Triclocarban

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Triclocarban
Triclocarban.png
Identifiers
CAS number101-20-2 YesY
PubChem7547
ChemSpider7266 YesY
UNIIBGG1Y1ED0Y YesY
ChEBICHEBI:48347 YesY
ChEMBLCHEMBL1076347 YesY
Jmol-3D imagesImage 1
Properties
Molecular formulaC13H9Cl3N2O
Molar mass315.58 g mol−1
Density1.53 g/cm3
Melting point254 to 256 °C (489 to 493 °F; 527 to 529 K)
Hazards
NFPA 704
Flash point>150 °C
LD50>5000 mg/kg (oral, mouse)[1]
2100 mg/kg (i.p., mouse)[1]
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 YesY (verify) (what is: YesY/N?)
Infobox references
 
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Triclocarban
Triclocarban.png
Identifiers
CAS number101-20-2 YesY
PubChem7547
ChemSpider7266 YesY
UNIIBGG1Y1ED0Y YesY
ChEBICHEBI:48347 YesY
ChEMBLCHEMBL1076347 YesY
Jmol-3D imagesImage 1
Properties
Molecular formulaC13H9Cl3N2O
Molar mass315.58 g mol−1
Density1.53 g/cm3
Melting point254 to 256 °C (489 to 493 °F; 527 to 529 K)
Hazards
NFPA 704
Flash point>150 °C
LD50>5000 mg/kg (oral, mouse)[1]
2100 mg/kg (i.p., mouse)[1]
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 YesY (verify) (what is: YesY/N?)
Infobox references

Originally introduced in the medical field, triclocarban is an antibacterial agent now common in personal care products, such as soaps.[2] Studies on its antibacterial qualities and mechanisms are growing. Preliminary data suggest that it is similar in its uses to triclosan and is effective in fighting infections by targeting the growth of bacteria such as Staphylococcus aureus. Additional research seeks to understand its potential effects on organism and environmental health.


Uses[edit]

Triclocarban has been used as an antimicrobial and antifungal compound since the 1960s.[3] It is commonly found in personal care products as antimicrobials such as in soaps, lotions, deodorants, toothpaste, and plastic.[4] About 80% of all antimicrobial bar soap sold in in United States contains triclocarban.[3] Additionally, the United States spends nearly 1 billion dollars annually on products containing triclocarban and triclosan.[5]

Chemical structure and properties[edit]

Triclocarban is a white powder that is insoluble in water. While triclocarban has two chlorinated phenol rings, it is structurally similar to carbanilide compounds often found in pesticides and some drugs. Solid triclocarban is insoluble in water and incompatible with strong oxidizing reagents and strong bases.[6]

Synthesis of triclocarban[edit]

There are two commercial routes used for the production of triclocarban:

  1. 4-chlorophenyl isocyanate [CAS# 104-12-1] is reacted with 3,4-dichloroaniline [CAS# 95-76-1] to give TCC.
  2. 3,4-dichlorophenyl isocyanate [CAS# 102-36-3] is reacted with 4-chloroaniline [CAS# 106-47-8] to give TCC.

The purity specification in the draft USP monograph for triclocarban is: not less than 97.0% w/w. The purity of commercial production is greater 98% w/w.[7]

Mechanism of action[edit]

In bacteria – triclocarban is predominantly active against gram positive bacteria (bacteria with a thick peptidoglycan wall). The precise mechanism of action of triclocarban is unknown, but it is shown to be bacterostatic, which prevents bacterial proliferation. Unlike other antibacterial compounds, triclocarban does not interfere with the membrane. As a result, it is hypothesized that triclocarban’s molecular mechanism resembles that of triclosan.[3]

