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EC number: 938-639-0 | CAS number: -
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Endpoint summary
Administrative data
Key value for chemical safety assessment
Genetic toxicity in vitro
Description of key information
The test substance did not induce mutations (base-pair substitution and frame-shift type) in Salmonella typhimurium strains TA98, TA100, TA1535 and TA1537 as well as in E. coli WP2 uvr A both in presence and absence of metabolic activation (Harlan 2013).
The test substance was tested in L5178Y cells in presence and absence of metabolic activation in a study performed according to OECD 476. In both experiments the test substance did not induce an increase in mutant frequency at the TK +/- locus and is therefore considered to be non-mutagenic (Harlan 2015).
In a chromosome aberration test in CHO-WBL cells, structural (with metabolic activation) and numerical (without metabolic activation) aberrations were reported after 3-hour treatment at concentrations up to cytotoxicity. Prolonged testing without metabolic activation did not induce any effects. Therefore it cannot be excluded that the substance exhibits clastogenic effects.
Link to relevant study records
- Endpoint:
- in vitro cytogenicity / chromosome aberration study in mammalian cells
- Remarks:
- Type of genotoxicity: chromosome aberration
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 22 Sep 2014 to 25 Feb 2015
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Guidelines study under GLP, positive and vehicle controls do not fall clearly within historical control ranges in part of the experiments
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 473 (In Vitro Mammalian Chromosome Aberration Test)
- GLP compliance:
- yes
- Type of assay:
- in vitro mammalian chromosome aberration test
- Species / strain / cell type:
- Chinese hamster Ovary (CHO)
- Details on mammalian cell type (if applicable):
- - Source: Genetic Toxicology Laboratory at Pfizer, Inc., Groton, CT, USA
- Type and identity of media: McCoy’s complete media
- Periodically checked for Mycoplasma contamination: yes
- Periodically checked for karyotype stability: yes, 12-14 hour cycling time, average 21 chromosomes
Each culture was prepared by seeding with 1.4 × 10E6 CHO cells per 75 cm2 flask in McCoy’s complete media and incubated at 37 ± 1°C in vented flasks in a humidified atmosphere of 5 ± 1% CO2 for approximately 24 hours prior to the initiation of treatment. - Metabolic activation:
- with and without
- Metabolic activation system:
- Aroclor™ 1254-induced rat liver S9 fraction
- Test concentrations with justification for top dose:
- Concentrations are based on the results of 3 pre-tests
Exp 1 (3 h without metabolic activation) : stock solution of 150 mg/mL further diluted with DMSO/ethanol(1/1) to:
6.25, 12.5, 25.0, 50.0, 75.0, 100, 125, 150, 225, 300, and 500 µg/mL
Exp 2 (20 h without metabolic activation) : stock solution of 50 mg/mL further diluted with DMSO/ethanol(1/1) to:
6.25, 12.5, 25.0, 50.0, 75.0, 100, 125, 150, 225, 300, and 500 µg/mL
Exp 3 (3 h with metabolic activation) : stock solution of 50 mg/L further diluted with DMSO/ethanol(1/1) to:
6.25, 12.5, 25.0, 50.0, 75.0, 100, 125, 150, 225, 300, and 500 µg/mL - Vehicle / solvent:
- - Vehicle(s)/solvent(s) used: DMSO/Ethanol (1/1)
- Justification for choice of solvent/vehicle: pre-test at 500 mg/L - Negative solvent / vehicle controls:
- yes
- Remarks:
- DMSO/Ethanol (1/1)
- Positive controls:
- yes
- Positive control substance:
- mitomycin C
- Remarks:
- tests without metabolic activation
- Negative solvent / vehicle controls:
- yes
- Remarks:
- DMSO/Ethanol (1/1)
- Positive controls:
- yes
- Positive control substance:
- cyclophosphamide
- Remarks:
- test with metabolic activation
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: in medium
DURATION
- Exposure duration: exp 1 3 hours without metabolic activation, exp 2 20 hours without metabolic activaton, exp3 3 hours with metabolic activation
- Expression time: until 20 hours
SPINDLE INHIBITOR: Colcemid (0.1 µg/mL) 2 hours before harvesting
FIXATIVE: 3:1 methanol:glacial acetic acid
NUMBER OF REPLICATIONS: 2
NUMBER OF CELLS EVALUATED: 100 metaphases per replicate (+ 15 aberrant cells per replicate)
DETERMINATION OF CYTOTOXICITY
- Method: relative population doubling (with Coulter counter) + mitotic index (1000 cells)+ visible signs of cytotoxicity
OTHER EXAMINATIONS:
- Determination of polyploidy: 200 cells/replicate
- Determination of endoreplication: 200 cells/replicate - Evaluation criteria:
- POSITIVE RESPONSE:
The test item would be considered positive for inducing chromosomal aberrations if a significant increase (p ≤0.01) in the mean percent of cells with chromosomal aberrations is observed at one or more dose levels, or if a significant increase (p ≤0.05) in the mean percent of cells with chromosomal aberrations is observed at two or more dose levels. If a significant increase is seen at one or more dose levels, a dose-response should be observed.
