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    METHOMYL

    EXPLANATION

         Methomyl was evaluated for acceptable daily intake by the Joint
    Meeting in 1978 (Annex 1, FAO/WHO, 1979a), but an ADI could not be
    allocated because of a lack of data. The present toxicological
    monograph summarizes the data that were submitted to the 1986 Joint
    Meeting.

    IDENTITY AND PROPERTIES

    CHEMICAL NAME

    IUPAC:   S-methyl-N-[(methylcarbamoyl)oxy]thioacetimidate

    CAS:     Methyl N-[[(methylamino)carbonyl]oxy]ethanimid-
             othioate (CAS Registry No. 16752-77-5)

    SYNONYMS              DPX-1179; Lannate(R); Nudrin(R); SD 14999;
                          WL 18236; Mesomile(R).

    STRUCTURAL FORMULA

                                            O
                                            "
                          CH3 - C = N - O - C - NH - CH3
                                '
                                S - CH3

    EMPIRICAL FORMULA     C5H10N2O2S

    MOLECULAR WEIGHT      162.23

    PHYSICAL STATE AND    White crystalline solid with a slight
    COLOR                 sulfurous odor

    DENSITY               1.2946 (at 24C)

    VAPOUR PRESSURE       5  10-5 mm Hg (25C)

    MELTING POINT         78 to 79C

    STABILITY             Stable in solid form and in aqueous solutions at
                          pH 7.0 or less. Rapidly decomposes in alkaline 
                          solutions and in moist soils.

    SOLUBILITY            Solvent             g/kg at 25C

                          Water                    58
                          Methanol               1000
                          Acetone                 730
                          Ethanol                 420
                          Isopropanol             220
                          Toluene                  30

    EVALUATION FOR ACCEPTABLE INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution, biotransformation, and excretion

         Each of 3 male Crl:CD(SD)BR rats was administered a single dose
    of 14C-methomyl (99% pure, labelled in the 1 position, the oximino
    carbon) after preconditioning by feeding a diet that contained 200 ppm
    unlabeled methomyl. Two of the rats were preconditioned for 8 days
    prior to being administered 14C-methomyl at a dose of 5 mg/kg b.w.
    The third rat was preconditioned for 19 days prior to dosing with
    14C-methomyl at 3.5 mg/kg b.w. Methomyl was rapidly absorbed and
    excreted, with a minor portion (10%) retained in the body after 24
    hours. Most of the radioactivity was eliminated as carbon dioxide,
    acetonitrile, and polar urinary metabolites in the ratio of 1:2:1. The
    urinary metabolites, which represented approximately 25% of the
    administered dose, were not identified. Methomyl, the S-oxide or
    S,S-dioxide of methomyl, the glucuronide or sulfate conjugates of
    methomyl, or S-methyl-N-hydroxythio-acetimidate were not detected in
    urine by counter-current distribution, enzymatic treatment, or
    thin-layer chromatography techniques (Harvey, et al., 1973).

         Syn-methomyl (the form of methomyl which is produced and sold)
    was metabolized differently by the rat than was the less stable
    anti-methomyl. The syn-isomer gave rise to an oxime that was
    metabolized primarily to CO2, while the anti-isomer primarily
    produced acetonitrile. It was shown that the syn-isomer was
    partially isomerized to the anti-configuration in the rat prior to
    hydrolysis of the ester linkage. This conversion was related to the
    formation of acetonitrile (Huhtanen & Dorough, 1976).

         A proposed metabolic pathway for methomyl is shown in Figure 1.
    For additional information on the metabolism of methomyl, see the
    toxicological monograph on thiodicarb that was published after the
    1985 Meeting (Annex 1, FAO/WHO, 1986c).

         The dermal penetration, tissue distribution, retention, and
    excretion of 14C-methomyl were compared with those of other
    pesticides in ICR mice. Approximately 88% of the applied methomyl had
    penetrated the skin within 6 hours of application. The penetration
    half-life of 13.3 minutes (time for one-half of the applied dose to
    penetrate the skin) was similar to that of other carbamates, but
    faster than that of the organophosphates that were evaluated,

    parathion, malathion, chlorpyrifos, and chlorpyrifos-methomyl. Within
    5 to 15 minutes after application, methomyl was detectable in blood,
    liver, fat, carcass, and excreta. There was a continual increase of
    methomyl in the blood, and by 8 hours it had attained a higher
    percentage of dose (6.1%) than the other pesticides examined
    (0.3 - 2.7%) (Shah et al., 1981).

    CHEMICAL STRUCTURE 3

    Effects on enzymes and other biochemical parameters

         Methomyl was administered in the diet to groups of Crl:CD(SD)BR
    rats at levels of 0, 5, 100, 200, 400, or 800 ppm for 5 months. There
    were 10 rats/sex/dose. Peripheral blood samples were taken at 4, 11,
    32, 43, 60, and 79 days and enzyme activities were measured in whole
    blood by the Ellman method. Significant inhibition was reported at
    800 ppm in both sexes, but not at 400 ppm (Singles, 1970).

