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bromadiolone (Bromone, Maki) Chemical Profile 1/85

                                    bromadiolone
      CHEMICAL name:      3-[3-[4'-bromo(1,1'-biphenyl)-4-yl]-3-hydroxy-1-
                          phenylpropyl]-4-hydroxy-2H-1-benzopyran-2-one (62)
      TRADE name(S):      Bromone, Maki, Supercaid (56)
      FORMULATION(S):     Concentrates, baits, pellets, paraffin blocks,
                          tracking powder (56).  Finished baits will contain
                          active ingredient of .005% concentration (8c).
      TYPE:               Rodenticide (anticoagulant)
      BASIC PRODUCER(S):  Chempar Products Div.
                          Lipha Chemicals, Inc.
                          660 Madison Ave.
                          New York, NY 10021
      STATUS:             General use
      PRINCIPAL USES:     Maki labeled for use against house mice, roof rats,
      and Norway rats (including Warfarin resistant strains).  Also
      authorized by USDA for use in official establishments operating under
      the Federal meat, poultry, shell egg grading and egg products
      inspection program (56).
      APPLICATION METHOD(S):  Applied over a period of time in bait boxes or
      at permanent bait stations (8c).
                                    I.  EFFICACY
           Gives excellent control of Warfarin resistant rodents.  No bait
      shyness has been noted.  Mortality occurs within 48 hours.  One or two
      feedings will control a total population.  Has a single feeding
      mortality rate of 90% (8c).
           It is an anticoagulant rodenticide, a single dose of a 50 mg/kg
      bait killing Rattus norvegicus and R. rattus from the 5th day.  It is
      particularly palatable to rodents (62).
            Advantages of Maki (Bromadiolone) Over Other Anticoagulants
      ACTIVITY
           Considerably higher on rats and mice.   Maki also acts on rats
      so-called "resistant" to conventional anticoagulants.
      Several examples:
      Experiments in the U.S.A.
      --   Norway rats (Bromadiolone at 0.005%)
           - Groups of 10 males and 10 females in individual cages
                 Days Feeding            Mortality              Dead By
                     1                      100%               6-11th day
                     2                      100%               6-10th day
                     3                      100%               6-10th day
      Experiments at L I P H A (Lyon, France)
      --   White mice (Bromadiolone at 0.005%)
           - 20 groups of 25 and 1 group of 20; 1/2 males and 1/2 females
                                                         Mortality Rate
                  1 day feeding                              90.76%
           - 6 groups of 25
                  4 day feeding                              97.33%
      --   Norway Rats
                  1 day feeding
                    Bromadiolone at 0.0025%                  90.00%
                    Bromadiolone at 0.005%                  100.00%
                  3 day feeding
                    Bromadiolone at .0025%                  100.00%
      Experiments at C N R Z
      --   Grey mice (Bromadiolone at 0.005%)
                  1 day feeding                               50%
                  3 day feeding                              100%
                  5 day feeding                              100%
                  8 day feeding                              100%
      --   Norway rats
                  1 day feeding
                    Warfarin at 0.025%                         5%
                    Bromadiolone at 0.005%                    81%
      --   Roof Rats
                  5 day feeding
                    Warfarin at 0.025%                        70%
                    Bromadiolone at 0.005%                    95%
      --   Resistant rats
           According to the British, rats surviving 6 day treatment of
      Warfarin at 0.005% are considered resistant.  Our test was more severe,
      as we used the commercial dosage of 0.025% Warfarin to verify the
      resistance of rats from the Loiret region (labeled as a "pocket of
      resistance").
                                                          Mortality of
                                                         Resistant Rats
                  6 day feeding
                    Warfarin at 0.025%                        28%
                    Chlorophacinone at 0.005%                 60%
                    Bromadiolone at 0.005%                   100%
      Experiments in the U.S.A.
      --   Wild mice (Bromadiolone at 0.005%)
           - 10 males and 10 females in individual cages.
                                    Acceptance              Mortality
                  15 day feeding        47.2%                   95%
           The minimum bait acceptance level required in the U.S.A. is 33%;
      internationally, 30%.
      --   Norway rats (Bromadiolone at 0.0025%)
                  9 day feeding         49.1%                   100%
                  Mortality between 5th and 9th days.
                    (Bromadiolone at 0.005%)
                  8 day feeding         54.1%                   100%
                  Mortality between 2nd and 10th days.
      --   Roof rats (Bromadiolone at 0.005%)
           - Per group of 10 males and 10 females in individual cages.
                  10 day feeding        49.4%                   100%
                  Mortality between 7th and 11th days.
