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    WORLD HEALTH ORGANIZATION             FOOD AND AGRICULTURE
                                          ORGANIZATION
    ORGANISATION MONDIALE DE LA SANTE     ORGANISATION POUR L'ALIMENTATION
                                          ET L'AGRICULTURE

                                          VBC/DS/78.35 
                                          ORIGINAL:   ENGLISH 


    WARFARIN

                                   CLASSIFICATION:
                                   Primary Use: Rodenticide
                                   Secondary Use: Medical
                                   Chemical Group: Hydroxycoumarin compound
                                   Date Issued:


         It must be noted that the issue of a Data Sheet for a
    particular pesticide does not imply endorsement of the pesticide by
    WHO or FAO for any particular use, or exclude its use for other
    purposes not stated. While the information provided is believed to
    be accurate according to data available at the time when the sheet
    was compiled, neither WHO nor FAO are responsible for any errors or
    omissions, or any consequences therefrom.

    The issue of this document does    Ce document ne constitue pas une
    not constitute formal              publication. Il ne doit faire
    publication. It should not be      l'objet d'aucun compte rendu ou
    reviewed, abstracted or quoted     résumé ni d'aucune citation sans
    without the agreement of the       l'autorisation de l'Organisation
    Food and Agriculture               des Nations Unies pour
    Organization of the United         l'Alimentation et l'Agriculture
    Nations or of the World Health     ou de l'Organisation Mondiale de
    Organization.                      la Santé.


    CLASSIFICATION: 

    Primary Use: Rodenticide 
      
    Secondary Use: Medical 

    Chemical Group: Hydroxycoumarin compound 

    Date Issued: 

    1.     GENERAL INFORMATION 

    1.1    COMMON NAME: Warfarin (ISO) 

    1.1.1  Identity: 4-hydroxy-3-(3-oxo-l-phenylbutyl)-2H-1-benzopyran-2-
           one 

           Structure

    1.1.2  Synonyms: 
           WARF 42
           Athrombine-K
           Coumadin
           Coumafene 
           Zoocoumarin 
                                    
           Local synonyms:                                            
     
    1.2    SYNOPSIS - An anticoagulant rodenticide that is highly toxic to 
           mammals on repeated ingestion, but of variable toxicity to 
           different species when given-as a single acute oral dose. It 
           does not accumulate in body tissues. 

    1.3    SELECTED PROPERTIES 

    1.3.1  Physical characteristics - Colourless, tasteless, and odourless 
           crystals of m.p. 159-161°C. 

    1.3.2  Solubility - Of a low solubility in water, benzene, cyclohexane 
           and hexane. Moderately soluble in alcohol and methanol and 
           readily soluble in acetone and dioxane. 

    1.3.3  Stability - The sodium salt of warfarin is relatively stable. 

    1.3.4  Vapour pressure - No information. 

    1.4    AGRICULTURE, HORTICULTURE AND FORESTRY 

    1.4.1  Common formulations - Powdered concentrates containing 0.5% 
           warfarin for mixture in ratio 1:19 with protein rich bait, e.g. 
           cornmeal, oatmeal, dogmeal, stockfeed; also 1% dusts. 

    1.4.2  Susceptible pests - A broad range of rodent species.  Resistance 
           to this compound has developed in geographically widely 
           scattered rat populations, based on changes in vitamin K 
           metabolism. 

    1.4.3  Use pattern - Used in rodent holes and runs as bait or dusts.  
           Baiting should be continued for 14 days. 

    1.4.4  Unintended effects - No information. 

    1.5    PUBLIC HEALTH PROGRAMME:  Widely used as a rodenticide:  see 
           above 1.4.2 

    1.6    HOUSEHOLD USE: May be used as a household rodenticide, usually 
           at concentrations of 0.005% to 0.25% w/w. 

    2.     TOXICOLOGY AND RISKS 

    2.1    TOXICOLOGY - MAMMALS 

    2.1.1  Absorption route - Absorbed from the gastrointestinal tract and 
           by inhalation; absorbed to a much lesser extent through the intact 
           skin. 

    2.1.2  Mode of action - Warfarin, possible as the 4-hydroxycoumarin 
           moiety, inhibits the formation of prothrombin by replacing 
           vitamin K in the complex and so reduces the clotting capacity of 
           blood; it also increases capillary permeability. 

