Registration Dossier

Administrative data

Description of key information

Skin irritation/corrosion:

In the key study, the test material induced positive irritation in 3 out of six female rabbits in a study conducted in accordance with OECD 404, EU Method B.4 and EPA OTS 798.4470. With the exception of very slight erythema in one animal (and desquamation in four animals), all animals had recovered by day 14.

Eye irritation:

In the key study, the eye irritation potential of the test material was evaluated in an in vivo study conducted in accordance with OECD 405, EU Method B.5 and EPA OPP 81 -4. Conjunctival irritation for all animals includede positive reaction for three animals persisted through to the termination of the study. The test material was concluded to induce irreversible ocular irritation under the conditions of the test.

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
Study period:
4th May 1993 to 18th May 1993
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OTS 798.4470 (Acute Dermal Irritation)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: Young adult
- Weight at study initiation: 4421 to 5333 grams
- Housing: Individual suspended mesh bottom cages
- Diet:ad libitum
- Water: tap water ad libitum
- Acclimation period: a minimum of 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24 °C
- Humidity (%): 42-76 %
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL
Duration of treatment / exposure:
4 hours
Observation period:
14 days
Number of animals:
6 females
Details on study design:
TEST SITE
- Area of exposure: Back
- Type of wrap if used: Each sample was applied under a 2.5 cm² gauze patch that was overwrapped with a gauze binder and secured with tape. Plastic restraint collars were applied and remained on the animals for the duration of exposure.

REMOVAL OF TEST SUBSTANCE
At the end of the exposure period, the test site was wiped with paper towels moistened with mineral oil (USP).

OBSERVATION TIME POINTS
The rabbits were observed at 1, 24, 48 and 72 hours after partch removal and daily thereafter through day 14 if irritation persisted.

SCORING SYSTEM:
- Method of calculation: Draize
Erythema and Eschar Formation
No erythema – 0
Very slight erythema (barely perceptible, edges of area not well defined) – 1
Slight erythema (pale red in colour) – 2
Moderate to severe erythema (definite red in colour and area well defined) – 3
Severe erythema (beet or crimson red) to slight eschar formation (injuries in depth) – 4
Oedema formation
No Oedema – 0
Very slight oedema (barely perceptible, edges of area not well defined) – 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 sever oedema extending beyond area of exposure) - 4
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
3
Max. score:
4
Reversibility:
not fully reversible within: 14 days
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 8 days
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 10 days
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
3
Max. score:
4
Reversibility:
fully reversible within: 12 days
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Basis:
animal #4
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 11 days
Irritation parameter:
edema score
Basis:
animal #4
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #5
Time point:
24/48/72 h
Score:
2.67
Max. score:
4
Reversibility:
fully reversible within: 12 days
Irritation parameter:
edema score
Basis:
animal #5
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 8 days
Irritation parameter:
erythema score
Basis:
animal #6
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 12 days
Irritation parameter:
edema score
Basis:
animal #6
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
The test material induced slight to moderate erythema on all rabbits and very slight to slight oedeman in four rabbits. Desquamation was presented on all sites by day 7. All oedema completely subsided by day 9 or earlier. Minor reversible (grade 1) erythema on one site and desquamation on four sites persisted through study termination.
Other effects:
There were no unscheduled deaths during the course of the study.
There were no significant effects on body weight changes during the study (animals were weighed on day 0 and at study termination).

Table 1: Results

 

