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EC number: 700-334-3 | CAS number: -
- Life Cycle description
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Endpoint summary
Administrative data
Description of key information
Skin sensitisation:
A study was performed to assess the skin sensitisation potential of the test material in the CBA/Ca strain mouse following topical application to the dorsal surface of the ear. The method was designed to meet the requirements of the following:
- OECD Guideline for the Testing of Chemicals No. 429 "Skin Sensitisation: Local Lymph Node Assay" (adopted)
- Method B42 Skin Sensitisation (Local Lymph Node Assay) of Commission Directive 2004/73/EC
Following a preliminary screening test in which no clinical signs of toxicity were noted at a concentration of 100% v/v, this concentration was selected as the highest dose investigated in the main test of the Local Lymph Node Assay. Three groups, each of four animals, were treated with 50 µl (25 µl per ear) of the undiluted test material or the test material as a solution in acetone/olive oil 4:1at concentrations of 50% or 25% v/v. A further group of four animals was treated with acetone/olive oil 4:1alone.
The Stimulation Index expressed as the mean radioactive incorporation for each treatment group divided by the mean radioactive incorporation of the vehicle control group are as follows:
Concentration (%v/v) in |
Stimulation Index |
Result |
25 |
1.89 |
Negative |
50 |
4.72 |
Positive |
100 |
6.69 |
Positive |
The test material was considered to be a sensitiser under the conditions of the test.
Key value for chemical safety assessment
Skin sensitisation
Link to relevant study records
- Endpoint:
- skin sensitisation: in vivo (LLNA)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 15th -30th September 2008
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Study conducted to GLP and in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not effect the quality of the relevant results.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.42 (Skin Sensitisation: Local Lymph Node Assay)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Type of study:
- mouse local lymph node assay (LLNA)
- Species:
- mouse
- Strain:
- other: CBA/Ca
- Sex:
- female
- Details on test animals and environmental conditions:
- TEST ANIMALS
- Source: Halan UK limited, Bicester, Oxon, UK.
- Age at study initiation: 8-12 weeks old
- Weight at study initiation: 15-23 g
- Housing: Animals were individually housed in suspended soild-floor polypropylene cages furnished with softwood woodflakes. Animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.
- Diet (e.g. ad libitum): Free assess to food supplied by Harlan Teklad.
- Water (e.g. ad libitum):Free assess to mains tap water
- Acclimation period: 5 days
-Other: nullparious and non-pregnant.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25 Deg C
- Humidity (%): 30 to 70%
- Air changes (per hr): 15 changes per hour
- Photoperiod (hrs dark / hrs light):12 hours light (06:00-18:00) and 12 hours darkness (18:00 - 06:00). - Vehicle:
- acetone/olive oil (4:1 v/v)
- Concentration:
- Groups of four mice per dose level were treated with the undiluted test material or the test material at concentrations of 50% or 25% in acetone/olive oil 4:1.
- No. of animals per dose:
- 4 animals per dose level.
- Details on study design:
- Preparation of Test Material:
For the purpose of the study, the test material was used undiluted and freshly prepared as a solution in acetone/olive oil 4:1. This vehicle was chosen as it produced the most suitable formulation at the required concentration
PROCEDURE
In the main test, one animal treated with the undiluted test material showed signs of systemic toxicity, pre-dose on Day 2, and was therefore killed for humane reasons due to the occurrence of clinical signs of toxicity that approached the moderate severity limit set forth in the UK Home Office Project Licence. The absence of this animal for the remainder of the study was considered not to affect the purpose or integrity of the study.
PRELIMINARY SCREENING TEST:
Using available information regarding the systemic toxicity/irritancy potential of the test material, a preliminary screening test was performed using one mouse. The mouse was treated by daily application of 25 µl of the undiluted test material to the dorsal surface of each ear for three consecutive days (Days 1, 2, 3). The mouse was observed twice daily on Days 1, 2 and 3 and once daily on Days 4, 5 and 6. Any signs of toxicity or excessive local irritation noted during this period were recorded. The bodyweight of the mouse was recorded on Day 1 (prior to dosing) and on Day 6.
MAIN TEST:
Test material administration:
Groups of four mice were treated with the undiluted test material or the test material at concentrations of 50% or 25% v/v in acetone/olive oil 4:1. The preliminary screening test suggested that the test material would not produce systemic toxicity or excessive local irritation at the highest suitable concentration. The mice were treated by daily application of 25 µl of the appropriate concentration of the test material to the dorsal surface of each ear for up to three consecutive days (Days 1, 2, 3). The test material formulation was administered using an automatic micropipette and spread over the dorsal surface of the ear using the tip of the pipette.
A further group of four mice received the vehicle alone in the same manner.
3H-Methyl Thymidine Administration:
Five days following the first topical application of the test material (Day 6) all mice were injected via the tail vein with 250 µl of phosphate buffered saline (PBS) containing 3H-methyl thymidine (3HTdR: 80 µCi/ml, specific activity 2.0 Ci/mmol, GE Healthcare UK Ltd) giving a total of 20 µCi to each mouse.
