WO2010106138A1

WO2010106138A1 - Pesticide composition

Info

Publication number: WO2010106138A1
Application number: PCT/EP2010/053545
Authority: WO
Inventors: Barry Charles Hosking; John Rossi
Original assignee: Novartis Ag
Priority date: 2009-03-20
Filing date: 2010-03-18
Publication date: 2010-09-23
Also published as: AR076140A1; UY32511A

Abstract

The present invention relates to a pesticide composition wherein the active ingredients consist solely of fluazuron or solely of a combination of fluazuron and benzyl benzoate and which has a carrier comprising natural vegetable oil and solvent. It also relates to the use of this composition as an acaricide, as well as to a method of inhibiting the growth of members of the order of acarina, such as ticks.

Description

Pesticide Composition

The present invention relates to a pesticide composition wherein the active ingredients consist solely of fluazuron or solely of a combination of fluazuron and benzyl benzoate. It also relates to the use of this composition as an acaricide, as well as to a method of inhibiting the growth of members of the order of acarina, such as ticks. In another aspect, the present invention relates to a process to produce a pesticide composition wherein the active ingredients consist solely of fluazuron or solely of a combination of fluazuron and benzyl benzoate.

Fluazuron is the name given to the compound 1- [4-chloro-3- (3-chloro-5- trifluoromethyl-2-pyridyloxy) phenyl]-3- (2, 6- difluorobenzoyl) urea, which is also alternatively named Λ/-[[[4-chloro-3-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]- amino]carbonyl]-2,6-difluorobenzamide. It has the structure given in formula I.

Formula I

Fluazuron and the preparation thereof is known from European patent EP 0 079

31 1 B1 .

Fluazuron has pesticidal activity, and in particular is an acaricide acting against members of the order of acarina, namely mites and ticks. In some classification systems the acarina are referred to as a sub-class rather than an order of arachnids, but in the following the term order will be used. Fluazuron is thought to act by interfering with chitin synthesis. In the case of ticks, treated immature ticks are unable to moult to the next stage, and no larvae will hatch from eggs laid by treated adult females.

Benzyl benzoate is a well known and readily available chemical [CAS registry number 120-51-4, prepared for example by the action of sodium benzylate on benzaldehyde: Kamm, Kamm, Organic Syntheses, Coll. Vol. 1, p.104 (1941); Vol. 2, p.5 (1922)], which may act as a lipophilic solvent, as well as possessing some degree of insect repellent and pesticidal activity, acting against lice, mites and ticks.

Mites are ectoparasites of mammals and birds and feed on external tegument and blood products. Mites of relevance to the present invention include, but are not limited to, the genera Psorergates, Cytodites, Cheyletiella, Trombiculidae, Pneumonyssus, Raillietia, Chorioptes, Otodectes, Psoroptes, Sarcoptes and Demodex.

Ticks are ectoparasites which attach to hosts such as mammals and birds and feed on the blood of their hosts. Ticks of relevance to the present invention are those which belong to, but are not limited to, the genera Amblyomma, Boophilus, Hyalomma, Ixodes, Rhipicephalus, Haemaphysalis and Dermacentor, especially the species Boophilus microplus, Boophilus decoloratus and Boophilus annulatus, and most especially Boophilus microplus and Boophilus decoloratus.

Ticks are responsible for the transmission of numerous diseases which can affect humans and animals, including bacterial, protozoan, rickettsial and viral diseases. These diseases can lead to the debilitation or even death of the host animals.

The ticks may themselves also weaken their host animals, such as cattle, in a condition sometimes known as "tick worry": a generalized state of unease and irritability of cattle severely infested with ticks, often leading to serious loss of energy and weight. Furthermore, the hides of the animals may also be damaged by the ticks.

In fact the tick species Boophilus microplus (also known as Rhipicephalus microplus and in some countries by the common name Southern Cattle Tick) causes high economic losses to livestock producers throughout the world. This tick can infest sheep, horses, goats, buffalo, donkeys, deer, pigs and dogs, but cattle are the economically most important hosts. Tick fever (also known as "red water") is a serious disease transmitted to cattle by Boophilus microplus. Three blood parasites Babesia bovis, Babesia bigemina and Anaplasma marginale populating the ticks are able to cause the disease. The cost of a tick fever outbreak can be substantial and range from production losses (meat and milk) to death. The fertility of bulls is lost for up to one breeding season and infected cows may abort their unborn calves. Additionally there are treatment costs, veterinary bills and loss of market access.

