CA1039182A - Rodenticide consisting essentially of 2-chloro-3-phytyl-1,4-naphthaquinone - Google Patents

Abstract

RODENTICIDE
John W. Suttie Abstract A rodenticide suitable for the control of anticoagulant rodenti-cide-resistant rats and normal rats wherein the active rodenticidal ingredient is 2-chloro-3-phytyl-1,4-naphthaquinone.

Description

~39~82 Specification This invention relates to rodenticides and food ba.its containing them.
More specifically, this invention relates to anticoagulant-type rodenticides.
The anticoagulant rodenticides, a.nd particularly warfarin, have for many years, been the rodenticides of choice, a.s opposed to the quick-acting stomach poisons, beca.use of their effica.cy a.nd sa.fety.
It is recognized that the a.nticoa.gulant rodenticides function by suppress-! lo ing the synthesis of the vita.min K-dependent clotting fa.ctors in the rodent and ca.using internal hemorrhaging. Such rodenticides are multiple dose baits, i. e. they normally have to be ea.ten over a period of about 3-6 days in order to be effective..
Some years a.go stra.ins of wild rats which were resista.nt to the action of anticoagula.nt rodenticides were discovered in a number of area.s in Scotland, Wales, and northern Europe where warfarin was being used as thP rodenticide. More recently, this trait ha.s been found in rats in certa.in area.s of the United States (see W. B. Jackson et al, Science, 176, 1343 (1972)) and the resista.nce reported is to a. number 20 of different coumarin a.nd indandione derivatives (see C. M. Boyle, - 1 - ~. .

10;~18Z
,.
Na.ture, 188, 517 (1960); J. 1~. Frea.ves et a.l, J. Hyg (Lond. ), 67, 311 (1969); and D. C. Drummoncl et al, E.P.P.O. Intern. Conference (Paris), pp. 57-59 (1967))-It ha.s now been found that these strains of a.nticoagulant-resistant rats can be effectively controlled through the use of 2-chloro-3-phytyl- 1,4-naphtha.quinone a.s the a.ctive rodenticide. This compound, which for purposes here will be referred to a.s chloro-K, in contra.st to the coumarin a.nticoa.gula.nts, appears to function a.s a. direct a.ntagonist of vitamin K.
It is reported that the anticoagula.nt rodenticide-resistant tra.it is a.n inherited one (see Greaves et al, Nature, 215, 877 (1967) a.nd Nature, 224, 284 (1969)) a.nd not related to altera.tions in warfarin metabolism (Grea.ves et al, Nature, 215 supra. and Hermodson et al, Am. J. Physiol., 217, 1316 (1969)). It ha.s also been shown that rats which are resistant to the anticoa.gulant a.ction ha.ve a. greatly increa.sed requirement for vitamin ~C (Hermodson et, al, supra) but that the metabolism of the vitamin is unaffected (M. J. Thierry et al, Am. J.
Physiol., 219, 854 (1970)). This suggests that the mutation might well .
be one which ha.s influenced a binding site on a. protein that is a. receptor 20 both for vitamin K a.nd the anticoa.gula.nt. It is fully expected that a.
direct vita.min K anta.gonist such a.s chloro-K, would bind to the genetically altered protein receptor site even less readily than the natural vita.min K. Consequently, it wa.s totally unexpected tha:t the chloro-K would exhibit effective anticoa.gula.nt activity in anticoagulant rodenticide-resistant rats.
In the following Examples the chloro-K used wa.s prepared from

