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EC number: 261-332-1 | CAS number: 58567-11-6
- 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
![](https://poisoncentres.echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2012-06-28 to 2013-03-15
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: The study was conducted under GLP according to OECD TG 422.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 013
- Report date:
- 2013
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: OPPTS 870.3650 (Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- (ethoxymethoxy)cyclododecane
- EC Number:
- 261-332-1
- EC Name:
- (ethoxymethoxy)cyclododecane
- Cas Number:
- 58567-11-6
- Molecular formula:
- C15H30O2
- IUPAC Name:
- (ethoxymethoxy)cyclododecane
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Harlan Laboratories BV, Netherlands
- Age at study initiation: 11 weeks
- Weight at study initiation: 290 to 326 g (males), 162 to 222 g (females)
- Fasting period before study: no
- Housing: in groups of three to five animals in Makrolon type-4 cages with wire mesh tops up to the day of randomization and afterwards individually in Makrolon type-3 cages with wire mesh tops and sterilized standard softwood bedding
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS
- The dose formulations were prepared weekly using the test item as supplied by the Sponsor. The test material was weighed into a glass beaker on a tared precision balance and approximately 80% of the vehicle was added (w/v). Using a magnetic stirrer, a homogeneous suspension was prepared. Having obtained a homogeneous mixture, the remaining vehicle was added. Separate formulations were prepared for each concentration. Homogeneity of the test item in the vehicle was maintained during the daily administration period using a magnetic stirrer.
DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Storage temperature of food: at room temperature (20 ± 5 °C) in glass beakers
VEHICLE
- Justification for use and choice of vehicle (if other than water): no data
- Concentration in vehicle: 0, 12.5, 75, 250 mg/mL
- Amount of vehicle: 4 mL/kg bw - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- On the first treatment day samples from the control group as well as three samples (top, middle and bottom) of about 2 g of each concentration were taken prior to dosing for analysis of concentration and homogeneity. To confirm the stability (8 days) samples of about 2 g of each concentration were taken from the middle of each aliquot used on day 7 of the treatment. During the last week of the treatment, samples were taken from the middle to confirm concentration. The aliquots for analysis of dose formulations were frozen (-20 ± 5 °C) and delivered on dry ice to analytic laboratory and stored there at -20 ± 5 °C until analysis. The samples received were dissolved in TBME by sonication for at least 5 minutes and then diluted to volume with TBME. Sample solutions were further diluted with TBME into the calibration range. The samples were analysed with gas chromatography coupled to an FID.
- Duration of treatment / exposure:
- The test substance was administered to male rats for 28 days and to female rats for 14 days prior to pairing, through the pairing and gestation periods until the F1 generation reached day 3 post-partum, one day before necropsy.
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 50 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 11
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels were selected based on a previous non-GLP dose range-finding toxicity study in Han Wistar rats, using dose levels of 0, 50, 200 and 1000 mg/kg/day.
- Positive control:
- no
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily cage-side clinical observations (during acclimatization and up to day of necropsy). Additionally females were observed for signs of difficult or prolonged parturition, and behavioral abnormalities in nesting and nursing.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: In males, it was performed once prior to the first administration of the test item and weekly thereafter. In females, it was prepared once prior to the first administration of the test item, weekly during the pre-pairing and pairing periods and on days 0, 6, 13 and 20 of the gestation period.
BODY WEIGHT: Yes
- Time schedule for examinations: Daily from treatment start to day of necropsy.
FOOD CONSUMPTION AND COMPOUND INTAKE:
- Males: Pre-pairing period days 1 - 4, 4 - 8, 8 - 11 and 11 - 13; after pairing period weekly.
- Females: Pre-pairing period days 1 - 4, 4 - 8, 8 - 11 and 11 - 13; gestation days 0 - 7, 7 - 14 and 14 - 21 and days 1 - 4 of lactation.
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: on day 14 of the pre-pairing period
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: 5 males and 5 females from each group
- Following parameters were examined: Erythrocyte count, Hemoglobin, Hematocrit, Mean corpuscular volume, Red cell volume distribution width, Mean corpuscular hemoglobin, Mean corpuscular hemoglobin concentration, Hemoglobin concentration distribution width, Leukocyte count (total), Differential leukocyte count, Platelet count, Prothrombin time (= Thromboplastin time), Activated partial Thromboplastin time
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on day 14 of the pre-pairing period
- Animals fasted: Yes
- How many animals: 5 males and 5 females from each group
- Following parameters were examined: Glucose, Urea, Creatinine, Bilirubin (total), Bile acids, Sodium, Potassium, Chloride, Cholesterol (total), Triglycerides, Aspartate aminotransferase, Alanine aminotransferase, Alkaline phosphatase, Gamma-glutamyl-transferase, Calcium, Phosphorus, Protein (total), Albumin, Globulin, Albumin/Globulin ratio
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: At one time during the study (males shortly before the scheduled sacrifice and females on day 3 post-partum) relevant parameters were performed. This FOB assessment was conducted following the daily dose administration.