         Groups of Crl:CD(SD)BR rats (8/sex/group) were fed technical
    methomyl in their diets at dose levels of 0, 100, 400, or 800 ppm for
    29 days. Analysis of erythrocyte, plasma, and brain cholinesterase,
    determined separately, demonstrated that brain cholinesterase was more
    sensitive to methomyl. Females at 100, 400, and 800 ppm demonstrated
    depressed brain cholinesterase activity after 29 days compared to
    controls, statistically significant at the high dose only. Erythrocyte
    and plasma cholinesterase activities, although depresses in males and
    females at 800 ppm, were not statistically different from controls
    (Barnes, 1978).

    Toxicological studies

    Special studies on mutagenicity

         Methomyl has been shown to be negative in a number of test
    systems that have assessed the ability of this compound to cause gene
    mutations, structural chromosomal defects, and direct DNA damage. A
    single positive result for sister chromatid exchange (SCE) was
    reported in an abstract (DeBuyst, B. & Van Larebeke, 1982); however,
    this study is not acceptable for evaluation, because methods, purity
    of the test substances, and actual results were not reported.

         Summary results are presented in Table 1.

    Special studies on reproduction

    Rats

         Groups of male and female Charles River CD rats (13 males/group
    and 26 females/group in the F0 generation, 20 males/group and 40
    females/group in the F1 generation) were fed diets containing 0, 75,
    600, or 1200 ppm technical methomyl continuously over 2 generations.
    Feed analyses indicated that the actual levels of methomyl in the test
    diets were within acceptable limits of the targeted values. Animals
    were observed twice daily for clinical signs of toxicity and body
    weights and food consumption were measured weekly. During gestation,
    females were weighed on day 3 and daily from days 6 through
    parturition. F0 and F1 males were sacrificed after mating, and
    sperm counts were performed. After birth, litter size, pup weights,
    sex, and numbers of live and dead pups were determined. Pups were
    examined daily during lactation for abnormalities of appearance or
    behaviour, and were weighed on days 1, 4, 7, 14, and 21 of lactation.
    After weaning, pups were weighed weekly. F0 and F1 parents were
    subjected to complete necropsies and haematological evaluations at the
    end of mating or weaning (males and females, respectively).
    Randomly-selected pups from each generation (10/sex/dose) were also
    necropsied.

         Mean body weights were significantly decreased at most of the
    measured intervals in mid- and high-dose male and female parents in
    the F0 generation, and in all parental treatment groups in the F1
    generation. The decrease in the F1 generation was dose-related, and
    ranged from 5 - 10% in the low-dose groups to 20 - 25% in the
    high-dose groups; a NOEL was not established for this finding. A
    similar pattern was noted in dams during gestation, as dose-related,
    statistically-significant decreases were noted in all F1 female
    treatment groups, and in mid- and high-dose F0 treatment groups.
    These decreases appeared to be related to decreases in food
    consumption.

        Table 1. Special studies on mutagenicity
                                                                                                                                

    Test system         Test object             Concentration           Purity            Results           References
                                                used
                                                                                                                                

    Ames test1          S. typhimurium          0.005, 0.05,            Technical         Negative2         Blevins,
                        TA98, TA100,            0.5, 5,                                                     et al., 1977
                        TA1535,                 50 nM
                        TA1537,
                        & TA1538

    Ames test1          S. typhimurium          1, 5, 10, 50,           Technical         Negative3         Simmon,
                        TA100,                  100, 500,                                                   et al., 1977
                        TA1535,                 1000 g/plate
                        TA1537,
                        & TA1538

    Ames test1          E. coli                 1, 10, 50,              Technical         Negative4         Simmon
                        WP2                     100, 500,                                                   et al., 1977
                                                1000 g/plate
                                                                                                                                

    1    Both with and without metabolic activation.
    2    The nitroso- derivative of methomyl was positive at 50 nM.
    3    The positive control, 4-o-tolylazo-o-toluidine at 25 g/plate, gave the expected positive response.
    4    The positive controls, AF-2 at 0.1 g/plate and 2-aminoanthracene at 10 g/plate, gave the expected positive responses.

    Table 1. (cont'd).
                                                                                                                                

    Test system         Test object             Concentration           Purity            Results           References
                                                used
                                                                                                                                

    DNA repair          E. coli                 1 mg/disc               Technical         Negative5         Simmon
    assay               W3110, p3478                                                                        et al., 1977
                        B. subtilis
                        H17, m45

    Mitotic             S. cerevisiae D3        1.0, 1.5, 2.0,          Technical         Negative6         Simmon
    recombination1                              2.5, 3.0                                                    et al., 1977
                                                3.5% w/v

    Gene mutations      Chinese                 1, 5, 10 mM             Unknown           Negative7         Wojciechowski
    in vitro1           hamster                                                                             et al., 1982
                        ovary V79

    CHO/HGPRT           Chinese                 Nonactivated:           99%               Negative8         McCooey
    gene                hamster                 10, 20, 40,                                                 et al., 1984
    mutation1           ovary cells             50, 55 mM.
                        CHO-K1,                 Activated:
                        BH4 clone               100, 150, 200,
                                                250, 350 mM
                                                                                                                                

    5    The positive control, 1-phenyl-3-dimethyltriazene at 1 mg/disc, and the negative control, chloramphenicol at
         0.03 mg/disc, gave the expected responses.
    6    The positive control, 0.025% 1,2,3,4-diepoxybutane, gave the expected positive response.
    7    This study is not acceptable for evaluation because the purity of the test substance was not identified.
    8    The positive control, 0.5 mM EMS, gave the expected positive response.

