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EC number: 948-260-2 | 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
Skin sensitisation
Administrative data
- Endpoint:
- skin sensitisation: in vivo (LLNA)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- Aug 2018
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 019
- Report date:
- 2019
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)
- Version / remarks:
- 22 July 2010
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- Landesamt für Umwelt Rheinland Pfalz
- Type of study:
- mouse local lymph node assay (LLNA)
Test material
- Reference substance name:
- Reaction mass of (4Z,8E)-dodeca-4,8,11-trienal and (4E,8Z)-dodeca-4,8,11-trienal
- EC Number:
- 701-295-5
- Molecular formula:
- C12 H18 O
- IUPAC Name:
- Reaction mass of (4Z,8E)-dodeca-4,8,11-trienal and (4E,8Z)-dodeca-4,8,11-trienal
Constituent 1
- Specific details on test material used for the study:
- Test material is the main constituent of the registered substance.
In vivo test system
Test animals
- Species:
- mouse
- Strain:
- CBA
- Remarks:
- CBA/CaOlaHsd/SPF
- Sex:
- female
- Details on test animals and environmental conditions:
- TEST ANIMALS
- Source: Envigo RMS GmbH, C/O Postfach 553, NL-5800 AN Venray
- Females nulliparous and non-pregnant: Not specified
- Age at study initiation: 8 - 12 weeks
- Microbiological status of animals, when known: SPF
- Weight at study initiation: 17.5g – 22.3g (pretest); 18.4g – 22.8g (main test)
- Housing: Single housed
- Diet (e.g. ad libitum): Kliba mouse/rat maintenance diet “GLP” supplied by Provimi Kliba SA (new name Granovit AG), Kaiseraugst, Basel,
Switzerland, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: At least 5 d befor 1st test substance application
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24°C
- Humidity (%): 45 - 65%
- Photoperiod (hrs dark / hrs light): 12 hours light from 06:00 h to 18:00 h; 12 hours darkness from 18:00 h to 06:00 h
Study design: in vivo (LLNA)
- Vehicle:
- other: ethanol
- Remarks:
- Ethanol was used as the vehicle because good solubility of the preparation was achieved. Ethanol is the preferred vehicle for application of the test substance.
- Concentration:
- 2.5%, 10%, 25% (w/w)
- No. of animals per dose:
- 5
- Details on study design:
- PRE-SCREEN TESTS:
- Compound solubility: A solubility experiment was performed according to the recommendations given by OECD 429
- Irritation: A pretest (experimental conduct in accordance with GLP, but without a GLP status) was performed.; two mice were treated with test-substance (conc. 1% and 10%; each on 3 consecutive days); Signs of
local irritation were assessed on day 1, 2 and 5
- Systemic toxicity: A pretest (experimental conduct in accordance with GLP, but without a GLP status) was performed.; two mice were treated with test-substance (conc. 1% and 10%; each on 3 consecutive days); clinical signs were assessed after 1, 2, 5d
- Ear thickness measurements: Prior to the first application; ear thickness was determined using a micrometer after 0, 2, 5d
MAIN STUDY
ANIMAL ASSIGNMENT AND TREATMENT
- Name of test method:
Randomization
- Criteria used to consider a positive response:
incorporation of 3H-thymidine at least 3-fold or greater than that determined in control mice as indicated by the stimulation index (SI ≥ 3.0)
thresholds used for assessment of cell counts and ear weights are represented by stimulation indices (SI) of ≥ 1.5 and ≥ 1.25, respectively
TREATMENT PREPARATION AND ADMINISTRATION:
- 4 test groups (0%, 2.5%, 10% and 25% (w/w)); 5 mice per group
- Form of application: Epicutaneous application is simulating dermal contact with the compound, which can occur under practical use conditions.
- Application volume: 25 μL per ear
- Site of application: Dorsal surface of both ears
- Frequency of application: 3 consecutive applications (day 0 – day 2) to the same application site
- On study day five (about 66 to 72 hours after the last application of test substance to the ears), 20 μCi 3H-thymidine* in 250 μL sterile saline were injected into the tail vein of the mice.
- The animals were sacrificed on study day 5 about 5 hours after 3H-thymidine injection by cervical dislocation under Isoflurane anesthesia.
