Dicumarin

log Kow = 2.07 @ pH 7.4

3.1

1.83

White or creamy white, crystalline powder

Minute crystals

NEEDLES

Very small crystals from cyclohexanone

Practically insol in water, alc, ether.

INSOL IN ACETONE

Sol in aq alkaline solns, in pyridine and similar org bases. Slightly sol in benzene and chloroform.

6.62e-02 g/L

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

287-293 °C

290 °C

White solid with a mild pleasant odor; [HSDB]

Solid

Danger

H302: Harmful if swallowed [Warning Acute toxicity, oral]

P260, P264, P270, P273, P301+P317, P319, P330, P391, and P501 (click each P-code to see the statement)

Danger

H302 (98.9%): Harmful if swallowed [Warning Acute toxicity, oral]

P260, P264, P270, P273, P301+P317, P319, P330, P391, and P501 (click each P-code to see the statement)

Hazard Traits - Developmental Toxicity

2H-1-Benzopyran-2-one, 3,3'-methylenebis[4-hydroxy-: Does not have an individual approval but may be used under an appropriate group standard

Freedman MD, Olatidoye AG; Drug Saf 10 (5): 381-94 (1994). Oral anticoagulants include coumarin derivatives (dicoumarol, phenprocoumon and acenocoumarol. ... The oral anticoagulants, and warfarin in particular are highly interactive with other drugs. Mechanisms of those interactions include both pharmacokinetic and pharmacodynamic mechanisms and may result in either hyperprothrombinemia or hypoprothrombinemia.

Acute Tox. 4 (98.9%)

Specific target organ toxicity (repeated exposure) - category 1

Acute toxicity (Oral) - Category 3

Acute Tox. 4 *

No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./

The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials.

The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article.

UN 3024; Coumarin derivative pesticides, liquid, flammable, toxic, NOS, flashpoint less than 23 °C

UN 3025; Coumarin derivative pesticides, liquid, toxic, flammable, NOS, flashpoint 23 °C or more

UN 3026; Coumarin derivative pesticides, liquid, toxic, NOS

UN 3027; Coumarin derivative pesticides, solid, toxic, NOS

For more Shipping Name/ Number DOT/UN/NA/IMO (Complete) data for DICUMAROL (6 total), please visit the HSDB record page.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Care should be taken ... not to contaminate foodstuffs ... not to leave material within reach of children; to use prepared baits rather than scatter poison; to collect and destroy dead rodents; to bury baits and powder when operation is completed. /coumarin derivatives/

Whereever possible, toxic chemicals, concentrates & bait preparations should be handled in a fume cupboard. When bait mixing has been done in the field, operators should take care to remain sheltered from the wind. /Rodenticides/

Scrupulous personal hygiene must be adhered to when dealing with poisons. All cuts & abrasions on the hands & forearms must be covered with waterproof adhesive dressings before any operations are started. When the work is finished or when a break is taken in the middle /of the day/, protective clothing should be removed & hands washed thoroughly with soap & hot water. Contaminated protective clothing must not be taken into "clean" areas. /Rodenticides/

Smoking, eating & drinking must be strictly prohibited in all rooms in which poisons are present. /Rodenticides/

For more Preventive Measures (Complete) data for DICUMAROL (7 total), please visit the HSDB record page.

Adequate protective clothing should be worn at all times. In the lab this will consist of a lab coat, rubber or polyethylene gloves & a /NIOSH approved respirator/ or respirator of a type applicable to the specific chemical being handled. /Rodenticides/

Dicumarol admin prolongs the half-life of chlorpropamide and phenytoin, resulting in hypoglycemia in the case of chlorpropamide and an increased plasma drug concn in the case of phenytoin.

...Sulfonamides (esp long-acting ones) displace dicumarol from plasma proteins & hence incr effect.

...Carbon tetrachloride & chloral hydrates are strong potentiators of its anticoagulant effects.

