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Description of key information

Not skin irritating.

Not eye irritating.

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:
From May 12 to15, 1987
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Test conducted according to internationally accepted testing guidelines.
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
adopted May 12, 1981
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Kleintierfarm Madoerin AG, CH-4414 Fuellinsdorf.
- Age at study initiation: approx. 12-14 weeks old.
- Weight at study initiation: between 2190 t o 2470 g.
- Housing: individually housed in metal cages.
- Diet: ad libitum, standard rabbit pellet NAFAG, N. 814 Gossau. All batches of the diet are assayed for nutritive ingredients and contaminant level by the manufacturer.
- Water: ad libitum. The quality of the drinking water was according to the specification of the "Schweizerisches Lebensmittelbuch" (Edition 1972).
- Acclimation period: 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature: constant room temperature of 20 ± 3 °C
- Humidity: relative humidity of 30-70 %
- Photoperiod: 12 hrs light cycle day.
Type of coverage:
occlusive
Preparation of test site:
shaved
Vehicle:
water
Controls:
yes, concurrent vehicle
Amount / concentration applied:
A gauze patch (20 cm2) bearing 0.5 g of the test substance was applied to the flank.
A control gauze patch was applied to the contra-lateral flank. Both gauze patches were moistened before application with distilled water.
Duration of treatment / exposure:
4 hours
Observation period:
The skin reactions were evaluated 1, 24, 48, and 72 hours after removing the gauze patches.
Number of animals:
3 males
Details on study design:
TEST SITE
- Area of exposure: an area of at least 6 cm2 was shaved on both flanks of the animals approximately 24 hours before treatment.
- Type of wrap if used: the patches were loosely covered with an aluminium foil (36 cm2 ) and held in place for 4 hours by an adhesive tape (Isoplast, Isoplast AG, CH-5200 Brugg).

OBSERVATION
The animals were checked daily for systemic symptoms and mortality.

SCORING SYSTEM
According to the OECD scoring system.
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
4
Reversibility:
fully reversible
Irritant / corrosive response data:
Because no reactions were observed at 24 hours to 7 2 hours after removing the bandages, the test was ended after the 72 hours evaluation.
It can be concluded that test item has no primary skin irritant potency in albino rabbits.

Evaluation of skin reaction

Animal no. Erythema Oedema
25/M 26/M 27/M 25/M 26/M 27/M
CF/TF CF/TF CF/TF CF/TF CF/TF CF/TF
After 1 hr 0/0 0/0 0/0 0/0 0/0 0/0
After 24 hrs 0/0 0/0 0/0 0/0 0/0 0/0
After 48 hrs 0/0 0/0 0/0 0/0 0/0 0/0
After 72 hrs 0/0 0/0 0/0 0/0 0/0 0/0
mean 24-72 hrs 0/0 0/0 0/0 0/0 0/0 0/0

CF = control flank; TF = test flank

Interpretation of results:
not irritating
Remarks:
Migrated information according to the CLP Regulation Criteria used for interpretation of results: EU
Conclusions:
Not irritating.
Executive summary:

Method

The skin irritation potential was assessed according to the OECD guideline No. 404, adopted May 12, 1981, by the OECD council.

Results

Under the experimental conditions employed test item did not induce skin irritation when applied to the clipped albino rabbit skin. Because no reactions were observed at 24 hours to 72 hours after removing the bandages, the test was ended after the 72 hours evaluation.

Conclusion

It can be concluded that test item has no primary skin irritant potency in albino rabbits.

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:
other: read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study conducted according to internationally accepted testing guidelines, well documented and the results scientifically acceptable. The test was performed on the analogous substance with salification sodium/potassium instead that sodium only. This difference is not relevant from the toxicological point of view for the assessment of the specific endpoint.
Principles of method if other than guideline:
The procedure adopted was the patch-test technique described in the "Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics" (1959) of the US Association of Food and Drug Officials (AFDO).
GLP compliance:
no
Remarks:
Pre GLP
Species:
rabbit
Strain:
Himalayan
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: WIGA Versuchstierzuchtanstalt Sulzfeld, Germany.
- Age at study initiation: adult.
- Weight at study initiation: 1.5 to 2.
- Housing: individually housed in metal cages.
- Diet: ad libitum, standard rabbit food NAFAG, Gossau SG.
- Water: ad libitum.
- Acclimation period: for a minimum of 4 days

