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Diss Factsheets

Administrative data

Description of key information

Not skin irritating

Eye Irrit 2 (H319), according to the CLP Regulation EC 1272/2008

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Principles of method if other than guideline:
The patch test technique described in the "Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics" (1959), the US Association of Food and Drug Officials (AFDO)
GLP compliance:
no
Species:
rabbit
Strain:
Himalayan
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 1.5 to 2 kg.
- Housing: animals were housed individually in metal cages.
- Diet: rabbit food - NAFAG, Gossau SG -, ad libitum.
- Water: ad libitum.
- Acclimation period: animals were adapted to our laboratories for a minimum of 8 days.

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 1 °C
- Relative humidity: 55 ± 5 %
- Photoperiod: 14 hours light cycle day.
Type of coverage:
occlusive
Preparation of test site:
other: abraded and intact
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
0.5 g
Duration of treatment / exposure:
24 hours
Observation period:
72 hours
Number of animals:
3 male and 3 female rabbits
Details on study design:
TEST SITE
- Area of exposure: two days before treatment the entire back and the flank of the rabbits were shaved with an electric clipper and immediately before treatment the shaven skin on the left side was slightly scarified. For treatment gauze patches of 2.5 x 2.5 cm with test material were applied to the prepared abraded and non abraded skin.
- Type of wrap if used: the patches were covered with an impermeable material and were fastened to the body of the rabbit with adhesive tape.

OBSERVATION TIME POINTS
The skin irritation was scored immediately and 48 hours after removal of the dressings (24 and 72 hours after initiation of treatment).

SCORING SYSTEM
The severity of skin irritation was rated as follows: a mean value of less than 2 indicated mild, from 2 to 6 moderate and above 6 severe skin irritation.
The primary irritation index is the mean value of the sum of the scores for erythema and edema from all 6 rabbits 24 and 72 hours after initiation of treatment. The maximum possible score is 8

Erythema and eschar formation
No erythema 0
Very slight erythema (barely perceptible) 1
Well defined erythema 2
Moderate to severe erythema 3
Severe erythema (beet redness) to slight eschar formation (injuries in depth) 4
Maximum possible erythema score 4

Edema formation
No edema 0
Very slight edema (barely perceptible) 1
Slight edema (edges of area well defined by definite raising) 2
Moderate edema (raised approximately 1 mm) 3
Severe edema (raised more than 1 mm and extending beyond area of exposure) 4
Maximum possible edema score 4
Irritation parameter:
erythema score
Basis:
animal: 6/6
Remarks:
both intact and abraded skin
Time point:
24/48/72 h
Score:
< 2.3
Reversibility:
fully reversible within: 72 hrs in the case of abraded skin
Remarks on result:
no indication of irritation
Remarks:
in the case of intact skin
Irritation parameter:
edema score
Basis:
animal: 6/6
Remarks:
both intact and abraded skin
Time point:
24/48/72 h
Score:
< 2.3
Reversibility:
fully reversible within: 72 hrs in the case of abraded skin
Remarks on result:
no indication of irritation
Remarks:
in the case of intact skin
Irritant / corrosive response data:
The primary skin irritation index in the experiment was established to be 0.1. The test material caused therefore a mild skin irritation to rabbits.

Skin irritation in individual rabbits

Animal Reaction Intact skin Abraded skin
24 hrs 72 hrs 24 hrs 72 hrs
Male 1 Erythema 0 0 0 0
Male 2 Erythema 0 0 0 0
Male 3 Erythema 0 0 2 0
Female 4 Erythema 0 0 0 0
Female 5 Erythema 0 0 1 0
Female 6 Erythema 0 0 0 0
Male 1 Oedema 0 0 1 0
Male 2 Oedema 0 0 0 0
Male 3 Oedema 0 0 0 0
Female 4 Oedema 0 0 0 0
Female 5 Oedema 0 0 0 0
Female 6 Oedema 0 0 0 0
Interpretation of results:
other: not classified, according to the CLP Regulation (EC) No 1272/2008
Conclusions:
Mild skin irritant.
Executive summary:

The skin irritation of the test item was evaluated in a study conducted according to 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). Six rabbits (3 males/3 females) of the Russian breed, weighing 1.5 to 2 kgs, were shaved on the whole back and flanks two days before treatment with an electric clipper. The shaven skin on the left side was slightly scarified immediately before treatment. A gauze patch of 2.5 x 2.5 cm with the test substance was applied to the prepared skin. The patches were covered with an impermeable material and were fixed to the body with adhesive tape. The substance was applied to each side in quantities of 0.5 g. The gauze patches were removed 24 hours after the application. The reaction of the skin was appraised upon removal and 72 hours after it. The primary irritation index as the measure of the acute skin irritation provoked by the substance is defined as the average of all the ratings found after 24 and 72 hours on the intact and slightly scarified skin. No erythema or edema were seen with the exposed intact skin. Slight irritation was observed with abraded skin of 3 rabbits. The primary irritation index was 0.1.

Conclusion

Mean values from gradings at 24, 48 and 72 hours after patch removal were lower than 2.3 in all the tested animals, for both intact and abraded skin and for both erythema/eschar and oedema reactions; therefore, the test item does not meet the criteria to be classified as irritating, according to the CLP Regulation (EC) No 1272/2008.

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Principles of method if other than guideline:
As per the procedure described in the "Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics" (1959), the US Association of Food and Drug Officials (AFDO).
GLP compliance:
no
Species:
rabbit
Strain:
Himalayan
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 1.5 to 2 kg.
- Housing: animals were housed individually in metal cages.
- Diet: rabbit food - NAFAG, Gossau SG -, ad libitum.
- Water: ad libitum.
- Acclimation period: animals were adapted to our laboratories for a minimum of 8 days. Only rabbits with normal ophthalmic findings were used for these tests.

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 1 °C
- Relative humidity: 55 ± 5 %
- Photoperiod: 14 hours light cycle day.
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
0.1 g
Duration of treatment / exposure:
In 3 out of 6 rabbits treated eye was flushed approximately 30 seconds after treatment; the remaining 3 rabbits did not receive any flushing during the entire study period.
Observation period (in vivo):
7 days
Number of animals or in vitro replicates:
3 male and 3 female rabbits
Details on study design:
APPLICATION OF TEST SUBSTANCE
The test material in an amount of 0.1 g was inserted into the conjunctival sac of the left eye of the 6 rabbits and the lids were gently closed for one second. The right eye was not treated and served as an untreated control.

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

TOOL USED TO ASSESS SCORE: hand-slit lamp.

OBSERVATION TIME POINTS
The eye irritation was appraised with a slit-lamp on day 1, 2, 3, 4 and 7.

SCORING SYSTEM
The eye irritation was scored for each individual rabbit. The primary eye irritation, index represents the sum of the mean values for cornea, iris and conjunctivae. This procedure was carried out separately for unrinsed and rinsed eyes respectively.

Score for eye irritation in rabbits:
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 adj acent 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

The total maximum score was thus 80 for the cornea, 10 for the iris, 20 for the conjunctivae and 110 for the entire eye. The severity of overall eye irritation was rated as:
0 - 10 minimal
11 - 25 slight
26 - 56 moderate
57 - 84 marked
above 84 extreme