A current means for controlling the tick species Boophilus microplus, found for example on cattle in Australia, is a pour-on formulation sold under the trade name of Acatak^® Pour-On. The formulation includes 25 g/l of fluazuron, as well as a carrier with the surfactants 1-dodecyl-2-pyrrolidinone and 1-octyl-2-pyrrolidinone and the solvent 1- methyl-2-pyrrolidinone. It is typically applied to the backs of these cattle at a final dosage rate of 1.5 mg/kg of body weight.

The fluazuron is thought to be absorbed through the skin of the animal (dermal absorption) or via ingestion as a result of the animals grooming (licking) behaviour of themselves and other treated cattle. Studies with cattle have indicated that fluazuron is taken up into the blood plasma stream of treated animals and once bound to plasma proteins, it circulates through the body for extended periods of time. Without being bound by theory, the pharmacokinetics of fluazuron can be described by a 'first order/two compartment' model, the compartments being represented by the blood plasma and fat. During the distribution phase a concentration equilibrium between the plasma and fat compartments is established and maintained over the full excretion period. During this period, fluazuron is ingested by the cattle ticks as they feed on the blood.

As a safety precaution, the operator applying Acatak^® Pour-On is instructed to wear cotton overalls buttoned to the neck and wrist, a washable hat, elbow length PVC gloves and a full face shield when opening the container and using the product. A maximum of 3 treatments with Acatak^® Pour-On of Australian beef cattle per annual tick season may be used. (The tick season is the period in which the climatic conditions are suitable for growth of the tick). Furthermore, these Australian beef cattle treated with Acatak^® Pour-On are subject to a withholding period of 42 days. The export slaughter interval for these Australian beef cattle is also 42 days.

The withholding period (WHP) is the minimum period which should elapse between last administration or application of a veterinary chemical product, including treated feed, and the slaughter, collection, harvesting or use of the animal commodity for human consumption. It is a reflection of the chemical residue levels in the treated animal.

The export slaughter interval (ESI) is the time that should elapse between administration of a veterinary chemical to animals and their slaughter for export. It is similarly a reflection of the chemical residue levels in the treated animal.

The maximum chemical residue limits for fluazuron in cattle tissues are 200 μg/kg in muscle, 500 μg/kg in kidneys, 7000 μg/kg in fat and 500 μg/kg in liver.

It is desirable to reduce the chemical residue levels in livestock such as cattle treated with a fluazuron composition, so that consumer safety is increased. Moreover it is preferably desirable that the withholding periods for cattle are also reduced so that cattle owners are less hampered in their ability to market their livestock.

This is achieved according to the present invention by a pesticide composition wherein the active ingredients consist solely of fluazuron or solely of a combination of fluazuron and benzyl benzoate, and which has a carrier comprising natural vegetable oil and solvent.

The term "active ingredient" or "active ingredients" means any compound or mixture of compounds that possesses some pesticidal activity, such as an insecticidal, acaricidal, antiparasitic and anti-helminthic activity.

In the present specification the words "comprise" or "comprises" or "comprising" are to be understood as to imply the inclusion of a stated item or group of items, but not the exclusion of any other item or group of items.

The words "consist" or "consists" or "consisting" are however used to mean the inclusion of a stated item or group of items, and the exclusion of any other item or group of items.

In a preferred embodiment, the pesticide composition is for topical use, preferably in the form of a pour-on composition, wherein the active ingredients consist solely of fluazuron or solely of a combination of fluazuron and benzyl benzoate, and which has a carrier comprising natural vegetable oil and solvent.

In one embodiment of the invention the active ingredients consist solely of fluazuron. In an alternative more preferred embodiment of the invention the active ingredients consist solely of a combination of fluazuron and benzyl benzoate. Any benzyl benzoate present in the pesticide composition may also act as a solvent for the fluazuron, in addition to having pesticidal activity.

In a preferred embodiment the solvent comprises 1-methylpyrrolidin-2-one. 1- methylpyrrolidin-2-one is also known by the alternative chemical name N-methyl-2- pyrrolidinone.

