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Brodifacoum

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Main brand names, main trade names
   1.6 Main manufacturers, main importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First-aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/form
      3.3.3 Description
   3.4 Hazardous characteristics
4. USES
   4.1 Uses
      4.1.1 Uses
      4.1.2 Description
   4.2 High risk circumstance of poisoning
   4.3 Occupationally exposed populations
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Others
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. TOXICOLOGY
   7.1 Mode of Action
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
      7.2.4 Workplace standards
      7.2.5 Acceptable daily intake (ADI) and other guideline levels
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological analyses and their interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple qualitative test(s)
         8.2.1.2 Advanced qualitative confirmation test(s)
         8.2.1.3 Simple quantitative method(s)
         8.2.1.4 Advanced quantitative method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple qualitative test(s)
         8.2.2.2 Advanced qualitative confirmation test(s)
         8.2.2.3 Simple quantitative method(s)
         8.2.2.4 Advanced quantitative method(s)
         8.2.2.5 Other dedicated method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall interpretation of all toxicological analyses and toxicological investigations
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central Nervous System (CNS)
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Others
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ears, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Others
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic treatment
   10.3 Decontamination
   10.4 Enhanced elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
12. ADDITIONAL INFORMATION
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)
    BRODIFACOUM

    International Programme on Chemical Safety
    Poisons Information Monograph 077
    Chemical

    1.  NAME

        1.1  Substance

             Brodifacoum

        1.2  Group

             Coumarin derivative

        1.3  Synonyms

             3-[-(4'-bromobiphenyl-4-yl)-1,2,3,4-tetrahydro-1-
             naphthyl]-4-3-[3-(4'-bromo[1,1'-biphenyl]-4-yl)-1,2,3,4-
             tetrahydro-1-bromfenacoum;
             super-warfarin

        1.4  Identification numbers

             1.4.1  CAS number

                    56073-10-0

             1.4.2  Other numbers

        1.5  Main brand names, main trade names

             Klerat (Uruguay, UK)
             Ratak  (USA)
             Talon  (USA, New Zealand)

        1.6  Main manufacturers, main importers

    2.  SUMMARY

        2.1  Main risks and target organs

             The target system is the haematological system, with
             impairment of clotting.  The main risks are associated with
             potentially fatal gastrointestinal and intracerebral
             haemorrhage.

        2.2  Summary of clinical effects

             If toxic amounts have been ingested, coagulation will be
             impaired, with gum bleeding, epistaxis, ecchymosis,
             haematomata, haematemesis, melenae, haematuria.

        2.3  Diagnosis

             The diagnosis is based on history of exposure (generally
             by ingestion of a rodenticide); clinical evidence of
             bleeding, which may appear even several days after exposure;
             and abnormal prothrombin time.
    
             A sample of the rodenticide should be kept for toxicological
             analysis (if feasible).  The most relevant biomedical
             analysis is coagulation studies including:
    
             *  Determination of clotting factors
             *  Prothrombin time (PT)
             *  Activated partial thromboplastin time (PTT)

        2.4  First-aid measures and management principles

             All cases of brodifacoum ingestion should be taken to a
             hospital for initial clinical and laboratory evalauation.  In
             ingestion was recent (within 3 to 6 hours) the following may
             be recommended:
    
             *  Decontamination of the patient through gastric
                lavage/emesis.
             *  Administration of activated charcoal followed by
                cathartics.
    
             Not all patients need to stay in the hospital but prolonged
             clinical and analytical follow-up is mandatory.
    
             If more than 24 hours have elapsed since ingestion,
             decontamination measures are not effective and the patient
             should be monitored closely using prothrombin time (PT) and
             plasma thromboplastin time (PTT). 
    
             Treatment is based in the administration of vitamin K1 
             (phytomenadione) as indicated by the prothrombin time.
    
             Fresh frozen plasma or whole blood are indicated in cases of
             acute bleeding.
    
             Close clinical observation is essential to detect occult
             bleeding or life-threatening haemorrhage.
    
