Note: Descriptions are shown in the official language in which they were submitted.
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'I~TLE OF THE INVENTION
PESTICIDAL FORMULATION
FIELD OF THE INVENTION
The present invention relates to pesticidal compositions
comprising a water-soluble pesticide and process for their manufacture.
More specifically, the invention relates to soluble granule (SG)
formulations comprising a water-soluble pesticide and a water-soluble
filler.
EACKGROUND OF THE INVENTION
Emulsifiable concentrate (EC) agricultural formulations of
pesticides are well known in the art. These formulations generally
comprise emulsifying and dispersing agents in addition to the pesticide
to give a uniform solution. However, these agricultural formulations
suffer numerous drawbacks because they are liquid. In particular,
liquid pesticidal formulations must be handled carefully to minimize
safety concerns, particularly dermal and ocular irritation.
Although solvent-free pesticidal compositions are known,
most solvent-free pesticidal formulations have lower bioactivity than the
corresponding emulsifiable concentrate formulations. Thus, one skilled
in the art frequently has been forced to choose between using a solvent
to give a more bioactive formulation but with higher dermal and ocular
toxicity, or having a Iess active solid formulation.
The present invention overcomes the drawbacks of liquid
formulations by taking advantage where possible of the water solubility
of the pesticide to furnish a composition in divided form so that it will
dissolve in water.
Certain methods for preparing water-soluble granules of
pesticides are known in the art. PCT Publication No. WO 90/12503
discloses the formation of alkaline salts of soluble acidic or phenolic
pesticides to give a granular composition. U.S. Patent No. 4.511 395
discloses wettable herbicidal powder compositions which comprise a
swelling hydrous silicate clay. EPO Publication No. EP 0 111 112
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discloses pesticide granules comprising an inert carrier and a pesticide,
and which are coated with finely divided silica.
The use of lactose as a solid filler to make tablets is well
known in the pharmaceutical industry. (See e.g. Lerk, C.F.,
"Consolidation and Compaction of Lactose" Drug Development and
Industrial Pharmacy, ~, 2359 (1993); "Role of Ingredients and
Excipients in Developing Pharmaceuticals" Manufacturing Chemist, p.
32 (April 1994). Nevertheless, the use of lactose or other water-soluble
fillers as agricultural inert ingredients is not common in formulating
pesticides for crop protection. Hudson and Tarwater (Reduction of
Pesticide Toxicity by Choices of Formulation, J.L. Hudson and O.R.
Tarwater, in ACS Symposium series #371 Pesticide Formulations, B.
Cross and H.B. Scher, eds.) discuss the effect the choice of formulation
on toxicity, and state (on p. 129) that the ocular irntation can be very
different for different formulations of the same active ingredient, and
that changes in the other toxicity categories may occur. Nevertheless,
they do not discuss how such diminished toxicity may be achieved.
Furthermore, they mention wettable powders (WP), water dispersible
granules (WDG) or dry flowables (DF), but they do not even mention
soluble granule (SG) formulations.
The soluble granule (SG) formulation of the present
invention has numerous advantages over the corresponding liquid
formulation of a given pesticide. Because it is a solid, the SG
formulation exhibits improved ease of handling relative to the liquid
formulation. Nevertheless, when dissolved in water the SG formulation
provides a clear solution which is aesthetically pleasing. The SG
formulation also minimizes the use of ingredients of environmental
concern by eliminating the need for volatile organic compounds and
employing fillers which are biologically derived, thereby diminishing
the potential environmental impact. In addition, formulations of higher
concentration (hence lower cost per kg of active ingredient formulated)
can be achieved without any loss in biological activity with respect to a
liquid formulation. Because the dried granules in the SG formulation
are of roughly constant bulk density, the granules may be measured by
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volume, thus making them equally convenient to liquid formulations in
ease of use.
More importantly, however, use of the instant SG
formulation is less risky to personnel than the corresponding liquid
formulation. Risk of exposure is generally evaluated under the guide:
risk = hazard x exposure. Because the instant SG formulation is less
toxic, the hazard is decreased. In addition, the probability of contact is
lower when the material is in a solid rather than a liquid form and hence
the degree of exposure is also reduced. The present invention also
affords relatively hard non-dusty granules, thereby even further
diminishing the risk of exposure to dust from the composition. Also,
the present invention may be practiced without the use of mineral fillers
which contain crystalline silica, a known carcinogen. Thus, the present
invention diminishes the risk of exposure and provides greater handler
safety, especially with regard to ocular irritation, than a liquid
formulation.
Accordingly, the present invention provides a relatively
safe, bionatural delivery system for a pesticide which is water soluble at
the concentration at which it is employed.
SUMMARY OF THE INVENTION
The present invention relates to a pesticidal composition of
a water-soluble pesticide and processes for its manufacture. More
specifically, the invention relates to a soluble granule (SG) pesticidal
formulation comprising a water-soluble pesticide and a water-soluble
filler. The present invention provides a pesticidal formulation with
efficacy equal to the corresponding li4uid formulation_ vet with
_ _ _ - ~ ~ ________,,__ ..___
improved handler safety, such as lower eye irritation.
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DETAILED DESCRIPTION OF THE INVENTION '
The present invention is directed to an pesticidal
composition comprising a water-soluble pesticide and processes for its
manufacture. More specifically, the invention relates to a soluble
granule (SG) formulation comprising a water-soluble pesticide, such as
emamectin benzoate, and a water-soluble filler, such as lactose.
The pesticidal composition of the present invention
comprises: a water-soluble pesticide; and a water-soluble filler.
The present pesticidal composition may further comprise:
a wetting surfactant; and/or a dispersing surfactant. Optionally, a
defoaming agent may also be present.
Preferably the water-soluble pesticide is selected from:
emamectin or an agriculturally acceptable salt thereof. Preferably the
water-soluble filler is selected from: lactose, sucrose, glucose, and the
like. Preferably the wetting surfactant is selected from: sodium N-
methyl-N-oleyl taurate, sodium N-methyl-N-palmityl taurate, sodium N-
methyl-N-oleoyl taurate, sodium dioctyl sulfosuccinate and other sodium
alkyl sulfosuccinates, sodium lauryl sulfate, alpha-(p-nonylphenyl)-
omega-hydroxy poly(oxyethylene) with an average of 8-12 moles of
ethylene oxide, and alpha-(p-octylphenyl)-omega-hydroxy
poly(oxyethylene) with an average of 7-12 moles of ethylene oxide.
