Registration Dossier

Administrative data

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Internationally accepted guideline, well documented and scientifically acceptable.
Qualifier:
according to guideline
Guideline:
other: "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
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Test animals: rabbits Russian.
- Weight at study initiation: 1.5 to 2 kg.
- Housing: individually housed in metal cages.
- Diet: ad libitum, standard rabbit food NAFAG, Gossau SG.
- Water: ad libitum.
- Acclimation period: for a minimum of 8 days.

ENVIRONMENTAL CONDITIONS
- Temperature: 18 ± 1 °C
- Humidity: 55 ± 5 %
- Photoperiod: 14 hrs light cycle day.
Type of coverage:
occlusive
Preparation of test site:
other: shaved and abraded skin.
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 0.5 g.
- Application: gauze patches of 2.5 x 2.5 cm with test substance were applied to the prepared abraded and non abraded skin.
Duration of treatment / exposure:
The dressing were removed after a 24 hrs exposure.
Observation period:
72 hours.
Number of animals:
3 males and 3 females.
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 one side was slightly scarified.
- Type of wrap if used: patches were covered with an impermeable material and were fastened to the body of the rabbit with adhesive tape.

SCORING SYSTEM
The skin irritation was scored immediately and 48 hours after removal of the dressings (24 and 72 hours after initiation of treatment).
The severity of skin irritation was rated as follow: a mean value of less than 2 indicated mild, from 2 to 5 moderate and above 6 severe skin irritation.

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

Oedema Formation
No oedema: 0
Very slight oedema (barely perceptible): 1
Slight oedema (edges of area well defined by definite raising): 2
Moderate oedema (raised approximately 1 mm): 3
Severe oedema (raised more than 1 mm and extending beyond area of exposure): 4
Maximum possible: 4
Irritation parameter:
erythema score
Basis:
mean
Time point:
24 h
Score:
>= 1.33 - < 1.5
Max. score:
4
Reversibility:
not specified
Irritation parameter:
erythema score
Basis:
mean
Time point:
72 h
Score:
ca. 0
Max. score:
4
Reversibility:
not specified
Irritation parameter:
erythema score
Basis:
mean
Time point:
48 h
Remarks on result:
not measured/tested
Irritation parameter:
edema score
Basis:
mean
Time point:
24 h
Score:
>= 0.33 - < 1
Max. score:
4
Reversibility:
not specified
Irritation parameter:
edema score
Basis:
mean
Time point:
48 h
Remarks on result:
not measured/tested
Irritation parameter:
edema score
Basis:
mean
Time point:
72 h
Score:
ca. 0
Max. score:
4
Reversibility:
not specified
Irritant / corrosive response data:
Primary irritation index was estimated to be 1.2; the substance caused therefore a mild skin irritation to rabbit.

* The scores for 48 hrs were not measured during the test and not reported in the report. The scores for the 48 hrs were inserted in the below table duplicating the highest score for each animal and the mean scores were calculated based on these values for the calculation purposes as required by CLP

Skin Irritation - Intact skin

Animal/sex

Reaction

24 hrs

48 hrs*

72 hrs

Mean (24,48,72 hrs)

1 M

Erythema

0

0

0

0

2 M

Erythema

1

1

0

0.66

3 M

Erythema

0

0

0

0

4 F

Erythema

1

1

0

0.66

5 F

Erythema

1

1

0

0.66

6 F

Erythema

1

1

0

0.66

1 M

Oedema

0

0

0

0

2 M

Oedema

0

0

0

0

3 M

Oedema

0

0

0

0

4 F

Oedema

0

0

0

0

5 F

Oedema

1

1

0

0.66

6 F

Oedema

1

1

0

0.66

Skin reactions - abraded skin

Animal/sex Reaction 24 hrs 72 hrs
1 M Erythema 2 0
2 M Erythema 2 1
3 M Erythema 1 1
4 F Erythema 2 1
5 F Erythema 2 0
6 F Erythema 2 1
1 M Oedema 0 0
2 M Oedema 2 1
3 M Oedema 1 0
4 F Oedema 1 0
5 F Oedema 1 0
6 F Oedema 2 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 skin 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

Primary irritation index was estimated to be 1.2; mild irritating.

Discussion and conclusion

The scoring system criteria used to record the hardness of the skin reactions followed in the current test are the same as those reported into the OECD guideline, therefore it is possible to re-evaluate the results, because the raw tables are included into the study report.

Despite the reaction scores at 48 hours were not reported, the mean value scored is reasonably expected to be less than 2.3 for erythema/eschar and for oedema in at least 2 of 3 tested animals, in both intact and abraded skin, from gradings at 24, 48 and 72 hours after patch removal.

In conclusion, it is reasonable to NOT classify the substance as skin irritant according to the CLP Regulation (EC 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:
other: Internationally accepted guideline, well documented and scientifically acceptable.
Qualifier:
according to guideline
Guideline:
other: "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
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Test animals: rabbit Russian.
- Weight at study initiation: 1.5 to 2 kg.
- Housing: individually housed in metal cages.
- Diet: ad libitum, standard rabbit food NAFAG, Gossau SG.
- Water: ad libitum.
- Acclimation period: for a minimum of 8 days.
- Other: only rabbith with normal ophthalmic findings were used for the test.

ENVIRONMENTAL CONDITIONS
- Temperature: 18 ± 1 °C
- Humidity: 55 ± 5 %
- Photoperiod: 14 hrs light cycle day.
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 0.1 ml.
Duration of treatment / exposure:
In 3 rabbits the treated eye was flushed with 10 ml of lukewarm water, 30 seconds after the treatment.
Observation period (in vivo):
7 days
Number of animals or in vitro replicates:
3 males and 3 females.
Details on study design:
APPLICATION
The test material was inserted in the conjunctival sac of the left eye of the rabbits and the lids were gently closed for one seconds. The right eye was not treated and served as an untreated control.

