AU2004242449A1

AU2004242449A1 - Pesticide Treatment

Info

Publication number: AU2004242449A1
Application number: AU2004242449A
Authority: AU
Inventors: Paul John Martin
Original assignee: Virbac SA
Current assignee: Virbac Australia Pty Ltd
Priority date: 1999-02-08
Filing date: 2004-12-22
Publication date: 2005-01-20
Also published as: AU2004101081A4

Description

P/00/011 Regulation 3.2

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION Invention Title: PESTICIDE TREATMENT The following statement is a full description of this invention, including the best method of performing it known to me: FIELD OF THE INVENTION: This invention relates to pesticidal compositions and a method of manufacturing such compositions in which the compositions have a 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.

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-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 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 determnnined on a per molecule of pesticide residue basis. Lower 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 Sand therefore necessitate a WHP. A typical example would be the treatment of cattle with (-i 200 ptg/kg of abamectin by subcutaneous injection or 500 tg/kg by pour on application.

I 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 ,I after treatment before it can be collected or otherwise handled. The wool WHPs in Australia, are still under 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 and inconvenient. Accordingly a number of solutions have been addressed. The majority of the solutions to date have centred 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 compounds.

OBJECT

It is an object of this invention to provide a method of manufacturing a pesticidal composition for the control of pests of plants and animals, or one which provides the public with a useful choice.

STATEMENT OF INVENTION

O

In one aspect the invention provides a method of manufacturing a pesticidal composition having both a desired high level of efficacy and a residue level sufficiently low to CI substantially minimize or avoid withholding periods for plants and animals treated with the composition, the method including: CI selecting a chemical class of actives useful as pesticides, (ii) selecting a first active with a desired mode of action from said chemical class of actives; (iii) selecting one or more subsequent actives from said chemical class of actives having the same mode of action as the first active, wherein each subsequent active differs chemically from the first active and from each other; (iv) determining a dosage level of each active until the resulting residue level of each active is below a threshold withholding amount for that said active having the desired mode of action; combining the first and each subsequent active with a suitable carrier, until the effect of the combined actives reaches the desired level of efficacy.

By chemical class of actives we mean compounds having recognised structural similarities, and examples of such well know pesticidal chemical classes include (but are not limited to) the avermectins, milbemycins, synthetic pyrethroids, benzimidazoles, benzophenol ureas and pyrazoles.

In using the term "chemically different actives" or "wherein each subsequent active differs

O

chemically from the first active and from each other" we mean that they are different compounds within the same chemical class (in practice they will be named as different N compounds each with its own defined residue limit) but we exclude optical isomers (as not (-i being sufficiently structurally different from one another to meet the requirement of having a uniquely defined residue profile.

The invention represents an improvement over the prior art such that it provides an economic advantage to primary producers and advantageously exposes animals to lower (-i concentrations of an active agent thus minimizing any toxic side effects that a single dosage form may elicit. The method of manufacture of a pesticidal composition that, when administered, both minimizes animal withholding periods and exhibits a kill rate in excess of LD90 means that farmers no longer incur the cost and inconvenience of maintaining animals for slaughter before drug residue levels meet threshold withholding concentrations.

A pesticidal composition obtained from the method of the invention is obtained from two or more actives having the same mode of action and being selected from the same chemical class, in which the actives have a combined effect, to provide a kill rate of at least LD90 and residue levels low enough to substantially avoid any withholding periods.

The first active can be chosen as an active known to kill a target pest, and determining at least the LD 90 quantity of the first active required for said target pest; and choosing the second active known to kill the same target pest, and determining the LD 90 of the second active for said target pest; checking that the LD 90 quantity of each active produces a resulting residue level for each said active below the legally defined maximum allowable residue level for that said active, wherein if this is the case combining the two actives into the composition to provide a composition having a combined LD 99 kill rate or greater whilst providing a composition which meets the legally defined maximum allowable residue level for each active; or if the LD 90 quantity of any one or more of the actives results Sin a residue level for that one or more actives above the legally defined maximum allowable (-i residue level for a particular active, then determining a lower level of kill rate for that or each active, say an LD 80 kill rate, checking the residue level for each active at that level of kill, and combining as many actives having the same mode of action as are necessary to bring the kill rate of the combined composition up to a kill rate of LD 99 or greater.

