Registration Dossier

Administrative data

Description of key information

Skin irritation: irritating (OECD TG 404, GLP, Read-across, K, rel. 1)
Eye irritation: not irritating (IECD TG 405, GLP, read-across, K, rel. 1)
Respiratory irritation: no data available

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:
key study
Study period:
From 11th February 1992 to 3rd March 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Study performed according to OECD test guideline No. 404 and in compliance with GLP
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
age and weight of animals not reported
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
age and weight of animals not reported
Principles of method if other than guideline:
not applicable
GLP compliance:
yes (incl. certificate)
Remarks:
UK GLP Compliance Programme (inspected on 1990-06-19/signed on 1990-10-05
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Ranch Rabbits, Crawley Down, Sussex, England
- Age at study initiation: not reported
- Weight at study initiation: 2.9-4..0 kg bw
- Housing: rabbits were individually housed in grid bottomed metal cages.
- Diet (e.g. ad libitum): ad libitum (antibiotic-free rabbit diet (SQC Standard rabbit pellets produced by Special Diets Services, Witham, Essex) and certificate of analysis))
- Water (e.g. ad libitum): ad libitum (certificate of analysis)
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-21
- Humidity (%): 39-59
- Air changes (per hr): no data (air conditionned)
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: not reported
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL of pure test material
Duration of treatment / exposure:
4 hours
Observation period:
1, 24, 48, and 72 hours after patch removal. Additional examination on day 7 and 14.
Number of animals:
4 females (preliminary screen: 1 , main study: 3)
Details on study design:
TEST SITE
- Area of exposure: 2.5 cm x 2.5 cm
- Type of wrap if used: The test patch (surgical lint) was held in position by encircling the trunk of the animal with a length of "Elastoplast" elastic adhesive bandage 7.5cm wide.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes, gently cleaned using cotton wool soaked in warm water
- Time after start of exposure: 4 hours


OBSERVATION TIME POINTS
1, 24, 48, and 72 hours after patch removal. Additional examination on day 7 and 14.


SCORING SYSTEM:

Erythema and Eschar Formation:
No erythema 0
Very slight erythema (barely perceptible) 1
Well-defined erythema 2
Moderate to severe erythema 3
Severe erythema (beef redness) to slight eschar formation (injuries in depth) 4

Oedema formation:
No oedema 0
Very slight oedema (barely perceptible) 1
Slight oedema (edges of area well defined by definite raising) 2
Moderate oedema (raised approximately 1mm) 3
Severe oedema (raised more than 1mm and extending beyond area of exposure) 4

Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1.33
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: desquamation observed after 7 days
Irritation parameter:
erythema score
Basis:
animal: #2 & #4
Time point:
24/48/72 h
Score:
2.67
Max. score:
4
Reversibility:
not fully reversible within: 14 days
Remarks on result:
other: desquamation and skin thickening observed after 7 and 14 days
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
3
Max. score:
4
Reversibility:
not fully reversible within: 14 days
Remarks on result:
other: desquamation observed after 7 and 14 days
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1.67
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
2.33
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
3
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritation parameter:
edema score
Basis:
animal #4
Time point:
24/48/72 h
Score:
1.67
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritant / corrosive response data:
One hour after the end of the dosing period, oedema was noted at the application site in 2 animals and, in one rabbit, this was accompanied by slight erythema.
Twenty-four hours after patch removal, erythema ranging in intensity from slight to moderate, accompanied by slight to moderate oedema, was apparent at the application site in all 4 animals. Over the next 24 hours these skin responses generally increased and, by the 72 hour observation, erythema was evident in 3 animals and well defined in the fourth. The the oedematous reaction varied from slight to Seven days after dosing, there was no sign of either erythema or oedema at the application site of the rabbit used in the preliminary screen and observations on this rabbit were discontinued at this stage. In the remaining 3 animals, well defined erythema and slight to moderate oedema were still apparent. Desquamation was noted at the application site in all 4 rabbits. Fourteen days after dosing, oedema was no longer apparent in any animal. Well defined or moderate erythema was noted in the 3 remaining animals and skin thickening and/or desquamation was observed at the application site in all these animals.
Other effects:
None

Table 7.3.1/1: Mean irritant/corrosive response data for each animals at each observation time up to removal of animals from the test

 

Score at time point / Reversibility

Erythema

Max. score 4

Edema

Max. score 4

1 h

0/0/1/0

0/0/2/1

24 h

1/2/3/2

2/2/3/1

48 h

1/3/3/3

2/2/3/2

72 h

2/3/3/3

1/3/3/2

Average 24h, 48h, 72h

1.33/2.67/3/2.67

1.67/2.33/3/1.67

7 d

0/2/2/2 a

0/1/3/2 a

14 d ($)

2b/2a/1b

0b/0a/0b

Reversibility*)

n.c.

c.

