Phenoxyethanol
Phenoxyethanol, also known as 2-phenoxyethanol, is an organic chemical compound with the molecular formula C₈H₁₀O₂ and a molecular weight of 138.16 g/mol, commonly used as a preservative in cosmetics, pharmaceuticals, and other products due to its broad-spectrum antimicrobial properties.[1][2] This colorless, oily liquid with a faint aromatic or rose-like odor is slightly viscous, has a boiling point of 245°C, and exhibits limited solubility in water (approximately 2.67 g/100 mL) while being highly soluble in alcohol and ether.[1][2] It functions not only as a preservative and perfume fixative but also as a solvent for resins and dyes, an antiseptic, an insect repellent, and an anesthetic agent in fish aquaculture.[1][2] In cosmetic formulations, phenoxyethanol is typically incorporated at concentrations below 1%, with regulatory limits such as a maximum of 1% approved by the European Economic Community and similar guidelines from Health Canada classifying it as an antimicrobial preservative.[2][1] Safety assessments indicate that phenoxyethanol is practically nontoxic via oral and dermal routes in animal studies, with LD₅₀ values of 1.3–1.9 g/kg orally and 13.0 mL/kg dermally in rats, though undiluted forms can cause eye irritation and slight skin irritation.[2] It shows no evidence of sensitization, mutagenicity, teratogenicity, or phototoxicity in relevant tests and human clinical studies, leading to the conclusion that it is safe for use as a cosmetic ingredient at current practices and concentrations.[2] Additionally, the U.S. Environmental Protection Agency has granted it an exemption from pesticide tolerance requirements, affirming low risk in approved applications.[3]Chemical Properties
Molecular Structure and Formula
Phenoxyethanol has the molecular formula C₈H₁₀O₂, which is commonly expanded to show its structural components as C₆H₅OCH₂CH₂OH.[1] Its preferred IUPAC name is 2-phenoxyethan-1-ol, reflecting the systematic nomenclature for this ether alcohol.[4] The compound's molecular weight is 138.16 g/mol, calculated from its atomic composition.[1] Structurally, phenoxyethanol is an aromatic ether featuring a phenyl ring (C₆H₅-) attached via an oxygen atom to a hydroxyethyl group (-CH₂CH₂OH), resulting in the ether linkage C₆H₅-O-CH₂- and a terminal primary alcohol functional group -CH₂OH.[1] This configuration positions the molecule as a glycol ether derivative, with the phenyl group providing aromatic character and the ethylene chain incorporating both ether and alcohol functionalities.[5] Phenoxyethanol is synonymous with ethylene glycol monophenyl ether, highlighting its relation to other phenyl-substituted glycol ethers that share the core phenoxyethanol motif but may differ in chain length or substitutions.[1]Physical and Chemical Characteristics
Phenoxyethanol is a colorless to slightly yellow oily liquid at room temperature, exhibiting a faint rose-like odor.[1][6] Key physical properties of phenoxyethanol include a boiling point of 245.2 °C, a melting point of 14 °C, a density of 1.109 g/cm³ at 20 °C, and a refractive index of 1.534 at 20 °C.[1]| Property | Value | Conditions |
|---|---|---|
| Boiling Point | 245.2 °C | - |
| Melting Point | 14 °C | - |
| Density | 1.109 g/cm³ | 20 °C |
| Refractive Index | 1.534 | 20 °C |
Natural Occurrence
Phenoxyethanol is found naturally in trace amounts in the leaves of green tea plants (Camellia sinensis), particularly in varieties such as Gyokuro.[1][2] These levels are typically very low and insufficient for commercial extraction, leading to reliance on synthetic production for industrial applications.[1] Documentation of its presence in other plant sources remains limited.[1] In natural contexts, phenoxyethanol concentrations do not exceed minor fractions, often below detectable thresholds for practical isolation.[1] Given its established antimicrobial properties, phenoxyethanol in plants like green tea may contribute to natural defense mechanisms against microbial threats, although this is not its primary biological function.[1][2]Production and Synthesis
Historical Development
Phenoxyethanol's historical development originated in the late 19th century amid advancements in organic synthesis. In 1894, Austrian chemist Ernst Roithner at the University of Vienna first described its synthesis through the reaction of phenol with ethylene oxide in a basic medium.[9] This method highlighted early explorations into glycol ethers, building on emerging techniques in ether formation. Two years later, in 1896, British chemists William Henry Perkin Jr., Edward Haworth, and William Henry Bentley reported an alternative preparation using sodium phenolate and ethylene chlorohydrin (2-chloroethanol), which became a foundational route for its production.[9] These syntheses occurred during the burgeoning growth of the organic chemical industry in the early 20th century, particularly post-World War I, when Allied nations rapidly expanded domestic capabilities in synthetic organics to reduce reliance on German imports of dyes and intermediates.