Chemistry:Rotenone

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Rotenone
Skeletal formula of rotenone
Space-filling model of the rotenone molecule
Names
IUPAC name
(5′′R)-4′,5′-Dimethoxy-5′′-(prop-1-en-2-yl)-4′′,5′′-dihydrofuro[2′′,3′′:7,8]rotenan-4-one
Systematic IUPAC name
(2R,6aS,12aS)-8,9-Dimethoxy-2-(prop-1-en-2-yl)-1,2,12,12a-tetrahydro[1]benzopyrano[3,4-b]furo[2,3-h][1]benzopyran-6(6aH)-one
Other names
Tubatoxin, Paraderil
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
KEGG
MeSH Rotenone
UNII
Properties
C23H22O6
Molar mass 394.423 g·mol−1
Appearance Colorless to red crystalline solid[1]
Odor odorless[1]
Density 1.27 g/cm3 @ 20 °C
Melting point 165 to 166 °C (329 to 331 °F; 438 to 439 K)
Boiling point 210 to 220 °C (410 to 428 °F; 483 to 493 K) at 0.5 mmHg
Solubility Soluble in ether and acetone, slightly soluble in ethanol
Vapor pressure <0.00004 mmHg (20°C)[1]
Hazards
Lethal dose or concentration (LD, LC):
60 mg/kg (oral, rat)
132 mg/kg (oral, rat)
25 mg/kg (oral, rat)
2.8 mg/kg (oral, mouse)[2]
NIOSH (US health exposure limits):
PEL (Permissible)
 TWA 5 mg/m3[1]
REL (Recommended)
 TWA 5 mg/m3[1]
IDLH (Immediate danger)
 2500 mg/m3[1]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references
Tracking categories (test):

Rotenone is an odorless, colorless, crystalline isoflavone used as a broad-spectrum insecticide, piscicide, and pesticide. It occurs naturally in the seeds and stems of several plants, such as the jicama vine, and in the roots of several other members of the Fabaceae. It was the first-described member of the family of chemical compounds known as rotenoids.

Discovery

The earliest written record of the now-known rotenone-containing plants used for killing leaf-eating caterpillars was in 1848; for centuries, these same plants had been used to poison fish.[3] The active chemical component was first isolated in 1895 by a French botanist, Emmanuel Geoffroy, who called it nicouline, from a specimen of Robinia nicou, now called Deguelia utilis, while traveling in French Guiana.[4] He wrote about this research in his thesis, published in 1895 after his death from a parasitic disease.[5] In 1902 Kazuo Nagai, Japanese chemical engineer of the Government-General of Taiwan, isolated a pure crystalline compound from Derris elliptica which he called rotenone, after the Taiwanese name of the plant 蘆藤 (Template:Lang-nan-TW) translated into Japanese rōten (ローテン).[6] By 1930, nicouline and rotenone were established to be chemically the same.[7]

Uses

Rotenone is used as a pesticide, insecticide, and as a nonselective piscicide (fish killer).[8] Rotenone has historically been used by indigenous peoples to catch fish. Typically, rotenone-containing plants in the legume family, Fabaceae, are crushed and introduced into a body of water, and as rotenone interferes with cellular respiration, the affected fish rise to the surface in an attempt to gulp air, where they are more easily caught.

In modern times it is frequently used as a tool to remove alien fish species,[9] as it has a relatively short half-life (days) and is gone from rivers in the course of days and from lakes within a few months, depending on (seasonal) stirring, organic content, availability of sunlight and temperature.[10] Rotenone has been used by government agencies to kill fish in rivers and lakes in the United States since 1952,[11] and in Canada[12] and Norway[13] since the 1980s. It is less frequently used in EU countries, due to strict regulations, but has seen some use in selected countries such as the UK (Topmouth gudgeon), Sweden (pike and pumpkinseed), Spain (Topmouth gudgeon, Gambusia) and Hungary (Prussian carp).

