Brodifacoum

Brodifacoum^[1]
Names
	IUPAC name 3-[3-[4-(4-Bromophenyl) phenyl]-1,2,3,4-tetrahydronaphthalen-1-yl]-2-hydroxychromen-4-one
	Other names Bromfenacoum
Identifiers
CAS Number	56073-10-0 ;
3D model (JSmol)	Interactive image;
ChEMBL	ChEMBL233451 ;
ChemSpider	10444663 ;
ECHA InfoCard	100.054.509
PubChem CID	41736;
RTECS number	GN4934750;
UNII	A25P3CP5S7 ;
CompTox Dashboard (EPA)	DTXSID5032529 ;
	InChI InChI=1S/C31H23BrO3/c32-24-15-13-20(14-16-24)19-9-11-21(12-10-19)23-17-22-5-1-2-6-25(22)27(18-23)29-30(33)26-7-3-4-8-28(26)35-31(29)34/h1-16,23,27,33H,17-18H2 Key: VEUZZDOCACZPRY-UHFFFAOYSA-N ; InChI=1/C31H23BrO3/c32-24-15-13-20(14-16-24)19-9-11-21(12-10-19)23-17-22-5-1-2-6-25(22)27(18-23)29-30(33)26-7-3-4-8-28(26)35-31(29)34/h1-16,23,27,33H,17-18H2 Key: VEUZZDOCACZPRY-UHFFFAOYAI;
	SMILES Brc1ccc(cc1)c2ccc(cc2)C4Cc3ccccc3C(C4)C\5=C(/O)c6ccccc6OC/5=O;
Properties
Chemical formula	C31H23BrO3
Molar mass	523.426 g·mol−1
Melting point	228–230 °C
Solubility in water	Insoluble
Pharmacology
Routes of; administration	Oral; dermal; inhalation (dusts) (for poisoning)
	Pharmacokinetics:
Bioavailability	100%
Metabolism	slow, incomplete, hepatic
Biological half-life	Slow; 20—130 days
Excretion	faeces; very slow
Hazards
	Lethal dose or concentration (LD, LC):
LD50 (median dose)	270 μg/kg (rat, oral)
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). verify (what is ?) Infobox references

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 mammalian pests such as possum.^[2]

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.

Toxicology

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.^[3]

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.

Brodifacoum is highly lethal to mammals and birds, and extremely lethal to fish. It is a highly cumulative poison, due to its high lipophilicity and extremely slow elimination.

Following are acute LD₅₀ values for various animals (mammals):^[4]

rats (oral) 0.27—0.30 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.
cats (oral) 25 mg/kg b.w. (approx.)^[5]^[6]^[7]^[8]
dogs (oral) 0.25–3.6 mg/kg b.w.^[5]^[6]^[7]^[8]

LD₅₀ values for various birds varies from about 1 mg/kg b.w. — 20 mg/kg b.w.^[3]

LC₅₀ for fish:

trout (96 hours exposure) 0.04 ppm^[9]

Given these extremely high toxicities in various mammals, brodifacoum is classified as "extremely toxic" (LD₅₀ < 1.0 mg/kg b.w.) and "very toxic" (T+; LD₅₀ < 25 mg/kg b.w.), respectively. Because of its persistency, 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.^[3] 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.

Brand names

Brodifacoum is marketed under a large variety of trade names, including Biosnap, d-Con, Finale, Fologorat, Havoc, Jaguar, Klerat, Matikus, Mouser, Pestanal (Sigma-Aldrich BT), Pestoff, Ratak+, Rodend, Ratsak, Talon, Volak, Vertox and Volid.

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 too much damage has been done to the victim's circulatory system. 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.^[10]

If unabsorbed poison is still in the digestive system, gastric lavage followed by administration of activated charcoal may be required.

Further treatments to be considered include infusion of blood or plasma to counteract hypovolemic shock; and in severe cases, infusion of blood clotting factor concentrate.

Administration of vitamin C may be useful as an adjunct (100 mg three times daily).^[4]

Another potential treatment is phenobarbital, which is believed to accelerate the metabolism of some anticoagulants via enzyme induction.^{[citation needed]}

Poisoning case reports

There have been at least ten case reports of brodifacoum intoxication in the medical literature.

In one report,^[11] 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 report,^[12] 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.

Environmental toxicology

The American Bird Conservancy has advocated that brodifacoum not be used by the general public. They cite several studies indicating that secondary poisonings of predatory birds and animals are common due to the extreme persistence of the pesticide within both target and non-target species. It may also be dispersed by insects that feed on poisoned bait without harm and retain the pesticide within their bodies.

References

^ Merck Index, 11th Edition, 1368
^ Eason, C.T. and Wickstrom, M. Vertebrate pesticide toxicology manual, New Zealand Department of Conservation
^ ^a ^b ^c Brodifacoum (HSG 93, 1995)
^ ^a ^b Brodifacoum (PDS)
^ ^a ^b KAUKEINEN, D.E. 1979. Experimental rodenticide (Talon) passes lab tests; moving to field trials in pest control industry. Pest Control 46(1):19-21.
^ ^a ^b Brodifacoum (Talon, Havoc) - Chemical Profile 1/85
^ ^a ^b Brodifacoum at InChem.com
^ ^a ^b MSDS Data Sheet for TALON RAT AND MOUSE KILLER
^ http://www.wil-kil.com/public/2005-06_labels-msds/WeatherBlok%20XT%20M.pdf#search=%22LC50%2Bbrodifacoum%22
^ Clin Toxicol (Phila). 2007 Jun-Aug;45(5):487-9. Brodifacoum poisoning with toxicokinetic data. Olmos V, López CM. PMID 17503253 Brodifacoum half-life
^ Lipton, R.A. & Klass, E.M. (1984) Human ingestion of a 'superwarfarin' rodenticide resulting in a prolonged anticoagulant effect. JAMA 252:3004-3005.
^ La Rosa, F, Clarke, S. & Lefkowitz, J. B. (1997) Brodifacoum intoxication with marijuana smoking. Archives of Pathology & Laboratory Medicine 121:67-69.