Registration Dossier

Administrative data

Description of key information

Skin irritation, 1 key study, non-irritating for rabbits (similar to OECD TG 404).
Eye irritation, 1 key study, non-irritating for rabbits (similar to OECD TG 406)

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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented study report similar or equivalent to OECD 404. GLP
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
multiple test sites per animal, including abraded test sites and occluded sites. 4h exposure was occluded
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
Three male and three female young adult New Zealand White rabbits obtained form Hazleton Research Products, Inc. (Denver, Pa) were used in this study. The animals were identified by individual ear tags and cage cards. The temperature of the study room was maintained at 68-71F with a relative humidity of 44-66%
Type of coverage:
occlusive
Preparation of test site:
other: intact and abraded
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
0.5ml
Duration of treatment / exposure:
4-hour (occluded) and 24 hours (occluded and non-occluded)
Observation period:
Following the 4 hour exposure, the test sites were evaluated for dermal irritation at 4.5, 28, 52, and 76 hours. Following the 24 hour exposure, clinical observations were recorded at approximately 1 and 4 hours post-dosing and the sites were evaluated for dermal irritation at 26 and 72 hours post-exposure.
Number of animals:
6 animals (3/sex).
Details on study design:
Three 1 sq. in. test sites were selected on both the left and right flank of each animal and designated as anterior (4-hour, occlusion), middle (24-hour occlusion), and posterior (24-hour, no occlusion). All sites on the right flank were abraded prior to administration prior to administration of the test substance. 0.5mls of the test substance was applied to the anterior and middle test sites under Webril patches. The patches were secured with an occlusive rubber dam followed by a non-irritating surgical tape. 0.5mls of the test substance was also applied to the posterior test sites without occlusion. Elizabethan style collars were fitted to each animal after administration of the test substance. Following a 4 hour exposure the anterior sites were unwrapped and evaluated fro dermal corrosion. The residual test substance was wiped from the test sites and the sites reevaluated fro corrosion 48 hours post-dosing. The test sites were also evaluated for dermal irritation at 4.5, 28, 52, 76 hours according to the Draize method.

Following a 24 hour exposure period the middle test sites were unwrapped and the residual test substance wiped from both the middle and posterior test sites. These sites were evaluated for dermal irritation at 26 and 72 hours according to the Draize method. Clinical observations were recorded at approximately 1 and 4 hours post-dosing and daily thereafter. T he condition of each animal (live, dead, moribund) was checked daily in the morning.
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24h
Score:
0
Remarks on result:
other: 4hr occluded exposure
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 48h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 72 hrs
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
erythema score
Remarks:
combined mean
Basis:
mean
Time point:
other: 24/48/72 hr average
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24 hrs
Score:
0.2
Reversibility:
fully reversible
Remarks:
by 48 hours
Remarks on result:
other: 4 hour occluded exposure
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 48 hrs
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 72 hrs
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
edema score
Remarks:
combined mean
Basis:
mean
Time point:
other: 24/48/72 hr average
Score:
ca. 0.07
Max. score:
0.2
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
erythema score
Basis:
animal #4
Time point:
24 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
erythema score
Basis:
animal #5
Time point:
24 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
erythema score
Basis:
animal #6
Time point:
24 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
48 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
48 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
48 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
erythema score
Basis:
animal #4
Time point:
48 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
erythema score
Basis:
animal #5
Time point:
48 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
erythema score
Basis:
animal #6
Time point:
48 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
72 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
72 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
72 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
erythema score
Basis:
animal #4
Time point:
72 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
erythema score
Basis:
animal #5
Time point:
72 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
erythema score
Basis:
animal #6
Time point:
72 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
edema score
Basis:
animal #4
Time point:
24 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
edema score
Basis:
animal #5
Time point:
24 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
edema score
Basis:
animal #6
Time point:
24 h
Score:
1
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
edema score
Basis:
animal #1
Time point:
48 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
edema score
Basis:
animal #2
Time point:
48 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
edema score
Basis:
animal #3
Time point:
48 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
edema score
Basis:
animal #4
Time point:
48 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
edema score
Basis:
animal #5
Time point:
48 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
edema score
Basis:
animal #6
Time point:
48 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
edema score
Basis:
animal #1
Time point:
72 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
edema score
Basis:
animal #2
Time point:
72 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
edema score
Basis:
animal #3
Time point:
72 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
edema score
Basis:
animal #4
Time point:
72 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
edema score
Basis:
animal #5
Time point:
72 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Irritation parameter:
edema score
Basis:
animal #6
Time point:
72 h
Score:
0
Remarks on result:
other: 4 hr occluded exposure
Other effects:
4 hour exposure of abraded skin under occlusive conditions resulted in a combined erythema mean of 0.2 and a combined edema mean of 0.23. Evidence of erythema and edema were reported at all time points. Neither edema nor erythema were fully reversible within the 72 hour timepoint.