NEGATIVE RESPONSE
The test item would be considered negative for inducing chromosomal aberrations if no statistically significant increase (p ≤0.05) is observed in the mean percent of cells with chromosomal aberrations at any of the test concentrations. - Statistics:
- One-tailed Fisher’s Exact test on cell numbers with aberrations
A response would be considered statistically significant for dose-response trend in the Cochran-Armitage test if p ≤0.05. - Species / strain:
- Chinese hamster Ovary (CHO)
- Metabolic activation:
- without
- Genotoxicity:
- ambiguous
- Remarks:
- no dose response
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- at 150 ug/mL and above
- Vehicle controls validity:
- other: within historical control ranges
- Positive controls validity:
- other: MMC (0.75 ug/mL) within historica control values
- Species / strain:
- Chinese hamster Ovary (CHO)
- Metabolic activation:
- without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- at 225 ug/mL and above; precipitate at 125 ug/mL and above
- Vehicle controls validity:
- other: outside historical control ranges
- Positive controls validity:
- other: MMC (0.10 ug/mL) within historical control ranges
- Species / strain:
- Chinese hamster Ovary (CHO)
- Metabolic activation:
- with
- Genotoxicity:
- positive
- Remarks:
- dose response
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- at 75 ug/mL and above
- Vehicle controls validity:
- other: at the upper range of historical control values
- Positive controls validity:
- other: CP (0.75 ug/mL) at the lower range of historical control values
- Additional information on results:
- TEST-SPECIFIC CONFOUNDING FACTORS
- Effects of pH: not reported
- Effects of osmolality: not reported
- Precipitation: see above
RANGE-FINDING/SCREENING STUDIES: performed, but only cytotoxicity part reported
COMPARISON WITH HISTORICAL CONTROL DATA: see above - Remarks on result:
- other: other: 3 hours exposure
- Remarks:
- Migrated from field 'Test system'.
- Conclusions:
- Interpretation of results (migrated information):
ambiguous
The substance was considered positive for inducing structural aberrations in CHO-WBL cells with metabolic activation and equivocal for inducing structural aberrations in CHO-WBL cells in the short-treatment without metabolic activation under the conditions of this test system. A significant test item-related increase in numerical aberrations (endoreduplication) was observed in the short-treatment without metabolic activation - Executive summary:
In a chromosome aberration test in CHO-WBL cells, structural (with metabolic activation) and numerical (without metabolic activation) aberrations were reported after 3-hour treament at concentrations upto cytotoxicity. Prolonged testing without metabolic activation did not induce any effects. Therefore it cannot be excluded that the substance exhibits clastogenic effects.
Reference
Exp 1Cell Count Reduction and Aberration Summary: 3-Hour Incubation without Metabolic Activation
Treatment
|
% Mitotic Reduction |
% Cytotoxicity RPD |
% Cells w/Abs |
% Cells w/>1 Abs |
% Endo Cells |
% Polyploid Cells |
Vehicle (1%) |
0.00 |
0.00 |
0.0 |
0.0 |
0.0 |
4.8 |
MMC 0.75 µg/mL |
35.39 |
10.69 |
66.7* |
46.7* |
0.0 |
4.5 |
37.5 µg/mL |
0.00 |
0.33 |
2.5** |
0.0 |
0.0 |
2.8 |
75.0 µg/mL |
0.00 |
0.67 |
2.5** |
0.0 |
0.3 |
3.3 |
150 µg/mLa
|
0.00 |
7.17 |
2.5** |
0.0 |
15.0* |
3.3 |
Exp 2 Cell Count Reduction and Aberration Summary: 20-Hour Incubation without Metabolic Activation
Treatment
|
% Cytotoxicity RPD |
% Cells w/Abs |
% Cells w/>1 Abs |
% Endo Cells |
% Polyploid Cells |
Vehicle (1%) |
0.00 |
4.0 |
0.0 |
0.0 |
5.0 |
MMC 0.10 µg/mL |
15.21 |
50.8* |
27.1* |
0.0 |
4.8 |
75.0 µg/mL |
13.14 |
1.0 |
0.0 |
0.0 |
5.3 |
100 µg/mL |
23.02 |
2.0 |
0.0 |
0.0 |
6.5 |
125µg/mLa
|
33.15 |
3.5 |
0.0 |
0.0 |
3.3 |
Exp 3 Cell Count Reduction and Aberration Summary: 3-Hour Incubation with Metabolic Activation
Treatment
|
% Cytotoxicity RPD |
% Cells w/Abs |
% Cells w/>1 Abs |
% Endo Cells |
% Polyploid Cells |
Vehicle (1%) |
0.00 |
2.0 |
0.0 |
8.5 |
4.8 |
CP 7.5 µg/mL |
19.40 |
15.5* |
3.5* |
5.3 |
4.3 |
12.5 µg/mL |
6.71 |
1.5 |
0.0 |
9.8 |
4.5 |
25.0 µg/mL |
30.33 |
6.0** |
1.0 |
9.8 |
5.0 |
75.0 µg/mLa
|
54.04 |
12.5* |
3.0** |
9.0 |
3.0 |
Endo -Endoreduplicated cells
Abs -Aberrations
MMC -Mitomycin C
CP -CycloPhosphamide
RPD- Relative Population Doubling
Vehicle- 50% Dimethylsulfoxide 50% Ethanol
Percent Aberrant cells: *p=0.01, **p=0.05 using Fisher's Exact Test
aPrecipitates observed at the end of treatment