      Experiments in Great britain
      --   White mice (Bromadiolone at 0.005%)
           - Per group of 20 animals
                  4 day feeding         68.5%                    95%
      ACCEPTANCE
           In the field, as well as in the laboratory, the baits treated with
      Bromadiolone (Maki) are in a high proportion more attractive, starting
      from Day 1.
      Experiments at L I P H A (Lyon, France)
      --   Norway rats
           Summary of tests of 10 Norway rats in individual cages, with
      untreated wheat and with wheat treated with Bromadilone at 0.005%.
                         Day 1               Day 2              Day 3
                   Untreated  Treated  Untreated  Treated  Untreated  Treated
      1st Test
      Average       6.3gm     13.6gm    13.5gm    14.3gm    13.2gm    10gm
       Consumption  32%         68%       49%       51%       57%       43%
       per rat
      2nd Test
      Average      10.3gm     11.8gm    10.0gm     9.3gm    11.7gm    6.1gm
       Consumption  47%        53%       52%       48%       66%       34%
       per rat
      Experiments in the U.S.A.
      --   Norway rats (Bromadiolone at 0.005%)
           Number of animals:  20
           Duration:            8 days
           Consumption of untreated bait:  45.9% of total bait
           Consumption of treated bait:    54.1% of total bait
           Mortality from 2nd to 10th day: 100.0%
      Experiments in Great Britain
      --   White rats
           Number of animals:  10
           Duration:            4 days
           Consumption of Bromadiolone treated bait:  68.84% of total bait
           Consumption of Warfarin treated bait:      31.16% of total bait
           Mortality:  100%
      --   White mice
           Number of animals:  20
           Duration:            4 days
           Consumption of Bromadiolone treated bait:  56.96% of total bait
           Consumption of Warfarin treated bait:      43.04% of total bait
           Mortality:  90% (70b).
                              II.  PHYSICAL PROPERTIES
      MOLECULAR FORMULA:  C30 H23 Br O4 (62)
      MOLECULAR WEIGHT:   527.4 (62)
      PHYSICAL STATE:     Yellowish powder (technical grade, 97% pure) (62)
      MELTING POINT:      200-210 C (mixture of two diastereoisomers) (62)
      SOLUBILITY:         19 mg/l water at 20 C (62)
                          III.  HEALTH HAZARD INFORMATION
      OSHA STANDARD:  NA
      NIOSH RECOMMENDED LIMIT:  NA
      ACGIH RECOMMENDED LIMIT:  NA
      TOXICOLOGY
           A.  ACUTE TOXICITY
               ORAL:  LD50 = 1.125 mg/kg (rat); 1.75 mg/kg (mouse); 1 mg/kg
                             (rabbit) (62).
                      LD50 = 1.125 mg/kg (rat, as 100% bromadiolone);
                             lethal dosage:  22.5 g/kg of 0.005% formulations
                             (56).
           B.  SUBACUTE AND CHRONIC TOXICITY:
           In 90-day feeding trials the only effect observed in rats and dogs
      was reduction of prothrombin rating (62).
                         IV.  ENVIRONMENTAL CONSIDERATIONS
      DOMESTIC ANIMALS
      Dogs:    Acute Toxicity - The maximum tolerated oral dosage (MTD) is 10
               mg/kg.  For a 10 kg dog, this corresponds to 100 mg of pure
               Bromadiolone; that is, 2 kilos of bait at the dosage of
               0.005%.  From 15 mg/kg on, hemorrhages begin to appear
               starting from the third day.  They are fatal unless we
               administer an intravenous injection of Vitamin K1 (5 mg/kg of
               body weight).
               Chronic Toxicity - Daily dosages of 0.5 mg to 1 mg/kg which
               corresponds to 10 to 20 g of bait at the dosage of 0.005% of
               active material per kilo of body weight, cause no fatal
               reaction.  On the other hand, the ingestion of 200 g of bait
               (10 mg/kg of active material) per kilo of body weight for
               several days can cause mortality.  This hazard is unrealistic,
               considering the total amount of bait that has to be consumed
               for several days.
      Cats:    The cat is more resistant than the dog.  The maximum tolerated
               oral dosage (MTD) stands at 25 mg/kg of active material, which
               represents, for an animal weighing 2 kgs., a consumption of
               one kilo of bait at 0.005%.
      Swine:   The tests were carried out with animals of an average weight
               of 25 kgs.
               The maximum tolerated dosage (MTD) for 5 days was 25 mg of
               active material per day, per animal; that is, 500 gms. of bait
               at 0.005% of active material.
               There was no noticeable effect after a daily ingestion of 10
               gms. of bait at 0.005% of active material for 45 days.
               No mortality was caused after two treatments of five days
               each, separated by an interval of 15 days' rest, of dosages
               corresponding to 125 gms., 250 gms., and 500 gms. of grains
               treated at 0.005% of active material.
