Bull. Org. mond. SantJ 1972, 47, 275-280 Bull. Wid Hith Org.
A review of anticoagulant rodenticides in current use
E. W. BENTLEY 1
The advent of anticoagulant rodenticides in the some are discernibly better than others for the control early 1950s undoubtedly marked a turning point in of certain species of rodent. In some instances this rodent control. These substances have two main can be ascribed to an obvious physiological effect. It advantages in comparison with the acute poisons. is well known, for example, that at the recommended First, when used in appropriate concentrations, dosages some anticoagulants affect the clotting fac- anticoagulants do not produce symptoms in the tors in mammalian blood much more quickly than rodent that cause it to stop feeding before a lethal others. Similarly, the effect of one anticoagulant on dose has been ingested. This characteristic makes the clotting factors may fall off more quickly than the complete eradication of discrete infestations that of another. In some instances, variations in the possible, provided that baiting is efficient and con- effectiveness of different anticoagulants in the field tinued over a long enough period. Second, birds are may reflect differences in palatability, which may de- relatively resistant to anticoagulants, and although pend partly on the concentration of the poison. all mammals are affected they generally acquire a In view of these differences in effectiveness, it is of lethal dose only after feeding on the bait on more interest to note that anticoagulant usage varies wide- than one occasion; moreover, vitamin K1 is a power- ly from one country to another. The literature on ful antidote if it is administered in time. Thus acci- rodent control published during the last few years dental deaths involving anticoagulants are easier to shows that, in addition to warfarin (with or with- prevent. Their main disadvantage is that bait must out the addition of N14-pyrimidinyl sulfanilamide usually be laid down more often than in treatments (" sulfaquinoxaline "), the following rodenticides with acute poisons, but this is only apparent if the are favoured: latter are conducted without pre-baiting, in which Country Anticoagulant case there would be an accompanying loss of effec- Canada coumachlor, pindone tiveness. Federal Republic coumachlor, coumafuryl, All the anticoagulant rodenticides on the market of Germany coumatetralyl at the present time are either coumarin derivatives Finland dicoumarol or indandiones. Except in a few small areas of the France chlorophacinone, coumachlor, world where " resistance " has appeared, these sub- 2-[1-(p-bromophenyl)-1-phenyl]- stances control at least the common rat, Rattus nor- acetyl-1,3-indandione vegicus, reasonably well. The best anticoagulants India coumatetralyl can be very effective indeed, although different Israel pindone sodium in different countries. For example, Malaysia coumachlor claims are made Mexico coumafuryl warfarin is expected to give 100 % control of R. nor- Philippines pindone vegicus infestations in built-up areas in some coun- Poland diphacinone tries, but in others an 85 % or higher rate of control United Kingdom coumatetralyl, chlorophacinone is considered to be " successful ". Such differences USA coumafuryl, diphacinone, pindone, may depend on the techniques used in control pro- 2-isovaleryl-1,3-indandione grammes, but basically they are almost certainly USSR chlorophacinone, diphacinone, related to the amount of control effort that it is con- 2-[1-(p-tolyl)-l-phenyl]acetyl-1,3- sidered economical to expend in different situations. indandione Although most of the anticoagulants on sale are These variations are undoubtedly due largely to generally effective, laboratory tests have shown that commercial and financial considerations and to patent laws. In some countries, for example, war- 1 Ministry of Agriculture, Fisheries, and Food, Tolworth, England. farin has become so well established that it would
2896 -275- 276 E. W. BENTLEY be difficult and commercially hazardous to market diphacinone was approximately as toxic and accept- another product. However, two other factors may able to M. musculus as 0.025% warfarin, and that also be involved-namely, the need for more com- 0.005 % chlorophacinone and 0.025 % pindone were parative studies on the effectiveness of the various rather more toxic than either of those substances. substances and for the better interchange of labora- However, pindone was somewhat less acceptable to tory and field results among control biologists work- mice than the other substances. Rowe & Redfern ing in different countries. (1968b) also concluded that 0.05 % coumatetralyl was Most of the published work on the comparative as acceptable and toxic to house mice as 0.025% evaluation of anticoagulants for use against com- warfarin; although coumatetralyl was more toxic mensal rodents has been carried out in government than warfarin against individual animals particularly laboratories. In the United Kingdom all