The Different Facets of Triclocarban: Comparison
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In the late 1930s and early 1940s, it was discovered that the substitution on aromatic rings of hydrogen atoms with chlorine yielded a novel chemistry of antimicrobials. However, within a few years, many of these compounds and formulations showed adverse effects, including human toxicity, ecotoxicity, and unwanted environmental persistence and bioaccumulation, quickly leading to regulatory bans and phase-outs. Among these, the triclocarban, a polychlorinated aromatic antimicrobial agent, was employed as a major ingredient of toys, clothing, food packaging materials, food industry floors, medical supplies, and especially of personal care products, such as soaps, toothpaste, and shampoo. Triclocarban has been widely used for over 50 years, but only recently some concerns were raised about its endocrine disruptive properties. In September 2016, the U.S. Food and Drug Administration banned its use in over-the-counter hand and body washes because of its toxicity. The withdrawal of triclocarban has prompted the efforts to search for new antimicrobial compounds and several analogues of triclocarban have also been studied. In this review, an examination of different facets of triclocarban and its analogues will be analyzed.

  • antimicrobials
  • diarylureas
  • bis-arylureas
  • triclocarban

1. Introduction

Triclocarban (TCC, Figure 1) is a highly effective and broad-spectrum antimicrobial and antiseptic agent that has been successfully used in personal care products for over 60 years [1,2][1][2]. It is often mentioned along with its congener triclosan (TCS, Figure 1). TCC is a diphenyl urea (N-(4-chlorophenyl)-N′-(3,4-dichlorophenyl)urea), whereas TCS is an ether (2,4,4′-trichloro-2′-hydroxydiphenyl ether). Although they substantially differ in their structures, TCC and TCS are often taken together probably because of their polychlorinated structure. They even share three chlorine atoms in their structures [3,4,5][3][4][5].
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Figure 1. Triclocarban and triclosan.
In this review, we will focus our attention on TCC, a small molecule also named 3,4,4′-trichlorocarbanilide that belongs to the class of diarylures or bis-arylureas. This interesting class of compounds has been recently reviewed by our research group as anticancer agents [6], and then, due to their multiple actions [7,8,9,10[7][8][9][10][11],11], they were also suggested for repositioning to antimicrobial agents and/or potential treatment for new pandemics, as COVID-19 [12,13][12][13]. TCC is a common ingredient in personal care products, especially dermal cleaning products such as antibacterial bar/Liquid soaps, body lotions, deodorants, detergents, medical disinfectants, aftershave soaps, hand sanitizers, toothpaste, handwash and mouthwash, body washes, cleansing lotions, baby teethers and wipes for its sanitizing properties and detergents [14,15,16,17][14][15][16][17]. It acts as a fungicide and preservative in air fresheners, fabric and leather finishing agents [18]. Its concentration in the products can be as high as 1.5% [19,20][19][20], even if its use has been approved by the European Union (EU) in a concentration of 0.2% [21].
Since its advent in 1957 [22], TCC has been produced and used on a large scale, and its consumption from personal care products in the United States reached 500,000–1,000,000 pounds per year [23]. The 2013–2014 National Health and Nutrition Examination Survey showed that 36.9% of the urine samples in the United States (U.S.) contained TCC [24]. Halden et al. (2017) [25] stated that its utility in healthcare settings is uncontested, whereas benefits to its antimicrobial activity are few to none. A 2003 report by the U.S. Centers for Disease Control and Prevention Healthcare Infection Control Practices Advisory Committee concluded that “no evidence is available to suggest that use of [antimicrobial-impregnated articles and consumer items bearing antimicrobial labeling] will make consumers and patients healthier or prevent disease” [26].
TCC belongs to pharmaceutical and personal care products (PPCPs) that comprise large and diversified groups of chemicals, including prescription and over-the-counter drugs and cleaning agents [27]. Unfortunately, PPCPs are often discharged into wastewater treatment plants (WWTPs) via excretion with urine and feces as parent compounds conjugated compounds, or metabolites, and through washing or direct disposal. TCC was demonstrated to be an endocrine disruptor that is hardly biodegradable, being a halogenated hydrocarbon [28,29][28][29]. Its extensive utilization in personal care products and its partial removal during conventional WWTPs led to its consideration as an environmental contaminant [30], placing it on the list of emerging organic contaminants (EOCs). Many studies have reported the occurrence of TCC and its intermediates in wastewater effluent, surface water, biosolid, sediment and soil [31,32][31][32]. TCC is ranked, in fact, in the top 10 Contaminant of Emerging Concern (CEC) occurrence [31,33,34][31][33][34]. Once conveyed to wastewater treatment plants, PPCPs can remain unchanged or undergo a partial or complete transformation during wastewater treatment processes before being discharged into the environment via effluent and biosolids for land application. Land application of biosolids, the end product of wastewater treatment plants, may be a potential important route through which PPCPs enter the environment [35]. PPCPs biodegradation is a potential removal mechanism, as well [36] and in a recent study TCC aerobic biodegradation was demonstrated to occur slowly (i.e., half-life value > 165 days) [37]. Although PPCPs in the effluent and biosolids of water resource recovery facilities (WRRFs) are currently not regulated, public interest has led the Metropolitan Water Reclamation District of Greater Chicago to monitor for 11 PPCPs in the influent, effluent, and biosolids.
Armstrong et al. studied how WRRFs can influence concentrations before biosolids land application [38]. A critical comprehensive review on TCC as a contaminant has been recently reported [39]. Environmental TCC could be efficiently taken up by food crops, leading to the bioaccumulation of TCC and potential human exposure through food consumption. Some common food crops, such as broccoli, potato, beet, cabbage, and pepper, can accumulate >100 ppm TCC in the root tissues, and onions can accumulate >800 ppm TCC in the bulbs [23]. Human exposure to TCC may also be due to daily supplies, drinking water and dust [26]. As a result, its detection is frequent in human tissue, such as fingernails and body fluids, including blood, urine and seminal plasma [40,41[40][41][42][43],42,43], thus causing a potential hazard to human health. It is noteworthy that TCC may represent a risk for children, as it has been recently found in urine of Brazilian children and its use also seems to be associated to DNA damage [44]. Human exposure to triclocarban is widely studied in several Asian countries, especially in Vietnam, Kuwait, and Japan [45]. In 2016, the U.S. Food and Drug Administration (FDA) issued a final rule establishing that 19 specific ingredients, including TCC and TCS, were no longer generally recognized as safe and effective, and prohibited companies from marketing soaps as antibacterial containing one or more of these ingredients [46]. This rule came into effect since September 2017 [47]. Though banned in consumer wash products in the U.S., triclocarban is still used in other countries [48]. The EU banned TCS from all human hygiene biocidal products starting from January 2017 [49], whereas China has not regulated TCS and TCC in these products yet [50]. Given the importance of these issues, this review will focus on the activity, occurrence, metabolism, toxicity of TCC and several analogues described in the literature, as well as on compounds potentially effective and usable as an alternative to TCC.

2. Metabolism and Transformation Products of TCC

Once applying the TCC-containing products on the skin, they can enter the human body, be metabolized and exert a potential risk for the human health [51]. Indeed, it has been detected in human blood (0.45 ng/mL) and urine (3.85 ng/mL) [52]. Several studies have indicated that a significant portion of TCC in soaps is percutaneously absorbed by humans during and after showering. In humans, it has been estimated that the 0.6% of TCC (approximately 70 μg) can be absorbed, based on the urinary excretion of TCC metabolites [53]. TCC is also present in sanitary pads, panty liners, and tampons, but the transfer rates are not known [54]. TCC exposure may also occur via consumption of water or food [23] and it has been reported that in the maternal and umbilical cord sera it reached the values of 2.75 and 0.82 μg/L, respectively [41]. TCC may undergo phase I and phase II metabolism [55]. The main metabolites detected in human and monkey urine, accounting for 25% of TCC elimination products, result from direct N-glucuronidation at one of the nitrogen atoms of the urea moiety of TCC giving N-Gluc-TCC and N’-Gluc-TCC (Figure 2) [56].
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Figure 2. Glucuronide transformation products of triclocarban.
TCC dechlorination reactions lead to carbanilides (Figure 3) including 4,4′-dichlorocarbanilide (DCC), 1-(3-chlorophenyl)-3-phenylurea (MCC), and carbanilide (NCC), or either biologically or abiotically to 4-chloroaniline (4-CA) [57]. Miller et al. (2010) suggested, for the first time, the occurrence of reductive dechlorination of TCC in estuarine sediments [58]. However, it is unclear whether TCC dechlorination was limited to the sediment environment or whether the WWTPs also contribute to the mitigation of TCC contamination through its dechlorination. Pycke et al. (2014) showed that the anaerobic digestion contribution to partial TCC dechlorination was limited (0.4−2.1%) and described toxic chloroanilines, including 3-chloroaniline (3-CA), and/or 3,4-dichloroaniline (3,4-DCA, Figure 3) [59].
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Figure 3. Dechlorinated transformation products of triclocarban.
TCC is also metabolized by cytochrome P450 enzymes to three hydroxylated species, namely 2′-hydroxytriclocarban (2′-OH-TCC), 3′-hydroxytriclocarban (3′-OH-TCC) and 6-hydroxytriclocarban (6-OH-TCC) (Figure 4) with the ortho-hydroxylated species, 2′-OH-TCC and 6-OH-TCC, as main metabolites [53,59][53][59]. All metabolites may undergo extensive phase II metabolism, and the glucuronic acid conjugates of the hydroxylated TCC species (2′-O-Gluc-TCC, 3′-O-Gluc-TCC and 6-O-Gluc-TCC) account for the majority of TCC metabolites in mammalian bile and in fishes [60,61][60][61]. However, the UDP-glucuronosyltransferases (UGTs) involved in the conjugation of TCC and its metabolites have not been completely defined, as well as the biochemistry and kinetics of the conversion. Schebb et al. 2012 [56] showed that all the major oxidative metabolites of TCC are rapidly conjugated with glucuronic acid by microsomes from the liver, kidney, and intestine. A wide variety of UGTs has high affinity for the hydroxylated TCC metabolites, with high activities, particularly for UGT1A7, UGT1A8, and UGT1A9. Zhang et al. (2020) [62] recently reported another hydroxylated metabolite of TCC called DHC (3′,4′-dichloro-4-hydroxycarbanilide).
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Figure 4. Structures of hydroxylated TCC transformation products and their glucuronides.

3. Biological Activity of TCC

Antimicrobial resistance, that is the progressive process by which microbes, such as bacteria, through evolutionary, environmental, and social factors develop the ability to become resistant to drugs that were once effective at treating them, is a threat from which no one can escape [63]. It is a slow but inexorable public health danger that has been defined a “wicked problem”. It has been estimated that globally approximately 700,000 deaths are attributed annually to antimicrobial resistance and this could rise to 10 million deaths per year by 2050 [64]. Intensive efforts are underway worldwide to develop new antimicrobial agents. TCC is an antibacterial and antiseptic agent. The antibacterial activity is generally tested by the determination of the minimum inhibitory concentrations (MICs). According to the FDA guidelines, Kim et al. (2016) [65] stated that MICs are not relevant in this case because consumers are exposed to antiseptic products for a very short time, whereas MIC tests require a long exposure time (at least one day) [66]. Thus, the authors compared the bactericidal effects of plain and antibacterial soaps containing 0.3% TCC. The study was carried out against ten Gram-positive and ten Gram-negative bacterial strains after exposure at 22 °C and 40 °C for 20 s. Gram-negative bacteria were more susceptible to both soaps than Gram-positive bacteria. The authors found no significant difference between the effects of plain and medicated soaps at either temperature, with the only exception of Enterococcus faecalis ATCC 19433 at 40 °C. The presence of TCC in soap did not lead to a significant reduction in bacterial levels during the use [65]. E. faecalis is a bacterium tragically famed to be part of the top agents responsible for nosocomial infections and is the third most frequent cause of the infective endocarditis (IE), a disease with high morbidity and mortality [67,68][67][68].
Another study of the effect of the antibacterial soap Santex, containing TCC, was carried out in a rural Malagasy population that practices subsistence agriculture in the absence of electricity and running water [69]. The authors found that the antibacterial soap influenced the structure of microbial communities, and that these changes persist for at least two weeks, suggesting that antibacterial products may have a lasting impact on skin microbes. Recently, Pujol et al. (2018) [70] determined the MIC value for TCC against Staphylococcus aureus ATCC 12600 (MIC = 0.5 µg/mL) and found that it was the same as ciprofloxacin. In a successive paper, the MIC value for TCC was 16 µg/mL against S. aureus ATCC 29213 and 6538P (versus 0.5–2 µg/mL of norfloxacin) [71]. Although TCC has been widely used as an antimicrobial for over 50 years, it was only recently that concerns were raised about its endocrine disruptive properties. In 2008, Chen et al. [72] suggested TCC as an endocrine disruptor that enhanced the action of endogenous hormones (androgens and estrogens) rather than directly activating hormone receptors in vitro and in vivo [73]. However, Cao et al. (2020) recently demonstrated that TCC is able to disrupt the estrogen system via the estrogen-related receptor γ (ERRγ) at human exposure levels, via a fluorescence competitive binding assay. TCC demonstrated higher binding potency with ERRγ than the synthetic ERRγ agonist GSK4716, with a dissociation constant of 96 ± 10 nM [74]. TCC has also been shown to disrupt the gut microbiome in animals and humans, leading to a myriad of effects on health [75].
A systematic review about estrogenic and androgenic activities and offspring growth has been reported some years ago [76]. Recently, it has been suggested that the exposure to a relevant dose of TCC may interfere with the human reproduction. For instance, it was associated with a decrease in gestational age [77] and could have implications for human health [52]. TCC could potently inhibit the human soluble epoxide hydrolase (sEH), involved in the biological regulation of pain, inflammation, and blood pressure [53]. TCC has been also demonstrated to induce oxidative stress and cause biological dysfunctions in both animals and humans [78,79][78][79]. A study on mouse oocytes showed that TCC exposure disrupted their maturation affecting the cell cycle progression, cytoskeletal dynamics, oxidative stress, early apoptosis, mitochondria function, and histone modifications in vitro [80]. TCC exposure is also a potential environmental risk factor for colitis and associated colonic diseases [81], indeed the exposure to low-dose of TCC exaggerated the severity of colitis and exacerbated the development of colitis-associated colon tumorigenesis, via gut microbiota-dependent mechanisms [23]. Mechanisms related to the toxicity of TCC have not yet been completely defined. For example, TCC exposure promoted the adipogenesis of preadipocytes and hepatocytes in vitro, resulting in toxic lipid accumulation and down-regulation of antioxidant metabolites in hepatocytes [82]. Moreover, Li et al. (2017) showed that TCC inhibited the human aromatase in vitro [83]. TCC activity seems to be related to the disturbance of fatty acid synthesis and the formation of the cell membrane of microbes [84]. More recently, TCC has been shown to disrupt the gut microbiome in animals and humans [85[85][86],86], which, in turn, can have myriad effects on health [87].

References

  1. Liao, C.; Kannan, K. A survey of alkylphenols, bisphenols, and triclosan in personal care products from China and the United States. Arch. Environ. Contam. Toxicol. 2014, 67, 50–59.
  2. Asimakopoulos, A.G.; Xue, J.; De Carvalho, B.P.; Iyer, A.; Abualnaja, K.O.; Yaghmoor, S.S.; Kumosani, T.A.; Kannan, K. Urinary biomarkers of exposure to 57 xenobiotics and its association with oxidative stress in a population in Jeddah, Saudi Arabia. Environ. Res. 2016, 150, 573–581.
  3. Xie, X.; Lu, C.; Wu, M.; Liang, J.; Ying, Y.; Liu, K.; Huang, X.; Zheng, S.; Du, X.; Liu, D.; et al. Association between Triclocarban and Triclosan Exposures and the Risks of Type 2 Diabetes Mellitus and Impaired Glucose Tolerance in the National Health and Nutrition Examination Survey (NHANES 2013–2014). Environ. Int. 2020, 136, 105445.
  4. Tran, T.M.; Trinh, H.T.; Anh, H.Q.; Van Le, T.; Le, S.N.; Minh, T.B. Characterization of triclosan and triclocarban in indoor dust from home micro-environments in Vietnam and relevance of non-dietary exposure. Sci. Total Environ. 2020, 732, 139326.
  5. Gomes, M.F.; de Paula, V.D.C.S.; Martins, L.R.R.; Garcia, J.R.E.; Yamamoto, F.Y.; de Freitas, A.M. Sublethal effects of triclosan and triclocarban at environmental concentrations in silver catfish (Rhamdia quelen) embryos. Chemosphere 2021, 263, 127985.
  6. Catalano, A.; Iacopetta, D.; Sinicropi, M.S.; Franchini, C. Diarylureas as Antitumor Agents. Appl. Sci. 2021, 11, 374.
  7. Qiao, L.; Hao, S. Novel trifluoromethylcoumarinyl urea derivatives: Synthesis, characterization, fluorescence, and bioactivity. Molecules 2018, 23, 600.
  8. Xue, D.; Chen, W.; Neamati, N. Discovery, structure-activity relationship study and biological evaluation of 2-thioureidothiophene-3-carboxylates as a novel class of CXC chemokine receptor 2 (CXCR2) antagonists. Eur. J. Med. Chem. 2020, 204, 112387.
  9. Aghcheli, A.; Toolabi, M.; Ayati, A.; Moghimi, S.; Firoozpour, L.; Bakhshaiesh, T.O.; Nazeri, E.; Norouzbahari, M.; Esmaeili, R.; Foroumadi, A. Design, synthesis, and biological evaluation of 1-(5-(benzylthio)-1, 3, 4-thiadiazol-2-yl)-3-phenylurea derivatives as anticancer agents. Med. Chem. Res. 2020, 29, 2000–2010.
  10. Perrey, D.A.; Zhang, Y. Therapeutics development for addiction: Orexin-1 receptor antagonists. Brain Res. 2020, 1731, 145922.
  11. Podlewska, S.; Bugno, R.; Lacivita, E.; Leopoldo, M.; Bojarski, A.J.; Handzlik, J. Low basicity as a characteristic for atypical ligands of serotonin receptor 5-HT2. Int. J. Mol. Sci. 2021, 22, 1035.
  12. Catalano, A. COVID-19: Could Irisin Become the Handyman Myokine of the 21st Century? Coronaviruses 2020, 1, 32–41.
  13. Catalano, A.; Iacopetta, D.; Pellegrino, M.; Aquaro, S.; Franchini, C.; Sinicropi, M.S. Diarylureas: Repositioning from antitumor to antimicrobials or multi-target agents against new pandemics. Antibiotics 2021, 10, 92.
  14. Sreevidya, V.S.; Lenz, K.A.; Svoboda, K.R.; Ma, H. Benzalkonium chloride, benzethonium chloride, and chloroxylenol—Three replacement antimicrobials are more toxic than triclosan and triclocarban in two model organisms. Environ. Pollut. 2018, 235, 814–824.
  15. Arifin, S.N.H.; Mohamed, R.; Al-Gheethi, A.; Lai, C.W.; Yashni, G. Heterogeneous photocatalysis of triclocarban and triclosan in greywater: A systematic and bibliometric review analysis. Int. J. Environ. Anal. Chem. 2021, 1–19.
  16. Asimakopoulos, A.G.; Elangovan, M.; Kannan, K. Migration of parabens, bisphenols, benzophenone-type UV filters, triclosan, and triclocarban from teethers and its implications for infant exposure. Environ. Sci. Technol. 2016, 50, 13539–13547.
  17. Moreta, C.; Tena, M.T.; Kannan, K. Analytical method for the determination and a survey of parabens and its derivatives in pharmaceuticals. Environ. Res. 2015, 142, 452–460.
  18. Li, W.; Zhang, W.; Chang, M.; Ren, J.; Xie, W.; Chen, H.; Zhang, Z.; Zhuang, X.; Shen, G.; Li, H. Metabonomics reveals that triclocarban affects liver metabolism by affecting glucose metabolism, β-oxidation of fatty acids, and the TCA cycle in male mice. Toxicol. Lett. 2018, 299, 76–85.
  19. European Commission, Scientific Committee on Consumer Products. Opinion on Triclocarban for Other Uses than as a Preservative; Colipa no. P29. SCCP/0851/04; European Commission: Brussels, Belgium, 2005.
  20. Musee, N. Environmental risk assessment of triclosan and triclocarban from personal care products in South Africa. Environ. Pollut. 2018, 242, 827–838.
  21. Chaudhari, U.; Nemade, H.; Sureshkumar, P.; Vinken, M.; Ates, G.; Rogiers, V.; Hescheler, J.; Hengstler, J.G.; Sachinidis, A. Functional cardiotoxicity assessment of cosmetic compounds using human-induced pluripotent stem cell-derived cardiomyocytes. Arch. Toxicol. 2018, 92, 371–381.
  22. Halden, R.U.; Paul, D.H. Co-occurence of triclocarban and triclosan in U.S. water resources. Environ. Sci. Technol. 2005, 39, 1420–1426.
  23. Yang, H.; Sanidad, K.Z.; Wang, W.; Xie, M.; Gu, M.; Cao, X.; Xiao, H.; Zhang, G. Triclocarban exposure exaggerates colitis and colon tumorigenesis: Roles of gut microbiota involved. Gut Microbes 2020, 12, 1690364.
  24. Ye, X.; Wong, L.Y.; Dwivedi, P.; Zhou, X.; Jia, T.; Calafat, A.M. Urinary concentrations of the antibacterial agent triclocarban in United States residents: 2013−2014 National health and nutrition examination survey. Environ. Sci. Technol. 2016, 50, 13548–13554.
  25. Halden, R.U.; Lindeman, A.E.; Aiello, A.E.; Andrews, D.; Arnold, W.A.; Fair, P.; Fuoco, R.E.; Geer, L.A.; Johnson, P.I.; Lohmann, R.; et al. The Florence statement on triclosan and triclocarban. Environ. Health Perspect. 2017, 125, 064501.
  26. CDC (Centers for Disease Control and Prevention). Recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee (HICPAC). 52(RR10). 2003. Available online: https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5210a1.htm (accessed on 15 April 2021).
  27. Guedes-Alonso, R.; Montesdeoca-Esponda, S.; Herrera-Melián, J.A.; Rodríguez-Rodríguez, R.; Ojeda-González, Z.; Landívar-Andrade, V.; Sosa-Ferrera, Z.; Santana-Rodríguez, J.J. Pharmaceutical and personal care product residues in a macrophyte pond-constructed wetland treating wastewater from a university campus: Presence, removal and ecological risk assessment. Sci. Total Environ. 2020, 703, 135596.
  28. Ahn, K.C.; Zhao, B.; Chen, J.; Cherednichenko, G.; Sanmarti, E.; Denison, M.S.; Lasley, B.; Pessah, I.N.; Kultz, D.; Chang, D.P.; et al. In vitro biologic activities of the antimicrobials triclocarban, its analogs, and triclosan in bioassay screens: Receptor-based bioassay screens. Environ. Health Perspect. 2008, 116, 1203–1210.
  29. Tarnow, P.; Tralau, T.; Hunecke, D.; Luch, A. Effects of triclocarban on the transcription of estrogen, androgen and aryl hydrocarbon receptor responsive genes in human breast cancer cells. Toxicol. Vitro 2013, 27, 1467–1475.
  30. Vimalkumar, K.; Arun, E.; Krishna-Kumar, S.; Poopal, R.K.; Nikhil, N.P.; Subramanian, A.; Ramaswamy, B.R. Occurrence of triclocarban and benzotriazole ultraviolet stabilizers in water, sediment, and fish from Indian rivers. Sci. Total Environ. 2018, 625, 1351–1360.
  31. Subedi, B.; Lee, S.; Moon, H.B.; Kannan, K. Emission of artificial sweeteners, select pharmaceuticals, and personal care products through sewage sludge from wastewater treatment plants in Korea. Environ. Int. 2014, 68, 33–40.
  32. Karthikraj, R.; Kannan, K.; Karthikraj, R. Mass loading and removal of benzotriazoles, benzothiazoles, benzophenones, and bisphenols in Indian sewage treatment plants. Chemosphere 2017, 181, 216–223.
  33. Vimalkumar, K.; Seethappan, S.; Pugazhendhi, A. Fate of Triclocarban (TCC) in aquatic and terrestrial systems and human exposure. Chemosphere 2019, 230, 201–209.
  34. Abbott, T.; Kor-Bicakci, G.; Islam, M.S.; Eskicioglu, C. A review on the fate of legacy and alternative antimicrobials and their metabolites during wastewater and sludge treatment. Int. J. Mol. Sci. 2020, 21, 9241.
  35. Xia, K.; Bhandari, A.; Das, K.; Pillar, G. Occurrence and Fate of Pharmaceuticals and Personal Care Products (PPCPs) in Biosolids. J. Environ. Qual. 2005, 34, 91–104.
  36. Onesios, K.M.; Yu, J.T.; Bouwer, E.J. Biodegradation and removal of pharmaceuticals and personal care products in treatment systems: A review. Biodegradation 2009, 20, 441–466.
  37. Thelusmond, J.R.; Kawka, E.; Strathmann, T.J.; Cupples, A.M. Diclofenac, carbamazepine and triclocarban biodegradation in agricultural soils and the microorganisms and metabolic pathways affected. Sci. Total Environ. 2018, 640, 1393–1410.
  38. Armstrong, D.L.; Rice, C.P.; Ramirez, M.; Torrents, A. Influence of thermal hydrolysis-anaerobic digestion treatment of wastewater solids on concentrations of triclosan, triclocarban, and their transformation products in biosolids. Chemosphere 2017, 171, 609–616.
  39. Yun, H.; Liang, B.; Kong, D.; Li, X.; Wang, A. Fate, risk and removal of triclocarban: A critical review. J. Hazard. Mater. 2020, 387, 121944.
  40. Yin, J.; Wei, L.; Shi, Y.; Zhang, J.; Wu, Q.; Shao, B. Chinese population exposure to triclosan and triclocarban as measured via human urine and nails. Environ. Geochem. Health 2016, 38, 1125–1135.
  41. Wei, L.; Qiao, P.; Shi, Y.; Ruan, Y.; Yin, J.; Wu, Q.; Shao, B. Triclosan/triclocarban levels in maternal and umbilical blood samples and their association with fetal malformation. Clin. Chim. Acta 2017, 466, 133–137.
  42. Buck Louis, G.M.; Smarr, M.M.; Sun, L.; Chen, Z.; Honda, M.; Wang, W.; Karthikraj, R.; Weck, J.; Kannan, K. Endocrine disrupting chemicals in seminal plasma and couple fecundity. Environ. Res. 2018, 163, 64–70.
  43. Li, A.J.; Xue, J.; Lin, S.; Al-Malki, A.L.; Al-Ghamdi, M.A.; Kumosani, T.A.; Kannan, K. Urinary Concentrations of Environmental Phenols and Their Association with Type 2 Diabetes in a Population in Jeddah, Saudi Arabia. Environ. Res. 2018, 166, 544–552.
  44. Rocha, B.A.; Asimakopoulos, A.G.; Honda, M.; da Costa, N.L.; Barbosa, R.M.; Barbosa, F., Jr.; Kannan, K. Advanced data mining approaches in the assessment of urinary concentrations of bisphenols, chlorophenols, parabens and benzophenones in Brazilian children and their association to DNA damage. Environ. Int. 2018, 116, 269–277.
  45. Iyer, A.P.; Xue, J.; Honda, M.; Robinson, M.; Kumosani, T.A.; Abulnaja, K.; Kannan, K. Urinary levels of triclosan and triclocarban in several Asian countries, Greece and the USA: Association with oxidative stress. Environ. Res. 2018, 160, 91–96.
  46. Brose, D.A.; Kumar, K.; Liao, A.; Hundal, L.S.; Tian, G.; Cox, A.; Zhang, H.; Podczerwinski, E.W. A reduction in triclosan and triclocarban in water resource recovery facilities’ influent, effluent, and biosolids following the US Food and Drug Administration’s 2013 proposed rulemaking on antibacterial products. Water Environ. Res. 2019, 91, 715–721.
  47. Food and Drug Administration. Safety and effectiveness of consumer antiseptics: Topical antimicrobial drug products for over-the-counter human use. Fed. Regist. 2016, 81, 61106–61130.
  48. Waidyanatha, S.; Black, S.R.; Patel, P.R.; Watson, S.L.; Snyder, R.W.; Sutherland, V.; Stanko, J.; Fennell, T.R. Disposition and metabolism of antibacterial agent, triclocarban, in rodents; a species and route comparison. Xenobiotica 2020, 50, 1469–1482.
  49. Juncker, J.-C. (Ed.) Commission Impementing Decision not Approving Triclosan as an Existing Active Substance for Use in Biocidal Products for Product-Type 1, 528/2012; Union European: Brussels, Belgium, 2016.
  50. Chen, J.; Meng, X.Z.; Bergman, A.; Halden, R.U. Nationwide reconnaissance of five parabens, triclosan, triclocarban and its transformation products in sewage sludge from China. J. Hazard. Mater. 2019, 365, 502–510.
  51. Costa, N.O.; Forcato, S.; Cavichioli, A.M.; Pereira, M.R.F.; Gerardin, D.C.C. In utero and lactational exposure to triclocarban: Age-associated changes in reproductive parameters of male rat offspring. Toxicol. Appl. Pharmacol. 2020, 115077.
  52. Ye, X.; Zhou, X.; Furr, J.; Ahn, K.C.; Hammock, B.D.; Gray, E.L.; Calafat, A.M. Biomarkers of exposure to triclocarban in urine and serum. Toxicology 2011, 286, 69–74.
  53. Schebb, N.H.; Inceoglu, B.; Ahn, K.C.; Morisseau, C.; Gee, S.J.; Hammock, B.D. Investigation of human exposure to triclocarban after showering and preliminary evaluation of its biological effects. Environ. Sci. Technol. 2011, 45, 3109–3115.
  54. Gao, C.-J.; Kannan, K. Phthalates, bisphenols, parabens, and triclocarban in feminine hygiene products from the United States and their implications for human exposure. Environ. Int. 2020, 136, 105465.
  55. De Bellis, M.; De Luca, A.; Rana, F.; Cavalluzzi, M.M.; Catalano, A.; Lentini, G.; Franchini, C.; Tortorella, V.; Conte Camerino, D. Evaluation of the pharmacological activity of the major mexiletine metabolites on skeletal muscle sodium currents. Br. J. Pharmacol. 2006, 149, 300–310.
  56. Schebb, N.H.; Franze, B.; Maul, R.; Ranganathan, A.; Hammock, B.D. In vitro glucuronidation of the antibacterial triclocarban and its oxidative metabolites. Drug Metab. Disposit. 2012, 40, 25–31.
  57. Armstrong, D.L.; Lozano, N.; Rice, C.P.; Ramirez, M.; Torrents, A. Degradation of triclosan and triclocarban and formation of transformation products in activated sludge using benchtop bioreactors. Environ. Res. 2018, 161, 17–25.
  58. Miller, T.R.; Colquhoun, D.R.; Halden, R.U. Identification of wastewater bacteria involved in the degradation of triclocarban and its non-chlorinated congener. J. Hazard. Mater. 2010, 183, 766–772.
  59. Pycke, B.F.G.; Roll, I.B.; Brownawell, B.J.; Kinney, C.A.; Furlong, E.T.; Kolpin, D.W.; Halden, R.U. Transformation products and human metabolites of triclocarban and triclosan in sewage sludge across the United States. Environ. Sci. Technol. 2014, 48, 7881–7890.
  60. Birch, C.G.; Hiles, R.A.; Eichhold, T.H.; Jeffcoat, A.R.; Handy, R.W.; Hill, J.M.; Willis, S.L.; Hess, T.R.; Wall, M.E. Biotransformation products of 3,4,4′-trichlorocarbanilide in rat, monkey, and man. Drug Metab. Dispos. 1978, 6, 169–176.
  61. Schebb, N.H.; Flores, I.; Kurobe, T.; Franze, B.; Ranganathan, A.; Hammock, B.D.; Teh, S. Bioconcentration, metabolism and excretion of triclocarban in larval Quart Medaka (Oryzias latipes). Aquat. Toxicol. 2011, 105, 448–454.
  62. Zhang, H.; Lu, Y.; Liang, Y.; Jiang, L.; Cai, Z. Triclocarban-induced responses of endogenous and xenobiotic metabolism in human hepatic cells: Toxicity assessment based on nontargeted metabolomics approach. J. Hazard. Mater. 2020, 392, 122475.
  63. World Health Organization. Antimicrobial Resistance: Global Report on Surveillance; World Health Organization: Geneva, Switzerland, 2014.
  64. O’Neill, J. Antimicrobial resistance: Tackling a crisis for the health and wealth of nations. Rev. Antimicrob Resist. 2014, 20, 1–16.
  65. Kim, S.A.; Rhee, M.S. Microbicidal effects of plain soap vs. triclocarban-based antibacterial soap. J. Hosp. Infect. 2016, 94, 276–280.
  66. US Food and Drug Administration. Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Overthe-Counter Human Use; Proposed Amendment of the Tentative Final Monograph; Reopening of Administrative Record; US Food and Drug Administration: Silver Spring, MD, USA, 2013. Available online: https://www.federalregister.gov/articles/2013/12/17/2013-29814/safetyand-effectiveness-of-consumer-antiseptics-topical-antimicrobialdrug-products-for (accessed on 15 April 2021).
  67. Pozzi, C.; Ferrari, S.; Cortesi, D.; Luciani, R.; Stroud, R.M.; Catalano, A.; Costi, M.P.; Mangani, S. The structure of Enterococcus faecalis thymidylate synthase provides clues about folate bacterial metabolism. Acta Crystallogr. D Biol. Crystallogr. 2012, 68, 1232–1241.
  68. Dahl, A.; Iversen, K.; Tonder, N.; Hoest, N.; Arpi, M.; Dalsgaard, M.; Chehri, M.; Soerensen, L.L.; Fanoe, S.; Junge, S. Prevalence of infective endocarditis in Enterococcus faecalis bacteremia. J. Am. Coll. Cardiol. 2019, 74, 193–201.
  69. Yu, J.J.; Manus, M.B.; Mueller, O.; Windsor, S.C.; Horvath, J.E.; Nunn, C.L. Antibacterial soap use impacts skin microbial communities in rural Madagascar. PLoS ONE 2018, 13, e0199899.
  70. Pujol, E.; Blanco-Cabra, N.; Julián, E.; Leiva, R.; Torrents, E.; Vázquez, S. Pentafluorosulfanyl-containing triclocarban analogs with potent antimicrobial activity. Molecules 2018, 23, 2853.
  71. Catalano, A.; Iacopetta, D.; Rosato, A.; Salvagno, L.; Ceramella, J.; Longo, F.; Sinicropi, M.S.; Franchini, C. Searching for small molecules as antibacterials: Non-cytotoxic diarylureas analogues of triclocarban. Antibiotics 2021, 10, 204.
