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EC number: 203-109-3 | CAS number: 103-41-3
- 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
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- 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
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- Endpoint summary
- Stability
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- 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
Endpoint summary
Administrative data
Description of key information
The substance was found not to be skin or eye irritating according to the CLP criteria.
Key value for chemical safety assessment
Skin irritation / corrosion
Link to relevant study records
- Endpoint:
- skin irritation: in vitro / ex vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 09.06 - 20.06.2016
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 439 (In Vitro Skin Irritation: Reconstructed Human Epidermis Test Method)
- Version / remarks:
- 2015
- Deviations:
- yes
- Remarks:
- However, the deviations did not influence the outcome or the validity of the study.
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.46 (In Vitro Skin Irritation: Reconstructed Human Epidermis Model Test)
- Version / remarks:
- 2009
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- Hess. Ministerium fuer Umwelt, Klimaschutz, Landwirtschaft und Verbraucherschutz, Wiesbaden
- Test system:
- human skin model
- Source species:
- human
- Cell type:
- non-transformed keratinocytes
- Cell source:
- other: not applicable
- Source strain:
- other: not applicable
- Justification for test system used:
- Dermal irritation is usually determined in vivo in the Draize rabbit skin irritation test as described in OECD guideline 404. Because systemic reactions play a minor role in modulating local skin toxicity potential of chemicals, skin irritation potential may be predicted by in vitro systems, provided they are sufficiently complex to mimic human skin barrier and cell reactivity. In an international prevalidation study performed by ECVAM, the in vitro skin irritation test using the human skin model EpiDermTM and EpiSkinTM and measurement of cell viability by dehydrogenase conversion of MTT into a blue formazan salt have turned out as a sufficiently promising predictor for skin irritancy potential.
- Vehicle:
- unchanged (no vehicle)
- Details on test system:
- RECONSTRUCTED HUMAN EPIDERMIS (RHE) TISSUE
- Model used: EpiDermTM tissues
- Tissue batch number(s): 23341
TEMPERATURE USED FOR TEST SYSTEM
- Temperature used during treatment / exposure: 37 ± 1.5°C, 5 ± 0.5% CO2
- Temperature of post-treatment incubation (if applicable): 37 ± 1.5°C, 5 ± 0.5% CO2
REMOVAL OF TEST MATERIAL AND CONTROLS
- Volume and number of washing steps: at least 15 times
MTT DYE USED TO MEASURE TISSUE VIABILITY AFTER TREATMENT / EXPOSURE
- MTT solution: 300 μL
- Incubation time: 42 hours at 37 ± 1°C, 5 ± 0.5% CO2
- Microplate reader: Versamax® Molecular Devices, Softmax Pro, version 4.7.1
- Wavelength: 570 nm
- Measurement: mean values from the 3 wells per tissue were calculated.
FUNCTIONAL MODEL CONDITIONS WITH REFERENCE TO HISTORICAL DATA
Positive control
- Viability: 4.64%
- Rel. Standard Deviation: 11.2%
- Range of Viabilities: 4.00% - 5.90%
- Mean Absorption: 0.0803
- Rel. Standard Deviation: 12.6%
- Range of Absorbance: 0.066 - 0.097
Negative control
- Mean Absorption: 1.74
- Rel. Standard Deviation: 8.68%
- Range of Absorbance: 1.48 – 1.98
Data of 31 studies performed from July 2015 until March 2016
NUMBER OF REPLICATE TISSUES: 3
PREDICTION MODEL / DECISION CRITERIA (choose relevant statement)
- The test item is considered Category 1 or Category 2 (UN GHS published 2003, last (6th) revision 2015) if the mean relative tissue viability of three individual tissues is reduced ≤ 50% of the negative control.
ACCEPTANCE CRITERIA
1. Negative control: The absolute OD 570 nm of the negative control tissues / tissue viability is meeting the acceptance criterion if the mean OD570 of the negative control tissues is ≥ 0.8 and ≤ 2.8.
2. Positive control: An assay is meeting the acceptance criterion if mean relative tissue viability of the positive control is ≤ 20%.
3. Standard deviation: The SD of 3 identical replicates should be < 18%. OD values should not be below historically established boundaries.
Historical data and the quality certificate of the supplier of the test kit demonstrated the robustness of the test system or rather of the test kit. - Control samples:
- yes, concurrent negative control
- yes, concurrent positive control
- Amount/concentration applied:
- undiluted
- Duration of treatment / exposure:
- 60 minutes
- Duration of post-treatment incubation (if applicable):
- 42.75 hours
- Number of replicates:
- 3
- Irritation / corrosion parameter:
- % tissue viability
- Run / experiment:
- 1
- Value:
- 86
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- no indication of irritation
- Other effects / acceptance of results:
- Prior to use, the test item was melted at 37±2°C for 25 minutes in a water bath and was, subsequently, treated as liquid. The test item passed the MTT- and the colour interference pre-tests.