             In cases of suspected serious ingestion, vitamin K1 is
             indicated before signs and symptoms of haemorrhage
             appear.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

             This synthetic anticoagulant is obtained by the
             condensation of 4-hydroxycoumarin with
             3-(4'-bromodiphenyl-4-yl)-1,2,3,4-tetrahydronaphtol
             (CCINFOdisc, 1989).
    
             It was first introduced in 1975 to deal with the public
             health problem of warfarin-resistant rodents (Lipton & Klaas,
             1984).

        3.2  Chemical structure

             3-[3-(4'-bromobiphenyl-4-yl)-1,2,3,4-tetrahydro-1-naphtyl]
             -4-hydroxcoumarin
    
             3-[3-(4'-bromo[1,1'-biphenyl]-4-yl)-1,2,3,4-tetrahydro
             -1-naphthalenyl]-4-hydroxy-2H-1-benzopyran-2-one
    
             Molecular weight = 523.44
    
             C31H23-BrO3 C 71.14%, H 4.43%, Br 15.27%, O 9.17% 
    
             Structural formula: 
    
    STRUCTURAL FORMULA 1
    
             (Budivari, 1996)
    
             Brodifacoum exists as cis and trans isomers that may be
             separated by chromatography and identified by nuclear
             magnetic resonance spectroscopy.  The commercially available
             preparation contains variable proportions of cis/trans
             isomers as 50:50 and 70:30.  There is no significant
             difference in activity between the two isomers (ICI).
    

             The lateral 4-bromo-biphenyl group provides greater stability
             to the compound and overcomes the development of resistance
             to the poison in the rat.
    
             Note: Difenacoum is very similar to brodifacoum in its
             chemical structure and anticoagulant effect (they are both
             4-hydroxycoumarin derivatives).

        3.3  Physical properties

             3.3.1  Colour

                    Off-white to fawn powder

             3.3.2  State/form

             3.3.3  Description

                    Melting point: 228°C to 230°C
                    < 0.13 mPa (25°C).
    
                    Vapour pressure is less than 10 mg/l at 20°C. 
                    Insoluble in water and ether, soluble in chloroform
                    and acetone, slightly soluble in: benzene, ethanol,
                    ethylglycerol acetate and polyethyleneglycol.
    
                    Brodifacoum is a weak acid which does not readily form
                    water-soluble salts.  It does not lose activity after
                    30 days in direct sunlight.

        3.4  Hazardous characteristics

             Storage:  commercial formulations are stable at least
             for two years if protected from extreme temperatures and
             sunlight.  The container should be kept closed to maintain
             activity of formulation (as a bait).

             As a solid, it is stable under normal storage conditions. It
             does not corrode commonly-used metallic objects. Forms amine
             salts of limited solubility in water.

    4.  USES

        4.1  Uses

             4.1.1  Uses

             4.1.2  Description

                    Rodenticide effective against
                    warfarin-resistant rats. It is usually sold as ready
                    to use bait in pellets, mini-pellets and waterproof
                    bait containing 0.005% brodifacoum (loose or in bait
                    packs).
    
                    Indicated for control of Norwegian rats, roof rats and
                    house mice in public, industrial and commercial
                    buildings, in residences and outdoor urban areas. The
                    application may be carried out by professional pest
                    control personnel orby the public in general.
    
                    Theoretically, the substance may be considered for
                    development as a therapeutic agent in anticoagulant
                    therapy, but the difficulty in reversal of effects
                    constitutes a major disadvantage (Jones et al.,
                    1984).

        4.2  High risk circumstance of poisoning

             This rodenticide is usually applied as a bait, and
             possibilities of food or environmental contamination are
             relatively low.
    
             Poisoning occurs usually after accidental ingestion by small
             children or suicide attempts by adults

        4.3  Occupationally exposed populations

             No specific data were found on risks of occupational
             exposure in the manufacturing industry when handling the pure
             substance.

    5.  ROUTES OF ENTRY

        5.1  Oral

             This is the commonest route of entry and the only one
             described in the published literature.

        5.2  Inhalation

             No data available.

        5.3  Dermal

             Only animal data are available:  acute dermal toxicity

             for the male rabbit is 0.25 to 0.625 mg/kg, but if skin is
             abraded the dermal toxic dose is 1.25 mg/kg (ICI Ltd).

        5.4  Eye

             No data available.