- Afterwards: Determination of ear weight, Removal and weight determination of the lymph nodes, Preparation of cell suspension and determination of cell count, Measurement of 3H-thymidine incorporation of the lymph node cells - Positive control substance(s):
- other: Alpha-Hexylcinnamaldehyde, techn. 85%
- Statistics:
- Mean values and standard deviations of the measured parameters were calculated per test
group from the individual values. The stimulation indices of 3H-thymidine incorporation, cell
count, lymph node weight and ear weight measurements were calculated by dividing the mean
values per test group and/or single animal values by the mean of the vehicle treated group.
Results for the parameter 3H-thymidine incorporation, cell count, lymph node weight and ear weight were statistically evaluated with the WILCOXON-test.
Results and discussion
- Positive control results:
- A concurrent positive control (reliability check) with a known sensitizer was not included in this study
In vivo (LLNA)
Resultsopen allclose all
- Parameter:
- EC3
- Value:
- 13.6
- Parameter:
- SI
- Remarks:
- 3H- thymidine incorporation stimulation index
- Value:
- 4.9
- Test group / Remarks:
- 25%
- Remarks on result:
- other: significant result compared to the mean of the vehicle control; biologically relevant result
- Cellular proliferation data / Observations:
- CELLULAR PROLIFERATION DATA
- The concentration of 25% has to be considered to indicate a skin sensitization potential because of lymph node responses clearly exceeding the respective cutoff values in the absence of sufficiently strong ear skin irritation
DETAILS ON STIMULATION INDEX CALCULATION
- Mean values and standard deviations of the measured parameters were calculated per test
group from the individual values. The stimulation indices of 3H-thymidine incorporation, cell
count, lymph node weight and ear weight measurements were calculated by dividing the mean
values per test group and/or single animal values by the mean of the vehicle treated group
EC3 CALCULATION :
-If applicable, the EC leading to the respective SI values were calculated by linear or semi-logarithmical regression between the data points directly below
and above the SI if possible or by using the two nearest points below or above the SI
CLINICAL OBSERVATIONS:
Pretest:
- No signs of systemic toxicity were observed
- The animals did not show any signs of local irritation
- Moderately increased lymph node weights (10% concentration)
Main test:
- No signs of systemic toxicity in all animals
- Biologically relevant and statistically significant response in the auricular lymph node cell counts (25% concentration)
- Statistically significant increases in lymph node weights (25% and 10% concentration)
- Moderate scaling of the ear skin was observed in all animals and slight incrustation in one animal at the 25% concentration on study day 5 (post-mortem observation)
BODY WEIGHTS:
- No influence on the mean body weight in the study
Any other information on results incl. tables
Tab. 2: Stimulation indices
Test Group |
Treatment |
³H-thymidine incorporation Stimulation Index1 |
Cell Count Stimulation Index1 |
Lymph Node Weight Stimulation Index1 |
Ear Weight Stimulation Index1 |
||||
1 |
vehicle ethanol |
1.00 |
|
1.00 |
|
1.00 |
|
1.00 |
|
2 |
2.5% in ethanol |
1.26 |
|
1.10 |
|
1.06 |
|
1.02 |
|
3 |
10% in ethanol |
2.41 |
## |
1.50 |
# |
1.47 |
## |
1.03 |
|
4 |
25% in ethanol |
4.90 |
## |
2.31 |
## |
1.92 |
## |
1.23 |
## |
1: versus mean of test group 1 (vehicle control)
The statistical evaluations were performed using the WILCOXON-test ( # for p ≤ 0.05, ## for p ≤ 0.01 )
Tab. 3: 3H-thymidine incorporation, cell count and lymph node weight: test group mean value, standard deviation and stimulation index
Test Group |
Treatment |
³H-thymidine incorporation [DPM/Lymph Node Pair] |
||
Mean |
S.D. |
Stimulation Index1 |
||
1 |
vehicle ethanol |
151.6 |
20.2 |
1.00 |
2 |
2.5% in ethanol |
191.0 |
42.4 |
1.26 |
3 |
10% in ethanol |
364.8 |
141.0 |
2.41 ## |
4 |
25% in ethanol |
