Registration Dossier

Administrative data

Description of key information

Skin irritation/corrosion: not irritating (OECD 404, GLP, analogue approach)
Eye irritation: not irritating (OECD 405, GLP, analogue approach)

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
14 - 21 Dec 1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study.
Reference:
Composition 0
Qualifier:
according to
Guideline:
EPA OPP 81-5 (Acute Dermal Irritation)
Deviations:
no
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
no
Test material information:
Composition 1
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: IVANOVAS GmBH, Med. Versuchstierzuchten KG, D-7964 Kisslegg
- Age at study initiation: adult, age not specified
- Weight at study initiation: 2 to 3 Kg
- Housing: individually in metal cages
- Diet: standard rabbit food NAFAG, No. 814 Gossau SG, ad libitum
- Water: ad libitum.
- Acclimation period: minimum 4 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 2 °C
- Humidity: 55 ± 10 %
- Photoperiod: 12 hours light cycle day
Type of coverage:
occlusive
Preparation of test site:
other: intact and abraded skin.
Vehicle:
other: polyethylene glycol (PEG 400) + Saline (70:30)
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 0.5 g of test material
- Application: gauze patches of 2.5 x 2.5 cm laden with the test material

VEHICLE
- Concentration: 50%
Duration of treatment / exposure:
The dressings were removed after a 24 hour application.
Observation period:
7 days
Number of animals:
3 male and 3 female
Details on study design:
TEST SITE
- Area of exposure: 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 with the help of a "SchröpfSchnäpper", Aesculap, Switzerland.
- 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.

SCORING SYSTEM
Skin reactions were assessed on removal and after 48 and 72 hours and 4 and 7 days.
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
Remarks:
out of all 6 animals
Time point:
other: mean over 24, 48 and 72 hours
Score:
0.625
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
mean
Remarks:
out of all 6 animals
Time point:
other: mean over 24, 48 and 72 hours
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Other effects:
One animal died after 6 days. No symptoms had been observed previously.

Intact skin reactions

Animal/sex Reaction 24 hrs 48 hrs 72 hrs 4 days 7 days Mean 24, 48 and 72 hrs
144 Erythema 2 1 0 0 0 0.75
145 Erythema 2 1 1 1 0 1.25
146 Erythema 2 1 0 0 0 0.75
147 Erythema 1 1 1 0 / 0.75
148 Erythema 1 0 0 0 0 0.25
149 Erythema 0 0 0 0 0 0.00
144 Oedema 2 1 0 0 0 0.75
145 Oedema 1 1 0 0 0 0.50
146 Oedema 2 1 0 0 0 0.75
147 Oedema 0 0 0 0 / 0.00
148 Oedema 0 0 0 0 0 0.00
149 Oedema 0 0 0 0 0 0.00

Abraded skin reactions

Animal/sex Reaction 24 hrs 48 hrs 72 hrs 4 days 7 days Mean 24, 48 and 72 hrs
144 Erythema 2 1 1 0 0 1.00
145 Erythema 2 2 1 1 0 1.50
146 Erythema 2 1 0 0 0 0.75
147 Erythema 2 2 1 1 / 1.50
148 Erythema 1 0 0 0 0 0.25
149 Erythema 1 0 0 0 0 0.25
144 Oedema 2 1 0 0 0 0.75
145 Oedema 1 0 0 0 0 0.25
146 Oedema 1 1 0 0 0 0.50
147 Oedema 2 1 1 1 / 1.25
148 Oedema 0 0 0 0 0 0.00
149 Oedema 0 0 0 0 0 0.00
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
CLP: not classified
DSD: not classified
Executive summary:

Method

The skin irritation potential was tested in New Zealand White rabbits. The procedure used is described in the 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.

Results

Under the conditions of the present experiment the test compound was found to cause a slight irritation when applied to intact and abraded rabbit skin. One animal died after 6 days.

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 according to the CLP Regulation (1272/2008), because the raw tables are included into the study report. Only the intact skin reactions were considered.

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 (in both intact and abraded skin).

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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
14 - 21 Dec 1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study.
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
no
Test material information:
Composition 1
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: IVANOVAS GmBH, Med. Versuchstierzuchten KG, D-7964 Kisslegg
- Weight at study initiation: 2 to 3 kg
- Housing: individually in metal cages
- Diet: standard rabbit food NAFAG, No. 814 Gossau SG, ad libitum
- Water: ad libitum
- Acclimation period: minimum 4 days
Only rabbits with normal ophthalmic findings were used for these tests

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 2 °C
- Humidity: 55 ± 10 %
- Photoperiod: 12 hours light cycle day
Vehicle:
unchanged (no vehicle)
Controls:
other: the right eye was not treated and served as an untreated control.
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 0.1 g
Duration of treatment / exposure:
single exposure; in 3 of the 6 rabbits approximately 30 seconds after the treatment the treated eye was washed out
Observation period (in vivo):
7 days
Number of animals or in vitro replicates:
3 females and 3 males
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 15 seconds. The right eye was not treated and served as an untreated control.

