Development of Spinosad and Attributes of A New Class of Insect Control Products

Gary D. Thompson, Scott H. Hutchins and Thomas C. Sparks
Dow AgroSciences LLC
9330 Zionsville Rd., Indianapolis, IN, 46268, USA

Introduction

The discovery and characterization of the soil actinomycete Saccharopolyspora spinosa represented a novel opportunity to develop a portfolio of progressive insect management tools (Thompson et al.1997, Sparks et al. 1998). Indeed, the discovery and subsequent development of this unique organism (Figure 1) has provided the world with an entirely new class of products - with Tracer* Naturalyte* Insect Control being the first to be commercialized.

The name is based on the utility of naturally produced metabolites that by definition possess rapid efficacy competitive with the best synthetic standards and safety profiles similar to benign biologicals. Spinosad is a mixture of the two most active naturally occurring metabolites (spinosyns A and D) produced by S. spinosa (Figure 2, Kirst et al., 1992).

Structurally, these compounds are macrolides and contain a unique tetracyclic ring system to which two different sugars are attached. A unique mode of action coupled with a high degree of activity on targeted pests and low toxicity to non-target organisms (including many beneficial arthropods) make spinosad an excellent new tool for management of insect pests. Dow AgroSciences is aggressively pursuing additional spinosyns and other metabolites from natural organisms as future entries to the Naturalyte class. This paper provides an overview of the physical and biological properties of spinosad. When these properties are considered, in total, it is clear that Naturalyte does not conform to the previous characteristics of either chemical or biological insecticides.

Physical Properties and Environmental Fate

Spinosad is a secondary metabolite from the aerobic fermentation of S. spinosa on nutrient media. Following fermentation, spinosad is extracted and processed to form a highly concentrated conventional aqueous suspension for ease of use and distribution. Spinosad is a light gray to white crystalline solid with an earthy odor similar to slightly stale water. It has a pH of 7.74, is stable to metal and metal ions for 28 days, and has a shelf life of three years as formulated material. It is considered nonvolatile with vapor pressures around 10-10 mm Hg. Table 1 summarizes other physical and chemical properties of spinosyns A and D (Anonymous, 1996).

Table 1. Physical and chemical properties of spinosyns A and D.

	Spinosyn A	Spinosyn D
Molecular Weight	731.98	746.00
Empirical Formula	C42H67NO16	C41H65NO16
Melting Point	84 - 99.5°C	161.5 - 170°C
Vapor Pressure	2.4 x 10-10	1.6 x 10-10
Solubility in Water at pH 5.0	290 ppm	29 ppm
Solubility in Water at pH 7.0	235 ppm	0.332 ppm
Solubility in Water at pH 9.0	16 ppm	0.053 ppm
Octanol/Water Partition Coefficient at pH 5.0	log P = 2.8	log P = 3.2
Octanol/Water Partition Coefficient at pH 7.0	log P = 4.0	log P = 4.5
Octanol/Water Partition Coefficient at pH 9.0	log P = 5.2	log P = 5.2

The degradation of spinosad in the environment occurs through a combination of routes, primarily photodegradation and microbial degradation to its natural components of carbon, hydrogen, oxygen and nitrogen. The half-life of spinosad degraded by soil photolysis is 9-10 days. It is less than 1 day for aqueous photolysis and leaf surface photolysis results in a half-life of 1.6 to 16 days. The half-life of spinosad degraded by aerobic soil metabolism in the absence of light is 9-17 days. Hydrolysis does not contribute significantly to degradation as spinosad is relatively stable in water at a pH of 5-7 and has a half-life of at least 200 days at a pH of 9. The leaching potential of spinosad is very low due to a moderate Kd (5-323), low to moderate water solubility and short residual in the environment. Thus, it does not pose a threat to groundwater when used properly and no buffer zones are required by the United States Environmental Protection Agency (Saunders and Bret, 1997).

Nontarget Toxicology

Table 2 summarizes acute mammalian, aquatic and avian toxicology (Anonymous, 1996). Spinosad is relatively low in toxicity to mammals and birds and is only slightly toxic to fish.

Table 2. Acute mammalian, aquatic and avian toxicity of spinosad.

Species	Test	Result	EPA Category
Mammalian
Rat (male/female)	Acute oral LD50	3738/>5000 mg/kg	Caution (IV)
Mouse	Acute oral LD50	>5000 mg/kg	Caution (IV)
Rabbit	Acute dermal LD50	>5000 mg/kg	Caution (IV)
Rat	Acute inhalation LC50	>5 mg/kg	Caution (IV)
Rabbit	Eye irritation	slight, clearing in 2 days	Caution (IV)
Rabbit	Skin irritation	no irritation	Caution (IV)
Guinea pig	Dermal sensitization	no sensitization	N. A.
Aquatic
Daphnia	48 hr acute LC50	92.7 mg/L	Slightly toxic
Grass shrimp	96 hr acute LC50	>9.8 mg/L	Slightly toxic
Carp	96 hr acute LC50	5.0 mg/L	Moderately toxic
Bluegill	96 hr acute LC50	5.9 mg/L	Moderately toxic
Sheepshead minnow	96 hr acute LC50	7.9 mg/L	Moderately toxic
Rainbow trout	96 hr acute LC50	30.0 mg/L	Slightly toxic
Avian
Bobwhite quail	Acute oral LD50	>2,000 mg/kg	Practically non-toxic
Mallard duck	Acute oral LD50	>2,000 mg/kg	Practically non-toxic
Bobwhite quail	5 day dietary LC50	>5,000 mg/kg	Practically non-toxic
Mallard duck	5 day dietary LC50	>5,000 mg/kg	Practically non-toxic