Rotenone decays through metabolites and its final product is reduced to water and carbon dioxide.[10] Furthermore, its use is more benign for the environment (as compared to other piscicides) as most species are seen to recolonize aquatic systems within weeks to a year after application.[14][15][16] Thus, it has also seen some use in other field studies in the marine environment needing only small quantities. Small-scale sampling with rotenone is used by fish researchers studying the biodiversity of marine fishes to collect cryptic, or hidden, fishes, which represent an important component of shoreline fish communities, since it has only minor and transient environmental side effects.[17]

It is commercialized as cubé, tuba, or derris, in single preparation or in synergistic combination with other insecticides.[18] In the United States and Canada, all uses of rotenone except as a piscicide are being phased out.[19][20] It is currently banned in the United States for any use in organic farming.[21] In the UK, rotenone insecticides (sold under the trade name Derris) were banned for sale in 2009.[22]

Rotenone is also used in powdered form to treat scabies and head lice on humans, and parasitic mites on chickens, livestock, and pet animals.

In agriculture it is also unselective in action and kills potato beetles, cucumber beetles, flea beetles, cabbage worms, raspberry beetles, and asparagus beetles, as well as most other arthropods. It biodegrades rapidly in soil, with 90% degraded after 1–3 months at 20 °C (68 °F) and three times faster at 30 °C (86 °F).[23]

Mechanism of action

Rotenone works by interfering with the electron transport chain within complex I in mitochondria, which places it in IRAC MoA class 21 (by itself in 21B).[24] It inhibits the transfer of electrons from iron-sulfur centers in complex I to ubiquinone. This interferes with NADH during the creation of usable cellular energy (ATP).[18] Complex I is unable to pass off its electron to CoQ, creating a back-up of electrons within the mitochondrial matrix. Cellular oxygen is reduced to the radical, creating reactive oxygen species, which can damage DNA and other components of the mitochondria.[25]

Rotenone also inhibits microtubule assembly.[26]

Presence in plants

Rotenone is produced by extraction from the roots and stems of several tropical and subtropical plant species, especially those belonging to the genera Lonchocarpus and Derris.

Some of the plants containing rotenone:

  • Hoary pea or goat's rue (Tephrosia virginiana) – North America
  • Jícama (Pachyrhizus erosus) – North America
  • Cubé plant or lancepod (Lonchocarpus utilis) – South America[27]
    • The root extract is referred to as cubé resin
  • Barbasco (Lonchocarpus urucu) – South America[27]
    • The root extract is referred to as cubé resin
  • Tuba plant (Derris elliptica) – southeast Asia and southwest Pacific islands
    • The root extract is referred to as derris or derris root
  • Jewel vine (Derris involuta) – southeast Asia and southwest Pacific islands
    • The root extract is referred to as derris or derris root
  • Common Mullein (Verbascum thapsus L.)[28]
  • Cork-bush (Mundulea sericea) – southern Africa[29]
  • Florida fishpoison tree (Piscidia piscipula) – southern Florida, Caribbean[30]
  • Several species of Millettia and Tephrosia in South-east Asian regions[31]

Human toxicity

Rotenone is classified by the World Health Organization as moderately hazardous.[32] It is mildly toxic to humans and other mammals, but extremely toxic to insects and aquatic life, including fish. This higher toxicity in fish and insects is because the lipophilic rotenone is easily taken up through the gills or trachea, but not as easily through the skin or the gastrointestinal tract. Rotenone is toxic to erythrocytes in vitro.[33]

The lowest lethal dose for a child is not known, but death occurred in a 3.5-year-old child who had ingested 40 mg/kg rotenone solution.[34] Human deaths from rotenone poisoning are rare because its irritating action causes vomiting.[35] Deliberate ingestion of rotenone can be fatal.[34]

The compound decomposes when exposed to sunlight and usually has an activity of six days in the environment.[36] It oxidizes to rotenolone, which is about an order of magnitude less toxic than rotenone. In water, the rate of decomposition depends upon several factors, including temperature, pH, water hardness and sunlight. The half-life in natural waters ranges from half a day at 24 °C to 3.5 days at 0 °C.[37]