but one of resistant to anticoagulants, both substances had the substances listed above have been examined for shortcomings in this respect. their effectiveness against R. norvegicus and Mus The most informative publication from the USA on musculus, and, to a lesser extent, R. rattus. As far the comparative efficacy ofanticoagulantrodenticides as R. norvegicus is concerned, Bentley & Rowe is that of Hayes & Gaines (1959), who endeavoured (1956) and Bentley & Larthe (1959) came to the to assess the probable field effectiveness of warfarin, conclusion, based on separate toxicity and palat- coumachlor, pindone, diphacinone, and the calcium ability tests, that warfarin and coumafuryl used at salt of2-isovaleryl-1,3-indandione by laboratory toxi- a concentration of 0.005% or 0.025% would pro- city tests in which plain bait was also available to the duce the best results in the field, and that couma- test animals. Their main conclusion was that " the chlor, pindone, chlorophacinone, 2-(1-naphthyl)-1,3- performance of warfarin against the commensal ro- indandione, or 2-isovaleryl-1,3-indandione would dents was not excelled by the other anticoagulant not give quite such good results at any concentration. compounds tested. Diphacinone was about as good Greaves & Ayres (1969) later compared warfarin as warfarin against wild Norway rats. [Pindone] was with coumatetralyl and found that the latter used at about equal to warfarin against roof rats (Rattus concentrations of 0.05% and 0.005% was about rattus) and mice, but, like coumachlor, was some- as toxic as warfarin used at a concentration of what inferior against wild Norway rats ". The cal- 0.005%, and was at least as palatable. Their view cium salt of2-isovaleryl-1,3-indandione was consider- that coumatetralyl would prove to be a good sub- ed to be inferior to the other poisons against all three stitute for warfarin has been borne out by subsequent species of rodent. Later, these findings seem to have field experience in the United Kingdom. been incorporated in an official recommendation (US The most effective poison against R. rattus was Public Health Service, 1962) to use diphacinone, found by Bentley & Larthe (1959) to be diphacinone coumafuryl, pindone, or warfarin against any of the at a concentration of 0.0125 %. Warfarin and couma- three commensal species at the dosage rates given in furyl, both used at a concentration of 0.025 %, were Table 1. less effective. Insufficient studies have been made to More recently, Merrill (1969) reported that these rank the effectiveness of coumachlor, 2-(1-naphthyl)- four anticoagulants and the calcium salt of 2-iso- 1,3-indandione, 2-isovaleryl-1 ,3-indandione, and valeryl-1,3-indandione were being used against R. chlorophacinone against R. rattus. norvegicus at concentrations in bait of 0.025 % for Rowe & Redfern (1968a) reported that 0.0125% warfarin, coumafuryl, and pindone, 0.05 % for the
Table 1. Dosage levels recommended by the US Public Health Service (1962) for anticoagulant rodenticides
Anticoagulant M. musculus R. rattus R. norvegicus
diphacinone 0.0125-0.025 % 0.005-0.01 % 0.005-0.01 % coumafuryl, pindone 0.025 -0.5 % 0.025 % 0.025 % warfarin 0.025 -0.05 % 0.025 % 0.005-0.025 % CURRENT ANTICOAGULANT RODENTICIDES 277 calcium salt, and 0.005% for diphacinone. It will about 10 tonnes per annum were being produced be seen that it is not now recommended to use by 1965. Compound (3) was said to be highly toxic warfarin at a concentration of 0.005%. In the not only to R. norvegicus but also to M. musculus and United Kingdom also, the recommended concentra- the susliks, Citellus citellus and C. suslicus. In 1968 tion is now 0.025 %, the reason being that it is opera- the All-Union Plant Protection Research Institute tionally more convenient to have a single concentra- of the USSR reported that compound (3) was widely tion for use against all three commensal species of used for controlling rats and mice, and that chloro- rodent, and that 0.025 % may, in some circum- phacinone was undergoing further field trials. stances, lead to more rapid mortality and a corre- In addition to the work described above, Telle spondingly shorter treatment. These advantages have (1963) investigated the palatability to R. norvegicus of course, to be balanced against the higher risk to and R. rattus of warfarin, coumachlor, couma- livestock and pets. tetralyl, and " pyranocoumarin". The two latter com- It will be seen that there is very little disagreement pounds were apparently undetectable at the concen- between workers in the United Kingdom and the trations studied. Both coumachlor and warfarin re- USA. Such differences as do occur may be explained veal some degree of unacceptability at about the in terms of differences between the rodents them- 0.05 % level; this finding agrees with results reported selves; certainly this could be so for M. musculus. elsewhere (e.g., Bentley & Larthe, 1959). In the USSR most attention has been paid to the A few other anticoagulant compounds have been