Permethrin

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Permethrin
Two-dimensional chemical structure of permethrin
Three-dimensional chemical structure of permethrin
Clinical data
Trade namesNix, Rid, Elimite, others
AHFS/Drugs.comMonograph
Routes of
administration		topical
ATC code
Legal status
Legal status
Pharmacokinetic data
MetabolismInsects are more affected by permethrin than humans or dogs because they are unable to metabolise the toxins as quickly as humans and dogs. Cats, although not experiencing the full effect of permethrin, are more sensitive to this toxin.[1]
Identifiers
  • (±)-3-Phenoxybenzyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.052.771 Edit this at Wikidata
Chemical and physical data
FormulaC21H20Cl2O3
Molar mass391.29 g·mol−1
3D model (JSmol)
Density1.19 g/cm3, solid g/cm3
Melting point34 °C (93 °F)
Boiling point200 °C (392 °F)
Solubility in water5.5 x 10−3 ppm, 0.2 [2] mg/mL (25°C)
  • Cl/C(Cl)=C/C3C(C(=O)OCc2cccc(Oc1ccccc1)c2)C3(C)C
  • InChI=1S/C21H20Cl2O3/c1-21(2)17(12-18(22)23)19(21)20(24)25-13-14-7-6-10-16(11-14)26-15-8-4-3-5-9-15/h3-12,17,19H,13H2,1-2H3
  • Key:RLLPVAHGXHCWKJ-UHFFFAOYSA-N

Permethrin is a medication and an insecticide.[3][4] As a medication, it is used to treat scabies and lice.[5] It is applied to the skin as a cream or lotion.[3] As an insecticide, it can be sprayed onto clothing or mosquito nets to kill the insects that touch them.[4]

Side effects include rash and irritation at the area of use.[5] Use during pregnancy appears to be safe.[3] It is approved for use on and around people over the age of two months.[3] Permethrin is in the pyrethroid family of medications.[3] It works by disrupting the function of the neurons of lice and scabies mites.[3]

Permethrin was discovered in 1973.[6] It is on the World Health Organization's List of Essential Medicines.[7] In 2020, it was the 427th most commonly prescribed medication in the United States, with more than 100 thousand prescriptions.[8]

Uses

Insecticide

  • In agriculture, to protect crops (a drawback is that it is lethal to bees)
  • In agriculture, to kill livestock parasites
  • For industrial and domestic insect control
  • In the textile industry, to prevent insect attack of woollen products
  • In aviation, the WHO, IHR and ICAO require arriving aircraft be disinsected prior to embarkation, departure, descent, or deplaning in certain countries. Aircraft disinsection with permethrin-based products is recommended only prior to embarkation. Prior to departure (after boarding), at the top of descent or on arrival, d-phenothrin-based (1R-trans phenothrin) aircraft insecticides are recommended.

Insect repellent

  • As a personal protective measure, permethrin is applied to clothing. It is a cloth impregnant, notably in mosquito nets and field wear. While permethrin may be marketed as an insect repellent, it does not prevent insects from landing. Instead it works by incapacitating or killing insects before they can bite.[9]
  • In pet flea preventive collars or treatment (safe for use on dogs but not cats[10])
  • In timber treatment

Medical use

Permethrin is available for topical use as a cream or lotion. It is indicated for the treatment and prevention in exposed individuals of head lice and treatment of scabies.[11]

For treatment of scabies: Adults and children older than 2 months are instructed to apply the cream to the entire body from head to the soles of the feet. Wash off the cream after 8–14 hours. In general, one treatment is curative.[12]

For treatment of head lice: Apply to hair, scalp, and neck after shampooing. Leave in for 10 minutes and rinse. Avoid contact with eyes.[13]

Pest control / effectiveness and persistence

In agriculture, permethrin is mainly used on cotton, wheat, maize, and alfalfa crops. Its use is controversial because, as a broad-spectrum chemical, it kills indiscriminately; as well as the intended pests, it can harm beneficial insects, including honey bees, as well as cats and aquatic life.[14][15]

Permethrin kills ticks and mosquitoes on contact with treated clothing. A method of reducing deer tick populations by treating rodent vectors involves stuffing biodegradable cardboard tubes with permethrin-treated cotton. Mice collect the cotton for lining their nests. Permethrin on the cotton kills any immature ticks feeding on the mice.