Preferably the dispersing surfactant is selected from: sodium alkyl
naphthalene sulfonate, sodium napthalene sulfonate, calcium
lignosulfonate, sodium lignosulfonate, and ammonium lignosulfonate.
Preferably the defoaming agent is selected from: methylated silicones,
polyorganosiloxane, and 2-ethylhexanol.
More preferably the water-soluble pesticide is emamectin
or emamectin benzoate. More preferably the water-soluble filler is
lactose. More preferably the wetting surfactant is sodium N-methyl N-
oleyl taurate. More preferably the dispersing surfactant is sodium alkyl
naphthalene sulfonate. More preferably the defoaming agent is
polyorganosiloxane.
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' The pesticidal composition of the present invention may be
provided in the form of a wettable powder but preferably
is in the form
of a water-soluble granule. Similarly, the pesticidal composition
of the
present invention may be provided as an aggregate, a matrix,
or a
S monolith, such as a brick, pellet, tablet, stick, film, sheet,
and the like.
Preferably, the pesticidal composition of the present invention
is
embedded in a water-soluble matrix or monolith. It also will
be
appreciated by one skilled in the art that the present invention
further
includes encasement of the instant pesticidal compositions
in a water-
soluble package, such as a pouch, sachet, bag, capsule, and
the like.
The pesticidal compositions of the present invention
comprise 0.1 to 90 % by weight of a water-soluble pesticide,
preferably
emamectin benzoate; and 30 to 99.9 % by weight of a water-soluble
filler, preferably lactose (not to the exclusion of other
ingredients).
It will be appreciated by one skilled in the art that the
sum
of the proportions of the water-soluble pesticide and the
water-soluble
filler are not greater than 100% by weight and that the exact
concentrations of the components may vary depending on the
presence
of impurities.
In a more preferred embodiment, the pesticidal
compositions of the present invention comprise 0.1 to 60
% by weight
of a water-soluble pesticide, preferably emamectin benzoate;
40 to 99.9
% by weight of a water-soluble filler; 0 to 50 % by weight
of a wetting
surfactant; 0 to 50 % by weight of a dispersing surfactant;
0 to 5 % by
weight of a defoaming agent (not to the exclusion of other
ingredients).
It will be appreciated by one skilled in the art that the
sum
of the proportions of the water-soluble pesticide, the water-soluble
filler, the wetting surfactant, the dispersing surfactant
and the
defoaming agent are not greater than 100% by weight and the
exact
concentrations of the components may vary depending on the
presence
of impurities.
In one embodiment of the present invention the formulation
contains about 0.1 to 90% by weight of the water-soluble
pesticide.
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Preferred pesticidal compositions of the present invention
comprise 0.1 to 60 % by weight of emamectin benzoate; 40 to 99.9 %
by weight of lactose; 0 to 25 % by weight of sodium N-methyl N-oleyl
taurate; 0 to 10 % by weight of sodium alkyl naphthalene sulfonate; and
0 to 3 % by weight of polyorganosiloxane (not to the exclusion of other
ingredients).
More preferred pesticidal compositions of the present
invention comprise 1 to 50 % by weight of emamectin benzoate; 40 to
99 % by weight of lactose; 0 to 10 % by weight of sodium N-methyl N-
oleyl taurate; 0 to 2 % by weight of sodium alkyl naphthalene sulfonate;
and 0 to 1 % by weight of polyorganosiloxane (not to the exclusion of
other ingredients). Even more preferred pesticidal compositions are
those which may comprise 1 to 20% by weight of emamectin benzoate.
Even more preferred pesticidal compositions of the present
invention comprise 1 to 20 % by weight of emamectin benzoate; 60 to
99 % by weight of lactose; 5 to 10 % by weight of sodium N-methyl N-
oleyl taurate; 0.5 to 2 % by weight of sodium alkyl naphthalene
sulfonate; and 0 to 0.5 % by weight of polyorganosiloxane (not to the
exclusion of other ingredients). Still more preferred pesticidal
compositions are those which comprise 1 to 10% by weight of
emamectin benzoate.
It will be appreciated by one skilled in the art that the sum
of the proportions of ernamectin benzoate, lactose, sodium N-methyl N-
oleyl taurate, sodium alkyl naphthalene sulfonate and polyorgano-
siloxane are not greater than 100% by weight and that the exact
concentrations of the components may vary depending on the presence
of impurities.
Especially preferred pesticidal formulations are as follows:
Soluble granules comprising about 5.3% by weight of
emamectin benzoate; about 86% by weight of lactose; about 7.5% by
weight of sodium N-methyl N-oleyl taurate; about 1 % by weight of
sodium alkyl naphthalene sulfonate; about 0.1 % by weight of
polyorganosiloxane.
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- The present invention further includes a process for
preparing a soluble granule formulation which process comprises:
( 1 ) forming a powder blend of a water-soluble pesticide
and a water-soluble filler;
(2) adding water to the blend;
(3) extruding the wet blend through a die to form
granules; and
(4) drying the granules to remove the water. .
The present invention is further directed to a soluble
granule formulation prepared by such process.
In a preferred embodiment, the process for preparing a
soluble granule formulation comprises:
( 1 ) forming a powder blend of a water-soluble pesticide,
a water-soluble filler, a wetting surfactant and a dispersing surfactant;
(2) adding water to the blend;
(3) extruding the wet blend through a die to form
granules; and
(4) drying the granules to remove the water.
Optionally, in this process a defoaming agent may be added
to the powder blend.
The present invention is further directed to a soluble
granule formulation prepared by such process.
Specifically exemplifying the present invention is the
process comprising the steps of:
( 1 ) forming a powder blend of a emamectin benzoate and
lactose;
(2) adding water to the blend;
(3) extruding the wet blend through a die to form
granules; and
(4) drying the granules to remove the water.
