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

Endpoint summary

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Peer reviewed scientific publication

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Principles of method if other than guideline:

Behavour in standard sensitisation tests were correlated with logP and chemical reactivity rates for four chemicals.

GLP compliance:

no

Type of study:

other: GP Maximization test, Adjuvant & Patch test and Buehler test

Justification for non-LLNA method:

Studies was already available and sufficient for classification. No further animal testing (LLNA) had to be conducted.

Species:

guinea pig

Strain:

Hartley

Sex:

not specified

Details on test animals and environmental conditions:

Purchased from Charles River Japan. They were 5-6 weeks old at the start of the test. They were housed as 5 animals per one aluminum cage (Yamato Scientific Co.l, Ltd, 450x550x350 mm) and given free access to filtered tap water and standard diet (GC-4, Oriental Yeast Co., Ltd) throughout the experimental period.

Route:

intradermal and epicutaneous

Vehicle:

other: acetone and corn oil

Concentration / amount:

varous concentrations

Route:

other: epicutaneous, wrapped and open

Vehicle:

other: acetone and corn oil

Concentration / amount:

varous concentrations

No. of animals per dose:

5

Details on study design:

The GPMT was carried out as reported previously (Magnusson and Kligman, 1969). The adjuvant and patch test (APT) was carried out as previously reported (Sato, et.al., 1981). The Buehler test (BT) was carried out as previously reported (Buehler, 1965).
The octanol:water partition coefficient (log P) was calculated using a computer system (BioByte software Release 3.55, C-QSAR, Sub system (CLOGP) (Hansch et al., 1995).
Chemical reactivity rates were estimated by the decrease in the amount of 2-phenylethylamine (PEA) in reaction with nDDSA and the positive control compounds. Solutions of 50 mM in DMSO were mixed with 40 mM 2-PEA in DMSO and stirred with a magnetic stirrer for 90 minutes at room temperature. After the reaction, the amount of PEA was measured by HPLC (SUMIPAX ODS column (L-05-4615, 5 µm) 4.6 mm x 15 cm) with a Hitachi L-5200 Intelligent Pump equipped with a Hitachi L-4000 UV detector at 256 nm. The flow rate of eluents (MeOH/H20 = 40:60, v/v, containing 2% PIC B7) through the detector was 1 ml/min. The peak area (A) of PEA reacting with the test compound was divided by the peak area (B) of PEA before the reaction in order to estimate the reactivity rate for each chemical. Reactivity rates = (1-B/A) x 100(%).

Positive control substance(s):

yes

Remarks:

2,4-dinitrochlorobenzene, maleic anhydride, alpha-hexylcinnamic aldehyde

Positive control results:

2,4-Dinitrochlorobenzene, maleic anhydride, alpha-hexylcinnamic aldehyde were positive in all three test protocols.

Reading:

other: GPMT challenge

Hours after challenge:

48

Group:

test chemical

Dose level:

1 ppm (0.0001%)

No. with + reactions:

1

Total no. in group:

5

Clinical observations:

at 1 ppm (0.0001%) induction and 1000 ppm (0.1%) challenge

Remarks on result:

other: Reading: other: GPMT challenge. . Hours after challenge: 48.0. Group: test group. Dose level: 1 ppm (0.0001%). No with. + reactions: 1.0. Total no. in groups: 5.0. Clinical observations: at 1 ppm (0.0001%) induction and 1000 ppm (0.1%) challenge.

Reading:

other: APT challenge

Hours after challenge:

72

Group:

test chemical

Dose level:

10 ppm (0.001%)

No. with + reactions:

2

Total no. in group:

5

Clinical observations:

10 ppm (0.001%) induction, 100000 ppm (10%) challenge

Remarks on result:

other: Reading: other: APT challenge. . Hours after challenge: 72.0. Group: test group. Dose level: 10 ppm (0.001%). No with. + reactions: 2.0. Total no. in groups: 5.0. Clinical observations: 10 ppm (0.001%) induction, 100000 ppm (10%) challenge.

Reading:

other: BT challenge

Hours after challenge:

48

Group:

test chemical

Dose level:

1000 ppm (0.1%)

No. with + reactions:

5

Total no. in group:

5

Clinical observations:

1000 ppm (0.1%) induction and 100000 ppm (10%) challenge

Remarks on result:

other: Reading: other: BT challenge. . Hours after challenge: 48.0. Group: test group. Dose level: 1000 ppm (0.1%). No with. + reactions: 5.0. Total no. in groups: 5.0. Clinical observations: 1000 ppm (0.1%) induction and 100000 ppm (10%) challenge.

Reading:

rechallenge

Group:

positive control

Remarks on result:

positive indication of skin sensitisation

Remarks:

details were not specified

Reading:

rechallenge

Group:

negative control

Remarks on result:

other: not specified

nDDSA is positive in three sensitization protocols. The minimum induction concentrations were 1 ppm or 0.0001% (GPMT), 10 ppm or 0.001% (APT) and 1000 ppm or 0.1% (BT) as measured at the challenge phase. Minimum rechallenge concentrations of nDDSA were 100 ppm or 0.01% (GMPT and APT) and 1000 ppm or 0.1% (BT).