A 2018 study, which examined the effects of rotenone administration on cell cultures that mimicked properties of developing brains, found that rotenone may be a developmental neurotoxicant; that is, that rotenone exposure in the developing fetus may impede proper human brain development, with potentially profound consequences later in life. The study found that rotenone was particularly damaging to dopaminergic neurons, consistent with prior findings.[38]

Parkinson's disease

In 2000, injecting rotenone into rats was reported to cause the development of symptoms similar to those of Parkinson's disease (PD). Rotenone was continuously applied over a period of five weeks, mixed with DMSO and PEG to enhance tissue penetration, and injected into the jugular vein.[39] The study does not directly suggest rotenone exposure is responsible for PD in humans, but is consistent with the belief that chronic exposure to environmental toxins increases the likelihood of the disease.[40] In 2011, a US National Institutes of Health study showed a link between rotenone use and Parkinson's disease in farm workers, suggesting a link between neural damage and pulmonary uptake by not using protective gear.[41] Exposure to the chemical in the field can be avoided by wearing a gas mask with filter, which is standard HSE procedure in modern application of the chemical.

Studies with primary cultures of rat neurons and microglia have shown low doses of rotenone (below 10 nM) induce oxidative damage and death of dopaminergic neurons,[42] and it is these neurons in the substantia nigra that die in Parkinson's disease. Another study has also described toxic action of rotenone at low concentrations (5 nM) in dopaminergic neurons from acute rat brain slices.[43] This toxicity was exacerbated by an additional cell stressor – elevated intracellular calcium concentration – adding support to the 'multiple hit hypothesis' of dopaminergic neuron death.

The neurotoxin MPTP had been known earlier to cause PD-like symptoms (in humans and other primates, though not in rats) by interfering with complex I in the electron transport chain and killing dopaminergic neurons in the substantia nigra. Further studies involving MPTP have failed to show development of Lewy bodies, a key component to PD pathology. However at least one study recently has found evidence of protein aggregation of the same chemical makeup as that which makes up Lewy bodies with similar pathology to Parkinson's disease in aged Rhesus monkeys from MPTP.[44] Therefore, the mechanism behind MPTP as it relates to Parkinson's disease is not fully understood.[45] Because of these developments, rotenone was investigated as a possible Parkinson-causing agent. Both MPTP and rotenone are lipophilic and can cross the blood–brain barrier.

In 2010, a study was published detailing the progression of Parkinson's-like symptoms in mice following chronic intragastric ingestion of low doses of rotenone. The concentrations in the central nervous system were below detectable limits, yet still induced PD pathology.[46]

Notable administrations

Rotenone was implemented in 2010 to kill an invasive goldfish population present in eastern Oregon's Mann Lake, with the intention of not disrupting the lake's trout population. Rotenone successfully achieved these aims, killing nearly 200,000 goldfish, and only three trout.[47]

Beginning May 1, 2006, Panguitch Lake, a reservoir in the southeastern portion of the U.S. state of Utah, was treated with rotenone, to potentially eradicate and control the invasive population of Utah chub, which were probably introduced accidentally by anglers who used them as live bait. The lake was restocked with 20,000 rainbow trout in 2006; as of 2016, the lake's fish population has recovered.

In 2012 rotenone was used to kill all remaining fish in Stormy Lake (Alaska) due to invasive pike destroying native species, which were reintroduced once the treatment was concluded.[48]

In 2014, rotenone was used to kill all remaining fish in San Francisco's Mountain Lake, which is located in Mountain Lake Park, in order to rid it of invasive species introduced since the migration of European settlers to the region.[49]

Rotenone is used in biomedical research to study the oxygen consumption rate of cells, usually in combination with antimycin A (an electron transport chain Complex III inhibitor), oligomycin (an ATP synthase inhibitor) and FCCP (a mitochondrial uncoupler).[50]

