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Administrative data

Description of key information

Skin irritation: Key study: Experimental result: According to OECD 404. GLP study. 
In the 4 hour rabbit skin irritancy test, the test material caused no skin reactions and is therefore not a skin irritant.
Eye irritation: Key study: Experimental result: According to OECD 405. GLP study.
In the rabbit eye irritancy test, the test material caused slight conjunctival redness within 1 hour of dosing which had cleared by 24 hours. The test material is therefore not an eye irritant in rabbits.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1976
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Limited reporting
Qualifier:
according to guideline
Guideline:
other: Draize method
Principles of method if other than guideline:
6 rabbits received patches of 0.5 g of the undiluted test substance to 2 clipped and 2 clipped and abraded areas of the skin.
The skin was covered with gauze pads for 24 h. Skin readings were performed after 24 and 72 h after application of the material.
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Type of coverage:
semiocclusive
Preparation of test site:
other: two clipped to abraded sites per animal
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g


Duration of treatment / exposure:
24 h
Observation period:
72 h
Number of animals:
6
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable as no irritation observed
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Irritant / corrosive response data:
No signs of irritation were observed in any of the animals at both time points.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Although the study had limited observation times, it can be concluded that the substance was not irritant to rabbit skin, even if abraded, after a 24 h semi-occlusive exposure.
Executive summary:

The tst substance was applied to clipped or abraded skin areas of 6 New Zealand hite rabbits for 24 h under semi-occlusive conditions. No irritation was observed in any animal at any of the observation time points (24 and 72h). It can therfore be cosnlcude that the substance was not irritating to rabbit skin under the conditions of this test.

Endpoint:
skin irritation: in vitro / ex vivo
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
an in vitro skin irritation study does not need to be conducted because adequate data from an in vivo skin irritation study are available
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: According to OECD 404. GLP study. The dose level applied to the skin of the animals was 250 mg instead of 500 mg for solids, as recommended in the guideline. However, it is considered that this deviation does not affect the outcome of the study.
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
(However, it is considered that this deviation does not affect the outcome of the study).
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Sittingbourne Research Centre Breeding unit
- Age at study initiation: 4-9 months old
- Weight at study initiation: males: 3888-4462 g; females: 4966-4994 g
- Housing: Animals were singly housed in hanging, stainless-steel cages with all-mesh floors and tops and half-mesh fronts; each cage measured 67 cm x 43 cm x 45 cm.
- Diet (e.g. ad libitum): Standard Rabbit Diet, S.Q.C., Special Diet Services Ltd., Essex, ad libitum.
- Water (e.g. ad libitum): Filtered from the public supply , ad libitum.
- Acclimation period: At least, two weeks.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16-19 ºC
- Humidity (%): Not documented.
- Air changes (per hr): Not documented.
- Photoperiod (hrs dark / hrs light): Lighting was automatically switched on for the day (06.00 to 18.00 hours GMT) and off for the night (18.00 to 06.00 hours GMT).


Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
other: moistened with water
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 250 mg
Duration of treatment / exposure:
4 hours
Observation period:
30 minutes after the removal of the patch and at 24, 48 and 72 hours and 7 days after patch removal.
Number of animals:
Three per sex
Details on study design:
TEST SITE
- Area of exposure: Dorsal hair between the shoulders and hindquarters was closely shorn with fine electric clippers. A 2 cm x 2 cm lint patch was applied.
- Type of wrap if used: The patch and surrounding skin were covered by a single layer of gauze and held in place by means of an elastic adhesive bandage.


REMOVAL OF TEST SUBSTANCE
- Washing (if done): After 4 hours the wrapping and patch were removed and the test site washed with water and gently dried.


SCORING SYSTEM: Erythema and oedema on a graded scale of 0 to 4.
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
other: Not applicable
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
other: Not applicable

Table 7.3.1: Dermal irritation scores

Erythema

Oedema

Animal No

1

2

3

4

5

6

1

2

3

4

5

6

after 4 h

0

0

0

0

0

0

0

0

0

0

0

0

after 24 h

0

0

0

0

0

0

0

0

0

0

0

0

after 48 h

0

0

0

0

0

0

0

0

0

0

0

0

after 72 h

0

0

0

0

0

0

0

0

0

0

0

0

after 7 days

0

0

0

0

0

0

0

0

0

0

0

0

Mean score 24 – 72 h

0.0

0.0

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
In the 4 hour rabbit skin irritancy test, the test material caused no skin reactions and is therefore not a skin irritant.
Executive summary:

Six New Zealand White rabbits (3 per sex) were exposed via the dermal route to 250 mg of the test substance. After a 4 hour exposure the dresssings were removed, the skin washed with water and dried. After treatment, animals were examined for erythema, oedema and other lesions at 4, 24, 48 and 72 hours and at 7 days after patch removal. The test material caused no skin reactions and was therefore considered as not irritanting to skin.