      Poultry: Poultry is more sensitive to Bromadiolone than to Warfarin or
               Chlorophacinone.  Therefore, precautions must be taken when
               material is used in poultry farms, to avoid the bait being
               consumed by these birds.
      AQUATIC SPECIES
      Rainbow
       Trout:  No effect within 96 hours up to 0.46 mg/litre of water, of
               active material; that is, 0.184 cc of a concentrate containing
               2.5 mg/litre.
               The LC50 at 96 hours is placed at 1.4 mg/litre of water; that
               is, 0.56 cc of a concentrate containing 2.5 gm/litre.
      Bluegill:  No effect within 96 hours up to 1.3 mg/litre.  The LC50 at 96
               hours is placed at 3 mg/litre of water; that is, 1.2 cc of a
               concentrate containing 2.5 gm/litre.
      Water
       flea:   No effect within 48 hours up to 0.088 mg/litre.  The LC50 at
               24 hours is higher than 8.8 mg/litre; that is, 3.52 cc of a
               concentrate containing 2.5 gm/litre (70b).
                       V.  EMERGENCY AND FIRST AID PROCEDURES
           The chemical information provided below has been condensed from
      original source documents, primarily from "Recognition and Management
      of Pesticide Poisonings", 3rd ed. by Donald P.  Morgan, which have been
      footnoted.  This information has been provided in this form for your
      convenience and general guidance only.  In specific cases, further
      consultation and reference may be required and is recommended.  This
      information is not intended as a substitute for a more exhaustive
      review of the literature nor for the judgement of a physician or other
      trained professional.
           If poisoning is suspected, do not wait for symptoms to develop.
      Contact a physician, the nearest hospital, or the nearest Poison
      Control Center.
      FREQUENT SYMPTOMS AND SIGNS OF POISONING:
           Coumarins, indandiones, and other anticoagulants:  In most cases
      of ingestion of anticoagulants, victims have remained asymptomatic, due
      to the small dosage taken.  Even in cases involving ingestion of
      substantial amounts of anticoagulant compound (more often medication
      than rodenticide), hypoprothrombinemia has occurred without symptoms of
      poisoning.  Hemorrhage appears only when extraordinary amounts have
      been absorbed.  In reported cases, the anticoagulants were either taken
      deliberately, were absorbed over long periods out of neglect of
      elementary hygienic standards, or were ingested by starving indigents
      who used quantities of rodent bait as food.
           Victims of large doses exhibit HEMATURIA, NOSEBLEED, HEMATOMATA,
      BLEEDING GUMS, and MELENA, ABDOMINAL PAIN and BACK PAIN probably
      reflect hemorrhage in the abdominal and retroperitoneal tissues.
      WEAKNESS occurs as a result of ANEMIA.  RENAL COLIC often complicates
      severe hematuria.  Nasal and gastrointestinal hemorrhages have
      occasionally caused death from exsanguination (25).
           INGESTION:  If swallowed, call a physician at once (70c).
           NOTES TO PHYSICIAN:
           If ingested, administer Vitamin K1 intramuscularly or orally, as
      indicated in bishydroxycoumarin overdoses.  Repeat as necessary, based
      on monitoring of prothrombin times (70c).
           Coumarins, indandiones, and other anticoagulants
      1.   If only a few grains of anticoagulant bait have been ingested by
           an adult or child having no antecedent liver or blood clotting
           disease, treatment is probably unnecessary.
           A.  If there is uncertainty about the amount of bait ingested or
               the general health of the patient, PHYTONADIONE (vitamin K1,
               Mephyton) given orally protects against the anticoagulant
               effect of these rodenticides.  For adults, give 15-25 mg; for
               children under 12, give 5-10 mg.  Alternatively, a colloidal
               solution of phytonadione, Aquamephyton, may be given
               intramuscularly.  For adults, give 5-10 mg; for children under
               12, give 1-5 mg.
               CAUTION:   PHYTONADIONE, specifically, is required.  Neither
                          vitamin K3 (menadione, Hykinone) nor vitamin K4
                          (menadiol) is an antidote for these anticoagulants.
           B.  Whatever the dosage, insure that patients (especially
               children) will be CAREFULLY OBSERVED for 4-5 days after
               ingestion.  The indandiones and the more recently introduced
               anticoagulants have toxic effects apart from anticoagulation
               that are not yet well defined.
      2.   If LARGE AMOUNTS of anticoagulant were ingested in the preceding
           2-3 hours, INDUCE VOMITING with SYRUP OF IPECAC, followed by 1-2
           glasses of water.  For adults, give 30 ml; for children under 12,
           15 ml.  Following emesis, give 30-50 gm ACTIVATED CHARCOAL in 4-6
           ounces of water to limit absorption of anticoagulant remaining in
           the gut.