743.0 |
136.5 |
4.90 ## |
Test Group |
Treatment |
Cell Counts [Counts/Lymph Node Pair] |
||
Mean |
S.D. |
Stimulation Index1 |
||
1 |
vehicle ethanol |
12,715,200 |
737,880 |
1.00 |
2 |
2.5% in ethanol |
13,945,600 |
1,375,842 |
1.10 |
3 |
10% in ethanol |
19,123,200 |
5,239,266 |
1.50 # |
4 |
25% in ethanol |
29,336,000 |
2,065,697 |
2.31 ## |
Test Group |
Treatment |
Lymph Node Weight [mg/Lymph Node Pair] |
||
Mean |
S.D. |
Stimulation Index1 |
||
1 |
vehicle ethanol |
5.5 |
0.2 |
1.00 |
2 |
2.5% in ethanol |
5.9 |
0.5 |
1.06 |
3 |
10% in ethanol |
8.2 |
1.5 |
1.47 ## |
4 |
25% in ethanol |
10.7 |
1.2 |
1.92 ## |
1: versus mean of test group 1 (vehicle control)
The statistical evaluations were performed using the WILCOXON-test ( # for p ≤ 0.05, ## for p ≤ 0.01 )
Tab. 4: Ear weight: test group mean value, standard deviation and stimulation index
Test Group |
Treatment |
Ear Weight [mg/animal] |
||
Mean |
S.D. |
Stimulation Index1 |
||
1 |
vehicle ethanol |
30.6 |
1.2 |
1.00 |
2 |
2.5% in ethanol |
31.3 |
1.1 |
1.02 |
3 |
10% in ethanol |
31.4 |
1.4 |
1.03 |
4 |
25% in ethanol |
37.6 |
3.1 |
1.23 ## |
1: versus mean of test group 1 (vehicle control)
The statistical evaluations were performed using the WILCOXON-test ( # for p ≤ 0.05, ## for p ≤ 0.01 )
Tab. 5: Nature and duration of local findings of individual animals
Test Group |
1 |
||||
Treatment |
vehicle ethanol |
||||
Animal Number |
1 |
2 |
3 |
4 |
5 |
|
- |
- |
- |
- |
- |
Test Group |
2 |
||||
Treatment |
2.5% in ethanol |
||||
Animal Number |
6 |
7 |
8 |
9 |
10 |
|
- |
- |
- |
- |
- |
Test Group |
3 |
||||
Treatment |
10% in ethanol |
||||
Animal Number |
11 |
12 |
13 |
14 |
15 |
|
- |
- |
- |
- |
- |
Test Group |
4 |
||||
Treatment |
25% in ethanol |
||||
Animal Number |
16 |
17 |
18 |
19 |
20 |
scaling / moderate1 |
d5 |
d5 |
d5 |
d5 |
d5 |
incrustation / slight1 |
d5 |
- |
- |
- |
- |
1: post mortem observation
Tab. 6: Periodic positive control data
Project No. |
Date of performance |
Name of positive control substance |
Concentrations |
Vehicle |
Stimulation Index 3H-thymidine incorporationa |
Stimulation Index Cell counts |
EC 3.0 |
EC 1.5 |
58V0288/98A008 |
Jun 2016 |
Alpha-Hexylcinnamaldehyde, techn. 85% |
1%, 5%, 15% |
MEK (methyl ethyl ketone) |
2.60, 7.08, 14.77 |
1.50, 2.21, 3.01 |
1.4 |
1.0 |
58V0288/98A009 |
Jan 2017 |
Alpha-Hexylcinnamaldehyde, techn. 85% |
1%, 5%, 15% |
MEK (methyl ethyl ketone) |
1.56, 3.20, 9.16 |
1.22, 2.0, 3.42 |
4.5 |
2.4 |
58V0288/98A010 |
Jul 2017 |
Alpha-Hexylcinnamaldehyde, techn. 85% |
1%, 5%, 15% |
MEK (methyl ethyl ketone) |
2.91, 4.29, 9.61 |
1.59, 2.14, 2.92 |
1.3 |
ca. 1 |
58V0288/98A011 |
Jan 2018 |
Alpha-Hexylcinnamaldehyde, techn. 85% |
1%, 5%, 15% |
MEK (methyl ethyl ketone) |
1.59, 3.17, 7.48 |
1.27, 1.66, 2.83 |
4.6 |
3.3 |
58V0288/98A012 |
Jun 2018 |
Alpha-Hexylcinnamaldehyde, techn. 85% |
1%, 5%, 15% |
MEK (methyl ethyl ketone) |
2.19, 4.91, 4.71 |
1.48, 2.42, 2.51 |
2.2 |
1.1 |
a Ratio of test group values to control group values (Stimulation index) ≥ 3.0 indicates a positive result
Tab. 7: Positive control data of further study-related experiments
Project No. |
Date of performance |
Name of positive control substance |
Concentration |
Vehicle |
Stimulation Index 3H-thymidine incorporationa |
Stimulation Index Cell counts |
|
|
Alpha- |
|
|
|
|
58V0165/16A074 |
|
Hexylcinnamaldehyde, |
|
MEK (methyl ethyl |
|
|
58V0174/16A060 |
Jul 2016 |
techn. 85% |
15% |
ketone) |
7.99 |
2.24 |
58V0010/16A057 |
Sep 2016 |
Alpha- Hexylcinnamaldehyde, techn. 85% |
15% |
MEK (methyl ethyl ketone) |
10.97 |
2.28 |
58V0486/16A247 |
May 2017 |
Alpha- Hexylcinnamaldehyde, techn. 85% |
15% |
MEK (methyl ethyl ketone) |
6.70 |
2.79 |
58V0740/13A516 |
Jul 2017 |
Alpha- Hexylcinnamaldehyde, techn. 85% |
15% |
MEK (methyl ethyl ketone) |
8.69 |
2.44 |
58V0154/17A1131 |
Jun 2018 |
Alpha- Hexylcinnamaldehyde, techn. 85% |
15% |
MEK (methyl ethyl ketone) |
4.57 |
2.80 |
a: Ratio of test group values to control group values (stimulation index) ≥ 3.0 indicates a positive result
