Warfarin

Teratogens

Pharmaceutical

Pesticide -> EPA IRIS

Rodenticides

Active substance -> EU Pesticides database: Not approved

Pesticides -> Rodenticides, Anticoagulant

Pesticide

log Kow = 2.70

2.70

2.6

2.4

Crystals from alcohol

White powder

The racemate forms colorless crystals

0.002 % (NIOSH, 2024)

Solubility: 1 g in 1.5 mL water, 1.9 mL alcohol, >10,000 mL chloroform, >10,000 mL ether /Warfarin potassium/

In water, 17 mg/L at 20 °C

Soluble in acetone, dioxane; moderately soluble in methanol, ethanol, isopropanol, some oils; freely soluble in alkaline aqueous solution (forms a water-sol sodium salt); practically insoluble in benzene, cyclohexane, Skellysolves A and B.

In acetone 65, chloroform 56, dioxane 100 (all in g/L, 20 °C)

Breast Feeding; Lactation; Milk, Human; Anticoagulants

Medicines affecting coagulation

Decomposes (NIOSH, 2024)

decomposes

356 °C @760 [mm Hg]

Decomposes

Danger

H300: Fatal if swallowed [Danger Acute toxicity, oral]

P203, P260, P262, P264, P270, P271, P273, P280, P284, P301+P316, P302+P352, P304+P340, P316, P318, P319, P320, P321, P330, P361+P364, P391, P403+P233, P405, and P501 (click each P-code to see the statement)

Danger

H300 (97%): Fatal if swallowed [Danger Acute toxicity, oral]

P203, P260, P262, P264, P264+P265, P270, P271, P273, P280, P284, P301+P316, P302+P352, P304+P340, P305+P351+P338, P316, P317, P318, P319, P320, P321, P330, P337+P317, P361+P364, P362+P364, P391, P403+P233, P405, and P501 (click each P-code to see the statement)

Hazard Traits - Developmental Toxicity; Reproductive Toxicity

06/05/EC, Reg (EU) 2015/408, Reg. (EU) 2022/801, Reg. (EU) No 186/2014, Reg. (EU) No 540/2011, Reg. (EU) No 823/2012

Status: Active Update: 16-08-2019 https://echa.europa.eu/registration-dossier/-/registered-dossier/17263

Warfarin: HSNO Approval: HSR002888 Approved with controls

The New Jersey Worker and Community Right to Know Act requires public and private employers to provide information about hazardous substances at their workplaces. (N.J.S.A. 34:5A-1 et. seq.)

Contact with strong oxidizers may cause fires and explosions. Toxic gases and vapors (e.g., carbon monoxide) may be released in heating to decomposition. Avoid strong oxidizers. (EPA, 1998)

Combustible.

It is classified as very toxic. Probable oral lethal dose in humans is 50-500 mg/kg, between 1 teaspoon and 1 ounce for a 150 lb. person. Material is an anticoagulant. Toxic effects other than hemorrhage are rarely seen in humans. Material is believed to be teratogenic in humans. Persons with a history of blood disorders with bleeding tendencies would be expected to be at increased risk from exposure. (EPA, 1998)

TLV Basis: bleeding; teratogenic; Human NOAEL (no measurable effect on coagulation) = 0.2 mg/day orally; 50% of rats die when exposed to 0.077 mg/kg/day for 90 days; Single doses in humans: not fatal; Ingestion of 1 to 2 mg/kg/day for up to 15 days: fatal to humans; Warfarin crosses the placenta and causes congenital malformations in humans after maternal exposure--63 cases of embryopathy reported; [ACGIH] There is one report of a farmer developing symptoms after prolonged skin contact of a liquid formulation. No other cases after occupational exposure have been reported. [LaDou, p. 609] There are rare case reports of acute liver injury caused by high-dose Warfarin ingestion. [Zimmerman, p. 330] One study on warfarin in rats has indicated developmental effects. Otherwise, there is no convincing evidence that anticoagulants are teratogenic in experimental animals. There is no evidence to suggest that any anticoagulant rodenticides are mutagenic, but there are insufficient data available on individual compounds to demonstrate an absence of mutagenicity. [Reference #2]

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including warfarin sodium, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Warfarin sodium/

Little BB et al; Drugs and Pregnancy (1992). Review of /the adverse effects of/ anticoagulants ... during pregnancy.

Hirsh J; N eng J Med 324: 1865-75 (1991). A review of anticoagulant drugs, including the pharmacology of warfarin. ...

USEPA/OPP; Reregistration Eligibility Document (RED): Warfarin & Appendices EPA 540/RS-92-164 (1992)

Greaves M; Pharmacol Ther 59 (3): 311-27 (1993). A review article concerning the use of anticoagulants in pregnancy.

(Non-Specific -- Poison B Solid) Wear full protective clothing and self-contained breathing apparatus.

Use water spray, foam, powder, carbon dioxide.

Refer for medical attention.

Remove contaminated clothes. Rinse and then wash skin with water and soap. Refer immediately for medical attention .

