2-Octen-1-ylsuccinic anhydride, mixture of cis and trans

Endpoint summary

Description of key information

The substance was experimentally determined to be a skin irritant in rabbits.  It is also acknowledged as an eye irritant based on "read-across" with in a category.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Mar 2012-April 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

Housing: The animals were singly housed in suspended stainless steel caging with mesh floors. Litter paper was placed beneath the cage and was changed at least three times per week.
Animal Room Temperature and Relative Humidity Ranges: 19-23°C and 31-56%, respectively.
Animal Room Air Changes/Hour: 12. Airflow measurements are evaluated regularly.
Photoperiod: 12-hour light/dark cycle
Acclimation Period: 6 or 7 days
Food: Harlan Teklad Global High Fiber Rabbit Diet® #2031. A designated amount of the diet was available to each rabbit (approximately 150 grams/day).
Water: Filtered tap water was supplied ad libitum by an automatic water dispensing system.

Type of coverage:

occlusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

Five-tenths of a milliliter was applied.

Duration of treatment / exposure:

4 hours.

Observation period:

30-60 minutes, 24, 48, and 72 hours, and 7 days.

Number of animals:

3

Details on study design:

Five-tenths of a milliliter of the test substance was applied to one 6cm2 intact dose site on each animal and covered with a 1-inch x 1-inch, 4-ply gauze ad. The pad and entire trunk of each animal were then wrapped with semi-occlusive 3-inch Micropore tape to avoid dislocation of the pad. Elizabethan collars were placed on each rabbit and they were returned to their cages.
After 4 hours of exposure to the test substance, the pads and collars were removed and the test sites were gently cleansed of any residual test substance.

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

7 d

Score:

0

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48 h

Score:

3

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

animal #1

Time point:

72 h

Score:

2

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

animal #1

Time point:

7 d

Score:

0

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

7 d

Score:

0

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

animal #2

Time point:

7 d

Score:

0

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

animal #3

Time point:

7 d

Score:

0

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48 h

Score:

3

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

animal #3

Time point:

72 h

Score:

2

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

7 d

Score:

0

Max. score:

7

Reversibility:

fully reversible

Evaluation Scale is provided below:

Skin Reaction	Value
Erythema and eschar formation
No erythema	0
Slight erythema	1
Well defined erythema	2
Moderate to severe erythema	3
Severe erythema to slight eschar formation	4
Edema formation
No edema	0
Very slight edema	1
Slight edema	2
Moderate edema	3
Severe edema	4

The resulting Primary Dermal Irritation Index (PDII) was classified as follows:

PDII                                                                               Classification

0                                                                                 Non-irritating

> 0 - 2.0                                                                           Slightly irritating

2.1 - 5.0                                                                            Moderately irritating

> 5.0                                                                             Severely irritating

Interpretation of results:

Category 2 (irritant) based on GHS criteria

Conclusions:

Under the conditions of this study, octenyl succinic anhydride is considered moderately irritating to the skin. It is classified as Category 2 according to Regulation EC No. 1272/2008

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Eye irritation

Link to relevant study records

Reference

Reference 1

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1/24/1983 to 2/7/1983

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP-like (QA signature), guideline study; restriction due to study being terminated prior to all effects had resolved.

Qualifier:

equivalent or similar to guideline

Guideline:

other: 16CFR 1500.42- Federal Hazardous Substances Act Regulations

Deviations:

no

GLP compliance:

yes

Remarks:

Study predates GLP regulations, but QA signature is available.

Species:

rabbit

Strain:

not specified

Details on test animals or tissues and environmental conditions:

TEST ANIMALS

- Housing: The animals were housed and maintained in accordance with standards set forth in the Guide for the Care and Use of Laboratory Animals (DHEW Publication No. 80-23). 1 rabbit/cage (stainless steel with elevated wire mesh flooring).
- Diet (e.g. ad libitum): Wayne 15% Rabbit Ration was provided ad libitum
- Water (e.g. ad libitum): tap water was provided ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature: 60-75°F
- Humidity (%): 40-45%

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml

Duration of treatment / exposure:

Test material was instilled into one eye of the test animal while the other eye remained untreated to serve as a control. The test material was not washed from the eyes.

Observation period (in vivo):

The eyes were examined and graded for ocular reaction at 1, 2, 3, 4, 7 and 14 days following instillation of test material into the eyes.

Number of animals or in vitro replicates:

6 rabbits

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no washing.