- Dose groups that were examined: five P generation males and five P generation females from each group
- Battery of functions tested: hand-held observations, open field observations, reflexes, counts: hind limb, fore limb grip strength - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see attached document Organ Weights and Preservation)
HISTOPATHOLOGY: Yes (see attached document Organ Weights and Preservation) - Statistics:
- The following statistical methods were used to analyze food consumption, body weights and reproduction data:
- Means and standard deviations of various data were calculated.
- The Dunnett-test (many to one t-test) based on a pooled variance estimate was applied if the variables could be assumed to follow a normal distribution for the comparison of the treated groups and the control groups for each sex.
- The Steel-test (many-one rank test) was applied instead of the Dunnett-test when the data could not be assumed to follow a normal distribution.
- Fisher's exact-test was applied if the variables could be dichotomized without loss of information.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- At the dose level of 1000 mg/kg bw/day, bedding in mouth and salivation in males starting from day 6 of the pairing period and in females starting from day 1 of the pairing period. At the dose level of 300 mg/kg bw/day, bedding in mouth in females starting from day 1 of the gestation period.
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No effects on absolute body weight or body weight gain were noted in males and females at any dose level.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- At the dose level of 1000 mg/kg bw/day in females, statistically significant reduction in food consumption was noted from day 1 to 4 of the pre-pairing period.
- 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:
- effects observed, treatment-related
- Description (incidence and severity):
- please see Details on results
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- please see Details on results
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Enlarged liver in one female at the dose level of 1000 mg/kg bw/day
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- please see Details on results
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY
At the dose level of 1000 mg/kg bw/day, bedding in mouth and salivation in males starting from day 6 of the pairing period and in females starting from day 1 of the pairing period. At the dose level of 300 mg/kg bw/day, bedding in mouth in females starting from day 1 of the gestation period. These observations were considered to be signs of discomfort caused by the treatment with the test item.
BODY WEIGHT AND WEIGHT GAIN
No effects on absolute body weight or body weight gain were noted in males and females at any dose level.
FOOD CONSUMPTION AND COMPOUND INTAKE
No test item-related effects on food consumption were noted in males at any dose level. At the dose level of 1000 mg/kg bw/day in females, statistically significant reduction in food consumption was noted from day 1 to 4 of the pre-pairing period. During the remaining study period, food consumption at the high-dose level was similar to the control values.
HAEMATOLOGY
No test item-related findings were noted in males and females at any dose level.
CLINICAL CHEMISTRY
In males statistically significantly higher creatinine concentration was noted in all dose groups. Mean creatinine concentration was 25.3 μmol/L at the dose level of 1000 mg/kg bw/day and 24.4 μmol/L at dose levels of 300 and 50 mg/kg bw/day versus 19.8 μmol/L in the control group. Further, at the dose levels of 1000 and 300 mg/kg bw/day, statistically significantly reduced concentration of phosphorus was noted. Mean phosphorus concentrations were 1.96 and 1.92 mmol/L at the dose levels of 1000 and 300 mg/kg bw/day, respectively, versus 2.11 mmol/L in the control group. Both findings may indicate renal dysfunction. Histopathological examination revealed lesions in the kidneys in males in the high- and mid-dose levels which were sex- and species-specific for male rats. Therefore, changes in creatinine and phosphorus concentrations were considered to most probably be secondary to these lesions and not relevant for humans. Furthermore, statistically significantly lower concentrations of total bilirubin and bile acids were noted in males at the dose level 1000 mg/kg bw/day. Mean total bilirubin concentration was 1.14 μmol/L at the high-dose level versus 1.88 μmol/L in the control group, mean concentration of bile acids was 14.46 μmol/L at the high-dose level versus 50.41 μmol/L in the control group. Lower total bilirubin and bile acids concentrations were considered to possibly be secondary to the adaptive changes in the liver metabolism caused by the treatment with the test item and not to be adverse. No test item-related effects on biochemistry parameters were noted in females at any dose level.
NEUROBEHAVIOUR
No effects observed.
ORGAN WEIGHTS
At the dose level of 1000 mg/kg bw/day, statistically significantly increased liver weights were noted in males. This finding was considered to be due to adaptive changes in the liver metabolism caused by the treatment with the test item and not as adverse.
GROSS PATHOLOGY
During macroscopically examination enlarged liver was found in one female at the dose level of 1000 mg/kg bw/day. This finding was considered to be related to the treatment with the test item.
