Difenacoum

444.52

444.52

259-978-4

SBA3K9U26B

DTXSID2058128

Colorless crystals|Off-white powder

46.5

6.09 - 6.13 at 20 deg, pH 6.5

off-white powder

1.27 at 21.5 deg C

228-232 °C

290 deg C (decomposes before boiling)

204.3ºC

1.676

In acetone, chloroform >50; ethyl acetate 2, benzene 0.6 (all in g/L at 25 deg C)

Technical difenacoum and formulations should be stored in sealed containers in locked, well-ventilated, dry areas away from frost, direct sunlight, and sources of heat and ignition. Keep products out of reach of children and unauthorized personnel. Do not store near food or animal feed.

5.0X10-11 mm Hg at 25 deg C (Estimated high-end value)

Oral-rat LD50: 0.68 mg/kg; Oral-Mouse LD50: 0.80 mg/kg

Flammable; burning produces irritating fumes

Odorless

Henry's Law constant = 1.4X10-12 atm-cu m/mol at 25 °C (est)

pKa = 4.84

log Kow = 7.62 (est)|Hydroxyl radical reaction rate constant = 6.2X10-11 cu cm/molec-sec at 25 °C (est)|Buff/beige powder /Technical/

I

6.1(a)

3027

3

28-48/25-50/53

36/37-45-60-61

T+,N

The warehouse is ventilated, low temperature and dry; stored and transported separately from food materials

Stable to light, and to temps up to 100 deg C.

P264-P273-P301 + P310-P314-P501

H300-H372-H410

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational harm/injury/toxicity or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal and plant life; and conformance with environmental and public health regulations.

USEPA; Office of Prevention, Pesticides and Toxic Substances, Pesticide Fact Sheet for Difenacoum, Reason for Issuance: New Rodenticide (September 2007).[Available from, as of February 12, 2014: http://www.epa.gov/opp00001/chem_search/reg_actions/registration/fs_PC-119901_01-Sep-2007.pdf]|Murphy MJ, Lugo AM; p. 207-223 in Handbook of Toxicology of Chemical Warfare Agents; Gupta RC, ed (2009)|California Department of Pesticide Regulation; Second Generation Anticoagulant Rodenticide Assessment, June 27, 2013[California Department of Pesticide Regulation; Second Generation Anticoagulant Rodenticide Assessment, June 27, 2013; Available from, as of March 13, 2014: http://www.cdpr.ca.gov/docs/registration/reevaluation/chemicals/brodifacoum_final_assess.pdf]|WHO; Difenacoum Health and Safety Guide No. 95 (1995)[WHO; Difenacoum Health and Safety Guide No. 95 (1995); Available from, as of March 13, 2014: http://www.inchem.org/documents/hsg/hsg/hsg095.htm]|California Environmental Protection Agency, Department of Pesticide regulation, Medical Toxicology Branch, October 13, 2006[California Environmental Protection Agency/Department of Pesticide Regulation; Toxicology Data Review Summary for Difenacoum (56073-07-5) p.5 (October 13, 2006). Available from, as of March 20, 2014: http://www.cdpr.ca.gov/docs/risk/toxsums/toxsumlist.htm]

|Danger|H300: Fatal if swallowed [Danger Acute toxicity, oral]|P201, P202, P260, P262, P264, P270, P271, P273, P280, P281, P284, P301+P310, P302+P350, P304+P340, P308+P313, P310, P314, P320, P321, P322, P330, P361, P363, P391, P403+P233, P405, and P501|H300 (100%): Fatal if swallowed [Danger Acute toxicity, oral]|Aggregated GHS information provided by 287 companies from 8 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.|Where risk assessment shows air-purifying respirators are appropriate use a full-face particle repirator type N100 (US) or type P3 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standars such as NIOSH (US) or CEN (EU).|Face shield and safety glasses. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH. ...

Not flammable or combustible.

Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.|Wear self contained breathing apparatus for fire fighting if necessary.|Heating of containers will cause a pressure rise, with the risk of bursting and subsequent ignition. Fire-exposed containers should be kept cool by spraying with water.|The use of carbon dioxide or dry powder is recommended for extinguishing small fires, and foam or water fog for larger fires. A water jet should not be used. Run-off water from the fire should be prevented from entering surface-water drains or water sources.

Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust.|Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided.|Dry spillages should be collected at once, by suction, and disposed of as toxic waste, according to local legislation.

Avoid all contact by mouth. Wash hands after handling bait.|After skin exposure, all areas should be thoroughly washed with soap and water. For respiratory exposure, removal from the source of the exposure is sufficient.

