Warfarin

Absorption

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

Toxicity

LD50 Values
Mouse: 3 mg/kg (Oral), 165 mg/kg (IV), 750 mg/kg (IP)
Rat: 1.6 mg/kg (Oral), 320 mg/kg (Inhaled), 1400 mg/kg (Skin)
Rabbit: 800 mg/kg (Oral)
Pig: 1 mg/kg (Oral)
Dog: 3 mg/kg (Oral)
Cat: 6 mg/kg (Oral)
Chicken: 942 mg/kg (Oral)
Guinea Pig: 180 mg/kg (Oral)
Overdose
Doses of 1-2 mg/kg/day over a period of 15 days have been fatal in humans. Warfarin overdose is primarily associated with major bleeding particularly from the mucous membranes, gastrointestinal tract, and genitourinary system. Epistaxis, ecchymoses, as well as renal and hepatic bleeding are also associated. These symptoms become apparent within 2-4 days of overdose although increases in prothrombin time can be observed within 24 hours. Treatment for overdosed patients includes discontinuation of warfarin and administration of [vitamin K]. For more urgent reversal of anticoagulation prothrombin complex concentrate, blood plasma, or coagulation factor VIIa infusion can be used. Patients can be safely re-anticoagulated after reversal of the overdose.
Carcinogenicity & Mutagenicity
The carcinogenicity and mutagenicity of warfarin have not been thoroughly investigated.
Reproductive Toxicity
Warfarin is known to be a teratogen and its use during pregnancy is contraindicated in the absence of high thrombotic risk. Fetal warfarin syndrome, attributed to exposure during the 1st trimester, is characterized by nasal hypoplasia with or without stippled epiphyses, possible failure of nasal septum development, and low birth weight. Either dorsal midline dysplasia or ventral midline dysplasia can occur. Dorsal midline dysplasia includes agenisis of the corpus callosum, Dandy-Walker malformations, midline cerebellar hypoplasia. Ventral midline dysplasia is characterized by eye anomalies which can potentially include optic atrophy, blindness, and microphthalmia. Exposure during the 2nd and 3rd trimester is associated with hypoplasia of the extremities, developmental retardation, microcephaly, hydrocephaly, schizencephaly, seizures, scoliosis, deafness, congenital heart malformations, and fetal death. The critical exposure period is estimated to be week 6-9 based on case reports. Effects noted in the Canadian product monograph include developing a single kidney, asplenia, anencephaly, spina bifida, cranial nerve palsy, polydactyl malformations, corneal leukoma, diaphragm hernia, and cleft palate.
Lactation
Official product monographs mention a study in 15 women. Warfarin was not detected in the breast milk of any woman and 6 infants were documented as having normal prothrombin times. The remaining 9 infants were not tested. Another study in 13 women using doses of 2-12 mg also revealed no detectable warfarin in breast milk. A woman who mistakenly took 25 mg of warfarin for 7 days while breastfeeding presented to an emergency room with an INR of 10 and prothrombin time of over 100 s. Her infant had a normal INR of 1.0 and prothrombin time of 10.3. The infant in this case has an increased prothrombin time of 33.8 s three weeks previous but this was judged not to be due to warfarin exposure.

Description

Warfarin is an anticoagulant coumarin derivative with two very different uses. In the 1930s, K. P. Link and co-workers at the University of Wisconsin identified warfarin as the constituent of spoiled hay that caused hemorrhaging in cattle. Its name combines the acronym for the Wisconsin Alumni Research Foundation and the “arin” in coumarin.



In the 1940s, WARF developed it as a rodenticide and in the 1950s as a drug to prevent thrombosis and embolism in humans under the trade name Coumadin. The article of commerce is the racemic mixture; the (S)-enantiomer is shown in the figure.

Description

Warfarin was the first of the synthetic anticoagulant rodenticides with structural features inspired by a natural product (88). This prototype coumarin derivative was developed in the 1940s by systematically altering the structure of dicumarol (46), recognized earlier as the causative agent of the sweet clover disease causing severe bleeding in grazing cattle (89). These rodenticides act by inhibiting the oxidoreductive recycling of vitamin K, a cofactor necessary for prothrombin synthesis involved in blood coagulation.