In another preferred embodiment the solvent comprises a glycol ether. Especially preferably the glycol ether is 2-(2-butoxyethoxy)ethanol.

It has surprisingly been found that such a pesticide composition with a natural vegetable oil based carrier for fluazuron has a remarkably reduced withholding period compared to the aforementioned prior art composition.

Advantageously, the pesticide composition of the present invention may be applied to a maximum of 4 treatments per annual tick season if necessary.

In the context of the present invention the term natural vegetable oil does not include epoxidised vegetable oils. The natural vegetable oil according to the invention is selected from the group consisting of castor oil, coconut oil, corn oil, cottonseed oil, linseed oil, olive oil, palm oil, peanut oil, rape seed oil, safflower oil, sesame oil, soybean oil, and sunflower oil, or mixtures of two or more of these oils. Preferably the natural vegetable oil is soybean oil.

Suitable glycol ethers according to the invention are 2-(2-butoxyethoxy)ethanol, diethylene glycol monoethyl ether, diethylene glycol diethyl ether, dipropylene glycol monomethyl ether and butyl icinol, preferably 2-(2-butoxyethoxy)ethanol. 2-(2- butoxyethoxy)ethanol is also known by the alternative chemical names, diethylene glycol monobutyl ether, butyl dioxitol, butyl digol and butyl di-icinol.

In a preferred embodiment, the solvent of the pesticide composition according to the invention further comprises aromatic alcohol. Suitable aromatic alcohols according to the invention are benzyl alcohol, ethyl benzyl alcohol, phenethyl alcohol, preferably benzyl alcohol.

In another preferred embodiment, the solvent of the pesticide composition according to the invention comprises a mixture of cetearyl ethylhexanoate and isopropyl myristate.

In a particularly preferred embodiment, the solvent of the pesticide composition according to the invention comprises 1-methylpyrrolidin-2-one, 2-(2- butoxyethoxy)ethanol and benzyl alcohol.

In a more preferred embodiment, the carrier of the pesticide composition according to the invention additionally further comprises antioxidant. The presence of the antioxidant is optional in the pesticide composition as it serves merely to stabilise the pesticide composition during storage. Suitable antioxidants according to the invention are butylated hydroxytoluene, butylated hydroxyl anisole, propyl gallate, and monothioglycerol, preferably butylated hydroxytoluene.

The carrier of the pesticide composition according to the invention may optionally also include further additives such as dyes and odour improvers. In a very particularly preferred embodiment the pesticide composition according to the invention consists of fluazuron, benzyl benzoate, natural vegetable oil, glycol ether, 1-methylpyrrolidin-2-one, aromatic alcohol and antioxidant.

In a most preferred embodiment the pesticide composition according to the invention consists of fluazuron, benzyl benzoate, soybean oil, 2-(2- butoxyethoxy)ethanol, 1-methylpyrrolidin-2-one, benzyl alcohol and butylated hydroxytoluene.

The most preferred pesticide composition of the present invention also has the advantage that the composition is considerably safer for the operator to use when compared to the aforementioned prior art composition, Acatak^® Pour-On. The only personal protective equipment the operator is required to wear when handling the pesticide composition according to the most preferred embodiment of the invention is elbow length PVC gloves. In Australia, this will also be reflected in different "poison schedule" classifications. The aforementioned prior art composition Acatak^® Pour-On is classified as a Schedule 6 poison, i.e. substances with a moderate potential for causing harm, the extent of which can be reduced through the use of distinctive packaging with strong warnings and safety directions on the label. The most preferred composition of the present invention warrants classification as Schedule 5, i.e. substances with a low potential for causing harm, the extent of which can be reduced through the use of appropriate packaging with simple warnings and safety directions on the label.

In another aspect the invention relates to a method of inhibiting the growth of members of the order of acarina, preferably ticks, which comprises applying the pesticide composition as defined above on an animal, preferably on a member of the group referred to collectively as cattle, or its environment, said animal being susceptible to infestation by members of the order of acarina, preferably ticks, in an amount effective to inhibit the growth of said members of the order of acarina, preferably ticks. In a preferred embodiment the composition is applied on the skin of a member of the group referred to collectively as cattle. For example, an amount effective to inhibit the growth of Boophilus microplus in Australia is at a dosage rate of 1.5 mg/kg body weight of the animal (i.e. the animal being the member of the group referred to collectively as cattle).

