WARFARIN AND RELATED AGENTS

Editor's Note: This material is not listed in the Emergency Response Guidebook. Based on the material's physical and chemical properties, toxicity, or chemical group, a guide has been assigned. For additional technical information, contact one of the emergency response telephone numbers listed under Public Safety Measures.

MOLECULAR FORMULA

C19-H16-O4

ERG GUIDE NUMBER

151-SUBSTANCES - TOXIC (NON-COMBUSTIBLE)

SYNONYM REFERENCE

(RTECS , 1990; EPA, 1985; HSDB , 1990; Sax & Lewis, 1989)

USES/FORMS/SOURCES

FORMS

Coumarins (drugs):

Dicoumarol (bishydroxycoumarin): 25, 50 and 100 mg tablets and 25 and 50 mg capsules
Warfarin potassium: 5 mg tablets
Warfarin sodium (ORAL): 1 (pink) , 2 (lavender), 2.5 (green), 3 (tan), 4 (blue), 5 (peach), 6 (teal), 7.5 (yellow) and 10 (white) mg single score tablets inscribed with COUMADIN on plain face (Prod Info COUMADIN(R) oral tablets, IV injection, 2007)
Warfarin sodium (INTRAVENOUS): 5 mg vial. Reconstitute with 2.7 mL of sterile water for injection to yield 2 mg/mL. Intramuscular administration NOT recommended (Prod Info COUMADIN(R) oral tablets, IV injection, 2007).

INDANDIONES (drugs):

Anisindione: 50 mg tablets
Phenindione: 50 mg tablets
Phenprocoumon: 3 mg tablets

COUMARINS (Rodenticides)

Coumachlor (Tomorin)
Coumafuryl (Tomarin, Fumarin)
Warfarin, coumafene, zoocoumarin (Kypfarin, Ratox, RAX, Rodex, Tox-Hid, Warfarin Plus)

-CLINICAL EFFECTS

GENERAL CLINICAL EFFECTS

USES: Therapeutic anticoagulation medication used for the treatment of deep venous thrombosis, pulmonary embolism, and other hypercoagulable states, and to prevent thromboembolic complications in patients with atrial fibrillation, prosthetic heart valves, or recent myocardial infarction. It may also be used to prevent thromboembolic complications in patients with stroke, impaired left ventricular function, or cancer.

EPIDEMIOLOGY: Exposures are common. Inadvertent exposures rarely produce clinical effects. A single deliberate overdose generally does not result in coagulopathy, but a large ingestion by a patient who is chronically using warfarin may produce significant coagulopathy. Adverse events during therapeutic dosing are common.

PHARMACOLOGY: Inhibits hepatic synthesis of Vitamin K dependent factors: II, VII, IX, and X, and also inhibits the activity of vitamin K 2,3-epoxide reductase.

TOXICOLOGY: Excessive inhibition of factors II, VII, IX, and X can cause significant prolongation of INR and excessive bleeding after minor trauma. The risk of hemorrhage depends on patient comorbidities and severity of anticoagulation.

WITH POISONING/EXPOSURE

OVERDOSE: GENERAL: Excessive chronic doses, drug interactions, and less commonly acute overdose can cause profound anticoagulation. Effects can include bleeding at virtually any site: epistaxis, bleeding from gums, ecchymosis, hematochezia, hematuria, menorrhagia, hemarthrosis, and bleeding from minor skin or soft tissue trauma.
SEVERE TOXICITY: More life-threatening complications include intracranial hemorrhage, retroperitoneal hemorrhage, or massive gastrointestinal bleed.

WITH THERAPEUTIC USE

ADVERSE EFFECTS: The primary adverse effect is bleeding, which can be more severe with comorbid conditions, such as advanced age and liver dysfunction. Warfarin can also cause skin necrosis. Warfarin is a human teratogen and increases the risk of fetal death.

POTENTIAL HEALTH HAZARDS - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)

Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin.
Avoid any skin contact.
Effects of contact or inhalation may be delayed.
Fire may produce irritating, corrosive and/or toxic gases.
Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution.