In humans – Carbanilides like triclocarban may sensitize the complex of receptor-associating proteins similar to cofactors or coactivators common in cells containing estrogen receptors (ER) and androgen receptors (AR).[8][9] Observations demonstrate that triclocarban activates nuclear xenobiotic receptors constitutive androstane receptor and estrogen receptor alpha both in vivo and in vitro and might have the potential to alter normal physiological homeostasis. Activation of these xenobiotic-sensing receptors amplifies gene expression profiles that might represent a mechanistic base for potential human health effects from exposure to triclocarban. However, further investigation is needed to determine whether triclocarban increases the activity of sex steroid hormones by binding to the receptors or to receptor coactivators.[10][11]

Antibacterial properties[edit]

Triclocarban acts to effectively treat both initial bacterial skin and mucosal infections as well as those infections at risk for superinfection. In vitro, triclocarban has been found to be effective against various resistant strains of staphylococcus, streptococcus, and enterococcus bacteria. It has been shown to be effective as an antibacterial even at very low levels. Triclocarban’s minimum inhibitory concentration has been found to range from 0.5 to 8 mg/L for these various resistant strains.[12] Triclocarban is only unquestionably bacteriostatic for gram-positive bacteria such as Staphylococcus aureus, which suggests that the mechanism of triclocarban’s antibacterial activity is through its destabilization of bacterial cell walls.[3]

Resistance[edit]

The risk of bacterial antibiotic resistance has been studied by quantitatively monitoring the abundance of tetQ (the gene for tetracycline resistance) in wasterwater microcosms. The number of copies of these genes was found to be significantly increased when antimicrobials such as tetracycline, triclosan, and triclocarban were added to the system. Experiments studying the effects of these antibiotic compounds when they are combined revealed that antibiotic resistance is readily induced through co-selection by multiple antibacterial reagents.[13]

Environmental concerns[edit]

Waste water[edit]

High concentrations of triclocarban may be found in waste water. It is among the top 10 most commonly detected organic wastewater compounds in terms of frequency and concentration. Triclocarban has been found in increasing concentrations over the past 5 years and is now more frequently detected than triclosan.[4]

Wildlife toxicity[edit]

Triclocarban has a hazard quotient rating of greater than one. Hazard quotients greater than one indicate the potential for adverse effects on organisms due to toxicity.[4] Because triclocarban is found in high concentrations in aquatic environments, there are concerns regarding its toxicity to aquatic species. Specifically, triclocarban has been shown to be toxic to amphibians, fish, invertebrates, and aquatic plants and traces of the compound have been found in Atlantic dolphins.[4][14] The antibacterial components of triclocarban have affect exposed wildlife and may to disrupt hormones critical to the developmental and endocrine processes in animal wildlife. The neurological and reproductive systems are particularly affected through contact with this compound. Triclocarban may also affect animal wildlife behavior.[14] For example, TCS and TCC are 100-1,000 times more effective in inhibiting and killing algae, crustaceans and fish than they are in killing microbes. TCC and triclosan have been observed in multiple organisms, including algae aquatic blackworms, fish and dolphins. Earth dwelling species include earth worms, and higher species up the food chain[15]

Bioaccumulation[edit]

Triclocarban has the potential to bioaccumulate in a number of organisms. Earthworms are known to store this chemical in their bodies and, because of their ecological role as a food source, they have the potential to move triclocarban up the food chain.[16] Microbial species found in soils also bioaccumulate triclocarban. However, the health of these microbes has not been found to be affected by the presence of the chemical.[17] Triclocarban is rapidly accumulated in both algae and adult caged snails.[18] Moreover, triclocarban is more likely than triclosan to bioaccumulate in aquatic organisms.[19]

Bioaccumulation does occur in plants treated with water containing triclocarban. However, it is estimated that less than 0.5% of the acceptable daily intake of triclocarban for humans is represented by vegetable consumption. Thus, the concentration of triclocarban in edible portions of plants is a negligible exposure pathway for humans.

