Safety Review of Phenoxyethanol When Used As a Preservative in Cosmetics
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DOI: 10.1111/jdv.15944 JEADV REVIEW ARTICLE Safety review of phenoxyethanol when used as a preservative in cosmetics B. Dreno, 1 T. Zuberbier,2 C. Gelmetti,3 G. Gontijo4, M. Marinovich5,* 1Dermatology Department, CHU Nantes, CIC 1413 CRCINA, University of Nantes, Nantes, France 2Department of Dermatology and Allergy, Charite - Universitatsmedizin€ Berlin, Berlin, Germany 3UOC Dermatologia Pediatrica, IRCCS Fondazione Ca’ Granda “Ospedale Maggiore Policlinico”, Dipartimento di Fisiopatologia Medico-Chirurgica, Universita degli Studi di Milano, Milan, Italy 4Department of Dermatology, UFMG Universidade Federal de Minas Gerais, Belo Horizonte, Brazil 5Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy *Correspondence: M. Marinovich. E-mail: [email protected] Abstract Phenoxyethanol, or 2-phenoxyethanol, has a large spectrum of antimicrobial activity and has been widely used as a preservative in cosmetic products for decades. It is effective against various Gram-negative and Gram-positive bacteria, as well as against yeasts, and has only a weak inhibitory effect on resident skin flora. According to the European Scien- tific Committee on Consumer Safety, phenoxyethanol is safe for all consumers – including children of all ages – when used as a preservative in cosmetic products at a maximum concentration of 1%. Adverse systemic effects have been observed in toxicological studies on animals but only when the levels of exposure were many magnitudes higher (around 200-fold higher) than those to which consumers are exposed when using phenoxyethanol-containing cosmetic prod- ucts. Despite its widespread use in cosmetic products, phenoxyethanol is a rare sensitizer. It can be considered as one of the most well-tolerated preservatives used in cosmetic products. Received: 17 July 2019; Accepted: 3 September 2019 Conflict of interest BD and GG are members of the Scientific Advisory Board of Cosmetique Active International. The authors declare they have no conflicts of interest that might be relevant to the contents of this manuscript. Funding source Medical writing was funded by Cosmetique Active International. Introduction Phenoxyethanol exhibits a weaker inhibitory effect on normal Phenoxyethanol (CAS n. 122-99-6) is an ether and aromatic skin-resident bacteria than other cosmetic chemical preservatives alcohol, which is also known as 2-phenoxyethanol, ethylene gly- (e.g. methylisothiazolinone, iodopropynyl butylcarbamate, col monophenyl ether, phenoxytol, 1-hydroxy-2-phenoxyethane ethylhexylglycerin and methylparaben6) and is used as a preser- and (2-hydroxyethoxy) benzene. vative in a large range of rinse-off and leave-on cosmetic prod- It has a large spectrum of antimicrobial activity and is effec- ucts. It is also a fragrance ingredient used in many fragrance tive against various Gram-negative (e.g. Pseudomonas aerugi- mixtures.3 In a recent study analysing the full ingredient infor- nosa) and Gram-positive (e.g. Staphylococcus aureus)1 bacteria, mation contained in the American Contact Dermatitis Society as well as against yeasts (e.g. Candida albicans).2,3 Phenoxyetha- database – the Contact Allergen Management Program – for a nol exerts its antimicrobial activity by uncoupling oxidative large panel of common cosmetic products marketed in the USA phosphorylation from respiration and by competitively inhibit- (n = 4737), phenoxyethanol was found in 23.9% (n = 1132) of ing malate dehydrogenase.4 It also acts as a bactericidal agent by the products.7 Moreover, a recent study conducted in Spain increasing the permeability of the cell membrane to potassium reported that 43.09% of cosmetics sold exclusively in pharma- ions and exerts a direct inhibitory effect on microbial DNA and cies, 23.29% of cosmetics sold in supermarkets and RNA synthesis.4 Due to its broad antimicrobial activity, phe- 14.1% of cosmetics from herbal shops, contained noxyethanol has been used for decades as a preservative in vari- phenoxyethanol.8 ous products such as medicines (e.g. in vaccines) and hand Some glycol ethers, such as ethylene glycol ethyl ether or disinfecting biocidal products up to a concentration of 5%, ethylene glycol methyl ether, have been shown to have toxic including products for toddlers.5 effects on reproduction and have been banned in Europe [see JEADV 2019, 33 (Suppl. 