ACUTE CLINICAL EFFECTS

WITH POISONING/EXPOSURE

Warfarin can be toxic if ingested, inhaled, or absorbed through the skin. The metabolism of warfarin is under genetic control, and large variations have been seen in different strains of rats and amongst different persons (HSDB). Although poisoning can occur from a single large dose (with generally delayed effects), its toxicity is mainly cumulative. Thus, its efficacy as a rodenticide relies on repeated ingestion of baits where it is present in low concentrations.
Warfarin suppresses the formation of PROTHROMBIN and FACTORS VII, IX, and X in the liver, resulting in markedly reduced blood clotting capability and increased fragility of the capillary walls (Hathaway et al, 1991). These two effects can lead to uncontrolled hemorrhage. Warfarin is considered an indirect anticoagulant because it acts only in vivo (in contrast, heparin is active both in vivo and in vitro).
Warfarin occurs as two optical isomers, the S- and R- forms. The S- form was 5.5 times more active than the R- form in a single dose in rats, as measured by increases in prothrombin time, and it was 8.5 times more active when given over 10 days. This relationship is also found in humans (Eble, 1966).
There is some evidence that the two aspects of warfarin toxicity (inhibition of clotting factor synthesis and increased capillary fragility) may be due to two different parts of the warfarin molecule, as 4-hydroxycoumarin inhibits the formation of prothrombin and benzalacetone produces the capillary damage (Sax, 1984). The inhibition of prothrombin formation does not become apparent until prothrombin reserves are depleted, a process which may require several days (NIOSH/OSHA).
General symptoms of poisoning, which begin after a few days or weeks of repeated exposure, include epistaxis (nosebleed), bleeding gums, pallor, petechial rash, and hematomas around the joints or on the buttocks (HSDB) (Andes & Edmunds, 1983). Bleeding may be initiated by normal movement of muscles and organs, or may occur spontaneously in organs which do not have substantial movement.
Bleeding continues unabated because the normal clotting mechanisms are not present. Blood may be present in the urine or feces. In the final stages of warfarin poisoning, paralysis may occur from cerebral hemorrhage, and death occurs from hemorrhagic shock (HSDB).

WITH THERAPEUTIC USE

In human clinical practice, a larger initial loading dose of 40 to 60 mg is sometimes given, followed by a daily maintenance dose of 2.5 to 10 mg (a relatively low dose is required to maintain anticoagulant effects when given chronically).

CHRONIC CLINICAL EFFECTS

WITH POISONING/EXPOSURE

Repeated warfarin exposure results in CUMULATIVE TOXICITY.
Warfarin can be absorbed through intact skin, as occurred in an epidemic of hemorrhagic disease among infants in Vietnam who had skin contact with talcum powder contaminated with 1.7 to 6.5% warfarin (Martin-Bouyer et al, 1984). By the time the contaminated powder was withdrawn from use, 741 poisonings had occurred, resulting in 177 deaths.
In another case, a farmer whose hands were intermittently wetted with a 0.5% solution of warfarin over a period of 24 days developed gross hematuria 2 days after the last contact with the solution. The following day, spontaneous hematomas appeared on the arms and legs. Within 4 days there were also punctate hemorrhages of the palate and mouth, bleeding from the lower lip, and epistaxis (NIOSH/OSHA).

WITH THERAPEUTIC USE

Because many patients receive warfarin as a life-long therapy for prevention of thromboembolism, there is a large literature on side effects of chronic exposure. Persons may vary greatly in warfarin sensitivity, depending on genetic background, general state of health, and exposure to other drugs or chemicals.
Chronic warfarin toxicity can produce internal hemorrhage and skin and nervous system disorders. The most common form of warfarin-induced PERIPHERAL NEUROPATHY is femoral nerve palsy (King & Bechtold, 1985). Women receiving warfarin are at increased risk for OVARIAN HEMORRHAGE during ovulation; numerous cases have been reported (Hill & Kassam, 1984; Runge, 1981; Krause & Amores, 1976; Waxman & Baird, 1978). Intraperitoneal bleeding from ruptured ovarian hematoma (Itskovitz, 1982) and rupture of ovarian cysts (Matseoane et al, 1976) have also been reported. Chronic warfarin therapy resulted in a pelvic hematoma in a 41-year-old woman following sexual intercourse (Marks, 1984). Warfarin can induce hair loss (Nagao et al, 1995).
A rare, but potentially lethal, complication of chronic warfarin administration is SKIN NECROSIS (Elliot, 1978). Pruritic skin eruptions have also been reported (Schiff & Kern, 1968). Skin necrosis developed in a woman deficient in protein C who had received warfarin as therapy for thrombosis (Locht & Lindstrom, 1993).
Warfarin has also been implicated in REYES SYNDROME (Sato, 1979).
Persons exposed to warfarin chronically may experience hemorrhagic complications from otherwise harmless medical procedures, such as a 69-year-old man who needed two units of blood after undergoing an electromyogram.
Spondyloarthropathy (destructive periosteal or osseous hemorrhagic mass, also called pseudotumor) has been reported as an unusual complication of chronic warfarin therapy at the L1-L2 region of the lumbar spine (Awwad et al, 1996).
Cholesterol embolization from a ruptured atherosclerotic plaque was seen in the fundus of an elderly patient who had been on warfarin prophylaxis. This was thought to be the result of inhibition of thrombus formation at the site of the ruptured plaque. This situation was accompanied by multiple bruits, purple or blue skin lesions, and endstage progressive renal failure requiring dialysis (Larry et al, 1996).

-FIRST AID

FIRST AID AND PREHOSPITAL TREATMENT

SUMMARY

Patients on chronic anticoagulation therapy should receive activated charcoal after an acute overdose unless contraindicated. Avoid emesis because of the risk of subsequent bleeding.

An average child eating a few mouthfuls of 0.025% to 0.05% rat bait at a single sitting is generally not at risk. Prophylactic treatment is not necessary. Recent ingestion of large amounts may require gastrointestinal decontamination with activated charcoal.

EMESIS/NOT RECOMMENDED

In the setting of a warfarin overdose, emesis should probably be avoided because of the risk of subsequent bleeding.

ACTIVATED CHARCOAL

PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

CHARCOAL DOSE

Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

ADVERSE EFFECTS/CONTRAINDICATIONS

Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

-MEDICAL TREATMENT

LIFE SUPPORT

Support respiratory and cardiovascular function.

SUMMARY

FIRST AID - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)

Move victim to fresh air.
Call 911 or emergency medical service.
Give artificial respiration if victim is not breathing.
Do not use mouth-to-mouth method if victim ingested or inhaled the substance;give artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device.
Administer oxygen if breathing is difficult.
Remove and isolate contaminated clothing and shoes.
In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes.
For minor skin contact, avoid spreading material on unaffected skin.
Keep victim warm and quiet.
Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed.
Ensure that medical personnel are aware of the material(s) involved and take precautions to protect themselves.

FIRST AID

INHALATION EXPOSURE

INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.

DERMAL EXPOSURE

DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

EYE EXPOSURE

DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.

ORAL EXPOSURE

PATIENTS NOT PRESENTLY ON ANTICOAGULANTS

ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
If a large or chronic ingestion is suspected, then vitamin K (phytonadione) may be given. DOSE: 1 to 5 mg (child); 5 to 10 mg (adult). Vitamin K may be administered orally in the absence of vomiting. With severe toxicity, IV dosing may be necessary. In serious cases transfusion of fresh frozen plasma and packed red blood cells may be needed.

PATIENTS PRESENTLY ON ANTICOAGULANTS

ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
Avoid emesis and lavage due to possible trauma and subsequent bleeding.
Get INR immediately. For patients with supratherapeutic INR without clinically significant bleeding, hold warfarin therapy and administer oral vitamin K1 (less than 5 mg vitamin K for INR of 5.0 to 9.0; 5 to 10 mg vitamin K for INR greater than 9.0). For life-threatening bleeding, IV vitamin K, fresh frozen plasma and packed red blood cells may be necessary.

Effects may be delayed; keep victim under observation.

-RANGE OF TOXICITY

MINIMUM LETHAL EXPOSURE

SUMMARY

Persons with a history of blood disorders with bleeding tendencies would be expected to be at increased risk from exposure (EPA, 1985).
The minimum lethal exposure would depend in part on whether or not an individual is on anticoagulant therapy; individuals on therapy would be expected to react to lower exposures than non-treated persons.
Hereditary resistance of people to warfarin, as well as, suspected hereditary susceptibility, has been reported (HSDB , 1991).
Death from severe hemorrhagic complications has been reported in persons who ate food made with warfarin sodium baited cornmeal. Ingestion of a total of 1 g of warfarin over a 13-day period resulted in death.
ANIMAL DATA: Animal toxicity studies show that warfarin is most toxic when ingested daily over a period of 5 to 7 days. Rats and mice are very susceptible and died after ingesting 1 mg/kg/day for 6 days (or 50 to 150 mg/kg in a single dose). Fowl are most resistant, horses are resistant, and pigs are more susceptible than rats and mice. Ingestion of 0.05 to 0.4 mg/kg/day for 7 days can kill pigs (HSDB , 1991).

ACUTE

The lowest oral lethal dose reported in humans ranges from 6 mg/kg (RTECS , 1991) to 15 mg/kg (Sax & Lewis, 1989).
LDLo (ORAL) HUMAN: 6667 mcg/kg (RTECS , 1990).
LDLo (ORAL) HUMAN: 15 mg/kg (Sax & Lewis, 1989).

CASE REPORTS

Ingestion of a total of 1 g of warfarin over a 13-day period resulted in death; the patient died on day 15 (Baselt & Cravey, 1989).
Death can occur from significant transcutaneous uptake of warfarin. In August, 1981, pediatric hospitals in Ho Chi Minh City (formerly Saigon), Vietnam, reported 741 cases of a hemorrhagic syndrome in infants. The cause of this phenomenon was identified as talcum powder contaminated with warfarin in concentrations between 1.7% and 6.5%. Of the 741 pediatric cases, 177 patients died (Martin-Bouyer et al, 1984).