/GUIDE 131: FLAMMABLE LIQUIDS-TOXIC/ Health: TOXIC; may be fatal if inhaled, ingested or absorbed through skin. Inhalation or contact with some of these materials will irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. /Coumarin derivative pesticide, liquid, flammable, poisonous; Coumarin derivative pesticide, liquid, flammable, toxic; Coumarin derivative pesticide, liquid, poisonous, flammable; Coumarin derivative pesticide, liquid, toxic, flammable/|/GUIDE 131: FLAMMABLE LIQUIDS-TOXIC/ Fire or Explosion: HIGHLY FLAMMABLE: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion and poison hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. /Coumarin derivative pesticide, liquid, flammable, poisonous; Coumarin derivative pesticide, liquid, flammable, toxic; Coumarin derivative pesticide, liquid, poisonous, flammable; Coumarin derivative pesticide, liquid, toxic, flammable/|/GUIDE 131: FLAMMABLE LIQUIDS-TOXIC/ Public Safety: CALL Emergency Response Telephone Number ... As an immediate precautionary measure, isolate spill or leak area for at least 50 meters (150 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. /Coumarin derivative pesticide, liquid, flammable, poisonous; Coumarin derivative pesticide, liquid, flammable, toxic; Coumarin derivative pesticide, liquid, poisonous, flammable; Coumarin derivative pesticide, liquid, toxic, flammable/|/GUIDE 131: FLAMMABLE LIQUIDS-TOXIC/ Protective Clothing: 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. /Coumarin derivative pesticide, liquid, flammable, poisonous; Coumarin derivative pesticide, liquid, flammable, toxic; Coumarin derivative pesticide, liquid, poisonous, flammable; Coumarin derivative pesticide, liquid, toxic, flammable/|For more DOT Emergency Guidelines (Complete) data for DIFENACOUM (16 total), please visit the HSDB record page.

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. /Coumarin derivative pesticide, liquid, flammable, toxic, flashpoint less than 23 °C; Coumarin derivative pesticide, liquid, toxic; Coumarin derivative pesticide, liquid, toxic, flammable, flashpoint 23 °C or more; Coumarin derivative pesticide, solid, toxic/|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. /Coumarin derivative pesticide, liquid, flammable, toxic, flashpoint less than 23 °C; Coumarin derivative pesticide, liquid, toxic; Coumarin derivative pesticide, liquid, toxic, flammable, flashpoint not less than 23 °C; Coumarin derivative pesticide, solid, toxic/

Difenacoum is not a skin or eye irritant.

Difenacoum was detected at concentrations of 0.86-0.87 ng/L in influent waters to wastewater treatment plants(1).

Soil and sediment samples collected from sites in Sweden in 2008 near sites where rodenticides had been used did not contain detectable levels of difenacoum (detection limit of <5 ng/L)(1).

most toxic

The pharmacological response to vitamin K1 (Konakion) /phytonadione/ in anticoagulated (prothrombin complex activity <30%) New Zealand white rabbits was determined by measuring prothrombin complex activity (P.C.A.) in peripheral plasma. In animals pretreated with ... difenacoum (0.85 mg/kg or 8.5 mg/kg) P.C.A. reached a max 4 hr after admin of vitamin K1 (0.5 mg/kg) and declined at a rate indicating complete inhibition of clotting factor synthesis. ... The duration of action of ... difenacoum was much longer than that of warfarin. ... Difenacoum /is a/ ... more potent and persistent antagonist of vitamin K1 than warfarin in vivo. ...|The following drugs ... may increase ... response to coumarin or indandione derivatives: alcohol (acute intoxication), allopurinol, aminosalicylic acid, amiodarone, anabolic steroids, chloral hydrate, chloramphenicol, cimetidine, clofibrate, co-trimoxazole, danazol, dextrothyroxine sodium, diazoxide, diflunisal, disulfiram, erythromycin, ethacrynic acid, fenoprofen calcium, glucagon, ibuprofen, indomethacin, influenza virus vaccine, isoniazid, meclofenamate, mefenamic acid, methylthiouracil, metronidazole, miconazole, nalidixic acid, neomycin (oral), pentoxifylline, phenylbutazone, propoxyphene, propylthiouracil, quinidine, quinine, salicylates, streptokinase, sulfinpyrazone, sulfonamides, sulindac, tetracyclines, thiazides, thyroid drugs, tricyclic antidepressants, urokinase, vitamin E. /Coumarin and indandione derivatives/|The following drugs ... may ... decrease ... response to coumarin or indandione derivatives: alcohol (chronic alcoholism), barbiturates, carbamazepine, corticosteroids, corticotropin, ethchlorvynol, glutethimide, griseofulvin, mercaptopurine, methaqualone, oral contraceptives containing estrogen, rifampin, spironolactone, vitamin K. /Coumarin and indandione derivatives/|The binding constants (K) of a series of anticoagulant rodenticides with the main soil organic component, humic acid (HA), were determined using frontal analysis approach. The order of the binding constants was identical as the one obtained in a previous paper, i.e. bromadiolone>brodifacoum>difenacoum>chlorophacinone>diphacinone, confirming the power of this frontal analysis approach for the determination of binding constants. Moreover, and for the first time, the concentration of unbound rodenticide to HAs could be determined. Thanks this approach, /researchers/ could clearly demonstrate that HA acid protected the human hepatoma cell line HepG2 against the cytotoxicity of all the rodenticides tested and that the toxicity of rodenticides was directly linked to the free rodenticide fraction in the medium (i.e. unbound rodenticide to HA).

