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

Basic toxicokinetics

Administrative data

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

Data source

Reference

Reference Type:

other: expert statement

Title:

No information

Author:

Dollenmeier P

Year:

2010

Materials and methods

Objective of study:

toxicokinetics

Test guideline

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

Test material

Test material information

Constituent 1

Reference substance name:

2,5-Furandione, dihydro-, mono-C15-20-alkenyl derivs.

EC Number:

272-221-2

EC Name:

2,5-Furandione, dihydro-, mono-C15-20-alkenyl derivs.

Cas Number:

68784-12-3

Molecular formula:

Due to a mixture of numerous isomers a specific molecular formular cannot be provided ( UVCB-substance) .

IUPAC Name:

2,5-Furandione, dihydro-, mono-C15-20-alkenyl derivs.

Results and discussion

Any other information on results incl. tables

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

Applicant's summary and conclusion

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.