Average time (day) for reversion**

-

14 d

 *) Reversibility: c. = completely reversible; n.c. = not completely reversible; n. = not reversible

**): correspond to the last day for which skin irritation signs in the last animal were observed

a = desquamation was observed

b = desquamation and skin thickening

($) = seven day after dosing there were no sign of either erythema or edema at the appllication site of the rabbit used in the preliminary screen and observations of this rabbit were discontinued at this stage.

Interpretation of results:
Category 2 (irritant) based on GHS criteria
Conclusions:
Under the test conditions, the test material is classified as Skin irr. Category 2 (H315: Causes skin irritation) according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP).
Executive summary:

In a dermal irritation study performed according to the EU B.4 test method and in compliance with GLP, 0.5 mL of undiluted test material was dermally applied on the clipped skin of the dorsal surface of the trunk of 4 New Zealand White rabbits.Test sites were covered with a semi-occlusive dressing for 4 hours. Animals were then observed for 14 days for oedema and erythema. 

Skin irritation was assessed and scored according to the Draize scale at 1, 24, 48 and 72 h after the removal of the patch. Additional assessments were carried out 7 and, in the last 3 animals dosed, 14 days after dosing to determine the degree of reversibility of the skin reaction.

The mean scores calculated for each animal tested within 3 scoring times (24, 48 and 72 h) were 1.33/2.67/3.00/2.67 for erythema and 1.67/2.33/3.00/1.67 for oedema.

 

One hour after the end of the dosing period, oedema was noted at the application site in 2 animals and, in one rabbit, this was accompanied by slight erythema. Twenty-four hours after patch removal, erythema ranging in intensity from slight to moderate, accompanied by slight to moderate oedema, was apparent at the application site in all 4 animals. Over the next 24 hours these skin responses generally increased and, by the 72 hour observation, erythema was evident in 3 animals and well defined in the fourth. The intensity of the oedematous reaction varied from slight to moderate. Seven days after dosing, there was no sign of either erythema or oedema at the application site of the rabbit used in the preliminary screen and observations on this rabbit were discontinued at this stage. In the remaining 3 animals, well defined erythema and slight to moderate oedema were still apparent. Desquamation was noted at the application site in all 4 rabbits. Fourteen days after dosing, oedema was no longer apparent in any animal. Well defined or moderate erythema was noted in the 3 remaining animals and skin thickening and/or desquamation was observed at the application site in all these animals.

 

Therefore, under the test conditions, the test material is classified as:

- Skin irr. Category 2 (H315: Causes skin irritation) 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:
skin irritation: in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
[Further information is included as attachment to the Iuclid section 13]

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar physico-chemical, toxicological and environmental fate properties because of their structural similarity.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The target and source substances are structurally related, in that both are trans-3,3-dimethyl-5-(2,2,3-trimethyl-cyclopent-3-en-1-yl)pent-4-en-2-ol. As two asymmetric (chiral) carbon atoms are present in this chemical structure (marked with a * in Table 1), the chemical exists as 2x2=4 enantiomers: RR, RS, SR and SS forms. The target substance is a reaction-mass between two of these stereoisomers (RS and SS) whereas the target substance is a mixture of the two others (SR and RR).

3. ANALOGUE APPROACH JUSTIFICATION
Based on structural similarity and comparable physicochemical and toxicological properties, the source and the target substances are expected similar skin irritation profile.
The study design (OECD 404, GLP) is adequate and reliable for the purpose of the prediction based on read-across. The test material used represents the source substance as described in the hypothesis in terms of purity and impurities. The results of the studies are adequate for the purpose of classification and labelling.
Therefore, based on the considerations above, it can be concluded that the results of the skin irritation study conducted in the rabbits with the source substance are likely to predict the properties of the target substance and are considered as adequate to fulfil the information requirement of Annex VIII, 8.6.1.