Treatment with the negative control was well within the required acceptability criterion of mean OD ≥ 0.8 and ≤ 2.8 for the 60 minutes treatment interval thus showing the quality of the tissues.
Treatment with the positive control induced a decrease in the relative absorbance as compared to the negative control to 4.5% thus ensuring the validity of the test system.
The relative standard deviations between the % variability values of the test item, the positive and negative controls in the main test were below 11%, ensuring the validity of the study. - Interpretation of results:
- other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008
- Conclusions:
- Under the experimental conditions reported, the test item is non irritant to skin.
- Executive summary:
In the current study the irritation potential of the test item was assessed in an in vitro study by means of the Human Skin Model Test according to OECD TG 439 and GLP.
The test consists of a topical exposure of the neat test item to a human reconstructed epidermis model followed by a cell viability test. Cell viability is measured by dehydrogenase conversion of MTT [3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl-tetrazoliumbromide], in mitochondria, into a blue formazan salt that is quantitatively measured after extraction from tissues. The percent reduction of cell viability in comparison to untreated negative controls is used to predict the skin irritation potential and is used for the purpose of classification as irritating or non-irritating. The test chemical is regarded as skin irritant (UN GHS and EU CLP) if the tissue viability after exposure and post-treatment incubation is less than or equal (≤) to 50%. However, a limitation of this test method is the unability to distinguish between Category 1 (skin corrosive) and Category 2 (skin irritant). Thus, a positive result in this assay requires further testing.
The test item did not reduce MTT in the direct MTT reduction pre-test, and did not change the colour in the colour interference pre-test. Also, its intrinsic colour was not intensive. Consequently, additional tests with freeze-killed or viable tissues were not necessary.
Tissues of the human skin model EpiDermTM were treated with the test item, the negative (DPBS) or the positive control (5% SLS) for 60 minutes. The test item, the negative control or the positive control were spread to match the surface of the tissue.
The absorbance values after treatment with the negative control were well within the required range of acceptability criterion of mean OD ≥ 0.8 and ≤ 2.8, assuring the quality of the tissues.
Treatment with the positive control induced a sufficient decrease in the relative absorbance compared to the negative control, assuring the validity of the test system.
After treatment with the test item the mean relative absorbance value decreased to 86.0% compared to the relative absorbance value of the negative control. This value is above the threshold for irritancy of ≤ 50%. Therefore, the test item is not to be considered to possess irritant potential.
In conclusion, under the experimental conditions reported, the test item is non irritant to skin.
Reference
Results after treatment with the test item and the controls
Dose Group | Tissue | Absorbance 570 nm Well 1 | Absorbance 570 nm Well 2 | Absorbance 570 nm Well 3 | Mean absorbance of 3 Wells | Mean absorbance of 3 Wells blank corrected | Mean absorbance of 3 tissues after blank correction* | Rel. Absorbance (%) Tissue 1,2 and 3* | Realtive Standard Deviation (%) | Mean Rel. Absorbance (% of Negative Control)** | ||
Blank | 0.037 | 0.038 | 0.038 | 0.038 | 0.000 | |||||||
NK | 1 | 1.870 | 1.865 | 1.837 | 1.857 | 1.820 | 1.889 | 96.3 | 3.3 | 100 | ||
2 | 1.954 | 1.947 | 1.944 | 1.948 | 1.911 | 101.1 | ||||||
3 | 1.997 | 1.966 | 1.963 | 1.975 | 1.938 | 102.6 | ||||||
PC | 1 | 0.123 | 0.127 | 0.127 | 0.126 | 0.088 | 0.086 | 4.7 | 6.5 | 4.5 | ||
2 | 0.131 | 0.126 | 0.126 | 0.128 | 0.090 | 4.8 | ||||||
3 | 0.118 | 0.117 | 0.117 | 0.117 | 0.079 | 4.2 | ||||||
TM | 1 | 1.823 | 1.804 | 1.818 | 1.818 | 1.780 | 1.626 | 88.4 | 10.6 | 86 | ||
2 | 1.483 | 1.467 | 1.477 | 1.477 | 1.440 | 94.2 | ||||||
3 | 1.707 | 1.687 | 1.694 | 1.694 | 1.657 | 76.2 |
* relative absorbance per tissue [rounded values]: 100*(absorbance tissue) / (mean absorbance negative control)
** relative absorbance per treatment group [rounded values]: 100*(mean absorbance test item/positive control) / (mean absorbance negative control)
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (not irritating)
Eye irritation
Link to relevant study records
- Endpoint:
- eye irritation: in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 04.10.1999 - 08.10.1999
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 405 (Acute Eye Irritation / Corrosion)
- Version / remarks:
- Feb. 1987
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: EEC Guideline B.5 "Acute Toxicity (Eye Irritation)"
- Version / remarks:
- Jan. 1997
- Deviations:
- no
- GLP compliance:
- yes
- Species:
- rabbit
- Strain:
- New Zealand White
- Details on test animals or tissues and environmental conditions:
- TEST ANIMALS
- Weight: 2.6 - 3.0 kg b.w.
