Scientific Committee on Consumer Safety SCCS Opinion on triclosan Antimicrobial Resistance

.........................................................................................6 EXECUTIVE SUMMARY..........................................................................6 1. BACKGROUND..............................................................................8 2. TERMS OF REFERENCE ..................................................................8 3. INTRODUCTION ...........................................................................9 3.1. Scope................................................................................................................................................................. 9 3.2. Physico-chemical properties......................................................................................................................... 10 3.3. Triclosan in biocidal formulations............................................................................................................... 12 3.4. Mode of action ............................................................................................................................................... 13 4. DEFINITIONS.............................................................................13 5. PRODUCTION, USE AND FATE OF TRICLOSAN.................................15 5.1. Triclosan in cosmetics ................................................................................................................................... 15 5.2. Triclosan in healthcare and medical devices............................................................................................... 16 5.3. Triclosan in household and other consumer products ............................................................................... 16 5.4. Triclosan in food and feed ............................................................................................................................ 17 5.4.1. Triclosan in food production.................................................................................................................... 17 5.4.2. Triclosan as disinfectant in food and feed production ........................................................................... 17 5.4.3. Triclosan as food preservative ................................................................................................................. 17 5.4.4. Triclosan in animal husbandry ................................................................................................................ 18 5.4.5. Triclosan as feed preservative.................................................................................................................. 18 5.5. Triclosan in the environment ....................................................................................................................... 18 5.5.1. Fate of triclosan in the environment........................................................................................................ 18 5.5.2. Effect of triclosan on micro-flora and toxicity of metabolites ............................................................... 21 5.6. Triclosan in the human body........................................................................................................................ 22 SCCP/1251/09 Opinion on triclosan – antimicrobial resistance 5 6. MECHANISMS OF RESISTANCE TO TRICLOSAN ...............................22 6.1. General considerations on biocide resistance in bacteria .......................................................................... 22 6.2. General considerations on the study of triclosan........................................................................................ 24 6.3. Mechanisms of bacterial resistance to triclosan ......................................................................................... 24 6.4. Mutation rates and transfer of resistance ................................................................................................... 27 6.5. Induction of resistance.................................................................................................................................. 27 6.6. Bacterial cross-resistance to triclosan and antibiotics ............................................................................... 28 6.6.1. General considerations ............................................................................................................................. 28 6.6.2. Triclosan and cross-resistance ................................................................................................................. 28 6.7. Triclosan resistance in bacteria in situ ........................................................................................................ 30 7. TRICLOSAN BIOAVAILABILITY AND FORMULATION EFFECTS.............31 8. MEASUREMENT OF RESISTANCE AND CROSS-RESISTANCE ..............32 9. DATA GAPS ON SCIENTIFIC KNOWLEDGE ......................................33 9.1. Scientific gaps:............................................................................................................................................... 33 9.2. Technical gaps: .............................................................................................................................................. 33 10. RISK ASSESSMENT...................................................................33 10.1. Limitation in activity................................................................................................................................. 34 10.2. Genetic and bacterial point of view ......................................................................................................... 34 10.3. Environment point of view ....................................................................................................................... 34 10.4. Biofilm formation in specific environmental conditions ........................................................................ 35 11. CONCLUSIONS.........................................................................35 12. OPINION.................................................................................36 13. COMMENTS RECEIVED DURING THE PUBLIC CONSULTATION .........37 14. MINORITY OPINION..................................................................37 15. REFERENCES ...........................................................................38 SCCP/1251/09 Opinion on triclosan – antimicrobial resistance 6 ABSTRACT Triclosan is a biocide used in many product categories, including cosmetics. The information on environmental concentrations of triclosan in the EU is limited and the bioavailability of the triclosan to bacteria in the environment is not known. 