24 hour exposure under occluded conditions of unabraded skin resulted in erythema scores of 0.3 and 0 at 24 and 72 hours respectively, and edema scores of 0.5 and 0 at 24 and 72 hours respectively. Under semiocclusive conditions, 24 hour exposure to unabraded skin resulted in erythema and edema scores of 0 at 24 and 72 hours.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The mean erythema and edema scores for the test material were 0 and 0.07 (4 hour occluded).This finding does not warrant classification of the test material as a dermal irritant under the new Regulation (EC) 1272/2008 on classification, labeling, and packaging of substances and mixtures (CLP) nor as an R38 skin irritant under the Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.
Executive summary:

The test material was administered to the skin of New Zealand White rabbits. Test sites were selected on both the left and right flank of each animals and designated as anterior (4-hour, occluded), middle (24-hour, occluded), and posterior (24-hour, non-occluded). All sites of the right flank were abraded. 0.5 ml of the test substance was applied to each test site. Following the 4 hour exposure, the test sites were evaluated for dermal irritation at 1/2, 24, 48, and 72 hours according to the Draize method. Following the 24 hour exposures, both test sites were evaluated at 26 and 72 hours. Clinical observations were recorded at approximately 1 and 4 hours post-dosing. Soft stool, decreased fecal output, and decreased food consumption were observed in one or more animals. The mean erythema and edema scores for the test material on unabraded skin were 0 and 0.7 (4 hour occluded), 0.15 and 0.25 (24 hour occluded), and 0 and 0 (24 hour non-occluded), respectively.This finding does not warrant classification of the test material as a dermal irritant under the new Regulation (EC) 1272/2008 on classification, labeling, and packaging of substances and mixtures (CLP) nor as an R38 skin irritant under the Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.

