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EC number: 700-163-4 | 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
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- 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:
- key study
- Study period:
- From July 21, 2009 to October 16, 2009
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Well conducted GLP guideline study.
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to other study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 009
- Report date:
- 2009
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
- Deviations:
- no
- Principles of method if other than guideline:
- Not applicable
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- micronucleus assay
Test material
Constituent 1
Test animals
- Species:
- mouse
- Strain:
- NMRI
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Harlan Laboratories GmbH, 33178 Borchen
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: males mean value 33.8 g (SD ± 3.0 g)
- Assigned to test groups randomly: yes
- Fasting period before study: no
- Housing: single, Makrolon Type II, with wire mesh top (EHRET GmbH, 79302 Emmendingen, Germany)
- Diet: pelleted standard diet, ad libitum (Harlan Laboratories GmbH, 33178 Borchen, Germany)
- Water: tap water, ad libitum (Gemeindewerke, 64380 Rossdorf, Germany)
- Acclimation period: minimum 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 + 2 °C
- Humidity (%): 45 - 65 %
- Air changes (per hr): no data
- Photoperiod: 12 hrs dark / 12 hrs light (artificial light 6.00 a.m. - 6.00 p.m.)
IN-LIFE DATES: no data
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- - Vehicle(s)/solvent(s) used: corn oil (Sigma-Aldrich Vertriebs GmbH, 82041 Deisenhofen)
- Justification for choice of solvent/vehicle: no data
- Concentration of test material in vehicle: no data
- Amount of vehicle: 10 mL/kg bw
- Lot/batch no. (if required): no data
- Purity: no data - Details on exposure:
- At the beginning of the treatment the animals (including the controls) were weighed and the individual volume to be administered was adjusted to the animal’s body weight. The animals received the test item, the vehicle or the positive control substance once.
- Frequency of treatment:
- once
- Post exposure period:
- 24 or 48 hours
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 75, 150, 300 mg/kg bw
Basis:
actual ingested
- No. of animals per sex per dose:
- 7 males/dose
- Control animals:
- yes, concurrent vehicle
- Positive control(s):
- cyclophosphamide (Sigma-Aldrich Vertriebs GmbH, 82041 Deisenhofen, Germany. Purity: > 98 %)
- Justification for choice of positive control(s): no data
- Route of administration: orally
- Doses / concentrations: 40 mg/kg bw (10 mL/kg bw)
Examinations
- Tissues and cell types examined:
- bone marrow cells from femora
- Details of tissue and slide preparation:
- CRITERIA FOR DOSE SELECTION: based on the results of the pre-experiments on toxicity.
A preliminary study on acute toxicity was performed with two animals per sex under identical conditions as in the mutagenicity study concerning: animal strain, vehicle, route, frequency, and volume of administration. The animals were treated orally with the test item and examined for acute toxic symptoms at intervals of approximately 1 h, 2-4 h, 6 h, 8 h (except for the fourth pre-experiment), 10 h (except for the third and fourth pre-experiment), 24 h, 30 h, and 48 h after administration of the test item.
TREATMENT AND SAMPLING TIMES: 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, 64293 Darmstadt, Germany)/Giemsa (Gurr, BDH Limited Poole, Great Britain). Cover slips were mounted with EUKITT (Kindler, 79110 Freiburg, Germany). 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. Per animal 2000 polychromatic erythrocytes (PCE) were analysed for micronuclei. To describe a cytotoxic effect the ratio between polychromatic and normochromatic erythrocytes was determined in the same sample and expressed in polychromatic erythrocytes per 2000 erythrocytes. The analysis was performed with
coded slides.
OTHER: The animals of all dose groups (excepted the positive control) were examined for acute toxic symptoms at intervals of approximately 1 h, 2 - 4 h, 6 h, 24 h and 48 h after administration of the test item. In case of problems occurred during the treatment of the animals connected to the corrosive characteristics of the test item it was considered to have two additional early observation intervals (8 h and 10 h after treatment). However, these were skipped since the animals did not show any abnormal clinical signs in the pre-experiments demonstrating the redundancy of further observation intervals. - 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. Statistical methods (nonparametric Mann-Whitney test (8)) will be used as an aid in evaluating the results. However, the primary point of consideration is the biological relevance of the results.
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:
- Statistical significance at the five per cent level (p < 0.05) was evaluated by means of the non-parametric Mann-Whitney test.
Results and discussion
Test results
- Sex:
- male
- Genotoxicity:
- negative
- Toxicity:
- yes
- Remarks:
- At 300 mg/kg bw, reduction of spontaneous activity in all the animals 1 h after treatment. At 150 mg/kg bw, ruffled fur in 1 animal 1 h after treatment.
- Vehicle controls validity:
- valid
- Negative controls validity:
- not examined
- Positive controls validity:
- valid
- Additional information on results:
- RESULTS OF RANGE-FINDING STUDY
- Dose range: 300 - 1000 mg/kg bw
- Clinical signs of toxicity in test animals:
1st test (100 mg/kg bw): The animals treated with 100 mg/kg b.w. did not express any toxic reactions.
2nd test (1000 mg/kg bw): reduction of spontaneous activity, abdominal position, apathy. The two males and one female died approximately 2 hours after application of the test item. The second female animal died 3 hours after application of the test item.
