820K88113
August,  1987
                                    METRIBUZIN

                                 Health Advisory
                             Office of Drinking Water
                       U.S. Environmental  Protection Agency
DRAFT
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, Logifor Probit models.  There is no current
   understanding of the biological mechanisms involved in cancer to suggest that
   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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    Metribuzin                                                   August,  1987

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II.  GENERAL INFORMATION AND  PROPERTIES

    CAS  No.   21087-64-9

    Structural Formula
          4-Amino-6-(1,1-dimethylethyl)-3-methylthio-1,2,4-triazin-5(4H)-one

    Synonyms

         0  Bayer  6159; Bayer  6443H;  Bayer  94337;  Lexone;  Sencor;  Sencoral;
           Sencorer;  Sencorex

    Uses
         o
            Herbicide  used  for  the  control  of  a  large  number  of  grass  and  broadleaf
            weeds  infesting  agricultural crops (Meister,  1983).

    Properties   (CHEMLAB,  1985)

            Chemical Formula                  CQH14ON4S
            Molecular  Weight                  214.28
            Physical State  (at  25°C)           white crystalline  solid
            Boiling Point                      —
            Melting Point                      125-126°C
            Density                            —
            Vapor  Pressure  (25°C)              10~5 nraHg  (20°C)
            Specific Gravity
            Water  Solubility (25eC)            1,200 mg/L
            Log  Octanol/Water Partition        -5.00 (calculated)
             Coefficient
            Taste  Threshold
            Odor Threshold                     —
            Conversion Factor                  —

    Occurrence

         0   Metribuzin has  been  found  in 1,517 of 3,580  surface  water  samples
            analyzed and in  54 of 240  ground water samples  (STORET,  1987).   These
            samples were collected  at  407 surface water  locations  and  204  ground
            water  locations; metribuzin was found in  14  states.  The 85th
            percentile of all nonzero  samples  was 4.79 ug/L in surface water and
            0.1  ug/L in ground water sources.  The maximum  concentration found  in
            surface water was 22.79 Ug/L and in  ground water, 1.25 ug/L.

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Metribuzin                                                  August, 1987

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     0  Metribuzin has been found in Iowa ground water resulting from
        agricultural uses;  typical positives were 1 to 4.3 ppb (Cohen et al.,
        1986).

Environmental Fate

     0  The rate of hydrolysis of metribuzin is pH dependent.   During a
        28-day test, little or no degradation was observed at pH 6 or 9 at
        25°C, or at pH 6 at 37°C or 52°C (Day et al.,  1976).

     o  14c-Metribuzin on silty clay soil degraded, with a half-life of 15
        days, when exposed  to natural sunlight (Khasawinah, 1972).  The half-life
        in control samples  kept in the dark was 56 days.  After 10 weeks,
        20.6, 6.5 and 7.0%  of the applied radioactivity was present in the
        irradiated soil as  6-t-butyl-l,2,4-triazin-3,5-(2H,4H)-dione (DADK),
        6-t-butyl-3-(methylthio)-l,2,4-trizin-5(4H)-one (DA) and parent compound,
        respectively.  A substantial portion of the applied radioactivity
        (56%) was bound to  the soil.  In the dark control, 4.6, 16.9, 44.0 and
        34% of the applied  radioactivity was present as DADK,  DA, parent or
        bound compound, respectively.

     0  Under aerobic conditions, metribuzin at 10 ppm degraded with a
        half-life of 35-63  days in silt loam and sandy loam soils treated
        with a 50% wettable powder (WP) formulation, and 63 days in soils
        treated with a 4-lb/gal FlC formulation (Pither and Gronberg, 1976).
        Degradates found were: 6-t-butyl-l,2,4-triazin-3,5-(2H,4H)-dione
        (DADK); 4-amino-6-butyl-l-2,4,-triazin-3,5-(2H,4H)-dione (DK); and
        6-t-butyl-3-(methylthio)-l,2,4-triazin-5-(4H)-one (DA).

     0  14c-Metribuzin residues degraded slowly in silty clay  soil under
        anaerobic conditions with a half-life of more than 70 days (Khasawinah,
        1972).  After 10 weeks of incubation, 10, 10.9, 57, and 19% of the
        applied radioactivity was present as DADK, DA, parent compound or
        bound to the soil,  respectively.

