Recent Developments in the Registration and Usage of Botanical

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Chapter 8

Recent Developments in the Registration and Usage of Botanical Pesticides in California Michael L. Grieneisen*,1 and Murray B. Isman2 1Department

of Land, Air & Water Resources, 1 Shields Ave., University of California, Davis, California 95616, United States 2Faculty of Land and Food Systems, 2357 Main Mall, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z4 *E-mail: [email protected]

California Department of Pesticide Regulation’s Pesticide Use Report (PUR) and Pesticide Label databases provide a unique opportunity to analyze trends in the plant-derived (botanical) pesticide industry in California based on product registration and commercial usage. While the role of botanical pesticides in commercial pest control remain minor, the number of registered botanical pesticide products (indicating registrants’ confidence in their marketability) and the mass of botanicals used commercially have seen marked increases in recent years. Registered product counts (as total number of products by 7/7/2017) are high and usage remains steady for the classical botanicals pyrethrins (4,862 products, ~250,000 kg products/yr) and strychnine (617 products, ~50,000 kg products/yr). By 2015, registration and usage had grown for some newer botanicals, including azadirachtin (65 products, ~150,000 kg/yr) and limonene (145 products, ~40,000 kg/yr). Pesticidal activity of essential oils often require multiple components, and the 37 different essential oils registered for use in California have achieved only marginal implementation according to PUR usage. As in the pyrethrin/pyrethroid story that began in the 1960s, natural products continue to serve as leads for new high-usage synthetics. For example, a unique intracellular calcium receptor class, discovered using the natural alkaloid ryanodine, has been used to develop the synthetic ryanoid insecticides chlorantraniliprole, cyantraniliprole and © 2018 American Chemical Society

ang et al.; Managing and Analyzing Pesticide Use Data for Pest Management, Environmental Monitoring, Public Health, and Public Pol ACS Symposium Series; American Chemical Society: Washington, DC, 2018.

flubendiamide. Entering the California market in 2009, ryanoids achieved ~350,000 kg of product usage in 2015. These trends underscore the importance of continuing the search for plant natural products with potent insecticidal activities, as they may lead to powerful synthetics with new modes of action in order to mitigate resistance to existing high-use pesticides.

Introduction Plants as Potential Sources of Pesticides (particularly insecticides) Plants have evolved chemical defenses to deter herbivores, including many insects now considered pests. These chemicals may be deterrents that are not particularly toxic but simply deter feeding or oviposition, or they may have specific, demonstrable toxicity. Mechanisms-of-action often involve neutotransmitter receptors (1) though other mechanisms are known, such as developmental disruption by juvabione and phytoecdysteroids, which were discovered over 50 years ago (2–5). Botanical pesticides are plant-derived products that are toxic to pests, and used to control them. Such products have been used for centuries (1), and a previous volume in this Series, Vol. 387, was entitled “Insecticides of Plant Origin” (6). A quick chronology of the modern history of botanical insecticides shows a progression from broad-spectrum toxicants, such as nicotine, to phytochemicals with more selective modes of action, such as azadirachtin and limonene (7). Botanical insecticide research efforts have grown dramatically in recent years, to about 1,300 published articles per year (Figure 1). However, the adoption of botanical pesticide products in commercial usage has been sluggish, though quantitative data on the registration and usage patterns of specific botanical pesticide products are limited (8).

Definition of Botanical Pesticides Various pesticide classification schemes appear to use different definitions of the term “botanical pesticides”. Some tend to lump all plant-derived pesticide components, including shredded paper and bran (http://www.pesticideinfo.org/ Search_Chemicals.jsp#ChemCategory) into this category, and plant-derived oils can kill insects through physical (smothering) rather than toxicological mechanisms. However, most researchers in this field define “botanical pesticides” more narrowly, reserving the term for those plant-derived substances that have physiologically-based antifeedant, repellent or toxicological activities toward pests (usually agricultural insect pests) (8). 150