4. DATA MATRIX
Please refer to Iuclid section 13.
Reason / purpose:
read-across source
Reason / purpose:
read-across: supporting information
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1.33
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: desquamation observed after 7 days
Irritation parameter:
erythema score
Basis:
animal: #2 & #4
Time point:
24/48/72 h
Score:
2.67
Max. score:
4
Reversibility:
not fully reversible within: 14 days
Remarks on result:
other: desquamation and skin thickening observed after 7 and 14 days
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
3
Max. score:
4
Reversibility:
not fully reversible within: 14 days
Remarks on result:
other: desquamation observed after 7 and 14 days
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1.67
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
2.33
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
3
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritation parameter:
edema score
Basis:
animal #4
Time point:
24/48/72 h
Score:
1.67
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritant / corrosive response data:
One hour after the end of the dosing period, oedema was noted at the application site in 2 animals and, in one rabbit, this was accompanied by slight erythema.
Twenty-four hours after patch removal, erythema ranging in intensity from slight to moderate, accompanied by slight to moderate oedema, was apparent at the application site in all 4 animals. Over the next 24 hours these skin responses generally increased and, by the 72 hour observation, erythema was evident in 3 animals and well defined in the fourth. The the oedematous reaction varied from slight to Seven days after dosing, there was no sign of either erythema or oedema at the application site of the rabbit used in the preliminary screen and observations on this rabbit were discontinued at this stage. In the remaining 3 animals, well defined erythema and slight to moderate oedema were still apparent. Desquamation was noted at the application site in all 4 rabbits. Fourteen days after dosing, oedema was no longer apparent in any animal. Well defined or moderate erythema was noted in the 3 remaining animals and skin thickening and/or desquamation was observed at the application site in all these animals.
Other effects:
None

Table 7.3.1/1: Mean irritant/corrosive response data for each animals at each observation time up to removal of animals from the test

 

Score at time point / Reversibility

Erythema

Max. score 4

Edema

Max. score 4

1 h

0/0/1/0

0/0/2/1

24 h

1/2/3/2

2/2/3/1

48 h

1/3/3/3

2/2/3/2

72 h

2/3/3/3

1/3/3/2

Average 24h, 48h, 72h

1.33/2.67/3/2.67

1.67/2.33/3/1.67

7 d

0/2/2/2 a

0/1/3/2 a

14 d ($)

2b/2a/1b

0b/0a/0b

Reversibility*)

n.c.

c.

Average time (day) for reversion**

-

14 d

 *) Reversibility: c. = completely reversible; n.c. = not completely reversible; n. = not reversible

**): correspond to the last day for which skin irritation signs in the last animal were observed

a = desquamation was observed

b = desquamation and skin thickening

($) = seven day after dosing there were no sign of either erythema or edema at the appllication site of the rabbit used in the preliminary screen and observations of this rabbit were discontinued at this stage.

Interpretation of results:
Category 2 (irritant) based on GHS criteria
Conclusions:
Based on the available data on the source substance, the target substance is classified as Skin irr. Category 2 (H315: Causes skin irritation) according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP).
Executive summary:

In a dermal irritation study performed according to the EU B.4 test method and in compliance with GLP, 0.5 mL of undiluted source substance was dermally applied on the clipped skin of the dorsal surface of the trunk of 4 New Zealand White rabbits.Test sites were covered with a semi-occlusive dressing for 4 hours. Animals were then observed for 14 days for oedema and erythema. 

Skin irritation was assessed and scored according to the Draize scale at 1, 24, 48 and 72 h after the removal of the patch. Additional assessments were carried out 7 and, in the last 3 animals dosed, 14 days after dosing to determine the degree of reversibility of the skin reaction.

The mean scores calculated for each animal tested within 3 scoring times (24, 48 and 72 h) were 1.33/2.67/3.00/2.67 for erythema and 1.67/2.33/3.00/1.67 for oedema.

 

One hour after the end of the dosing period, oedema was noted at the application site in 2 animals and, in one rabbit, this was accompanied by slight erythema. Twenty-four hours after patch removal, erythema ranging in intensity from slight to moderate, accompanied by slight to moderate oedema, was apparent at the application site in all 4 animals. Over the next 24 hours these skin responses generally increased and, by the 72 hour observation, erythema was evident in 3 animals and well defined in the fourth. The intensity of the oedematous reaction varied from slight to moderate. Seven days after dosing, there was no sign of either erythema or oedema at the application site of the rabbit used in the preliminary screen and observations on this rabbit were discontinued at this stage. In the remaining 3 animals, well defined erythema and slight to moderate oedema were still apparent. Desquamation was noted at the application site in all 4 rabbits. Fourteen days after dosing, oedema was no longer apparent in any animal. Well defined or moderate erythema was noted in the 3 remaining animals and skin thickening and/or desquamation was observed at the application site in all these animals.

