Tefluthrin

Tefluthrin is the ISO common name[3] for an organic compound that is used as a pesticide.[1] It is a pyrethroid, a class of synthetic insecticides that mimic the structure and properties of the naturally occurring insecticide pyrethrin which is present in the flowers of Chrysanthemum cinerariifolium. Pyrethroids such as tefluthrin are often preferred as active ingredients in agricultural insecticides because they are more cost-effective and longer acting than natural pyrethrins.[4] It is effective against soil pests because it can move as a vapour without irreversibly binding to soil particles: in this respect it differs from most other pyrethroids.[5]

Tefluthrin

tefluthrin (racemic)
Names
Preferred IUPAC name
rac-(2,3,5,6-Tetrafluoro-4-methylphenyl)methyl (1R,3R)-2,2-dimethyl-3-[(1Z)-2-chloro-3,3,3-trifluoroprop-1-en-1-yl]cyclopropane-1-carboxylate
Other names
Tefluthrine
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.124.968
EC Number
  • 616-699-6
KEGG
UNII
  • InChI=1S/C17H14ClF7O2/c1-6-11(19)13(21)7(14(22)12(6)20)5-27-15(26)10-8(16(10,2)3)4-9(18)17(23,24)25/h4,8,10H,5H2,1-3H3/b9-4-/t8-,10-/m1/s1 checkY
    Key: ZFHGXWPMULPQSE-SZGBIDFHSA-N checkY
  • InChI=1/C17H14ClF7O2/c1-6-11(19)13(21)7(14(22)12(6)20)5-27-15(26)10-8(16(10,2)3)4-9(18)17(23,24)25/h4,8,10H,5H2,1-3H3/b9-4-/t8-,10-/m1/s1
    Key: ZFHGXWPMULPQSE-SZGBIDFHBO
  • CC1=C(C(=C(C(=C1F)F)COC(=O)[C@@H]2[C@@H](C2(C)C)/C=C(/C(F)(F)F)\Cl)F)F
Properties[1]
C17H14ClF7O2
Molar mass 418.74 g·mol−1
Appearance colorless solid
Density 1.48 g/mL
Melting point 44.6 °C
Boiling point 156 °C at 1 mmHg
0.02 mg/L in water

>500 g/L in acetone, hexane, toluene

log P 6.4
Hazards[2]
GHS labelling:
GHS06: ToxicGHS09: Environmental hazard
Danger
H300, H310, H330, H410
P260, P262, P264, P270, P271, P273, P280, P284, P301+P310, P302+P350, P304+P340, P310, P320, P321, P322, P330, P361, P363, P391, P403+P233, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Synthesis

Tefluthrin (X=CH3) is manufactured by the esterification of cyhalothrin acid chloride[6] with 4-methyl-2,3,5,6-tetrafluorobenzyl alcohol.[7] The latter was a novel compound when tefluthrin was invented[8] and the choice of routes to it has been discussed.[9]

History
Further information: Pyrethroids

By 1974, a team of Rothamsted Research scientists had discovered three pyrethroids suitable for use in agriculture, namely permethrin, cypermethrin and deltamethrin.[10] These compounds were subsequently licensed by the NRDC, as NRDC 143, 149 and 161 respectively, to companies which could then develop them for sale in defined territories. Imperial Chemical Industries (ICI) obtained licenses to permethrin and cypermethrin but their agreement with the NRDC did not allow worldwide sales. Also, it was clear to ICI's own researchers at Jealott's Hill that future competition in the marketplace might be difficult owing to the greater potency of deltamethrin compared to the other compounds. For that reason, chemists there sought patentable analogues which might have advantages compared to the Rothamsted insecticides by having wider spectrum or greater cost-benefit. The first breakthrough was made when a trifluoromethyl group was used to replace one of the chlorines in cypermethrin, especially when the double bond was in its Z form. The second relied on process chemists developed a practical manufacturing process for the Z-cis acid, by controlling the stereochemistry of the cyclopropane ring in addition to that of the double bond.[6] This led to the commercialisation of cyhalothrin and made available a relatively large supply of the acid. Exploratory studies continued in which it was combined with a large number of commercially available benzyl alcohols. In the main, these had little or no biological activity but when penta-fluorobenzyl alcohol was used the ester with X=F not only had substantial intrinsic activity on Diabrotica balteata but continued to be effective when soil was present, in contrast to other known pyrethroids. Further research allowed the analogue with X=CH3 (i.e. what became tefluthrin) to be identified after field trials as the optimum for development under the ICI code number PP993.[5] It was first marketed in 1987 using the trademark Force.[11] In 2000, the agrochemical business of ICI merged with that of Novartis to form Syngenta, which still manufactures and supplies tefluthrin. The US patent covering the parent compound expired in November 2002.[12] Tefluthrin was registered for sale in the European Union until December 5, 2008, when it was added to a group of pesticides whose authorization was withdrawn and it could no longer be sold.[13] However, on January 1, 2012, it was re-approved for use.[14][15]

