Registration Dossier

Administrative data

Description of key information

Skin irritation (WoE), rabbit: not irritating (RA from CAS 131459-39-7 and CAS 67762-53-2 and (QSAR) prediction)

Eye irritation (WoE), rabbit: not irritating (RA from CAS 131459-39-7 and CAS 67762-53-2)

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:
weight of evidence
Study period:
16. Dec. - 23. Dec 1998
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented study report which meets basic scientific principles. (observation period limited to 7 days, no analytical purity reported)
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
(Observation period up to 7 days. Desquamation seen at day 7 in 2 animals, no data on test substance purity.)
Qualifier:
equivalent or similar to guideline
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
(Observation period up to 7 days. Desquamation seen at day 7 in 2 animals, no data on test substance purity.)
GLP compliance:
yes (incl. QA statement)
Remarks:
Safepharm Laboratories Limited, Derby, UK
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: David Percival Ltd., Moston, Sandbach, Chesire, UK
- Age at study initiation: 12 - 16 weeks
- Weight at study initiation: 2.74 - 3.07 kg
- Housing: individual housing in suspended metal cages
- Diet: STANRAB SQC Rabbit Diet, Special Diets Services Ltd, Witham, Essex, UK, ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 - 20
- Humidity (%): 50 - 60
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
other: not required: untreated site of the same animal served as control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied: 0.5 mL
- Concentration: undiluted
Duration of treatment / exposure:
4 hours
Observation period:
7 days
Reading time points: 1, 24, 48 and 72 hours and 7 days
Number of animals:
3 (2 males and 1 female)
Details on study design:
TEST SITE
- Area of exposure: 2.5 x 2.5cm on the back of each rabbit
- Type of wrap if used: cotton gauze patch secured with a strip of surical adhesive tape and wrapped with an elasticated corset

REMOVAL OF TEST SUBSTANCE
- Washing (if done): residual test material was removed by gentle swabbing with cotton wool soaked in 74% Industrial Methylated Spirits
- Time after start of exposure: 4 hours

SCORING SYSTEM: Draize Scoring System
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: mean over 24, 48 and 72 hours
Score:
0.7
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: mean over 24, 48 and 72 hours
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: loss of skin elasticity at 72 hours and desquamation after 7 days
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: mean over 24, 48 and 72 hours
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: desquamation after 7 days
Irritation parameter:
edema score
Basis:
animal #1
Time point:
other: mean over 24, 48 and 72 hours
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: mean over 24, 48 and 72 hours
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
animal #3
Time point:
other: mean over 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: reversibility: not applicable
Irritant / corrosive response data:
Very slight erythema was noted at all treated skin sites at the 24 and 48-hour observations and at two treated skin sites at the 72-hour observation. Very slight edema was noted at all treated skin sites at the 24-hour observation and persisted at two treated skin site at the 48 and 72-hour observations.
Other effects:
Loss of skin elasticity was noted at one treated skin site at the 72-hour observation. Slight desquamation was noted at two treated skin sites at the 7-day observation.

Table 1: Results of skin irritation study

Observation time

Rabbit No.

1

2

3

Erythema

Edema

Erythema

Edema

Erythema

Edema

1 h

0

0

0

0

0

0

24 h

1

1

1

1

1

1

48 h

1

0

1

1

1

1

72 h

0

0

1

1

1

1

7 days

0

0

0

0

0

0

Mean value

24 + 48 + 72 h

0.67

0.33

1

1

1

1

Mean value

24 + 48 + 72 h

(all animals)

0.89

0.78

 

