Isman 2016
Isman 2016
                                                                                  additives and all “generally regarded as safe” (GRAS), can be used as active
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                                                                                       In South Africa, Prev-AMR is an insecticide/fungicide containing 50%
                                                                                  orange oil as an active ingredient; a similar product containing 60% orange oil
                                                                                  is sold in France and the Netherlands under the same brand. In the European
                                                                                  Union, orange oil is one of only two plant oils approved for use as insecticides,
                                                                                  although clove, spearmint, citronella and rape seed oils (and geraniol) are
                                                                                  approved for use as insect repellents. In China there are two registered
                                                                                  insecticides containing eucalyptol (= 1,8-cineole, from Eucalyptus globulus and
                                                                                  related species), five insecticides containing camphor (from camphor wood oil,
                                                                                  Cinnamomum camphora), plus fungicides based on eugenol (from clove oil,
                                                                                  Syzygium aromaticum) and carvacrol (from oregano oil, Origanum sativum).
                                                                                  In India, eucalyptus leaf extract (rich in 1,8-cineole) is approved for use as an
                                                                                  insecticide while in Australia an insecticide/miticide has recently been approved
                                                                                  containing both eucalyptus and tea tree (Melaleuca alternifolia) oils as active
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                                                                                  of rosemary oil in the Balkan Peninsula (19). Even significant diural changes
                                                                                  in chemical composition have been observed in the essential oil of Ocimum
                                                                                  gratissimum growing in Benin (20).
                                                                                       Certain species of essential oil-producing plants exist as distinct chemotypes
                                                                                  or races that can differ markedly in chemical composition (e.g., wormwood,
                                                                                  Artemsia absinthium) (21). To a large extent this variation is managed or
                                                                                  mitigated by major producers of plant essential oils who rely on well established
                                                                                  supply chains starting with plant biomass that is propagated, grown and harvested
                                                                                  consistently following good agricultural practices. Nonetheless essential oils
                                                                                  as pesticides constitute a conundrum for regulatory authorities owing to their
                                                                                  potential chemical variation, the likelihood that toxicity cannot be attributed to
                                                                                  a single, major constituent, and the fact that – at least for use as pesticide active
                                                                                  ingredients – there is no strict chemical definition for a particular essential oil.
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                                                                                  Even the botanical definition of an essential oil can be subject to question; the
                                                                                  taxonomic boundries of some of the most common essential oils remain unclear
                                                                                  or controversial at best. Faced with this dilemma, a regulatory agency could
                                                                                  either recognize a major (and presumably toxic) constituent of the essential oil as
                                                                                  the active ingredient of a pesticide product, or alternatively, recognize the intact
                                                                                  oil itself as the active ingredient, the lack of definition of the oil noted above
                                                                                  notwithstanding.
                                                                                  Figure 1. Toxicity of rosemary oil and its major constituents to 3rd instar cabbage
                                                                                  looper (Trichoplusia ni) via topical administration. Based on data from reference
                                                                                                                         (14).
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                                                                                                               Practical Considerations
                                                                                  Regulatory Concerns
                                                                                       In the developed world, regulatory approval remains the final, and often
                                                                                  most difficult, barrier to overcome in commercializaing a pesticide. Without such
                                                                                  approval, no product can be sold and no revenue realized. The only obvious
                                                                                  exception to this is the exempt active ingredient status afforded to certain essential
                                                                                  oils in the USA as noted above (Table 1). In other jurisdictions, approval for
                                                                                  essential oil-based pesticides has been problematic because pesticide regulatory
                                                                                  guidelines developed historically to evaluate synthetic pesticides where there is
                                                                                  a single active ingredient with no ambiguity. The EU is only now preparing to
                                                                                  publish criteria for “low risk active substance” that some essential oils may meet,
                                                                                  possibly clearing a path for approval of more pesticidal products based on such
                                                                                  oils (22).
