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EC number: 607-240-0 | CAS number: 23511-73-1
- 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
Endpoint summary
Administrative data
Description of key information
Repeated dose toxicity (oral, OECD 407): NOAEL = 1000 mg/kg bw/day (male/female)
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 26 Oct - 02 Dec 2001
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- adopted in Oct 2008
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Version / remarks:
- adopted in 2008
- Deviations:
- not specified
- Qualifier:
- according to guideline
- Guideline:
- other: OPPTS 870.3050, Repeated dose 28-day oral toxicity study in rodents
- Version / remarks:
- adopted in 2000
- Deviations:
- not specified
- GLP compliance:
- yes
- Species:
- rat
- Strain:
- Wistar
- Remarks:
- Crl:WI(Han) (outbred, SPF-Quality)
- Details on species / strain selection:
- This rat strain was used as it is recognized by international guidelines as the recommended test species.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: Approximately 6 weeks
- Weight at study initiation: Ranges: 155 - 191 g (males); 122 - 147 g (females)
- Housing: 5 animals per sex were housed in Macrolon cages (MIV type, height 18 cm) with sterilized sawdust as bedding material (Litalabo, S.P.P.S., Argenteuil, France) and paper as cage enrichment (Enviro-dri, Wm. Lilico & Son, Surrey, UK).
- Diet: Pelleted rodent diet (SM R/M-Z from SNIFF® Spezialdiäten GmbH, Soest, Germany), ad libitum
- Water: Tap water, ad libitum
- Acclimation period: At least 5 days
DETAILS OF FOOD AND WATER QUALITY: Analysis of diet and water did not reveal any findings that were considered to have affected the integrity of the study.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.3 - 21.9
- Humidity (%): 44 - 66
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: gavage
- Vehicle:
- polyethylene glycol
- Remarks:
- Polyethylene glycol 400
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: Formulations (w/w) were prepared daily within 6 h prior to dosing and were homogenized to visually acceptable levels. Adjustment was made for specific gravity of the test substance and vehicle.
VEHICLE
- Justification for use and choice of vehicle: Based on trial formulations performed at the testing facility and on information from the sponsor.
- Amount of vehicle (if gavage): 5 mL/kg bw - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analyses were conducted on a single occasion during the treatment phase, according to a validated method (project 489876 of the testing facility). Samples of formulations were analyzed for homogeneity (highest and lowest concentration) and accuracy of preparation (all concentrations). The stability in vehicle over 6 hours at room temperature under protection from light was also determined (highest and lowest concentration). The accuracy of preparation was considered acceptable if the mean measured concentrations were 90-110% of the target concentration for solutions. Homogeneity was demonstrated if the coefficient of variation was ≤ 10%. Formulations were considered stable if the relative difference before and after storage was maximally 10%.
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- once daily, 7 days/week
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Dose levels were based on results of a 5-day dose range finding study at the same testing facility (project 497713, study period: 13 - 17 Oct 2011). Three females per group were orally exposed to 500 and 1000 mg/kg bw/day for 5 days at the same testing facility, respectively. No mortality occurred in both dose groups. In the high-dose group hunched posture was seen in all females on Day 5, and piloerection was observed in 1/3 females on Day 4. 1/3 females of the low-dose group showed salivation on Day 4. No weight gain was observed in one female of the low-dose group had, however the body weight of the other two low-dosed females and all females of the high-dose group were normal. At every dose group no abnormalities were noted during the macroscopic examination and the liver and kidney weights were reported to be normal. Based on the results of this range finding study, dose levels suggested for the main study (28-day toxicity study) were 100, 300 and 1000 mg/kg bw/day.
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes, all animals were observed for mortality and viability.
- Time schedule: At least twice daily
DETAILED CLINICAL OBSERVATIONS: Yes, observations were made outside the cage in a standard arena.
- Time schedule: Immediately after dosing, once prior to start of treatment and at weekly intervals.
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly
FOOD CONSUMPTION: Yes, the food consumption for each animal was determined weekly and mean calculated as g food/kg body weight/day.
WATER CONSUMPTION: Subjective appraisal was maintained during the study, but no quantitative investigation performed as no effect was suspected.
