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Triclosan and Antibiotics resistance

1. What is the biocide triclosan?

  • 1.1 What are biocides?
  • 1.2 What is triclosan?

1.1 What are biocides?

The SCCS opinion states:

4. DEFINITIONS

According to the Directive 98/8/EC of the European Parliament and Council of the 16 February 1998, biocidal products are defined as active substances and preparations containing one or more active substances, put up in the form in which they are supplied to the user, intended to destroy, render harmless, prevent the action of, or otherwise exert a controlling effect on any harmful organism by chemical or biological means.

Within the scope of this mandate, the proposition is to apply the following definitions:

Source & ©: SCCS,  Opinion on triclosan (antimicrobial resistance) (2010) , p.13

1.2 What is triclosan?

The SCCS opinion states:

3. INTRODUCTION

Triclosan is an antimicrobial agent that has been used for more than 40 years as an antiseptic, disinfectant or preservative in clinical settings, in various consumer products including cosmetics, plastic materials, toys, etc. It has a broad range of activity that encompasses many, but not all, types of Gram-positive and Gram-negative non-sporulating, bacteria, some fungi (Jones et al. 2000, Schweizer 2001), Plasmodium falciparum and Toxoplasma gondii (McLeod et al. 2001). It has also been shown to be ecotoxic, particularly to algae in aquatic environments (Tatarazako et al. 2004). Additionally, it has been shown to interfere with the cycling of nitrogen in natural systems (Fernandes et al. 2008, Waller and Kookana 2009).

Triclosan is bacteriostatic at low concentrations, but higher levels are bactericidal (Suller and Russell 1999, 2000). At sublethal concentrations, it acts by inhibiting the activity of the bacterial enoyl-acyl carrier protein reductase (FabI), a critical enzyme in bacterial fatty acid biosynthesis (Heath et al. 2002, Zhang et al. 2004). At bactericidal concentrations, it is suggested to act through multiple nonspecific mechanisms including membrane damage (Gilbert and McBain 2002).

There are concerns that the widespread use of a low concentration of triclosan in various applications might lead to or select for bacterial resistance to antibiotics. Antibiotic resistance has become an increasingly serious problem worldwide, and the continued use of biocides including triclosan may exacerbate this problem. The main cause of antibiotic resistance remains the use and misuse of antibiotics. During the last decade, antibiotic resistance has increased in bacterial pathogens leading to treatment failures in both human and animal infectious diseases (Harbarth and Samore 2005; for reports see: EARSS Annual Report 2005, WHO 2007).

The safety of continued use of triclosan in cosmetic products has recently been assessed by the EU Scientific Committee on Consumer Products (SCCP 2009). The SCCP emphasised that this risk assessment concerns only the toxicological profile of triclosan and that before a final conclusion on the safety of triclosan in cosmetic products can be reached, the potential development of resistance to triclosan and cross-resistance by certain micro- organisms must be assessed. Earlier evaluations of triclosan, on the basis of available data, EU Scientific Committees concluded that there was no convincing evidence that triclosan poses a risk to humans and environment by inducing or transmitting antibacterial resistance (SSC 2002) as well as there was no evidence of clinical resistance and cross-resistance occurring from the use of triclosan in cosmetic products (SCCP 2006). Further information was sought for an update of these evaluations.

The present evaluation of triclosan is based both on the information submitted by COLIPA1 to SCCS and on research published in peer-reviewed scientific journals. It aims at determining whether the continued use of triclosan may be associated to the development of resistance in certain micro-organisms. It also aims at identifying additional research needs.

3.1. Scope

Triclosan is used as a preservative in consumer products including cosmetics, where the maximum allowed concentration according to the EU Cosmetics Directive 76/768/EEC is 0.3%. The SCCP has recently performed a risk assessment of the use of triclosan in cosmetic products. Although the present mandate concerns the evaluation of a possible association between the use of triclosan in cosmetic products and the development of resistance by certain micro-organisms, the SCCS has taken into account all evidence available from all uses of triclosan to perform its assessment. This is in line with the SCCP conclusions of 2006 (SCCP/1040/06) and it is scientifically sound as 1) cosmetic uses of triclosan account for most of the total use of this biocide in the EU and 2) it is scientifically impossible at present to assess the use of triclosan in cosmetics only, without taking into account its uses in otherAnu applications. In the absence of a clear answer, research needs will be identified. The effect of triclosan on microflora in the environment on the basis of published literature will also be covered, since environmental bacteria represent a pool of antimicrobial resistance genes.

Most of the information provided here relates to bacteria, since studies of the effects of triclosan on other micro-organisms are scarce.

Empirical formula: C12H7Cl3O2
Molecular weight: 289.5
Physical form: White crystalline powder

3.2. Physico-chemical properties

INCI Name: Chemical Name: Synonyms:
Trade Names:
CAS Reg. No.: EC:

Triclosan 2,4,4’-trichloro-2’-hydroxy-diphenylether Phenol, 5-chloro-2-(2,4-dichlorophenoxy)-; Ether, 2'-hydroxy-2,4,4'- trichlorodiphenyl; 5-Chloro-2-(2,4-dichlorophenoxy)phenol, Trichloro-2'- hydroxydiphenylether Irgasan® DP300, Irgasan® PG60, Irgacare® MP, Irgacare® CF100, Irgacide® LP10, ; Cloxifenolum, Irgagard® B 1000, Lexol 300, Ster-Zac 3380-34-5 222-182-2

Chemical structure:

The purity of batches of triclosan used in personal care products since the 1970s is described in the Table 1 (SCCP 2009). These data were provided by COLIPA. The purity and contaminants might be different in triclosan from other sources.

Test Point

Table 1: Purity specifications for triclosan

Table 2: Impurities / accompanying contaminants

The solubility of triclosan is described in Table 3.

Table 3: Solubility of triclosan in selected solvents and chemicals

3.3. Triclosan in biocidal formulations

Biocidal products that contain triclosan as the main antimicrobial are usually complex formulations due to the lack of solubility of this bisphenol. Components of the formulation might affect the activity of triclosan positively (e.g. through synergism) or negatively (e.g. antagonism). There is some information on the effect of formulation components on biocide activity (Alakomi et al. 2006, Ayres et al. 1999, Denyer and Maillard 2002, Maillard 2005b), but by large this information is restricted due to proprietory restrictions, or the lack of understanding on how formulation components work in term of antimicrobial potentiation.

In the scientific literature, where triclosan activity has been reported, there is little reference to the use of formulation. Instead triclosan is often dissolved in a solvent such as DMSO.

3.4. Mode of action

Chemical biocides are generally considered to have multiple target sites against microbial cells, although such interactions are concentration dependent (Russell et al. 1997; Maillard 2005a). The bisphenol triclosan is no exception. At a sub-inhibitory concentration, triclosan was found to profoundly affect bacterial growth, indicating a strong interaction with the bacterial targets, despite the high concentration exponent of triclosan (McDonnell and Russell 1999). At higher concentrations, Gomez Escalada et al. (2005a) observed that triclosan was both rapid-acting and active at all phases of population growth, although some marked differences in its lethality were observed.

These observations substantiated earlier findings with Staphylococcus aureus (Regos and Hitz 1974; Suller and Russell 2000). Inhibition of key metabolic pathway and synthesis (Regos and Hitz 1974; McMurry et al. 1998b) might be part of the lethal action mechanisms of triclosan. Indeed, triclosan was found to target specifically fatty acid synthesis with the inhibition of the enzyme enoyl reductase (enoyl-acyl carrier protein reductase, FabI) (McMurry et al. 1998a). It acts as a potent irreversible inhibitor of FabI by mimicking its natural substrate (Heath et al. 1998; Levy et al. 1999) and this inhibition has been described as being slow and competitive (Heath et al. 1999). The propensity of triclosan to inhibit fatty acid synthesis in Plasmodium falciparum and Toxoplasma gondii (McLeod et al. 2001) has led to the development of a number of antimalarial and antibacterial pro-drugs based on triclosan (Mishra et al. 2008; Freundlich et al. 2009).

The rapid action of triclosan at a high concentration might be indicative of membrane damage (Villalain et al. 2001) and it is clear that fatty acid synthesis targeting cannot solely explain the lethal effect of triclosan (Gomez Escalada et al. 2005b). Triclosan membranotropic effects result in destabilised structures compromising the functional integrity of cell membranes without inducing cell lysis (Villalain et al. 2001). Intercalation of triclosan into bacterial cell membranes is likely to compromise the functional integrity of those membranes, thereby accounting for some of triclosan antibacterial effects (Guillén et al. 2004).

Recently, the first genome-wide transcriptional analysis of Staphylococcus aureus exposed to triclosan (0.05 μM), reported that triclosan down regulated primary metabolism-related and carbohydrate transport, the cap operon which is essential for virulence, the clpB chaperone-related genes which might trigger the expression of resistant determinants, genes involved in fatty acid production and utilisation (Jang et al. 2008).

A number of factors affect the antimicrobial activity of triclosan. These can be divided into intrinsic factors derived from the biocide and its application (e.g. concentration, contact time, pH) and extrinsic factors which derive from the environment during application (e.g. temperature, soiling). Understanding the complex relationship between concentration and contact time (sometimes referred to as CT concept) is crucial to ensure efficacy (Maillard 2005a). The stability of triclosan in particular environments will also influence efficacy.

Source & ©: SCCS,  Opinion on triclosan (antimicrobial resistance) (2010) Table 2 , p.9


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