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 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: Warfarin (ICSC) Warfarin (PIM 563)