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A preferred embodiment which specifically exemplifies the
present invention is the process comprising the steps of:
( 1 ) forming a powder blend of a emamectin benzoate,
lactose, sodium alkyl naphthalene sulfonate, sodium N-methyl N-oleyl
taurate, and polyorganosiloxane;
(2) adding water to the blend;
(3) extruding the wet blend through a die to form
granules; and
(4) drying the granules to remove the water.
The present invention is further directed to a soluble
granule formulation of emamectin benzoate prepared by such process.
The present invention is further directed to a
delivery system for water-soluble pesticides, in particular, emamectin
benzoate, which comprises soluble granules and the use thereof.
The present invention further provides a method for
administering the water-soluble pesticide comprising:
( 1 ) formulating the water-soluble pesticide as a soluble
granule;
(2) mixing with water a portion of the soluble granule
sufficient to give the desired amount of active ingredient of the water-
soluble pesticide; and
(3) applying the pesticide/water mixture.
The present invention is further directed to a
pesticide/water mixture prepared by such process.
The application of the pesticide/water mixture may be
conducted by methods well known in the art, including, spraying,
misting, dripping, infusing, injecting, irngating, and the like.
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- The term "water-soluble pesticide" as used herein includes
any biologically active pesticidal agent or crop protection
chemical
which is water soluble at the concentration in which it is
employed (i.e.
the agent is water soluble at the volume used in Held application).
Such
water-soluble pesticides include certain fungicides, herbicides,
such as
plant growth regulators, and insecticides, such as nematocides,
anti-
helmentics, and miticides. Exemplary water-soluble pesticides
which
may be employed in the present invention include: the fungicides:
blasticidin-S, kasugamycin, and hymexanol; the herbicides:
acifluorfen,
glyphosate, and glufosinate; the plant growth regulants:
gibberellic acid,
malefic hydrazide and dikegulac; and the insecticides: acephate,
emamectin, and emamectin benzoate. A particularly preferred
water-
soluble pesticide is emamectin, or an agriculturally acceptable
salt
thereof, such as the salt formed with benzoic acid, salicyclic
acid, gallic
acid, benzenesulfonic acid, hydrochloric and citric acid,
especially
emamectin benzoate. One skilled in the art will readily appreciate
that
these pesticides exhibit sufficient water solubility that
they will dissolve
when mixed with water at the labeled use rate. For example,
commercial label use rates of acephate are as high as 1.33
lb (0.60 kg)
in a minimum of 3 gallons (11.4 liters) of water. Because
650 g of
acephate is soluble in 1 liter of water, the acephate is
fully soluble in
water at its maximum label use rate. Similarly, ernamectin
benzoate is
soluble at about 100 ppm in water. Thus, at a typical use
rate 3.4 g of
emamectin benzoate will be soluble in about 34 liters of
water.
The term "water-soluble granule" as used herein is intended
to include any granular or pelletized compositions which
permit the
active ingredient to be in solution after dissolving in water.
It is not
necessary for all of the ingredients of the water-soluble
granule to be in
solution as long as the active ingredient itself is in solution.
Thus, the
present invention includes within its scope water-soluble
granules in
which some of the ingredients may be relatively insoluble.
The actual
physical form of the instant pesticidal composition is not
critical to the
proper function of the present invention.
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The term "water-soluble filler" as used herein includes any '
water soluble or water dispersible agent which may be employed to
dilute the pesticide. Preferred water-soluble agents include those which '
are biologically derived. Appropriate water-soluble fullers include
lactose, glucose, fructose, mannose, mannitol, sucrose, such as
confectioner's sugar, black sugar, brown sugar, soft brown sugar, other
sugars or saccharides, microcrystalline cellulose, powdered cellulose,
calcium phosphate(s), inorganic water-soluble salts, and the like, and
mixtures thereof. Examples of lactose which can be used in the present
invention include hydrated oc-lactose, anhydrous oc-lactose, hydrated (3-
lactose, anhydrous (3-lactose, and the like, and mixtures thereof.
Any surfactants can be used as the surfactant in the present
invention, as long as it will emulsify the desired pesticide, or the
pesticide when mixed with water. Examples of such surfactants include
1 S glycerine fatty acid esters, sucrose fatty acid esters, sorbitan fatty
acid
esters, fatty acid salts, alkyl sulfates, alkylbenzene sulfonic acid salts,
alkyl aryl ethers and polyoxyethylenated products thereof, ethylene
oxide addition products of higher alcohols, polyoxyethylene
polyoxypropylene glycol, lignin sulfonic acid salt, polyoxyethylene
styrylphenyl ether, polyoxyethylene alkyl esters, alkyl aryl sulfates, and
the like. The surfactants may be used singly or in a suitable
combination. Surfactants which can uniformly mix with the desired
pesticide or the pesticides and water are preferred but it is not always
necessary to use such surfactants. It is sufficient that surfactants be
dissolved in water when the pesticidal composition is diluted with water.
The term "wetting surfactant" as used herein includes any
agent which may be employed to enhance the wetting properties of the
formulation such as sodium N-methyl-N-oleyl taurate, sodium N-
methyl-N-palmityl taurate, sodium N-methyl-N-oleoyl taurate, sodium
dioctyl sulfosuccinate and other sodium alkyl sulfosuccinates, sodium
lauryl sulfate, alpha-(p-nonylphenyl)-omega-hydroxy poly(oxyethylene)
with an average of 8-12 moles of ethylene oxide, and alpha-(p-
octylphenyl)-omega-hydroxy poly(oxyethylene) with an average of 7-12
moles of ethylene oxide.
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The term "dispersing surfactant" as used herein includes
any agent which may be employed to enhance the dispersion of the
formulation when mixed in water such as sodium alkyl naphthalene
sulfonate, sodium naphthalene sulfonate, calcium lignosulfonate, sodium
lignosulfonate, and ammonium lignosulfonate.
The term "defoaming agent" as used herein includes any
agent which may be employed to reduce the tendency of the formulation
to induce the generation of foam when added to water such as
methylated silicones, polyorganosiloxane, and 2-ethylhexanol.
In addition to the pesticide, the water-soluble filler, the
wetting surfactant, the dispersing surfactant and the defoaming agent,
the instant pesticidal compositions may also appropriately contain
stabilizers, synergists, coloring agents, etc.