[10] By the mid-20th century, phenoxyethanol transitioned from laboratory curiosity to practical industrial application, notably as a preservative in cosmetics and inks, due to its effective antimicrobial properties in stable formulations.[11][12] Widespread adoption occurred in the 1950s as preservation needs in consumer goods evolved.[11] This period marked its integration into consumer products, reflecting broader innovations in chemical preservation techniques. Regulatory scrutiny intensified in the 1970s, with expert panels affirming its generally recognized as safe (GRAS) status for use as a flavoring agent, based on safety evaluations.[13] These developments solidified phenoxyethanol's role in industrial and related contexts, paving the way for its expanded applications.Synthetic Methods
Phenoxyethanol is primarily synthesized through a variant of the Williamson ether synthesis, involving the nucleophilic ring-opening reaction of phenol with ethylene oxide in an alkaline medium.[9] The reaction proceeds as follows: \ce{C6H5OH + C2H4O -> C6H5OCH2CH2OH} This process typically employs sodium hydroxide as a catalyst to deprotonate phenol, forming the phenoxide ion, which attacks the less substituted carbon of the epoxide ring.[14] The reaction is conducted at elevated temperatures of 120–150 °C and pressures of 2–5 atm to ensure efficient conversion and minimize side reactions such as polymerization of ethylene oxide.[15] In industrial production, the synthesis utilizes continuous flow reactors to achieve high throughput and yields exceeding 90%, often reaching 98% under optimized conditions.[16] Recent advancements include "green chemistry" approaches to improve sustainability and reduce waste in the process.[16] The raw materials include phenol, derived from petroleum via the cumene process involving benzene and propylene, and ethylene oxide, produced by the direct partial oxidation of ethylene with oxygen over a silver catalyst.[17][18] Following the reaction, the crude product is purified by distillation under reduced pressure to remove unreacted phenol, water, and by-products, yielding high-purity phenoxyethanol suitable for commercial applications.[19] Alternative synthetic routes are less commonly employed due to lower efficiency and higher costs compared to the ethylene oxide method. These include the reduction of phenoxyacetic acid using strong reducing agents like lithium aluminum hydride, which converts the carboxylic acid group to a primary alcohol, and the classic Williamson ether synthesis via reaction of sodium phenoxide with 2-chloroethanol (ethylene chlorohydrin).[20]Applications
In Cosmetics and Personal Care
Phenoxyethanol serves primarily as a broad-spectrum preservative in cosmetics and personal care products, preventing microbial growth in water-based formulations at concentrations typically ranging from 0.5% to 1.0%.[21] This low usage level helps maintain product stability and extend shelf life without significantly altering the formulation's sensory properties.[22] It is particularly valued for its effectiveness across a wide pH range of 3 to 10, making it suitable for diverse cosmetic matrices.[23] Common applications include lotions, shampoos, makeup products, soaps, and fragrances, where it not only acts as a preservative but also functions as a fixative in perfumes to stabilize scents.[24] In these products, phenoxyethanol is odorless at typical use levels, ensuring it does not interfere with the fragrance profile or overall user experience.[1] Its compatibility with surfactants and other cosmetic ingredients further enhances its versatility in emulsion-based systems like creams and conditioners.[25] Phenoxyethanol holds a significant market position, with blends containing it accounting for approximately 35% of the personal care and cosmetic preservatives market due to its proven efficacy and regulatory acceptance.[26] In formulation practice, it is often combined with parabens for synergistic broad-spectrum protection or with EDTA as a chelator to boost antimicrobial activity in natural or extract-rich products, allowing for lower overall preservative concentrations.[27][28] This approach optimizes preservation while minimizing potential irritation risks in sensitive skin formulations.[29]In Pharmaceuticals and Vaccines
Phenoxyethanol serves as a preservative in multi-dose vaccine vials to inhibit bacterial and fungal contamination, ensuring sterility during repeated access. In certain formulations, such as the inactivated polio vaccine IPOL, it is included at a concentration of 0.5% to maintain product integrity. Similarly, it functions in diphtheria-tetanus-acellular pertussis (DTaP) vaccines like Daptacel at 0.6% v/v, where it acts primarily as a stabilizer but contributes to antimicrobial protection. This role is particularly vital in resource-limited settings where multi-dose formats enable broader immunization coverage without refrigeration challenges.[30][31][32] In pharmaceutical applications beyond vaccines, phenoxyethanol provides broad-spectrum antimicrobial activity in topical ointments, ophthalmic solutions like eye drops, and oral syrups, preventing microbial growth in these formulations. For instance, it is incorporated into antibiotic ointments and ear drops as a preservative to extend shelf life and safety. Concentrations in these products typically range from 0.5% to 1.0%, selected to balance efficacy with minimal irritation potential. In injectable pharmaceuticals, such as certain vaccines, usage is limited to lower levels around 0.5% due to heightened risks of systemic exposure via injection routes.[1][33][34] Historically, phenoxyethanol has been part of polio vaccine compositions since the development of inactivated formulations in the mid-20th century, with its current inclusion in products like IPOL reflecting ongoing reliance for preservation. In modern DTaP vaccines, such as those administered in routine pediatric schedules, it remains at 0.6% to support stability without compromising immunogenicity. However, the pharmaceutical industry has increasingly adopted single-dose vaccine formats, which eliminate the need for preservatives like phenoxyethanol by avoiding multi-dose contamination risks, thereby enhancing safety profiles in high-income settings.[35][31][36]Industrial and Other Uses
Phenoxyethanol serves as a versatile solvent in various industrial processes, particularly for dissolving cellulose acetate, dyes, inks, and resins, leveraging its solvency properties to facilitate material processing and formulation stability.[1][9] In the textile industry, it is employed during printing, dyeing, and finishing operations to aid in color dispersion and fabric treatment.[1] Additionally, phenoxyethanol functions as an insect repellent in textile applications, where it is incorporated to provide protective qualities against pests.[1] Beyond textiles, phenoxyethanol acts as an antiseptic component in certain industrial disinfectants, contributing to microbial control in non-consumer settings.[1] It also serves as a fixative in perfume manufacturing, helping to stabilize and prolong fragrance release in industrial-scale production.[1] In paint and adhesive formulations, phenoxyethanol enhances stability and acts as a preservative, improving product longevity and performance in these materials.[37] A notable niche application is in aquaculture, where phenoxyethanol is used as an anesthetic for fish sedation at concentrations of 200-500 ppm, enabling safe handling, transport, and procedures while minimizing stress.[1][38] Globally, industrial uses account for approximately 35% of phenoxyethanol production as of 2023, underscoring its significance in manufacturing sectors beyond consumer products.[39]Preservative Efficacy
Mechanism of Action
Phenoxyethanol primarily exerts its antimicrobial effects by disrupting the integrity of microbial cell membranes in bacteria and fungi, primarily through solubilization of membrane lipids. This action compromises the lipid bilayer structure, leading to increased permeability and leakage of essential cellular components such as potassium ions, which ultimately impairs cellular function and viability.[40][41][42] In addition to membrane disruption, phenoxyethanol exhibits secondary effects by inhibiting key enzyme activities and interfering with macromolecular synthesis. It directly suppresses DNA and RNA synthesis in microorganisms, independent of indirect impacts on ATP production, and can precipitate nucleic acids and proteins at higher concentrations, contributing to protein denaturation. These multi-faceted interactions further hinder microbial metabolism and replication.[43][2][44] The preservative's activity is concentration-dependent, acting in a bacteriostatic manner at concentrations around or below the minimum inhibitory concentration (typically 0.3–1.0%) by inhibiting growth without immediate cell death, while becoming bactericidal at higher concentrations depending on the organism, where it causes rapid cell lysis and death. Its efficacy is also influenced by pH, effective over a broad pH range of 3 to 12, with good performance in formulations typically at pH 3–10.[41][29] Due to its multi-target mechanism involving both membrane damage and intracellular inhibition, phenoxyethanol demonstrates a low incidence of microbial resistance development, as pathogens are less likely to evolve single-point adaptations to evade its broad biochemical disruptions.[45][42]Antimicrobial Spectrum and Effectiveness
Phenoxyethanol demonstrates a broad antimicrobial spectrum, with particularly strong activity against Gram-negative bacteria, requiring lower concentrations for inhibition compared to Gram-positive bacteria. For instance, the minimum inhibitory concentration (MIC) against Pseudomonas aeruginosa ranges from 0.32% to 0.5%, indicating high efficacy in preventing growth of this challenging pathogen often associated with cosmetic contamination.[2][46] Against Gram-positive bacteria, efficacy is moderate to high, with an MIC of approximately 0.85% to 1.0% for Staphylococcus aureus, allowing effective control in formulations where skin flora contamination is a concern.[2][46] This differential activity stems from its mechanism of membrane disruption, which is more pronounced in the thinner cell walls of Gram-negative organisms.[21] For fungi and yeasts, phenoxyethanol provides effective inhibition at concentrations of 0.5% to 0.54%, as evidenced by its MIC against Candida albicans, a common contaminant in water-based products.[2][46] In preservative challenge tests, formulations containing 0.5% to 1.0% phenoxyethanol typically meet the criteria of USP <51> and ISO 11930 standards, achieving significant log reductions in inoculated bacteria, yeasts, and molds over 28 days.[47][48] However, its activity is weaker against bacterial spores and certain molds, necessitating combination with synergists such as caprylyl glycol to enhance broad-spectrum protection and ensure compliance in challenging formulations.[49] In practical applications, phenoxyethanol at typical use levels of 0.5% to 1.0% contributes to maintaining microbial stability, helping to extend the shelf life of cosmetic and pharmaceutical products to 2-3 years under normal storage conditions and proper formulation.[50] This preservation efficacy is particularly valuable in emulsions and aqueous systems, where it prevents spoilage without significantly altering product sensory attributes.[21]Safety and Health Considerations
Toxicological Profile
Phenoxyethanol exhibits low to moderate acute toxicity across various routes of administration. In rats, the oral LD50 is approximately 1.26 g/kg body weight, indicating moderate toxicity following ingestion. Dermal LD50 values exceed 2.2 g/kg in rabbits, with no mortality observed at this dose under occluded conditions. Acute inhalation toxicity is low, with an LC50 greater than 1,000 mg/m³ in rats exposed for 6 hours, attributed to its low volatility. Phenoxyethanol causes mild skin irritation in rabbits when applied undiluted, resulting in reversible erythema that resolves within 24 hours. Concentrations above 2% may produce slight to moderate reddening, but it is not classified as a severe skin irritant at typical cosmetic levels. Undiluted phenoxyethanol is an eye irritant in rabbits, producing maximal effects such as conjunctival redness and chemosis at 48-72 hours post-exposure, with partial recovery by day 15 in most animals; however, at 2.2%, it is non-irritating to eyes. Dermal absorption of phenoxyethanol in humans is significant, with approximately 78% penetration for leave-on products at 1% concentration and 37% for rinse-off formulations, based on in vitro and in vivo studies using human skin. Inhalation exposure is minimal due to low vapor pressure (about 0.42 Pa at 20°C), limiting systemic uptake via this route. Oral exposure leads to rapid absorption, with over 90% bioavailability in rats. Following absorption, phenoxyethanol is rapidly metabolized primarily in the liver to 2-phenoxyacetic acid via alcohol and aldehyde dehydrogenases, with minor pathways forming phenol conjugates. The metabolite is quickly excreted in urine, with over 90% recovery within 24 hours in both rats and humans; no significant accumulation occurs in tissues. In subchronic and chronic animal studies, phenoxyethanol induces organ effects such as increased liver and kidney weights at doses exceeding 369 mg/kg/day in rats, but no carcinogenicity or genotoxicity is observed. Neurotoxic effects are absent in standard repeated-dose animal studies, though unsteady gait was noted in rats at 1,000 mg/kg/day orally; occupational human exposures have reported headaches and cognitive symptoms at high vapor levels. Reproductive and developmental toxicity studies show no teratogenic effects, with NOAELs of 300 mg/kg/day for maternal toxicity in rats and rabbits; the EU SCCS deems it safe for topical use in infants at concentrations up to 1%. Allergic contact dermatitis to phenoxyethanol is rare, with sensitization prevalence of 0.1-0.24% in large-scale human patch tests among dermatological patients. It is not a skin sensitizer in guinea pigs, though isolated cases of hand dermatitis have been documented in sensitive individuals.Regulatory Approvals and Restrictions
Phenoxyethanol is regulated as a preservative in cosmetics and other products worldwide, with concentration limits generally set at 1% or lower to ensure safety based on toxicological data. In the European Union, it is authorized under Regulation (EC) No 1223/2009, Annex V, for use in cosmetic products at a maximum concentration of 1.0%. The Scientific Committee on Consumer Safety (SCCS) evaluated its safety in 2016 and concluded that phenoxyethanol is safe at this level when used as a preservative, considering exposure from all sources including vaccines and pharmaceuticals. In 2017, France's ANSM recommended limiting to 0.4% in products for children under 3 years and avoiding in nappy areas, though EU SCCS maintained the 1% limit as safe, including for infants.[21][51][52] In the United States, the Food and Drug Administration (FDA) lists phenoxyethanol as Generally Recognized as Safe (GRAS) for food contact substances under 21 CFR Parts 170-186. It is permitted as an inactive ingredient in over-the-counter (OTC) drugs and as a preservative in vaccines, commonly at concentrations up to 0.5%, as seen in product package inserts for licensed vaccines. The Cosmetic Ingredient Review (CIR) Expert Panel has repeatedly affirmed its safety for use in cosmetics at current levels, with initial assessments in the 1980s and 1990, and the safety conclusion standing without reopening based on subsequent reviews.[53][2] Other regions align closely with these standards. In Japan, the Ministry of Health, Labour and Welfare permits phenoxyethanol in cosmetics up to 1.0% under the Standards for Cosmetics. Canada, via Health Canada's Cosmetic Ingredient Hotlist, restricts it to a maximum of 1% in cosmetics, similar to U.S. guidelines. Internationally, the World Health Organization (WHO) accepts phenoxyethanol as a preservative in vaccines, supporting its use in global immunization programs where efficacy and safety are established. In the 2020s, while regulatory attention has shifted toward nanomaterials in cosmetics, no significant changes to phenoxyethanol limits have occurred, though the rise of "clean beauty" movements has promoted preservative alternatives in product formulations.[54][55]Environmental Aspects
Biodegradation and Persistence
Phenoxyethanol undergoes rapid biodegradation under aerobic conditions in aquatic environments, qualifying as readily biodegradable according to standardized tests. In OECD 301 screening methods, such as the CO2 evolution test (301B) and manometric respirometry test (301F), degradation reaches 90% within 28 days, while the closed bottle test (301D) reports 74.9% degradation over the same period.[56][57] European Chemicals Agency (ECHA) evaluations confirm this, noting over 60% biodegradation within 10 days of the lag phase in ready biodegradability assays, indicating efficient microbial utilization under oxygen-rich settings. Under anaerobic conditions, biodegradation proceeds more slowly but ultimately achieves complete mineralization through microbial cleavage of the ether bond. Studies with denitrifying and homoacetogenic bacteria, such as Pseudomonas and Acetobacterium strains, demonstrate stoichiometric conversion to phenol and acetaldehyde, with the latter oxidized to acetate.[58][59] These primary metabolites—phenol, acetaldehyde, and acetate—are further degraded by anaerobic consortia to simpler compounds like CO2 and methane, though the process requires longer incubation times compared to aerobic pathways.[60] The environmental half-life of phenoxyethanol varies with biotic activity; in microbially active soil and water, it ranges from 1 to 5 days due to enhanced enzymatic breakdown, but persists significantly longer (up to weeks or months) in sterile or low-microbial environments.[61] Factors influencing degradation include microbial acclimation, which reduces lag phases and accelerates rates in repeated exposures, as observed in adapted sludge communities. Low oxygen levels slow the process by favoring less efficient anaerobic routes, while high salinity can inhibit microbial activity, reducing overall breakdown efficiency in marine or brackish systems.[62][63]Ecological Toxicity and Impact
Phenoxyethanol exhibits moderate acute toxicity to aquatic organisms, with toxicity levels varying by species and test duration. In fish, the 96-hour LC50 values range from 344 to 366 mg/L, indicating low acute hazard to this group.[64] For aquatic invertebrates such as Daphnia magna, the 48-hour EC50 exceeds 500 mg/L, suggesting minimal short-term effects at environmentally relevant concentrations.[65] Algae show moderate sensitivity, with a 72-hour EC50 >100 mg/L (biomass) for Pseudokirchneriella subcapitata.[66] Chronic exposure assessments reveal lower no-observed-effect concentrations (NOECs) compared to acute endpoints, particularly for invertebrates. A 21-day reproduction test with Daphnia magna yielded a NOEC of 9.43 mg/L and a lowest-observed-effect concentration (LOEC) of 20.5 mg/L, based on reduced offspring production. This value represents the most sensitive reliable chronic endpoint among standard test species. Limited data exist for chronic fish toxicity, but overall, phenoxyethanol is not classified as acutely or chronically hazardous to aquatic life under EU GHS criteria due to these thresholds exceeding typical environmental exposure levels.[67]| Organism Group | Endpoint | Value (mg/L) | Duration | Species | Source |
|---|---|---|---|---|---|
| Fish (acute) | LC50 | 344 | 96 h | Not specified (likely Pimephales promelas) | Acme-Hardesty SDS |
| Daphnia (acute) | EC50 | >500 | 48 h | Daphnia magna | Sigma-Aldrich SDS |
| Algae (acute) | EC50 (biomass) | >100 | 72 h | Pseudokirchneriella subcapitata | ECHA Dossier |
| Daphnia (chronic) | NOEC (reproduction) | 9.43 | 21 d | Daphnia magna | ECHA Dossier |