytes with occasional
    periportal histiolymphocytic infiltration of the liver were observed
    in both treated and control animals (Hess, 1975).

         Methidathion (97% purity) was administered to groups of 4
    beagle dogs per sex in the daily feed at dietary levels of 0, 0.5,
    4, 45 or 140 ppm equal to 0, 0.02, 0.16, 1.96 or 5.67 mg/kg bw/day,
    respectively, for a period of 90 days. An additional group of 4 dogs
    per sex was treated orally by gelatin capsule at a dose level of
    0.14 mg/kg bw/day, equal to a daily dietary intake level of 4 ppm,
    for a similar treatment duration. A NOAEL of 4 ppm was assessed
    based upon the evidence of cholestasis in all male and female dogs
    treated at 45 and 140 ppm. Cholestasis was similarly described in a
    single male dog treated by capsule at 0.14 mg/kg bw/day. Other
    consequences of treatment evident in both sexes at dietary levels of
    45 ppm and higher were discoloration of the liver and markedly
    enhanced enzyme activity, expressed as increased levels of ALP,
    SGOT, SGPT, GGT and sorbitol dehydrogenase. RBC cholinesterase
    activity was significantly (75-88%) inhibited in dogs of both sexes
    treated at 140 ppm. Brain cholinesterase activity was inhibited
    (26.8%) in the 140 ppm treated females when compared to the
    controls. There were no effects of methidathion treatment on serum
    cholinesterase levels. Clinical signs of tremor and reduced activity
    post-dosing, observed during the latter part of the study, were
    exhibited in a single male dog at the high dose level. Reduced
    activity was also noted in a single male treated at 45 ppm. Other
    effects of treatment were significantly decreased mean food intake
    values in the high dose treated males when compared to the control
    group. There were no treatment-related effects observed with respect
    to survival, body-weights, ophthalmoscopic examination,
    haematological parameters, urinalysis or organ weights (Chang &
    Wyand, 1990).

         Six groups of 4 beagle dogs/sex were treated with methidathion
    (96% purity) at dietary levels of 0, 0.5, 2, 4, 40 or 140 ppm, equal
    to 0, 0.02, 0.07, 0.15, 1.34 or 4.51 mg/kg bw/day, respectively, for
    a period of 12 months. A NOAEL of 4 ppm was indicated based on
    treatment-related hepatic effects observed grossly as general
    discoloration of the liver and characterized histomorphologically as

    cholestasis and chronic inflammation of the liver in both sexes at
    dietary levels of 40 ppm and higher. Associated changes in blood
    biochemical parameters were denoted by elevated ALP, SGOT, SGPT,
    sorbitol dehydrogenase and bilirubin levels. Other significant
    clinical changes recorded only in the females were increased GGT and
    decreased total protein and albumin values. RBC choline-sterase
    activity was markedly inhibited (76-87%) in both male and females
    dogs treated with methidathion at 140 ppm. Serum cholinesterase
    activity was not adversely affected by treatment at any dietary
    level. Brain cholinesterase activity was significantly depressed
    (16-27%) in both sexes treated at 140 ppm when compared to the
    controls. Another effect of treatment was related to decreased food
    consumption in male dogs treated with methidation at a dietary level
    of 140 ppm. There were no effects of treatment on survival, clinical
    signs, body-weights, ophthalmoscopy, haematology, urinalysis, faecal
    examination or organ weights (Chang and Walberg, 1991).

    Monkeys

         Three groups of Rhesus monkeys (approximately equal number of
    each sex) were administered 0, 0.25 or 1.0 mg methidathion/kg bw/day
    by stomach tube, 6 days a week for 23 months. Two of each group were
    autopsied after 12 months. Plasma and erythrocyte cholinesterase
    activity were inhibited in the 1 mg/kg bw/day group, but not at the
    lower level. Brain cholinesterase was unaltered by treatment.
    Growth, results of haemological tests, results of chemical analyses
    of serum (including SGPT and ALP) and macro- and microscopic
    examination of tissues were similar in control and test groups
    (Fabran  et al., 1971).

