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norflurazon (Zorial, Solicam) Herbicide Profile 12/84

                         CHEMICAL FACT SHEET FOR:
                   1.  DESCRIPTION OF THE CHEMICAL
- Generic Name:  4-chloro-5-(methylamino)-2-(alpha, alpha,
- Common Name:  norflurazon
- Trade Name:  Zorial, Solicam, and Evital
- EPA Shaughnessy Code:  105801
- Chemical Abstracts Service (CAS) Number:  27314-13-2
- Year of Initial Registration:  1974
- Pesticide Type:  Herbicide
- Chemical Family:  fluorinated pyridazinone
- U.S. and Foreign Producers:  Sandoz, Inc.
- Application sites:  Norflurazon is registered for use as a selective
  preemergent herbicide to control germinating annual grasses and
  broadleaf weeds in cranberries, cotton, soybeans, almonds, apples,
  apricots, cherries, citrus (all), filberts. hops, nectarines, peaches,
  pears, pecans, plums, prunes, walnuts, and noncrop areas such as
  storage areas, airports, and rights-of-way.
- Types of formulations:  Norflurazon is the sole active ingredient in
  the following:  97% active ingredient (a.i.) technical manufacturing-
  use product, 80% a.i. wettable powder, 50% a.i. flowable, and 5% a.i.
- Types and methods of applications:  Band or broadcast ground
  application to soil surface. Aerial application is registered for
  cotton, cranberry, and soybean use.
- Application rates:  0.5 to 8 lb. a,i. per acre (A):  cranberries 4-8
  lb. a.i./A; cotton and soybeans 1-2 lb. a.i./A (split application
  0.5-1.0 lb. a.i./A); tree fruit, nut tree, citrus, and hops 2-4 lb.
  a.i./A; and noncrop sites 4-8 lb. a.i./A.
- Usual carrier:  Water
                         3.  SCIENCE FINDINGS
Chemical Characteristics
- Norflurazon is a buff-white, odorless, crystalline solid.  The melting
  point is 177 +/-3 degrees C.  The solubility of norflurazon at 25
  degrees C is 5 grams (g)/100 milliliters (ml) in acetone, insoluble in
  carbon disulfide, 14.2 g/100 ml in ethyl alcohol, 0.25 g/100 ml in
  xylol, and 28 parts per million (ppm) (w:w) in water.  The vapor
  pressure is <1 x 10(-5) Torr (25 degrees C).  Norflurazon is quite
  stable in dilute acidic or basic aqueous solution, and storage
  stability is greater than two years.  No unusual handling
  characteristics were noted.
Toxicological Characteristics
- Acute studies indicate the following:
  - Rat acute oral LD50:  9,000 milligrams (mg)/kilogram (kg),
    Toxicity Category IV.
  - Rabbit acute dermal LD50:  >20,000 mg/kg, Toxicity Category IV.
  - Male rat acute inhalation LC50 of 80% WP:  >200 mg/liter (1)/1
    hour, Toxicity Category IV.
  - Not an eye or skin irritant, Toxicity Category IV.
  - Not a skin sensitizer.
- Subchronic studies indicated the following:
  - In a 6-month dog feeding study, the primary effects seen were
    congestion of the liver, hepatocyte swelling, increased liver
    weight, and an increase in colloidal vacuole in thyroid at 450
    ppm.  The No Observed Effect Level (NOEL) was 150 ppm.  Levels
    tested were 0, 50, 150, and 450 ppm.
  - In a 90-day rat feeding study, the primary effect was hypertrophic
    change in the thyroid glands at 2,500 ppm.  The NOEL was
    500 ppm.  Levels tested were 0, 250, 500, and 2,500 ppm.
  - In a 28-day mouse feeding study, diffuse and smooth granular
    livers and increased liver/body weight ratios were observed at
    2,520 ppm.  The NOEL was 420 ppm.  Levels tested were 0, 70, 210,
    420, and 2,520 ppm.
  - A 14-day inhalation study in the rat was submitted.  Levels tested
    were 0.1, 1.0, and 10.0 mg/l.  The NOEL was 10 mg/l.