     0  Metribuzin adsorption was significantly correlated to  soil organic
        matter, clay and bar soil water contents  (Savage, 1976).  Calculated
        K<3 values ranged from 0.27 for a sandy loam soil (0.75% organic
        matter, 11% clay and 12% bf 0.33 bar soil water content), to 3.41 for
        a clay soil (42% organic matter, 71% clay and 42% of 0.33 bar soil
        water content).

     o  14c-Metribuzin residues were very mobile in Amarillo sandy loam and
        Louisiana Commerce  silt loam soils; after leaching 12-inch soil
        columns with 20 inches of water, 96.6 and 91.6% of the applied radio-
        activity, respectively, was found in the leachate (Houseworth and
        Tweedy, 1973).  !4C-Metribuzin residues were relatively immobile in
        Indiana silt loam and New York muck soils; after leaching 12-inch
        soil columns, 90.6  and 89.4% of the applied radioactivity was detected
        in the top 3 cm of  the Indiana silt loam and New York  muck, soil
        columns, respectively.  No radioactivity was detected  in column
        leachates.

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     Metribuzin                                                  August,  1987

                                         -4-


          0   14c-Metribuzin  residues  (test substance  not  characterized) aged 30
             days  were  moderately mobile in an Amarillo sandy  loam soil column;
             after  leaching  a  12-inch column with 22.5 inches  of water, 7.3% of
             the applied  radioactivity was found in the leachate (Tweedy  and
             Houseworth,  1974).  In the soil column,  85.2% of  the applied radio-
             activity remained within the top 2 inches.

          o   14c-Metribuzin  residues  (test substance  not  characterized) were
             intermediately  mobile in sandy clay loam and silt loam soils
             (Rf 0.61 to  0.62) and mobile in sandy, sandy loam, and two silty
             clay  soils (Rf  0.68 to 0.77), based on soil  thin-layer chromatography
             (TIC)  tests  (Thornton et al. , 1976).  14c-Metribuzin residues  (test
             substance  not characterized) were intermediately  mobile  in sand (Rf
             0.61),  sandy clay loam (Rf 0.64), two silty  clay  soils (Rf 0.62 and
             0.71),  silt  loam  (Rf 0.66) and sandy loam  (Rf 0.82) soils, based  on
             soil  TLC tests  (Obrist and Thorton, 1979).   14c-Metribuzin (purity not
             specified) at 1.5 ug/spot had low mobility  (Rf  0.13 to 0.26) in two
             muck  soils and  intermediate mobility  (Rf 0.42 to  0.53) in six  mineral
             soils  ranging in  texture from sand to clay,  based on soil TLC  plates
             developed  in water  (Sharon and Stephenson, 1976).

          0   In  the field, metribuzin dissipates with half-lives of less  than
             1 month to 6 months.  Three metribuzin degradates were detected:
             6-t-butyl-l,2,4-triain-3,5-(2H,4H)-dione (DADK);  4-amino-6-t-butyl-
             l,2,4-triazin-3,5-(2H,4H)-dione  (DK); and  6-t-butyl-3-(methylthio)l,2,4-
             triazin-5-(4H)-one  (DA).  Soil type and  characteristics, chemical
             formulation or  application rates did not discernibly affect  the
             dissipation rate  of metribuzin (Stanley  and  Schumann, 1969;  Finlayson,
             1972;  Rockwell, 1972a; Rockwell, 1972b;  Rockwell, 1972c; Rowehl,
             1972a;  Rowehl,  1972b; Schultz, 1972; Mobay Chemical, 1973; Fisher,
             1974;  Murphy, 1974; United States Borax  and  Chemical Corp.,  1974;
             Potts  et al., 1975; Analytical Biochemistry  Laboratories, 1976;
             Ballantine,  1976; and Ford, 1979).


III.  PHARMACOKINETICS

     Absorption

          0   A study was conducted in four dogs using oral dosing of  radiolabeled
             metribuzin (Khasawinah,  1972) to evaluate  absorption, distribution
             and metabolites.  Analysis of blood samples  showed a peak level
             at  4  hours.

