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    PESTICIDE RESIDUES IN FOOD - 1982


    Sponsored jointly by FAO and WHO






    EVALUATIONS 1982





    Data and recommendations of the joint meeting
    of the FAO Panel of Experts on Pesticide Residues
    in Food and the Environment and the
    WHO Expert Group on Pesticide Residues
    Rome, 23 November - 2 December 1982

    Food and Agriculture Organization of the United Nations
    Rome 1983


    METHAMIDOPHOS

    CH3O   O
         \ "
           P - NH2
         /
    CH3S

    Explanation

         Methamidophos was evaluated for an ADI by the Joint FAO/WHO
    Meeting in 1976.1 An ADI was allocated based on a no-effect level
    observed in a 90-day dog study not carried out by Industrial Bio-Test
    Laboratories (IBT).

         Some relevant toxicological studies supporting the 1976
    Evaluation of Methamidophos were carried out by IBT, namely,
    antidotes, mutagenicity, neurotoxicity, reproduction, teratology,
    short-term (rat, dog), long-term (rat) and observations in humans.

         The 1982 JMPR was requested to determine the validity of the
    various IBT studies. Some substitutive studies have been made
    available and are summarized in this monograph addendum.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Absorption, Distribution and Excretion

    Fish

         Bluegill  (Lepomis macrochirus) were continuously exposed to
    14C-methamidophos for a 30-day period at concentrations of 10 and 100
    ppb and were held an additional 30 days in fresh, untreated
    water. Throughout the 30 days of exposure, the concentration of
    14C-methamidophos in the water was in the range of 8 to 10 ppb and 74
    to 119 ppb for the expected levels of 10 and 100 ppb, respectively.
    14C residues in fish reached a maximum level of 63 and 1 120 ppb in
    bluegill exposed to 10 and 100 ppb concentrations, respectively. The
    accumulation factors of 8 and 13 ca. were reached in 3 to 7 days and
    were maintained for 30 days. The non-edible portion (head, viscera and
    scales) contained 44% and 97% of 14C-residues from 10 and 100 ppb
    levels, with 99% of the residues extracted into the polar solvent
    acetonitrile.

              

    1  See Annex 2 for WHO and FAO documentation

         The rate of elimination of accumulated 14C-residues was slow,
    and approximately 51 and 39% of the residues from the 10 and 100 ppb
    aquaria, respectively, were dissipated in 30 days of withdrawal (Lamb
     et al 1980c).

    Metabolism

         Female houseflies (N-AIDM susceptible strain, and dimethoate-
    resistant strain) were treated topically with 32p-methamidophos at
    doses of 10, 24 or 48 ng/fly.

         32p residues were determined in the holding container rinse, fly
    external rinse, fly internal extract and fly unextractable residue.
    The data for both external rinses and total penetration show that
    absorption was greater and faster in the susceptible NAIDM strain than
    in the dimethoate resistant strain, thus, at least in part, explaining
    the small but higher cross-resistance of the latter to methamidophos.
    Only the parent compound was detected in the holding container,
    external fly rinses and internal fly extracts. Fly head ChE bioassay
    of the radioactivity quantitated fractions showed no greater
    inhibition than would have been produced by similar amounts of
    methamidophos. Thus, no direct evidence for the in vivo conversion of
    methamidophos to either activation or degradation products was
    demonstrable.

         The results of incubating methamidophos with cockroach gut or
    mouse liver slices, followed by bioassay utilizing housefly head ChE
    inhibition, showed that inhibition after incubation essentially
    paralleled that of the methamidophos standard. This suggests that
    methamidophos did not undergo any major activation or degradative
    changes in these systems. When the in vitro incubation extracts were
    analysed by paper-chromatography, and the various chromatographic
    spots were bioassayed for anticholinesterase activity, only those
    spots corresponding to methamidophos were active, and thus the other
    spots represent breakdown rather than activation products.