                                                                                       Regulatory approval is based on review of data on product chemistry,
                                                                                  environmental fate, and toxicology to laboratory animals and nontarget organisms
                                                                                  including fish, wildlife and pollinators. Some regulatory agencies require efficacy
                                                                                  data while others do not. For essential oils used as flavoring agents in foods and
                                                                                  beverages, as fragrances in consumer products and cosmetics, and medicinally in
                                                                                  aromatherapy, product chemistry and laboratory animal toxicology are often well
                                                                                  established and documented, although such data is usually considered proprietary
                                                                                  and therefore not freely accessible. Less well documented is the environmental
                                                                                  fate of plant essential oils, although published studies consistently indicate
                                                                                  that these materials are minimally persistent in the environment owing to their
                                                                                  volatility and consequential evaporative loss (23), except in closed containers
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                                                                                  where fumigation is the goal. Fewer still are investigations of the effects of
                                                                                  plant essential oils on nontarget organisms, although there is some evidence that
                                                                                  they can be used with a margin of safety towards biocontrol agents and fish (24,
                                                                                  25). Essential oils have been evaluated and sometimes used to manage Varroa
                                                                                  devastator, an ectoparasitic mite in honeybee colonies, but within the closed
                                                                                  confines of a hive the margin of safety to bees is rather narrow (26).
                                                                                       Given the widespread use of essential oils in foods, beverages and consumer
                                                                                  products, it is not surprising that most of the commonly used oils have minimal
                                                                                  or low toxicity to lab animals, typically with rat, oral acute LD50 values >2000
                                                                                  mg kg-1. One notably exception is pennyroyal (from the mint Mentha pulegium)
                                                                                  with a rat LD50 of 400 mg kg-1. The major constituent, pulegone, has a rat LD50
                                                                                  of 470 mg kg-1. Most importantly, there are reports that pennyroyal is a potential
                                                                                  abortifacent in humans (27). Among the more common essential oils, carvacrol,
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                                                                                                                Commerical Challenges
                                                                                       Apart from the obvious issues of cost, availability and consistency, there are
                                                                                  a number of challenges for those producing pesticides based on plant essential
                                                                                  oils. The first of these is long term stability of a formulation containing essential
                                                                                  oils, in storage and transport. Typically an agrochemical product is expected
                                                                                  to remain stable for up to two years in storage; short term stability trials at
                                                                                  elevated temperatures (e.g., 50°C for 90 days) attempt to simulate this. Though
                                                                                  relatively stable, some oils are susceptible to oxidation in the absence of any
                                                                                  antioxidants, even though certain oils themselves have been reported to have
                                                                                  antioxidant properties. Given the volatility of many constituents of essential oils,
                                                                                  the packaging material (bottles) used can be a factor in maintaining chemical
                                                                                  consistency and stability of a product containing an essential oil, with the least
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                                                                                                                       Future Sources
                                                                                       Research interest in the insecticidal and repellent effects of plant essential
                                                                                  oils has grown dramatically since 2000. By 2011, 23% of all published papers
                                                                                  on botanical insecticides focused on essential oils, representing almost 5% of all
                                                                                  published papers on insecticides (32). Between 2004 and 2014, over 3,600 papers
                                                                                  were published on essential oils associated with insects and arthropods, according
                                                                                  to the Web of Science. The vast majority of these reported on the screening
                                                                                  and bioactivity of relatively exotic essential oils to insects, so the ‘discovery’
                                                                                  end of the R&D spectrum is well represented in the literature. Unfortunately
                                                                                  there is a relative dearth of papers toward the ‘development’ end of the spectrum,
                                                                                  although to be fair, a high proportion of the research effort in that regard is expected
                                                                                  to be protected information (i.e., intellectual property) that might only reach the
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                                                                                  scientific literature after patent protection has been secured. But it is easy to
                                                                                  observe that only a handful of essential oil-based pesticides have seen successful
                                                                                  commercialization, relative to the expansive scientific literature devoted to the
                                                                                  area.