SCORING SYSTEM: Interpretation of the results was made in accordance with the Draize technique for scoring ocular lesions

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: All scores were 0

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: all scores were 0

Irritation parameter:

conjunctivae score

Remarks:

Redness

Basis:

mean

Time point:

24/48/72 h

Score:

1.7

Max. score:

3

Reversibility:

not fully reversible within: 14d

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

2.5

Max. score:

4

Reversibility:

not fully reversible within: 14d

Irritant / corrosive response data:

In a primary eye irritation study, 0.1 ml of undiluted test substance was placed into one eye of each of the rabbits (6 animals).
The mean Draize scores (24, 48 and 72 h) were:
Cornea = 0
Iris = 0
Conjunctivae – redness = 1.7
Chemosis = 2.5
 
The test substance produced ocular irritation which was not cleared until day 14.

Draize Scores

Animal #	1	2	3	4	7	14
Conjunctivae-chemosis
1	3	3	3	2	1	1
2	4	2	2	2	1	1
3	2	2	1	1	1	1
4	4	3	3	3	3	1
5	2	2	1	1	1	1
6	3	2	3	2	1	1
Conjunctivae-redness
1	2	2	1	1	1	1
2	2	2	1	1	1	0
3	2	2	2	1	1	0
4	2	2	2	2	2	1
5	2	2	1	2	1	1
6	2	2	1	1	0	0
Cornea
1	0	0	0	0	0	0
2	0	0	0	0	0	0
3	0	0	0	0	0	0
4	0	0	0	0	0	0
5	0	0	0	0	0	0
6	0	0	0	0	0	0
Iritis
1	0	0	0	0	0	0
2	0	0	0	0	0	0
3	0	0	0	0	0	0
4	0	0	0	0	0	0
5	0	0	0	0	0	0
6	0	0	0	0	0	0

Interpretation of results:

Category 2 (irritating to eyes) based on GHS criteria

Conclusions:

Tetrapropenyl succinic anhydride (TPSA), a category member, was tested for eye irritation in rabbits according to a US test guideline, comparable to the OECD 405. The substance is classified as irritating to the eyes according to Regulation EC No. 1272/2008. Data can be read-across among members of the C8-12 Alkenyl Succinic Anhydrides Category, based on common functional groups, similar break-down products and potency patterns among carbon-chain length. This is adequate to fulfill the information requirements, to be the basis for classification and labelling decisions, and for risk assessment.

Reference 2

Endpoint:

eye irritation: in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

1/24/1983 to 2/7/1983

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP-like (QA signature), guideline study; restriction due to study being terminated prior to all effects had resolved.

Justification for type of information:

A category approach will be used for the hazard assessment of several endpoints. The hypothesis for the category of C8-12 Alkenyl Succinic Anhydrides is that data can be read-across among members of the category because their properties and behaviours are similar, based on common functional groups and similar breakdown products, and based on a constant pattern in changing of the potency of properties of the various carbon chain lengths. These features are in accordance with Annex XI, Section 1.5, of Regulation EC No. 1907/2006.  Common functional groups are: a dihydro-2,5 -furandione (cyclic anhydride) ring, carbon chain of length 8 to 12 carbons, with or without branching methyl groups, and a single double bond in the carbon chain, location unspecified. There are no additional functional groups which would contribute incremental or different toxicity.
 
The breakdown products are the dioic acids of the corresponding anhydride; these also have common functional groups. A constant pattern may also be displayed in acute toxicity, dermal irritancy and biodegradation, with the lowest carbon chain length (C8) displaying the highest activity. Irritation, toxicity and degradation potential diminish with increasing carbon chain length. Read-across among the category members is substantiated by the common behaviour in physico-chemical and toxicity behaviours, as provided in the Chemical Category Report Format (CCRF) attached to the IUCLID file. It is adequate to fulfill the information requirements of Annex IX, to be the basis for classification and labelling decisions, and for risk assessment. 

Reason / purpose for cross-reference:

read-across source

Qualifier:

equivalent or similar to guideline

Guideline:

other: 16CFR 1500.42- Federal Hazardous Substances Act Regulations

Deviations:

no

GLP compliance:

yes

Remarks:

Study predates GLP regulations, but QA signature is available.

Species:

rabbit

Strain:

not specified

Details on test animals or tissues and environmental conditions:

TEST ANIMALS

- Housing: The animals were housed and maintained in accordance with standards set forth in the Guide for the Care and Use of Laboratory Animals (DHEW Publication No. 80-23). 1 rabbit/cage (stainless steel with elevated wire mesh flooring).
- Diet (e.g. ad libitum): Wayne 15% Rabbit Ration was provided ad libitum
- Water (e.g. ad libitum): tap water was provided ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature: 60-75°F
- Humidity (%): 40-45%

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml

Duration of treatment / exposure:

Test material was instilled into one eye of the test animal while the other eye remained untreated to serve as a control. The test material was not washed from the eyes.