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed (positive)
Genetic toxicity in vivo
Description of key information
In a study according to OECD 474 5 male mice/groupwere dosed twice via oral gavage with vehicle (corn oil), the substance at 2000, 1000 and 500 mg /kg bw or with 40 mg/kg cyclophosphamide (dosed only once). One animal dosed at 1000 mg/kg bw died and one at 500 mg/kg bw showed lethargy and a rough coat after the second dosing but recovered within 23 hours. No treatment related clinical signs or mortality were noted in the other animals. Blood samples collected at 0.5, 1, 2, 4, 6 and 8 hours after dosing from three satellite animals (dosed at 2000 mg/kg bw) per time point treated with 2000 mg showed concentrations of the substance above the upper limit of quantification (> 10000 ng/L), which confirms exposure.
Bone marrow was sampled 48 hours after the first dosing. No biological relevant increase in the mean frequency of micronucleated polychromatic erythrocytes was observed in the bone marrow of animals treated with the substance compared to the vehicle treated animals. No toxicity on erythropoiesis of the substance was observed (expressed as the ratio of polychromatic to normochromatic erythrocytes).
The substance is not clastogenic in the bone marrow micronucleus test of mice up to a dose of 2000 mg/kg.
Link to relevant study records
- Endpoint:
- in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 24 April 2015 to 28 September 2015
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- This testing was performed for the purpose of chemical notification in China. Therefore no testing proposal was included.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
- Version / remarks:
- 2014
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.12 (Mutagenicity - In Vivo Mammalian Erythrocyte Micronucleus Test)
- GLP compliance:
- yes
- Type of assay:
- other: in vivo micronucleus teste
- Species:
- mouse
- Strain:
- NMRI
- Details on species / strain selection:
- recommended by international guidelines
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River, Sulzfeld, Germany
- Age at study initiation: 7 weeks
- Weight at study initiation: 31-40 g
- Assigned to test groups randomly: yes
- Fasting period: withheld 3 - 4 hours prior to dosing until 3 - 4 hours after administration
- Housing:
- Diet: pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH,
Soest, Germany) ad libitum)
- Water : tap water ad libitum
- Acclimation period: at least 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.5 - 22.6°C
- Humidity (%): 38-73%
- Air changes (per hr): ca 10/h
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: gavage
- Vehicle:
- - Vehicle(s)/solvent(s) used: corn oil
- Justification for choice of solvent/vehicle: solubility/stability of the substance
- Amount of vehicle (if gavage or dermal): 10 mL - Details on exposure:
- dosing solutions prepared on day of treatment (doses based on the outcome of a pre-test in 3 males and 3 females at 2000 mg/kg bw)
- Duration of treatment / exposure:
- 2 days
- Frequency of treatment:
- once at 0 and 24 h
- Post exposure period:
- 24 hour after last dose
- Dose / conc.:
- 500 mg/kg bw/day
- Dose / conc.:
- 1 000 mg/kg bw/day
- Dose / conc.:
- 2 000 mg/kg bw/day
- No. of animals per sex per dose:
- 5 males/ dose + additional 18 animals at 2000 mg/kg for blood sampling at 0.5, 1, 2, 4, 6 and 8 hours after the second dosing
- Control animals:
- yes, concurrent vehicle
- Positive control(s):
- cyclophosphamide;
- Justification for choice of positive control(s): according to the guideline
- Route of administration: oral gavage
- Doses / concentrations: 40 mg/kg bw - Tissues and cell types examined:
- bone marrow for normo- and poly-chromated erithocytes
- Details of tissue and slide preparation:
- Bone marrow was sampled 48 hours after the first dosing from both femurs, flushed withetal calf serum and the cell suspension was centrifuged at 216 g for 5 min. Smears were prepared after removal of the supernatant (one drop left behind) and suspended on a clean slide that was coloured by Giemsa based staining (Wright-stain-procedure)
- Evaluation criteria:
- A test substance is considered positive in the micronucleus test if:
It induces a biologically as well as a statistically significant (Dunnett’s test, one-sided, p < 0.05)
increase in the frequency of micronucleated polychromatic erythrocytes and the number of
micronucleated polychromatic erythrocytes in the animals should be above the historical control
data range.