    Table 1. (cont'd).
                                                                                                                                

    Test system         Test object             Concentration           Purity            Results           References
                                                used
                                                                                                                                

    Sister              In vitro                Unknown                 Unknown           Positive9         DeBuyst &
    chromatid           human                                                                               Van Larebeke,
    exchange1           lymphocytes                                                                         1982

    Sex-linked          Drosophila              4 & 10 ppm              Technical         Negative10        Valencia,
    recessive           melanogaster                                                                        1981
    lethal

    Unscheduled         Primary rat             0, 1, 10, 100,          99%               Negative11        Vincent
    DNA                 hepatocytes             1000, 5000,                                                 et al., 1985
    synthesis           from male               10,000,
                        Crl:CD rats             75,000 M

    Unscheduled         WI38                    10-7, 10-6,             Technical         Negative12        Simmon
    DNA                 fibroblasts             10-5, 10-4,                                                 et al., 1977
    synthesis                                   10-3 M
                                                                                                                                

    9    This study is unacceptable for evaluation because it is in abstract form; methods and data were not reported.
    10   The positive controls, EMS, EDB, TMP, and EI, gave the expected positive responses when tested at the appropriate
         concentrations.
    11   The positive control, 100 and 500 M DMBA, gave the expected positive response.
    12   The positive control, 10-5 M 4-nitroquinoline, gave the expected positive response.

    Table 1. (cont'd).
                                                                                                                                

    Test system         Test object             Concentration           Purity            Results           References
                                                used
                                                                                                                                

    In vivo             Sprague-Dawley          0, 2, 6,                99%               Negative13        Farrow
    bone marrow         male and female         20 mg/kg                                                    et al., 1984
    cytogenetics        rats
                                                                                                                                

    13   The positive control, 40 mg/kg cyclosphosphamide, gave the expected positive response.
             At necropsy of the F0 parents, dose-related, statistically-
    significant decreases in red cell count, haemoglobin concentration,
    and haematocrit were noted in mid- and high-dose females; males were
    not similarly affected. No statistically-significant decreases in
    blood ChE activity were noted; however, mean plasma ChE activity was
    decreased by 15% and 25% in high-dose F0 males and females,
    respectively. Haematology/ChE results were not reported for F1
    animals. Absolute and relative weights of several organs were altered
    in a manner consistent with the treatment-related changes in body
    weights, as absolute organ weights tended to decrease whereas relative
    organ weights tended to increase, relative to the controls. No effects
    of treatment on histopathological examination of F0 or F1
    parents were noted.

         Fertility, gestation length, and male sperm counts were not
    adversely affected by treatment. However, dose-related statistically-
    significant decreases in litter size and mean number of live pups
    born were noted in all F1 treatment groups and in high-dose
    F0 rats; a NOEL was not established for this finding. Pup survival
    during lactation was significantly reduced in high-dose F1 pups
    (born of F0 dams), but survivial did not appear to be affected
    in F2 pups (born of F1 dams) after day 7 of lactation (a
    significant decrease was noted in high-dose pups on day 4). Mean body
    weights during lactation were significantly reduced in a dose-related
    manner in all F1 pups; however, body weights were reduced only in
    the mid- and high-dose groups of the F2 generation; a NOEL was not
    established for this finding. No treatment-related histopathological
    changes were noted in F1 or F2 pups (Lu, 1983).

         Groups of Charles River CD rats (10 males/group and 20
    females/group) were fed diets containing 0, 50, or 100 ppm methomyl
    (purity unspecified) over 3 generations. F3b weanlings (10 sex/dose)
    were subjected to necropsy and examined for histopathological changes.
    A third group of weanlings (F3c) was fed test diets for 9 weeks and
    then control diet during weeks 10 through 14 to assess the effect of
    treatment on growth.

         The study report indicated that no effects of treatment on
    fertility, litter size, number of live pups, or pup survivial were
    noted. A slight (10%) decrease in the mean body weights of male and
    female pups at weaning in the F2 and F3 generations was not
    considered to be related to treatment. No effects of treatment on
    absolute or relative organ weights were noted. No treatment-related
    changes in the gross or microscopic appearance of tissues were
    reported; however, actual data were not submitted. Growth of F3c
    weanlings fed 100 ppm methomyl was significantly less than that of
    control rats, which was related to decreased food intake. This trend
    was not reversed by removal of animals from the test diet for 4 weeks
    (Kundzin & Busey, 1968).

    Special studies on teratogenicity

    Rats

         Groups of naturally-bred Charles River (ChR-CD) female rats
    (25/group) were randomly assigned to treatment groups that received
    test diets containing 0, 50, 100, or 400 ppm technical methomyl
    (< 99% active ingredient) and 1% Mazola corn oil over days 6 - 15 of
    presumed gestation. Average doses were calculated to be 0, 4.9, 9.4,
    and 34 mg/kg b.w./day, based on mean food consumption and body
    weights. Control rats received rat laboratory feed with 1% corn oil.
    Body weights, food consumption, and clinical signs were recorded
    periodically during the gestation period. On day 21 of gestation, rats
    were sacrificed with chloroform, and the ovaries and uteri were
    removed and examined. The following parameters were determined: number
    of corpora lutea, number of implantations, number and location of live
    and dead fetuses and resorptions, body weights and crown-rump lengths
    of live fetuses, and any gross fetal abnormalities. Approximately
    one-half of the fetuses from each litter were cleared and stained for
    skeletal examination, and the remaining fetuses were fixed and
    examined for visceral anomalies.

