AU2783700A - Pesticide treatment - Google Patents

Description

WO 00/47048 PCT/AUOO/00071 -1 PESTICIDE TREATMENT FIELD OF THE INVENTION: 5 This invention relates to pesticidal compositions having the particular, but not sole, characteristic of reduced withholding periods for food and animal products. BACKGROUND: Many primary and secondary industries rely on plants and animals to produce goods that are then modified and processed for sale. 10 The yields produced by such plants and animals are often detrimentally affected by their infestation with pests. This has necessitated the use of pesticides to curb infection rates and pest loads on primary producers. However, the compounds used may cause detrimental effects on humans and other animals, and therefore various Administrative Bodies, including the Australian National Registration Authority, impose 'withholding periods' on the goods of so 15 treated plants and animals. Withholding periods (WHPs) for plant and animal products are the periods following treatment with a pesticide, during which so-treated plant and animal products cannot be used or consumed by humans or other animals. These periods are based on the level of pesticide residue in plant or animal tissue following treatment. Maximum Residue Levels (MRLs) are the maximum 20 acceptable level of pesticide residue in tissues at the time of slaughter or harvest. MRLs act as a safety threshold, above which a WHP must be imposed. MRLs are specific for tissue type and pesticide. They are generally determined on a per molecule of pesticide residue basis. Lower WO 00/47048 PCT/AUOO/00071 -2 levels of residue equate to shorter WHP. If the pesticide residue levels of a tissue are below the MRL then no WHP will be imposed. Current methods of pesticide treatment result in tissue residue levels in excess of the MRLs and therefore necessitate a WHP. A typical example would be the treatment of cattle with 200 5 [tg/kg of abamectin by subcutaneous injection or 500 [tg/kg by pour on application. This results in a residue level well above the MRL of 0.005 mg/kg in milk after treatment. The situation is similar for the wool industry with there being a maximum acceptable residue level for the handling of wool. This necessitates wool being subjected to a WHP after treatment before it can be collected or otherwise handled. The wool WHPs in Australia, are still under 0 discussion between various Registry Bodies, but the current recommendation is not to use products within 2 to 6 months of harvesting the wool. The use of chemicals on crop species necessitates a withholding period for consumption of the products by humans or other animals. The imposition of a WHP may lead to delays in processing of products which can be expensive 5 and inconvenient. Accordingly a number of solutions have been addressed. The majority of the solutions to date have centered on finding new pesticidal compounds which are without the harmful residues or at least have decreased the levels of residues, eliminating or at least decreasing the period of the applicable WHP. This approach has had varying levels of success, however is expensive and requires the discovery and registration of new parasiticidal .0 compounds.

WO 00/47048 PCT/AUOO/00071 -3 OBJECT: It is an object of this invention to provide an improved pesticidal composition for the control of pests of plants and animals, or one which provides the public with a useful choice. It is a further object of this invention to provide an improved method of designing a pesticidal 5 composition for the control of pests and plants and animals, or one which provides the public with a useful choice. STATEMENT OF INVENTION: In one aspect the invention relates to a composition including two or more actives where each active is present in the amount which is less than the amount of that active which would give 10 rise to a residue which exceeds the maximum residue level. Preferably the combination of actives provide a high kill rate. Preferably the composition is suitable for administration to warm blooded animals. Preferably the actives are selected from the group comprising anthelmintics, miticides, tickicides, antibiotics and insecticides, and other compounds used to treat pests of plants and 15 animals. More preferably the actives are selected from the group comprising avermectins, synthetic pyrethroids, benzimidizoles, benzophenol ureas, insect group regulators, antibodies, and pyrazoles. Preferably the actives selected for the composition share the same mode of action.

