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EC number: - | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
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- Particle size distribution (Granulometry)
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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
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- 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
Introduction
The study was performed to assess the irritancy potential of the test item to the skin of the New Zealand White rabbit.
Results
A single 4-Hour, semi occluded application of the test item to the intact skin of three rabbits produced very slight to well-defined erythema and very slight to slight edema. Other skin reactions noted were light brown discoloration of the epidermis, loss of skin elasticity, slight desquamation and glossy skin. One treated skin site appeared normal at the 72-Hour observation and one other treated skin site appeared normal at the 7-Day observation. No corrosive effects were noted.
Conclusion
The test item produced individual mean scores of 2.0, 1.0 and 0.7 for erythema and 1.7, 1.0 and 0.3 for edema. In accordance with EU CLP Regulation (EC) No. 1272/2008, classification of this substance is not required for dermal irritation as scores for erythema and oedema did not fulfil the criteria for classification and were fully reversible by the end of the 14-day observation period.[LE1]
Key value for chemical safety assessment
Skin irritation / corrosion
Link to relevant study records
- Endpoint:
- skin corrosion: in vitro / ex vivo
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- an in vitro skin irritation study does not need to be conducted because adequate data from an in vivo skin irritation study are available
- Endpoint:
- skin irritation: in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- Experimental start date: 26 January 2016 Experimental completion date 12 February 2016
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
- Version / remarks:
- OECD Guideline for the Testing of Chemicals No. 404 "Acute Dermal Irritation/Corrosion" (adopted 28 July 2015)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
- Version / remarks:
- Method B4 Acute Toxicity (Skin Irritation) of Commission Regulation (EC) No. 440/2008
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Species:
- rabbit
- Strain:
- New Zealand White
- Remarks:
- New Zealand White (Hsdlf:NZW)
- Details on test animals or test system and environmental conditions:
- Three New Zealand White (Hsdlf:NZW) strain rabbits were supplied by Envigo RMS (UK) Limited, Leicestershire, UK. At the start of the study the animals weighed 2.69 or 4.00 kg and were 12 to 20 weeks old. After an acclimatization period of at least 5 days each animal was given a number unique within the study which was written with a black indelible marker-pen on the inner surface of the ear and on the cage label.
The animals were individually housed in suspended cages. Free access to mains drinking water and food (2930C Teklad Global Rabbit diet supplied by Envigo RMS (UK) Limited, Oxon, UK) was allowed throughout the study. The diet and drinking water were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.
The temperature and relative humidity were set to achieve limits of 17 to 23 °C and 30 to 70% respectively. The rate of air exchange was at least fifteen changes per hour and the lighting was controlled by a time switch to give 12 hours continuous light and 12 hours darkness.
The 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. - Type of coverage:
- semiocclusive
- Preparation of test site:
- clipped
- Vehicle:
- unchanged (no vehicle)
- Controls:
- no
- Amount / concentration applied:
- A quantity of 0.5 mL of the test item was applied directly to the skin
- Duration of treatment / exposure:
- Four hours
- Observation period:
- Immediately following removal of the patches and approximately 1, 24, 48 and 72 hours later, the test sites were examined for evidence of primary irritation
- Number of animals:
- 3
- Details on study design:
- Please see below
- Irritation parameter:
- other: Erythema/Eschar Formation
- Basis:
- mean
- Time point:
- 24/48/72 h
- Score:
- 1.23
- Max. score:
- 2
- Reversibility:
- not fully reversible within:
- Remarks on result:
- other: The test item produced individual mean scores of 2.0, 1.0 and 0.7 for erythema
- Remarks:
- Very slight erythema, with or without very slight edema, were noted at all treated skin sites immediately after patch removal. Well-defined erythema and slight edema were noted at one treated skin site and very slight erythema and very slight edema were noted at two treated skin sites 1 hour after patch removal. Well-defined erythema and slight edema were noted at one treated skin site and very slight erythema, with or without very or slight edema, were noted at two treated skin sites at the 24 and 48-Hour observations. Well-defined erythema and very slight edema were noted at one treated skin site and very slight erythema was noted at one other treated skin site at the 72-Hour observation. At the 72-Hour observation, light brown discoloration of the epidermis and loss of skin elasticity were also noted at one treated skin site and slight desquamation was noted at one other treated skin site. Slight desquamation and glossy skin were noted at one treated skin site at the 7-Day observation.
- Irritant / corrosive response data:
- Very slight erythema, with or without very slight edema, were noted at all treated skin sites immediately after patch removal. Well-defined erythema and slight edema were noted at one treated skin site and very slight erythema and very slight edema were noted at two treated skin sites 1 hour after patch removal. Well-defined erythema and slight edema were noted at one treated skin site and very slight erythema, with or without very or slight edema, were noted at two treated skin sites at the 24 and 48-Hour observations. Well-defined erythema and very slight edema were noted at one treated skin site and very slight erythema was noted at one other treated skin site at the 72-Hour observation.
