Health and Safety Guide No. 96






    This is a companion volume to Environmental Health Criteria 175:
    Anticoagulant Rodenticides

    Published by the World Health Organization for the International
    Programme on Chemical Safety (a collaborative programme of the United
    Nations Environment Programme, the International Labour Organisation,
    and the World Health Organization)

    This report contains the collective views of an international group of
    experts and does not necessarily represent the decisions or the stated
    policy of the United Nations Environment Programme, the International
    Labour Organisation, or the World Health Organization

    WHO Library Cataloguing in Publication Data

    Health and safety guide for Warfarin

         (Health and safety guide ; no. 96)

         1.Warfarin - toxicity  2.Rodenticides  3.Anticoagulants
         4.Environmental exposure  I.Series

         ISBN 92 4 151096 X          (NLM Classification: WA 240)
         ISSN 0259-7268

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         1.1. Identity
         1.2. Physical and chemical properties
         1.3. Analytical methods
         1.4. Production and uses


         2.1. Identity, physical and chemical properties, and
               analytical methods
         2.2. Sources of human and environmental exposure
         2.3. Environmental transport, distribution, and
         2.4. Environmental levels and human exposure
         2.5. Kinetics and metabolism in laboratory animals and humans
         2.6. Effects on laboratory mammals and  in vitro test
         2.7. Effects on humans
         2.8. Effects on other organisms in the laboratory and field
         2.9. Evaluation of human health risks and effects on the
               2.9.1. Evaluation of human health risks
               2.9.2. Evaluation of effects on the environment


         3.1. Conclusions
         3.2. Recommendations for the protection of human health and
               the environment


         4.1. Main human health hazards, prevention and protection,
               first aid
               4.1.1. Advice to physicians
               4.1.2. Health surveillance advice
         4.2. Explosion and fire hazards
         4.3. Storage
         4.4. Transport
         4.5. Spillage
         4.6. Disposal




         7.1. Previous evaluations by international bodies
         7.2. Exposure limit values
         7.3. Specific restrictions
         7.4. Labelling, packaging, and transport
         7.5. Waste disposal



    The Environmental Health Criteria (EHC) monographs produced by the
    International Programme on Chemical Safety include an assessment of
    the effects on the environment and on human health of exposure to a
    chemical or combination of chemicals, or physical or biological
    agents. They also provide guidelines for setting exposure limits.

    The purpose of a Health and Safety Guide is to facilitate the
    application of these guidelines in national chemical safety
    programmes. The first three sections of a Health and Safety Guide
    highlight the relevant technical information in the corresponding EHC.
    Section 4 includes advice on preventive and protective measures and
    emergency action; health workers should be thoroughly familiar with
    the medical information to ensure that they can act efficiently in an
    emergency. Within the Guide is a Summary of Chemical Safety
    Information which should be readily available, and should be clearly
    explained, to all who could come into contact with the chemical. The
    section on regulatory information has been extracted from the legal
    file of the International Register of Potentially Toxic Chemicals
    (IRPTC) and from other United Nations sources.

    The target readership includes occupational health services, those in
    ministries, governmental agencies, industry, and trade unions who are
    involved in the safe use of chemicals and the avoidance of
    environmental health hazards, and those wanting more information on
    this topic. An attempt has been made to use only terms that will be
    familiar to the intended user. However, sections 1 and 2 inevitably
    contain some technical terms. A bibliography has been included for
    readers who require further background information.

    Revision of the information in this Guide will take place in due
    course, and the eventual aim is to use standardized terminology.
    Comments on any difficulties encountered in using the Guide would be
    very helpful and should be addressed to:

    The Director
    International Programme on Chemical Safety
    World Health Organization
    1211 Geneva 27



    1.1  Identity

    Common name:                  warfarin

    Chemical formula:             C19H16O4

    Chemical structure:

                                  CHEMICAL STRUCTURE 1

    Common synonyms:              coumafène, warfarine, zoocoumarin

    Common trade names:           Athrombine-K; Brumolin; Compound 42;
                                  Coumadin; Coumafen; Coumarin;
                                  Coumefene; Dethmore; Dethnel; Eastern
                                  States Duocide; Fasco Fascrat Powder;
                                  Frass-Ratron; Kumader; Kumadu; Kypfarin;
                                  Maag Rattentod Cum; Mar-Frin; Maveran;
                                  Panwarfin; Prothromadin; Rat-a-way;
                                  Rat-b-gon; Rat-Gard; Rat-Kill; Rat-Mix;
                                  Rat-ola; Ratro; Rats-No-More; Rodafarin;
                                  Temus W; Warf 42; Warf Compound 42;
                                  Warf-12; Warfarat; Warfarin +;
                                  Warficide; Zoocoumarin

