Diethyl succinate

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

90

Absorption rate - dermal (%):

3

Additional information

According to JECFA (JECFA, 2000. Evaluation of certain food additives and contaminants. Fifty-third meeting of the Joint FAO/WHO Expert Committee on Food Additives. WHO Technical Report Series no. 896., 1–10 June 1999 and JECFA, 2002. Evaluation of certain food additives and contaminants. Fifty-seventh report of the Joint FAO/WHO Expert Committee on Food Additives. WHO Technical Report Series, no. 909. Geneva, 5–14 June 2001), studies on the absorption, metabolism and elimination of aliphatic primary alcohols, aldehydes, carboxylic acids, acetals and esters with additional oxygenated functional groups show that these substances are readily hydrolysed and absorbed and are completely metabolized.

 

Many of these substances or their metabolites are endogenous in humans. Mono-esters (ethyl acetoacetate, ethyl 4-oxovalerate and aliphatic esters of lactic acid) and di-esters (diethyl succinate and diethyl malonate) are expected to undergo hydrolysis in humans to yield their corresponding alcohol and acid components (i.e. β- or γ-keto or α-hydroxy acids; or diacids), which would be further metabolised and excreted through the common pathways of detoxication of aliphatic alcohols and carboxylic acids.

 

JECFA stated also that the presence of a second oxygenated functional group has little if any effect on hydrolysis of these esters.

 

Hydrolysis is catalysed by classes of enzymes recognised as carboxylesterases or esterases (Heymann E, 1980. Carboxylesterases and amidases. In: Jakoby WB (Ed.). Enzymatic basis of detoxication. 2nd Ed. Academic Press,, pp. 291–323), the most important of which are the β-esterases (Heymann, 1980; Anders, 1989).

 

Acetyl esters are the preferred substrates of C-esterases (Heymann, 1980). Mammalian carboxylesterases represent a multigene family and play an important role in the hydrolytic biotransformation of a vast number of structurally diverse drugs (Satoh and Hosokawa 1998). Carboxylesterase activity also plays a significant role in detoxification processes in fish (Di Giulio, R. T.; Hinton, D. E. (2008): The toxicology of fishes.: CRC Press; Tocher D R, 2003. Metabolism and Functions of Lipids and Fatty Acids in Teleost Fish. In: Reviews in Fisheries Science, Vol.11, No. 2, pp. 107–184) as well as in birds (Beasley V, 1999. Absorption, Distribution, Metabolism, and Elimination: Differences Among Species. In: Veterinary Toxicology). The most probable metabolic reactions of the hydrolysis products are: oxidation of alcohols to aldehydes and acids; conjugations of alcohols and acids to glucuronides and sulphates; β-oxidation of carboxylic acids; ω-oxidation of carboxylic acids.

 

β-Keto acids and derivatives like acetoacetic acid undergo decarboxylation. Along with α-keto and α-hydroxyacids (lactic acid), they yield breakdown products, which are incorporated into normal biochemical pathways. The γ-keto-acids and related substances (4-oxovaleric acid) may undergo complete or partial β-oxidation to yield metabolites that are eliminated in the urine. Simple aliphatic di-carboxylic acids (succinic acid and fumaric acid) and their precursors (2-oxopropanal) are metabolised in the fatty acid β-oxidation pathway or tricarboxylic acid cycle (EFSA Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food (AFC), 2009. Scientific Opinion on Flavouring Group Evaluation 10, Revision 1 (FGE.10Rev1). Aliphatic primary and secondary saturated and unsaturated alcohols, aldehydes, acetals, carboxylic acids and esters containing an additional oxygenated functional group and lactones from chemical group 9,13 and 30. EFSA Journal, ON-934, 1–114).