Registration Dossier

Administrative data

Description of key information

Skin irritation: non irritating in vivo (US FHSA, GLP, Read-across, K, rel. 2)
Eye irritation:non irritating in vivo (US FHSA, similar to OECD 405, GLP, K, rel. 2)
Respiratory irritation: no data available

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation / corrosion, other
Remarks:
Old in-vivo study from 1979 so no new amnimals have been used.
Type of information:
experimental study
Adequacy of study:
key study
Study period:
December 7, 1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study performed similarly to US-FHSA guideline. Deviations from standard method : no data on test animals, 24 h exposure instead of 4h, occlusive dressing instead of semi-occlusive, observation at 24 and 72 h only (no 48h scoring), no reversibility period although effects have been observed until the end of the study. Even if full reversibility was not achieved for lesions, the observation period was only 3 days and effects were very slight and decreasing.
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Reference:
Composition 0
Qualifier:
according to
Guideline:
other: Section 1500.41 - Hazardous Substances and articles, Administration and Enforcement Regulations, Federal Register, Vol. 38, No. 187, P. 27019, 27 September 1973.
Deviations:
yes
Remarks:
purity of test item not reported; environmental conditions of experimental room not reported; occlusive patch 24 h instead of semi-occlusive patch 4 h; no details on removal of substance after patch removal; no observation for 14 days but only 72 h
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes
Test material information:
Composition 1
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: approved USDA supplier
- Weight at study initiation: 3.27-3.60 kg
- Housing: Animals were housed individually in wire-meshed cages.
- Diet: Charles River Rabbit Formula, ad libitum
- Water, ad libitum
Type of coverage:
occlusive
Preparation of test site:
other: one side intact and clipped
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL
- Concentration (if solution): Undiluted
Duration of treatment / exposure:
24 h
Observation period:
24 and 72 h
Number of animals:
6
Details on study design:
PRETREATMENT
- 24 h prior to the dermal applications the backs and flanks of each rabbit were clipped free of hair with a commercial electric clipper with a No. 40 blade. The animals were then returned to their cages.

TEST SITE (intact skin)
- Area of exposure: Left side of the animal's back
- Type of wrap if used: The test sites were then immediately occluded with a one-inch by one-inch square gauze patch, two single layers thick. The patches were secured in place with masking tape. The trunk of each animal was wrapped with impervious plastic sheeting which helped hold the patches in position and retard evaporation of the test material during the 24 h exposure period.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): No
- Time after start of exposure: 24 h

SCORING SYSTEM: Draize method
Irritation parameter:
erythema score
Basis:
mean
Remarks:
(6 animals)
Time point:
other: mean 24 and 72 h
Score:
1
Max. score:
4
Reversibility:
other: erythema cleared in the intact skin of 2/6 animals & no reversibility in 4/6 animals at 72h
Remarks on result:
other: Intact skin
Irritation parameter:
edema score
Basis:
mean
Remarks:
(6 animals)
Time point:
other: mean 24 and 72 h
Score:
0.58
Max. score:
4
Reversibility:
other: edema cleared in the intact skin of 5/6 animals & no reversibility in 1/6 animals at 72h
Remarks on result:
other: Intact skin
Irritant / corrosive response data:
Slight erythema and edema were observed in the intact skin of all six animals. Erythema cleared in the intact skin of two animals during the 72 h observation period and edema cleared in the intact skin of five animals during the 72 h observation period.
Other effects:
None

Table 7.3.1/1: Primary Skin Irritation Scores of Rabbits

Findings

Exposure Time (h)

Exposure unit (value)

 

Rabbit No.

1

2

3

4

5

6

Erythema and eschar formation:

Intact Skin

24

1

1

1

2

1

2

Intact Skin

72

1

1

1

1

0

0

Mean (24 and 72 h)

 

1

1

1

1.5

0.5

1.0

Edema formation:

Intact Skin

24

1

1

1

1

1

1

Intact Skin

72

0

0

0

1

0

0

Mean (24 and 72 h)

 

0.5

0.5

 

0.5

1.0

0.5

0.5

Interpretation of results:
slightly irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the test conditions, the test material induced slight irritation to the skin of rabbits. Even if full reversibility was not achieved, the observation period was only 3 days and effects were slight and decreased between 48-hour and 72-hour observation periods.
Executive summary:

In a dermal irritation study, 0.5 mL of undiluted test material was dermally applied on the intact or abraded side surface of 6 New Zealand White rabbits. Test sites were covered with an occlusive dressing for 24 h. Animals were then observed for 72 h for edema and erythema.  Skin irritation was assessed and scored according to the Draize scale at 24 and 72 h after the removal of the patch.

Slight to mild erythema and slight edema were observed in the intact skin of all six animals at 24h and 72h observation periods. All the individual mean scores for erythema/eschar or oedema, from gradings at 24 and 72h after patch removal, were below the limit of classification (2.3). At 72h observation period, 4/6 animals were scored for erythema/eschar with a very low score (1). Erythema cleared in the intact skin of two animals during the 72 h observation period and edema cleared in the intact skin of five animals during the 72 h observation period.

Based on the weakness of the observed effects, that remain stable or cleared at 72h time point, and since this study was performed under worst case conditions (24h under occlusive conditions instead of 4h under semi-occlusive conditions), it is highly likely that the slight effects observed at 72h will clear in at least 4/6 animals within a 14 -day observation period.

Based on this expert judgement, the test material is not classified as irritant to the skin according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP).

This study is considered as acceptable and satisfies the requirement for skin irritation endpoint.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation, other
Remarks:
Old in-vivo study from 1979 so no new amnimals have been used.
Type of information:
experimental study
Adequacy of study:
key study
Study period:
December 13, 1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was performed according to 16 CFR 1500.42 (US) test guideline. The study was conducted prior to the OECD Test Guideline No. 405 but the protocol is similar to that guidance.
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Reference:
Composition 0
Qualifier:
according to
Guideline:
other: Section 1500.42 - Hazardous Substances and Articles, Administration and Enforcement Regulations, Federal Register, Vol. 38. No. 187, p. 27019, 27 September 1973.
Deviations:
no
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
(no details on test animals and environmental conditions)
Principles of method if other than guideline:
Not applicable
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
- Source: approved USDA supplier
- Weight at study initiation: 2.18-3.26 g
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated eye served as control.
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
- Concentration (if solution): Undiluted
Duration of treatment / exposure:
No wash: The eyes of six animals were not washed out after instillation of the test material.
Washout: The eyes of three animals were washed out 4 seconds after instillation of the test material, with distilled water for approximately 10 seconds or until all test material was removed from the eye.
Observation period (in vivo):
7 days
Number of animals or in vitro replicates:
No wash: six animals
Washout: three animals
Details on study design:
PRETREATMENT
The eyes of each rabbit were examined with sodium fluorescein and an ultraviolet lamp (prior to instillation of the test material) and only those rabbits whose eyes were free of irritation and corneal lesions were used.

REMOVAL OF TEST SUBSTANCE
- No wash: The eyes of six animals were not washed out after instillation of the test material.
- Washout: The eyes of three animals were washed out 4 seconds after instillation of the test material, with distilled water for approximately 10 seconds or until all test material was removed from the eye.

SCORING SYSTEM: Draize method
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
6 animals
Time point:
other: 24, 48 and 72 h
Score:
0
Max. score:
4
Remarks on result:
other: no wash out
Irritation parameter:
iris score
Basis:
mean
Remarks:
6 animals
Time point:
other: 24, 48 and 72 h
Score:
0
Max. score:
2
Remarks on result:
other: no wash out
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
6 animals
Time point:
other: 24, 48 and 72 h
Score:
0.5
Max. score:
3
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: no wash out
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
6 animals
Time point:
other: 24, 48 and 72 h
Score:
0
Max. score:
4
Remarks on result:
other: no wash out
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
3 animals
Time point:
other: 24, 48 and 72 h
Score:
0
Max. score:
4
Remarks on result:
other: wash out
Irritation parameter:
iris score
Basis:
mean
Remarks:
3 animals
Time point:
other: 24, 48 and 72 h
Score:
0
Max. score:
2
Remarks on result:
other: wash out
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
3 animals
Time point:
other: 24, 48 and 72 h
Score:
0
Max. score:
3
Remarks on result:
other: wash out
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
3 animals
Time point:
other: 24, 48 and 72 h
Score:
0
Max. score:
4
Remarks on result:
other: wash out
Irritant / corrosive response data:
One animal in the 4-second washout group of the original study was observed to have corneal damage after 72 h. This finding was thought to be an artifact, as even the no washout group demonstrated absolutely no corneal damage. The 4 second washout group was repeated and no corneal damage was observed.

No wash out: Conjunctival effects were observed in three animals. This effect cleared in one animal during the 48 h reading and two animals cleared during the 7-day observation period.

Wash out: No ocular reactions were observed.
Other effects:
None

Table 7.3.2/1: Eye irritation response data for each animal at each observation time

Score at time

point

Cornea

Iris

(/2)

Conjunctivae

Opacity

(/4)

Area

(/4)

Redness

(/3)

Chemosis

(/4)

Discharge

(/3)

Washout

24 h (Day 1)

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

48 h (Day 2)

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

72 h (Day 3)

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

Day 7

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

Mean individual score

24, 48 and 72 h

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

Reversibility

-

-

-

-

-

-

No wash

24 h (Day 1)

0 / 0 / 0 / 0 / 0 / 0

0 / 0 / 0 / 0 / 0 / 0

0 / 0 / 0 / 0 / 0 / 0

2 / 0 / 1 / 0 / 0 / 1

0 / 0 / 0 / 0 / 0 / 0

0 / 0 / 0 / 0 / 0 / 0

48 h (Day 2)

0 / 0 / 0 / 0 / 0 / 0

0 / 0 / 0 / 0 / 0 / 0

0 / 0 / 0 / 0 / 0 / 0

2 / 0 / 1 / 0 / 0 / 0

0 / 0 / 0 / 0 / 0 / 0

0 / 0 / 0 / 0 / 0 / 0

72 h (Day 3)

0 / 0 / 0 / 0 / 0 / 0

0 / 0 / 0 / 0 / 0 / 0

0 / 0 / 0 / 0 / 0 / 0

1 / 0 / 1 / 0 / 0 / 0

0 / 0 / 0 / 0 / 0 / 0

0 / 0 / 0 / 0 / 0 / 0

Day 7

0 / 0 / 0 / 0 / 0 / 0

0 / 0 / 0 / 0 / 0 / 0

0 / 0 / 0 / 0 / 0 / 0

0 / 0 / 0 / 0 / 0 / 0

0 / 0 / 0 / 0 / 0 / 0

0 / 0 / 0 / 0 / 0 / 0

Mean individual score 24, 48 and 72 h

0 / 0 / 0 / 0 / 0 / 0

0 / 0 / 0 / 0 / 0 / 0

0 / 0 / 0 / 0 / 0 / 0

1.67 / 0 / 1.00 / 0 / 0 / 0.33

0 / 0 / 0 / 0 / 0 / 0

0 / 0 / 0 / 0 / 0 / 0

Reversibility

 -

 -

-

fully reversible within: 7 days

-

-

Interpretation of results:
not irritating
Remarks:
Migrated information cannot be evaluated Criteria used for interpretation of results: EU
Conclusions:
Under the test conditions, the test material induced mild irritation being reversible within 7 days. Therefore, the test material is not classified as irritant to the eyes.
Executive summary:

In an eye irritation study, 0.1 mL of undiluted test material was instilled into one eye of 9 New Zealand white rabbits while the untreated eye remained untreated and served as control. In Group 1, the eyes of six animals were not washed out after instillation of the test material. In Group 2, the eyes of three animals were washed out 4 seconds after instillation of the test material, with distilled water for approximately 10 seconds or until all test material was removed from the eye. Animals were observed at 24, 48 and 72 h after instillation of test material and then on Days 7. The reactions in the conjunctivae (redness, chemosis and discharge), the iris and the cornea (opacity and area involved) were scored according to the Draize scale.

One animal in the 4-second washout group of the original study was observed to have corneal damage after 72 h. This finding was thought to be an artifact, as even the no washout group demonstrated absolutely no corneal damage. The 4 second washout group was repeated and no corneal damage was observed. 

Conjunctival effects (redness) were observed in three animals of the unwashed group. Those conjunctival redness, calculated as the mean scores following grading at 24, 48 and 72 hours after installation of the test material, were below the limit of classification (1.67 / 1 / 0.33 ≤ 2), cleared in one animal during the 48 h reading and in the two other animals during the 7-day observation period. 

 

Under the test conditions, the test material is not classified as irritating to the eyes according to the annex VI of the Regulation EC No. 1272/2008 (CLP).

Although some details on test animals and experimental conditions were missing, this study is considered as acceptable and satisfies the requirement for eye irritation endpoint.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation / corrosion:

A study was available on the substance itself (Klimisch score = 2). Although the protocol deviates from standard method (no data on test animals, 24-hour exposure instead of 4 -hour, occlusive dressing instead of semi-occlusive dressing, observation at 24- and 72-hour only (no 48-hour scoring), reversibility not assessed but only slight and decreasing effects were osberved at 72 -hour osbervation times) (FDRL, 1979).

Even if the test material induced a slight irritation not being reversible within the end of the observation period (i.e. 72 hours),

based on the weakness of the observed effects, that remain stable or cleared at 72h time point, and since this study was performed under worst case conditions (24h under occlusive conditions instead of 4h under semi-occlusive conditions), it is highly likely that the slight effects observed at 72h will clear in at least 4/6 animals within a 14 -day observation period.

Based on this expert judgement, the test material is not classified as irritant to the skin.

Eye irritation:

A study was available on the substance itself regarding eye irritation (FDRL, 1979, Rel.2). This eye irritation study was performed prior to the OECD test guideline No. 405 but the protocol is similar to that guidance. Undiluted test material was instilled into the eye of 6 rabbits. The eyes were not rinsed after instillation of the test item. Animals were observed at 24, 48 and 72 h after instillation of test material into eyes and then on day 7.

The calculated mean score for each animal within 3 scoring times (24, 48 and 72 h) were 0.5 for redness, 0.0 for chemosis, 0.0 for iris lesions and 0.0 for corneal opacity. The observed conjunctival reactions were fully reversible within 7 days.

Thus the registered substance does not require classification for eye irritation.



Justification for selection of skin irritation / corrosion endpoint:
A study was available on the substance itself and was of good quality (Klimisch score = 2).

Justification for selection of eye irritation endpoint:
A study was available on the substance itself and was of good quality (Klimisch score = 2).

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification according to the Regulation (EC) No. 1272/2008 including ATP7.

Self-classification:

Based on the available data no additional self-classification is proposed regarding skin irritation according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP).

Based on the available data no additional self-classification is proposed regarding eye irritation according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP).

No information was available regarding respiratory irritation. However, based on the absence of skin or eye irritation, it is unlikely that respiratory irritation occurs.