    CAS chemical name:            4-hydroxy-3-(3-oxo-1-phenylbutyl)-
                                  2 H-1-benzopyran-2-one (9CI) (8CI) (I)

    IUPAC chemical name:          (RS) 4-hydroxy-3-(3-oxo-1-phenylbutyl)

    CAS registry number:          81-81-2 (unstated stereochemistry);
                                  5543-58-8 (R)-(+) isomer

    RTECS registry number:        GN4550000

    1.2  Physical and Chemical Properties

    Warfarin forms colourless crystals. It is practically insoluble in
    water, readily soluble in acetone and dioxane and moderately soluble
    in alcohols. It is acidic. The sodium salts are soluble in water but
    insoluble in organic solvents.

    Further physical and chemical properties of warfarin are given in the
    "Summary of Chemical Safety Information" (section 6).

    1.3  Analytical Methods

    The determination of warfarin is mainly based on high-performance
    liquid chromatography with fluorescence detection. The detection limit
    in animal tissues is 0.02 mg/kg. The other methods include UV
    spectrometry and reversed-phase liquid chromatography, the latter with
    a detection limit in blood serum of 20 µg/litre.

    1.4  Production and Uses

    The anticoagulant properties of warfarin were reported in 1944, and,
    in 1948, it was proposed as a rodenticide. Warfarin is used in
    agriculture and urban rodent control in the form of baits containing
    0.025% active ingredient. The sodium salt is available at 0.5%
    concentrate for use at a final concentration of 0.05% in liquid base.
    Warfarin is also used as a drug for the treatment of thromboembolic
    disease in humans.


    2.1  Identity, Physical and Chemical Properties, and Analytical

    Warfarin is a colourless, crystalline compound with a melting point of
    151-161°C. It is practically insoluble in water, readily soluble in
    acetone and dioxane, and moderately soluble in alcohols. Analytical
    methods for the determination of warfarin are mainly based on high
    performance liquid chromatography.

    2.2  Sources of Human and Environmental Exposure

    Warfarin does not occur naturally. It is used as a rodenticide as well
    as a drug, and acts by disrupting the normal blood clotting mechanisms
    causing an increased tendency to bleed.

    2.3  Environmental Transport, Distribution, and Transformation

    Warfarin is unlikely to enter the atmosphere, because of its low
    volatility. It is practically insoluble in water. The rate of
    degradation is relatively slow.

    2.4  Environmental Levels and Human Exposure

    No information is available on concentrations in air, water, and soil.

    Warfarin is not intended for direct application to growing crops or
    for use as a food additive. The controlled medical use of warfarin
    exposes more people to higher concentations over a longer period than
    would be expected to occur as a result of accidental human exposure
    due to its use as a rodenticide. Accidental overexposures to warfarin
    as a rodenticide are most commonly reported in children and domestic

    2.5  Kinetics and Metabolism in Laboratory Animals and Humans

    Warfarin is easily absorbed through the gastrointestinal tract and
    skin, and is bound to serum proteins. Warfarin is readily hydroxylated
     in vitro and  in vivo by rat liver microsomal enzymes to form 6-,
    7-, and 8-hydroxywarfarin. It is eliminated through both the urine and

    When a single oral dose of 1.5 mg warfarin/kg was given to male and
    female volunteers, maximum concentration in plasma was reached in
    2-12 h. The half-life for disappearance from human plasma ranged from
    15 to 58 h.

    2.6  Effects on Laboratory Mammals and in vitro Test Systems

    The acute oral toxicity of warfarin for rats is high. Reported LD50
    values range from 11 to 323 mg/kg, females being more susceptible than
    males. For classification purposes, the accepted WHO LD50 value is
    10 mg/kg. Genetic resistance to warfarin among rodents and humans has
    been reported. Signs of poisoning are those associated with an
    increased tendency to bleed.

    One study on rats showed some developmental effects. There are no data
    on mutagenicity. 

    In feeding studies on rats, the only effect found was associated with
    anticoagulant action.

    2.7  Effects on Humans

    Vitamin K functions as an essential element in the synthesis of
    several blood coagulation factors. Warfarin inhibits this process and
    consequently affects the blood coagulation mechanisms. Prolonged
    inhibition of the vitamin K synthesis will lead to severe bleeding and
    death, if not corrected.

