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EC number: 224-169-7 | CAS number: 4223-03-4
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
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- Density
- Particle size distribution (Granulometry)
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- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
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- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
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- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
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- Endpoint summary
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- Environmental data
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- 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 1998-04-11 to 1998-08-05
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Guideline-conform study performed under GLP
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 998
- Report date:
- 1998
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
- Deviations:
- no
- GLP compliance:
- yes
- Type of assay:
- micronucleus assay
Test material
- Reference substance name:
- N-(1,1,3,3-tetramethylbutyl)acrylamide
- EC Number:
- 224-169-7
- EC Name:
- N-(1,1,3,3-tetramethylbutyl)acrylamide
- Cas Number:
- 4223-03-4
- Molecular formula:
- C11H21NO
- IUPAC Name:
- N-(1,1,3,3-tetramethylbutyl)acrylamide
- Details on test material:
- - Name of test material (as cited in study report): N-tert-Octylacrylamide (937-64)
- Physical state: off-white, fluffy crystalline solid
- Analytical purity: not reported
- Impurities (identity and concentrations): not reported
- Purity test date: not reported
- Lot/batch No.: not reported
- Expiration date of the lot/batch: not reported
- Date received: 13 March 1998
Constituent 1
Test animals
- Species:
- mouse
- Strain:
- other: Crl:CD-1 (ICR) BR
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Raleigh, North Carolina
- Age at study initiation: approximately 8 weeks (dose range finding 1 and micronucleus assay), approximately 9 weeks (dose range finding 2),
- Weight at study initiation: 28.8 - 35.8 g (males, dose range finding 1), 21.6 - 25.0 g (females, dose range finding 1), 34.1-35.5 g (males, dose range finding 2), 22.8 - 27.8 g (females, dose range finding 2), 31.4 - 38.4 g (micronucleus assay)
- Assigned to test groups randomly: yes
- Fasting period before study: no
- Housing: in groups of up to 5 animals in sanitary polycarbonate cages containing bedding
- Diet (e.g. ad libitum): PMI Feeds, Inc., Certified Rodent Diet # 5002 ad libitum
- Water (e.g. ad libitum): tap water ad liblitum
- Acclimation period: at least 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.8 - 26.1
- Humidity (%): 30-70
- Air changes (per hr): >=10
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From 1998-03-24 to 1998-04-11
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- - Vehicle(s)/solvent(s) used: corn oil
- Justification for choice of solvent/vehicle: not reported
- Concentration of test material in vehicle: 20, 50, 80, 150, 200 mg/mL
- Amount of vehicle (if gavage or dermal): 10 mL/kg - Details on exposure:
- PREPARATION OF DOSING SOLUTIONS (micronucleus assay): Prior to dosing, the top stock solution of the test article was prepared by adding the appropriate volume of the vehicle, corn oil , to a preweighed quantity of the test article. The stock was mixed by stirring with a spatula for about 7 minutes, homogenising for about 3 minutes, and stirring on a plate for about 2 minutes. The remaining stocks were prepared by dilution from the top stock. The stocks were cloudy, slightly viscous, light yellow oil suspensions with small evenly distributed particles. All dosing stocks were continuously mixed on a plate during the dosing procedure and protected from light during preparation and dosing.
- Duration of treatment / exposure:
- single oral dose
- Frequency of treatment:
- single oral dose
- Post exposure period:
- 175 mg/kg: 24 hour treatment
350 mg/kg: 24 hour treatment
700 mg/kg: 24 and 48 hour treatment
Vehicle control: 24 and 48 hour treatment
Positive control: 24 hour treatment
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
dose range finding 1: 200, 500, 800, 1500, 2000 mg/kg
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
dose range finding 2: 600, 700 mg/kg
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
micronucleus assay, 24 h preparation interval: 173, 350, 700 mg/kg
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
micronucleus assay, 48 h preparation interval: 700 mg/kg
Basis:
actual ingested
- No. of animals per sex per dose:
- dose range finding 1: 3 males and 3 females per dose
dose range finding 2: 3 males and 3 females per dose (One female of the 2000 mg/kg group not dosed due to breakage of the dosing stock bottle)
micronucleus assay: 6 males per dose and harves timepoint - Control animals:
- yes, concurrent vehicle
- Positive control(s):
- cyclophosphamide
- Justification for choice of positive control(s): not reported, but substance proposed in OECD TG 474
- Route of administration: oral gavage
- Doses / concentrations: 80 mg/kg
Examinations
- Tissues and cell types examined:
- - clinical signs: examination for toxic signs and mortalities at least daily
- bone marrow cells: sampling at 24 or 48 hours after treatment - Details of tissue and slide preparation:
- CRITERIA FOR DOSE SELECTION:
Based on the results of both dose range finding studies (some mortality at the 700 mg/kg dose level and high mortality at the 800 mg/kg dose level), the maximum tolerated dose was estimated to be 700 mg/kg. Based on these results, dose levels of 175, 350 and 700 mg/kg were selected for testing in this study. Since there were no differences in toxicity observed between the sexes, only male mice were used for the micronucleus study.
