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3D model (JSmol)
|Molar mass||523.43 g·mol−1|
|Melting point||228 to 230 °C (442 to 446 °F; 501 to 503 K)|
|Oral; dermal; inhalation (dusts) (for poisoning)|
|slow, incomplete, hepatic|
|Slow; 20—130 days|
|faeces; very slow|
|Lethal dose or concentration (LD, LC):|
LD50 (median dose)
|270 μg/kg (rat, oral)[inconsistent]|
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
|what is ?)(|
Brodifacoum is a highly lethal 4-hydroxycoumarin vitamin K antagonist anticoagulant poison. In recent years, it has become one of the world's most widely used pesticides. It is typically used as a rodenticide but is also used to control larger pests such as possum.
Brodifacoum has an especially long half-life in the body, which ranges to several months, requiring prolonged treatment with antidotal vitamin K for both human and pet poisonings. It has one of the highest risks of secondary poisoning to both mammals and birds. In March 2018, cases of severe coagulopathy and bleeding associated with synthetic cannabinoid use contaminated with brodifacoum were reported in five states of the US.
Brodifacoum is a derivative of the 4-hydroxy-coumarin group. Compound 1 is the starting ester needed to synthesize brodifacoum. To obtain this starting compound, a simple Wittig condensation of ethyl chloroacetate with 4’-bromobiphenylcarboxaldehyde is accomplished. Compound 1 is transformed into 2 by consecutive hydrolysis, halogenation to form an acid chloride, and then reacted with the required lithium anion. This is done using KOH and EtOH for hydrolysis, and then adding SOCl2 for chlorination to form the acid chloride which reacts with the addition of lithium anion. Compound 2 is then transformed using organocopper chemistry to yield compound 3 with good regioselectivity of about 98%. Typically a Friedel-Crafts type cyclization would then be utilized to obtain the two-ring system portion of compound 4, but this results in low yield. Instead, trifluoromethanesulfonic acid in dry benzene catalyzes the cyclization with good yield. The ketone is then reduced with sodium borohydride yielding a benzyl alcohol. Condensation with 4-hydroxycoumarin under HCl yields compound 5, brodifacoum.
Brodifacoum is a 4-hydroxycoumarin anticoagulant, with a similar mode of action to its historical predecessors dicoumarol and warfarin. However, due to very high potency and long duration of action (elimination half-life of 20 – 130 days), it is characterised as a "second generation" or "superwarfarin" anticoagulant.
Brodifacoum inhibits the enzyme vitamin K epoxide reductase. This enzyme is needed for the reconstitution of the vitamin K in its cycle from vitamin K-epoxide, and so brodifacoum steadily decreases the level of active vitamin K in the blood. Vitamin K is required for the synthesis of important substances including prothrombin, which is involved in blood clotting. This disruption becomes increasingly severe until the blood effectively loses any ability to clot.
In addition, brodifacoum (as with other anticoagulants in toxic doses) increases permeability of blood capillaries; the blood plasma and blood itself begins to leak from the smallest blood vessels. A poisoned animal will suffer progressively worsening internal bleeding, leading to shock, loss of consciousness, and eventually death.
Following are acute LD50 values for a variety of animals:
|* rats (oral)||0.27 mg/kg b.w.|
|* mice (oral)||0.40 mg/kg b.w.|
|* rabbits (oral)||0.30 mg/kg b.w.|
|* guinea-pigs (oral)||0.28 mg/kg b.w.|
|* squirrels (oral)||0.13 mg/kg b.w.|
|* cats (oral)||0.25 mg/kg — 25 mg/kg|
|* dogs (oral)||0.25 — 3.6 mg/kg b.w.|
|* birds||LD50 values for various birds vary from about 1 mg/kg b.w. — 20 mg/kg b.w.|
|* fish — LC50 for fish:|
|** trout (96 hours exposure)||0.04 ppm|
Given these extremely high toxicities, brodifacoum is classified as "extremely toxic" (LD50 < 1.0 mg/kg b.w.)for mammals and "very toxic" (T+; LD50 < 25 mg/kg b.w.), for birds. Because of its persistence, cumulative potential and high toxicities for various wildlife species, it is also considered an environmental pollutant (N; noxious to the environment). The readiness of brodifacoum to penetrate intact skin should be noted, and brodifacoum and commercial preparations containing it should be handled with respective care and precaution because of its skin resorptivity.
The estimated average fatal dose for an adult man (60 kg b.w.) is about 15 mg, without treatment. However, due to low bait concentrations (usually 10 – 50 mg/kg bait, i.e. 0.001 — 0.005%) and slow onset of symptoms, and the existence of a highly effective antidote (appropriately dosed vitamin K1), brodifacoum is considered to be of relatively low hazard to humans. A caveat is that the poisoning must be identified specifically, so that vitamin K supplementation and monitoring may be maintained for periods that range up to months. The same is true for pets which ingest the substance.