      3.   If anticoagulant has been ingested any time in the preceding 15
           days, determination of PROTHROMBIN TIME provides a basis for
           judging the severity of poisoning.
           A.  If the prothrombin time is lengthened, give Aquamephyton,
               intramuscularly:  adult dose, 5-10 mg; child's dose:  1-5 mg.
               Decide dose according to the degree of prothrombin time
               lengthening and, in children, the age and weight of the child.
           B.  Repeat prothrombin time in 24 hours.  If it has not decreased
               from the original value, repeat Aquamephyton dosage.
      4.   If victim shows SYMPTOMS or SIGNS of ANTICOAGULANT POISONING
           (bleeding) in addition to hypoprothrombinemia, administer
           Aquamephyton intramuscularly, up to 25 mg in the adult, and up to
           0.6 mg/kg in children under 12 years.  Phytonadione administration
           may be repeated in 24 hours if bleeding continues.
           A.  In cases of SEVERE BLEEDING, it may be necessary to give
               Aquamephyton intravenously.  This is especially true if the
               bleeding tendency is so severe that intramuscular injection is
               likely to cause hematoma formation.  Dosage is up to 25 mg in
               the adult, up to 0.6 mg/kg in children under 12 years.  Repeat
               this dose in 24 hours if bleeding continues.  Inject at rates
               not exceeding 5% of the total dose per minute.  INTRAVENOUS
               INFUSION of the Aquamephyton DILUTED IN SALINE OR GLUCOSE
               SOLUTION is recommended.  Bleeding is usually controlled in
               3-6 hours.
               CAUTION:   Adverse reactions, some fatal, have occurred from
                          INTRAVENOUS phytonadione injections, even when
                          recommended dosage limits and injection rates were
                          observed.  For this reason, the INTRAVENOUS route
                          should be used ONLY IN cases of SEVERE POISONING.
                          Flushing, dizziness, hypotension, dyspnea, and
                          cyanosis have characterized adverse reactions.
           B.  Antidotal therapy IN cases of SEVERE BLEEDING should be
               supplemented with TRANSFUSIONS of FRESH BLOOD or FRESH FROZEN
               PLASMA.  Use of fresh blood or plasma represents the most
               rapidly effective method of stopping hemorrhage due to these
               anticoagulants.
           C.  Determine PROTHROMBIN TIMES (and hemoglobin concentrations, if
               appropriate) every 6-12 hours to assess effectiveness of
               antihemorrhagic measures.
           D.  When normal blood coagulation is restored, it may be advisable
               to drain large hematomata.
           E.  Ferrous sulfate therapy may be appropriate in the recuperative
               period to rebuild lost erythrocyte mass (25).
                        VI.  FIRE AND EXPLOSION INFORMATION
           To be developed.
                                VII.  COMPATIBILITY
           To be developed.
                             VIII.  PROTECTIVE MEASURES
      STORAGE AND HANDLING:   Do not contaminate water, food or feed by
      storage or disposal.  Keep away from humans, domestic animals, and
      pets.  May be harmful or fatal if swallowed or absorbed through the
      skin because this material may reduce the clotting ability of the blood
      and cause bleeding.  Do not get in eyes, on skin, or on clothing.  Wash
      arms, hands, and face with soap and water after applying and before
      eating and smoking.  Exposure to Maki during pregnancy should be
      avoided (70c).
                        IX.  PROCEDURES FOR SPILLS AND LEAKS
                      IN CASE OF EMERGENCY, CALL, DAY OR NIGHT
                                   (800) 424-9300
                       PESTICIDE TEAM SAFETY NETWORK/CHEMTREC
                               X.  LITERATURE CITED
       8c. Thomson, W.T.  1980.  Agricultural chemicals - book III:
               fumigants, growth regulators, repellents, and rodenticides.
               1981 revised ed.  Thomson Publications, Fresno, CA.  182 pp.
      25.  Morgan, D.P.  1982.  Recognition and management of pesticide
               poisonings, 3rd ed.  U.S. Environmental Protection Agency,
               Washington, DC.  120 pp.
      56.  Farm Chemicals Handbook, 70th ed.  1984.  R. T. Meister, G. L.
               Berg, C. Sine, S. Meister, and J. Poplyk, eds.  Meister
               Publishing Co., Willoughby, OH.
      62.  The Pesticide Manual:  A World Compendium, 7th ed.  1983.  C.R.
               Worthing, ed.  The British Crop Protection Council, Croydon,
               England.  695 pp.
      70b. Chempar Chemical Co., Inc.  ?  Rodenticide technical bulletin:
               Maki (bromadiolone).  New York, NY.
      70c. Chempar Chemical Co., Inc.  ?  Specimen label:  Maki.  New
               York, NY.
      1/23/85