Interpretation of results:
GHS criteria not met
Conclusions:
CLP: not classified
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
02 Feb - 05 Feb 1999
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study with acceptable restrictions (no analytical purity reported)
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
adopted in 1992
Deviations:
yes
Remarks:
no analytical purity reported
GLP compliance:
no
Species:
rabbit
Strain:
other: Albino Rabbits; New Zealand White, HM: (NZW)fBR
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hare-Marland, Inc., Hewitt, NJ, USA
- Age at study initiation: at least 8 weeks old
- Weight at study initiation: 2.5 – 2.8 kg
- Housing: individually housed in suspended, stainless steel cages with wire mesh bottoms
- Diet: certified Lab Rabbit Diet, HF, No. 5325; PMI Feeds, Inc. St. Louis, MO (approx 125 g/day while on test)
- Water: automatic watering system, municipal water supply, ad libitum
- Acclimation period: 60 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16 - 22
- Humidity (%): 30 – 70
- Photoperiod (hrs dark / hrs light): 12/12


Type of coverage:
semiocclusive
Preparation of test site:
other: clipped
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated sites of the same animal served as control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied: 0.5 mL
Duration of treatment / exposure:
4 h
Observation period:
3 days
Reading time points: 1, 24, 48, and 72 hours
Number of animals:
3 females
Details on study design:
TEST SITE
- Area of exposure: intact skin of the dorsal trunk surface
- Type of wrap if used: 6 cm² gauze square placed directly on the intact test site per animal and directly held in place with tape. Gauze was then wrapped around the animal and secured with tape to keep the test material in contact with the skin.

REMOVAL OF TEST SUBSTANCE
- Washing: The site was wiped free of test material with 0.9% saline and gauze
- Time after start of exposure: At the end of the exposure period

SCORING SYSTEM: Draize scoring system
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: mean over 24, 48 an 72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: mean over 24, 48 and 72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: mean over 24, 48 and 72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
edema score
Basis:
mean
Remarks:
out of all 3 animals
Time point:
other: mean over 24, 48 and 72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Irritant / corrosive response data:
All three animals showed a very slight or slight erythema 1 hour after the test item application. Within 48 hours after removal of the patches the dermal effects were completely reversible.
Interpretation of results:
GHS criteria not met
Conclusions:
CLP: not classified
Endpoint:
skin irritation: in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose for cross-reference:
read-across source
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: David Percival Ltd., Moston, Sandbach, Chesire, UK
- Age at study initiation: 12 - 16 weeks
- Weight at study initiation: 2.74 - 3.07 kg
- Housing: individual housing in suspended metal cages
- Diet: STANRAB SQC Rabbit Diet, Special Diets Services Ltd, Witham, Essex, UK, ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 - 20
- Humidity (%): 50 - 60
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
other: not required: untreated site of the same animal served as control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied: 0.5 mL
- Concentration: undiluted
Duration of treatment / exposure:
4 hours
Observation period:
7 days
Reading time points: 1, 24, 48 and 72 hours and 7 days
Number of animals:
3 (2 males and 1 female)
Details on study design:
TEST SITE
- Area of exposure: 2.5 x 2.5cm on the back of each rabbit
- Type of wrap if used: cotton gauze patch secured with a strip of surical adhesive tape and wrapped with an elasticated corset

REMOVAL OF TEST SUBSTANCE
- Washing (if done): residual test material was removed by gentle swabbing with cotton wool soaked in 74% Industrial Methylated Spirits
- Time after start of exposure: 4 hours

SCORING SYSTEM: Draize Scoring System
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: mean over 24, 48 and 72 hours
Score:
0.7
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: mean over 24, 48 and 72 hours
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: loss of skin elasticity at 72 hours and desquamation after 7 days
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: mean over 24, 48 and 72 hours
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: desquamation after 7 days
Irritation parameter:
edema score
Basis:
animal #1
Time point:
other: mean over 24, 48 and 72 hours
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: mean over 24, 48 and 72 hours
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
animal #3
Time point:
other: mean over 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: reversibility: not applicable
Irritant / corrosive response data:
Very slight erythema was noted at all treated skin sites at the 24 and 48-hour observations and at two treated skin sites at the 72-hour observation. Very slight edema was noted at all treated skin sites at the 24-hour observation and persisted at two treated skin site at the 48 and 72-hour observations.
Other effects:
Loss of skin elasticity was noted at one treated skin site at the 72-hour observation. Slight desquamation was noted at two treated skin sites at the 7-day observation.