WO 00/47048 PCT/AU0O/00071 -4 In another related aspect the invention relates to a method of devising a composition, including two or more active ingredients, wherein the amount of each active included is less than the amount giving rise to a level of residue which exceeds the maximum residue level. In a further related aspect the invention relates to a method of manufacturing a pesticidal 5 composition containing two or more actives, including taking a first active which is known to kill a target pest and to determine the LD 90 quantity of the first active for said target pest and determining the LD 90 of a second active for said target pest, combining the LD 90 quantity of the first and second actives with a suitable carrier to provide an effective pesticidal composition. In another related aspect the invention relates to a method of treating a warm blooded animal by 10 administering to that animal the compositions of the present invention or compositions made by the method of the present invention. In another related aspect the invention relates to a method of treating a warm blooded animal by administering to the animal simultaneously or within a relatively short period of time at least two actives, the dose of each active administered being less than results in a residue exceeding 15 the maximum residue levels or at least in a reduced withholding period or export slaughter interval. This invention may also broadly be said to consist in the parts, elements and features referred to or indicated in the specification of the application, individually or collectively, and any or all combinations of any two or more of the parts, elements or features, and where specific features 20 are mentioned herein which have known equivalents such equivalents are deemed to be incorporated herein as individually set forth.

WO 00/47048 PCT/AUOO/00071 -5 PREFERRED EMBODIMENT: The following examples are given by way of illustration only and shall not be taken as being in any way limiting as to the spirit or scope of the invention. Pesticides can be classed in different groups on the basis of their mode of action. The mode of 5 action is the pharmacological or pharmacokinetic actions of the active ingredient. For example, the mode of action of the avermectins is thought to be by inhibition of the neuron transmitter, gamma amino butyric acid (GABA). All the members of this class of molecule, eg abamectin, ivermectin, eprinomectin. moxidectin act by this mode. The synthetic pyrethroids are a different class of nerve poisons but all synthetic pyrethroids work the same way. 0 Where pesticides with the same mode of action are chosen for the composition it is likely that there will be synergy between those products in dealing with a particular pest (although synergy is not a necessary feature of this invention). It is preferable although not vital for the different actives to share the same mode of action. The proviso being that a composition which is suitable for each of the active compounds can be arrived at. It may be that the use of a mixture 5 of compounds with different modes of action may confer advantage in a given composition which compensate for any potential loss in kill rate, for example through overlap of susceptible and resistant individuals. It has been discovered that effective control of pests of plants and animals may be achieved by treatment with a composition which contains two or more actives each present in a level which 20 results in residue levels which are less than the Maximum Residue Level.

WO 00/47048 PCT/AUOO/00071 -6 The important feature of the invention is that the composition consists of two or more pesticidally active compounds each present in lower levels than would individually give rise to an effective kill rate. The total activity of the composition is at least the sum of that of the individual pesticidally active compounds but the residue (and consequently the withholding 5 period) is calculated on the basis of individual molecules. For example if two actives with the same mode of action are used at the LD 90 level for a target pest one after the other then active A will kill 90% of the pests. Active B will kill 90 % of the remaining 10%, of the combined effect will be a kill rate of 99% - known as a combined LD 99. Similarly if A and B are administered together. Giving a lower dose of each individual pesticidally active compound 10 which is a component of the composition means that the residue levels for each active should fall below the maximum residue level, therefore we expect a decreased or nil withholding period for products of plants and animals treated with these compositions. The compositions of the present invention may be arrived at in a number of ways. Some examples are given below: 15 A first active is selected and the maximum of allowable residue level is determined. This will usually be set by from the government departments responsible for registration of veterinary formations or health and safety regulations. The amount of the fist active added should be less than will give rise to a level of residue which exceeds the maximum residue level. A second active is selected and the maximum residue level should be determined. In addition 20 the maximum amount of this second active which will give rise to a residue level below the allowable maximum should be determined and the amount of the second active added to the composition should not exceed this amount.