 

Based on the available data on the source substance, the target substance is classified as:

- Skin irr. Category 2 (H315: Causes skin irritation) 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:
adverse effect observed (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:
From 7th April 1992 to 21st April 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Study performed according to OECD test guideline No. 405 and in compliance with GLP.
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Principles of method if other than guideline:
not applicable
GLP compliance:
yes (incl. certificate)
Remarks:
UK GLP Compliance Programme (inspected on 1990-06-19/signed on 1990-10-05
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Ranch Rabbits, Crawley Down, Sussex, U.K.
- Age at study initiation: not provided in the study report
- Weight at study initiation: Rabbit 1: 2.4 kg, rabbit 2: 3.0 kg, rabbit 3: 3.5 kg
- Housing: individually housed in grid bottomed metalcages.
- Diet (e.g. ad libitum): ad libitum (SQC standard· rabbit pellets produced by Special Diets Services, witham, Essex)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: > 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-21 °C
- Humidity (%): 41-59%
- Air changes (per hr): not mentionned in the study report (air conditioned room)
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
other: contralateral eye (left eye)
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
Duration of treatment / exposure:
The eye was not rinsed after the instillation of the test item
Observation period (in vivo):
Examination made 1, 24, 48 and 72 hours following instillation. An additional examination was conducted on the last 2 animals to be dosed, 7 days after dosing, in order to assess the reversibility of the response.
Number of animals or in vitro replicates:
3 females
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): N.A.
- Time after start of exposure: N.A.

SCORING SYSTEM: Draize scale according to the OECD guideline No. 405
See "Any other information on material and methods incl. tables"

TOOL USED TO ASSESS SCORE: standard light source designed to comply with the requirements of BS 950 Part 1 (Artificial Daylight for the Assessment of Colour)
Irritation parameter:
iris score
Basis:
animal: # 1, #2 & #3
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
cornea opacity score
Basis:
animal: #1, #2 & #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
conjunctivae score
Basis:
animal: #1 & #3
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 72 h
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1.33
Max. score:
3
Reversibility:
fully reversible within: 7 d
Irritation parameter:
chemosis score
Basis:
animal: #1 & #3
Time point:
24/48/72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 48 h
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1.33
Max. score:
4
Reversibility:
fully reversible within: 72 h
Irritant / corrosive response data:
One hour after dosing, conjunctival hyperaemia was noted in the treated eye of all 3 rabbits. In 2 animals this was accompanied by conjunctival chemosis and discharge from the treated eye. Twenty-four hours after dosing, discharge was no longer apparent in any animal but hyperaemia and chemosis were noted in all 3 rabbits. Forty-eight hours after dosing, hyperaemia, at a reduced level, was still apparent in all 3 animals whilst conjunctival chemosis was noted in only one rabbit. Seventy-two hours after dosing, the treated eye of 2 animals appeared to be free of all signs of irritation. Observations on the first rabbit, used in the preliminary screen, were discontinued at this time. Slight conjunctival hyperaemia persisted in the treated eye of one animal. Seven days after dosing, the treated eye of this rabbit appeared to be normal. No signs of corneal or iridial irritation were apparent in any animal, at any examination, throughout the study.
Other effects:
None

Table 7.3.2/1: Individual irritant/corrosive response data of the 3 animals at each observation time up to removal from the test

 

Score at time point / Reversibility

Cornea

Iris

(/2)

Conjunctivae

Opacity

(/4)

Area

(/4)

Redness

(/3)

Chemosis

(/4)

Discharge

(/3)

1 h

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

1 / 2 / 2

0 / 2 / 2

0 / 1 / 1

24 h

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

2 / 2 / 2

2 / 3 / 2

0 / 0 / 0

48 h

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

1 / 1 / 1

0 / 1 / 0

0 / 0 / 0

72 h

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

0 / 1 / 0

0 / 0 / 0

0 / 0 / 0

Average 24-48-72

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

1.00 / 1.33 / 1.00

0.67 / 1.33 / 0.67

0 / 0 / 0

7 d

- / 0 / 0

- / 0 / 0

- / 0 / 0

- / 0 / 0

- / 0 / 0

- / 0 / 0

Reversibility*)

-

-

-

c.

c.

c.

Average time (unit) for reversion

-

-

-

7 d

72 h

24 h

*) Reversibility: c. = completely reversible; n.c. = not completely reversible; n. = not reversible

Interpretation of results:
GHS criteria not met
Conclusions:
Under the test conditions, the test material is not classified as irritating to eyes according to the criteria of the Annex VI of the Regulation (EC) No 1272/2008 (CLP).
Executive summary:

In an eye irritation study performed according to the EU B.5 test method, and in compliance with GLP, 0.1 mL of undiluted test material was instilled into the right eye of 3 female New Zealand White Rabbit. The eyes were not rinsed after the instillation of the test item. The left eye of each rabbit served as control. Animals were observed at 1, 24, 48 and 72 hours after dosing under a standard light source. An additional observation was conducted on the last 2 animals to be dosed, 7 days after dosing in order to assess the reversibility of the eye reaction. The reactions in the conjunctiva (redness, chemosis and discharge), the iris and the cornea (opacity and area involved) were scored according to the Draize scale. 