ENVIRONMENTAL CONDITIONS
- Temperature: constant room temperature of 22 ± 1°C
- Humidity: relative humidity of 55 ± 5%
- Photoperiod: 10 hrs light cycle day.
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 0.1 ml
Observation period (in vivo):
7 days
Number of animals or in vitro replicates:
Six animals
Details on study design:
APPLICATION
The test material in an amount of 0.1 ml was inserted into the conjunctival sac of the left eye of the 6 rabbits and the lids were gently closed for a few seconds. The right eye was not treated and served as an untreated control.

REMOVAL OF TEST SUBSTANCE
- Washing: in 3 of the 6 rabbits the treated eye was flushed with 10 ml of physiological saline.
- Time after start of exposure: approximately 30 seconds after treatment.

SCORING SYSTEM
CORNEA:
A Opacity and degree of density (most dense area scored) .
No opacity: 0
Scattered or diffuse area, details of iris clearly visible: 1
Easily discernible translucent areas, details of iris slightly obscured: 2
Opalescent areas, no details of iris visible, size of pupil barely discernible: 3
Opaque, iris invisible: 4
B Area of cornea involved
One quarter (or less) but not zero: 1
Greater than one quarter, but less than half: 2
Greater than half, but less than three quarters: 3
Greater than three quarters, up to whole area: 4
A x B x 5; Maximum possible score = 80

IRIS:
A Values
Normal: 0
Folds above normal, congestion, swelling, circumcornea injection (any or all of these or combination of any thereof) iris still reacting to light (sluggish reaction is positive: 1
No reaction to light, hemorrhage, gross destruction (any or all of these): 2
A x 5; Maximum possible score = 10

CONJUNCTIVAE:
A Redness (refers to palpebral and bulbar conjunctivae excluding cornea and iris)
Vessels normal: 0
Vessels definitely injected above normal: 1
More diffuse, deeper crimson red, individual vessels not easily discernible: 2
Diffuse beefy red: 3
B Chemosis
No swelling: 0
Any swelling above normal (includes nictitating membrane): 1
Obvious swelling with partial eversion of lids: 2
Swelling with lids about half closed: 3
Swelling with lids about half closed to completely closed: 4
C Discharge
No discharge: 0
Any amount different from normal (does not include small amounts observed in inner canthus of normal animals): 1
Discharge with moistening of the lids and hairs just adjacent to lids: 2
Discharge with moistening of the lids and hairs, and considerable area around the eye: 3
(A + B + C) x 2; Maximum possible score = 20

TOOL USED TO ASSESS SCORE: eye irritation was appraised with a slit-lamp on day 1, 2, 3, 4 and 7.
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
cornea opacity score
Basis:
animal #4
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
cornea opacity score
Basis:
animal #5
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
cornea opacity score
Basis:
animal #6
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
2
Reversibility:
fully reversible
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
2
Reversibility:
fully reversible
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
2
Reversibility:
fully reversible
Irritation parameter:
iris score
Basis:
animal #4
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
2
Reversibility:
fully reversible
Irritation parameter:
iris score
Basis:
animal #5
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
2
Reversibility:
fully reversible
Irritation parameter:
iris score
Basis:
animal #6
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
2
Reversibility:
fully reversible
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
3
Reversibility:
fully reversible
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
3
Reversibility:
fully reversible
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
3
Reversibility:
fully reversible
Irritation parameter:
conjunctivae score
Basis:
animal #4
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
3
Reversibility:
fully reversible
Irritation parameter:
conjunctivae score
Basis:
animal #5
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
3
Reversibility:
fully reversible
Irritation parameter:
conjunctivae score
Basis:
animal #6
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
3
Reversibility:
fully reversible
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
chemosis score
Basis:
animal #4
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
chemosis score
Basis:
animal #5
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
chemosis score
Basis:
animal #6
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
4
Reversibility:
fully reversible
Irritant / corrosive response data:
The primary irritation index in unrinsed eyes was estimated to be 0.
The primary irritation index in rinsed eyes was estimated to be 0.