    2.1.3  Excretion products - Warfarin is metabolised by the liver. 
           Excretion by the rat after intraperitoneal dosage, is two-thirds 
           via the urine and one-third via the faeces.  The metabolites 
           found include warfarin itself, 4, 6, 7 and 8 hydroxy coumarins 
           and 2,3-dihydro-2-methyl-4-phenyl-5-oxo- e-pyrano (3,2-CX1) 
           benzopyran. 7 and 4 hydroxycol-arins make up approximately 56% 
           of the metabolites in urine. 

    2.1.4  Toxicity, single dose 

           Oral:  LD50 rats (M) 323 mg/kg 
                       rats (F) 58  kg/kg 
                       in aqueous suspension 

                  LD50 rats (M) 3.0 mg/kg 
                       dissolved in peanut oil 

           From a single dose, the maximum effect on the prothrombin level 
           is seen at 4 days: spontaneous recovery to normal occurs at about 
           8 days. 

           Most susceptible species:  probably the pig.  Deaths have been 
           recorded in this species at 5.0, 10.0 and 30.0 mg/kg. 

    2.1.5  Toxicity, repeated doses 

           Oral:  The 5 day, repeated dose, oral LD50 is given as:
        
           Pig 0.4 mg,/kg/day 
           Rat 1.0 mg,/kg/day 
           Cat and dog 3.0 mg,/kg,/day 
           Poultry 10.0 mg,/kg/day 

           Inhalation: No information available. 

           Cumulation of compound:  Warfarin does not accumulate to any 
           extent in body tissues; most is excreted within two days after 
           an intraperitoneal dose; after seven days only trace amounts can 
           be found in urine. 

           Cumulation of effect: Repeated ingestion of warfarin causes a 
           drastic lowering of prothrombin levels and is the basis of its 
           rodenticidal action. 

    2.1.6  Dietary studies 

           Short-term: Four rats of both sex survived for eight months when 
           fed at a level of 1 mg/kg diet; 6.25 mg/kg diet proved fatal to 
           all the rats with the mean survival time 10.7 days.  Deaths in 
           pigs have been recorded at eight daily doses at 0.2 mg/kg bw. 
           Three out of four dogs survived 175 days feeding experiments at 
           levels of 10 mg/kg diet.  Two dogs out of four survived for 220 
           days when fed at 20 mg/kg diet. 

           Long-term: No information available. 

    2.1.7  Supplementary studies of toxicity 

           Increased susceptibility to warfarin toxicity has been observed 
           during pregnancy in dogs, with foetal death. It is probable that 
           warfarin can cross the placenta and is secreted in the milk.  
           Deaths in foetuses and newborn have been due to haemorrhage; 
           some resorptions were observed. 
           
    2.1.8  Modification of toxicity - Predosing with phenobarbitone, 
           chlorinated hydrocarbons or other enzyme inducers may decrease 
           the toxicity by a factor of 10 by increasing the rate of 
           metabolism of warfarin. 

    2.2    TOXICOLOGY - MAN 

    2.2.1  Absorption - Warfarin may be absorbed from the gastrointestinal 
           tract or by inhalation, and to a much lesser extent, through the 
           intact skin. 

    2.2.2  Dangerous doses 

           Single: Acute poisoning from a single dose contained in a bait 
           is unlikely. 

           Repeated: 1-2 mg/kg for periods of 6-15 days has caused serious 
           illness and death in man.  Serious illness was induced by the 
           ingestion of 1.7 mg/kg,/day for six consecutive days with 
           suicidal intent.  All signs and symptoms were caused by 
           haemorrhage. 

    2.2.3  Observations of occupational exposed workers - No information 
           available. 

    2.2.4  Observations of exposure of the general population - No exposure 
           of the general population to warfarin should occur when used 
           correctly. 

    2.2.5  Observations of volunteers - Warfarin has been used in human 
           therapy as anticoagulant.  A single intravenous dose of 1 mg/kg 
           increases the prothrombin time within 14 hours.  In the 
           treatment of thromboembolic disease, a dose of 5-10 mg/day may 
           be required to keep the prothrombin level at 10-30% of nomal.  
           Patients have been thus maintained for years.  Dematologic side 
           effects have been observed in patients undergoing warfarin 
           therapy. 

    2.2.6  Reported mishaps - A family of 14 persons lived for 15 days on a 
           diet consisting almost entirely of cornmeal containing warfarin.  
           The dosage was determined as 1-2 mg/kg/day.  As a result of this 
           exposure and without treatment, two of the 1. persons died. 

