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EC number: 700-867-1 | 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
Genetic toxicity: in vivo
Administrative data
- Endpoint:
- in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
- Remarks:
- Type of genotoxicity: chromosome aberration
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- From 2007-07-23 to 2007-08-24
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- Well documented GLP study performed in accordance with the OECD guideline N°474, Commission Directive 2000/32/EC, Annex 4C, dated May 19, 2000, and ICH-Harmonised Tripartites guidelines S2A and S2B, with minor deviations which do not impact the validity of the study.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 007
- Report date:
- 2007
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
- Deviations:
- no
- Remarks:
- but data lacking about: some endpoints not recorded for toxic reactions during pre-experiment
- Qualifier:
- according to guideline
- Guideline:
- other: Commission Directive 2000/32/EC, Annex 4C, dated May 19, 2000.
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: ICH-Harmonised Tripartite Guideline S2A (CPMP/ICH/141/95), dated April 1996
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: ICH-Harmonised Tripartite Guideline S2B (CPMP/ICH/174/95), dated July 1997
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- micronucleus assay
Test material
- Reference substance name:
- rel-(4aR,8aR)-1-bromo-3-methoxy-4a,5,9,10,11,12-hexahydro-6H-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-one hydrochloride (1:1)
- EC Number:
- 700-867-1
- Molecular formula:
- C16H16BrNO3.HCl
- IUPAC Name:
- rel-(4aR,8aR)-1-bromo-3-methoxy-4a,5,9,10,11,12-hexahydro-6H-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-one hydrochloride (1:1)
- Test material form:
- solid
- Details on test material:
- - Name of test material (as cited in study reports): T002102
- Physical state: solid
- Appearance: white (SDS)
Constituent 1
Test animals
- Species:
- mouse
- Strain:
- NMRI
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Harlan Winkelmann GmbH D-33178 Borchen
- Age at study initiation: 7-8 weeks
- Weight at study initiation: males mean value 37.3 g (SD ± 1.4 g) ; females mean value 31.1 g (SD ± 1.7 g)
- Animals were distributed into the test groups at random and identified by cage number.
- Fasting period before study: no data
- Housing: single housing in Makrolon Type I cages, with wire mesh top
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: minimum of five days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3°C
- Humidity (%): 30-84%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12h/12h
Administration / exposure
- Route of administration:
- oral: unspecified
- Vehicle:
- - Vehicle(s)/solvent(s) used: 0.9 % NaCl
- Justification for choice of solvent/vehicle: chosen to its relative non-toxicity for the animals
- Concentration of test material in vehicle: 10 mL/kg bw - Details on exposure:
- On the day of the experiment, the test item was formulated in 0.9 % NaCl. All animals received a single standard volume of 10 mL/kg body weight orally.
- Duration of treatment / exposure:
- one single administration
- Frequency of treatment:
- one single administration
- Post exposure period:
- Three adequately spaced dose levels spaced by a factor of 2 were administered, and samples were collected at the central sampling interval 24 h after treatment. For the highest dose level an additional sample was taken at 48 h after treatment. Sampling of the bone marrow was done 24 and 48 hours after treatment, respectively.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 125 mg/kg bw/day (nominal)
- Remarks:
- 24 h preparation interval for the female animals
- Dose / conc.:
- 250 mg/kg bw/day (nominal)
- Remarks:
- 24 h preparation interval for the male and female animals
- Dose / conc.:
- 500 mg/kg bw/day (nominal)
- Remarks:
- 24 h preparation interval for the male and female animals, and 48 h preparation interval for the female animals
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Remarks:
- 24 h preparation interval for the male animals, and 48 h preparation interval for the male animals
- No. of animals per sex per dose:
- Twelve animals, six males and six females, were treated per dose group and sampling time (except highest dose: 12 animals per sex, 6 per time point).
- Control animals:
- yes, concurrent vehicle
- Positive control(s):
- Cyclophosphamide
- Justification for choice of positive control(s): no
- Route of administration: orally, once
- Doses / concentrations: dissolved in deionised water, administered at 10 mL/kg bw (dose 40 mg/kg bw)
Examinations
- Tissues and cell types examined:
- Bone marrow -at least 2000 polychromatic erythrocytes (PCEs) per animal were scored for micronuclei.
- Details of tissue and slide preparation:
- CRITERIA FOR DOSE SELECTION: It is generally recommended to use the maximum tolerated dose or the highest dose that can be formulated and administered reproducibly or 2000 mg/kg as the upper limit for non-toxic test items.
The maximum tolerated dose level is determined to be the dose that causes toxic reactions without having major effects on survival within 48 hours.
The volume to be administered should be compatible with physiological space available.
Three adequately spaced dose levels spaced by a factor of 2 were administered, and samples were collected at the central sampling interval 24 h after treatment. For the highest dose level an additional sample was taken at 48 h after treatment.
TREATMENT AND SAMPLING TIMES ( in addition to information in specific fields): At the beginning of the treatment, the animals (including the controls) were weighed and the individual volume to be initiated was adjusted to the animal body weight. The animals received the test item, the vehicle or the positive control substance once. Twelve animals, six males and six females, were treated per dose group and sampling time (24 or 48h). The animals of all dose groups were examined for acute toxic symptoms at intervals of around 1h, 2-4h, 6h and 24h after administration of the test item. Sampling of bone marrow was done 24 and 48 hours after treatment.