    Long-term toxicity/carcinogenicity studies

    Mice

         A 23-month study was conducted with groups of 50 Charles River
    CD-1 mice per sex/group fed diets containing methidathion (purity
    not stated) at levels of 0, 3, 10, 50 or 100 ppm equal to 0.43,
    1.42, 6.99 or 13.70 mg/kg bw/day, respectively. An additional 120
    mice/sex/group were assigned to the chronic phase of this bioassay.
    Interim sacrifices of 20 mice/sex/group were scheduled after 3, 6,
    12 and 13 months. Animals sacrificed at 13 months were maintained on
    control diet for one month as recovery animals following 12 months
    of continuous treatment. The remaining animals (40/sex/group,
    maximum) were sacrificed after 18 months of treatment. Treatment of
    mice with methidathion resulted in slightly decreased survival of
    the 100 ppm treated males when compared to the controls. The only
    clinical sign remarked upon was discoloration of the urine in the 50
    and 100 ppm treated males. Potentially reversible increases in liver
    enzyme activity were reported in males at 50 ppm and higher and in
    females at 100 ppm. Significantly decreased but potentially
    reversible RBC cholinesterase activity values (26-46%) were

    registered in males at 100 ppm and in females at 50 ppm and higher.
    Brain cholinesterase activity was markedly inhibited (15-49%) in
    both sexes at 100 ppm. There were no inhibitory effects of treatment
    on plasma cholinesterase activity. There were no effects of
    methidathion treatment noted with respect to body-weights, food and
    water consumption or ophthalmoscopy. Treatment-related target organ
    alterations were manifest in the gall bladder and liver at dietary
    levels of 50 ppm and higher in males and in females at 100 ppm.
    Microscopic changes were described in the gall bladder as
    cholecystitis and hyperplasia and, hepatic findings were denoted as
    bile duct hyperplasia, bile stasis, cholangiofibrosis, chronic
    hepatitis and hypertrophy. Increased extramedullary haematopoiesis
    of the spleen, associated with increased spleen weights were
    observed in the 100 ppm treated males. Treatment of male mice with
    methidathion resulted in a significantly increased incidence of
    hepatocellular tumours (adenomas, carcinomas and adenomas/carcinomas
    combined).

                   0         3         10        50        100 ppm

    Adenoma        1/46      9/45      7/47      8/43      21/45
    Carcinoma      8/46      6/45      4/47      13/43     17/45
    Combined       9/46      15/45     11/47     21/43     38/45

         Historical control data (Quest  et al. 1990) generated from 14
    studies conducted at the same test facility with the same strain of
    mouse, revealed that the incidences of hepatocellular tumours
    reported in the present study exceeded the historical control range
    at dietary levels of 50 ppm and higher. Latency, expressed in terms
    of time to appearance of first tumour, was not apparently decreased
    in the treated male groups when compared to the concurrent controls.
    The incidence of hepatocellular tumours was not increased in female
    mice treated with methidathion The NOAEL in this study was 10 ppm,
    equal to 1.4 mg/kg bw/day (Goldenthal, 1986).

    Rats

         In order to investigate the long-term toxic effects and
    possible carcinogenic action of methidathion, four groups of 25 male
    and 25 female rats each were fed for three weeks on diets containing
    0, 2, 8 or 32 ppm and for a further 101 weeks on diets containing 0,
    4, 16 or 64 ppm methidathion. The rate of gain in body weight was
    reduced from week 8 in male animals of the 64 ppm group. After the
    first year the rates of gain became erratic in all groups, making
    interpretation of the findings difficult. Female rats on test diets
    grew at a rate comparable to controls. Erythrocyte cholinesterase
    was inhibited in the 16 and 64 ppm groups, while plasma
    cholinesterase showed minimal inhibition at 100 weeks in the 64 ppm
    group only. Brain cholinesterase was inhibited in the 64 ppm group,
    with marginal and no reduction in the 16 and 4 ppm groups,
    respectively. Decreased relative adrenal weights were found in

    females of the 16 ppm and 64 ppm groups, and decreased ovary weights
    in the 64 ppm group. The relative kidney weights of males was
    increased in the 16 and 64 ppm groups. A greater frequency of
    hepatic degenerative changes was noted in rats fed methidathion in
    the diet; the high incidence of pulmonary infections in the rats
    renders this finding of doubtful toxicological significance. The
    food intake, results of haematological investigations and chemical
    analysis of serum (including SPGT) and the survival rate were
    similar in the test groups and in the control group. The incidence
    of tumours was variable between groups but was low and not dose-
    related, and no unusual tumours were found. The NOAEL in this study
    was 4 ppm methidathion in the diet (Johnston, 1967).