For the control of Boophilus microplus and B. decoloratus in Latin America and Africa a dosage rate of 2.5 mg/kg body weight of the animal is preferred (i.e. the animal being the member of the group referred to collectively as cattle).

The invention in a further aspect relates to a method of treating tick-infested cattle that comprises applying the pesticide composition as defined above on the skins of said cattle in an amount effective to treat said cattle.

In yet another aspect the invention relates to the use of the pesticide composition as defined above for the preparation of an acaricide. Preferably, the acaricide inhibits the growth of members of the Boophilus genus of ticks, most preferably Boophilus microplus.

The pesticide composition according to the invention may be a combined preparation of 1 ) fluazuron and 2) benzyl benzoate, in a carrier comprising natural vegetable oil and solvent for simultaneous, separate or sequential use in the treatment of tick-infested cattle.

In another aspect, the invention relates to a process for the preparation of a pesticide composition as defined above comprising

step a1 ) dissolving fluazuron in solvent, and

step b1 ) adding to the dissolved fluazuron natural vegetable oil and mixing.

In a preferred embodiment in step a1 ) fluazuron is dissolved in benzyl benzoate that is pre-heated to 40-45⁰C and solvent comprising 1-methylpyrrolidin-2-one that is pre-heated to 40-45⁰C and/or glycol ether. More preferably, both 1-methylpyrrolidin-2- one that is pre-heated to 40-45⁰C and glycol ether are used. It is to be noted that if benzyl benzoate is present it may act as both a solvent for fluazuron, as well as having some pesticidal activity itself. Preferably the glycol ether is 2-(2-butoxyethoxy)ethanol.

Optionally the process may include step a2) wherein an antioxidant, such as butylated hydroxytoluene, is added. In this case the butylated hydroxytoluene is first dissolved in an appropriate quantity of glycol ether, such as 2-(2-butoxyethoxy)ethanol, and then added to a fluazuron/solvent mix, before the natural vegetable oil is added.

Furthermore, optionally the solvent used may further comprise benzyl alcohol or a cetearyl ethylhexanoate and isopropyl myristate mixture.

In another preferred embodiment in step b1 ) the natural vegetable oil is soybean oil. The soybean oil is added as a suspending agent.

The pesticide composition according to the invention preferably comprises 10 to 30 g/L, more preferably 12 to 28 g/L, and most preferred 15 to 25 g/L of fluazuron.

Benzyl benzoate is optionally preferably present in the pesticide composition according to the invention at 190 to 450 g/L, more preferably 200 to 325 g/L, and most preferably 225 to 300 g/L.

The pesticide composition according to the invention preferably comprises 100 to 650 g/L, more preferably 125 to 550 g/L, and most preferred 150 to 500 g/L of natural vegetable oil as suspending agent. Especially preferably the pesticide composition according to the invention comprises 150 to 500 g/L of soybean oil as the natural vegetable oil.

The pesticide composition according to the invention preferably comprises 30 to 700 g/L, more preferably 70 to 650g/L, and most preferred 90 to 625 g/L of the solvent glycol ether. Especially preferably the solvent comprises 90 to 625 g/L of 2-(2- butoxyethoxy)ethanol as the glycol ether.

If present, the solvent 1-methylpyrrolidin-2-one is preferably present in the pesticide composition according to the invention at 30 to 160 g/L, more preferably 45 to 150 g/L, and most preferred 50 to 130 g/L.

If present, the solvent benzyl alcohol is preferably present in the pesticide composition according to the invention at 5 to 20 g/L, preferably at 7.5 to 15 g/L, and most preferred at about 10 g/L. Optionally the pesticide composition of the present invention may additionally comprise Crodamol CAP (mixture of cetearyl ethylhexanoate and isopropyl myristate) as a solvent. If present, it is preferably present at 10 to 25 g/L, more preferably 12 to 20 g/L, and most preferred at about 15 g/L.

The pesticide composition according to the invention preferably comprises 1 to

7.5 g/L, more preferably 2 to 5 g/L, and most preferred about 2.5 g/L of antioxidant. Especially preferably it comprises about 2.5 g/L of butylated hydroxytoluene as the antioxidant.

