Reaction products of furan-2,5-dione and octadec-1-ene

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics

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:

guideline study with acceptable restrictions

Justification for type of information:

This study was conducted on 2,5-furandione, dihydro-, mono-C15- 20-alkenyl derivatives (CAS 68784-12-3), an analogue substance used as the source of information for the assessment of the target substance through read-across. Therefore, this study is informative for evaluation of the environmental fate and toxicity of the target substance, Reaction products of furan-2,5-dione and octadec-1-ene (known here as n-ODSA EC 701-338-8; no CASRN available), and it is adequate for classification and risk assessment.

Reason / purpose for cross-reference:

read-across source

Objective of study:

toxicokinetics

Qualifier:

equivalent or similar to guideline

Guideline:

other: ECHA REACH Guidance R.7.12

Principles of method if other than guideline:

Paper based review of toxicokinetics

GLP compliance:

no

Non-human information

An experimental study on the toxicokinetics of ASA is not available.

Because ASA is an UVCB substance, model calculations have been done with an idealized molecule (ASA1, structure inserted, Smiles: C1(C(C=CCCCCC)CCCCCC)CC(=O)OC1=O) ) , which may be a component of ASA:

ASA1 as well as the other components of ASA is highly lipophilic. Calculation of the water solubility and the partition coefficient of ASA1, by EPISuite 4.0, results in a water solubility of 7.4 µg/L and a log P_owof 7.32. 

Absorption

Skin absorption

According to the skin permeability model of Fitzpatrick et. al. (2004) the model substance ASA1 is able to penetrate the skin. The result of the model calculation is confirmed with the observation of a skin sensitizing potential of ASA in the study according to Magnusson-Kligman (OECD 406).

 

Skin permeability according to Fitzpatrick et al. (2004)		Values
Chemical		ASA
Molecular weight of chemical	Mw (Da)	294.44
Logarithm octanol/water partition coefficient	logKow	7.32
Logarithm skin permeation coefficient	logKp	0.236594
Interpretation:		permeable
non-permeable	< -10
marginally permeable	< -06 >= -10
slightly permeable	< -03 >= -06
moderately permeable	< -01 >= -03
permeable	> = -01

 

Oral absorption

The combined repeated dose / reproductive toxicity study in the rat (OECD 422) showed in the top dose of 1000 mg/kg bw/day elevated levels of liver-derived enzymes in the plasma and at the top and lower doses signs of reduced maternal care. It is therefore concluded that ASA is absorbed and enters circulation following oral exposure.

Metabolism

An experimental study on the metabolism of ASA is not available.

It is considered that enzymatic hydrolysis of ASA is an early step in metabolism. Hydrolases (EC 3.6) are known to be present in the cells of the intestinal tract, in the plasma, the liver and other organs. The resulting alkenylated succinic acid is similar to (rare) naturally occurring fatty acids, alkylitaconates, which are known to be degraded in the liver (Ref [1]).

It is considered that the metabolic breakdown of alkenylated succinic acid occurs by the binding of CoA and subsequent release of Acetyl-CoA, which is used in many metabolic steps (e.g. fatty acid synthesis) or deg­radation in the citric acid cycle. The other resulting molecule is an unsaturated fatty acid, which in turn is degraded similar to natural fatty acids. 

 

Human information

No human information is available.

 

Summary and discussion of toxicokinetics

Experimental data on the toxicokinetics of ASA are not available. Based on observations made in repeated dose toxicity studies it is considered ASA is absorbed following oral exposure. Model calculation show that the substance is also absorbed following dermal exposure.

It is considered that ASA is metabolized and degraded similarly to fatty acids.

  

 

References

 

Fitzpatrick, D., Corish, J., Hayes, B. (2004). Modelling skin permeability in risk assessment – the future. Chemosphere 55 , 1309 –1314.

Adler, J. Shu-Fang Wang, AND Henry A. Lardy (1957): The metabolism of itaconic acid by liver mito­chon­dria. .J Biol Chem.1957 Dec;229(2):865-79. Available from:www.jbc.org/content/229/2/865.full.pdf

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results
Based on observations made in repeated dose toxicity studies on a structural analogue substance, 2,5-furandione, dihydro-,mono-C15-20-alkenyl deriv., it is considered that the substance is absorbed following oral exposure. Model calculations show that the substance is also absorbed following dermal exposure. It is considered that the test substance, and so by analogy, the target substance (n-ODSA EC 701-338-8), is metabolized and degraded similarly to fatty acids.