LD50 Rat oral (male) 1.8 mg/kg|LD50 Mouse oral (male) 0.8 mg/kg|LD50 Cat oral 100 mg/kg|LD50 Rat dermal 50 mg/kg|For more Non-Human Toxicity Values (Complete) data for DIFENACOUM (22 total), please visit the HSDB record page.

/BIRDS and MAMMALS/ Mice (weighing 35 g) were fed for 1 day (no choice) on a mixture containing either 0.005% difenacoum or 0.002% brodifacoum. The mean mass of residue on the day of death in a whole mouse was estimated to be 10.17 g for difenacoum and 15.36 g for brodifacoum. Difenacoum- and brodifacoum poisoned mice were fed to captive barn owls for successive periods of 1, 3 and 6 days. All of the owls fed on difenacoum-poisoned mice survived the treatments and none showed external bleeding.|/BIRDS and MAMMALS/ Despite the documented risk of secondary poisoning to non-target species by anticoagulant rodenticides there is no statutory post-approval monitoring of their use in the UK. This paper presents results from two Scottish monitoring schemes for the period 2000-2010; recording rodenticide use on arable farms and the presence of residues in raptor carcasses. More than three quarters of arable farms used anticoagulant rodenticides; predominately the second generation compounds difenacoum and bromadiolone. There was widespread exposure to anticoagulant rodenticides in liver tissues of the raptor species tested and the residues encountered generally reflected agricultural use patterns. As found in other studies, Red Kites (Milvus milvus) appeared to be particularly vulnerable to rodenticide exposure, 70% of those sampled (n = 114) contained residues and 10% died as a result of rodenticide ingestion. More unexpectedly, sparrowhawks (Accipiter nisus), which prey almost exclusively on birds, had similar exposure rates to species which prey on rodents. Although, with the exception of kites, confirmed mortality from rodenticides was low, the widespread exposure recorded is concerning, particularly when coupled with a lack of data about the sub-lethal effects of these compounds. This raises questions regarding whether statutory monitoring of use is needed; both to address whether there are deficiencies in compliance with approval conditions or whether the recommended risk management procedures are themselves adequate to protect non-target wildlife.|/BIRDS and MAMMALS/ Rock hyraxes (Procavia capensis) were individually caged and were given 2 second-generation anticoagulants, difenacoum and difethialone, in fresh sliced apple bait. Mortality caused by 0.1-0.2 g/kg difenacoum bait was rather low: 0/6, 1/4 and 2/4 only.|/BIRDS and MAMMALS/ Residues of difenacoum were detected in dead barn owls in the United Kingdom at levels of 0.005-0.106 mg/kg.|For more Ecotoxicity Excerpts (Complete) data for DIFENACOUM (10 total), please visit the HSDB record page.

SRP: Persons with bleeding disorders or who are taking anticoagulants should be protected from exposure.|If anemia or liver disease is present then the above features may be more severe and persistent and the poisoning may be more difficult to control. /Anticoagulant rodenticides/