Animal

Observation

1 hour

24 hours

48 hours

72 hours

4 days

5 days

6 days

7 days

8 days

9 days

10 days

11 days

12 days

13 days

14 days

1

Erythema

2

3

3

3

3

3d

2d

2d

1d

1d

1d

1d

1d

1d

1d

Oedema

0

1

1

1

2

2

1

1

1

0

0

0

0

0

0

2

Erythema

2

2

2

2

2d

2d

2d

1d

1d

1d

0d

0d

0d

0

-

Oedema

0

1

0

0

0

0

0

0

0

0

0

0

0

0

-

3

Erythema

2

3

3

3

3

3d

2d

2d

2d

1d

1d

1d

0d

0d

0d

Oedema

0

1

1

1

1

1

1

0

0

0

0

0

0

0

0

4

Erythema

2

2

2

2

2

2

1

1d

1d

1d

1d

0d

0d

0d

0d

Oedema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

5

Erythema

2

3

2

3

3d

3d

3d

2d

2d

1d

1d

1d

0d

0d

0d

Oedema

1

1

1

1

2

2

1

1

0

0

0

0

0

0

0

6

Erythema

2

2

2

2

2

2d

1d

1d

1d

1d

1d

1d

0d

0

-

Oedema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

-

d = desquamation
- = animal terminated from study, irritation previously subsided.

 

Interpretation of results:
GHS criteria not met
Conclusions:
The test material induced slight to moderate erythema on all rabbits. Four sites had very slight to slight oedema. Desquamation was present on all sites by the end of the first week of the study. In general erythema and oedema had completely subsided by day 12 or earlier with the exception of one animal where very slight erythema persisted to day 14. Four animals had desquamation at study termination. The primary irritation index was calculated as 2.8 which equates to the description of moderately irritating, however in accordance with the criteria outlined in Regulation EC 1272/2008 (CLP), the test material is not classified.
Executive summary:

The skin irritation of the test material was investigated in female albino rabbits in accordance with OECD 404, EU Method B.4 and EPA OTS 798.4470. The test material induced slight to moderate erythema on all rabbits. Four sites had very slight to slight oedema. Desquamation was present on all sites by the end of the first week of the study. In general erythema and oedema had completely subsided by day 12 or earlier with the exception of one animal where very slight erythema persisted to day 14. Four animals had desquamation at study termination.  The primary irritation index was calculated as 2.8 which equates to the description of moderately irritating, however in accordance with the criteria outlined in Regulation EC 1272/2008 (CLP), the test material is not classified (the test material induced a positive response in 3/6 animals).

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
Study period:
17th May 1993 to 10th June 1993
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
EPA OPP 81-4 (Acute Eye Irritation)
Deviations:
no
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Age at study initiation: Young adult
- Weight at study initiation: 2477 to 3420 g
- Housing: Individual suspended mesh-bottom cages
- Diet: ad libitum
- Water: ad libitum, tap water
- Acclimation period: a minimum of 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-24 °C
- Humidity (%): 42-84 %
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
Observation period (in vivo):
14 days
Number of animals or in vitro replicates:
6 (3 males and 3 females)
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): Washing was not performed

SCORING SYSTEM:
1. Cornea:
(A) Opacity- Degree of density (area most dense taken for reading)
No ulceration or opacity – 0
Dulling of normal lustre, details of iris clearly visible – 1*
Easily discernible translucent areas, details of iris slightly obscured – 2*
Nacreous areas, no details of iris visible, size of pupil barely discernible – 3*
Opaque cornea, iris not discernible through the opacity – 4*
(B) Area of cornea involved
No ulceration or opacity – 0
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*
Score equals A X B X 5
Total Maximum = 80
2. Iris
(A) Values
Normal – 0
Markedly deepened rugae, congestion, swelling, circumcorneal 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, haemorrhage, gross destruction (any or all of these) – 2*
Score equals A X 5
Totally maximum = 10
Conjunctivae
(A) Redness (refers to palpebral and bulbar conjunctivae excluding cornea and iris)
Blood vessels normal – 0
Some blood vessels definitely hyperaemic (injected above) normal – 1
Diffuse, deeper crimson colour, individual vessels not easily discernible – 3*
Diffuse beefy red – 3*
(B) Chemosis (lids and/or nictitating membranes)
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 more than half closed - 4*
(C) Discharge
No discharge – 0
Any amount of 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 the lids – 2
Discharge with moistening of the lids and hair, and considerable area around the eye – 3
Score equals (A + B + C) X 2
Total maximum = 20
Total maximum score possible = 110
* Indicates a positive reaction