         Groups of 65 Crl:COBS CD(SD) BR rats/sex were treated with
    methidathion (97.3% purity) at dietary levels of 0, 4, 40 or 100 ppm
    equal to 0.16, 1.72 or 4.91 mg/kg bw/day, respectively for a period
    of 104 weeks. For interim sacrifice purposes, an additional 15
    rats/sex/group were assigned on study. At 52 weeks, 10
    rats/sex/group were sacrificed with the remaining 5 rats/sex/ group
    sacrificed at week 93 of study. Treatment with methidathion resulted
    in clinical signs expressed in the 40 and 100 ppm groups as
    alopecia, chromorhinorrhea, hyperactivity, skin lesions, tremors,
    hypersensitivity to the touch and fasciculation. Mean body-weights
    and weight gains were decreased in both sexes at 100 ppm throughout
    the course of treatment. Body-weight gains were decreased at a
    dietary level of 40 ppm during the initial few weeks of treatment,
    with comparable weight gain thereafter. Mean food intake was
    significantly increased in both sexes treated at dietary levels of
    40 ppm and higher, whereas water consumption was decreased at 100
    ppm and occasionally at 40 ppm. Treatment-related haematological
    findings were exhibited at a dietary level of 100 ppm as inverted
    neutrophil:lymphocyte ratios, reduced RBC parameters and increased
    platelet counts. Variations in blood biochemical parameters were
    observed at 40 ppm and higher as decreased total bilirubin,
    decreased total protein as well as changes in electrolyte levels
    (decreased potassium and calcium, and increased inorganic phosphorus
    and chloride). Significant inhibition of RBC (14-38%), serum (22-
    66%) and brain (42-74%) cholinesterase activity were determined in
    both sexes of rats treated at dietary levels of 40 ppm and higher.
    Notable changes in urinalyses were revealed as decreased volume and
    increased specific gravity at 40 ppm and higher which correlated
    well with the reduced fluid intake reported in these groups. Gross
    necropsy findings showed an increased incidence of skin lesions in
    the 40 and 100 ppm levels which were associated microscopically with
    ulceration and/or chronic purulent inflammation. Other pathological
    alterations were related to an increased incidence in focal
    accumulations of foamy macrophages in the alveoli of the 100 ppm
    treated males and females. There were no effects of treatment on
    survival or ophthalmoscopy. The NOAEL for in-life parameters was
    determined to be 4 ppm, equal to 0.16 mg/kg bw/day. There was no

    evidence of methidathion-induced carcinogenic potential (Yau  et
     al., 1986).

    Reproduction studies

    Rats

         In a three-generation study, three groups of 10 male and 20
    female rats were fed on a diet containing 0, 2 or 16 ppm
    methidathion for three weeks, and thereafter on a diet containing 0,
    4 or 32 ppm methidathion. Litters from the second mating were used
    to provide the new generations. The F1b litters did not receive
    test diets until 26 days and the F2b until 22 days after weaning.
    F0, Flb and F2b generations received diets for 27-28 weeks
    during which they produced two litters. The number of young
    surviving at weaning was reduced in all generations of litters from
    animals fed 32 ppm methidathion and the mean liver weight of F3b
    weanlings of this group was slightly increased. Body weights,
    reproductive capacity and mortality of parents and the number of
    litters, litter size, mean birth and weaning weights of test groups
    were comparable to controls. The number of stillbirths and incidence
    of congenital abnormalities were unaltered by treatment. No
    histological damage was found in the organs of the F3b animals
    examined. The NOAEL in this study was 4 ppm methidathion (Lobdell &
    Johnston, 1966).

         A two-generation (one litter per generation) reproduction study
    was conducted with groups of 15 male and 30 female Charles River SD
    CR1:CD BR rats fed methidathion (purity not specified) at dietary
    levels of 0, 5, 25 or 50 ppm equal to 0, 0.43, 2.08 or 4.23 mg/kg
    bw/day, respectively. With respect to reproductive performance,
    statistically (p < 0.05) reduced mating indices were recorded for
    the 25 and 50 ppm groups in the F1 generation. Although the mating
    indices were reduced in these groups (69% and 66%, respectively)
    relative to the concurrent F1 control group (88%), they were
    nevertheless not significantly different from those calculated for
    the F0 generation control (73%) or treated groups (60-65%). The
    fertility and gestation indices were comparable among groups.
    Treatment-related effects on maternal animals fed dietary levels of
    25 ppm and higher were revealed by clinical signs of toxicity
    manifest during lactation as slight and/or intermittent tremors.
    Mean body-weights of F1 50 ppm-treated males were decreased prior
    to and during the 12-week premating period. Mean body-weights gains
    were not, however, significantly different from controls. Body-
    weights of females recorded during lactation of both generations
    were decreased at 50 ppm when compared to the concurrent control.
    Decreased ovary weights recorded in females at 25 and 50 ppm were
    not correlated with histopathological changes. Effects of treatment
    on progeny were expressed as decreased survival in the 50 ppm group
    of the F1 generation, decreased body-weights and clinical signs in
    both generations at 25 and 50 ppm. The clinical signs were

    suggestive of poor maternal care and were described as
    weakness/lethargy, coolness to the touch and starving appearance. On
    the basis of the reported findings, a NOAEL of 5 ppm, equal to 0.43
    mg/kg bw/day, was indicated (Salamon, 1987).