         The affinity of methamidophos for ChE and its phosphorylation and
    bimolecular inhibition rates are all relatively slow. In treated
    flies, knockdown and mortality were first evident nearly 8 hours after
    treatment at the LD25 and LD50 levels, but occurred earlier at 4
    hours at the LD90 level. The onset and severity of symptoms, and the
    degree of ChE inhibition in survivors, were relatively dependent on
    the dosage level. With methamidophos, both knockdown and inactivation
    of ChE are slow (compared to other effective organophosphorus
    insecticides), requiring about 4 to 8 hours for maximum effect. This
    appears to be a reflection of the kinetics of its enzyme inhibition,
    although the rate of penetration and accumulation in critical
    concentrations at the site of activation may also be involved. Its

    relative stability and low in vivo degradation appear to be of
    critical importance in accumulating and maintaining a sufficient
    internal concentration for a sufficiently long period of time to
    permit the development of slowly expressed toxicity toward flies
    (Khasawinah  et al 1978).

         In another study, the metabolism of O,S-dimethyl-, propionyl-,
    and hexanoyl-phosphoramidothioate was investigated in the Swiss white
    mouse and housefly. Compared to the hexanoyl-phosphoramidothioate, the
    propionyl analogue is approximately 35-fold more toxic to houseflies
    and is 10-fold less toxic to mice. On a percentage basis,
    substantially larger amounts of methamidophos were detected in
    houseflies treated topically with the propionyl-phosphoramidothioate
    than in flies treated with the hexanoyl derivative. The reverse was
    evident in the case of the mouse, where much larger amounts of
    methamidophos were formed after oral treatment with hexanoyl-
    phosphoramidothioate. Minor amounts of other metabolic products
    also were detected, including an unknown from hexanoyl-
    phosphoramidothioate. Metabolism of the O,S-methyl moiety to carbon
    dioxide appeared to be a major pathway for metabolic degradation of
    both compounds in both the white mouse and housefly. The difference in
    toxicity of the two acyl phosphoramidothioates to the mouse and
    housefly is attributed to the differences in the amounts of
    methamidophos formed in the animals (Kao and Fukuto 1977).

    Effects on Enzymes and other Biochemical Parameters

         In vitro determination of cholinesterase (ChE) inhibition showed
    that methamidophos is a moderate ChE inhibitor in comparison to other
    organophosphates of comparable toxicity. Further, it shows essentially
    no selectivity among the three sources of enzyme considered, i.e.
    housefly head, honey bee worker head and white mouse brain (I50 (M)
    1.1 3.5, 8.2 × 10-5, respectively). Paralleling its
    anticholinesterase activity, methamidophos is only a moderate
    inhibitor of housefly and bee abdomen aliesterase (AliE).

         The results of the in vivo inhibition studies of ChE and AliE in
    surviving flies treated topically with methamidophos at the LD25,
    LD50 and LD90 levels showed that knockdown and mortality were first
    evident nearly 8 hours after treatment at the LD25 and LD50 levels,
    but occurred earlier - at 4 hours - at the LD90 level. ChE activities
    at these times were drastically reduced in knocked-down and and dead
    flies to below 10% of normal activity in heads and to essentially 0%
    in thoraxes. In surviving flies, ChE inhibition was slowly progressive
    and reached its maximum with the appearance of knockdown effects when
    head ChE activities at the LD25, LD50 and LD90 levels were,
    respectively, 64, 16 and 16% of normal, and thoracic ChE activities
    were, respectively, 56, 12 and 2%. AliE inhibition at LD50 level
    after treatment with methamidophos occurs sooner and is more complete

    in surviving flies than ChE inhibition, reaching essentially 0% of
    normal in 15 hours. AliE and ChE did not recover over a period of
    16 hours in the surviving flies. Since essentially total AliE
    inhibition occurred much earlier than the appearance of symptoms of
    poisoning, its inhibition by methamidophos appears to have little
    significance relative to poisoning effects toward flies. Although
    inhibition of AliE is not directly related to the toxicity, it may
    play an important role in toxicological interactions, such as the
    potentiation of toxicity of malathion (Khasawinah  et al 1978).