Table 1: Results of skin irritation study

Observation time

Rabbit No.

1

2

3

Erythema

Edema

Erythema

Edema

Erythema

Edema

1 h

0

0

0

0

0

0

24 h

1

1

1

1

1

1

48 h

1

0

1

1

1

1

72 h

0

0

1

1

1

1

7 days

0

0

0

0

0

0

Mean value

24 + 48 + 72 h

0.67

0.33

1

1

1

1

Mean value

24 + 48 + 72 h (all animals)

0.89

0.78

 

Interpretation of results:
GHS criteria not met
Conclusions:
CLP: not classified
Endpoint:
skin irritation: in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose for cross-reference:
read-across source
Species:
rabbit
Strain:
other: Albino Rabbits; New Zealand White, HM: (NZW)fBR
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hare-Marland, Inc., Hewitt, NJ, USA
- Age at study initiation: at least 8 weeks old
- Weight at study initiation: 2.5 – 2.8 kg
- Housing: individually housed in suspended, stainless steel cages with wire mesh bottoms
- Diet: certified Lab Rabbit Diet, HF, No. 5325; PMI Feeds, Inc. St. Louis, MO (approx 125 g/day while on test)
- Water: automatic watering system, municipal water supply, ad libitum
- Acclimation period: 60 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16 - 22
- Humidity (%): 30 – 70
- Photoperiod (hrs dark / hrs light): 12/12


Type of coverage:
semiocclusive
Preparation of test site:
other: clipped
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated sites of the same animal served as control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied: 0.5 mL
Duration of treatment / exposure:
4 h
Observation period:
3 days
Reading time points: 1, 24, 48, and 72 hours
Number of animals:
3 females
Details on study design:
TEST SITE
- Area of exposure: intact skin of the dorsal trunk surface
- Type of wrap if used: 6 cm² gauze square placed directly on the intact test site per animal and directly held in place with tape. Gauze was then wrapped around the animal and secured with tape to keep the test material in contact with the skin.

REMOVAL OF TEST SUBSTANCE
- Washing: The site was wiped free of test material with 0.9% saline and gauze
- Time after start of exposure: At the end of the exposure period

SCORING SYSTEM: Draize scoring system
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: mean over 24, 48 an 72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: mean over 24, 48 and 72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: mean over 24, 48 and 72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
edema score
Basis:
mean
Remarks:
out of all 3 animals
Time point:
other: mean over 24, 48 and 72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Irritant / corrosive response data:
All three animals showed a very slight or slight erythema 1 hour after the test item application. Within 48 hours after removal of the patches the dermal effects were completely reversible.
Interpretation of results:
GHS criteria not met
Conclusions:
CLP: not classified
Endpoint:
skin irritation / corrosion, other
Remarks:
QSAR prediction
Type of information:
(Q)SAR
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Validated QSAR model
Justification for type of information:
The OECD QSAR Toolbox v3.3.5 is a Quantitative Structure-Activity Relationship model that was developed by the Laboratory of Mathematical Chemistry, Bourgas, Bulgaria (http://toolbox.oasis-lmc.org). It contains several different databases with data on chemicals. The model was used to predict the skin irritation/corrosion potential of the test substance either structural alert-based (“inclusion rules by BfR”) or PC-parameter based (“exclusion rules by BfR”) (BfR refers to Bundesinstitut für Risikobewertung (German Federal Institute of Risk Assessment) where the rule schemes were developed).
Principles of method if other than guideline:
Prediction based on OECD QSAR Toolbox v3.3.5 QSAR prediction of the skin irritation potential of the test substance. Profilers relevant for skin irritation/corrosion are either structural alert-based (“inclusion rules by BfR”) or PC-parameter based (“exclusion rules by BfR”).
GLP compliance:
no
Irritation parameter:
other: QSAR prediction
Basis:
other: inclusion/exclusion rules of BfR
Time point:
other: not applicable
Reversibility:
other: not applicable
Remarks on result:
no indication of irritation

The predicted skin irritation/corrosion potential of the test substance was modelled in the OECD QSAR Toolbox v3.3.5. The test substance falls within the model applicability domain for the BfR inclusion rules. No alerts were found. Therefore, the test substance is not expected to exhibit skin irritating or corrosive properties.