Difenacoum's production may result in its release to the environment through various waste streams; its use as a rodenticide(1) will result in its direct release to the environment(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 4.8X10+6(SRC), determined from a structure estimation method(2), indicates that difenacoum is expected to be immobile in soil(SRC). The pKa of difenacoum is 4.84(3), indicating that this compound will exist partially in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). While ionized difenacoum may adsorb less strongly to soil than the neutral form, the low mobility of difenacoum in soil is supported by results of soil column leaching studies(3). Volatilization of difenacoum from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.4X10-12 atm-cu m/mole(SRC), using a fragment constant estimation method(2). Difenacoum is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.0X10-11 mm Hg at 25 °C(3). Difenacoum is susceptible to direct photolysis(3); therefore, photodegradation on soil surfaces exposed to sunlight may occur(SRC). Difenacoum is not readily or inherently biodegradable(3). In the ready biodegradability tests according to OECD 301B, OECD 301D, and OECD 301F guidelines, the level of degradation reached only 0-31%(3). In the inherent biodegradation test according to OECD 302D draft guideline, the degradation was only 3%(3). Difenacoum degrades slowly in soil with a half-life of 439 days(3).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 4.8X10+6(SRC), determined from a structure estimation method(2), indicates that difenacoum is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surface is not expected(3) based upon an estimated Henry's Law constant of 1.4X10-12 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). According to a classification scheme(4), an estimated BCF of 6580(SRC), from an estimated log Kow of 7.62(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is very high, provided the compound is not metabolized by the organism(SRC). Using the OECD 111 test method, difenacoum was determined to be stable to hydrolysis at pH 5, pH 7 and pH 9 with half-lives greater than 1 year at 25 °C(5). Difenacoum undergoes rapid phototransformation in water with half-lives on the order of about 8 hours or less(5). Aqueous photolysis half-lives at pH 5, pH 7 and pH 9 are reported to be 0.14, 0.34 and 0.30 days respectively(6). Difenacoum is not readily or inherently biodegradable(5). In the ready biodegradability tests according to OECD 301B, OECD 301D, and OECD 301F guidelines, the level of degradation reached only 0-31%(5). In the inherent biodegradation test according to OECD 302D draft guideline, the degradation was only 3%(5). Difenacoum was stable to anaerobic biodegradation in an aquatic test after 49 days of incubation(6).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), difenacoum, which has an estimated vapor pressure of 5.0X10-11 mm Hg at 25 °C(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase difenacoum may be removed from the air by wet and dry deposition(SRC). Difenacoum is susceptible to direct photolysis in sunlight(2).

Using the OECD 111 test method, difenacoum was determined to be stable to aqueous hydrolysis at pH 5, pH 7 and pH 9 with half-lives greater than 1 year at 25 °C(1). When tested under EPA Guidelines at 25 °C, difenacoum did not hydrolyze at pH 5, had a half-life of about a 1000 days at pH 7, and had a half-life of about a 80 days at pH 9(1). Difenacoum undergoes rapid phototransformation in water with half-lives on the order of about 8 hours or less(1). Aqueous photolysis half-lives at pH 5, pH 7 and pH 9 are reported to be 0.14, 0.34 and 0.30 days respectively(2).

An estimated BCF of 6580 was calculated in fish for difenacoum(SRC), using an estimated log Kow of 7.62(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is very high(SRC), provided the compound is not metabolized by the organism(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of difenacoum can be estimated to be 4.8X10+6(SRC). According to a classification scheme(2), this estimated Koc value suggests that difenacoum is expected to be immobile in soil. The pKa of difenacoum is 4.84(3), indicating that this compound will exist partially 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(4). Using an HPLC approximation method (OECD 121), difenacoum was found to have a Koc value of 4.27X10+5 at pH 3-4 and a Koc range of 17-165 at pH 7-8.5(3); however, this method was considered unsuitable for difenacoum because it did not use measurements in real soil(3). It does suggest that lower adsorption may occur in neutral or alkaline soils(3). The low mobility of difenacoum in soil is supported by results of soil column leaching studies(3).

The Henry's Law constant for difenacoum is estimated as 1.4X10-12 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that difenacoum is expected to be essentially nonvolatile from water surfaces(2). Difenacoum's Henry's Law constant indicates that volatilization from moist soil surfaces is not expected to occur(SRC). Difenacoum is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.0X10-11 mm Hg(3).

SURFACE WATER: Surface waters and storm waters collected from urban sites in Sweden in 2008 did not contain detectable levels of difenacoum (detection limit of <5 ng/L)(1).

Occupational exposure to difenacoum may occur through dermal contact with this compound at workplaces where difenacoum is produced or used(1). The general population may be exposed to difenacoum via dermal contact with rodenticide products containing difenacoum(SRC).

Agents that prevent BLOOD CLOTTING. (See all compounds classified as Anticoagulants.)|Chemicals used to destroy pests of any sort. The concept includes fungicides (FUNGICIDES, INDUSTRIAL); INSECTICIDES; RODENTICIDES; etc. (See all compounds classified as Pesticides.)|Substances used to destroy or inhibit the action of rats, mice, or other rodents. (See all compounds classified as Rodenticides.)