Figure 1. Number of articles in the CAB Abstracts database (CABI, Wallingford, England) each year from 1980-2015. Counts for query: (antifeed* or deterr* or repell* or acaricid* or insecticid* or larvicid*) and (precocene* or neem* or azadiracht* or margosan* or (plant and extract*) or ‘essential oil*’ or ‘botanical insecticid*’ or ‘plant oil*’ or ‘vegetable oil*’ or derris or ‘insecticid* plant*’ or ‘leaf extract*’ or limonoid* or triterpen* or diterpen* or sesquiterpen* or saponin* or terpenoid* or flavonoid*). (Adapted/modified with permission from reference (7). Copyright 2014 Elsevier.) (see color insert) Widespread Lack of Chemical Characterization of Active Fractions Plant-derived pesticides face challenges unlike those associated with synthetic chemical pesticides. Several factors contribute to inconsistency in the efficacy of extracts of a given plant species, which can cast doubt on their claims of efficacy. For example, the concentrations of substances with clearly demonstrated pesticidal activities can vary widely across tissues, developmental stages or varieties for a given plant species. In addition, the active secondary metabolites may be stimulated by various biotic and abiotic factors, such as herbivore activity (9, 10). Thus, a plant grown without herbivore pressure, for example, may not produce the desired active compounds. Our previous analysis of the botanical pesticide literature found that reports on the biological activities of plant extracts rarely included chemical characterization of the active agents (7), and numerous studies have reported pesticide contamination of natural plant extracts used as organic pesticides (e.g., (11)) or medicinal herbs (12). For these reasons, it is crucial for studies on pesticidal activities of plant extracts to include chemical characterization and quantification of the active compounds, in addition to as much information as possible about the plant source. Activity of Crude Plant Extracts May Require Multiple Synergistic Components Synthetic chemical pesticide usage involves the application of a specific pesticide product at a rate that imparts acceptable levels of efficacy based on 151


previous field trials using a similar chemical composition. In many cases, the activity of pure pesticide active ingredients (AI) can be enhanced by the synergistic activity of other compounds, such as the enhancement of pyrethroid activity by piperonyl butoxide (13). Crude plant extracts, such as essential oils, typically consist of dozens of different compounds. In some cases the efficacy of individual components can be enhanced synergistically in the presence of other components (14) or affected by different ratios of individual components (15). The interactions between components on biological activity can complicate the chemical characterization of active agents from crude plant extracts using standard fractionation and bioassay.

Botanical Pesticide Registration and Usage in California: Historical Development and Current Status We have used California’s uniquely detailed data on commercial pesticide usage, and product registration, to analyze the current status and trends in botanical pesticides in California. While the California commercial agricultural sector is substantial, grossing ~$45 billion in 2016 (16), it is also the most populous state in the US (over 37 million in 2010 census) with several major urban regions (e,g,, the greater San Francisco, Los Angeles, and San Diego areas). Therefore, the many pesticide uses outside of commercial agriculture that are listed below are also well-represented in this state. Our study uses two main lines of evidence to delineate recent developments in the botanical pesticide industry in California. One line of evidence is the registration of botanical AIs and products, documented in the Department of Pesticide Regulation’s “Label Database” (http://www.cdpr.ca.gov/docs/label/ labelque.htm). Trends in product registration reflect the registrants’ confidence in the market potential of those products, given the expense and effort required to register them. The second line of evidence is actual product usage in the Pesticide Use Report (PUR) database (http://www.cdpr.ca.gov/docs/pur/purmain.htm, accessed on 30 Oct 2017). PUR usage data reflect the collective confidence of primarily commercial pesticide users (or their clients) that a product will provide an economic benefit by reducing pest pressure.