Interpretation of results:
study cannot be used for classification
Conclusions:
The test material is not predicted to have skin irritating/corrosive potential.
Endpoint:
skin irritation / corrosion, other
Remarks:
QSAR prediction
Type of information:
other: (Q)SAR (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Validated QSAR model
Justification for type of information:
The OECD QSAR Toolbox v3.3.5 is a Quantitative Structure-Activity Relationship model that was developed by the Laboratory of Mathematical Chemistry, Bourgas, Bulgaria (http://toolbox.oasis-lmc.org). It contains several different databases with data on chemicals. The model was used to predict the skin irritation/corrosion potential of the analogue substances either structural alert-based (“inclusion rules by BfR”) or PC-parameter based (“exclusion rules by BfR”) (where BfR refers to Bundesinstitut für Riskiobewertung (German Federal Institute of Risk Assessment) where the rule schemes were developed).


Principles of method if other than guideline:
Prediction based on OECD QSAR Toolbox v3.3.5 QSAR prediction of the skin irritation potential of the analogue substances. Profilers relevant for skin irritation/corrosion are either structural alert-based (“inclusion rules by BfR”) or PC-parameter based (“exclusion rules by BfR”).
GLP compliance:
no
Irritation parameter:
other: QSAR prediction
Basis:
other: inclusion/exclusion rules of BfR
Time point:
other: not applicable
Reversibility:
other: not applicable
Remarks on result:
no indication of irritation

The predicted skin irritation/corrosion potential of the analogue substances was modelled in the OECD QSAR Toolbox v3.3.5. The analogue substances fall within the model applicability domain for the BfR inclusion rules. No alerts were found for the analogue substances with the exception of Isononanoic acid, C16-18 alkyl esters (CAS 111937-03-2) containing an alert for “Esters including acrylic and methacrylic esters”. However, experimental data on skin irritation/corrosion Isononanoic acid, C16-18 alkyl esters (CAS 111937-03-2) is available which is conclusive but not sufficient for classification according to Regulation EC No. 1272/2008 (please refer to analogue justification provided in IUCLID section 13). Therefore, the analogue substances are not expected to reveal skin irritating or corrosive potential.

Interpretation of results:
study cannot be used for classification
Conclusions:
The analogue substances are not predicted to have skin irritating/corrosive potential.
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:
weight of evidence
Study period:
23. Dec. 1989 - 01. Jan. 1999
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented study report which meets basic scientific principles (no analytical purity reported)
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
(no data on test substance purity)
Qualifier:
equivalent or similar to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
GLP compliance:
yes (incl. QA statement)
Remarks:
Safepharm Laboratories Limited, Derby, UK
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: David Percival Ltd, Moston, Sandbach, Cheshire, UK
- Age at study initiation: 12 - 16 weeks
- Weight at study initiation: 3.12 - 3.29 kg
- Housing: individual housing in suspended metal cages
- Diet: STANRAB SQC Rabbit Diet, Special Diets Services Ltd, Witham, Essex, UK
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 - 19
- Humidity (%): 43 - 64
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
other: the untreated eye served as control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied: 0.1 mL
- Concentration: undiluted
Duration of treatment / exposure:
Single application without washing
Observation period (in vivo):
72 hours
Reading time points: 1, 24, 48, 72 hours
Number of animals or in vitro replicates:
2 male and 1 female
Details on study design:
SCORING SYSTEM: Draize Scoring System

