820K88114
                                                           August, 1987
                                                            DRAFT
              METHOMYL

          Health Advisory
      Office of Drinking Water
U.S.  Environmental  Protection Agency
I.  INTRODUCTION

        The  Health Advisory (HA)  Program,  sponsored by the Office of Drinking
   Water (ODW), provides information on the  health effects, analytical method-
   ology and treatment technology that would be  useful in dealing with the
   contamination of drinking water.  Health  Advisories describe nonregulatory
   concentrations of drinking water contaminants at which adverse health effects
   would not be anticipated to occur over  specific exposure durations.  Health
   Advisories contain a margin of safety to  protect sensitive members of the
   population.

        Health Advisories serve as informal  technical guidance to assist Federal,
   State and local officials responsible for protecting public health when
   emergency spills or contamination situations  occur.  They are not to be
   construed as legally enforceable Federal  standards.  The HAs are subject to
   change as new information becomes available.

        Health Advisories are developed for  one-day, ten-day, longer-term
   (approximately 7 years, or 10% of an individual's lifetime) and lifetime
   exposures based on data describing noncarcinogenic end points of toxicity.
   Health Advisories do not quantitatively incorporate any potential carcinogenic
   risk from such exposure.  For  those substances that are known or probable
   human carcinogens, according to the Agency classification scheme (Group A or
   B),  Lifetime HAs'are not recommended.  The chemical concentration values for
   Group A or B carcinogens are correlated with  carcinogenic risk estimates by
   employing a cancer potency (unit risk)  value  together with assumptions for
   lifetime  exposure and the consumption of  drinking water.  The cancer unit
   risk is usually derived from the linear multistage model with 95% upper
   confidence limits.  This provides a low-dose  estimate of cancer risk to
   humans that is considered unlikely to pose a  carcinogenic risk in excess
   of the stated values.  Excess  cancer risk estimates may also be calculated
   using the one-hit, Weibull, logit or probit models.  There is no current
   understating of the biological mechanisms involved in cancer to suggest th t
   any one of these models is able to predict risk more accurately than another.
   Because each model is based on differing  assumptions, the estimates that are
   derived can differ by several  orders of magnitude.

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    Methomyl
                   August,
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II.  GENERAL INFORMATION AND PROPERTIES
    CAS No.   16752-77-5
    Structural Formula
                                         0
                           CH,-C=N-0-C-N-CH3
                                 S-CH,     H
                   S-Methyl-N[(methylcarbamoyl)oxy]-thioacetimidate
    Synonyms
            Dupont Insecticide  1179; Dupont  1179; Insecticide 1,179; Insecticide
            1179; IN 1179,  Lannate; Mesomile; Nudrin; SD 14999; WL  18236  (Meister,
            1983).
    Uses

         0  Methomyl is a carbamate  insecticide used  to control a broad spectrum
            of insects in agricultural  and ornamental crops  (Meister, 1983).

    Properties (Meister, 1983; Windholz et al., 1983; Cohen, 1984; CHEMLAB, 1985;
                and TDB, 1985)
            Chemical Formula
            Molecular Weight
            Physical State (25°C)
            Boiling Point
            Melting Point
            Density (24°C)
            Vapor Pressure (25°C)
            Specific Gravity
            Water Solubility (25°C)
            Log Octanol/Water Partition
              Coefficient
            Taste Threshold
            Odor Threshold
            Conversion Factor
C5H10°2N2S
162.20
White crystalline solid

78 to 79°C
U29
5 x 10~5 mm Hg

10,000 mg/L
-3.56
    Occurrence
            Methomyl has been found  in 2  of  446 surface water  samples analyzed
            and in 25 of 1,023 ground water  samples  (STORET, 1987).  Samples were
            collected at 110 surface water locations  and  1,000 ground water
            locations, and methomyl  was found in California, Georgia and Texas.
            The 85th percentile of all non-zero samples was  2  ug/L in surface
            water and 10 ug/L in ground water sources.  The  maximum concentration
            found in surface water was 2  ug/L and in  ground  water it was 10 ug/L.

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     Methomyl                                                   August,  1987

                                          -3-


     Environmental  Fate

          8  In  laboratory  and  greenhouse  studies,  methomyl was more rapidly
            degraded  in  a  sandy loam  and  a California  soil than in silt loam
            soils,  with  21,  31,  and 44  to 48%  of  the applied methomyl  remaining in
            the respective soils 42-45  days after  treatment.  The major degra-
            dation product was carbon dioxide,  which accounted for 23  to 47% of
            the applied  methomyl after  42 to 45 days.   A minor degradation product,
            S-methyl-N-hydroxy-thioacetimidate (a  possible hydrolysis  product),
            was also  found.  Methomyl half-lives  were  less than 30 days in sandy loam
            soil,  less than 42 days in  California  soil,  and approximately 45 days
            in  muck and  silt loam soils.  In a sterilized Flanagan silt loam
            soil,  89% of the methomyl remained 45  days after application, indicating
            that methomyl  degradation in  soil  is  primarily a microbial process
             (Harvey,  1977a,b).

          0  The nitrogen-fixing ability of some bacteria was severely  reduced
             (by as much  as 85%) when  methomyl  was  applied at 20 to 160 ppm (Huang,
             1978).

          0  In  another study,  methomyl  (18 ppm) had no effect on fungal and
            bacterial population or on  carbon  dioxide  production in .either silt
            loam or fine sand  soils  (Peeples,  1977).

          0  No  methomyl  residues were detected in a muck soil 7 to 32  days after
             treatment (E.I.  DuPont de Nemours  and  Co., 1971).