Rinse with plenty of water (remove contact lenses if easily possible).

Rinse mouth. Give a slurry of activated charcoal in water to drink. Refer immediately for medical attention.

Signs and Symptoms of Warfarin Exposure: Warfarin is an anticoagulant. Hemorrhage is the most common sign and may be manifested by hemorrhagic skin rashes and lip, nose, and upper airway bleeding. Upper airway pain, difficulty in speaking and swallowing, and dyspnea (shortness of breath) may occur. Vomiting, abdominal pain, and bloody stools are common. Back pain may be noted.

(General first aid procedures)

Warfarin /therapeutic/ prepn should be stored at a temp less than 40 °C, preferably between 15-30 °C; warfarin potassium & warfarin sodium tablets should be stored in tight, light-resistant containers & warfarin sodium powder for injection should be protected from light. Reconstituted solutions of warfarin sodium should be used immediately. /Warfarin potassium & warfarin sodium/

Do not store near feed and food. ... Store away from heat and open flames.

Personal precautions: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

Do not touch spilled material. Eating and smoking should not be permitted in areas where it is handled, processed or stored. For small spills: sweep onto paper or other suitable material. Place in an appropriate container and burn in a safe place. Large quantities may be destroyed by dissolving in a flammable solvent (e.g., alcohol) and atomizing in a combustion chamber. (EPA, 1998)

Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number P001, U248, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste.

FOR SMALL QUANTITIES, SWEEP ONTO PAPER OR OTHER SUITABLE MATERIAL, PLACE IN AN APPROPRIATE CONTAINER AND BURN IN A SAFE PLACE (SUCH AS A FUME HOOD). LARGE QUANTITIES MAY BE RECLAIMED; HOWEVER, IF THIS IS NOT PRACTICAL, DISSOLVE IN A FLAMMABLE SOLVENT (SUCH AS ALCOHOL) AND ATOMIZE IN A SUITABLE COMBUSTION CHAMBER.

Incineration: 1) Stuff a package with paper or flammable materials. Burn in the furnace. 2) Dissolve in a combustible solvent. Burn in the furnace by spraying the soln.

Personal protection: chemical protection suit including self-contained breathing apparatus. Do NOT let this chemical enter the environment. Sweep spilled substance into sealable containers. If appropriate, moisten first to prevent dusting. Carefully collect remainder. Then store and dispose of according to local regulations.

SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place.

Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product.

Keep away from children and animals. ... Avoid contact with mouth, eyes, skin.

The worker should immediately wash the skin when it becomes contaminated.

For more Preventive Measures (Complete) data for WARFARIN (11 total), please visit the HSDB record page.

The primary antidote to warfarin poisoning is immediate administration of vitamin K1 (initially slow intravenous injections of 10-25 mg repeated all 3-6 hours until normalisation of the prothrombin time; then 10 mg orally four times daily as a "maintenance dose"). It is an extremely effective antidote, provided the poisoning is caught before too much damage has been done to the victim's circulatory system. At high doses warfarin can affect the body for many months, and the antidote must be administered regularly for a long period of time. (L1257)

The pharmacokinetic complex activity after a single iv coadministration with warfarin (1.2 mg/kg) and furosemide (1.67 mg/kg) were not significantly different as compared with those in the group injected with warfarin alone; however, when coadministered with 5 mg/kg of furosemide, the elimination rate constant was significantly increased and the pharacokinetic complex activity was markedly enhanced beyond 60 hours after administration. These results suggest that the interactions, such as the displacement of warfarin binding at albumin binding sites, between warfarin and furosemide are produced, when a high dose of furosemide was coadministered.

REVIEW ON CLINICALLY IMPORTANT DRUG INTERACTIONS WITH CIMETIDINE. THE METABOLISM OF WARFARIN (AND PROBABLY OTHER COUMARIN ANTICOAGULANTS) IS DECREASED BY CIMETIDINE.

... Metronidazole had no effect on the serum protein binding of racemic warfarin in vitro over a wide concn range but decreased the protein binding of R-(+)-warfarin & S-(-)-warfarin in vitro ... (in rats) Treatment with ip metronidazole, 100 mg/kg every 6 hours, decreased the plasma clearance of free warfarin. ... Metronidazole did not affect plasma prothrombin complex activity in vitro but reduced it in vivo. ...

... Chloramphenicol had no apparent effect on the serum protein binding of R-(+)-warfarin or S-(-)-warfarin in vitro or in vivo /in rats/. Treatment with ip chloramphenicol, 50 mg/kg every 4 hrs or 30 mg/kg every 6 hrs decreased the plasma clearance of free warfarin by 1/2 or more, with no apparent stereoselectivity. The volume of distribution was not significantly affected; the serum half-life of each warfarin enantiomer was appreciably increased by chloramphenicol. ... It appears that the pronounced potentiation of the anticoagulant effect of warfarin by chloramphenicol is due only to inhibition of warfarin metabolism & that this effect is not stereoselective.

For more Interactions (Complete) data for WARFARIN (85 total), please visit the HSDB record page.