TOOL USED TO ASSESS SCORE: light source from a standard ophthalmoscope
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
(out of all 3 animals)
Time point:
other: mean over 24 m 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: reversibility: not applicable
Irritation parameter:
iris score
Basis:
mean
Remarks:
(out of all 3 animals)
Time point:
other: mean over 24, 48 and 72 hours
Score:
0
Max. score:
2
Reversibility:
other: reversibility: not applicable
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
other: mean over 24, 48 and 72 hours
Score:
0.7
Max. score:
3
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
animal #2 and animal #3
Time point:
other: mean over 24, 48 and 72 hours
Score:
0.3
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
other: mean over 24, 48 and 72 hours
Score:
0.7
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
other: mean over 24, 48 and 72 hours
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
other: mean over 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: reversibility: not applicable
Irritant / corrosive response data:
No corneal or iridal effects were noted. Moderate conjunctival irritation was noted in all treated eyes at the 1-hour observation with minimal conjunctival irritation noted in all treated eyes at the 24-hour observation and one treated eye at the 48-hour observation. Treated eyes appeared normal 48 to 72 hours after treatment.
Table 1: Results of eye irritation study 
Rabbit # Time [h] conjunctivae   iris cornea   conjunctivae   iris cornea
redness swelling redness swelling    
1 1 2 1 0 0  
24 1 1 0 0
48 1 1 0 0
72 0 0 0 0
average 0,7 0,7 0,0 0,0 Time to reversion (h)  72,0 72,0 0,0 0,0
2 1 2 2 0 0    
24 1 1 0 0
48 0 0 0 0
72 0 0 0 0
average 0,3 0,3 0,0 0,0 Time to reversion (h) 48,0 48,0 0,0 0,0
3 1 2 1 0 0    
24 1 0 0 0
48 0 0 0 0
72 0 0 0 0
average 0,3 0,0 0,0 0,0 Time to reversion (h)  48,0 0,0 0,0 0,0
       
Time [h] conjunctivae   iris cornea
  redness swelling     avg. time to reversion 56,0 40,0 0,0 0,0
average
score
1 2,00 1,33 0,00 0,00  
24 1,00 0,67 0,00 0,00
48 0,33 0,33 0,00 0,00
72 0,00 0,00 0,00 0,00
24+48+72 0,44 0,33 0,00 0,00
Interpretation of results:
GHS criteria not met
Conclusions:
CLP: not classified
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
5 Feb 1999 - 12 Feb 1999
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study with acceptable restrictions (no analytical purity reported)
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
no data on test substance purity given
GLP compliance:
no
Species:
rabbit
Strain:
other: albino rabbits; New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Hare-Marland, Inc., Hewitt, NJ, USA
- Age at study initiation: at least 8 weeks
- Weight at study initiation: 2.8 – 2.9 kg
- Housing: individually housed in suspended, stainless steel cages with wire mesh bottoms
- Diet: certified Lab Rabbit Diet HF, No. 5325; PMI Feeds, Inc. St. Louis, MO (approximately 125 g/day while on test)
- Water: automatic watering system (municipal water supply), ad libitum
- Acclimation period: 53 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 1
- Humidity (%): 34 - 54
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
other: the untreated eye served as control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied: 0.1 mL
Duration of treatment / exposure:
24 h, single application without washing
Observation period (in vivo):
3 days
Reading time points: 1, 24, 48, and 72 h
Number of animals or in vitro replicates:
3 (1 male and 2 females)
Details on study design:
SCORING SYSTEM: Draize scoring system