Issues Regarding Pesticide Usage Reported in PUR PUR records a broad spectrum of commercial pesticide uses in California, but not household or personal pesticide uses by the public. While the control of crop pests, pathogens and weeds are a major source of commercial usage, pesticides are also used in many other contexts (Table 1), some of which are of particular interest as potential botanical pesticide markets. 152


Table 1. Broad categories of pesticide usage and PUR reporting status PUR reported (when applied commercially): Agricultural field crops—control insects, mites, weeds, nematodes, microbes, vertebrate pests Post-harvest—Storage pests (both invertebrate and vertebrate), decomposition Greenhouse products Non-crop agricultural uses—Aquaculture, livestock, dairy, apiculture Municipal uses—Vector control, rights-of-way (roadside, utility lines, etc.) Institutional uses—Schools, hospitals, food service Structural & household pest control (when applied by licensed applicators) Other commercial uses (e.g., golf course turf protection) PUR reporting generally not required: Applications made by the consumer—Structural & household pest control, home gardens, pet treatments, personal hygiene products and mosquito repellents, household swimming pool products, etc. Products which contain pesticides as sold—Pesticide treated seeds (even when used in commercial agriculture), silver nanoparticle-impregnated clothing, etc. Products which invoke FIFRA 25b exempt status when all ingredients appear on EPA’s “minimal risk” chemical lists.

Issues Regarding the Registration of AIs and Individual Pesticide Products In the US, separate registration processes exist for active ingredients (AI) and individual pesticide products. For both, initial registration begins at the US Environmental Protection Agency (USEPA). However, California has many agricultural uses that are unique in the US. This, together with the intensity of agriculture and environmental issues in certain areas, has necessitated pesticide usage regulations that are sometimes more stringent than USEPA guidelines. Thus, any AI or product registered for sale and use in California must undergo a separate registration process with the California Department of Pesticide Regulation (DPR). At both USEPA and DPR levels, the legally allowable specific uses of the product (such as individual crops) and conditions under which usage may be restricted (such as no use near surface water sources) are clearly defined and stated on approved product labels. Periodically, both AIs and individual products undergo re-review, and their allowable uses may change, or their use may be discontinued altogether based on newly available information. Without going into the details of the registration processes, the registration of a single AI or product is an expensive undertaking. Therefore, registrants only invest in the registration, and continuing re-registration, of AIs and products that they believe have sufficient market potential. That said, over 60,000 registered pesticide products are listed in the DPR Product/Label database 153


(http://www.cdpr.ca.gov/docs/label/labelque.htm), ~14,000 of them were active as of 18 Oct 2017 and about 1,400 new products are added each year. As discussed below, thousands of these products have contained botanical ingredients as AIs and the registration activity for botanical products can shed light on the overall trends in the development of the botanical pesticide industry. The major pesticide legislation at the US federal level is the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA). FIFRA guidelines include Section 25b, which exempts so-called “minimum risk” pesticide products from any registration requirements. If all ingredients in a product are on minimum risk chemical lists maintained by USEPA (https://www.epa.gov/minimumrisk-pesticides), then it can legally be identified as “FIFRA 25b exempt,” manufactured, sold and used without registration in the US. The use of these products is not reported in PUR. Many botanical pesticide ingredients appear on the the “minimum risk” list, including many plant essential oils which are also widely used in food and cosmetic products. Therefore, these exempt products are a source of underestimation of botanical pesticide usage in California based on PUR-reported figures.

The Registration of New Botanical AIs and Products Continues Newly Registered AIs A few botanical AIs, such as pyrethrins, rotenone and strychnine, have been used as pesticides in the US for many decades. Each year about 15-30 new AIs are registered in California. Eight new botanical AIs, including six essential oils, have been registered since 2010 (Table 2). Their uses include both agricultural and non-agricultural control of microbial, insect and vertebrate pests. As mentioned above, the registration of a new AI represents a substantial investment on the part of registrants, and the registration of these botanical AIs indicates that the registrants are confident that the products containing them will sell.