After a single oral (14)C-difenacoum dose of 1.2 mg/kg bw, the highest concn of radioactivity (41.5% of the dose) was found in the rat liver 24 hr after dosing. The elimination from the liver was biphasic. The half-life of elimination of the radioactivity during the first rapid phase was 3 days, and for the slower phase was 118 days. A similar biphasic elimination was also apparent in the kidney. In the pancreas the concn declined more slowly than in any of the other tissues (182 days). The parent compound was the major component in the liver 24 hr after dosing (42%).|... In our first experiment difenacoum (0.5 mg/kg) killed 50% of male mice within 9 days of its admin, whereas no female mice died during this study. In a second group of experiments, the anticoagulant effect of difenacoum in male and female rats was determined. Under resting conditions, the prothrombin complex activities (PCA) of male and female rats were not significantly different. Over the first 24 hr after admin of difenacoum (0.4 mg/kg ip), there was a monoexponential fall in PCA in both sexes. However, 6, 12 and 24 hr after difenacoum, the PCA in male rats was significantly (P<0.05) lower than in female rats. PCA began to recover over the subsequent 48 hr in both sexes, during which time there was marked variability in recovery in female rats. The difference between the onset of action of difenacoum in male and female rats did not appear to be due to a greater rate of elimination of the drug in female rats, since the plasma concns of difenacoum 24 hr after its admin were the same in both sexes. The concn of vitamin K1 in rat liver was also investigated. Vitamin K1 levels were 35.1 +/- 18.6 ng/(g liver) (male), and 29.4 +/- 5.4 ng/(g liver) (females) in control rats, but 24 hr after difenacoum, vitamin K1 levels were either very low, or undetectable in all rats.|Thirty two male rats were dosed orally by gavage with 1.2 mg/kg of (14)C-labeled-Difenacoum (phenyl-ring of coumarin moiety) (specific activity: 1961 Mbq/mmole; radiochemical purity: 93.1%, cis:trans ratio: 44:56). Three animals per time point were euthanized at 1, 4 and 8 days and 2, 4, 8, 12 and 26 weeks after dosing. Blood was collected by cardiac puncture and the liver, kidneys, pancrease, salivary glands and a sample of abdominal fat were removed for radioanalysis. The prothrombin time and kaolin- cephalin time were measured for each blood sample. The liver was the primary tissue in which the radiolabel was isolated. Forty one percent of the administered dose was recovered from the organ 24 hours after dosing. Even 6 months after dosing, 3% of the administered dose was still present in the liver. A biphasic elimination process was noted with a half-life for the rapid phase being 3 days and a half-life of the slow phase of 118 days. The cis isomer of the active ingredient demonstrated a longer residence time in the liver. By 14 days, the trans form was no longer detectable. Other metabolites were also isolated in the liver, but were not chemically identified in the study. ...|The concentration in fat was relatively low. Difenacoum is highly lipophilic, but that does not significantly affect tissue distribution due to a high affinity for specific binding sites in tissues.|For more Absorption, Distribution and Excretion (Complete) data for DIFENACOUM (8 total), please visit the HSDB record page.

Bromadiolone, brodifacoum and coumatetralyl were also found in rats as unchanged parent compounds, whereas in the case of difenacoum metabolites predominated. The metabolism and elimination of the difenacoum trans isomer was more rapid than for the cis isomer.

The pharmacokinetics and pharmacodynamics of the 4-hydroxycoumarin anticoagulants, /including/ difenacoum ...have been studied in the rabbit. ...After admin of a single iv dose (20 umol/kg), ...plasma concns of ...difenacoum underwent bi-exponential decay with /a/ terminal half-/life/ of ...83.1 +/- 10.3 hr... . ...|After a single oral (14)C-difenacoum dose /to rats/ of 1.2 mg/kg bw, the ...half-life of elimination of the radioactivity /in the liver/ during the first rapid phase was 3 days, and for the slower phase was 118 days. A similar biphasic elimination was also apparent in the kidney. ...|/In humans/, an intentional difenacoum ingestion resulted in a plasma half-life of 11.5 days.|/In laboratory animals/, the elimination from the liver and kidney is biphasic with an initial rapid phase of three days and a slower phase with a half-life of 118-120 days. In the pancreas, the concentration declined more slowly (a half-life of 182 days).|... A terminal half life of 11.7 days /in human plasma/.