Hematologic

Blood, cardiovascular system

Liver injury due to warfarin therapy is rare, but clinically apparent acute liver injury attributable to it has been reported. Liver injury is more common with other coumarin derivatives such as phenprocoumon and acenocoumarol, which are available in other countries but not in the United States. The typical case of acute liver injury arises within 3 to 8 weeks of starting warfarin, although rare instances of liver injury arising after months or years of therapy have been reported (and these long latencies are common with phenprocoumon hepatotoxicity). The pattern of liver enzyme elevations is typically cholestatic, but hepatocellular and mixed patterns have also been reported. Eosinophilia can occur, but other immunoallergic manifestations are not common nor are autoantibodies. Recovery can be prolonged, particularly with cholestatic injury. Recurrence upon reexposure has been described and can be more severe and result in death.

LC50; Species: Rasbora heteromorpha (harlequin fish); Concentration: 17 mg/L for 24 hr; 14 mg/L for 48 hr; 12 mg/L for 96 hr /Conditions of bioassay not specified/

LC50; Species: Ictalurus punctatus /(Channel catfish)/; Conditions: static bioassay without aeration, pH 7.2-7.5, water hardness 40-50 mg/L as calcium carbonate and alkalinity of 30-35 mg/L; Concentration: 34.3 mg/L for 96 hr

LD50; Species: /Colinus virginianus/ (Bobwhite quail) oral >2000 mg/kg

LC50; Species: Anas platyrhynchos (Mallard duck) age 10 days; diet 1726 ppm (95% confidence interval: 625-33111 ppm) for 30 days

For more Ecotoxicity Values (Complete) data for WARFARIN (19 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), reported Koc values of 30.5 to 912(2-4), indicate that warfarin is expected to very high to low mobility in soil(SRC). The pKa of warfarin is 5.87(5), indicating that this compound will partially exist in anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(6). Volatilization of the neutral form of warfarin from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.7X10-10 atm-cu m/mole(SRC), based upon its vapor pressure, 1.13X10-8 mm Hg(7), and water solubility, 17 mg/L(7). The anion form of warfarin is not expected to volatilize from soil based upon the pKa(SRC). Warfarin is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(7). Biodegradation in soil may not be an important environmental fate process with only a 13% degradation (COD reduction) over a 28-day incubation period using activated sludge and the sodium salt(8).

AQUATIC FATE: Based on a classification scheme(1), reported Koc values of 30.5 to 912(2-4), indicates that warfarin is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces of the neutral form of warfarin is not expected(5) based upon an estimated Henry's Law constant of 2.7X10-10 atm-cu m/mole(SRC), derived from its vapor pressure, 1.13X10-8 mm Hg(6), and water solubility, 17 mg/L(6). A pKa of 5.87(7) indicates warfarin will partially exist in the anion form at pH values of 5 to 9 and, therefore, volatilization from water surfaces of the anion is not expected to be an important fate process(SRC). According to a classification scheme(8), an estimated BCF of 28(SRC), from its log Kow of 2.70(9) and a regression-derived equation(10), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Warfarin has a reported neutral hydrolysis half-life of 16.1 years(11). Biodegradation in water may not be an important environmental fate process with only a 13% degradation (COD reduction) over a 28-day incubation period using activated sludge and the sodium salt(12).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), warfarin, which has a vapor pressure of 1.13X10-8 mm Hg at 21 °C(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase warfarin is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 6.5 hours(SRC), calculated from its rate constant of 5.4X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). The rate constant for the vapor-phase reaction of warfarin with ozone has been estimated as 1.4X10-16 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). This corresponds to an atmospheric half-life of about 2.0 hours at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(4). Particulate-phase warfarin may be removed from the air by wet or dry deposition(SRC). Warfarin contains chromophores that absorb at wavelengths 330 nm(5) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Occupational hepatotoxin - Secondary hepatotoxins: the potential for toxic effect in the occupational setting is based on cases of poisoning by human ingestion or animal experimentation.

Severe adverse effects of warfarin include bleeding and significant hemorrhage. Significant hemorrhage, examples of which include intracranial hemorrhage, gastrointestinal bleeding, hematemesis, intraocular bleeding, and hemarthrosis, can occur at virtually any body site. Patients should receive education about easy bleeding or bruising, a common adverse effect. A clinician should also counsel patients about properly managing cuts, bruises, and nosebleeds. The risk of bleeding and hemorrhage is dependent on multiple variables, including the intensity of anticoagulation and patient susceptibility. Patients should undergo a risk assessment, with appropriate adjustments to their treatment plan made accordingly. Other adverse effects include nausea, vomiting, abdominal pain, bloating, flatulence, and an altered sense of taste.

The substance can be absorbed into the body by inhalation of its aerosol, through the skin and by ingestion.

inhalation, skin absorption, ingestion, skin and/or eye contact

Oral ; Inhalation ; Dermal Rapidly absorbed following oral administration with considerable interindividual variations. Also absorbed percutaneously.