         No effects of treatment on the incidence of clinical signs were
    apparent, and no deaths were noted. Mean maternal body weight was
    reduced to 92 and 95% of the mean control weight on days 16 and 21,
    respectively, in high-dose dams (p < 0.05 by Dunnett's LSD). Mean
    feed consumption was also reduced by about 15% in high-dose dams over
    days 6 - 16, but it was similar to feed consumption of control animals
    over days 16 - 21 (treatment was terminated on day 16). Maternal
    weight gain and feed consumption in the low- and mid-dose groups did
    not appear to be significantly affected. No effects of treatment on
    any maternal reproductive indices were apparent. Mean fetal body
    weights and crown-rump lengths were not affected in any test groups.
    No effects of treatment on the fetal or litter incidences of visceral
    or skeletal anomalies were noted at doses up to and including a
    maternally-toxic dose of 400 ppm (34 mg/kg b.w./day) (Rogers et
    al., 1978).

    Rabbits

         Groups of artificially-inseminated New Zealand white (DLI:NZW)
    rabbits were randomly assigned to test groups (20/group) that were
    administered 0, 2, 6, or 16 mg/kg b.w./day technical methomyl (98.7%
    active ingredient) over days 7 -19 of presumed gestation. The route of
    administration was by gavage (5 ml/kg of deionized water), and dosages
    were selected on the basis of a preliminary study which demonstrated
    that a dose of 24 mg/kg b.w./day was lethal to 2/4 rabbits, and
    produced significant clinical signs in the remaining 2 does. Control
    animals received only deionized water. Rabbits were examined daily for
    clinical signs of toxicity, and body weights were recorded

    periodically. On day 29 of gestation, does were sacrificed by CO2
    asphyxiation, and uteri were removed and weighed. The following
    parameters were determined: number of corpora lutea, number and
    placement of implantations, resorptions, and live and dead fetuses.
    Fetuses were individually weighed, and live fetuses were killed and
    examined for gross external, visceral, and skeletal abnormalities.

         One mid-dose and 6 high-dose rabbits died as a result of
    treatment, and a statistically-significant increase in the incidence
    of signs related to cholinesterase inhibition (tremours, hyper-
    activity, salivation, etc.) was noted in high-dose animals. Mean
    body weights were increased by about 5% on day 29 in surviving
    high-dose does, and mean weight gain over days 0 - 29 was increased
    about 3-fold in these rabbits (p < 0.01 by Dunnett's LSD). No effects
    of treatment on the number of resorptions or litter size were
    apparent. Statistically-significant increases in mean fetal body
    weights of 14 - 19% were noted in all dose groups, which appeared to
    be treatment-related. This change was reported to be related to
    increased food consumption in treated rabbits in the latter portion of
    the study; however, actual food consumption data were not submitted.
    No evidence of oedema was noted in treated fetuses, nor was any effect
    of treatment on the incidences of fetal malformations or variations
    apparent, at doses up to and including a maternally-toxic dose of
    16 mg/kg b.w./day (Christian et al., 1983).

         Data were combined from 2 older studies, conducted 6 months
    apart, in which a total of 12 rabbits/group were treated with 0, 45 -
    50, or 90 - 100 mg/kg b.w./day technical methomyl (purity 90 - 100%)
    mixed into the diet at appropriate concentrations to achieve the
    desired dosages. The animals were treated from days 8 - 16 of presumed
    gestation. Clinical signs and food consumption were recorded daily and
    body weights were measured weekly. One-half of the does in each group
    were sacrificed on day 29 and subjected to caesarean necropsy, whereas
    the remaining rabbits in each group were allowed to deliver normally.
    One-third of the fetuses or pups from each litter were examined for
    skeletal anomalies. The extent of soft tissue examinations was not
    adequately described, but appeared to be restricted to gross
    observations of internal organs.

         One control and 1 low-dose rabbit died during the study period,
    neither of which was pregnant. One other control doe delivered a
    full-term litter on the second day of treatment, and was excluded. One
    control doe and one low-dose doe aborted. High-dose rabbits were
    reported to have consistent weight loss related to decreased food
    consumption; however, actual data were not submitted. The incidences
    of pregnancy, after combination of the 2 studies, were 4/12, 8/12, and
    5/12 in the control, mid-dose, and high-dose groups, respectively. No
    effects of treatment on maternal reproductive indices, fetal body
    weights or size, or visceral/skeletal findings were noted
    (Busey, 1967a).

    Acute toxicity

         The acute toxicity of methomyl to several animal species is
    summarized in Table 2. Methomyl is highly toxic via both the oral and
    inhalation routes of exposure. The severity and onset of cholinergic
    signs were related to the administered dose.