  - A 21-day dermal toxicity study in the rabbit was performed on
    80% WP (wettable powder) norflurazon.  Levels tested were 750
    mg/kg/day and 2,000 mg/kg/day.  The NOEL was >2,000 mg/kg/day.
- The chronic studies indicated the following:
  - Chronic feeding studies:
    - A 2-year rat feeding study was conducted using technical
      norflurazon.  Rats were fed dietary levels of 2, 15, 125, 375,
      and 1,025 ppm.  In the high dose group, histopathological
      alterations included an increase in the number of chromophobe
      adenomas of the pituitary, nodular or cortical hypertrophy in
      adrenals, and nephritis and/or casts in kidneys of the male
      rats; and fatty changes in adrenals, endometritis and squamous
      metaplasia of the uterus, cystic ovaries, and hyaline casts
      and/or nephritis in kidneys of the females.  A NOEL was
      demonstrated at 375 ppm.  Norflurazon demonstrated no tumorigenic
      effect in the test animals in any of the dose levels tested.
    - In a 2-year feeding study, mice were fed 0, 0 (double control),
      85, 340, and 1,360 ppm of technical norflurazon. Histopathological
      alterations included hepatoma/hyperplasia-hypertrophy in the liver
      at 1,360 ppm.  The NOEL level observed was 340 ppm.  There was no
      significant increase in these lesions in the lower levels over
      that of the control.  The failure to induce such lesions in the
      other long-term studies permits the conclusion that this is not a
      potential carcinogenic response but a toxic response to a rather
      high level of chemical insult.
  - Reproduction studies:
    - A 3-generation reproduction study was conducted in the rat.
         Norflurazon was fed at dietary levels of 0, 125, 375, and 1,025
        ppm for three generations.  At 1,025 ppm, norflurazon caused
        reduced fertility, gestation, and viability indices.  No
        teratogenic effects were seen at any dose tested.  The NOEL was
        established at 375 ppm.
      - In a 1-generation reproduction study in the mouse, norflurazon
        was fed at dietary levels of 0, 0, 85, 170, and 340 ppm.  No
        adverse findings were observed in any of the doses tested.  The
        NOEL was established at 340 ppm.
  - Teratogenicity studies:
    - Pregnant rabbits were fed a diet containing 0, 10, 30, and 60
      mg/kg norflurazon on gestation days 6 through 15.  Norflurazon
      was not teratogenic at 60 mg/kg/day.  Maternal body weight was
      decreased at 60 mg/kg.  Fetotoxic effects seen at 30 and 60 mg/
      kg/day were decreased weight and incomplete ossified variations.
      Maternal toxic NOEL was observed at 30 mg/kg/day.  Fetotoxic
      NOEL was observed at 10 mg/kg/day.
    - In the second teratology study, pregnant rats were fed 0, 100,
      200, and 400 mg/kg/day of norflurazon on gestation days 6
      through 15.  Norflurazon was not embryotoxic or teratogenic.
      The NOEL was 400 mg/kg/day.
  - Mutagenicity studies:
    - In two Ames mutagenic assays, norflurazon was tested in
      Salmonella typhimurium strains, TA-1535, TA-1537, TA-1538,
      TA-98, TA-100, and D-4 Saccharomyces cerevisiae strain.
      The doses employed ranged from 0.1 micrograms (ug) to 5,000 ug
      per plate.  The compound was tested directly in the presence of
      liver microsomal enzyme preparation from Aroclor-induced rats.
      Norflurazon did not demonstrate mutagenic activity.
    - A reverse mutagenicity assay using Salmonella typhimurium
      strains TA-1535, TA-1537, TA-1538, TA-98, and TA-100, and E.
      coli, WP2 hcr strain (tryptophan-requiring strain) was
      conducted.  The doses employed were 5, 10, 50, 100, 1,000, and
      5,000 ug per plate.  Norflurazon was negative in this test.
  - Metabolism studies:
    - (3H, 14C)-norflurazon was administered by gavage to 10 male
      Wistar strain rats at a dose of 10 mg/day for 15 days.  Approxi-
      mately 17% of the administered dose was excreted in the urine,
      and about 57% in the feces.  Small amounts of the parent
      compound were isolated from the urine (0.1%), and larger amounts
      from the feces (5.4%).  Only traces of radioactivity were
      present in the tissues examined.  Three major pathways seem to
      be operative in detoxification of norflurazon in the rat:
      desmethylation, yielding desmethyl metabolite of norflurazon; a
      hydroxylation process involving the replacement of chlorine on
      carbon-4 of the pyridazinon ring; and conjugation through sulfur
      introduced at carbon-4 of the pyridazinon ring.