Antipyrine (in vivo) & sulfinpyrazone (in vitro) have been reported to interact with warfarin and should be used cautiously in pt receiving anticoagulants. /anticoagulants/

For more Interactions (Complete) data for DICUMAROL (20 total), please visit the HSDB record page.

LC50 Pimephales promelas (fathead minnow) 5.11 mg/l/96 hr (95% confidence limit 4.18 - 6.24 mg/l), flow-through bioassay with measured concentrations, 24.5 °C, dissolved oxygen 7.2 mg/l, hardness 44.3 mg/l calcium carbonate, alkalinity 44.0 mg/l calcium carbonate, and pH 7.8.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 320(SRC), determined from a log Kow of 2.07(2) and a regression-derived equation(3), indicates that dicumarol is expected to have moderate mobility in soil(SRC). Volatilization of dicumarol from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.4X10-13 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Dicumarol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.0X10-17 mm Hg(SRC), determined from a fragment constant method(5).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 320(SRC), determined from a log Kow of 2.07(2) and a regression-derived equation(3), indicates that dicumarol is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.4X10-13 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 8(SRC), from its log Kow(2) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC), provided the compound is not altered physically or chemically after released into the environment(SRP).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), dicumarol, which has an estimated vapor pressure of 6.0X10-17 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase dicumarol may be removed from the air by wet and dry deposition(SRC).

Dicoumarol is an anticoagulant that competitively inhibits vitamin K, preventing the formation of prothrombin. It does this by inhibiting the enzyme NAD(P)H:quinone oxidoreductase-1, which is required for the reduction of vitamin K to its hydroquinone. Reduced vitamin K is a cofactor needed in the conversion of prothrombin precursor protein to active prothrombin, an essential protein for blood clotting. In addition, inhibition of NAD(P)H:quinone oxidoreductase-1 induces the generation of superoxide anion radicals that inhibit cell growth. Dicoumarol can also potently and reversible inhibit gap junctional intercellular communication, though the precise mechanism is unknown. (L1960, A2994, A2995, A2996, A2997)

Dicumarol concentration in 272 cured sweet clover samples from 4 counties in North Dakota (USA) was determined. Dicumarol concentrations ranged from 0-164.7 mg/kg sweet clover, with 64.6% of 272 samples containing less than 10 mg/kg. Round bales were significantly higher in dicumarol concentration than were stacks or silage. The outer section of core samples taken from round bales contained significantly higher concentrations of dicumarol than did the inner section of the core, with means of 30.8 and 16.6 mg/kg, respectively. A significant correlation existed between crude protein and dicumarol values.

A complete history and physical examination: The purpose is to detect preexisting conditions that might place the exposed employee at increased risk, and to establish a baseline for future health monitoring. Persons with a history of blood disorders with bleeding tendencies would be expected to be at increased risk from exposure. Examination of the blood should be stressed. /Warfarin/

The Koc of dicumarol is estimated as 320(SRC), using a log Kow of 2.07(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that dicumarol is expected to have moderate mobility in soil.

B - Blood and blood forming organs

QB - Blood and blood forming organs

Dicumarol 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 decresed prothrombin levels and a decrease in the amount of thrombin generated and bound to fibrin. This reduces the thrombogenicity of clots.

These compounds depress the hepatic synthesis of vitamin K1-dependent clotting factors (II, VII, IX, X) by inhibiting the vitamin K1 2,3-reductase enzyme in the vitamin K1-epoxide cycle. /Anticoagulant rodenticides/

The oral anticoagulants block the regeneration of reduced vitamin K and thereby induce a state of functional vitamin K deficiency. The mechanism of the inhibition of reductase(s) by the coumarin drugs is not known. There exist reductases that are less sensitive to these drugs but that act only at relatively high concentrations of oxidized vitamin K; this property may explain the observation that administration of sufficient vitamin K can counteract even large doses of oral anticoagulants. /Oral Anticoagulants/

Dicumarol a specific and potent inhibitor of DT-diaphorase.