         Reactivation of acetylcholinesterase (AChE) inhibited by
    MeO(NH2)P(O)SMe (methamidophos) and by MeS(NH2)P (O) SMe was studied
    at pH 7.5 and 25°C. The former inhibited enzyme shows a rather rapid
    spontaneous reactivation (t1/2=3.7 h); this reactivation is
    accelerated by 1 µM of the bispyridinium oximes TMB4 and obidoxime,
    and, to a lesser extent, by the monopyridinium oximes P2S and its
    1-benzyl analogue (benzyl-P2A). The latter inhibited enzyme shows
    rapid ageing (t1/2 = 0.6 h). Reactivation with 1 mM of the
    bispyridinium oximes is incomplete and reactivation with 1 mM of the
    mono pyridinium oximes proceeds very slowly. These large differences
    between the properties of the two inhibited enzymes indicate that the
    methylthio group is the leaving group during inhibition of Ache by
    methamidophos. Additional support is afforded by the observation of
    induced ageing of the former inhibited enzyme by thiourea.

         On comparison of the reactivation of AChE inhibited by
    methamidophos with that of AChE inhibited by an N-methyl analogue,
    crufomate, and an N,N-dimethyl analogue,tabun, it appears that the
    rate of spontaneous reactivation decreases with increasing alkylation
    of the P-NH2 group. Whereas benzyl-P2A is somewhat less active than
    P2S for reactivation of AChE inhibited by methamidophos, it is
    superior to P2S for reactivation of AChE inhibited by crufomate and
    also superior to P2S and to the bispyridinium oximes for AChE
    inhibited by tabun (de Jong  et al 1982).

    TOXICOLOGICAL STUDIES

    Special Studies on Embryotoxicity and Teratogenicity

         Groups of rabbits (15 pregnant Himalayan rabbits/group) were
    administered single daily doses of methamidophos (62% purity) by oral
    intubation equivalent to 0, 0.1, 0.5, 2.5 mg/kg bw from gestation day
    6 through 18 (a total of 13 times). Himalaysan rabbits are reported
    sensitive to the toxic effect of thalidomide on their embryos/
    foetuses. The highest dose (2.5 mg/kg/day) was selected because an
    oral dose of 5 mg/kg/day administered 13 times in a preliminary
    experiment on 3 female rabbits had produced a weight loss and caused
    diarrhoea in one of them. On gestation day 29, the dams were
    sacrificed and foetuses were removed by caesarean section for
    external, viscera] and skeletal examination. Neither adverse effects

    on appearance and behaviour, nor treatment-related mortality were seen
    in any of the treated animals. Average weight increase of animals of
    all treated groups was clearly lower than control animals (even though
    not strictly dose-related) over both the dosing and the entire
    gestation period. Since the litter size and foetus weights were
    comparable in all groups, the reduced body weight gain of dams was
    considered a maternally toxic effect of the treatment. There were no
    significant differences between control and treated groups with
    respect to fertility rate, pregnancy rate, sex distribution of
    foetuses and average numbers of implantations, dead and live foetuses,
    resorptions (which includes the number of aborted foetuses), foetus
    weight, placentaweight and stunted foetuses (weighing less than
    25 grams). Skeletal retardations were found only in the control group
    (sternum) and one in the 2.5 mg/kg/day group (os pubis). Some
    malformations occurred in all treated groups but not in the control.
    However malformations found in treated animals were neither uniform in
    type nor dose-related, and both frequency of malformed foetuses and
    type of malformations were within the normal limits for this strain of
    rabbit. On the basis of the data, there are no indications of
    methamidophos having embryotoxic or teratogenic effects on Himalayan
    rabbits at oral doses up to and including 2.5 mg/kg/day (Machemer
    1979).