        5.5  Parenteral

             No data available.

        5.6  Others

             No data available.

    6.  KINETICS

        6.1  Absorption by route of exposure

             Brodifacoum is readily absorbed in the gastrointestinal
             tract.

        6.2  Distribution by route of exposure

             Brodifacoum and related compounds bind more strongly to
             a lipophilic site in the liver than does warfarin.  In the
             poisoned rat, hepatic concentrations of the substance are 20
             times higher than the serum concentrations (Bachman &
             Sullivan, 1983).

        6.3  Biological half-life by route of exposure

             As with all super-warfarins, brodifacoum has a very long
             plasma half-life. Metabolic studies in animals have shown a
             half-life of approximately 24 days (Fitzgerald & Bronstein,
             1987), 120 days in the dog (Lipton & Klaas, 1984), and 156
             hours in the rat (Bachman & Sullivan, 1983).
    
             Warfarin has a plasma half-life of 42 hours and, assuming a
             normal liver function and diet, its anticoagulant effect
             disappears in a few days.  By contrast, the anticoagulant
             effect of brodifacoum may last for more than 7 weeks in the
             poisoned patient (Jones et al., 1984).

        6.4  Metabolism

             The metabolism of brodifacoum has not been fully
             defined, but considering that it has a substituted

             4-hydroxycoumarin ring structure, it is probably metabolized
             in a similar manner to warfarin.  It is hydroxylated to
             inactive compounds by mixed function oxidase enzymes in
             hepatic microsomes (Jones et al., 1984).

             Phenobarbital is known to increase the activity of the
             hepatocellular microsomal enzyme system, and would increase
             brodifacoum's metabolism as it does with warfarin.  In the
             animal, it has been demonstrated that pretreatment with
             phenobarbital decreases the anticoagulant effect of
             brodifacoum (Bachman & Sullivan, 1983).

        6.5  Elimination by route of exposure

             The elimination of brodifacoum is probably similar to
             that of warfarin: compounds resulting from the hydroxylation
             in the hepatocellular mixed function oxidases system are
             excreted in the urine (Jones et al., 1984).

    7.  TOXICOLOGY

        7.1  Mode of Action

             Brodifacoum acts by inhibiting the vitamin K epoxide
             reductase in the vitamin K1-epoxide cycle (Park et al.,
             1979), impeding the cyclic regeneration of vitamin K1,
             resulting in hypoprothrombinemia. Under physiological
             conditions, the oxidation of vitamin K in the hepatocyte is
             coupled to a carboxylation step essential for activation of
             prothrombin factors from inactive precursors. Brodifacoum
             produces hypoprothrombinaemia because the coupled
             carboxylationreaction is inhibited (Lipton & Klaas, 1984). If
             therapeutic doses of vitamin K1 are given, additional
             substrate becomes available to resume the cycle and continue
             the carboxylation process, reversing the
             hypoprothrombinaemia(Lipton & Klaas, 1984).
    
             The superwarfarins produce a diminution of the vitamin
             K-dependent carboxylation of glutamic acid residues in
             prothrombin factor precursors. This effect is 100 times
             greater on molar basis than that of warfarin. This, with
             brodifacoum's very long plasma half-life, results in a potent
             anticoagulant effect.
    
             A longitudinal analysis of alterations in specific
             coagulation factors in a poisoning case reported by Hoffman
             et al. (1988) demonstrated a profound decrease of factors II,
             VII, IX and X, lasting at least 43 days post-ingestion.

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             The ingestion of thirty 50 g
                             packages of brodifacoum over a two-day period
                             by a 31-year-old psychotic woman produced
                             generalized ecchymosis and abortion.  The
                             estimated ingested dose was 75 mg (Lipton &
                             Klaas, 1984).
    
                             A 17-year-old male adolescent ingested
                             approximately 7.5 mg (0.12 mg/kg) of
                             brodifacoum and was admitted to the hospital
                             with flank pain and important haematuria,
                             followed by epistaxis and gum bleeding. 
                             Therapy with vitamin K1 had to be maintained
                             for over 50 days (Jones et al., 1984).
    