N, In another aspect the invention provides a method of manufacturing a pesticidal composition having two or more actives chosen from the same chemical class each active having the same mode of action against a target pest, including taking a first active which is known to kill the target pest and determining the LD 90 quantity of the first active for said target pest and determining the resulting residue level of that LD 90 quantity of the first active when applied to a plant or animal, and determining the LD 90 quantity of a second active when applied to said plant or animal, checking that the residue level of both the first and second actives at the LD90 amounts when applied to said plant or animal are below the maximum allowable residue level for each active for that plant or animal, and if so, combining the LD 90 quantity of the first and second actives with a suitable carrier to provide an effective pesticidal composition, and if not then reducing the quantity of each active until the resulting composition meets the legally allowable maximum residue level for each active, whilst at the same time providing an effective pesticidal composition by adding a suitable amount of a third, or subsequent active which meets the maximum allowable residual level for that third or subsequent active, until the combined additive effect of the actives is sufficient to reach a kill level of LD 99 or greater.

In another aspect the invention provides a method of manufacturing a pesticidal Scomposition suitable for application to plants or animals used for the production of foodstuffs or beverages for human consumption, comprising: choosing a chemical class of actives having the same mode of action against a target pest, selecting a first active from said class, and determining the maximum allowable dosage of IC said first active which will result in a residue level at or below the legally defined maximum residue level for that particular active, then determining the effectiveness or kill rate for that N, dosage or that active against the target pest, selecting a second (or subsequent) active from the same class, wherein the second (or subsequent) active differs from the first said active, and from each subsequent active, and repeating the determination of the maximum allowable dosage of said second or subsequent active which will result in residue level at or below the legally defined maximum residue level for that particular second or subsequent active, then determining the effectiveness or kill rate for that dosage of that active against the target pest, then combining a sufficient number of said different actives from said class with a suitable carrier to provide effective pesticidal composition in which the additive effect of all of the selected actives in the composition reaches a desired level of efficacy, whilst at the same time the composition results in residue levels at or below any legally defined maximum allowable residue level for each of the actives within the composition.

In another aspect the invention provides a method of manufacturing a pesticidal composition wherein the desired level of efficacy can be a kill rate of LD 99 or greater.

The chemical class of actives can be selected from the group comprising avermectins, synthetic pyrethroids, benzimidazoles, benzophenol ureas, and pyrazoles.

The class of actives can be the class of avermectins, and said first active is chosen is

O

abamectin, and the second active chosen is ivermectin (or vice versa).

The first active can be triflumuron and the second active can be diflubenzuron (or vice

(N

C, versa).

The first active can be cypermethrin and the second active can be deltamethrin (or vice C versa).

SThe invention also includes a method of manufacturing a pesticidal composition

(N

substantially as herein described with reference to any one of the examples.

The invention also includes a pesticidal composition suitable for administration to warm blooded animals, for the control of internal and external parasites of cattle, containing less than the LD 99 quantity of abamectin and less than the LD 99 quantity of ivermectin.

The abamectin can be present in the quantity of 2.5 g/L and the ivermectin can be present in the quantity of 2.5 g/L.

The invention also includes a method of treating a warm blooded animal (other than humans), by administering to that animal a pesticidal composition as described above.

The invention also includes a method of treating a warm blooded animal (other than humans) by administering to the animal simultaneously or within a relatively short period of time at least two different actives selected from the same class of actives, the dose of each active administered being less than that result which would in a residue level exceeding the maximum residue level, or at least in a reducing the withholding period or export slaughter interval.

