Registration Dossier

Administrative data

Description of key information

SKIN IRRITATION
Irritating, New Zealand White, United States EPA, Paragraph 163.81-5 “Primary dermal irritation study”, Federal Register, Vol. 43 No. 163, August 22, 1978, Seifert 1982a
EYE IRRITATION
Irritating, New Zealand White, United States EPA, Paragraph 163.81-4 “Primary eye irritation study”, Federal Register, Vol. 43 No. 163, August 22, 1978, Seifert 1982b

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation / corrosion, other
Remarks:
According to OECD 404
Type of information:
experimental study
Adequacy of study:
key study
Study period:
18 October 1982 to 25 October 1982
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted to GLP in accordance with generally accepted scientific principles, possibly with incomplete reporting or methodological deficiencies, which do not affect the quality of the relevant results.
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
other: Procedure similar to the proposed guidelines of the United States EPA, Paragraph 163.81-5 “Primary dermal irritation study”, Federal Register, Vol. 43 No. 163, August 22, 1978
Deviations:
yes
Remarks:
: the procedure was based upon the guideline but was not in every part identical.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
: the animals were exposed to the test material for 24 hours in an occlusive fashion; there was no evaluation 60 minutes after patch removal and the observation period lasted only 7 days.
GLP compliance:
yes
Test material information:
Composition 1
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 2 - 3 kg
- Housing: Individually in metal cages.
- Diet (e.g. ad libitum): Rabbit food, ad libitum.
- Water (e.g. ad libitum): ad libitum.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 55 ± 15 %
- Air changes (per hr): Approximately 15 per hour.
- Photoperiod (hrs dark / hrs light): 12 hours light per day.

IN-LIFE DATES: From: 18 October 1982 To: 25 October 1982
Type of coverage:
occlusive
Preparation of test site:
other: shaved and abraded
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
- Volume: 0.5 mL of the test material
Duration of treatment / exposure:
24 hours
Observation period:
7 days
Number of animals:
6; 3 male and 3 female
Details on study design:
SITE PREPARATION:
-24 hours before exposure, the flanks of the test animals were shaved using an electric clipper. Immediately prior to treatment, the skin on one side was slightly scarified by means of a "Schroepfschnaepper".

TEST SITE
- Patch Size: Gauze patches 2.5 x 2.5 cm soaked with the test material were applied to intact and abraded skin sites. The patches were covered with an impermeable material and were fastened to the body of the rabbit with adhesive tape.

SCORING SYSTEM: The skin reactions were assessed upon patch removal and during the subsequent 7 day observation period in accordance with the Draize scale (1977).
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Remarks:
of 6 animals
Time point:
other: mean of 24 and 72 hour evaluations
Score:
5.6
Max. score:
4
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: Both shaved and abraded skin
Irritation parameter:
erythema score
Basis:
mean
Remarks:
of 6 animals
Time point:
other: mean of 24, 48 and 72 hour evaluations
Score:
3
Max. score:
3
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: Shaved skin
Irritation parameter:
erythema score
Basis:
mean
Remarks:
of 6 animals
Time point:
other: mean of 24, 48 and 72 hour evaluations
Score:
2.9
Max. score:
3
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: Abraded skin
Irritation parameter:
edema score
Basis:
mean
Remarks:
of 6 animals
Time point:
other: mean of 24, 48 and 72 hour evaluations
Score:
2.7
Max. score:
4
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: Shaved skin
Irritation parameter:
edema score
Basis:
mean
Remarks:
of 6 animals
Time point:
other: mean of 24, 48 and 72 hour evaluations
Score:
2.6
Max. score:
4
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: Abraded skin
Irritant / corrosive response data:
Necrosis and extended erythema was observed in all 6 animals.

Table 1 PII at 24 and 72 hours.