          0  The environmental  fate of methomyl has also been the subject of
            several undated, unpublished  reports  (Harvey, undated a,b; Harvey
            and Pease; Han).
III. PHARMACOKINETICS

     Absorption

          0  Single oral doses of 1-14C-methomyl  (purity not specified) were ad-
             ministered  via gavage to female  CD rats  as  a suspension in 1% aqueous
             methylcellulose.   Ninety-five  percent of the dose could be accounted
             for in excretory  products or  tissue  residues,  indicating virtual
             complete absorption from the  gastrointestinal tract (Andrawes et al,
             1976).

          0  Baron (1971)  reported that in  rats given a  single oral dose of 5 mg/kg
             of 1-14C-labeled  methomyl (purity not specified),  approximately 2% of
             the original  label was excreted  in the feces after 3 days, indicating
             essentially complete gastrointestinal absorption.

     Distribution

          0  Baron (1971)  fed  a single oral dose  of 1-14c-labeled methomyl (5 mg/kg,
             purity not  specified) to rats  and analyzed  13 major tissues for residues
             at 1  and 3  days after dosing.  Only  10%  of  the label was present in

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Methomyl                                                  August, 1987

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        tissues 24 hours after dosing, with no evidence of accumulation at
        any site.  By this time, over 40% of the label had been excreted via
        the lung.  At 3 days after dosing, tissue residues were essentially
        unchanged from day 1, suggesting incorporation of label into tissue
        components.

     8  Baron (1971) reported that feeding methomyl to a lactating cow at
        levels of 0.2 or 20 ppm in the diet (duration not specified) resulted
        in very low residues (less than 0.02 ppm) in the milk, meat, fat,
        liver and kidney.

Metabolism

     0  According to Baron (1971), in 72 hours approximately  15 to 23% of a
        5-mg/kg oral dose of I-14C-labeled methomyl in rats could be accounted
        for as carbon dioxide, 33% as another metabolite in expired air, and 25%
        as metabolites in the urine.

     0  Harvey (1974) reported that in the rat, 1-14C-labeled methomyl (dose
        and purity not specified) was metabolized to carbon dioxide  (25%) or
        acetonitrile (50%) within 72 hours.

     0  Andrawes et al.  (1976) reported that single oral doses of 4 mg/kg
        were rapidly metabolized in the rat.  In exhaled air, carbon dioxide
        and acetonitrile were the major metabolites.  In 24-hour urine samples,
        polar metabolites (80%) and acetonitrile (18%), both  free and conjugated,
        were found with  free methomyl, methy(o), the oxime and the sulfoxide
        oxime detected at low levels.

     0  Dorough  (1977),  in a series of studies with 14C-labeled isomeric  forms
        of methomyl, confirmed the report by Harvey (1974) of the excretion of
        labeled  carbon dioxide and acetonitrile in the expired air of treated
        rats.  In  addition, nearly complete  (79 to 84%) hydrolysis of the
        ester linkage was apparent within 6 hours, prior to the major
        formation  of carbon dioxide and acetonitrile from methomyl.  The
        author suggested the following pathway:  partial isomerization of
        methomyl is followed by hydrolysis of the two isomeric forms to yield
        two isomeric oximes that  then break down to carbon dioxide and
        acetonitrile at  different rates.  No additional metabolites  were
        identified.
 Excretion
         Baron (1971) stated that within  72 hours  after receiving  a  single
         oral dose  of 1-14C-labeled methomyl,  rats excreted  15  to  23% as
         carbon dioxide,  33% as  other  metabolites  in  the  expired air and
         approximately  16 to 27% as methomyl and metabolites  in the  urine.

         Harvey (1974)  reported  that 75%  of an oral dose  of  1-1 "^-labeled
         methomyl  (dose and purity not specified)  was excreted  by  rats within
         72 hours,  50%  as acetonitrile and 25% as  carbon  dioxide in  the expired
         air.  In contrast to other carbamates, sulfur-containing  metabolites
         were not found in the urine.

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    Wethomyl                                                  August,  1987

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            Andrawes  et al.  (1976)  reported that single oral doses (4 mg/kg) of
            1-14c-labeled methomyl  were rapidly excreted,  with 32% of the dose
            recovered in urine,  19% in feces and 40% in exhaled air after 4 days.
IV. HEALTH EFFECTS
    Humans
       Short-term Exposure

         8  Liddle et al.  (1979)  reported a case of methomyl poisoning in Jamaica,
            W.I., involving five  men who had eaten a meal that included unleavened
            bread.  Methomyl was  discovered in an unlabeled plastic bag in a tin
            can,  and had evidently been used as salt in preparation of the bread.
            Approximately 3 hours after the meal, the men were found critically
            ill,  frothing at the  mouth, twitching and trembling.  Three were dead
            on arrival at the hospital.  One of the two survivors showed generalized
            twitching and spasms, fasciculation, and respiratory impairment
            thought to be due to  severe bronchiospasms.  The other patient walked
            unaided and appeared  generally normal.  Both patients were given
            atropine intravenously, and the symptomatic patient recovered within
            2 hours after treatment.  Methomyl was confirmed in the stomach
            contents of each of the men who died, and analysis of the bread
            indicated that it contained 1.1% methomyl.  It was stated that two of
            the victims had eaten about 75 to 100 g of bread each, or 0.82 to
            1.1  g of methomyl.  From these data it may be calculated that a dose
            of 12 to 15 mg/kg body weight can be fatal in humans.