DETAILS OF SLIDE PREPARATION:
At the appropriate harvest timepoints, the animals were euthanized by CO2 inhalation followed by incision of the diaphragm. The hind limb bones (tibias or femurs) were removed from the first 5 surviving animals for marrow extraction. The marrow was flushed from the bone and transferred to centrifuge tubes containing 3-5 mL fetal bovine serum (one tube per animal). Animals in excess of the first 5 survivors were euthanized but no marrow was extracted. Following centrifugation to pellet the tissue, the supernatant was removed by aspiration and portions of the pellet were spread on slides and air dried. The slides were fixed in methanol, stained in May-Grünwald Solution followed by Giemsa, and protected by mounting with coverslips. For control of bias, all slides were coded prior to analysis.
METHOD OF ANALYSIS:
The micronucleus frequency (expressed as percent micronucIeated cells) was determined by analyzing the number of micronucleated PCEs from at least 2000 PCEs per animal. The frequency of PCE:NCE ratio was determined by scoring the number of PCEs and NCEs observed in the optic fields while scoring at least the first 200 erythrocytes on the slide. Micronuclei were darkly stained and generally round, although almond and ringshaped micronuclei occasionally occurred. Micronuclei had sharp borders and were generally between 1120 and 115 the size of the PCEs. The unit of scoring was the micronucleated cell, not the micronucleus; thus, the occasional cell with more than 1 micronucleus was counted as 1 micronucleated PCE, not 2 (or more) micronuclei . - Evaluation criteria:
- The criteria for a positive response was the detection of a statistically significant positive response for at least 1 dose level and a statistically significant dose related response. A test article that did not induce both of these responses was considered negative. Statistical significance was not the only determinant of a positive response, the study director also considered the biological relevance of the results in the final evaluation.
- Statistics:
- Assay data analysis was performed using an analysis of variance (Winer, 1971) on untransformed proportions of cells with micronuclei per animal and on untransformed PCE:NCE ratios when the variances were homogeneous. Ranked proportions were used for heterogeneous variances. If the analysis of variance was statistically significant (p < 0.05), a Dunnett's t-test was used to determine which dose groups, if any, were statistically significantly different from the vehicle control. Analyses were performed separately for each sampling time. Additionally, parametric or nonparametric tests for trend may have been employed to identify any dose-related response.
Results and discussion
Test results
- Sex:
- male
- Genotoxicity:
- negative
- Toxicity:
- yes
- Remarks:
- signs of clinical toxicity in animals treated with 350 and 700 mg/kg and cytotoxic to the bone marrow (i.e., a statistically significant decrease in the PCE:NCE ratio) at 700 mg/kg, at the 48 hour harvest timepoint
- Vehicle controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- RESULTS OF RANGE-FINDING STUDY
- Dose range: 200 - 2000 mg/kg
- Solubility: small evenly distributed particles observed in suspension
- Clinical signs of toxicity in test animals: See table in "Any other information on results incl. tables"
- Evidence of cytotoxicity in tissue analyzed: No tissue analyzed
- Rationale for exposure: not reported
- Gender specific differences in toxicity: no
RESULTS OF DEFINITIVE STUDY
- Induction of micronuclei (for Micronucleus assay): N-tert-Octylacrylamide induced no statistically significant increases in micronucleated polychrornatic erythrocytes over the levels observed in the vehicle controls at any of the harvest timepoints.