At the 72-Hour observation, light brown discoloration of the epidermis and loss of skin elasticity were also noted at one treated skin site and slight desquamation was noted at one other treated skin site. Slight desquamation and glossy skin were noted at one treated skin site at the 7-Day observation. - Interpretation of results:
- GHS criteria not met
- Conclusions:
- The test item produced individual mean scores of 2.0, 1.0 and 0.7 for erythema and 1.7, 1.0 and 0.3 for edema.
- Executive summary:
Introduction
The study was performed to assess the irritancy potential of the test item to the skin of the New Zealand White rabbit.
Results
A single 4-Hour, semi occluded application of the test item to the intact skin of three rabbits produced very slight to well-defined erythema and very slight to slight edema. Other skin reactions noted were light brown discoloration of the epidermis, loss of skin elasticity, slight desquamation and glossy skin. One treated skin site appeared normal at the 72-Hour observation and one other treated skin site appeared normal at the 7-Day observation. No corrosive effects were noted.
Conclusion
The test item produced individual mean scores of 2.0, 1.0 and 0.7 for erythema and 1.7, 1.0 and 0.3 for edema.
Referenceopen allclose all
Skin Reactions
The individual scores and mean scores for erythema/eschar and edema are given in the attached Appendix 1.
Very slight erythema, with or without very slight edema, were noted at all treated skin sites immediately after patch removal. Well-defined erythema and slight edema were noted at one treated skin site and very slight erythema and very slight edema were noted at two treated skin sites 1 hour after patch removal. Well-defined erythema and slight edema were noted at one treated skin site and very slight erythema, with or without very or slight edema, were noted at two treated skin sites at the 24 and 48-Hour observations. Well-defined erythema and very slight edema were noted at one treated skin site and very slight erythema was noted at one other treated skin site at the 72-Hour observation.
At the 72-Hour observation, light brown discoloration of the epidermis and loss of skin elasticity were also noted at one treated skin site and slight desquamation was noted at one other treated skin site. Slight desquamation and glossy skin were noted at one treated skin site at the 7-Day observation.
The third treated skin site appeared normal at the 72-Hour observation and one of the initial treated skin sites appeared normal at the 7-Day observation.
BodyWeight
Individual body weights and body weight change are given in the attached Appendix 2. All animals showed expected gain in body weight during the study.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (not irritating)
Eye irritation
Link to relevant study records
- Endpoint:
- eye irritation: in vitro / ex vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- Experimental start date: 11 February 2016 Experimental completion date: 11 February 2016
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- other: The Rabbit Enucleated Eye Test
- Version / remarks:
- The Rabbit Enucleated Eye Test has been included in evaluations of the validity of eye irritancy test methods, but is not currently considered to be a validated 'stand-alone' test method. No formally adopted test guideline is available, but a protocol has been proposed which was based upon the method detailed in this document (ICCVAM, 2006 and 2009).
A positive result in the rabbit enucleated eye test is accepted within the EU as an indication of severe eye irritancy potential without the need for confirmation in a rabbit eye irritation test (European Chemicals Bureau, 2006). - Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Species:
- rabbit
- Strain:
- not specified
- Details on test animals or tissues and environmental conditions:
- New Zealand White (Hsdlf:NZW) strain rabbits were supplied by Envigo RMS (UK) Limited, Leicestershire, UK. At the start of the study the animals were 12 to 20 weeks old. Rabbits that have previously been used in skin or eye irritation studies at the test facility may. be used as eye donors. If the donor animals have been used in an eye irritation study, only the untreated eyes were used.
- Vehicle:
- unchanged (no vehicle)
- Remarks:
- For the purpose of the study the test item was used as supplied.
- Controls:
- yes
- yes, concurrent no treatment
- Amount / concentration applied:
- Three eyes were treated with the test item. Two additional eyes remained untreated for control purposes. The treatment eye was removed from the superfusion apparatus whilst still being held in the perspex clamp. The clamp/eye was then placed horizontally into a petri dish.
The test item was used undiluted as supplied.
A volume of 0.1 mL of the test item was applied as evenly as possible to the surface of the cornea - Duration of treatment / exposure:
- After ten seconds the test item was washed off the cornea using a minimum of 20 mL of 0.9% saline solution (pre-warmed to approximately 32 °C).
Immediately following washing of the corneal surface, the treated eye was returned to the superfusion chamber and the saline drip repositioned to irrigate the eye.