In addition, chronic toxicology tests in mammals have shown that spinosad is not carcinogenic, teratogenic, mutagenic or neurotoxic. Spinosad exhibits wide margins of safety to many beneficial insects and related organisms (Schoonover and Larson, 1995). Spinosad has relatively low activity against predaceous beetles, sucking insects, lacewings and mites. Table 3 demonstrates the reduced activity of spinosad on some.

Table 3. Toxicity of spinosad and cypermethrin to selected beneficial organisms.

Beneficial species	Spinosad LC50	Cypermethrin LC50
Honeybee, Apis mellifera	11.5 ppm	1.2 ppm
Whitefly parasitoid, Encarsia formosa	29.1 ppm	1.9 ppm
Minute pirate bug, Orius insidiosus	200 ppm	0.2 ppm
Lady beetle, Hippodamia convergens	>200 ppm	0.2 ppm
Lacewing, Chrysopa rufilabris	>200 ppm	<0.2 ppm
Predaceous mite, Phytoseiulus persimilis	>200 ppm	<0.2 ppm

 

Against lepidoptera targets the activity values for spinosad and cypermethrin generally overlap. It is extremely exciting to have this level of activity coupled with large margins of selectivity, for predacious insects, which are an important component of IPM programs. The topical acute activity of spinosad against honeybees is less than 1 µg per bee which places spinosad in the highly toxic to bees category of the EPA. However, once residues have dried completely, toxicity of foraging bees is considered negligible (Mayer and Lunden, 1998). There are minimal safety precautions and preharvest and reentry intervals for this reduced risk product.

Physiological Properties and Resistance Management

Spinosad demonstrates rapid contact and ingestion activity in insects which is unusual for a biological product. The mode of action of spinosad is characterized by excitation of the insect nervous system, leading to involuntary muscle contractions, prostration with tremors, and paralysis. These effects are consistent with the activation of nicotinic acetylcholine receptors by a mechanism that is clearly novel and unique among known insect control products. Spinosad also has effects on GABA receptor function that may contribute further to its insect activity. This mode of action is unique. Imidacloprid and other nicotinic receptor-based insecticides act at a different site than spinosad. Avermectin, although a natural product and a macrocyclic lactone, also acts at a different site than spinosad. No other class of products affects the insect nervous system with the same mode of action and no cross resistance to spinosad has been demonstrated (Salgado et al., 1997; Salgado, 1998; Salgado et al. 1998).

The unique mode of action, lack of cross resistance, selectivity that leaves predacious insects, and moderate residual profile result in a low probability of resistance development. This is particularly true if Naturalyte insect control products are brought into rotations with current and other new insect control products. However, the adaptability of insects has been proven over and over. Therefore, Dow AgroSciences is promoting resistance management of spinosad through labeling, education and marketing efforts in support of good stewardship and IPM practices but not because of any underlying concerns that would affect spinosad more than any other active ingredient.

In the field, spinosad activity is characterized by cessation of feeding and paralysis of exposed insects within minutes. However, these insects may remain on the plant for up to two days. For this reason, growers and scouts should wait a minimum of two to three days to evaluate control.

Foliar applications of spinosad are not highly systemic in plants although some translaminar movement in leaf tissue has been demonstrated. The addition of a penetrating surfactant increases translaminar movement and activity on pests that mine leaves (Larson, 1997). No phytotoxicity has been demonstrated with this product.

Spectrum of Activity and Labeling Efforts

Spinosad has been tested extensively on a global basis since 1990 (Carson and Trumble, 1997; Fouche et al., 1998; Kerns, 1996; Linduska et al., 1998; McLeod, 1998; Palumbo, 1997; Riley, 1998; Schuster, 1997, Stansly and Connor, 1998; Walgenbach and Palmer, 1997; Webb, 1998). Table 4 lists several of the insect pests against which spinosad is being labeled.

Table 4. Examples of Insect pests controlled by spinosad on current or future labels.