         0  Araki et al. (1982) reported a case of a 31-year old woman who
            committed suicide,  giving methomyl in drinks to herself and her two
            children.  The 9-year-old elder son survived.  In autopsies performed
            on the mother and the 6-year-old son, the mucous membranes of the
            stomach were blackish-brown, markedly edematous and congested.  The
            lungs were heavy and  congested.  On the basis of measured stomach
            contents and tissue levels, it was estimated that the total doses
            taken were 2.75 g (55 mg/kg) by the mother and 0.26 g (13 mg/kg) by
            the child.

       Long-term Exposure

         0  Morse and Baker (1979) reported on a survey of the health of workers
            in a plant that manufactured methomyl.  The plant had also manufactured
            propanil, an herbicide manufactured from 3,4-dichloroaniline.  The
            plant employed 111  workers in seven job categories.  A complete work
            history, symptoms or  history of poisoning, personal habits, and
            sources of other chemical exposure were obtained.  Blood samples were
            collected from 100 of.the 111 workers (96% males).  Blood chemistries,
            blood counts,  and cholinesterase (ChE) determinations were carried
            out.   A routine urinalysis was also performed.  Average employment at
            the  plant was  2 years.   Packaging workers had the highest rate of
            "methomyl" symptoms:   small pupils (46%), nausea and vomiting (46%),
            blurred vision (46%)  and increased salivation (27%).  Biomedical

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                                     -6-
        examination did not demonstrate significant effects, and acetylcholin-
        esterase findings were normal.  Other effects, such as chloracne,
        were reported but were considered related to propanil exposure.
Animals
   Short-term Exposure

     0  The acute oral LDgQ reported for methomyl in the fasted male  and  female
        rat ranged from 17 to 25 mg/kg  (Bedo and Cieleszky, 1980; Dashiell
        and Kennedy, 1984; Kaplan and Sherman, 1977).  The oral LD^Q  in the
        nonfasted rat was 40 mg/kg  (Dashiell and Kennedy, 1984).  Clinical signs
        in rats included chewing motions, profuse salivation, lacrimation,
        bulging eyes, fasciculations and tremors characteristic of ChE inhibition,

     0  The acute oral I>D$Q for methomyl in the mouse ranged from 27  to
        55 mg/kg  (Boulton et al., 1971; El-Sebae et al., 1979; Natoff and
        Reiff, 1973).

     0  The oral LDjg in hens was 28 mg/kg and in Japanese quail, 34  mg/kg.
        (Kaplan and Sherman, 1977).

     e  The 4-hour inhalation ££50  of methomyl in rats was 300 mg/m^.  Animals
        showed the typical signs of ChE inhibition, including salivation,
        lacrimation and tremors  (ACGIH, 1984).

     0  Bedo and Cieleszky  (1980) administered single oral doses of methomyl
        (purity not specified) by gavage to stock colony rats at dose levels
        of 0, 2,  3 or 10 mg/kg.  The high dose (10 mg/kg) produced typical
        tremors in rats, and brain  ChE  levels were d.ecreased.  Mixed-function
        oxidase, glucose-6-phosphatase  activity, glycogen, and vitamin A
        levels in the liver were unaffected.  Apparently, dose levels of  2 or
        3 mg/kg did not produce  these effects.

      0  Woodside  et al.  (1978) fed  methomyl  (purity not specified) in the diet
        to male and female Wistar rats  for 7 days at dose levels of 0, 5.0,
        17 or 41  mg/kg/day  in males and 0, 6.3,  15 or 39 mg/kg/day in females.
        Body weight gain was depressed  at doses  of 17 and 41 mg/kg/day in the
        males and at  15 and 39 mg/kg/day in  the  females.  Liver and kidney
        weight were also depressed  at 41 mg/kg/day in the male rat and at
        15 and 39 mg/kg/day in the  female rat.   No effects were noted at  the
        lowest doses.  This study did not mention clinical signs of toxicity,
        and no measurements of plasma or brain ChE activity were reported.
        The No-Observed-Adverse-Effect-Level  (NOAEL) identified in this
        study is  5.0  mg/kg/day.

      0  Bedo  and  Cieleszky  (1980) fed methomyl  (purity not specified) in  the
        diet at levels of 0, 100, 400 or 800 ppm to young adult male  and  female
        stock colony  rats for 10 days.  Assuming that 1 ppm in the diet of
        rats  is equivalent  to 0.05  mg/kg/day  (Lehman, 1959), these doses
        correspond  to 0,  5, 20 or 40 mg/kg/day.  Brain ChE inhibition could
        not be detected  at  any dietary  level.  The only  findings were increased
        mixed-function oxidase activity in  the livers of  female rats  at  400
        and  800 ppm.  This  study identified  a NOAEL of 800 ppm  (40 mg/kg/day).

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Methomyl                                                  August, 1987

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     0  Kaplan and Sherman (1977) administered methomyl (90% pure) to six
        male Charles River-Cesarian Derived (ChR-CD) rats at 0 or 5.1 mg/kg/day,
        five times a week for 2 weeks.  Following treatment, survival, clinical
        signs, ChE activity and histopathology were evaluated.  All rats
        survived the dosing period.  Clinical signs in treated rats included
        chewing motions, profuse salivation, lacrimation, bulging eyes,
        fasciculations and tremors characteristic of ChE inhibition.  The
        authors reported that the signs became less pronounced after the
        first week of dosing, indicating some degree of adaptation.  Plasma
        ChE was comparable to control levels, and no compound-related histo-
        pathologic effects were reported.  A Lowest-Observed-Adverse-Effect-
        Level (LOAEL) of 5.1 mg/kg/day was identified from this study.

   Dermal/Ocular Effects

     0  Kaplan and Sherman (1977) applied a 52.8% aqueous suspension of
        methomyl to the clipped, intact skin of six adult male albino rabbits
        and covered the area with an occlusive patch for a 24-hour period.
        The lethal dose was found to be greater than 5,000 mg/kg, the maximum
        feasible dose.