The untreated eyes were similarly washed and used for control purposes. - Duration of post- treatment incubation (in vitro):
- Immediately following washing of the corneal surface, the treated eye was returned to the superfusion chamber and the saline drip repositioned to irrigate the eye.
- Number of animals or in vitro replicates:
- 5 eyes
- Details on study design:
- Please see below
- Irritation parameter:
- percent corneal swelling
- Remarks:
- Mean Corneal Swelling
- Run / experiment:
- 60 runs
- Value:
- 31.3
- Vehicle controls validity:
- valid
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- positive indication of irritation
- Irritation parameter:
- percent corneal swelling
- Remarks:
- Mean Corneal Swelling
- Run / experiment:
- 120 runs
- Value:
- 54.7
- Vehicle controls validity:
- valid
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- positive indication of irritation
- Irritation parameter:
- percent corneal swelling
- Remarks:
- Mean Corneal Swelling
- Run / experiment:
- 240 runs
- Value:
- 90
- Vehicle controls validity:
- valid
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- positive indication of irritation
- Interpretation of results:
- Category 1 (irreversible effects on the eye) based on GHS criteria
- Conclusions:
- Following assessment of the data for all endpoints, the test item was considered to have the potential to cause severe ocular irritancy in viva.
- Executive summary:
Introduction
Itis a legal and ethical duty under the Animals (Scientific Procedure) Act 1986 that, in the interest of animal welfare, the unnecessary use of animals is avoided, and that any testing which is likely to produc esevere responses in animals is minimized.
Therefore, before in vivo irritation testing is performed, all existing information on the test item, or its analogues should be reviewed. Available information indicated that the test item had the potential to produce severe effects in a rabbit eye and to confirm this initial assessment, a Rabbit Enucleated Eye Test (REET) was performed.
This step-wise procedure is in accordance with OECD Test Guideline 405,UK Home Office regulations and Envigo Research Limited Ethical Testing Strategy.
A study was performed to assess the ocular irritancy potential of the test item in the rabbit following application onto the cornea of the enucleated eye. The results of the study are believed to be of value in predicting the ocular irritation potential of the test item in man.
Method
0.1 mL of the test item was applied onto the cornea of each of three enucleated eyes which had been maintained at a temperature of 32 ±1.5 °C within the superfusion chamber. A further two enucleated eyes remained untreated for control purposes.
Results
Maximal ocular irritation observations recorded for the test eyes were as follows:
Corneal Opacity
FluoresceinUptake
Mean Corneal Swelling(%)
Condition of Corneal Epithelium
Test Eyes a
Control Eyes b
Cldy x Area
Int x Area
60
ruins
120
ruins
240
ruins
60
ruins
120
ruins
240
ruins
3
4+
31.3+
54.7+
90.0+
7.9
9.0
7.8
sloughing+
a= For each time point the swelling recorded is the mean of three eyes
b= For each time point the swelling recorded is the mean of two eyes
Cldy = Corneal cloudiness
Int= Intensity of fluoresceinuptake
mms = Minutes following treatment
+= Meets or exceeds cut-off value indicating a severe ocular irritant
Conclusion
Following assessment of the data for all endpoints the test item was considered to have the potential to cause severe ocular irritancy in vivo.
Reference
Corneal Opacity
Individual scores for corneal opacity are given in the attached Appendix 1.
Some loss of transparency was noted in all test eyes. No corneal effects were noted in the control eyes during the study period.
Corneal Thickness
Individual and mean measurements for corneal thickness are given in the attached Appendix 2. The determination of corneal swelling is given in Table 1 and Table 2. The calculated mean corneal swellings are given in Table 3.
Corneal swelling of the test eyes was considerably greater than that observed in the control eyes over the same period and exceeded the 2.25% cut-off value.
Corneal Condition
The condition of the corneal epithelium following treatment is given in the attached Appendix 3.
Sloughing of the corneal epithelium was noted in test eyes. The condition of the corneal epithelium of the control eyes appeared normal during the study.
Fluorescein Uptake
Individual scores for fluorescein uptake are given in the attached Appendix 4.
Fluorescein uptake was noted in the test eyes 240 minutes following test item application. No fluorescein uptake was noted in the control eyes 240 minutes following treatment.