The ratio unrinsed Vs rinsed eyes indicates the effect of rinsing the eyes 30 seconds after instillation of the compound.
<1 = rinsing increased the effect of the compound
1.1-1.5 = practically no effect
R = 1.6-2 = little but assessable effect
2.1-4 = good effect
4.1-10 = very good effect
>10 = action of the compound practically abolished
Irritation parameter:
cornea opacity score
Basis:
animal: 2/3
Remarks:
rinsed eyes
Time point:
24/48/72 h
Score:
>= 1
Reversibility:
fully reversible within: 4 days
Irritation parameter:
iris score
Basis:
animal: 3/3
Remarks:
rinsed eyes
Time point:
24/48/72 h
Score:
< 1
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal: 3/3
Remarks:
rinsed eyes
Time point:
24/48/72 h
Score:
< 2
Remarks on result:
no indication of irritation
Irritation parameter:
chemosis score
Basis:
animal: 3/3
Remarks:
rinsed eyes
Time point:
24/48/72 h
Score:
< 2
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
The irritation index was established as 3.4 for the cornea, 0 for the iris and 1.6 for the conjunctivae.
The test material caused therefore a minimal overall eye irritation to rabbits.
Effect of rinsing was determined to be 3.1, indicating the 'good effect' of rinsing in minimising the irriatation effect of the test substance.

Animal N./sex Effect Days after application
1 2 3 4 7
RINSED EYES
1 F Cornea 5 5 0 0 0
2 F Cornea 5 5 5 0 0
3 F Cornea 5 5 5 0 0
1 F Iris 0 0 0 0 0
2 F Iris 0 0 0 0 0
3 F Iris 0 0 0 0 0
1 F Conjuntivae 0 0 0 0 0
2 F Conjuntivae 0 0 0 0 0
3 F Conjuntivae 0 0 0 0 0
NOT RINSED EYES
4 M Cornea 10 10 5 0 0
5 M Cornea 10 5 5 0 0
6 M Cornea 10 5 5 0 0
4 M Iris 0 0 0 0 0
5 M Iris 0 0 0 0 0
6 M Iris 0 0 0 0 0
4 M Conjuntivae 8 10 6 0 0
5 M Conjuntivae 6 6 0 0 0
6 M Conjuntivae 6 6 0 0 0
Interpretation of results:
other: eye irrit 2 (H319), according to the CLP Regulation (EC) No 1272/2008
Conclusions:
Minimal eye irritating
Executive summary:

The eye irritation potential of the test substance was evaluated in a study conducted as per the procedure described in the "Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics" (1959), the US Association of Food and Drug Officials (AFDO). The test was performed on 3 male and 3 female rabbits of Himalayan breed weighing 1.5 to 2 kgs. The test material in an amount of 0.1 g was inserted into the conjunctival sac of the left eye of the 6 rabbits and the lids were gently closed for one second. The right eye was not treated and served as an untreated control. In 3 of the 6 rabbits approximately 30 seconds after treatment the treated eye was flushed with 10 ml of lukewarm water. The eye irritation was appraised with a slit-lamp on day 1, 2, 3, 4 and 7 and was scored for each individual rabbit.

A slight persistent blue coloration of the sclera was observed throughout the test. The irritation index was established as 3.4 for the cornea, 0 for the iris and 1.6 for the conjunctivae. The test material caused therefore a minimal overall eye irritation to rabbits. Rinsing the eyes following instillation was found to be of ‘good effect’ in minimizing the irritation.

Conclusion

Although the criteria for the evaluation of the eye irritation potential followed in the test are different from those reported into the OECD guideline currently in force, the scoring system used for corea opacity and degree of density, for the iris and for the conjunctivae redness and chemosis is the same of that reported into the OECD. Thus, 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 rinsed eyes were equal to 1 for corneal opacity, lower than 1 for irtitis, lower than 2 for both conjunctival redness and oedema, in at least 2 out of 3 tested animals.

Therefore the substance meets the criteria to be classified as eye irritating, according to the CLP (EC) 1272/2008 Regulation.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

SKIN IRRITATION

Three studies are available for assessment of the skin irritation potential of test item.

In the key study, the skin irritation of the test item was evaluated in a study conducted according to 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). 3 males and 3 females rabbits (intact and scarified skin) were occlusively treated with 0.5 g of the test substance. The gauze patches were removed 24 hours after the application. The reaction of the skin was appraised upon removal and 72 hours after it. No erythema or edema were seen with the exposed intact skin. Slight irritation was observed with abraded skin of 3 rabbits.