One hour after dosing, conjunctival hyperaemia was noted in the treated eye of all 3 rabbits. In 2 animals this was accompanied by conjunctival chemosis and discharge from the treated eye. Twenty-four hours after dosing, discharge was no longer apparent in any animal but hyperaemia and chemosis were noted in all 3 rabbits. Forty-eight hours after dosing, hyperaemia, at a reduced level, was still apparent in all 3 animals whilst conjunctival chemosis was noted in only one rabbit. Seventy-two hours after dosing, the treated eye of 2 animals appeared to be free of all signs of irritation. Observations on the first rabbit, used in the preliminary screen, were discontinued at this time. Slight conjunctival hyperaemia persisted in the treated eye of one animal. Seven days after dosing, the treated eye of this rabbit appeared to be normal. No signs of corneal or iridial irritation were apparent in any animal, at any examination, throughout the study..

 

The calculated mean score for each individual lesion for each animals within 3 scoring times (24, 48 and 72 h) were 1.00 / 1.33 / 1.00 for redness, 0.67 / 1.33 / 0.67 for chemosis and 0.00 / 0.00 / 0.00 for discharge, iris and corneal lesions.

 

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

This study is considered as acceptable and satisfies the requirement for eye irritation endpoint.

Endpoint:
eye irritation: in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
[Further information is included as attachment to the Iuclid section 13]

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar physico-chemical, toxicological and environmental fate properties because of their structural similarity.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The target and source substances are structurally related, in that both are trans-3,3-dimethyl-5-(2,2,3-trimethyl-cyclopent-3-en-1-yl)pent-4-en-2-ol. As two asymmetric (chiral) carbon atoms are present in this chemical structure (marked with a * in Table 1), the chemical exists as 2x2=4 enantiomers: RR, RS, SR and SS forms. The target substance is a reaction-mass between two of these stereoisomers (RS and SS) whereas the target substance is a mixture of the two others (SR and RR).

3. ANALOGUE APPROACH JUSTIFICATION
Based on structural similarity and comparable physicochemical and toxicological properties, the source and the target substances are expected similar eye irritation profile.
The study design (OECD 405, GLP) is adequate and reliable for the purpose of the prediction based on read-across. The test material used represents the source substance as described in the hypothesis in terms of purity and impurities. The results of the studies are adequate for the purpose of classification and labelling.
Therefore, based on the considerations above, it can be concluded that the results of the eye irritation study conducted in the rabbits with the source substance are likely to predict the properties of the target substance and are considered as adequate to fulfil the information requirement of Annex VIII, 8.6.2.

4. DATA MATRIX
Please refer to Iuclid section 13.
Reason / purpose:
read-across source
Reason / purpose:
read-across: supporting information
Irritation parameter:
iris score
Basis:
animal: # 1, #2 & #3
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
cornea opacity score
Basis:
animal: #1, #2 & #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
conjunctivae score
Basis:
animal: #1 & #3
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 72 h
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1.33
Max. score:
3
Reversibility:
fully reversible within: 7 d
Irritation parameter:
chemosis score
Basis:
animal: #1 & #3
Time point:
24/48/72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 48 h
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1.33
Max. score:
4
Reversibility:
fully reversible within: 72 h
Irritant / corrosive response data:
One hour after dosing, conjunctival hyperaemia was noted in the treated eye of all 3 rabbits. In 2 animals this was accompanied by conjunctival chemosis and discharge from the treated eye. Twenty-four hours after dosing, discharge was no longer apparent in any animal but hyperaemia and chemosis were noted in all 3 rabbits. Forty-eight hours after dosing, hyperaemia, at a reduced level, was still apparent in all 3 animals whilst conjunctival chemosis was noted in only one rabbit. Seventy-two hours after dosing, the treated eye of 2 animals appeared to be free of all signs of irritation. Observations on the first rabbit, used in the preliminary screen, were discontinued at this time. Slight conjunctival hyperaemia persisted in the treated eye of one animal. Seven days after dosing, the treated eye of this rabbit appeared to be normal. No signs of corneal or iridial irritation were apparent in any animal, at any examination, throughout the study.
Other effects:
None