... The pharmacological response /of rabbits/ to the anticoagulants was measured as changes in prothrombin complex activity, from which the rate of clotting factor synthesis was determined. Clotting factor synthesis recovered in a monophasic fashion after a single iv dose of warfarin, compared with a more complex biphasic, pattern of recovery of clotting factor synthesis after admin of ...difenacoum. The slope (m) of the intensity of effect-log (amount of drug in the body) curve was derived for each anticoagulant. There was no significant difference in the value of m after single iv doses of racemic, R-, and S-warfarin, difenacoum and brodifacoum, which is consistent with the hypothesis that all the 4-hydroxycoumarin anticoagulants produce their anticoagulant effect by acting at the same receptor site, vitamin K epoxide reductase. ...|Both 4-hydroxycoumarin derivatives and indandiones (also known as oral anticoagulants) are antagonists of vitamin K. Their use as rodenticides is based on the inhibition of the vitamin K-dependent step in the synthesis of a number of blood coagulation factors. The vitamin K-dependent proteins involved in the coagulation cascade are the procoagulant factors II (prothrombin), VII (proconvertin), IX (Christmas factor) and X (Stuart-Prower factor), and the coagulation-inhibiting proteins C and S. All these proteins are synthesized in the liver. Before they are released into the circulation the various precursor proteins undergo substantial (intracellular) post-translational modification. Vitamin K functions as a co-enzyme in one of these modifications, namely the carboxylation at well-defined positions of 10-12 glutamate residues into gamma-carboxyglutamate (Gla). The presence of these Gla residues is essential for the procoagulant activity of the various coagulations factors. Vitamin K hydroquinone (KH2) is the active co-enzyme, and its oxidation to vitamin K 2,3-epoxide (KO) provides the energy required for the carboxylation reaction. The epoxide is than recycled in two reduction steps mediated by the enzyme KO reductase. The latter enzyme is the target enzyme for coumarin anticoagulants. Their blocking of the KO reductase leads to a rapid exhaustion of the supply of KH2, and thus to an effective prevention of the formation of Gla residues. This leads to an accumulation of non-carboxylated coagulation factor precursors in the liver. In some cases these precursors are processed further without being carboxylated, and (depending on the species) may appear in the circulation. At that stage the under-carboxylated proteins are designated as descarboxy coagulation factors. Normal coagulation factors circulate in the form of zymogens, which can only participate in the coagulation cascade after being activated by limited proteolytic degradation. Descarboxy coagulation factors have no procoagulant activity (i.e. they cannot be activated) and neither they can be converted into the active zymogens by vitamin K action. Whereas in anticoagulated humans high levels of circulating descarboxy coagulation factors are detectable, these levels are negligible in warfarin-treated rats and mice. /Anticoagulant rodenticides/|Second-generation anticoagulant rodenticide. Inhibits the vitamin K-dependent steps in the synthesis of clotting factors II, VII, IX, and X. Duration of action is much longer than that of warfarin.|Rodenticide anticoagulants inhibit the dithiothreitol-dependent vitamin K reductase reactions and prevent vitamin K hydroquinone regeneration, which is evident by the significant incr in serum vitamin 2,3 epoxide levels and a concurrent incr in the serum vitamin K epoxide-vitamin K ratio. Inhibition of vitamin K reductases indirectly inhibits active prothrombin complex protein formation. Rodenticide anticoagulants inhibit vitamin K regeneration almost immediately, but the anticoagulant effect is delayed until the vitamin K stores are depleted and sufficient active coagulation factors are removed from circulation.

Human exposure to second-generation and indandione anticoagulants produces symptoms consistent with anticoagulation effects (e.g., hematomas, hematemesis, hematuria, easy bruisability). Treatment of cases of exposure, particularly of substantial and repeated exposure, may require vitamin K1 therapy and monitoring of prothrombin times for periods of many months.|Vitamin K1. ... For suicidal ingestions with large amounts taken, if there is uncertainty about the amount of bait ingested or the general health of the patient, phytonadione (vitamin K1) given orally protects against the anticoagulant effect of these rodenticides, with essentially no risk to the patient. In accidental ingestions with healthy children involving only a taste or single swallow, no medical treatment is required, but children should be observed for bleeding and bruising. If a larger amount may have been ingested, prothrombin time (PT) should be monitored at 24 and 48 hours, with phytonadione therapy initiated for elevated PT or clinical signs of bleeding. CAUTION: Phytonadione, specificaly, is required. Neither vitamin K3 (menadione, Hykinone) nor vitamin K4 (menadiol) is an antidote for these anticoagulants. /Coumarins and Indandiones/|Gastrointestinal decontamination. If large amounts of anticoagulant have been ingested within several hours prior to treatment, consider gastric decontamination procedures ... . /Coumarins and Indandiones/|Determine prothrombin time. If anticoagulant has been ingested any time in the preceding 15 days, determination of the prothrombin time (PT) provides a basis for judging the severity of poisoning. Patients who ingest large amounts, particularly of the superwarfarin compounds, will likely have a very prolonged period of decreased prothrombin activity. Patients may need to be treated for as long as 3 or 4 months. If the PT is significantly lengthened, give Aquamephyton /(Vitamin K1)/ intramuscularly. ... /Coumarins and Indandiones/|For more Antidote and Emergency Treatment (Complete) data for DIFENACOUM (14 total), please visit the HSDB record page.