Product Counts for Botanical AIs Among dozens of individual botanical AIs, several have served as the AIs in numerous registered products (Table 3). The botanical AIs registered decades ago are present in the most products: pyrethrins (4,862 products, 503 active), strychnine (617 products, 11 active), rotenone (211 products, 1 active) and oil of citronella (199 products, 20 active). The very large number of pyrethrin products may have resulted from their use in numerous consumer products. Other purified chemicals such as azadirachtin, limonene and thymol, as well as an extract of Capsicum oleoresin, are each present in 65-145 products, with 19-28 active (Table 3). They function either as disinfectants, control agents for insects or vertebrates, or repellents. Six plant essential oils, used mainly in repellents, are present in 12-199 products (2-20 active). 154


Table 2. Botanical AIs registered in California for 2010-2016, and their primary uses. (source: http://www.cdpr.ca.gov/docs/registration/ais/newreg/ ais.htm, accessed 30 Oct 2017) Primary uses

Newly registered botanical AI Chenopodium quinoa saponins

Agricultural bactericide/fungicide

Clove oil

Post-harvest potato sprouting

Corn mint oil

Non-agricultural rodent control

Methyl eugenol

Ag/non-ag fruit fly attractant

Oil of camphor

Non-agricultural rodent control

Tagetes oil

Agricultural insecticide

Thyme oil

Mosquito repellent

Wintergreen oil

Agricultural insecticide

Usage of Botanical Pesticides by AI As Reported in PUR A survey of dozens of botanicals from the DPR list of actively registered AIs (http://www.cdpr.ca.gov/docs/label/actai.htm) revealed that six included usage at >5,000 kg of products per year for at least one year since 2000 (Figure 2). Primary Uses of the Main Botanical AIs in California Individual pesticide application records in the PUR database include information on what the product was applied to, in the “site-code” field. The top botanical products fell into three categories based on whether they were used mainly for structural pest control (primarily termites), agricultural crops, or vertebrate control (mainly rodents). The top three site-codes for each of the top botanical AIs are shown in Table 4. These data show the versatility of botanicals in a variety of pest control settings (see Table 1), and the ability to track the uses of specific AIs (or products) using PUR data. Noteworthy Features of Individual Botanical AIs in Commercial Usage in California Azadirachtin The biological activities ascribed to various neem tree (Azadirachta indica) extracts are numerous and varied, including pest and pathogen mortality, behavioral effects in insects, and a wide range of pharmacological effects in humans and other organisms (17). Although its pesticidal properties had been studied for many years in India, beginning in the 1980s a great deal of research in Europe (and elsewhere) focused on the potential of various neem tree extracts, and in particular the chemical compound azadirachtin from neem seeds, for use as pesticides (18, 19). 155


Table 3. Total and active number of registered products for key botanical AIs in California. # products Active ingredient

All

Active

Main product uses

Azadirachtin

65

28

Insect control

Capsicum oleoresin

82

19

Repellents (Vertebrate)

Chenopodium ambrosioides

4

1

Insect control

Limonene

145

23

Repellents, Structural Pest Control

Pyrethrins

4862

503

Insect control

Rotenone

211

1

Vertebrate control

Strychnine

617

11

Vertebrate control

Thymol

71

28

Disinfectants

Crude essential oils

All

Active

Main product uses

Eucalyptus oil

25

8

Repellents

Oil of cedarwood

38

10

Repellents

Oil of citronella

199

20

Repellents

Oil of lemongrass

41

2

Repellents

Oil of peppermint

20

6

Repellents

Rosemary oil

12

6

Repellents

156


Figure 2. Pesticide Use Report (PUR) data for botanical pesticide usage in California by total kg products (A) or kg active ingredients (AI) (B). The differences between the two are due to dramatic differences in percentage of AIs in the most widely used products, ranging from limonene (95% AI) to strychnine, typically only 0.005% AI in the very potent and efficient rodent baits. “Chenopodium amb.” Is short for “Chenopodium ambrosioides near ambrosioides”. (see color insert)

157


Table 4. Top three site-codes for the major botanical active ingredients used in California. Three primary use categories each include two of the main botanical AIs: Structural pest control (pyrethrins and limonene), agricultural crops (azadirachtin and “Chenopodium”), and vertebrate control (strychnine and rotenone). Percentages represent the mass of products for each AI in the PUR-defined usage category. Structural pest control

Agricultural crops

Vertebrate control

Pyrethrins

Azadirachtin

Strychnine

Structural (60%)

Strawberry (15%)

Landscape (35%)

Pub. health (9%)

Lettuce (12%)