  72. Chen, J.; Ki, C.A.; Gee, N.A.; Ahmed, M.I.; Duleba, A.J.; Zhao, L.; Gee, S.J.; Hammock, B.D.; Lasley, B.L. Triclocarban enhances testosterone action: A new type of endocrine disruptor? Endocrinology 2008, 149, 1173–1179.
  73. Duleba, A.J.; Ahmed, M.I.; Sun, M.; Gao, A.C.; Villanueva, J.; Conley, A.J.; Turgeon, J.L.; Benirschke, K.; Gee, N.A.; Chen, J.; et al. Effects of triclocarban on intact immature male rat: Augmentation of androgen action. Reprod. Sci. 2011, 18, 119–127.
  74. Cao, L.Y.; Xu, Y.H.; He, S.; Ren, X.M.; Yang, Y.; Luo, S.; Xie, X.D.; Luo, L. Antimicrobial triclocarban exhibits higher agonistic activity on estrogen-related receptor γ than triclosan at human exposure levels: A novel estrogenic disruption mechanism. Environ. Sci. Technol. Lett. 2020, 7, 434–439.
  75. Gálvez-Ontiveros, Y.; Páez, S.; Monteagudo-Sanchez, C.; Rivas, A. Endocrine disruptors in food: Impact on gut microbiota and metabolic diseases: A systematic review. Nutrients 2020, 12, 1158.
  76. Rochester, J.R.; Bolden, A.L.; Pelch, K.E.; Kwiatkowski, C.F. Potential developmental and reproductive impacts of triclocarban: A scoping review. J. Toxicol. 2017, 2017, 9679738.
  77. Aker, A.M.; Ferguson, K.K.; Rosario, Z.Y.; Mukherjee, B.; Alshawabkeh, A.N.; Cordero, J.F.; Meeker, J.D. The associations between prenatal exposure to triclocarban, phenols and parabens with gestational age and birth weight in northern Puerto Rico. Environ. Res. 2019, 169, 41–51.
  78. Watkins, D.J.; Ferguson, K.K.; Anzalota Del Toro, L.V.; Alshawabkeh, A.N.; Cordero, J.F.; Meeker, J.D. Associations between urinary phenol and paraben concentrations and markers of oxidative stress and inflammation among pregnant women in Puerto Rico. Int. J. Hyg. Environ. Health 2015, 218, 212–219.
  79. Wei, J.; Zhou, T.; Hu, Z.; Li, Y.; Yuan, H.; Zhao, K.; Zhang, H.; Liu, C. Effects of triclocarban on oxidative stress and innate immune response in zebrafish embryos. Chemosphere 2018, 210, 93–101.
  80. Ding, Z.M.; Ahmad, M.J.; Meng, F.; Chen, F.; Wang, Y.S.; Zhao, X.Z.; Zhang, S.X.; Miao, Y.L.; Xiong, J.J.; Huo, L.J. Triclocarban exposure affects mouse oocyte in vitro maturation through inducing mitochondrial dysfunction and oxidative stress. Environ. Pollut. 2020, 262, 114271.
  81. Xie, M.; Zhang, H.; Wang, W.; Sherman, H.L.; Minter, L.M.; Cai, Z.; Zhang, G. Triclocarban Exposure Exaggerates Spontaneous Colonic Inflammation in Il-10−/− Mice. Toxicol. Sci. 2020, 174, 92–99.
  82. Dong, M.; Yuan, P.; Song, Y.; Lei, H.; Chen, G.; Zhu, X.; Wu, F.; Chen, C.; Liu, C.; Shi, Z.; et al. In vitro effects of triclocarban on adipogenesis in murine preadipocyte and human hepatocyte. J. Hazard. Mater. 2020, 122829.
  83. Li, H.; Zhao, Y.; Chen, L.; Su, Y.; Li, X.; Jin, L.; Ge, R.S. Triclocarban and triclosan inhibit human aromatase via different mechanisms. BioMed Res. Int. 2017, 2017, 8284097.
  84. Taweetanawanit, P.; Ratpukdi, T.; Siripattanakul-Ratpukdi, S. Performance and kinetics of triclocarban removal by entrapped Pseudomonas fluorescens strain MC46. Bioresour. Technol. 2019, 274, 113–119.
  85. Kennedy, R.C.; Fling, R.R.; Robeson, M.S.; Saxton, A.M.; Donnell, R.L.; Darcy, J.L.; Bemis, D.A.; Liu, J.; Zhao, L.; Chen, J. Temporal development of gut microbiota in triclocarban exposed pregnant and neonatal rats. Sci. Rep. 2016, 6, 33430.
  86. Ribado, J.V.; Ley, C.; Haggerty, T.D.; Tkachenko, E.; Bhatt, A.S.; Parsonnet, J. Household triclosan and triclocarban exposure impacts the adult intestinal microbiome but not the infant intestinal microbiome. BioRxiv 2017, 126334.
  87. Pflughoeft, K.J.; Versalovic, J. Human microbiome in health and disease. Annu. Rev. Pathol. 2012, 7, 99–122.
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