The pesticidal compositions of the present invention are
generally spread after diluting with water. One skilled in the art will
appreciate that when diluted with water, the dilution magnification of
the pesticidal composition varies depending upon the kind of pesticide,
the kind of harmful organism to be controlled, the kind of crops to be
treated, the kind of blight to be mitigated, the kind of weeds to be
controlled, the time period for treatment, the method of application, etc.
and is not definitively given but is generally in a range of from 20 to
10,000 times.
A preferred water-soluble pesticide for use in the
formulations of the present invention is emamectin benzoate. Certain
avermectin B la/B lb compounds which have activity as agricultural
insecticides are disclosed in U.S. Patent No. 4,310,519 (issued January
12, 1982). The compound 4"deoxy-4"-epi-methylaxnino avermectin
hydrochloride is disclosed in U.S. Patent No. 4,874,749 (issued October
17, 1989) as having properties as an agricultural insecticide. Stable salts
of 4"-deoxy-4"-epi-methylamino avermectin B laB lb are disclosed in
U.S. Patent No. 5,288,710 (issued February 22, 1994).
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In particular, U.S. Patent No. 5,288,710 discloses the
benzoate salt of 4"-deoxy-4"-epi-methylamino avermectin B 1 aB 1 b
(emamectin benzoate) which has the structure, e.g.:
CH3 OCH3
H~N
OCH3
CH3 OJ~~~O,,,.
CH3 O ~~,, H CH3 H O / .,,.CH3
0.,,. ~ .,,~0 CH3
O ,~ H
CH3''~~ ~,, H
OH H ~ O O H (H or CH3)
oH~ H
O~CH3
H OH
This compound may be readily prepared by the
methodology describe therein. The other ingredients in the subject
formulations are either commercially available, or are readily prepared
by methods known in the art.
The use of the present formulations will be readily apparent
to one skilled in the art. In particular, formulations comprising
emamectin benzoate may be utilized e.g. as described in U.S. Patent No.
5,288,710.
The pesticidal compositions of the present invention may be
used to exterminate or control harmful organisms or regulate plant
1 S growth.
The pesticidal compositions of the present invention are
particularly useful in combating agricultural pests that inflict damage
upon crops while they are growing or while in storage. The compounds
are applied using known techniques as sprays, dusts, emulsions and the
like, to the growing or stored crops to effect protection from such
agricultural pests.
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For example, the compound emamectin and the
agriculturally acceptable salts thereof, in particular, emamectin benzoate
exhibit significant parasiticidal activity as anthelmintics,
ectoparasiticides, insecticides and acaricides, in human and animal health
and in agriculture.
Emamectin and the agriculturally acceptable salts thereof
are useful against insect pests of stored grains such as Tribolium sp.,
Tenebrio sp., and of agricultural plants such as spider mites,
(Tetranychus sp.), aphids, (Acyrthiosiphon sp.); against migratory
orthopterans such as locusts and immature stages of insects living on
plant tissue. These pesticides are useful as a nematocide for the control
of soil nematodes and plant parasites such as Meloidogyne sp. which
may be of importance in agriculture. These pesticides are also active
against other plant pests such as the southern army worm and Mexican
bean beetle larvae. These pesticides also have activity against
Dirofllaria in dogs; Namatospiroides, Syphacia, Aspiculuris in rodents;
the arthropod ectoparasites of animals and birds such as ticks, mites,
lice, fleas, and blowfly; in sheep Lucilia sp.; biting insects and such
migrating diperous larvae as Hypoderma sp. in cattle; Gastrophilus in
horses; and Caterebra sp. in rodents. In addition these compounds are
also active against parasitic worms known as helminths. Helininthiasis is
a prevalent and serious economic problem in domesticated animals such
as swine, sheep, horses, cattle, goats, dogs, cats and poultry. Among the
helminths, the group of worms described as nematodes causes
widespread and often times serious infection in various species of
animals. The most common genera of nematodes infecting the animals
referred to above are Haemonchus, Trichostrongylus, Ostertagia,
Nematodirus, Cooperia, Ascaris, Bunostomum, Oesophagostomum,
Chabertia, Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria,
Heterakis, Toxocara, Ascaridis, Oxyuris, Ancylostoma, Uncinaria,
Toxascaris and Parascaris. Certain of these, such as Nematodirus,
Cooperia and Oesphagostomum attack primarily the intestinal tract
while others, such as Haemonchus and Ostertagia, are more prevalent in
the stomach while still others such as Dictyocaulus are found in the
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lungs. These pesticides are also useful against parasites which infect
humans. The most common genera of parasites of the gastro-intestinal
tract of man are Ancylostoma, Necator, Ascaris, Strongyloides,
Trichinella, Capillaria, Trichuris, and Enterobius. Other medically
important genera of parasites which are found in the blood or other
tissues and organs outside the gastrointestinal tract are the filiarial
worms such as Wuchereria, Brugia, Onchocerca and Loa, Dracunculus
and extra intestinal stages of the intestinal worms Strongyloides and
Trichinella. The compounds are also of value against arthropods
parasitizing man, biting insects and, other dipterous pests causing
annoyance to man. These pesticides are also active against household
pests such as the cockroach, Blatella sp., clothes moth, Tineola sp.,
Carpet beetle, Attagenus sp., and the housefly Musca domestica.
If desired, the pesticidal compositions of the present
invention may be employed to formulate a liquid drench. The drench is
normally a solution, suspension or dispersion of the active ingredient
usually in water together with suspending agent such as bentonite and a
wetting agent or like excipient. Generally, the drenches also contain an
antifoaming agent.
The optimum amount of pesticide to be employed for best
results will, of course, depend upon the particular pesticide employed,
the species of animal or plant to be treated and the type and severity of
parasitic infection or infestation. The optimum amount of pesticide to
be employed is considered to be readily determined by one skilled in the
art without undue experimentation.
Methods for preparing the formulations of the present
invention are illustrated in the following Examples. The following
examples are given for the purpose of illustrating the present invention
and shall not be construed as being limitations on the scope or spirit of
the instant invention.