Physiological and Biochemical Behavioral Characteristics
- Norflurazon is absorbed by the roots of weeds as they germinate and is
  translocated to the growing parts, where it inhibits carotenoid
  biosynthesis, resulting in chlorophyll photodegradation in susceptible
  species.  On emergence from the soil, the weed seedlings turn white
  or pinkish, become necrotic, and die.
Environmental Characteristics
- Norflurazon residues appear to be relatively mobile in most mineral
  soils, and immobile in soils with high organic matter.  The half-life
  in soils ranges from 38 days to 731 days.
Ecological Characteristics
- Avian studies:
  - Acute oral (mallard duck) LD50:  >2,510 mg/kg.
  - Acute dietary (bobwhite quail) LD50:  >10,000 mg/kg.
  - Acute dietary (mallard duck) LD50:  >10,000 mg/kg.
  - Reproduction (mallard duck and bobwhite quail) was not affected up
  to 40 ppm dietary exposure (highest dose tested).
- Aquatic species studies:
  - Daphnia magna acute 48-hour no effect level was 15 ppm (the
    highest level tested due to solubility of norflurazon technical).
  - Daphnia magna chronic lifecycle minimum threshold concentration was
    >1.0 <2.6 ppm due to effect on offspring production.
  - Bluegill sunfish 96-hour acute was 16.3 ppm.
  - Rainbow trout 96-hour acute was 8.1 ppm.
  - Fathead minnow partial chronic maximum toxicant concentration
    (MATC) was >1.1 <2.1 ppm based on growth.
  - Rainbow trout partial chronic MATC was >0.77 <1.5 ppm based upon
    survival and growth.
  - Atlantic oyster larvae acute NOEL was 10 ppm.
Tolerance Assessment
- U.S. tolerances for residues of norflurazon and its desmethyl
  metabolite in or on raw agricultural commodities are as follows
  (40 CFR 180.356(a)):
  Commodities                           Maximum Residue Limit (ppm)
  ___________                           ___________________________
    Almond, hulls                                     1.0
    Almonds, meat                                     0.1
    Apricots                                          0.1
    Apples                                            0.1
    Cattle, fat                                       0.1
    Cattle, meat                                      0.1
    Cattle, meat byproducts (mbyp)                    0.1
    Cherries                                          0.1
    Citrus fruit                                      0.2
    Cottonseed                                        0.1
    Cranberries                                       0.1
    Filberts                                          0.1
    Goats, fat                                        0.1
    Goats, meat                                       0.1
    Goats, mbyp                                       0.1
    Hogs, fat                                         0.1
    Hogs, meat                                        0.1
    Hogs, mbyp                                        0.1
    Hops, green                                       1.0
    Horses, fat                                       0.1
    Horses, meat                                      0.1
    Horses, mbyp                                      0.1
    Milk                                              0.1
    Nectarines                                        0.1
    Pecans                                            0.1
    Peaches                                           0.1
    Pears                                             0.1
    Plums (fresh prunes)                              0.1
    Poultry, fat                                      0.1
    Poultry, meat                                     0.1
    Poultry, mbyp                                     0.1
    Sheep, fat                                        0 1
    Sheep, meat                                       0 1
    Sheep, mbyp                                       0.1
    Soybeans                                          0.1
    Soybean forage                                    1.0
    Soybean hay                                       1.0
    Walnuts                                           0.1
- U.S. tolerances for indirect residues of norflurazon and its
  desmethyl metabolite in raw agricultural commodities, when present
  as a result of application to cotton when peanuts are a replacement
  or follow-up crop, are as follows (40 CFR 180.356(b)):
  Commodities                           Maximum Residue Limit (ppm)
  ___________                           ___________________________
    Peanuts                                           0.2
    Peanut, hay                                       0.5
    Peanut, hulls                                     0.5
    Peanut, vines                                     0.5
- A food additive tolerance has been established for residues of
  norflurazon and its desmethyl metabolite in dried hops at 3.0 ppm (21
  CFR 193.324). Feed additive tolerances have been established for
  residues of norflurazon and its desmethyl metabolite in citrus
  molasses at 1.0 ppm and dried Citrus pulp at 0.4 ppm (21 CFR 561.283).