Mechanism of action

Pyrethroid insecticides, including tefluthrin, disrupt the functioning of the nervous system in an organism. They are fast-acting axonic excitotoxins, which affect the voltage-gated sodium channels.[16] The sodium channels are heteromultimeric complexes consisting of one large 𝛼-subunit and two smaller 𝛽-subunits. The binding site of tefluthrin is on the 𝛼-subunit, which also forms the pore of the channel. It alters the functioning of the channel by blocking the inactivation and slowing the deactivation.[17] This results in persistent and prolonged activation of sodium channels and inflow of sodium, which is lethal to the insect. There are many different forms of sodium channels: in mammals, nine different sodium channel 𝛼-subunits have been identified (named Nav1.1-Nav1.9).[18] The channel isoforms differ in affinity for tefluthrin; for example the Nav1.6 is at least 15-fold more sensitive than the Nav1.2 isoform.[19][20]

Formulations

Tefluthrin is made available to end-users only in formulated products. Its main use is for the control of soil-dwelling insects in maize when formulated as granules.[21] It can also be incorporated in seed treatments.

Usage

All pesticides are required to seek registration from appropriate authorities in the country in which they will be used.[22] In the United States, the Environmental Protection Agency (EPA) is responsible for regulating pesticides under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Food Quality Protection Act (FQPA).[23] A pesticide can only be used legally according to the directions on the label that is included at the time of the sale of the pesticide. The purpose of the label is "to provide clear directions for effective product performance while minimizing risks to human health and the environment". A label is a legally binding document that mandates how the pesticide can and must be used and failure to follow the label as written when using the pesticide is a federal offense.[24] The current (2020) label for tefluthrin in the USA covers its use on field corn, popcorn, seed corn and sweetcorn and specifies the amount to be applied.[25] Within the European Union, a 2-tiered approach is used for the approval and authorisation of pesticides. Firstly, before a formulated product can be developed for market, the active substance must be approved for the European Union. After this has been achieved, authorisation for the specific product must be sought from every Member State that the applicant wants to sell it to. Afterwards, there is a monitoring programme to make sure the pesticide residues in food are below the limits set by the European Food Safety Authority.

Adult stages of some Diabrotica pests controlled by tefluthrin

The main use of tefluthrin is to control the larvae of corn rootworms (Diabrotica spp) and it is also lethal to cutworm and wireworm larvae. Related insects share this susceptibility to the compound, including pests such as springtails, symphylids, millipedes, pygmy beetle, fire ants and white grubs.[1] The advantage to the farmer comes in the form of improved yield at harvest. Farmers can act in their best economic interest: the value of the additional yield can be estimated and the total cost of using the insecticide informs the decision to purchase. This cost-benefit analysis by the end user sets a maximum price which the supplier can demand. The estimated annual use of tefluthrin in US agriculture is mapped by the US Geological Survey.[26] This shows that use peaked in 2003 but by 2017, the latest date for which figures are available, has fallen to about 150,000 pounds (68,000 kg) annually, almost exclusively in the corn belt. The ability of tefluthrin to control soil pests, in contrast to other pyrethroids, is due to its relatively high volatility, which allows its vapour to move from the site of application to the surrounding soil.[5] Its vapour pressure at 20 °C is 8.4 mPa while that of permethrin, for example, is 0.007 mPa.[1]