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- EXAMPLE 1
Representative compositions of the emulsifiable concentrate
(EC) formulation and of the soluble granule (SG) formulation are
given below:
Emulsifiable Concentrate Formulation of Emamectin Benzoate
Ingredient Trade name %w/w
Emamectin Benzoate (Technical AI) 2.40
Butylated hydroxytoluene BHT 1.00
Paraffinic oil Semtol 70 6.40
POE 30 castor oil Witconol 300 18.00
Polysorbate 80 Tween 80 18.00
1-hexanol Epal 6 54.20
The emulsifiable composition
was made by blending all
ingredients together and stirring until dissolved.
Soluble Granule Formulation of Emamectin Benzoate
Ingredient Trade name ow/w
Emamectin Benzoate (Technical AI) 5.31
Polyorganosiloxane Rhodorsil EP 6703 0.10
Sodium alkyl naphthalene sulfonates Sellogen DFL 1.00
Sodium N-methyl N-oleyl taurate Adinol OT-64 7.50
Anhydrous lactose Direct Tableting 86.09
Grade
Ingredient Trade name leg
Emamectin Benzoate (Technical AI) 1.078
Polyorganosiloxane Rhodorsil EP 6703 0.020
Sodium alkyl naphthalene sulfonates Sellogen DFL 0.200
Sodium N-methyl N-oleyl taurate Adinol OT-64 1.500
Anhydrous lactose Direct Tableting 17.207
Grade
Water (Technical) 2.795
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The soluble granule formulation was prepared as follows
on a pilot scale in 5 X 20 kg lots to give 100 kg of formulation. The
first step in the process was the dry blending of the active ingredient
emamectin benzoate with the excipients followed by the addition of
approximately 14% by weight of water in a 60 liter portable blender.
The wet mass was then transfered to a basket extruder filled with a 0.8
mm screen. The extrudate was dried on a fluidized bed dryer for
approximately 12 minutes at about 60°C. The granules were transfered
to sieving equipment where particles outside the specified range of 4 to
50 mesh were segregated. The overall campaign yield was 91 % with
yield losses due to segregation of product falling outside the particle size
specification. The final product meeting the particle size was bulk
packaged in 10 kg bags.
IS
Soluble Granule Formulation of Emamectin Benzoate
Ingredient Trade name %w w
Emamectin Benzoate (Technical AI) 5.20
Polyorganosiloxane Antifo am/IZhodorsil EP-67030.10
Sodium alkyl naphthalene sulfonatesSellogen DFL 1.00
Sodium N-methyl N-oleyl taurate Adinol OT-64 7.50
Lactose Lactose DCL 21 86.2
Ingredient Trade name
Emamectin Benzoate (Technical AI) 5.12
Polyorganosiloxane Antifoam/Rhodorsil 0.098
EP-6703
Sodium alkyl naphthalene sulfonatesSellogen DFL 0.984
Sodium N-methyl N-oleyl taurate Adinol OT-64 7.3g
Lactose Lactose DCL 21 84.gg
Water
(Technical) 10.0
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The soluble granule formulation was prepared on a larger
scale in 8 X 100 kg lots to give 800 kg of formulation. The first step in
- the process was the dry blending of the active ingredient emamectin
benzoate with the excipients for 5-10 minutes until uniform in a 200
liter blender followed by the addition of approximately 10 kg of water
( 10-12.5 %) in the blender. The water was added as a single spray and
blending was continued for 1 minute after addition. It was determined
that in large scale formulation, less water was required (presumably due
to the humidity of the lactose, variation in the temperature of the mixer
or the difference in batch size). The wet mass was then transfered to a
basket extruder and extruded to a to a 0.8 mm screen into a fluid bed
dryer. Each batch was separated into two sub-batches and dried in a
single drying cycle without the need for additional stirring during the
drying cycle. The extrudate was dried on a fluidized bed dryer for
approx. 12-20 minutes at about 60°C inlet temperature, at air flow 1
m3/min. The granules were transfered vacuum to vibrating sieving
equipment where particles outside the specified range of 4 to 50 mesh
were segregated. The overall yield was about 90% with yield losses due
to segregation of product falling outside the particle size specification.
The final product meeting the particle size was bulk packaged.
EXAMPLE 2
Soluble Granule Formulation of Emamecdn Benzoate
Ingredient Trade name %w w
Emamectin Benzoate (Technical AI) 5.5
Fumed silica Cab-O-Sil M5 0.75
Sodium N-methyl N-oleyl taurate Geropon T77 0.75
Polyorganosiloxane EP 6703 0.1
Mixture of anionic surfactants Witcosperse D60 3.0
Starch Sta-RX 10.0
Anhydrous lactose Direct Tableting Grade79.9
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The dry blend soluble granule formulation was made by
blending all of the powders together. To the dry blend was added 15%
water, and the resulting powder was extruded using a LCI Benchtop
extruder with 0.8 mm screen to give wet granules which were then
S dried overnight at 54 °C.
In field studies comparing efficacy described below, the
efficacy of the soluble granule formulation was statistically equal to that
of the emusifiable composition formulation. Both formulations were
tested for acute ocular irritation as described below and it was observed
that the emusifiable composition was extremely irritating whereas the
soluble granule formulation was only mildly irritating.
IS
ESA MPLE 3
Soluble Granule Formulations of Emamectin Benzoate -
Variation of Percentage of Active Ingredient
Ingredient (%w/w) ~ B
Emamectin Benzoate 1 2 5 IO 25 50
Polyorganosiloxane 0.1 0.1 0. 0. 0.1 0.1
I I
Sodium N-methyl-N-oleyl taurate 7.5 7.5 7.5 7.5 7.5 7.5
Sodium alkyl naphthalene sulfonateI.0 1.0 1.0 1.0 1.0 1.0
Anhydrous lactose 90.4 89.4 86.4 8I.4 66.4 41.4
As demonstrated in this example, the amount of active
ingredient (emamectin benzoate) need not be limited to 5% and may be
greater than 5%. Each of the noted compositions was prepared by
blending the dry powders, adding water, and the extruding the resultant
powder using an LCI Benchtop extruder with an 0.8 mm screen to give
wet granules which were then dried overnight at 54 °C. When dispersed
in water, the granules gave a clear solution containing emamectin
benzoate.
