Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 222-746-8 | CAS number: 3598-16-1
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- <2015
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 2 015
Materials and methods
- Objective of study:
- absorption
- distribution
- excretion
- metabolism
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: OECD 427
- Version / remarks:
- 2004; for the topical application.
- Deviations:
- not specified
- Principles of method if other than guideline:
- An analytical method is described to simultaneously determine phenoxyethanol and phenoxyacetic acid in biological matrices. Application to i.v. and dermal ADME in vivo studies. Only the in vivo studies are reported here.
- GLP compliance:
- not specified
Test material
- Reference substance name:
- 2-phenoxyethanol
- EC Number:
- 204-589-7
- EC Name:
- 2-phenoxyethanol
- Cas Number:
- 122-99-6
- Molecular formula:
- C8H10O2
- Test material form:
- liquid
- Details on test material:
- Oily, slightly viscous liquid at room temperature.
Constituent 1
- Specific details on test material used for the study:
- 2-Phenoxyethanol (PE) and phenoxyacetic acid (PAA) were purchased from Tokyo Chemical Ind. (Tokyo, Japan).
- Radiolabelling:
- no
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- Male Sprague–Dawley rats (8 weeks, body weight 230–280 g) were kept in plastic cages with free access to water and standard rat diet. Rats were housed at a temperature of 23 ± 2 °C with a 12-h light–dark cycle and relative humidity of 50 ± 10%, and were acclimatized for at least 1 week prior to the experiment.
Administration / exposure
- Route of administration:
- other: An i.v. injection study and a topical application study were performed.
- Vehicle:
- other: Isotonic saline for the i.v. study; two sunscreen formulations for the topical application.
- Details on exposure:
- Intravenous injection study:
After overnight fasting, PE was injected at doses of 0.2, 0.5, and 2 mg/kg (n = 8 per dose) via the penile vein. The dosing solutions were prepared by dissolving PE in isotonic saline at concentrations of 0.2, 0.5, and 2 mg/mL. The volume of injected dosing vehicles was kept constant (1 mL/kg) regardless of the dose level.
Topical application study
Two reference sunscreen formulations of emulsion and lotion were prepared to examine the percutaneous absorption of PE by modifying the formulations reported by the European Commission on Cosmetics and Medical Devices (2006). Each formulation consisted of 2 phases and the final product weighed 10 g. The final preparations were kept in light-resistant containers at room temperature until use.
Approximately 24 h prior to experimentation, rats were anesthetized by diethyl ether and the dorsal skin covering the area of 5 x 5 cm2 was shaved with an electric clipper. The shaved skin surface was gently wiped with acetone to remove sebum. After overnight fasting, each formulation was applied to the shaved dorsal skin of rats covering the area of 4 x 4 cm2 (n = 6 per each formulation). The applied amount of each formulation was 234 mg/kg, and the applied PE dose was 2.34 mg/kg.
At 12 h after topical application, the applied area was softly rinsed off with acetone to remove sunscreen remaining on the skin. - Duration and frequency of treatment / exposure:
- Once.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0.2 mg/kg bw/day (nominal)
- Remarks:
- For i.v. application.
- Dose / conc.:
- 0.5 mg/kg bw/day (nominal)
- Remarks:
- For i.v. application.
- Dose / conc.:
- 2 mg/kg bw/day (nominal)
- Remarks:
- For i.v. application.
- Dose / conc.:
- 2.34 mg/kg bw/day (nominal)
- Remarks:
- PE within each of the 2 sunscreen formulations.
- No. of animals per sex per dose / concentration:
- I.v. experiment: 8 per dose.
Dermal experiment: 6 per formulation. - Control animals:
- not specified
- Details on study design:
- Tissue distribution study:
The tissue distribution study was conducted in rats (n = 5) after constant rate intravenous infusion to steady-state. Prior to the infusion, a polyethylene tubing (0.58 mm i.d., 0.96 mm o.d., Natume, Tokyo, Japan) was implanted in jugular (for sampling) and femoral (for infusion) veins after anesthesia with intraperitoneal injection of Zoletil (20 mg/kg). Rats were allowed to recover for 2 days and fasted overnight. The rats were given continuous intravenous infusions for 2 h at a rate of 0.83 mg/kg/h. The infusion rate was determined as the product of the target steady state plasma concentration (Css = 100 ng/mL) and the systemic clearance obtained from the intravenous injection study. The dosing solution was prepared by dissolving PE in isotonic saline at a concentration of 0.195 mg/mL. Blood samples were collected at 0, 15, 30, 45 min, and 1, 1.25, 1.5, 1.75, and 2 h after initiation of the intravenous infusion. Plasma samples were harvested by centrifugation at 4000g for 10 min and then immediately stored at –20 °C until analysis. The animals were sacrificed after bleeding, and tissues of brain, heart, lung, liver, spleen, kidney, and testis were collected. The tissues samples were homogenized in adequate volumes of isotonic saline (Tissue tearer, Biospec Co., Bartlesville, OK, USA) and stored at –20 °C until analysis. The partition coefficient (Kp) was calculated as the steady state tissue-to-plasma PE (or PAA) concentration ratio. The tissue and plasma PE and PAA concentrations determined at 2 h after intravenous infusion were used as the steady state concentrations. - Details on dosing and sampling:
- I.v. experiment: Venous blood samples (approximately 0.2 mL) were collected from the jugular vein at 0, 2, 5, 10, 15, 30, 45 min, and 1, 1.5, 2, 2.5, 3, and 4 h after injection. Plasma samples were harvested by centrifugation at 4000 g for 10 min and stored at -20 °C until analysis. Urine samples were collected for 24 h after intravenous injection.
Dermal experiment: Blood samples (0.2 mL each) were collected from jugular vein at 0, 5, 15, 30, 45 min, and 1, 1.5, 2, 3, 4, 6, 8, and 12 h after topical application. Plasma samples were harvested by centrifugation at 4000 g for 10 min and stored at –20 °C until analysis. - Statistics:
- Was performed.
Results and discussion
Toxicokinetic / pharmacokinetic studies
- Details on absorption:
- See below under "Any other information ..."
- Details on distribution in tissues:
- Tissue distribution study
Due to continuous dermal exposure of PE as a preservative from cosmetic products, the tissue distribution characteristics of PE and PAA were determined under steady-state conditions. After the initiation of infusion, steady-state plasma concentrations of PE and PAA were achieved within 45 min and 1.25 h, respectively. The observed steady-state plasma PE concentrations (mean 113.4 ± 10.6 ng/mL) were comparable to the target concentration of 100 ng/mL. Throughout the infusion period, plasma PAA levels were consistently higher (305.0 ± 35.9 ng/mL) than corresponding PE levels. The steady-state concentrations of PE and PAA in plasma and 7 different tissues (liver, kidney, lung, testis, brain, spleen, and heart) were determined and also their tissue-to-plasma partition coefficients (Kp). For PE, the highest Kp was observed for kidney (Kp = 3.9) followed by spleen, heart, brain, testis, liver, and lung, with the Kp values greater than unity for all tissues but lung and liver.
For PAA, the highest Kp was also found for kidney (Kp = 5.0) followed by liver, heart, testis, spleen, and brain, and the Kp values were greater than unity for kidney, liver, lung, and testis only.
- Details on excretion:
- See below under "Any other information ..."
Metabolite characterisation studies
- Metabolites identified:
- yes
- Details on metabolites:
- Phenoxyacetic acid is the main metabolite of 2-phenoxyethanol.
Any other information on results incl. tables
Intravenous injection study:
This study was conducted to characterize the disposition of PE and to determine the absolute topical bioavailability. The average plasma concentration–time profiles of PE and PAA in rats after intravenous injection of PE (doses 0.2, 0.5, and 2 mg/kg) were obtained. After intravenous injection, PE was extensively converted to PAA, with the average PAA-to-PE AUC ratio (AUCPAA/AUCPE) of 5.2, 4.5, and 5.0 for the intravenous doses of 0.2, 0.5 and 2 mg/kg, respectively. The disposition of PE was characterized by a relatively small volume of distribution (Vz, 1.6–2.0 L/kg), high systemic clearance (Cls, 123–132 mL/min/kg), and short terminal half- life (t1/2, 10–11 min). These values remained unaltered as a function of the injected dose range of 0.2–2 mg/kg, indicating a dose-linear kinetics.
Immediately after injection of PE, PAA was formed rapidly, with the time to peak concentration (Tmax) of 9–10 min. For PAA, the average terminal half-life (15–34 min) and Tmax (9 – 10 min) also remained unaltered as a function of the injected dose.
PE was not excreted unchanged in urine, but PAA was found to be extensively excreted in urine (64.7–75.7% of the equivalent dose of PE).
Topical application study:
The in vivo percutaneous absorption of PE was characterized in rats after topical application of emulsion and lotion (applied dose of PE = 2.34 mg/kg). Upon topical application, both PE and PAA were quantifiable in the first plasma samples (5 min) and reached Cmax at approximately 1 h. The assay sensitivity was high enough to characterize the initial absorption and terminal elimination processes.
Following topical application, PE was rapidly absorbed and, throughout the sampling period, plasma PAA levels were consistently higher than corresponding PE levels.
The absolute topical bioavailability (F) of PE was high (mean 75.4% and 76.0% for emulsion and lotion, respectively). The apparent terminal half-life of PE found after topical application of emulsion and lotion (mean range, 96–102 min) was significantly longer than that found after intravenous injections (mean range, 10–11 min). Similarly, the apparent terminal half-life of PAA after topical application were significantly longer (108–126 min) than that found after intravenous injections (mean range 15–34 min). These observations indicate that the percutaneous absorption of PE and subsequent formation of PAA are slower than their respective elimination processes. The average AUCPAA/AUCPE ratios following topical application (mean range 4.4–5.3) were comparable to those found after intravenous injection (4.5–5.2). Although the skins are known to contain enzymes (alcohol dehydrogenase and aldehyde dehydrogenase), these comparable AUC ratios suggest that no significant dermal first-pass metabolism of PE occurred during the percutaneous penetration process.
Applicant's summary and conclusion
- Executive summary:
A LC-ESI–MS/MS method with polarity switching was developed and validated. It was applied for the simultaneous analysis of phenoxyethanol (PE) and its major metabolite, phenoxyacetic acid (PAA), in rat plasma, urine, and 7 different tissues. The percutaneous absorption, distribution, metabolism, and excretion were studied in rats.
The absolute topical bioavailability of PE was 75.4% and 76.0% for emulsion and lotion, respectively. Conversion of PE to PAA was extensive, with the average AUCPAA-to-AUCPEratio being 4.4 and 5.3 for emulsion and lotion, respectively.
Immediately after injection of PhE, PhAA was formed rapidly, with the time to peak concentration Tmax of 9–10 min. For PhAA, the average terminal half-life (15–34 min) and Tmax remained unaltered as a function of the injected dose. PhE was not excreted unchanged in urine, but PhAA was found to be extensively excreted in urine (64.7–75.7% of the equivalent dose of PhE).
The steady-state tissue-to-plasma PE concentration ratio (Kp) was higher than unity for kidney, spleen, heart, brain, and testis and was lower (≤0.6) for lung and liver, while the metabolite Kp ratio was higher than unity for kidney, liver, lung, and testis and was lower (≤0.3) for other tissues.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.