Structural (11%)

Strawberry (6%)

Broccoli (7%)

Vertebrate (9%)

Limonene Structural (81%)

“Chenopodium” Grape, wine (25%)

Rotenone Vertebrate (50%)

Carrot (6%)

Leek (13%)

Tomato (15%)

Landscape (2%)

Almond (12%)

Lettuce (10%)

As of 7 Jul 2017, 65 pesticide products registered in California include azadirachtin as an AI, 28 of which were active (Table 5). The dates of product registration and inactivation in the DPR Product/Label Database allow us to analyze the dynamics and trends in azadirachtin product registration (Table 5). While some products remained active for only a few years (e.g., Align-XL), others have maintained active registration for well over a decade (e.g., Aza-Direct) (Table 5). While long-term registration is expected to indicate commercial success, short-term registration may be affected by factors that operate independently of product market success, such as changes in company or brand identity.

158


Table 5. Registration data for a sample of the alphabetical list of azadirachtin products registered in California. “Active” status was determined on 7 Jul 2017. Product name

Date registered

Inactive date or Active status

Years active

Agroneem

30-Aug-00

31-Dec-08

9

Agroneem Plus

30-Nov-05

31-Dec-11

7

Align Biological Insecticide

31-May-95

31-Dec-97

3

Align-XL

22-Jul-96

31-Dec-97

2

Amazin 3% EC

13-May-99

31-Dec-08

10

Amazin Plus 1.2% ME

17-Jun-09

31-Dec-15

7

AMVAC Aza 3% EC

13-May-99

31-Dec-08

10

Aza-Direct

10-Aug-00

Active

18

Azaguard

3-Mar-10

Active

8

Azahar

17-Feb-09

31-Dec-12

4

Azamax

15-Jul-08

Active

10

The registration of new azadirachtin products in California continues. The most recent one as of this writing was The Ecology Works Soluneem (Ecology Works, West Palm Beach, FL) registered on 18 Apr 2017. The number of actively registered azadirachtin products in each year has increased steadily over the past 2 decades, as previously registered products have maintained active status while a few new products have been entering the market each year (Figure 3). The increased number of active products has coincided with the increased usage of azadirachtin-containing pesticides recorded in PUR during this time (Figure 2).

159


Figure 3. Total active and newly registered pesticides in California with azadirachtin as active ingredients for each year from 1993-2017 (through 7 Jul 2017). (see color insert) Another California registered pesticide AI derived from the neem tree is “clarified hydrophobic extract of neem oil” (DPR chem_code: 3979; CAS: 947173-77-5). While this oil is derived from the azadirachtin-containing seeds of the tree, the insecticidal azadirachtin component has been removed from it by ethanol or methanol extraction. Therefore, any insecticidal properties of clarified hydrophobic neem oil are due to its physical smothering effects (like any other vegetable or mineral oil) rather than the inherent insecticidal properties of azadirachtin. As a result, the clarified extract is not considered to be a “botanical insecticide” in this survey.

Limonene Commercially extracted from citrus peels, limonene was granted “Generally Regarded as Safe” (GRAS) status in 1965, and is used as a flavoring and scent ingredient in food, soap and perfume products (20, 21). It has been registered as a pesticide AI in California since the mid-1980s, owing to its toxic effects toward insects and mites (22). Of the 145 limonene-containing products in the DPR Product/Label Database, 23 were active as of 7 Jul 2017, and they are primarily insect repellent and structural pest control products (Tables 3 and 4). The PUR-reported usage of limonene products has increased markedly since the introduction of the product XT-2000 (XT-2000, Inc., Santee, CA) in 2002, and subsequent related products (XT-2000 Orange Oil and XT-2000 Orange Oil Plus). These products now constitute the bulk of reported limonene product usage in PUR (Figure 4). 160


Figure 4. PUR-reported usage of pesticides with limonene as active ingredient in California. The XT-2000 family of structural pest control products (XT-2000, XT-2000 Orange Oil, and XT-2000 Orange Oil Plus) constitute the bulk of commercial limonene usage in CA today. (see color insert)