Skin necrosis usually occurs within the first week of therapy, and management strategies include discontinuing treatment with warfarin, administering fresh frozen plasma and vitamin K, and initiating anticoagulation therapy with unfractionated heparin or low molecular weight heparin. Warfarin toxicity may be assessed by observing the signs and symptoms of bleeding, as well as the determination of a supratherapeutic INR level. The risk of bleeding is significantly greater for patients with an elevated INR, especially above 5.0. When managing warfarin toxicity, the initial step would be to discontinue warfarin and then administer vitamin K (phytonadione). Vitamin K may be administered orally, intravenously, or subcutaneously. However, the initial administration of oral vitamin K is often preferable for patients without significant bleeding or elevated INR. A reduction in INR should occur within 24 hours of administration. After that, intravenous vitamin K may be administered if necessary. Due to erratic and unpredictable absorption, subcutaneous vitamin K is often not recommended for warfarin toxicity or reversal. Administering prothrombin complex concentrate, fresh frozen plasma, or activated Factor VII may be considered for patients with significant bleeding.

Warfarin inhibits vitamin K reductase, resulting in depletion of the reduced form of vitamin K (vitamin KH2). As vitamin K is a cofactor for the carboxylation of glutamate residues on the N-terminal regions of vitamin K-dependent proteins, this limits the gamma-carboxylation and subsequent activation of the vitamin K-dependent coagulant proteins. The synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X and anticoagulant proteins C and S is inhibited. Depression of three of the four vitamin K-dependent coagulation factors (factors II, VII, and X) results in decreased prothrombin levels and a decrease in the amount of thrombin generated and bound to fibrin. This reduces the thrombogenicity of clots.

/BIRDS and MAMMALS/ The anticoagulant chemical warfarin has been used successfully against common vampire bats. In much of Latin America these bats, whose populations are probably significantly increased by the presence of cattle, spread rabies to cattle resulting in serious economic losses. Warfarin in petroleum jelly is applied to backs of vampires netted around cattle that are being fed upon. When these bats return to the colony, they are groomed by other vampires causing mortality of most or all bats. This is a relatively sensible use of a toxic chemical because it kills only the offending bats, at the same time, it effectively stops the spread of rabies. In the absence of this method, people typically destroy all known or discoverable nearby bat roosts irrespective of what species occur there.

/BIRDS and MAMMALS/ Warfarin has been shown experimentally to cause secondary poisoning in weasels.

/FIELD STUDIES/ ...In the field trials, 71.28%, 30% and 66.24% mortality was observed with Racumin as tracking powder, as ready to use bait containing 0.0375%, and Rodafarin C (Warfarin) containing 0.025%, respectively, within 2 weeks, in R rattus and Mus musculus. Racumin as tracking powder in bait was readily accepted by rats and mice and caused earlier mortality than Warfarin.

Warfarin was not detected (detection limit <0.08 ug/g) in the liver of 4 kestrel falcon, 10 barn-owl, 5 tawny owl, 15 mallard, or 1 common moorhen; but was detected in the livers of 7 of 11 common buzzards at 0.35 to 2 ug/g and in 1 of 13 black coot at 23.52 ug/g(1). The raptors and water birds were collected in 2003 from Loire Atlantique, France(1). Warfarin was not detected (detection limit <0.02 mg/kg) in the livers of 20 Eurasian otters (Lutra lutra) from the upper Loire River catchment, France(2).

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including warfarin sodium, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Warfarin sodium/

P001; As stipulated in 40 CFR 261.33, when warfarin when present at concentrations greater than 0.3%, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to federal and/or state hazardous waste regulations. Also defined as a hazardous waste is any container or inner liner used to hold this waste or any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5(e)). /Warfarin, and salts, when present at concentrations greater than 0.3%/

U248; As stipulated in 40 CFR 261.33, when warfarin, when present in concentrations of 0.3% or less, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). /Warfarin, & salts, when present at concentrations of 0.3% or less/

This notice announces the availability of EPA's final risk mitigation decision for 10 rodenticides ... The 10 rodenticides covered by this risk mitigation decision are brodifacoum, bromadiolone, bromethalin, chlorophacinone, cholecalciferol, difenacoum, difethialone, diphacinone (and its sodium salt), warfarin (and its sodium salt), and zinc phosphide. EPA's final decision on the rodenticides includes two major components. To minimize children's exposure to rodenticide products used in homes, EPA is requiring that in the future, all rodenticide bait products available for sale to general consumers be sold only in bait stations. To reduce wildlife exposures and ecological risks, the Agency intends to prevent general consumers from purchasing bait products containing the rodenticides that pose the greatest risk to wildlife (the second generation anticoagulants - brodifacoum, bromadiolone, difethialone, and difenacoum) by requiring various measures to control sales and distribution. The Agency's decision will reduce rodenticide exposures to children and non-target wildlife, while ensuring residential users, livestock producers, and professional applicators access to a variety of effective and affordable rodent control products.

Section 4(g)(2)(A) of FIFRA calls for the Agency to determine, after submission of relevant data concerning an active ingredient, whether products containing the active ingredient are eligible for reregistration. The Agency has previously identified and required the submittal of all the generic (i.e., active ingredient specific) data required to support reregistration of products containing warfarin and its sodium salt as an active ingredient. The Agency has completed its review of these generic data, and has determined that the data are sufficient to support reregistration of products containing warfarin and its sodium salt. ... The data identified in Appendix A were sufficient to allow the Agency to conduct a reasonable risk assessment for all registered uses of warfarin and its sodium salt and to determine for all such uses that warfarin and its sodium salt can be used without resulting in unreasonable adverse effects on the environment. The Agency finds that all products which contain warfarin and its sodium salt as an active ingredient are eligible for reregistration.

As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their continued use. Under this pesticide reregistration program, EPA examines newer health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether the use of the pesticide does not pose unreasonable risk in accordance to newer saftey standards, such as those described in the Food Quality Protection Act of 1996. Warfarin is found on List A, which contains most pesticides that are used on foods and, hence, have a high potential for human exposure. List A consists of the 194 chemical cases (or 350 individual active ingredients) for which EPA issued registration standards prior to FIFRA '88. Case No: 0011; Pesticide type: rodenticide; Registration Standard Date: 09/01/81; Case Status: RED Approved 06/91; OPP has made a decision that some/all uses of the pesticide are eligible for reregistration, as reflected in a Reregistration Eligibility Decision (RED) document.; Active ingredient (AI): warfarin; Data Call-in (DCI) Date(s): 05/21/91; AI Status: OPP has completed a Reregistration Eligibility Decision (RED) for the case/AI..

As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their continued use. Under this pesticide reregistration program, EPA examines newer health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether the use of the pesticide does not pose unreasonable risk in accordance to newer saftey standards, such as those described in the Food Quality Protection Act of 1996. Sodium warfarin is found on List A, which contains most pesticides that are used on foods and, hence, have a high potential for human exposure. List A consists of the 194 chemical cases (or 350 individual active ingredients) for which EPA issued registration standards prior to FIFRA '88. Case No: 0011; Pesticide type: rodenticide; Registration Standard Date: 09/01/81; Case Status: RED Approved 06/91; OPP has made a decision that some/all uses of the pesticide are eligible for reregistration, as reflected in a Reregistration Eligibility Decision (RED) document.; Active ingredient (AI): warfarin; Data Call-in (DCI) Date(s): 05/21/91; AI Status: OPP has completed a Reregistration Eligibility Decision (RED) for the case/AI. /Sodium warfarin/

Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV.D.3.b).

Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. Warfarin is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 500 or 10,000 lbs. Extremely hazardous substances that are solids are subject to either of two threshold planning quantities ... The lower quantity applies only if the solid exists in powdered form and has a particle size less than 100 microns; or is handled in solution or in molten form; or meets the criteria for a National Fire Protection Association (NFPA) rating of 2, 3 or 4 for reactivity. If the solid does not meet any of these criteria, it is subject to the upper ... threshold planning quantity ... .

B01AA03

B - Blood and blood forming organs

QB - Blood and blood forming organs

B01AA03

Warfarin is an anticoagulant, as such it disrupts the coagulation cascade to reduce frequency and extent of thrombus formation. In patients with deep vein thrombosis or atrial fibrillation there is an increased risk of thrombus formation due to the reduced movement of blood. For patients with cardiac valve disease or valve replacements this increased coagulability is due to tissue damage. Thrombi due to venous thrombosis can travel to the lungs and become pulmonary emboli, blocking circulation to a portion of lung tissue. Thrombi which form in the heart can travel to the brain and cause ischemic strokes. Prevention of these events is the primary goal of warfarin therapy. Limitation of thrombus formation is also a source of adverse effects. In patients with atheroscelotic plaques rupture typically results in thrombus formation. When these patients are anticoagulated plaque rupture can allow the escape of cholesterol from the lipid core in the form of atheroemboli or cholesterol microemboli. These emboli are smaller than thrombi and block smaller vessels, usually less than 200 μm in diameter. The consequences of this are varied and depend on the location of the blockage. Effects include visual disturbances, acute kidney injury or worsening of chronic kidney disease, central nervous system ischemia, and purple or blue toe syndrome. Blue toe syndrome can be reversed if it has not progressed to tissue necrosis but the other effects of microemboli are often permanent. Antocoagulation appears to mediate warfarin-related nephropathy, a seemingly spontaneous kidney injury or worsening of chronic kidney disease associated with warfarin therapy. Nephropathy in this case appears to be due to increased passage of red blood cells through the glomerulus and subsequent blockage of renal tubules with red blood cell casts. This is worsened or possibly triggered by pre-existing kidney damage. Increased risk of warfarin-related nephropathy occurs at INRs over 3.0 but risk does not increase as a function of INR beyond this point. Warfarin has been linked to the development of calciphylaxis. This is thought to be due to warfarin's inhibition of [vitamin K](VKA) recycling as VKA is needed for the carboxylation of matrix Gla protein. This protein is an anti-calcification factor and its inhibition through preventing the carboxylation step in its production leads to a shift in calcification balance in favor of calciphylaxis. Tissue necrosis can occur early on in warfarin therapy. This is attributable to half lives of the clotting factors impacted by inhibition of vitamin K recycling. Proteins C and S are anticoagulation factors with half lives of 8 and 24 hours respectively. The coagulation factors IX, X, VII, and thrombin (factor II) have half lives of 24, 36, 6, and 50 hours respectively. This means proteins C and S are inactivated sooner than pro-coagulation proteins, with the exception of factor VII, resulting in a pro-thrombotic state for the first few days of therapy. Thrombi which form in this time period can occlude arterioles in various locations, blocking blood flow and causing tissue necrosis due to ischemia.