    Special studies on teratogenicity

    Rats

         A teratology study was conducted with groups of 25 mated female
    Crl: COBS CD(SD)BR rats administered methidathion (93.2-96% purity)
    at 0.25, 1.0 and 2.5 mg/kg bw/day or the control (vehicle, 3%
    aqueous cornstarch with 0.5% Tween 80) orally by gavage from days 6
    to 15 of gestation, inclusive. Confirmation of mating was determined
    by presence of sperm in the vaginal washing, and this day was
    designated day 0 of gestation. A NOAEL for maternal toxicity was
    indicated at 1.0 mg/kg bw/day based on mortality, decreased body-
    weights, food intake and clinical signs at 2.5 mg/kg bw/day.
    Clinical signs of toxicity in the high dose (2.5 mg/kg bw/day) group
    were suggestive of organophosphorus intoxication including,
    lethargy, tremors, lacrimation, salivation, raspy respiration,
    exophthalmia, chromodacryorrhea. A NOAEL for embryofetal toxicity
    was set at the highest dose level tested of 2.5 mg/kg bw/day. There
    were no significant differences noted with respect to the mean
    number of implantations, live fetuses or mean number of resorptions
    on a litter basis. There was similarly no significant variability in
    the post-implantation loss, fetal sex ratio or in the mean fetal
    litter weight in the treated groups when compared to the control.
    Treatment with methidathion failed to uncover any evidence of
    teratogenic potential (Mainiero  et al. 1987).

    Rabbits

         Methidathion (purity not specified) was administered orally by
    gavage at 0 (vehicle control, 3% cornstarch with 0.5% Tween 80), 2,
    6 or 12 mg/kg bw/day to groups of 19 artificially inseminated New
    Zeeland white rabbits on days 7 through 19 of gestation. The day of
    artificial insemination was designated as day 0 of gestation.
    Treatment-related clinical signs of toxicity at the high dose (12
    mg/kg bw/day) treated animals were manifest as ataxia, tremors,
    salivation and miosis. In the absence of similar effects in the
    control or other treated groups, the NOAEL for maternal toxicity was
    demonstrated to be 6 mg/kg bw/day. There was no evidence of
    embryofetal developmental toxicity or potential for teratogenicity
    at any of the dose levels investigated, including the highest dose
    of 12 mg/kg bw/day (Hummel  et al. 1987).

    Special studies on genotoxicity

         A battery of mutagenicity assays were conducted with technical
    methidathion, the results of which are presented in Table 3. The
    tests performed to evaluate potential for gene mutation in bacteria,
    DNA damage as well as chromosome aberration were negative. A
    dominant lethal study in mice was also negative. Positive responses
    were observed in the  in vitro assays with  Saccharomyces
     cerevisiae and in the Chinese hamster test for sister chromatid
    exchange.  In vivo tests conducted to examine the similar
    endpoints, did not however elicit any evidence of mutagenic
    potential in mammalian cells.

    Special studies on delayed neurotoxicity

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

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

         The delayed neurotoxic potential of methidathion (purity not
    specified) was investigated in groups of 10-30 female white leghorn
    hens. The animals were administered the test material twice, 21 days
    apart, at 0 (vehicle, CMC 2%), 43.75, 87.5, 175 or 350 mg/kg bw.
    Animals receiving methidathion at 350 mg/kg bw were pretreated with
    an intramuscular injection of atropine sulfate, 10 mg/kg bw, one
    hour prior to treatment. Groups of 3 male and 3 female hens received
    a single oral dose of the positive control, TOCP at 215, 464, 600,
    1000 or 2150 mg/kg bw and were then observed for 21 days post-
    dosing. A preliminary acute oral study indicated that the LD50 of
    methidathion in the hen was 175 mg/kg bw. Clinical signs of
    intoxication were expressed as ataxia, slight tremor, curved or
    ventral body position and sedation, with subsequent recovery in
    surviving animals, 8-10 h post-dosing. Histopathological evaluation
    of the spinal cord and peripheral nerves did not reveal any
    treatment-related lesions of the nervous system, whereas TOCP
    toxicity was evidenced as central-peripheral, distally accentuated
    neuropathy. Treatment with methidathion did not produce any signs of
    delayed neurotoxicity (Ullmann  et al. 1977).