Deactivation

Rotenone can be deactivated in water with the use of potassium permanganate to lower toxicity to acceptable levels.[51]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 NIOSH Pocket Guide to Chemical Hazards. "#0548". National Institute for Occupational Safety and Health (NIOSH). https://www.cdc.gov/niosh/npg/npgd0548.html. 
  2. ↑ "Rotenone". Immediately Dangerous to Life and Health Concentrations (IDLH). National Institute for Occupational Safety and Health (NIOSH). https://www.cdc.gov/niosh/idlh/83794.html. 
  3. ↑ Metcalf, R. L. (1948). The Mode of Action of Organic Insecticides. National Research Council, Washington DC. https://books.google.com/books?id=PmcrAAAAYAAJ&q=rotenone+isolated&pg=PA29. 
  4. ↑ Ambrose, Anthony M.; Harvey B. Haag (1936). "Toxicological study of Derris". Industrial & Engineering Chemistry 28 (7): 815–821. doi:10.1021/ie50319a017. 
  5. ↑ "Useful tropical plants". ASNOM. 2008-01-02. http://www.asnom.org/en/730_plantes_tropicales_utiles.html. 
  6. ↑ Nagai, Kazuo (1902). Journal of the Chemical Society of Tokyo 23: 744. 
  7. ↑ "The Determination of the structure of rotenone". Chemical Reviews 18 (2): 181–213. 1933. doi:10.1021/cr60042a001. 
  8. ↑ Peter Fimrite (2007-10-02). "Lake poisoning seems to have worked to kill invasive pike". San Francisco Chronicle. http://sfgate.com/cgi-bin/article.cgi?f=/c/a/2007/10/02/BAOHSI41V.DTL. 
  9. ↑ "The effectiveness of non-native fish removal techniques in freshwater ecosystems: A systematic review" (in English). Environmental Reviews 27 (1): 71–94. 2018. doi:10.1139/er-2018-0049. http://eprints.bournemouth.ac.uk/31355/1/Rytwinski%20et%20al_Fish%20removal%20SR_FINAL.pdf, summary in French 
  10. ↑ 10.0 10.1 (in English) Planning and Standard Operating Procedures for the Use of Rotenone in Fish Management – Rotenone SOP Manual. Bethesda, Maryland: American Fisheries Society. 2010. pp. 1–200. 
  11. ↑ Schmidt, Peter (28 February 2010). "One Strange Fish Tale". The Chronicle of Higher Education. http://chronicle.com/article/One-Strange-Fish-Tale/64348/. Retrieved 24 September 2015. 
  12. ↑ "Invasive Goldfish management". 10 January 2023. https://www.rmwb.ca/en/parks-and-recreation/invasive-goldfish-management.aspx#Why-are-we-using-Rotenone. 
  13. ↑ Mo, TO; Holthe, E; Andersen, O (2022) (in Norwegian). Har myndighetene lyktes i kampen mot Gyrodactylus salaris? (Report). Norsk institutt for naturforskning, NINA rapport. pp. 1–62. ISBN 978-82-426-4950-8, summary in English 
  14. ↑ Kjærstad, Gaute (2022) (in English). The eradication of invasive species using rotenone and its impact on freshwater macroinvertebrates. Trondheim: Doctoral theses at NTNU. pp. 1–100. ISBN 978-82-326-6270-8. 
  15. ↑ Fjellheim, A. (2004). "Virkning av rotenonbehandling på bunndyrsamfunnene I et område ved Stigstu, Hardangervidda" (in Norwegian). Lfi-122 (LFI, University of Bergen): 1–60. ISSN 0801-9576. http://hdl.handle.net/11250/2630458. 
  16. ↑ Vinson, V; Dinger, EC; Vinson, DK (2010). "Piscicides and invertebrates: after 70 years, does anyone really know?". Fisheries 35 (2): 61–71. doi:10.1577/1548-8446-35.2.61. 
  17. ↑ Robertson, D. Ross; Smith-Vaniz, William F. (2008). "Rotenone: An Essential but Demonized Tool for Assessing Marine Fish Diversity". BioScience 58 (2): 165. doi:10.1641/B580211. 