Two additional studies are also available; however, they were conducted on samples characterized by a limited content of the Fluorescent Brightener 363, thus the obtained results should be considered only in supporting approach.

In one case, the skin irritation potential of the test substance was evaluated according to the procedure described in Proposed Guidelines of the United States Environmental Agency (EPA) § 163.81-5 "Primary dermal irritation study", Federal Register, Vol. 43, No. 163, August 22, 1978. The test was performed on 3 male and 3 female rabbits. 0.5 g of the test material were applied to the prepared abraded and intact skin. The patches were covered with an impermeable material and the dressings were removed after a 24 hour application. The test item was found to cause no irritation when applied to intact and abraded rabbit skin.

In the other case, the skin irritation potential of the test substance was evaluated according to OECD Guideline 404. The test was performed on 3 male rabbits. 0.5 ml of the test substance was applied to the skin and exposure duration was 4 hours. Slight erythema was found with one of the treated animals after 1 hour of dressing removal. The animals were free of findings at the 24 hours scoring.

EYE IRRITATION

Three studies are available for assessment of the eye irritation potential of test item.

In the key study, the eye irritation potential of the test substance was evaluated in a study conducted as per the procedure described in the "Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics" (1959), the US Association of Food and Drug Officials (AFDO). The test was performed on 3 male and 3 female rabbits and the test material was applied in an amount of 0.1 g. In 3 of the 6 rabbits approximately 30 seconds after treatment the treated eye was flushed with 10 ml of lukewarm water. A slight persistent blue coloration of the sclera was observed throughout the test. Based on the scoring system, the mean values from gradings at 24, 48 and 72 hours for rinsed eyes can be calculated to be equal to 1 for corneal opacity, lower than 1 for irtitis, lower than 2 for both conjunctival redness and oedema, in at least 2 out of 3 tested animals.

Two additional studies are also available; however, they were conducted on samples characterized by a limited content of the Fluorescent Brightener 363, thus the obtained results should be considered only in supporting approach.

In one case, the eye irritation potential of the test substance was evaluated in a study conducted according to the Proposed Guidelines of the United States Environmental Protection Agency (EPA) § 163.81-4 "Primary eye irritation study", Federal Register, Vol. 43, No. 163, August 22, 1978. The test was performed on 3 male and 3 female rabbits and the test material was applied in an amount of 0.1 g. In 3 of the 6 rabbits approximately 30 seconds after treatment the treated eye was flushed with 10 ml of physiological saline. No irritation was seen in the study. Primary irritation index in unrinsed as well as rinsed eyes was 0.

In the other case, the eye irritation potential of the test substance was evaluated according to OECD Guideline 405. The test was performed on 3 female rabbits, applying an amount of 0.1 ml of the test material. The test item resulted to be slightly irritant and not corrosive when applied to the rabbit eye mucosa; the animals were free of findings at the 48 hours scoring.

Justification for classification or non-classification

According to the CLP Regulation (EC) No 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 the key study, mean values from gradings at 24, 48 and 72 hours after patch removal were lower than 2.3 in all animals for both erythema/eschar and oedema reactions, thus the test item does not meet the criteria to be classified as irritating, according to the CLP Regulation (EC) No. 1272/2008.

According to the CLP Regulation (EC) No 1272/2008, serious eye damage means the production of tissue damage in the eye, or serious physical decay of vision, following application of a test substance, which is not fully reversible within 21 days of application. Eye irritation means the production of changes in the eye, which are fully reversible within 21 days of application.

In the key study, based on the scoring system, the mean values from gradings at 24, 48 and 72 hours for rinsed eyes can be calculated to be equal to 1 for corneal opacity, lower than 1 for irtitis, lower than 2 for both conjunctival redness and oedema, in at least 2 out of 3 tested animals; all the reactions resulted to be fully reversible within 4 days. Therefore, the substance meets the criteria to be classified as eye irritating, (Eye Irrit 2, H319), according to the CLP Regulation (EC) No. 1272/2008.