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Administrative data

Description of key information

The test item was found to be not skin corrosive and not skin irritant in vitro and in vivo. It was found to be mild irritant to the eye in vitro. However, in vivo the mean scores of each effect in each animal indicated the substance to be not irritating to the rabbit eye. Additionally, all effects were fully reversible within 7 days. Thus, according to regulation EC/1272/2008, the test item is not irritating to eyes and skin.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
17 September 2009 - 12 October 2009
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:
(2002)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Strain as stated in the report: New Zealand white Crl:KBL (NZW) SPF
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, 88353 Kisslegg
- Age at study initiation: ca. 9 months
- Weight at study initiation: 2300 - 2700 g
- Housing: individually in terulan cages
- Diet ad libitum: Ssniff K-H maintenance diet for rabbits
- Water ad libitum: tap water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12 / 12
Type of coverage:
semiocclusive
Preparation of test site:
other: clipped
Vehicle:
water
Controls:
other: untreated skin area served as control
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 0.5 g (minimally moistened with highly deionised water)
Duration of treatment / exposure:
4 h
Observation period:
0, 1, 24, 48 and 72 h after removal of the patch.
Number of animals:
3 animals
Details on study design:
0.5 g of moistened test article was applied to intact skin on a patch of 2.5 cm x 2.5 cm and covered with semiocclusive dressing. After removal of the patch the application area was washed off with Lutrol and Lutrol/water (1:1). Since no effects were observed within 72 h the study was discontinued therafter.
The evaluation of skin reactions was performed according to the quoted guidelines.


EVALUATION
For evaluation, the calculation of the mean values of erythema and edema for readings at 24, 48 and 72 hours were quoted. Additionally, the reversibility of the observed findings was taken into account.
The evaluation is based on the criteria of the OECD Harmonized Integrated Classification System that was in place on the date of report signature (November 2009)

SCORING SYSTEM
Erythema and eschar formation
Grading
0 No erythema
1 Very slight erythema (barely perceptible)
2 Well defined erythema
3 Moderate to severe erythema
4 Severe erythema (beet redness) to eschar formation preventing grading of erythema

Edema formation
Grading
0 No edema
1 Very slight edema (barely perceptible)
2 Slight edema (edges of area well defined by definite raising)
3 Moderate edema (raised approx. 1 mm)
4 Severe edema (raised more than 1 mm and extending beyond area of exposure)

Descriptions of any dermal findings not covered by this scale were recorded.


Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24; 48; 72 h
Score:
0
Max. score:
4
Reversibility:
other: since no erythema was observed, not applicable
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24, 48, 72 h
Score:
0
Max. score:
4
Reversibility:
other: since no edema was observed, not applicable
Other effects:
No cutaneous reactions were observed in all animals during the study. No clinical signs of intoxication were reported in the study.
Interpretation of results:
GHS criteria not met
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
7 October 2009 - 17 November 2009
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:
(2002)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Strain as stated in the report: New Zealand white Crl:KBL (NZW) SPF
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, 88353 Kisslegg
- Age at study initiation: ca. 9 months
- Weight at study initiation: 2300 - 2600 g
- Housing: individually in terulan cages
- Diet ad libitum: Ssniff K-H maintenance diet for rabbits
- Water ad libitum: tap water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12 / 12

Vehicle:
unchanged (no vehicle)
Controls:
other: untreated left eye
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 0.1 ml bulk volume (about 49 mg of the comminuted test item) into the right eye.
Duration of treatment / exposure:
24 h after single application into the conjunctival sac of the right eyelid the eye was rinsed with hand warm tap water.
Observation period (in vivo):
Readings were 1, 24, 48 and 72 h after application and on day 7 in 2/3 of the animals.
Mortality was checked twice each workday and once daily at weekends.
Since all effects were fully reversible within 7 days the study was discontinued thereafter.
Number of animals or in vitro replicates:
3 animals
Details on study design:
REMOVAL OF TEST SUBSTANCE:
- Washing: 24 h after treatment the treated eye was rinsed with hand warm tap water

EVALUATION:
For evaluation, the calculation of the mean values of corneal opacity, iris, conjunctival redness and chemosis for readings 24, 48 and 72 hours were quoted. Additionally, the reversibility of the observed findings was taken into account. The evaluation is based on the criteria of the OECD Harmonized Integrated Classification System that was in place on the date of report signature (November 2009). In addition to specific observations recommended by the regulatory authorities, evaluations were made of discharge from the eye and the area of cornea affected by the lesions.

SCORING SYSTEM:
Cornea opacity:
Degree of density (the most dense area is taken for reading)
Grading
0 No ulceration or opacity
1 Scattered or diffuse areas of opacity (other than slight dulling of normal lustre), details of iris clearly visible
2 Easily discernible translucent area, details of iris slightly obscured
3 Nacreous area, no details of iris visible, size of pupil barely discernible
4 Opaque cornea, iris not discernible through the opacity

Area of cornea involved (The assessment of these ocular reactions is performed independent of the quoted guidelines)
Grading
1 > 0 ≤ ¼, 2 > ¼ < ½, 3 > ½ < ¾, 4 > ¾

Iris:
Grading
0 Normal
1 Markedly deepened rugae, congestion, swelling, moderate circumcorneal hyperaemia or injection, any of these observations or combination of any thereof, iris still reacting to light (sluggish reaction is positive)
2 No reaction to light, haemorrhage, gross destruction (any or all of these)

Conjunctivae redness (Refers to palpebral and bulbar conjunctivae, not to cornea and iris):
Grading
0 Blood vessels normal
1 Some blood vessels definitely hyperaemic (injected)
2 Diffuse, crimson colour, individual vessels not easily discernible
3 Diffuse beefy red

Chemosis:
Lids and/or nictitating membrane
Grading
0 No swelling
1 Any swelling above normal (includes nictitating membranes)
2 Obvious swelling with partial eversion of lids
3 Swelling with lids about half closed
4 Swelling with lids more than half closed

Discharge (The assessment of these ocular reactions is performed independent of the quoted guidelines)
Grading
0 No discharge
1 Any amount different from normal (does not include small amounts observed in inner canthus of normal animals)
2 Discharge with moistening of the lids and hairs just adjacent to lids
3 Discharge with moistening of the lids and hairs, and considerable area around the eye

Descriptions of any ocular findings not covered by this scale were recorded.