Permethrin is used in tropical areas to prevent mosquito-borne disease such as dengue fever and malaria. Mosquito nets used to cover beds may be treated with a solution of permethrin. This increases the effectiveness of the bed net by killing parasitic insects before they are able to find gaps or holes in the net. Personnel working in malaria-endemic areas may be instructed to treat their clothing with permethrin as well.

Permethrin is the most commonly used insecticide worldwide for the protection of wool from keratinophagous insects such as Tineola bisselliella.[16]

To better protect soldiers from the risk and annoyance of biting insects, the British[17] and US armies are treating all new uniforms with permethrin.[18]

Permethrin (as well as other long-term pyrethroids) is effective over several months, in particular when used indoors. International studies report that permethrin can be detected in house dust, in fine dust, and on indoor surfaces even years after the application. Its degradation rate under indoor conditions is approximately 10% after 3 months.[19][20]

Resistance

Contrary to the most common mechanism of insecticide resistance evolution – selection for preexisting, low-frequency alleles – in Aedes aegypti permethrin resistance has arisen through the mechanism common to pyrethroids and DDT known as "knockdown resistance" (kdr) mutations. García et al 2009 found that a kdr allele has rapidly spread throughout Mexico and recently become dominant there.[21]

Side effects

Permethrin application can cause mild skin irritation and burning. Permethrin has little systemic absorption, and is considered safe for topical use in adults and children over the age of two months. The FDA has assigned it as pregnancy category B. Animal studies have shown no effects on fertility or teratogenicity, but studies in humans have not been performed. The excretion of permethrin in breastmilk is unknown, and it is recommended that breastfeeding be temporarily discontinued during treatment.[13] Skin reactions are uncommon.[22] Excessive exposure to permethrin can cause nausea, headache, muscle weakness, excessive salivation, shortness of breath, and seizures. Worker exposure to the chemical can be monitored by measurement of the urinary metabolites, while severe overdose may be confirmed by measurement of permethrin in serum or blood plasma.[23]

Permethrin does not present any notable genotoxicity or immunotoxicity in humans and farm animals, but is classified by the EPA as a likely human carcinogen when ingested, based on reproducible studies in which mice fed permethrin developed liver and lung tumors.[24]

Pharmacokinetics

Permethrin is a chemical categorized in the pyrethroid insecticide group.[25] The chemicals in the pyrethroid family are created to emulate the chemicals found in the chrysanthemum flower.[25]

Absorption

Absorption of topical permethrin is minimal. One in vivo study demonstrated 0.5% absorption in the first 48 hours based upon excretion of urinary metabolites.[26]

Distribution

Distribution of permethrin has been studied in rat models, with highest amounts accumulating in fat and the brain.[27] This can be explained by the lipophilic nature of the permethrin molecule.

Metabolism

Metabolism of permethrin occurs mainly in the liver, where the molecule undergoes oxidation by the cytochrome P450 system, as well as hydrolysis, into metabolites.[26] Elimination of these metabolites occurs via urinary excretion.

Stereochemistry

Permethrin has four stereoisomers (two enantiomeric pairs), arising from the two stereocenters in the cyclopropane ring. The trans enantiomeric pair is known as transpermethrin. (1R,3S)-trans and (1R,3R)-cis enantiomers are responsible for the insecticidal properties of permethrin.[28]

  • (1S,3R)-trans enantiomer
    (1S,3R)-trans enantiomer
  • (1R,3S)-trans enantiomer
    (1R,3S)-trans enantiomer
  • (1S,3S)-cis enantiomer
    (1S,3S)-cis enantiomer
  • (1R,3R)-cis enantiomer
    (1R,3R)-cis enantiomer

History

Permethrin was first made in 1973.[29]