Description

(±)-Warfarin (Item No. 13566) is a vitamin K antagonist, a coumarin derivative, and a racemic mixture of (+)-warfarin and (–)-warfarin . It is an anticoagulant that interferes with interconversion of vitamin K and vitamin K epoxide and the role of vitamin K in carboxylation of several clotting cascade proteins, inhibiting the initiation of clotting. Formulations containing warfarin have been used to treat and prevent blood clots in atrial fibrillation, heart valve replacement, venous thrombosis, and pulmonary embolism.

Chemical properties

Colorless crystals; odorless; tasteless. Soluble in acetone, dioxane; slightly soluble in methanol, ethanol; very soluble in alkaline aqueous solution; insoluble in water and benzene.

Chemical properties

Warfarin is a colorless, odorless crystalline solid.

Originator

Coumadin ,Endo,US,1954

The Uses of Warfarin

Coumadin is widely used as an anticoagulant for various systemic diseases such as venous thromboembolism, cardiac arrhythmia, following myocardial infarction, and hematologic abnormalities, among others. However, the efficacy of coumadin for CRVO is not established. It was reported that 13 of 354 patients taking warfarin developed CRVO despite maintaining therapeutic levels of the anticoagulant.

The Uses of Warfarin

Pesticide and rodenticide

What are the applications of Application

Warfarin is A synthetic derivative of coumarin used for preventing thrombosis and embolism

Background

Warfarin is an anticoagulant drug normally used to prevent blood clot formation as well as migration. Although originally marketed as a pesticide (d-Con, Rodex, among others), Warfarin has since become the most frequently prescribed oral anticoagulant in North America. Warfarin has several properties that should be noted when used medicinally, including its ability to cross the placental barrier during pregnancy which can result in fetal bleeding, spontaneous abortion, preterm birth, stillbirth, and neonatal death. Additional adverse effects such as necrosis, purple toe syndrome, osteoporosis, valve and artery calcification, and drug interactions have also been documented with warfarin use. Warfarin does not actually affect blood viscosity, rather, it inhibits vitamin-k dependent synthesis of biologically active forms of various clotting factors in addition to several regulatory factors.

Indications

Indicated for:
1) Prophylaxis and treatment of venous thromboembolism and related pulmonary embolism.
2) Prophylaxis and treatment of thromboembolism associated with atrial fibrillation.
3) Prophylaxis and treatment of thromboembolism associated with cardiac valve replacement.
4) Use as adjunct therapy to reduce mortality, recurrent myocardial infarction, and thromboembolic events post myocardial infarction.
Off-label uses include:
1) Secondary prevention of stroke and transient ischemic attacks in patients with rheumatic mitral valve disease but without atrial fibrillation.

What are the applications of Application

Warfarin is an anti-coagulant used to prevent heart attacks, strokes, and the formation of blood clots. It interferes with the use of vitamin K in the required carboxylation of several vitamin K-dependent proteins in the clotting cascade, preventing the initiating of clotting. (±)-Warfarin is a racemic mixture of 2 optically active isomers. (±)-Warfarin has a half-life of 36-42 hours in circulation, bound to plasma proteins, and accumulates in the liver, where the two isomers are metabolized by different pathways.

Definition

ChEBI: 4-hydroxy-3-(3-oxo-1-phenylbutyl)-1-benzopyran-2-one is a member of the class of coumarins that is 4-hydroxycoumarin which is substituted at position 3 by a 1-phenyl-3-oxo-1-butyl group. It is a methyl ketone and a hydroxycoumarin.

Manufacturing Process

About 0.1 mol each of 4-hydroxycoumarin and benzalacetone are dissolved, in any desired order, in about three times their combined weight of pyridine. The solution is refluxed for about 24 hours, and then allowed to cool; after which it is poured into about 15 volumes of water, and acidified to about pH 2 by the addition of hydrochloric acid. An oil separates, and on cooling and standing overnight solidifies. The solid product is recovered, as by filtration, and recrystallized from ethanol, according to US Patent 2,427,578.
The base melts at about 161°C. It is a white crystalline solid, soluble in hot ethyl alcohol and substantially insoluble in cold water; it dissolves in alkali solutions with formation of the salt. The yield is about 40%.
Then, as described in US Patent 2,777,859, warfarin may be reacted with NaOH to give a sodium salt solution. Crystalline warfarin sodium may be prepared as described in US Patent 2,765,321.

brand name

Athrombin- K (Purdue Frederick);Coumadine;Marevan;Mervan;Sofarin;Waran;Warfilone.

