Difenacoum

A number of reports have established the presence of rodenticides in predators and scavengers found dead in the field (see, for example, reports of U.K. Wildlife Incident Investigation Scheme [WHS]). Brodifacoum, difenacoum, bromodiolone, and flo-coumafen have all been found, albeit at low levels in most cases (<1 ppm in liver). Sometimes, more than one type of rodenticide has been found in one individual. The toxicological significance of these residues will be discussed in Section 11.5. 

One study conducted in Britain between 1983 and 1989 was of barn owls found dead in the field 10% of the sample of 145 birds contained anticoagulant rodenticide residues in their livers, and difenacoum and brodifacoum were prominent among them (Newton et al. 1990). In another study, barn owls were fed rats that had been dosed with flocoumafen. It was found that a substantial proportion of the rodenticide ingested by owls was eliminated in pellets (Eadsforth et al. 1991). The authors suggest that exposure of owls to rodenticides in the field may be monitored by analysis of pellets dropped at roosts or regular perching places. 

Brodifacoum, difenacoum, flocoumafen, and other superwarfarins bind strongly to proteins of the hepatic endoplasmic reticulum and consequently have long half-lives in vertebrates, often exceeding 100 days. Thus, they present a hazard to predators and scavengers that feed on rodents which have been exposed to superwarfarins. A number of species of predatory and scavenging birds have died as a consequence... 

Anticoagulant rodenticides (ARs) Rodenticides that cause hemorrhaging, usually through disturbing the synthesis of clotting proteins (e.g., warfarin, brodi-facoum, difenacoum). 

Dieldrin halogenated hydrocarbon Dienochlor halogenated hydrocarbon Diethatyl-ethyl amide Diethofencarb carbamate Diethyltoluamide amide Difenacoum coumarin... 

Rabon tretachlorvinphos Racer flurochloridone Racumin coumatetralyl Radapon dalapon-sodium Radar propiconazole Ramik diphacinone Ramrod propachlor Rancho mefenacet Randox allidochlor Rangado dimethylvinphos Ratak brodifacoum/difenacoum... 

Coumarin (4 hydroxy) brodifacoum, bromadiolone, coumatetralyl, difenacoum, flocoumafen, warfarin Coumarin (4 methyl 7 hydroxy) coumaphos m-Cresol acifluorfen, clomeprop, metolcarb o-Cresol DNOC, MCDA, MCPB, mecoprop... 

Diphenyl brodifacoum, bromadiolone, difenacoum, difethialone a a Diphenyl acetone diphacinone... 

Malonic acid alloxydim, bensulfuron, brodifacoum, chlorimuron, difenacoum, difethiolone, fenclorim, flazasulfuron, flocoumafen, glufosinate, nicosulfuron, isoprothiolane, oxolinic acid, primisulfuron, pyrazosulfuron, sethoxydim, tralkoxydim Malonic acid acetamide glufonisate Malonic acid dimitrile thicyofen Maneb mancozeb... 

Phenyl acetyl chloride benalaxyl, brodifacoum, difenacoum, difethialone, flocoumafen Phenyl bromo acetic acid phentoate... 

Phosphorus tribromide brodifacoum, difenacoum, fenpropidin, flocoumafen, pyriproxifen Phosphorus trichloride chloretoxyfos, disulfoton, EPN, ethephon, ethoprop, fonofos, fosamine ammonium, fosetyl aluminium, fosthiazate, glufosinate, glyphosate, isofenphos, merphos, propaphos, sulprofos, SSS-tributyl phosphorotrithioate, trichlorfon, trichloronat Phthalic acid pindone, tecloftalam... 

Polyphosphoric acid brodifacoum, difenacoum, flocoumafen Potassium t.butoxide bifenthrin, cyhalotrin Potassium cyanate cymoxanil, sulfentrazone... 

Sodium borohydride brodifacoum, diclobutrazol, difenacoum, difethialone, diniconazole, fenpropidin, flocoumafen, imidacloprid, imizalil, inabenfide, paclobutrazol, penconazole, triadimenol, uniconazole Sodium butyl mercaptide see Butyl mercaptan Sodium chlorate cloroneb... 