REMOVAL OF TEST SUBSTANCE
- Washing: 3 rabbits eyes wasehd with 10 ml lukewarm water.
- Time after start of exposure: 30 seconds.

TOOL USED TO ASSESS SCORE: hand-slit lamp; the irritation was appraised on day 1, 2, 3, 4 and 7 and was scored for each individual rabbit.
The primary irritation index represents the sum of the mean values for cornea, iris and conjunctivae.

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

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
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:
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:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Remarks on result:
other: see "any other information on results incl. tables" section
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Remarks on result:
not measured/tested
Irritant / corrosive response data:
In the present experiments the irritation index was established as 2.8 for the cornea, 0 for the iris and 2.7 for the conjunctivae.
The substance caused therefore a minimal overall eye irritation to rabbits.

Animal Eye 24 hrs 48 hrs 72 hrs 4 days 7 days Mean 24, 48, 72 hrs

Cornea

1 F rinsed  0 0 0 0 0 0
2 F rinsed  0 0 0 0 0 0
3 F rinsed  0 0 0 0 0 0

Iritis

1 F rinsed  0 0 0 0 0 0
2 F rinsed  0 0 0 0 0 0
3 F rinsed  0 0 0 0 0 0

Conjunctival reactions

1 F rinsed  6* 0 0 0 0 *not evaluable
2 F rinsed  0 0 0 0 0 0
3 F rinsed  0 0 0 0 0 0

* Effect reported only in one rabbit; results are not re-evaluable according to the current regulation and, in any case, it would be not sufficient to classify, according to the CLP criteria (which require at least in 2 of 3 tested animals).

Animal Eye 24 hrs 48 hrs 72 hrs 4 days 7 days Mean 24, 48, 72 hrs

Cornea

4 M Unrinsed 15 10 5 0 0 not evaluable
5 M Unrinsed 10 10 5 0 0 not evaluable
6 M Unrinsed 15 10 5 0 0 not evaluable

Iritis

4 M Unrinsed 0 0 0 0 0 0
5 M Unrinsed 0 0 0 0 0 0
6 M Unrinsed 0 0 0 0 0 0

Conjunctival reactions

4 M Unrinsed 10 8 0 0 0 not evaluable
5 M Unrinsed 15 10 5 0 0 not evaluable
6 M Unrinsed 12 10 8 0 0 not evaluable
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 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 irritation index was established as 2.8 for the cornea, 0 for the iris and 2.7 for the conjunctivae; minimum irritating.

Discussion and conclusion

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 calculation of results for the evaluation of the eye irritation potential followed in the test is different from that reported into the OECD guideline. The raw tables are not included into the study report, thus the scores related to the reactions of the unrinsed eye can not be re-evaluated according to the CLP Regulation (EC 1272/2008).

Despite also the timing for the removal of the substance is very different between AFDO and OECD (30 seconds in this experiment and 1 hours in the OECD), the results clearly indicate that the mean values from gradings at 24, 48 and 72 hours for rinsed eyes were lower than 1 for corneal opacity, lower than 1 for irtitis, lower than 2 for both conjunctival redness and oedema, in all animals.

Therefore, the substance can be classified as not irritating.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

SKIN IRRITATION

The skin 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). Primary irritation index was estimated to be between 0.6 and 1.2 as a range from four different assay that set the substance as mild irritating.

The scoring system criteria used to record the hardness of the skin reactions followed in the current test are the same as those reported into the OECD guideline, therefore it is possible to re-evaluate the results, because the raw tables are included into the study report.

Despite the reaction scores at 48 hours were not reported, the mean value scored is reasonably expected to be less than 2.3 for erythema/eschar and for oedema in at least 2 of 3 tested animals, in both intact and abraded skin, from gradings at 24, 48 and 72 hours after patch removal.

In conclusion, the substance is not classified as skin irritant according to the CLP Regulation (EC 1272/2008) (Ciba-Geigy Ltd., 1975).

 

Further three studies are available on the substance under registration and all confirm the outcomes of the key study.

EYE IRRITATION

The eye irritation potential was assessed following the procedure 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). Four reports were presented.

In the key study, where the substance tested has the highest purity (> 80 %) the irritation index was established as 2.8 for the cornea, 0 for the iris and 2.7 for the conjunctivae; minimum irritating.

The scoring system used for the cornea opacity and degree of density, for the iris and conjunctivae redness and chemosis is the same of that reported into the OECD, but the calculation of results for the evaluation of the eye irritation potential followed in the test is different from that reported into the OECD guideline. The raw tables are not included into the study report, thus the scores related to the reactions of the unrinsed eye cannot be re-evaluated according to the CLP Regulation (EC 1272/2008).

Despite also the timing for the removal of the substance is very different between AFDO and OECD (30 seconds in this experiment and 1 hours in the OECD), the results clearly indicate that the mean values from gradings at 24, 48 and 72 hours for rinsed eyes were lower than 1 for corneal opacity, lower than 1 for irtitis, lower than 2 for both conjunctival redness and oedema, in all animals.

Therefore, the substance is not classified as irritating for the eye according to the CLP Regulation (EC 1272/2008) (Ciba-Geigy Ltd., 1975).

 

All the further three studies reported confirm the outcomes of the key study.

Justification for classification or non-classification

According to 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 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 were lower than 1 for corneal opacity, lower than 1 for irtitis, lower than 2 for both conjunctival redness and oedema, in all animals.

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