DIPHENADIONECASRN

DIPHENADIONE
CASRN: 82-66-6
For other data, click on the Table of Contents

Human Health Effects:

Human Toxicity Excerpts:

... CLINICAL SIDE EFFECTS OF INDANDIONES INCL AGRANULOCYTOSIS, PYREXIA, DIARRHEA, HEPATITIS, RENAL TUBULAR NECROSIS, EXFOLIATIVE DERMATITIS & PARALYSIS OF ACCOMMODATION. ... OCCASIONALLY LETHAL COMPLICATION ... INVOLVES ... . SKIN LESIONS CHARACTERIZED BY PETECHIA, ECCHYMOSES & HEMORRHAGIC INFARCTS WITH NECROSIS. /INDANDIONES/
[Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. III-396]**PEER REVIEWED**

HEMORRHAGE IS THE MAIN UNWANTED EFFECT CAUSED BY THERAPY WITH ORAL ANTICOAGULANTS. ... IN ORDER OF DECREASING FREQUENCY, COMPLICATIONS INCLUDE ... HEMATURIA, UTERINE BLEEDING, MELENA OR HEMATOCHEZIA, EPISTAXIS, HEMATOMA, GINGIVAL BLEEDING, HEMOPTYSIS, AND HEMATEMESIS. /ORAL ANTICOAGULANTS/
[Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. 1358]**PEER REVIEWED**

A 5 yr old boy ingested 3 to 4 tablets of diphenadione several days before admission. A lip laceration continued to bleed. On admission, his bleeding time, coagulation time, factor V assay, fibrinogen level, and platelet counts were normal. The prothrombin time and partial thromboplastin time were prolonged. Assays of factors VII, IX, and X showed greatly deceased levels. The euglobulin lysis time was somewhat increased. He was treated with fresh blood (250 ml), fresh plasma (250 ml), and vitamin K (10 mg im), with complete resolution of his hematuria, epistaxis, and other hemorrhagic manifestations.
[Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. 218]**PEER REVIEWED**

Drug Warnings:

THE ONLY SIDE EFFECTS /OF DIPHENADIONE/ REPORTED IN MAN ARE MILD GI DISORDERS.
[Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. 1359]**PEER REVIEWED**

HEMORRHAGE IS THE MAIN UNWANTED EFFECT CAUSED BY THERAPY WITH ORAL ANTICOAGULANTS. ANTICOAGULANT THERAPY MUST ALWAYS BE MONITORED BY DETERMINATION OF ONE-STAGE PROTHROMBIN TIMES, AND THE PATIENT MUST BE OBSERVED CAREFULLY FOR DEVELOPMENT OF BLEEDING. BLEEDING OFTEN OCCURS EVEN WHEN THE PROTHROMBIN TIME IS WITHIN THE EXPECTED THERAPEUTIC RANGE. ... IDENTIFIED FACTORS THAT INCREASE THE RISK OF HEMORRHAGIC COMPLICATIONS DURING LONG-TERM THERAPY INCLUDE POOR SUPERVISION OF THE PATIENT, USE OF THE DRUG DESPITE MEDICAL CONTRAINDICATIONS, POOR CONTROL OF THE DRUG IN RELATION TO LABORATORY VALUES, ADMINISTRATION OF LARGE LOADING DOSES, ADMINISTRATION OF THERAPY THAT IS TOO INTENSIVE FOR THE PATIENT, CONCOMITANT ADMINISTRATION OF INTERACTING DRUGS, OR THERAPY OF THE ELDERLY OR POST PARTUM PATIENT OR THOSE WITH DISORDERS OF THE GASTROINTESTINAL OR GENITOURINARY SYSTEMS. /ORAL ANTICOAGULANTS/
[Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. 1358]**PEER REVIEWED**

FACTORS ... INCR RISK OF HEMORRHAGE ... INCL VIT K DEFICIENCY, SCURVY, MALNUTRITION OR CACHEXIA, HEPATIC DYSFUNCTION ... RENAL IMPAIRMENT ... FEVER OR HYPERTHYROIDISM, INFECTIOUS DISEASE, CARCINOMA, COLLAGEN DISEASE, CONGESTIVE HEART FAILURE ... MENSTRUATION AND MENSTRUAL DISORDERS ... . /COUMARIN & INDANDIONE DERIV/
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 824]**PEER REVIEWED**

COUMARIN AND INDANDIONE DERIVATIVES ARE CONTRAINDICATED DURING PREGNANCY. ... NEONATES ARE PARTICULARLY SENSITIVE TO COUMARIN AND INDANDIONE DERIVATIVES AS A RESULT OF VITAMIN K DEFICIENCY. /COUMARIN & INDANDIONE DERIV/
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 822]**PEER REVIEWED**

HARMLESS ORANGE OR REDDISH DISCOLORATION OF URINE MAY BE OBSERVED IN PT TAKING DIPHENADIONE. PT SHOULD BE WARNED ABOUT THIS REACTION TO AVOID FALSE IMPRESSION OF HEMATURIA.
[American Medical Association, AMA Department of Drugs, AMA Drug Evaluations. 3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977. 123]**PEER REVIEWED**

DURING PREGNANCY A STATE OF DECREASED RESPONSIVENESS TO ORAL ANTICOAGULANTS RESULTS FROM INCREASED ACTIVITY OF FACTORS VII, VIII, IX, AND X. HOWEVER, THIS AFFECTS ONLY THE MOTHER, AND THE FETUS IS HIGHLY SUSCEPTIBLE TO ORAL ANTICOAGULANTS BECAUSE THESE DRUGS CROSS THE PLACENTA FREELY AND THE FETUS HAS A LIMITED CAPACITY TO SYNTHESIZE CLOTTING FACTORS. /ORAL ANTICOAGULANTS/
[Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. 1355]**PEER REVIEWED**

HEREDITARY RESISTANCE TO ORAL ANTICOAGULANTS, WHICH HAS BEEN OBSERVED IN TWO HUMAN KINDREDS AND IN RATS IN MANY GEOGRAPHIC LOCI, IS AN AUTOSOMAL DOMINANT TRAIT. THE METABOLISM OF THE DRUG IS NORMAL, BUT THE REQUIREMENT FOR VITAMIN K IS MARKEDLY INCREASED IN BOTH SPECIES. /ORAL ANTICOAGULANTS/
[Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. 1356]**PEER REVIEWED**

PARTICULARLY SERIOUS BLEEDING EPISODES IN PATIENTS WHO ARE CHRONICALLY RECEIVING EITHER HEPARIN OR ORAL ANTICOAGULANTS INCLUDE COMPRESSION NEUROPATHY FOLLOWING BRACHIAL ARTERY PUNCTURE FOR ARTERIOGRAPHIC OR BLOOD-GAS STUDIES, INTRAPERITONEAL HEMORRHAGE RESULTING FROM RUPTURE OF A CORPUS LUTEUM, RETROPERITONEAL HEMORRHAGE WITH COMPRESSION FEMORAL NEUROPATHY, HEMOPERICARDIUM EVEN IN THE ABSENCE OF MYOCARDIAL INFARCTION OR PERICARDITIS, INTRACRANIAL HEMORRHAGE, ADRENAL HEMORRHAGE, AND NECROSIS OF SKIN AND BREASTS. /ORAL ANTICOAGULANTS/
[Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. 1358]**PEER REVIEWED**

Populations at Special Risk:

Emergency Medical Treatment:

EMT Copyright Disclaimer:

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The following Overview, *** DIPHACINONE ***, is relevant for this HSDB record chemical.

Life Support:

  o   This overview assumes that basic life support measures
      have been instituted.

Clinical Effects:

  SUMMARY OF EXPOSURE
   0.2.1.1 ACUTE EXPOSURE
     o   Diphacinone is an indandione anticoagulant.  In massive
         overdose, these agents have produced rapid and
         persistent hypoprothrombinemia and associated bleeding
         diathesis.  Once coagulation defects occur, they may
         persist for weeks to months.  Daily exposures are
         likely to produce cumulative toxicity.  No chronic data
         were found for diphacinone in humans, however.  This
         review is based on the properties of coumarin and other
         long-acting anticoagulants.  In addition to the
         anticoagulant effects, indandiones have produced
         pulmonary edema and neurologic effects in animals.
  HEENT
   0.2.4.1 ACUTE EXPOSURE
     o   Epistaxis may be noted.
  RESPIRATORY
   0.2.6.1 ACUTE EXPOSURE
     o   Pulmonary edema has been produced by ingestion of
         diphacinone in dogs.
  NEUROLOGIC
   0.2.7.1 ACUTE EXPOSURE
     o   Neurologic damage has been seen in experimental
         animals.
  GASTROINTESTINAL
   0.2.8.1 ACUTE EXPOSURE
     o   Spontaneous emesis and bloody stools may occur.
   0.2.8.2 CHRONIC EXPOSURE
     o   Mild gastrointestinal upset has been reported with
         therapeutic doses.
  GENITOURINARY
   0.2.10.2 CHRONIC EXPOSURE
     o   A harmless red or orange discoloration of the urine may
         occur with therapeutic doses.  Hematuria and renal
         tubular necrosis may also be noted.
  HEMATOLOGIC
   0.2.13.1 ACUTE EXPOSURE
     o   Hemorrhage is the most common toxic sign and may be
         manifested by epistaxis, gum bleeding, hemoptysis,
         hematuria, GI bleeding, ecchymosis, bloody or melenotic
         stools, bruising, abdominal and flank pain.  Lengthened
         prothrombin time may be evident within 24 hours and
         maximal in 36 to 72 hours.  In overdose PT prolongation
         and clinical bleeding have persisted for 45 days to 8
         months.
   0.2.13.2 CHRONIC EXPOSURE
     o   The hemorrhagic effects are generally cumulative with
         repeated exposure.
  DERMATOLOGIC
   0.2.14.1 ACUTE EXPOSURE
     o   Ecchymoses and hematomas occur due to reduced clotting
         capacity.
  PSYCHIATRIC
   0.2.18.1 ACUTE EXPOSURE
     o   Lethargy was one of the early signs of diphacinone
         intoxication in dogs.
  IMMUNOLOGIC
   0.2.19.2 CHRONIC EXPOSURE
     o   Coumarin may be a mild allergen.
  REPRODUCTIVE HAZARDS
    o   At the time of this review, no data were available to
        assess the reproductive hazards specific to diphacinone.
    o   HUMAN TERATOGEN - Some coumarin anticoagulants,
        primarily WARFARIN, have been linked with human birth
        defects.  Characteristic skeletal defects, called FETAL
        WARFARIN SYNDROME, arise when exposure is during the
        first trimester (Schardein, 1985).
    o   The indandiones are excreted in breast milk.
  CARCINOGENICITY
   0.2.21.2 HUMAN OVERVIEW
     o   At the time of this review, no data were available to
         assess the carcinogenic potential of this agent.
  GENOTOXICITY
    o   At the time of this review, no data were available to
        assess the mutagenic or genotoxic potential of this
        agent.

Laboratory:

  o   Monitor prothrombin time (PT) or INR and PTT.  Obtain PT
      or INR at 24 and 48 hours postingestion.  If any
      prolongation is observed, repeat PT or INR every 6 to 12
      hours.
  o   Factor assays (II, VII, IX, X) may be abnormal in patients
      with a normal PT, INR and PTT.  Vitamin K therapy should
      not be discontinued until factor assays are normal.

Treatment Overview:

  ORAL EXPOSURE
    o   Emesis is contraindicated in patients with a prolonged
        PT or INR due to the risk of bleeding following
        ipecac-induced increased intracranial pressure.  Ipecac
        may be indicated in the home setting for pediatric
        patients with an accurate history of recent one-time
        acute ingestion of these rodenticides.
     1.  EMESIS:  Use is controversial.  May be indicated in the
         prehospital setting if administered soon (within 30
         minutes) after substantial ingestion.
         CONTRAINDICATIONS:  loss of airway protective reflexes;
         CNS depression; seizures; ingestion of a substance that
         might impair airway protective reflexes or require
         advanced life support within 60 minutes; ingestion of a
         corrosive substance or hydrocarbon with high aspiration
         potential; debilitated patient.  (Dose of Ipecac Syrup:
         ADULT:  15 - 30 mL; CHILD 1 to 12 years:  15 mL; CHILD
         6 to 12 months of age:  5 - 10 mL; CHILD under 6 months
         of age:  Not recommended for prehospital use.).
    o   GASTRIC LAVAGE:  Consider after ingestion of a
        potentially life-threatening amount of poison if it can
        be performed soon after ingestion (generally within 1
        hour).  Protect airway by placement in Trendelenburg and
        left lateral decubitus position or by endotracheal
        intubation.  Control any seizures first.
     1.  CONTRAINDICATIONS:  Loss of airway protective reflexes
         or decreased level of consciousness in unintubated
         patients; following ingestion of corrosives;
         hydrocarbons (high aspiration potential); patients at
         risk of hemorrhage or gastrointestinal perforation; and
         trivial or non-toxic ingestion.
    o   ACTIVATED CHARCOAL/CATHARTIC:  Administer charcoal
        slurry, aqueous or mixed with saline cathartic or
        sorbitol.  The FDA suggests 240 mL of diluent/30 g of
        charcoal.  Usual charcoal dose is 25 to 100 grams in
        adults and adolescents, 25 to 50 grams in children (1 to
        12 years old), and 1 gram/kilogram in infants less than
        1 year old.
     1.  Routine use of cathartics is NOT recommended.  If used,
         administer only ONE dose of cathartic.  Administer one
         dose of a cathartic, mixed with charcoal or given
         separately.  See "Treatment:  Prevention of Absorption"
         in the main document.
    o   PULMONARY EDEMA (NONCARDIOGENIC):  Maintain ventilation
        and oxygenation and evaluate with frequent arterial
        blood gas or pulse oximetry monitoring.  Early use of
        PEEP and mechanical ventilation may be needed.
    o   FOR PATIENT PRESENTLY ON ANTICOAGULANT THERAPY - Careful
        gastric lavage followed by frequent analysis of gastric
        return for blood is permissible, when the physician
        keeps in mind that GI hemorrhage is a possibility.
    o   VITAMIN K1 (PHYTONADIONE) - is a specific antidote and
        should be administered to any patient with a prolonged
        PT or INR.  Menadione (vitamin K3) should NOT be used.
        Oral therapy may be indicated in small ingestions or
        when the amount is uncertain.  Administer 15 to 25 mg in
        adult and 5 to 10 mg in children.  Daily maintenance
        doses of 100 to 125 mg/day may be required for 1.5 to 8
        months.  IV injection is preferable in severe cases
        where rapid correction is required.  DOSE - ADULTS - 10
        mg IV diluted in saline or glucose at a rate not
        exceeding 5% of the total dose/min.  IM injection may be
        indicated in mild ingestions where the risk of hematoma
        is low, DOSE - ADULT - 5 to 10 mg.  CHILD - 1 to 5 mg.
    o   There is no specific therapeutic maneuver other than
        restoration of PT or INR to normal if toxicity occurs.
        Exchange transfusion, fresh whole blood or plasma may be
        considered.  Fresh blood or plasma is the most rapid
        effective method of stopping hemorrhage.
    o   PATIENTS PRESENTLY ON ANTICOAGULANT THERAPY - Get PT or
        INR immediately.  If patient is anticoagulated for
        prosthetic valve or other procedure requiring absolute
        anticoagulation, do not give vitamin K unless
        anticoagulation is excessive.  Give a small IV dose (1
        to 5 mg and titrate to return PT or INR to therapeutic).
        Substitution of heparin as an anticoagulant may be
        necessary until PT or INR is therapeutic.
    o   NOTE - See treatment of oral exposure in the main body
        of this document for complete information.
  INHALATION EXPOSURE
    o   INHALATION:  Move patient to fresh air.  Monitor for
        respiratory distress.  If cough or difficulty breathing
        develops, evaluate for respiratory tract irritation,
        bronchitis, or pneumonitis.  Administer oxygen and
        assist ventilation as required.  Treat bronchospasm with
        beta2  agonist and corticosteroid aerosols.
    o   PULMONARY EDEMA (NONCARDIOGENIC):  Maintain ventilation
        and oxygenation and evaluate with frequent arterial
        blood gas or pulse oximetry monitoring.  Early use of
        PEEP and mechanical ventilation may be needed.
    o   FOR PATIENT PRESENTLY ON ANTICOAGULANT THERAPY - Careful
        gastric lavage followed by frequent analysis of gastric
        return for blood is permissible, when the physician
        keeps in mind that GI hemorrhage is a possibility.
    o   VITAMIN K1 (PHYTONADIONE) - Is a specific antidote and
        should be administered to any patient with a prolonged
        PT or INR.  Menadione (vitamin K3) should NOT be used.
        Oral therapy may be indicated in small ingestions or
        when the amount is uncertain.  Administer 15 to 25 mg in
        adult and 5 to 10 mg in children.  Daily maintenance
        doses of 100 to 125 mg/day may be required for 1.5 to 8
        months.  IV injection is preferable in severe cases
        where rapid correction is required.  DOSE - ADULTS - 10
        mg IV diluted in saline or glucose at a rate not
        exceeding 5% of the total dose/min.  IM injection may be
        indicated in mild ingestions where the risk of hematoma
        is low, DOSE - ADULT - 5 to 10 mg.  CHILD - 1 to 5 mg.
    o   There is no specific therapeutic maneuver other than
        restoration of PT or INR to normal if toxicity occurs.
        Exchange transfusion, fresh whole blood or plasma may be
        considered.  Fresh blood or plasma is the most rapid
        effective method of stopping hemorrhage.
    o   PATIENTS PRESENTLY ON ANTICOAGULANT THERAPY - Get PT or
        INR immediately.  If patient is anticoagulated for
        prosthetic valve or other procedure requiring absolute
        anticoagulation, do not give vitamin K unless
        anticoagulation is excessive.  Give a small IV dose (1
        to 5 mg and titrate to return PT or INR to therapeutic).
        Substitution of heparin as an anticoagulant may be
        necessary until PT or INR is therapeutic.
    o   NOTE - See treatment of inhalation exposure in the main
        body of this document for complete information.
  EYE EXPOSURE
    o   DECONTAMINATION:  Irrigate exposed eyes with copious
        amounts of tepid water for at least 15 minutes.  If
        irritation, pain, swelling, lacrimation, or photophobia
        persist, the patient should be seen in a health care
        facility.
    o   Follow treatment recommendations in the DERMAL EXPOSURE
        section where appropriate.
  DERMAL EXPOSURE
    o   DECONTAMINATION:  Remove contaminated clothing and wash
        exposed  area thoroughly with soap and water.  A
        physician may need to  examine the area if irritation or
        pain persists.
    o   PULMONARY EDEMA (NONCARDIOGENIC):  Maintain ventilation
        and oxygenation and evaluate with frequent arterial
        blood gas or pulse oximetry monitoring.  Early use of
        PEEP and mechanical ventilation may be needed.
    o   FOR PATIENT PRESENTLY ON ANTICOAGULANT THERAPY - Careful
        gastric lavage followed by frequent analysis of gastric
        return for blood is permissible, when the physician
        keeps in mind that GI hemorrhage is a possibility.
    o   VITAMIN K1 (PHYTONADIONE) - is a specific antidote and
        should be administered to any patient with a prolonged
        PT or INR.  Menadione (vitamin K3) should NOT be used.
        Oral therapy may be indicated in small ingestions or
        when the amount is uncertain.  Administer 15 to 25 mg in
        adult and 5 to 10 mg in children.  Daily maintenance
        doses of 100 to 125 mg/day may be required for 1.5 to 8
        months.  IV injection is preferable in severe cases
        where rapid correction is required.  DOSE - ADULTS 10 mg
        IV diluted in saline or glucose at a rate not exceeding
        5% of the total dose/min.  IM injection may be indicated
        in mild ingestions where the risk of hematoma is low,
        DOSE - ADULT - 5 to 10 mg.  CHILD - 1 to 5 mg.
    o   There is no specific therapeutic maneuver other than
        restoration of PT or INR to normal if toxicity occurs.
        Exchange transfusion, fresh whole blood or plasma may be
        considered.  Fresh blood or plasma is the most rapid
        effective method of stopping hemorrhage.
    o   PATIENTS PRESENTLY ON ANTICOAGULANT THERAPY - Get PT or
        INR immediately.  If patient is anticoagulated for
        prosthetic valve or other procedure requiring absolute
        anticoagulation, do not give vitamin K unless
        anticoagulation is excessive.  Give a small IV dose (1
        to 5 mg and titrate to return PT or INR to therapeutic).
        Substitution of heparin as an anticoagulant may be
        necessary until PT or INR is therapeutic.
    o   NOTE - See treatment of dermal exposure in the main body
        of this document for complete information.

Range of Toxicity:

  o   Minimum lethal dose and effective dose have not been
      determined for humans.  Actual minimum lethal dose would
      depend on the aggressiveness of medical treatment.

[Rumack BH: POISINDEX(R) Information System. Micromedex, Inc., Englewood, CO, 2001; CCIS Volume 110, edition exp November, 2001. Hall AH & Rumack BH (Eds):TOMES(R) Information System. Micromedex, Inc., Englewood, CO, 2001; CCIS Volume 110, edition exp November, 2001.] **PEER REVIEWED**

Animal Toxicity Studies:

Non-Human Toxicity Excerpts:

TISSUE RESIDUES IN NUTRIA KILLED WITH DRUG PROVED TOXIC WHEN THEIR MEAT WAS FED TO MINK.
[Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 184]**PEER REVIEWED**

MULTIPLE DOSE TOXICITY ... /OF DIPHENADIONE/ INVOLVES SAME HEMORRHAGIC PHENOMENAAS WITH HYDROXYCOUMARINS. MASSIVE SINGLE ORAL DOSES /100-200 MG/KG/ ... KILLED RATS & RABBITS WITHIN 2-12 HR. IN ... ACUTE EXPOSURES HEMORRHAGES WERE NOT USUALLY FOUND ON POSTMORTEM EXAM, & PROTHROMBIN LEVELS WERE NOT INVARIABLY DEPRESSED.
[Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. III-396]**PEER REVIEWED**

ANIMALS RECEIVING ... SINGLE LETHAL DOSES OF SUBSTITUTED INDANDIONES /DIPHENADIONE/ (100-200 MG/KG) EXHIBITED LABORED BREATHING, PROGRESSIVE MUSCULAR WEAKNESS, HYPEREXCITABILITY, PULMONARY CONGESTION, VENOUS ENGORGEMENT, & CARDIAC STANDSTILL IN SYSTOLE.
[Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. III-396]**PEER REVIEWED**

CLINICAL SIGNS RELATE TO MASSIVE HEMORRHAGE ... VISIBLE HEMATOMAS UNDER SKIN ...PURPURA ... WEAKNESS, & SIGNS OF SHOCK. DEATH MAY OCCUR UNOBSERVED. ABORTION MAY OCCUR IN CATTLE. /WARFARIN & CONGENERS/
[Jones, L.M., et al. Veterinary Pharmacology & Therapeutics. 4th ed. Ames: Iowa State University Press, 1977. 1155]**PEER REVIEWED**

ANTICOAGULANT RODENTICIDES ARE MOST TOXIC WHEN INGESTED DAILY OVER PERIOD OF 5-7 DAYS. SINGLE-DOSE TOXICITY MAY BE 5-100 TIMES THE MULTIPLE-DOSE TOXICITY, DEPENDING ON SPECIES. /WARFARIN & CONGENERS/
[Jones, L.M., et al. Veterinary Pharmacology & Therapeutics. 4th ed. Ames: Iowa State University Press, 1977. 1153]**PEER REVIEWED**

RATS WERE FED DIETS CONTAINING 0.0313-0.5 PPM DIPHACINONE FOR 90 DAYS OR 0.125-4.0 PPM FOR 21 DAYS. IN THE 90 DAY TEST, ONLY 2 OF 72 RATS DIED, AND SURVIVORS SHOWED LITTLE CHANGE IN PROTHROMBIN CLOTTING TIME AND BLOOD CHEMISTRY VALUES. THE FIBRINOGEN LEVELS WERE DECREASED IN RATS FED 0.5 PPM. IN 21 DAY STUDY, ALL RATS FED 2 AND 4 PPM DIED. IN SURVIVORS FED LOWER DOSES, PROTHROMBIN TIMES WERE NOT AFFECTED.
[ELIAS DJ, JOHNS BE; BULL ENVIRON CONTAM TOXICOL 27 (4): 559 (1981)]**PEER REVIEWED**

RATS OR MICE WERE KILLED WITH DIPHENADIONE AND FED TO OWLS. OWLS DIED OF HEMORRHAGING AFTER FEEDING ON THE RATS.
[MENDENHALL VM, PANK LF; WILDL SOC BULL 311: (1980)]**PEER REVIEWED**

AGAINST MICE, 60-100% MORTALITIES WERE OBTAINED AFTER THE SUCCESSIVE ADMINISTRATIONS OF DIPHACINONE BAITS RANGING FROM 0.0005-0.02% FOR 6 DAYS.
[KUSANO T; JPN J SANIT ZOOL 24 (3): 207 (1974)]**PEER REVIEWED**

DIPHACINONE WAS STUDIED BY ACUTE ORAL TOXICITY TESTS WITH CAPTIVE AND FREE-RANGING COYOTES. THE LD50 WITH 95% CONFIDENCE LIMITS IN CAPTIVE COYOTES WAS 0.6 (0.3-1.2) MG/KG. TIME TO DEATH DID NOT DIFFER FOR THE TWO GROUPS. THERE IS A SECONDARY HAZARD TO SUSCEPTIBLE ANIMALS THAT FEED REPEATEDLY ON TISSUE CONTAINING AT LEAST 0.5 PPM DIPHENADIONE. SEVEN GOLDEN EAGLES AND RATS WERE FED SHEEP MEAT CONTAINING 2.7 PPM DIPHENADIONE AS THE SOLE SOURCE OF FOOD FOR 5 AND 10 DAYS. ALL EAGLES SURVIVED, BUT VARIOUS DEGREES OF TOXICITY WERE NOTED, AND SOME RATS DIED.
[SAVARIE PJ ET AL; AVIAN MAMM WILDL TOXICOL: 69 (1979)]**PEER REVIEWED**

DIPHENADIONE (1 MG/KG, INTO RUMEN) CAUSED 3-FOLD INCR IN CLOTTING TIMES FOR CALVES RELATIVE TO ADULTS. CASES OF POISONING INDICATE THAT TREATMENT OF YOUNG CALVES INVOLVES HIGH DEGREE OF RISK.
[ELIAS DJ ET AL; BULL ENVIRON CONTAM TOXICOL 20 (1): 71 (1978)]**PEER REVIEWED**

Non-irritating to skin and eyes. Non-sensitizing to skin (guinea pigs). Non-mutagenic in the Ames test.
[Hartley, D. and H. Kidd (eds.). The Agrochemicals Handbook. 2nd ed. Lechworth, Herts, England: The Royal Society of Chemistry, 1987.,p. A164/Aug 87]**PEER REVIEWED**

RATS FED LIVER FROM TEST CATTLE GIVEN SINGLE 1 MG/KG INJECTIONS IN 14-DAY SECONDARY FEEDING STUDY. NO RATS DIED, DRUG WAS NOT DETECTED IN LIVER OR BLOOD OF TREATED RATS. RESIDUE LEVELS INDICATE THAT HUMANS MAY SAFELY EAT MEAT OF TREATED CATTLE.
[BULLARD RW ET AL; J AGRIC FOOD CHEM 24 (2): 261 (1976)]**PEER REVIEWED**

Non-Human Toxicity Values:

LD50 Rat oral 3-17 mg/kg
[Humphreys, D.J. Veterinary Toxicology. 3rd ed. London, England: Bailliere Tindell, 1988. 175]**PEER REVIEWED**

LD50 Mouse oral 340 mg/kg
[Humphreys, D.J. Veterinary Toxicology. 3rd ed. London, England: Bailliere Tindell, 1988. 175]**PEER REVIEWED**

LD50 Rabbit oral 35 mg/kg
[Humphreys, D.J. Veterinary Toxicology. 3rd ed. London, England: Bailliere Tindell, 1988. 175]**PEER REVIEWED**

LD50 Rat percutaneous <200 mg/kg
[Worthing, C.R. and S.B. Walker (eds.). The Pesticide Manual - A World Compendium. 8th ed. Thornton Heath, UK: The British Crop Protection Council, 1987. 313]**PEER REVIEWED**

LC50 Rat inhalation <2 mg/l/4 hr, following exposure to dust
[Worthing, C.R. and S.B. Walker (eds.). The Pesticide Manual - A World Compendium. 8th ed. Thornton Heath, UK: The British Crop Protection Council, 1987. 313]**PEER REVIEWED**

LD50 Cat oral 14.7 mg/kg
[Hartley, D. and H. Kidd (eds.). The Agrochemicals Handbook. 2nd ed. Lechworth, Herts, England: The Royal Society of Chemistry, 1987.,p. A164/Aug 87]**PEER REVIEWED**

Ecotoxicity Values:

LD50 Anas platyrhynchos (Mallard duck) oral 3158 mg/kg
[Worthing, C.R. and S.B. Walker (eds.). The Pesticide Manual - A World Compendium. 8th ed. Thornton Heath, UK: The British Crop Protection Council, 1987. 313]**PEER REVIEWED**

LC50 Lepomis macrochirus (Bluegill) 7.6 mg/l/96 hr /Conditions of bioassay not specified/
[Worthing, C.R. and S.B. Walker (eds.). The Pesticide Manual - A World Compendium. 8th ed. Thornton Heath, UK: The British Crop Protection Council, 1987. 313]**PEER REVIEWED**

LC50 Salmo gairdneri (Rainbow trout) 2.8 mg/l/96 hr /Conditions of bioassay not specified/
[Worthing, C.R. and S.B. Walker (eds.). The Pesticide Manual - A World Compendium. 8th ed. Thornton Heath, UK: The British Crop Protection Council, 1987. 313]**PEER REVIEWED**

LC50 Ictaluras punctatus (Channel catfish) 2.1 mg/l/96 hr /Conditions of bioassay not specified/
[Worthing, C.R. and S.B. Walker (eds.). The Pesticide Manual - A World Compendium. 8th ed. Thornton Heath, UK: The British Crop Protection Council, 1987. 313]**PEER REVIEWED**

Metabolism/Pharmacokinetics:

Metabolism/Metabolites:

Coumarin and indandione derivatives are hydroxylated by hepatic microsomal enzymes to inactive metabolites. ... Individual patients vary greatly in the rate at which they metabolize a specific coumarin or indandione derivative. /Coumarin & indandione derivatives/
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 822]**PEER REVIEWED**

(14)C LABELED DIPHACINONE (O.2-1.5 MG/KG) WAS ADMINISTERED ORALLY TO RATS AND MICE. IN ADDITION TO UNCHANGED DIPHACINONE, 4-HYDROXYLATED METABOLITES WERE IDENTIFIED IN FECES AND LIVER. HYDROXYLATION OCCURRED ON EITHER OR BOTH THE INDANDIONE OR PHENYL RINGS. THE POSITIONS OF THE HYDROXY GROUPS ON THE RINGS WERE NOT ESTABLISHED.
[YU CC ET AL; DRUG METAB DISPOS 10 (6): 645 (1982)]**PEER REVIEWED**

Absorption, Distribution & Excretion:

Individuals differ in the rate at which they absorb oral coumarin and indandione derivatives. ... /They/ are usually detectable in plasma within 1 hr following oral admininstration, and peak plasma concentrations of the drugs are usually attained within 1-12 hr, depending on the drug administered. /Coumarin & indandione deriv/
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 822]**PEER REVIEWED**

COUMARIN AND INDANDIONE DERIV ARE 97% OR MORE BOUND TO PLASMA PROTEINS. ... UPTAKE ... BY ERYTHROCYTES IS VARIABLE. DRUGS ARE DISTRIBUTED TO LIVER, LUNGS, SPLEEN, & KIDNEYS. /COUMARIN & INDANDIONE DERIV/
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 822]**PEER REVIEWED**

Coumarin and indandione derivatives cross the placenta, and fetal plasma drug concentrations may be equal to maternal plasma concentrations. /Coumarin & indandione deriv/
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 822]**PEER REVIEWED**

In general, coumarin and indandione derivatives are excreted in bile as inactivemetabolites, are reabsorbed, and excreted in urine. /Coumarin & indandione derivatives/
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 822]**PEER REVIEWED**

WHEN (14)C LABELED DIPHACINONE WAS ADMINISTERED ORALLY TO MICE, RADIOACTIVITY REACHED ITS HIGHEST LEVELS IN THE LIVER AND LUNGS. THE CONCENTRATION IN THE LIVER REACHED ITS MAXIMUM IN 7.5 AND 3 HOURS IN MALES AND FEMALES, RESPECTIVELY.
[Hayes, Wayland J., Jr. Pesticides Studied in Man. Baltimore/London: Williams and Wilkins, 1982. 513]**PEER REVIEWED**

BLOOD & TISSUE OF CATTLE WERE TESTED FOR RESIDUES. HEIFERS GIVEN SINGLE 1 MG/KG INJECTIONS, DETECTABLE LEVELS COULD NOT BE FOUND IN BLOOD, BRAIN, HEART, FAT, & MUSCLE TISSUE @ 30, 60, 90 DAYS POST TREATMENT.
[BULLARD RW ET AL; J AGRIC FOOD CHEM 24 (2): 261 (1976)]**PEER REVIEWED**

EXAMINATION OF THE BLOOD AND TISSUES OF TREATED CATTLE FOR RESIDUES OF DIPHENADIONE REVEALED THAT VERY SMALL CONCENTRATIONS (LESS THAN 0.15 UG/G) PERSISTED IN THE LIVER AND KIDNEY UP TO 90 DAYS POST TREATMENT ... .
[The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 5: A Review of the Literature Published during 1976 and 1977. London: The Chemical Society, 1979. 436]**PEER REVIEWED**

(14)C LABELED DIPHACINONE (O.2-1.5 MG/KG) WAS ADMINISTERED ORALLY TO RATS AND MICE. MORE THAN 60% WAS ELIMINATED IN FECES AND ABOUT 10% IN URINE IN 4 DAYS FROM MICE AND IN 8 DAYS FROM RATS. THE MOST RADIOACTIVITY APPEARED IN LIVER. IN ADDITION TO UNCHANGED DIPHACINONE, 4-HYDROXYLATED METABOLITES WERE IDENTIFIED IN FECES AND LIVER.
[YU CC ET AL; DRUG METAB DISPOS 10 (6): 645 (1982)]**PEER REVIEWED**

Biological Half-Life:

IT HAS A HALF-LIFE IN MAN OF 2-3 WEEKS.
[Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. 1359]**PEER REVIEWED**

Mechanism of Action:

THE ORAL ANTICOAGULANTS ARE ANTAGONISTS OF VITAMIN K. THEIR ADMINISTRATION TO MAN OR ANIMALS LEADS TO THE APPEARANCE OF PRECURSORS OF THE FOUR VITAMIN K-DEPENDENT CLOTTING FACTORS IN PLASMA AND LIVER. THESE PRECURSOR PROTEINS ARE ANTIGENICALLY ACTIVE BUT ARE BIOLOGICALLY INACTIVE IN TESTS OF COAGULATION. THE PRECURSOR PROTEIN TO PROTHROMBIN CAN BE ACTIVATED TO THROMBIN NONPHYSIOLOGICALLY BY SEVERAL SNAKE VENOMS, DEMONSTRATING THAT THE PORTION OF THE MOLECULE NECESSARY FOR THIS ACTIVITY IS INTACT. HOWEVER, THE PRECURSOR PROTEINS CANNOT BIND DIVALENT CATIONS SUCH AS CALCIUM, AND THEY CANNOT INTERACT WITH PHOSPHOLIPID-CONTAINING MEMBRANES, WHICH ARE THEIR NORMAL SITES OF ACTIVATION. THE VITAMIN K-SENSITIVE STEP IN THE SYNTHESIS OF CLOTTING FACTORS IS THE POSTRIBOSOMAL CARBOXYLATION OF TEN OR MORE GLUTAMIC ACID RESIDUES AT THE AMINO-TERMINAL END OF THE PRECURSOR PROTEIN TO FORM A UNIQUE AMINO ACID, GAMMA-CARBOXYGLUTAMATE. THESE AMINO ACID RESIDUES CHELATE CALCIUM, WHICH IS APPARENTLY NECESSARY FOR THE BINDING OF THE FOUR VITAMIN K-DEPENDENT CLOTTING FACTORS TO PHOSPHOLIPID-CONTAINING MEMBRANES.
[Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. 1354]**PEER REVIEWED**

DIPHENADIONE DELAYED INHIBITION OF PROTHROMBIN SYNTHESIS, CORRELATED WITH DELAYED INHIBITION OF VIT K1 2,3-EPOXIDE IN VIVO. RESULTS PROVIDE EVIDENCE FOR PROPOSED MECHANISM OF ACTION BY PREVENTING REGENERATION OF VIT K1 FROM ITS METABOLITE VIT K1 2,3-EPOXIDE.
[REN P ET AL; J PHARMACOL EXP THER 201 (3): 541 (1977)]**PEER REVIEWED**

Interactions:

DRUGS MOST COMMONLY TAKEN THAT INTERACT WITH ORAL ANTICOAGULANTS ARE BARBITURATES, SALICYLATES, AND PHENYLBUTAZONE. ... DRUGS THAT INCREASE THE RESPONSE TO ORAL ANTICOAGULANTS /INCLUDE/ ... ACETYLSALICYLIC ACID. ... EVEN ONE 325 MG TABLET OF ASPIRIN CAN REDUCE THE RELEASE OF ADENOSINEDIPHOSPHATE BY PLATELETS AND THEREBY IMPAIR THEIR AGGREGATION. ... PHENYLBUTAZONE AND OXYPHENBUTAZONE CAN CAUSE SEVERE HEMORRHAGE DURING ANTICOAGULANT THERAPY BY IMPAIRMENT OF PLATELET AGGREGATION, INDUCTION OF PEPTIC ULCERATION, AND AUGMENTATION OF HYPOPROTHROMBINEMIA. ... SULFONAMIDES AND OTHER ANTIMICROBIAL AGENTS HAVE LITTLE EFFECT ON ANTICOAGULANT THERAPY UNLESS BOTH INTESTINAL AND DIETARY SOURCES OF VITAMIN K ARE REDUCED SIMULTANEOUSLY. CIMETIDINE PROLONGS THE PROTHROMBIN TIME BY AN UNKNOWN MECHANISM; THIS HAS ALSO BEEN REPORTED FOR SULFINPYRAZONE. /ORAL ANTICOAGULANTS/
[Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. 1356]**PEER REVIEWED**

INCREASED RESPONSIVENESS TO ORAL ANTICOAGULANTS OCCURS WITH OTHER HYPOLIPIDEMIC DRUGS, SUCH AS D-THYROXINE, AND ALSO WITH ANABOLIC STEROIDS. ... DRUGS THAT DECREASE THE RESPONSE TO ORAL ANTICOAGULANTS/:/ INDUCTION OF HEPATIC MICROSOMAL ENZYMES BY BARBITURATES INCREASES THE CLEARANCE OF ORAL ANTICOAGULANTS, WHICH CORRELATES WITH A DECREASE IN THE DEGREE OF HYPOPROTHROMBINEMIA. GLUTETHIMIDE HAS SIMILAR EFFECTS. ... RIFAMPIN MARKEDLY REDUCES BOTH THE CONCENTRATIONS OF DRUG IN THE BLOOD AND THE HYPOPROTHROMBINEMIA PRODUCED BY ORAL ANTICOAGULANTS. DIURETICS EITHER HAVE NO EFFECT OR DECREASE THE RESPONSE TO ORAL ANTICOAGULANTS. THE LATTER EFFECT MAY BE DUE TO CONCENTRATION OF CLOTTING FACTORS IN PLASMA SUBSEQUENT TO DIURESIS, AS REPORTED FOR CHLORTHALIDONE AND SPIRONOLACTONE. CHOLESTYRAMINE REDUCES THE HYPOPROTHROMBINEMIA AND ENHANCES THE PLASMA CLEARANCE OF ORAL ANTICOAGULANTS BY INCREASING THE ELIMINATION OF UNCHANGED DRUG IN THE STOOL. ... VITAMIN C IN MASSIVE DOSES REDUCES THE HYPOPROTHROMBINEMIC RESPONSE OF SOME PATIENTS ON LONG-TERM THERAPY WITH ORAL ANTICOAGULANTS. /ORAL ANTICOAGULANTS/
[Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. 1357]**PEER REVIEWED**

DIPHENADIONE DECREASED THE BINDING OF THE SULFONYLUREAS ACETOHEXAMIDE, CHLORPROPAMIDE, AND TOLBUTAMIDE TO HUMAN SERUM ALBUMIN IN VITRO.
[JUDIS J; J PHARM SCI 62 (2): 232 (1973)]**PEER REVIEWED**

THE ANTICOAGULANT EFFECT OF PHENINDIONE IN RATS WAS INFLUENCED BY THE MONOAMINE OXIDASE INHIBITORS PHENYLCYCLOPROPYLAMINE-HYDROCHLORIDE, ISOCARBOXAZIDE, IPRONIAZID, NIALAMIDE, 1-P-CHLOROBENZOYL-2-(ALPHA-METHYL-BETA-N-ISOPROPYLCARBAMYL ETHYLISOPROPYL)HYDRAZINE, AND AMITRIPTYLINE.
[REBER K, STUDER A; THROMB DIATH HAEMORRH 14 (1-2): 83 (1965)]**PEER REVIEWED**

Pharmacology:

Therapeutic Uses:

Anticoagulants; Rodenticides
[National Library of Medicine's Medical Subject Headings online file (MeSH, 1999)]**QC REVIEWED**

DIPHENADIONE, USP (DIPAXIN), IS ... AN /ANTICOAGULANT/ INDANDIONE DERIVATIVE, AND, ALTHOUGH IT IS MUCH LESS TOXIC THAN PHENINDIONE, ITS USE HAS BEEN LIMITED. IT HAS A HALF-LIFE IN MAN OF 2-3 WEEKS, AND ITS DURATION OF ACTION IS THUS VERY LONG. ...
[Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. 1359]**PEER REVIEWED**

THE ANTICOAGULANT MODEL FOR PREVENTION OF THROMBOEMBOLIC DISEASE SUGGESTS THAT SLOWING THE RATE OF FORMATION OF FIBRIN SHOULD HAVE THERAPEUTIC EFFICACY. BECAUSE FIBRIN THROMBI OCCUR PRIMARILY IN THE VENOUS SYSTEM, ANTICOAGULANT DRUGS ARE USED IN THE PROPHYLAXIS OF VENOUS THROMBOSIS. ... ORAL ANTICOAGULANTS HAVE BEEN USED AS SECONDARY PROPHYLAXIS TO PREVENT THE EXTENSION OF RECURRENCE OF VENOUS THROMBI, THROMBOPHLEBITIS, OR PULMONARY EMBOLI. /ORAL ANTICOAGULANTS/
[Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. 1362]**PEER REVIEWED**

MEDICATION (VET): ANTICOAGULANT, ATHEROSCLEROTIC
[Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 184]**QC REVIEWED**

Drug Warnings:

Interactions:

Environmental Fate & Exposure:

Environmental Standards & Regulations:

FIFRA Requirements:

As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA, as amended in 1988, were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. 2-Diphacinone, and salts is found on List B. Case No: 2205; Pesticide type: Rodenticide; Case Status: RED Approved 09/97; OPP has made a decision that some/all uses of the pesticide are eligible for reregistration, as reflected in a Reregistration Eligibility Decision (RED) document.; Active ingredient (AI): 2-Diphacinone, and salts; Data Call-in (DCI) Date(s): 06/06/91, 10/13/95; AI Status: OPP has completed a Reregistration Eligibility Decision (RED) document for the case/AI.
[USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.176 (Spring, 1998) EPA 738-R-98-002]**QC REVIEWED**

CERCLA Reportable Quantities:

Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. Diphacinone is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 10/10,000 lbs.
[40 CFR 355 (7/1/97)]**QC REVIEWED**

FDA Requirements:

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).
[21 CFR 200-299, 300-499, 820, and 860 (4/1/93)]**PEER REVIEWED**

Chemical/Physical Properties:

Molecular Formula:

C23-H16-O3
[Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 522]**PEER REVIEWED**

Molecular Weight:

340.36
[Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 522]**PEER REVIEWED**

Color/Form:

PALE YELLOW CRYSTALS FROM ETHANOL
[Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 523]**PEER REVIEWED**

Crystalline powder
[Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 427]**PEER REVIEWED**

Odor:

ODORLESS
[Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 764]**PEER REVIEWED**

Melting Point:

146-147 DEG C
[Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 523]**PEER REVIEWED**

Corrosivity:

NON-CORROSIVE
[Hartley, D. and H. Kidd (eds.). The Agrochemicals Handbook. 2nd ed. Lechworth, Herts, England: The Royal Society of Chemistry, 1987.,p. A164/Aug 87]**PEER REVIEWED**

pH:

ACID REACTION
[Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 523]**PEER REVIEWED**

Solubilities:

PRACTICALLY INSOL IN WATER; SLIGHTLY SOL IN HOT ETHANOL, BENZENE
[Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 523]**PEER REVIEWED**

SOL IN METHYL CYANIDE, CYCLOHEXANE
[Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-278]**PEER REVIEWED**

SOL IN ETHER, GLACIAL ACETIC ACID
[Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 764]**PEER REVIEWED**

SOL IN ACETONE, ACETIC ACID
[Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 73rd ed. Boca Raton, FL: CRC Press Inc., 1992-1993.,p. 3-219]**PEER REVIEWED**

In chloroform 204, toluene 73, xylene 50, ethanol 2.1, heptane 1.8 (all in g/kg); soluble in alkalis with the formation of salts.
[Hartley, D. and H. Kidd (eds.). The Agrochemicals Handbook. 2nd ed. Lechworth, Herts, England: The Royal Society of Chemistry, 1987.,p. A164/Aug 87]**PEER REVIEWED**

Spectral Properties:

INDEX OF REFRACTION: 1.670 C/D
[Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 73rd ed. Boca Raton, FL: CRC Press Inc., 1992-1993.,p. 3-219]**PEER REVIEWED**

MAX ABSORPTION (0.1 N SODIUM HYDROXIDE & ETHANOL): 246, 275, 284, 312, 323 NM
[Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. 248]**PEER REVIEWED**

Intense mass spectral peaks: 173 m/z (100%), 167 m/z (89%), 340 m/z (57%), 165 m/z (40%)
[Hites, R.A. Handbook of Mass Spectra of Environmental Contaminants. Boca Raton, FL: CRC Press Inc., 1985. 389]**PEER REVIEWED**

MASS: 4951 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63)
[Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 568]**PEER REVIEWED**

Other Chemical/Physical Properties:

FORMS A SODIUM SALT WHICH IS SPARINGLY SOL IN WATER
[Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 523]**PEER REVIEWED**

Yellow powder (95% pure); mp: 145 deg C; density: 1.281 at 25 deg C; vapor pressure: 13.7 nPa (25 deg C) /Technical diphenadione/
[Worthing, C.R. and S.B. Walker (eds.). The Pesticide Manual - A World Compendium. 8th ed. Thornton Heath, UK: The British Crop Protection Council, 1987. 313]**PEER REVIEWED**

Chemical Safety & Handling:

Hazardous Decomposition:

When heated to decomposition it emits acrid smoke and fumes.
[Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 1231]**PEER REVIEWED**

Stability/Shelf Life:

SENSITIVE TO LIGHT
[Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. 45]**PEER REVIEWED**

Stable at pH 6-9 for 14 days, it is partly converted to a tautomer at pH 4 and hydrolyzed in < 24 hr. /Technical diphenadione/
[Worthing, C.R. and S.B. Walker (eds.). The Pesticide Manual - A World Compendium. 8th ed. Thornton Heath, UK: The British Crop Protection Council, 1987. 313]**PEER REVIEWED**

Shelf-life of 3 yr for P.C.Q., Rodent Cake. Keep dry.
[Farm Chemicals Handbook 1993. Willoughby, OH: Meister Publishing Co., 1993.,p. C-124]**PEER REVIEWED**

Stable in weakly acidic and weakly alkaline media at room temperature. Hydrolyzed by strong acids. Rapidly decomposed in water by sunlight. Decomposes at 338 deg C (without boiling).
[Hartley, D. and H. Kidd (eds.). The Agrochemicals Handbook. 2nd ed. Lechworth, Herts, England: The Royal Society of Chemistry, 1987.,p. A164/Aug 87]**PEER REVIEWED**

Occupational Exposure Standards:

Manufacturing/Use Information:

Major Uses:

MEDICATION (VET)
**QC REVIEWED**

MEDICATION
**QC REVIEWED**

RODENTICIDE, USED TO CONTROL MICE, RATS, PRAIRIE DOGS (CYNOMYS SPECIES), GROUND SQUIRRELS, VOLES AND OTHER RODENTS.
[Worthing, C.R. and S.B. Walker (eds.). The Pesticide Manual - A World Compendium. 8th ed. Thornton Heath, UK: The British Crop Protection Council, 1987. 313]**PEER REVIEWED**

BATICIDE
[Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 184]**PEER REVIEWED**

THE SYSTEMIC METHOD OF VAMPIRE BAT CONTROL.
[BULLARD RW, THOMPSON RD; INTERCIENCIA 2 (3): 149 (1977)]**PEER REVIEWED**

Manufacturers:

Atomergic Chemetals Corp, Hq, 222 Sherwood Ave, Farmingdale, NY 11735-1527, (516) 694-9000; Production site: Farmingdale, NY 11735
[SRI. 1992 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1992. 754]**PEER REVIEWED**

Methods of Manufacturing:

...BY CONDENSATION OF DIMETHYL PHTHALATE WITH DIPHENYLACETONE IN AN INERT SOLVENT IN PRESENCE OF SODIUM METHOXIDE.
[Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 522]**PEER REVIEWED**

General Manufacturing Information:

... DIPHACINONE ... INDUCED DEVELOPMENT OF RESISTANT POPULATION OF NORWAY RAT ONFARM IN WESTERN SCOTLAND.
[White-Stevens, R. (ed.). Pesticides in the Environment: Volume 1, Part 1, Part 2. New York: Marcel Dekker, Inc., 1971. 459]**PEER REVIEWED**

THIS IS MOST TOXIC OF ANTICOAGULANTS IN USE AT PRESENT /IN RODENT CONTROL/. WHILE OTHER CHEM IN THIS CLASS ARE USUALLY USED, IN BAIT, AT CONCN OF 0.025%, DIPHACINONE IS EFFECTIVE IN 0.005% CONCN.
[Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980. 1204]**PEER REVIEWED**

DIPHACINONE PARTIALLY EFFECTIVE IN TOXIC SHEEP COLLARS, IN REDUCING PREDATION BY COYOTES. IMPROVEMENTS IN CONSTRUCTION & CONFIGURATION OF TOXIC COLLAR ARE REPORTED.
[CONNOLLY GE ET AL; TOXIC COLLAR FOR CONTROL OF SHEEP-KILLING COYOTES: A PROGRESS REPORT, PROC- VERTEBR PEST CONF 8: 197 (1978)]**PEER REVIEWED**

DIPHENADIONE ... IS ... EFFECTIVE IN KILLING VAMPIRE BATS (DESMODUS ROTUNDUS). THE BATS ARE KILLED WITHIN 3 DAYS AFTER DOSING /CATTLE/ WITH A SINGLE INTRARUMINAL DOSE (ABOUT 1 MG/KG). IT IS ESTIMATED THAT THIS CHEMICAL MAY SAVE THE LATIN AMERICAN CATTLE INDUSTRY UP TO 250 MILLION DOLLARS ANNUALLY. VAMPIRE BATS ARE CARRIERS OF PARALYTIC RABIES THAT AFFECTS AN ESTIMATED 1 MILLION HEAD OF CATTLE EACH YEAR. ... IT HAS BEEN CONCLUDED THAT HUMANS MAY SAFELY CONSUME /MEAT AND MILK/ ... FROM ANIMALS TREATED WITH DIPHENADIONE.
[Booth, N.H., L.E. McDonald (eds.). Veterinary Pharmacology and Therapeutics. 5th ed. Ames, Iowa: Iowa State University Press, 1982. 1093]**PEER REVIEWED**

SINGLE INTRARUMINAL INJECTIONS /1 MG/KG/ (ORAL EFFECT) CAUSED BLOOD OF TREATED BEEF CATTLE TO BECOME TOXIC TO BATS WITHOUT ... HARM TO CATTLE (WIDE MARGIN OF SAFETY). ... 2 WEEK POST-TREATMENT CHECK ON 3 MEXICAN CATTLE RANCHES REVEALED 93 REDUCTION IN VAMPIRE BAT BITES.
[Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 184]**PEER REVIEWED**

/DIPHENADIONE IS/ MORE POTENT THAN WARFARIN IN MULTIPLE DOSE EXPT & ESPECIALLY AFTER SINGLE DOSE EXPOSURES.
[Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-348]**PEER REVIEWED**

Chemically and physically compatible with other rodenticides.
[Hartley, D. and H. Kidd (eds.). The Agrochemicals Handbook. 2nd ed. Lechworth, Herts, England: The Royal Society of Chemistry, 1987.,p. A164/Aug 87]**PEER REVIEWED**

Formulations/Preparations:

5 MG TABLETS
[Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. 1359]**PEER REVIEWED**

'Diphacin', bait concentrate (1 g ai/kg) for mixing with cereals; 'Gold Crest', 'Promar', 'Ramik', bait (ready for use) (50 mg/kg).
[Worthing, C.R. and S.B. Walker (eds.). The Pesticide Manual - A World Compendium. 8th ed. Thornton Heath, UK: The British Crop Protection Council, 1987. 313]**PEER REVIEWED**

Pellets, concentrates
[Farm Chemicals Handbook 1993. Willoughby, OH: Meister Publishing Co., 1993.,p. C-124]**PEER REVIEWED**

Laboratory Methods:

Clinical Laboratory Methods:

DIPHENADIONE WAS DETERMINED IN ANIMAL BLOOD PLASMA, TISSUES, MILK SAMPLES BY GLC WITH LOWER LIMIT OF 10 PPB FOR PLASMA & 0.5 PPB FOR MILK.
[BULLARD RW ET AL; J AGRIC FOOD CHEM 23 (1): 72 (1975)]**PEER REVIEWED**

A liquid chromatographic method was developed for the analysis of indandione and 4-hydroxycoumarin anticoagulant rodenticides in blood serum and liver.
[Chalermchaikit T et al; J Anal Toxicol 17 (1): 56-61 (1993)]**PEER REVIEWED**

Analytic Laboratory Methods:

DIPHACINONE WAS EXTRACTED AT THE 0.005% LEVEL FROM GRAIN OR PARAFFIN-COATED BAITS WITH ACETIC ACID. THE FILTERED SUPERNATANT WAS CHROMATOGRAPHED ON A PARTISIL PXS ODS 10/25 LIQUID CHROMATOGRAPHY COLUMN WITH PREMIXED AND DEGASSED ACETIC ACID-TETRAHYDROFURAN-WATER (14:2:9) AND DETECTED AT 288 NM. RECOVERY AVERAGED 96.6%. RESPONSE WAS LINEAR FROM 0.001-0.04 MG/ML. COEFFICIENT OF VARIATION OF WITHIN-DAY REPLICATES RANGED FROM 1.1 TO 2.5%.
[BENNETT BR, GRIMES GS; J ASSOC OFF ANAL CHEM 65 (4): 927 (1982)]**PEER REVIEWED**

DIPHENADIONE WAS DETECTED IN FOLIAGE, & GRAIN SAMPLES BY GLC.
[BULLARD RW ET AL; J AGRIC FOOD CHEM 23 (1): 72 (1975)]**PEER REVIEWED**

Spectrophotometric procedure is described for the quant detn of diphenadione, based on direct spectrophotometric measurements of the absorbances of its Fe(III), Fe(II), and Co(II) metal complexes at 488, 505 and (334 and 372 nm), respectively.
[El-Khateeb SZ; Anal Lett 22 (13-14): 2813-34 (1988)]**PEER REVIEWED**

Special References:

Synonyms and Identifiers:

Synonyms:

P.C.Q.
**PEER REVIEWED**

U-1363
**PEER REVIEWED**

DIDANDIN
**PEER REVIEWED**

DIDION
**PEER REVIEWED**

DIPAXIN
**PEER REVIEWED**

DIPHACIN
**PEER REVIEWED**

DIPHACINONE
**PEER REVIEWED**

Diphacins
**PEER REVIEWED**

Diphacin (Turkey)
**PEER REVIEWED**

DIPHENACIN
**PEER REVIEWED**

DIPHENANDIONE
**PEER REVIEWED**

2-DIPHENYLACETYL-1,3-DIKETOHYDRINDENE
**PEER REVIEWED**

2-(Diphenylacetyl)-1,3-indandione
**PEER REVIEWED**

2-Diphenyl acetyl-1,3-indanedione
**PEER REVIEWED**

2-(DIPHENYLACETYL)-1H-INDENE-1,3(2H)-DIONE
**PEER REVIEWED**

2-(Diphenylacetyl)-1H-indene-2,3(2H)dione
**PEER REVIEWED**

Gold Crest
**PEER REVIEWED**

1,3-INDANDIONE, 2-DIPHENYLACETYL-
**PEER REVIEWED**

Kill-Ko Rat Killer
**PEER REVIEWED**

ORAGULANT
**PEER REVIEWED**

Parakakes
**PEER REVIEWED**

PCQ
**PEER REVIEWED**

PID
**PEER REVIEWED**

PROMAR
**PEER REVIEWED**

RAMIK
**PEER REVIEWED**

RATINDAN 1
**PEER REVIEWED**

Rodent Cake
**PEER REVIEWED**

SOLVAN
**PEER REVIEWED**

Formulations/Preparations:

Pellets, concentrates
[Farm Chemicals Handbook 1993. Willoughby, OH: Meister Publishing Co., 1993.,p. C-124]**PEER REVIEWED**
RTECS Number:

NIOSH/NK5600000

Administrative Information:

Hazardous Substances Databank Number: 2788
Last Revision Date: 20010809
Last Review Date: Reviewed by SRP on 3/2/1994
Update History:

Complete Update on 08/09/2001, 1 field added/edited/deleted.
Complete Update on 11/06/2000, 1 field added/edited/deleted.
Complete Update on 03/09/2000, 1 field added/edited/deleted.
Complete Update on 02/08/2000, 1 field added/edited/deleted.
Complete Update on 02/02/2000, 1 field added/edited/deleted.
Complete Update on 11/10/1999, 1 field added/edited/deleted.
Complete Update on 09/21/1999, 1 field added/edited/deleted.
Complete Update on 05/06/1999, 1 field added/edited/deleted.
Complete Update on 10/20/1998, 1 field added/edited/deleted.
Complete Update on 06/02/1998, 1 field added/edited/deleted.
Complete Update on 02/27/1998, 1 field added/edited/deleted.
Complete Update on 09/17/1997, 1 field added/edited/deleted.
Complete Update on 04/23/1997, 1 field added/edited/deleted.
Complete Update on 03/17/1997, 2 fields added/edited/deleted.
Complete Update on 01/27/1997, 1 field added/edited/deleted.
Complete Update on 10/15/1996, 1 field added/edited/deleted.
Complete Update on 05/11/1996, 1 field added/edited/deleted.
Complete Update on 01/24/1996, 1 field added/edited/deleted.
Complete Update on 12/28/1994, 1 field added/edited/deleted.
Complete Update on 05/18/1994, 35 fields added/edited/deleted.
Field Update on 03/25/1994, 1 field added/edited/deleted.
Field update on 12/26/1992, 1 field added/edited/deleted.
Complete Update on 10/10/1990, 1 field added/edited/deleted.
Complete Update on 04/16/1990, 1 field added/edited/deleted.
Complete Update on 03/06/1990, 1 field added/edited/deleted.
Field update on 03/06/1990, 1 field added/edited/deleted.
Complete Update on 06/04/1985
Record Length: 67615