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Between 7.00 and 10.30 a.m. on the day of necropsy
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes, animals were deprived of food overnight for a maximum of 20 h.
- How many animals: All animals in every group
- Parameters checked: White blood cells (WBC), differential leucocyte count (neutrophils, lymphocytes, monocytes, eosinophils, basophils), red blood cells, reticulocytes, red blood cell distribution width (RDW), haemoglobin, haematocrit, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), platelets, prothrombin time and activated partial thromboplastin time.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Between 7.00 and 10.30 a.m. on the day of necropsy
- Animals fasted: Yes, animals were deprived of food overnight for a maximum of 20 h.
- How many animals: All animals in every group
- Parameters checked: Alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), alkaline phosphatase (ALP), total protein, albumin, total bilirubin, bile acids, urea, creatinine, glucose, cholesterol, sodium, potassium, chloride, calcium, inorganic phosphate (Inorg. Phos.)
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: During week 4 of treatment
- Dose groups that were examined: All animals in every group
- Battery of functions tested: Hearing ability, pupillary reflex, static righting reflex, grip strength, motor activity test - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
The weight of the following organs from all animals was recorded: liver, kidneys, adrenal glands, testes, epididymides, prostate, seminal vesicles including coagulating glands, thymus, spleen, brain, heart, ovaries, uterus including cervix and thyroid including parathyroid.
HISTOPATHOLOGY: Yes. All organ and tissue samples were processed, embedded in paraffin wax, sliced and stained with haematoxylin and eosin. The samples of all tissues (except the tissues/organs listed below) collected at the scheduled sacrifice from animals in the control and high-dose group and all gross lesions were examined by a pathologist.
- The following organs and tissues were collected and fixed in a 10% buffered formalin: ovaries, adrenal glands, Peyer's patches (jejunum, ileum), brain (cerebellum, mid-brain, cortex), caecum, cervix, prostate gland, rectum, colon, duodenum, sciatic nerve, epididymides, seminal vesicles including coagulating gland, eyes including optic nerve and harderian gland, skeletal muscle, spinal cord (cervical, midthoracic, lumbar), femur including joint, spleen, heart, sternum with bone marrow, ileum, stomach, jejunum, testes, kidneys, thymus, thyroid including parathyroid, liver, trachea, lung (infused with formalin), urinary bladder, lymph nodes (mandibular, mesenteric), uterus, vagina and all gross lessions.
Following tissues/organs were not examined by the pathologist, since no signs of toxicity were noted at macroscopic examination: pancreas, aorta, pituitary gland, preputial gland, clitoral gland, salivary glands (mandibular, sublingual), skin, female mammary gland area, larynx, oesophagus, lacrimal gland (exorbital), tongue, nasopharynx. - Statistics:
- The following statistical methods were used to analyze the data:
- If the variables could be assumed to follow a normal distribution, the Dunnett-test (many-to-one ttest) based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex.
- The Steel-test (many-to-one rank test) was applied when the data could not be assumed to follow a normal distribution.
- The exact Fisher-test was applied to frequency data.
Motor activity data was subjected to the Kruskal-Wallis nonparametric ANOVA test to determine intergroup differences followed by the Wilcoxon test to compare the treated groups to the control group.
All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance. Group means were calculated for continuous data and medians were calculated for discrete data (scores) in the summary tables. Test statistics were calculated on the basis of exact values for means and pooled variances. Individual values, means and standard deviations may have been rounded off before printing. Therefore, two groups may display the same printed means for a given parameter, yet display different test statistics values. - Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Control: Scabs were observed in 1/5 males on Days 12 - 28 (left shoulder) and on Days 21 - 28 (right shoulder).
100 mg/kg bw/day: Missing upper incisors were noted in 1/5 males on Days 14 - 28.
1000 mg/kg bw/day: Exophthalmos was seen in 1/5 males on Days 22 - 28.
According to the study director, these findings occurred within the range of background findings to be expected for rats of this age and strain which are housed and treated under the conditions in this study. At the incidence observed, these findings were considered to have no toxicological significance. - Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- 300 mg/kg bw/day: A significantly lower body weight gain of males over Days 1 - 8 (88%) and 15 - 22 (81%) was observed compared with the control group.