TOOL USED TO ASSESS SCORE: fluorescein
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
out of all 3 animals
Time point:
other: mean over 24, 48 and 72 h
Score:
0
Max. score:
4
Reversibility:
other: reversibility: not applicable
Irritation parameter:
iris score
Basis:
mean
Remarks:
out of all 3 animals
Time point:
other: mean over 24, 48 and 72 h
Score:
0
Max. score:
2
Reversibility:
other: reversibility: not applicable
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
out of all 3 animals
Time point:
other: mean over 24, 48 and 72 h
Score:
0.67
Max. score:
3
Reversibility:
fully reversible within: 72 h
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
out of all 3 animals
Time point:
other: mean over 24, 48 and 72 h
Score:
0
Max. score:
4
Reversibility:
other: reversibility not applicable
Irritant / corrosive response data:
One animal exhibited moderate conjunctival redness whereas the other 2 animals showed mild conjuctival redness; all three animals exhibited severe discharge. No iridial or corneal changes were evident throughout the study. At 24 h post-treatment, one animal was free of conjuctival redness. All 3 animals were free of ocular irritation within 72 h after treatment.
Interpretation of results:
GHS criteria not met
Conclusions:
CLP: not classified
Endpoint:
eye irritation: in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose for cross-reference:
read-across source
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: David Percival Ltd, Moston, Sandbach, Cheshire, UK
- Age at study initiation: 12 - 16 weeks
- Weight at study initiation: 3.12 - 3.29 kg
- Housing: individual housing in suspended metal cages
- Diet: STANRAB SQC Rabbit Diet, Special Diets Services Ltd, Witham, Essex, UK
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 - 19
- Humidity (%): 43 - 64
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
other: the untreated eye served as control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied: 0.1 mL
- Concentration: undiluted
Duration of treatment / exposure:
Single application without washing
Observation period (in vivo):
72 hours
Reading time points: 1, 24, 48, 72 hours
Number of animals or in vitro replicates:
2 male and 1 female
Details on study design:
SCORING SYSTEM: Draize Scoring System

TOOL USED TO ASSESS SCORE: light source from a standard ophthalmoscope
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
(out of all 3 animals)
Time point:
other: mean over 24 m 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: reversibility: not applicable
Irritation parameter:
iris score
Basis:
mean
Remarks:
(out of all 3 animals)
Time point:
other: mean over 24, 48 and 72 hours
Score:
0
Max. score:
2
Reversibility:
other: reversibility: not applicable
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
other: mean over 24, 48 and 72 hours
Score:
0.7
Max. score:
3
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
animal #2 and animal #3
Time point:
other: mean over 24, 48 and 72 hours
Score:
0.3
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
other: mean over 24, 48 and 72 hours
Score:
0.7
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
other: mean over 24, 48 and 72 hours
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
other: mean over 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: reversibility: not applicable
Irritant / corrosive response data:
No corneal or iridal effects were noted. Moderate conjunctival irritation was noted in all treated eyes at the 1-hour observation with minimal conjunctival irritation noted in all treated eyes at the 24-hour observation and one treated eye at the 48-hour observation. Treated eyes appeared normal 48 to 72 hours after treatment.
Table 1: Results of eye irritation study 
Rabbit # Time [h] conjunctivae   iris cornea   conjunctivae   iris cornea
redness swelling redness swelling    
1 1 2 1 0 0  
24 1 1 0 0
48 1 1 0 0
72 0 0 0 0
average 0,7 0,7 0,0 0,0 Time to reversion (h)  72,0 72,0 0,0 0,0
2 1 2 2 0 0    
24 1 1 0 0
48 0 0 0 0
72 0 0 0 0
average 0,3 0,3 0,0 0,0 Time to reversion (h) 48,0 48,0 0,0 0,0
3 1 2 1 0 0    
24 1 0 0 0
48 0 0 0 0
72 0 0 0 0
average 0,3 0,0 0,0 0,0 Time to reversion (h)  48,0 0,0 0,0 0,0
       