    Symptoms of warfarin poisoning begin a few days or weeks after
    ingestion. They include nose bleeding, bleeding gums, pallor, and,
    sometimes, haematomas around joints and on the buttocks, and blood in
    the urine and faeces. Later, paralysis due to cerebral haemorrhage
    and, finally, haemorrhagic shock and death may occur.

    Poisoning incidents have been reported. Outbreaks of poisoning have
    been observed in relation to warfarin-contaminated meal and also in
    infants after dermal application of warfarin-contaminated talc. A case
    of poisoning from prolonged skin contact during the preparation of
    warfarin baits has also been reported.

    Developmental effects known as "warfarin embryopathy" or "fetal
    warfarin syndrome" were reported when warfarin was administered as a
    therapeutic agent during pregnancy. No cases of embryopathy following
    the use of warfarin as a rodenticide have been reported.

    2.8  Effects on other Organisms in the Laboratory and Field

    Some secondary toxicity laboratory studies on wildlife have shown that
    captive predators could be intoxicated by sufficient no-choice feeding
    of warfarin-poisoned rodents.

    2.9  Evaluation of Human Health Risks and Effects on the Environment

    2.9.1  Evaluation of human health risks

    Warfarin is used as both a rodenticide and a drug. In agriculture and
    urban rodent control, it is used as a tracking dust or bait containing
    0.025-0.05% of active ingredient. Increased levels in air, water, and
    food are unlikely. Occupational exposure may occur during manufacture,
    formulation, and bait application, but data concerning the levels are
    not available.

    Warfarin is easily absorbed through the gastrointestinal tract and
    skin, and readily hydroxylated by liver microsomal enzymes in the rat.
    The half-life for disappearance of warfarin from human plasma has been
    reported to be between 15 and 58 h.

    Warfarin is highly toxic for mammalian species. Signs of poisoning in
    all species, including humans, are associated with an increased
    tendency to bleed.

    Poisoning incidents after massive oral or dermal exposure have been
    reported. When used therapeutically, warfarin has been given to
    patients for long periods without signs of toxicity, other than
    bleeding. Warfarin is known as a human teratogen. Developmental
    effects have been observed following the administration of warfarin as
    a therapeutic agent during pregnancy. No cases of embryopathy
    following its use as a rodenticide have been reported.

    The specific and potent antidote in case of poisoning is vitamin K1.

    2.9.2  Evaluation of effects on the environment

    Warfarin is applied to discrete sites as low-concentration baits. It
    is practically insoluble in water and, when it is used as a
    rodenticide, it is unlikely to be a source of environmental

    Non-target organisms are potentially at risk in two ways: from direct
    consumption of baits (primary hazard) and through eating poisoned
    rodents (secondary hazard). The main reason for the poisoning of
    domestic animals is direct consumption of baits.

    Some secondary toxicity laboratory studies have shown that predators
    can be intoxicated by eating warfarin-poisoned rodents. No cases of
    secondary poisoning of predators in the field following the use of
    warfarin as a rodenticide have been found.


    3.1  Conclusions

    Exposure of the general population to warfarin as a rodenticide
    through air, drinking-water, or food is unlikely and does not
    constitute a significant health hazard. Poisoning incidents may occur
    in cases of massive intentional or unintentional ingestion, massive
    dermal exposure, and during manufacture and formulation. Warfarin is
    teratogenic in humans at therapeutic doses. The use of warfarin as a
    rodenticide is not expected to be a significant source of air, water,
    soil, or food contamination. Direct or secondary poisoning of birds,
    domestic and farm animals, and wildlife may occur.

    3.2  Recommendations for the Protection of Human Health and the

    Potentially exposed workers should receive appropriate biomonitoring
    and health evaluation.

    Exposure of pregnant women to concentrate material must be kept to a
    minimum. Uneaten baits as well as killed rodents should be burned or
    buried to reduce the risk of primary or secondary poisonings in
    non-target organisms.


    4.1  Human Health Hazards, Prevention and Protection, First Aid

    Warfarin is highly toxic for mammalian species, including humans. The
    probable lethal oral dose in humans is believed to be between 50 and
    500 mg/kg. A cumulative total dose of about 1000 mg of warfarin
    consumed in 13 days has been reported to be fatal for an adult man,
    equivalent to about 1.1 mg/kg per day.

    The main features of warfarin poisoning in less severe cases are
    excessive bruising, nose and gum bleeding, and blood in the urine and
    faeces. Bleeding from several organs within the body, leading to shock
    and possibly death, occurs in the more severe cases. The onset of the
    signs of poisoning may not be evident until a few days after exposure.