  18. ↑ 18.0 18.1 Hayes W. J. (1991). Handbook on Pesticides. 1. Academic Press. ISBN 978-0-12-334161-7. https://books.google.com/books?id=sUrLT9z9i3IC&q=rotenone+millettia&pg=PA135. 
  19. ↑ Reregistration Eligibility Decision for Rotenone,[|permanent dead link|dead link}}] EPA 738-R-07-005, March 2007, United States Environmental Protection Agency
  20. ↑ Re-evaluation Note: Rotenone (REV2008-01, 29 January 2008),[|permanent dead link|dead link}}] Consumer Product Safety, Health Canada
  21. ↑ "7 CFR § 205.602 - Nonsynthetic substances prohibited for use in organic crop production". Cornell Law School Legal Information Institute. https://www.law.cornell.edu/cfr/text/7/205.602. Retrieved 20 May 2021. 
  22. ↑ "RHS advice for the garden - Rotenone withdrawal". 2 October 2008. https://www.telegraph.co.uk/gardening/gardeningadvice/3350291/RHS-advice-for-the-garden.html. 
  23. ↑ Cavoski, Ivana; Caboni, Pierluigi; Sarais, Giorgia; Miano, Teodoro (2008-08-06). "Degradation and Persistence of Rotenone in Soils and Influence of Temperature Variations" (in EN). Journal of Agricultural and Food Chemistry 56 (17): 8066–8073. doi:10.1021/jf801461h. PMID 18681442. 
  24. ↑ IRAC International MoA Working Group (March 2020). "IRAC Mode of Action Classification Scheme Version 9.4". Insecticide Resistance Action Committee. http://irac-online.org/documents/moa-classification/. 
  25. ↑ Mehta, Suresh (2009). "Neuroprotective role of mitochondrial uncoupling protein 2 in cerebral stroke". Journal of Cerebral Blood Flow and Metabolism 29 (6): 1069–78. doi:10.1038/jcbfm.2009.4. PMID 19240738. 
  26. ↑ "Mechanistic Investigations of the Mitochondrial Complex I Inhibitor Rotenone in the Context of Pharmacological and Safety Evaluation". Scientific Reports 7: 45465. 2017. doi:10.1038/srep45465. PMID 28374803. Bibcode: 2017NatSR...745465H. 
  27. ↑ 27.0 27.1 "Cubé resin insecticide: identification and biological activity of 29 rotenoid constituents". J Agric Food Chem 47 (5): 2130–6. 1999. doi:10.1021/jf981188x. PMID 10552508. 
  28. ↑ Peterson Field Guides to Medicinal Plants and Herbs of Eastern and Central North America (2nd ed.). pp. 130–131. 
  29. ↑ Coates Palgrave, Keith (2002). Trees of Southern Africa. Struik. ISBN 978-0-86977-081-8. 
  30. ↑ Nellis, David N. (1994). Seashore plants of South Florida and the Caribbean. Pineapple Press. 160 p.
  31. ↑ Comprehensive Natural Products Chemistry. Pergamon. 1999. ISBN 978-0-08-091283-7. https://books.google.com/books?id=AqdTiNIaA74C&q=rotenone+millettia&pg=PT10698. 
  32. ↑ International Programme on Chemical Safety; United Nations Environment Programme (UNEP); International Labour Organization; World Health Organization (2007). The WHO Recommended Classification of Pesticides by Hazard. World Health Organization. ISBN 978-92-4-154663-8. https://www.who.int/ipcs/publications/pesticides_hazard/en/. Retrieved 2007-12-02. 
  33. ↑ Lupescu, Adrian; Jilani, Kashif; Zbidah, Mohanad; Lang, Florian (October 2012). "Induction of apoptotic erythrocyte death by rotenone". Toxicology 300 (3): 132–7. doi:10.1016/j.tox.2012.06.007. PMID 22727881. 
  34. ↑ 34.0 34.1 "Fatality after deliberate ingestion of the pesticide rotenone: a case report". Critical Care 9 (3): R280–4. June 2005. doi:10.1186/cc3528. PMID 15987402. 
  35. ↑ "Rotenone". Pesticides News 54: 20–21. 2001. http://www.pan-uk.org/pestnews/Actives/rotenone.htm. 