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

Eye irritation

Link to relevant study records

Referenceopen allclose all

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1976
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: limited reporting
Qualifier:
equivalent or similar to guideline
Guideline:
other: Draize method
Principles of method if other than guideline:
6 New Zealand white rabbits received 0.1 g of the substance as powder in the conjunctival sac of one eye. The other eye served as control. Obersvations were performed at the end of 1,2,3, and 7 days after application.
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 g
Duration of treatment / exposure:
7 days
Observation period (in vivo):
7 days
Number of animals or in vitro replicates:
6
Details on study design:
SCORING SYSTEM: Draize,
endpoints evaluated: Cornea opacity and area, Iris redness, Conjuctivae: redness, chemosis and discharge
Irritation parameter:
cornea opacity score
Remarks:
opacity and area
Basis:
mean
Time point:
other: 24 h
Score:
0.2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 2 days
Score:
0.2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 3 d
Score:
0.2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 7 d
Score:
0
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24 h, 2, 3 and 7 days
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
mean
Time point:
other: 24 h
Score:
0.7
Max. score:
4
Reversibility:
fully reversible within: 3 days
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
mean
Time point:
other: 2 days
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 3 days
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
mean
Time point:
other: 3d and 7 d
Score:
0
Max. score:
4
Reversibility:
fully reversible within: 3 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24 h
Score:
0.2
Max. score:
4
Reversibility:
fully reversible within: 2 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 2 days, 3 days and 7 days
Score:
0
Max. score:
4
Reversibility:
fully reversible within: 2 days
Irritation parameter:
other: discharge
Basis:
mean
Time point:
other: 24 h
Score:
0.5
Max. score:
4
Reversibility:
fully reversible within: 2 days
Irritation parameter:
other: discharge
Basis:
mean
Time point:
other: 2 days, 3 days, 7 days
Score:
0
Max. score:
4
Reversibility:
fully reversible within: 2 days
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 24 h
Score:
3.5
Max. score:
110
Reversibility:
fully reversible within: 7 days
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 2 days
Score:
1.5
Max. score:
110
Reversibility:
fully reversible within: 7 days
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 3 days
Score:
0.8
Max. score:
110
Reversibility:
fully reversible within: 7 days
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 7 days
Score:
0
Max. score:
110
Reversibility:
fully reversible within: 7 days
Irritant / corrosive response data:
Except for one animal between days 1 and 3 where slight corneal opacity was observed, no corneal involvement was seen in the animals. Slight conjuctival irritation was observed in 5 animals on the first dau of observation. All effects were fully reversible within 7 days. The substance was reproted to be non-irritating in this test.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the test slight conjunctival irritation grade 1 was observed in the first rading at day 1 in 5 animals and one animal had slight corneal reactions (grade 1) that were reverisble after 7 days. According to regulation EC 1272/2008 and amendments no classification for eye irritation is warranted.
Executive summary:

Eye irritation of the substance was invstigated byu the method of Draize in 6 rabbits receiving 0.1 g of the test substance in the conjunctival sac of one eye. The observation period was 7 days. Only slight irritation was observed that was reversible within the observation period. According to the scale of Draize the substance was non-irritating to rabbit eye in this experiment. According to the criteria of regulation EC 1272/2008 and amendments no classification for eye irritation is warranted.

Endpoint:
eye irritation: in vitro / ex vivo
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
an in vitro eye irritation study does not need to be conducted because adequate data from an in vivo eye irritation study are available
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1976
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study without detailed documentation.
Qualifier:
according to guideline
Guideline:
other: 16 Code of Federal Regulation (CFR) 1500.42 (Formerly 21 CFR 191.12)
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: No data
- Age at study initiation: No data
- Weight at study initiation: 1.9 to 2.3 kg
- Housing: Rabbits were individually housed and equilibrated in the testing laboratory Bio/dynamics Inc.
- Diet (e.g. ad libitum): No data
- Water (e.g. ad libitum): No data
- Acclimation period: No data
Note: Only animals which were determined to be free of ocular defects prior to compound administration were used in this study.