This effect occured in the absence of a dose-related trend and was slight in nature, therefore this effect has no toxicological relevance. - Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- effects observed, non-treatment-related
- Description (incidence and severity):
- 1000 mg/kg bw/day: A significantly lower mean of total movements was noted in males.
This effect was considered to have no toxicological relevance since the change was slight in nature (mean remained well within the range considered normal for rats of this age and strain), and the clinical appearance of these animals was normal. All groups showed a similar motor activity habituation profile with high activity in the first interval that decreased over the duration of the test period. - Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- 100 mg/kg bw/day: A significantly lower absolute (35%) and relative (33%) thyroid weight was observed for males compared to control animals.
300 mg/kg bw/day: The absolute (45%) and relative (41%) thyroid weight and the absolute (32%) and relative (26%) seminal vesicle weight was reduced in males compared with the control group.
These effects occurred in the absence of a dose-related trend, since the organ weights of the 1000 mg/kg bw/day group were in the same range as the organ weights of the control group. Moreover, histopathological examination of these organs revealed no abnormalities in the 100 and 300 mg/kg bw/day group. Therefore, these effects were not considered to be toxicologically relevant. - Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- MALES
Scab formation of the skin was observed in 1/5 control males and pelvic dilation in kidneys occurred in 1/5 control males. A missing upper incisor and enlarged mandilubular lymph nodes were noted in one male of the 100 mg/kg bw/day group. In the 300 mg/kg bw/day group enlarged mandilubular lymph nodes and an accessory liver of the left median lobe were observed in 1/5 males, respectively. Several reddish foci in thymus, isolated reddish foci in stomach and exophthalmus were noted in 1/5 males of the 1000 mg/kg bw/day group, respectively.
FEMALES:
An enlarged mandilubular lymph node and isolated foci in clitorial glands were seen in 1/5 control animals. An uterus that contained fluid was noted in 2/5 females of the control group and in 1/5 females of the 100 mg/kg bw/day group. Pelvic dilation in kidneys was observed in 2/5 females of the 300 mg/kg bw/day group.
The macroscopic findings among control and treated animals were considered to be indicental without a dose-related incidence trend. These necropsy findings were therefore regarded to be of no toxicological relevance. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Heart:
- Myofiber degeneration: 1/5 control females (grade 1)
- Inflammation lymphocytic: 1/5 females of the 1000 mg/kg bw/day group (grade 1)
Lung:
- Mineralization, vascular: 1/5 males of the 1000 mg/kg bw/day group (grade 2), 2/5 males of the 1000 mg/kg bw/day group (grade 1), 2/5 females of the 1000 mg/kg bw/day group (grade 1)
- Alveolar macrophages: 3/5 control males (1/5: grade 2; 2/5: grade 1) and 1/5 males of the 1000 mg/kg bw/day group (grade 1), 1/5 males of the 1000 mg/kg bw/day group (grade 1)
- Inflammation infiltrate: 2/5 control males (grade 1), 2/5 control females (grade 1), 3/5 males of the 1000 mg/kg bw/day group (grade 1), 1/5 females of the 1000 mg/kg bw/day group (grade 1)
- Alveolar inflammation: 1/5 males of the 1000 mg/kg bw/day group (grade 1), 1/5 females of the 1000 mg/kg bw/day group (grade 1)
Liver:
- Hemopoietic cells: 1/5 control males (grade 1), 1/5 control females (grade 1), 1/5 males of the 1000 mg/kg bw/day group (grade 1)
- Inflammation cell foci: 3/5 control males (grade 1), 3/5 control females (2/5: grade 1, 1/5: grade 2), 3/5 females of the 1000 mg/kg bw/day group (grade 1), 4/5 males of the 1000 mg/kg bw/day group (3/5:grade 1, 1/5: grade 2)
- Vacuolation, hepatocytes: 1/5 control females (grade 1)
- Macro noted: 1/5 males of the 100 mg/kg bw/day group (severity not scored)
Kidneys:
- Mineralization, tubular: 1/5 control males (grade 1), 1/5 control females (grade 1), 1/5 males of the 1000 mg/kg bw/day group (grade 1)
- Hyaline droplets: 1/5 control males (grade 2)
- Hyaline cast(s): 1/5 females of the 300 mg/kg bw/day group (grade 1)