Observations:
Clinical Observations: Animals were observed twice daily on Day 1, pre-dose on Day 2 and the surviving animals post-dose on Day 2, twice daily on Day 3 and on a daily basis on Days 4, 5 and 6. Any signs of toxicity or signs of ill health during the test were recorded.
Bodyweights: The bodyweight of each mouse was recorded on Day 1 (prior to dosing) and Day 6 (prior to termination), or at death.
TERMINAL PROCEDURES:
Termination: Approximately five hours following the administration of 3HTdR the surviving mice were killed by carbon dioxide asphyxiation. The draining auricular lymph nodes from the mice were excised and pooled for each experimental group. For each group 1 ml of PBS was added to the pooled lymph nodes.
Preparation of Single Cell Suspension: A single cell suspension of pooled lymph node cells was prepared by gentle mechanical disaggregation through a 200-mesh stainless steel gauze. The lymph node cells were rinsed through the gauze with 4 ml of PBS into a petri dish labelled with the project number and dose concentration. The lymph node cell suspension was transferred to a centrifuge tube. The petri dish was washed with an additional 5 ml of PBS to remove all remaining lymph node cells and these were added to the centrifuge tube. The pooled lymph node cells were pelleted at 1400 rpm (approximately 190 g) for ten minutes. The pellet was resuspended in 10 ml of PBS and re-pelleted. To precipitate out the radioactive material, the pellet was resuspended in 3 ml of 5% Trichloroacetic acid (TCA).
Determination of 3HTdR Incorporation:
After approximately eighteen hours incubation at approximately 4°C, the precipitates were recovered by centrifugation at 2100 rpm (approximately 450 g) for ten minutes, resuspended in 1 ml of TCA and transferred to 10 ml of scintillation fluid (Optiphase 'Trisafe'). 3HTdR incorporation was measured by beta-scintillation counting. The "Poly QTM" vials containing the samples and scintillation fluid were placed in the sample changer of the scintillator and left for approximately twenty minutes. The purpose of this period of time in darkness was to reduce the risk of luminescence, which has been shown to affect the reliability of the results. After approximately twenty minutes, the vials were shaken vigorously. The number of radioactive disintegrations per minute was then measured using the Beckman LS6500 scintillation system (Beckman Instruments Inc, Fullerton, CA, USA).
Interpretation of Results:
The proliferation response of lymph node cells was expressed as the number of radioactive disintegrations per minute per lymph node (disintegrations per minute/node) and as the ratio of 3HTdR incorporation into lymph node cells of test nodes relative to that recorded for the control nodes (Stimulation Index).
The test material will be regarded as a sensitiser if at least one concentration of the test material results in a threefold or greater increase in 3HTdR incorporation compared to control values. Any test material failing to produce a threefold or greater increase in 3HTdR incorporation will be classified as a "non sensitiser". - Positive control substance(s):
- other: alpha-Hexylcinnamaldehyde, Tech, 85%
- Positive control results:
- One group of five animals was treated with 50 µl (25 µl per ear) of alpha-Hexylcinnamaldehyde, Tech, 85% as a solution in acetone/olive oil 4:1 at a concentration of 15% v/v. A further group of five animals was treated with acetone/olive oil 4:1 alone.
The Stimulation Index expressed as the mean radioactive incorporation for the treatment group divided by the mean radioactive incorporation of the vehicle control group are as follows:
Concentration % v/v in acetone/olive oil 4:1: 15
Stimulation index: 10.91
Result: Positive.
alpha-Hexylcinnamaldehyde, Tech, 85% was considered to be a sensitiser under the conditions of the test. - Parameter:
- SI
- Value:
- 1.89
- Test group / Remarks:
- 25%
- Remarks on result:
- other: negative
- Parameter:
- SI
- Value:
- 4.72
- Test group / Remarks:
- 50%
- Remarks on result:
- other: positive
- Parameter:
- SI
- Value:
- 6.69
- Test group / Remarks:
- 100% (undlluted)
- Remarks on result:
- other: positive
- Parameter:
- other: Disintergrations per minute (dpm)
- Value:
- 6 343.22
- Test group / Remarks:
- Vehicle
- Parameter:
- other: Disintergrations per minute (dpm)
- Value:
- 12 019.06
- Test group / Remarks:
- 25%
- Parameter:
- other: Disintergrations per minute (dpm)
- Value:
- 29 928.53
- Test group / Remarks:
- 50%
- Parameter:
- other: Disintergrations per minute (dpm)
- Value:
- 31 846.38
- Test group / Remarks:
- 100% (undiluted)
- Interpretation of results:
- Category 1B (indication of skin sensitising potential) based on GHS criteria
- Remarks:
- Criteria used for interpretation of results: EU
- Conclusions:
- The test material was considered to be a sensitiser under the conditions of the test.
- Executive summary:
Introduction.
A study was performed to assess the skin sensitisation potential of the test material in the CBA/Ca strain mouse following topical application to the dorsal surface of the ear. The method was designed to meet the requirements of the following:
- OECD Guideline for the Testing of Chemicals No. 429 "Skin Sensitisation: Local Lymph Node Assay" (adopted)
- Method B42 Skin Sensitisation (Local Lymph Node Assay) of Commission Directive 2004/73/EC
Methods.
Following a preliminary screening test in which no clinical signs of toxicity were noted at a concentration of 100% v/v, this concentration was selected as the highest dose investigated in the main test of the Local Lymph Node Assay. Three groups, each of four animals, were treated with 50 µl (25 µl per ear) of the undiluted test material or the test material as asolutioninacetone/olive oil 4:1at concentrations of 50% or 25% v/v. A further group of four animals was treated withacetone/olive oil 4:1alone.
Results.
The Stimulation Index expressed as the mean radioactive incorporation for each treatment group divided by the mean radioactive incorporation of the vehicle control group are as follows:
Concentration (%v/v) in
acetone/olive oil 4:1Stimulation Index
Result
25
1.89
Negative
50
4.72
Positive
100
6.69
Positive
Conclusion.
The test material was considered to be a sensitiser under the conditions of the test.
Reference
Preliminary Screening Test:
No signs of systemic toxicity were noted.
Based on this information the dose levels selected for the main test were100%, 50% and 25% v/v in acetone/olive oil 4:1.
Main Test
Estimation of the Proliferative Response of Lymph Node Cells
The radioactive disintegrations per minute per lymph node and the stimulation index are given in table below:
A stimulation index of greater than 3 was recorded for the two concentrations of the test material (100% and 50% v/v in acetone/olive oil 4:1).
A stimulation index of less than 3 was recorded for the lowest concentration of the test material (25% v/v in acetone/olive oil 4:1).
Disintegrations per Minute, Disintegrations per Minute/Node and Stimulation Index
Concentration |
dpm |
dpm/Nodea |
Stimulation Indexb |
Result |
Vehicle |
6343.22 |
792.90 |
na |
na |
25 |
12019.06 |
1502.38 |
1.89 |
Negative |
50 |
29928.53 |
3741.07 |
4.72 |
Positive |
100 |
31846.38 |
5307.73* |
6.69 |
Positive |
dpm= Disintegrations per minute
a= Disintegrations per minute/node obtained by dividing the disintegrations per minute value by 8 (total number of lymph nodes)
b= Stimulation Index of 3.0 or greater indicates a positive result
* = Dpm/node obtained by dividing the Dpm value by 6 (due to the death of one animal on Day 2)
na = Not applicable
Clinical Observations and Mortality Data
One animal, treated with the undiluted test material, was killed for humane reasonsdue to the occurrence of clinical signs of toxicity that approached the moderate severity limit set forth in the UK Home Office Project Licence. Signs of systemic toxicity noted were hunched posture, lethargy, ptosis and splayed gait. A 2g bodyweight loss was also noted. No other signs of systemic toxicity were noted in the surviving test or control animals during the test.
Bodyweight:
Bodyweight changes of the surviving test animals between Day 1 and Day 6 were comparable to those observed in the corresponding control group animals over the same period.
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed (sensitising)
- Additional information:
The test material was considered to be a sensitiser under the conditions of the test.
The EC3 value was calculated to be 35%. The EC3value is the concentration of test item expected to cause a 3 fold increase in 3HTdR incorporation (i.e. a positive result for skin sensitisation).
Respiratory sensitisation
Endpoint conclusion
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
A skin sensitiser is defined as a substance that will lead to an allergic response following skin contact.
Substances are classified as skin sensitisers (Category 1) if there is evidence in humans that the substance can lead to sensitisation by skin contact in a substantial number of persons, or if there are positive results from an appropriate animal test.
Substances may also be classified into:
sub-category 1A: substances showing a high frequency of occurrence in humans and/or a high potency in animals can be presumed to have the potentail to produce significant sensitisation in humans) or
sub-category 1B: substances showing a low to moderate frequency of occurrence in humans and/or a low to moderate potency in animals can be presumed to have the potential to produce sensitisation in humans.
A Local Lymph Node Assay (LLNA) was performed on the substance.
For Category 1 classification, a stimulation index of three or more is considered a positive response in the LLNA.
A stimulation index of greater than 3 was recorded for the two concentrations of the test material (100% and 50% v/vin acetone/olive oil 4:1) in the study and the test material was considered to be a sensitiser under the conditions of the test.
Classification into sub-category was based on EC3 value. The EC3 value was calculated as 35%. Where the EC3 value is >2% sub-category 1B is appropriate.
The substance is therefore classified for skin sensitisation (Sub-Category 1B).
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