     Distribution                                    --

          0   No  information  was  found in the  available  literature on  the  distribution
             of  metribuzin.

     Metabolism

          0   No  information  was  found in the  available  literature on  the  metabolism
             of  metribuzin.

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    Metribuzin                                                   August,  1987

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    Excretion

         0   Khasawinah  (1972)  reported  that 52  to  60%  of  the administered dose of
            metribuzin  in  dogs was  excreted in  the urine  and 30% in the  feces.


IV.  HEALTH  EFFECTS

    Humans

         No information was  found  in the available literature on the health
    effects of  metribuzin  in humans.

    Animals

       Short-term Exposure

         0   Crawford and Anderson  (1974) reported  the  acute oral LD50 values
            following the  administration of technical  metribuzin to guinea pigs
            and rats as 245 and 1,090 mg/kg,  respectively, for male animals,
            and 274 and 1,206 mg/kg, respectively, for females.

         0   Mobay Chemical (1978)  reported the  acute oral LD50 values for a
            wettable granular formulation  of  metribuzin to be 2,379 and
            2,794 mg/kg for male and female rats,  respectively.

         0   Mobay Chemical (1978)  reported the  acute dermal LD50 for a wettable
            granular formulation of metribuzin  to  be >5,000 mg/kg for both male
            and female rats.

         0   Mobay Chemical (1978)  reported the  acute (1-hour) inhalation LC5Q in
            rats for a wettable granular formulation to be >20 mg/L.

       Dermal/Ocular Effects

         0   In studies conducted by Mobay  Chemical (1978), metribuzin (wettable
            granular) was  determined to be a  very  slight irritant to rabbit eyes
            and skin.

       Long-term Exposure

         0   Loser et al. (1969) administered  metribuzin to Wistar rats (15/sex/dose)
            for 3 months in their feed at  levels of 0, 50, 150, 500 or 1,500 ppm
            (about 2.5, 7.5, 25 or 75 mg/kg/day, bashed on calculations in Lehman
            et al., 1959).  Following treatment, food  consumption, growth, body
            weight, organ  weight,  clinical chemistry,  hematology, urinalysis and
            histopathology were measured.   No significant efects on these parameters
            were observed  in either sex at 50 ppm  (2.5 mg/kg/day).  Among females,
            enlarged livers were found in  the 150, 500 or 1,500 ppm (7.5, 25 or
            75 mg/kg/day)  dosage groups (p <0.05), and thyroid glands were also
            enlarged in the 500 or 1,500 ppm  (25 or 75 mg/kg/day) groups (p <0.05
            and p <0.01, respectively).  In the males, enlarged thyroids were
            reported among the 500 (25 mg/kg/day)  (p <0.05) and 1,500 ppm

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Metribuzin                                                  August,  1987

                                     -6-
        (75 mg/kg/day)  (p <0.01)  dosage groups,  while an enlarged heart was
        reported at 1,500 ppm (75 mg/kg/day)  (p  <0.05).   At 1,500 ppm
        (75 mg/kg/day),  lower body weights (p <0.01)  were reported in both
        sexes when compared  to untreated controls.

     0  In studies conducted by Lindberg and  Richter  (1970),  beagle dogs
        (four/sex/dose)  administered oral doses  of  50,  150 or 500 ppm (about
        1.25, 3.75 or 12.5 mg/kg/day,  based on calculations in Lehman et al.,
        1959) technical  metribuzin for 90 days showed no significant differences
        in body weights,  food consumption, behavior,  mortality, hematologic
        findings, urinalysis, gross pathology or histopathology.

     e  Loser and Mirea  (1974) reported that  dietary  concentrations of 1.5,
        2 or 20 mg/kg/day metribuzin did not  significantly affect physical
        appearance, behavior, mortality, hematologic  clinical chemistry,
        urinalysis or histopathology in rats  (40/sex/dose) fed technical
        metribuzin in the diet for 24 months.  The  body  weights of females at
        the 20 mg/kg/day dose level were usually lower (p <0.05) than those of
        controls; at the end of the test period, however,, no significant
        differences were noted.