    
    Table 3.  Genotoxicity of technical methidathion
                                                                                                                                      
    Test                  Test system                Concentration                  Purity    Results        References
                                                     (vehicle)
                                                                                                                                      

    Reverse mutation      S. typhimurium             25, 75, 225, 675, 2025         98.4%     negative       Arni & Muller (1980a)
    (in vivo)             TA98, 100, 1535, 1537      µg/0.1 mL (DMSO)                         1., 2.

                          S. typhimurium             25, 75, 225, 675, 2025         93.4%     negative       Arni & Muller (1980b)
                          TA98, 100, 1535, 1537      µg/0.1 mL (DMSO)                         1., 2.

                          S. typhimurium             0, 0.1, 0.5, 1, 5, 10, 50      99.95%    negative       Satou  et al. (1979)
                          TA98, 100, 1535, 1537      mg/mL (DMSO)                             1., 2.

                          E. coli
                          B/r WP2 Try- Hcr-

                          S. typhimurium             10, 50, 100, 500, 1000,        ?         negative       Simmon  et al. (1977)
                          TA98, 100, 1535, 1537,     5000 µg/plate (DMSO)                     1., 2.
                          1538

    Rec assay (in vitro)  B. subtilis                5, 25, 100 mg/mL (DMSO)        99.95%    negative       Satou  et al. (1979)
                          H17, M45

    Reverse mutation/     S. typhimurium             10, 20, 40 mg/kg bw            ?         negative       Simmon  et al. (1977)
    Host-mediated         TA1535, 1538/Male Swiss    (single oral doses)
    (in vivo)             Webster mouse
                          (inocculated ip)

                                                     5, 10, 20 mg/kg bw                       negative
                                                     (5 oral doses) (DMSO)

                          S. typhimurium             0, 5, 10, 20 mg/kg bw          93.4%     negative       Arni & Muller (1980c)
                          TA98, 100, 1537/           (3 oral doses: 2 h, 1 h
                          male mouse                 and prior to innoculation)
                          (inocculated iv)           (CMC, 0.5%)

    Table 3 (cont'd)
                                                                                                                                      
    Test                  Test system                Concentration                  Purity    Results        References
                                                     (vehicle)
                                                                                                                                      

    Gene conversion/      S. cerevisiae MP-1         675, 1250, 2500, 5000,         93.4      conversion:    Arni & Muller (1981)
    forward mutation                                 10000 µg/mL (DMSO)                       slight (+ ve)
    (in vivo)                                                                                 mutation:
                                                                                              (+ ve)

    Forward mutation      Mouse lymphoma cells -     0, 15 mg/kg bw (3 oral         93.4%     negative       Strasser & Muller (1980)
    host-mediated (in     L5 178Y/mouse              doses post-innoculation)
    vivo)                 (DBA/Bom)                  (CMC)

    DNA repair            Mouse (male CD-1)          5 x 10-7 to 1% (DMSO)          ?         negative       Tong (1982a)
    (in vivo)             hepatocytes

                          Rat (male F344)            5 x 10-9 to 1% (DMSO)          ?         negative       Tong (1982b)
                          hepatocytes

                          Rat hepatocytes            0.128, 0.64, 3.2, 16           97.2%     negative       Puri & Muller (1982a)
                                                     µg/mL (DMSO)

                          Rat hepatocytes            1.85, 5.56, 16.67, 50, 100,    96%       negative       Hertner & Arni (1990)
                                                     200 µg/mL (DMSO)

                          Human fibroblasts          1.024, 5.12, 25.6, 128         ?         negative       Puri & Muller (1982b)
                                                     µg/mL (DMSO)

    SCE (in vivo)         Chinese hamster            0, 10, 20, 40, 80 µg/mL        99.1%     slight (+ ve)  Chem  et al. (1981)
                          cell line V79              (DMSO)                                   at 40, 80
                                                                                              ug/mL

    SCE (in vivo)         Chinese hamster            0, 17, 34, 68 mg/kg bw         93.4%     negative       Hool & Muller (1980)
                          (bone marrow)              (CMC)

    Table 3 (cont'd)
                                                                                                                                      