- Inflammation, interstit.: 2/5 control males (grade 1), 2/5 control females (grade 1), 1/5 females of the 300 mg/kg bw/day group (grade 1), 1/5 males of the 1000 mg/kg bw/day group (grade 1), 1/5 females of the 1000 mg/kg bw/day group (grade 1)
- Inflammation, pelvic: 1/5 control males (grade 1)
- Basophilia, tubular: 3/5 control males (grade 1), 1/5 control females (grade 1), 1/5 females of the 300 mg/kg bw/day group (grade 1), 4/5 males of the 1000 mg/kg bw/day group (grade 1), 1/5 females of the 1000 mg/kg bw/day group (grade 1)
- Pelvic dilation: 2/5 females of the 300 mg/kg bw/day group (severity not scored)
Uterus:
- Proestrus epithelium: 1/5 females of the 100 mg/kg bw/day group (severity not scored)
Epididymides:
- Sperm granuloma: 1/5 males of the 1000 mg/kg bw/day group (grade 2)
- Inflammation, lymphocyti: 1/5 males of the 1000 mg/kg bw/day group (grade 1)
Thyroid gland:
- Hyperplasia/hypertrophy: 2/5 males of the 1000 mg/kg bw/day group (grade 1)
Thymus: 1/5 males of the 1000 mg/kg bw/day group (severity not scored)
- Lymphocytolysis, increased: 1/5 males of the 1000 mg/kg bw/day group (grade 1)
Eyes:
- Atrophy, retinal: 1/5 males of the 1000 mg/kg bw/day group (grade 2)
These microscopic findings were considered to be incidental effects and not related to the treatment. - Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No toxicologically significant changes were noted in any of the parameters investigated in this study up to and including the highest dose level.
- Key result
- Critical effects observed:
- no
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- The available information comprises an adequate and reliable study, and is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.6, of Regulation (EC) No 1907/2006.
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
An oral 28-day oral repeated dose toxicity study performed in rats with 2-phenoxyethyl octanoate according to OECD guideline 407 and under GLP conditions is available. Male and female Wistar rats were treated with 100, 300 and 1000 mg/kg bw/day of the test substance in polyethylene glycol for 28 days by gavage (Notox, 2012). The concurrent vehicle was included in the study design as a control. All animals were observed for clinical signs and mortality at least daily. A functional behaviour test was performed in week 4. Body weights and food consumption were recorded weekly. At the end of the exposure period, all the animals were necropsied and any macroscopic abnormalities were recorded. At necropsy, selected organ weights were recorded. The tissues/organs of the control and the high dose group, and all gross lesions were histopathologically examined. No mortality occurred, and no toxicologically relevant clinical signs, effects on body weight or body weight gains were observed during treatment. The food consumption was not affected by the test substance treatment when compared with the vehicle treatment. No treatment-related differences between the treatment groups and control group was observed during the behavioural tests. The gross necropsy and histopathological examination revealed no toxicologically relevant abnormalities. No adverse or treatment-related changes in haematology and clinical chemistry parameters in male or female rats were observed in the study. There were statistically significant decreases in absolute and relative thyroid weights in low- and mid-dose male rats and decreases in absolute and relative seminal vesicle weights in mid-dose male rats compared to control values. However, since no abnormalities were observed at the histopathological examination and the effects on the organ weight occurred in the absence of a dose-related trend, these findings were not regarded to be toxicologically relevant. Under the conditions of this study and based on the toxicological parameters evaluated, the NOAEL systemic was considered to be 1000 mg/kg bw/day for male and female rats.
Justification for classification or non-classification
The available data with 2-phenoxyethyl octanoate (23511-73-1) do not meet the criteria for classification according to Regulation (EC) No 1272/2008, and are therefore conclusive but not sufficient for classification.
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