Numerous synthetic routes exist for the production of the DV-acid ester precursor.[30] The pathway known as the Kuraray Process uses four steps.[31] In general, the final step in the total synthesis of any of the synthetic pyrethroids is a coupling of a DV-acid ester and an alcohol. In the case of permethrin synthesis, the DV-acid cyclopropanecarboxylic acid, 3-(2,2-dichloroethenyl)-2,2-dimethyl-, ethyl ester, is coupled with the alcohol, m-phenoxybenzyl alcohol, through a transesterification reaction with base. Tetraisopropyl titanate or sodium ethylate may be used as the base.[31]

The alcohol precursor may be prepared in three steps. First, m-cresol, chlorobenzene, sodium hydroxide, potassium hydroxide, and cuprous chloride react to yield m-phenoxytoluene.[32] Second, oxidation of m-phenoxytoluene over selenium dioxide provides m-phenoxybenzaldehyde. Third, a Cannizzaro reaction of the benzaldehyde in formaldehyde and potassium hydroxide affords the m-phenoxybenzyl alcohol.[31]

Brand names

In Nordic countries and North America, a permethrin formulation for lice treatment is marketed under trade name Nix, available over the counter. Johnson & Johnson's UK brand Lyclear covers an assortment of different products, mostly non-insecticidal, but a few of which are based on permethrin.[33]

Stronger concentrations of permethrin are used to treat scabies (which embed inside the skin), compared to lice (which remain outside the skin). In the U.S. the more concentrated products such as Elimite are available by prescription only.[34]

Other animals

It is known to be highly toxic to cats, fish and aquatic species with long-lasting effects.[35][36]

Cats

Permethrin is toxic to cats; however, it has little effect on dogs.[25][37][38] Pesticide-grade permethrin is toxic to cats. Many cats die after being given flea treatments intended for dogs, or by contact with dogs having recently been treated with permethrin.[39] In cats it may induce hyperexcitability, tremors, seizures, and death.[40]

Toxic exposure of permethrin can cause several symptoms, including convulsion, hyperaesthesia, hyperthermia, hypersalivation, and loss of balance and coordination. Exposure to pyrethroid-derived drugs such as permethrin requires treatment by a veterinarian, otherwise the poisoning is often fatal.[41][42] This intolerance is due to a defect in glucuronosyltransferase, a common detoxification enzyme in other mammals, that also makes the cat intolerant to paracetamol (acetaminophen).[43] The use of any external parasiticides based on permethrin is contraindicated for cats.

Aquatic organisms

Permethrin is listed as a "restricted use" substance by the US Environmental Protection Agency (EPA)[44] due to its high toxicity to aquatic organisms,[45] so permethrin and permethrin-contaminated water should be properly disposed of. Permethrin is quite stable, having a half life of 51–71 days in an aqueous environment exposed to light. It is also highly persistent in soil.[46]

See also

References

  1. ^ "Permethrin General Fact Sheet". National Pesticide Information Center. Archived from the original on 18 July 2018. Retrieved 24 July 2018.
  2. ^ Metcalf deceased, Robert L.; Horowitz, Abraham Rami (19 November 2014). "Insect Control, 2. Individual Insecticides". Ullmann's Encyclopedia of Industrial Chemistry: 1–94. doi:10.1002/14356007.s14_s01. ISBN 9783527306732.
  3. ^ a b c d e f "Permethrin". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
  4. ^ a b Keystone, J. S.; Kozarsky, Phyllis E.; Freedman, David O.; Connor, Bradley A. (2013). Travel Medicine. Elsevier Health Sciences. p. 58. ISBN 978-1-4557-1076-8. Archived from the original on 20 December 2016.
  5. ^ a b World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. p. 213. hdl:10665/44053. ISBN 9789241547659.
  6. ^ Zweig, Gunter; Sherma, Joseph (2013). Synthetic Pyrethroids and Other Pesticides: Analytical Methods for Pesticides and Plant Growth Regulators. Academic Press. p. 104. ISBN 978-1-4832-2090-1. Archived from the original on 20 December 2016.
  7. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  8. ^ "Permethrin - Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
  9. ^ Jeneen, Interlandi. "Can Permethrin Treated Clothing Help You Avoid Mosquito Bites?". Consumer Reports. Archived from the original on 31 May 2019. Retrieved 31 May 2019.
  10. ^ Malik, Richard; Ward, Michael P; Seavers, Aine; Fawcett, Anne; Bell, Erin; Govendir, Merran; Page, Stephen (2010). "Permethrin Spot-On Intoxication of Cats: Literature Review and Survey of Veterinary Practitioners in Australia". Journal of Feline Medicine and Surgery. 12 (1): 5–14. doi:10.1016/j.jfms.2009.12.002. PMID 20123482. S2CID 1234198.
  11. ^ "Permethrin (Lexi-Drugs)". Lexicomp Online. Wolters Kluwer. Archived from the original on 17 April 2014. Retrieved 19 April 2014.
  12. ^ "Permethrin Patient Package Insert" (PDF). FDA. Archived (PDF) from the original on 20 April 2014. Retrieved 19 April 2014.
  13. ^ a b "Package Label" (PDF). Alpharma, USPD, Inc. Baltimore. Archived (PDF) from the original on 20 April 2014. Retrieved 19 April 2014.
  14. ^ R. H. Ian (1989). "Aquatic organisms and pyrethroids". Pesticide Science. 27 (4): 429–457. doi:10.1002/ps.2780270408.
  15. ^ Drago, Bonny; Shah, Namrata S.; Shah, Samir H. (2014). "Acute permethrin neurotoxicity: Variable presentations, high index of suspicion". Toxicology Reports. 1: 1026–1028. doi:10.1016/j.toxrep.2014.09.007. PMC 5598406. PMID 28962315.
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  18. ^ Insect-repelling ACUs now available to all Soldiers Archived 4 October 2013 at the Wayback Machine, United States Army, Canadian and
  19. ^ Nakagawa, L. E.; Do Nascimento, C. M.; Costa, A. R.; Polatto, R.; Papini, S. (2020). "Persistence of indoor permethrin and estimation of dermal and non-dietary exposure". Journal of Exposure Science & Environmental Epidemiology. 30 (3): 547–553. doi:10.1038/s41370-019-0132-7. PMID 30926895. S2CID 85566713.
  20. ^ Berger-Preiess, Edith; Preiess, Alfred; Sielaff, Kriemhild; Raabe, Mechthild; Ilgen, Bert; Levsen, Karsten (1997). "The Behaviour of Pyrethroids Indoors: A Model Study". Indoor Air. 7 (4): 248–262. doi:10.1111/j.1600-0668.1997.00004.x.
  21. ^ Labbé, Pierrick; Alout, Haoues; Djogbénou, Luc; Pasteur, Nicole; Weill, Mylène (2011). "Evolution of Resistance to Insecticide in Disease Vectors". In Tibayrenc, Michel (ed.). Genetics and Evolution of Infectious Disease. Elsevier. pp. 363–409. ISBN 978-0-12-384890-1.
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  23. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1215–1216.
  24. ^ Permethrin Facts Archived 8 August 2016 at the Wayback Machine, US EPA, June 2006.
  25. ^ a b c "Permethrin General Fact Sheet". npic.orst.edu. July 2009. Archived from the original on 15 June 2018. Retrieved 2 June 2018.
  26. ^ a b van der Rhee, HJ; Farquhar, JA; Vermeulen, NP (1989). "Efficacy and transdermal absorption of permethrin in scabies patients". Acta Dermato-Venereologica. 69 (2): 170–3. PMID 2564238.
  27. ^ Tornero-Velez, R; Davis, J; Scollon, EJ; Starr, JM; Setzer, RW; Goldsmith, MR; Chang, DT; Xue, J; Zartarian, V; DeVito, MJ; Hughes, MF (November 2012). "A pharmacokinetic model of cis- and trans-permethrin disposition in rats and humans with aggregate exposure application". Toxicological Sciences. 130 (1): 33–47. doi:10.1093/toxsci/kfs236. PMID 22859315. S2CID 20980566.
  28. ^ Dornetshuber, Julia; Bicker, Wolfgang; Lämmerhofer, Michael; Lindner, Wolfgang; Karwan, Anneliese; Bursch, Wilfried (14 November 2007). "Impact of stereochemistry on biological effects of permethrin: induction of apoptosis in human hepatoma cells (HCC-1.2) and primary rat hepatocyte cultures". BMC Pharmacology. 7 (Supplement 2): A65. doi:10.1186/1471-2210-7-S2-A65. ISSN 1471-2210. Stereochemistry plays a crucial role in determining the toxicological profile of many chiral xenobiotics, e.g. the insecticidal action of mixtures containing the four stereoisomers of permethrin is essentially brought about by the (1R, cis)- and (1R, trans)-forms.
  29. ^ Elliott, M; Farnham, AW; Janes, NF; Needham, PH; Pulman, DA; Stevenson, JH (16 November 1973). "A photostable pyrethroid". Nature. 246 (5429): 169–70. Bibcode:1973Natur.246..169E. doi:10.1038/246169a0. PMID 4586114. S2CID 4176154.
  30. ^ DV-acid = 3-(2,2-Dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid
  31. ^ a b c Leonard A. Wasselle, "Pyrethroid Insecticides." SRI International Report #143, Menlo Park, CA, 94025, June 1981.
  32. ^ US 4229594A, Colby, Thomas H., "Preparation of meta-phenoxytoluene", published 1980-10-21 
  33. ^ "Head Lice Treatments". Lyclear UK. Archived from the original on 25 September 2018. Retrieved 24 September 2018.
  34. ^ "Resources for Health Professionals: Scabies Medications". U.S. CDC. 19 April 2019. Archived from the original on 30 April 2015. Retrieved 24 September 2018.
  35. ^ "Permethrin General Fact Sheet". npic.orst.edu. Archived from the original on 3 January 2018. Retrieved 6 January 2018.
  36. ^ "Permethrin". pubchem.ncbi.nlm.nih.gov. PubChem. Archived from the original on 28 June 2020. Retrieved 28 June 2020.
  37. ^ Roberts, Catherine (22 October 2018). "Should You Use Natural Tick Prevention for Your Dog or Cat?". Consumer Reports. Consumer Reports Inc. Archived from the original on 15 December 2018. Retrieved 12 December 2018.
  38. ^ Englar, Ryane E. (2019). Common Clinical Presentations in Dogs and Cats. John Wiley & Sons. p. 333. ISBN 978-1-119-41459-9. Archived from the original on 19 August 2020. Retrieved 31 May 2020.
  39. ^ Linnett, P.-J. (2008). "Permethrin toxicosis in cats". Australian Veterinary Journal. 86 (1–2): 32–35. doi:10.1111/j.1751-0813.2007.00198.x. PMID 18271821.
  40. ^ Stephen W. Page (2008). "10: Antiparasitic drugs". In Jill E. Maddison (ed.). Small Animal Clinical Pharmacology. Stephen W. Page, David Church. Elsevier Health Sciences. p. 236. ISBN 978-0-7020-2858-8. Archived from the original on 24 March 2017.
  41. ^ "Archived copy" (PDF). ASPCA Pro. Archived from the original on 3 December 2013. Retrieved 1 December 2013.{{cite web}}: CS1 maint: archived copy as title (link) CS1 maint: unfit URL (link)
  42. ^ Dymond NL, Swift IM (2008). "Permethrin toxicity in cats: a retrospective study of 20 cases". Australian Veterinary Journal. 86 (6): 219–23. doi:10.1111/j.1751-0813.2008.00298.x. PMID 18498556.
  43. ^ "Archived copy" (PDF). Archived from the original (PDF) on 27 December 2013. Retrieved 26 January 2015.{{cite web}}: CS1 maint: archived copy as title (link)
  44. ^ Environmental Protection Agency. "Restricted Use Products (RUP) Report: Six Month Summary List". Archived from the original on 11 January 2010. Retrieved 1 December 2009.
  45. ^ Environmental Protection Agency (June 2006). "Permethrin Facts (Reregistration Eligibility Decision (RED) Fact Sheet)" (PDF). epa.gov. EPA Special Review and Reregistration Division. Archived (PDF) from the original on 6 August 2020. Retrieved 13 May 2020.
  46. ^ Heather Imgrund (28 January 2003). "Environmental Fate of Permethrin" (PDF). Environmental Monitoring Branch, California Department of Pesticide Regulation, California Environmental Protection Agency. Archived (PDF) from the original on 7 October 2013.

External links


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