2-chloro- 1,4-naphthaquinone in a.ccordance with the procedure of lV3~ 32 Lo~venthal et al, Can. T. Chcm, 4S, 3957 (1970).
Example_ The efficacy of the chloro-I~ as an anticoagulant was shown by injecting an aqueous solution containing 2 mg. of c~loro-K, 14 mg.
~f ~ween-~0 ~a surface-active emulsifying agent) consisting of oleate esters of polyoxyethylene sorbitan marketed by Armour ~; Co. of Chicago, Tll, ) a.nd lO mg. of ethanol per ml. into the tail vein of the rats 21 hours before blood was dra~vn by ca.rdiac p~mcture and a.nalyzed for prothrombin. (The analysis was by the two stage metllod of Ware and Seegers as modified by Shapiro ~ Wa.ugh, Thromb. piath._Elaemorrha.g., 16, 496, (1966)), The anticoa.gula.nt rodenticide-resistant rats used were descendants of a colony homozygous for the trait. These rats were fed a normal commercially available la.boratory chow, e. g. Purina R at ¢how, marlceted by Ralston Purina Co. of St. Louis, Mo., or Wayne Lab- - .
~lox, marketed by Allied Mills Inc. of Chicago, Ill,, and, except when on experiments, were given water ad libitum containing 0. 5 mg/l of menadione sodium bisulfate (trihydrate) to maintain normal prothrombin concentration. (Normal plasma prothrombin levels are 220-250 units/ml. ) 20 Prothrombin concentrations in these rats a~e not affected by an intra-. peritoneal injection of 5 mg. of warfarin per l~g. of body weight or byfeeding them a diet containing 0. 02a~ warfarin.
Results obtained are shown in the fol1Owing table.

*Trade Mark 10391~3Z
Ta~

E2c-. of .h~ Chloro Analog of Vitamin Kl on Pro-~hrombin Synthesis - , . , . _ _ Dose o, Nor~.al Rats Warlarin-Resistant Ra~s . . _ . . . _ . . _ . . .
Cnloro-X Male ~'emale Male FemalP
._ ...... _ 0.2 mg/Xg I - 2~0+8:: _ 113~1 0.~ _ 240_5 _ 88~10 2.0 204_12 189_26 27_6 72_10 __ 1~6 T 9_ _ _ __ 6 8 t l O : .

. *
Units o~ prothrombin per ml of plasma + S.E. : _ It can be seen from the above table that chloro-K is an effective anticoagulant in warfarin-resista.nt rats; is considerably more ef~ective in this strain than in normal rats; and is a more effective anticoagulant in male warfarin-resistant rats (male warfarin-resistant ra.ts have a lo higher vitamin-K requirement than females).
Example 2 The rodenticidal effica.cy of diets conta.ining varying amolmts of warfarin or chloro-K alone or in admixture were conducted on normal and war-farin-resistant rats (see description in Example 1).
The diet used was the standard Environrnental Protection Agency - rodenticide test diet consisting of 65~ coarse ground corn, 25~ ground oa.ts, S~ powdered sugar and 5~ corn oil, The chloro-K, warfarin, and chloro-K and warfarin mixtures were dissolved in corn <~il and the tllen toxified corn oil was a.dded to the diet in amount 5~ by weight of the diet. These diets containing the a.nticoa.gula.nts were the only food a~ta.ilable to the ra~s duriTIg each 20 day test period.
The results obtained are shown in the following table wherein the closed circles represent male rats and the open circles female ra.ts.
The normal ra.ts are design.a.ted (N) and warfarin-resistant rats (WR). The percentage of warfarin (WARF) a.nd chloro-K (cl-K) fed in the diets is indicated in the }: ottom line.

Table 2 S~ 9~

0 12 i O I 0 C~ I ~ ~ ~ 00~ 0 1 ~ 01 O 001 ~ I 00 ~ O 0 ~ O 090~ ~0 1l c)~ Z~ 10 0g 1 _ ~ I l ~ool l ~ Ul I 1 WR I N WR ¦ N WR I N WR I N WR r N WR I N WR I N
3M 3F 1 6M 6F 5M 5F ~ 5M 5F 5M 5F I 6M 6F 5M 4F ~ 5M 5F 5M SF ~ 5M 5F 6U 5F, 5hl 5F 5M 3F ! 4M 4F
0 025X WARF 0.005% Cl-K 0.010 X CI-K 0.020 % CI-K 0.025 % WARF 0.025 % WARF 0.02S ,. WARF .
0.005X Cl-K 0.010 % Cl-K 0.020 % CI-K
.__ Exa.mple 3 The procedures described in Example 2 were followed in evaluating, i at the concentrations shown in the table below, the efficacy of chloro-K, pival (2-pivalyl-1, 3-indandione) a.nd chloro-K-pival mixtures in the control of normal and anticoagulant-resistant ra.ts (the rats were from the same colony described in Example ]. above).
The results obtained are shown in Table 3 wherein tlle legends applied are the same as in Table 2. above.

