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EC number: 266-719-9 | CAS number: 67564-91-4
- 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
Genetic toxicity: in vivo
Administrative data
- Endpoint:
- in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2. Nov. 1993 - 28. Oct. 1994
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 994
- Report date:
- 1994
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
- Deviations:
- yes
- Remarks:
- No positive response in positive control of Exp.1 with Cyclophosphamide. No analytical verification of substance bloodlevel
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- mammalian bone marrow chromosome aberration test
Test material
- Reference substance name:
- cis-4-[3-(p-tert-butylphenyl)-2-methylpropyl]-2,6-dimethylmorpholine
- EC Number:
- 266-719-9
- EC Name:
- cis-4-[3-(p-tert-butylphenyl)-2-methylpropyl]-2,6-dimethylmorpholine
- Cas Number:
- 67564-91-4
- Molecular formula:
- C20H33NO
- IUPAC Name:
- (2R,6S)-4-[3-(4-tert-butylphenyl)-2-methylpropyl]-2,6-dimethylmorpholine
Constituent 1
Test animals
- Species:
- mouse
- Strain:
- NMRI
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River GmbH, WIGA, Sulzfeld,
- Age at study initiation: Not specified
- Weight at study initiation: Animals witha mean weight of about 28g were used for the study.
- Assigned to test groups randomly: yes, under following basis: according to a randomization plan prepared with an appropriate computer program.
- Fasting period before study: Not specified
- Housing: During the test animals were housed individually in Makrolon cages type MI
- Diet: Standardized pelleted feed (Kliba Haltungs Diät, Klingenthalmühle AG, Kaiseraugst, Switzerland)
- Water: ad libitum
- Acclimation period: 2 weeks in groups of 5
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70%
- Air changes (per hr): Not specified
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: To: Not specified
Administration / exposure
- Route of administration:
- intraperitoneal
- Vehicle:
- Aqueous solution of 0.5% carboxy methyl cellulose
- Details on exposure:
- Route = intraperitoneal
- Duration of treatment / exposure:
- once
- Post exposure period:
- 24h and 48h
Doses / concentrationsopen allclose all
- Dose / conc.:
- 1 000 mg/kg bw (total dose)
- Remarks:
- Experiment 2
24h and 48h sacrifice interval
- Dose / conc.:
- 1 000 mg/kg bw (total dose)
- Remarks:
- Experiment 1
24h and 48h sacrifice interval
- Dose / conc.:
- 500 mg/kg bw (total dose)
- Remarks:
- Experiment 1
24h sacrifice interval
- Dose / conc.:
- 250 mg/kg bw (total dose)
- Remarks:
- Experiment 1
24h sacrifice interval
- No. of animals per sex per dose:
- 5 males and 5 females
- Control animals:
- yes, concurrent vehicle
- Positive control(s):
- 20 mg Cyclophosphamide
0.15 mg Vincristine
Examinations
- Tissues and cell types examined:
- Bone marrow smears
- Details of tissue and slide preparation:
- CRITERIA FOR DOSE SELECTION:
In a pretest for the determination of the acute intraperitoneal toxicity deaths were observed down to a dose of 1250 mg/kg bodyweight. 1000 mg/kg were survived by all animals but led to clinical signs such as apathy and abdominal position; the general state of the animals was poor. Therefore, a dose of 1000 mg/kg bodyweight was selected as the highest dose in the present cytogenetic study. 500 mg/kg and 250 mg/kg bodyweight were administered as further doses.
TREATMENT AND SAMPLING TIMES ( in addition to information in specific fields): Sampling was performed 24 h and/ or 48 h after treatment
DETAILS OF SLIDE PREPARATION:
The bone marrow was prepared according to the method described by SCHMID, W. The two femora were prepared from the animals, and all soft tissues were removed. After cutting off the epiphyses, the bone marrow was flushed out of the diaphysis into a centrifuge tube using a cannula filled with fetal calf serum which was at 37°C (about 2 ml/femur). The suspension was mixed thoroughly with a pipette, centrifuged at 1500 rpm for 5 minutes, the supernatant was removed except for a few drops, and the precipitate was resuspended.
1 drop of this suspension was dropped onto clean microscopic slides, using a Pasteurpipette. Smears were prepared using slides with ground edges, the preparations were dried in the air and subsequently stained. The slides were stained in eosin and methylene blue solution for 5 minutes, rinsed in aqua dest. and then placed in fresh aqua dest. for 2 or 3 minutes. They were finally stained in Giemsa solution for 12 minutes. After being rinsed twice in aqua dest. and clarified in xylene, the preparations were embedded in Corbit-Balsam.
METHOD OF ANALYSIS:
In general, 1000 polychromatic erythrocytes from each of the male and female animals of every test group are evaluated and investigated for micronuclei. The normochromatic erythrocytes (= normocytes), which occur, are also scored. The following parameters are recorded:
-Number of polychromatic erythrocytes
-Number of polychromatic erythrocytes containing micronuclei The increase in the number of micronuclei in polychromatic erythrocytes of treated animals as compared with the solvent control group provides an index of a chromosome breaking (clastogenic) effect or of a spindle activity of the substance tested.
-Number of normochromatic erythrocytes
-Number of normochromatic erythrocytes containing micronuclei The number of micronuclei in normochromatic erythrocytes at the early sacrifice intervals represents the situation before test substance administration and may serve as a control value. A substance induced increase in the number of micro nuclei in normocytes may be found with an increase in the duration of the sacrifice intervals.
-Ratio of polychromatic to normochromatic erythrocytes: this ratio indicates an influence of the test substance specifically on the bone marrow. Number of small micronuclei (d < D/4) and of large micronuclei (d > D/4) (d= diameter of micronucleus, D = cell diameter) The size of micronuclei may give an indication on the possible mode of action of the test substance, i.e. aclastogenic or a spindle poison effect. Slides were coded before microscopic analysis.
OTHER: - Statistics:
- The statistical evaluation of the data was carried out using the program system MUKERN (BASF AG). The number of micronuclei in polychromatic erythrocytes were analysed. A comparison of the dose group with the vehicle control was carried out using the Wilcoxon test for the hypothesis of equal medians. Here, the relative frequencies of cells with micronuclei of each animal were used. If the results of this test were significant, labels (+ for p < 0.05, ++for p < 0.01) were printed with the group means in the tables. This test was performed one sided. This analysis was done separately for each sex and combined for both sexes.
Results and discussion
Test results
- Sex:
- male/female
- Genotoxicity:
- negative
- Toxicity:
- yes
- Vehicle controls validity:
- valid
- Negative controls validity:
- not examined
- Positive controls validity:
- other: No positive response with Cyclophosphamid in Exp.1
Applicant's summary and conclusion
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