- Ratio of PCE/NCE (for Micronucleus assay): cytotoxic to the bone marrow (i.e., a statistically significant decrease in the PCE:NCE ratio) at 700 mg/kg, at the 48 hour harvest timepoint
- Appropriateness of dose levels and route: signs of clinical toxicity observed, cytotociy to the bone marrow at 700 mg/kg at 48 harvest timepoint
Any other information on results incl. tables
Table 1: Toxicity observed in dose range finding test
Target Dose Level (mg/kg) |
Sex |
Time after dosing |
|||
IPD |
1 h PD |
1 day |
2 days |
||
200 |
M |
1, 2 |
0 |
0 |
14 |
1, 2 |
5 |
2, 13, 14 |
2, 13, 14 |
||
1, 2 |
5 |
2, 13, 14 |
2, 13, 14 |
||
F |
1, 2, 3 |
1 |
0 |
0 |
|
1, 2 |
1 |
0 |
0 |
||
1, 2 |
1 |
0 |
0 |
||
500 |
M |
1, 2, 5 |
2, 3, 4, 5, 7 |
2, 13, 14 |
2, 13, 14 |
1, 2, 5 |
3, 4, 5, 7 |
2, 13, 14 |
2, 13, 14 |
||
1, 2, 5 |
2, 4, 5 |
2, 13, 14 |
2, 13, 14 |
||
F |
2, 4 |
3, 7, 9 |
0 |
0 |
|
4, 5, 6 |
7, 9 |
4, 5, 8 |
0 |
||
1, 2 |
2, 4, 5, 7 |
2, 3, 4 |
0 |
||
600 |
M |
4, 15 |
3, 9 |
2, 14 |
0 |
4 |
3, 4, 15 |
2, 14 |
0 |
||
4 |
3, 4, 15 |
2, 14 |
0 |
||
F |
15 |
3, 9, 16 |
3, 4, 6, 14, 15 |
0 |
|
15 |
3, 9, 16 |
14 |
0 |
||
15 |
3, 4, 7, 15 |
14 |
0 |
||
700 |
M |
15 |
3, 4, 15 |
14, 17 |
0 |
15 |
3, 9 |
14 |
0 |
||
15 |
3, 6 |
2, 13, 14 |
0 |
||
F |
15 |
3, 4, 15 |
14 |
0 |
|
15 |
3, 9 |
4, 7, 14, 15 |
0 |
||
0 |
3, 7, 9 |
11 |
- |
||
800 |
M |
4, 5, 7, 8 |
3, 7, 8, 9 |
0 |
- |
4, 5, 7, 8 |
3, 7, 8, 9 |
4, 5, 8 |
- |
||
1, 2, 5, 7 |
2, 4, 5, 7, 8 |
2, 3, 4 |
14 |
||
F |
4, 5, 6 |
3, 7, 8, 9 |
11 |
13, 14 |
|
3, 4, 5 |
7, 8, 9 |
11 |
- |
||
2, 5, 8 |
7, 9 |
2, 3, 4, 5, 13, 14 |
13, 14 |
||
1500 |
M |
4, 5, 6, 7, 8 |
7, 9, 10 |
11 |
- |
4, 5, 7, 8 |
7, 9, 10 |
11 |
- |
||
4, 5 |
7, 9, 10 |
11 |
- |
||
F |
3, 6, 7, 9, 10 |
7, 9, 10 |
3, 6, 7, 9, 10 |
4, 5, 6, 8 |
|
3, 6, 7, 9, 10 |
6, 7, 9, 12 |
11 |
- |
||
3, 6, 7, 9, 10 |
7, 9, 10 |
11 |
- |
||
2000 |
M |
1, 5 |
1 |
1, 2, 13, 14 |
13, 14 |
4, 5, 8 |
8, 9 |
2, 4, 13, 14 |
2, 13, 14 |
||
7, 9, 10 |
11 |
- |
- |
||
F |
11 |
- |
- |
- |
|
|
7, 9, 10 |
11 |
- |
- |
|
|
|
|
|
|
|
Key: 0=Normal, 1=slightly hypoactive, 2=hunchedposture, 3=squintedeyes, 4=hypoactivem, 5=ataxic, 6=cold to touch, 7= tremors, 8=polypnea, 9=prostrate, 10=dyspnea, 11=found dead, 12=gasping, 13=rough haircoat, 14=distended abdomen, 15=ataxic, 16=convulsions, 17=fecal stains
IPD=immediately post dosing last animal,PD=post dosing last animal
Table 2: Toxicity observed in micronucleus assay
Target Dose Level (mg/kg) |
Harvest time point |
Time after dosing |
|||
IPD |
1 h PD |
1 day |
2 days |
||
350 |
24 |
1 |
0 |
0 |
- |
1 |
0 |
0 |
- |
||
1 |
0 |
0 |
- |
||
1 |
0 |
0 |
- |
||
1 |
5, 7 |
0 |
- |
||
1 |
0 |
0 |
- |
||
500 600 |
24 |
2 |
2, 3, 7 |
0 |
- |
2 |
2, 3, 7 |
0 |
- |
||
2 |
2 |
0 |
- |
||
2 |
2, 3, 6, 7 |
0 |
- |
||
2 |
2, 3, 7 |
0 |
- |
||
2 |
2, 3, 7 |
0 |
- |
||
48 |
2 |
2, 6, 7, 8 |
0 |
0 |
|
2 |
2, 3 |
0 |
0 |
||
3 |
2, 3 |
0 |
0 |
||
3 |
6, 9 |
0 |
0 |
||
2 |
2, 3 |
0 |
0 |
||
2 |
2, 3 |
0 |
0 |
||
Secondary |
2 |
1 |
0 |
0 |
|
3 |
9, 10 |
0 |
0 |
||
2 |
2, 3 |
0 |
0 |
||
3 |
2, 3 |
0 |
0 |
||
2 |
2, 3, 10 |
0 |
0 |
||
2 |
3, 7 |
0 |
0 |
Key:0=, 1=slightly hypoactive, 2=hypoactive, 3=ataxic,5=urinestains,6=squintedeyes,7=hunched posture, 8=polypnea, 9=prostrate, 10=tremors
IPD=immediately post dosing last animal, PD=post dosing last animal
Micronucleus data
Treatment |
Dose |
Harvest time |
% micronucleated PCEs mean of 2000 per animal ± SE Males |
Ratio PCE:NCE Mean ± SE Males |
Vehicle control |
Corn oil |
24 h |