- Housing: individually in PPO cages (floor area: 2576 cm2) with performed floor.
- Diet: pelleted complete rabbit diet "Altromin 2123" from Altromin, D-32791 Lage, Lippe; ad libitum.
- Water: free access to domestic drinking water acidified with hydrochloric acid to pH 2.5
- Acclimation period: at least 1 week
ENVIRONMENTAL CONDITIONS
- Temperature: 20°C ± 3°C
- Humidity: 55% ± 15%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): cycle of 12 hours light (06 to 18h) and 12 hours darkness - Vehicle:
- unchanged (no vehicle)
- Controls:
- not required
- Amount / concentration applied:
- TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
- Concentration (if solution): undiluted - Duration of treatment / exposure:
- Single exposure without rinsing.
- Observation period (in vivo):
- 1, 24, 48 and 72 hours after treatment
- Number of animals or in vitro replicates:
- 4 females
- Details on study design:
- TESTING PROCEDURE
- The day before testing both eyes of the animals were examined with a hand held inspection lamp fitted with white and UV-light and magnifying glass with 2 x magnification to ensure there were no defects or irritation. The examination was performed before and after instillation of Fluorescein.
- The left eye was treated. The right eye remained untreated and served as control.
- 0.1 ml of the warmed test item was placed in the left eye of the rabbits by gently pulling the lower lid away from the eyeball to form a cup into which the test article was dropped. The lids were then gently held together for 1 second.
- The eyes were examined and the grade of ocular reaction was recorded one hour and 24 hours later. After the first 24 hour reading Fluorescein was instilled. After rinsing with 20 ml 0.9% sodium chloride solution the eyes were examined again using UV-light to detect possible comeal damage.
- The eyes were also examined 48 and 72 hours after the treatment.
EVALUATION OF THE REACTIONS (see tables below)
ASSESSMENT
A substance or a preparation is considered to be irritant if it causes ocular lesions which occur within 72 hours after exposure and which persist for at least 24 hours.
Ocular lesions are significant if the rnean scores of the eye irritation test have any of the following values:
- cornea opacity ≥ 2 but < 3
- iris lesion ≥ 1 but < 1.5
- redness of conjunctivae ≥ 2.5
- oedema of conjunctivae (chemosis) ≥ 2
or, in the case where the test has being completed using three animals if the lesions, on two or more animals, are equivalent to any of the above values except that for iris lesion the value should be equal or greater than 1 but less than 2 and for redness of the conjunctivae the value should be equal or greater than 2.5.
In both cases all scores at each of the reading times (24, 48 and 72 hours) for an effect should be used in calculating the respective mean values.
A substance or a preparation is considered to be able to cause serious damage to eyes if it causes severe ocular lesions which occur within 72 hours after exposure and which persist for at least 24 hours.
Ocular lesions are severe if the means of the scores of the eye Irritation test have any of the values:
- cornea opacity ≥3
- iris lesion ≥ 1.5
The same shall be the case where the test has been completed using three animals if these lesions, on two or more animals, have any of the values:
- cornea opacity ≥ 3
- iris lesion = 2
In both cases all scores at each of the reading times (24, 48 and 72 hours) for an effect should be used in calculating the respective mean values.
Ocular lesions are also severe when they are still present at the end of the observation time.
Ocular lesions are also severe if the substance or preparation causes irreversible colouration of the eyes. - Irritation parameter:
- cornea opacity score
- Basis:
- animal: #1, #2, #3, #4
- Time point:
- 24/48/72 h
- Score:
- 0
- Max. score:
- 4
- Reversibility:
- other: reversibility: not applicable
- Irritation parameter:
- iris score
- Basis:
- animal: #1, #2, #3, #4
- Time point:
- 24/48/72 h
- Score:
- 0
- Max. score:
- 2
- Reversibility:
- other: reversibility: not applicable
- Irritation parameter:
- conjunctivae score
- Basis:
- animal: #1, #2, #3, #4
- Time point:
- 24/48/72 h
- Score:
- 0.33
- Max. score:
- 3
- Reversibility:
- fully reversible within: 48 h
- Irritation parameter:
- chemosis score
- Basis:
- animal: #1, #2, #3, #4
- Time point:
- 24/48/72 h
- Score:
- 0
- Max. score:
- 4
- Reversibility:
- other: reversibility: not applicable
- Irritant / corrosive response data:
- One hour after application of the test article animals No. 1565, No. 1571, No. 1572 and No. 1573 showed some conjunctival vessels definitely injected.
After 24 hours some conjunctival vessels were definitely injected in all animals. After 48 and 72 hours all animals were free of any signs of eye irritation. - Interpretation of results:
- other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008
- Conclusions:
- The test substance shall not be classified as eye irritating.
- Executive summary:
In the current study the eye irritant effect of the test item was investigated according to the method recommended in the OECD Guideline 405 and EEC Guideline B.5.
Four female albino rabbits were exposed to 0.1 mL of the undiluted test articie in the left eye, while the other eye remained untreated and served as control. The eyes were examined and the changes were graded according to a numerical scale one hour, 24, 48 and 72 hours after dosing.
Slight signs of irritation were observed on the treated eyes, however, these were reversible and according to the criteria set out in the CLP regulation the test item shall not be classified as eye irritant.
Reference
Scores for ocular lesions:
*individual mean score: Only the scores from the readings after 24, 48 and 72 hours are included in the calculation of the individual mean scores.
Rabbit No/Weight (kg) | Parameters | Individual mean score* |
1565/2.9 | cornea opacity | 0.00 |
iris | 0.00 | |
conjunctiva redness | 0.33 | |
conjunctiva chemosis | 0.00 | |
1571/2.6 | cornea opacity | 0.00 |
iris | 0.00 | |
conjunctiva redness | 0.33 | |
conjunctiva chemosis | 0.00 | |
1572/2.8 | cornea opacity | 0.00 |
iris | 0.00 | |
conjunctiva redness | 0.33 | |
conjunctiva chemosis | 0.00 | |
1573/3.0 | cornea opacity | 0.00 |
iris | 0.00 | |
conjunctiva redness | 0.33 | |
conjunctiva chemosis | 0.00 |
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (not irritating)
Respiratory irritation
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Skin irritation
There are 3 studies available that assess the possible irritation potential of the test substance to the skin. The study from 2016 was performed according to GLP and internationally accepted guidelines, the supporting studies were not in conformance to any guideline nor to GLP. The key study is used for classification, the supporting studies could not be used for classification because they lack e.g. individual animal results. The supporting studies are studies designed for other endpoints as well, however, the information was added here because of their relevance.
In the key study the irritation potential of the test item was assessed in an in vitro study by means of the Human Skin Model Test according to OECD TG 439 and GLP.
The test item did not reduce MTT, change the colour or have intensive, intrinsic colour and so no additional tests with freeze-killed or viable tissues were necessary.
The human skin model EpiDermTM was treated with the test item, the negative (DPBS) or the positive control (5% SLS) for 60 minutes. The acceptance criteria of the test were met.
The test item showed a mean relative absorbance value of 86.0% compared to the negative control. This value is above the threshold for irritancy of ≤ 50% and thus the test item is not considered to possess irritant potential.
In the first supporting study (1976) the skin irritation effects were assessed as part of an OET test on guinea pigs. Only a mean scoring value of 6 -8 animals after 1 day of treatment is presented in the study and some slight irritation after a single application of the test item was observed, however, this was not again assessed at 48 and 72 hours.
In the second supporting study (1977) the skin irritation of test substance was assessed in guinea pigs as part of an OET test and the lowest concentration to produce mild redness was determined to be 3% after 1 application (minimal irritating concentration).
Taken together, the test item shall not be classified as skin irritating.
Eye irritation
There is only one study available assessing the eye irritation potential of the test substance and it was performed according to GLP and internationally accepted guidelines.
The study was according to the OECD Guideline No. 405 and 4 female albino rabbits were exposed to 0.1 mL of the test article in the left eye, while the other eye remained untreated and served as control. The eyes were examined and the changes were graded according to a numerical scale one hour, 24, 48 and 72 hours after dosing.
Slight signs of irritation were observed on the treated eyes. However, according to the CLP criteria, the test substance shall not be classified as eye irritating.
Justification for classification or non-classification
Skin irritation
In a recent in vitro skin irritation study the test item showed a mean relative tissue viability of 86.0%.
The test item is considered irritant to the skin if the mean relative tissue viability of three individual tissues is reduced ≤ 50% of the negative control.
Thus, based on the available data on skin irritation, the test item does not meet the criteria for classification according to Regulation (EC) 1272/2008 (CLP).
Eye irritation
The observed effects of conjunctival redness are slight, with a mean (24 - 48 - 72h) score of 0.33 in all tested animals. As this value is below 2, and the observed effects are fully reversible, classification of the test substance is not required according to the criteria set out in EU Regulation No. 1272/2008 on the Classification, Labelling and Packaging of Substances and Mixtures (CLP).
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