HISTOPATHOLOGY: NON-NEOPLASTIC
During microscopic examinations, test item-related findings were noted in the liver of males and females at the dose level of 1000 mg/kg bw/day. These changes consisted of centrilobular hypertrophy of the hepatocytes and were considered to be an adaptive change due to the increased metabolism of the liver. In addition, hypertrophy of the follicular epithelium of the thyroid gland was noted in males at the dose level of 1000 mg/kg bw/day. This finding was considered to be very likely secondary to the increased metabolism in the liver. Further findings related to the treatment were noted in the kidneys of males at the dose levels of 1000 and 300 mg/kg bw/day; hyaline droplets associated with tubular basophilia and presence of granular casts. These findings were considered to be specific for male rats and adverse in this species but not toxicologically relevant for humans.
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Remarks:
- systemic
- Effect level:
- 50 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: see 'Remark'
- Dose descriptor:
- NOAEL
- Remarks:
- systemic
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: no adverse effects observed
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- Based on the study findings in the rats, the relevant NOAEL for human toxicity is 1000 mg/kg bw/day.
- Executive summary:
The purpose of this study was to generate preliminary information concerning the effects of the substance on possible health hazards likely to arise from repeated exposure over a relatively limited period of time. In addition it provides information on possible effects on male and female reproductive performance such as gonadal function, mating behaviour, conception, development of the conceptus and parturition. The substance was administered to male rats for 28 days and to female rats for 14 days prior to pairing, through the pairing and gestation periods until the F1 generation reached day 3 post-partum, one day before necropsy.
The following dose levels were applied:
Group 1: 0 mg/kg body weight/day (control group)
Group 2: 50 mg/kg body weight/day
Group 3: 300 mg/kg body weight/day
Group 4: 1000 mg/kg body weight/day
A standard dose volume of 4 mL/kg body weight with a daily adjustment to the actual body weight was used. Control animals were dosed with the vehicle alone (corn oil).
Mortality and General Tolerability
All animals survived scheduled study period. Bedding in mouth and salivation were noted in males and females at the dose level of 1000 mg/kg bw/day. Bedding in mouth alone was noted in females at the dose level of 300 mg/kg bw/day. These observations were considered to be sign of discomfort caused by the treatment with the test item. No further clinical signs or observations were noted in males or females at any dose level.
Functional Observational Battery
With exception for salivation noted in one male and one female at the dose level of 1000 mg/kg bw/day, no further test item-related findings were noted during the tests of functional observational battery or measurement of locomotor activity.
Food Consumption
At the dose level of 1000 mg/kg bw/day in females, transient reduction in food consumption was noted at the beginning of the treatment. No test item-related effects on food consumption were noted in males at any dose level or females at dose levels of 50 and 300 mg/kg bw/day.
Body Weights
No effects on absolute body weights or body weight gain were noted in males or females at any dose level.
Clinical Laboratory Investigations
In males statistically significantly higher creatinine concentration was noted in all dose groups. This finding was accompanied by statistically significantly reduced concentration of phosphorus in high- and mid-dose groups. These findings were considered to most probably be secondary to lesions in the kidneys which were considered sex- and species-specific for male rats and therefore not relevant for humans. Further findings were statistically significantly lower concentrations of total bilirubin and statistically significantly lower concentration of bile acids in males at the dose level of 1000 mg/kg bw/day. These findings were considered to possibly be secondary to the adaptive changes in the liver metabolism caused by the treatment with the test item and not to be adverse. No further test item-related changes in hematology or biochemistry parameters were noted in males or females at any dose level.
Organ Weights
At the dose level of 1000 mg/kg bw/day, statistically significantly increased liver weights were noted in males. This finding was considered to be due to adaptive changes in the liver metabolism caused by the treatment with the test item and not adverse.
Macroscopical Findings and Histopathological Examinations
During macroscopical examination enlarged liver was found in one female at the dose level of 1000 mg/kg bw/day. This finding was considered to be related to the treatment with the test item.
During microscopic examinations, test item-related findings were noted in the liver of males and females at the dose level of 1000 mg/kg bw/day. These changes consisted of centrilobular hypertrophy of the hepatocytes and were considered to be an adaptive change due to the increased metabolism of the liver. In addition, hypertrophy of the follicular epithelium of the thyroid gland was noted in males at the dose level of 1000 mg/kg bw/day. This finding was considered to be very likely secondary to the increased metabolism in the liver.
Conclusion
Based on the lesions in the kidneys found in males at the dose levels of 1000 and 300 mg/kg bw/day which were considered to be adverse, general NOAEL (No Observed Adverse Effect Level) for males was established at 50 mg/kg bw/day. However, lesions in the kidneys were considered to be specific for male rats and therefore not toxicologically relevant for humans. NOAEL for females was considered to be 1000 mg/kg bw/day, the highest dose level used in the study.
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