ENVIRONMENTAL CONDITIONS : No data
Vehicle:
not specified
Controls:
no
Amount / concentration applied:
TEST MATERIAL
The test material was instilled into one eye of each of the six rabbits using a 0.1 mL eye-cup .
Duration of treatment / exposure:
7 days
Observation period (in vivo):
The eyes were examined and scored for ocular reactions on Days 1, 2, 3, 4 and 7 following compound administration.
Number of animals or in vitro replicates:
Six rabbits - Test material was instilled into one eye of each of the 6 rabbits.
Details on study design:
SCORING SYSTEM: Similar to the score system presented in the OECD guideline 405 Acute eye irritation/corrosion
TOOL USED TO ASSESS SCORE: fluorescein
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
6
Time point:
24/48/72 h
Score:
0.055
Max. score:
1
Reversibility:
fully reversible
Remarks:
After 7 days
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
6 animals
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible
Remarks:
After 7 days
Irritation parameter:
iris score
Basis:
mean
Remarks:
6 animals
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible
Remarks:
After 7 days
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
6 animals
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible
Remarks:
After 7 days
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
6 animals
Time point:
other: 2, 3 & 4 days
Score:
0
Max. score:
0
Reversibility:
fully reversible
Remarks:
After 7 days
Irritation parameter:
iris score
Basis:
mean
Remarks:
6 animals
Time point:
other: 2, 3 & 4 days
Score:
0
Max. score:
0
Reversibility:
fully reversible
Remarks:
After 7 days
Irritation parameter:
conjunctivae score
Remarks:
Redness
Basis:
mean
Remarks:
6 animals
Time point:
other: 2, 3 & 4 days
Score:
0.055
Max. score:
1
Reversibility:
fully reversible
Remarks:
After 7 days
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
6 animals
Time point:
other: 2, 3 & 4 days
Score:
0
Max. score:
0
Reversibility:
fully reversible
Remarks:
After 7 days
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
According to the experiment, the substance 4,4 '-Methylenebis (2,6-di-tert-butylpehnol) is not considered as irritating to eyes.
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: According to OECD 405. GLP study.
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute 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
- Source: Sittingbourne Research Centre Breeding unit
- Age at study initiation: 4-9 months old
- Weight at study initiation: males: 3872-4184 g; females: 3276-4806 g
- Housing: Animals were singly housed in hanging, stainless-steel cages with all-mesh floors and tops and half-mesh fronts; each cage measured 67 cm x 43 cm x 45 cm.
- Diet (e.g. ad libitum): Standard Rabbit Diet, S.Q.C., Special Diet Services Ltd., Essex, ad libitum.
- Water (e.g. ad libitum): Filtered from the public supply , ad libitum.
- Acclimation period: At least, two weeks.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16-19 ºC
- Humidity (%): Not documented.
- Air changes (per hr): Not documented.
- Photoperiod (hrs dark / hrs light): Lighting was automatically switched on for the day (06.00 to 18.00 hours GMT) and off for the night (18.00 to 06.00 hours GMT).


Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 25 mg
Duration of treatment / exposure:
The eyes were not washed.
Observation period (in vivo):
A visual assessment of eye irritancy was made at 1, 4, 24, 48 and 72 hours and 7 days after instillation.
Number of animals or in vitro replicates:
Three per sex
Details on study design:
SCORING SYSTEM: Irritancy was scored for the cornea, iris and conjunctivae using the standard scores included in the study report.


TOOL USED TO ASSESS SCORE: At 24 hours and in the event of any corneal damage visualization was aided by the instillation of one drop of 2% fluorescein solution.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Irritant / corrosive response data:
The instillation of the test substance powder into the conjunctival sac of one eye of each of six rabbits resulted in slight initial pain. The only occular effect was slight conjunctival redness in all rabbits within 1 hour of dosing which had cleared by 24 hours.

Table 7.3.2: Mean eye irritation scores

Redness

Chemosis

Discharge

Opacity

Iris

24 hours

0

0

0

0

0

48 hours

0

0

0

0

0

72 hours

0

0

0

0

0

7 days

0

0

0

0

0

Mean score

24-72 h

0.0

0.0

0.0

0.0

0.0

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
In the rabbit eye irritancy test, the test material caused slight conjunctival redness within 1 hour of dosing which had cleared by 24 hours. The test material is therefore not an eye irritant in rabbits.
Executive summary:

The test material (25 mg) was applied to the eyes of six New Zealand White rabbits (3 per sex). A visual assessment of eye irritancy was made at 1, 4, 24, 48 and 72 hours and 7 days after instillation. The test material caused slight conjunctival redness within 1 hour of dosing which had cleared by 24 hours.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation: Key study: Experimental result: According to OECD 404. GLP study.

In the 4 hour rabbit skin irritancy test, the test material caused no skin reactions and is therefore not a skin irritant.

Eye irritation: Key study: Experimental result: According to OECD 405. GLP study.

In the rabbit eye irritancy test, the test material caused slight conjunctival redness within 1 hour of dosing which had cleared by 24 hours. The test material is therefore not an eye irritant in rabbits.


Justification for selection of skin irritation / corrosion endpoint:
Only one study available. Klimisch 2.

Justification for selection of eye irritation endpoint:
Only one study available. Klimisch 2.

Justification for classification or non-classification

Based on the available data, the substance is not classified as irritating.