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O ~ O ~ O ~ ~ r~
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, O O ~ O ~ ~ ~P.J
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_ _ . _ . _ _ _ __ _ _ _ _ _ _ _ _. _ _ _ O O O O O L~ ~ ~
. ~0 ~ ~ o o ._ . .. _ - 00 ~0~ Z U' i -~0~ ~ ._ .
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. . ~ 0 O ~ ~ o . ........ ... _ .. . . . _ , 0 00 0 0 Z~
0 e~o ~ c~
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1039~8Z
It is apparent :from the foregoing that chloro-K in a.mounts of abo~lt 0. 025~ shows significant rodcnticidal effica.cy even a.gainst normal rats and tha.t against anticoa.gulant-resistant rats it has a. significant rodenticidal effect in concentrations a.s low a.s 0. 005~ by weight of the rodenticide ba.it. Amounts in excess of 0. 02~ by weight a.re, of course, usable, the maximum amount being dicta.ted only by economic considera.tions. Amounts of chloro-IC in the range from about 0. 005~
to a.bout 0. 03~ ha.ve been found to be quite suitable. Little real benefit is ga.ined insofar a.s rodenticidal effica.cy is concerned, however, above about 0. 025~.
It will be apparent tha.t to be effective a.s a general rodenticide all the ra.ts in a. given population would have to be killed. Since under normal field conditions, a.nticoagulant rodenticide-resistant rats are interspersed with so-called normal rats, i. e. rats which do not exhibit resistance to anticoagulant rodenticides, an admixture of chloro-K
with another anticoa.gulant which is even more effective in controlling normal rats would be the rodenticide of choice. Such other anticoa.gula.nts, e. g. warfarin, 3-(cy-acetonylbenzyl)-4-hydroxycoumarin and its water-soluble sodium salt; phenprocoumon,3-(cy-ethylbenzyl)-4-hydroxy-20 coumarin and its chloro deriva.tives, 3-(~-ethyl-p-chlorobenzyl-4-hydroxycoumarin; Coumachlor, 3 (~-acetonyl-4-chlorobenzyl-4-hydroxy-coumarin; Fumarin, 3-(~-a.cetonylfurfuryl)-4-hydroxycoumarin; Pival, 2 -pivalyl- 1, 3, indandione; Diphacinone, 2 -diphenyl- a.cetyl- 1, 3-indandione; and 4-hydroxycoumarins or indandiones in general, can be used in concentra.tions which are well recognized in the art and which range from about 0. 0005~ to about 0. 2~ by weight of tl~e food bait in which they are incorporated (see for example U. S. Letters Pa.tent No.

3, 113, 071).

~o;~ z For purposes of the present invention the preferred rodenticide food ba.it conta.ins about 0. 025~ by weight of a.n anticoa.gula.nt rodenticide and a.bout 0. 02~ by weight of chloro-K in combina.tion. With this combination, both stra.ins of ra.t, i. e. the a.nticoagulant rodenticide-resistant rat and the normal ra.t, are killed in a.bout one week.
It is also a.pparent that in any given locale where only anticoa.gula.nt rodenticide-resistant ra.ts are encountered, chloro-K can be used a.s the sole rodenticide in a. rodenticide food ba.it. In addition, chloro-K
alone or in combination with other anticoa.gulant rodenticides can be 10 used to control other rodent pest populations such a.s mice a.s shown in the following Example.
Example 4 Wild mice (Mus musculus) were tra.pped froIn local infestations.
These mice were divided into two groups. One group (24 mice) was . maintained on the diet shown in Example 2 to which ha.d been a.dded 5 by weight of corn oil conta.ining 0. 025~ warfalin by weight of the diet.
The second group (28 mice) wa.s maintained on the diet shown in Example 2 to which ha.d been added 5~ by weight of corn oil conta.ining 0. 0255~ chloro-K by weight of the diet. Results are shown in the table 2 o below.
Table 4 Number Dead .
Rodenticide in Diet 7 days 17 da.ys Warfarin 16 24 Chloro-K 15 25 lV~91~
It is evident from the above data that chloro-K is effective to control mice populations The food used in the bait of the present invention can be any edibl~ product such a.s, for example, cra.cked corn, corn meal, mixtures of various gra.ins, e. g. mixtures of corn, oats and wheat, ground meat, and mixtures of meat and gra.in, etc. For purposes of ~afety, however, it is preferred to use a. gra.in ba.se bait which, while attractive to the rodent, is not a.s attractive to children and household pets as a ba.it containing mea.t or like edible products. The final ba.it 10 mixtures ca.n be used a.s such or be pelleted in a.ccordance with standard practices in the a.rt.

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Claims (11)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A rodenticide suitable for use in controlling rat populations consisting essentially of from about 0.005% to about 0.03% by weight of 2-chloro-3-phytyl-1,4-naphthaquinone in an inert carrier.

2. The rodenticide of claim 1 wherein the 2-chloro-3-phytyl-1,4-naphthaquinone is present in an amount about 0.02%
by weight.

3. A rodenticide suitable for use in controlling rat populations containing anticoagulant rodenticide resistant rats consisting essentially of an anticoagulant rodenticide selected from the group consisting of 3-substituted 4-hydroxycoumarin anticoagulants, 2-pivalyl-1,3-indandione and 2-diphenyl-acetyl-1,3-indandione in an amount from about 0.00025% to about 0.2%
by weight and 2-chloro-3-phytyl-1,4-naphthaquinone in an amount from about 0.005% to about 0.03% by weight in an inert carrier.

4. The rodenticide of claim 3 wherein the anticoagulant rodenticidal ingredient is a 4-hydroxycoumarin.

5. The rodenticide of claim 4 wherein the anticoagulant rodenticidal ingredient is warfarin.

6. The rodenticide of claim 3 wherein the anticoagulant rodenticidal ingredient is an indandione.

7. The rodenticide of claim 6 wherein the anticoagulant rodenticidal ingredient is 2-pivalyl-1,3-indandione.

8. A rodenticide food bait suitable for controlling rat populations containing anticoagulant rodenticide-resistant rats containing as essential rodenticial ingredients about 0.00025% to about 0.2% by weight of an anticoagulant rodenticide selected from the group consisting of 3-substituted 4-hydroxycoumarin anticoagulants, 2-pivalyl-1,3-indandione and 2-diphenyl-acetyl-1,3-indandione, and about 0.005% to about 0.03% by weight of 2-chloro-3-phytyl-1,4-naphthaquinone.

9. The rodenticide food bait of claim 8 wherein the anticoagulant rodenticidal ingredient is warfarin.

10. The rodenticide food bait of claim 9 wherein the warfarin is present in an amount about 0.025% by weight and the 2-chloro-3-phytyl-1,4-naphthaquinone is present in an amount about 0.02% by weight.

11. A method for controlling rat populations containing anticoagulant rodenticide-resistant rats which comprises making available to such rat populations a rodenticide food bait which comprises edible material acceptable to rats and, as the essential rodenticidal ingredients from about 0.005% to about 0.03% by weight of 2-chloro-3-phytyl-1,4-naphthaquinone and from about 0.00025% to about 0.2% by weight of an anticoagulant rodenticide selected from the group consisting of 3-substituted 4-hydroxy-coumarin anticoagulants, 2-pivalyl-1,3-indandione and 2-diphenyl-acetyl-1,3-indandione.