     0  McAlack (1973) reported a 10-day subacute exposure of rabbit skin to
        methomyl.  Male albino rabbits, six per dosage group, were treated
        with 0, 50 or 100 mg/kg/day for 10 days.  The compound was diluted in
        water (29% solution), placed on the skin and covered with an occlusive
        covering for 6 hours per day.  No signs of ChE inhibition were noted
        in any of the animals.

     0  Ten rabbits survived 15 daily doses of 200 mg/kg/day of methomyl
        applied to intact skin.  When the same dose of methomyl was applied
        to abraded skin, rabbits showed labored respiration, nasal discharge,
        salivation, excessive mastication, tremors, poor coordination, hyper-
        sensitivity and abdominal hypertonia.  These effects occurred within
        1 hour after dosing in most animals.  One animal died after the first
        dose, and another died after the eighth application.  These deaths
        appeared to be compound-related (Kaplan and Sherman, 1977).

   Long-term Exposure

     0  Kaplan and Sherman (1977) reported a 90-day feeding study in
        ChR-CD rats (10/sex/group) given food containing methomyl (90% purity)
        at dietary levels of 0, 10, 50, 125 or 250 ppm active ingredient  (a.i.).
        Assuming that 1 ppm in the diet of rats is equivalent to 0.05 mg/kg/day
        (Lehman, 1959), this corresponds to doses of about 0, 0.5, 2.5, 6.2 or
        12.5 mg/kg/day.  After 6 weeks, the 125-ppm dose was increased to 500
        ppm (25 mg/kg/day) for the remainder of the study.  Clinical signs,
        biochemical analyses (including plasma ChE) and urinalyses were not
        abnormal.  In a few cases, lower hemoglobin valves were observed at one
        month in females receiving 50 ppm (2.5 ug/kg/day) and at two months
        in males receiving 250 ppm.  At three months, the red cell count of
        female rats at 250 ppm was somewhat lower than controls, but still
        within normal limits.  These findings were consistent with moderate
        increases of erythroid components observed histologically in the bone

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Methomyl                                                  August, 1987

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        marrow.  Microscopic examination of all other tissues showed no
        consistent abnormalities.  Based on these observations, this study
        identified a NOAEL of 50 ppm (2.5 mg/kg/day) and a LOAEL of 250 ppm
        (12.5 mg/kg/day).

     0  In a 90-day study using dogs, Kaplan and Sherman (1977) fed methomyl
        (90% pure) to four males and four females, 11 to 13 months of age,
        at dietary levels of 0, 50, 100 or 400 ppm a.i.  Assuming that 1 ppm
        in the diet of dogs is equivalent to 0.025 mg/kg/day (Lehman, 1959),
        this corresponds to doses of about 0, 1.25, 2.5 or 10 mg/kg/day.
        Hematological, biochemical and urine analyses were conducted at least
        three times on each dog prior to the study and then at  1, 2 and 3
        months during the exposure period.  Body weight was monitored weekly.
        At necropsy, organ weights were recorded, and over 30 tissues were
        prepared for histopathologic examination.  No effects attributable to
        methomyl were found during or at the conclusion of the  study.  Based
        on these data, a NOAEL of  10 mg/kg/day was identified.

     0  Homan et al.  (1978) reported a 13-week dietary study of methomyl
        (purity not specified) in F-344 rats.  Dose levels were reported
        to be 0, 1, 3, 10.2, or 30.2 mg/kg/day for male rats, and 0, 1, 3, 9.9
        or 29.8 mg/kg/day for female rats.  There were no deaths or clinical
        signs of toxicity.  The body weight gain of females  (but not males)
        was significantly depressed at all dose levels from day 28 until
        completion of the study.   Kidney weight to body weight  ratios were
        significantly increased in female rats at the two highest dose levels.
        Red blood cell ChE activity was elevated at the high dose levels, but
        plasma and brain ChE levels were normal at all dose levels.  Histo-
        pathological  examination of 31 tissues from representative high-dose
        and control animals revealed no significant effects.  Weights of
        brain, liver, kidney, spleen, heart, adrenals and testes were not
        altered.  This study identified a NOAEL of 3 mg/kg/day  and a LOAEL of
        9.9 mg/kg/day.

     0  Bedo and Cieleszky  (1980)  reported a 90-day feeding study of methomyl
        in male and female rats receiving dietary levels of 100 or 200 ppm.
        Assuming that 1 ppm in the diet of rats is equivalent to 0.05 mg/kg/day
        (Lehman, 1959), this corresponds to doses of 5 or 10 mg/kg/day.  At
        200 ppm, the  female rats showed decreased brain ChE activity, decreased
        liver vitamin A content and elevated total serum lipids.  This study
        identified a  NOAPL of  100  ppm (5 mg/kg/day).

     0  Kaplan and Sherman  (1977)  reported a 22-month dietary feeding study
        in which Charles River-CD  male and female rats were fed methomyl
        (90 or 100% pure) at dietary levels of 0,  50,  100, 200  or 400 ppm
        a.i.  Assuming that 1 ppm  in the diet of  rats  is equivalent to
        0.05 mg/kg/day  (Lehman,  1959), this corresponds to doses of about 0,
        2.5, 5, 10 or 20 mg/kg/day.  Mortality data were not reported.  At
        autopsy, 9 of 13 males and 21 of 23 females at the 400-ppm level had
        kidney tubular hypertrophy and vacuolization of epithelial cells of
        the proximal  convoluted  tubules.  Compound-related histological
        alterations were also  seen in the spleens of female rats at the
        200-ppm dose  level.  No  effects were seen on ChE levels in plasma or

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Methomyl                                                  August, 1987

                                     -9-


        red blood cells.   This  study identified a LOAEL of 200 ppm
        (10 mg/kg/day)  and a NOAEL of 100 ppm (5 mg/kg/day).