A particularly preferred embodiment of the pesticide composition of the invention has 12 to 28 g/L of fluazuron, 200 to 325 g/L of benzyl benzoate, 70 to 650 g/L of 2-(2- butoxyethoxy)ethanol, 45 to 150 g/L of 1-methylpyrrolidin-2-one, 7.5 to 15 g/L of benzyl alcohol, 2 to 5 g/L of butylated hydroxytoluene and soybean oil to 1000.

The particularly preferred pesticide composition of the present invention has the advantage that it is not readily washed off the treated animal by rain.

Furthermore the particularly preferred pesticide composition according to the present invention is well tolerated on the skin of cattle.

The pesticide composition according to the invention may be applied topically by way of a pour-on or spray-on composition. Pour-on or spray-on compositions are generally applied with the aid of an applicator to the skin of an area on the animal, wherein different size and shapes of the nozzle of the applicator influence whether the composition is poured or sprayed on. Often pour-on or spray-on compositions are applied to the back of an animal, for example by applying two bands on each side of the spine of cattle between the rump and shoulders.

The pesticide composition according to the invention is preferably applied at a final dosage rate of 2.5 to 1.5 mg/kg body weight of the animal (i.e. the animal being the member of the group referred to collectively as cattle). For example, for the control of Boophilus microplus in Australia the preferable dosage rate is 1.5 mg/kg body weight of the animal. For the control of Boophilus microplus and B. decoloratus in Latin America and Africa a dosage rate of 2.5 mg/kg body weight of the animal is preferred.

A number of specific examples of the invention will now be described, however these are for illustrative purposes only and the scope of the invention is not to be considered as limited to the examples shown below.

Examples 1-10

Table 1 : all values given in g/L

The examples in Table 1 are prepared according to the following general procedure. If present in the composition, separately heat 1-methylpyrrolidin-2-one (Agsolex® 1 , APS Speciality Chemicals) and benzyl benzoate (Redox Chemicals Pty Ltd) for 24 to 48 hours at 40-45⁰C maximum.

Prepare a butylated hydroxytoluene premix: add appropriate quantity of 2-(2- butoxyethoxy) ethanol (Butyl DI-GLYSOLV® solvent, Huntsman Corp. Australia Pty Ltd.) to manufacturing vessel, then add to this butylated hydroxytoluene (IMCD Australia Ltd) and dissolve with mixing.

Preparation of bulk pesticide composition: Where applicable, add to a formulation tank the required quantity of heated 1-methylpyrrolidin-2-one. Where applicable, then add heated benzyl benzoate. Under agitation add the required quantity of fluazuron and mix until the fluazuron dissolves. The preparation of fluazuron is disclosed in EP 0 079 31 1 B1 , compound 17. Pages 9-10 of EP 0 079 311 B1.

Add the butylated hydroxytoluene premix to the formulation tank and stir until dissolved. Add the remainder of the 2-(2-butoxyethoxy) ethanol and disperse with mixing. Where applicable, add benzyl alcohol (Redox Chemicals Pty Ltd) and disperse with mixing. Where applicable, add and disperse with mixing Crodamol CAP (CRODA Surfactants). Add and disperse with mixing soybean oil (Oilseed Products Australia Pty Ltd). Stir at least 30 minutes until the solution is homogenous. Filter through a 25μm filter.

Example 1 1 : Preparation of pesticide composition with fluazuron and benzyl benzoate