Human safety

Tefluthrin is a restricted use pesticide. One consequence of this is that, in the US, it is a violation of Federal law to use the product in a manner inconsistent with its labelling and the labelling must be in possession of the user at the time of the application. It can be absorbed into the body by inhalation of dust or mist and by ingestion. It causes moderate eye irritation. Prolonged or frequently repeated skin contact may cause allergic reactions in some individuals. Skin exposure may result in a transient sensation described as a tingling, itching, burning, or prickly feeling. Onset may occur immediately to four hours after exposure and may last 2–30 hours, without apparent skin damage.[25] First aid measures are included with the label information.[25]

Metabolism

The mammalian LD50 is 21.8 mg/kg (rats, oral).[1] Phase I metabolism of tefluthrin proceeds via both oxidation and hydrolysis.[27] Initial targets for oxidation are its methyl groups. Those on the cyclopropane ring and on the tetrafluorobenzene ring are oxidized to alcohol groups which can be further oxidized into carboxylic acids. Hydrolysis of tefluthrin occurs at the ester bond which results in cyhalothrin acid and 4-methyl-2,3,5,6-tetrafluorobenzyl alcohol, which can be further oxidized into the corresponding carboxylic acid. In phase II metabolism, the phase I metabolites are glucuronidated on any available alcohol groups to facilitate membrane transport and eventually excretion.

Environmental effects

Tefluthrin is very highly toxic to freshwater and estuarine fish and invertebrates.[25] Its properties and effects on the environment have been summarized in several publications.[1][2][28] Ultimately it is the regulatory authorities in each country who must weigh up the benefits to end users and balance these against the compound's inherent hazards and consequent risks to consumers and the wider environment. These authorities stipulate the conditions under which tefluthrin may be used.

Resistance management

Species have the ability to evolve and develop resistance to pyrethroids (and, indeed, almost all pesticides). This potential can be mitigated by careful management. Reports of individual pest species becoming resistant to tefluthrin are monitored by manufacturers, regulatory bodies such as the EPA and the Insecticide Resistance Action Committee (IRAC).[29] In some cases, the risks of resistance developing can be reduced by using a mixture of two or more insecticides which each have activity on relevant pests but with unrelated mechanisms of action. IRAC assigns insecticides into classes so as to facilitate this.

