Permethrin

Permethrin
Names
IUPAC name
(±)-3-Phenoxybenzyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate
Identifiers
52645-53-1 YesY
3D model (Jmol) Interactive image
ChEBI CHEBI:34911 YesY
ChEMBL ChEMBL1525 YesY
ChemSpider 36845 YesY
DrugBank DB04930 YesY
ECHA InfoCard 100.052.771
KEGG C14388 YesY
PubChem 40326
UNII 509F88P9SZ YesY
Properties
C21H20Cl2O3
Molar mass 391.29 g·mol−1
Appearance Colorless crystals
Density 1.19 g/cm3, solid
Melting point 34 °C (93 °F; 307 K)
Boiling point 200 °C (392 °F; 473 K)
5.5 x 10−3 ppm
Pharmacology
P03AC04 (WHO) QP53AC04 (WHO)
Hazards
Main hazards Irritating to skin and eyes,
damaging to lungs
Related compounds
Related pyrethroids
 Bifenthrin
Deltamethrin
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
YesY verify (what is YesYN ?)
Infobox references

Permethrin is a medication and chemical widely used as an insecticide, acaricide, and insect repellent. Permethrin is a first-line treatment for scabies when used as a cream.

It belongs to the family of synthetic chemicals called pyrethroids and functions as a neurotoxin, affecting neuron membranes by prolonging sodium channel activation. It is not known to rapidly harm most mammals or birds, but is toxic to fish and cats. In cats it may induce hyperexcitability, tremors, seizures, and death.[1] In general, it has a low mammalian toxicity and is poorly absorbed by skin.[2]

It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[3]

Uses

Permethrin is used:

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.[4]

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.[5]

For treatment of head lice: Apply to hair, scalp, and neck after shampooing. Leave in for 10 minutes and rinse. Avoid contact with eyes.[6]

Pest control

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, and aquatic life.[7]

Permethrin kills ticks 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 instantly 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. Military personnel training in malaria-endemic areas may be instructed to treat their uniforms with permethrin, as well.

Permethrin is the most commonly used insecticide worldwide for the protection of wool from keratinophagous insects such as Tineola bisselliella.[8]

Side effects

Permethrin application can cause mild skin irritation and burning. Discontinue use if hypersensitivity occurs.

Safety

Permethrin has little systemic absorption, and is considered safe for topical use in adults and children over the age of 2 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 breastfeeding is recommended to be temporarily discontinued during treatment.[6]

Pharmacokinetics

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.[9]

Distribution

Distribution of permethrin has been studied in rat models, with highest amounts accumulating in fat and the brain.[10] 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.[9] Elimination of these metabolites occurs via urinary excretion.

Military use

To better protect soldiers from the risk and annoyance of biting insects, the US[11] and British[12] armies are treating all new uniforms with permethrin.

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.

Toxicology and safety

Permethrin acts as a neurotoxin, slowing down the nervous system through binding to sodium channels. This action is negatively correlated to temperature, thus, in general, showing more acute effects on cold-blooded animals (insects, fish, frogs, etc.) over warm-blooded animals (mammals and birds):

Permethrin is listed as a "restricted use" substance by the US Environmental Protection Agency (EPA)[14] due to its high toxicity to aquatic organisms,[15] so permethrin and permethrin-contaminated water should be properly disposed. 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.[16]

Human exposure

According to the Connecticut Department of Public Health, permethrin "has low mammalian toxicity, is poorly absorbed through the skin, and is rapidly inactivated by the body. Skin reactions have been uncommon."[17]

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.[18]

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, based on reproducible studies in which mice fed permethrin developed liver and lung tumors.[19] Carcinogenic action in nasal mucosal cells due to inhalation exposure is suspected, due to observed genotoxicity in human tissue samples, and in rat livers the evidence of increased preneoplastic lesions raises concern over oral exposure.[20][21]

Animal studies by Bloomquist et al.[22] suggest a possible link of permethrin exposure to Parkinson's disease, including very small exposures:

2002 study – "Our studies have documented low-dose effects of permethrin, doses below one-one thousandth of a lethal dose for a mouse, with effects on those brain pathways involved in Parkinson's disease [...] We have found effects consistent with a pre-parkinsonsian condition, but not yet full-blown parkinsonism." [23][24]

However, a 2007 study by the same researcher concluded "little hazard to humans" existed.

2007 study – "long-term, low-dose exposure to permethrin alone did not cause signs of neurotoxicity to striatal dopaminergic neural terminals, or enhance the effects of MPTP. We conclude that, under typical use conditions, permethrin poses little parkinsonian hazard to humans, including when impregnated into clothing for control of biting flies"[25]

A 2006 study in South Africa found residues of permethrin in breast milk in an area that experienced the use of pyrethroids in small-scale agriculture.[26]

Domestic animals

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.[27]

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.[28][29] This intolerance is due to a defect in glucuronosyltransferase, a common detoxification enzyme in other mammals (that also makes the cat intolerant to paracetamol and many essential oils).[30] The use of any external parasiticides based on permethrin is contraindicated for cats. (Cat ecotoxicology : cutaneous 100 mg/kg - oral 200 mg/kg.)

Synthesis

Permethrin was first synthesized in 1973.[31]

Numerous synthetic routes exist for the production of the DV-acid ester precursor. The pathway known as the Kuraray Process uses four steps.[32] 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.[32]

The alcohol precursor may be prepared in three steps. First, m-cresol, chlorobenzene, sodium hydroxide, potassium hydroxide, and copper chloride react to yield m-phenoxytoluene. 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.[32]

Brand names

It is marketed by Johnson & Johnson under the name Lyclear. In Nordic countries and North America, it is marketed under trade name Nix, often available over the counter.

See also

References

  1. ↑ Stephen W. Page (2008). "10: Antiparasitic drugs". In Jill E. Maddison. Small Animal Clinical Pharmacology. Stephen W. Page, David Church. Elsevier Health Sciences. p. 236. ISBN 0-7020-2858-4. Retrieved 27 August 2014.
  2. ↑ "Permethrin". Pmep.cce.cornell.edu. 16 April 1986. Retrieved 5 January 2011.
  3. ↑ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  4. ↑ "Permethrin (Lexi-Drugs)". Lexicomp Online. Wolters Kluwer. Retrieved 19 April 2014.
  5. ↑ "Permethrin Patient Package Insert" (PDF). FDA. Retrieved 19 April 2014.
  6. 1 2 "Package Label" (PDF). Alpharma, USPD, Inc. Baltimore. Retrieved 19 April 2014.
  7. ↑ R. H. Ian (1989). "Aquatic organisms and pyrethroids". Pesticide Science. 27 (4): 429–457. doi:10.1002/ps.2780270408.
  8. ↑ Ingham P. E.; McNeil S. J.; Sunderland M. R. (2012). "Functional finishes for wool – Eco considerations". Advanced Materials Research. 441: 33–43. doi:10.4028/www.scientific.net/amr.441.33.
  9. 1 2 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.
  10. ↑ Tornero-Velez, R; Davis, J; Scollon, EJ; Starr, JM; Setzer, RW; Goldsmith, MR; Chang, DT; Xue, J; Zartarian, V; DeVito, MJ; Hughes, MF (Nov 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.
  11. ↑ Insect-repelling ACUs now available to all Soldiers, United States Army, Canadian and
  12. ↑ Personal Clothing - British Army Website, What's In The Black Bag? Accessed 14 October 2015
  13. ↑ "report "Cats 'killed by flea treatment'"". BBC News. 10 November 2007. Retrieved 5 January 2011.
  14. ↑ Environmental Protection Agency. "Restricted Use Products (RUP) Report: Six Month Summary List". Retrieved 1 December 2009.
  15. ↑ Environmental Protection Agency. "Permethrin Facts (RED Fact Sheet)". Retrieved 2 September 2011.
  16. ↑ Heather Imgrund (January 28, 2003). "Environmental Fate of Permethrin" (PDF). Environmental Monitoring Branch, California Department of Pesticide Regulation, California Environmental Protection Agency.
  17. ↑ Kirby C. Stafford III (February 1999). "Tick Bite Prevention". Connecticut Department of Public Health.
  18. ↑ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1215–1216.
  19. ↑ Permethrin Facts, US EPA, June 2006.
  20. ↑ M. Tisch; P. Schmezer; M. Faulde; A. Groh; H. Maier (2002). "Genotoxicity studies on permethrin, DEET and diazinon in primary human nasal mucosal cells". European Archives of Oto-Rhino-Laryngology. 259 (3): 150–153. doi:10.1007/s004050100406.
  21. ↑ K. Hakoi; R. Cabral; T. Hoshiya; R. Hasegawa; T. Shirai; N. Ito (1992). "Analysis of carcinogenic activity of some pesticides in a medium-term liver bioassay in the rat". Teratogenesis, Carcinogenesis, and Mutagenesis. 12 (6): 269–276. doi:10.1002/tcm.1770120605.
  22. ↑ Bloomquist, J. R.; Barlow, R. L.; Gillette, J. S.; Li, W.; Kirby, M. L. (2002). "Selective effects of insecticides on nigrostriatal dopaminergic nerve pathways". Neurotoxicology. 23 (4–5): 537–544. doi:10.1016/S0161-813X(02)00031-1. PMID 12428726.
  23. ↑ BBC News, March 2006.
  24. ↑ Virginia Tech, March 2003.
  25. ↑ Kou, J.; Bloomquist, J. R. (2007). "Neurotoxicity in murine striatal dopaminergic pathways following long-term application of low doses of permethrin and MPTP.". Toxicol Lett. 171 (3): 154–161. doi:10.1016/j.toxlet.2007.05.005. PMID 17597311.
  26. ↑ Bouwman, H.; Sereda, B.; Meinhardt, H. M. (2006). "Simultaneous presence of DDT and pyrethroid residues in human breast milk from a malaria-endemic area in South Africa". Environmental Pollution. 144 (3): 902–917. doi:10.1016/j.envpol.2006.02.002. PMID 16564119.
  27. ↑ 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.
  28. ↑ http://www.aspcapro.org/sites/pro/files/d-veccs_april00.pdf
  29. ↑ Dymond NL, Swift IM (2008). "Permethrin toxicity in cats: a retrospective study of 20 cases.". nih.gov. 86: 219–23. doi:10.1111/j.1751-0813.2008.00298.x. PMID 18498556.
  30. ↑ http://www.depecheveterinaire.com/basedocudv/actualites_dermatologiques_etude_retrospective_australienne_signes_nerveux_digestifs.pdf
  31. ↑ Elliott, M; Farnham, AW; Janes, NF; Needham, PH; Pulman, DA; Stevenson, JH (16 November 1973). "A photostable pyrethroid.". Nature. 246 (5429): 169–70. PMID 4586114.
  32. 1 2 3 Leonard A. Wasselle, "Pyrethroid Insecticides." SRI International Report #143, Menlo Park, CA, 94025, June 1981.
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