        Table 2. Acute toxicity of methomyl
                                                                                              

                                     Solvent         LD50           LC50
    Species    Route         Sex     (vehicle)       (mg/kg b.w.)   (mg/1)      Reference
                                                                                              

    Rat        Oral          M       Peanut oil1     26             -           Sherman, 1964

               Oral          M       Peanut oil1     17             -           Sherman, 1966
                             F                       23.5

               Oral          M       Water2          45             -           Trivits, 1979

               Dermal        M       Water1          > 1000         -           Morrow, 1972

               Inhalation,   M       Aerosol         -              0.30        Foster, 1966a
               4 hours

    Rat        Inhalation,   M       Vapour          -              0.04        Foster, 1966b
               4 hours

               Inhalation,   M       Spray           -              0.45        Hornberger,
               4 hours                                                          1967

    Rabbit     Oral          M       Acetone/        30             -           Sherman, 1968a
                                     peanut oil1

               Dermal        M       Water1          > 5000         -           Dashiell, 1971

               Dermal        M&F     Water1          > 1500         -           Majut & Hood,
                                                                                1966

    Chicken    Oral          F       Acetone/        28             -           Krauss & Stula,
                                     peanut oil1                                1967

    Dog        Oral          M       Gelatin         20             -           Sherman, 1968b
                                     capsule1
                                                                                              
    1    Technical methomyl having a purity > 98% was used.
    2    Technical methomyl having a purity of 100% was used.
    
    Short-term studies

    Rats

         Groups of Charles River (CD) rats, 10/sex/group, were adminis-
    tered methomyl (technical, 100%) in the diet for 90 days at dose
    levels of 0, 10, 50, or 250 ppm. An additional group was fed diets
    that contained 125 ppm methomyl for 42 days and 500 ppm methomyl to
    the end of the study. Observations included mortality, serological,
    haematological, and urological examinations, plasma and erythryocyte
    ChE activities, food and water consumption, body weights, and gross
    and microscopic analyses. No deaths or dose-related behavioural,
    clinical, haematological, serological, urological, or pathological
    effects were observed. Body weights were depressed in males at 250 ppm
    and at 125/500 ppm, and in females at 125/500 ppm. Sporadic decreases
    in haemoglobin content or erythrocyte count were observed in test-
    group males and females, but the responses were not time or dose
    dependent. Moderate erythroid hyperplasia was observed in the bone
    marrow of male rats fed 250 ppm. The NOEL was 50 ppm methomyl, based
    on body-weight depression in males (Paynter, 1966).

    Rabbits

         Methomyl (90% soluble concentrate) was administered dermally to
    New Zealand albino rabbits (5/sex/dose) at 0 or 200 mg/kg b.w. to both
    intact and abraded skin areas. Applications were 5 days a week for 21
    days. There were no toxic symptoms noted in animals with intact skin.
    There were signs of ChE inhibition and 2 deaths in animals with
    abraded skin, although ChE activity was comparable to controls. There
    was no evidence of cumulative toxicity or of compound-related effects
    on organ weights or histopathology (Busey, 1967b).

    Dogs

         Groups of 11- to 13-month old beagle dogs (4/sex/group) were fed
    diets that contained methomyl (97.5% methomyl, 2.5% HiSil 233) in corn
    oil at dosages of 0, 50, 100, or 400 ppm for 3 months. Mean daily
    intakes corresponded to 0, 1.44, 3.18, and 14.7 mg/kg b.w./day for
    males and 0, 1.45, 3.01, and 12.5 mg/kg b.w./day for females, respect-
    ively. Animals were examined routinely for physical/behavioural
    changes, food and water consumption, body-weight changes, and haemato-
    logical, clinical chemical, and urological effects. Cholinesterase
    activities were not determined. Organs were weighed and gross necropsy
    and histopathology were performed at terminal sacrifice. No compound-
    related effects were reported. However, a NOEL for this study could

    not be determined because blood cholinesterase activities were not
    determined and the animals were older than is recommended by currently
    acceptable international guidelines (i.e. OECD test methods) for
    conducting short-term non-rodent feeding studies (preferably they
    should be 4-6 months of age, but not older than 9 months) (Sherman
    et al., 1967).

    Long-term studies

    Mice

         Groups of 80 male and 80 female albino weanling CD-1 mice (6
    weeks old) were administered methomyl (technical, purity 99%) in the
    diet for 104 weeks at initial dose levels of 10, 50, 100, or 800 ppm.
    Due to high mortality, the high dose was reduced to 400 ppm at week 28
    and then to 200 ppm at week 39. The mid-dose level was also reduced at
    week 39 to 75 ppm. Mean dietary intakes were 8.7, 15.4, and 93.5 mg/kg
    b.w./day for males and 10.6, 19.1, and 118 mg/kg b.w./day for females,
    respectively.

         All animals were observed routinely for clinical signs,
    mortality, moribundity, body-weight changes, and food consumption.
    Haematological evaluations were performed periodically throughout the
    study. Selected organs were weighed, including the brain, thymus,
    lungs, heart, spleen, liver, kidneys, testes (w/epididymides),
    adrenals, and pituitary. Complete gross and microscopic analyses of
    tissues were performed on each animal.