Therapeutic Function

Anticoagulant

World Health Organization (WHO)

Warfarin, a coumarin anticoagulant, was introduced into medicine in 1950 for the prevention and managementof thrombo-embolic disorders. Its use during the first trimester of pregnancy has been associated with birth malformations, particularly in relation to cranial and limb development, and there have been reports of foetal death due to haemorrhage following administration of the drug during the late stages of pregnancy. The decision of the Egyptian agency to requrie a warning regarding teratogenicity to be included in the approved information of products containing warfarin beings the text of the package insert in line with those approved in other countries. Warfarin is included in the WHO Model List of Essential Drugs.

Reactivity Profile

Warfarin is incompatible with the following: Strong oxidizers .

Health Hazard

Warfarin 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.

Health Hazard

Highly toxic substance; exhibits acute,delayed and chronic effects. Ingestion of adose of 3–15 g is thought to be fatal toadult human. It is an anticoagulant causinghemorrhage. The toxic symptoms whichbegin a few days or weeks after ingestioninclude bleeding of nose and gums, pallorand blood in the urine and feces. Anothersymptom may be hematomas around jointsand hip. If the dose is large or lethalthe delayed effects may lead to cerebralhemorrhage, paralysis and death. It exhibitedteratogenic effects in laboratory animals.The LD50 values reported in the literaturewidely vary.

Fire Hazard

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.

Agricultural Uses

Rodenticide: Warfarin and its sodium salt is an anticoagulant rodenticide used for controlling rats and house mice in and around homes, animal and agricultural premises, and commercialand industrial sites. It is effective in very low dosages. About a week is required before a marked reduction in the rodent population is noticeable. Rodents do not become bait-shy after once tasting warfarin; they continue to consume it until its anti-clotting properties have produced death through internal hemorrhaging. It can be used year-after-year wherever a rodent problem exists. Warfarin and its sodium salt are only slightly dangerous to humans and domestic animals when used as directed, but care must be taken with young pigs, which are especially susceptible. The sodium salt is also used to treat people with blood hypercoagulation problems. Registered for use in EU countries . Registered for use in the U.S.

Pharmaceutical Applications

A group of naturally occurring antibiotics chemically related to the coumarin group of anticoagulants. The best known is novobiocin, but a few naturally occurring coumarins and some semisynthetic derivatives have been studied. They share a narrow range of antimicrobial activity largely directed against aerobic Gram-positive organisms. Novobiocin inhibits susceptible strains of Staph. aureus (including β-lactamaseproducing and methicillin-resistant strains), Str. pyogenes and Str. pneumonia at a concentration of 0.1–2 mg/L and it has been considered for the treatment of infection with multiresistant Staph. aureus and other Gram-positive cocci. However, since resistance arises readily and side effects are common, the general consensus is that it no longer has a place in antibacterial therapy.
There has been some revived interest in coumarins as potentiating agents of antineoplastic drugs.

Trade name

ARAB RAT DETH®; ATROMBINE-K®; BRUMIN®; COMPOUND 42®; D-CON®; CO- RAX®; DETHMORE®; EAGLES-7®; EASTERN STATES DUOCIDE®; GROVEX SEWER BAIT®; HOPKINS BAR BAIR®; HOPKINS COV-R-TOX®; HOPKINS RODEX®; KILLGERM SEWARIN P®; KILMOL®; LIQUA-TOX®; MAR-FIN®; MOUSE PAK®; PLUSBAIT®; RAT-A-WAY®; RAT-B-GON®; RAT-O-CIDE®; RAT-GARD®; RAT & MICE BAIT®; RATRON®; RATS-NO-MORE®; RATTUNAL®; RAX®; RCR SQUIRREL KILLER®; RENTOKIL®; RENTOKIL BIOTROL®; RODEX BLOX®; RODENTEX®; RO- DETH®; RODEX®; ROUGH & READY MOUSE MIX®; SAKARAT®; SOLFARIN®; SOREXA PLUS®; SOREX CR1®; SEWARIN®; SPRAY-TROL BRANCH®; TWIN LIGHT RAT AWAY®; RODEN-TROL®; WARFARAT®; WARF COMPOUND®; VAMPIRINIP® Sodium Salt: ATHROMBIN®; LIQUA-TOX®; PANWARFIN®; RATSUL SOLUBLE®; TINTORANE®; VARFINE®; WARAN®; WARCOUMIN®; WARFILONE®