PII = total ÷ 4

Time After Exposure (hours) Mean Erythema Scores Mean Oedema Scores
Intact Skin Abraded Skin Intact Skin Abraded Skin
24 3.0 3.0 2.8 2.7
72 3.0 2.8 2.7 2.5
     
Subtotal 6.0 5.8 5.5 5.2
Total 22.5      
PII 5.6      

Table 2 Individual Scores

Shaved

Time After Exposure (hours) Male Female Average
1 2 3 1 2 3  
Erythema 24 hours 3 3 3 3 3 3 3.0
  48 hours 3 3 3 3 3 3 3.0
  72 hours 3 3 3 3 3 3 3.0
  4 days 3 3 3 3 3 3 3.0
  7 days 3 2 3 2 2 3 2.5
Oedema 24 hours 3 3 3 2 3 3 2.8
  48 hours 3 2 2 2 3 3 2.5
  72 hours 4 2 2 2 3 3 2.7
  4 days 4 2 2 2 3 3 2.7
  7 days 4 2 2 2 2 2 2.3
    Abraded
Erythema 24 hours 3 3 3 3 3 3 3.0
  48 hours 2 3 3 3 3 3 2.8
  72 hours 2 3 3 3 3 3 2.8
  4 days 2 3 3 3 3 3 2.8
  7 days 2 2 3 2 2 2 2.2
Oedema 24 hours 2 3 3 2 3 3 2.7
  48 hours 2 2 3 2 3 3 2.5
  72 hours 2 2 4 2 3 2 2.5
  4 days 2 2 4 2 3 2 2.5
  7 days 2 2 3 1 2 2 2.0
Interpretation of results:
Category 2 (irritant)
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the study, the test material was shown to cause marked irritation to the skin of rabbits and as such is classified as a category 2 skin irritant in accordance with EU criteria.
Executive summary:

The skin irritancy potential of the test material was assessed in a GLP compliant in vivo study that was based upon the procedure outlined in the guidelines of the United States EPA, Paragraph 163.81-5 “Primary dermal irritation study”, Federal Register, Vol. 43 No. 163, August 22, 1978.

Six New Zealand White rabbits were exposed to the test material in an occlusive fashion for 24 hours on both intact and abraded skin. The skin reactions were evaluated in accordance with the Draize scale at 24, 48 and 72 hours followed by observations after 4 and 7 days.

Under the conditions of this study, the test material produced marked irritation to the skin and as such requires classification as “Category 2, H315: Causes skin irritation” with signal word “Warning” in accordance with EU criteria.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation, other
Remarks:
According to OECD 405
Type of information:
experimental study
Adequacy of study:
key study
Study period:
18 October 1982 to 25 October 1982
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted to GLP in accordance with generally accepted scientific principles, possibly with incomplete reporting or methodological deficiencies, which do not affect the quality of the relevant results.
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
other: Procedure similar to the proposed guidelines of the United States EPA, Paragraph 163.81-4 “Primary eye irritation study”, Federal Register, Vol. 43 No. 163, August 22, 1978
Deviations:
yes
Remarks:
The procedure was based upon the guideline but was not in every part identical.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
The animals were not evaluated 60 minutes after exposure and the observation period lasted only 7 days.
GLP compliance:
yes
Test material information:
Composition 1
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 2 - 3 kg
- Housing: Individually in metal cages.
- Diet (e.g. ad libitum): Rabbit food, ad libitum.
- Water (e.g. ad libitum): ad libitum.
- Acclimation period: 4 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 55 ± 15 %
- Air changes (per hr): Approximately 15 per hour.
- Photoperiod (hrs dark / hrs light): 12 hours light per day.

IN-LIFE DATES: From: 18 October 1982 To: 25 October 1982
Vehicle:
unchanged (no vehicle)
Controls:
other: The right eye of each animal remained untreated and served as concurrent control.
Amount / concentration applied:
- Volume: 0.1 mL
Duration of treatment / exposure:
After insertion of the test material into the conjunctival sac, the eyelids were gently closed for 15 seconds.
Observation period (in vivo):
7 days
Number of animals or in vitro replicates:
9; 6 male and 3 female
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): in 3 of the 9 rabbits the eye was flushed with 10 mL of sterile physiological saline
- Time after start of exposure: approximately 30 seconds after treatment

SCORING SYSTEM:
- Eyes were scored according to the Draize scale (1977)