WO 00/47048 PCT/AUOO/00071 -7 The kill rate of the composition can be estimated by comparing amount of each active added with the LD 99 levels of each of the actives. A more accurate kill rate can be determined by trials. If the kill rate is less than is desired a third or fourth active can be added following the same 5 process as set out above for the second active. Alternatively the composition can be arrived at by taking a first active which is known to kill the target pests and determining the quantity of the first active necessary for achieving LD 99 and LD 90, kill rates. Likewise the LD 99 and LD 90 quantity of a second active should be determined. A check should be made to ensure that the LD 90 amounts of the active do not give 0 rise to a residue level which exceeds the maximum residue level. If the LD 90 amount exceeds the maximum residue level a lower kill rate, eg LD 80 will need to be selected and perhaps a third active added. The selected quantities of each active are combined in suitable carriers and excipients to provide a stable composition. Those skilled in the art will know suitable carriers for use with each active. 15 It will be understood that different combinations of actives will interact differently so that a composition with a LD 99 or greater effective kill rate of the target pest may be achieved with quantities of actives, which are below the quantity required to attain a LD 90 kill rate, lower or higher than an LD 90 level. Further it will be understood by those skilled in the art that the pesticidal composition may 20 contain more than two actives, where this is the case the amount of each of the independent WO 00/47048 PCT/AUOO/00071 actives required to give a combined LD 99 or greater effective kill rate of the target pest may be less than the levels indicated in the paragraph above. It is envisaged that the combination of active may have an additive if not synergistic effect on reduction of pest numbers. 5 In addition it is desirable but not essential that each of the actives selected behaves independently with respect to metabolism, excretion and detoxification of the active Obviously the selection of actives which break down to give the same residue should not be used together. It is hoped that the use of the compositions the subject of this invention will lead to a decreased incidence of resistance pesticides, due to the reliance on a combination of pesticides together 0 giving the effective kill rate. TRIALS/EXAMPLES These and other aspects of this invention, which should be considered an in all it's novel aspects, will be apparent from the following examples. Examples 5 Anthelmintic Pour On for treatment and control of internal and external pests of beef cattle. Dose rate is 1 mL/lOkg. Example ] Abamectin 2.5 g/L Ivermectin 2.5 g/L WO 00/47048 PCT/AUOO/00071 -9 N-propyl gallate 0.2 g/L Thiodipropionic acid 0.15 g/L Icinol PM 10 mL Butyl icinol 10 mL 5 Butyl diicinol to 1 L Dissolve the preservatives in the icinol PM. Add the butyl icinol and dissolve the actives. Add and dissolve the dye. Make up the final volume with butyl diicinol. 0 Example 2 Abamectin 2.5 g/L Ivermectin 2.5 g/L Oily Carrier 640 g/L Isopropyl alcohol to 1 L .5 The composition is prepared by dissolving the actives in the oily carrier. The final volume is made up with HDPE containers. Topical lousicide for treatment and control of the sheep body louse. Dose rate 1 mL/2.55 kg 20 Example 3 Triflumuron 12.5 g/L Diflubenzuron 12.5 g/L WO 00/47048 PCT/AU00/00071 - 10 Methyl pyrolidinone 250 mL FDC Blue NO 1 0.05 g/L Icinol DPN to 1 L Dissolve the actives in methyl pyrolidinone. Add and dissolve the dye in 300 ml make up with 5 200 mL of icinol. Example 4: Dose rate ] mL/5 kg Cypermethrin 12.5 g/L Deltamethrin 5 g/L 10 Sudan Blue 0.25 g/L Dowanol to I L In addition it is possible to use a low amount of active ingredients from two or more different classes. This may reduce the residue levels even further, and result in a nil or much reduced WHP. This would depend on the composition requirements of the different actives. 15 TRIAL Trials were conducted using the compositions in Example 1 (ABA/IVM-ICI) and Example 2 (ABA/IVM-OIL). The compositions were administered to beef cattle as at a rate of 1 ml per 10 kg. 20 The milk residue levels were tested every 12 hours for 7 days from administration. The milk was tested for the presence of residues of abamectin (see table I and figure 1) and for the WO 00/47048 PCT/AUOO/00071 - 11 presence of residues of ivermectin (table 2, and figure 2). The data obtained is summarized on table I and table 2 entitled "Milk residue levels in nanograms per mL from animals treated with abamectin or a combination of abamectin and ivermectin". As can be clearly seen the abamectin and ivermectin residues remained low throughout the test period, both levels remaining below 5 the maximum residue level. The data clearly shows that the abamectin alone gives a high level of residue, peaking at around 7.3 mg/mL at day 3, whereas when half the level is given in combination with ivermectin the peak is less defined and reaches a level of around 2.4, less than half the level of abamectin alone. The data illustrates that the use of lower levels of a combination of parasiticially active 0 compounds will provide decreased residue levels. These decreased residue levels will in turn allow reduction or elimination of withholding periods of animals so-treated.

