530R86107
      WATER
                   T T IT V
                  L, 1 1  I
          ADVISORY
                METRIBUZIN
         CritEria  and  Standards Division




      Office of  Water  Regulations  and  Standards
                  United States
           n vir a
nrnental Protection  Rgency
                MRRCH  1  9 8 G

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                                    WATER QUALITY ADVISORY
                                         Number  7 .

                                          METRIBUZIN

                               Criteria and Standards Division
                          Office of Water Regulations and Standards
                        United States Environmental Protection Agency


                The advisory concentration for Metribuzin in ambient water for the
          protection of freshwater aquatic life  is estimated  to be  100  ug/L. No
          saltwater toxicological  data were reviewed and no advisory concentra-
          tion for the protection of saltwater aquatic organisms has been
          estimated.  Care should be taken in the application of this advisory,
 -         with consideration of its derivation,  as stated in the attached
J         support  document.
 "i
              A value given to protect aquatic life  can be derived  from no
x         observed effect  levels (NOEL),  the  lowest  concentration found in the
 "l        data which has been observed to cause  acute or  chronic toxicity or
^        other experimental  data  which may be applicable. When there is no
^-'       valid experimental evidence, a value may be derived from a model which
          uses structure-activity  relationships  (SAR) as  its basis.  The advisory
          concentrations should be used with  caution, since they are derived
x        from minimal experimental  evidence,  or in  the case of SAR derived
          values,  no data  on the specific chemical.

              The advisory concentration for  Metribuzin  in ambient  water for the
          protection of human health is estimated to be  5,250 ug/L,  based on
          data and information  which are  available to U.S. EPA. Care should be
          taken in the application of  this advisory,  with consideration of its
          derivation, as  stated in the attached  support  document.

              An advisory  concentration can be derived  from  a number of sources:
          The Office of Drinking Water Health Effects Advisories; Acceptable
          Daily Intake(ADI) values from EPA;  Office  of Pesticides and Toxic
          Substances risk  assessments;  Carcinogen Assessment  Group(CAG) cancer
          risk estimates; risk  estimates  derived from the open literature; or
          other sources which will be given in the support document. The
          advisory concentrations  derived from these sources will vary  in
          confidence and usefulness,  based on the amount  and  quality of data
          used as well  as  the assumptions behind the original estimates. The
          user is advised  to read  the  background information carefully  to
          determine the strengths  or deficiencies of the values given in the
          advisory.
                               U.S. Environmental Protection Agency
                               Region 5, Library (PI.-12J)
                               77 West Jackson Boulevatd, 12th Floor
                               Chicago, IL  60604-3590

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 HUMAN HEALTH AND AQUATIC LIFE LITERATURE
   SEARCH AND DATA BASE EVALUATION FOR
                METRIBUZIN
   U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF WATER REGULATIONS AND STANDARDS
     CRITERIA AND STANDARDS DIVISION
         WASHINGTON, D.C.  20460

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                    HUMAN HEALTH AND AQUATIC  LIFE
                      LITERATURE SEARCH AND DATA
                         BASE EVALUATION FOR
                              METRIBUZIN
                 U.S.  ENVIRONMENTAL PROTECTION AGENCY
              OFFICE OF WATER REGULATIONS  AND STANDARDS
                   CRITERIA AND STANDARDS  DIVISION
                       WASHINGTON,  D.C.  20460
                             INTRODUCTION


    Metribuzin is a member of the triazine class of pesticides (heter-
ocyclic nitrogen compounds) with the chemical  formula 4-amino-6-tert-
butyl-3-(methylthic)-as-triazine-5(4H)-one  (McEwen  and Stephenson,
1979).  It is a white crystalline solid with a melting point of 125-
126.5 c.   Metribuzin is soluble  in methanol, ethanol,  glycol  ether
acetate,  and water (1,200 ppm).   The compound  is  a  methylthiotriazine
developed in the early 1970's for controlling  grasses and broadleaf
weeds in soybeans and tomatoes,  but  is  also registered for  use in
wheat, barley,  peas,  lentils, sugarcane, alfalfa, sainfoin  and aspara-
gus  (McEwen and Stephenson,  1979).