Time [h] conjunctivae   iris cornea
  redness swelling     avg. time to reversion 56,0 40,0 0,0 0,0
average
score
1 2,00 1,33 0,00 0,00  
24 1,00 0,67 0,00 0,00
48 0,33 0,33 0,00 0,00
72 0,00 0,00 0,00 0,00
24+48+72 0,44 0,33 0,00 0,00
Interpretation of results:
GHS criteria not met
Conclusions:
CLP: not classified
Endpoint:
eye irritation: in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose for cross-reference:
read-across source
Species:
rabbit
Strain:
other: albino rabbits; New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Hare-Marland, Inc., Hewitt, NJ, USA
- Age at study initiation: at least 8 weeks
- Weight at study initiation: 2.8 – 2.9 kg
- Housing: individually housed in suspended, stainless steel cages with wire mesh bottoms
- Diet: certified Lab Rabbit Diet HF, No. 5325; PMI Feeds, Inc. St. Louis, MO (approximately 125 g/day while on test)
- Water: automatic watering system (municipal water supply), ad libitum
- Acclimation period: 53 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 1
- Humidity (%): 34 - 54
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
other: the untreated eye served as control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied: 0.1 mL
Duration of treatment / exposure:
24 h, single application without washing
Observation period (in vivo):
3 days
Reading time points: 1, 24, 48, and 72 h
Number of animals or in vitro replicates:
3 (1 male and 2 females)
Details on study design:
SCORING SYSTEM: Draize scoring system

TOOL USED TO ASSESS SCORE: fluorescein
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
out of all 3 animals
Time point:
other: mean over 24, 48 and 72 h
Score:
0
Max. score:
4
Reversibility:
other: reversibility: not applicable
Irritation parameter:
iris score
Basis:
mean
Remarks:
out of all 3 animals
Time point:
other: mean over 24, 48 and 72 h
Score:
0
Max. score:
2
Reversibility:
other: reversibility: not applicable
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
out of all 3 animals
Time point:
other: mean over 24, 48 and 72 h
Score:
0.67
Max. score:
3
Reversibility:
fully reversible within: 72 h
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
out of all 3 animals
Time point:
other: mean over 24, 48 and 72 h
Score:
0
Max. score:
4
Reversibility:
other: reversibility not applicable
Irritant / corrosive response data:
One animal exhibited moderate conjunctival redness whereas the other 2 animals showed mild conjuctival redness; all three animals exhibited severe discharge. No iridial or corneal changes were evident throughout the study. At 24 h post-treatment, one animal was free of conjuctival redness. All 3 animals were free of ocular irritation within 72 h after treatment.
Interpretation of results:
GHS criteria not met
Conclusions:
CLP: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for read-across

There are no data available on skin and eye irritation of Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid. In order to fulfil the standard information requirements set out in Annex VII and VIII, 8.1. and 8.2., in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances was conducted. In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across) “to avoid the need to test every substance for every endpoint”. For each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across. A detailed justification for the analogue read-across approach is provided in the technical dossier (see IUCLID Section 13) and within Chapter 5.1 of the CSR.

Skin irritation

CAS 131459-39-7

In the skin irritation study performed equivalent or similar to OECD TG 404 and in compliance with GLP two male and one female New Zealand White rabbits were exposed to 0.5 mL of 3,5,5-trimethylhexanoic acid mixed tetraesters with PE and valeric acid (CAS 131459-39-7) onto the shaved skin for 4 h via semi-occlusive coverage (Allen, 1999c). Skin reactions were evaluated according to the Draize scoring system 1, 24, 48 and 72 h and 7 days post-application. No symptoms of systemic toxicity were observed in any animal during the test period and no mortality occurred during the course of the study. Loss of skin elasticity was noted at one treated skin site at the 72-hour observation time point and slight desquamation was noted at two treated skin sites at the 7-day observation time point. Very slight erythema formation (grade 1) was noted in 3/3 animals within 24 h post-application of the test material, but being fully reversible within 72 in 1/3 animals and 7 days in 2/3 animals, respectively. Moreover, slight edema formation (grade 1) was recorded in 3/3 animals within 24 h post-application of the test material, being fully reversible within 48 h in 1/3 animals and 7 days within 7 days, respectively. The mean values for erythema and edema were calculated to be 0.89 and 0.78, respectively. Based on the study results and according to EU classification criteria, the test substance is not considered to be irritating to the skin.