     0  Kaplan and Sherman (1977)  performed a 2-year feeding study in beagle
        dogs (four/sex/dose).   Methomyl (90 or 100% pure) was supplied at
        dietary levels  of 0,  50,  100, 400 or 1,000 ppm a.i.  Assuming that
        1  ppm in the diet of dogs  is equivalent to 0.025 mg/kg/day (Lehman,
        1959), this corresponds to doses of about 1.25,  2.5, 10 or 25 mg/kg/day.
        Hematological,  biochemical (including plasma- and red-blood-cell ChE
        activity) and urinanalyses were conducted once on each dog prior to
        the start of the  study, at 3, 6, 12, 18 months during the exposure
        period and at 24-month sacrifice.  At 1 year, one male and one female
        per dose group were sacrificed for histopathological examination.
        One female dog at the 1,000-ppm dose level died after 8 weeks ,in the
        study, and a replacement dog died after 18 days.  Death was preceded
        by convulsive seizures and coma.  These deaths appear to be compound-
        related.  Two male dogs in the 1,000-ppm dose group showed clinical
        signs during week 13,  including tremors, salivation, incoordination
        and circling movements.  Hematological studies revealed slight-to-
        moderate anemia in five dogs (1,000-ppm dose group) at 3 months,
        which persisted in one dog to sacrifice.  No compound-related signs
        or effects were noted with respect to appetite,  body weight changes,
        biochemical studies (including ChE) and urinanalyses.  Dose-related
        histopathological changes were seen in kidney and spleen of animals
        receiving 400 and 1,000 ppm.  Changes were also seen in livers and
        bone marrow of animals receiving 1,000 ppm.  Pigment deposition was
        noted in the epithelial cells of the proximal convoluted tubules of
        the kidney in males at 400 and 1,000 ppm and in females at 1,000 ppm.
        A minimal-to-slight increase in bile duct proliferation and a slight
        increase in bone marrow activity was seen in animals receiving
        1,000 ppm.  The authors concluded that histological results indicated
        a NOAEL of 100 ppm (2.5 mg/kg/day).  Minimal histopathological changes
        seen in the kidneys and spleen of animals receiving 400 ppm (10 mg/kg/day),
        identified this level as the LOAEL.

     8  Hazelton Laboratories (1981) reported a 2-year study of methomyl
        (purity not specified) in mice.  Male and female CD-1 mice (80/sex/dose)
        were fed methomyl in the diet at dose levels of 0, 50, 100, or 800 ppm
        for 104 weeks.   Assuming 1 ppm in the diet to be equivalent
        to 0.15 mg/kg/day (Lehman, 1959), this corresponds to doses of about
        0, 7.5, 15 or 120 mg/kg/day.  Survival was significantly reduced (no
        details provided) in both males and females at the 800-ppm dose level by
        week 26.  The 800 ppm dose level was reduced to 400 ppm (1.0 mg/kg/day)
        at week 28 and then further reduced to 200 ppm (30 mg/kg/day) at week
        39.  At week 39,  the 100 ppm was decreased to 75 ppm (11.2 mg/kg/day).
        Survival was depressed in all groups of treated males at 104 weeks.
        No compound-related histopathological changes were noted in tissues
        of animals necropsied at 104 weeks.  A LOAEL of 50 ppm (7.5 mg/kg/day;
        the lowest dose tested) may be identified based on decreased survival.

   Reproductive Effects

     0  Male and female weanling Charles River-CD rats were fed methomyl
        (90% pure) at dietary levels of 0, 50, or 100 ppm a.i.. for 3 months.

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Methomyl                                                  August,  1987

                                     -10-
        Assuming that 1  ppm in the diet of weanling rats is equivalent to
        0.05 mg/kg/day (Lehman,  1959),  these doses correspond to about 0, 2.5
        or 5 mg/kg/day.   Ten males and twenty females from each group were
        bred and continued on the diet through three generations.  No adverse
        effects were reported on reproduction or lactation., and no pathologic
        changes were found in the weanling pups of the F-^ generation (Kaplan
        and Sherman, 1977).  A NOAEL of 5 mg/kg/day was identified from the
        highest dose tested.

   Developmental Effects

     0  New Zealand White rabbits, five per group, were dosed with 0, 2, 6 or
        16 mg/kg of methomyl (98.7% pure) on days 7 through 19 of gestation.
        One animal died at the 16 mg/kg dose level, exhibiting characteristic
        signs of ChE inhibition, including tremors, excitability, salivation
        and convulsions.  No adverse effects were observed at any dose level
        on embryo viability or on the frequency of soft-tissue or skeletal
        malformations (Feussner et al., 1983).   This study identified a
        maternal NOAEL of 6 mg/kg and a teratogenic NOAEL of 16 mg/kg/day,
        the highest dose tested.

     0  Kaplan and Sherman (1977) fed methomyl (90% pure) to pregnant New
        Zealand White rabbits on days 8 to 16 of gestation at dietary levels
        of 0, 50 or 100 ppm active ingredient.  Assuming that 1 ppm in the
        diet of rabbits is equivalant to 0.03 mg/kg/day (Lehman, 1959), this
        corresponds to doses of about 0, 1.5 or 3 mg/kg/day.  One-third of
        the fetuses were stained with Alizarin Red S and cleared for skeletal
        examination.  Since no soft tissue or skeletal abnormalities were
        observed at any dose level tested, a NOAEL of 3 mg/kg/day was identified.