TOOL USED TO ASSESS SCORE: Both eyes of all rabbits were examined for ocular abnormalities prior to study initiation. The pre-initiation examination was performed using sodium fluorescein and ultraviolet light. Only rabbits with no pre-existing ocular abnormalities were used.
Both eye of all rabbits were examined macroscopically for ocular irritation using a hand-held penlight at approximately one, 24, 48 and 72 hours after dosing and at 4, 7, 14 and 21 days. In addition, both eye of all animals were further examined at 72 hours and 7, 14 and 21 days with sodium fluorescein and ultraviolet light.
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1.3
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
cornea opacity score
Basis:
animal #4
Time point:
24/48/72 h
Score:
1.33
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
cornea opacity score
Basis:
animal #5
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
cornea opacity score
Basis:
animal #6
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.33
Max. score:
2
Reversibility:
fully reversible within: 4 days
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 21 days
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.67
Max. score:
2
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
iris score
Basis:
animal #4
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 21 days
Irritation parameter:
iris score
Basis:
animal #5
Time point:
24/48/72 h
Score:
0.67
Max. score:
2
Reversibility:
fully reversible within: 21 days
Irritation parameter:
iris score
Basis:
animal #6
Time point:
24/48/72 h
Score:
0.33
Max. score:
2
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2.67
Max. score:
3
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
2.67
Max. score:
3
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
conjunctivae score
Basis:
animal #4
Time point:
24/48/72 h
Score:
2
Max. score:
3
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
conjunctivae score
Basis:
animal #5
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
conjunctivae score
Basis:
animal #6
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2.33
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
3
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
2.67
Max. score:
4
Reversibility:
fully reversible within: 21 days
Irritation parameter:
chemosis score
Basis:
animal #4
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
chemosis score
Basis:
animal #5
Time point:
24/48/72 h
Score:
3
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
chemosis score
Basis:
animal #6
Time point:
24/48/72 h
Score:
2.67
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Irritant / corrosive response data:
None of the rabits vocalised upon instillation of the test material.
There were no significant changes or differences observed in body weights during the study period (measured on day 0 and 21).
There were no unscheduled deaths during the study.

Table 1: Results

Animal

Sex

Observation

Examination

1

hour

24

hours

48

hours

72

hours

4

days

7

days

14

days

21

days

1

Male

Cornea - opacity

0

1

1

2

2

2

0

0

Cornea - area

0

1

2

3

4

4

0

0

Iris

1

0

0

1

0

0

0

0

Conjunctivae - Redness

2

3

2

3

2

2

1

1

Conjunctivae - Chemosis

3

2

2

3

3

2

1

1

Conjunctivae - Discharge

3

2

2

2

2

1

0

0

2

Male

Cornea - opacity

1

1

1

1

2

2

2

1

Cornea - area

2

3

4

4

4

4

2

1

Iris

1

1

1

1

1

1

1

0

Conjunctivae - Redness

2

2

3

3

3

3

2

1

Conjunctivae - Chemosis

3

3

3

3

3

4

3

2

Conjunctivae - Discharge

3

2

1

1

2

1

1

1

3

Male

Cornea - opacity

1

1

1

1

1

0

1

1

Cornea - area

1

3

3

2

1

0

1

1

Iris

1

1

1

0

0

0

1

0

Conjunctivae - Redness

2

3

3

3

2

1

2

1

Conjunctivae - Chemosis

2

3

3

2

2

1

1

0

Conjunctivae - Discharge

2

2

0

0

0

0

0

0

4

Female

Cornea - opacity

1

1

1

2

3

3

3

2

Cornea - area

1

3

4

4

4

4

4

2

Iris

1

1

1

1

1

0

1

0

Conjunctivae - Redness

2

2

2

2

2

2

3

1

Conjunctivae - Chemosis

2

2

2

2

2

3

3

2

Conjunctivae - Discharge

2

2

2

2

2

0

1

0

5

Female

Cornea - opacity

1

1

1

1

2

2

2

2

Cornea - area

3

4

4

4

4

4

4

4

Iris

1

0

1

1

1

0

1

0

Conjunctivae - Redness

2

3

3

3

3

3

2

2

Conjunctivae - Chemosis

3

3

3

3

4

4

4

3

Conjunctivae - Discharge

3

2

2

2

3

3

2

1

6

Female

Cornea - opacity

1

1

1

1

2

2

2

1

Cornea - area

3

3

3

3

2

2

1

1

Iris

1

1

0

0

0

0

0

0

Conjunctivae - Redness

2

3

3

3

2

2

2

1

Conjunctivae - Chemosis

3

3

2

3

3

3

1

1

Conjunctivae - Discharge

3

1

1

0

1

1

0

0

Total

168

191

198

235

302

277

213

111

Mean

28.0

31.8

33.0

39.2

50.3

46.2

35.5

18.5

 

