Dimethyl succinate

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result:

Basic information on toxicokinetics has been compiled from available information.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

9

Additional information

Dimethyl succinate is an approved food additive/flavouring agent (JECFA 616, FEMA 2396) and, 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 absorption, metabolism and elimination show that the evaluated substances are readily absorbed, hydrolysed and are completely metabolised. Many of the substances or their metabolites are endogenous in humans. Mono-esters and di-esters (such as dimethyl succinate) 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. 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).

Absorption

Dimethyl succinate has been shown to be rapidly absorbed via the digestive tract of rats (Malaisse-Lagae et.al. (1994). Arch. Int. Pharmacodyn.328: 235-242). There are no quantitative data on dermal absorption although modelling suggests approximately 9% of dermally applied dimethyl succinate my be absorbed. The inhaled substance is deposited in the upper respiratory tract, one study demonstrating >97% deposition (Morris et.al. (1991).Toxicol. Appl. Pharmacol.108: 538 -546).

Metabolism and excretion

Dimethyl succinate is metabolised by hydrolysis and is able to form the corresponding monomethyl ester, dicarboxylic acid and methanol. This has been demonstrated both in-vitro with tissue homogenates, nasal explants and isolated cells and in-vivo in rats. In rats, the inhaled ester is rapidly hydrolysed by carboxylesterases, this occurring mainly in the upper airways, particularly the olfactory epithelium, and the liver. A structure-activity relationship has been observed in the rate of hydrolysis with dimethyl succinate being the slowest of 3 esters examined (dimethyl succinate, dimethyl adipate and dimethyl glutarate) to be hydrolysed. The activity of carboxylesterase in olfactory epithelium from humans has been reported to be 100 to 1000 times lower than that of rats (Kee et.al. (1989). Toxicologist 9: 284). A metabolite of dimethyl succinate, succinic acid, is an endogenous metabolite in the body and is a component of the Krebs cycle (Voet, D. & Voet, J.G., eds. (1990)  Biochemistry, New York: John Wiley & Sons, pp. 506-527, 632-633, 690).