    Metribuzin controls  the  growth of grasses  and broadleaf weeds by
inhibitinoPhotosystem II of photosynthesis (McEwen and Stephenson,
1979).  -4Pfcs produced under the trade  names Sencor and Lexone by
Bayer AG., Federal Republic  of Germany; E.I.   Dupont de Nemours and
Co.,  USA;  and by Mobay Chemical  Corporation, USA.   Metribuzin is
moderately persistent in soils with  half-lives ranging from 15 to 377
days  depending upon moisture, temperature,  exposure to sunlight, and
soil  composition  (Hyzak and  Zimdahl, 1974; Schmidt, 1974).  Smith and
Hayden  (1982)  found 18 to 20 percent of the applied dose in the upper
10 cm of clay loam and heavy clay soils after a period of 22  weeks.
Photodegradation was found to accelerate the disappearance  of metri-
buzin in  soil  (3-fold) and water  (10-fold) (Schmidt, 1974).   Tempera-
ture also affected the rate  of degradation of  metribuzin with half-
lives of  377 days at 5 C,  46 days at 20 C, and 16 days at 35  C  (Hyzak
and Zimdahl, 1974).  A half-life of 43 days at 18 C in field soils
correlated well with  the laboratory results (Hyzak and Zimdahl, 1974).
Metribuzin is slowly degraded by microbes in soil and readily adsorbs
to clay and organic matter which increases its persistence  in soils
causing carry-over of residues from  year to year (McEwen and
Stephenson, 1977).

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                           SCOPE OF SEARCH

    Computerized literature searches and printed abstracts of TOXLINE,
TOXBACK,  NTIS and the Toxicology Data Base were used as primary
sources for identifying data on aquatic toxicity and human health
effects,  focusing primarily on laboratory studies of dose-response of
aquatic organisms and mammalian species.   The  quality assurance/
quality control measures used in these studies were  evaluated for
their use of positive and negative controls, replication,  and chemical
analysis of test concentrations.   Additionally, the  quality-of experi-
mental methods were evaluated by comparison to guidelines  established
by the U.S.   EPA in "Guidelines  and Methodology Used in Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Quality
Criteria Documents"  (FR 45:79347,  November 28, 1980) and the "Guide-
lines for Deriving Numerical National Water Quality Criteria for the
Protection of Aquatic Life and Their Uses" (Stephan et al., 1985).

    Data other than  dose-response relationships  (e.g.,  metabolic
studies,  field observations, and bioaccumulation) were  also collected
to provide ancillary information relevant to aquatic toxicity and
human health effects.

                         SUMMARY OF FINDINGS


                           Aquatic Toxicity


    Metribuzin  inhibited the growth of several species of fresh water
algae (Table l).  At levels of 0.1 ppm,  growth was significantly
inhibited in a blue  green algae (Anacystis nidulans) culture but
variable  (12-55 percent of controls) in four other species of algae
(Eley et al., 1983; Arvik et al., 1973).   Significant inhibition of
algal growth also occurred from metribuzin at 0.05 ppm (Arvik et al.,
1973).   Metribuzin also bioconcentrates in algae 59  times  the  levels
in water  (Freitag et al., 1982).

    Levels  of metribuzin  at 40 ppm  resulted in no toxicity to daphnids
(U.S. Dept.  of  Interior,  1981), and  only  one source  was found that
reported an  acute  toxicity value (10  ppm)  for fishes  (Schmidt, 1974).
However, this information was taken from an abstract and neither the
species, duration of exposure,  nor the quality assurance measures  of
the study were reported.  Exposure of metribuzin to  catfish finger-
lings at  10  ppm for  48 hours resulted in only 10 percent mortality
(McCorkel et al., 1977), while levels of 2*20 ppm shoved no toxic
effect to the same species  (Chambers and Fabacher,  1975).   Exposure of
rainbow trout to 40 ppm DCPA resulted in no toxicity; however, neither
the duration nor the quality assurance measures of the study were
reported  (U.S.  Dept.  Interior,  1981).   A  bioconcentration  factor of 11
was found for golden orfes exposed to 50 ppb metribuzin in water for a
period of 3 days  (Freitag et al., 1982).

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                            Health Effects

    The values of acute toxicity for metribuzin to rats and mice are
fairly consistent for similar routes of exposure (Table 2).  Oral LD50
(estimated dose at which 50 percent mortality occurs)  values ranged
from 2,000 to 2,500 rag/kg metribuzin in three different studies
(Loeser and Kimmerle, 1972; Schmidt, 1974; Kasimov, 1980).   Oral
exposure of metribuzin was more toxic to mice than rats (Loeser and
Kimmerle, 1972; Kasimov, 1980).   A single intraperitoneal injection of
metribuzin resulted  in a mean LD50 value  of 210 mg/kg for mice (Bleeke
et al.,  1985).   Single intraperitoneal injections of metribuzin in
mice at 200-250 mg/kg resulted in increased serum glutamicpyruvic
transaminase, decreased glutathione, and increased  necrotic lesions in
the liver.  After a  single  injection of  50 mg/kg metribuzin effects
in the livers of mice were observed (Bleeke et al., 1985).   Ingestion
of 0.5  to 25 ppm metribuzin in  the diet  for 3  months had  no observable
effect on rats (Schmidt,  1974;  Kasimov,  1980).  After an 8-day expo-
sure of metribuzin to rats by stomach intubation (1 ppm),  85 percent
of the dose was excreted.  Less than 0.1 percent had been retained in
liver,  lung,  and  adipose tissue  (Freitag  et al., 1982).   A summary of
the toxic effects for metribuzin to algae and animals is presented in
Figure 1.

              CR1IIBIA  EVALUATION AND  RECOMMENDATIONS

                             Aquatic Life

    No water-quality criteria for metribuzin was found in the litera-
ture search or in various water-quality criteria documents.  The lack
of adequate dose-response data makes a numerical  calculation of a
criterion impossible.  Although little information is  available on
dose-response relationships metribuzin does not appear very toxic to
fish and daphnids but may be significantly toxic to fresh water algae.
Levels of  40 ppm metribuzin  resulted in no toxicity to daphnids and
rainbow trout, and 20 ppm resulted in no toxic effects in catfish
fingerlings  (U.S.  Dept.  of Interior, 1981; Chambers and Fabacher,
1975).   Additionally, bioconcentration of metribuzin by fishes does
not appear to be significant (llx) even at levels  of 50 ppb in water
(Freitag et al.,  1982).   However,  metribuzin inhibited the  growth of
certain species of algae at  0.05  ppm and was significantly concen-
trated (59x) by one green algal species (Arvik et al.,  1973; Freitag
et al., 1982).   Therefore, the toxicity of metribuzin to fresh water
algae may be the most important consideration in determining a water
quality criterion to protect aquatic life.  Because levels of 50 and
100 ppb resulted in  moderate growth inhibition (12-76 percent of
controls) of algae and 0.1 ppm resulted in total inhibition of growth,
a level  of 0.1 ppm might be an  appropriate maximum  level  allowable to
protect fresh water  algae.  A concentration of 0.1  ppm would probably
be safe for daphnids and  fishes as  this concentration represents 0.25
percent of  a no toxic effect concentration  (40 ppm) for daphnia and 10
percent of the LC50  for  fish reported by  Schmidt (1974).

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                              Health  Effects

       The available information on metribuzin suggests  that the long-
  term feeding study with rats is  the most  appropriate parameter to use
  in deriving a water quality criterion to  protect human health.  These
  data were  available through a secondary reference (ACGIH,  1984).  in
  the study,  a dietary concentration  of 100 ppm did not  produce any
  effects, but 300 ppm did.   The 300  ppm concentration is regarded as a
  LOEL or a  lowest observed effect level and may be transformed to a
  daily dosage by multiplying the LOEL by  a constant 0.05 (FR 45:79353)
  for the rat.  The dosage is, therefore,  15 mg/kg/day.   Current U.S.
  EPA methodology (FR 45:79355)  indicates that  a LOEL, LOAEL,  or NOAEL
  from a long-term feeding study is appropriate for calculating an
  acceptable daily intake (ADI)  level.   The ADI may be calculated as
  follows:

                ADI = (150 mg/kg/day)  (70 kg)
                              100

                ADI = 10.5 mg/day

  where:
                15 mg/kg/day = LOEL
                70 kg        = average  body weight of an adult
                             = uncertainty  factor when adequate chronic
                               toxicity data are available/ but no
                               studies  of human ingestion are  available.

  A proposed advisory level for metribuzin in water, taking into effect
  ingestion  of water only, is derived as:

                Advisory = 10.5 mg/day
                               2 I/day

                Advisory =5.25 mg/L

  where:
              10.5 mg/day = ADI
              2 I/day     = average daily drinking water volume for adult.

This water quality advisory does not take into account additional
exposures that may result from dietary exposure to metribuzin  through
ingestion of contaminated fish.  The  only bioconcentration factor
found, 11,  would probably not change the advisory significantly if it
were used in the calculations.

    There is almost a complete  lack of data for appropriate acute and
chronic studies of metribuzin for aquatic organisms and  a lack of
chronic studies of mammals for human health effects. The kinds of
data required for calculating water quality criteria are summarized in
Tables  3 and 4.  Of 14 tests needed,  only one was found  to be  appro-
priate for use in deriving a water quality criterion for freshwater
life.  This value involves exposure  of metribuzin to freshwater algae

                                  8

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     TABLE 3.  DATA REQUIREMENTS FOR CALCULATION OF AQUATIC LIFE
               INTERIM CRITERIA—METRIBU2IN
 Criterion Requirements
     Aquatic Toxicity
Available
   Data
Acute Test Results from tests on:

  A salmonid (class Osteichthyes)     NO

  A warm water species commercially   NO
  commercially or recreationally
  important (class Osteichthyes)

  Another family in the phylum        YES
  Chordata (fish, amphibian, etc.)

  A planktonic crustacean             NO
  (cladoceran, copepod, etc.)

  Benthic crustacean  (ostracod,       NO
  isopod, scud, crayfish, etc.)

  Insect  (mayfly, dragonfly,          NO
  damselfly, stonefly, mosquito,
  etc.)

  Phylum other than Arthropoda/       NO
  Chordata (Rotifera, Annelida,
  Mollusca)

  Another family of insect            NO

Acute-chronic ratios with species from
three different families:
  One fish

  One invertebrate

  Acutely sensitive freshwater
  animal species
    NO

    NO

    NO
Acceptable test results from a test with:

  Freshwater algae                    YES

  A vascular plant                    NO

Bioaccumulation factor with a fresh-  YES
water species (if a maximum permissible
tissue concentration is available)
    Data
Acceptability
                       NO
            (not native U.S. species)
                       YES
                       NO
            (not native U.S. species)
                                  10

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      TABLE 4.  DATA REQUIREMENTS FOR CALCULATION OF HUMAN HEALTH
               INTERIM CRITERIA--METRIBUZIN
  Criterion Requirements
    Aquatic Toxicity

Nonthreshold:
Available
  Data
  Carcinogen                            NO
  Tumor incidence tests (incidence      NO
    of tumor formation signficantly
    more than the control for at least
    one dose level),  or
  Data set which gives estimate         NO
    of carcinogenetic risk, or
  Lifetime average exposure tests, or   NO
  Human epidemiology studies            NO
    (if available, not required)

Threshold:

  Non-carcinogens                       NO
  No observed adverse effect level      NO
    (at least 90-day), or
  Lowest observed effect level          YES

  Lowest observed adverse effect level  NO

Acceptable Daily Intake:

  Daily water consumption               YES

  Daily fish consumption                YES

  Bioconcentration factor               NO
  Non-fish dietary intake               YES

  Daily intake by inhalation            NO

Threshold Limit Value:

  (Based on 8-hour time-weighted        YES
    average concentrations in air)

Inhalation Studies:

  Available pharmokinetic data          NO
  Measurements of absorption            NO
    efficiency
  Comparative excretion data            YES
     Data
Acceptability
                      YES
                (ACGIH, 1984)
                      YES
                (EPA assumption)
                      YES
                (EPA assumption)

                      YES
                (EPA assumption)
                      YES
                 (ACGIH, 1984)
                      NO
                                  11

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                           LITERATURE CITED

ACGIH.   1984.  TLVs, Threshold  limit  values for  chemical  substances
and physical agents in the work environment and  biological  exposure
indices with intended>changes  for 1984-85.  lSBN:0-9367-54-6.   Ameri-
can Conference of Governmental  Industiral Hygienists.  Cincinnati,
Ohio.

Arvik, J., D.  L. Hyzak, and R. L. Zimdahl.  1973.  Effect of metri-
buzin and two analogs on five  species of algae.   Weed Science 21:ITS-
ITS.

Bleeke, M. S., M.  T. Smith, and J. E.  Casida.  1985.   Metabolism and
toxicity of metribuzin in mouse liver.  Pesticide Biochemistry and
Physiology  23:123-130.

Chambers,  H.,  and D.  L.  Fabacher.   1975.   Acute  toxicity  of pesticides
to channel catfish fingerlings.  Mississippi Agricultural Forest
Experimental Station  37:1  Abstract.

Eley, J. H., J. F. McConnell, and R. H. Catlett.  1983.  Inhibition of
metribuzin on growth and phtosynthesis of the  blue-green  alga
Anacystis nidulans.  Environmental and Experimental Botany 23:365-368.

Federal Register  (FR).  1980.  U.S. Government Printing Office,  Wash-
ington,  D.C.,  November 28,  45(231) :79347-79356.

Freitag,  D., H.  Geyer, A.  Karus, R. Viswanthan,  D. Kotzias, A. Attar,
W. Klein,  and F.  Korte.   1982.   Ecotoxicological profile  analysis VII.
Screening chemicals for their environmental behavior by comparative
evaluation.  Ecotoxicology and Environmental Safety 6:60-81.

Hyzak, D.  L., and  R. L. Zimdahl.  1974.  Rate of  degradation of metri-
buzin and two analogs in  soil.  Weed Science  22:75-79.

Kasimov, R. A.   1980.   Toxicology of  Sencor.   Zdravookhr  Tadzh 6:11-13
Abstract.

Loeser,  E.,  and G. Kimmerle.   1972.   Acute  and subchronic toxicity of
Sencor active ingredient.  Pflanzenschutz-Nachr.   25:186-209 Abstract.

McCorkel, F. M., J. E. Chambers, and  J.  0. Yarbrough.  1977.  Acute
toxicities of selected herbicides to  fingerling  channel  catfish,
Ictalurus punctatus.   Bulletin of Environmental  Contamination and
Toxicology.   18:267-270.

McEwen, F. L.  and G. R. Stephenson.  1979.  The use and significance
of Pesticides in the environment.  John Wiley and Sons,  Inc.  New York.
pp  124-133.

Schmidt, R. R.  1974.   Sencor  in the biosphere.   Nachrictenbl. Deut.
Pflanzenschutzdients  26:69-71  Abstract.


                                  12

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U.S. Environmental Protection ARency
Region 5, Library (PL-12J)
77 West Jackson Boulevard, 12th Floor
Chicago,  11  60604-3590

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of Environmental Contamination and Toxicology 29:243-247.


    w'  ?' I* Mount'  D'  J- Hansen,  J.  H. Gentile, G.  A.
                                    Protection Agency
                                                96"05"
                                          servioe-
                       13

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