In yet a further aspect of the invention there is described a method of manufacturing a pesticidal composition having both a desired high level of efficacy and a residue level sufficiently low to substantially minimize or avoid withholding periods for plants and N, animals treated with the composition, the method including: selecting a first active with a desired mode of action from a chemical class of actives useful as pesticide; (ii) selecting one or more subsequent actives from a chemical class of actives, N, useful as pesticides, whereby said one or more subsequent actives have the same or different mode of action as the first active, wherein said one or more subsequent actives is selected from the same or different chemical class as the first active and each differs chemically from the first active and from each other; (iii) determining a dosage level of each active until the resulting residue level of each active is below a threshold withholding amount for that said active having the desired mode of action; (iv) combining the first and each subsequent active with a suitable carrier, until the effect of the combined actives reaches the desired level of efficacy.

In a related aspect the invention further includes a composition for administration to animals or plants, the composition including at least two actives being useful as pesticides, whereby said at least two actives have the same or different mode of action, wherein the at least two actives are selected from the same or different chemical class and each of said at least two actives differ chemically from the first active and from each other.

SEach of the at least two actives can be present in a combined amount to provide a kill rate

O

Sof at least LD90 and a tissue residue level for said each active which is less than or equal to U a threshold withholding concentration level, and each of the said at least two actives can be CN an insect growth regulator including one of said at least two actives being selected from the chemical class ofbenzophenyl ureas.

The benzophenyl urea can be diflubenzuron and a second of said at least two actives can be C selected from the pyrimidine chemical class of compounds.

C A further related aspect there is described a pesticide composition for administration to animals or plants including at least two chemically different actives selected from the same or different class of actives including avermectins, abamectins, benzimidazoles, insect growth regulators, pyrazoles, pyrimidines, pyrimidinamines, synthetic pyrethroids; said at least two actives having the same or different mode of action and being present in an amount such that administration of an effective dose of said composition provides a kill rate of at least LD90 and a tissue residue level not exceeding a maximum residue level to substantially minimize or avoid a withholding period or export slaughter interval.

The invention also includes a method of treating pests on plants, where the plants are used for human consumption, by administering to the plants a pesticidal composition as (-i described above.

(-i I In yet a further aspect the invention there is disclosed a composition including two or more chemically different actives having the same mode of action from the same chemical class where each active is present in an amount which is less than the amount of that active which (-i N, would give rise to a residue which exceeds the maximum residue level.

In yet a further aspect the invention there is disclosed a pesticidal composition for administration to animals or plants, the composition including at least two actives having the same mode of action, selected from the same chemical class and wherein the at least two actives are chemically different, such that each active is present in a combined amount to provide a kill rate of at least LD90 and a tissue residue level for said each active which is less than or equal to a threshold withholding concentration level.

The invention further relates to a composition for the treatment of pests or parasites in warm blooded animals, the composition including two or more chemically different actives, wherein the chemically different actives have the same mode of action and are from the same chemical class, and where each of the two or more actives is present in an amount which is less than an amount of each active that would give rise to a tissue residue which exceeds a threshold withholding amount, wherein the two or more actives have an accumulative kill rate greater than The combination of actives can provide a high kill rate. The kill rate can be at least an or more preferably an LD99 or greater.

The composition can be suitable for administration to warm blooded animals.

The chemical classes of actives can be selected from the group comprising anthelmintics, miticides, tickicides, antibiotics and insecticides, and other compounds used to treat pests of CI plants and animals.

This invention may also broadly be said to consist in the parts, elements and features N 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 CI specific features are mentioned herein which have known equivalents such equivalents are deemed to be incorporated herein as individually set forth.

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 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, e.g. 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.

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 using the method of the

O

present invention. It may be that the use of a mixture 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 N which results in residue levels which are less than the Maximum Residue Level.

N The important feature of the invention is that as a result of the method of the present invention a composition is arrived at which 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 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 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: 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 Sshould be less than will give rise to a level of residue which exceeds the maximum residue level.

(-i Ni A second active is selected and the maximum residue level should be determined. In addition 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 (-i N, added to the composition should not exceed this amount.

N, 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 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 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, e.g. 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.

