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EC number: 909-034-9 | CAS number: -
- 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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 1996-09-24 to 1996-11-07
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 997
- Report date:
- 1997
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Cyclododecanol
- EC Number:
- 217-031-2
- EC Name:
- Cyclododecanol
- Cas Number:
- 1724-39-6
- Molecular formula:
- C12H24O
- IUPAC Name:
- cyclododecanol
- Details on test material:
- TS: Cyclododecanol of Hüls AG, Sample from drum 1-358, ID 0637/81783, produced Jan/Feb 1996. Purity 99.3-99.4 % (2 GC analyses)
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ORGANISMS
- Strain: Wistar, Hsd/Win:WU
- Source: Harlan Winkelmann GmbH, D-33176 Borchen
- Age: approximately 6 to eight weeks at beginning of treatment
- Weight at study initiation: Group means 137-142 g (females) / 205-219 g (males)
- Number of animals: 5 per sex and dose group, total 60: 3 dose + 1 control + 2 recovery groups (high dose + control) = 6 groups
- Housing: five rats in MAKROLON cages
- Diet: ad libitum pelleted diet, Ssniff R 10
- Water: ad libitum, tab water
- Acclimation period: at least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 °C +/- 3 °C
- Humidity (%): 30 % - 70%
- Air changes (per hr): 15 fold
- Photoperiod (hrs dark / hrs light): 12h/12h
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- ADMINISTRATION / EXPOSURE
- Vehicle: Corn oil. Formulations prepared weekly
- Concentration in vehicle: 30 / 100 / 200 mg/ml
- Total volume applied: 5 ml/kg bw/day - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The concentration (weight-%) was determined by gas-liqiud chromatography. The density was determined by a density meter or a density bottle
and used to calculate concentration in weight/volume. Details see below under: other informations on results - Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- daily (i.e. 28 administrations)
Doses / concentrations
- Remarks:
- Doses / Concentrations:
150; 500; 1000 mg/kg bw/day
Basis:
- No. of animals per sex per dose:
- 5 per sex and dose group, total 60:
3 dose + 1 control + 2 recovery groups (high dose + control) = 6 groups - Control animals:
- yes, concurrent vehicle
- Details on study design:
- Post-exposure period: 2 weeks (recovery groups only)
- Positive control:
- no positive control
Examinations
- Observations and examinations performed and frequency:
- CLINICAL OBSERVATIONS AND FREQUENCY:
- Clinical signs: Twice daily (weekends: once daily); detailed examination once a week
- Mortality: Twice daily (weekends: once daily)
- Body weight: Before first dose and at 7 day intervals thereafter
- Food consumption: In each cage (i.e. for 5 animals) in weekly intervals
- Water consumption: Once daily for each cage group
- Ophthalmoscopic examination: During 5 day acclimatization and prior to terminal sacrifice, using an opthalmoscope and treating one eye with
Mydriaticum Stulln(R) prior to investigation.
- Hematology: End of treatment / recovery period: red blood cell count, total white blood cell count, platelet count, hemoglobin, hematocrit,
erythrocyte indices (mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration), differential white
blood cell count.
- Biochemistry: End of treatment / recovery period: sodium, potassium, calcium, aspartate aminotransferase, alanine aminotransferase, alkaline
phosphatase, glucose, triglycerides, cholesterol, total bilirubin, blood urea nitrogen, creatinine, total protein, albumin.
- Urinalysis: End of treatment / recovery period: volume, specific gravity, pH, color. Semiquantitative: protein, glucose, keton, urobilinogen, blood
ingredients. Microscopic urine sediment analysis: Leucocytes, erythrocytes, bacteria, epithelial cells (squamous), oxalate crystals, triple phosphate crystals, urate crystals. - Sacrifice and pathology:
- ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC):
- Macroscopic: Complete autopsy including macropathological examination. Weights of adrenals, kidneys, liver, spleen, testes.
- Microscopic: Selection of organs depended on macroscopic findings. Histopathological examination was performed for epididymis, kidney, liver,
lung, mandibular lymph node, ovary, testis and uterus of control and high-dose groups. It was extended to other groups in case of substance
related findings (liver: all; lung: 7 selected individuals; uterus: 1 female). - Other examinations:
- no other examinations
- Statistics:
- STATISTICAL METHODS:
- Kruskal Wallis non parametric analysis of variance; in case of significance pairwise comparison using a Wilcoxon, Mann, and Whitney U-Test:
Absolute body weights, body weight changes, absolute and relative organ weights, differential blood count and urine analysis data.
- One way analysis of variance (ANOVA) incorporating a Bartlett's test for homogeneity of variance; in case of heterogenous variances Kruskal Wallis test; in case of significant ANOVA Scheffe Test: Hematological data (except differential blood count) and serum clinical chemistry data.
- Group means with standard deviation, medians, ranges, or geometric means where appropriate.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Higher relative liver weights were noted in the female high and medium dose groups when compared with controls.
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- The livers of 4 females and 3 males of the high-dose group showed mild to moderate centrolobular hypertrophy.
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- TOXIC RESPONSE/EFFECTS BY DOSE LEVEL:
- Mortality and time to death: There were no mortalities.
- Clinical signs: One high dose male animal showed at the end of the first treatment week for a duration of two days aggravated breath and salivation No other clinical signs were observed during treatment and recovery period.
- Body weight gain: No findings of toxicological importance were found.
- Food/water consumption: Mean food consumption was similar in all groups. The highest differences between treated and control were observed
for low-dose females (5-7 % below control, not statistically significant). The food conversion rate was insignificantly increased in all dosed groups when compared with control, which was considered to be substance-related. Evidence of reversibility was found at the end of the recovery period. There were no overt intergroup differences in water consumption.