   Mutagenicity

     0  Methomyl has been reported to be negative in the Ames test utilizing
        Salmonella  typhimurium strains TA 98, TA 1OO, TA 1535, TA 1537, and
        TA 1538 without metabolic activation  (Blevins et al., 1977; Moriya
        et al., 1983).  Waters et al.  (1980) reported methomyl as negative
        with and without metabolic activation in strains TA 10O, TA  1535,
        TA 1537 and TA  1538.

   Carcinogenicity

     0  Kaplan and  Sherman  (1977) fed ChR-CD rats  (35/sex/dose) methomyl  (90%
        pure) in the diet at levels of 0, 50, 100, 200 or 400 ppm active
        ingredient  for  22 months.  Assuming that 1 ppm in the diet of rats is
        equivalent  to 0.05 mg/kg/day  (Lehman, 1959), these doses correspond
        to about 0, 2.5, 5, 10 or 20 mg/kg/day.  Gross and histological
        examination revealed no increased tumor incidence in either male or
        female rats.

     0  Hazelton Laboratories  (1981) reported the results of a 2-year study
        of methomyl  (purity not specified)  in CD-1 mice  (80/sex/dose).   Initial
        dose levels were 0, 50, 100, or  800 ppm.  Assuming that 1 ppm in the
        diet of mice  is equivalent to  0.15  mg/kg/day  (Lehman, 1959), these

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   Methomyl                                                  August, 1987

                                        -11-
           doses correspond to 0,  7.5,  15 or 120 mg/kg/day.  Because of early
           mortality,  the 800-ppm  dose  was reduced to 400 ppm (60 mg/kg/day)
           at week 28,  and then to 200  ppm (30 mg/kg/day) at week 39.  At week
           29, the 100-ppm dose was reduced to 75 ppm (11.2 mg/kg/day).  Histo-
           logical examination at  necropsy did not reveal any treatment-related
           effects on  tumor incidence.
V. QUANTIFICATION OF  TOXICOLOGICAL EFFECTS

        Health Advisories (HAs)  are generally determined for one-day, ten-day,
   longer-term (approximately 7  years) and lifetime exposures if adequate data
   are available that identify a sensitive noncarcinogenic end point of toxicity.
   The HAs for noncarcinogenic toxicants are derived using the following formula:

                 HA = JNOAEL or  LOAEL) X (BW) „ 	 mg/L (	 ug/L)
                        (UF) x (	 L/day)

   where:

           NOAEL or LOAEL = No-  or Lowest-Observed-Adverse-Effect-Level
                            in mg/kg bw/day.

                       BW = assumed body weight of a child (10 kg) or
                            an adult (70 kg).

                       UF = uncertainty factor (10, 100 or 1,000), in
                            accordance with NAS/ODW guidelines.

                	 L/day = assumed daily water consumption of a child
                            (1 L/day) or an adult  (2 L/day).

   One-Day Health Advisory

        No information found in  the available literature was suitable for deter-
   mination of the One-day HA value for methomyl.  It is, therefore, recommended
   that the Drinking Water Equivalent Level (DWEL), adjusted for a child,
   (0.25 mg/L) be used at this time as a conservative estimate of the One-day HA
   value.

   Ten-day Health Advisory

        The health effects associated with acute and subchronic exposure to
   methomyl are primarily associated with cholinesterase (ChE) inhibition.
   Symptoms of ChE inhibition have been shown in rats at doses (via gavage) as
   low as 5.1 mg/kg/day for 2 weeks (Kaplan and Sherman, 1977).  Methomyl
   incorporated into the diet may have less dramatic effects; no ChE effects
   were observed in rats exposed subchronically to methomyl at dietary levels of
   100 ppm (5 mg/kg/day)(Kaplan  and Sherman, 1977; Bedo and Cieleszky, 1980).
  •Animal studies may be misleading in assessment of human toxicity.  No
   controlled human studies have been performed, but human fatalities from
   methomyl ingestion after a single exposure to an estimated dose of 12 mg/kg
   in bread or 13 mg/kg in drinks have been reported (Liddle et al., 1979;  Araki
   et al., 1982).

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Methomyl                                                  August, 1987

                                     -12-
     Because the timing and nature of administration can profoundly
affect the expression of methomyl toxicity, and little margin of safety
can be expected between doses that are fatal and those that cause little or
no acute toxicity, the available studies were judged to be inadequate  for  the
basis of the Ten-day HA value.  Therefore, it is recommeded that the DWEL,
adjusted for a 10-kg child (0.25 mg/L), be used at this time as a conservative
estimate of the Ten-day HA value.

Longer-term Health Advisory

     The onset of subchronic or chronic methomyl toxicity appears to occur at
doses similar to those that cause acute toxicity.  Kidney toxicity  (increased
kidney weight and hypertrophy) in acute, subchronic and chronic conditions
has been reported at doses of 15, 9.9 and 10 mg/kg/day, respectively (Woodside
et al., 1978; Homan et al., 1978; Kaplan and Sherman, 1977).  Acute ChE
inhibition in rats exposed to methomyl via gavage has been reported to occur
at doses as low as 5.1 mg/kg/day, and human fatalities from methomyl ingestion
of approximately 12 mg/kg in bread and 13 mg/kg in drinks have been reported
 (Liddle et al, 1979; Araki et al., 1982).

     Little margin of safety can be expected between doses of methomyl that
are fatal and those that cause little or no longer-term toxicity.   Therefore,
it is recommended that the DWEL adjusted for the child  (0.25 mg/L)  be  used at
this time as a conservative estimate of the Longer-term HA value.