 

CAS 67762-53-2

In a further skin irritation study performed equivalent or similar to OECD TG 404 three female New Zealand White rabbits were exposed to 0.5 mL of Carboxylic acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) onto the clipped skin for 4 h via semi-occlusive coverage (Zolyniene, 1999b). Skin reactions were evaluated according to the Draize scoring system 1, 24, 48 and 72 h post-application. No symptoms of systemic toxicity were observed in any animal during the test period and no mortality occurred during the course of the study. 3/3 animals showed a very slight or slight erythema formation (grade 1-2) 1 h after test item administration. These effects were fully reversible within 24 h in 2/3 animals and 48 h in 1/3 animal, respectively. No edema formation was observed in any animal during the study period. The mean values for erythema and edema were calculated to be 0.11 and 0, respectively. Based on the study results and according to EU classification criteria, the test substance is not considered to be irritating to the skin.

Furthermore, no structural alerts indicative for skin irritating properties were identified in the OECD Toolbox v3.3.5 for the main components of the target and analogue substances with the exception of Isononanoic acid, C16-18 alkyl esters (CAS 111937-03-2). For this analogue substance, an alert for “Esters including acrylic and methacrylic esters” was identified. However, an in vivo skin irritation/corrosion test is available for Isononanoic acid, C16-18 alkyl esters (CAS 111937-03-2) which is conclusive but not sufficient for classification according to Regulation EC No. 1272/2008 (please refer to analogue justification provided in IUCLID section 13).

 

Eye irritation

CAS 131459-39-7

In the eye irritation study with 3,5,5-trimethylhexanoic acid mixed tetraesters with PE and valeric acid (CAS 131459-39-7) performed equivalent or similar to OECD TG 405 and in compliance with GLP (Allen, 1999d) 0.1 mL of the neat test substance was instilled in the eyes of two male and one female New Zealand White rabbits. The eyes were examined and the changes were graded according to the Draize scoring system 1, 24, 48 and 72 h post-application. Neither corneal nor iridal effects were noted were observed in any animal during the study period. Moderate conjunctival irritation (grade 1-2) were observed in 3/3 animals but being fully reversible within 48 h in 2/3 animals and 72 h in 1/3 animal. Chemosis (grade 1-2) was also noted in 3/3 animals but was fully reversible within 24, 48 or 72 h, respectively. The mean values for cornea opacity, iris, conjunctivae and chemosis were calculated to be 0, 0, 0.44 and 0.33, respectively. Based on the study results and according to EU classification criteria, the test substance is not considered to be irritating to eyes.

 

CAS 67762-53-2

In a further eye irritation study with Carboxylic acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) performed equivalent or similar to OECD TG 405 (Zolyniene, 1999c) 0.1 mL of the neat test substance was instilled in the eyes of one male and two female New Zealand White rabbits. The eyes were examined and the changes were graded according to the Draize scoring system 1, 24, 48 and 72 h post-application. Neither corneal nor iridal effects and chemosis were noted were observed in any animal during the study period. Moderate conjunctival irritation (grade 1-2) were observed in 3/3 animals but being fully reversible within 24, 48 h or 72 h in all animals. The mean values for cornea opacity, iris, conjunctivae and chemosis were calculated to be 0, 0, 0.33 and 0, respectively. Based on the study results and according to EU classification criteria, the test substance is not considered to be irritating to eyes.

Overall conclusion for skin and eye irritation

The QSAR predictions performed with the analogue substances revealed one alert for the analogue substance Isononanoic acid, C16-18 alkyl esters (CAS 111937-03-2) following the BfR rules which was considered to be not of significant toxicological relevance. Therefore, following the analogue approach, Tetraesters of pentaerythritol with heptanoic acid and 3,5,5-trimethylhexanoic acid is not considered to be irritating towards the skin or eyes.

Justification for classification or non-classification

Based on the analogue read-across approach, the available data on skin and eye irritation/corrosion do not meet the classification criteria according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification.