Triclosan

Not to be confused with triclocarban.
Triclosan
Names
IUPAC name
5-chloro-2-(2,4-dichlorophenoxy)phenol
Other names
2,4,4'-trichloro-2'-hydroxydiphenyl ether, 5-chloro-(2,4-dichlorophenoxy)phenol, trichloro-2'-hydroxydiphenyl ether, CH-3565, Lexol 300, Irgasan DP 300, Ster-Zac
Identifiers
3380-34-5 YesY
ChEBI CHEBI:164200 YesY
ChEMBL ChEMBL849 YesY
ChemSpider 5363 YesY
DrugBank DB08604 YesY
Jmol 3D model Interactive image
KEGG D06226 YesY
PubChem 5564
UNII 4NM5039Y5X YesY
Properties
C12H7Cl3O2
Molar mass 289.54 g·mol−1
Appearance White solid
Density 1.49 g/cm3
Melting point 55–57 °C (131–135 °F; 328–330 K)
Boiling point 120 °C (248 °F; 393 K)
Pharmacology
D08AE04 (WHO) D09AA06 (WHO) (medicated dressing)
Hazards
Safety data sheet MSDS
NFPA 704
Flammability code 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g., canola oil Health code 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g., chloroform Reactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g., liquid nitrogen Special hazards (white): no codeNFPA 704 four-colored diamond
1
2
0
Flash point 162.2 °C (324.0 °F; 435.3 K)
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

Triclosan, similar in its uses and mechanism of action to triclocarban, is an antibacterial and antifungal agent found in consumer products, including toothpaste, soaps, detergents, toys, and surgical cleaning treatments. Its efficacy as an antimicrobial agent, the risk of bacterial resistance and its possible role in disrupted hormonal development remain controversial. Additional research seeks to understand its potential effects on organisms and environmental health.

Uses

Triclosan was used as a hospital scrub in the 1970s. Since then, it has expanded commercially and is now prevalent in soaps (0.10-1.00%), shampoos, deodorants, toothpastes, mouth washes, cleaning supplies and pesticides.[1] It is part of consumer products, including kitchen utensils, toys, bedding, socks and trash bags.[1][2]

In healthcare, triclosan is used in surgical scrubs and hand washes.[3] Use in surgical units is effective with a minimum contact time of approximately two minutes.[4][5] More recently, showering with 2% triclosan has become a recommended regimen in surgical units for the decolonization of patients whose skin carries methicillin-resistant Staphylococcus aureus (MRSA).[6] Triclosan is also used in the coatings for some surgical sutures.[7][8]

Triclosan has been employed as a selective agent in molecular cloning. A bacterial host transformed by a plasmid harboring a triclosan resistant mutant FabI gene (mFabI) as a selectable marker can grow in presence of high dose of triclosan in growth media.[9]

Chemical structure and properties

This organic compound is a white powdered solid with a slight aromatic, phenolic odor. Categorized as a polychloro phenoxy phenol, triclosan is a chlorinated aromatic compound that has functional groups representative of both ethers and phenols. Phenols often demonstrate antibacterial properties. Triclosan is soluble in ethanol, methanol, diethyl ether, and strongly basic solutions such as a 1M sodium hydroxide solution, but only slightly soluble in water. Triclosan can be synthesized from 2,4-dichlorophenol.

Synthesis

Under a reflux process, 2,4,4'-trichloro-2'-methoxydiphenyl ether is treated with aluminium chloride.[10]

Triclosan can be synthesized through a three-step process starting with 1-(2-hydroxyethyl)pyrrolidin-2-one. The 1-(2-hydroxyethyl)pyrrolidin-2-one is dehydrated with either zinc or calcium oxide into 1-vinylpyrrolidin-2-one.[11] Then, 1-vinylpyrrolidin-2-one can be reacted with 5-chloro-2-(2,4-dichlorophenoxy)phenyl acrylate in n-heptane to form triclosan.[12]

The United States Pharmacopeia formulary has published a monograph for triclosan that sets purity standards.[13]

Mechanism of action

At high concentrations, triclosan acts as a biocide with multiple cytoplasmic and membrane targets.[14] However, at the lower concentrations seen in commercial products, triclosan appears bacteriostatic, and it targets bacteria primarily by inhibiting fatty acid synthesis.