Table 1 Determination of Corneal Swelling-Test Eyes
Chamber Number |
Observation Period (minutes) |
Mean Corneal Thickness(µm) |
Corneal Swelling(%)a |
Chamber Number |
Observation Period (minutes) |
Mean Corneal Thickness(µm) |
Corneal Swelling(%)a |
Chamber Number |
Observation Period (minutes) |
Mean Corneal Thickness(µm) |
Corneal Swelling(%)a |
IA |
Post equilibration |
355.8 |
na |
3A |
Post equilibration |
400.0 |
na |
5A |
Post equilibration |
414.2 |
na |
60 Post treatment |
520.2 |
46.2 |
60 Post treatment |
514.0 |
28.5 |
60 Post treatment |
493.8 |
19.2 |
|||
120 Post treatment |
643.8 |
80.9 |
120 Post treatment |
578.4 |
44.6 |
120 Post treatment |
573.6 |
38.5 |
|||
180 Post treatment |
771.6 |
116.9 |
180 Post treatment |
612.8 |
53.2 |
180 Post treatment |
633.8 |
53.0 |
|||
240 Post treatment |
854.0 |
140.0 |
240 Post treatment |
655.4 |
63.9 |
240 Post treatment |
688.6 |
66.2 |
a = % corneal swelling = (mean corneal thickness post-treatment) - (mean corneal thickness post equilibration) / mean corneal thickness post equilibrium x 100
Na = Not applicable
Table2 Determination of Corneal Swelling - Control Eyes
ChamberNumber |
Observation Period (minutes) |
Mean Corneal Thickness (µm) |
Corneal Swelling(%)a |
Chamber Number |
Observation Period(minutes) |
Mean Corneal Thickness (µm) |
Corneal Swelling(%)a |
2A |
Post equilibration |
353.0 |
na |
4A |
Post equilibration |
403.8 |
na |
60 Post treatment |
368.4 |
4.4 |
60 Post treatment |
449.8 |
11.4 |
||
120 Post treatment |
356.4 |
1.0 |
120 Post treatment |
472.6 |
17.0 |
||
180 Post treatment |
350.4 |
0.0 |
180 Post treatment |
468.4 |
16.0 |
||
240 Post treatment |
348.6 |
0.0 |
240 Post treatment |
466.6 |
15.6 |
a = % corneal swelling = (mean corneal thickness post-treatment) - (mean corneal thickness post equilibration) / mean corneal thickness post equilibrium x 100
Na = Not applicable
Table3 Mean Corneal Swelling
|
Time After Treatment |
||
60 minutes |
120 minutes |
240 minutes |
|
Test Eyes |
31.3+ |
54.7+ |
90.0+ |
Control Eyes |
7.9 |
9.0 |
7.8 |
+ = Meets or exceeds cut-off value indicating a severe ocular irritant
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed (irreversible damage)
Respiratory irritation
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed (irritating)
Additional information
Introduction
It is a legal and ethical duty under the Animals (Scientific Procedure) Act 1986 that, in the interest of animal welfare, the unnecessary use of animals is avoided, and that any testing which is likely to produc e severe responses in animals is minimized.
Therefore, before in viva irritation testing is performed, all existing information on the test item, or its analogues should be reviewed. Available information indicated that the test item had the potential to produce severe effects in a rabbit eye and to confirm this initial assessment, a Rabbit Enucleated Eye Test (REET) was performed.
This step-wise procedure is in accordance with OECD Test Guideline 405,UK Home Office regulations and Envigo Research Limited Ethical Testing Strategy.
A study was performed to assess the ocular irritancy potential of the test item in the rabbit following application onto the cornea of the enucleated eye. The results of the study are believed to be of value in predicting the ocular irritation potential of the test item in man.
Method
0.1 mL of the test item was applied onto the cornea of each of three enucleated eyes which had been maintained at a temperature of 32 ±1.5 °C within the superfusion chamber. A further two enucleated eyes remained untreated for control purposes.
Results
Maximal ocular irritation observations recorded for the test eyes were as follows:
Corneal Opacity |
FluoresceinUptake |
Mean Corneal Swelling(%) |
Condition of Corneal Epithelium |
|||||
Test Eyes a |
Control Eyes b |
|||||||
Cldy x Area |
Int x Area |
60 ruins |
120 ruins |
240 ruins |
60 ruins |
120 ruins |
240 ruins |
|
3 |
4+ |
31.3+ |
54.7+ |
90.0+ |
7.9 |
9.0 |
7.8 |
sloughing+ |
a= For each time point the swelling recorded is the mean of three eyes
b= For each time point the swelling recorded is the mean of two eyes
Cldy = Cornealc loudiness
Int= Intensity of fluoresceinu ptake
mms = Minutes following treatment
+= Meets or exceeds cut-off value indicating a severe ocular irritant
Conclusion
Following assessment of the data for all endpoints the test item was considered to have the potential to cause severe ocular irritancy in vivo.
Justification for classification or non-classification
Following assessment of the data for all endpoints the test item was considered to have the potential to cause severe ocular irritancy in vivo.
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