Lifetime Health Advisory

     The Lifetime HA  represents that portion of an  individual's  total  exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure.  The  Lifetime  HA
is derived  in a three-step process.  Step  1 determines the Reference Dose
 (RfD),  formerly called the Acceptable Daily Intake  (ADI).  The RfD  is  an
estimate of a daily exposure  to the human population  that is  likely to be
 without appreciable risk of deleterious effects over  a lifetime, and is
 derived from  the NOAEL  (or LOAEL), identified  from  a  chronic  (or subchronic)
 study,  divided  by an  uncertainty factor(s).  From  the RfD, a  Drinking  Water
 Equivalent  Level  (DWEL) can be determined  (Step  2).   A  DWEL is a medium-specific
 (i.e.,  drinking water) lifetime  exposure  level, assuming  100%  exposure from
 that medium,  at which adverse, noncarcinogenic health effects  would not  be
 expected to occur.   The DWEL  is  derived from  the multiplication  of  the RfD by
 the  assumed body  weight  ^f an adult  and divided by  the assumed daily water
 consumption of  an adult.   The Lifetime  HA  is determined  in Step  3 by factoring
 in other sources  of  exposure, the  relative  source  contribution (RSC).   The
 RSC  from drinking water is based on  actual  exposure data  or,  if  data are not
 available,  a  value  of 20%  is  assumed  for  synthetic  organic chemicals and  a
 value of 10%  is assumed for  inorganic  chemicals.   If  the  contaminant is
 classified  as a Group A or B  carcinogen,  according  to the Agency's  classifi-
 cation scheme of  carcinogenic potential (U.S.  EPA,  1986),  then caution should
 be exercised  in assessing  the risks  associated with lifetime  exposure  to this
 chemical.

      Chronic  exposure to  methomyl  in the  diet induces renal  toxicity in rats
 and dogs.   Rats exposed  to 900 ppm (20 mg/kg/day)  for 22  months  exhibited

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Methomyl                                                  August, 1987

                                     -13-


kidney tubular hypertrophy and vacuolation of the eptithelial cells, and
dogs exposed to 400 ppm (10 mg/kg/day) for 2 years exhibited swelling and
increased pigmentation of the epithelial cells of the proximal tubules
(Kaplan and Sherman, 1977).  Effects on the kidney (increased weight) have
also been observed in rats exposed to 9.9 mg/kg/day in the diet for 13 weeks
(Homan et al., 1978).  The NOAEL of 2.5 mg/kg/day identified from the dog
study is a conservative estimate of the NOAEL and serves as the basis for the
Lifetime HA.

     In the Kaplan and Sherman (1977) study, beagle dogs (4/sex/dose) were
exposed to 50, 100, 400 or 1,000 ppm methomyl in the diet for 2 years (1.25,
2.5, 10 and 25 mg/kg/day).  Dogs receiving 1.25 or 2.5 mg/kg/day showed no
evidence of toxic effects.  Those receiving  10 mg/kg/day exhibited histopatho-
logical changes in the kidney and spleen.  In addition to these effects,
animals receiving the highest dose also exhibited symptoms of central nervous
system  (CNS)  toxicity, as well as liver and  bone marrow effects.

     Using a  NOAEL of 2.5 mg/kg/day,  the Lifetime HA is calculated as
follows:

Step 1:  Determination of the Reference Dose (RfD)

                   KfD =  (2.5 mg/kg/day) =  Q.025 mg/kg/day
                               (100)

where:

         2.5 mg/kg/day = NOAEL, based  on absence of  effects on blood  chemistry
                         (including ChE activity), hematology, urinalysis,
                        histopathology or body weight  in dogs exposed in  the
                        diet  for  2 years.

                   100 = uncertainty  factor,  chosen  in  accordance with NAS/ODW
                        guidelines for use  with a NOAEL  from an  animal  study.

Step  2:   Determination of  the  Drinking Water Equivalent  Level  (DWEL)

           DWEL  = (0*025 mg/kg/day)  (70 kg)  = Q.875  mg/L  (875 ug/L)
                          (2 L/day)

where:

         0.025 mg/kg/day  =  RfD.

                   70 kg  =  assumed body  weight of  an adult.

                 2 L/day  =  assumed daily  water consumption of  adult.

          For  the 10-kg  child,  the DWEL  is  calculated as  follows:


            DWEL       =  (0*025 mg/kg/day)  (1Qkg)  = 0.25 mg/L  (250 ug/L)
               child         (1 L/day)

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    Methomyl                                                   August, 1987

                                         -14-


    where:

            0.025  mg/kg/day  -  RfD

                     10  kg   -  assumed  body  weight  of  a  child

                   1  L/day   =  assumed  daily water  consumption of child

    Step 3:   Determination of  a  Lifetime  Health  Advisory

               Lifetime  HA = (0.875  mg/L)  (20%)  -  0.175 mg/L (175 ug/L)

    where:

                0.875 mg/L  =  DWEL.

                        20%  =  assumed  relative source contribution from water.


    Evaluation of  Carcinogenic Potential

         0   Two-year  carcinogenicity studies in  rats  and mice (Kaplan and Sherman,
            1977;  Hazelton Laboratories,  1981) have not revealed any evidence of
            carcinogenici.ty.

         0   The International  Agency for  Research  on  Cancer has not evaluated the
            carcinogenic potential of  methomyl.

         0   Applying  the criteria  described in EPA's  final guidelines for assess-
            ment of carcinogenic risk  (U.S. EPA, 1986), methomyl is classified
            in Group  Ds   not classifiable as to  human carcinogenicity.  This group
            is used for  agents with inadequate human  and animal evidence of
            carcinogenicity.