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EXAMPLE 4
Soluble Granule Formulations of Emamectin
Benzoate -
Variation of Filler
Ingredient (lowlw)
Emamectin Benzoate 5.4 5.4 5.4
Polyorganosiloxane 0.1 0.1 0.1
Sodium alkyl
naphthalene sulfonate 1.0 1.0 1.0
Sodium N-methyl-N-
oleyl taurate 7.5 7.5 7.5
Hydrous lactose 86.1
Confectioner's sugar (sucrose) 86.1
Powdered glucose 86.1
As demonstrated by this example, other water-soluble bio-
derived fillers may be used in the practice of the present invention.
Each of these compositions was prepared by blending the dry powders,
adding water, and extruding the resultant powder by using an LCI
Benchtop Extruder with an 0.8 mm screen to give wet granules which
were then dried overnight at 54 °C. When dispersed in water, the
granules gave a clear solution containing emamectin benzoate.
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EXAMPLE 5
Soluble Granule Formulations of Emamectin Benzoate - -
Absence of Surfactants
S
Ingredient (°lowlw) ~ g
Emamectin Benzoate 5.4 5.4 5.4 5.4
Anhydrous lactose 94.6 93.6
Hydrous lactose 94.6
Confectioner's sugar (sucrose) 94.6
Sodium alkyl
naphthalene sulfonate 1.0
As demonstrated by this example, the presence of wetting
and/or dispersing surfactants is not necessary for the practice of the
present invention. Each of these compositions was prepared by blending
the dry powders, adding water, and extruding the resultant powder by
using an LCI Benchtop Extruder with an 0.8 mm screen to give wet
granules which were then dried overnight at 54 °C. When dispersed in
water, the granules gave a clear solution containing emamectin benzoate.
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EXAMPLE 6
Soluble Granule Formulation of Emamectin Benzoate -
Efficacy Study
Performance of the 5% soluble granule formulation of
emamectin benzoate (prepared as described in Example 1 ) was
compared with that of the 2% emulsifiable concentrate formulation of
emamectin benzoate (prepared as described in Example 1 ) and the
commercial standards lambda-cyhalothrin and esfenvalerate, and the
Dipel 2x formulation of acillus thuringiensis kurstaki when applied
weekly for control of tomato fruitworm (Helicoverpa zea on tomato.
When applied at 0.0075 lb active ingredient (AI) per acre, both
formulations of emamectin benzoate were equally effective and were
comparable to the commercial chemical and B. thurin iensis standards
in reducing fruit damage by Helicoverpa zea. The overall mean
percentage of damaged fruit in the untreated control was 18.5%,
whereas that with the emulsifiable concentrate formulation and soluble
granule formulation of emamectin benzoate were 2.0% and 0.5%,
respectively. Fruit damage in the lambda-cyhalothrin, esfenvalerate and
the B thuringiensis kurstaki treatments averaged 1.0%, 0.0% and 1.5%,
respectively.
'Roma' tomato transplants were planted in the field on June
10. Each plot was one row (5 ft centers) by 20 feet (= 0.0022957 acre).
Plots were separated within rows by at least 6 feet of unplanted ground
and across rows by 24 feet. A single row of sweet corn ('Silver Queen')
was planted mid-way between rows. Weeds are allowed to grow in the
ground between the tomato and sweet corn rows, but were kept mowed.
Weeds were controlled within tomato rows by a single application of
Sencor 75 DF applied as a directed spray at the rate of 0.5 lb a.i./acre
on June 20. Foliar applications of Dithane M45 at 1.5 lb a.i./ acre were
made every 5 days beginning July 1 and continuing through harvest for
control of foliar diseases. In addition, calcium nitrate at 4 lb/acre was
applied on July 10, 17, 24 and 31 for control of blossom-end rot. All
insecticide treatments were applied as foliar sprays on July 23, 30,
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August 6, and 13. Applications were made using a C02-powered, '
backpack sprayer calibrated to deliver SS gallons of spray per acre at 42
psi. The spray was delivered through 3 hollow cone nozzles (D-3 disk, '
25 core) directing spray toward each side of the row (equivalent 6
nozzles per row). Sprays were initiated on July 23 in response to an
increase in capture of ~ielicover~a yea moths in a nearby blacklight trap
and the appearance of -.~.sI zea eggs on the tomato foliage. The
experimental treatments were:
1. Emulsifiable concentrate formulation of 2% emamectin
benzoate applied at 0.0075 lb active ingredient per acre
2. Soluble granule formulation of 5% emamectin benzoate
applied at 0.0075 lb active ingredient per acre
3. Lambda-cyhalothrin (Karate lE) applied at 0.02 lb active
ingredient per acre
4. Esfenva.lerate (Asana XL 0.66 EC) applied at 0.036 lb
active ingredient per acre
5. acillu thurin iensis rstaki (Dipel 2X) applied at 1.0 lb
formulation per acre
6. Untreated control
The experimental treatments were replicated 4 times in a
randomized complete block experimental design. The incidence of
fruitworm damage to the fruit was determined in each plot on August
11, when the first fruit reached market maturity, and again on August
16. On each sample date, 25 randomly selected ripe fruit were
harvested and examined for insect damage. Insect damaged fruit were
classified as unmarketable and cut open to identify the insect responsible
for the damage, if it was present. Undamaged fruit were classified as
marketable. All insects found in fruits were -~Z. zea, and damage to fruit
was, in all cases, characteristic of that caused by ~ zea. Although the
experimental protocol called for three evaluations of damage to fruit, a
third evaluation was not possible because southern blight began to
spread rapidly through the plots between the first and second harvest.
The number of dead and dying plants in the plots rose quickly after the
second evaluation and made it impossible to obtain meaningful data.
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from a third harvest. The southern blight first appeared
on scattered
plants in early July, following excessive rainfall throughout
June. Little
- spread of the disease was observed until after the planting
was irrigated
on August 8. Because most plants in all plots appeared healthy
at the
S time of each harvest and diseased plants were not harvested,
there is no
reason to suspect that the incidence of southern blight compromised
the
data generated in this trial.