A test substance is considered negative in the micronucleus test if:
None of the tested concentrations show a statistically significant (Dunnett’s test, one-sided,
p < 0.05) increase in the incidence of micronucleated polychromatic erythrocytes and the number
of micronucleated polychromatic erythrocytes in the animals should be within the historical control
data range. - Statistics:
- ToxRat Professional version 3.0
- Key result
- Sex:
- male
- Genotoxicity:
- negative
- Toxicity:
- no effects
- Vehicle controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- One animal dosed with 1000 mg/kg test substance died immediately after the second dosing due to a technical error while dosing and one animal dosed with 500 mg/kg showed lethargy and a rough coat after the second dosing but recovered within 23 hours after second dosing. No treatment-related clinical signs or mortality were noted in the other animals.
Analyzed blood concentrations of the substance (from the 2000 mg/kg bw additional mice) were above the upper limit of quantification as validated in the analytical method (> 10000 ng/L). - Conclusions:
- The substance is not clastogenic in the bone marrow micronucleus test of mice up to a dose of 2000 mg/kg
- Executive summary:
In a study according to OECD 474 5 male mice/groupwere dosed twice via oral gavage with vehicle (corn oil), the substance at 2000, 1000 and 500 mg /kg bw or with 40 mg/kg cyclophosphamide (dosed only once). One animal dosed at 1000 mg/kg bw died and one at 500 mg/kg bw showed lethargy and a rough coat after the second dosing but recovered within 23 hours. No treatment related clinical signs or mortality were noted in the other animals. Blood samples collected at 0.5, 1, 2, 4, 6 and 8 hours after dosing from three satellite animals (dosed at 2000 mg/kg bw) per time point treated with 2000 mg showed concentrations of the substance above the upper limit of quantification (> 10000 ng/L), which confirms exposure.
Bone marrow was sampled 48 hours after the first dosing. No biological relevant increase in the mean frequency of micronucleated polychromatic erythrocytes was observed in the bone marrow of animals treated with the substance compared to the vehicle treated animals. No toxicity on erythropoiesis of the substance was observed (expressed as the ratio of polychromatic to normochromatic erythrocytes).
The substance is not clastogenic in the bone marrow micronucleus test of mice up to a dose of 2000 mg/kg.
Reference
GroupTreatment |
Dose (mg/kg bw |
Number of micronucleatedpolychromatic erythrocytes (mean ± S.D.)(1,2 |
Ratio polychromatic/ normochromatic erythrocytes (mean ± S.D.)(1,2 |
|
Vehicle control |
0 |
3.6 ±0.9 |
0.95 ±0.07 |
|
Test substance |
2000 |
4.0 ±1.0 |
0.90 ±0.08 |
|
Test substance |
1000 |
4.5 ±1.7 |
0.94 ±0.05 |
|
Test substance |
500 |
3.4 ±1.1 |
0.91 ±0.06 |
|
CP |
40 |
38.2 ± 6.8(4) |
0.54 ±0.12 |
|
Vehicle control = Corn oil
CP = Cyclophosphamide.
(1) Four to five animals per treatment group.
(2) At least 4000 polychromatic erythrocytes were evaluated with a maximum deviation of 5%.
(3) The ratio was determined from at least the first 1000 erythrocytes counted.
(4) Significantly different from corresponding control group (Studentsttest, P = 0.01).
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (negative)
Additional information
The potential clastogenic effects seen in the in vitro chromosome aberration test were further investigated in an in vivo micronucleus test, where blood test substance concentrations (above the upper limit of quantification as validated in the analytical method (> 10000 ng/L)) were confirmed. No increase of the frequency of micronucleated polychromatic erythrocytes was reported at any of the doses tested.
Therefore it can be concluded that the substance is not clastogenic and does not need to be classified.
Justification for classification or non-classification
The available in vitro data together with the in vivo micronucleus test are not indicative for mutagenic or clastogenic effects of the substance and therefore the criteria for classification according to Regulation (EC) 1272/2008 are not met.
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