Brodifacoum is marketed under a large variety of trade names, including Vertox, Ratshot Red, Biosnap, d-CON, Finale, Fologorat, Havoc, Jaguar, Klerat, Matikus, Mouser, Pestoff, Ratak+, Rodend, Rodenthor, Ratsak, Talon, Volak, Rakan, Volid, and Rataquill Colombia. Plantations in Malaysia are using rodenticide of this type under the market name of "Matikus" from Syngenta and / or "Arakus" from Advansia
Treatment for humans
The primary antidote to brodifacoum poisoning is immediate administration of vitamin K1 (dosage for humans: initially slow intravenous injections of 10–25 mg repeated all 3–6 hours until normalisation of the prothrombin time; then 10 mg orally four times daily as a "maintenance dose"). It is an extremely effective antidote, provided the poisoning is caught before excessive bleeding ensues. As high doses of brodifacoum can affect the body for many months, the antidote must be administered regularly for a long period (several months, in keeping with the substance's half-life) with frequent monitoring of the prothrombin time.
Poisoning case reports
There have been case reports of brodifacoum intoxication in the human medical literature.
In one report, a woman deliberately consumed over 1.5 kilograms of rat bait, constituting about 75 mg brodifacoum, but made a full recovery after receiving conventional medical treatment.
In another case reported in 2013, a 48-year-old female patient reported 4 days of mild dyspnea, dry cough, bilateral popliteal fossae pain and diffuse upper abdominal pain. She had no history of liver disease or alcohol or illicit substance abuse. Initial physical examination was remarkable only for mildly pale conjunctivae and mild abdominal tenderness and pain in the left popliteal fossa. A complete blood count and complete metabolic panel were normal. Prothrombin time (PT) was above 100 s, partial thromboplastin time (PTT) was above 200 s and international normalized ratio (INR) was reported as above 12.0. Urinalysis revealed hematuria (blood in the urine). Venous Doppler ultrasound of lower extremities demonstrated left popliteal vein thrombosis. Computed tomography scan of the abdomen demonstrated transmural hematoma, and a fecal occult blood test was positive. A full anticoagulant work-up showed critical reduction of vitamin K-dependent factors II, VII, IX and X. PT and PTT corrected with mixing studies proving factor deficiency as the cause of the coagulopathy. Lupus anticoagulant studies were negative. Superwarfarin toxicity was suspected and confirmed with an anticoagulant poison panel positive for brodifacoum. The patient was hospitalized and successfully treated with fresh frozen plasma, cryoprecipitate and vitamin K. In conclusion, paradoxical thrombosis and hemorrhage should raise the suspicion for superwarfarin toxicity in the appropriate clinical setting. It was concluded that concomitant presentation for thrombosis and hemorhhage with remarkably abnormal PT and PTT should raise the suspicion for brodifacoum poisoning.
In another report, a 17-year-old boy presented to the hospital with a severe bleeding disorder. It was discovered that he habitually smoked a mixture of brodifacoum and marijuana. Despite treatment with vitamin K, the bleeding disorder persisted for several months. He eventually recovered.
In 2015, 19 inmates in New York City's Rikers Island jail claimed that they had been poisoned with the chemical. The inmates had noticed "what appeared to be blue and green pellets in the meatloaf" they were eating on March 3, and felt ill afterwards. A sample was analyzed and tested positive for brodifacoum; the NYC Department of Corrections stated it was investigating the incident.
A 20-year-old female college student presented with abdominal pain and blood in urine. She was tested for warfarin, a common anticoagulant also used in some rodenticides, which returned a negative result. Vitamin K and fresh plasma was administered to treat symptoms. 3 weeks later she returned with bleeding into her calf, and was subsequently tested for superwarfarin chemicals. The test showed that Brodifacoum was in her bloodstream. She later admitted to consuming seven packets of rodenticide.
A 48-year-old businessman was admitted with a severe nosebleed as well as abnormal coagulation parameters. Standard treatment of Vitamin K and fresh plasma was administered to stem the nosebleed. Two weeks later he presented again with bleeding into the calf. Continual doses of Vitamin K were necessary to counteract the Brodifacoum. He denied taking any of the Brodifacoum found in his home contained within packages of Contrac.
As of April 26, 2018, cases of severe coagulopathy and bleeding associated with synthetic cannabinoid use had been reported in six states (159 cases in Illinois, two cases in Florida, two cases in Indiana, two cases in Missouri, one case in Wisconsin, and one case in Maryland). Four deaths have been reported in Illinois. The first case occurred in Illinois on March 7, 2018.  Brodifacoum was suspected to be present in these products in Illinois. Products named Matrix and Blue Giant from a convenience store in Chicago have tested positive for brodifacoum and AMB-FUBINACA (FUB-AMB).
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