         Body-weight gain and food consumption of animals in the treated
    groups were equivalent to controls. Mortality was increased among mid-
    and high-dose animals throughout the study. Mortality in the low-dose
    males was initially increased, in comparison to controls, but was
    comparable at the termination of the study. Survival was greater than
    50% in all groups at 11 months and approximately 25 - 30% at 2 years.

         Red cell mass was apparently decreased during the first 26 weeks
    at the mid- and high-dose levels, as evidenced by lower haemoglobin
    levels, RBC counts, and haematocrit. These effects were reversed when
    the amount of methomyl in the diet was reduced to 75 and 200 ppm in
    the mid- and high-dose levels, respectively.

         Necropsy and pathological examinations were unremarkable and
    there were no compound-related histological changes. A substantial
    amount of autolysis occurred in animals found dead prior to term,
    which precluded any meaningful analysis of treatment-related effects
    in these early deaths. There were no compound-related increases in
    neoplastic changes at doses up to and including 200 ppm for 104 weeks.
    The NOEL was 50 ppm, based on adverse effects on red cell mass at
    higher dose levels (Serota et al., 1981).

    Rats

         Groups of Charles River rats (35 males and 35 females/group; 70
    males and 70 females used as controls) were administered methomyl in
    the diet at dose levels of 0, 50, 100, 200, or 400 ppm for 22 months.
    These diets corresponded to 0, 2.4, 4.8, 9.6, and 20 mg/kg b.w./day
    for males and 0, 2.8, 5.8, 11, and 24 mg/kg for females, respectively.
    Body weights, food consumption, appearance, and behaviour were
    recorded weekly from weeks 1 through 26 and monthly thereafter to week
    96. Clinical chemistry observations included BUN, SGPT, SAP, glucose,
    plasma, red blood cell, and brain cholinesterases, and, at the
    conclusion of the study, bone-marrow differential counts. The
    cholinesterase assays were performed using a delta pH method. This
    method is considered inadequate for evaluating cholinesterase
    inhibition by carbamates and the data are therefore unreliable.
    Haematology determinations included haematocrit, haemoglobin, red
    blood cell counts, and total and differential leukocyte counts;
    urinalysis included pH, specific gravity, sugar, protein, bilirubin,
    occult blood, and microscopic examination of the sediment. At 12
    months, 5 rats of each sex in each group were sacrificed. At 22
    months, because of the presence of respiratory disease and high
    mortality, all surviving animals were sacrificed. Terminal body
    weights and gross and microscopic examinations were performed. Organ
    weights were obtained for the following tissues: brain, heart, liver,
    spleen, kidneys, and testes. Organ and organ-to-body-weight ratios
    were recorded and calculated. Microscopic examinations were performed
    on the following tissues from rats in the control and 400 ppm groups:
    brain, thyroid, heart, liver, spleen, kidneys, adrenals, stomach,
    small intestine, large intestine, testes, bone marrow, muscle, and
    sciatic nerve. The liver, kidneys, and spleen from rats in the other
    groups were examined.

         Growth and food consumption, measured only over the first year,
    were reduced at 400 ppm. At 200 ppm, growth of males was reduced when
    compared with control values. Haematology, blood chemistry, and
    urinalysis values were similar in treated and control groups, although
    there was a dose-related trend toward decreased haemoglobin in female
    treatment groups. This was significant at 18 and 22 months in females
    in the 200 and 400 ppm groups. Males were not similarly affected.
    Compound-related increases in the incidence and severity of
    extramedullary haematopoiesis were observed in the spleens of females
    fed 200 or 400 ppm methomyl.

         Gross and microscopic examinations were performed at 12 and 22
    months. Increased testes, adrenal, liver, and brain weights were
    observed at 400 ppm. At 200 and 400 ppm increased thyroid weights in
    females were observed. Macroscopic changes in the kidneys, including
    enlargement, discoloration, and texture changes were not reflected in
   
    weight differences. Microscopic changes were evident in the kidneys of
    both males and females at 400 ppm. The histopathological changes were
    characterized by tubular hypertrophy and vacuolation of the epithelial
    cells of the proximal convoluted tubules. At 200 and 400 ppm,
    extramedullary haematopoiesis was noted in the spleen of females. No
    microscopic changes were evident in other tissues, including those in
    which weight increases were noted. There was no evidence of oncogenic
    potential at any dose level. The 100 ppm dose level could be
    considered the NOEL in this study, based on macro- and microscopic
    changes in the thyroid, spleen, and kidneys, as well as on body-weight
    changes. However, since cholinesterase activity was not measured by an
    appropriate and sensitive method for such a potent ChE inhibitor, an
    accurate NOEL for this study could not be determined (Busey, 1968a).

         In a chronic feeding/oncogenicity study, ChR-CD rats were
    administered methomyl (> 99% pure) in the diet for 24 months. Groups
    of 80 male and 80 female rats were fed diets containing 0, 50, 100, or
    400 ppm methomyl. These concentrations were equal to 0, 2.4, 4.8, and
    20 mg/kg b.w./day for males and 0, 2.3, 6.3, and 26 mg/kg b.w./day for
    females, respectively. Food consumption and body weights were
    measured, and haematological, clinical chemistry, and urological
    evaluations were conducted routinely throughout the study. Erythrocyte
    and brain acetytcholinesterase activities were measured by the Ellman
    method. After 12 months, 10 rats/sex/treatment group were sacrificed
    and necropsied, selected organs were weighed, and selected tissues/
    organs were examined histologically. At the end of the study all rats
    were sacrificed and examined in a similar manner. Tissues from rats
    found dead or killed in extremis were examined histologically.