Table 7.3.2/1: Individual irritant/corrosive response data of the 3 animals at each observation time up to removal from the test

 

Score at time point / Reversibility

Cornea

Iris

(/2)

Conjunctivae

Opacity

(/4)

Area

(/4)

Redness

(/3)

Chemosis

(/4)

Discharge

(/3)

1 h

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

1 / 2 / 2

0 / 2 / 2

0 / 1 / 1

24 h

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

2 / 2 / 2

2 / 3 / 2

0 / 0 / 0

48 h

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

1 / 1 / 1

0 / 1 / 0

0 / 0 / 0

72 h

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

0 / 1 / 0

0 / 0 / 0

0 / 0 / 0

Average 24-48-72

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

1.00 / 1.33 / 1.00

0.67 / 1.33 / 0.67

0 / 0 / 0

7 d

- / 0 / 0

- / 0 / 0

- / 0 / 0

- / 0 / 0

- / 0 / 0

- / 0 / 0

Reversibility*)

-

-

-

c.

c.

c.

Average time (unit) for reversion

-

-

-

7 d

72 h

24 h

*) Reversibility: c. = completely reversible; n.c. = not completely reversible; n. = not reversible

Interpretation of results:
GHS criteria not met
Conclusions:
Based on the available data on the source substance, the target substance is not classified as irritating to eyes according to the criteria of the Annex VI of the Regulation (EC) No 1272/2008 (CLP).
Executive summary:

In an eye irritation study performed according to the EU B.5 test method, and in compliance with GLP, 0.1 mL of undiluted source substance was instilled into the right eye of 3 female New Zealand White Rabbit. The eyes were not rinsed after the instillation of the test item. The left eye of each rabbit served as control. Animals were observed at 1, 24, 48 and 72 hours after dosing under a standard light source. An additional observation was conducted on the last 2 animals to be dosed, 7 days after dosing in order to assess the reversibility of the eye reaction. The reactions in the conjunctiva (redness, chemosis and discharge), the iris and the cornea (opacity and area involved) were scored according to the Draize scale. 

One hour after dosing, conjunctival hyperaemia was noted in the treated eye of all 3 rabbits. In 2 animals this was accompanied by conjunctival chemosis and discharge from the treated eye. Twenty-four hours after dosing, discharge was no longer apparent in any animal but hyperaemia and chemosis were noted in all 3 rabbits. Forty-eight hours after dosing, hyperaemia, at a reduced level, was still apparent in all 3 animals whilst conjunctival chemosis was noted in only one rabbit. Seventy-two hours after dosing, the treated eye of 2 animals appeared to be free of all signs of irritation. Observations on the first rabbit, used in the preliminary screen, were discontinued at this time. Slight conjunctival hyperaemia persisted in the treated eye of one animal. Seven days after dosing, the treated eye of this rabbit appeared to be normal. No signs of corneal or iridial irritation were apparent in any animal, at any examination, throughout the study..

 

The calculated mean score for each individual lesion for each animals within 3 scoring times (24, 48 and 72 h) were 1.00 / 1.33 / 1.00 for redness, 0.67 / 1.33 / 0.67 for chemosis and 0.00 / 0.00 / 0.00 for discharge, iris and corneal lesions.

 

Based on the available data on the source substance, the target substance is not classified as irritating to eyes according to the criteria of the Annex VI of the Regulation (EC) No. 1272/2008 (CLP).

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:

Since no key study was identified on the registered substance, the testing and assessment strategy, as described in ECHA R.7a Endpoint specific guidance (December 2016), was used to evaluate the skin corrosion/irritation potential of the registered substance:

 

Element

Information

Conclusion

Comments

Existing data on physico
- chemical properties

1a

Is the substance spontaneously flammable in contact with air (pyrophoric) or water at room temperature?

NO

 

1b

Is the substance an organic hydroperoxide or an organic peroxide?

NO

 

1c

Is the pH of the substance ≤ 2.0 or ≥ 11.5?

NO

 

1d

Are there other physical or chemical properties that
indicate that the substance is corrosive/irritant?

NO

 

Existing human data

2

Are there adequate existing human data which provide evidence that the substance is a corrosive
or irritant?

NO

 

Existing animal data from corrosion/irritation studies

3

Are there data from existing studies on corrosion and irritation in laboratory animals, which provide sound conclusive evidence that the substance is a corrosive, irritant or non-irritant?

NO

 

Existing data from general toxicity studies via the dermal route and from sensitisation studies

4a

Is the substance classified as fatal in contact with skin (LD50 ≤ 50 mg/kg bw, CLP hazard statement
H310)

NO

 

4b

Has the substance proven to be a corrosive, irritant or non-irritant in a suitable acute dermal toxicity test?