MAXIMUM TOLERATED EXPOSURE

SUMMARY

Usual oral maintenance range is 2 to 10 mg/day. A maintenance dose of 2 to 10 mg once daily is typical (Prod Info COUMADIN(R) oral tablets, intravenous injection powder lyophilized for solution, 2011).

Evidence of overdose is not based on a specific dose, but rather the appearance of bleeding (eg, occult blood, hematuria, excessive menstrual bleeding, melena, petechia, excessive bruising or persistent oozing from superficial injuries, and unexplained decrease in hemoglobin) as a sign of excessive anticoagulation (Prod Info COUMADIN(R) oral tablets, intravenous injection powder lyophilized for solution, 2011).

SPECIFIC SUBSTANCE

WARFARIN/DRUG PRODUCTS

ADULT

SUMMARY: The lowest toxic dose in humans ranges from 10 mg/kg to 15 mg/kg (RTECS , 1991; Sax & Lewis, 1989).

TDLo (ORAL) MAN: 10200 mcg/kg (Blood) (RTECS , 1990)
TDLo (ORAL) WOMAN: 15 mg/kg/21wk-I (Gastrointestinal and Blood) (RTECS , 1990)
An estimated dose of 0.075 to 0.48 mg/kg in an adult may produce a peak total warfarin concentration of 0.5 to 3 mcg/mL. This is associated with a prothrombin ratio value of 1.5 to 2.5. (See calculation explanation in section 6.7.B.)
Dosing adults with 5 to 20 mg/day produces the desired degree of hypocoagulability. While toxicity occasionally occurs at this level, monitoring of prothrombin time allows for reductions of dosage before major toxicity. Ingestion in excess of this level may cause complications.

CASE SERIES: In one study, the mean minimum warfarin concentration necessary for any inhibition of active clotting factor synthesis was 0.39 mcg/mL in 26 inpatients and 0.36 mcg/mL in 30 outpatients (Murray et al, 1985). This corresponds to an estimated dose of 0.054 to 0.0624 mg/kg.
CASE REPORT/OVERDOSE: A 59-year-old woman intentionally ingested 540 mg of warfarin, clonazepam (4 mg) and 3 mouthfuls of bleach 6 hours prior to presentation. She vomited once after ingesting the bleach. Her physical exam was within normal limits with no evidence of bleeding. She was noted to have superficial self-inflicted cuts on her extremities. Upon admission, laboratory values included an INR of 5.1; PT, 18 and PTT, 57.2 seconds. Coagulation factors were VII, 7%; IX, 24%; and X, 8% (normal ranges, 75% to 150%). The patient received vitamin K (10 mg IV) and recombinant factors Vlla, and 3-factor concentrates shortly after admission. Six hours after vitamin K administration, INR was 0.5. The patient was then maintained on vitamin K 5 mg orally every 6 hours. After her transfer to psychiatry, vitamin K (5 mg) was reduced to 3 times a day. Thirteen days after admission, INR was 1.0 and vital signs were stable. She was discharged on aspirin only (Matthews et al, 2014).
CASE REPORTS/OVERDOSE: Overdose ingestions of warfarin (120 to 150 mg) in 3 patients resulted in increased INRs, ranging from approximately 2.5 to approximately 10. There was no clinical evidence of bleeding in any of the patients (Isbister et al, 2003).

PEDIATRIC

SUMMARY: Extrapolation from the amount needed in adults to acutely and reliably prolong the PT (40 mg) predicts a dose of about 0.5 mg/kg in children that would be considered potentially toxic. This dose resulted in PTs between 18 and 30 seconds in children receiving a single loading dose after heart valve surgery (Carpentieri et al, 1976).
CASE REPORT: A 20-month-old child ingested approximately 50 mg (4 mg/kg) of warfarin sodium and subsequently developed prolonged PT. The child, however, remained asymptomatic with no signs of bleeding or bruising (Montanio et al, 1993).
CASE REPORTS: A dose of 0.2 mg/kg/day for 2 days resulted in a wide range of PTs independent of age, weight, or body surface area in 15 children. The mean PT was 19.5 +/- 4.6 seconds (Doyle et al, 1988).
CASE REPORT: A 15-year-old adolescent's INR peaked at 5.0, without any other signs or symptoms, 3 days after intentionally ingesting 50 5-mg and 100 1-mg warfarin tablets. The patient's INR normalized after receiving fresh frozen plasma and vitamin K (Ramanan et al, 2002).
CASE SERIES: REGULATING INR IN PEDIATRIC PATIENTS: In a study to analyze warfarin therapy in children requiring anticoagulation, therapeutic dosing of warfarin was found to be highly variable. Younger children required higher doses of warfarin than older children to achieve a therapeutic concentration. To achieve a therapeutic INR range, daily warfarin doses of 0.16 mg/kg were required in young children compared to 0.04 to 0.08 mg/kg in adults (Streif et al, 1999a).

WARFARIN/RODENTICIDES

ACUTE: 100 g (3-1/3 ounces) of 0.025% rat bait contains 25 mg of warfarin, and is poorly absorbed in these large quantities of grain.
CHRONIC: Ingestion of a few ounces of rat poison over 3 to 5 days will produce marked hypoprothrombinemia and bleeding.

Fourteen reported cases of unintentional poisoning in Korea involved eating cornmeal containing 0.25% warfarin included in rat bait. The corn meal was eaten over a period of 15 days. All 14 became severely ill with hemorrhage; 2 patients died. The estimated dosage was 1 to 2 mg/kg/day (HSDB , 1991; Baselt & Cravey, 1989; Morgan, 1989).

ACENOCOUMAROL

3-(alpha-acetonyl-4-nitrobenzyl)-4-hydroxycoumarin is more potent than warfarin. Ingestion of 60 mg by a 27-year-old woman resulted in a severe hemorrhagic diathesis 5 days later (Prod Info Sintrom(R), acenocoumarol, 1968).

ANIMAL DATA

WARFARIN

Warfarin was administered to adult female albino rats as a technical grade (99.8%) carried in peanut oil. The dose levels were 1, 2, 4, 8 and 12 mg/kg body weight. None of adult female albino rats died from a single dose of warfarin as high as 12 mg/kg. Repeated doses between 4 and 6 days killed 25.0, 37.5, 75.0 and 100% of the rats (Bai et al, 1992).

ROUTE OF EXPOSURE

WARFARIN/DERMAL EXPOSURE

Talcum powder contaminated with 1.7% to 6.5% warfarin resulted in 177 infant deaths in Vietnam in 1981. Experimentally, a baboon exposed daily to talc containing 3% warfarin applied on the buttocks under a diaper, died of hemorrhagic diathesis 5 days later (Martin-Bouyer et al, 1983).
One case of a hemorrhagic diathesis resulted from mixing successive batches of poisoned bait. Inhalation, or more probably, cutaneous absorption was the mechanism of exposure (Green, 1955).
A farmer whose hands were intermittently wetted with an 0.5% solution of warfarin over a period of 24 days developed gross hematuria 2 days after the last contact with the solution; the following day, spontaneous hematomas appeared on the arms and legs. Within 4 days, other effects included epistaxis, punctate hemorrhages of the palate and mouth, and bleeding from the lower lip. Four days later, after treatment for 2 days with phytonadione, hematologic indices had returned to the normal range (Proctor et al, 1988).