Preparation of a butylated hydroxytoluene premix: 1.125kg of butylated hydroxytoluene is added to 9.00 kg of Butyl DI-GLYSOLV® [2-(2-butoxyethoxy)-ethanol] solvent. Preparation of bulk pesticide composition: 40.5 kg of 1-methylpyrrolidin-2-one that is heated to 40-45⁰C maximum is added to a formulation tank. 130.5 kg of benzyl benzoate that is heated to 40-45⁰C maximum is next added. Under agitation 7.17 kg of 98.8% pure fluazuron technical grade is added and mixed until the fluazuron dissolves. To this the previously prepared butylated hydroxytoluene premix is added. 36.0 kg of Butyl DI-GLYSOLV® solvent is added and dispersed with mixing. 4.5 kg of benzyl alcohol is added and dispersed with mixing. Finally 214.9 kg of soybean oil is added and dissolved with mixing until the solution is homogenous. Filter through a 25μm filter. The efficacy of the aforementioned pesticide composition was tested against Boophilus microplus in four different cattle breeds (Droughtmaster, Simmental, Brahman, Charolais) at four commercial farm sites in Australia. Results are compared with untreated controls (Table below). Cattle, including lactating cows with calves at foot, that were treated according to the invention showed declining tick burdens within 2 weeks of treatment, which is a classical response for fluazuron. Tick populations then remained depressed until weeks 5-8, indicating that the development of juvenile tick populations on the treated cattle were being suppressed. Treatments were re-applied. Tick burdens generally increased after treatment in accordance with favourable environmental conditions and while fluazuron in the blood of the treated cattle re-established to required concentrations. When the desirable blood concentrations were reached, the parasite populations again declined to, or near to, zero. The treatment process was then repeated at some sites approximately 12 weeks and 19 weeks after study commencement with similar findings. The benefits of the treatment programmes became more evident with the tick populations remaining depressed in comparison to untreated control herds, whose tick burdens fluctuated in according to prevailing climatic conditions.

^* Cattle were treated with 1.5 mg/kg body weight of the formulation of the present invention in these weeks

Claims

1. Pesticide composition wherein the active ingredients consist solely of fluazuron or solely of a combination of fluazuron and benzyl benzoate and which has a carrier comprising natural vegetable oil and solvent.

2. Pesticide composition according to claim 1 , wherein the active ingredients consist solely of a combination of fluazuron and benzyl benzoate.

3. Pesticide composition according to claim 1 or 2, wherein the solvent comprises 1 -methylpyrrolidin-2-one.

4. Pesticide composition according to any one of claims 1 to 3, wherein the solvent comprises a glycol ether, preferably 2-(2-butoxyethoxy)ethanol.

5. Pesticide composition according to claim 3 or 4, wherein the solvent further comprises aromatic alcohol, preferably benzyl alcohol.

6. Pesticide composition according to any one of claims 3 to 5, wherein the solvent further comprises a mixture of cetearyl ethylhexanoate and isopropyl myristate.

7. Pesticide composition according to any one of claims 1 to 6, wherein the carrier additionally further comprises antioxidant, preferably butylated hydroxytoluene.

8. Pesticide composition according to any one of claims 1 to 7, wherein the natural vegetable oil is selected from the group consisting of castor oil, coconut oil, corn oil, cottonseed oil, linseed oil, olive oil, palm oil, peanut oil, rape seed oil, safflower oil, sesame oil, soybean oil, and sunflower oil, or mixtures of two or more of these oils, preferably soybean oil.

9. Pesticide composition according to claim 7, consisting of fluazuron, benzyl benzoate, natural vegetable oil, glycol ether, 1 -methylpyrrolidin-2-one, aromatic alcohol and antioxidant.

10. Method of inhibiting the growth of members of the order of acarina, preferably ticks, which comprises applying the pesticide composition as defined in any one of claims 1 to 9 on an animal, preferably on a member of the group referred to collectively as cattle, or its environment, said animal being susceptible to infestation by members of the order of acarina, preferably ticks, in an amount effective to inhibit the growth of said members of the order of acarina, preferably ticks.

1 1. Method of treating tick-infested cattle that comprises applying the pesticide composition as defined in any one of claims 1 to 9 on the skins of said cattle in an amount effective to treat said cattle.

12. Use of the pesticide composition according to any one of claims 1 to 9 for the preparation of an acaricide.

13. Use according to claim 12, wherein the acaricide inhibits the growth of members of the Boophilus genus of ticks.

14. Process for the preparation of a pesticide composition as defined in claim 1 comprising

step a1 ) dissolving fluazuron in solvent, and

step b1 ) adding to the dissolved fluazuron natural vegetable oil and mixing.

15. Process as claimed in claim 14, wherein in step a1 ) fluazuron is dissolved in benzyl benzoate that is pre-heated to 40-45⁰C and solvent comprising 1- methylpyrrolidin-2-one that is pre-heated to 40-45⁰C and/or glycol ether.