    2.3    TOXICITY TO NON-MAMMALIAN SPECIES 

    2.3.1  Fish - No information available 

    2.3.2  Birds - Moderately toxic 

    2.3.3  Other species - No data available 

    3.     FOR REGULATORY AUTHORITIES - RECOMMENDATIONS OF REGULATIONS OF 
           COMPOUND 

    3.1    RECOMMENDED RESTRICTIONS ON AVAILABILITY 

           (for definition of categories, see introduction) 

           All formulations Category 4 except pre-prepared baits,  
           Category 5 

    3.2    TRANSPORTATION AND STORAGE 

           All formulations should be stored in clearly labelled, sealed 
           containers under lock and key, secure from access by 
           unauthorized persons or children.  No food or drink should be 
           stored in the same compartment. 

    3.3    HANDLING 

           All formulations - Adequate washing facilities should be 
           available at all times during handling and should be close to 
           the site of handling.  Eating, drinking and smoking should be 
           prohibited during handling and before washing after handling.  
           Warfarin baits should be removed when their purpose has been 
           fulfilled. 

           Pre-prepared baits - No facilities other than those for handling 
           of any chemical need be required. 

    3.4    DISPOSAL AND/OR DECONTAMINATION OF CONTAINER 

           All formulations - Containers must either be crushed and buried 
           below the topsoil or burned.  Care must be taken to avoid 
           subsequent contamination of water sources.  Decontamination of 
           containers in order to use them for other purposes should not be 
           pemitted. 

    3.5    SELECTION, TRAINING AND MEDICAL SUPERVISION OF WORKERS 

           All formulations - Pre-employment and routine medical 
           examination of workers desirable.  Special account should be 
           taken of the workers' mental ability to comprehend and follow 
           instructions. 

    3.6    ADDITIONAL REGULATIONS RECOMMENDED IF DISTRIBUTED BY AIRCRAFT 

           All fomulations - Not applicable. 

    3.7    LABELLING 

           All formulations - Minimum cautionary statement: Warfarin is a 
           toxic substance.  Do not inhale dust.  Keep this material or 
           baits containing it, out of reach of children and domestic 
           animals and well away from foodstuffs, animal feed and their 
           containers. 

    3.8    RESIDUES IN FOOD 

    3.8.1  Maximum residue levels - The Joint FAO/WHO Meeting on Pesticide 
           Residues has not recommended any maximum residue level.  If used 
           correctly as a bait, residues of warfarin will not appear in 
           human food. 

    4.     PREVENTION OF POISONING IN MAN AND EMERGENCY AID 

    4.1    PRECAUTIONS IN USE 

    4.1.1  General - Warfarin is an anticoagulant rodenticide which is 
           highly toxic on repeated ingestion.  It is readily absorbed by 
           the gastrointestinal tract and by inhalation but not very 
           readily through the intact skin. 

    4.1.2  Manufacture and formulation - TLV: (ACGIH) 0.I/mg/m3 (USSR).  
           Closed system and forced ventilation may be required to reduce 
           as much as possible the exposqre of workers to the chemical. 

    4.1.3  Mixers and applicators - Particularly when opening the container 
           and when mixing baits, Tlean overalls and gloves should be worn.  
           Contact with the mouth should be avoided.  Particular care is 
           needed when equipment is being washed after use.  Before eating, 
           drinking or smoking, hands and other exposed skin should be 
           washed.  Baits should not be used where there is a risk of 
           contaminating food, animal feeding stuffs, or drinking or 
           washing water.  Exposed baits should be laid in containers 
           clearly marked.  Poison baits should not be laid unless all 
           access by children or domestic animals can be prevented.  All 
           exposed baits and their containers should be removed after 
           treatment and burned.  Rodent bodies should be searched for and 
           destroyed by burning. 

    4.1.4  Other associated workers (including flagmen in aerial 
           operations) - not applicable. 

    4.1.5  Other populations likely to be affected - With correct use as 
           described under mixers and applicators (4.1.3 above) other 
           populations will not be exposed to hazardous amounts of 
           warfarin. 

    4.2    ENTRY OF PERSONS INTO TREATED AREAS - Care should be taken that 
           children and animals cannot gain access to exposed baits. 

    4.3    DECONTAMINATION OF SPILLAGE AND CONTAINERS - Residues in 
           containers should be emptied into a deep pit, taking care to 
           avoid contamination of ground waters.  Decontamination of 
           containers to use them for other purposes should not be 
           permitted.  Spillage should be removed as much as possible into 
           a deep dry pit and the remainder washed away with large 
           quantities of water. 