Warfarin is a [vitamin K] antagonist which acts to inhibit the production of vitamin K by vitamin K epoxide reductase. The reduced form of vitamin K, vitamin KH₂ is a cofactor used in the γ-carboxylation of coagulation factors VII, IX, X, and thrombin. Carboxylation induces a conformational change allowing the factors to bind Ca²⁺ and to phospholipid surfaces. Uncarboxylated factors VII, IX, X, and thrombin are biologically inactive and therefore serve to interrupt the coagulation cascade. The endogenous anticoagulation proteins C and S also require γ-carboxylation to function. This is particularly true in the case of thrombin which must be activated in order to form a thrombus. vitamin KH₂ is converted to vitamin K epoxide as part of the γ-carboxylation reaction catalyzed by γ-glutamyl carboxylase. Vitamin K epoxide is then converted to vitamin K₁ by vitamin K epoxide reductase then back to vitamin KH₂ by vitamin K reductase. Warfarin binds to vitamin K epoxide reductase complex subunit 1 and irreversibly inhibits the enzyme thereby stopping the recycling of vitamin K by preventing the conversion of vitamin K epoxide to vitamin K₁. This process creates a hypercoagulable state for a short time as proteins C and S degrade first with half lives of 8 and 24 hours, with the exception of factor VII which has a half life of 6 hours. Factors IX, X, and finally thrombin degrade later with half lives of 24, 36, and 50 hours resulting in a dominant anticoagulation effect. In order to reverse this anticoagulation vitamin K must be supplied, either exogenously or by removal of the vitamin K epoxide reductase inhibition, and time allowed for new coagulation factors to be synthesized. It takes approximately 2 days for new coagulation factors to be synthesized in the liver. Vitamin K₂, functionally identical to vitamin K₁, is synthesized by gut bacteria leading to interactions with antibiotics as elimination of these bacteria can reduce vitamin K<sub>2</sub supply and result in a greater anticoagulation effect.

Animals poisoned by warfarin ... die of tissue hypoxia resulting from massive internal bleeding of 2-5 days onset. Bleeding is due to incr capillary permeability & decr blood coagulability. The exact cause of capillary damage is not known, but its presence is evidenced by the fact that hemorrhages occur in tissues not subjected to much mechanical stress. The coagulation defect is the result decreased blood concentrations of the coagulation proteins factor II (prothrombin), factor VII (proconvertin, autoprothrombin I), factor IX (Christmas factor, autoprothrombin II, PTC), and factor X (Stuart factor, autoprothrombin III). These coagulation factors are decreased because their synthesis in the liver has been inhibited. Biosynthesis of these particular proteins is inhibited becaused each one requires adequate activity of vitamin K for biosynthesis, but the rodenticide interferes with the normal function of vitamin K.

Hepatic synthesis of prothrombin and factors VII, IX, and X is dependent upon adequate supplies of vitamin K. The molecular and even the cellular mechanism of the anti-vitamin K action of the coumarin compounds remain uncertain. These drugs seem to act as antimetabolites in synthesis of affected clotting factors. Since large doses of vitamin K can overcome or surmount action of dicumarol, competitive type of interaction is thought to be involved. Perhaps coumarin anticoagulants simply inhibit transport of vitamin K to the cellular sites wheresynthesis takes place. In any event, there is some evidence that dicumarol interferes with involvement of vitamin K in synthesis of a prothrombin precursor that may also be common to factors VII, IX, and X.

Anticoagulants interfere with fibrin formation and are used to prevent thrombus development and extension. Their major therapeutic application has traditionally been for venous thromboembolic disorder in which stasis, rather than vessel wall damage, plays an important etiologic role. Antiplatelet drugs (antithrombotics) are used to prevent arterial occlusions. Thrombolytics dissolve existing fresh thrombi and emboli by catalyzing the conversion of plasminogen to plasmin and thereby activating the endogenous fibrinolytic system.