                             The ingestion of 1 mg of brodifacoum in an
                             adult produced bleeding that persisted for
                             more than 2 months (Chong et al., 1986).
    
                             No clearly defined toxic dose has been
                             established in the human, and few clinical
                             reports are available.

                    7.2.1.2  Children

                             Very few reports are available
                             specifying the toxic dose, although ingestion
                             of long-acting rodenticides have been
                             reported in children.
    
                             Anticoagulation has been detected but without
                             clinical symptomatology in most cases 
                             (Smolinske et al., 1987).

             7.2.2  Relevant animal data

                    LD50 oral (female rat)   0.37 to 0.68 mg/kg
    
                    LD50 oral (beagle dog)   0.25 to 1 mg/kg
    
                    LD50 oral (cat) estimated as 25 mg/kg.
    

                    The acute dermal toxicity (male rabbits) with intact
                    skin was estimated to be 0.25 to 0.625 mg/kg.  When
                    the skin is abraded, the dose is 1.25 mg/kg (ICI
                    Ltd).
    
                    Brodifacoum is slightly irritant when applied to the
                    skin of rabbits and to the eye.

             7.2.3  Relevant in vitro data

                    No data available.

             7.2.4  Workplace standards

                    No data available.

             7.2.5  Acceptable daily intake (ADI) and other guideline levels

                    No data available.

        7.3  Carcinogenicity

             No effect has been demonstrated with technical
             brodifacoum in carcinogenicity tests (ICI Ltd.).

        7.4  Teratogenicity

             Studies in rats and rabbits have demonstrated no
             fetotoxic embryotoxic or teratogenic effects.

        7.5  Mutagenicity

             No data available.

        7.6  Interactions

             Warfarin interacts with many drugs but, although a
             similar pattern is expected with brodifacoum, no specific
             data were found.

    8.  TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

        8.1  Material sampling plan

             8.1.1  Sampling and specimen collection

                    8.1.1.1  Toxicological analyses

                    8.1.1.2  Biomedical analyses

                    8.1.1.3  Arterial blood gas analysis

                    8.1.1.4  Haematological analyses

                    8.1.1.5  Other (unspecified) analyses

             8.1.2  Storage of laboratory samples and specimens

                    8.1.2.1  Toxicological analyses

                    8.1.2.2  Biomedical analyses

                    8.1.2.3  Arterial blood gas analysis

                    8.1.2.4  Haematological analyses

                    8.1.2.5  Other (unspecified) analyses

             8.1.3  Transport of laboratory samples and specimens

                    8.1.3.1  Toxicological analyses

                    8.1.3.2  Biomedical analyses

                    8.1.3.3  Arterial blood gas analysis

                    8.1.3.4  Haematological analyses

                    8.1.3.5  Other (unspecified) analyses

        8.2  Toxicological analyses and their interpretation

             8.2.1  Tests on toxic ingredient(s) of material

                    8.2.1.1  Simple qualitative test(s)

                    8.2.1.2  Advanced qualitative confirmation test(s)

                    8.2.1.3  Simple quantitative method(s)

                    8.2.1.4  Advanced quantitative method(s)

             8.2.2  Tests for biological specimens

                    8.2.2.1  Simple qualitative test(s)

                    8.2.2.2  Advanced qualitative confirmation test(s)

                    8.2.2.3  Simple quantitative method(s)

                    8.2.2.4  Advanced quantitative method(s)

                    8.2.2.5  Other dedicated method(s)

             8.2.3  Interpretation of toxicological analyses

        8.3  Biomedical investigations and their interpretation

             8.3.1  Biochemical analysis

                    8.3.1.1  Blood, plasma or serum

                    8.3.1.2  Urine

                    8.3.1.3  Other fluids

             8.3.2  Arterial blood gas analyses

             8.3.3  Haematological analyses

             8.3.4  Interpretation of biomedical investigations

        8.4  Other biomedical (diagnostic) investigations and their 
             interpretation

        8.5  Overall interpretation of all toxicological analyses and
             toxicological investigations

             Collect a sample of the product blood/urine/faeces.
    
