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Description of key information

Two skin irritation/corrosion tests with albino New Zealand rabbits were evaluated. The key study was performed under GLP and scored Klimisch 2. The test substance was classified as skin corrosive Cat. 1C.
One in vivo eye irritation study with one male and one female albino rabbit was evaluated. The study was performed under GLP and scored Klimisch 2. Clear but reversible signs of eye irritation were observed. Skin damage was noted near each rabbit's eye, what corresponds to the results of the reported skin irritation/corrosion tests. The test substance was classified as serious eye damage/eye irritation Cat. 2.

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: Well-described study according to solid protocol. According to GLP. Conclusion only addresses corrosivity, not irritation.
Justification for type of information:
Key study, GLP, Klimisch score 2
Qualifier:
according to
Guideline:
other: Department of Transportation Hazardous Materials Regulations of the Code of Federal Regulations, Title 49, section 173.240
Deviations:
not specified
Qualifier:
according to
Guideline:
other: for the scoring: Federal Hazardous Substances Act Grading Code 16 CFR 1500.41
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
other: New Zealand Albino
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Ray Nichols Rabbitry, Lumberton, Texas
- Age at study initiation: no data
- Weight at study initiation: 2148-2350g
- Housing: individually, in elevated stainless steel cages
- Diet (e.g. ad libitum): Wayne Rabbit Ration, ad libitum
- Water (e.g. ad libitum): city tap water, ad libitum
- Acclimation period: 6 days (quarantine)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): controlled, but no data on actual temperature
- Humidity (%): controlled, but no data on actual humidity
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
not specified
Amount / concentration applied:
0.5 mL of test substance
Duration of treatment / exposure:
4 hours
Observation period:
2 weeks
Number of animals:
6 (3 males, 3 females)
Details on study design:
TEST SITE
24 Hours prior to application of the test article, the fur of the animals was clipped on the dorsal trunk surfaces with an Oster small animal clipper. There was one test site (approximately 5 cm square) per animal within the clipped area. The 5 cm square test site was not abraded. A single application of 0.5 mL of the test article was applied dermally to the 5 cm square prepared site on each animal. The test site was covered with two thicknesses of surgical gauze, 5 cm square, and secured with Coban elastic bandage and Johnson and Johnson Zonas porous adhesive tape. The entire trunk of each animal was wrapped with plastic, 2 mils thick, to retard evaporation of volatile substances and to prevent ingestiont of the test article. In addition, the trunk of each animal was wrapped with a cotton towel, 15 cm x 45 cm, which was secured in place with Johnson and Johnson's Zonas porous adhesive tape.

REMOVAL OF TEST SUBSTANCE
At the end of the 4 hours, the gauze patches were removed. A 30 minute period was allowed for pressure and hydration effects to subside, then the animals were scored. After the 4 hour scoring the test sites were washed with a water moistened cloth towel

SCORING SYSTEM:
Scoring for erythema, eschar formation, and corrosion of the skin according to the Federal Hazardous Substances Act Grading Code at 16 CFR 1500.41
Irritation parameter:
erythema score
Basis:
animal: 1-6
Time point:
other: 4 hours
Score:
4
Max. score:
4
Remarks on result:
other: 6/6 animals scored 4
Irritation parameter:
erythema score
Basis:
animal: 1-6
Time point:
other: 24 and 48 hours
Score:
3 - 4
Max. score:
4
Remarks on result:
other: 5/6 animals scored 4, 1/6 animal scored 3
Irritation parameter:
erythema score
Basis:
animal: 1-6
Time point:
other: 72 hours and 1 week
Score:
2 - 4
Max. score:
4
Remarks on result:
other: 5/6 animals scored 4, 1/6 animal score 2
Irritation parameter:
erythema score
Basis:
animal: 1-6
Time point:
other: 2 weeks
Score:
0 - 4
Max. score:
4
Remarks on result:
other: 4/6 animals scored 4, 2 animals scored 0
Irritation parameter:
edema score
Basis:
animal: 1-6
Time point:
other: 4 and 24 hours
Score:
4
Max. score:
4
Remarks on result:
other: 6/6 animals scored 4
Irritation parameter:
edema score
Basis:
animal: 1-6
Time point:
other: 48 hours
Score:
1 - 2
Max. score:
4
Remarks on result:
other: 3/6 animals scored 2, 3/6 animals scored 1
Irritation parameter:
edema score
Basis:
animal: 1-6
Time point:
other: 72 hours
Score:
0 - 2
Max. score:
4
Remarks on result:
other: 2/6 animals scored 2, 3/6 animals scored 1, 1/6 animal scored 9
Irritation parameter:
edema score
Basis:
animal: 1-6
Time point:
other: 1 week
Score:
0 - 2
Max. score:
4
Remarks on result:
other: 3/6 animals scored 2, 2/6 animals scored 1, 1/6 animal scored 0
Irritation parameter:
edema score
Basis:
animal: 1-6
Time point:
other: 2 weeks
Score:
0 - 1
Max. score:
4
Remarks on result:
other: 4/6 animals scored 1, 2/6 animals scored 0