The oral anticoagulants are antagonists of vitamin K. Coagulation factors II, VII, IX, & X & the anticoagulant proteins C & S are synthesized mainly in the liver & are biologically inactive unless 9-12 of the amino-terminal glutamic acid residues are carboxylated. The gamma-carboxyglutamate (Gla) residues confer /calcium ion/ binding properties on these proteins that are essential for their assembly into an efficient catalytic complex on a membrane surface. This reaction requires carbon dioxide, molecular oxygen, reduced vitamin K, & a precursor form of the target protein containing a propeptide recognition site. It is catalyzed in the rough endoplasmic reticulum by a 758-residue protein that has been purified, cloned, & characterized. Carboxylation is directly coupled to the oxidation of vitamin K to the epoxide. Reduced vitamin K must be regenerated from the epoxide for sustained carboxylation & synthesis of biologically competent proteins. The vitamin K epoxide reductase is composed of two proteins in the endoplasmic reticulum: microsomal epoxide reductase & a member of the glutathione-S-transferase gene family. This enzyme complex is inhibited by therapeutic doses of oral anticoagulants. Vitamin K (but not vitamin K epoxide) also can be converted to the hydroquinone by a second reductase, DT-diaphorase. The latter enzyme requires high concns of vitamin K & is less sensitive to coumarin drugs, which may explain why admin of sufficient vitamin K can counteract even large doses of oral anticoagulants. /Oral Anticoagulants/

For more Mechanism of Action (Complete) data for WARFARIN (6 total), please visit the HSDB record page.

R-warfarin is cleared more slowly than S-warfarin, at about half the rate. T_1/2 for R-warfarin is 37-89 hours. T_1/2 for S-warfarin is 21-43 hours.

The terminal half-life of warfarin after a single dose is approximately 1 week; however, the effective half-life ranges from 20 to 60 hours, with a mean of about 40 hours. The clearance of R-warfarin is generally half that of S-warfarin, thus as the volumes of distribution are similar, the half-life of R-warfarin is longer than that of S-warfarin. The half-life of R-warfarin ranges from 37 to 89 hours, while that of S-warfarin ranges from 21 to 43 hours.

Metabolism of warfarin is both stereo- and regio-selective. The major metabolic pathway is oxidation to various hydroxywarfarins, comprising 80-85% of the total metabolites. CYP2C9 is the major enzyme catalyzing the 6- and 7-hydroxylation of S-warfarin while 4'-hydroxylation occurs through CYP2C18 with minor contributions from CYP2C19. R-warfarin is metabolized to 4'-hydroxywarfarin by CYP2C8 with some contirbuting by CYP2C19, 6- and 8-hydroxywarfarin by CYP1A2 and CYP2C19, 7-hydroxywarfarin by CYP1A2 and CYP2C8, and lastly to 10-hydroxywarfarin by CYP3A4. The 10-hydroxywarfarin metabolite as well as a benzylic alcohol metabolite undergo an elimination step to form dehydrowarfarin. The minor pathway of metabolism is the reduction of the ketone group to warfarin alcohols, comprising 20% of the metabolites. Limited conjugation occurs with sulfate and gluronic acid groups but these metabolites have only been confirmed for R-hydroxywarfarins.

Of all metabolites recovered, only 4'-hydroxywarfarin & DHG /2,3-dihydro-2-methyl-4-phenyl-5-oxo-gamma-pyranol(3.2-c)(1)benzopyran/ showed anticoagulant activity.

The oxidative biotransformation of (R)-warfarin and (S)-warfarin was studied in human liver microsomes. The quantitative pattern of oxidized products obtained from warfarin in vitro changed dramatically as a function of substrate concentration. Apparent Km values for the formation of 4', 6, 7, and 8-hydroxywarfarin showed the presence of two easily distinguishable subsets of human liver cytochrome p450: a high affinity subset with Km of to 15 uM and a low affinity subset of isozymes with Km >200 uM. The high affinity subset was primarily responsible for the metabolic profile of the biologically more potent (S)-warfarin in vivo, whereas the low affinity subset was largely responsible for metabolism of (R)-warfarin. Apparent Vmax values alone did not reflect the relative in vivo formation of the phenolic metabolites from either compound because the low affinity, high capacity component masked the metabolic profile of (S)-warfarin. The rank order of intrinsic clearance (Vmax/Km) for each metabolite agreed well with regioselective and steroeselective metabolism in vivo.

In humans, the (S) isomer is primarily 7-hydroxylated, whereas the (R) form is reduced to the (R,S)-alcohol. In rats, the (S) isomer is primarily 4'-hydroxylated, whereas the (R) enantiomer is 7-hydroxylated. Involvement of different cytochrome P-450 forms were used to explain these results.

The contribution of human p450 2A6 and mouse p450 2a-5 isoenzymes both highly active in coumarin 7-hydroxylation to the metabolism of warfarin was studied in several in vitro systems with human and mouse liver preparations. The reconstituted p450 2a-5 purified from DBA/2 mouse liver did not metabolize warfarin. An anti-p450 2a-5 antibody did not consistently inhibit any of the warfarin biotransformation reactions catalyzed by human or mouse liver microsomes although coumarin 7-hydroxylation was inhibited by over 90%. In some human microsomal samples 4- and 8-hydroxylations of warfarin were inhibited to some extent by the anti-p450 2a-5 antibody. Warfarin (less than 1 uM) did not inhibit coumarin 7-hydroxylation by human or mouse liver microsomes in vitro. /Results indicate/ that mouse and human coumarin 7-hydroxylases do not oxidize warfarin.