Rabbit eye irritation scores

Animal Eye Parameter hrs days
24 48 72 4 7

Cornea

1 Rinsed Opacity 0 0 0 0 0
Area involved 0 0 0 0 0
Unrinsed Opacity 0 0 0 0 0
Area involved 0 0 0 0 0
2 Rinsed Opacity 0 0 0 0 0
Area involved 0 0 0 0 0
Unrinsed Opacity 0 0 0 0 0
Area involved 0 0 0 0 0
3 Rinsed Opacity 0 0 0 0 0
Area involved 0 0 0 0 0
Unrinsed Opacity 0 0 0 0 0
Area involved 0 0 0 0 0
4 Rinsed Opacity 0 0 0 0 0
Area involved 0 0 0 0 0
Unrinsed Opacity 0 0 0 0 0
Area involved 0 0 0 0 0
5 Rinsed Opacity 0 0 0 0 0
Area involved 0 0 0 0 0
Unrinsed Opacity 0 0 0 0 0
Area involved 0 0 0 0 0
6 Rinsed Opacity 0 0 0 0 0
Area involved 0 0 0 0 0
Unrinsed Opacity 0 0 0 0 0
Area involved 0 0 0 0 0

Iritis

1 Rinsed 0 0 0 0 0
Unrinsed 0 0 0 0 0
2 Rinsed 0 0 0 0 0
Unrinsed 0 0 0 0 0
3 Rinsed 0 0 0 0 0
Unrinsed 0 0 0 0 0
4 Rinsed 0 0 0 0 0
Unrinsed 0 0 0 0 0
5 Rinsed 0 0 0 0 0
Unrinsed 0 0 0 0 0
6 Rinsed 0 0 0 0 0
Unrinsed 0 0 0 0 0

Conjunctival

1 Rinsed Redness 0 0 0 0 0
Chemosis 0 0 0 0 0
Discharge 0 0 0 0 0
Unrinsed Redness 0 0 0 0 0
Chemosis 0 0 0 0 0
Discharge 0 0 0 0 0
2 Rinsed Redness 0 0 0 0 0
Chemosis 0 0 0 0 0
Discharge 0 0 0 0 0
Unrinsed Redness 0 0 0 0 0
Chemosis 0 0 0 0 0
Discharge 0 0 0 0 0
3 Rinsed Redness 0 0 0 0 0
Chemosis 0 0 0 0 0
Discharge 0 0 0 0 0
Unrinsed Redness 0 0 0 0 0
Chemosis 0 0 0 0 0
Discharge 0 0 0 0 0
4 Rinsed Redness 0 0 0 0 0
Chemosis 0 0 0 0 0
Discharge 0 0 0 0 0
Unrinsed Redness 0 0 0 0 0
Chemosis 0 0 0 0 0
Discharge 0 0 0 0 0
5 Rinsed Redness 0 0 0 0 0
Chemosis 0 0 0 0 0
Discharge 0 0 0 0 0
Unrinsed Redness 0 0 0 0 0
Chemosis 0 0 0 0 0
Discharge 0 0 0 0 0
6 Rinsed Redness 0 0 0 0 0
Chemosis 0 0 0 0 0
Discharge 0 0 0 0 0
Unrinsed Redness 0 0 0 0 0
Chemosis 0 0 0 0 0
Discharge 0 0 0 0 0
Interpretation of results:
not irritating
Remarks:
Migrated information according to the CLP Regulation Criteria used for interpretation of results: EU
Conclusions:
Not irritating
Executive summary:

Method

The eye irritation potential was assessed following the procedure of the patch-test technique described in the "Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics" (1959) of the US Association of Food and Drug Officials (AFDO).

Results

The primary irritation index in unrinsed eyes was estimated to be 0.

The primary irritation index in rinsed eyes was estimated to be 0.

Therefore, the substance resulted not irritating.

Discussion and conclusion

The criteria for the evaluation of the eye irritation potential followed in the test are different from those reported into the OECD guideline. The scoring system used for the corea opacity and degree of density, for the iris and conjunctivae redness and chemosis is the same of that reported into the OECD, but the timing for the removal of the substance are very different (30 seconds in the current study and 1 hours in the OECD). Nevertheless, because the raw tables are included into the study report, it is possible to re-evaluate the results according to the CLP Regulation (EC 1272/2008).