    Special Studies on Mutagenicity

    Mouse - dominant lethal test

         Groups of mice (50 male, NMRI/ORIG Kissleg strain/group) were
    administered by intubation a single oral dose of 0 and 5 mg/kg bw of
    methamidophos (62.6% purity). The mouse strain used for the study is
    reported to display a sensitive response to known chemical mutagens,
    e.g. cyclophosphamide, MMS or trenimon. The dose of methamidophos was
    selected on the basis of the results of a preliminary experiment on
    female mice, in which groups of five mice were orally dosed with
    7.5 mg/kg and 15 mg/kg, respectively, of methamidophos; in that
    experiment the dose level of 7.5 mg/kg was tolerated with only mild
    symptoms. Immediately after administration, each male was mated with
    one untreated virgin female. After a 4-day mating period, this female
    was removed and replaced by another female, and so on for 12 mating
    periods, for a total of 48 days. After about 14 days from the mid-
    period of each mating, the females were sacrificed and uteri removed
    for examination. The total implants, viable implants, dead implants
    (sum of the deciduomata, resorptions and the dead embryos and
    foetuses) and the corpora lutea were counted. The treated males
    exhibited no signs of toxicity. There was no compound-related
    mortality. The fertility rate in the treated group was somewhat lower
    than that in the control group in mating periods 2, 3 and 4. However,
    as a similar low value was observed in the control group in mating
    period 1, the findings were not considered to have been due to an

    effect of the test compound. There were no statistically significant
    differences between the control and treated groups with respect to
    total implantations, viable implants, dead implants and pre-
    implantation loss (estimated both directly as the difference between
    corpora lutea and implantations and indirectly as implantations per
    fertilized female).

         Thus, the dominant lethal test on the male mouse does not provide
    any relevant indication that methamidophos has a mutagenic activity at
    the acute oral dose of 5 mg/kg bw (Herbold 1980a).

    Rat - micronucleus test

         Groups of rats (5 male and 5 female, NMRI/W77 strain/group) were
    administered methamidophos (62.6% purity) twice by oral intubation at
    doses of 0, 5 and 10 mg/kg bw. A positive control group received
    twice 0.125 mg/kg bw of trenimon intraperitoneally. Delay time
    between administrations was 24 hours. Six hours after the second
    administration, animals were decapitated and bone-marrow smears were
    prepared. The doses were selected after a preliminary test in which 5
    animals received 2 × 5, 2 × 10 and 2 × 20 mg/kg of methamidophos, and
    animals tolerated 2 × 10 mg/kg with slight symptoms. Poly-chromatic
    erythrocytes, 1 000 per animal, were observed and the frequency of
    such cells with micronuclei was calculated. Also the ratio of
    polychromatic to normochromatic erythrocytes was determined. No
    compound-related mortality occurred. Behaviour and motor activity were
    not affected by the treatment. There were no significant differences
    between negative control and methamidophos treated groups with respect
    to the presence of micronucleated polychromatic erythrocytes. The
    frequency of such cells was 2.6% in the negative control and 2.1% and
    1.6% in 5 and 10 mg/kg groups, respectively. Activity of the positive
    control was clearly observed in that a frequency of 53.7%
    micronucleated polychromatic erythrocytes occurred in the trenimon-
    treated group. There were no significant differences between control
    and both trenimon and methamidophos treated groups, also with respect
    to the ratio of polychromatic to normochromatic erythrocytes, i.e.
    these compounds did not affect erythropoiesis. Thus, in the
    micronucleus test on the rat, there was no indication of mutagenic
    activity of methamidophos at doses up to and including 2 × 10 mg/kg
    per os (Herbold 1981).

     Salmonella/microsome test

         Strains of  Salmonella typhimurium (TA 1535, TA 1537, TA 100,
    TA 98), with and without a metabolic activation system (S-9 mix
    derived from the liver of Sprague-Dawley rats treated
    intraperitoneally with Arochlor 1254) were tested at concentrations of
    20, 100, 500, 2 500 and 12 500 µg/plate of methamidophos (62.6%
    purity). Positive controls were cyclophosphamide (only for TA 1535 and
    TA 100) and trypaflavin (only for TA 1537 and TA98). Negative controls

    were dimethylsulphoxide (DMSO) for methamidophos and trypaflavin and
    demineralized water for cyclophosphamide. Four plates per substance,
    per dose, per strain were used. In all groups, two plates were used
    for the total cell count. Results were considered positive when in at
    least one strain a reproducible, dose-related increase of mutant cells
    at least double that of the negative control occurred. Concentrations
    higher than 500 µg/plate were slightly bacteriotoxic both with and
    without S-9 mix, but were nevertheless useful for the evaluations of
    the test. An increase of mutants greater than the double of the
    respective negative controls, but not dose-related, was observed only
    in two strains (TA 1535 and TA 1537) at 100 µg/plate without S-9 in
    TA 1535, and at 100 µg/plate with S-9 and 100, 500, 2 500 µg/plate
    without S-9 in TA1537. However, these results could not be reproduced
    in a repetition experiment with TA 1535 and TA 1537. Positive controls
    displayed the expected mutagenic effects.