Table 2: Individual observations

Animal

Sex

Time

Observation

1

Male

1 hour

b

24 hours

b,e(20 %)

48 hours

b,e(40 %),i(40 %)

72 hours

a,c,e(80 %),r(80 %)

4 days

b,e(80 %),j

7 days

b,e(40 %),j,r(40 %)

14 days

r(0 %)

21 days

r(0 %)

2

Male

1 hour

b,e(25 %)

24 hours

b

48 hours

b

72 hours

a,r(90 %)

4 days

b,e(90 %),j

7 days

b,e(50 %),j,r(50 %)

14 days

b,e(20 %),k,r(20 %)

21 days

b,k,r(0 %)

3

Male

1 hour

b,e(30 %)

24 hours

b,e(80 %)

48 hours

e(80 %)

72 hours

e(50 %),r(50 %)

4 days

e(40 %)

7 days

e(5 %),r(5 %)

14 days

e(20 %),k,r(20 %)

21 days

r(0 %)

4

Female

1 hour

b,e(20 %)

24 hours

b,e(25 %)

48 hours

b

72 hours

b,e(85 %),r(85 %)

4 days

b,e(85 %),j

7 days

e(40 %),j,k,r(40 %)

14 days

a,e(35 %),k,r(35 %)

21 days

e(20 %),k,r(20 %)

5

Female

1 hour

b,e(40 %)

24 hours

b,e(80 %)

48 hours

a,e(80 %)

72 hours

a,c,e(100 %),r(100 %)

4 days

b,e(100%),j

7 days

b,e(90 %),k,r(90 %)

14 days

b,e(70 %),k,r(70 %)

21 days

a,e(5 %),k,r(5 %)

6

Female

1 hour

b,e(20 %)

24 hours

b,e(50 %)

48 hours

a,e(40 %)

72 hours

c,e(40 %),r(40 %)

4 days

b,e(40 %)

7 days

b,e(25 %),j,r(25 %)

14 days

e(20 %),k,r(20 %)

21 days

e(10 %),k,r(10 %)

a = Purulent discharge
b = Clear discharge
c = Petite haemmorhage
e = Corneal epithelial damage, peeling (% of area)
j = Pannus
k = Corneal neovascularisation
r = Sodium fluorescein stain retention (% of area)

 

 

Interpretation of results:
Category 1 (irreversible effects on the eye) based on GHS criteria
Conclusions:
Under the conditions of the test, positive irritation was present for all ocular tissues examined. Iridial irritation subsided by day 21 or earlier in all animals.Corneal irritation persisted throughout the study until termination in five rabbits. Conjunctival irritation for all animals includede positive reaction for three animals persisted through to the termination of the study. The test material was concluded to induce irreversible ocular irritation under the conditions of the test.
Executive summary:

The eye irritation potential of the test material was evaluated in an in vivo study conducted in accordance with OECD 405, EU Method B.5 and EPA OPP 81 -4. Six albino rabbits (3 male and 3 females) were instilled with 0.1 mL undiluted test material and observed for 21 days. Under the conditions of the test, positive irritation was present for all ocular tissues examined. Iridial irritation subsided by day 21 or earlier in all animals.Corneal irritation persisted throughout the study until termination in five rabbits. Conjunctival irritation for all animals includede positive reaction for three animals persisted through to the termination of the study. The test material was concluded to induce irreversible ocular irritation under the conditions of the test.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

In accordance with regulation EC 1272/2008 (CLP), the test material is classified as H318 (Category 1) Causes serious eye damage. The test material did not meet the classification criteria for skin irritation and corrosion.