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, O lower or higher than an LD 90 level. (-i Further it will be understood by those skilled in the art that the pesticidal composition may (-i (Ni contain more than two actives, where this is the case the amount of each of thile independent 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.

(-i (-i It is envisaged that the combination of active may have an additive if not synergistic effect C-i on reduction of pest numbers.

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. It is advisable that 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 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 Anthelmintic Pour On for treatment and control of internal and external pests of beef cattle. Dose rate is I mL/1Okg.

Example 1 0 O Abamectin 2.5 g/L S Ivermectin 2.5 g/L C N-propyl gallate 0.2 g/L

(N

Thiodipropionic acid 0.15 g/L Icinol PM 10 mL Butyl icinol 10 mL Butyl diicinol to 1 L

O

,I 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.

Example 2 Abamectin 2.5 g/L Ivermectin 2.5 g/L Oily Carrier 640 g/L Isopropyl alcohol to 1 L The composition is prepared by dissolving the actives in the oily carrier. The final volume is made up with HDPE containers.

Topical lousicidefor treatment and control of the sheep body louse. Dose rate 1 mL/2.55 kg Example 3 0 Triflumuron 12.5 g/L S Diflubenzuron 12.5 g/L C Methyl pyrolidinone 250 mL FDC Blue NO 1 0.05 g/L Icinol DPN to 1 L 1-i Dissolve the actives in methyl pyrolidinone. Add and dissolve the dye in 300 ml make up with 200 mL of icinol.

Example 4: Dose rate 1 mL/5 kg Cypermethrin 12.5 g/L Deltamethrin 5 g/L Sudan Blue 0.25 g/L Dowanol to 1 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.

TRIAL

O

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

(N

(N per 10 kg.

The milk residue levels were tested every 12 hours for 7 days from administration. The C milk was tested for the presence of residues of abamectin (see table 1 and figure 1) and for the presence of residues of ivermectin (table 2, and figure The data obtained is C summarized on table 1 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 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 parasiticidally active compounds will provide decreased residue levels. These decreased residue levels will in turn allow reduction or elimination of withholding periods of animals so-treated.

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 C for primary and secondary industries. For example, decreased periods before cows can be milked or slaughtered after treatment. 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 (-i 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.

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.

CS.

Ifllfc ResIdlue Lawb I narhgrm per mUhllIr om animafa teaftd vdi abamoecn or a camb,nallo' at abomecin and hmrmectn.

Table 1. Abamacft. 19hIWIL

CD

-0 *E N~

CE

*N

.D

a, 02V D a~aDW1 PMjVy2 aiDaY PM Da 3 m ~v3 gi Ia4 am 4am s Da.3wn 8a mrn Vaz 0 ay arn 7 Contml O.M 0.0513 O" 0.04?I030mi 058 0. 05; 0,04%4 0.0015 0.036051 0.03805 0.W63 0 .0573 0.0122 01.041911 AeAAVN -ICI 1.5721 0.0=33 2.78 25 2.43481 1. 48 .4 84 1 40 4 1.50135 2.13146 1.109"6 .8 51 1.5545 1.586 0.88 ABAIV 0.4350 MUM88 1.6821 2.491451 13S640 82 1.1761 1.9097 1.5065 0.95255 1.1 406 1.14061 0.8211 0.515575 Table 2X Wrmtn n tL Dayl a unOvo Iv atntkwi 2 an Oav amia 10e pin 10*a4 uam Om Da6 5m~yo D0 I GmiDaveem ~DavT aznluv7 Coibvl OAS D1.5315 0.12=5 0~ CU 01 0.010 0 00117 0.0,16MI 0.32 I 0.1252S AVU.IC1 I 6.118435 0.54-1 i.2W7 IMS3161 1.0097 IA11025% 0.30821 0.872 0.771 0.S2925! 0.7M6 0.72937% 0-6743751 0.8825! A" M -011L 0-2095 &5 1333 1.0327 1-2011 1.77425 0.910151 0.5702 0.9176C 01.60705 0.46W7 441152 0.485T751 0.84=31 0.5831 ABA 0.21133 0.07155 0- B65 0.0962' 0.2981 0.0351 009 .88 0 01 0.947825 0.5 0.00 tOOZ DOG ZZ 6tt~t~tOOZ