Chenopodium Ambrosioides near Ambrosioides This plant is native to Central and South America, and is considered an invasive in North America. It has a fragrance described as similar to turpentine or creosote, and has been used as an aromatic, medicinal and culinary herb for centuries (23, 24). Its oil was used as an anthelmintic in humans and livestock in the early 1900s, but that usage was discontinued due to fatal overdoses of the component ascaridole (25). Due to demonstrated insect neurotoxicity activity, “Chenopodium ambrosiodes near ambrosiodes” [sic] was registered as a pesticide AI in California in 2009. Four products under the trade name RequiemR are now registered for use against major pests of fruit, vegetable and oil crops, and have achieved ~40,000 kg of product usage per year (Figure 5). However, the active ingredient in RequiemR products is a mixture of the three main monoterpenoid components of the essential oil of this plant (α- terpinene, p-cymene and limonene), rather than the actual essential oil obtained from the plant; the AI is described on the Safety Data Sheet for the product (Version 2.0 / USA, revision date: 08/07/2015) as “Terpene constituents of extract of Chenopodium ambrosioides near ambrosioides as synthetically manufactured” at 16.75% by weight (26). 161


Figure 5. Usage of active ingredient “Chenopodium ambrosiodes near ambrosiodes” [sic] reported in the Pesticide Use Report database. Usage represents a family of products with brand name RequiemR, first used in California in 2009. (see color insert)

Essential Oils Essential oils are hydrophobic plant extracts that typically have very aromatic sensory properties. They consist mainly of terpenoids, in contrast to the glyceridic (mainly of fatty acid triglycerides) composition of “vegetable oils” (27). An analysis of the published botanical insecticide literature indicates that research on essential oils has increased dramatically in recent years (7). Many different biological properties have been ascribed to various essential oils, which has given rise to a variety of pharmacological and commercial uses, including pest control (28). A total of 37 essential oils have been registered as active ingredients in California (Table 6). Many of these oils have components with specific toxicological activities against insects, though the activity often requires the synergistic activity of multiple components (e.g., (14)). “Margosa” is another name for the neem tree (Azadirachta indica), and many different parts of the tree (e.g., leaves, seeds, bark, roots) may yield hydrophobic extracts. This has led to the ambiguous use of the term “margosa oil” (CAS 8002-65-1) for both essential and glyceridic oil extracts from various parts of this plant.

162


Table 6. Crude plant essential oils registered as pesticide active ingredients in California. Each oil listed is accompanied by its corresponding Department of Pesticide Regulation (DPR) chem-code and CAS number. Essential oil (DPR chem code; CAS no.)

Essential oil (DPR chem code; CAS no.)

Aloe Vera Oil (5454; 977023-61-2)

Oil of Jasmine (5063; 8022-96-6)

Balsam Fir Oil (5969; 8021-28-1)

Oil of Jojoba (3833; 61789-91-1)

Cinnamon Oil (5577; null)

Oil of Lavender (1888; 8000-28-0)

Clove Oil (5018; 8000-34-8)

Oil of Lemon (440; 8008-56-8)

Corn Mint Oil (6032; 68917-18-0)

Oil of Lemon Eucalyptus (5782; 129828-24-6)

Essential Oils (873; 8014-17-3)

Oil of Lemongrass (1009; 5392-40-5)

Eucalyptus Oil (281; 8000-48-4)

Oil of Lemongrass (1136; 8007-02-1)

Fir Needle Oil, Siberian (2570; 8021-29-2)

Oil of Mustard (1153; 57-06-7)

Lavandin Oil (5017; 8022-15-9)

Oil of Orange (441; 8008-57-9)

Oil of Anise (1051; 8007-70-3)

Oil of Pennyroyal (1325; 8007-44-1)

Oil of Bay (2072; null)

Oil of Peppermint (2058; 8006-90-4)

Oil of Bergamot (1517; 8007-75-8)

Oil of Rue (2206; 8014-29-7)

Oil of Black Pepper (5847; 8006-82-4)

Oil of Spearmint (1508; 8008-79-5)

