Spinosad: A Green Natural Product for Insect Control - American

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Spinosad: A Green Natural Product for Insect Control Downloaded by UNIV MASSACHUSETTS AMHERST on September 3, 2012 | http://pubs.acs.org Publication Date: July 19, 2002 | doi: 10.1021/bk-2002-0823.ch005

Gary D. Thompson and Tom C . Sparks Dow AgroSciences, 9330 Zionsville Road, Indianapolis, IN 46268

Spinosad is manufactured using a new and unique marcolide chemistry produced by fermentation of a naturally occurring soil microorganism. Spinosad's discovery is the direct result of long-standing natural product research programs at Dow Chemical, Eli Lilly and Company, and Dow AgroSciences, all with the goal of discovering greener solutions for agriculture that incorporate high levels of efficacy coupled with benign environmental effects. However, an extraordinary development and manufacturing effort was required to meet the volume and cost hurdles associated with agricultural products. The first product containing spinosad received expedited review by the U.S. Environmental Protection Agency and was granted registration as a "reduced risk" insect control product for cotton in early 1997. Production agriculture is finding that spinosad is a highly effective tool for producing more food and fiber on fewer acres while also protecting the environment. The use of spinosad establishes a new standard for low environmental and human risk and offers a new tool for integrated pest management (IPM) and insect resistance management. Spinosad does not leach, bioaccumulate, volatilize, or persist in the environment. In hundreds of field trials conducted over several years, spinosad left 70 to 90% of beneficial insects unharmed. The insect selectivity, coupled with a novel, rapid mode-of-action on many problem insects, allows a "scout and treat only as

© 2002 American Chemical Society

In Advancing Sustainability through Green Chemistry and Engineering; Lankey, R., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2002.

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Downloaded by UNIV MASSACHUSETTS AMHERST on September 3, 2012 | http://pubs.acs.org Publication Date: July 19, 2002 | doi: 10.1021/bk-2002-0823.ch005

needed" approach that results in a powerful I P M tool. Although natural products are not necessarily greener than conventional pesticides and their development can be just as long and costly as traditional synthetic organic insect control agents, spinosad is an explicit example of how natural product discovery based programs can provide greener solutions for agricultural needs.

Introduction The discovery, characterization and development of spinosad required over twelve years, but the vision of an insect control product that was safe, effective, and based on natural products spanned forty years and two companies. Dow Chemical and E l i Lilly and Company merged their plant science divisions in 1989 to form DowElanco. DowElanco evolved into Dow AgroSciences when Dow Chemical assumed full ownership in 1997. The soil actinomycete Saccharopolyspora spinosa and its metabolite spinosad were discovered at E l i Lilly and Company prior to the merger, but there was a parallel natural products effort at Dow. The discovery resulted from a dedicated program with clear product concepts that set hurdle rates for selectivity, cost and customer needs for efficacy on insect targets. Interestingly, the soil sample that produced S. spinosa was collected by one of the program's scientists vacationing in the Caribbean, not from professional collections, which is the origin of most samples.

From Discovery to Market The development of spinosad required a tremendous effort and commitment to overcome a host of technical, perceptive, and developmental issues. Hundreds of employees and scores of teams were involved over a twelve-year time period. As shown in Figure 1, these teams at Dow included Discovery Research, where entomologists designed the novel assays that allowed the discovery and characterization of the initial activity, and natural products chemists who, in a close working relationship with the entomologists, worked to identify the molecule and its complex stereochemical structure. Natural Products Research provided the screening samples, isolation and identification efforts, and initial production. Strain development was an enormous long-term effort, because, not uncommonly, initial titers were very low. Technology


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Timeline (Years) Commercial

Discovery Biological Activity

Market Research -


Product Goals

Natural Products Goals - Sourcing - Production

Preliminary

Species Profile

Toxicology

Mode of Action

Technology Development

Formulation Sciences

Field Performance

Process Research Global Health, Environmental Safety & Regulatory

Scale Up Purification

Global Operations Manufacturing Supply Chain Full toxicology

Characterization Label Development Product Champion

Non-target Effects Environmental Fate

Commercial Positioning

EPA Submission

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First Commercial Launch Figure I. An overview of the organizational complexities and teamwork required to discover and develop spinosad.



64 Development defined the field performance and use patterns and transferred knowledge to the commercial divisions; they were also the primary product champions and were responsible for justifying continued investment. Formulation Science and Technology developed aqueous-based formulations that maintained the environmental benefits and optimized performance. Process Research did not have to develop chemical reactions, because these take place within the microorganism, but this group had much to do with the manufacturing scale up and the extraction process. The Global Operations division is a collection of smaller departments that detail the important tasks around manufacturing, packaging, supply chain, and quality assurance that are required to get the product to market. Global Health, Environmental Safety and Regulatory coordinated the efforts in toxicology, environmental fate, risk modeling, and regulatory issues. Commercial developed the business and marketing plans, transferred knowledge to the end user, and built awareness and value for green properties, but this group was also involved early on with product goal inputs. Developing crop protection products is one of the most regulated and complicated product development endeavors. Developing spinosad was even more challenging due to the uniqueness of the chemistry and complexities in manufacturing, and development would have not been possible without a true team effort focused on a common vision. As many of the older insecticides are unable to meet increasing safety standards or to remain economically viable, it is essential that we continue to develop and preserve as many crop protection tools as possible, because high production agriculture is extremely important in maintaining the quality of our environment by reducing land requirements for food and fiber production (/).

The Compound Saccharoployspora spinosa produces a family of novel, secondary metabolites known as the spinosyns. Spinosad (Figure 2) is a mixture of two of the most abundant and lepidopteran-active members of this family, spinosyns A and D (2). Structurally, these compounds are macrolides and contain a unique tetracyclic ring system to which two different sugars (forosamine and tri-Omethylrhamnose) 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.



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R

Molecular Weight: spinosyn A = 731.98, spinosyn D = 746.00 Empirical Formula: spinosyn A = C ^ H ^ N J O , spinosyn D = C H 7 N 0 o 4 2

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1

Figure 2. Spinosad structure.

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 and a shelf life of three years as formulated material, and it is stable and nonreactive. With vapor pressures around 10" mm Hg, spinosad is considered nonvolatile as well. The degradation of spinosad in the environment occurs through a combination of routes, primarily photodegradation and microbial degradation, ultimately to C 0 , H 0 , and nitrogen oxides. The half-life of spinosad degraded by soil photolysis is 9 to 10 days. The half-life is less than one 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 to 17 days. Hydrolysis does not contribute significantly to degradation, as spinosad is relatively stable in water at a pH of 5 to 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 K (5 to 323), low to moderate water solubility, and short residual in the environment. Thus, it does not pose a threat to groundwater (3-5). 10

2

2

d


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Nontarget Toxicology Spinosad is relatively low in toxicity to mammals and birds and is only slightly to moderately toxic to aquatic organisms (Table I). 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 (6). Spinosad has relatively low activity against predaceous beetles, sucking insects, lacewings and mites (Table II). One of the unique characteristics of spinosad is its high level of efficacy against target pest insects coupled with large margins of selectivity for beneficial insect predators, adding an important biological control component to integrated pest management (IPM) programs. Although the topical acute activity of spinosad against honeybees (

Spinosad: A Green Natural Product for Insect Control - American

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