Reference 2

Endpoint:

basic toxicokinetics

Type of information:

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

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods

Justification for type of information:

This study was conducted on dodecenyl succinic anhydride (CAS 19780-11-1, also known as DDSA), one of several analogue substances used as the source of information for the assessment of the target substance through read-across. Therefore, this study is informative for evaluation of the environmental fate and toxicity of the target substance, Reaction products of furan-2,5-dione and octadec-1-ene (known here as n-ODSA EC 701-338-8; no CASRN available), and it is adequate for classification and risk assessment.

Reason / purpose for cross-reference:

read-across source

Objective of study:

toxicokinetics

Qualifier:

no guideline available

Principles of method if other than guideline:

Performed according to ECHA Technical Guidance, R.7. Information requirements and the chemical safety assessment, 2010.

GLP compliance:

no

Type:

metabolism

Results:

The substance readily hydrolyses, and the corresponding dicarboxylic acid is formed.

Details on absorption:

Upon oral exposure the ASA substances would be absorbed by the gastrointestinal tract. The structural and physical properties including comparatively high molecular weight, the presence of long carbon chains and sparing water solubility, is expected to reduce the rate and extent of dermal absorption, thus dermal absorption rate is likely low. A high boiling point, low vapor pressure, and high viscosity suggests the substance would have a low propensity to form vapors or aerosols, so the inhalation absorption rate is also likely low.

Details on distribution in tissues:

Following absorption, distribution can occur to highly perfused organs such as the kidney. The lack of target organ toxicity other than the kidney is an indication that this substance is not widely distributed in the body.

Details on excretion:

The substance is sparingly water soluble, rapidly hydrolytically degraded to dicarboxylic acids, and based on excretion data for other acid anhydrides, is eliminated quickly with a half time that would indicate little bioaccumulation potential.

Details on metabolites:

The substance reacts easily with water (hydrolysis), and the corresponding dicarboxylic acid ester is formed. The formation of acid explains the irritating effects on the skin and the mucous membranes of the eyes. Acid anhydride groups react readily with amino acids and this reaction explains their conjugation with human serum albumin an explains the irritating effects in the forestomach after oral administration. In an Ames assay, metabolic activation with rat liver enzymes does not result in formation of metabolites which are mutagenetic.

Alkenyl succinic anhydride compounds are viscous liquid or semisolid substances with low octanol/water partition coefficients and sparingly soluble to insoluble water solubilities. These characteristics indicate that alkenyl succinic anhydrides are slightly lipophilic, and thus, capable of passive diffusion across biological membranes. ASA compounds are also hydrolytically unstable and the resulting species are known to react with proteins. Thus it can be predicted that upon oral exposure these chemical substances would be absorbed by the gastrointestinal tract with an absorption rate >50%. The structural and physical properties of each compound including comparatively high molecular weight, the presence of long-chain moieties and sparing water solubility, is expected to reduce the rate and extent of dermal absorption, thus the dermal absorption rate is likely <10%. The alkenyl succinic anhydrides have relatively high boiling points, low vapor pressure, and are viscous liquids and thus have a low propensity to form vapors or aerosols, therefore exposure via inhalation is not likely and the inhalation absorption rate is also likely < 10%. Following absorption distribution can occur to highly perfused organs such as the kidney. The lack of target organ toxicity other than the kidney is an indication that members of the ASA category are not widely distributed in the body. Alkenyl succinic anhydrides are hydrolyzed to dicarboxylic acids and excreted in urine as the corresponding acids. While ASA compounds are sparingly water soluble, they hydrolytically degrade to dicarboxylic acid esters and based on excretion data for other acid anhydrides are eliminated with a half time that would indicate little bioaccumulation potential.

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
This analogue substance has low water solubility, a moderate octanol/water partition coefficient, and low vapour pressure. It is rapidly hydrolyzed (within minutes) to the corresponding butanedioic acid. The substance may be absorbed from the gastrointestinal tract, but dermal and inhalation absorption are low. Distribution may occur to highly perfused organs, but a lack of target organ toxicity (other than kidney) for tripropenyl succinic anhydride indicates that the substance is not widely distributed in the body. Reactivity of the hydrolysed substance likely occurs in the local environment. The substance is excreted in the urine as the corresponding acid with a half-life that would indicate little bioaccumulation potential. These data, specific for a structural analogue, are applicable for the target substance.

Reference 3

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Objective of study:

toxicokinetics

Qualifier:

equivalent or similar to guideline

Guideline:

other: ECHA REACH Guidance R.7.12

Principles of method if other than guideline:

Paper based review of toxicokinetics

GLP compliance:

no

Non-human information

An experimental study on the toxicokinetics of ASA is not available.