Oil of Camphor Sassafrassy (897; 8008-51-3)

Rosemary Oil (5450; 8000-25-7)

Oil of Cedarwood (1011; 8000-27-9)

Tagetes Oil (6196; null)

Oil of Chenopodium (1524; 8006-99-3)

Tea Tree Oil (6012; 85085-48-9)

Oil of Citronella (143; 8000-29-1)

Thyme Oil (6014; 8007-46-3)

Oil of Citrus (1931; null)

Wintergreen Oil (6220; null)

Oil of Geranium (1887; 8000-46-2)

Despite their collective presence in hundreds of registered products (Table 3), the adoption of essential oil pesticide products by commercial users in California has been somewhat limited. The total usage of all essential oil-based pesticides reported in PUR remains below 2,000 kg product and 50 kg of AI per year (Table 7). Our analysis excludes the AI “margosa oil” because it is a glyceridic oil extract, rather than an essential oil, and much like other “vegetable oils” kills arthropod pests by physically smothering them. The limited adoption of essential oil pesticides may reflect the well-founded perceptions of low efficacy and limited persistence. As discussed above in the “Issues with Registration” section, the apparent low usage also does not reflect the use of FIFRA List 25B (“exempt active ingredients”) essential oils and constituents as pesticides in California.

163


Table 7. Pesticide Use Reports data for 37 essential oils as pesticide active ingredients. Year

kg prod

kg AI

2010

182

51

2011

461

34

2012

60

16

2013

59

5

2014

1901

16

2015

1374

15

Total

4038

138

Phytochemicals as Leads for Synthetics: Are Ryanoids the Pyrethroids of the 21st Century? The pyrethrin/pyrethroid story is very familiar to insecticide researchers. In the early 1900s, insecticidal pyrethrins were isolated from Chrysanthemum flowers. The ensuing decades saw the development of many related synthetic compounds—termed pyrethroids—with improved toxicity and degradation properties for use as insecticides. PUR-reported synthetic pyrethroid usage is currently at several million kg products/yr, compared to less than 500,000 kg/yr of the naturally occurring pyrethrins (Figure 6A). A parallel story is now unfolding with another naturally occurring product, the alkaloid ryanodine. In the 1980s, ryanodine-binding assays revealed a new class of neurotransmitter receptor in the muscles of insects and both skeletal and cardiac muscles of vertebrates (29). The unique mode of action of ryanodine held promise for the control of insects which had developed resistance to the chemistries widely-used at the time. Ryanodine-based insecticides achieved limited usage in the 1990s, however its use was short-lived due to the high toxicity of ryanodine to vertebrates (Figure 6B). To capitalize on ryanodine’s unique mode of action, a series of synthetic anthranilic diamines were developed which activate the ryanodine receptors of insects (and are termed “ryanoids”) but have reduced affinities for vertebrate ryanodine receptors (30). The ryanoids (primarily chlorantraniliprole, cyantraniliprole and flubendiamide) hit the California market in 2009, and by 2015 they achieved ~350,000 kg of product usage per year (Figure 6B). The continuing growth of ryanoid use in California may be impacted by USEPA’s 2016 “Notice of intent to cancel pesticide registrations” for several prominent flubendiamide products due to the discovery of their toxicity towards aquatic invertebrates (31). The products listed in that notice under trade names BeltR, TourismoR and VeticaR, represented ~100,000 of the 340,000 kg of ryanoid products reported in PUR for 2015. Despite this setback, additional ryanoid AIs may reach the market in the coming years. 164


Figure 6. Usage of (A) naturally-occurring pyrethrins and synthetic pyrethroids; (B) naturally-occurring ryanodine and the three main synthetic ryanoids (chlorantraniliprole, cyantraniliprole and flubendiamide) reported in Pesticide Use Reports database. In both cases, basic research on the natural products was instrumental in the discovery and development of the synthetics, and the latter have achieved far greater usage. (see color insert)