         Thus, under the conditions of the test, methamidophos showed no
    mutagenic activity toward the tested strains of  Salmonella 
     typhimurium at doses up to and including 12 500 µg/plate, both with
    and without S-9 Mix (Herbold 1980b).

    Special Studies on Neurotoxicity

         Groups of adult hens (9 to 18 months old) were given a single
    dose of methamidophos (74% purity) by gastric intubation at levels of
    0, 30 and 50.63 mg/kg body weight on days 0 and 21 simultaneously with
    50 mg/kg of atropine sulphate intramuscularly. Eight hens for the
    control and 10 and 12, respectively, for the treated groups were used.
    Concurrently 500 mg/kg of tri-orthocresyl phosphate (TOCP) and
    50 mg/kg of atropine sulphate were administered to 10 hens for a
    positive control. In a separate portion of the study the acute oral
    LD50 was found to be 29.75 mg/kg.

         No delayed neurotoxic signs were observed in the control and
    treated groups during a 42-day post-treatment observation period. The
    dose level in the delayed neurotoxicity study were above the acute
    oral LD50 and atropine was given as protection against acute death.
    However some acute deaths did occur both at day 0 and 21. Acute signs
    of toxicity did occur in most cases but disappeared by 24 hours. Hens
    were sacrificed on day 42 or 43, and 7 hens from the control group,
    9 from the TOCP group, 3 from the 33.75 mg/kg group or the LD50
    study, 6 from the 30 mg/kg group and 4 from the 50.63 mg/kg group were
    used for histopathological examination of the spinal cord and
    peripheral nerves. No compound-related histopathological changes or
    variations from normal were observed in the nervous tissues of the
    examined hens. TOCP treated hens developed clinical signs of
    neurotoxicity. Five had marked neuronal histological lesions, three
    moderate and one slight (Kruckenberg  et al 1979).

    Special Studies on Antidotes

         The lethality of methamidophos to rats (i.p. LD50, 15 mg/kg) is
    similar to that of such potent organophosphate compounds as parathion
    and paraoxon. Certain distinctive features of its chemical structure
    and reported failure of cholinesterase inhibited with methamidophos to
    reactivate spontaneously in insects prompted this study of its
    reactions with mammalian cholinesterase to determine if the treatment
    of poisoning requires modification. Atropine (10 mg/kg) or pradiloxime
    (60 mg/kg) produced significant protection against lethality from
    methamidophos (LD50 60 ± 0.4 and 52 ± 4.9 mg/kg, respectively).
    Partial spontaneous recovery of inhibited cholinesterase activity was
    observed. However, a single dose of pralidoxime, given simultaneously
    with methamidophos, did not hasten the recovery of cholinesterase
    activity (Robinson  et al 1978).

    Special Studies on Combined Toxicity

    Methamidophos/mercaprophos

         Acute oral LD50 values in male rats (Wistar albino) were
    determined for methamidophos (62% purity), mercaprophos (88% purity)
    separately administered, and for the equitoxic mixture of the two
    compounds.

         The comparison of the LD50 found for the equitoxic mixture with
    the expected LD50 (assuming an additive effect) showed that
    simultaneous oral administration of methamidophos and mercaprophos
    resulted in only an additive acute toxic effect (Flucke 1978).

    Methamidophos/parathion-ethyl

         A similar study showed that simultaneous oral administration of
    methamidophos (63.7% purity) and parathion-ethyl (97.8% purity)
    resulted in only an additive acute toxic effect (Flucke and Kimmerle
    1977).