LogP was estimated through CLOGP QSAR program to be 5.0

Chemical reactivity of nDDSA with 2-phenylethylamine was 100%. Reactivity for maleic anhydride was 100%, for 2,4 -dinitrochlorobenzene was 60% and for alpha-hexylcinnamic aldehyde was 10%.

Interpretation of results:

Category 1A (indication of significant skin sensitising potential) based on GHS criteria

Conclusions:

2-Dodecenyl-1-yl succinic anhydride (nDDSA) was tested in three standard sensitization protocols in guinea pigs, the guinea pig maximization test, adjuvant and patch test and Buehler test. The substance was positive in all three tests. The substance is classified as a dermal sensitizer, category 1A, according to Regulation EC No. 1272, 2008 and Regulation EU No. 286/2011. 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:

skin sensitisation: in vivo (non-LLNA)

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Peer reviewed scientific publication

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:

OECD Guideline 406 (Skin Sensitisation)

Principles of method if other than guideline:

Behavour in standard sensitisation tests were correlated with logP and chemical reactivity rates for four chemicals.

GLP compliance:

no

Type of study:

other: GP Maximization test, Adjuvant & Patch test and Buehler test

Justification for non-LLNA method:

Studies was already available and sufficient for classification. No further animal testing (LLNA) had to be conducted.

Species:

guinea pig

Strain:

Hartley

Sex:

not specified

Details on test animals and environmental conditions:

Purchased from Charles River Japan. They were 5-6 weeks old at the start of the test. They were housed as 5 animals per one aluminum cage (Yamato Scientific Co.l, Ltd, 450x550x350 mm) and given free access to filtered tap water and standard diet (GC-4, Oriental Yeast Co., Ltd) throughout the experimental period.

Route:

intradermal and epicutaneous

Vehicle:

other: acetone and corn oil

Concentration / amount:

varous concentrations

Route:

other: epicutaneous, wrapped and open

Vehicle:

other: acetone and corn oil

Concentration / amount:

varous concentrations

No. of animals per dose:

5

Details on study design:

The GPMT was carried out as reported previously (Magnusson and Kligman, 1969). The adjuvant and patch test (APT) was carried out as previously reported (Sato, et.al., 1981). The Buehler test (BT) was carried out as previously reported (Buehler, 1965).
The octanol:water partition coefficient (log P) was calculated using a computer system (BioByte software Release 3.55, C-QSAR, Sub system (CLOGP) (Hansch et al., 1995).
Chemical reactivity rates were estimated by the decrease in the amount of 2-phenylethylamine (PEA) in reaction with nDDSA and the positive control compounds. Solutions of 50 mM in DMSO were mixed with 40 mM 2-PEA in DMSO and stirred with a magnetic stirrer for 90 minutes at room temperature. After the reaction, the amount of PEA was measured by HPLC (SUMIPAX ODS column (L-05-4615, 5 µm) 4.6 mm x 15 cm) with a Hitachi L-5200 Intelligent Pump equipped with a Hitachi L-4000 UV detector at 256 nm. The flow rate of eluents (MeOH/H20 = 40:60, v/v, containing 2% PIC B7) through the detector was 1 ml/min. The peak area (A) of PEA reacting with the test compound was divided by the peak area (B) of PEA before the reaction in order to estimate the reactivity rate for each chemical. Reactivity rates = (1-B/A) x 100(%).

Positive control substance(s):

yes

Remarks:

2,4-dinitrochlorobenzene, maleic anhydride, alpha-hexylcinnamic aldehyde

Positive control results:

2,4-Dinitrochlorobenzene, maleic anhydride, alpha-hexylcinnamic aldehyde were positive in all three test protocols.

Reading:

other: GPMT challenge

Hours after challenge:

48

Group:

test chemical

Dose level:

1 ppm (0.0001%)

No. with + reactions:

1

Total no. in group:

5

Clinical observations:

at 1 ppm (0.0001%) induction and 1000 ppm (0.1%) challenge

Remarks on result:

other: Reading: other: GPMT challenge. . Hours after challenge: 48.0. Group: test group. Dose level: 1 ppm (0.0001%). No with. + reactions: 1.0. Total no. in groups: 5.0. Clinical observations: at 1 ppm (0.0001%) induction and 1000 ppm (0.1%) challenge.

Reading:

other: APT challenge

Hours after challenge:

72

Group:

test chemical

Dose level:

10 ppm (0.001%)

No. with + reactions:

2

Total no. in group:

5

Clinical observations:

10 ppm (0.001%) induction, 100000 ppm (10%) challenge

Remarks on result:

other: Reading: other: APT challenge. . Hours after challenge: 72.0. Group: test group. Dose level: 10 ppm (0.001%). No with. + reactions: 2.0. Total no. in groups: 5.0. Clinical observations: 10 ppm (0.001%) induction, 100000 ppm (10%) challenge.