- Ophthalmoscopic examination: No signs of test substance related effects on lenses or cornea were observed in either dose group.
- Clinical chemistry: Findings at the end of the treatment or recovery period were considered to be of no toxicological importance. In females,
statistically significant differences between treated and control were confined to the mid-dose group. In high-dose males, aspartate
aminotransferase (-43 %) and alkaline phosphatase (-32 %) were significantly reduced and also slightly outside the range of historical background data, however evidence of reversibility was found in the recovery animals.
Blood urea nitrogen was increased in mid- (+18 %) and high-dose males (+30 %), and triglycerides were decreased in low- (-19 %) and high-dose
(-41 %) males. Although statistically significant, these differences were minor and within the normal range of historical background data. Evidence of reversibility was found in the recovery groups.
- Hematology: No relevant findings were noted in treated animals.
Statistically significant differences between treated and control were confined to recovery males, low, and within the range of historical control data- Urinalysis: No findings of toxicological importance were noted. Statistically significant differences between treated and control were confined to mi d-dose males, low, and within the range of historical control data.
- Organ weights: Statistically significantly higher relative (not absolute) liver weights were noted in the female high (+19 %) and medium
(+16 %) dose groups when compared with controls. These differences were considered to be treatment-related. Evidence of reversibility was found at the end of the recovery period (treated 4.8 % above control). No other statistically significant differences between treated and control were
observed at the end of the treatment period. At the end of the recovery period, dosed males showed statistically significantly higher absolute
(+13 %) and relative (+13 %) kidney weights when compared with the recovery control group. This was mainly due to a severe increase in one
animal and was not associated with any relevant finding. Thus it was considered to be of minor toxicological importance.
- Gross pathology: No macroscopical lesions were considered to be related to treatment with the test substance.
- Histopathology: The histopathological findings in the high dose and control groups consisted of spontaneous lesions such as hydrometriosis of
the uterus, focal cortical calcification of the kidney, focal hemopoiesis in the liver and mild to moderate pneumonia characterized by multifocal
interstitial lymphocyte infiltrates. The lesions in the lung were most likely caused as part of a virus infection. The other changes were considered
part of the normal background.
The livers of 4 females and 3 males of the high-dose group showed mild to moderate centrolobular hypertrophy. Therefore the livers of all other
groups including the recovery groups were examined. Mild to moderate centrolobular hypertrophy was also found in 4 mid-dose and 1 low-dose males and in 5 mid-dose and 3 low-dose females but not in treated or control recovery rats. None of the livers examined showed nuclear or
cytoplasmic degenerative or necrotic changes of hepatocytes. The hepatocellular hypertrophy was correlated with higher relative liver weights in
medium- and high-dose females. These findings were considered to be substance-related. Evidence of reversibility was found at the end of the
recovery period. It is suggested that the reversible liver changes observed are an expression of an adaptive response of the liver to the test
substance. As such, it is generally not considered as an adverse effect.
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- clinical biochemistry
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
ACTUAL DOSE RECEIVED BY DOSE LEVEL BY SEX
Two formulations per dose level were analyzed at two different times
separated by one week, leading to four analytical values per dose level:
---------------------------------------------------------
Nominal first analysis repeat analysis mean
30 28.5 / 29.4 29.5 / 29.9 29.3 mg/cm3
100 92.5 / 92.1 92.5 / 94.7 92.9 mg/cm3
200 137.6 / 185.1 143.7 / 187.3 163.4 mg/cm3
---------------------------------------------------------
The analytical values are slightly reduced by measuring the density in
a pycnometer at 100 °C. The repeat analyses confirm the stability of the
formulations. Only for one high concentration formulation the analytical
result was clearly below the nominal concentration. The mean analytical
concentrations correspond to dose levels of 147; 465; 817 mg/kg bw/day.
Applicant's summary and conclusion
- Conclusions:
- The increased food conversion rate noticed in treated males and females during the treatment period was reversible and therefore not regarded as an adverse effect. The reversible liver changes are regarded as a transient adaptive response of the liver to the test substance. As such they are generally not considered as an adverse effect. Therefore the NOAEL is 1000 mg/kg bw/day.
- Executive summary:
In this 28-day repeated dose oral toxicity study three groups of male and female rats were dosed with 150, 500, and 1000 mg Cyclododecanol /kg bw daily for 4 weeks by oral gavage. A concurrrent control group received corn oil only. A control and a high dose recovery group each consisting of five males and 5 females, were observed for a perios of 14 days after the end of the dosing period. There were no mortalities during the study. Apart from one male which showed during the treatment period for a duration of 2 days aggravated breath and salivation, no clinical signs were observed. For Ophthalmological examination, bodyweight, water consumption, Serum clinical chemistry, haematology, urine analysis and necroscopy no findings of toxiclogical importance were noted. The increased food conversion rate noticed in treated males and females during treatment period was reversible and therefore not regarded as adverse effect. Centrolobular hypertrophy was observed predominantly in the liver of male and female animals in the high and medium dose group, but was also found to a certain extent in male and female animals of the low dose group. The hepatocellular hypertrophy was correlated with statistically significant higher relative liver weights in medium and high dose females. These findings were considered to be substance-related. Evidence of reversibility was found at the end of the recovery period. The reversible liver changes are regarded as a transient adaptive response of the liver to the test substance. As such, it is gerenerally not considered as adverse effect.
Therefore, in our experimental conditions, the no-observed-adverse-effect level (NOAEL is 1000 mg/kg/day.
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