Discussion Sources of Usage Underestimation Using PUR Data This analysis of trends in the botanical pesticide usage in California relies on two main sources of data from DPR: The Product/Label database and PUR. By design, certain types of pesticides and sources of pesticide usage are not recorded in these databases; and are thus sources of the underestimation of botanical pesticide registration and usage in California. 165


Non-Commercial Uses (mainly household and personal uses) Are Not Reported in PUR These “non-commercial” pesticide uses include pest control measures applied by the homeowner for structural pests (e.g., termites, ants and cockroaches); personal use of mosquito repellents; parasite control agents for pets; and lawn, garden and swimming pool treatments. Some estimates suggest that residential pesticide usage rivals that of commercial agriculture, and surveys conducted in the early 2000s suggest the former accounted for ~450 million kg of active ingredients in the US (32). While many of the pesticides sold for such non-commercial, household and personal uses in California must be registered with DPR and appear in the Product/Label Database, their usage is not reported in PUR. Given the scarcity of reliable data on non-commercial product and AI usage, the scale of underestimation from this factor is difficult to quantify. However, anecdotal information suggests a growing market for botanicals in household and personal use pesticide products (e.g., http://www.orangeguard.net/ home-pest-control/). One reason for this is the perception among the general public that natural products are inherently “safer” to use on the body and in and around the home, avoiding exposure of themselves, their children and their pets to the “synthetic chemicals” that are perceived to be less safe than natural products. Moreover, the homeowner is less concerned with the financial consideration of treatment cost versus economic loss, which often drives the pest control decisions of growers and other commercial interests. Thus, even if the “natural” products cost more than the synthetics, the additional cost may not overrule the homeowner’s perception that “natural” products are safer to use.

PUR and Pesticide/Label Databases Only Track Pesticide “Active Ingredients” Both the Pesticide/Label and PUR databases only track the “active ingredients” in pesticide products. However, botanical ingredients are often present in pesticide products as non-active, or so-called “inert” ingredients. These inerts are listed on product Safety Data Sheets (SDS) when they appear on various regulatory lists, such as the Clean Air Act. Using limonene to gauge the scale of this source of underestimation, PUR indicates that 25,953 kg of limonene was used as an AI in 2015. However, we found limonene listed as an inert ingredient on the SDS of two adjuvant products, Rocket DL and R-Agent-DL, at 41% and 37.5% of the formulations, respectively. The PUR-reported usage of these two adjuvants show that they accounted for an additional 6,482 kg of limonene, or about 25% of its AI usage level. A more comprehensive SDS survey would likely reveal additional sources of limonene in PUR reported products that are not listed in PUR as limonene AI usage.

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FIFRA 25b Exempt Products Are Not Registered and Their Usage Is Not Reported in PUR Many FIFRA 25b exempt products, such as EcoExempt Jet Wasp & Hornet Killer (https://www.zoecon.com/-/media/Files/Zoecon-NA/US/Product %20Labels/Specimen/EcoEXEMPT%20Jet%20Wasp%20and%20Hornet%20 Spray%20Specimen%20Label.pdf) contain botanical ingredients. However, many botanical pesticide ingredients that are on the FIFRA 25b exempt lists (https://www.epa.gov/minimum-risk-pesticides) are also registered with California DPR as active ingredients. Examples include at least 10 essential oils with insecticidal properties (e.g., Table 1 in reference (33)). Whether products containing them are registered with DPR, and their usage reported in PUR, often depends upon whether ALL ingredients in the product are on the FIFRA 25b exempt chemical lists. As with household and personal use products in general, it is not possible to estimate the scale of this source of underestimation.

Conclusions New pesticide products with botanical active ingredients continue to be registered for use in California. Despite recent increases in the usage of individual botanical active ingredients, the overall usage of botanical pesticides reported in the Pesticide Use Report database remains very modest, representing only a fraction of a percentage of California’s commercial pesticide use. However, their appearance in numerous household and personal use products remains an unquantifiable source of usage underestimation. The recent emergence of substantial ryanoid-class insecticide usage demonstrates that plant-derived chemicals continue to serve as leads in the development of effective, novel pest control chemistries.

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Recent Developments in the Registration and Usage of Botanical

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