Claims

1. A method of manufacturing a pesticidal composition having both a desired high level of efficacy and a residue level sufficiently low to substantially minimize or avoid (N N, withholding periods for plants and animals treated with the composition, the method including: ,I selecting a first active with a desired mode of action from a chemical class of (-i actives useful as pesticide; (vi) selecting one or more subsequent actives from a chemical class of actives, useful as pesticides, whereby said one or more subsequent actives have the same or different mode of action as the first active, wherein said one or more subsequent actives is selected from the same or different chemical class as the first active and each differs chemically from the first active and from each other; (vii) determining a dosage level of each active until the resulting residue level of each active is below a threshold withholding amount for that said active having the desired mode of action; (viii) combining the first and each subsequent active with a suitable carrier, until the effect of the combined actives reaches the desired level of efficacy.

2. A method of manufacturing a pesticidal composition as claimed in claim 1, wherein: the first active is chosen as an active known to kill a target pest, and determining at least the LD 90 quantity of the first active required for said target pest; and choosing the second active known to kill the same target pest, and determining the LD 90 of the second active for said target pest; checking that the LD 90 quantity of each active produces a resulting residue level for Ni each said active below the legally defined maximum allowable residue level for that said active, wherein if this is the case combining the two actives into the composition to provide a composition having a combined LD 99 kill rate or greater N, whilst providing a composition which meets the legally defined maximum allowable residue level for each active; or if the LD 90 quantity of any one or more of the actives results in a residue level for that one or more actives above the legally defined maximum allowable residue level for a particular active, then determining a lower level of kill rate for that or each active, say an LD 80 kill rate, checking the residue level for each active at that level of kill, and combining as many actives having the same or different mode of action as are necessary to bring the kill rate of the combined composition up to a kill rate of LD 99 or greater.

3. A method of manufacturing a pesticidal composition having two or more actives chosen from the same or different chemical class, each active having the same or different mode of action against a target pest, including taking a first active which is known to kill the target pest and determining the LD 90 quantity of the first active for said target pest and determining the resulting residue level of that LD 90 quantity of the first active when applied to a plant or animal, and determining the LD 90 quantity of a second active when applied to said plant or animal, checking that the residue level of both the first and second actives at the LD90 amounts when applied to said plant or animal are below the maximum allowable residue level for each active for that plant or animal, and if so, combining the LD 90 quantity of the first and second actives with a suitable carrier to provide an effective pesticidal composition, and if not then reducing Sthe quantity of each active until the resulting composition meets the legally allowable Smaximum residue level for each active, whilst at the same time providing an effective pesticidal composition by adding a suitable amount of a third, or subsequent active which meets the maximum allowable residual level for that third or subsequent active, until the combined additive effect of the actives is sufficient to reach a kill level of LD 99 or greater.

4. A method of manufacturing a pesticidal composition suitable for application to plants or animals used for the production of foodstuffs or beverages for human consumption, comprising: selecting a first active from a first chemical class, and determining the maximum allowable dosage of said first active which will result in a tissue residue level at or below a maximum withholding residue level for that particular active, then determining the effectiveness or kill rate for that dosage or that active against the target pest, selecting a second (or subsequent) active from the same or different class, wherein the second (or subsequent) active has the same or different mode of action as the first said active and each subsequent active, and repeating the determination of the maximum allowable dosage of said second or subsequent active which will result in residue level at or below a maximum withholding residue level for that particular second or subsequent active, then determining the effectiveness or kill rate for that dosage of that active against the target pest, then combining a sufficient number of said different actives from said same or different class with a suitable carrier to provide effective pesticidal 1 composition in which the additive effect of all of the selected actives in the O composition reaches a desired level of efficacy, whilst at the same time the U composition results in residue levels at or below any legally defined maximum N1 allowable residue level for each of the actives within the composition.