7),15–24 © 2019 European Academy of Dermatology and Venereology 16 B. Dreno et al. European Regulation (EC) No 1272/2008]. However, the Data searching methods chemical and physical properties of phenoxyethanol differ The SCCS conducted a review of available safety data on phe- from those of these glycol ethers (e.g. it is not volatile) and noxyethanol, which included both data from peer-reviewed sci- phenoxyethanol was not classified as a reproductive toxicant entific journals and safety data from unpublished studies carried in EC No 1272/2008 unlike some other glycol ethers. Never- out by cosmetic product manufacturers, often at the request of theless, some concerns about its safety were raised due to its the SCCS. These data, as well as other data from ANSM assess- assimilation to the whole glycol ether family. Furthermore, ments, were used in the current review. In addition, an updated controversial claims that phenoxyethanol has an effect on the search of safety data on phenoxyethanol was performed using blood and liver, and that it disrupts endocrine activity, have PubMed. The following search terms were used: ‘phe- been a matter of public debate and received media attention. noxyethanol’ OR ‘Ethylene glycol monophenyl ether’ OR ‘(2- According to Commission Regulation 2018/605 amending hydroxyethoxy) benzene’ OR ‘glycol ether’ OR ‘phenoxyacetic Plant Protection Regulation No. 1107/2009, a substance acid’. As the most recent publication used in the SCCS opinion should be considered as having endocrine disrupting activity study was dated November 2015, the date limits for publications in humans if: it shows an adverse effect in an intact organism used in our review were set as 1 November 2015 to 31 May 2019. or its progeny leading to functional changes; it has an endo- Articles were screened by two reviewers based on titles and crine mode of action (anti-oestrogenic, androgenic or anti- abstracts, and only those dealing with the safety of phe- androgenic activity, alters steroidogenesis or has thyroid and noxyethanol were selected. anti-thyroid hormone activity); or the adverse effect is a con- sequence of the endocrine mode of action. In June 2015, the Review of safety data high-throughput Endocrine Disruptor Screening Program of the U.S. Environmental Protection Agency (US-EPA) deter- Dermal/percutaneous absorption mined that phenoxyethanol had no oestrogenic activity.9 In The percutaneous absorption of phenoxyethanol at concentra- addition, although phenoxyethanol may be a rare sensitizer, it tions of 0.2 and 1% was evaluated in vitro using rat and human has not been classified as a skin sensitizer by the European skin samples in two studies.3,12 The study of Roper et al.12 con- Chemicals Agency (ECHA). tained some deficiencies and was not considered as relevant by In Europe, preservatives allowed for use in cosmetic prod- the SCCS. ucts are regulated by Annex V of Cosmetics Regulation (EC) The results of an unpublished study (Vincent CM and Marty JP No. 1223/2009.10 According to this regulation, phenoxyethanol (2002), as cited by the SCCS 3) showed that in vitro dermal is authorized as a preservative in cosmetic formulations at a absorption of phenoxyethanol in humans was high and rapid, maximum concentration of 1% (Annex V/29). The safety pro- regardless of its concentration in the formulation tested. After file of phenoxyethanol as a preservative in cosmetic products 24 h of exposure, very small amounts (<0.1%) remained in the was assessed at the European level by the Scientific Committee various layers of the skin and most of the phenoxyethanol was on Consumer Safety (SCCS) in 2016.3 This assessment led the recovered in the receptor fluid, indicating that phenoxyethanol committee to conclude that phenoxyethanol was safe for con- does not bind to or accumulate in the skin. The dermal absorption sumers – including children of all ages – when used as a of phenoxyethanol (i.e. the total amount of phenoxyethanol in the preservative in cosmetic products at a maximum concentra- receptor fluid, dermis and epidermis) after a 24-h period for a for- tion of 1%. However, the French National Agency for the mulation containing 1% phenoxyethanol was 37% Æ 10% for the Safety of Medicines and Health Products (ANSM) recom- rinse-off products and 78% Æ 7% for the leave-on products. mended that phenoxyethanol should not be used as a preser- vative in cosmetic products intended for application on the Bioavailability nappy area (including wipes) of children aged under 3 years.11 Numerous in vivo kinetic studies using oral and topical routes – This recommendation was based on a worst-case aggregate have been conducted in animals,3,12 15 as well as in humans.14 exposure calculation covering the five most used cosmetic These studies showed that phenoxyethanol is rapidly absorbed, products in French children. When wipes and cosmetic prod- distributed, metabolized and excreted. It can be metabolized ucts intended for application to the nappy area were excluded either in the skin or in the liver; however, its metabolism rate is from exposure calculation, the risk assessment conducted by higher in the liver. The major metabolite of phenoxyethanol, 2- the ANSM indicated that phenoxyethanol used at a maximum phenoxyacetic acid, is formed in a two-step oxidation process by concentration of 1% in cosmetic products was also safe for cytosolic alcohol dehydrogenase and aldehyde dehydrogenase.12 children aged under 3 years. In humans, regardless of the route of exposure – i.e. after The objective of this report was to review the safety of phe- topical exposure in clinical trials with adults14 or preterm noxyethanol, taking into account the opinion of the SCCS and babies,16 or after oral administration in a study conducted in an published scientific literature.