For more Metabolism/Metabolites (Complete) data for WARFARIN (9 total), please visit the HSDB record page.

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WARFARIN

Established Pharmacologic Class [EPC] - Vitamin K Antagonist

Mechanisms of Action [MoA] - Vitamin K Inhibitors

Warfarin is a Vitamin K Antagonist. The mechanism of action of warfarin is as a Vitamin K Inhibitor.

WARFARIN

Agents that prevent BLOOD CLOTTING.

Substances used to destroy or inhibit the action of rats, mice, or other rodents.

Completely absorbed from the GI tract. The mean Tmax for warfarin sodium tablets is 4 hours.

The elimination of warfarin is almost entirely by metabolism with a small amount excreted unchanged. 80% of the total dose is excreted in the urine with the remaining 20% appearing in the feces.

Vd of 0.14 L/kg. Warfarin has a distrubution phase lasting 6-12 hours. It is known to cross the placenta and achieves fetal serum concentrations similar to maternal concentrations.

Clearance of warfarin varies depending on CYP2C9 genotype. The \*2 and \*3 alleles appear in the Caucasian population at frequencies of 11% and 7% and are known to reduce clearance warfarin. Additional clearance reducing genotypes include the \*5, \*6, \*9 and \*11 alleles. Genotypes for which population clearance estimates have been found are listed below. \*1/\*1 = 0.065 mL/min/kg \*1/\*2, \*1/\*3 = 0.041 mL/min/kg \*2/\*2, \*2/\*3, \*3/\*3 = 0.020 mg/min/kg

Warfarin sodium is rapidly and extensively absorbed from the GI tract, but considerable interindividual variation in absorption exists. Absorption of oral warfarin sodium is dissolution-rate controlled, and the rate and extent of absorption of the drug may vary from one commercially available tablet to another. Studies using warfarin sodium indicate that the rate, but not the extent, of absorption of the drug is decreased by the presence of food in the GI tract. /Warfarin sodium/

Warfarin crosses the placenta, and fetal plasma drug concentrations may be equal to maternal plasma concentrations.

Warfarin and its sodium salt are registered for use in controlling rats and mice; has been used successfully against common vampire bats; a blood anticoagulant; its sodium salt is used medically to treat people with blood hypercoagulation problems; [HSDB] Warfarin competes with vitamin K and inhibits hepatic synthesis of clotting factors to increase the prothrombin time. Typical therapeutic doses are 2 to 10 mg/day. [ACGIH]

Farming (Pesticides) [Category: Industry]

For warfarin (USEPA/OPP Pesticide Code: 086002) ACTIVE products with label matches. /SRP: Registered for use in the U.S. but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./

Warfarin and its sodium salt are registered for use in controlling commensal rodents (rats and mice) in and around homes, animal and agricultural premises, and commercial and industrial sites.

Warfarin is a blood anticoagulant; its sodium salt is used medically to treat people with blood hypercoagulation problems.

... Warfarin has been used successfully against common vampire bats.

By addition of 4-hydroxycoumarin to benzalacetone under the catalytic influence of a mildly basic substance such as ammonia or piperidine. The reaction is a typical Michael condensation. Conversion to the sodium salt is effected by reacting purified warfarin with an equimolar portion of dilute NaOH solution at room temperature.

Prepared by the Michael condensation of benzylidene acetone with 4-hydroxycourmarin.

Preparation: M. A. Stahmann et al., United States of America patent 2427578 (1947 to Wisconsin Alumni Research Foundation)

Formulation types /incl/ bait /&/ concentrate. Mixed formulations /incl/ (warfarin +) pindone; calciferol; sulfaquinoxaline.

Rat baits are usually made up by mixing 1 part of commercial prepn containing 0.5 or 0.1% warfarin with 20 parts of oatmeal or other suitable diluent.

Warfarin Plus rodenticide - Discontinued by HACCO, Inc.; Warfarin Q rodenticide (warfarin) - Discontinued by Bell Labs; Warfotox rodenticide (warfarin) - Discontinued 2008 by Aimco Pesticides Ltd.

Table: Warfarin Sodium Preparations [Table#3584]

For more Formulations/Preparations (Complete) data for WARFARIN (38 total), please visit the HSDB record page.

2H-1-Benzopyran-2-one, 4-hydroxy-3-(3-oxo-1-phenylbutyl)-: ACTIVE

The WHO Recommended Classification of Pesticides by Hazard identifies warfarin (technical grade) as Class IB: highly hazardous; Main Use: rodenticide.

Warfarin, a potent anticoagulant, was first isolated from spoiled clover hay and identified as the agent responsible for the hemorrhagic symptoms associated with the death of livestock in the 1930s.

Warfarin is a racemic mixture whether it is used as rodenticide or as a drug.

Marketed as the racemate; the S(-)-form is the more potent isomer.