TOOL USED TO ASSESS SCORE:
otoscope lamp
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
other: 24, 48, 72 h
Score:
0.7
Max. score:
4
Reversibility:
fully reversible within: 72 h
Irritation parameter:
cornea opacity score
Basis:
other: animal # 2 and # 3
Time point:
other: 24, 48, 72 h
Score:
0
Max. score:
4
Reversibility:
other: no effects
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24, 48, 72 h
Score:
0.2
Max. score:
4
Remarks on result:
other: Corneal opacity was only seen in one animal.
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24, 48, 72 h
Score:
0
Max. score:
2
Reversibility:
other: not applicable, since no effects on iris were seen
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
other: 24, 48, 72 h
Score:
1.3
Max. score:
3
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
other: 24, 48, 72 h
Score:
0.7
Max. score:
3
Reversibility:
fully reversible within: 72 h
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
other: 24, 48, 72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24, 48, 72 h
Score:
1
Max. score:
3
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
other: 24, 48, 72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
other: 24, 48, 72 h
Score:
0.7
Max. score:
4
Reversibility:
fully reversible within: 72 h
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
other: 24, 48, 72 h
Score:
1.3
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24, 48, 72 h
Score:
1.3
Max. score:
4
Remarks on result:
other: All animals showed chemosis graded 4 after 1h, which decreased (grade 1 and 2) within 24 h.
Other effects:
Slight discharge (grade 1) was noted in all animals after 1 h, which disappeared after 48 h latest.
No clinical observations were reported in the study.
Interpretation of results:
GHS criteria not met
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation

In a GLP-compliant assay following OECD guideline 404 the potential of the test item to cause acute dermal irritation or corrosion was assessed by a single topical application of an amount of 0.5 g of the test item for 4 hours to the intact skin of three White New Zealand rabbits (stepwise procedure starting with one animal and supplementing two additional animals) using a patch of 2.5 cm x 2.5 cm, covered with semiocclusive dressing. After removal of the patch the application area was washed off with Lutrol®** and Lutrol® / water (1 : 1). The cutaneous reactions were assessed immediately after removal of the patch, approximately 1, 24, 48 and 72 hours after removal of the patch.

No adverse skin reactions were observed in all animals at any examination term. Mean scores over 24, 48 and 72 hours for each animal were 0.0, 0.0 and 0.0 for erythema and 0.0, 0.0 and 0.0 for edema.

Considering the described cutaneous reactions as well as the average score for irritation, the test item does not show a skin irritation potential under the test conditions chosen.

In addition, two in vitro tests are available assessing the dermal irritation potential. The ability of the test item to induce skin corrosion in vitro was evaluated using a human three dimensional epidermal model (EpiDerm Skin Model). Since the mean relative tissue viability was not below 50% after the 3-minute treatment and not below 15% after the 1-hour treatment, the test item is considered not to be corrosive. The in vitro skin irritation potential was determined using a human three dimensional epidermal model (EPISKIN Standard model). The relative mean tissue viability obtained after 15 minutes treatment with the test substance compared to the negative control was 94%. Since the result was above 50% after 15 minutes, the test item is considered as not skin irritant in vitro.

Eye irritation

In a GLP-compliant assay following OECD guideline 405 the potential of the test item to cause damage to the conjunctiva, iris or cornea was assessed by a single ocular application of 0.1 mL bulk volume (about 49 mg) of the test item to one eye of three White New Zealand rabbits (stepwise procedure starting with one animal and supplementing two additional animals). About 24 hours after application the eye was rinsed with tap water. The ocular reactions were assessed approximately 1, 24, 48 and 72 hours after application and then in weekly intervals until day 7 at latest. Slight corneal opacity (area involved < ¼ , circular, in the central part of the eye) was observed in one animal from 24 h until 48 h p.a. Slight to moderate conjunctival redness, slight to severe conjunctival chemosis and slight discharge were observed in the animals

during the course of the study. The ocular reactions were reversible in all animals within 7 days after application at latest. Mean scores calculated for each animal over 24, 48 and 72 hours were 0.7, 0.0 and 0.0 for

corneal opacity, 0.0, 0.0 and 0.0 for iris lesions, 1.3, 0.7 and 1.0 for redness of the conjunctiva and 2.0, 0.7 and 1.3 for chemosis. Considering the described ocular reactions as well as the average score for irritation, the test item is not irritating to eyes under the test conditions chosen.

In addition, an in vitro assay is available. The ocular irritation potential was tested through topical application for 240 +/- 10 minutes using the BCOP assay. The test item induced a mean in vitro irritancy score of 5.4 after 240 minutes of treatment. The test item is mildly irritant in the BCOP assay.

Respiratory Irritation

Experimental data on respiratory irritation are not available.

Justification for classification or non-classification

Classification, Labeling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is not considered to be classified for skin or eye irritation under Regulation (EC) No. 1272/2008.