Tomato fruitworm was the only insect pest to develop
damaging populations in this trial, and the damage levels
in the
untreated control plots were typical for early August in
the Coastal
Plain of North Carolina. The percentages of total fruit damaged
by H
zea in the untreated check in the August 11 and 16 samples
were 17 and
percent, respectively. Unfortunately, the trial was not
continued into
late August when tomato fruitworm populations reach very
high levels.
15 On both harvest dates, all treatments had significantly fewer
damaged
fruits than the untreated check, and there were no significant
differences
among any of the experimental treatments. Both formulations
provided
control of tomato fruitworm comparable to the chemical standards
lambda-cyhalothrin and esfenvalerate, as well as the biological
standard
20 ~ thuringiensis kurstaki (Dipel 2X).
These results indicate that both the emulsifiable concentrate
formulation and soluble granule formulation of emamectin
benzoate
were equally effective in controlling tomato fruitworm when
each
applied on a 7 day schedule at a rate of 0.0075 lb active
ingredientlacre.
Both formulations were as effective as lambdacyhalothrin
at 0.02 lb
active ingredient/acre, esfenvalerate at 0.036 lb active
ingredient/acre,
and the Dipel 2X formulation of ~ thuringiensis kurstaki
applied at 1.0'
lb formulation/acre on a 7 day schedule.
In subsequent efficacy studies, the emulsifiable concentrate
" 30 formulation and soluble granule formulation of emamectin
benzoate
were equally effective in controlling diamondback moth, fall
armyworm
and cabbage webworm upon aerial application.
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EXAMPLE 7
Soluble Granule Formulation of Emamectin Benzoate -
Acute Ocular Irritation Studv in Rabbits
The potential primary ocular irritation of S% soluble
granule (SG) formulation of the agricultural pesticide emamectin
benzoate (prepared as described in Example 1) was evaluated in New
Zealand albino rabbits. The study was conducted in accordance with
Standard Operating Procedures. Six rabbits (3 males and 3 females)
were used in the test group of this study. At the experimental start of
the study, the animals were approximately 15 weeks old and ranged in
weight from 2.85 to 3.05 kg. On Study Day 0, I00 milligrams of the
formulation were placed in the conjunctival sac of the left eye (the right
eye was untreated and used a.s a control). All animals were observed
daily for 7 days for mortality and clinical signs. Body weights were
recorded for alI rabbits on Study Day 0 before administration and on
Study Day 7. General survey of the eyes, direct pupillary and corneal
reflexes of both eyes, and scoring of ocular reactions of the treated eye,
according to Draize scoring system (J. Pharmacol Exp Ther~p.
$2:377-390 ( 1944)), were done before treatment 15 and 120 minutes,
24, and 48 and 72 hours, 4 to 7 days after treatment in all rabbits. All
rabbits were euthanized on Study Day 9 by an overdose of barbiturate
and discarded without necropsy. There were no drug-related in body
weight gain, neither clinical signs except ocular signs described below.
25. At 15 minutes, very slight conjunctival redness, slight
chemosis (one animal) and very slight to slight discharge were noted in
the treated eyes of all rabbits. By 120 minutes, slight conjunctival
redness, slight chemosis and slight discharge (all animals) and slight
iritis (2 animals out of 6) were observed. By 24 hours, alI previous
ocular reactions decreased in severity and only very slight conjunctival
redness, and slight iritis (one animal) persisted. However, very slight
corneal opacity (<1.4 corneal surface) was present in 2 animals. By 48
to 72 hours, all ocular reactions regressed, and only very slight
conjunctival redness lasted in one animal. By Day 4 through Day 7 all
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rabbit eyes were normal. The values of the Draize scores correlated
with the clinical signs. The individual total scores were very low and
never exceeded 15 (the maximum score achievable by this method being
110). Throughout the study, direct pupillary reflexes and corneal
reflexes were normal in all rabbits. Subsequent testing of a 10% and a
25% soluble granule (SG) formulation of emamectin benzoate suggested
that the 10% formulation was moderately irritating, but the 25%
formulation exhibited severe irritation.
EXAMPLE 8
Emulsifiable Concentrate Formulation of Emamectin Benzoate -
Acute Ocular Irritation Study in Rabbits
The purpose of this study was to determine the ocular
irritation potential of a 2% Emulsifiable Concentrate (EC) formulation
of the agricultural pesticide emamectin benzoate when instilled once in
the eye of a rabbit.
One male albino rabbit (New Zealand White)
approximately 22 weeks of age and weighing 2.76 kg was used in this
study. The animal was housed in an individual stainless steel cage in a
temperature-controlled room. The diet consisted of Purina Certified
High Fiber Rabbit Chow. Drinking water was available at all times.
The rabbit was treated with 0.1 ml of emulsifiable concentrate
formulation of emamectin benzoate (prepared as described in Example
1 ) placed in the conjunctival sac of the left eye. Immediately after
administration, the eyelids of the treated eye were held together for one
second and released. The right eye was used as an untreated control.
The rabbit was observed for 21 days for signs of systemic
toxicity and ocular irritation. Ocular examinations were made pretest
and approximately 60 minutes after ocular application and daily
thereafter, except for weekends (Days 5, 6, 12, 13, 19, 20). These
observations were scored by the Draize Method (J. Pharmacol. Ex~.
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Therap. X2:377-390 (1944)). Body weights were taken pretest and on
Days 7, 14 and 21. At the end of the observation period, the rabbit was
discarded without necropsy. The formulation did not produce any
treatment-related systemic effects or changes in body weight. However,
the formulation produced slight opacity covering the whole cornea,
moderate redness and chemosis, and severe discharge at 60 minutes.
The eye worsened at 24 hours with corneal anesthesia and the iris
showing some congestion including circumcorneal injection in addition
to the previous signs. The eye slowly improved and from Day 18 to the
end of the observation period on Day 21, only corneal anesthesia and
very slight opacity covering the whole cornea was seen.
In conclusion, the emulsifiable concentrate formulation of
emamectin benzoate was extremely irritating to the eye of a rabbit.
Because evidence of ocular irritation was still present after 21 days, no
additional rabbits were tested for ocular irritation with the emulsifiable
concentrate formulation of emamectin benzoate.
