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
CAS Number	3380-34-5 Y
ChEBI	CHEBI:164200 Y
ChEMBL	ChEMBL849 Y
ChemSpider	5363 Y
DrugBank	DB08604 Y
Jmol 3D model	Interactive image
KEGG	D06226 Y
PubChem	5564
UNII	4NM5039Y5X Y
InChI InChI=1S/C12H7Cl3O2/c13-7-1-3-11(9(15)5-7)17-12-4-2-8(14)6-10(12)16/h1-6,16H Y Key: XEFQLINVKFYRCS-UHFFFAOYSA-N Y InChI=1/C12H7Cl3O2/c13-7-1-3-11(9(15)5-7)17-12-4-2-8(14)6-10(12)16/h1-6,16H Key: XEFQLINVKFYRCS-UHFFFAOYAS
SMILES Clc2cc(Cl)ccc2Oc1ccc(Cl)cc1O
Properties
Chemical formula	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
ATC code	D08AE04 D09AA06 (medicated dressing)
Vapor pressure	{{{value}}}
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Y verify (what is YN ?)
Infobox references

Triclosan, similar in its uses and mechanism of action to triclocarban, is an antibacterial and antifungal agent found in consumer products, including 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. It is part of consumer products, including kitchen utensils, toys, bedding, socks and trash bags.

In healthcare, triclosan is used in surgical scrubs and hand washes. Use in surgical units is effective with a minimum contact time of approximately two minutes. 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).

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.

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.

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. Then, 1-vinylpyrrolidin-2-one can be reacted with 5-chloro-2-(2,4-dichlorophenoxy)phenyl acrylate in n-heptane to form triclosan.

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

Mechanism of action

At high concentrations, triclosan acts as a biocide with multiple cytoplasmic and membrane targets. 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, 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. 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. Triclosan-containing toothpastes are marginally beneficial in reduction of tooth cavities and reduce dental plaque, gingival inflammation, and gingival bleeding.

Health concerns

Triclosan safety is under review by the FDA and Health Canada.

Allergy

Triclosan has been associated with a higher risk of food allergy. 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. Other studies have linked triclosan to allergic contact dermatitis in some individuals. Additionally, triclosan concentrations have been associated with allergic sensitization, especially inhalant and seasonal allergens, rather than food allergens.

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). The dioxins that can form from triclosan are not considered to be congeners of toxicologic concern for mammals, birds and fish.

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.

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. 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. In a study on effluent from wastewater treatment facilities, approximately 75% of triclocarban was present in sludge. 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. Triclosan can attach to other substances suspended in aquatic environments, which potentially endangers marine organisms and may lead to further bioaccumulation. 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.

During wastewater treatment, a portion of triclosan is degraded, while the remaining adsorbs to sewage sludge or exits the plant as effluent. 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. In humans, triclosan does not bioaccumulate as it is rapidly metabolized and excreted.

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. 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.

Resistance concerns

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

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.

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

Policy

The U.S. Food and Drug Administration, the Environmental Protection Agency, and the European Union are regulatory bodies for triclosan. 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.

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. 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.

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.

Synthesis

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

See also

3