Triclosan binds to bacterial enoyl-acyl carrier protein reductase (ENR) enzyme,[15] which is encoded by the gene FabI. This binding increases the enzyme's affinity for nicotinamide adenine dinucleotide (NAD+). This results in the formation of a stable, ternary complex of ENR-NAD+-triclosan, which is unable to participate in fatty acid synthesis. Fatty acids are necessary for building and reproducing cell membranes. Humans do not have an ENR enzyme and thus are not affected.

Effectiveness

Antimicrobial hand soaps containing triclosan provide a slightly greater bacterial reduction on the hands compared to plain soap.[16] As of 2013 the FDA has found clear benefit to health for some consumer products containing triclosan but not in others; for example the FDA had no evidence that triclosan in antibacterial soaps and body washes provides any benefit over washing with regular soap and water.[17]

A Cochrane review of 30 studies [18][19] concluded that triclosan/copolymer-containing toothpastes produced a 22% reduction in both dental plaque and gingival inflammation when compared with fluoride toothpastes without triclosan/copolymer. There was weak evidence of a reduction in tooth cavities and no evidence of reduction in Periodontitis.

Health concerns

Triclosan is considered safe but is under ongoing review by the FDA.[17] Health Canada have completed their review, concluding "that triclosan is not harmful to human health but can cause harm to the environment when used in significant amounts. This preliminary assessment confirms that Canadians can continue to safely use products such as toothpaste, shampoo and soap containing triclosan" [20]

Allergy

Triclosan has been associated with a higher risk of food allergy.[21] This may be because exposure to bacteria reduces allergies, as predicted by the hygiene hypothesis and not toxicology of the triclosan itself. This would also occur with chlorhexidine gluconate and PCMX, among other antibacterial agents.[22][23] Other studies have linked triclosan to allergic contact dermatitis in some individuals.[24][25] Additionally, triclosan concentrations have been associated with allergic sensitization, especially inhalant and seasonal allergens, rather than food allergens.[26]

By-products

Triclosan can react with the free chlorine in tap water to produce lesser amounts of other compounds, such as 2,4-dichlorophenol. Some of these intermediates convert into dioxins upon exposure to UV radiation (from the sun or other sources).[27] The dioxins that can form from triclosan are not considered to be congeners of toxicologic concern for mammals, birds and fish.[28][29]

Hormone

Concerns on the health effects of triclosan have been raised after it was detected in human breast milk, blood, and urine samples. While no human data exists, studies on rats have shown that triclosan exposure modulates estrogen-dependent responses.[30]

Environmental concerns

Treatment and disposal

The duration of triclosan in personal product use is relatively short. Upon disposal, triclosan is sent to municipal sewage treatment plants, where about 97-98% of triclosan is removed.[31] Studies show that substantial quantities of triclosan (170,000 – 970,000 kg/yr) can break through wastewater treatment plants and damage algae on surface waters.[31] In a study on effluent from wastewater treatment facilities, approximately 75% of triclocarban was present in sludge.[32] This poses a potential environmental and ecological hazard, particularly for aquatic systems. The volume of triclosan re-entering the environment in sewage sludge after initial successful capture from wastewater is 44,000 ± 60,000 kg/yr.[31] Triclosan can attach to other substances suspended in aquatic environments, which potentially endangers marine organisms and may lead to further bioaccumulation.[33] Ozone is considered to be an effective tool for removing triclosan during sewage treatment. As little triclosan is released through plastic and textile household consumer products, these are not considered to be major sources of triclosan contamination.[33]

During wastewater treatment, a portion of triclosan is degraded, while the remaining adsorbs to sewage sludge or exits the plant as effluent.[34][35] In the environment, triclosan may be degraded by microorganisms or react with sunlight, forming other compounds, which include chlorophenols and dioxins.

Bioaccumulation

While studies using semi-permeable membrane devices have found that triclosan does not strongly bioaccumulate, methyl-triclosan is comparatively more stable and lipophilic and thus poses a higher risk of bioaccumulation. The ability of triclosan to bioaccumulate is affected by its ionization state in different environmental conditions.[36]

Global warming may increase uptake and effects of triclosan in aquatic organisms.[37]

Ecotoxicity

Triclosan is toxic to aquatic bacteria at levels found in the environment. It is highly toxic to various types of algae and has the potential to affect the structure of algal communities, particularly immediately downstream of effluents from wastewater treatment facilities that treat household wastewaters.[38] Triclosan has been observed in multiple organisms, including algae aquatic blackworms, fish and dolphins. It has also been found in land animals including earthworms and species higher up the food chain.[31]

Resistance concerns

Concern pertains to the potential for cross-resistance or co-resistance to other antimicrobials. Studies investigating this possibility have been limited.[39]

Alternatives

A comprehensive analysis in 2007 from the University of Michigan School of Public Health indicated that plain soaps are just as effective as consumer-grade antibacterial soaps with triclosan in preventing illness and removing bacteria from the hands.[40]

Nonorganic antibiotics and organic biocides are effective alternatives to triclosan, such as silver and copper ions and nanoparticles.[41]

Policy

The U.S. Food and Drug Administration, the Environmental Protection Agency, and the European Commission are regulatory bodies for triclosan. Triclosan was not approved by the European Commission as an active substance for use in biocidal products for product-type 1 in January 2016.[42] In the United States, manufacturers of products containing triclosan must indicate its presence on the label. In Europe, triclosan is regulated as a cosmetic preservative and must be listed on the label.[43] Usage of triclosan in cosmetic products was restricted by the EU commission in 2014.[44]

In light of the health concerns, the FDA in the 1970s reviewed the safety of triclocarban and triclosan, but took no regulatory action. In 2010, the Natural Resources Defense Council forced the FDA to review triclosan after suing them for their inaction. Since the FDA prohibited hexachlorophene, a compound similar to triclosan, Halden and others argued the FDA should also ban triclosan.[31] On December 17, 2013, the FDA issued a draft rule revoking the Generally Regarded as Safe status of triclosan as an ingredient in hand wash products, citing the need for additional studies of its potential endrocrine and developmental effects; impact on bacterial resistance; and carcinogenic potential.[45]

On May 16, 2014, Minnesota governor Mark Dayton signed a bill banning the use of triclosan in most retail consumer hygiene products sold in the state. The ban is set to take effect January 1, 2017.[46]

Synthesis

Triclosan synthesis (Example 4): E. Model, J. Bindler, U.S. Patent 3,506,720 (1970 to Geigy).

See also

References

  1. 1 2 Thompson, A.; Griffin, P.; Stuetz, R.; Cartmell, E. (2005). "The Fate and Removal of Triclosan during Wastewater Treatment". Water Environment Research 77 (1): 63–7. doi:10.2175/106143005X41636. JSTOR 25045839. PMID 15765937.
  2. ↑ Record in the Household Products Database of NLM
  3. ↑ Food and Drug Administration (17 June 1994). "Federal Register Notice: Tentative Final Monograph for OTC Healthcare Antiseptic Drug Products" (PDF).
  4. ↑ Brady, L. M.; Thomson, M; Palmer, M. A.; Harkness, J. L. (1990). "Successful control of endemic MRSA in a cardiothoracic surgical unit". The Medical journal of Australia 152 (5): 240–5. PMID 2255283.
  5. ↑ Zafar, A.B.; Butler, R.C.; Reese, D.J.; Gaydos, L.A.; Mennonna, P.A. (1995). "Use of 0.3% triclosan (Bacti-Stat) to eradicate an outbreak of methicillin-resistant Staphylococcus aureus in a neonatal nursery". American Journal of Infection Control 23 (3): 200–8. doi:10.1016/0196-6553(95)90042-X. PMID 7677266.
  6. ↑ Coia, J.E.; Duckworth, G.J.; Edwards, D.I.; Farrington, M.; Fry, C.; Humphreys, H.; Mallaghan, C.; Tucker, D.R.; Joint Working Party of the British Society of Antimicrobial Chemotherapy; Hospital Infection, Society; Infection Control Nurses Association (2006). "Guidelines for the control and prevention of meticillin-resistant Staphylococcus aureus (MRSA) in healthcare facilities". Journal of Hospital Infection 63: S1–44. doi:10.1016/j.jhin.2006.01.001. PMID 16581155.
  7. ↑ Tobias, Karen M.; Johnston, Spencer A. Veterinary Surgery: Small Animal: 2-Volume Set. Elsevier Health Sciences. p. 190. ISBN 9780323263375. Retrieved 26 January 2016. Triclosan is a commonly used antibiotic coating
  8. ↑ Singer, Adam J.; Hollander, Judd E.; Blumm, Robert M. Skin and Soft Tissue Injuries and Infections: A Practical Evidence Based Guide. PMPH-USA. p. 95. ISBN 9781607950295. Retrieved 26 January 2016. Examples of antibacterial sutures that are coated with the antibacterial agent triclosan include... In many institutions these have replaced the comparable non-antibacterial sutures.
  9. ↑ Jang, Chuan-Wei; Magnuson, Terry (2013). "A Novel Selection Marker for Efficient DNA Cloning and Recombineering in E. Coli". PLoS ONE 8 (2): e57075. Bibcode:2013PLoSO...857075J. doi:10.1371/journal.pone.0057075. PMC 3577784. PMID 23437314.
  10. ↑ Commonwealth of Australia. Department of Health and Ageing. National Industrial Chemicals Notification and Assessment Scheme. Priority Existing Chemical Assessment Report No. 30. National Industrial Chemicals Notification and Assessment Scheme, Jan. 2009. Web. Apr. 2014.
  11. ↑ US patent 6982337, "Kahn, A.P. Production of N-Vinyl Pyrrolidone"., Apr 1, 2004.
  12. ↑ US 6315987. Nov 13, 2001.
  13. ↑ US Pharmacopoeia National Formulary. United States Pharmacopeial. 2012. ISBN 1936424126.
  14. ↑ Russell AD (May 2004). "Whither triclosan?". J. Antimicrob. Chemother. 53 (5): 693–5. doi:10.1093/jac/dkh171. PMID 15073159.
  15. ↑ The WHO Guidelines on Hand Hygiene in Healthcare (Advanced Draft), WHO, 2006, page 37 "9.9 Triclosan"
  16. ↑ Montville, Rebecca; Schaffner, Donald W. (2011). "A Meta-Analysis of the Published Literature on the Effectiveness of Antimicrobial Soaps". Journal of Food Protection 74 (11): 1875–82. doi:10.4315/0362-028X.JFP-11-122. PMID 22054188.
  17. 1 2 "Triclosan: What Consumers Should Know". FDA. 2013-12-16. Retrieved 2014-07-15.
  18. ↑ . doi:10.1002/14651858.CD010514.pub2. Missing or empty |title= (help)
  19. ↑ . 1996. doi:10.1002/14651858. Missing or empty |title= (help)
  20. ↑ Health Canada. Health Canada http://www.hc-sc.gc.ca/cps-spc/cosmet-person/labelling-etiquetage/ingredients-eng.php#a4.14. Missing or empty |title= (help)
  21. ↑ Sicherer, Scott H.; Leung, Donald Y.M. (2013). "Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects in 2012". Journal of Allergy and Clinical Immunology 131 (1): 55–66. doi:10.1016/j.jaci.2012.11.007. PMID 23199604.
  22. ↑ Clayton, Erin M. Rees; Todd, Megan; Dowd, Jennifer Beam; Aiello, Allison E. (2010). "The Impact of Bisphenol a and Triclosan on Immune Parameters in the U.S. Population, NHANES 2003–2006". Environmental Health Perspectives 119 (3): 390–6. doi:10.1289/ehp.1002883. PMC 3060004. PMID 21062687. Lay summary – ScienceDaily (Nov 30, 2010).
  23. ↑ Fulton, April (November 29, 2010). "New Questions Raised On Chemicals In Soaps, Plastics". NPR. Retrieved 2010-11-30.
  24. ↑ Bhutani, Tina; Jacob, Sharon E. (2009). "Triclosan". Dermatologic Surgery 35 (5): 888–9. doi:10.1111/j.1524-4725.2009.01151.x. PMID 19389086.
  25. ↑ Campbell, Lauren; Zirwas, Matthew J.; Mowad, Christen M. (2006). "Triclosan". Dermatitis 17 (4): 204–7. doi:10.2310/6620.2006.06014. PMID 17150172.
  26. ↑ Bertelsen, R. J.; Longnecker, M. P.; Løvik, M.; Calafat, A. M.; Carlsen, K-H.; London, S. J.; Lødrup Carlsen, K. C. (2013). "Triclosan exposure and allergic sensitization in Norwegian children". Allergy 68 (1): 84–91. doi:10.1111/all.12058. PMC 3515701. PMID 23146048.
  27. ↑ Bedoux, Gilles; Roig, Benoit; Thomas, Olivier; Dupont, Virginie; Le Bot, Barbara (2011). "Occurrence and toxicity of antimicrobial triclosan and by-products in the environment". Environmental Science and Pollution Research 19 (4): 1044–65. doi:10.1007/s11356-011-0632-z. PMID 22057832.
  28. ↑ "Triclosan Registration Review Preliminary Work Plan". Environmental Protection Agency. 27 March 2013.
  29. ↑ van den Berg, M; van Birgelen, A; Birnbaum, L; Brouwer, B; Carrier, G; Dragan, Y; Farland, W; Feeley, M; Fýrst, P; Galli, CL; Greig, J; Hayashi, Y; Kogevinas, M; Kurokawa, Y; Larsen, JC; Liem, AKD; Matsumura, F; Mocarelli, P; Moore, MR; Newhook, RC; Peterson, RE; Poellinger, L; Portier, C; Rogan, WJ; Schrenk, D; Sweeney, MH; Tohyama, C; Tuomisto, J; Water; Zeilmaker, M (2000). "Consultation on assessment of the health risk of dioxins; re-evaluation of the tolerable daily intake (TDI): Executive Summary". Food Additives and Contaminants 17 (4): 223–40. doi:10.1080/713810655. PMID 10912238.
  30. ↑ "Triclosan exposure modulates estrogen-dependent responses in the female wistar rat." Toxicol Sci. 2010 Sep;117(1):45-53. doi:10.1093/toxsci/kfq180.
  31. 1 2 3 4 5 Halden, Rolf U. (2014). "On the Need and Speed of Regulating Triclosan and Triclocarban in the United States". Environmental Science & Technology 48 (7): 3603–11. Bibcode:2014EnST...48.3603H. doi:10.1021/es500495p. PMC 3974611. PMID 24588513.
  32. ↑ Clarke, Bradley O.; Smith, Stephen R. (2011). "Review of 'emerging' organic contaminants in biosolids and assessment of international research priorities for the agricultural use of biosolids". Environment International 37 (1): 226–47. doi:10.1016/j.envint.2010.06.004. PMID 20797791.
  33. 1 2 "Triclosan Facts". Environmental Protection Agency. Retrieved 17 Feb 2014.
  34. ↑ Singer, Heinz; Müller, Stephan; Tixier, Céline; Pillonel, Laurent (2002). "Triclosan: Occurrence and Fate of a Widely Used Biocide in the Aquatic Environment: Field Measurements in Wastewater Treatment Plants, Surface Waters, and Lake Sediments". Environmental Science & Technology 36 (23): 4998–5004. Bibcode:2002EnST...36.4998S. doi:10.1021/es025750i. PMID 12523412.
  35. ↑ Heidler, Jochen; Halden, Rolf U. (2007). "Mass balance assessment of triclosan removal during conventional sewage treatment". Chemosphere 66 (2): 362–9. doi:10.1016/j.chemosphere.2006.04.066. PMID 16766013.
  36. ↑ Brausch, John, and Gary Rand: A review of personal care products in the aquatic environment: Environmental concentrations and toxicity. Chemosphere 82.11 (2011): 1518-1532. doi:10.1016/j.chemosphere.2010.11.018.
  37. ↑ Tiffany L. Hedrick-Hoppera, Lauren P. Kostera, Sandra L. Diamond (2015). "Accumulation of triclosan from diet and its neuroendocrine effects in Atlantic croaker (Micropogonias undulatus) under two temperature Regimes". Marine Environmental Research. doi:10.1016/j.marenvres.2015.09.006.
  38. ↑ "Estimates Of Exposures And Risks To Aquatic Organisms From Releases Of Triclosan To Surface Water As A Result Of Uses Under EPA’S Jurisdiction" (PDF). Retrieved 2014-09-22.
  39. ↑ Yazdankhah, Siamak P.; Scheie, Anne A.; Høiby, E. Arne; Lunestad, Bjørn-Tore; Heir, Even; Fotland, Tor Øystein; Naterstad, Kristine; Kruse, Hilde (2006). "Triclosan and Antimicrobial Resistance in Bacteria: An Overview". Microbial Drug Resistance 12 (2): 83–90. doi:10.1089/mdr.2006.12.83. PMID 16922622.
  40. ↑ Aiello, A. E.; Larson, E. L.; Levy, S. B. (2007). "Consumer Antibacterial Soaps: Effective or Just Risky?". Clinical Infectious Diseases 45: S137–47. doi:10.1086/519255. PMID 17683018. Lay summary – Phys.org (Aug 15, 2007).
  41. ↑ Kim, Jun Sung; Kuk, Eunye; Yu, Kyeong Nam; Kim, Jong-Ho; Park, Sung Jin; Lee, Hu Jang; Kim, So Hyun; Park, Young Kyung; Park, Yong Ho; Hwang, Cheol-Yong; Kim, Yong-Kwon; Lee, Yoon-Sik; Jeong, Dae Hong; Cho, Myung-Haing (2007). "Antimicrobial effects of silver nanoparticles". Nanomedicine: Nanotechnology, Biology and Medicine 3: S137–47. doi:10.1016/j.nano.2006.12.001. PMID 17379174.
  42. ↑ http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=uriserv:OJ.L_.2016.021.01.0086.01.ENG&toc=OJ:L:2016:021:FULL
  43. ↑ "REGULATION (EC) No 1223 /2009 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 30 November 2009 on cosmetic products". Official Journal of the European Union. 2009.
  44. ↑ Commission Regulation (EU) No 358/2014 of 9 April 2014
  45. ↑ "Federal Register" (PDF). Retrieved 2014-09-22.
  46. ↑ STEVE KARNOWSKI (2014-05-20). "Minnesota Becomes First State To Ban Antibacterial Chemical Triclosan From Soaps". Huffingtonpost.com. Retrieved 2014-07-15.
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