EXAMPLE 9
Neat Emamectin Benzoate - Acute Ocular Irritation Study in Rabbits
The purpose of this study was to determine the ocular
irritation potential of neat emamectin benzoate when instilled once in the
eye of a rabbit.
Three male and three female albino rabbits (New Zealand
White) 25 to 26 weeks of age and weighing 3.23 to 3.66 kg was used in
this study. The test compound was ground into a fine powder and a
volume of 0.1 cc (approximately 28 mg) was placed in the conjunctival
sac of the left eye of each rabbit. Immediately after administration, the
eyelids of the treated eye were held together for one second to prevent
30. loss of material and released. The right eye was used as an untreated
control.
Ocular examinations were made recorded at 1, 24, 48 and
72 hours post-instillation in all rabbits and were scored by the Draize
Method (J. Pharmacol. Exp. Theran. $2:377-390 (1944)). Because of
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severe ocular reactions, three rabbits were euthanized following
the 72-
hour reading. Scores were recorded for the three remaining
rabbits
once daily through 14 days post-instillation except on weekends.
The test compound neat emamectin benzoate was found to
S be severely irritating to the rabbit eye. At one hour the
eyes of four
rabbits had congestion of the iris. All of the eyes had corneal
anesthesia
and conjunctival irritation. The latter consisted of moderate
redness,
slight or moderate chemosis and severe colorless discharge.
Subsequently, the severity of the signs generally increased.
At 24 hours
an additional rabbit had congestion of the iris. Another
animal had very
slight corneal opacity covering less than 1/4 of the corneal
surface. No
other opacities were seen. In the three rabbits that were
euthanized
early, chemosis became severe and interfered with reading
some of the
other signs. Redness, where seen, also became severe and
the discharge
15. consisted mostly of white mucoid material. One eye did not
react to
light (no blink response). The eyes of these three rabbits
mostly
remained unchanged through 72 hours. In the eyes of the three
remaining rabbits at 24 hours, corneal anesthesia was still
present,
redness was severe, chemosis was never more than moderate
and in two
of the eyes white mucoid material appeared in the discharge.
The eye of
the rabbit with no white mucoid discharge appeared normal
in 48 hours
and for the remainder of the 14-day observation period. Signs
in the
other two eyes remained generally unchanged at 48 hours,
but
subsequently diminished. Corneal anesthesia lasted through
72 hours.
On Days 8, 9, and 10, one of the eyes had an unusual red
spot that
appeared to be in the iris. However, localization was difficult
due to
positioning of the nictitating membrane. The eye appeared
normal by
Day 13. The remaining rabbit's eye appeared normal on Days
13 and
14 except for some slight white mucoid discharge. Some body
weight
loss (less than 7%) occurred in the rabbits euthanized early,
otherwise
body weight gain appeared unaffected by drug administration.
In conclusion, neat emamectin benzoate itself is a severe,
irreversible eye irritant.
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TAB LE I
A Toxicity Criteria and Categories
FIFRA Categc~riec
Acute
Hazard Study Category Category Category Category
I III IV
Signal Word "DANGER' "WAR1VING" "CAUTION" "CAUTION"
Rat Oral 0 - 50 >50 - S00 >500 - 5000 >5000
LD50 (mg~g)
Rabbit Dermal0 - 200 >200 - 2,000>2,000 - > 20,000
LD50 (mg~g) 20,000
Rat Inhalation0 - 0.2 >0.2 - 2 >2 - 20 >20
LD50 (mg/L)
Rabbit OcularCorrosive, Corneal No corneal No irritation
Irritation corneal opacity opacity;
opacity reversible irritation
not
reversible within 7 reversible
within 7 days; within 7
days irritation days
persisting
for
7 days
Rabbit DermalCorrosive Severe Moderate Mild or
Irritation irritation irritation slight
at at
72 hours 72 hours irritation
at
72 hours
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It is noted that rabbit ocular irritation studies are required
for assignment of the appropriate level of precautionary labeling
statements which must be made on the product label. For purposes of
information, Table I lists the types of hazard studies, the appropriate
signal words on the product label and the FIFRA categories (see Federal
Insecticide, Fungicide, and Rodenticide Act (Labeling Requirements For
Pesticides and Devices, Fed. Rep., pp. 37960-37995, Sept. 26, 1984); 40
C.F.R. ~ 156.10).
Under FIFRA Guidelines, the signal word for the
precautionary labeling statements on the product label is determined by
the most severe result of any of the acute hazard studies conducted. A
product in the highest category (Category I, "DANGER") presents
increased hazards to the user and in certain cases must be regulated by
the EPA as a "Restricted Use Pesticide."
Because ocular irritation studies on the emulsifiable
concentrate formulation of 2% emamectin benzoate showed evidence of
ocular irritation persisting after 21 days, the formulation is considered a
severe irritant and is placed in Category I ("DANGER"). Similarly, the
active ingredient itself, neat emamectin benzoate, was also a severe
irntant in ocular irritation studies. Surprisingly, however, ocular
irritation studies on the soluble granule formulation of 5% emamectin
benzoate showed that ocular irritation had cleared within 7 days and that
this formulation was only a mild irntant. Accordingly, the soluble
granule formulation of emamectin benzoate would be placed in
Category III ("CAUTION"). Such results are intended to be
representative of the intrinsic advantages which may be afforded by the
present invention.
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While the invention has been described and illustrated with
reference to certain particular embodiments thereof, those skilled in the
art will appreciate that various adaptations, changes, modifications,
substitutions, deletions, or additions of procedures and protocols may be
S made without departing from the spirit and scope of the invention. For
example, effective concentrations other than the particular
concentrations as set forth herein above may be applicable as a
consequence of variations in the application of the formulations of this
invention. Likewise, the specific biological responses observed may
vary according to and depending upon the particular active compound
selected or whether there are present other pharmaceutical carriers, as
well as the specific type of formulation and mode of administration
employed, and such expected variations or differences in the results are
contemplated in accordance with the objects and practices of the present
invention. It is intended, therefore, that the invention be defined by the
scope of the claims which follow and that such claims be interpreted as
broadly as is reasonable.
s
L