5. A method of manufacturing a pesticidal composition as claimed in claim 4 wherein the desired level of efficacy is a kill rate of LD 99 or greater.

6. A method as claimed in claim 4 or claim 5 wherein the chemical class of actives is CN selected from the group comprising avermectins, synthetic pyrethroids, benzimidazoles, insect growth regulators, pyrimidines, pyrazoles.

7. A method of manufacturing a pesticidal composition as claimed in any one of the preceding claims, wherein the class of actives is the class of avermectins, and said first active is chosen is abamectin, and the second active chosen is ivermectin (or vice versa).

8. A method of manufacturing a pesticidal composition as claimed in any one of claims 1 to 6, wherein the first active is triflumuron and the second active is diflubenzuron (or vice versa).

9. A method of manufacturing a pesticidal composition as claimed in any one of claims 1 to 6, wherein the first active is cypermethrin and the second active is deltamethrin (or vice versa).

10. A method of manufacturing a pesticidal composition substantially as herein described with reference to any one of the examples.

11. A method of manufacturing a pesticidal composition as claimed in any one of claims 1 to 9 wherein said first and subsequent active(s) are chosen from the chemical class of Sinsect growth regulators including benzophenyl ureas. NI

12. A pesticidal composition manufactured in accordance with any one of the preceding claims.

13. A method of treating a warm blooded animal (other than humans), by administering to that animal a pesticidal composition manufactured in accordance with any one of NI claims 1 to 12.

14. A method of treating a warm blooded animal (other than humans) by administering to the animal simultaneously or within a relatively short period of time at least two chemically different actives selected from the same or different class of actives, the dose of each active administered being less than an amount that would result in a residue level exceeding a maximum residue level to substantially minimize or avoid a withholding period or export slaughter interval.

15. A method of treating pests on plants, where the plants are used for human consumption, by administering to the plants a pesticidal composition as claimed in claim 12.

16. A pesticidal composition for administration to animals or plants, the composition including at least two actives being useful as pesticides, said at least two actives having the same or different mode of action, such that each active is present in a combined amount to provide a kill rate of at least LD90 and a tissue residue level for said each active which is less than or equal to a threshold withholding concentration level, wherein at least one of said at least two actives is selected from the chemical Sclass of insect growth regulators including benzophenyl ureas.

17. A composition for administration to animals or plants, the composition including at (N (CN least two actives being useful as pesticides, whereby said at least two actives have the same or different mode of action, wherein the at least two actives are selected from the same or different chemical class and each of said at least two actives differ chemically C from the first active and from each other. (C

18. A composition for administration to animals or plants according to claim 17 wherein each of the said at least two actives is present in a combined amount to provide a kill rate of at least LD90 and a tissue residue level for said each active which is less than or equal to a threshold withholding concentration level, and each of the said at least two actives is an insect growth regulator including one of said at least two actives being selected from the chemical class of benzophenyl ureas.

19. A composition for administration to animals or plants according to claim 18 wherein the benzophenyl urea is diflubenzuron and a second of said at least two actives is selected from the pyrimidine chemical class of compounds.

A pesticide composition for administration to animals or plants including at least two chemically different actives selected from the same or different class of actives including avermectins, abamectins, benzimidazoles, insect growth regulators, pyrazoles, pyrimidines, pyrimidinamines, synthetic pyrethroids; said at least two actives having the same or different mode of action and being present in an amount such that administration of an effective dose of said composition provides a kill rate of at least LD90 and a tissue residue level not exceeding a maximum residue level to substantially minimize or avoid a withholding period or export slaughter interval.

21. A composition substantially as hereinbefore described with reference to any one of the O i examples. 0

22. A method of devising a composition substantially as hereinbefore described with N reference to any one of the examples.

23. A method of treating a warm blooded animal substantially as hereinbefore described c s with reference to any one of the examples PIPERS MILLS OAKLEY Patent Attorneys for Virbac SA