The potential for triclocarban to bioaccumulate in plants has been exploited in the construction of wetlands meant to help remove triclocarban from wastewater. These constructed wetlands are considered a cost-effective treatment option for the removal of PPCPs, including triclocarban and triclosan, from domestic water effluent. Such compounds tend to concentrate in the roots of wetland plants. Potential ecological risks associated with this method is the decrease of root systems in wetland plants, reduced nutrient uptake, decreased competitive ability, and increased potential for uprooting. Due to these risks, the long term exposure of wetland ecosystems to wastewater containing triclocarban as a major solution to wastewater pollution is still under discussion.[20]

Breakdown of product[edit]

When triclocarban is manufactured, 139 toxic, carcinogenic byproducts, such as 4-chloroaniline and 3,4-dichloroaniline, are released. More of these carcinogens can be released upon chemical, physical and biological attack of triclocarban.[15] The duration of triclocarban chemical in personal product use is relatively short. Upon disposal, the triclocarban is washed down the drain to municipal wastewater treatment plants, where about 97-98% of triclocarban is removed from the water. Studies show that substantial quantities of triclocarban (227,000 – 454,000 kg/y) can break through wastewater treatment plants and damage algae on surface waters.[15]

Discharge of effluent from these treatment plants and disposal of sludge on land is the primary route of environmental exposure to triclocarban. Research shows that triclocarban and triclosan have been detected in sewage effluents and sludge (biosolids) due to their incomplete removal during wastewater treatment(Chelew and Halden, 2009). Because of their hydrophobic nature, significant amounts of them in wastewater streams partition into sludge, with concentrations at mg/kg levels. The volume of triclocarban reentering the environment in sewage sludge after initial successful capture from wastewater is s 127,000 ± 194,000 kg/yr. This is equivalent to a 4.8 – 48.2% of its total U.S consumption volume. Crops shown to take up antimicrobials from soil include barley, meadow fescue, carrots and pinto beans.[15]

Health concerns[edit]

Personal care[edit]

One study has investigated how triclocarban remains in the human system after using a bar of soap with traces of triclocarban. Analysis of urine samples from human test subjects shows that, after triclocarban has undergone glucuronidation, its oxidative metabolites are less readily excreted than triclocarban itself. This same study performed topical treatments of triclocarban on rats and, by analyzing urine and plasma levels, demonstrated that triclocarban does remain in the organism's system.[21]

Endocrine disorders[edit]

Triclocarban induces weak responses mediated by aryl hydrocarbon, estrogen, and androgen receptors in vitro. This has yet to be confirmed in vivo.[22] In vitro, the dihydrotestosterone-dependent activation of androgen receptor-responsive gene expression is enhanced by triclocarban by up to 130%.[23] Triclocarban is also a potent inhibitor of the enzyme soluble epoxide hydrolase (sEH) in vitro.[21] Additionally, triclocarban amplifies the bioactivity of testosterone and other androgens. This increased activity may have adverse implications for reproductive health[5][16] Triclocarban studies on rats exhibited increased size of the specimens' prostate glands.[24]

Allergies[edit]

Triclocarban causes irritation of the lungs, eyes, and skin. Many countries, such as Canada and Japan, restrict the content of triclocarban in cosmetics.[25] Triclocarban may also cause sensitization to aeroallergens and food.[15]

Safety[edit]

Spillage may increase the risk of human, ecological, and environmental exposure to triclocarban. Immediate removal and restraint of the spill, including triclocarban as dust, is urged.[26] Although triclocarban has few to no direct detrimental effects on health aside from allergic reactions, preventing exposure to triclocarban is recommended. Wearing gloves, properly washing hands, and overall proper hygiene reduces the risk of skin exposure and irritation. High concentrations of triclocarban dust may remain in the lungs and inhibit lung and respiratory function. For individuals with prior respiratory conditions, triclocarban exacerbates the severity of respiratory diseases, and proper protection is recommended as a precaution. In the cases of exposure to triclocarban, the individual is suggested to wash the area with water or to clear the respiratory pathways.[27] In addition to its adverse effects on humans and the environment, solid triclocarban is a fire hazard. It is particularly combustible as dust. Contamination with other oxidizing agents may also result in combustion.[28]