Because ASA is an UVCB substance, model calculations have been done with an idealized molecule (ASA1, structure inserted, Smiles: C1(C(C=CCCCCC)CCCCCC)CC(=O)OC1=O) ) , which may be a component of ASA:

ASA1 as well as the other components of ASA is highly lipophilic. Calculation of the water solubility and the partition coefficient of ASA1, by EPISuite 4.0, results in a water solubility of 7.4 µg/L and a log P_owof 7.32. 

Absorption

Skin absorption

According to the skin permeability model of Fitzpatrick et. al. (2004) the model substance ASA1 is able to penetrate the skin. The result of the model calculation is confirmed with the observation of a skin sensitizing potential of ASA in the study according to Magnusson-Kligman (OECD 406).

 

Skin permeability according to Fitzpatrick et al. (2004)		Values
Chemical		ASA
Molecular weight of chemical	Mw (Da)	294.44
Logarithm octanol/water partition coefficient	logKow	7.32
Logarithm skin permeation coefficient	logKp	0.236594
Interpretation:		permeable
non-permeable	< -10
marginally permeable	< -06 >= -10
slightly permeable	< -03 >= -06
moderately permeable	< -01 >= -03
permeable	> = -01

 

Oral absorption

The combined repeated dose / reproductive toxicity study in the rat (OECD 422) showed in the top dose of 1000 mg/kg bw/day elevated levels of liver-derived enzymes in the plasma and at the top and lower doses signs of reduced maternal care. It is therefore concluded that ASA is absorbed and enters circulation following oral exposure.

Metabolism

An experimental study on the metabolism of ASA is not available.

It is considered that enzymatic hydrolysis of ASA is an early step in metabolism. Hydrolases (EC 3.6) are known to be present in the cells of the intestinal tract, in the plasma, the liver and other organs. The resulting alkenylated succinic acid is similar to (rare) naturally occurring fatty acids, alkylitaconates, which are known to be degraded in the liver (Ref [1]).

It is considered that the metabolic breakdown of alkenylated succinic acid occurs by the binding of CoA and subsequent release of Acetyl-CoA, which is used in many metabolic steps (e.g. fatty acid synthesis) or deg­radation in the citric acid cycle. The other resulting molecule is an unsaturated fatty acid, which in turn is degraded similar to natural fatty acids. 

 

Human information

No human information is available.

 

Summary and discussion of toxicokinetics

Experimental data on the toxicokinetics of ASA are not available. Based on observations made in repeated dose toxicity studies it is considered ASA is absorbed following oral exposure. Model calculation show that the substance is also absorbed following dermal exposure.

It is considered that ASA is metabolized and degraded similarly to fatty acids.

  

 

References

 

Fitzpatrick, D., Corish, J., Hayes, B. (2004). Modelling skin permeability in risk assessment – the future. Chemosphere 55 , 1309 –1314.

Adler, J. Shu-Fang Wang, AND Henry A. Lardy (1957): The metabolism of itaconic acid by liver mito­chon­dria. .J Biol Chem.1957 Dec;229(2):865-79. Available from:www.jbc.org/content/229/2/865.full.pdf

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results
Based on observations made in repeated dose toxicity studies, it is considered that the substance is absorbed following oral exposure. Model calculations show that the substance is also absorbed following dermal exposure. It is considered that ASA is metabolized and degraded similarly to fatty acids.

Reference 4

Endpoint:

basic toxicokinetics

Type of information:

other: paper-based review of toxicokinetics

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods

Justification for type of information:

Performed according to ECHA Technical Guidance, R.7. Information requirements and the chemical safety assessment, 2010.

Objective of study:

toxicokinetics

Qualifier:

no guideline available

Principles of method if other than guideline:

Performed according to ECHA Technical Guidance, R.7. Information requirements and the chemical safety assessment, 2010.

GLP compliance:

no

Specific details on test material used for the study:

n-DDSA, along with other category members such as C-8 ASA and TPSA. The primary functional group is the succinic anhydride (2,5-furandione, dihydro), acknowledging the shorter carbon chains attached.

Type:

metabolism

Results:

The substance readily hydrolyses, and the corresponding dicarboxylic acid is formed.