/SIGNS AND SYMPTOMS/ ... Substantial ingestion produces epistaxis, gingival bleeding, widespread bruising, hematomas, hematuria with flank pain, menorrhagia, gastrointestinal bleeding, rectal bleeding and hemorrhage into any internal organ; anemia may result. Spontaneous hemoperitoneum has been described. Severe blood loss may result in hypovolemic shock, coma and death. The first clinical signs of bleeding may be delayed and patients may remain anticoagulated for several days (warfarin) or days, weeks or months (long-acting anticoagulants) after ingestion of large amounts...|/SIGNS AND SYMPTOMS/ Symptoms of acute intoxication by difenacoum include an increased tendency to bleed in less severe cases of poisoning and massive haemorrhaging in more severe cases. The signs of poisoning develop with a delay of one to several days after ingestion.|/SIGNS AND SYMPTOMS/ Typical features of poisoning result from increased bleeding tendency and include: minor poisoning: coagulation disturbance detected only by laboratory analyses; moderate poisoning: coagulation disturbance resulting in hematomata, hematuria, blood in feces or excessive bleeding from minor cuts or abrasions, gum bleeding; severe poisoning: retroperitoneal hemorrhage, severe GI bleeding, cerebrovascular accidents, massive hemorrhage (internal bleeding) resulting in shock. If anemia or liver disease is present then the above features may be more severe and persistent and the poisoning may be more difficult to control. The onset of the signs of poisoning may not be evident until a few days after ingestion. /Anticoagulant rodenticides/|/SIGNS AND SYMPTOMS/ Hematuria, ecchymoses, gingival bleeding, epistaxis, abdominal pain, bleeding wounds, oral mucosa bleeding, melena, flank pain, heme positive stool, hematomas, anemia, decreasing hemoglobin concns, intracranial bleeding, vaginal bleeding, back pain, hematochezia, menorrhagia, hemoperitoneum, compartment syndrome, coma, tachycardia, tachypnea, fever, hemoptysis, urethral bleeding, fatigue, headache, seizures (from table). /Adult- long acting rodenticide anticoagulants/|For more Human Toxicity Excerpts (Complete) data for DIFENACOUM (14 total), please visit the HSDB record page.

difenacoum

Ready-to-use cereal based bait in pellets, whole and broken grains, water proof wax blocks, loose, or bait packets.|Premix Partners: Calciferol.|Mixtures: difenacoum + calciferol.|Trade Names: Neosorexa PP580, WBA 8107, Ratak, PP 580.|For more Formulations/Preparations (Complete) data for DIFENACOUM (10 total), please visit the HSDB record page.

The WHO Recommended Classification of Pesticides by Hazard identifies difenacoum (technical grade) as Class IA: extremely hazardous; Main Use: rodenticide.|Appearing in 1974, difenacoum was the first of the new generation of anticoagulants to be commercialized for the control of rodents resistant to warfarin and related compounds.|Chemical warfare agents may be manufactured from a wide range of commercially manufactured household industrial products such as bleach, antifreeze, fertilizers containing anhydrous ammonia, pesticides, or anticoagulant rodenticides particularly superwarfarins, to name a few. ... Superwarfarins may be used to harm or terrorize people through the ingestion of contaminated food or water. /Superwarfarins/|Rodenticide anticoagulants are used in the control of rodent populations. In addition to accidental ingestions in humans, such agents have also been used for homicidal and suicidal purposes. There are two major groups of rodenticide anticoagulants - hydroxycoumarins and indanediones. /Rodenticide anticoagulants/

