Registration Dossier

Administrative data

Description of key information

Skin irritation in vivo: An analogue test item (EC 271-638-7) was found to be non-irritating in two studies (EPA OPPTS 870.2500 and CFR Title 16).

Eye irritation in vivo: An analogue test item (EC 271-638-7) was found to be non-irritating (EPA OPPTS 870.2400).

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:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Justification for type of information:
See read-across justification attached in Section 13.
Reason / purpose:
read-across source
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
0.56
Max. score:
2
Reversibility:
fully reversible within: 3 days
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
0.22
Max. score:
4
Reversibility:
fully reversible within: 2 days
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
12 December 2000 to 15 December 2000
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
according to
Guideline:
EPA OPPTS 870.2500 (Acute Dermal Irritation)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Sgarlat's Rabbitry, Harvey's Lake, PA
- Weight at study initiation: 2.2 - 2.6 kg
- Housing: individually in suspended wire cages. Bedding was placed underneath the cages and changed at least three times per week.
- Diet: Fresh Purina Rabbit Chow (Diet #5321) was provided daily
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Animals were kept in a temperature-controlled room with a 12 hour light/dark cycle.

IN-LIFE DATES: From 29 November 2000 to 15 December 2000
Type of coverage:
semiocclusive
Preparation of test site:
clipped
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:
72 hours following patch removal
Number of animals:
3 (2 males, 1 female)
Details on study design:
TEST SITE
- Area of exposure: on the day prior to exposure, an area of approximately 10 x 15 cm on the dorsal trunk of each animals was clipped free of hair. 0.5 mL test material was applied to the test site.
- Type of wrap if used: the test material was covered with a 2.5 x 2.5 cm, 4 ply, gauze patch which was secured with non-irritating tape. The torso was wrapped with plastic in a semi-occlusive manner and secured with non-irritating tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): at the end of the exposure period the wrappings were removed. Residual test material was removed from the test sites by gentle washing with distilled water prior to scoring for dermal reaction.
- Time after start of exposure: 4 hours

SCORING SYSTEM:
The Draize scale, presented as Table 1 in the field "Any other information on material and methods incl. tables" was used to assess the degree of erythema and oedema at the application sites approximately 1 hour and 1, 2 and 3 days after the removal of the dressings. Any other clinical signs were also noted. Bodyweights were measured and recorded immediately before dose administration and at the 72 hour examination.
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24, 48, 72 hours
Score:
0.56
Max. score:
2
Reversibility:
fully reversible within: 3 days
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24, 48, 72 hours
Score:
0.22
Max. score:
4
Reversibility:
fully reversible within: 2 days
Irritant / corrosive response data:
Erythema was barely perceptible at 60 minutes following patch removal, barely perceptible to well defined at 24 hours, absent to barely perceptible at 48 hours, and absent at 72 hours. Oedema was absent to barely perceptible at 60 minutes and 24 hours following patch removal, and absent at 48 and 72 hours.
Other effects:
There were no abnormal physical signs noted during the observation period. The dose site on one animal was stained yellow throughout the 72 hour observation period.
All bodyweight changes were normal.

Table 2: Results

Sex

M

M

F

Pre-test bodyweight (kg)

2.5

2.6

2.2

Terminal bodyweight (kg)

2.8

2.8

2.2

Time after patch removal (h)

Erythema

1

1a

1a

1a

24

1

1

2a

48

0

0

1a

72

0

0

0a

Edema

1

1

1

0

24

1

0

1

48

0

0

0

72

0

0

0

Systemic observations

1

A

A

A

24

A

A

A

48

A

A

A

72

A

A

A

A = Normal

a = dose site stained yellow

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the test, the test material did not elicit any reaction in any of the animals during the course of the study that meant the test material required classification as a skin irritant in accordance with EU criteria. The study is considered to be reliable, relevant and adequate for risk assessment and classification and labelling purposes.
Executive summary:

The skin irritation potential of the test material was determined in accordance with the standardised guideline EPA OPPTS 870.2500.

Three New Zealand White rabbits received a single four hour semi-occluded application of 0.5 mL of the test material and were assessed for the following 3 days for any signs of skin irritation. Erythema was barely perceptible at 60 minutes following patch removal, barely perceptible to well defined at 24 hours, absent to barely perceptible at 48 hours and absent at 72 hours. Oedema was absent to barely perceptible at 60 minutes and 24 hours following patch removal, and absent at 48 and 72 hours. There were no abnormal physical signs noted during the observation period and all bodyweight changes were normal.

Under the conditions of the test, the test material did not elicit any reaction in any of the animals during the course of the study that meant the test material required classification as a skin irritant in accordance with EU criteria.

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
Not reported
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
according to
Guideline:
other: Code of Federal Regulations, Title 16, Chapter IIc, Paragraph 1500.41
Deviations:
no
GLP compliance:
not specified
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
No information is provided on test animals and environmental conditions.
Type of coverage:
occlusive
Preparation of test site:
other: clipped and abraded
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:
24 hours
Observation period:
72 hours post administration
Number of animals:
6
Details on study design:
TEST SITE
- Area of exposure: the back and flank of the animals was clipped free of hair. 0.5 mL of test material was applied to both an abraded and unabraded area on each animal.
- Type of wrap if used: 2.5 x 2.5 cm surgical gauze was applied over the test material on both abraded and unabraded sites using thin bands of mild adhesive tape. The trunks of the animals were then wrapped with rubberised cloth (or other neutral impervious material) to hold the patches in position.

REMOVAL OF TEST SUBSTANCE
- Not reported

SCORING SYSTEM
- The scale as presented as table 1 in the field "Any other information on material and methods incl. tables" was used to assess the degree of erythema and oedema at the application sites 24 and 72 hours after the removal of the dressings.
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
0.5
Max. score:
1
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: abraded skin
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
0.17
Max. score:
1
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: unabraded skin
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
0
Max. score:
0
Reversibility:
other: not applicable - no reaction observed
Remarks on result:
other: abraded skin
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
0
Max. score:
0
Reversibility:
other: not applicable - no reaction observed
Remarks on result:
other: unabraded skin
Irritation parameter:
other: primary irritation score
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
0.33
Max. score:
1
Remarks on result:
other: primary irritation score was calculated at the sum of all average scores divided by 4
Irritant / corrosive response data:
All of the animals tested had slight erythema on the abraded sites. Two out of the six animals had slight erythema on the unabraded sites. No oedema was noted on animal on either the abraded or unabraded sites.
Other effects:
None reported.

Table 1: Results

Erythema & eschar

Period (hours)

1

2

3

4

5

6

Average

abraded

24

1

1

1

1

1

1

1.0

abraded

72

0

0

0

0

0

0

0.0

unabraded

24

0

0

1

0

1

0

0.33

unabraded

72

0

0

0

0

0

0

0

Oedema

abraded

24

0

0

0

0

0

0

0

abraded

72

0

0

0

0

0

0

0

unabraded

24

0

0

0

0

0

0

0

unabraded

72

0

0

0

0

0

0

0

Primary Irritation Score (Total ÷ 4) = 0.33

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the study, the test material did not elicit any reaction in any of the animals during the course of the study that meant the test material required classification as a skin irritant in accordance with EU criteria. The study is considered to be reliable, relevant and adequate for risk assessment and classification and labelling purposes.
Executive summary:

The skin irritation potential of the test material was determined in accordance with the Code of Federal Regulations, Title 16, Chapter IIc, paragraph 1500.41.

During the study six New Zealand Albino rabbits received a single 24 hour occluded application of 0.5 mL of test material to abraded and unabraded skin; following application, they were assessed for any signs of skin irritation over a 72 hour period. All of the animals tested had slight erythema on the abraded sites and two out of the six animals had slight erythema on the unabraded sites after 24 hours. No erythema was present in any animal after 72 hours. No oedema was noted in any animal on either the abraded or unabraded sites at any time.

Under the conditions of the study, the test material did not elicit any reaction in any of the animals during the course of the study that meant the test material required classification as a skin irritant in accordance with EU criteria.

Endpoint:
skin corrosion: in vitro / ex vivo
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint:
skin irritation: in vitro / ex vivo
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
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:
key study
Study period:
12 December 2000 to 22 December 2000
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
according to
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Millbrook Breeding Labs, Amherst, MA, USA
- Weight at study initiation: 2.4 - 2.7 kg
- Housing: individually in suspended cages. Bedding was placed underneath cages and changed three times per week.
- Diet: Fresh Purina Rabbit Chow (Diet #5321) was provided daily
- Water: ad libitum
- Acclimation period: at least 5 days
- Health: all animals were found to be free from evidence of ocular irritation or abnormalities before being assigned to the study

ENVIRONMENTAL CONDITIONS
- Animals were placed in a temperature controlled room which had a 12 hour light/dark cycle

IN-LIFE DATES: From: 29 November 2000 To: 22 December 2000

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
Duration of treatment / exposure:
- Dose administration: Approximately 0.1 mL of the test material was placed by syringe into the conjunctival sac which was formed by gently pulling the lower eyelid away from the eye. After instillation, the lids were held together for approximately one second to insure adequate distribution of the test material. One eye of each rabbit was dosed. The contralateral eye served as a control.
Observation period (in vivo):
Animals were observed for 72 hours post administration.
Number of animals or in vitro replicates:
One animal initially, followed by a further two animals once the irritation potential was fully assessed in the first animal.
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Not reported

SCORING SYSTEM
- The reactions observed were scored 1, 24, 48 and 72 hours post administration, in accordance with the criteria of Draize. The scale for scoring ocular reactions is presented as Table 1 in the field "Any other information on materials and methods incl. tables".
- Bodyweights were recorded pre-test
- The general health of the animals was monitored at each observation time

TOOL USED TO ASSESS SCORE
- Sodium fluorescein dye was used at the 24 hour observation interval. These examinations were performed using a Mini-Maglite flashlight equipped with a high intensity bulb.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: not applicable - no reactions seen
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
2
Reversibility:
other: not applicable - no reactions seen
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
other: discharge
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
0.22
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Irritant / corrosive response data:
There was no corneal opacity or iritis noted at any observation period. Conjunctival irritation noted in all 3 eyes, cleared by 72 hours.
Other effects:
There were no abnormal physical signs noted during the observation period.

Table 2: Results

Animal

Tissue

Reading

1 hour

24 hours

48 hours

72 hours

1 M

Cornea

Opacity

0

0

0

0

Area

0

0

0

0

1. Total

0

0

0

0

Iris

0

0

0

0

2. Total

0

0

0

0

Conjunctiva

Redness

2

2

2

0

Chemosis

1

1

0

0

Discharge

2

1

0

0

3. Total

10

8

4

0

Total = 1 + 2 + 3

10

8

4

0

Systemic observations

A

A

A

A

Sodium fluorescein

0

Pre-test bodyweight

2.4 kg

2 M

Cornea

Opacity

0

0

0

0

Area

0

0

0

0

1. Total

0

0

0

0

Iris

0

0

0

0

2. Total

0

0

0

0

Conjunctiva

Redness

1

1

1

0

Chemosis

1

0

0

0

Discharge

1

0

0

0

3. Total

6

2

2

0

Total = 1 + 2 + 3

6

2

2

0

Systemic observations

A

A

A

A

Sodium fluorescein

0

Pre-test bodyweight

2.7 kg

3 M

Cornea

Opacity

0

0

0

0

Area

0

0

0

0

1. Total

0

0

0

0

Iris

0

0

0

0

2. Total

0

0

0

0

Conjunctiva

Redness

2

2

1

0

Chemosis

1

1

1

0

Discharge

2

1

0

0

3. Total

10

8

4

0

Total = 1 + 2 + 3

10

8

4

0

Systemic observations

A

A

A

A

Sodium fluorescein

0

Pre-test bodyweight

2.5 kg

 

A = Normal

Interpretation of results:
not classified
Conclusions:
Under the conditions of the study, the test material only elicited slight reactions in the animals during the course of the study that meant the test material does not require classification as an eye irritant in accordance with EU criteria. The study is considered to be reliable, relevant and adequate for risk assessment and classification and labelling purposes.
Executive summary:

The eye irritation potential of the test material was determined in accordance with the standardised guideline EPA OPPTS 870.2400. During the study, 0.1 mL of test material was applied into one eye of three New Zealand White rabbits; the animals were assessed for 72 hours to determine the grade of ocular reaction.

There was no corneal opacity or iritis noted at any observation period. Conjunctival irritation, which was noted in all three treated eyes, had fully cleared by 72 hours.

Under the conditions of the study, the test material only elicited slight reactions in any of the animals during the course of the study that meant the test material does not require classification as an eye irritant in accordance with EU criteria.

Endpoint:
eye irritation: in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Justification for type of information:
See read-across justification attached in Section 13.
Reason / purpose:
read-across source
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable - no reactions seen
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
other: not applicable - no reactions seen
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
other: discharge
Basis:
mean
Time point:
24/48/72 h
Score:
0.22
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Endpoint:
eye irritation: in vitro / ex vivo
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin corrosion in vitro

An in vitro skin corrosion study does not need to be conducted because no reaction leading to classification was reported in any of the animals during an in vivo skin irritation study involving an analogue substance.

 

Skin irritation in vitro

An in vitro skin irritation study does not need to be conducted because adequate data from an in vivo skin irritation study on an analogue substance are available.

 

Skin irritation in vivo

Key study: Skin irritation potential of an analogue test material (EC 271-638-7) was determined in accordance with the standardised guideline EPA OPPTS 870.2500 to GLP standards. Three New Zealand White rabbits received a single four-hour semi-occluded application of 0.5 mL of the test material and were assessed for the following 3 days for any signs of skin irritation. Erythema was barely perceptible at 60 minutes following patch removal, barely perceptible to well defined at 24 hours, absent to barely perceptible at 48 hours and absent at 72 hours. Oedema was absent to barely perceptible at 60 minutes and 24 hours following patch removal, and absent at 48 and 72 hours. There were no abnormal physical signs noted during the observation period and all bodyweight changes were normal. Under the conditions of the test, the test material did not elicit any reaction in any of the animals during the course of the study that meant the test material required classification as a skin irritant in accordance with EU criteria.

Supporting study: Skin irritation potential of the test material (EC 271-638-7) was determined in accordance with the Code of Federal Regulations, Title 16, Chapter IIc, paragraph 1500.41. During the study six New Zealand Albino rabbits received a single 24 hour occluded application of 0.5 mL of test material to abraded and unabraded skin; following application, they were assessed for any signs of skin irritation over a 72-hour period. All of the animals tested had slight erythema on the abraded sites and two out of the six animals had slight erythema on the unabraded sites after 24 hours. No erythema was present in any animal after 72 hours. No oedema was noted in any animal on either the abraded or unabraded sites at any time. Under the conditions of the study, the test material did not elicit any reaction in any of the animals during the course of the study that meant the test material required classification as a skin irritant in accordance with EU criteria.

Eye irritation in vitro

An in vitro eye irritation study does not need to be conducted because adequate data from an in vivo eye irritation study on an analogue substance are available.

 

Eye irritation in vivo

The eye irritation potential of an analogue test material (EC 271-638-7) was determined in accordance with the standardised guideline EPA OPPTS 870.2400 to GLP standards. During the study, 0.1 mL of test material was applied into one eye of three New Zealand White rabbits; the animals were assessed for 72 hours to determine the grade of ocular reaction. There was no corneal opacity or iritis noted at any observation period. Conjunctival irritation, which was noted in all three treated eyes, had fully cleared by 72 hours. Under the conditions of the study, the test material only elicited slight reactions in any of the animals during the course of the study that meant the test material does not require classification as an eye irritant in accordance with EU criteria.

Justification for classification or non-classification

Skin irritation in vivo: Mean scores (24/48/72 hours) were < 2.3 for erythema and oedema when an analogue substance (EC 271-638-7) was investigated in two studies and all effects fully reversed. Classification for skin irritation is therefore unnecessary under the terms of Regulation 1272/2008 and subsequent amendments.

 

Eye irritation in vivo: When an analogue substance (EC 271-638-7) was investigated, mean scores (24/48/72 hours) were < 1 for corneal opacity and iritis and < 2 for conjunctival redness and chemosis. All effects reported fully reversed. Classification for eye irritation is therefore unnecessary under the terms of Regulation 1272/2008 and subsequent amendments.