F E A T U R E Active Insight: Rodenticides In this series, the chemisty of major pesticide groups are examined Steve Broadbent

he development of the modern medicinal ‘thinning’ of blood. A few years later, anticoagulant rodenticides is a in 1945, while recovering from a recurrence Tfascinating story, and quite different of tuberculosis, Dr Link was reading about the to what one might expect. For centuries history of rat control. Rodents were a serious ‘physicians’ had proposed that ‘thinning’ the problem for the farmers he had worked with in blood was an effective treatment for various the isolation of dicoumarol, and he wanted to maladies. In earlier centuries the prescription of see if he could help them out. He considered leeches was common for this purpose. dicoumarol but thought it better to avoid its use as a rodenticide, as he felt it would detract from With this in mind, the story of the development its human therapeutic uses. He therefore looked of modern oral anticoagulants starts with at the range of products his lab had developed haemorrhagic disease in cattle in the Midwest from the coumarin work overall. of the USA in the 1920s. This disease was These efforts to develop an effective rodenticide characterised by severe internal bleeding. resulted in his team’s synthesis of warfarin The cause was eventually traced back to the (derived from Wisconsin Alumni Research ingestion of spoiled sweet clover. Scientists Foundation). Warfarin was first introduced as worked to determine what the substance a rodenticide in 1952 and, oddly enough, two was that was causing the bleeding. This years later it was approved for human medical was eventually extracted and identified as a use, despite this having been Dr Link’s concern coumarin compound. This work, by Dr Karl Paul with dicoumarol! Link and his team, working at the University of Wisconsin, went on to prove that it was actually Coumarins, as these compounds are known, a fungal metabolite that had developed in the block the chemical reduction of vitamin K, spoiled sweet clover which had caused the which is an essential component in the clotting internal bleeding. of blood. The ‘K’ in vitamin K comes from the German word koagulation. Today warfarin is This led to the development and probably most well known as a therapeutic commercialisation of dicoumarol in 1941 for the agent given to humans to prevent thrombosis,

44 || FAOPMA Newsletter - April 2020 F Acute LD50* Active Rattus norvegicus E Warfarin 10.0 – 20.0 mg/Kg A Fumarin 125.0 mg/Kg T U Diphacinone 2.3 – 43.0 mg/Kg R Chlorphacinone 20.5 mg/Kg E Pindone 10.0 mg/Kg Coumatetralyl 16.0 mg/Kg Difenacoum 1.8 mg/Kg Brodifacoum 0.22 – 0.27 mg/Kg Bromadiolone 1.1 – 1.8 mg/Kg Flocoumafen 0.25 – 0.56 mg/Kg Difethialone 0.56 mg/Kg

*Source: Rodent Pests and their Control. Dr. AP Buckle & Prof. RH Smith ISBN: 0 85198 8202 the formation of potentially life-threatening very poor as a mouse killer. clots in veins or arteries. In the 1960s the rodenticidal value of pindone Warfarin has a strong taste deterrent that has was recognised. Pindone had originally been to be disguised to ensure the rodents are not developed as an insecticide by Motomco Ltd. deterred from feeding, and will eat poisoned As an anticoagulant rodenticide it also exhibits feed for several days; or at least until the insecticidal and mould inhibiting qualities, symptoms of poisoning set in. Rodent death even in its commercial form at 0.025%. All these from warfarin typically takes up to six days. It products are multi-feed, so the rodent has to causes a slow death through the gradual onset feed over several days to incur a lethal dose. of internal bleeding. Further first-generation rodenticides entered the market during the Within a decade of warfarin’s introduction, 1950s and 60s, and still remain in use. In the rats and mice resistant to the poison were 1950s came fumarin from Amchem, a subsidiary discovered. The demise of warfarin in rodent of Union Carbide. Then came a more potent control programs though is more attributable to group of products starting with diphacinone, the development of the more effective, second- patented by Upjohn Corporation; coumatetralyl generation anticoagulant rodenticides. from Bayer was developed in 1956; and in 1961 Ward Benkinsop in the United Kingdom, the chlorphacinone came from Liphatech. These company that became Sorex (now part of BASF), latter products offer greater toxicity to rodents, developed the first of these second-generation but also to non-target species. Diphacinone is

WWW.FAOPMA.COM || 45 F products, difenacoum, which was quickly Whilst death may occur from a single ingestion, followed by brodifacoum. At about the same it usually takes 3 – 4 days for the rodents to E time, Liphatech developed bromadiolone, and actually die, which minimises the onset of A later difethialone. As a small UK based company, bait shyness. Mice are generally much harder Ward Benkinsop licensed brodifacoum and to kill with anticoagulants, which has given T difenacoum to ICI for worldwide development. brodifacoum an edge as it is the best mouse Later, when Shell bought out Sorex, the team killing compound. U from Ward Benkinsop were asked to develop a R further compound. This led to the development The major control technology for rodents is of flocoumafen. These are all coumarin derived the use of baits formulated from proprietary E compounds. They remain highly effective, mixtures of cereals and wax-based substances. though genetic mutations conferring resistance An important aspect of bait development is the to them has been identified in both atsr and presence of both olfactory compounds that mice. will draw the rodents to the bait; and then the presence of high-quality cereal and protein feed Second-generation actives are used at much to ensure rodent feeding. The wax component lower dose rates, but have raised concerns is a trade-off in block baits. Higher wax content over secondary poisoning, especially of raptors baits will keep their form better in high (birds of prey), which feed on the rodents killed temperature environments, but this is ‘traded- by these poisons. This has led again to the use off’ against their reduced palatability. This has of first-generation products in some sensitive led to the development of extruded block baits, areas; though recent studies indicate these too which are compressed and therefore use less are of concern with respect to the poisoning of wax. More recently, soft baits, often referred birds, especially diphacinone. to as pasta baits and gel baits, which have the highest palatability have entered the market. It is the single-feed aspects of the second- The single-feed action of the second-generation generation anticoagulants that has conferred baits is dependent upon a highly attractive the greatest benefits. Technically, only feed component, which usually means a more brodifacoum and flocoumafen are true ‘single- expensive product to ensure consumption.  feed’ products, as their potency allows for the control of all rodents under all conditions, Steve Broadbent is the Regional Director, through a single-feed. The reality though is Australia, SE Asia, South Africa & Gulf Region, that all the second-generation products are Ensystex, Australia. single feed in most conditions on most species. Email: [email protected]

46 || FAOPMA Newsletter - April 2020