                                                                                       That being said, and noting the practical considerations and challenges
                                                                                  described above, what are the prospects for the introduction of new pesticides
                                                                                  based on plant essential oils not currently in wide use in other industries? As
                                                                                  of this writing, even the most successful essential oil-based pesticides occupy
                                                                                  only a paper-thin share of the global insecticide market, although all indications
                                                                                  are that they are at a very earlier stage in that market and are poised for faster
                                                                                  market growth over the next decade than conventional pest management products.
                                                                                  Perhaps if these predictions have any accuracy, essential oil-based pesticides will
                                                                                  become significant participants in the rapidly expanding biopesticide market and
                                                                                  in so doing make the prospects for the introduction of pesticides based on exotic
                                                                                  oils more economically attractive.
                                                                                       One such example that has been subject to an extensive research effort
                                                                                  in recent years is the essential oil from wormwood, Artemisia absinthium
                                                                                  (Asteraceae) growing in Spain. This aromatic plant with a long history of
                                                                                  medicinal use is also the botanical source of absinthe, a bitter liqueur banned for
                                                                                  many years owing to its human toxicity, attributable to its major constituents, α-
                                                                                  and β-thujone. Thujone-rich oils have also been demonstrated to be insecticidal.
                                                                                  Although commercial samples of wormwood oil are often rich in thujones, there
                                                                                  are numerous chemotypes of the species, some of which lack these compounds
                                                                                  entirely (21). A series of thorough investigations of domesticated plants collected
                                                                                  from two locations in Spain and grown under both field conditions and controlled
                                                                                  conditions (in a growth chamber, greenhouse and in aeroponic culture) have
                                                                                  documented chemical variations in their essential oils (33). The major constituents
                                                                                  of essential oils produced from these cultivated plants, which lack thujones, are
                                                                                  cis-epoxycimene, chrysanthenol and chrysanthenyl acetate. Though less active
                                                                                  than thujones as antifeedants to the green peach aphid (Myzus persicae), bird
                                                                                  cherry oat aphid (Rhopalosiphum padi) and the cotton leafworm (Spodoptera
                                                                                  littoralis), oils containing the above noted compounds are effective antifeedants.
                                                                                  Interestingly, bioactivity to insects was not well correlated to concentrations
                                                                                  of any of the three compounds, providing another example of internal synergy
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                                                                                  amongst constituents of an essential oil. These oils and extracts also have valuable
                                                                                  bioactivity against the human parasites causing leshmaniasis and trypanosomiasis
                                                                                  (33, 34). Rather striking quantitative year-to-year differences (up to 10-fold
                                                                                  for individual constituents) in oil composition were found in cultivated plants
                                                                                  from the two populations, and these in turn differed from plants grown under
                                                                                  controlled conditions and from wild conspecifics (33, 34). However, supercritical
                                                                                  fluid extraction of these plants gave much higher yields of the three compounds
                                                                                  relative to hydrodistillation or organic solvent extraction, and the SF extracts
                                                                                  were significantly more bioactive against all three pests (11, 35). Thujone-free
                                                                                  cultivated A. absinthium appears to have good potential for the production of
                                                                                  essential oils and extracts that can be formulated as biopesticides and for use
                                                                                  as antiparasitic agents, but production practices will require standardization to
                                                                                  achieve the consistency seen in other essential oils produced commercially over
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                                                                                                                    Acknowledgments
                                                                                       David Herbst (Berjé Inc.) generously provided valuable insight on the
                                                                                  essential oil industry to the author, as did Rod Bradbury (EcoSafe Natural Proucts
                                                                                  Inc.) on formulation chemistry. Dr. Rita Seffrin assisted with literature review.
                                                                                  Supported in part by grants from the Natural Sciences and Engineering Research
                                                                                  Council of Canada (NSERC).
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