    Test                  Test system                Concentration                  Purity    Results        References
                                                     (vehicle)
                                                                                                                                      

    Chromosome            Chinese hamster ovary      43, 75, 87.5, 175, 350         96%       negative       Strasser & Arni (1990)
    aberration            CCL 61                     µg/mL (DMSO)
    (in vivo)                                                                       96.9%     negative       Hool  et al. (1980)

    Nucleus anomaly       Chinese hamster            0, 17, 34, 68 mg/kg bw
    (in vivo)             (bone marrow)              (2 oral doses) (CMC)           98.4%     negative       Fritz (1976)

    Dominant lethal       Mice, NMRI                 0, 15, 45 mg/kg bw (CMC)
    (in vivo)
                                                                                                                                      

    1. = in the presence of metabolic activation
    2. = in the absence of metabolic activation


    
    Special studies on irritation and sensitization

         The eye irritation potential of technical methidathion was
    investigated in 3 English Silver strain rabbits/sex. Administration
    of 0.1 grams of methidathion into the conjunctival sac of the left
    eye (right eye served as control) produced irritating conjunctival
    reaction in the unwashed eye of a single male rabbit (Sachsse,
    1973a).

         Technical methidathion (as a 50% polyethylene glycol
    suspension) was applied under occlusive conditions to the shaved
    backs of male and female English Silver strain rabbits for 24 h.
    Skin reactions were observed as very slight erythema in one male and
    moderate to severe erythema in association with slight oedema in one
    female rabbit (Sachsse, 1973b).

         The shaved backs of male Hartley albino guinea-pigs were
    repeatedly treated with technical methidathion as a 10% solution in
    diethyl ether. There was no evidence of skin sensitization potential
    (Cannelongo, 1984).

    Special studies on potentiation

         The potentiating effects of methidathion (purity not specified)
    with profenofos (Sachsse & Bathe, 1977b) and methacrifos (Sachsse &
    Bathe, 1978) were investigated in male and female Tif:RAIf rats by
    comparing the theoretical LD50 values, based on an assumption of
    strictly additive toxicity, with that of the experimentally derived
    LD50 values for the equitoxic mixtures. There was no potentiating
    effect of methidathion with profenofos, whereas a slight enhancement
    of acute toxicity was observed with an equitoxic mixture of
    methidathion and methacrifos.

    Special studies on promoting activity

         Male F344 DuCrj strain rats received a single ip injection of
    the initiator, N-nitrosodiethylamine (DEN) at 200 mg/kg bw. Two
    weeks thereafter, the rats were treated with methidathion (92.7%
    purity) at dietary levels of 0, 10, 30, 100 or 300 ppm (equal to 0,
    1.0, 2.3, 7.6 or 22.9 mg/kg bw, respectively) or the positive
    control, 3'-methyl-4-dimethyl amino azobenzene (3'-Me-DAB) at 600
    ppm (equal to 33.9 mg/kg bw) for a period of 6 weeks. Three weeks
    following treatment with DEN, partial hepatectomy was performed on
    all animals. Histochemical evaluation of 4 liver sections from each
    animal after 8 weeks on study, revealed a significantly increased
    number of GGT positive foci per unit area in rats treated with
    methidathion at 100 and 300 ppm and in the 600 ppm 3'-Me-DAB
    positive control group. No increases in the number of GGT positive
    foci were observed in additional groups of rats treated with
    methidathion at 100 and 300 ppm alone, without previous initiation

    with DEN. The number of foci in rats treated with methidathion at 30
    ppm and lower were not different from the controls (Arai, 1981).

         A second short-term study of the promoting activity in the rat
    liver was conducted with groups of male Fischer 344 DuCrj strain
    rats administered methidathion (98.6% purity) at dietary levels of
    0, 35, 46, 59, 77 or 100 ppm (equal to 0, 2.7, 3.5, 4.8, 6.0 or 7.6
    mg/kg bw/day, respectively) for a period of 6 weeks. Two weeks prior
    to feeding with methidathion, the rats were pretreated with a single
    ip injection of the initiator DEN at 200 mg/kg bw. Partial (two-
    thirds) hepatectomy was performed three weeks after initiation and
    the animals were sacrificed after 8 weeks on study. Histochemical
    analysis unveiled a significant dose-related increase in the number
    of GGT positive foci in rats treated with methidathion at dietary
    levels of 59 ppm and higher. The number of GGT positive foci at
    dietary levels of 46 ppm and lower were comparable to the controls.
    No increases in the number of GGT positive foci were recorded in an
    additional group of rats treated with methidathion at 100 ppm alone,
    without previous initiation with DEN (Daiyu-Kai Institute of Medical
    Science, 1983).