Observation period (in vivo):

The eyes were examined and graded for ocular reaction at 1, 2, 3, 4, 7 and 14 days following instillation of test material into the eyes.

Number of animals or in vitro replicates:

6 rabbits

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no washing.

SCORING SYSTEM: Interpretation of the results was made in accordance with the Draize technique for scoring ocular lesions

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: All scores were 0

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: all scores were 0

Irritation parameter:

conjunctivae score

Remarks:

Redness

Basis:

mean

Time point:

24/48/72 h

Score:

1.7

Max. score:

3

Reversibility:

not fully reversible within: 14d

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

2.5

Max. score:

4

Reversibility:

not fully reversible within: 14d

Irritant / corrosive response data:

In a primary eye irritation study, 0.1 ml of undiluted test substance was placed into one eye of each of the rabbits (6 animals).
The mean Draize scores (24, 48 and 72 h) were:
Cornea = 0
Iris = 0
Conjunctivae – redness = 1.7
Chemosis = 2.5
 
The test substance produced ocular irritation which was not cleared until day 14.

Draize Scores

Animal #	1	2	3	4	7	14
Conjunctivae-chemosis
1	3	3	3	2	1	1
2	4	2	2	2	1	1
3	2	2	1	1	1	1
4	4	3	3	3	3	1
5	2	2	1	1	1	1
6	3	2	3	2	1	1
Conjunctivae-redness
1	2	2	1	1	1	1
2	2	2	1	1	1	0
3	2	2	2	1	1	0
4	2	2	2	2	2	1
5	2	2	1	2	1	1
6	2	2	1	1	0	0
Cornea
1	0	0	0	0	0	0
2	0	0	0	0	0	0
3	0	0	0	0	0	0
4	0	0	0	0	0	0
5	0	0	0	0	0	0
6	0	0	0	0	0	0
Iritis
1	0	0	0	0	0	0
2	0	0	0	0	0	0
3	0	0	0	0	0	0
4	0	0	0	0	0	0
5	0	0	0	0	0	0
6	0	0	0	0	0	0

Interpretation of results:

Category 2 (irritating to eyes) based on GHS criteria

Conclusions:

Tetrapropenyl succinic anhydride (TPSA), a category member, was tested for eye irritation in rabbits according to a US test guideline, comparable to the OECD 405. The substance is classified as irritating to the eyes according to Regulation EC No. 1272/2008. Data can be read-across among members of the C8-12 Alkenyl Succinic Anhydrides Category, based on common functional groups, similar break-down products and potency patterns among carbon-chain length. This is adequate to fulfill the information requirements, to be the basis for classification and labelling decisions, and for risk assessment.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

The substance was experimentally determined to be a moderate skin irritant in rabbits, demonstrating moderate irritation which was fully reversible after 7 days. No specific testing was performed for eye irritation. It is acknowledged to be an eye irritant, "reading-across" from the findings of other members of the C8-12 Alkenyl Succinic Anhydride category. This specifically applies to tetrapropenyl succinic anhydride, where conjunctival irritation did not fully resolve by day 14 after administration. Tripropenyl succinic anhydride is also an eye irritant.

A category approach is used for the hazard assessment of several endpoints. The hypothesis for the category of C8-12 Alkenyl Succinic Anhydrides is that data can be read-across among members of the category because their properties and behaviours are similar, based on common functional groups and similar breakdown products, and based on a constant pattern in changing of the potency of properties of the various carbon chain lengths. Functional groups include a dihydro-2,5 -furandione cyclic anhydride ring, a carbon chain of length 8 -12 carbons, and a single double-bond within the carbon chain. The primary functional group associated with toxicity is the succinic anhydride moiety, which quickly is hydrolysed to form a butanedioic acid. A constant pattern may also be displayed in acute toxicity, dermal irritancy and biodegradation, with the lowest carbon chain length (C8) displaying the highest activity. Irritation, toxicity and degradation potential diminish with increasing carbon chain length. Read-across among the category members is substantiated by the common behaviour in physico-chemical and toxicity behaviours, as provided in the Chemical Category Report Format (CCRF) attached to the IUCLID file. It is adequate to fulfill the information requirements of Annex IX, to be the basis for classification and labelling decisions, and for risk assessment. 

Justification for selection of skin irritation / corrosion endpoint:
guideline study under GLP

Justification for selection of eye irritation endpoint:
guideline study, scientifically valid

Effects on skin irritation/corrosion: irritating

Effects on eye irritation: irritating

Justification for classification or non-classification

The substance is a moderate skin irritant, and meets the dermal irritation criteria of Category 2 of Regulation EC. No. 1272/2008. The substance is classified as a severe eye irritant, Category 2.