Registration Dossier

Administrative data

Description of key information

According to an OECD TG 404 compliant study in the rabbit, the test item was found to be not irritating to the skin (reference 7.3.1 -1).

According to an OECD TG 405 compliant study in the rabbit, the test item was found to be not irritating to the eye (reference 7.3.2 -1).

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:
May 25, 2000 - Jun 01, 2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Wiga GmbH
- Age at study initiation: about 33 weeks
- Weight at study initiation: 4,31 kg (3,77-4,76)
- Housing: separately
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature: 20 - 22 °C
- Humidity: 50 to 64 %
- Air changes: not specified
- Photoperiod: 12 / 12 hrs dark / hrs light
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
water
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 0.5 g
Duration of treatment / exposure:
4 hours
Observation period:
24, 48, 72 hours after removal of patches
Number of animals:
3 female rabbits
Details on study design:
TEST SITE
- Area of exposure: back
- Type of wrap if used: semi-occlusive

REMOVAL OF TEST SUBSTANCE
- Washing: yes
- Time after start of exposure: 4 h

OBSERVATION TIME POINTS :
1 h after removal of the test item and then daily for further 7 days.

SCORING SYSTEM:
- Method of calculation: according to the guideline and Draize:
Grading scale for evaluation:
Erythema and eschar formation Scores
No erythema 0
Very slight erythema (barely perceptible) 1
Well defined erythema 2
Moderate to severe erythema 3
Severe erythema to eschar formation preventing grading of erythema 4

Maximum possible: 4

Edema formation Scores
No edema 0
Very slight edema (barely perceptible) 1
Slight edema (edges of area well defined by definite raising) 2
Moderate edema (raised approx. 1 mm) 3
Severe edema (raised more than 1 mm and extending beyond area of exposure) 4

Maximum possible: 4

Total possible irritation score (maximum): 8

Mean score = Mean grading for erythema or edema of all the rabbits per time point
Mean cumulative score = Mean grading of all readings for erythema and edema per time point
Mean score per animal = Mean grading for each animal of erythema or edema (24, 48, and 72 hours after removal of the patches)
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
After a single application to the intact dorsal skin of rabbits, for a 4 hours period of exposure under semiocclusive conditions, no signs of irritation were observed in the treated areas.
Other effects:
None

Clinical findings

After a single application to the intact dorsal skin of rabbits, for a 4 hours period of exposure under semiocclusive conditions, no signs of irritation were observed in the treated areas. No signs of clinical toxicity were detected.

Mortality

All animals survived the observation period.

Body weight

Body weight development of the treated rabbits was inconspicuous.

Table 1 Individual findings

 

Mean score (24, 48, 72 h)

Maximum value (24, 48, 72 h)

Animal No

4

6

10

4

6

10

Erythema

0 00

000

0.00

0

0

0

Edema

0.00

000

0.00

0

0

0

Interpretation of results:
GHS criteria not met
Conclusions:
The test item was not irritating to the skin in this assay.
Executive summary:

The purpose of this assay was to identify the skin irritation/corrosion potential of the test item when applied to the intact skin of previously shaven rabbits for a 4 hours period under semiocclusive conditions. This study should provide a rational basis for risk assessment to the irritating potential of the test item in man. To test for primary skin irritation, the test item was mixed with some drops of Aqua pro injectione to ensure good contact to the skin. Afterwards the test material was spread onto patches and applied to the intact skin of three previously shaven rabbits for a 4 hours period under semiocclusive conditions. The first examination of the treated skin sites followed 1 hour after removal of the patches. Then, examinations were performed daily for further 7 days. Under the conditions of the present study no signs of irritation were seen. The evaluation of all animals yields a zero mean score. The test item was not irritating to the skin in this assay.