NO

 

4c

Has the substance proven to be a corrosive or an irritant in sensitisation studies or after repeated
exposure?

NO

 

Existing/new (Q)SAR data and read
-across

5a

Are there structurally related substances (suitable “read-across” or grouping), which are classified as corrosive to the skin (Skin Corrosive Cat. 1), or do suitable (Q)SAR methods indicate corrosion
potential of the substance?

NO

 

5b

Are there structurally related substances (suitable “read-across” or grouping), which are classified as irritant to the skin (Skin Irritant Cat. 2), or indicating that the substance is non-irritant, or do suitable (Q)SAR methods indicate irritant or non-irritant potential of the substance?

YES

"read-across" substance is classified as SCI2 based on an in vivo study (OECD TG 404).

Toxtree (v.2.6.6): Irritating to skin (aliphatic alcohols)

Existing in vitro data

6a

Has the substance demonstrated corrosive properties in an EU/OECD adopted in vitro test?
Data from in vitro test methods that have been validated and are considered scientifically valid but
are not yet adopted by EU and/or OECD may also be used if the provisions defined in Annex XI are met

NO

 

6b

Has the substance demonstrated irritant or non-irritant properties in an EU/OECD adopted
in vitro test?
Data from in vitro test methods that have been validated and are considered scientifically valid but
are not yet adopted by EU and/or OECD may also be used if the provisions defined in Annex XI are
met.

NO

 

6c

Are there data from a non-validated suitable in vitro test(s), which provide sound conclusive evidence that the substance is corrosive/ irritant?

NO

 

Weight-of- Evidence analysis

7

The “elements” described above may be arranged as appropriate. Taking all available existing and
relevant data mentioned above (Elements 1-6) into account, is there sufficient information to make a decision on whether classification/labelling is necessary, and –if so –how to classify and label?

YES

Skin Irritant Category 2 (H315: Causes skin irritation)

New in vitro test for corrosivity

8

Does the substance demonstrate corrosive properties in (an) EU/OECD adopted in vitro test(s) for skin corrosion?

NO

 

New in vitro test for irritation

9

Does the substance demonstrate irritating or non-irritating properties in (an) EU/OECD adopted in vitro test(s) for skin irritation?

NO

 

New in vivo test for corrosion/irritation

10

To be used only as a last resort

NO

 

The source substance is considered adequate for read-across purposes (see Iuclid section 13 for additional justification).

A key study was identified on the source substance (Toxicol, 1992, rel. 2). In this dermal irritation study performed according to the EU B.4 test method and in compliance with GLP, undiluted test material was applied on the dorsal surface of the trunk of 4 rabbits. The mean scores calculated for each animal tested within 3 scoring times (24, 48 and 72 h) were 1.33/2.67/3.00/2.67 for erythema and 1.67/2.33/3.00/1.67 for oedema. One hour after the end of the dosing period, oedema was noted at the application site in 2 animals and, in one rabbit, this was accompanied by slight erythema. Twenty-four hours after patch removal, erythema ranging in intensity from slight to moderate, accompanied by slight to moderate oedema, was apparent at the application site in all 4 animals. Over the next 24 hours these skin responses generally increased and, by the 72 hour observation, erythema was evident in 3 animals and well defined in the fourth. The intensity of the oedematous reaction varied from slight to moderate. Seven days after dosing, there was no sign of either erythema or oedema at the application site of the rabbit used in the preliminary screen and observations on this rabbit were discontinued at this stage. In the remaining 3 animals, well defined erythema and slight to moderate oedema were still apparent. Desquamation was noted at the application site in all 4 rabbits. Fourteen days after dosing, oedema was no longer apparent in any animal. Well defined or moderate erythema was noted in the 3 remaining animals and skin thickening and/or desquamation was observed at the application site in all these animals.

Based on the available data on the source substance, the target substance requires classification for skin irritation.

Eye irritation:

Since no key study was identified on the registered substance, the testing and assessment strategy, as described in ECHA R.7a Endpoint specific guidance (December 2016), was used to evaluate the skin corrosion/irritation potential of the registered substance:

 

Element

Information

Conclusion

Comments

Conclusion of the information strategy on skin corrosion/irritation

0

Is the substance classified as a skin corrosive?

NO

 

Existing data on physico
- chemical properties

1a

Is the substance spontaneously flammable in contact with air (pyrophoric) or water at room temperature?

NO

 

1b

Is the substance an organic hydroperoxide or an organic peroxide?