  No Codex Alimentarius or Mexican or Canadian tolerances have been
  established for residues of norflurazon on the above commodities. 
- The acceptable daily intake (ADI) was established using the 6-month
  dog feeding study with a no observed effect level of 150 ppm (3.750
  mg/kg/day).  Using a 1,000-fold safety factor, the ADI is calculated
  to be 0.0038 mg/kg/day.  The maximum permitted intake (MPI) for a 60-
  kg human is calculated to be 0.2250 mg/day.  The current theoretical
  maximum residue contribution (TMRC) for norflurazon, based on the
  established tolerances, is 0.0877 mg/day for a 1.5 kg diet, and the
  percent ADI utilized is 38.98%. 
- Residue studies are adequate to support tolerances established for
  almonds, apricots, cherries, cranberries, cottonseed, filberts,
  grapes, nectarines. peaches, peanut hulls, pears, pecans, walnuts,
  milk, and the fat, meat, and meat by-products of cattle, goats,
  hogs, horses, poultry, and sheep.
Summary Science Statement
- Norflurazon has a low acute toxicity and is not an eye or skin
  irritant or a skin sensitizer.  The subchronic, chronic feeding, and
  reproduction studies did not produce results of toxicological concern.
  Norflurazon is not considered to be an oncogen or a teratogen.  The
  mutagenicity studies reviewed thus far are negative.  Norflurazon
  appears to be mobile in mineral soils and immobile in soils with high
  organic material and is persistent in soil.  Norflurazon is relatively
  non-toxic to avian test species and is moderately to slightly toxic
  to aquatic (freshwater and marine) organisms.  Data are available to
  determine and establish tolerances for residues of norflurazon and
  its desmethyl metabolite in over half of the commodities with
  established tolerances.  Based on the established tolerances and the
  6-month dog feeding study, the percent of the acceptable daily intake
  utilized is 39%.
- Use, formulation, manufacturing process, or geographical restrictions:
  None are required.
- Unique precautionary statements, protective clothing requirements, or
  reentry intervals:  None required.
- Risk/benefit review:  None of the risk criteria set forth in Title 40
  Code of Federal Regulations 162.11 have been exceeded by norflurazon.
- Groundwater contamination potential:  Because of the mobility and long
  half-life, norflurazon presents a potential for groundwater contamina-
  tion.  The groundwater studies will be requested in an accelerated
  time frame.  Due to the inadequate data base, and since norflurazon to
  date has not been found in groundwater, no interim restrictions were
  imposed.  Any future decisions depend on the results of the required
                 5.  SUMMARY OF MAJOR DATA GAPS
- Groundwater studies:
- Hydrolysis, photodegradation, and mobility are required within six
  months after receipt of the Guidance Package.
- Metabolism, soil and aquatic (sediment) dissipation are required
  within two years after receipt of the Guidance Package.
- Soil, long-term dissipation is required within four years after
  receipt of the Guidance Package.
- Short-term studies required to be filled within six months after
  receipt of the Guidance Package:
- Product chemistry:  Description of manufacturing process, discussion
  of formation of impurities, analysis of product, density, dissociation
  constant. octanol/water partition coefficient, oxidizing or reducing
  action, explodability, pH, and stability.
- Honeybee acute contact.
- Female rat metabolism.
- Mutagenicity studies for chromosomal aberration and other mechanisms
  of mutagenicity are required to be filled within one year after the
  receipt of the Guidance Package.
- Long-term studies required to be filled within two years after the
  receipt of the Guidance Package:
- Rotational crops
- Plant and animal metabolism
- Analytical methods and stability of residues under storage
- Crop residues studies for soybeans, citrus, apples, plums, hops,
  and peanuts.
                      6.  CONTACT PERSON AT EPA
Richard F. Mountfort
Product Manager (23)
Environmental Protection Agency (TS-767C)
401 M Street S.W.
Washington, DC  20460
(703) 557-1830