The mean values from gradings at 24, 48 and 72 hours for both rinsed and unrinsed eyes were 0 in all animals for all the reactions scored.

In conclusion, the test item can be classified as NON irritating, according to the CLP Regulation (EC 1272/2008).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

SKIN IRRITATION

Under the experimental conditions employed test item did not induce skin irritation when applied to the rabbits skin. No reactions were observed at 24 hours to 72 hours after removing the bandages in both the occlusive tests, in which the substance was applied to the intact skin (Ciba-Geigy Ltd., 1987 (purity: 90 %) and Ciba-Geigy Ltd., 1974 (purity: 97 %)); in the semiocclusive test (Tomlinson 1993 (purity: 20 %)) the substance produced in three rabbits well-defined erythema and very slight oedema; all treated skin sites appeared normal at the 48-hour observation.

Nevertheless in all the three tests available, it can be concluded that test item has no skin irritant potency in rabbits.

EYE IRRITATION

In the Ciba-Geigy Ltd., 1987 study, a positive response in all the three rabbits tested was reported for corneal opacity at score 1, therefore according to the CLP regulation the substance would be classified as Eye Irrit. 2. Nevertheless the procedures described in the OECD guideline 405 report that "when testing solids, pastes, and particulate substances, the amount used should have a volume of 0.1 mL or a weight of not more than 100 mg. [... ] If the solid test substance has not been removed from the eye of the test animal by physiological mechanisms at the first observation time point of 1 hour after treatment, the eye may be rinsed with saline or distilled water"; in the test it is not specified if the substance was removed after 1 hour or not. Considering that the classification is strictly borderline this aspect may be discriminating. In conclusion, the results obtained in the present test have to be confirmed in order to evaluate a correct classification according to the current regulation on classification, labelling and packaging EC 1272/2008.

A study was performed to assess the irritancy potential of the test material to the skin of the New Zealand white rabbit, with negative results (Tomlinson, 1993); nevertheless the tested substance purity was too low to correctly evaluate the end point (22 %).

The study reported as key study was performed on CAS 70942-01-7, the analogous substance with salification sodium/potassium instead that sodium only. This difference is not relevant from the toxicological point of view for the assessment of the specific endpoint. Therefore in order to correctly assess the classification properties of the substance, the results on the analogous have been considered.

The eye irritation potential was assessed following the procedure of the patch-test technique described in the "Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics" (1959) of the US Association of Food and Drug Officials (AFDO). The mean values from gradings at 24, 48 and 72 hours for both rinsed and unrinsed eyes were 0 in all animals for all the reactions scored, therefore, the substance resulted not irritating.

Justification for selection of skin irritation / corrosion endpoint:

Test conducted according to internationally accepted testing guidelines.

Justification for selection of eye irritation endpoint:

Test conducted according to internationally accepted testing guidelines on an analogous substance.

Justification for classification or non-classification

According to the CLP Regulation (EC 1272/2008), 3.2 Skin corrosion/irritation section, skin Irritation means the production of reversible damage to the skin following the application of a test substance for up to 4 hours.

In all the studies available, the mean values from gradings at 24, 48 and 72 hours after patch removal were lower than 2.3 in at least 2 of 3 animals for both erythema/eschar and oedema reactions.

According to the Regulation 1272/2008 (CLP) substances that have the potential to induce reversible eye irritation are classified in Category 2 (irritating to eyes) if, when applied to the eye of an animal, a substance produces at least in 2 of 3 tested animals, a positive response of corneal opacity ≥ 1 and/or iritis ≥ 1, and/or conjunctival redness ≥ 2 and/or conjunctival oedema (chemosis) ≥ 2, calculated as the mean scores following grading at 24, 48 and 72 hours after installation of the test material, and which fully reverses within an observation period of 21 days.

The mean values from gradings at 24, 48 and 72 hours for both rinsed and unrinsed eyes were 0 in all animals for all the reactions scored, therefore, the substance resulted not irritating.

In conclusion, the available experimental data are adequate for classification and labelling and the substance is not classified for the eye/skin irritation, according to the CLP Regulation (EC 1272/2008).

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