3rd test (500 mg/kg bw): reduction of spontaneous activity, abdominal position, ruffled fur
4th test (300 mg/kg bw): reduction of spontaneous activity, ruffled fur
Any other information on results incl. tables
Table 7.6.2/1: Summary of micronucleus test results
Test group |
Dose (mg/kg bw) |
Sampling time (h) |
PCEs with micronuclei (%) |
Range |
PCE per 2000 erythrocytes |
Significance |
p |
Vehicle |
0 |
24 |
0.129 |
0-5 |
1376 |
- |
|
Test item |
75 |
24 |
0.179 |
1-6 |
1355 |
- |
0.1949 |
Test item |
150 |
24 |
0.143 |
1-6 |
1340 |
- |
0.3569 |
Test item |
300 |
24 |
0.171 |
1-7 |
1356 |
- |
0.2756 |
Positive control |
40 |
24 |
3.107 |
34-99 |
1175 |
+ |
0.0003 |
Test item |
300 |
48 |
0.129 |
0-4 |
1237 |
n.t. |
- |
- = not significant
+ = significant
n.t = not tested, as the mean micronucleus frequency was not above the vehicle control value
Table 7.6.2/2: Toxic symptoms in the main experiment
Toxic reactions |
Hours post-treatment |
||||
1 h |
2-4 h |
6 h |
24 h |
48 h |
|
300 mg/kg bw : reduction of spontaneous activity |
14 |
0 |
0 |
0 |
0* |
150 mg/kg bw : ruffled fur |
1 |
0 |
0 |
0 |
- |
*: data only from 7 males.
Table 7.6.2/3: Pre-experiments results for toxicity
Toxic reactions |
Dose (mg/kg bw) |
Hours post-treatment (male / female) |
|||||||
1 h |
2-4 h |
6 h |
8 h |
10 h |
24 h |
30 h |
48 h |
||
Reduction of spontaneous activity |
100 |
0/0 |
0/0 |
0/0 |
0/0 |
0/0 |
0/0 |
0/0 |
0/0 |
1000 |
2/2 |
0/1 |
- |
- |
- |
- |
- |
- |
|
500 |
2/2 |
2/2 |
0/2 |
0/2 |
-/- |
0/2 |
0/0 |
0/0 |
|
300 |
2/2 |
0/1 |
0/0 |
-/- |
-/- |
0/0 |
0/0 |
0/0 |
|
Abdominal position |
100 |
0/0 |
0/0 |
0/0 |
0/0 |
0/0 |
0/0 |
0/0 |
0/0 |
1000 |
2/2 |
0/1 |
- |
- |
- |
- |
- |
- |
|
500 |
2/2 |
1/2 |
0/0 |
0/0 |
-/- |
0/0 |
0/0 |
0/0 |
|
300 |
0/0 |
0/0 |
0/0 |
-/- |
-/- |
0/0 |
0/0 |
0/0 |
|
Apathy |
100 |
0/0 |
0/0 |
0/0 |
0/0 |
0/0 |
0/0 |
0/0 |
0/0 |
1000 |
0/0 |
0/1 |
- |
- |
- |
- |
- |
- |
|
500 |
0/0 |
0/0 |
0/0 |
0/0 |
-/- |
0/0 |
0/0 |
0/0 |
|
300 |
0/0 |
0/0 |
0/0 |
-/- |
-/- |
0/0 |
0/0 |
0/0 |
|
Ruffled fur |
100 |
0/0 |
0/0 |
0/0 |
0/0 |
0/0 |
0/0 |
0/0 |
0/0 |
1000 |
- |
- |
- |
- |
- |
- |
- |
- |
|
500 |
0/0 |
1/2 |
1/2 |
1/2 |
-/- |
1/2 |
1/0 |
1/1 |
|
300 |
0/0 |
0/1 |
0/1 |
-/- |
-/- |
0/0 |
0/0 |
0/0 |
|
Death |
100 |
0/0 |
0/0 |
0/0 |
0/0 |
0/0 |
0/0 |
0/0 |
0/0 |
1000 |
0/0 |
2/2 |
- |
- |
- |
- |
- |
- |
|
500 |
0/0 |
0/0 |
0/0 |
0/0 |
-/- |
0/0 |
0/0 |
0/0 |
|
300 |
0/0 |
0/0 |
0/0 |
-/- |
-/- |
0/0 |
0/0 |
0/0 |
-/- no observation made
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information): negative
Under the reported experimental conditions, the substance did not induce micronuclei as determined by the micronucleus test in the bone marrow cells of the mouse. - Executive summary:
In an in vivo micronucleus assay, performed according to the OECD guideline No. 474 and in compliance with GLP, male NMRI mice (7/dose) were exposed to the substance (98 % pure) diluted in corn oil by a single gavage dose.
On the basis of pre-experiments data, 300 mg/kg bw was estimated to be suitable as top dose. No gender specific differences were observed, therefore, the main experiment wasperformed using males only.The following dose levels of the test item were investigated:
- 24 h preparation interval: 75, 150, and 300 mg/kg bw
- 48 h preparation interval: 300 mg/kg bw.
The volume administered orally was 10 mL/kg bw. 24 h and 48 h after a single administrationof the test item the bone marrow cells were collected for micronuclei analysis.Per animal 2000polychromatic erythrocytes (PCEs) were scored for micronuclei.
The same assay was done with the vehicle control and the positive control (Cyclophosphamide at 40 mg/kg bw).
The animals treated with 300 mg/kg bw expressed reduction of spontaneous activity 1 hour after treatment. One animal treated with 150 mg/kg bw showed ruffled fur 1 hour after treatment. All the observed effects were reversible within 2 -4 hours.
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 the substance did not have any cytotoxic properties in the bone marrow.
In comparison to the corresponding vehicle controls there was no statistically significant or biologically relevant enhancement in the frequency of the detected micronuclei at any preparation interval and dose level after administration of the test item. The mean values of micronuclei observed after treatment with the substance were below or near to the value of the vehicle control group. The positive control showed a statistically significant increase of induced micronucleus frequency.
Under the experimental conditions, the test item did not induce a significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow after any treatment time.
This study is acceptable and satisfies the requirement of the OECD 474 guideline for the cytogenicity.
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