TOXICITY AND RISK ASSESSMENT VALUES

TOXICITY VALUES

LC50- (INHALATION)RAT:
- 320 mg/m(3) (RTECS, 1990)
LD50- (INTRAVENOUS)CHICKEN:
- 200 mg/kg (Sax & Lewis, 1989)
LD50- (ORAL)CHICKEN:
- 942 mg/kg (RTECS, 1990)
LD50- (INTRAVENOUS)DOG:
- 200 mg/kg (Sax & Lewis, 1989)
LD50- (ORAL)DOG:
- 200 mg/kg (Sax & Lewis, 1989)
LD50- (ORAL)GUINEA_PIG:
- 182 mg/kg (Sax & Lewis, 1989)
LD50- (INTRAVENOUS)MOUSE:
- 165 mg/kg (RTECS, 1990)
LD50- (ORAL)MOUSE:
- 60 mg/kg (RTECS, 1990)
- 331 mg/kg (Sax & Lewis, 1989)
LD50- (INTRAVENOUS)RABBIT:
- 100 mg/kg (Sax & Lewis, 1989)
LD50- (ORAL)RABBIT:
- 800 mg/kg (Sax & Lewis, 1989)
LD50- (INTRAVENOUS)RAT:
- 186 mg/kg (Sax & Lewis, 1989)
LD50- (ORAL)RAT:
- 1600 mcg/kg (RTECS, 1990)
- 3 mg/kg (Sax & Lewis, 1989)
- Female, 5.63 mg/kg
LD50- (SKIN)RAT:
- 1400 mg/kg (RTECS, 1990)
LDLo- (ORAL)CAT:
- 12 mg/kg (RTECS, 1990)
LDLo- (ORAL)HUMAN:
- 6667 mcg/kg (RTECS, 1990)
- 15 mg/kg (Sax & Lewis, 1989)
LDLo- (SUBCUTANEOUS)MOUSE:
- 800 mg/kg (RTECS, 1990)
LDLo- (ORAL)PIG:
- 1200 mcg/kg (RTECS, 1990)
LDLo- (INTRAPERITONEAL)RAT:
- 420 mg/kg (RTECS, 1990)
TDLo- (ORAL)HUMAN:
- 10,200 mcg/kg -- BLOOD (RTECS, 1990)
- 15 mg/kg for 21W-I -- GI,BLOOD (RTECS, 1990)
- 28 mg/kg for 1-20W preg -- TER (Sax & Lewis, 1989)
- 8400 mcg/kg for 1-8W preg -- TER (Sax & Lewis, 1989)
- 33,600 mcg/kg for 1-32W preg -- TER (Sax & Lewis, 1989)
TDLo- (INTRAVENOUS)MOUSE:
- 240 mg/kg for 2-3D preg -- REP (Sax & Lewis, 1989)
LD50- (INTRAVENOUS)CHICKEN:
- 200 mg/kg
LD50- (INTRAVENOUS)DOG:
- 200 mg/kg
LD50- (ORAL)DOG:
- 200 mg/kg
LD50- (ORAL)GUINEA_PIG:
- 182 mg/kg
LD50- (INTRAVENOUS)MOUSE:
- 160 mg/kg
LD50- (ORAL)MOUSE:
- 374 mg/kg
LD50- (INTRAVENOUS)RABBIT:
- 100 mg/kg
LD50- (ORAL)RABBIT:
- 800 mg/kg
LD50- (INTRAVENOUS)RAT:
- 25 mg/kg (Lewis, 1996)
LD50- (ORAL)RAT:
- 8700 mcg/kg
TDLo- (ORAL)HUMAN:
- Female, 300 mcg/kg for 2D -- SKN
- Female (1-35W preg), 37 mg/kg -- TER (Lewis, 1996)

-STANDARDS AND LABELS

SHIPPING REGULATIONS

SURFACE

DOT -- Table of Hazardous Materials and Special Provisions (49 CFR 172.101, 2005):

Not Listed

ICAO International Shipping Name (ICAO, 2002):

Not Listed

-HANDLING AND STORAGE

STORAGE

CONTAINER

Warfarin potassium and warfarin sodium tablets should be stored in tight, light-resistant containers (HSDB , 1990).

ROOM/CABINET RECOMMENDATIONS

Therapeutic warfarin preparations should be stored at a temperature less than 40 degrees C, preferably between 15 to 30 degrees C (HSDB , 1990).
Warfarin rodenticides should be stored away from heat and open flames and should not be stored near feeds and foodstuffs (HSDB , 1991).

-PERSONAL PROTECTION

SUMMARY

RECOMMENDED PROTECTIVE CLOTHING - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)

Wear positive pressure self-contained breathing apparatus (SCBA).
Wear chemical protective clothing that is specifically recommended by the manufacturer. It may provide little or no thermal protection.
Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations where direct contact with the substance is possible.

Use of full protective clothing is recommended for fire fighting and spill response activities (EPA, 1985).

Remove and isolate contaminated clothing at the site for later disposal (HSDB , 1991).

RESPIRATORY PROTECTION

Refer to "Recommendations for respirator selection" in the NIOSH Pocket Guide to Chemical Hazards on TOMES Plus(R) for respirator information.

Use of a self-contained breathing apparatus is recommended for fire fighting and spill response activities (EPA, 1985).

-PHYSICAL HAZARDS

FIRE HAZARD

SUMMARY

Editor's Note: This material is not listed in the Emergency Response Guidebook. Based on the material's physical and chemical properties, toxicity, or chemical group, a guide has been assigned. For additional technical information, contact one of the emergency response telephone numbers listed under Public Safety Measures.
POTENTIAL FIRE OR EXPLOSION HAZARDS - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)
- Non-combustible, substance itself does not burn but may decompose upon heating to produce corrosive and/or toxic fumes.
- Containers may explode when heated.
- Runoff may pollute waterways.
This material will burn, but will not ignite easily (HSDB , 1991).
Keep unnecessary people away; isolate hazard area and deny entry (HSDB , 1991).
Stay upwind; keep out of low areas (HSDB , 1991).
Ventilate closed spaces before entering them (HSDB , 1991).
Wear full protective clothing and self-contained breathing apparatus for fire fighting activities (EPA, 1985).
- Fire may produce irritating and poisonous gases (HSDB , 1991).
Remove and isolate contaminated clothing at the site for later disposal (HSDB , 1991).
If water pollution occurs, notify appropriate authorities. For emergency assistance, call CHEMTREC, 1-800-424-9300 (HSDB , 1991).