4-Hydroxycoumarin deriv (dicumarol...) Inhibit rat liver /drug metabolizing enzymes/ in vitro. Mechanism is complex, being caused by several factors, including conversion of cytochrome P450 into P420, inhibition of NADPH-cytochrome P450 reductase, and competition for active site.

For more Mechanism of Action (Complete) data for DICUMAROL (7 total), please visit the HSDB record page.

1-2 days

...T/2 of dicumarol is dose dependent, ranging from 10 hr at low dosage to 30 hr at high dosage.

Dicumarol has a dose dependent plasma half-life (one to two days); therapy is therefore somewhat difficult to control and frequent monitoring is usually indicated.

Elimination half-life: 1 to 2 days

Dicoumarol is not conjugated in either man or dog...

Dicumarol...hydroxylated to inactive cmpd by enzymes of hepatic endoplasmic reticulum.

Despite their structural similarity to coumarin, the anticoagulants dicumarol and warfarin do not appear to be substrates for CYP2A6. The overall rate of dicumarol metabolism varied approx 5 fold among the human liver microsomal samples, but this variation correlated poorly (r2= 0.126) with the variation observed in CYP2A6 levels and hydroxycoumarin levels.

Agents that prevent BLOOD CLOTTING.

Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.

Chemical agents that uncouple oxidation from phosphorylation in the metabolic cycle so that ATP synthesis does not occur. Included here are those IONOPHORES that disrupt electron transfer by short-circuiting the proton gradient across mitochondrial membranes.

Considerable individual variation in t/2 of dicumarol has been attributed to genetic factors. ... dicumarol...hydroxylated to inactive compounds by enzymes of hepatic endoplasmic reticulum. These metabolites and traces of parent drugs are excreted in urine. Some unabsorbed dicumarol appears in feces.

In man, absorption of dicumarol from gi tract is slow and erratic. ... There is considerable variation in absorption from one individual to another. Within circulation...almost entirely but loosely bound to plasma albumin, & only small percentage of total plasma concentration is represented by unbound drug. ... Appreciable amount ...found in erythrocytes, but little or none is present in cerebrospinal fluid. ...accumulate/s/ mainly in lung, liver, spleen and kidney.

Whole-body autoradiography of rats given anticoagulant, [(14)C]-dicumarol by intracardiac injection, indicated that (14)C distributed in most tissues, maximally in liver, lungs, heart, and kidneys. After 24 hr, (14)C levels were high in intestinal tract owing, presumably, to biliary excretion. Initially, iv dose of dicoumarol was more readily excreted in bile than in urine; in 3 hr, 4% was eliminated in bile and less than 0.4% in urine.

...71% of iv dose of...[(14)C]-dicoumarol, was excreted in feces and 23% in urine in 5 days.

Used as rodenticide and therapeutic anticoagulant; Discontinued as a medication; [HSDB]

Farming (Pesticides) [Category: Industry]

Rodenticide

MEDICATION

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies discontinued drug products. Dicumarol is included on this list.

Dicoumarol is a mycotoxin of combined plant and fungal origin. It is a derivative of coumarin, a substance made by plants which is transformed in mouldy feeds by a number of species of fungi into active dicoumarol. Dicoumarol is an anticoagulant that is used along with heparin for the treatment of deep venous thrombosis, as well as in biochemical experiments as an inhibitor of reductases. (L1960)

Originally isolated from spoiled sweet clover (improperly cured Melilotus hay) ... now prepared synthetically by the action of formaldehyde on 4-hydroxy-coumarin (obtained as the Na derivative by the action of sodium metal on methyl acetylsalicylate) ... .

2H-1-Benzopyran-2-one, 3,3'-methylenebis[4-hydroxy-: ACTIVE

ADVANTAGE AS RAT POISON IS THAT TREATED ANIMALS DO NOT DEVELOP "BAIT SHYNESS". AS RODENTICIDE, DICOUMAROL IS NOWADAYS SUPERSEDED BY WARFARIN.

...Synthetically by the action of formaldehyde on 4-hydroxycoumarin (obtained as sodium deriv by action of sodium metal on methyl acetylsalicylate)... .