         Body-weight gains of males and females in the 400 ppm group were
    depressed for the first 1 to 1.5 years, but they recovered thereafter
    and were comparable to control body-weight gains by 24 months.
    Significantly decreased haemoglobin, RBC counts, and haematocrits were
    evident in females in the 400 ppm group. Significant differences were
    not observed between control and test-group animals with regard to
    erythrocyte or brain cholinesterase activities. However, due to a
    possible effect of storage of blood samples prior to measurement, the
    potential effect of the test compound on cholinesterases could have
    been undiscovered due to fast spontaneous reactivation of carbamylated
    enzyme.

         Relative testes weights of high-dose males were significantly
    greater than those of controls, but there were no observed
    pathological changes. Female rats fed > 100 ppm methomyl had
    increased relative liver weights, but no associated histopathological
    alterations were identified. Female rats fed 400 ppm methomyl also had

 

    increased relative spleen weights, but no noticeable pathological
    tissue responses. The incidence of bone marrow hyperplasia, focal
    hyperplasia in the adrenal medulla, and focal degeneration/angiectasis
    in the adrenal cortex were increased in male rats fed 400 ppm
    methomyl. There were no other significant pathological changes and no
    oncogenic potential was evident at any of the doses administered in
    this study. A NOEL of 100 ppm was estimated based on body-weight
    changes and on the haematologic response at 400 ppm (Kaplan et al.,
    1981).

    Dogs

         Groups of young adult (> 12 months of age) beagles (4 male and 4
    females/group) were administered methomyl in the diet at dose levels
    of 0, 50, 100, 400, or 1000 ppm for 2 years. Methomyl was incorporated
    into a ground dry dog meal. Diet mixtures were prepared weekly. Daily
    observations were made of behaviour and appearance, and body-weight
    and food-consumption data were recorded weekly. Clinical chemistry
    studies were performed initially and at 3, 6, 12, 18, and 24 months.
    Determinations were made of blood sugar, BUN, SAP, SGPT, SGOT, and
    prothrombin time. Serum electrolytes, total protein, and albumin were
    determined at 18 and 24 months. Haematology examinations included the
    following: haematocrit and haemoglobin concentration, red blood cell
    count, total and differential leukocyte count, and bone marrow
    differential count at the termination of the study. Urinalysis
    included: appearance, pH, specific gravity, sugar, acetone, protein,
    bilirubin, occult blood, and microscopic examination of the sediment.
    At 24 months, urinary sodium, potassium, chloride, glucose, protein,
    and phosphorous were determined. Plasma and erythrocyte cholinesterase
    activities were measured by the monometric method at the ninth week in
    animals in the control and 1000 ppm groups and during the thirteenth
    week in animals in the 1000 ppm group. At the end of 1 year, 1
    dog/sex/group was sacrificed and the following organ weights recorded
    after gross examination: brain, thyroid, heart, liver, spleen,
    kidneys, adrenals, and testes. Organ-to-body weight ratios were
    calculated. At 24 months the remaining dogs were sacrificed and the
    following tissues were examined from each dog: brain, pituitary,
    thyroid, thymus, lungs, heart, liver, spleen, kidneys, adrenals,
    stomach, pancreas, duodenum, jejunum, ileum, colon, mesenteric lymph
    node, urinary bladder, ovary, uterus, skin, bone, bone marrow, muscle,
    sciatic nerve, and testes. The same organs were weighed as after 1
    year.

         Two out of 4 females in the 1000 ppm group died within 8 weeks of
    the beginning of the study. Signs of poisoning included tremours,
    salivation, and incoordination, which were observed only once in males
    at 1000 ppm. Haematology studies in 1 high-dose male indicated severe
    anaemia and moderate leukopenia (decreased haematocrit, haemoglobin,
    RBC count and platelet count; increased reticulocyte count; and

    changes in the differential count). This condition improved when the
    dog was placed on a control diet at 84 weeks, but worsened when
    1000 ppm methomyl was replaced in the diet at the ninety-fifth week.
    Enlarged spleen and kidneys were noted at sacrifice (24 months). The
    remaining high-dose males and 2/4 high-dose females demonstrated
    similar haematologic abnormalities at 3 months, but recovered to
    normal by 24 months. Growth and food consumption were unaffected by
    treatment; however, all dogs were young adults at the start of the
    test and therefore were already beyond the critical growth months for
    this species. This is considered a deficiency in this study. Clinical
    chemistry and urinalyses were comparable between treated groups and
    controls. Since plasma and erythrocyte cholinesterase activities were
    assayed by a method considered inadequate for carbamate inhibition,
    these data are unreliable for estimating the cholinesterase inhibiting
    properties of methomyl in dogs.