FIRE CONTROL/EXTINGUISHING AGENTS

SMALL FIRE PRECAUTIONS - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)
- Dry chemical, CO2 or water spray.
LARGE FIRE PRECAUTIONS - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)
- Water spray, fog or regular foam.
- Move containers from fire area if you can do it without risk.
- Dike fire control water for later disposal; do not scatter the material.
- Use water spray or fog; do not use straight streams.
TANK OR CAR/TRAILER LOAD FIRE PRECAUTIONS - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)
- Fight fire from maximum distance or use unmanned hose holders or monitor nozzles.
- Do not get water inside containers.
- Cool containers with flooding quantities of water until well after fire is out.
- Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank.
- ALWAYS stay away from tanks engulfed in fire.
- For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn.
Extinguish fire using agent suitable for type of surrounding fire (EPA, 1985).
Move containers from fire area if it can be done without risk (HSDB , 1991).
Fight fire from maximum distance (HSDB , 1991).
Dike fire control water for later disposal; do not scatter the material (HSDB , 1991).

COMBUSTION TOXICITY

When heated to decomposition, warfarin emits acrid smoke and fumes (Sax & Lewis, 1989).
- Carbon monoxide may be released when warfarin is heated to decomposition (EPA, 1985).
Contact with strong oxidizers may cause fires and explosions (EPA, 1985).

EXPLOSION HAZARD

Contact with strong oxidizers may cause fires and explosions (EPA, 1985).

Cylinders/containers may explode in the heat of fire (HSDB , 1991).

DUST/VAPOR HAZARD

When heated to decomposition, warfarin emits acrid smoke and fumes (Sax & Lewis, 1989).

Carbon monoxide may be released when warfarin is heated to decomposition (EPA, 1985).

Fire may produce irritating and poisonous gases (HSDB , 1991).

Runoff from fire control water may give off poisonous gases (HSDB , 1991).

REACTIVITY HAZARD

Warfarin is not compatible with strong oxidizers (EPA, 1985) NIOSH, 1990).

When heated to decomposition, warfarin emits acrid smoke and fumes (Sax & Lewis, 1989).

Carbon monoxide may be released when warfarin is heated to decomposition (EPA, 1985).

EVACUATION PROCEDURES

SUMMARY

Editor's Note: This material is not listed in the Table of Initial Isolation and Protective Action Distances.
SPILL - PUBLIC SAFETY EVACUATION DISTANCES - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)
- Increase, in the downwind direction, as necessary, the isolation distance of at least 25 to 50 meters (80 to 160 feet) in all directions.
FIRE - PUBLIC SAFETY EVACUATION DISTANCES - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)
- If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions.
PUBLIC SAFETY MEASURES - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)
- CALL Emergency Response Telephone Number on Shipping Paper first. If Shipping Paper not available or no answer, refer to appropriate telephone number:
- For additional details see the section entitled "WHO TO CALL FOR ASSISTANCE" under the ERG Instructions.
- As an immediate precautionary measure, isolate spill or leak area in all directions for at least 50 meters (150 feet) for liquids and at least 25 meters (75 feet) for solids.
- Keep unauthorized personnel away.
- Stay upwind.
- Keep out of low areas.
Keep unnecessary people away; isolate hazard area and deny entry (HSDB , 1991).
Stay upwind; keep out of low areas (HSDB , 1991).

CONTAINMENT/WASTE TREATMENT OPTIONS

SUMMARY

SPILL OR LEAK PRECAUTIONS - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)
- Do not touch damaged containers or spilled material unless wearing appropriate protective clothing.
- Stop leak if you can do it without risk.
- Prevent entry into waterways, sewers, basements or confined areas.
- Cover with plastic sheet to prevent spreading.
- Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers.
- DO NOT GET WATER INSIDE CONTAINERS.
RECOMMENDED PROTECTIVE CLOTHING - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)
- Wear positive pressure self-contained breathing apparatus (SCBA).
- Wear chemical protective clothing that is specifically recommended by the manufacturer. It may provide little or no thermal protection.
- Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations where direct contact with the substance is possible.
Do not permit eating or smoking in areas where warfarin is handled, processed or stored (EPA, 1985).
Wear full protective clothing and self-contained breathing apparatus (EPA, 1985).
Do not touch spilled material; stop leak if it can be done without risk (EPA, 1985; HSDB , 1991).
Use water spray to reduce vapors (HSDB , 1991).
Storage: Warfarin rodenticides should be stored away from heat and open flames and should not be stored near feeds and foodstuffs (HSDB , 1991).
Storage: Therapeutic warfarin preparations should be stored at a temperature less than 40 degrees C, preferably between 15-30 degrees C (HSDB , 1991).
Storage: Warfarin potassium and warfarin sodium tablets should be stored in tight, light-resistant containers (HSDB , 1991).
Storage: Warfarin sodium powder for injection should be protected from light (HSDB , 1991).
Storage: Reconstituted solutions of warfarin sodium should be used immediately (HSDB , 1991).