NO

 

1c

Is the pH of the substance ≤ 2.0 or ≥ 11.5?

NO

 

1d

Are there other physical or chemical properties that indicate that the substance causes serious eye damage or eye irritation?

NO

 

Existing human data

2

Are there adequate existing human data which provide evidence that the substance has the potential to cause serious eye damage or eye irritation?

NO

 

Existing animal data from corrosion/irritation studies

3

Are there data from existing studies on corrosion and irritation in laboratory animals, which provide sound conclusive evidence that the substance is a corrosive, irritant or non-irritant?

NO

 

Existing/new (Q)SAR data and read-across

4

Are there structurally related substances (suitable “read-across” or grouping), which are classified as causing serious eye damage/eye irritation, or indicating that the substance is non-irritant, or do valid (Q)SAR methods indicate serious eye damage/eye irritation or non-irritation of the substance?

YES

"read-across" substance is not irritant in an in vivo study (OECD TG 405).

Toxtree (v.2.6.6) Not eye irritation (R36)

Existing in vitro data

5a

Has the substance demonstrated serious eye damage, eye irritation or non-irritating properties in an EU/OECD adopted in vitro test?
Data from in vitro test methods that have been validated and are considered scientifically valid but are not yet adopted by EU and/or OECD may also be used if the provisions defined in Annex XI are met.

NO

 

5b

Are there acceptable data from (a) non-validated suitable in vitro test(s), which provide sound evidence that the substance causes serious eye damage/eye irritation?

NO

 

Weight-of- Evidence analysis

6

The “elements” described above may be arranged as appropriate. Taking all available existing and relevant data mentioned above (Elements 0 – 5) into account, is there sufficient information to make a decision on whether classification/labelling is necessary, and – if so – how to classify and label?

YES

Not classified for eye irritation

New in vitro tests for serious eye damage/eye irritation (Annex VII to the REACH Regulation)

7a

Does the substance demonstrate serious eye damage, eye irritation or non-irritant properties in (an) EU/OECD adopted in vitro test(s) for the eye hazard charaterisation?
Data from in vitro test methods that have been validated and are considered scientifically valid but are not yet adopted by EU and/or OECD may also be used if the provisions of Annex XI are met.

NO

 

8b

Does the substance demonstrate serious eye damage or eye irritant properties in (a) non-validated suitable in vitro test(s) for serious eye damage/eye irritation?

NO

 

New in vivo test for serious eye damage/eye irritation as a last resort (Annex VIII to the REACH Regulation)

8b

Does the substance demonstrate serious eye damage or eye irritation in an OECD adopted in vivo test?

NO

 

The source substance is considered adequate for read-across purposes (see Iuclid section 13 for additional justification).

A key study was identified on the source substance (Toxicol, 1992, rel. 2). In this eye irritation study performed according to the EU B.5 test method, and in compliance with GLP, undiluted test material was instilled into the eye of 3 rabbits. The eyes were not rinsed after the instillation of the test item. One hour after dosing, conjunctival hyperaemia was noted in the treated eye of all 3 rabbits. In 2 animals this was accompanied by conjunctival chemosis and discharge from the treated eye. Twenty-four hours after dosing, discharge was no longer apparent in any animal but hyperaemia and chemosis were noted in all 3 rabbits. Forty-eight hours after dosing, hyperaemia, at a reduced level, was still apparent in all 3 animals whilst conjunctival chemosis was noted in only one rabbit. Seventy-two hours after dosing, the treated eye of 2 animals appeared to be free of all signs of irritation. Observations on the first rabbit, used in the preliminary screen, were discontinued at this time. Slight conjunctival hyperaemia persisted in the treated eye of one animal. Seven days after dosing, the treated eye of this rabbit appeared to be normal. No signs of corneal or iridial irritation were apparent in any animal, at any examination, throughout the study. The calculated mean score for each individual lesion for each animals within 3 scoring times (24, 48 and 72 h) were 1.00 / 1.33 / 1.00 for redness, 0.67 / 1.33 / 0.67 for chemosis and 0.00 / 0.00 / 0.00 for discharge, iris and corneal lesions.

Based on the available data on the source substance, the target substance does not require classification for eye irritation.

Justification for classification or non-classification

Harmonized classification:

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

Self classification:

Based on the available information on the analogue, the registered substance should be classified as:

- Skin irr. Category 2 (H315: Causes skin irritation) according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) as mean erythema and oedema value were greater than 2.3 in at least two out of four animals.

Morevover inflammation persisted after the end of the observation period in three animals, together with desquamation and skin thickening.

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.