WO 00/47048 PCT/AUOO/00071 - 12 mwwuo wwwo 0 ?5 E2I o 0 -c 0 bi 0 Wl C) (na ( oKI n O ~ 0 > CD (A~ Cn= (a w 1 0 en La Io tj -. 3 co~A WID ) CCD M)I D Co -4 o4 4 -4 0 -L 0) 0t 00 o 0r pa L1(h - M ) L-' o0 0 -4 a A 0 -4 to U 17 0 m o1 ~10 0 00A) o in0 b o 0 G'WwS.( t h -I - I A W ~ m Clnil. 1 c, Il in o- WO 00/47048 PCT/AUOO/00071 - 13 ADVANTAGES The invention provides the advantage of limiting the WHP to which valuable commodities are subjected, whilst maintaining an effective level of control of pests. This has advantages for primary and secondary industries. For example, decreased periods before cows can be milked or 5 slaughtered after treatment. Obviously the longer the cows are not producing commercial grade milk the longer the dairy farmer is not making money from the sale of that milk. The costs in other primary industries may not be so direct. However they will centre around costs of storage for goods during the WHP lost production time, and also the restriction placed on pest control strategies. 10 The elimination or reduction of WHPs for these products will be of great economic benefit to those involved in our primary industries. In addition shorter export slaughter levels may be achieved.

Claims (10)

1. A composition including two or more actives where each active is present in the amount which is less than the amount of that active which would give rise to a residue which exceeds the maximum residue level. 5

2. A composition as claimed in claim 1, wherein the combination of actives provide a high kill rate.

3. A composition as claimed in any of claims I or 2 which is further suitable for administration to warm blooded animals.

4. A composition as claimed in any of claims 1 to 3, wherein the actives are selected from the 10 group comprising anthelmintics, miticides, tickicides, antibiotics and insecticides, and other compounds used to treat pests of plants and animals.

5. A composition as claimed in any of claims I to 4, wherein the actives are selected from the group comprising avermectins, synthetic pyrethroids, benzimidizoles, benzophenol ureas, insect group regulators, antibodies, and pyrazoles. 15

6. A composition as claimed in any of claims I to 4, wherein the actives selected for the composition share the same mode of action.

7. A method of devising a composition, including two or more active ingredients, wherein the amount of each active included is less than the amount giving rise to a level of residue which exceeds the maximum residue level. WO 00/47048 PCT/AUOO/00071 - 15

8. A method of manufacturing a pesticidal composition containing two or more actives, including taking a first active which is known to kill a target pest and to determine the LD 90 quantity of the first active for said target pest and determining the LD 90 of a second active for said target pest, combining the LD 90 quantity of the first and second actives with 5 a suitable carrier to provide an effective pesticidal composition.

9. A method of treating a warm blooded animal by administering to that animal a composition as claimed in any of claims I to 6 or made by the method of claims 7 to 8.

10. A method of treating a warm blooded animal by administering to the animal simultaneously or within a relatively short period of time at least two actives, the dose of each active 10 administered being less than results in a residue exceeding the maximum residue levels or at least in a reduced withholding period or export slaughter interval.