Triclocarban has low toxicity (LD50 >5000 mg/kg) and its absorption across human skin is very low.[29]

Policy[edit]

In light of the difficulties of finding antimicrobial alternatives, the Food and Drug Administration began in the 1970s to review the safety of triclocarban and triclosan, but no enacted policy, or "drug monograph," is available to date.[15] Legal recourse by the Natural Resources Defense Council in 2010 forced the FDA to review triclocarban triclosan.[15] However, the United States Environmental Protection Agency maintains regulatory control over triclocarban and triclosan to date.[15]

Similar in its use and its adverse health impacts as triclosan, hexachlorophene became prohibited by the FDA.[15]

Current and future research[edit]

The future of triclocarban is unknown, but scientists are searching for more sustainable antimicrobials that maintain its antibacterial properties while being minimally toxic to the environment, humans, and wildlife. This entails low degrees of bioaccumulation and rapid, clean biodegradation in existing wastewater treatment facilities. A lowered potential or no potential for resistance is also preferable.[15] These next generation chemicals should aim to act on a broad spectrum of microbes and pathogens while also being minimally toxic and bioaccumulating in non-target species.

Synthesis of these compounds could be improved upon by finding renewable sources for their production that lacks occupational hazards.[15] Research regarding the sustainability of chemical production is currently being used to help formulate green pharmaceuticals. These same principles may be applied to the development of improved antimicrobials.[15] Development in this area would benefit both people and the environment.[15]

References[edit]