    4.4    EMERGENCY AID 

    4.4.1  Early symptoms of poisoning - Acute poisoning from a single dose 
           of warfarin is unlikely.  On repeated exposure symptoms may 
           occur from the sixth or seventh day and include back and 
           abdominal pain followed by vomiting, nose and gum bleeding, 
           massive bruising and haematoma fomation. 

    4.4.2  Treatment before person is seen by a physician, if these 
           symptoms appear following exposure - Medical help should be 
           obtained.  Vitamin KI is a specific antidote. 

    5.     FOR MEDICAL AND LABORATORY PERSONNEL 

    5.1    MEDICAL DIAGNOSIS AND TREATMENT IN CASES OF POISONING 

    5.1.1  General information - Warfarin is an anticoagulant rodenticide 
           normally used in bait form.  It is readily absorbed from the 
           gastrointestinal tract and by inhalation and to a much lesser 
           extent through the intact skin.  Its main toxic hazard is from 
           repeated exposure.  It inhibits prothrombin formation with a 
           resultant decrease in the clotting capacity of the blood. 

    5.1.2  Symptoms and signs - Symptoms are likely to occur after 5-7 days 
           repeated exposure.  Initially there is back and stomach pain, 
           followed later by nose and gum bleeding, bruising and 
           haemorrhage formation.  All symptoms are associated with 
           haemorrhage either into body cavities or tissues.  Haemorrhagic 
           shock may occur teminally. 

    5.1.3  Laboratory - Of greatest significance is the markedly reduced 
           prothrombin activity of blood plasma, which can be measured by 
           the method of Quick or its modifications.  Though less specific, 
           the clotting time will also be altered.  If haemorrhage has been 
           extensive, haematological indices will also be affected. 

    5.1.4  Treatment - Vitamin Kl in a dose of 65 mg should be given three 
           times on the first day of treatment irrespective of symptoms.  
           (it will be noted that the suggested dosage of vitamin K is far 
           in excess of the 1 mg dosage recommended in the Pharmacopoeia.  
           It is however, a safe dosage and is based on that already used 
           successfully for some years in the treatment of excessive 
           hypoprothrombinemia in the course of medication with coumarin 
           drugs.)  Smaller doses of vitamin KI should be continued until 
           the prothrombin time has reached normal.  In a seriously ill 
           patient, in addition to vitamin K treatment, a transfusion of 
           carefully matched whole blood should be given and repeated daily 
           as necessary.  Any large haematoma should be the subject of 
           surgical consultation, but no action should be taken until the 
           clotting power of the blood has returned to normal. 

    5.1.5  Prognosis - The prognosis is good; however, bleeding associated 
           with the central nervous system may give rise to serious 
           complications. 

    5.1.6  References of previously reported cases -  W. J. Hayes,  
           Clinical  Handbook  on  Economic Poisons.  US Dept.  Hlth Educ. 
           & Welfare, Atlanta, Georgia, 1963. 

    5.2    SURVEILLANCE TESTS - The progress of the patient should be
           followed by the prothrombin test (Quick or its modifications) 
           which should be made at least twice daily until a return to 
           normal is clearly established. 

    5.3    LABORATORY METHODS 

    5.3.1  Detection and assay of compound - Methods for the detection and 
           assay of warfarin, both in baits and in post-mortem tissues are 
           given and discussed, see:  H. Wanntorp, Acta Pharm et Tox, Vol 
           16 Supplementum 2, 1960.  Two methods of analysis involving thin 
           layer chromatography have also been published, see: Ruessel H. 
           A. (1970) Z Anal. Chem. 250(2) 125 and Welling, P. G. (1970)  
           J. Pharm. Sci. 59(11) 1621. 

    5.3.2  Other tests in cases of poisoning - Methods of estimation of 
           prothrombin and coaaulation time will be found in most 
           haematology handbooks, e.g.: Disorders of the Blood, Whitby and 
           Britton, 10th edition, J. A. Churchill Ltd., London 1979.  
           Laboratory Medicine Haematology, John B. Miable.  The C. V. 
           Mosby Co. 1958. Measurement of coagulation time method can be 
           used to confirm exposure.  Note that bleeding time is not 
           affected by warfarin poisoning; prothrombin time is the method 
           of choice in diagnosing warfarin poisoning. 






    See Also:
       Toxicological Abbreviations
       Warfarin (HSG 96, 1995)
       Warfarin (ICSC)
       Warfarin (PIM 563)