  36. ↑ Vitax Safety Data Sheet for Derris dust, revised October 1998
  37. ↑ Kevin C. Ott. "Rotenone. A Brief Review of its Chemistry, Environmental Fate, and the Toxicity of Rotenone Formulations". http://www.newmexicotu.org/Rotenone%20summary.pdf. 
  38. ↑ Pamies, David; Block, Katharina; Lau, Pierre; Gribaldo, Laura; Pardo, Carlos A.; Barreras, Paula; Smirnova, Lena; Wiersma, Daphne et al. (2018-09-01). "Rotenone exerts developmental neurotoxicity in a human brain spheroid model" (in en). Toxicology and Applied Pharmacology. Alternative Approaches to Developmental Neurotoxicity Evaluation 354: 101–114. doi:10.1016/j.taap.2018.02.003. ISSN 0041-008X. PMID 29428530. 
  39. ↑ "Rotenone, deguelin, their metabolites, and the rat model of Parkinson's disease". Chem Res Toxicol 17 (11): 1540–8. 2004. doi:10.1021/tx049867r. PMID 15540952. 
  40. ↑ Summary of the article by Dr. Greenamyre on pesticides and Parkinson's Disease at ninds.nih.gov
  41. ↑ "Rotenone, Paraquat and Parkinson's Disease". Environmental Health Perspectives 119 (6): 866–72. 2011. doi:10.1289/ehp.1002839. ISSN 0091-6765. PMID 21269927. 
  42. ↑ "Critical role for microglial NADPH oxidase in rotenone-induced degeneration of dopaminergic neurons". The Journal of Neuroscience 23 (15): 6181–7. July 2003. doi:10.1523/JNEUROSCI.23-15-06181.2003. PMID 12867501. 
  43. ↑ "Acute action of rotenone on nigral dopaminergic neurons--involvement of reactive oxygen species and disruption of Ca2+ homeostasis". The European Journal of Neuroscience 30 (10): 1849–59. November 2009. doi:10.1111/j.1460-9568.2009.06990.x. PMID 19912331. 
  44. ↑ "Phosphorylated α-Synuclein Accumulations and Lewy Body-like Pathology Distributed in Parkinson's Disease-Related Brain Areas of Aged Rhesus Monkeys Treated with MPTP" (in en). Neuroscience 379: 302–315. 2018-05-21. doi:10.1016/j.neuroscience.2018.03.026. ISSN 0306-4522. PMID 29592843. 
  45. ↑ Neurotransmitters and Disorders of the Basal Ganglia -- Basic Neurochemistry -- NCBI Bookshelf, American Society for Neurochemistry
  46. ↑ Kleinschnitz, Christoph, ed (2010). "Progression of Parkinson's Disease Pathology Is Reproduced by Intragastric Administration of Rotenone in Mice". PLOS ONE 5 (1): e8762. doi:10.1371/journal.pone.0008762. PMID 20098733. Bibcode: 2010PLoSO...5.8762P. 
  47. ↑ Monroe, Bill (December 3, 2010). "Mann Lake Gets a Second Round of Rotenone for Cutthroat Restoration". The Oregonian (Oregon Live LLC). http://www.oregonlive.com/sports/oregonian/bill_monroe/index.ssf/2010/12/mann_lake_gets_a_second_round.html. 
  48. ↑ Earl, Elizabeth, Fish population booms in Stormy Lake Peninsula Clarion, 10/7/2015
  49. ↑ Fimrite, Peter (12 November 2014). "Alien fish poisoned by the thousands to save S.F.'s Mountain Lake". SFGate / Hearst. http://www.sfgate.com/bayarea/article/Workers-pour-poison-into-Mountain-Lake-begin-5888355.php. 
  50. ↑ "Measuring Mitochondrial Function in Permeabilized Cells Using the Seahorse XF Analyzer or a Clark-Type Oxygen Electrode". Curr Protoc Toxicol 60: 25.2.1–16. 2014. doi:10.1002/0471140856.tx2502s60. PMID 24865646. 
  51. ↑ Donald L Archer (2001), Rotenone Neutralization Methods, American Fisheries Society, http://www.fisheriessociety.org/rotenone/rewards/01archer.pdf 

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