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. A number of scientific and technical data gaps about the occurrence and understanding of the resistance profile of triclosan have been identified and should be addressed. At present, several distinct hazards have been identified: (i) the effect of triclosan on the triggering/regulation of resistance genes in bacteria (ii) the existence of defined mechanisms that can promote resistance and cross-resistance to biocides and antibiotics in bacteria, (iii) high concentrations of triclosan (compared to concentrations known to select for resistance in in vitro experiments) have been measured in certain environmental compartments and (iv) bacterial biofilms, which are widespread in the environment and are able to survive exposure to adverse environmental factors. The first two of these hazards have been identified in vitro. The presence of resistance genes in soil bacteria should be investigated further. Based on the six in situ studies and the one meta-analysis quoted in this document and recent data from in vitro investigations (proteomic and genomic analyses), it is not possible to quantify the risk associated with triclosan (including its use in cosmetics) in terms of development of antimicrobial resistance (i.e. selection for less susceptible population), genetic basis for resistance and dessemination of resistance. In view of the concentrations of triclosan reported to trigger resistance in vitro, some of the environmental concentrations found in a number of geographical distinct areas are high enough to suggest that bacterial resistance could be triggered. However, no studies have been conducted on this aspect. The applications of triclosan which contribute to those high environmental concentrations cannot be properly identified nor quantified at present and the presence of other chemicals (e.g. antibiotics, surfactants, other biocides, etc.) in the environment, which may also affect microbial populations, would preclude assessing the effects of triclosan independently. Thus, additional in situ information is needed to provide an answer on the level of risk. EXECUTIVE SUMMARY Triclosan is a biocide used in many product categories, including cosmetics. The information on environmental concentrations of triclosan in the EU is limited and bioavailability of the triclosan to bacteria in the environment is not known. 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. Triclosan is the most studied biocide with respect to bacterial resistance. Such a level of information, notably on its activity against bacteria, the identification of mechanisms of microbial resistance including genomic and proteomic aspects, is commendable and should be extended to other biocides. Low concentrations of triclosan can trigger the expression of resistance and cross-resistance mechanisms in bacteria in vitro. In view of the concentrations of triclosan reported to trigger resistance in vitro, some of the environmental concentrations found in a number of SCCP/1251/09 Opinion on triclosan – antimicrobial resistance 7 geographical distinct areas are high enough to suggest that bacterial resistance could be triggered. It is however difficult to predict whether microbial resistance would be triggered in these environments. The few in situ studies performed to date did not show any bacterial resistance emerging following triclosan exposure. In addition, the presence of other chemicals (e.g. antibiotics, surfactants, other biocides, etc.) in the environment, which may also affect microbial populations, would preclude assessing the effects of triclosan independently. The emergence of resistance induced/selected by triclosan is related to the genetic control on the resistance gene(s) present on chromosomal and genetic mobile elements. This represents the origin for a hazard about selection and dissemination of cross-resistance with other anti-bacterial molecules including biocides and antibiotics. Triclosan, like any other biocide, contributes to the selection of less susceptible bacteria in a complex microcosm in vitro. The impact of such a selection is unclear, as is the fitness of the “selected” bacterial species following triclosan exposure. The few in situ studies investigating long-term triclosan exposure (i.e. at least 6 months) did not indicate changes in the resistance susceptibility in the predominant bacteria selected for monitoring, but the changes in the entire flora were not evaluated. Thus additional in situ information is needed to provide a definitive opinion. There are, so far, no epidemiological data linking outbreaks of antimicrobial resistant human and zoonotic pathogens to exposure to triclosan. A number of scientific and technical data gaps about the occurrence and understanding of the resistance profile of triclosan have been identified and should be addressed. In particular, where biocides, including triclosan are used intensely, monitoring for emerging resistance in the microbial flora should be conducted. A more detailed research strategy for investigating the antimicrobial resistance effect of biocides is presented in a separate opinion from the SCENIHR (2010). There is an apparent discrepancy between in situ information that suggests the absence of induction of bacterial resistance and cross-resistance triggered by triclosan, and in vitro studies describing the mechanistic and genetic aspect of triclosan-resistance in bacteria. A better translation of in vitro findings to in situ situations is needed, making full use of molecular tools and environmental conditions used in laboratory investigations. Standardized protocols and similar parameters should be applied to both in vitro and in situ investigations. Although triclosan resistance was not observed in situ, this is not sufficient to conclude that there is no risk. Information is still lacking to provide a risk assessment on the use of triclosan in cosmetic products, including the genetic aspects of resistance, changes in environmental microcosm, maintenance and transfer of virulence and resistance determinants in situ. Due to the limited number of in situ studies of resistance induced by triclosan to date, SCCS can only recommend the prudent use of triclosan, for example in applications where a health benefit can be demonstrated. However, conclusions from in vitro studies cannot be ignored, notably the role of triclosan (and other biocides) in triggering resistance and in the dissemination (horizontal or vertical transfer of) resistance determinants. Research focused on triggering mechanisms of resistance, maintenance of the gene pool and the transfer of resistance and virulence determinants, and improving the translational application of laboratory results to situations in situ are needed. Hence,the SCCS appreciates that research investment from the industry will be maintained to contribute to a better understanding of the potential risks associated with triclosan applications. SCCP/1251/09 Opinion on triclosan – antimicrobial resistance