indandiones. Yegorova (1961) examined 13 of these tested in the laboratory and sometimes in the field compounds and reported that 3 of them, chloro- without, apparently, having reached the stage of phacinone and the sodium salts of chlorophacinone commercial production. Bartog (1964) mentioned and 2-isovaleryl-1,3-indandione deserved further laboratory tests on 4-hydroxy-3-[1-(4-oxo-4H-1- study. Yegorova later reported that 42 indandiones benzopyran-3-yl)ethyl]coumarin in Czechoslovakia, had been examined and that the best were dipha- and gave details of field trials against R. norvegicus cinone, pindone, and pindone sodium; the concen- in which this compound was used. At a concentra- trations recommended were as follows: diphacinone, tion of0.025 % it appeared to be as effective as 0.05 % 0.01-0.015%, pindone, 0.05%, pindone sodium (in warfarin, but since, as noted above, this concentra- drinking-water sweetened with 5% sucrose), 0.025- tion of warfarin can lead to poor acceptance, 0.05 %. No specific recommendation was made for trials with lower dosages would have been more the control of mice but it was pointed out that in informative. laboratory experiments mice drank the pindone Three other anticoagulants have been studied by sodium solution less readily than rats did. Yegorova Japanese workers-namely, 2-oxo-2H-1-benzopy- also confirmed the findings of other authors that, ranocarboxylic acid and its thallium and 6-amino- at corresponding concentrations, diphacinone is more coumarin derivatives (Motizuki et al., 1963; and toxic to rats than warfarin or pindone and concluded Kitagawa et al., 1963). All three compounds affect that it could be used as a single-dose poison. How- thermoregulation in rodents, and chronic toxicity ever, acceptance tests carried out in various labora- tests were therefore carried out at 3 temperature tories elsewhere indicate that the use of diphacinone ranges between 10°C and 31°C and at 2 concentra- as an acute poison would raise problems of bait tions-namely, 0.6% and 0.3%. In all tests, except palatability and probably necessitate the use of pre- those involving the 6-aminocoumarin derivative at baiting techniques. 0.6% and 20-31 0C, more rapid mortality of R. nor- Following the work reported by Yegorova (op. cit.), vegicus was obtained than with warfarin; however, studies on the indandiones were continued in the the concentration of warfarin used was not stated. USSR; Vanag et al. (1965) stated that the number Some degree of unpalatability was observed but it ofcompounds investigated was about 100. The most was not thought to be important. Evidence suggested effective agents for controlling R. norvegicus were that the three compounds were relatively harmless if reported to be (1) diphacinone, (2) chlorophacinone, eaten by dogs and cats-partly because they induced and (3) 2-[1-(p-tolyl)-1-phenyl]acetyl-1,3-indandione. vomiting. Diphacinone sodium, pindone, and 2-isovaleryl-1,3- The use of anticoagulants for the control of field indandione were not quite as effective. Vanag et al. rodents has not increased as quickly as might have (op. cit.) stated that diphacinone had been used in been expected considering their success against com- agricultural areas in the USSR since 1957, and that mensal rodents. Several factors, including those that 278 E. W. BENTLEY follow, may be responsible. (1) Their toxicity for countered (Bates, 1962). More recently Howard some species of agricultural importance is generally et al. (1970), on the basis of field trials, have recom- lower, perhaps because vitamin K1 is more available mended the use of 0.01 % diphacinone in oat groats to these rodents. (2) The large areas of land that usu- applied at the rate of about 2 kg/ha to control ally require to be baited encourage the use of acute Peromyscus maniculatus. In Louisiana, Evans & poisons (without pre-baiting). (3) For practical pur- Ward (1967) experimented with various anticoagu- "poses, a degree of control well short of 100 % is usu- lants including warfarin, diphacinone, pindone, and ally acceptable. (4) Difficulties are encountered in the calcium salt of 2-isovaleryl-1,3-indandone for maintaining bait fresh for any length of time because controlling Myocastor coypus (coypu), which has ofattack by bacteria, moulds, ants, cockroaches, land also been the subject of field trials with warfarin in crabs, etc. Nevertheless, anticoagulants have been England (Davis, unpublished data). Evans & Ward used with considerable success against field rodents in (op. cit.) fed meat from coypus killed with warfarin several countries. to dogs and mink and observed that some animals Pingale & Muthu (1953) used warfarin against died from secondary poisoning. As a result, they Bandicota malabarica (B. indica). At the Asian- concluded that the control of Mycocastor with anti- Pacific Conference on Rodents held in Honolulu coagulants could not be recommended in Louisiana, in 1968 it was reported that warfarin had also been where coypu meat is commonly used for pet food. effective in a campaign to control rodents infesting Since there are no other reports of secondary sugarcane and other crops in Taiwan in 1957; the poisoning following the use of anticoagulants against species mentioned were Bandicota indica, Rattus rodents there is probably no immediate need to losea, and Mus formosanus. At the same conference modify existing safety procedures, but obviously Soekarna referred to the use of warfarin against further laboratory investigations are required. R. r. brevicaudatus in ricefields in Java. On the other Finally, in Europe, field trials have been made in hand, Fernando et al. (1967) reported poor results France by Mimaud (1968) against Microtus arvalis, with " coumarin derivatives " against Bandicota ben- Pitymus duodecimcostatus, Arvicola terrestris, and galensis (Gunomys kok) in ricefields in Ceylon. Ondatra zibethica, using mainly chlorophacinone in Warfarin has also been tested against Rattus exu- a variety of formulations. Mimaud (op. cit.) reported lans. Strecker et al. (1962) described preliminary good control of both Microtus and Pitymus but trials in the Pacific area, and their work has since been found that chlorophacinone was not as effective followed up by Wodzicki (1968) in the Tokelau as aluminium phosphide for controlling Arvicola. Islands and by Smith (1969) in the Gilbert and Ellice Sliced carrots steeped in a 0.25 % oily concentrate of group. Hechter-Schulz (1962) found that 0.025% chlorophacinone gave good results against Ondatra. warfarin was effective against Rhabdomys and Successful field trials for the control of Ondatra with Otomys spp. in pine forests of the eastern Transvaal chlorophacinone have also been carried out in region of South Africa, while dosages of 0.05 % were Belgium (Moens, 1969) and the Federal Republic employed with success against Arvicanthis niloticus of Germany (Rau, 1970). in grain stores in Egypt (Kassab et al., 1961). Undoubtedly there are many more rodents of eco- A. niloticus and R. (Mastomys) natalensis have been nomic importance against which the anticoagulants controlled with warfarin in villages in the Sudan, may ultimately prove to be effective. In many in- using crushed dura with the addition of sugar and stances, however, the use of these poisons must await cottonseed oil as a bait (Schmutterer, 1969). Another further investigation of the ecology and of the feeding African rodent that has recently been the subject and other behaviour of the species concerned. of laboratory tests is Cricetomys gambianus, an With regard to techniques for the application of important pest of cocoa and other crops. It is anticoagulant compounds, more research is needed reported to be susceptible to coumatetralyl (Everard, on liquid baits and dust formulations. One method 1968). of applying dusts, which has been tried against R. In the New World, warfarin and coumafuryl norvegicus in Armenia (Megalyan, 1969) and which have been used to control Sigmodon hispidus in may deserve further attention, is to place balls of Mexican sugarcane plantations (Collado & Ruano, cottonwool impregnated with the poison in the holes 1962), and warfarin has also been used effectively used by rodents. It is probable, however, that, except against Holochilus sciureus in sugar cane plantations in special situations, liquid and dust formulations of in Guyana although some resistance was later en- anticoagulants will continue to find their greatest CURRENT ANTICOAGULANT RODENTICIl)ES 279 application in conjunction with solid baits-the ap- mixed with grain at a concentration of 0.025 % and proach tried by Rowe & Chudley (1963) against incorporated in blocks ofparaffin, other workers have M. musculus. used the same technique; thus, Gillbanks & Turner One method of offering anticoagulants to rodents (1970) reported good control of R. tiomanicus (R. that is being given increasing attention is to incor- jalorensis) in oil palms in Malaysia with warfarin in porate poison bait in paraffin. This technique has paraffin blocks, and Smith (1969) found similar been used in the United Kingdom for many years blocks to be effective against R. exulans in coconut for controlling R. norvegicus in sewer systems palms on Tarawa Atoll and against R. rattus else- (Bentley, 1960), although it is less effective than a where in the Gilbert and Ellice Islands. simple pile of bait, except in conditions where the As regards the future for anticoagulants, the ap- bait is liable to be washed away or to be attacked pearance of strains of R. norvegicus and M. musculus quickly by moulds. In some tropical and subtropical resistant to anticoagulants in Britain, Denmark, conditions, however, the moulding of bait is a con- Holland, and the USA is a matter of concern, but tinual problem when chronic poisons are used. there is no reason why other countries should not Since Smith (1967) reported the successful control of continue to develop and use anticoagulant roden- R. rattus in coconut palms in Jamaica with warfarin ticides wherever they are suitable.
ACKNOWLEDGEMENTS
The author is indebted to Miss Yvonne Larthe for her help in searching the literature on anticoagulants.
R]tSUMIt REVUE DES RODENTICIDES ANTICOAGULANTS ACTUELLEMENT EN USAGE
Tous les anticoagulants actuellement disponibles sur a 0,025%, la chlorophacinone a 0,005% et le coumat& le marche sont soit des derives de la coumarine soit des tralyl a 0,05 %, alors que la saveur du pindone a 0,025 % indandiones. Ils font preuve d'une efficacite variable est un obstacle a son utilisation. Aux Etats-Unis, le contre Rattus rattus, R. norvegicus et Mus musculus. pindone a 0,025 % est considere comme presque aussi Malgre les informations publiees a ce sujet, la faveur efficace que la warfarine. En URSS, le 2-[1-(p-tolyl)- dont ils jouissent differe suivant les pays. Il faut probable- I-phenyl] acetyl-1,3-indandione s'est montre actif contre ment en chercher les raisons dans la diversit6 des legis- M. musculus et contre Citellus spp. lations nationales sur les brevets et dans des imperatifs Les rodenticides anticoagulants n'ont pas ete utilises financiers et commerciaux. contre les rongeurs presentant de l'inter& sur le plan eco- Au Royaume-Uni, on a obtenu des resultats opti- nomique avec l'intensite qu'on aurait pu escompter. maux contre R. norvegicus en utilisant la warfarine et le Dans une certaine mesure, cela est du au fait que de nom- coumafuryl a la concentration de 0,005-0,025 % ou le breux aspects du comportement et de l'ecologie de ces coumatetralyl a la dose de 0,005-0,05 %. Aux Etats-Unis derniers doivent encore etre elucides. Cependant, on d'Amerique, des epreuves de laboratoire ont d6montre a entrepris, avec succes de lutter contre de nombreuses l'efficacite des deux premiers de ces produits ainsi que especes: Rattus exulans, Bandicola bengalensis, B. indica, celle de la diphacinone A la dose de 0,005-0,01 %. En Rhabdomys spp., Otomys spp., Arvicanthis niloticus, URSS, les essais effectues plaident plut6t en faveur de Mastomys natalensis, Sigmodon hispidus, Holochilus la diphacinone A 0,01-0,015% et du 2-[1-(p-tolyl)-1-phe- sciureus, Peromyscus maniculatus, Myocastor coypus, nyl]acetyl-1,3-indandione. Pitymus duodecimcostatus et Ondatra zibethica. Au Royaume-Uni, on considere que la diphacinone A En ce qui concerne les techniques actuelles d'appli- 0,0125 % est legerement plus active contre R. rattus cation, il semble qu'on devrait s'attacher a ameliorer que la warfarine ou le coumafuryl, alors qu'aux Etats- les formulations liquides et poudreuses ainsi que les Unis le pindone et la warfarine ont fait preuve d'une appats * solides *. Dans les pays tropicaux et subtropicaux efficacite du meme ordre. oiu, a certaines epoques de l'annee, les appats risquent En ce qui conceme M. musculus, les recherches effec- d'etre emport6s par les pluies ou attaques par les moisis- tu6es au Royaume-Uni montrent de legeres differences sures, on tend de plus en plus A utiliser les anticoagulants d'activite entre la diphacinone a 0,0125%, la warfarine incorpores a des blocs de paraffine. 280 E. W. BENTLEY
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