             Biomedical analysis
    
             Prothrombin time (PT) monitoring is essential.  For the first
             5 to 6 days it should be done at least daily, and repeated
             even if results were normal uponadmission.  Prothrombin time
             may initially be normal, even in a severe poisoning because
             vitamin K-dependent clotting factors have a long half-life
             and are still circulating several hours after brodifacoum
             starts its effect.
    
             Activated partial thromboplastin time (PTT) is abnormal.
    
             Coagulation tests in general may be normal (e.g. coagulation
             time, thromboelastogram).
    
             Haemoglobin:                 Red blood count
             Urinalysis (haematuria):     Stools
    

             Toxicological analysis
    
             Although a sensitive HPLC technique exists, it is not
             clinically useful.
    
             Other investigations
    
             Specific organ evaluation for bleeding as clinically
             indicated.

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    Ingestion of brodifacoum is initially
                    asymptomatic, and may continue as such even with
                    prolonged alterations in prothrombin time.  No
                    gastrointestinal tract or other symptomatology
                    occurs.
    
                    Coagulation disturbances may become evident a few days
                    after ingestion, and may be detected only by
                    laboratory studies.  In severe poisoning,
                    gum-bleeding, epistaxis, petechiae, ecchymoses,
                    haematomata, blood in urine and faeces, and genital
                    haemorrhage may occur.  Internal bleeding and cerebral
                    haemorrhage may complicate the patient's
                    prognosis.

             9.1.2  Inhalation

                    No data available.

             9.1.3  Skin exposure

                    The commercial product is not irritating to the
                    skin.  Animal studies showed that the pure substance
                    is absorbed through the skin.

             9.1.4  Eye contact

                    Slightly irritant.

             9.1.5  Parenteral exposure

                    No data available.

             9.1.6  Other

                    No data available.

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    Ingestion of brodifacoum may be repeated,
                    leading to severe poisoning (Basehore & Mowry,
                    1987).

             9.2.2  Inhalation

                    No data available.

             9.2.3  Skin exposure

                    No data available.

             9.2.4  Eye contact

                    No data available.

             9.2.5  Parenteral exposure

                    No data available.

             9.2.6  Other

                    No data available.

        9.3  Course, prognosis, cause of death

             The course of poisoning is characteristically long. 
             Alterations of coagulation parameters and clinical symptoms
             of bleeding may be maintained for several days if no
             treatment is provided.
    
             The prognosis is poor in cases with internal bleeding or
             intracerebral haemorrhage, and also in patients with previous
             haematological illnesses or renal insufficiency.
    
             Death is uncommon (Basehore & Mowry, 1987).

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    No direct cardiotoxic effects have been
                    described in man.

             9.4.2  Respiratory

                    No effects have been reported but theoretically
                    haemoptysis would be a possibility.

             9.4.3  Neurological

                    9.4.3.1  Central Nervous System (CNS)

                             Intracerebral haemorrhage has been
                             described as a secondary complication
                             (Basehore & Mowry, 1987).

                    9.4.3.2  Peripheral nervous system

                             No effects have been reported.

                    9.4.3.3  Autonomic nervous system

                             No effects have been reported.

                    9.4.3.4  Skeletal and smooth muscle

                             Muscular haematoma may occur,
                             especially on the elbows, knees and buttocks
                             (CCINFOdisc, 1989).

             9.4.4  Gastrointestinal

                    Haematemesis and melena may occur.  Abdominal
                    and flank pain have been reported after
                    intra-abdominal bleeding (Jones et al., 1984).

             9.4.5  Hepatic

                    Although the liver is the site of metabolism of
                    brodifacoum, no observable clinical effects are
                    apparent, except coagulopathy.

             9.4.6  Urinary

                    9.4.6.1  Renal

                             Haematuria may be clinically evident
                             or detected only by the laboratory (Jones et
                             al., 1984).  Urinary tract haemorrhage has
                             been reported (Hollinger & Pastoor,
                             1993).

                    9.4.6.2  Others

                             No data available.

             9.4.7  Endocrine and reproductive systems

                    No data available.

             9.4.8  Dermatological

                    Petechial rashes may be seen.

             9.4.9  Eye, ears, nose, throat: local effects

                    Epistaxis and gum bleeding.

             9.4.10 Haematological

                    Coagulation is impaired after ingestion of
                    significant quantities of brodifacoum. The usual
                    haematological symptoms are: gum bleeding, epistaxis,
                    ecchymoses, haematoma, and haematuria; there may be
                    internal bleeding.

             9.4.11 Immunological

                    No data available.

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             No data available.

                    9.4.12.2 Fluid and electrolyte disturbances

                             No data available. 

                    9.4.12.3 Others

                             No data available.

             9.4.13 Allergic reactions

                    No data available.

             9.4.14 Other clinical effects

                    No data available.

             9.4.15 Special risks

                    One case of abortion has been reported by
                    Lipton & Klaas (1984).  Data on breast milk secretion
                    are not available and therefore breast feeding should
                    not be recommended.  Individuals with bleeding
                    diatheses may be at higher risk.

        9.5  Others

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             In all cases of brodifacoum ingestion, the patient
             (especially children) should be clinically monitored by daily
             laboratory studies for at least 4 or 5 days.
    
             Gastric lavage or emesis is indicated if the ingested amount
             is uncertain or possibly toxic. Administration of activated
             charcoal and cathartics is useful. If initial coagulation
             disorders have been detected, the prothrombin time should be
             monitored (for at least 60 days).  The treatment is based
             upon the administration of vitamin K1.  Fresh frozen plasma
             or whole blood should be given in severe cases of poisoning
             in order to provide clotting factors.
    
             Clinical observation should be very strict in order to
             diagnose any possibility of bleeding.

        10.2 Life supportive procedures and symptomatic treatment

             Life-saving procedures are indicated if serious
             complications arise.
    
             Symptomatic treatment for bleeding is the administration of
             fresh frozen plasma or fresh whole blood for correcting
             coagulopathy.

        10.3 Decontamination

             If more than 24 hours have elapsed decontamination
             measures are not effective.
    
             Emesis or gastric lavage may be effective if attempted within
             3 to 6 hours of ingestion.
    

             Administration of activated charcoal and cathartics may be
             considered.

        10.4 Enhanced elimination

             Enhancement of elimination is not indicated.

        10.5 Antidote treatment

             10.5.1 Adults

                    Phytomenadione (vitamin K1) should be
                    administered.  If prothrombin time is significantly
                    reduced vitamin K1 should be administered
                    intravenously starting with 10 mg each 6 h (40
                    mg/day).  The intramuscular route may be chosen under
                    appropriate clinical settings.  The dosage should be
                    adjusted according to the prothrombin time. 

             10.5.2 Children

                    Indication and dosage is the same as in adults.

        10.6 Management discussion

             There is no consensus on the appropriate administration
             schemes for vitamin K. Some authors give oral vitamin K
             prophylactically in cases where ingestion is uncertain. The
             usual route for treatment is intravenous, although in
             somecases it has been given intramuscularly or
             subcutaneously.  The use of phenobarbital as a hepatic
             microsomal enzyme inducer is controversial.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             Lipton & Klaas (1984) reported a case of a psychotic
             31-year-old woman who ingested thirty 50 g packages of
             commercial rodenticide containing brodifacoum.  Five days
             later, she was admitted to hospital with slash marks on both
             wrists and blood clots in the gums.  Laboratory results were:
             haemoglobin 12.2 g/dL, Ht 37.9%, WBC 5.6/mm3, platelets
             390.000, prothrombin time 72s (control = 12 s), activated
             partial thromboplastin time greater than 100s (normal = 25 to
             35s), fibrinogen 380 mg/dL.  Urinalysis was negative for
             blood and protein.  Treatment was started with 25 mg of
             vitamin K1 and fresh frozen plasma.  The dose of vitamin K1
             was increased to 125 mg per day after little improvement in

             the prothrombin time.  Phenobarbital was also administered as
             an hepatic enzyme inducer.  This case was complicated by a
             complete and apparently spontaneous abortion.
    
             Basehore & Mowry (1987) reported a patient who, following
             chronic ingestion of the rodenticide, was admitted to
             hospital with nose-bleeding, haematuria and multiple
             ecchymoses.  Laboratory studies showed: prothrombin time = 60
             seconds (normal = 12.4), partial prothrombin time = 79.2
             seconds (normal = 27), bleeding time 15 minutes.  Treatment
             was started with vitamin K1 and frozen fresh plasma.  The
             patient was discharged 9 days afterwards with almost normal
             prothrombin time and partial thromboplastin time and
             prescribed oral phytomenadione. Three weeks later, he
             presented with status epilepticus; intradural haemorrhage was
             diagnosed by CAT-Scan.  Prothrombin time was again over 60
             seconds.  He deteriorated and died 4 hours after
             admission.

    12. ADDITIONAL INFORMATION

        12.1 Specific preventive measures

             As any other pesticide, these rodenticides should be
             kept out of the reach of children and irresponsible persons. 
             Use of superwarfarin, such as brodifacoum, should be
             restricted to agronomical application and not widely
             advertised or sold without restriction for household
             use.

        12.2 Other

             No data available.

    13. REFERENCES

        Bachman KA & Sullivan TJ (1983)  Dispositional and
        pharmacodynamics characteristics of brodifacoum in
        warfarin-sensitive rats.  Pharmacology, 27(5): 251-288.
    
        Basehore LM & Mowry JM (1987)  Death following ingestion of
        superwarfarin rodenticide: A case report.  Vet & Human Toxicology,
        29 (6 Dec.).
    
        Budivari S (ed) (1996)  The Merck Index, An Encyclopedia of
        Chemicals, Drugs and Biologicals, 12th ed., Merck & Co., Inc.,
        Whitehouse Station, NJ, USA.
    
        CCINFO (1989)
    

        Chong L, Chan W, Ho C (1986)  A case of superwarfarin poisoning. 
        Scand J Haematol, 36: 314-315.
    
        Fitzgerald K & Bronstein AC (1987).  Comparison of first and
        second generation anticoagulant rodenticide poisonings: fourteen
        canine cases.  Abstracts from the AACT/AAPCC/ABMT/CAPCC scientific
        meetings. Sept. 27.
    
        Hoffman RS, Smilkstein MJ, Goldfrank LR (1988)  "Evaluation of
        coagulation factor abnormalities in long-acting anticoagulant
        overdose".  J Toxicol Clin Toxicol, 26 (3-4): 48. 
    
        Hollinger B & Pastoor TP (1993). Case management and plasma
        half-life in a case of brodifacoum poisoning. Arch Intern Med, 153
        (16):1925-8
    
        Jones E, Growe GH, Naiman SC (1984)  Prolonged anticoagulation in
        rat poisoning.  JAMA, 252: 3005-3007.
    
        ICI Ltd. - Technical Information
    
        Lipton RA & Klaas EM (1984)  Human ingestion of superwarfarin
        rodenticide resulting in a prolonged anticoagulant effect.  JAMA,
        Dec 7., vol. 252, No. 21.
    
        Park BK et al. (1979)  A study of the effect of anticoagulants on
        (3H) vitamin K1 metabolism and prothrombin complex activity in the
        rabbit. Biochem Pharmacol, 28 (8): 1323-9.
    
        Smolinske SC, Sherger DS, Kearus PS & Rumack BH (1987)  Long
        acting coagulant rodenticide ingestion in children.  Vet & Hum
        Toxicology, 29 (6 Dec.).

    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
        ADDRESS(ES)

        Authors:    Dr C. Dell Acqua
                    Dr J. Pronczuk
                    CIAT
                    Piso 7, Hospital de Clinicas
                    Av. Italia s/n
                    Montevideo
                    Uruguay
    
                    Tel: 598-2-470300 and 598-2-804000
                    Fax: 598-2-470300
    
        Date:       February 1990
    
        Peer
        review:     London, United Kingdom, March 1990.
    
                    Informal Consultation, post JMPR meeting, September
                    1991
    
        Original
        Editor:     Dr S. Chaplin, Newcastle-upon-Tyne, United Kingdom
                    (September 1991)
    
        Update:     International Programme on Chemical Safety (May
                    1992)
    
        Editor:     Mrs J. Duménil, International Programme on Chemical
                    Safety
                    (July 1999)
    
         
    



    See Also:
       Toxicological Abbreviations
       Brodifacoum (HSG 93, 1995)
       Brodifacoum (PDS)