Difenacoum CAS 56073-07-5 C31-H24-O3 Compo , Diphenacoum , Frunax DS , Matrak , Neosorexa , Rastop , Ratak , Ratrick , Silo ... 

This group of compounds have a 4-hydroxycoumarin ring with different side-chain substituents at the 3-position. Commonly used superwarfarin anticoagulant rodentieides in this group are bromadiolone, brodifacoum, coumate-tralyl, coumafuryl, and difenacoum. Brodifacoum, difena-coum and bromadiolone are three of the most commonly used rodentieides around the world. Brodifacoum is the most frequently used rodenticide in the USA. These rodentieides share most of their physical and chemical characteristics, as well as their toxicokinetics, toxicody-namics, and mechanism of toxicity, and the medical toxicological management is the same for all superwarfarins. 

Difenacoum [3 -(3 -p-diphenyl-1,2,3,4-hydronaphth-1 -yl)-4-hydroxycoumarin] was synthesized in the UK and marketed in 1975 by Sorex Ltd under the trademark... 

Neosorexa , and by ICI Plant Protection Division under the trademark Ratak as a 0.005% pelleted bait, and as a wax block. Pure difenacoum is an off-white powder with a solubility of greater than 50 g/1 in acetone, 600 mg/1 in benzene, and less than 10 mg/1 in water. It is more toxic than warfarin, but less palatable (IPCS, 1995c). Difenacoum is still effective against many populations of warfarin-resistant rats (Desideri et al, 1979), but resistance maybe developing in the UK (Greaves et al, 1982). 

Cats may be more resistant to the toxic effects of bro-difacoum and difenacoum than dogs. Cases of abortion and hemorrhage in sheep and goats after misuse of brodifacoum have been reported (Jones, 1996 Watt, 2005). 

Tissue methods include a solid phase cartridge extraction from liver with recoveries ranging from 52% for difenacoum to 78% for warfarin. The limit of detection is 10 ppb for warfarin and difenacoum and 110 ppb for chlor-ophacinone (Fauconnet et al, 1997 Jones, 1996 Addison, 1982). 

Serum concentration of dogs with anticoagulant roden-ticide poisoning ranged from less than 10 ng/1 to 851 ng/1 for brodifacoum, difethialone, and difenacoum (Robben et al, 1998). 

Desideri, D., Aldighieri, R., Le Louet, M., Tardieu, A. (1979). Murine resistance to anticoagulants in the port of Marseille. Response to difenacoum. Bull. Soc. Pathol. Exot. Filiales 72(3) 278-83. (In French)... 

Greaves, J.H., Shepherd, D.S., Quy, R. (1982). Field trials of second-generation anticoagulants against difenacoum-resistant Norway rat populations. J. Hyg. (Lond.) 89(2) 295-301. 

Kelly, M.J., Chambers, J., MacNicoll, A.D. (1993). Simple and rapid method for the determination of the diastereomers of difenacoum in blood and liver using high-performance liquid chromatography with fluorescence detection. J. Chromatogr. 620(1) 105-12. 

Mundy, D.E., Machin, A.F. (1977). Determination of the roden-ticide difenacoum in biological materials by high-pressure liquid chromatography with confirmation of identity hy mass spectrometry. J. Chromatogr. 139(2) 321-9. 

Park, B.K., Leek, J.B. (1982). A comparison of vitamin K antagonism by warfarin, difenacoum and brodifacoum in rabbit. Biochem. Pharmacol. 31 3635-9. 

As a result of intensive research, derivatives of 4-hydroxycoumarin were found, which proved to be particularly efficient against rodents and resistant to anticoagulant rodenticides. Difenacoum (34) is a chronic rodenticide, which acts as a typical indirect blood anticoagulant similar to warfarin. However, it is effective against rats and mice, which are resistant to warfarin and other anticoagulant rodenticides, and is more toxic than warfarin to susceptible strains of these rodents. The chemical composition of difenacoum is 3-(3-p-biphenyl-1,2,3,4-tetrahydro-naphth-l-yI)-4-hydroxycoumarin. Its acute oral LD50 is 1.8 mg/kg for Norway rats (Hadler et al., 1975a,b). 

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