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

TOOL USED TO ASSESS SCORE: hand-slit lamp

SCORING SYSTEM
The eye irritation was assessed at 24, 48, 72 hours and 4 and 7 days after treatment.
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
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
out of all 3 animals
Time point:
other: mean over 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: reversibility: not applicable
Irritation parameter:
iris score
Basis:
mean
Remarks:
out of all 3 animals
Time point:
other: mean over 24, 48 and 72 hours
Score:
0
Max. score:
2
Reversibility:
other: reversibility: not applicable
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
other: mean over 24, 48 and 72 hours
Score:
0.67
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
other: mean over 24, 48 and 72 hours
Score:
0
Max. score:
3
Reversibility:
other: reversibility: not applicable
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
other: mean over 24, 48 and 72 hours
Score:
0
Max. score:
3
Reversibility:
other: reversibility: not applicable
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
out of all 3 animals
Time point:
other: mean over 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: reversibility: not applicable
Other effects:
One animal died 7 days after instillation of the test material and it was stated that no symptoms had been observed prior to death.

Eye reactions

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

Cornea

144 not rinsed 0 0 0 0 0 0.00
145 not rinsed 0 0 0 0 0 0.00
146 not rinsed 0 0 0 0 0 0.00
147 rinsed 0 0 0 0 / 0.00
148 rinsed 0 0 0 0 0 0.00
149 rinsed 0 0 0 0 0 0.00

Iris

144 not rinsed 0 0 0 0 0 0.00
145 not rinsed 0 0 0 0 0 0.00
146 not rinsed 0 0 0 0 0 0.00
147 rinsed 0 0 0 0 / 0.00
148 rinsed 0 0 0 0 0 0.00
149 rinsed 0 0 0 0 0 0.00

Conjunctivae Redness

144 not rinsed 2 0 0 0 0 0.67
145 not rinsed 0 0 0 0 0 0.00
146 not rinsed 0 0 0 0 0 0.00
147 rinsed 1 0 0 0 / 0.33
148 rinsed 0 0 0 0 0 0.00
149 rinsed 0 0 0 0 0 0.00

Conjunctivae Chemosis

144 not rinsed 0 0 0 0 0 0.00
145 not rinsed 0 0 0 0 0 0.00
146 not rinsed 0 0 0 0 0 0.00
147 rinsed 0 0 0 0 / 0.00
148 rinsed 0 0 0 0 0 0.00
149 rinsed 0 0 0 0 0 0.00
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
CLP: not classified
DSD: not classified
Executive summary:

Method

The test was performed on 3 male and 3 female New Zealand White rabbits. The test material in an amount of 0.1 g was inserted into

the conjunctival sac of the left eye of the rabbits and the lids were gently closed for a few seconds. 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.

The eye irritation was appraised with a slit-lamp on day 1, 2, 3, 4 and 7 and was scored for each individual rabbit.

Results

Results

Under the conditions of this experiment the test material was found to cause a minimal irritation when applied to the rabbit eye mucosa.

One animal died at Day 7. No symptoms had been observed previously.

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 (1272/2008).

The mean values from gradings at 24, 48 and 72 hours for both rinsed and unrinsed 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 does not meet the criteria to be classified as eye irritating.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

There are no data available for the skin and eye irritation potential of CAS 12004488-68-5. In order to fulfil the standard information requirements, a read-across from structurally related substance was conducted.

An acute dermal irritation study performed similar to OECD Guideline 404 to evaluate the skin irritation potential of CAS# 16470-24-9 is available. Six New Zealand rabbits were treated with 0.5 g of the test substance for 24 h under occlusive conditions. The animals were observed for 7 days. Under the conditions of the present experiment the test compound was found to cause a slight irritation when applied to intact and abraded rabbit skin. The calculated primary irritation index was 1.5. One animal died after 6 days but no symptoms had been observed previously. 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 (in both intact and abraded skin). Therefore, the test substance is not considered irritating to the skin.

An acute eye irritation study was performed according to OECD Guideline 405 under GLP conditions. 0.1 g of the unchanged test substance was instilled to the left eye of three male and three female New Zealand White rabbits. The untreated right eye served as control. In 3 of the 6 rabbits approximately 30 seconds after treatment the treated eye was flushed. The eye irritation was appraised with a slit-lamp on Day 1, 2, 3, 4 and 7 and was scored for each individual rabbit. Under the conditions of this experiment the test material was found to cause a minimal irritation when applied to the rabbit eye mucosa. The primary irritation index was found to be: unrinsed eyes = 0.4; rinsed eyes = 0.1. One animal died at Day 7 but no symptoms had been observed previously. All effects were fully reversible within 48 hours. Therefore, the test substance is not considered eye irritating in this study.


Justification for selection of skin irritation / corrosion endpoint:
Study conducted according to internationally accepted testing guidelines

Justification for selection of eye irritation endpoint:
Study conducted according to internationally accepted testing guidelines

Justification for classification or non-classification

Based on read-across from the structurally similar substances, the available data for skin and eye irritation do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.