Gross observations of corrosion were noted in 2/6 rabbits at the 1 week reading and 4/6 rabbits at the 2 week reading.

A corrosive material is defined as one that causes alteration or tissue destruction to the intact skin on an albino rabbit after an exposure period of 4 hours or less. Tissue destruction is considered to have occurred if ulceration or necrosis is noted at the 4 hour, 24 hour or 48 reading.

Therefore, Antioxidant PDA sample No. 1549 -83 is not considered to be a corrosive material when applied to the intact skin of albino rabbits by the method described in the Department of Transportation Hazardous Materials Regulation of the Code of Federal Regulations, Title 49, section 173.240

Interpretation of results:
Category 1C (corrosive)
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Gross observations of corrosion were noted in 2/6 rabbits at the 1 week reading and 4/6 rabbits at the 2 week reading. Antioxidant PDA sample No. 1549 -83 is 1) not considered to be a corrosive material when applied to the intact skin of albino rabbits by the method described in the Department of Transportation Hazardous Materials Regulation of the Code of Federal Regulations, Title 49, section 173.240 2) classified as a skin corrosive Cat. 1C according to the CLP regulation (EC 1272/2008)
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (corrosive)

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: GLP study. No internationally accepted protocol followed, but study well documented and acceptable protocol.
Justification for type of information:
Key study, GLP, Klimisch score 2
Qualifier:
no guideline followed
Principles of method if other than guideline:
Two yound adult New Zealand White rabbits were randomly assigned to this study from a pool of animals which had been determined to have no previous corneal damage by the use of sterile fluorescein sodium. A volume of 0.1 mL test material, as received, was instilled into the conjunctival sac of the right eye of each test animal by gently pulling the lower eyelid away from the eyeball to form a cup. The lids were then held together for approximately one second, after which the animals were returned to their cages.
Observations for signs of ocular irritation and other clinical effects were conducted on the first, second, third, seventh, tenth, fourteenth and seventeenth day after dosing. The untreated eye of each animal served as the negative control. As considered necessary for evaluation of potential corneal involvement, sterile fluorescein sodium was applied to the eyes. After approx. 10 seconds, the excess fluorescein was flushed from the eyes with physiological saline, and an ultraviolet lamp was used to determine whether staining persisted. The method of Draize was used for scoring of eye irritation.
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Isaac's Farm, Litchfield, Illinois
- Age at study initiation: young adults
- Weight at study initiation: 2.73 and 2.92 kg
- Housing: individually, stainless steel cages
- Diet (e.g. ad libitum): Purina Rabbit Chow, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: quarantine, at least 5 days

ENVIRONMENTAL CONDITIONS: no data

Vehicle:
unchanged (no vehicle)
Controls:
other: Left eye served as negative control.
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied: 0.1 mL
Duration of treatment / exposure:
single treatment, no rinsing reported
Observation period (in vivo):
17 days
Number of animals or in vitro replicates:
2
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): no

SCORING SYSTEM: Draize

TOOL USED TO ASSESS SCORE: fluorescein
Irritation parameter:
overall irritation score
Basis:
animal #1
Time point:
other: average of 24, 48 and 72 hours
Score:
28
Max. score:
110
Irritation parameter:
overall irritation score
Basis:
animal #2
Time point:
other: average of 24, 48 and 72 hours
Score:
16.3
Max. score:
110
Other effects:
All corneal and iridal involvement in both animals' eyes has subsided by the 7th day after exposure, and all conjunctival irritation had abated by day 14. Hardened skin around the eye occurred in both animals and was observed from the first through tenth day after exposure. The male also had blistered conjunctival tissue on the first two days after dosing. By day 14, scabs and/or scars were evident near each rabbit's eye, and scarring of perioccular skin was also observed in both animals on day 17, when the study was terminated. Since these changes in the skin near the eyes appeared to be the result of topical contact with the test material, it is likely that some material was expelled from the eyes after instillation.