Reading:

other: BT challenge

Hours after challenge:

48

Group:

test chemical

Dose level:

1000 ppm (0.1%)

No. with + reactions:

5

Total no. in group:

5

Clinical observations:

1000 ppm (0.1%) induction and 100000 ppm (10%) challenge

Remarks on result:

other: Reading: other: BT challenge. . Hours after challenge: 48.0. Group: test group. Dose level: 1000 ppm (0.1%). No with. + reactions: 5.0. Total no. in groups: 5.0. Clinical observations: 1000 ppm (0.1%) induction and 100000 ppm (10%) challenge.

Reading:

rechallenge

Group:

positive control

Remarks on result:

positive indication of skin sensitisation

Remarks:

details were not specified.

Reading:

rechallenge

Group:

negative control

Remarks on result:

other: not specified

nDDSA is positive in three sensitization protocols. The minimum induction concentrations were 1 ppm or 0.0001% (GPMT), 10 ppm or 0.001% (APT) and 1000 ppm or 0.1% (BT) as measured at the challenge phase. Minimum rechallenge concentrations of nDDSA were 100 ppm or 0.01% (GMPT and APT) and 1000 ppm or 0.1% (BT).

LogP was estimated through CLOGP QSAR program to be 5.0

Chemical reactivity of nDDSA with 2-phenylethylamine was 100%. Reactivity for maleic anhydride was 100%, for 2,4 -dinitrochlorobenzene was 60% and for alpha-hexylcinnamic aldehyde was 10%.

Interpretation of results:

Category 1A (indication of significant skin sensitising potential) based on GHS criteria

Conclusions:

2-Dodecenyl-1-yl succinic anhydride (nDDSA) was tested in three standard sensitization protocols in guinea pigs, the guinea pig maximization test, adjuvant and patch test and Buehler test. The substance was positive in all three tests. The substance is classified as a dermal sensitizer, category 1A, according to Regulation EC No. 1272, 2008 and Regulation EU No. 286/2011. 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 (sensitising)

Additional information:

2-Dodecenyl-1-yl succinic anhydride, a member of a chemical category which includes octenyl succinic anhydride,was tested in three standard sensitisation protocols, the guinea pig maximization test, the adjuvant and patch test and Buehler test. The substance was positive in all three tests. The chemical reactivity of nDDSA with 2-phenylethylamine was also tested and found to be highly reactive. The log P was estimated to be 5.0. These data, taken altogether, suggest that nDDSA penetrates the skin and reacts readily with proteins containing amine groups. This may explain the sensitisation results observed.

A chemical category is established for alkenyl succinic anhydrides with C8-C12 alkenyl side chains, based on common functional groups, similar physico-chemical properties, common breakdown/metabolic products via physical and biological processes, and a constant pattern in the changing of the potency across the category.  These include tetrapropenyl succinic anhydride (CAS 26544-38-7), octenyl succinic anhydride (CAS 26680-54-6), n-dodecenyl succinic anhydride (CAS 19780-11-1) and tripropenyl succinic anhydride (CAS 28928-97-4). Common functional groups are a dihydro-2,5 -furandione (cyclic anhydride) ring, a carbon chain of length 8 to 12 carbons (with or without branching methyl groups), and one double bond in the carbon chain, location unspecified.   Common breakdown products are the dioic acids of the corresponding anhydride. A constant pattern may also be displayed in acute toxicity, dermal irritancy and biodegradation, with the lowest carbon chain length (C8) displaying the highest irritation potential in vivo and highest biodegradation potential. Irritation and degradation diminishes with increasing carbon chain length. Using the precautionary principle, all category members are classified as dermal sensitisers, so there is no variability in Classification and Labeling, or hazard assessment.

Migrated from Short description of key information:
2-Dodecenyl-1-yl succinic anhydride, a category member, was tested in three standard sensitisation protocols, the guinea pig maximization test, adjuvant and patch test and Buehler test. The substance was positive in all three tests.

Justification for selection of skin sensitisation endpoint:
scientifically valid study employing three standard sensitisation protocols

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information:

The vapour pressure of octenyl succinic anhydride is low, 43.5 Pa at 20 degrees C.

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 2,5 -furanedione 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 classification or non-classification

A category member, 2-Dodecenyl-1-yl succinic anhydride (nDDSA), was positive (sensitising) in three standard sensitisation protocols in guinea pigs, the guinea pig maximization test, adjuvant and patch test and Buehler test. All members of the C8 -C12 Alkenyl Succinic Anydrides, including octenyl succinic anhydride, are considered dermal sensitisers. This study meets the criteria for classification as a dermal sensitiser according to Regulation EC No. 1272, 2008.