    Methamidophos/chlorpyrifos, cytrolane, cyolane

         Equitoxic mixtures of methamidophos with either chlorpyrifos,
    cytrolane or cyolane were acutely administered to male Wistar-II
    albino rats to evaluate possible potentiation of acute toxic effects.
    Comparison of the found and the expected LD50 (assuming an additive
    effect) showed that simultaneous oral administration of each
    combination resulted in only an additive or slightly under-additive
    acute toxic effect between the two components (Thyssen 1977c).

    Special Studies on Skin and Eye Irritation

         A dermal irritation study using New Zealand white rabbits
    indicated that 24 hours exposure to methamidophos (73.2% purity) was
    not irritant for either abraded or non-abraded skin (Lamb  et al 
    1980a).

         Results of an eye irritation test using New Zealand white rabbits
    indicated that methamidophos is a positive eye irritant. An
    irreversible response was observed in one rabbit of the group, which
    received an eye wash 45 seconds after the treatment (Lamb  et al 
    1980a).

    Special Studies on Feedingstuffs Palatability

         Cattle were fed alfa alfa pellets treated with methamidophos at
    levels of 0, 5 and 15 ppm (at or above the level expected in field-
    treated plant material) for 4 weeks.

         No significant differences in feed consumption or body weights
    were observed between animals fed treated or untreated feed; the
    animals initially showed some preference for treated feed, but by the
    end of a week no preference was detected (Murphy  et al 1976).

    Acute Toxicity

         Signs of toxicity were similar in mouse and rat and included
    severe tremors, salivation, dyspnoea and, rarely, clonic convulsions.
    These signs were evident within 5-10 minutes. Death occurred between
    20-30 minutes and 72 hours. Animals surviving 72 hours showed complete
    recovery within seven days. Autopsies done on animals dying shortly
    after dosing showed pulmonary congestion and oedema and distension of
    the stomach and intestines with gas (Cavalli and Hallesy 1968c).

         The acute toxicity of methamidophos and of two impurities found
    in technical methamidophos are summarized in Tables 1 and 2.

    Short-Term Studies

    Rabbit-dermal

         Groups of rabbits (6 male and 6 female New Zealand/group) were
    administered methamidophos (64.5% purity) dermally to either intact or
    abraded skin with single daily applications corresponding to dose
    levels of 0, 0.5, 5 mg/kg. The application was made 6 hours/day, 5
    days/week for 3 weeks. The sample was applied as an aqueous emulsion.

        Table 1.  Acute Toxicity of Methamidophos
                                                                                                                     

                                                                          LD50
    Species        Sex       Route               Vehicle                  (mg/kg bw)     References
                                                                                                                     

    Mouse          F         oral                water                      16.20        Cavalli et al 1968a
                             (95% pure)

    Rat            M         oral                deionized water            15.60        Cavalli and Hallesy 1968c
                             (95% pure)
                   F                                                        13.00

    Rat            M         oral                dist. water                32.90        Thyssen 1977a

    Rat            M         oral                dist. water                21.60        Thyssen 1927b

    Rat            M         oral                Cremophor EL and           24.00        Thyssen 1977c
                             (63.7% pure)        dist. water

    Rat            M         oral                Cremophor EL and           30.00        Flucke and Kimmerle 1977
                             (63.7% pure)        dist. water

    Rat            M         oral                Cremophor EL and           28.95        Flucke 1978
                             (62% pure)          dist. water

    Rat            M         oral                dist. water                18.00        Mihail 1981
                             (64.5% pure)
                   F                                                        26.00

    Rat            M         dermal                                        162.00        Heinmann 1981
                             24-h exp.
                             (64.5% pure)
                   F                                                       108.00
                                                                                                                     

    Table 1.  (con't)
                                                                                                                     

                                                                          LD50
    Species        Sex       Route               Vehicle                  (mg/kg bw)     References
                                                                                                                     

    Rabbit         M         dermal              undiluted                 118.00        Cavalli and Hallesy 1968b
                             24-h exp.
                             (75% pure)