SMALL LEAK/SPILL

Take up with sand or other noncombustible absorbent material and place into containers for later disposal (HSDB , 1991).
Small Dry Spills: With clean shovel place material into clean, dry container and cover; move containers from spill area (HSDB , 1991).

LARGE LEAK/SPILL

Dike far ahead of spill for later disposal (HSDB , 1991).
Destroy large quantities of warfarin by dissolving in a flammable solvent (eg, alcohol) and atomizing in a combustion chamber (EPA, 1985).

-ENVIRONMENTAL HAZARD MANAGEMENT

POLLUTION HAZARD

Runoff from fire control or dilution water may cause pollution (HSDB , 1991).

Warfarin can potentially be released to the environment as dust or pellets in connection with its use as a rodenticide. It may also be released in wastewater or spills during its manufacture, storage and transport (HSDB , 1991).

ENVIRONMENTAL FATE AND KINETICS

OTHER

OTHER
- TERRESTRIAL FATE: Although warfarin contains several potentially reactive chemical groups, warfarin's degradation rate in soil is unknown. It has moderate adsorption to soil, but would adsorb less under alkaline conditions since it forms a soluble salt (HSDB , 1991).
- AQUATIC FATE: If released into water, warfarin would not be expected to volatilize significantly and would only adsorb moderately to sediment. Although it absorbs UV light and contains potentially reactive groups, no data could be found concerning its reactivity, so its fate in natural water must be considered unknown (HSDB , 1991).
- ATMOSPHERIC FATE: Warfarin would most likely be released into air as particulates or aerosols and would be subject to gravitational settling. The estimated vapor phase half-life for warfarin is 11.6 minutes due to reactions with photochemically produced hydroxyl radicals and ozone in the atmosphere (HSDB , 1991).
- Warfarin's persistence due to biotic or abiotic processes is unknown (HSDB , 1991).
- Warfarin is expected to have a relatively low potential for bioconcentration in fish (HSDB , 1991).
- Evaporation from water or solid surfaces is not a significant transport mechanism for warfarin (HSDB , 1991).

ENVIRONMENTAL TOXICITY

Ecotoxicity Values (HSDB , 1991):

1. LC50 Rasbora heteromorpha (harlequin fish): 17 mg/L/24h; 14 mg/L/48h; 12 mg/L/96h

-PHYSICAL/CHEMICAL PROPERTIES

MOLECULAR WEIGHT

308.35 (RTECS , 1991; Sax & Lewis, 1989)

308.32 (EPA, 1985; ACGIH, 1986)

DESCRIPTION/PHYSICAL STATE

Warfarin is a colorless, odorless, tasteless crystalline solid (Sax & Lewis, 1989; HSDB , 1991).

WARFARIN SODIUM and WARFARIN POTASSIUM, two formulations of warfarin available as therapeutic anticoagulant drugs, are white, odorless, crystalline powders, having a slightly bitter taste (HSDB , 1991).
WARFARIN SODIUM is discolored by exposure to light (Martindale, 1992).

7.2-8.3 (HSDB , 1991)

SOLUBILITY

IN WATER

Warfarin is practically insoluble in water (Budavari, 1989; ACGIH, 1986).
Warfarin sodium is freely soluble in water (Budavari, 1989).
Warfarin sodium is soluble up to 40% in water (HSDB , 1991).
Warfarin Potassium: 1 g in 1.5 mL water (HSDB , 1991)

IN ORGANIC SOLVENTS

Warfarin is soluble in acetone and dioxane, slightly soluble in methanol and ethanol, and very soluble in alkaline aqueous solutions (Sax & Lewis, 1989; Budavari, 1989). Warfarin is also soluble in alcohol and ether (ACGIH, 1986) and moderately soluble in isopropanol and some oils (HSDB , 1991; Budavari, 1989).
Warfarin is soluble in benzene (HSDB , 1991).
Warfarin is practically insoluble in benzene, cyclohexane, (Budavari, 1989; ACGIH, 1986) and Skellysolves A and B (Budavari, 1989).
Warfarin sodium is freely soluble in alcohol and very slightly soluble in chloroform and ether (Budavari, 1989).
Warfarin potassium: 1 g in 1.9 mL alcohol (HSDB , 1991)
Warfarin potassium: 1 g in >10,000 mL chloroform (HSDB , 1991)
Warfarin potassium: 1 g in >10,000 mL ether (HSDB , 1991)

HENRY'S CONSTANT

1.0x10(-15) atm-m(3)/mol (Ehrenfeld et al, 1986)

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