0.05 ± 0.03 |
0.42 ± 0.02 |
Vehicle control |
Corn oil |
48 h |
0.02 ± 0.02 |
0.48 ± 0.06 |
Positive control |
Cyclophpsphamide 80 mg/kg |
24 h |
3.78 ± 0.15 * |
0.41 ±0.05 |
Test article |
175 mg/kg |
24 h |
0.00 ± 0.00 |
0.30 ± 0.02 |
Test article |
350 mg/kg |
24 h |
0.03 ± 0.02 |
0.34 ± 0.04 |
Test article |
700 mg/kg |
24 h |
0.05 ± 0.02 |
0.36 ± 0.06 |
Test article |
700 mg/kg |
48 h |
0.06 ± 0.01 |
0.31 ± 0.04 ** |
* Significantly greater than the corresponding vehicle control, p<0.01
** Significantly less than the corresponding vehicle control, p<= 0.05
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information): negative
The test article, N-tert-Octylacrylamide, induced signs of clinical toxicity in the treated animals and was cytotoxic to the bone marrow (i.e., a statistically significant decrease in the PCE:NCE ratio) at 700 mg/kg, at the 48 hour harvest timepoint. N-tert-Octylacrylamide did not induce a statistically significant increase in micronuclei in bone marrow polychromatic erythrocytes and is considered negative in the mouse bone marrow micronucleus test under the conditions of exposure in this assay. - Executive summary:
The objective of this study was to evaluate the test article, N-tert-Octylacrylamide, for in vivo clastogenic activity and/or disruption of the mitotic apparatus by detecting micronuclei in polychromatic erythrocyte cells in Crl:CD-1 (ICR) BR mouse bone marrow. The study was conducted according to the principles of GLP and according to the methods outlined in OECD TG 474.
In the initial dose range finding study, the test article was suspended in corn oil and dosed by oral gavage to 3 males and 3 females per dose level. The animals were dosed at 200, 500, 800, 1500 and 2000 mg/kg (only 2 females were dosed at 2000 mg/kg) and observed for 2 days after dosing for toxic signs and/or mortality. In the second dose range finding study, the test article was suspended in corn oil and dosed by oral gavage to 3 males and 3 females per dose level. The animals were dosed at 600 and
700 mg/kg and observed for 2 days after dosing for toxic signs and/or mortality. Based on the results of the dose range finding studies, the maximum tolerated dose was estimated to be 700 mg/kg. Since there were no differences in toxicity observed between the sexes, only male mice were used for the micronucleus study. In the micronucleus assay, the test article was suspended in corn oil and dosed by oral gavage to 6 males per dose level and harvest timepoint. The animals were dosed at 175, 350 and 700 mg/kg. The first 5 surviving animals dosed at the 175 and 350 mg/kg dose levels and with the positive control were euthanised approximately 24 hours after dosing for extraction of the bone marrow . The first 5 surviving animals dosed at the 700 mg/kg dose level and with the vehicle control were euthanised approximately 24 and 48 hours after dosing for extraction of the bone marrow.
The test article, N-tert-Octylacrylamide, induced signs of clinical toxicity in the treated animals and was cytotoxic to the bone marrow (i.e., a statistically significant decrease in the PCE:NCE ratio) at 700 mg/kg, at the 48 hour harvest timepoint. N-tert-Octylacrylarnide did not induce a statistically significant increase in micronuclei in bone marrow polychrornatic erythrocytes and is considered negative in the mouse bone marrow micronucleus test under the conditions of exposure in this assay.
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