Common name	Scientific name	gm/ha
European corn borer	Ostrinia nubilalis	25 -50
Tomato fruitworm	Helicoverpa zea	40 - 100
Cabbage Looper	Trichoplusia ni	50 - 100
Diamondback moth	Plutella xylostella	15 -50
Southern armyworm	Spodoptera eridania	50 - 100
Leafminers	Liriomyza spp.	70 - 150
Melon thrips	Thrips palmi	70 - 100
Fall armyworm	Spodoptera frugiperda	25 - 100
Beet armyworm	Spodoptera exigua	50 - 100
Colorado potato beetle	Leptinotarsa decemlineata	25 - 80
Imported cabbageworm	Pieris rapae	50 - 100
Tomato pinworm	Keiferia lycopersicella	50 - 100
Grape Berry Moth	Lobesia lobina	25 - 50
Cotton Leafworm	Alabama argillacea	25-50
American bollworm	Heliothis armigera	50 -100
Tomato hornworm	Manduca quinquemaculata	40 - 100
Western flower thrips	Frankliniella occidentalis	70 - 100

In general, spinosad provides effective control of pests in the insect orders Lepidoptera, Diptera, and Thysanoptera. It is also effective for some species Coleoptera and Orthoptera that consume large amounts of foliage. Spinosad is generally not effective for control of most sucking insects, and mites but some use patterns are being investigated.

Product Labeling

Spinosad is currently labeled in the U.S. on the brassica vegetable group (broccoli, Chinese broccoli, Brussels sprouts, cabbage, Chinese cabbage - bok choy and napa, cauliflower, cavalo, collards, kale, kohlrabi, mizuna, mustard greens, mustard spinach, Chinese mustard cabbage - gai choy, and rape greens), fruiting vegetable group (eggplant, ground cherry, pepino, pepper, tomatillo, and tomato), leafy vegetable group (including head and leaf lettuce, celery, arugula, chervil, edible chrysanthemum, corn salad, cress, dandelion, dock, endive, fennel, parsley, garden purslane, radicchio, rhubarb, spinach, and Swiss chard), apples, almonds and citrus. Crops for which additional U. S. labeling is being pursued include cucurbits, legumes, sweet corn, potatoes, and strawberries. Table 5 lists the global registration status at the time this paper was

Table 5. Current and Pending Naturalyte* Insect Control Registrations

County	Trademarks	Crops	First Registration**
Argentina	Tracer*, Success*	Cotton, Tomato	1998
Australia	Tracer	Cotton	1998
	Laser	Brassica	1999
	Success	Vegetables	2000
Benelux	-	Pome fruit, Vegs.	2002
Bolivia	Tracer	Cotton/Soybeans	1998
Brazil	Tracer, Credence*	Tomato, Corn	1998
		Soybean, Cotton,	1999
Canada	Success	Apples, Potatoes	1999
		Stone Fruit	2000
Chile	Success	Nectarines, Tomato	1998
China	Success Tracer	Vegetable Cotton	1998 1998
Columbia	Tracer 120SC	Flowers, Cotton, Begs.	1998
Cyprus	Tracer 48 SC	Vegetables, Potatoes	1998
Ecuador	Tracer	Corn, Vegetables	1998
France	-	Vines	2001
		Ornamentals	2001
Germany	-	Flybait, Ornamentals	2000
Greece	-	Vines, Pome fruit, Vegs.	2001
Guatemala	Tracer	Cotton Cucurbits, Brassica	1998 2000
Honduras	Tracer	Cotton	1998
Indonesia	Success	Vegetable	1998
Israel	_	Vines, Vegetables	1998
Italy	_	Ornamentals, Vegs.	2001
		Grapes, Pome fruit	2001
Japan	Spinoace*, Naturalyte Caribstar*	Turf Brassica Peach, Pear	1999 1999 2001
Korea	Boomerang	Cucumber	1997
		Cabbage, Rose	1998
Lebanon	-	Vegetable, Potatoes	1998
Malaysia	Success 25SC	Vegetables	1998
Mexico	Tracer, Success	Cotton	1997
		Fruiting Vegetables	1998
		Brassica & Leafy Veg.	1998
New Zealand	Success	Vegetables	1998
Philippines	Success 25 SC	Vegetable	1998
Spain	-	Vines	2001
		Pepper, Tomatoes	2001
Taiwan	Success	Vegetable	1999
Thailand	Success	Vegetable	1998
Tunisia		Vegetables, Citrus	1998
Turkey	-	Grapes	1998
U.S.	Tracer, Conserve* SpinTor*, Success	Cotton Turf & Ornamentals	1997 1997
		Brassica Crops	1998
		Apple, Tomato	1998
		Tobacco	1998
		Leafy Vegetables	1998
		Citrus, Almonds	1998
		Cucurbits, Legumes	1998
		Stone Fruit, Potatoes	1999
		Cereal Grains	1999
		Minor Crops	1999+
UAE	_	Vegetable	1998
Uruguay	Success	Citrus	1998
Venezuela	Tracer	Corn	1998

*Trademark of Dow AgroSciences LLC

** Registration Dates are estimates

The favorable mammalian and environmental profile, insect selectivity and IPM fit, unique mode of action and resistance management properties, and outstanding efficacy are resulting in rapid registrations and adoption by growers around the world documenting the value to agriculture.

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