VI. OTHER CRITERIA, GUIDANCE AND STANDARDS

         0  The National Academy of Sciences (NAS, 1983) has a Suggested-No-Adverse-
            Response-Level  (SNARL) of  0.175 mg/L,  which was calculated using an
            uncertainty  factor of  100  and a NOAEL  of  2.5 mg/kg/day identified in
            the 2-year dog study by Kaplan  and Sherman  (1977).

         0  Residue tolerances have been  established  for methomyl in or on raw
            agricultural commodities (U.S.  EPA,  1985).   These tolerances are
            based  on  an  ADI  value  of 0.025  mg/kg/day, based on a NOAEL of
            2.5 mg/kg/day in dogs  and  an  uncertainty  factor of 100.  Residues
            range  from  0.1  (negligible)  to  40 ppm.

         0  The World Health Organization identified  a  Temporary ADI of 0.01
            ing/kg/day (Vettorazzi  and  Van den Hurk, 1985).

         0   ACGIH  (1984) has adopted a threshold limit  value (TLV) of 0.2 mg/m3
            as a time-weighted average exposure  for an  8-hour day.

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      Wethomyl                                                  August, 1987

                                           -15-


 VII. ANALYTICAL METHODS

           0  Analysis of methomyl  is  by a high-performance liquid chromatographic
              (HPLC)  procedure  used for the determination of N-methyl carbamoyloximes
              and N-methylcarbamates in drinking water (U.S. EPA,  1984).  In this
              method,  the water sample is filtered  and a 400-uL aliquot is injected
              into a  reverse-phase  HPLC column.   Compounds are separated by gradient
              elution chromatography.   After elution from the HPLC column, the
              compounds are hydrolyzed with sodium  hydroxide.  The methyl amine
              formed  during hydrolysis is reacted with o-phthalaldehyde to form a
              fluorescent derivative that is detected using a fluorescence detector.
              The method detection  limit for methomyl has been estimated to be
              approximately 0.7 ug/L.


VIII. TREATMENT TECHNOLOGIES

              Available data  indicate  that granular-activated carbon (GAC) adsorption
              will remove methomyl  from water.   Whittaker (1980)  experimentally
              determined adsorption isotherms for methomyl solutions on GAC.

           0  Whittaker (1980)  reported the results of GAC columns operating under
              benchscale conditions.   At a flow  rate of 0.8 gpm/sq ft and empty
              bed contact time  of 6 minutes,  methomyl breakthrough (when effluent
              concentration equals  10% of influent  concentration)  occurred after
              124 bed  volumes (BV).  When a bi-solute methomyl-metribuzin solution
              was passed over the same column, methomyl breakthrough occurred after
              55 BV.

              Treatment technologies for the removal of methomyl from water are
              available and have been  reported to be effective (Whittaker,  1980).
              However, 'the  selection of  individual  or combinations of technologies
              must be  based on  a case-by-case technical evaluation,  and  an assessment
              of the  economics  involved.

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    Methomyl                                                  August, 1987

                                         -16-


IX. REFERENCES

    ACGIH.   1984.   American Conference of Governmental Industrial Hygienists.
         Documentation of  the threshold limit values for substances in workroom
         air,  3rd  ed.   Cincinnati,  OH:  ACGIH.

    Andrawes,  W.R.,  R.H. Bailey and G.C. Holsing.*  1976.  Metabolism of acetyl-
         1-14c-methomyl in the rat.  Report No.  26946.  Unpublished study.

    Araki,  M., K.  Yonemitsu, T. Kambe, D. Idaka, S. Tsunenari, M. Kanda and
         T.  Kambara.   1982.  Forensic toxicological investigation on fatal cases
         of carbamate  pesticide methomyl (Lannate) poisoning.  Nippon Hoigaku
         Zasshi.   36:584-588.

    Baron,  R.L.  1971.  Toxicological considerations of metabolism of carbamate
         insecticides: methomyl and carbaryl. Pesticide Terminal Residues, Invited
         Paper, Int. Symp.  Washington, DC.  pp. 185-197.

    Bedo, M.,  and  V. Cieleszky.  1980.  Nutritional toxicology in the evaluation
         of pesticides. Bibl. "Nutr. Dieta."  29:20-31.

    Blevins, R.D., M.  Lee  and J.D.  Regan.  1977.  Mutagenicity screening of five
         methyl carbamate  insecticides and their nitroso derivatives using mutants
         of Salmonella typhimurium  LT2.  Mutat.  Res.  56:1-6.
                                                      /
    Boulton, J.J., C.B. Boyce, P.J. Jewess and R.F. Jones.  1971.  Comparative
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    CHEMLAB.   1985.  The Chemical Information System, CIS, Inc., Bethesda, MD.

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    E.I. du Pont de Nemours and Co.   1971.*  Methomyl decomposition in muck soil—
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    El-Sebae,  A«H., S.A. Soliman, A. Khalil and E. Sorya.  1979.  Comparative
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    Feussner,  E.,  M. Christian, G.  Lightkep et al.*  1983.  Embryo-fetal toxicity
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                                     -17-
Han, J.C.  Undated.*  Evaluation of possible effects of methomyl on nitrifying
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                                     -18-
McAlack, J.W.*  1973.  10-day subacute exposure of rabbit skin to lannate  (R)
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                                     -19-
Woodside, M.D., L.R. DePasso and J.B. Reid.*  1978.  UC 45650:  Results of
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•Confidential Business Information submitted to the Office of Pesticide
 Programs.

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