1: = Stimulation Index (SI) calculated with historical control data for the vehicle MEK
Applicant's summary and conclusion
- Interpretation of results:
- Category 1B (indication of skin sensitising potential) based on GHS criteria
- Conclusions:
- It is concluded that the test substance exhibits a skin sensitizing potential in the Murine Local Lymph Node Assay under the test conditions chosen.
- Executive summary:
The skin sensitizing potential of the test substance was assessed using the radioactive Murine Local Lymph Node Assay. The assay simulates the induction phase for skin sensitization in mice. It determines the response of cells in the auricular lymph nodes to repeated application of the test substance to the dorsal skin of the ears.
Groups of 5 female CBA/CaOlaHsd mice each were treated with 2.5%, 10% and 25% (w/w) preparations of the test substance in ethanol or with the vehicle alone.
Each test animal was treated with 25 μL per ear of the appropriate test-substance preparation or the vehicle alone, applied to the dorsal surfaces of both ears on three consecutive days.
Three days after the last application, 20 μCi 3H-thymidine in 250 μL sterile saline were injected into the tail vein of the mice. About 5 hours after the 3H-thymidine injection, the mice were
sacrificed, and the auricular lymph nodes were removed. Lymph node response was evaluated measuring 3H-thymidine incorporation (indicator of cell proliferation). Cell count and weight of
each animal’s pooled lymph nodes were also determined. In addition, a 0.8 cm diameter sample was punched out of the apical part of each ear, and for each animal, the weight of the
pooled punches was determined to obtain an indication of possible skin irritation.
No signs of systemic toxicity were noticed in all animals during general observation. When applied as 25% preparation in ethanol, the test substance induced a biologically relevant
(increase to 3-fold or above of control value = stimulation index (SI) ≥ 3), statistically significant and concentration-dependent increase of 3H-thymidine incorporation into the cells from the
auricular lymph nodes. The increase of the 10% test-substance preparation was statistically significant but failed to reach the cut-off value. Concomitantly, the 25% test-substance preparation induced a biologically relevant (increase to 1.5-fold or above of control value = stimulation index (SI) ≥ 1.5) and statistically significant
response in the auricular lymph node cell counts. The SI of the 10% test-substance preparation lies at the border of biological relevance and was statistically significant.
In addition, statistically significant increases in lymph node weights were noted at the 25% and 10% concentration. The test-substance concentrations did not cause relevant increases in ear weights (SI ≥ 1.25),
demonstrating the absence of excessive ear skin irritation. However, statistically significant and considerably increased ear weight (mean SI 1.23) was noted at the 25% concentration. In
addition, moderate scaling of the ear skin was observed in all animals and slight incrustation in one animal at the 25% concentration on study day 5 (post-mortem observation).
Nevertheless, the concentration of 25% has to be considered to indicate a skin sensitization potential because of lymph node responses clearly exceeding the respective cutoff values in
the absence of sufficiently strong ear skin irritation. Thus, it is concluded that Dodecatrienal exhibits a skin sensitizing potential in the Murine Local Lymph Node Assay under the test conditions chosen. The threshold concentration for sensitization induction was >10% <25% for 3H-thymidine incorporation. The EC 3 (estimated concentration that leads to the SI of 3.0) was calculated by
linear regression from the results of these concentrations to be 13.6%. The EC 1.5 (estimated concentration that leads to the SI of 1.5) for cell count was calculated by linear regression from the results of all concentrations to be 10.0%.
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