Early HPLC (High Performance Liquid Chromatography) focused on an individual chemical. For example, methods to detect chlorophacinone in formulations, brodifacoum in serum, brodifacoum, bromadiolone, chlorophacionone, difethiolone, and difenacoum in tissue have been reported.|Rodenticide anticoagulants are used in the control of rodent populations. In addition to accidental ingestions in humans, such agents have also been used for homicidal and suicidal purposes. There are two major groups of rodenticide anticoagulants - hydroxycoumarins and indanediones. Before the advent of LC-MS/MS, analysis for such agents was relegated to such techniques as TLC and HPLC with nonspecific modes of detection. LC-MS/MS has been used to determine any given number of rodenticide anticoagulants in animal tissues, foods, plasma, etc. Use of this technique allows for the simultaneous identification of individual compounds within both classes of rodenticide anticoagulants. The LC-MS/MS method presented allows for simultaneous qualitative identification of brodifacoum, bromadiolone, chlorphacinone, dicumarol, difenacoum, diphacinone, and warfarin in blood, serum, and plasma using ESI in the negative mode. Two transitions are monitored for each analyte after a simple sample preparation. Chromatographic separation is accomplished using a gradient of ammonium hydroxide in water and ammonium hydroxide in methanol. Chloro-warfarin is used as internal standard.|The purpose of this study was to develop and validate a liquid chromatography-tandem mass spectrometry method for the identification and quantification of anticoagulant (anti-vitamin K or AVK) compounds, including rodenticides, drugs, and natural products because no published method could be found. The proposed method is based on ion-trap technology with electrospray ionization (ESI) and multiple reaction monitoring (MRM) technique. Each AVK is identified by means of its retention time, precursor ion, and two product ions. Plasma samples are extracted by liquid-liquid partition on Toxi-tube B(R). The method was validated on dog plasma and gave good results in terms of specificity, linearity, and percent recovery for the 14 AVK tested (warfarin, acenocoumarol, bromadiolone, brodifacoum, chlorophacinone, coumatetralyl, dicoumarol, difenacoum, difethialone, flocoumafen, fluindione, phenindione, and tioclomarol). The limits of detection ranged from 5 to 25 ng/mL. Intraday repeatability was good, but interday repeatability was more variable though still sufficient for our diagnostic purposes. The technique was successfully applied in a series of clinical investigations to demonstrate its applicability in various animal species and gave very high sensitivity and specificity results.|Anticoagulant rodenticides are frequently a cause of poisoning of domestic animals, wildlife, and human beings. A toxicosis in 6,000 laying hens caused by the malicious addition of unknown amounts of coumatetralyl bait as well as the insecticides aldicarb, methomyl, and imidacloprid in the drinking water, was investigated in the current study. In order to determine a possible carryover of coumatetralyl into eggs, a rapid and reliable analytical method was developed and fully validated for the simultaneous detection of 6 anticoagulant rodenticides (warfarin, coumatetralyl, coumachlor, bromadiolone, difenacoum, and brodifacoum) in yolk and albumen using high-performance liquid chromatography (HPLC) with fluorescence detection. The method developed was reproducible, sensitive, accurate, and linear within the range of 0.01-1 mg/kg, which is the concentration range of bromadiolone and warfarin found in yolk in previously reported studies. The coefficient of variations of within and between days was 1.0-8.5% for yolk and 0.6-3.8% for albumen, while recoveries from spiked albumen and yolk samples were all in the range of 79-99% and 51-95%, respectively. Limits of detection in yolk were 0.01 mg/kg for warfarin and 0.003 mg/kg for the remaining compounds; in albumen, the limit of detection was 0.003 mg/kg for warfarin, coumatetralyl, and coumachlor, and 0.0015 mg/kg for difenacoum and brodifacoum. The application of the validated method revealed the presence of coumatetralyl in the yolk only at levels of 0.0057 mg/kg and 0.0052 mg/kg on the second and fourth day of the poisoning. In conclusion, the HPLC method demonstrated suitability for application in official analysis of anticoagulants in hen eggs.|For more Analytic Laboratory Methods (Complete) data for DIFENACOUM (8 total), please visit the HSDB record page.

This paper presents a fully validated method for the qualitative identification of bromadiolone, brodifacoum, coumachlor, coumatetralyl, difenacoum and warfarin in whole blood specimens. Samples are protein precipitated with acetonitrile, processed via solid-phase extraction and analyzed by high-performance liquid chromatography with high resolution tandem mass spectrometric detection. Limits of detection were 10 ng/mL or better for all analytes.|Analyte: Difenacoum; Matrix: Animal tissues; Procedure: HPLC/FD; Detection Level: 2 ug/kg. /from table/|Analyte: Difenacoum; Matrix: Serum; Procedure: HPLC; Detection Level: 10 ug/l. /from table/|A quick and easy method for the analysis of anticoagulant rodenticides in blood or tissue using principles of dispersive solid-phase extraction (dSPE), commonly known as QuEChERS (short for quick, easy, cheap, effective, rugged, and safe), was developed. Briefly, a combination of magnesium sulfate, PSA, florisil, and basic alumina was used to cleanup blood samples. Further, to cleanup liver tissue samples, C(18) sorbent was included along with the previously mentioned. The samples were analyzed using high-performance liquid chromatography equipped with a reversed-phase C(18) column (150 x 4.6 mm, 5-microm particle size) and a UV and fluorescence detector. The mobile phase consisted of 0.03 M tetrabutylammonium hydroxide (TBA) adjusted to pH 7/methanol (1:1, v/v) as solvent A and methanol as solvent B in a gradient run. The method detection limit was as low as 10 ng/mL for brodifacoum and difenacoum in blood and 10 ng/g in liver; 50 ng/mL for bromadiolone, difethialone, and chlorphacinone in blood and similarly 50 ng/g in liver; and 100 ng/mL for coumafuryl, pindone, warfarin, and diphacinone in blood and 100 ng/g in liver samples. A number of clinical samples of both blood and liver were analyzed; the comparison of this modified QuEChERS and traditional solid-phase extraction data was found to be in close agreement. This method resulted in drastic reduction in processing time and solvent cost both in terms of consumption and disposal, thus making it an attractive alternative to the traditional solid-phase extraction.

Agrochemicals -> Rodenticides