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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Acceptble, Well-documented study report similar or equivalent to OECD 405. glp
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
Three male and three female young adult New Zealand White rabbits obtained form Hazleton Research Products, Inc. (Denver, Pa) were used in this study. The animals were identified by individual ear tags and cage cards. The temperature of the study room was maintained at 68-71F with a relative humidity of 44-66%
Vehicle:
unchanged (no vehicle)
Controls:
other: left eye was test eye, right eye was control
Amount / concentration applied:
0.1 ml of the test substance was instilled into the left conjunctival sac of six animals.
Duration of treatment / exposure:
After insitillation the eyelids were gently held together for approximately 1 second. Both eyes were grossly examined and the test scored according to the Draize method at 1, 24, 48, and 72 hours post-dosing.
Observation period (in vivo):
After insitillation the eyelids were gently held together for approximately 1 second. Both eyes were grossly examined and the test scored according to the Draize method at 1, 24, 48, and 72 hours post-dosing. Plastic collars were placed on each animal after instillation to prevent mechanical irritation of the eye. The condition of each animal (live, dead, moribund) was checked once daily in the morning.
Number of animals or in vitro replicates:
six (3/sex)
Details on study design:
Both eyes were grossly examined and the test scored according to the Draize method at 1, 24, 48, and 72 hours post-dosing. All eyes were stained with 2% sodium fluorescein during the 24 hour evaluation.
Irritation parameter:
cornea opacity score
Remarks:
opacity
Basis:
mean
Time point:
other: 24/48/72 hr average
Score:
0
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24/48/72h average
Score:
0
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
mean
Time point:
other: 24/48/72 hr average
Score:
0.7
Max. score:
1.2
Reversibility:
not fully reversible within: 72h
Remarks on result:
other: 72 hours was the last observation point
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24/48/72 hr average
Score:
0.5
Max. score:
1
Reversibility:
not fully reversible within: 72h
Remarks on result:
other: 72 hours was the last observation point
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24 h
Score:
0
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24 h
Score:
0
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24 h
Score:
0
Irritation parameter:
cornea opacity score
Basis:
animal #4
Time point:
24 h
Score:
0
Irritation parameter:
cornea opacity score
Basis:
animal #5
Time point:
24 h
Score:
0
Irritation parameter:
cornea opacity score
Basis:
animal #6
Time point:
24 h
Score:
0
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
48 h
Score:
0
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
48 h
Score:
0
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
48 h
Score:
0
Irritation parameter:
cornea opacity score
Basis:
animal #4
Time point:
48 h
Score:
0
Irritation parameter:
cornea opacity score
Basis:
animal #5
Time point:
48 h
Score:
0
Irritation parameter:
cornea opacity score
Basis:
animal #6
Time point:
48 h
Score:
0
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
72 h
Score:
0
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
72 h
Score:
0
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
72 h
Score:
0
Irritation parameter:
cornea opacity score
Basis:
animal #4
Time point:
72 h
Score:
0
Irritation parameter:
cornea opacity score
Basis:
animal #5
Time point:
72 h
Score:
0
Irritation parameter:
cornea opacity score
Basis:
animal #6
Time point:
72 h
Score:
0
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24 h
Score:
0
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24 h
Score:
0
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24 h
Score:
0
Irritation parameter:
iris score
Basis:
animal #4
Time point:
24 h
Score:
0
Irritation parameter:
iris score
Basis:
animal #5
Time point:
24 h
Score:
0
Irritation parameter:
iris score
Basis:
animal #6
Time point:
24 h
Score:
0
Irritation parameter:
iris score
Basis:
animal #1
Time point:
48 h
Score:
0
Irritation parameter:
iris score
Basis:
animal #2
Time point:
48 h
Score:
0
Irritation parameter:
iris score
Basis:
animal #3
Time point:
48 h
Score:
0
Irritation parameter:
iris score
Basis:
animal #4
Time point:
48 h
Score:
0
Irritation parameter:
iris score
Basis:
animal #5
Time point:
48 h
Score:
0
Irritation parameter:
iris score
Basis:
animal #6
Time point:
48 h
Score:
0
Irritation parameter:
iris score
Basis:
animal #1
Time point:
72 h
Score:
0
Irritation parameter:
iris score
Basis:
animal #2
Time point:
72 h
Score:
0
Irritation parameter:
iris score
Basis:
animal #3
Time point:
72 h
Score:
0
Irritation parameter:
iris score
Basis:
animal #4
Time point:
72 h
Score:
0
Irritation parameter:
iris score
Basis:
animal #5
Time point:
72 h
Score:
0
Irritation parameter:
iris score
Basis:
animal #6
Time point:
72 h
Score:
0
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24 h
Score:
1
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24 h
Score:
1
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24 h
Score:
2
Irritation parameter:
conjunctivae score
Basis:
animal #4
Time point:
24 h
Score:
1
Irritation parameter:
conjunctivae score
Basis:
animal #5
Time point:
24 h
Score:
1
Irritation parameter:
conjunctivae score
Basis:
animal #6
Time point:
24 h
Score:
1
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
48 h
Score:
1
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
48 h
Score:
1
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
48 h
Score:
1
Irritation parameter:
conjunctivae score
Basis:
animal #4
Time point:
48 h
Score:
0
Irritation parameter:
conjunctivae score
Basis:
animal #5
Time point:
48 h
Score:
0
Irritation parameter:
conjunctivae score
Basis:
animal #6
Time point:
48 h
Score:
1
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
72 h
Score:
0
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
72 h
Score:
0
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
72 h
Score:
1
Irritation parameter:
conjunctivae score
Basis:
animal #4
Time point:
72 h
Score:
1
Irritation parameter:
conjunctivae score
Basis:
animal #5
Time point:
72 h
Score:
0
Irritation parameter:
conjunctivae score
Basis:
animal #6
Time point:
72 h
Score:
0
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24 h
Score:
1
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24 h
Score:
1
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24 h
Score:
1
Irritation parameter:
chemosis score
Basis:
animal #4
Time point:
24 h
Score:
0
Irritation parameter:
chemosis score
Basis:
animal #5
Time point:
24 h
Score:
1
Irritation parameter:
chemosis score
Basis:
animal #6
Time point:
24 h
Score:
2
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
48 h
Score:
0
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
48 h
Score:
0
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
48 h
Score:
0
Irritation parameter:
chemosis score
Basis:
animal #4
Time point:
48 h
Score:
0
Irritation parameter:
chemosis score
Basis:
animal #5
Time point:
48 h
Score:
1
Irritation parameter:
chemosis score
Basis:
animal #6
Time point:
48 h
Score:
0
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
72 h
Score:
0
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
72 h
Score:
0
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
72 h
Score:
0
Irritation parameter:
chemosis score
Basis:
animal #4
Time point:
72 h
Score:
0
Irritation parameter:
chemosis score
Basis:
animal #5
Time point:
72 h
Score:
1
Irritation parameter:
chemosis score
Basis:
animal #6
Time point:
72 h
Score:
0
Other effects:
The following clinical observations were noted in one or more animals: soft stool, decreased fecal output, and decreased food consumption.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The mean corneal opacity, iris lesion, conjunctivae redness, and chemosis scores for the test material were 0, 0, 0.7, and 0.5, respectively. These findings do not warrant classification of the test material as an ocular irritant under the new Regulation (EC) 1272/2008 on classification, labeling, and packaging of substances and mixtures (CLP) or under the Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.
Executive summary:

The test material was administered to one eye of six New Zealand White rabbits to assess for ocular irritation; the other eye was used as a control. Clinical observations were made 1 and 4 hours immediately after treatment and daily thereafter for 3 days. Ocular damage was assessed and scored according to the Draize method. Slight irritation was noted at 1, 24, 48, and 72 hours post dosing. The mean corneal opacity, iris lesion, conjunctivae redness, and chemosis scores for the test material were 0, 0, 0.7, and 0.5, respectively. These findings do not warrant classification of the test material as an ocular irritant under the new Regulation (EC) 1272/2008 on classification, labeling, and packaging of substances and mixtures (CLP) or under the Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin: The dermal irritation potential of the submission substance has been evaluated under occluded conditions. The results indicate negligible dermal irritation.

 

Eye: The ocular irritation potential of the submission substance has been evaluated in a manner similar or equivalent to currently established OECD guidelines. The results indicate negligible ocular irritation.

Respiratory: The respiratory tract irritation potential of the submission substance is not known, as no data are available for this endpoint.

 

Justification for classification or non-classification

Based on assessment of the available data for the submission substance, classification is not warranted as an eye or skin irritant under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under the Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.

However, due to the existence of a harmonized classification for this substance in CLP Annex VI, the registrant has classified this as a Category 2 eye irritant.

There is no evidence of irritation to the respiratory tract warranting classification.