References
  1. Pesticide Properties Database. "Tefluthrin". University of Hertfordshire.
  2. "Tefluthrin". US National Library of Medicine. Retrieved 2020-02-02.
  3. "Compendium of Pesticide Common Names: tefluthrin". BCPC.
  4. Metcalf, Robert L.; Horowitz, Abraham R. (2014). "Insect Control, 1. Fundamentals". Ullmann's Encyclopedia of Industrial Chemistry. Wiley-VCH. doi:10.1002/14356007.a14_263.
  5. McDonald, E.; Punja, N.; Jutsum, A. R. (1986). "Rationale in the invention and optimization of tefluthrin, a pyrethroid for use in soil". British Crop Protection Conference--Pests and Diseases, Proceedings (1): 199–206.
  6. GB withdrawn 2085000, Crosby, John, "An improved process for the preparation of certain cyclopropane pyrethroid intermediates having a high cis-content", published 1982-04-21, assigned to ICI plc
  7. US patent 4551546, Punja, N, assigned to ICI plc
  8. McDonald, Edward; Punja, Nazim (1986). "A note on the synthesis and biological activity of polyfluorobenzyl pyrethroid esters". Pesticide Science. 17 (4): 459–463. doi:10.1002/ps.2780170418.
  9. Milner, D.J. (1989). "Routes to the insecticides tefluthrin: Unusual steps on the road to the 4-methyl-2,3,5,6-tetrafluorobenzyl unit". Journal of Fluorine Chemistry. 45: 107. doi:10.1016/S0022-1139(00)84479-6.
  10. Elliott, Michael (1977). "Synthetic pyrethroids". ACS Symposium Series. Vol. 42. American Chemical Society,Washington. pp. 1–28. doi:10.1021/bk-1977-0042.ch001. ISBN 978-0-8412-0368-6.
  11. "Syngenta: Celebrating 75 years of scientific excellence at Jealott's Hill International Research Centre" (PDF). Syngenta. 2003. Archived from the original (PDF) on October 11, 2007.
  12. "US4551546, Halogentated esters".
  13. "EUR-Lex - 32008D0934 - EN". eur-lex.europa.eu. 2008-12-05.
  14. "EUR-Lex - 02008D0934-20120101 - EN". 2012-01-01.
  15. "EU Pesticides database - European Commission". ec.europa.eu.
  16. Tan, Jianguo; Soderlund, David M. (2008). "Human and Rat Nav1.3 Voltage-Gated Sodium Channels Differ in Inactivation Properties and Sensitivity to the Pyrethroid Insecticide Tefluthrin". Neurotoxicology. 30 (1): 81–89. doi:10.1016/j.neuro.2008.10.008. ISSN 0161-813X. PMC 2696113. PMID 19026681.
  17. Trainer, Vera L.; Mcphee, Jancy C.; Boutelet-Bochan, Helene; Baker, Carl; Scheuer, Todd; Babin, Didier; Demoute, Jean-Pierre; Guedin, Denis; Catterall, William A. (1 April 1997). "High Affinity Binding of Pyrethroids to the α Subunit of Brain Sodium Channels". Molecular Pharmacology. 51 (4): 651–657. doi:10.1124/mol.51.4.651. ISSN 0026-895X. PMID 9106631. S2CID 89494224.
  18. Goldin, Alan L.; Barchi, Robert L.; Caldwell, John H.; Hofmann, Franz; Howe, James R.; Hunter, John C.; Kallen, Roland G.; Mandel, Gail; Meisler, Miriam H.; Netter, Yoheved Berwald; Noda, Masahara; Tamkun, Michael M.; Waxman, Steven G.; Wood, John N.; Catterall, William A. (1 November 2000). "Nomenclature of Voltage-Gated Sodium Channels". Neuron. 28 (2): 365–368. doi:10.1016/S0896-6273(00)00116-1. ISSN 0896-6273. PMID 11144347.
  19. Tan, Jianguo; Soderlund, David M. (15 September 2010). "Divergent actions of the pyrethroid insecticides S-bioallethrin, tefluthrin, and deltamethrin on rat Nav1.6 sodium channels". Toxicology and Applied Pharmacology. 247 (3): 229–237. doi:10.1016/j.taap.2010.07.001. ISSN 0041-008X. PMC 2929565. PMID 20624410.
  20. Klaassen, Curtis D., ed. (2001). Casarett and Doull's toxicology: the basic science of poisons (6th. ed.). New York: McGraw-Hill, Medical Pub. Division. ISBN 978-0-07-134721-1.
  21. "Force 6.5g insecticide". Syngenta United States. Retrieved 2020-02-02.
  22. Willson HR (1996). "Pesticide Regulations". In Radcliffe EB, Hutchison WD, Cancelado RE (eds.). Radcliffe's IPM World Textbook. St. Paul: University of Minnesota. Archived from the original on July 13, 2017.
  23. "Pesticides and Public Health". Pesticides: Health and Safety. US EPA. 2015-08-20. Archived from the original on January 14, 2014. Retrieved 2020-02-04.
  24. EPA (27 February 2013). "The Pesticide Label". Retrieved 2020-02-04.
  25. "Force 6.5g". Syngenta United States. Retrieved 2020-02-02.
  26. US Geological Survey (2020-06-18). "Estimated Agricultural Use for tefluthrin, 2017". Retrieved 2020-09-04.
  27. Marrs, Tim (2012). Mammalian Toxicology of Insecticides. Cambridge: The Royal Society of Chemistry. pp. 156–158. ISBN 978-1-84973-300-7.
  28. Tefluthrin. Pest Management Regulatory Agency. 2010. p. 116. ISBN 978-1-100-14618-8.
  29. "IRAC website".

Further reading
  • Leahy, J.P., ed. (1985). The Pyrethroid Insecticides. Taylor and Francis, London. p. 440. ISBN 0-85066-283-4.
  • Naumann, Klaus (2013). Synthetic Pyrethroid Insecticides: Structures and Properties. Springer. p. 244. ISBN 978-3-642-74851-6.
  • Naumann, Klaus (2012). Synthetic Pyrethroid Insecticides: Chemistry and Patents. Springer. p. 412. ISBN 978-3-642-74854-7.
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