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:
May 25, 2000 - Jun 01, 2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Charles River Wiga GmbH
- Age at study initiation: about 33 weeks
- Weight at study initiation: 4,31 kg (3,68 - 5.05)
- Housing: separately
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature: 20 - 22 °C
- Humidity: 50 to 64 %
- Air changes: not specified
- Photoperiod: 12 / 12 hrs dark / hrs light
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
0.1 g test material
Duration of treatment / exposure:
0.1 g test material was instilled into the conjunctival sac of the left eye of each animal by gently pulling the lower lid away from the eyeball to form a cup into which the test material was placed. The right eye remained untreated and served as control. After instillation, the eyelids were closed for about 30 seconds.
Observation period (in vivo):
1 hour after treatment, after 24, 48, and 72 hours, then daily up to day 8
Number of animals or in vitro replicates:
3 female rabbits
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing: not done

TOOL USED TO ASSESS SCORE: fluorescein & ophthalmoscope

SCORING SYSTEM: according to the guideline and Draize scoring system:

Evaluation of eye reactions

Cornea Scores

A) Opacity-degree of density (area most dense taken for reading)No ulceration or opacity 0
Scattered or diffuse areas of opacity (other than slight dullingof normal lustre), details of iris clearly visible 1
Easily discernible translucent area, details of iris slightly obscured 2
Nacrous area, 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 not evaluated (Rating according to the DRAIZE method)


Iris

Normal 0
Markedly deepened rugae, congestion, swelling, moderate circumcorneal hyperemia, or injection,
any 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

Conjunctivae

A) Redness (refers to palpebral and bulbar conjunctivae, cornea and iris)Blood vessels normal 0
Some blood vessels definitely hyperemic (injected) 1
Diffuse, crimson color, individual vessels not easily discernible 2
Diffuse beefy red 3

B) Chemosis: lids and/or nictating membranesNo swelling 0
Any swelling above normal (includes nictating membranes) 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 (Rating according to the DRAIZE method )
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 of a considerable area around the eye 3

Mean score of all animals = Mean grading for irritations of cornea, iris, and conjunctivae per time point
Mean score per animal = Mean grading for each animal of irritations of cornea, iris, and conjunctivae (1, 24, 48, and 72 hours after application)
Maximum value = Maximum grading of a sign of irritation within a period
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
3
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
3
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
3
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
No signs of irritation were observed at the cornea and iris. The conjunctivae showed redness (score 1) on day 1 (1 hour) of the study. Later on no signs of irritation were observed. The untreated eyes were unchanged.
Other effects:
No signs of clinical toxicity were detected.

Eye alterations

Clinical findings

No signs of irritation were observed at the cornea and iris. The conjunctivae showed redness (score 1) on day 1 of the study. Later on no signs of irritation were observed. The untreated eyes were unchanged. No signs of clinical toxicity were detected.

Mortality

All animals survived the observation period.

Body weight

Body weight development of the treated rabbits was inconspicuous.

Interpretation of results:
GHS criteria not met
Conclusions:
The test material is not regarded as an irritant for the eyes.
Executive summary:

The purpose of this primary eye irritation assay was to provide information on possible health hazards in case of acute eye contact with a test material and serve as a rational basis for risk assessment to the eye irritating potential of the test item in man. The test material was tested for its toxicological properties. For the test of primary eye irritation, 0.1 g of the ground test material was applied into the conjunctival sac of rabbits. The first examination of the eyes followed 1 hour after instillation. The examinations were performed daily for further 7 days. No signs of irritation were observed at the cornea and iris. The conjunctivae showed redness (score 1) on day 1 of the study. Later on no signs of irritation were observed. The untreated eyes were unchanged. The test material is not regarded as an irritant for the eyes.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation:

In a primary dermal irritation study, young adult New Zealand White rabbits (3 females) were dermally exposed to 0.5 g of moistened test material for 4 hours under semi-occlusive conditions. Animals then were observed 1, 24, 48 and 72 hours, as well as 7 days after treatment. No erythema and no edema were observed within the observation period. The cumulative irritation score was 0.00 based on the DRAIZE scheme indicating no irritant potential. In this study, the test item is not a dermal irritant.


Eye irritation:

In a primary eye irritation study 0.1 g of the test item was instilled into the conjunctival sac of the left eye of young adult New Zealand White rabbits (3 females). Animals then were observed 1, 24, 48 and 72 hours, as well as 7 days after treatment. Besides redness (score 1 at day 1) of the conjunctiva, no signs of irritation were observed at the cornea or iris within the course of the observation period. The cumulative irritation score of the test item was 0.00 based on the DRAIZE scheme indicating no irritant potential. In this study, the test item is not an eye irritant.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on available data on local irritation properties, the test item does not require classification as skin or eye irritant according to Regulation (EC) No 1272/2008 (CLP), as amended for the twelfth time in Regulation (EU) 2019/521.