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EC number: 244-311-1 | CAS number: 21282-97-3
- 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:
- key study
- Study period:
- 12 January 2016 - 3 March 2016
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: OECD Guideline study and performed according to GLP requirements.
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 016
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.12 (Mutagenicity - In Vivo Mammalian Erythrocyte Micronucleus Test)
- Deviations:
- no
- Principles of method if other than guideline:
- Not applicable
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- Envigo CRS GmbH
- Type of assay:
- micronucleus assay
Test material
- Test material form:
- other: liquid
- Details on test material:
- Identification: LZ 649
Appearance: Clear colourless to yellowish liquid
Retest Date: 2 July 2016
Storage Conditions
(provided by the Sponsor): Keep refrigerated (2-8°C) and in the dark
Constituent 1
Test animals
- Species:
- mouse
- Strain:
- NMRI
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- Number of animals for
the pre-test: 2 males and 2 females for each pre-test
Number of animals for
the main study: 42 males for the main study
9 additional males for determination of bioavailability
Age (beginning of treatment): 6 – 10 weeks
Body weight: between 32.1 g and 40.0 g
Acclimation: At least 5 days prior to the start of dosing under test conditions after health examination.
Only animals without any visible signs of illness were used for the study.
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- 70 % Polyethylene glycol
- Details on exposure:
- Application volume: 10 mL/kg b.w.
- Duration of treatment / exposure:
- The animals of all dose groups, except the positive control group, were examined for acute toxic symptoms at intervals of around 0-1 h, 2-4 h, 5-6 h, 24 h, and 48 h after administration of the test item. Sampling of the bone marrow was done 24 and 48 h after treatment, respectively.
- Frequency of treatment:
- 1
- Post exposure period:
- Pre-Experiment on Toxicity: 0-1 h, 2-4 h, 5-6 h, 24 h, and 48 h after administration of the test item.
Main experiment: 0-1 h, 2-4 h, 5-6 h, 24 h, and 48 h after administration of the test item.
24h + 48h
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
500 mg/kg b.w.
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
1000 mg/kg b.w.
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
2000 mg/kg b.w.
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
Positive control 40 mg/kg b.w. Cyclophosphamide
Basis:
actual ingested
- No. of animals per sex per dose:
- Number of animals for the pre-test: 2 males and 2 females for each pre-test
Number of animals for the main study: 42 males for the main study
Main study: 7 males per test group
24 h preparation interval: 500, 1000, and 2000 mg/kg b.w.
48 h preparation interval: 2000 mg/kg b.w. - Control animals:
- yes, concurrent vehicle
- Positive control(s):
- Cyclophosphamide 40 mg/kg b.w.
Examinations
- Tissues and cell types examined:
- Tissue: bone marrow
Cell type: polychromatic erythrocytes (PCE) - Details of tissue and slide preparation:
- Evaluation of the slides was performed using NIKON microscopes with 100x oil immersion objectives.
4000 polychromatic erythrocytes (PCE) per animal were analysed for micronuclei. - Evaluation criteria:
- To describe a cytotoxic effect the ratio between polychromatic and normochromatic erythrocytes was determined in the same sample and expressed in polychromatic erythrocytes per total erythrocytes. The analysis was performed with coded slides.
- Statistics:
- Statistical significance at the five per cent level (p < 0.05) was evaluated by means of the non-parametric Mann-Whitney test using the validated statistical program RScript Wilcoxon_2.Rnw.
Results and discussion
Test results
- Sex:
- male
- Genotoxicity:
- negative
- Toxicity:
- yes
- Remarks:
- clinical signs
- Vehicle controls validity:
- valid
- Negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Additional information on results:
- As estimated by a pre-experiment 2000 mg LZ 649 per kg b.w. (the maximum guideline-recommended dose) was suitable as highest treatment dose.Clinical symptoms in the main experiment included ruffled fur, reduced spontaneous activity and eyelid closure in some of the animals treated with the high dose of test item. The animals treated with the mid and low dose did not exhibit any clinical symptoms.The observed systemic toxicity suggests a systemic distribution of the test item. Thus, bioavailability of the test item under the tested conditions is assumed. This was additionally confirmed by analytical detection of the test item in plasma (Study Number 41502651).
The mean number of polychromatic erythrocytes was not substantially decreased after treatment with the test item as compared to the mean value of PCEs of the vehicle control indicating that the test item 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 test item were below or near to the value of the vehicle control group.
Any other information on results incl. tables
|
hours post-treatment (males) |
||||
Clinical symptoms |
1 |
2-4 |
6 |
24 |
48 |
High dose: 2000 mg/kg b.w. (14 males at 1 to 24 h; 7 males at 48 h) |
|||||
reduction of spontaneous activity |
1 |
2 |
0 |
1 |
0 |
eyelid closure |
0
|
2 |
0 |
0 |
0 |
ruffled fur |
1
|
2 |
1 |
2 |
0 |
The animals treated with the vehicle control (PEG 400), or with the low and mid dose of the test item did not express any clinical symptoms.
Summary of Micronucleus Test Results:
Test Group |
Dose mg/kg b.w. |
Sampling time |
Mean MN/4000 PCE |
SD MN/4000 PCE |
Range |
Ratio PCE / total Ery |
% ratio Vehicle |
|
min |
max |
|||||||
Vehicle |
0 |
24 |
4.1 |
2.6 |
1 |
9 |
0.572 |
100.00 |
Dose 1 |
500 |
24 |
4.7 |
2.6 |
2 |
8 |
0.577 |
100.87 |
Dose 2 |
1000 |
24 |
3.7 |
1.9 |
1 |
5 |
0.591 |
103.32 |
Dose 3 |
2000 |
24 |
2.6 |
1.6 |
0 |
4 |
0.621 |
108.57 |
Positive |
40 |
24 |
90.4 |
33.8 |
51 |
144 |
0.654 |
114.34 |
Dose 3 |
2000 |
48 |
4.0 |
2.2 |
2 |
8 |
0.546 |
95.45 |
MN= micronuclei
PCE= polychromatic erythrocytes
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information): negative
The test substance does not produce relevant increases of the numbers of micronuclei in polychromatic erythrocytes after in vivo treatment of mice of either sex of the test strain at doses of 500, 1000 and 2000 mg/kg b.w. Therefore, the test item is considered to be non-mutagenic in this in vivo micronucleus assay. - Executive summary:
The in vivo study was peformed to investigate the potential of the tests item to induce micronuclei in polychromatic erythrocytes (PCE) in the bone marrow of the mouse. The study was performed in year 2016 according to OECD Guideline 474 and GLP.
The observed systemic toxicity suggests a systemic distribution of the test item. Thus, bioavailability of the test item under the tested conditions is assumed. This was additionally confirmed by analytical detection of the test item in plasma (supporting phase report 41502651).
After treatment with the test item the number of PCEs was not substantially decreased as compared to the mean value of PCEs of the vehicle control thus indicating that the test item did not exert any cytotoxic effects in the bone marrow.
In conclusion, in can be stated that under the experimental conditions reported, the test item did not induce micronuclei as determined by the micronucleus test with bone marrow cells of the mouse.
Therefore, the test item is considered to be non-mutagenic in this in vivo micronucleus assay.
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