    Special studies on therapeutic activity of antidotes

         The therapeutic potential of antidotes was tested by
    administering methidathion (purity not specified) orally by gavage
    to Tif.RAIf rats at the LD80 of 46 mg/kg bw. The therapeutic
    agents, atropine sulfate alone, toxogonin alone, PAM alone and
    toxogonin combined with atropine sulfate were then administered
    intramuscularly after the first appearance of clinical signs of
    poisoning. A further aspect of therapeutics was investigated, by
    administering 5 repeated daily oral doses of methidathion at the
    LD50 (34 mg/kg bw) to rats and then, upon observation of clinical
    signs, commencing with the respective combination of antidotes. All
    therapeutic agents were, according to the treatment regimen,
    effective against the oral LD80 of methidathion. A positive
    protective effect against repeated LD50 doses of methidathion were
    observed with atropine and toxogonin. PAM and toxogonin in
    combination with atropine had minimal protective effect against
    repeated challenges to methidathion (Sachsse & Bathe, 1977a).

    Observations in humans

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

         Two groups of eight men received 0.04 or 0.11 mg
    methidathion/kg bw/day orally in capsules for 6 weeks. Four men
    received placebo capsules. The treatment with methidathion was

    without effect on plasma and RBC cholinesterase, SGPT and SGOT and
    results of urinalyses or on EEG pattern or clinical condition of the
    subject (Coulston, 1970).

         A case of massive poisoning was reported to have occurred where
    a 25-year old man weighing 60 kg ingested a number of mouthfuls of
    supracide 40 (methidathion, 40% active ingredient). The man was
    discovered approximately 2 hours after the event, in an unconscious,
    semi-comatose condition. Upon admission to hospital the patient was
    treated intravenously with atropine and toxogonin. The
    cholinesterase activity in the serum was found to be zero a few
    hours after admission. The patient was discharged after 15 days of
    hospitalization. The laboratory findings were normal with exception
    of cholinesterase activity which remained low. Follow-up examination
    at 2, 5 and 10 months revealed no abnormalities with no evidence of
    delayed neurotoxicity (Teitelman  et al. 1975).

         A case of attempted suicide occurred in a 50-year old man
    weighing 67 kg who had ingested approximately 6.2 g or 40 ml of
    Supracid 20 (methidathion, 15.5% active ingredient). About 1.5 h
    after the incident, the subject was admitted to hospital suffering
    from mental confusion, muscle fasciculations, bradycardia, miosis,
    sweating, salivation and lacrimation. The patient underwent gastric
    lavage followed by treatment with atropine sulphate and pralidoxime.
    Six hours after ingestion of methidathion, the incidence of muscle
    fasciculations increased followed by bronchorrhea and coma. Serum
    and RBC cholinesterase values, as measured over eight days following
    poisoning were generally less than 50% of normal values.
    Cholinesterase values assessed after 45 days were normal.
    Lymphocytic NTE activity was normal as determined on days 5, 10, 17
    and 45 after poisoning. The patient was discharged after 21 days of
    hospitalization. A follow-up examination after 7 months failed to
    establish any evidence of delayed polyneuropathy or other
    neurological abnormality (Zoppellari  et al. 1990).

    COMMENTS

         Methidathion was extensively absorbed when administered orally
    to rats. The routes of elimination were via the urine and expired
    CO2. There were no significant differences in elimination patterns
    with regard to dose levels administered, pre-treatment or sex.

         In the rat, the predominant urinary metabolites were the
    sulfide, sulfoxide, sulfone and desmonomethyl derivative. Negligible
    quantities of the parent and oxygen analog were detected in the
    urine. The predominant metabolic pathway of methidathion in the goat
    was via O-demethylation with the desmonomethyl derivative as the
    principal urinary metabolite. Cysteine conjugates were identified in
    each species.

         Methidathion has a high acute oral toxicity. The World Health
    Organization has classified methidathion as highly hazardous (WHO,
    1992).

         Methidathion was administered to dogs for 90 days at dietary
    concentrations of 0, 0.5, 4, 45 or 140 ppm, or 0.14 mg/kg bw/day
    (equal to 4 ppm) by capsule, and for a period of 12 months at 0,
    0.5, 2, 4, 40, or 140 ppm in the diet. In both studies the dietary
    NOAEL was determined to be 4 ppm, equal to 0.16 mg/kg bw/day, based
    on liver effects, most notably cholestasis and increased liver
    enzymatic activity in serum at dietary levels of 40 ppm and above.
    Cholestasis was observed in a single male dog treated by capsule at
    0.14 mg/kg bw/day. Erythrocyte and brain cholinesterase activities
    were affected only at the highest level of 140 ppm.