    When handling technical material or powder concentrates, full air-fed
    protection and an impervious suit suitable for wash-down are
    necessary. Operations with liquid concentrates require the use of PVC
    or nitrile-rubber gloves, armlets, and an apron, with a face shield
    and rubber boots.

    All persons who are bleeding, or suspected to be heavily exposed, must
    receive medical attention.

    4.1.1  Advice to physicians

    If poisoning is recent (within a few hours), gastric lavage is
    recommended. Administration of active charcoal in repeated doses is
    also recommended.

    Take a venous blood sample for measurement of the haemoglobin level,
    prothrombin time, blood grouping, and cross-matching.

    In less severe cases of poisoning give vitamin K1 (phytomenadione)
    (5-10 mg), by slow intravenous infusion, 3 times daily on the first
    day. After initial intravenous administration, oral treatment can be
    continued until normalization of prothrombin tests.

    In more severe cases, transfusion of matched whole blood or fresh,
    frozen plasma should also be given and repeated daily until
    prothrombin tests have returned to normal. Administration of factor
    concentrate may be considered to prevent a volume overload.

    Prothrombin tests should be made at least twice daily until a return
    to normal is clearly established.

    Keep the patient in hospital until the prothrombin time has remained
    normal for three days.

    4.1.2  Health surveillance advice

    Workers handling concentrates should undergo periodic determinations
    of blood prothrombin time. Persons with a history of blood disorders
    with bleeding tendencies would be expected to be at increased risk in
    case of exposure.

    4.2  Explosion and Fire Hazards

    Flash point and flammable limits have not been found. Contact with
    strong oxidizers may cause fires and explosions. Recommended
    extinguishers are foam, carbon dioxide, or dry chemicals.

    High temperature decomposition or burning may lead to the formation of
    toxic gases and vapours. Wear full protective clothing and
    self-contained breathing apparatus in fire-fighting.

    Run-off water from the fire should be prevented from entering
    surface-water drains or water courses.

    4.3  Storage

    Technical material and formulations should be stored in sealed
    containers in locked, well-ventilated, dry areas away from frost,
    direct sunlight, and sources of heat and ignition. Keep products out
    of reach of children, unauthorized personnel, and domestic animals. Do
    not store near food or animal feed.

    4.4  Transport

    Comply with any local regulations regarding the movement of hazardous
    goods. Before despatch ensure that the containers are sound and that
    labels are securely fixed and undamaged.

    4.5  Spillage

    During decontamination, the operator must wear protective clothing,
    PVC or nitrile gloves, a face shield, and rubber boots.

    Small spills should be collected and disposed of as toxic waste
    according to local legislation.

    Large quantities may be destroyed by dissolving in a flammable solvent
    (e.g., alcohol) and atomizing in a combustion chamber.

    Contaminated areas should be washed down with cold water containing
    surfactant or detergent; the washings must be prevented from entering
    surface water and drains.

    4.6  Disposal

    No specific data are available.


    Warfarin is practically insoluble in water. It is unlikely to be a
    source of environmental contamination.

    Do not place baits where domestic or farm animals and birds can reach
    them. Burn or bury any uneaten bait. Do not dump it in water. Look for
    dead rats and mice and burn or bury them.


     This summary should be easily available to all health workers
     concerned with, and users of, warfarin. It should be displayed at, or
     near, entrances to areas where there is potential exposure to
     warfarin, and on processing equipment and containers. The summary
     should be translated into the appropriate language(s). All persons
     potentially exposed to the chemical should also have the instructions
     in the summary clearly explained.

     Space is available for insertion of the National Occupational
     Exposure Limit, the address and telephone number of the National
     Poison Control Centre, and local trade names.


    Chemical formula: C19H16O4

    CAS chemical name: 4-hydroxy-3-(3-oxo-1-phenylbutyl)-2 H-1-benzopyran-2-one
    IUPAC chemical name: (RS) 4-hydroxy-3-(3-oxo-1-phenylbutyl) coumarin
    CAS registry number: 81-81-2 (unstated stereochemistry)
    PHYSICAL PROPERTIES                                                                  OTHER CHARACTERISTICS

    Physical state                                  crystalline                          When used as a rodenticide it is formulated as 
    Colour                                          colourless                           baits containing 250-1000 mg active ingredient/kg
    Relative molecular mass                         308.6
    Melting point (°C)                              159-161
    Solubility in water                             insoluble
    Solubility in
      alcohols                                      moderate
      acetone                                       readily
      dioxane                                       readily
    HAZARD SYMPTOMS                                 PREVENTION AND PROTECTION            FIRST AID