Mechanism of action

Warfarin sodium is rapidly and completely absorbed (~100% bioavailability) following oral, intramuscular, intravenous, or rectal administration. Peak plasma concentrations occur at approximately 3 hours. Its anticoagulant effect is not immediately present, however, following initiation of therapy. Instead, a delay in onset of anticoagulation occurs while the clotting factors with normal activity are cleared and those that have not been carboxylated because of the actions of warfarin reach physiologically significant levels. On average, this delay is approximately 5 hours for factor V turnover and 2 to 3 days for factor II (thrombin). Consequently, because of the rapid decline in protein C levels, the anticoagulated state frequently is preceded by a period of hypercoagulability (25).
Warfarin also is highly protein bound (95–99%) and, as a result, has numerous interactions with other drugs. The free drug (i.e., that not bound to plasma proteins) is the active constituent. Therefore, any other substance that displaces bound drug from protein binding sites increases the levels of free drug and, as a result, can cause warfarin toxicity, which usually is manifested by hemorrhage. The volume of distribution(Vd) is quite small (0.1–0.2 L/kg), and the plasma half-life is quite long, both of which presumably result from the high degree of plasma protein binding.

Pharmacokinetics

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 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.

Pharmacokinetics

Warfarin sodium is rapidly and completely absorbed (~100% bioavailability) following oral, intramuscular, intravenous, or rectal administration. Peak plasma concentrations occur at approximately 3 hours. Its anticoagulant effect is not immediately present, however, following initiation of therapy. Instead, a delay in onset of anticoagulation occurs while the clotting factors with normal activity are cleared and those that have not been carboxylated because of the actions of warfarin reach physiologically significant levels. On average, this delay is approximately 5 hours for factor V turnover and 2 to 3 days for factor II (thrombin). Consequently, because of the rapid decline in protein C levels, the anticoagulated state frequently is preceded by a period of hypercoagulability (25).
Warfarin also is highly protein bound (95–99%) and, as a result, has numerous interactions with other drugs. The free drug (i.e., that not bound to plasma proteins) is the active constituent. Therefore, any other substance that displaces bound drug from protein binding sites increases the levels of free drug and, as a result, can cause warfarin toxicity, which usually is manifested by hemorrhage. The volume of distribution(Vd) is quite small (0.1–0.2 L/kg), and the plasma half-life is quite long, both of which presumably result from the high degree of plasma protein binding.

Safety Profile

A human poison by ingestion. Poison by inhalation and intravenous routes. Moderately toxic by skin contact, subcutaneous, and intraperitoneal routes. Human systemic effects by ingestion: hemorrhage, ulceration or bleeding from small intestine, blood clotting factor change. Human reproductive effects by ingestion and intramuscular routes: fetal death and physical abnormalities at birth. Human teratogenic effects include developmental abnormalities of the craniofacial area, musculoskeletal system, and respiratory system. An experimental teratogen. Other experimental reproductive effects. Used as an oral anticoagulant and as a rodenticide. When heated to decomposition it emits acrid smoke and fumes.

Synthesis

Warfarin, 3-(|á-acetonylbenzyl)-4-hydroxycoumarin (24.1.10), is synthesized via Michael reaction by attaching 4-hydroxycoumarin (24.1.7) to benzalacetone in the presence of pyridine.

Potential Exposure

Warfarin is used as an oral anticoagulant and as a rodenticide or rat poison.

Carcinogenicity

No data suggest that warfarin is either mutagenic or carcinogenic.