         Long-term dietary treatment of mice with methidathion for 23
    months at 0, 3, 10, 50 or 100 ppm revealed an increased incidence of
    hepatocellular tumours in males at 50 ppm and above, resulting in a
    NOAEL of 10 ppm, equal to 1.4 mg/kg bw/day. Erythrocyte
    cholinesterase was inhibited at 50 ppm (equal to 7 mg/kg bw/day) and
    above, whereas brain cholinesterase activity was affected at 100 ppm
    (equal to 13.7 mg/kg bw/day).

         A 104-week long-term toxicity/carcinogenicity study in rats fed
    methidathion at 0, 4, 40 or 100 ppm indicated a NOAEL of 4 ppm,
    equal to 0.16 mg/kg bw/day, based on inhibition of erythrocyte and
    brain cholinesterase activity at 40 ppm and above. Methidathion was
    not carcinogenic in rats.

         In a two-generation reproduction study in rats at dietary
    concentrations of 0, 5, 25 or 50 ppm, the NOAEL was 5 ppm, equal to
    0.43 mg/kg bw/day. At 25 ppm, reduced mating indices in the F1
    generation and decreased progeny body weights were observed.

         There were no teratogenic effects observed when methidathion
    was administered by gavage to rats at doses of 0, 0.25, 1.0, or 2.5

    mg/kg bw/day or to rabbits at doses of 0, 2, 6 or 12 mg/kg bw/day.
    Maternal effects were demonstrated at the highest doses in both the
    rat and rabbit as clinical signs of toxicity. In the rat, increased
    mortality as well as decreased body-weights and food consumption
    were also observed. The NOAELs in the rat and rabbit were determined
    to be 1 and 6 mg/kg bw/day, respectively.

         Treatment of hens with methidathion did not produce any
    clinical or pathological evidence of delayed neurotoxicity.

         In two reported cases of poisoning with methidathion, each of
    the male subjects exhibited classic clinical and biochemical signs
    of organophosphorus intoxication. Both subjects recovered, with no
    evidence of delayed neurotoxicity uncovered upon follow-up
    examination. In one of the cases jaundice was reported during the
    recovery period.

         Two human volunteer studies failed to reveal any inhibition of
    erythrocyte or serum cholinesterase activity at doses up to 0.11
    mg/kg bw/day.

         After reviewing the available genotoxicity data, the Meeting
    concluded that methidathion was not genotoxic.

         In the dog, the effects on the liver appeared to have occurred
    at levels lower than the levels causing inhibition of cholinesterase
    activity, giving a NOAEL of 0.1 mg/kg bw/day. Whether or not there
    was a relationship to the potential induction of liver effects in
    man could not be ascertained.

         The Meeting concluded, after consideration of the
    hepatocellular tumours found in male mice in the long-term toxicity
    study, together with the lack of genotoxicity, that methidathion did
    not present a carcinogenic hazard for humans.

         The previous ADI, based on a NOAEL in man of 0.11 mg/kg bw/day,
    was revised. The revised ADI is based on the NOAEL in the dog and a
    100-fold safety factor.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Mouse:    10 ppm, equal to 1.4 mg/kg bw/day (23-month study)

         Rat       4 ppm, equal to 0.16 mg/kg bw/day (104-week study)
                   5 ppm, equal to 0.43 mg/kg bw/day (reproduction
                   study)

         Dog:      0.1 mg/kg bw/day (90-day, one-year, and two-year
                   studies)

         Human:    0.11 mg/kg bw/day.

    Estimate of acceptable daily intake for humans

         0 - 0.001 mg/kg bw

    Studies which will provide information valuable in the continued
    evaluation of the compound

         Further observations in humans

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    poisoning with methidathion: A case.  Human & Experimental
     Toxicology, 9(6), 415-419.


    See Also:
       Toxicological Abbreviations
       Methidathion (ICSC)
       Methidathion (WHO Pesticide Residues Series 2)
       Methidathion (WHO Pesticide Residues Series 5)
       Methidathion (Pesticide residues in food: 1979 evaluations)
       Methidathion (Pesticide residues in food: 1997 evaluations Part II Toxicological & Environmental)