         At 24 months, gross pathology examinations showed liver and
    spleen enlargement in the male that was severely anaemic. Kidney
    weights were increased in males at 1000 ppm and in 1 male at 400 ppm.
    Microscopic examination showed alterations in the spleen
    (extramedullary haematopoiesis) and kidneys (pigment in the cytoplasm
    and swelling of the epithelial cells of the proximal convoluted
    tubules in males and females), liver (bile duct proliferation) and
    bone marrow (increased activity in both erythroid and myeloid series)
    at 1000 ppm. At 400 ppm similar kidney abnormalities were present only
    in males. Alterations were not observed in the lower-dose groups. A
    no-effect level of 100 ppm (equal to 3.1 mg/kg b.w./day) was
    tentatively estimated, based on the adverse haematologic effects and
    on kidney and spleen morphologic changes at > 400 ppm. However, in
    the absence of adequate data for adverse effects on cholinesterase
    activity an accurate estimate of a NOEL cannot be determined
    (Busey, 1968b).

    Observations in humans

         Epidemiological studies of poisonings from the ingestion of
    contaminated food indicate that a single oral dose as low as
    12-15 mg/kg b.w. can be fatal in humans (Liddle et al., 1979;
    Araki et al., 1982).

         An assessment of workers who routinely handled methomyl in a
    factory indicated that workers were occasionally inadvertently exposed
    and required hospitalization and treatment for symptoms of
    cholinesterase inhibition, presumably due to methomyl intoxication.
    Blood cholinesterase levels were normal for these workers, however,
    and no quantitation of dose was presented. The methodology and timing
    of ChE measurements were questionable (Morse et al., 1979).

    COMMENTS

         Methomyl is rapidly absorbed from the gastrointestinal tract or
    through the skin, and is rapidly metabolized and eliminated. The
    metabolic fate of methomyl depends on the isomeric configuration, as
    the syn form (the technical product) is primarily degraded to CO2,
    whereas the anti form is degraded to acetonitrile. Some conversion
    of syn-methomyl to anti-methomyl apparently occurs in rats.

         The acute toxicity of methomyl is due to inhibition of
    acetylcholinesterase. The oral LD50 in experimental animals ranges
    from 20 to 45 mg/kg b.w.; atropine is an antidote to these acute toxic
    effects.

         Long-term feeding studies in mice and rats do not suggest any
    evidence of oncogenicity for methomyl. Toxic effects included anaemia
    (mice, rats, and dogs), decreased weight gain (rats), and
    histopathological changes in the kidney (dogs). The no-observed-effect
    levels for chronic toxicity, calculated from dietary intake, were;
    8.7 mg/kg b.w./day in mice, 4.8 mg/kg b.w./day in rats, and 3.1 mg/kg
    b.w./day in dogs.

         The available chronic toxicity data are somewhat limited by the
    lack of adequate determinations of cholinesterase activity. However,
    the effects on cholinesterases are reversible. In order to estimate
    the rate of spontaneous reactivation in man, the submission of the
    results of additional in vitro studies is required. These studies
    should provide data on the inhibition and reactivation rate constants
    for the effect of methomyl on human plasma and erythrocyte
    cholinesterases.

         Available epidemiological data for humans indicate that a dose of
    12 - 15 mg/kg b.w. methomyl, ingested as a bolus with food, can be
    lethal owing to suppression of cholinesterase activity. This value is
    similar to the acute lethal doses identified in animal studies.

         No evidence of teratogenicity or embryotoxicity was apparent in
    rats or rabbits. The available rat reproduction studies, when
    considered together, demonstrate a NOEL of 50 ppm (equivalent to
    2.5 mg/kg b.w./day), based on decreases in body-weight gain and food
    consumption in a study reported in 1968, and on slight decreases in
    litter size at 75 ppm in a study reported in 1983. No other evidence
    of effects on fertility or other reproductive parameters was noted.

         No evidence of mutagenicity was noted in a number of genotoxicity
    studies.

    TOXICOLOGICAL EVALUATION

    LEVEL CAUSING NO TOXICOLOGICAL EFFECT

         NOELs for chronic oral toxicity are established as;

         Mouse:    50 ppm, equal to 8.7 mg/kg b.w./day.
         Rat:      50 ppm, equivalent to 2.5 mg/kg b.w./day.
         Dog:      100 ppm, equal to 3.1 mg/kg b.w./day.

    ESTIMATE OF TEMPORARY ACCEPTABLE DAILY INTAKE FOR HUMANS

         0 - 0.01 mg/kg b.w.

    STUDIES WITHOUT WHICH THE DETERMINATION OF A FULL ADI IS
    IMPRACTICABLE, TO BE SUBMITTED TO WHO BY 1988:

         Additional in vitro studies in human blood to demonstrate the
    time-course of plasma and red blood cell cholinesterase inhibition and
    reactivation.

    STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE FOR THE CONTINUED
    EVALUATION OF THE COMPOUND

         Further observations in humans.

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    See Also:
       Toxicological Abbreviations
       Methomyl (EHC 178, 1996)
       Methomyl (HSG 97, 1995)
       Methomyl (ICSC)
       Methomyl (WHO Pesticide Residues Series 5)
       Methomyl (Pesticide residues in food: 1976 evaluations)
       Methomyl (Pesticide residues in food: 1977 evaluations)
       Methomyl (Pesticide residues in food: 1978 evaluations)
       Methomyl (Pesticide residues in food: 1989 evaluations Part II Toxicology)
       Methomyl (JMPR Evaluations 2001 Part II Toxicological)