Environmental Fate

Photolytic. Warfarin may undergo direct photolysis since the pesticide showed an absorption maximum of 330 nm (Gore et al., 1971)
Chemical/Physical. The hydrolysis half-lives at 68.0°C and pH values of 3.09, 7.11 and 10.18 were calculated to be 12.9, 57.4 and 23.9 days, respectively. At 25°C and pH 7, the half-life was estimated to be 16 years (Ellington et al., 1986)

Metabolic pathway

The metabolism of warfarin in rat, man and other species has been studied in depth, mainly because of its use in anti-coagulant therapy to prevent thrombo-embolic disease. Having one chiral centre the molecule exists as R and S enantiomers but it is used in rodent control as the racemate. The S isomer is about six times more effective than the A isomer as judged by a single oral dose to the rat and using prothrombin time (clotting time) as a measure. The interaction of warfarin at its receptor, vitamin K₁ epoxide reductase (see Overview), is completely nonstereoselective, suggesting that the 4-hydroxycoumarin ring system binds with the enzyme. Absorption is also non-selective and, therefore, the differential efficacy must be related to metabolism and disposition.
Warfarin is metabolised by aryl hydroxylation, alkyl hydroxylation and keto-reduction. The regioselective hydroxylation is catalysed by different isozymes of cytochrome P450 and warfarin has been used extensively as a probe for these enzymes.
Metabolism studies on soils and plants do not appear to have been reported. This is due to the use pattern of the compound (see Overview). Most aspects of the medical use of warfarin have been reviewed by Sutcliffe et ul. (1987). Mention should also be made of the work of Trager and co-workers (Black et ul., 1996, and earlier papers) on the chemistry and metabolism (particularly in man) of warfarin. This group has also conducted several of the many studies on potential warfarin-drug interactions.

Metabolism

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.

Metabolism

Warfarin and other coumarin derivatives undergo extensive hepatic oxidative metabolism catalyzed by CYP2C9 isozyme to give 6- and 7-hydroxywarfarins as the major inactive metabolites. Warfarin also undergoes, to a lesser extent, reductive metabolism of the ketone on the C-3 side chain to a pair of pharmacologically active, diastereomeric 2-hydroxywarfarins). Almost no unchanged drug is excreted in the urine. As expected, those individuals with compromised hepatic function are at greater risk for warfarin toxicity secondary to diminished clearance. Many of the drug–drug interactions are associated with enhanced or inhibited metabolism of warfarin via CYP2C9 induction or inhibition. Many additional drugs and conditions have profound effects on warfarin therapy. A partial list of these factors is shown in Table 31.2.

Shipping

UN3027 Coumarin derivative pesticides, solid, toxic, Hazard Class: 6.1; Labels: 6.1-Poisonous materials. UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required.

Purification Methods

dl-Warfarin crystallises from EtOH or MeOH. UV: max at 308nm ( 13,610) in H2O. The acetate has m 117-118o, the O-triflate has m 90-91o, and the 2,4-dinitrophenylhydrazone has m 215-216o. It is an effective anticoagulant and rodenticide. [West et al. J Am Chem Soc 83 2676 1961, HPLC: Banfield & Rowland J Pharm Sci 72 921 1983, Beilstein 17 III/IV 6794.] dl-Warfarin is resolved via recrystallisation of the quinidine salt, and the free acids are recrystallised (70g) from 600mL of 80% aqueous Me2CO. Large prismatic crystals of the pure enantiomers are obtained by slow crystallisation from Me2CO or AcOH. The solubilities of the pure enantiomers at 25o are 11.2% in Me2CO and 2.6% in AcOH, whereas the racemate has solubilities of 6.5% in Me2CO and 2% in AcOH. The IR spectra are the same with max (CHCl3) at 2.78 (w), 5.88, 6.16 and 6.38. [West et al. J Am Chem Soc 83 2676 1961, Cbz-proline diastereoisomeric esters were used for HPLC analysis: Banfield & Rowland J Pharm Sci 72 921 1983.] Poisonous, anticoagulant and rodenticide.

Degradation

Warfarin is a very weak acid which forms alkali metal salts when dissolved in base. Studies have indicated that, as well as existing in the open chain form (illustrated above), warfarin may exist as a cyclic hemiketal, particularly in a lipid environment (see Park, 1988).

Incompatibilities

Incompatible with oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explosions. Keep away from alkaline materials, strong bases, strong acids, oxoacids, epoxides. Dust mixtures with air may cause explosion.

Waste Disposal

Consult with environmental regulatory agencies for guidance on acceptable disposal practices. Generators of waste containing this contaminant (≥100 kg/mo) must conform to EPA regulations governing storage, transportation, treatment, and waste disposal. Incineration.