     0  Hayes et al. (1981)  administered technical  metribuzin in the diet
        to albino CD mice (50/sex/dose) at 200,  800 or 3,200 ppm (about 30,
        120 or 480 mg/kg/day, based on calculations in Lehman et al., 1959)
        for 24 months.   Following treatment,  feed consumption, general behavior,
        body and organ weights, mortality, hematology and histopathology were
        analyzed.  No adverse effects were observed in these parameters in
        either sex at 800 ppm (120 mg/kg/day).  However, a significant
        (p <0.05) increase in absolute and relative liver and kidney weights
        was observed in  female mice receiving 3,200 ppm  (480 mg/kg/day).

     0  In studies conducted by Loser and Mirea  (1974),  four groups of beagle
        dogs (four/sex/dose) were administered metribuzin in the diet at dose
        levels of 0, 25, 100 or 1,500 ppm (about 0, 0.625, 2.5 or 37.5 mg/kg/day,
        based on calculations in Lehman, 1959) for 24 months.  Following
        treatment, food  consumption, general  behavior and appearance, clinical
        chemistry, hematology, urinalysis, body and organ weights and histo-
        pathology were evaluated.  No toxicologic effects were reported in
        animals administered 100 ppm metribuzin  (2.5 mg/kg/day) or less for
        any of the parameters measured.  Necrosis of the renal tubular cells,
        slight iron deposition as well as slight hyp°rglycemia and temporary
        hypercholesterolemia were noted in animals administered 1,500 ppm
        (37.5 mg/kg/day).

   Reproductive Effects                          -~

     0  In a 3-generation reproduction study. Loser and Siegmund (1974)
        administered technical metribuzin in  the feed at dose levels of 0,
        35,  100 or 300 ppm (about 0, 1.75, 5  or 15 mg/kg/day, based on
        calculations in Lehman et al., 1959)  to FB30 (Elberfeld breed) rats
        during mating, gestation and lactation.   Following treatment,
        fertility, lactation performance and  pup development were evaluated.
        No treatment-related effects were reported at any dose tested.

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   Metribuzin                                                 August,  1987

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      Developmental Effects

        0  Unger and Shellenberger (1981)  administered  technical  metribuzin by
           gastric intubation to pregnant  female  rabbits  (16 to 17/dose)  on days
           6 through 18 of gestation at daily  doses  of  15,  45 or  135 mg/kg/day.
           Following treatment,  there was  a  statistically significant (p  <0.05)
           decrease in body weight gain in the high-dose  does (135 mg/kg).   No
           maternal toxicity was reported  in animals administered metribuzin at
           levels of 45 mg/kg/day or less.   No treatment-related  effects  were
           reported at any dose  level in fetuses  based  on gross,  soft tissue and
           skeletal examinations.

        0  Machemer (1972) reported no maternal toxicity, embryotoxicity  or
           teratogenic effects following oral  administration (via stomach tube)
           of technical metribuzin to FB30 rats (21  to  22/dose) on days 6 through
           15 of gestation at dose levels  of 5, 15,  50  or 100 mg/kg/day.

      Mutagenicity

        0  Metribuzin showed no  mutagenic  activity in several bacterial assays
           (Inukai and lyatomi,  1977; Shirasu  et  al., 1978)  or in dominant
           lethal tests in mice  (Machemer  and  Lorke, 1974,  1976).  The results
           of microbial point mutation assays  (Machemer and  Lorke,  1974)  did not
           indicate a mutagenic  potential  for  metrirazin  in  the test systems
           utilized.  The results of dominant  lethal mutations in mice or
           chromosomal aberrations in hamster  spermatogonia  at dose levels  of
           300 mg/kg and 100 mg/kg, respectively,  did not indicate any mutagenic
           effects of metribuzin.

      Carcinogenicitjy

        0  Hayes et al. (1981) conducted studies  in  which technical metribuzin
           was administered in the diet to albino CD-1  mice  (50/sex/dose) at 200,
           800 or 3,200 ppm (30, 120 or 380  mg/kg/day)  for 24 months.  Minimal
           toxic effects were observed at  the  high-dose level in  the form of
           increased liver weight and changes  in  the hematocrit and hemoglobin
           measurements.  Although some increase  in  the number of tumor-bearing
           animals was observed  in low- and  mid-dose animals, significant
           increases in the incidence of specific  tumor types were not observed
           at any dose level. It was concluded that, under  the conditions  of the
           test, there was no increase in  the  incidence of  tumors in mice.


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 = (NOAEL or  LOAEL) x (BW)  = 	   /L  (	  /L)
                        (UF) x (    L/day)                      y/

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Metribuzin                                                  August,  1987

                                     -8-
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 was found in the available literature that was suitable
for determination of a One-day HA for metribuzin.  It is therefore recommended
that the Ten-day HA value for a 10-kg child (4.5 mg/L, calculated below) be
used at this time as a conservative estimate of the One-day HA value.

Ten-day Health Advisory

     The study by Unger and Shellenberger (1981) has been selected to serve
as the basis for determination of the Ten-day HA for metribuzin.  In this
study, pregnant rabbits (16 or 17/dose) that were administered technical
metrizubin by gastric intubation at dosage levels of 0, 15, 45 or 135 mg/kg/day
on days 6 through 18 of gestation showed a statistically significant (p <0.05)
decrease in body weight gain at the 135-mg/kg dose.  No maternal toxicity was
reported at or below the 45-mg/kg dose.  No treatment-related effects were
reported at any dose level in fetuses based on gross, soft tissue and skeletal
examinations.  The NOAEL identified in this study was, therefore, 45 mg/kg/day.
While a reproductive end point is not the most appropriate basis for derivation
of an HA for a 10-kg child, this study is the only one available for the
appropriate duration.

      Using a NOAEL of 45 mg/kg/day, the Ten-day HA for a 10-kg child is
calculated as follows:

          Ten-day HA =  (45 mg/kg/day)  (10 kg) = 4.5 mg/L (4,500 ug/L)
                           (100)  (1 L/day)
 where:
         45 mg/kg/day = NOAEL, based on absence of body weight reduction in
                       rabbits exposed to metribuzin via gastric intubation
                       on days 6 through 18 of gestation.

               10 kg = assumed body weight of a child.

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

              1 L/day = assumed daily water consumption of a child.

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Metribuzin                                                  August,  1987

                                     -9-


Longer-term Health Advisory

     The study by Loser et al.  (1969) has been selected to serve as the basis
for the Longer-term HA for metribuzin.  In this study, rats (15/sex/dose)
were fed diets containing metribuzin at doses of 50, 150, 500 or 1,500 ppm
(about 2.5, 7.5, 25 or 75 mg/kg/day based on calculations in Lehman et al.,
1959) for 90 days.  Thyroid glands were enlarged in males in the 500 or
1,500 ppm (25 or 75 mg/kg/day)  dosage groups, while the heart was enlarged at
the 1,500 ppm (75 mg/kg/day) dose level.  In females,  enlarged  livers were
detected in the 150, 500 or 1,500 ppm (7.5,  25 or 75 mg/kg/day)  dosage groups,
and the thyroid was enlarged in the 500 or 1,500 ppm (25 or 75 mg/kg/day)
dosage groups.  Body weights were reduced in both sexes at 1,500 ppm
(75 mg/kg/day), compared to untreated controls.  The NOAEL identified in this
study was, therefore,  50 ppm (2.5 mg/kg/day).  Lindberg and Richter (1970)
determined a NOAEL of  12.5 mg/kg/day in dogs; however, this study was'not
chosen, since the NOAEL was higher than the LOAEL of 7.5 mg/kg/day identified
by Loser et al. (1969) in the rat.

     Using a NOAEL of  2.5 mg/kg/day, the Longer-term HA for a 10-kg child is
 calculated as follows:

       Longer-term HA  = (2.5 mg/kg/day) (10 kg) = 0.25 mg/L (250 ug/L)
                            (100) (1 L/day)
where:

        2.5 mg/kg/day  = NOAEL,  based on absence of increased absolute organ
                        weights in rats exposed to metribuzin via the diet
                        for 90 days.

                10 kg  = assumed body weight of a child.

                  1 00 = uncertainty factor,  chosen in accordance with NAS/ODW
                        guidelines for use with a NOAEL from an animal study.

              1 L/day  = assumed daily water consumption of a child.

     Using a NOAEL of  2.5 mg/kg/day, the Longer-term HA for a 70-kg adult is
calculated as follows:

       Longer-term HA  = (2.5 mg/kg/day) (70 kg) = 0<875   /L (875   /L)
                            (100) (2 L/day)
where:

        2.5 mg/kg/day  = NOAEL,  based on absence of increased absolute organ
                        weights in rats exposed"to metribuzin via the diet
                        for 90 days.

                70 kg  = assumed body weight of an adult.

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

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

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Metribuzin                                                  August, 1987

                                     -10-


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 esti-
mate 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 of 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 classification scheme of
carcinogenic potential (U.S.  EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.

     The study by Loser and Mirea (1974) has been selected to serve as the
basis for the Lifetime HA for metribuzin.  In this study, dogs (four/sex/dose)
were administered metribuzin in the diet at dose levels of 0, 25, 100 or
1,500 ppm (0, 0.625, 2.5 or 37.5 mg/kg/day) for 24 months.  Necrosis of the
renal tubular cells was reported as well as slight and temporary changes in
certain clinical chemistry parameters (e.g., blood glucose and cholesterol)
at the high-dose level.  No other toxicologic effects were reported.  Based
on this information, a NOAEL of 100 ppm  (2.5 mg/kg/day) and a LOAEL of
1,500 ppm (37.5 mg/kg/day) were reported.  Loser and Mirea (1974) reported a
NOAEL of 20 mg/kg/day in rats.  This study was not selected because no dose-
related toxicologic responses were observed, and the rat may be less sensitive
than the dog.  Hayes et al. (1981) determined a NOAEL of 120 mg/kg/day in
mice; however, this value exceeded the LOAEL (37.5 mg/kg/day) reported by Loser
and Mirea (1974).

     Using this study, the Lifetime HA is calculated as follows:

Step  1:  Determination of the Reference  Dose (RfD)

                   RfD = (2.5 mg/kg/day) = Q. 025_ mg/kg/day
                               (100)
where:
        2.5 mg/kg/day = NOAEL, based on absence of organ toxicity and clinical
                        chemistry effects in dogs exposed to metribuzin via
                        the diet for 24 months.

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    Metribuzin                                                  August,  1987

                                         -11-


                      1 00 = 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)  _ 0<875 mg/day (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 an adult.

    Step 3:   Determination of  the  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   In a study by Hayes et al.  (1981),  metribuzin was administered in the
            feed of mice (50/sex/dose)  at  dose  levels of 200, 800 or 3,200 ppm
            (30, 120 or  480 mg/kg/day)  for 24 months.  Following treatment, the
            incidence of tumor formation was analyzed in a variety of tissues.
            Neoplasms of various tissues and organs  were similar in type,
            localization,  time of  occurrence and incidence in control and treated
            animals.  It was concluded that under the conditions of the  test,
            there was no increase  in the incidence of tumors in mice.

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

         0   Applying the criteria  described in  EPA's guidelines for assessment
            of carcinogen risk (U.S. EPA,  1986), metribuzin may be classified in
            Group D:  not classified.   This category is used for substances with
            inadequate animal  evidence of  carcinogenicity.


VI.  OTHER CRITERIA, GUIDANCE AND STANDARDS

         0   A Threshold  Limit  Value-Time-Weighted Average (TLV-TWA) of 5 mg/m3
            was determined, based  on animal studies  substantiated by repeated
            inhalation tests,  a safety  factor of 5,  and assuming a total pulmonary
            absorption (ACGIH,  1984).

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      Metribuzin                                                  August,  1987

                                           -12-


 VII.  ANALYTICAL  METHODS

           0   Analysis  of metribuzin is by  a gas chromatography  (GC) method  appli-
              cable  to  the determination of certain organonitrogen pesticides in
              water  samples  (U.S.  EPA, 1985).  This method  requires a  solvent
              extraction of  approximately 1 L of sample with methylene chloride
              using  a separatory funnel.  The methylene chloride extract is  dried
              and exchanged  to acetone during concentration to a volume of 10 mL or
              less.  The compounds in the extract are  separated by GC  and  measurement
              is  made with a thermionic bead detector.  The method detection limit
              for metribuzin is 0.46 ug/L.


VIII.  TREATMENT TECHNOLOGIES

           0   Available data indicate that  granular-activated carbon (GAC) adsorption
              and a  conventional treatment  scheme will remove metribuzin from water.

           0   Whittaker (1980) experimentally determined  adsorption isotherms for
              metribuzin on  GAC.

           0   Whittaker (1980) reported the results of GAC  columns operating under
              bench-scale conditions.  At a flow rate  of  0.8 gpm/sq ft and an empty
              bed contact time of  6 minutes, metribuzin breakthrough (when effluent
              concentration  equals 10% of influent concentration) occurred after
              112 bed volumes  (Bv).

           0   In  the same study, Whittaker  (1980) reported  the results for four
              metribuzin bi-solute solutions when passed  over the same GAC continuous
              flow column.

           0   Another study  investigated  the effectiveness  of two different  GAC
              columns in removing  metribuzin from contaminated wastewater  (Whittaker,
              et  al.,  1982).  One  type of GAC showed breakthrough for  metribuzin
              (6  mg/L)  from  an initial concentration of  140 mg/L after 50  gallons
              of  the wastewater had been  treated.  No  pesticide  was found  in the
              effluent  from  the second type of GAC.

           0   Conventional water treatment, coagulation and sedimentation  with alum
              and an anionic polymer  removed more  than 50%  of the metribuzin present
              (Whittaker et  al.,  1980).   The optimum alum dosage was 200 mg/L.   Also
              equivalent dosages of ferric  chloride were  found to be equally effective.

           0   Treatment technologies  for  the removal of metribuzin from water are
              available and  have been reported to be effective.  However,  selection
              of  individual  or combinations of technologies to attempt metribuzin
              removal  from  water  must be  by a case-by-case  technical evaluation,
              and an assessment of the economics  involved.

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   Metribuzin                                                   August,  1987

                                        -13-


[X. REFERENCES

   ACGIH.  1984.  American Conference of Governmental Industrial  Hygienists.
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   Analytical Biochemistry Laboratories.  1976.  Chemagro agricultural  division
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   Ballantine, L.G.  1976.  Metolachlor plus metribuzin tank mix  soil dissipation:
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   Day, E.W., W.L. Sullivan and O.D. Decker.  1976.  A hydrolysis study of  the
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   Ford, J.J.  1979.  Herbicide combination—soil  dissipation study involving
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   Hayes, R.H., D.W. Lamb, D.R. Mallicout et al.*  1981.  Metribuzin (R)  (Sencor)
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   Houseworth, L.D. and E.G. Tweedy.  1973.  Report on parent leaching  studies
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Metribuzin                                                  August, 1987

                                     -14-
Inukai, H. and A. lyatomi.*  1977.  Bay 94337:  Mutagenicity test on bacterial
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Khasawinah, A.M.  1972.   The metabolism of Sencor (Bay 94337) in soil:
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Lehman, W.J., W.F. Reehl and D.H. Rosenblatt.  1959.  Handbook of chemical
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Machemer, L. and D. Lorke.*  1976.  (R) Sencor:  Additional dominant lethal
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Meister, R., ed.  1983.   Farm Chemicals Handbook.  Willoughby, OH:  Meister
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Mobay Chemical.  1973.  Mobay Chemical Corporation.  Sencor:  Metabolic,
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Murphy, H.  1974.  Mobay Chemical Corporation residue experiment, Presque
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     Corp., Kansas City, MO.

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M,etribuzin                                                  August, 1987

                                     -15-
Obrist, J.J. and J,S. Thornton.  1979.  Soil thin-layer mobility of Baycor
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Pither, K.M. and R.R. Gronberg.  1976.  A comparison of the rate of metabolic
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Potts,  C.R., M.M. Laporta, J. Devine et al.  1975.  Prowl (CL 92, 553):
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     benzenamine and Sencor 4-Amino-6-t-butyl-3-(methylthio)-l,2,4-triazin-
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                                      -16-


 Shirasu,  Y.,  M.  Moriya and  T.  Ohta.*   1978.   Metribuzin mutagenicity test on
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*Unger,  T.M. and T.E.  Shellenberger.  1981.  A teratological evaluation of
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 *Confidential Business Information submitted to the Office of Pesticide
  Programs.

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