Details on absorption:

Upon oral exposure the ASA substances would be absorbed by the gastrointestinal tract. The structural and physical properties including comparatively high molecular weight, the presence of long carbon chains and sparing water solubility, is expected to reduce the rate and extent of dermal absorption, thus dermal absorption rate is likely low. A high boiling point, low vapor pressure, and high viscosity suggests the substance would have a low propensity to form vapors or aerosols, so the inhalation absorption rate is also likely low.

Details on distribution in tissues:

Following absorption, distribution can occur to highly perfused organs such as the kidney. The lack of target organ toxicity other than the kidney is an indication that this substance is not widely distributed in the body.

Details on excretion:

The substance is sparingly water soluble, rapidly hydrolytically degraded to dicarboxylic acids, and based on excretion data for other acid anhydrides, is eliminated quickly with a half time that would indicate little bioaccumulation potential.

Details on metabolites:

The substance reacts easily with water (hydrolysis), and the corresponding dicarboxylic acid ester is formed. The formation of acid explains the irritating effects on the skin and the mucous membranes of the eyes. Acid anhydride groups react readily with amino acids and this reaction explains their conjugation with human serum albumin an explains the irritating effects in the forestomach after oral administration. In an Ames assay, metabolic activation with rat liver enzymes does not result in formation of metabolites which are mutagenetic.

Alkenyl succinic anhydride compounds are viscous liquid or semisolid substances with low octanol/water partition coefficients and sparingly soluble to insoluble water solubilities. These characteristics indicate that alkenyl succinic anhydrides are slightly lipophilic, and thus, capable of passive diffusion across biological membranes. ASA compounds are also hydrolytically unstable and the resulting species are known to react with proteins. Thus it can be predicted that upon oral exposure these chemical substances would be absorbed by the gastrointestinal tract with an absorption rate >50%. The structural and physical properties of each compound including comparatively high molecular weight, the presence of long-chain moieties and sparing water solubility, is expected to reduce the rate and extent of dermal absorption, thus the dermal absorption rate is likely <10%. The alkenyl succinic anhydrides have relatively high boiling points, low vapor pressure, and are viscous liquids and thus have a low propensity to form vapors or aerosols, therefore exposure via inhalation is not likely and the inhalation absorption rate is also likely < 10%. Following absorption distribution can occur to highly perfused organs such as the kidney. The lack of target organ toxicity other than the kidney is an indication that members of the ASA category are not widely distributed in the body. Alkenyl succinic anhydrides are hydrolyzed to dicarboxylic acids and excreted in urine as the corresponding acids. While ASA compounds are sparingly water soluble, they hydrolytically degrade to dicarboxylic acid esters and based on excretion data for other acid anhydrides are eliminated with a half time that would indicate little bioaccumulation potential.

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
This substance has low water solubility, a moderate octanol/water partition coefficient, and low vapour pressure. It is rapidly hydrolyzed (within minutes) to the corresponding butanedioic acid. The substance may be absorbed from the gastrointestinal tract, but dermal and inhalation absorption are low. Distribution may occur to highly perfused organs, but a lack of target organ toxicity (other than kidney) for tripropenyl succinic anhydride indicates that the substance is not widely distributed in the body. Reactivity of the hydrolysed substance likely occurs in the local environment. The substance is excreted in the urine as the corresponding acid with a half-life that would indicate little bioaccumulation potential.

Description of key information

n-ODSA and other alkenyl succinic anhydrides are rapidly hydrolysed and further metabolised enzymatically.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

10

Additional information

This information is from the substance 2,5-furandione, dihydro-,mono-C15-20-alkenylderivatives (CAS 68784-12-3, a mixture of a hexadecenyl- and octadecenyl succinic anhydrides), an analogue used for the assessment of several endpoints through read-across. The hypothesis for read-across between the substance being registered (Reaction products of furan-2,5-dione and octadec-1-ene; known here asn-ODSA EC 701-338-8; no CASRN available), and the analogue substance is a common functional group: a 2,5-furandione, dihydro- structure, also known as a succinic anhydride, to which is attached a long-chain monounsaturated olefin. In the environment, the anhydride moiety is quickly hydrolysed to form a dioic acid.  When the substance to be registered and the analogue substance are compared, changes in the purity of the starting olefin stock, or small differences in the length (between sixteen and twenty) or arrangement (linear or branched) of the carbon chain are not anticipated to significantly affect the environmental fate properties or the toxicity of the substances. For each endpoint study based upon read-across, the analogue approach is substantiated by an evaluation provided in the Analogue Approach Report Format (AARF) attached to the endpoint study summary file. The AARF allows the read-across information to fulfil the information requirements of the REACH Annexes VII-X, to be the basis for classification and labelling decisions, and for risk assessment.