  1. ^ a b Marty, J. P.; Wepierre, J. (1979). "Toxicity evaluation of cosmetically active substances: case of trichlorocarbanilide". Labo-Pharma - Problemes et Techniques 27 (286): 306–10. 
  2. ^ "Anti-bacterial personal hygiene products may not be worth potential risks." UC Davis Health System Feature Story: Anti-bacterial personal hygiene products.... UC Davis Health System, n.d. Web. 12 Mar. 2014. <http://www.ucdmc.ucdavis.edu/welcome/features/20080903_anti-bacterial/>.
  3. ^ a b c d Orsi, Mario, Massimo Noro, and Jonathan Essex. "Dual-resolution molecular dynamics simulation of antimicrobials in biomembranes." Journal of The Royal Society Interface 8.59 (2010): 826-841. PubMed Central. Web. 17 Feb. 2014. http://www.ncbi.nlm.nih.gov.proxy.bc.edu/pmc/articles/PMC3104353/
  4. ^ a b c d 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. ScienceDirect. Web. 17 Feb. 2014. http://ac.els-cdn.com/S0045653510013007/1-s2.0-S0045653510013007-main.pdf?_tid=c685833c-9812-11e3-87db-00000aab0f6c&acdnat=1392669395_a731b9c664c4e98737d93755500c43dd
  5. ^ a b Ahn, Ki Chang, Bin Zhao, Shirley Gee, Bruce Hammock, Jiangang Chen, Gennady Cherednichenko, Enio Sanmarti, Michael Denison, Bill Lasley, Isaac Pessah, Dietmar Kultz, and Daniel Chang. "In Vitro Biologic Activities of the Antimicrobials Triclocarban, Its Analogs, and Triclosan in Bioassay Screens: Receptor-Based Bioassay Screens." Environmental Health Perspectives 116.9 (2008): 1203-1210. PubMed Central. Web. 17 Feb. 2014. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2535623/
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  14. ^ a b http://www.nrdc.org/living/chemicalindex/triclosan.asp
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  16. ^ a b Higgins, Christopher , Zachary Paesani, Talia Chalew, Rolf Halden, and Lakhwinder Hundal. "Persistence of triclocarban and triclosan in soils after land application of biosolids and bioaccumulation in Eisenia foetida." Environmental Toxicology and Chemistry 30.3 (2011): 556-563. PubMed. Web. 17 Feb. 2014. http://www.ncbi.nlm.nih.gov.proxy.bc.edu/pubmed/21128266
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  18. ^ Coogan, Melinda , and Thomas La Point. "Snail Bioaccumulation Of Triclocarban, Triclosan, And Methyltriclosan In A North Texas, USA, Stream Affected By Wastewater Treatment Plant Runoff." Environmental Toxicology and Chemistry 27.8 (2008): 1788-1793. PubMed. Web. 17 Feb. 2014. http://www.ncbi.nlm.nih.gov.proxy.bc.edu/pubmed/18380516
  19. ^ Prosser, Ryan, Linda Lissemore, Edward Topp, and Paul Sibley. "Bioaccumulation of triclosan and triclocarban in plants grown in soils amended with municipal dewatered biosolids." Environmental Toxicology and Chemistry (2013) PubMed. Web. 17 Feb. 2014. http://www.ncbi.nlm.nih.gov.proxy.bc.edu/pubmed/24375516
  20. ^ Zarate, Frederick , Sarah Schulwitz, Kevin Stevens, and Barney Venables. "Bioconcentration of triclosan, methyl-triclosan, and triclocarban in the plants and sediments of a constructed wetland." Chemosphere 88.3 (2012): 323-329. ScienceDirect. Web. 17 Feb. 2014. http://www.sciencedirect.com.proxy.bc.edu/science/article/pii/S0045653512003190
  21. ^ a b Schebb, Nils Helge, Bora Inceoglu, Ki Chang Ahn, Christophe Morisseau, Shirley Gee, and Bruce Hammock. "Investigation of Human Exposure to Triclocarban after Showering and Preliminary Evaluation of Its Biological Effects." Environmental Science & Technology 45.7 (2011): 3109-3115. PubMed. Web. 17 Feb. 2014. http://www.ncbi.nlm.nih.gov.proxy.bc.edu/pubmed/21381656
  22. ^ Witorsch, Raphael, and John Thomas. "Personal Care Products And Endocrine Disruption: A Critical Review Of The Literature." Critical Reviews in Toxicology 40.S3 (2010): 1-30. PubMed. Web. 17 Feb. 2014. http://www.ncbi.nlm.nih.gov.proxy.bc.edu/pubmed/20932229
  23. ^ Christen, Verena, Pierre Crettaz, Aurelia Oberli-Schrämmli, and Karl Fent. "Some flame retardants and the antimicrobials triclosan and triclocarban enhance the androgenic activity in vitro." Chemosphere 81.10 (2010): 1245-1252. PubMed. Web. 17 Feb. 2014. http://www.ncbi.nlm.nih.gov.proxy.bc.edu/pubmed/20943248
  24. ^ "Triclocarban: sc-213106 Material Safety Data Sheet." Santa Cruz Biotechnology. Santa Cruz Biotechnology, Web. 17 Feb. 2014. <http://datasheets.scbt.com/sc-213106.pdf>.
  25. ^ "Triclocarban." EWG's Skin Deep® Cosmetics Database. Web. 17 Feb. 2014. <http://www.ewg.org/skindeep/ingredient/706622/TRICLOCARBAN/>.
  26. ^ "Triclocarban: sc-213106 Material Safety Data Sheet." Santa Cruz Biotechnology. Santa Cruz Biotechnology, Web. 17 Feb. 2014. <http://datasheets.scbt.com/sc-213106.pdf>.
  27. ^ "Triclocarban: sc-213106 Material Safety Data Sheet." Santa Cruz Biotechnology. Santa Cruz Biotechnology, Web. 17 Feb. 2014. <http://datasheets.scbt.com/sc-213106.pdf>.
  28. ^ "Triclocarban: sc-213106 Material Safety Data Sheet." Santa Cruz Biotechnology. Santa Cruz Biotechnology, Web. 17 Feb. 2014. <http://datasheets.scbt.com/sc-213106.pdf>.
  29. ^ Marty, J. P.; Wepierre, J. (1979). "Toxicity evaluation of cosmetically active substances: case of trichlorocarbanilide". Labo-Pharma - Problemes et Techniques 27 (286): 306–10.