TOOL USED TO ASSESS SCORE: slit-lamp
Irritation parameter:
other: PII
Basis:
mean
Time point:
other: 7 days
Score:
29.6
Remarks on result:
other: Unrinsed eyes
Irritation parameter:
other: PII
Basis:
mean
Time point:
other: 7 days
Score:
22.1
Remarks on result:
other: Rinsed eyes
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
of 6 animals
Time point:
other: mean of 24, 48 and 72 hour evaluations
Score:
1
Max. score:
1
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: Unrinsed eyes
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
of 3 animals
Time point:
other: mean of 24, 48 and 72 hour evaluations
Score:
1
Max. score:
1
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: Rinsed eyes
Irritation parameter:
iris score
Basis:
mean
Remarks:
of 6 animals
Time point:
other: mean of 24, 48 and 72 hour evaluations
Score:
0.5
Max. score:
1
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: Unrinsed eyes
Irritation parameter:
iris score
Basis:
mean
Remarks:
of 3 animals
Time point:
other: mean of 24, 48 and 72 hour evaluations
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Remarks on result:
other: Rinsed eyes
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
of 6 animals
Time point:
other: mean of 24, 48 and 72 hour evaluations
Score:
2.9
Max. score:
3
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: Unrinsed eyes
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
of 3 animals
Time point:
other: mean of 24, 48 and 72 hour evaluations
Score:
3
Max. score:
3
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: Rinsed eyes
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
of 6 animals
Time point:
other: mean of 24, 48 and 72 hour evaluations
Score:
2.8
Max. score:
3
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: Unrinsed eyes
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
of 3 animals
Time point:
other: mean of 24, 48 and 72 hour evaluations
Score:
2.7
Max. score:
3
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: Rinsed eyes
Irritation parameter:
other: discharge
Basis:
mean
Remarks:
of 6 animals
Time point:
other: mean of 24, 48 and 72 hour evaluations
Score:
2.7
Max. score:
3
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: Unrinsed eyes
Irritation parameter:
other: discharge
Basis:
mean
Remarks:
of 3 animals
Time point:
other: mean of 24, 48 and 72 hour evaluations
Score:
2.6
Max. score:
3
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: Rinsed eyes
Irritant / corrosive response data:
The test material was found to cause moderate irritation.
Other effects:
No other effects reported.

Table 1 Calculation of Primary Eye Irritation Index

Time After Exposure Mean Reaction Score
Unrinsed Eyes Rinsed Eyes
Cornea Iris Conjunctiva Cornea Iris Conjunctiva
24 hrs 11.7 2.5 17.0 10.0 0.0 16.0
48 hrs 13.3 2.5 16.7 10.0 0.0 18.0
72 hrs 14.2 2.5 16.7 10.0 0.0 15.3
4 days 14.2 2.5 14.0 8.3 0.0 10.0
7 days 10.0 1.7 8.7 6.7 0.0 6.0
Subtotal 63.4 11.7 73.1 45.0 0.0 65.3
Total 148.2   110.3  
PII 29.6     22.1    

Table 2 Individual Irritation Scores at 24, 48, 72 hours and days 4 and 7

Unrinsed   Rinsed  
Observation Time Observation Male 1 Male 2 Male 3 Female 1 Female 2 Female 3 Average Male 4 Male 5 Male 6 Average
24 hrs Opacity 1 1 1 1 1 1 1.0 1 1 1 1.0
  Iris 1 1 1 0 0 0 0.5 0 0 0 0.0
  Conjunctivae 3 3 3 3 3 3 3.0 3 3 3 3.0
  Chemosis 3 3 3 3 3 2 2.8 3 2 3 2.7
48 hrs Opacity 1 1 1 1 1 1 1.0 1 1 1 1.0
  Iris 1 1 1 0 0 0 0.5 0 0 0 0.0
  Conjunctivae 3 3 3 3 3 2 2.8 3 3 3 3.0
  Chemosis 3 3 3 3 3 1 2.7 3 3 3 3.0
72 hrs Opacity 1 1 1 1 1 1 1.0 1 1 1 1.0
  Iris 1 1 1 0 0 0 0.5 0 0 0 0.0
  Conjunctivae 3 3 3 3 3 3 3.0 3 3 3 3.0
  Chemosis 3 3 3 2 3 3 2.8 3 2 2 2.3
4 days Opacity 1 1 1 1 1 1 1.0 1 1 1 1.0
  Iris 1 0 1 0 1 0 0.5 0 0 0 0.0
  Conjunctivae 3 3 2 3 3 3 2.8 2 2 2 2.0
  Chemosis 2 2 2 2 2 3 2.2 2 2 2 2.0
7 days Opacity 1 1 1 1 1 1 1.0 1 1 1 1.0
  Iris 1 0 1 0 0 0 0.3 0 0 0 0.0
  Conjunctivae 2 1 2 2 2 1 1.7 1 2 1 1.3
  Chemosis 2 1 2 2 2 1 1.7 1 1 1 1.0
Interpretation of results:
other: Category 2
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the test, the test material was shown to be irritating to the eyes. In accordance with EU criteria the test material is classified as Category 2.
Executive summary:

The eye irritancy potential of the test material was assessed in a GLP compliant in vivo study that was based upon the procedure outlined in the guidelines of the United States EPA, Paragraph 163.81-4 “Primary eye irritation study”, Federal Register, Vol. 43 No. 163, August 22, 1978.

Nine New Zealand White rabbits were exposed to the test material; the treated eye of three animals was rinsed with saline 30 seconds after exposure. The reactions to the test material were evaluated in accordance with the Draize scale (1977) after 24, 48 and 72 hours followed by further observations after 4 and 7 days. The test material was determined to cause moderate irritation.

 

Under the conditions of this study, the test material was shown to cause irritation to the eye which would require classification under regulation directive 1272/2008. The test material requires classification as "Category 2, H319: Causes serious eye irritation" with signal word "Warning".

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin Irritation

In the GLP compliant key study, the skin irritancy potential of the test material was assessed in vivo using a method based upon the procedure outlined in the guidelines of the United States EPA, Paragraph 163.81-5 “Primary dermal irritation study”, Federal Register, Vol. 43 No. 163, August 22, 1978.

Six New Zealand White rabbits were exposed to the test material in an occlusive fashion for 24 hours on both intact and abraded skin. The skin reactions were evaluated in accordance with the Draize scale at 24, 48 and 72 hours followed by observations after 4 and 7 days.

Under the conditions of this study, the test material produced marked irritation to the skin.

 

The study was performed to a good standard with a sufficient level of detail to assess the quality of the study. As such it was assigned a reliability score of 2 using the principles for assessing data quality as set out in Klimisch (1997) and considered suitable as an accurate reflection of the test material.

 

Eye Irritation

In the GLP compliant key study, the skin irritancy potential of the test material was assessed in vivo using a method based upon the procedure outlined in the guidelines of the United States EPA, Paragraph 163.81-4 “Primary eye irritation study”, Federal Register, Vol. 43 No. 163, August 22, 1978.

Nine New Zealand White rabbits were exposed to the test material; the treated eye of three animals was rinsed with saline 30 seconds after exposure. The reactions to the test material were evaluated in accordance with the Draize scale (1977) after 24, 48 and 72 hours followed by further observations after 4 and 7 days. The test material was determined to cause moderate irritation under the conditions of the study.

 

The study was performed to a good standard with a sufficient level of detail to assess the quality of the study. As such it was assigned a reliability score of 2 using the principles for assessing data quality as set out in Klimisch (1997) and considered suitable as an accurate reflection of the test material.


Justification for selection of skin irritation / corrosion endpoint:
Only one study available.

Justification for selection of eye irritation endpoint:
Only one study available.

Effects on skin irritation/corrosion: irritating

Effects on eye irritation: irritating

Justification for classification or non-classification

Skin Irritation

The skin irritation study indicates that the test material requires classification under regulation 1272/2008. The test material requires classification as “Category 2, H315: Causes skin irritation” with signal word “Warning”.

Eye Irritation

The eye irritation study indicates that the test material requires classification under regulation 1272/2008. The test material requires classification as “Category 2, H319: Causes serious eye irritation" with signal word " Warning".