    GENERAL:  Easily absorbed                       Avoid exposure                       Obtain medical attention; antidote - vitamin K1
    following ingestion and through
    the skin; if absorbed, may cause
    increased bleeding tendency
    to massive haemorrhage

    SKIN:  Absorption may occur                     Wear gloves when handling            Wash with soap and water;  seek medical
                                                    concentrate material                 attention

    EYES:                                           Use a face shield when handling      Flush eyes with water for at least 15 min
                                                    concentrate material

    WARFARIN (cont'd)
    HAZARD SYMPTOMS                                 PREVENTION AND PROTECTION            FIRST AID

    INHALATION:  Significant                        Avoid breathing aerosols or dust     Move patient to fresh air;  call emergency
    hazard                                                                               medical care

    INGESTION:  An unlikely                         Wash hands before eating, drinking,
    occupational hazard                             or smoking

    Accidental or intentional ingestion             Keep out of reach of children and    Transfer to hospital immediately; rinse out
    may lead to poisoning in several                under lock and key                   the mouth with water
    SPILLAGE                                        STORAGE                              FIRE/EXPLOSION

    Wear protective clothing during                 Store in sealed containers in a      Burning in air may lead to the formation of
    decontamination;  dry spillage - collect        dry, ventilated and locked           toxic gases and vapours; use alcohol foam,
    by suction and dispose of as toxic              storeroom, away from children and    carbon dioxide, or dry chemicals; keep 
    waste; large spillage - dissolve in             unauthorized persons, food, and      containers cool by spraying with water
    a flammable solvent for atomizing               animal feed
    in a combustion chamber; do not
    contaminate surface-water drains
    WASTE DISPOSAL                                  NATIONAL INFORMATION

    Proper incineration

    7.1  Previous Evaluations by International Bodies

    Warfarin has been classified by WHO in Class Ib - Highly Hazardous,
    based on an acute oral LD50 of 10 mg/kg for rats.

    7.2  Exposure Limit Values

         ACGIH TLV, TWA 0.1 mg/m3

         STEL 0.3 mg/m3

         OSHA PEL, TWA 0.1 mg/m3

    7.3 Specific Restrictions

    Warfarin has been approved for use as a rodenticide in many countries.
    In some countries, specific uses are defined, as well as limitations
    and precautions.

    7.4  Labelling, Packaging, and Transport

    The United Nations Committee of Experts on the Transportation of
    Dangerous Goods classifies warfarin in:

         Hazard Class:       6.1 -- poisonous substance.

         Packing Group:      I --  very dangerous substance when active
                             ingredient = 100-60%.

                             II -- substance presenting medium danger when
                             active ingredient = 60-6%.

                             III -- substance presenting minor danger when
                             active ingredient 6-1.5% (solid) or 6-0.6%

    The European Economic Community legislation requires labelling of
    warfarin as a dangerous substance using the symbol T - toxic.

    R 26/27/28 Very toxic by inhalation, in contact with skin, and if

    7.5  Waste Disposal

    In the USA, warfarin waste is identified as an "acute hazardous


    CEC (1987) Legislation in dangerous substances - Classification and
    labelling in the European Communities - Vol. 1 & 2. Commission of the
    European Communities, London, Graham & Trotman, Ltd.

    Hayes WJ Jr & Laws ER Jr (1991) Handbook of pesticide toxicology,
    Vol. 3, New York, Academic Press.

    IPCS (1992) Poisons information monograph - Warfarin,

    IPCS (1995) Environmental Health Criteria 175: Anticoagulant
    rodenticides, Geneva, World Health Organization.

    IPCS-CEC (1993) International Chemical Safety Card No. 0821, Warfarin.

    IRPTC (1987) IRPTC legal file 1986, Geneva, International Register for
    Potentially Toxic Chemicals, United Nations Environment Programme.

    IPCS/INTOX Project, Geneva, World Health Organization (unpublished
    document IPCS/INTOX/PIM.563).

    United Nations (1989) Recommendations on the transport of dangerous
    goods, Sixth edition, New York, United Nations.

    US NIOSH/OSHA (1981) Occupational health guidelines for chemical
    hazards, 3 vol., Washington DC, US Department of Health and Human
    Services. US Department of Labour (Publication No. DHHS (NIOSH)

    WHO (1994) The WHO recommended classification of pesticides by hazard
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    Worthing CR & Hance RJ, ed. (1991) The pesticide manual, 9th ed.,
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    See Also:
       Toxicological Abbreviations
       Warfarin (ICSC)
       Warfarin (PIM 563)