    Rabbit         M         dermal              undiluted                 122.00        Lamb et al 1980b
                             24-h exp.
                             (73.2% pure)
                   F                                                        69.00

    Hen            F         oral                not specified              29.75        Kruckenberg et al 1979
                             (74% pure)

    Bobwhite       M         oral                PEG-400                    10.10        Nelson 1979b
    quail          F                                                        11.00
                                                                                                                     

    Table 2.  Acute Toxicity of Impurities of Technical Methamidophos
                                                                                                                           

                                                                                    LD50
    Compound            Species        Sex       Route          Vehicle             (mg/kg bw)     References
                                                                                                                           

    Dimethyl Ac.        rat            M         Oral           Prop.glycol:        694            Lamb and Anderson 1974a
    (CH3O)2P(S) (SH)                                            Ethanol 8:2
                                       F                        Ethanol, 8:2        708

                        rabbit         M&F       Dermal         undiluted           >2 000         Lamb and Anderson 1974b
                                                 abraded
                                                 24-h exp.

    Amidate             rat            M&F       oral           Prop. glycol:       410            Lamb and Anderson 1974a
    (CH3O)2P(S)NH2                                              Ethanol, 8:2
                        rabbit         M&F       Dermal         undiluted           >2 000         Lamb and Anderson 1974b
                                                 abraded
                                                 24-h exp.
                                                                                                                           
             No mortalities occurred and all the animals were normal in
    behaviour and appearance during the treatment period. No significant
    differences were observed with respect to mean body weight in all
    groups. Neither inflammation nor thickening of the treated skin was
    seen. There were no noteworthy differences between control and treated
    groups with respect to haematological, clinical-chemical and
    urinalysis parameters. Marginal to distinct (19-35%) depression of
    serum and erythrocyte cholinesterase activity occurred in the 5 mg/kg
    groups. Brain cholinesterase was not significantly different between
    control and treated groups. No treatment-related differences between
    control and treated groups were seen in absolute and relative organ
    weights or in gross and histopathological examinations. The no-effect
    level for cholinesterase activity was 0.5 mg/kg bw/day, 5 mg/kg bw/day
    being tolerated without apparent somatic effects (Heinmann and Nash
    1981).

    Observations in Humans

         Thirteen reports on persons involved discontinuously in
    activities related to synthesis, process development and pilot-plant
    manufacture of methamidophos for 1 to 3 years, and 38 reports on
    persons engaged in normal spraying operations (back-pack-, tractor-,
    and helicopter-mounted equipment), including foliar, ground and
    greenhouse applications of diluted emulsifiable formulations, did not
    record any relevant complaints (Chevron Chemical Company 1968).

    COMMENTS

         Methamidophos was evaluated by the 1976 JMPR. An ADI was
    allocated, based on a no-effect level observed in a 90-day dog study
    which was not from IBT.

         Some relevant toxicological studies supporting the 1976
    Evaluation were carried out by IBT. Valid substitute studies have been
    provided for some of the IBT studies.

         No-effect levels for embryotoxic and teratogenic effects for
    methamidophos were observed in the Himalayan rabbit.

         Methamidophos was not mutagenic in the dominant lethal,
    micronucleus and Ames tests.

         A delayed neurotoxicity test was negative.

         No valid long-term toxicity, reproduction or carcinogenicity
    studies have been provided.

         As no-effect levels could be determined in short-term studies
    only, a temporary ADI was allocated.

    TOXICOLOGICAL EVALUATION

    Level Causing no Toxicological Effect

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

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

    Estimate of Temporary Acceptable Daily Intake for Man

         0 - 0.0004 mg/kg bw.

    FURTHER WORK OR INFORMATION

    Required (by 1985)

    1.   Long-term studies, or validation of the IBT long-term study on
         rats.

    2.   A carcinogenicity study.

    3.   A reproduction study in mammals.

    Desirable

    Observations in humans.

    REFERENCES

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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: 1984 evaluations)
       Methamidophos (Pesticide residues in food: 1985 evaluations Part II Toxicology)
       Methamidophos (Pesticide residues in food: 1990 evaluations Toxicology)