   
   
   
   
   
   
   
   
   
   
   
   
   
 
Executive summary:

0.1 mL of test substance was administered to the right eye of each of one male and one female albino rabbits. Observations for signs of ocular irritation and other clinical effects were conducted on days 1, 2, 3, 7, 10, 14 and 17 after exposure. The method of Draize was used for the scoring of eye irritation.

Eye irritation effects were observed at the cornea, iris and conjunctivae on the first 3 days after exposure. All corneal, iridal and conjunctival irritation had subsided by the fourteenth day after exposure. However, scarring of the exterior of the upper eyelid and/or skin near the eye had occurred in both animals by the 17th day after dosing, at which time the study was terminated.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation corrosion

Irritation or corrosion of the skin was evaluated in two skin corrosion tests (Ethyl Corporation, 1983, report nr. XX84X144 (key) and Monsanto Company, 1983, report nr. ML-82-022 (supporting)) (the Monsanto report is presented in the CSR under the section for skin irritation, while the Ethyl Corporation report is presented in the CSR under the heading for skin corrosion).

In the key study, the test substance was administered to a clipped area on the dorsal trunk surface of New Zealand Albino rabbits. The exposure period was 4h, followed by a 14 day observation period. Gross observations of corrosion were noted in 2/6 rabbits at the 1 week reading and 4/6 animals at the 2 week reading. For the purpose of the study, the observed skin effects were compared to the criteria described in the Department of Transportation Hazardous Materials Regulations of the Code of Federal Regulations, Title 49, Section 173.240. Based on this evaluation, the test substance was found to not fulfil the criteria for corrosivity. Nevertheless, when comparing the test results available from this study with the criteria for corrosion as described in the CLP regulation (EC 1272/2008), the substance would fulfil the criteria described for Skin corrosive Category 1C.

 

In the supporting study, the test substance was applied on the dorsal shaved surface, of young adult New Zealand White rabbits. The test substance was held in contact with each of two intact abraded sites on each of 6 albino rabbits for approximately 24h. In general, the skin became hardened during the first week, sloughing occurred during the second and third week, and scarring was observed during the third week.

Eye irritation

The serious eye damage or eye irritation of the test substance was assessed in anin vivo eye irritation study (Monsanto Company, 1983, ML-82-022). 0,1 mL of the test substance was administered to the right eye of one male and one female albino rabbit. The Draize scoring was used to assess the effects of the test substance. The scores that were recorded after 24 hours showed clear signs of eye irritation in both animals. In the following days the effects decreased and all corneal and iridal involvement in both animal’s eyes had subsided by the seventh day after exposure. All conjunctival irritation had abated by day 14. On the other hand, by day 14, scabs and/or scars were evident near each rabbit’s eye, and scarring of periocular skin was also observed in both animals on day 17, when the study was terminated. The observed reported skin damage corresponds to the results of the reported skin irritation/corrosion tests.


Justification for classification or non-classification

Skin irritation/corrosion

Based on the fact that several animals showed signs of corrosion 14 days after a 4 hour exposure to the test substance, classification as skin corrosive Cat. 1C is warranted according to regulation 1272/2008 (CLP). The corresponding hazard statement is H314: Causes severe skin burns and eye damage. For the labelling the GHS05 pictogram (corrosion) and the signal word “Danger” are assigned to this hazard category.

 

The classification according to Directive 67/548 (DSD) is “ Causes burns” with R34 as the corresponding risk phrase.

Eye irritation

Comparison of the observed eye effects (severity and reversibility) with the criteria described in regulation 1272/2008 (CLP) warrant classification of the test compound as Serious eye damage/eye irritation Cat. 2. The corresponding hazard statement is H319: Causes serious eye irritation. For the labelling the GHS07 pictogram (exclamation mark) and the signal word “Warning” are assigned to this category.