DETAILS OF SLIDE PREPARATION: The animals were sacrificed using CO2 followed by bleeding. The femora were removed, the epiphyses were cut off and the marrow was flushed out with foetal calf serum using a syringe. The cell suspension was centrifuged at 1500 rpm (390 x g) for 10 minutes and the supernatant was discarded. A small drop of the re-suspended cell pellet was spread on a slide. The smear was air-dried and then stained with May-Grünwald (Merck, D-64293 Darmstadt)/ Giemsa (Merck, D-64293 Darmstadt). Cover slips were mounted with Eukitt (Kindler, D-79110 Freiburg). At least one slide was made from each bone marrow sample.
METHOD OF ANALYSIS: Evaluation of the slides was performed using NIKON microscopes with 100x oil immersion objectives. At least 2000 polychromatic erythrocytes (PCE) were analysed per animal for micronuclei. To describe a cytotoxic effect the ratio between polychromatic and normochromatic erythrocytes was determined in the same sampled and expressed in polychromatic erythrocytes per 2000 erythrocytes. The analysis was performed with coded slides.
Twelve animals (6F+6M) per test groups were evaluated as described. - Evaluation criteria:
- A test item is classified as mutagenic if it induces either a dose-related increase or a clear increase in the number of micronucleated polychromatic erythrocytes in a single dose group.
A test item that fails to produce a biological relevant increase in the number of micronucleated polychromatic erythrocytes is considered non-mutagenic in this system. - Statistics:
- The non parametric Mann-Whitney test was used as an aid in evaluating the results. However, the primary point of consideration is the biological relevance of the results.
Results and discussion
Test results
- Sex:
- male/female
- Genotoxicity:
- negative
- Toxicity:
- no effects
- Vehicle controls validity:
- valid
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- The mean number of polychromatic erythrocytes was not decreased after treatment with the test item as compared to the mean value of PCEs of the vehicle control indicating that T2102 did not have any cytotoxic properties in the bone marrow.
The highest dose (500 mg/kg b.w. for the female animals and 1000 mg/kg b.w. for the male animals) was estimated by pre-experiments to be suitable.
40 mg/kg b.w. cyclophosphamide administered orally was used as positive control which showed a statistically significant increase of induced micronucleus frequency.
Any other information on results incl. tables
Pre-experiment results:
In a pre-experiment 4 animals (2 males, 2 females) received orally a single dose of 100 mg/kg b.w. T2102 formulated in 0.9 % NaCl. The volume administered was 10 mL/kg b.w.. The animals treated with 100 mg/kg b.w. expressed no toxic reactions.
In a second pre-experiment 4 animals (2 males, 2 females) received orally a single dose of 1000 mg/kg b.w. T2102 formulated in 0.9 % NaCl. The volume administered was 10 mL/kg b.w. A female died 2 -4 hours after administration of the test item.
In a third pre-experiment 2 males received orally a single dose of 1500 mg/kg b.w and 2 females received orally a single dose of 750 mg/kg b.w. T2102 formulated in 0.9 % NaCl. The volume administered was 10 mL/kg b.w. One male and one female died during the hour following the oral administration.
In a fourth pre-experiment 2 males received orally a single dose of 1250 mg/kg b.w and 2 females received orally a single dose of 500 mg/kg b.w. T2102 formulated in 0.9 % NaCl. The volume administered was 10 mL/kg b.w.. One male died during the hour following the oral administration.
On the basis of these data 1000 mg/kg b.w. was estimated to be suitable as the highest dose for the male and 500 mg/kg b.w. for the female animals.
Main experiment:
The animals treated with 1000 mg/kg and 500 mg/kg b.w. respectively expressed toxic reactions as shown in the table (left number: males, rigth number:females):
Toxic reactions following administration | 1h | 2 -4h | 6h | 24h | 48h* |
Reduction of spontaneous activity | 9/10 | 10/12 | 9/8 | 0/0 | 0/0 |
ruffled fur | 12/12 | 12/12 | 12/12 | 7/8 | 0/0 |
tremor | 8/9 | 7/9 | 1/4 | 0/0 | 0/0 |
*data from only 6 animals
Summary of micronucleus test results (main experiment, males)
Test group | dose mg/kg b.w. | sampling time (h) | PCEs with micronuclei (%) | range | PCE per 2000 erythrocytes |
Vehicle | 0 | 24 | 0.175 | 1 -6 | 1298 |
Test item | 250 | 24 |
0.142 |
1 -4 |
1138 |
Test item |
500 |
24 |
0.167 |
1 -6 |
1236 |
Test item |
1000 |
24 |
0.092 |
0 -4 |
1204 |
positive control |
40 |
24 |
3.492 |
56 -97 |
1066 |
Test item |
1000 |
48 |
0.120 |
1 -4 |
1119 |
Summary of micronucleus test results (main experiment, females)
Test group | dose mg/kg b.w. | sampling time (h) | PCEs with micronuclei (%) | range | PCE per 2000 erythrocytes |
Vehicle | 0 | 24 | 0.108 | 1 -4 | 1249 |
Test item | 125 | 24 |
0.142 |
0 -6 |
1281 |
Test item |
250 |
24 |
0.100 |
1 -4 |
1224 |
Test item |
500 |
24 |
0.108 |
0 -3 |
1265 |
positive control |
40 |
24 |
2.758 |
39 -78 |
1113 |
Test item |
500 |
48 |
0.150 |
1 -6 |
1139 |
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results: negative
In conclusion, it can be stated that during the study described and under the experimental conditions reported, the test item did not induce micronuclei as determined by the micronucleus test in the bone marrow cells of the mouse. Based on these results and the criteria in the CLP Regulation, the test substance is considered not classified as mutagenic.
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