Fumaric acid

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result:

Information regarding the distribution of fumaric acid is available from an older published study (Marshall et al, 1948). These data, combined with the role of fumaric acid in mammalian metabolism and its long history of safe therapeutic use (SCAN, 2003; JECFA, 1999), provide sufficient toxicological information such that additional testing in animals is not necessary.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Information regarding the distribution of fumaric acid in the rat and its role in mammalian metabolism is available in the published literature. Average concentrations in the blood, brain tissue, kidney tissue, liver and muscle were 3 mg/L, 150 mg/kg, 95 mg/kg, 78 mg/kg, and 23 mg/kg, respectively. Fumaric acid plays an essential role in aerobic respiration and has a long history of safe use as a human therapeutic agent. The European Commission's Scientific Committee for Animal Nutrition stated that a dose of 0.9g fumaric acid equivalent per day was considered safe for humans. The Joint FAO/WHO Committee on Food Additives concluded that there is no safety concern at current levels of intake when fumaric acid is used as a flavouring agent. Based on the available data, fumaric acid is of low concern for toxicity and additional toxicokinetic testing is not required.

Fumaric acid is an organic dicarboxylic acid (C4H4O4). Fumaric acid occurs naturally in the metabolism. It plays a role in the tricarboxylic cycle (TCA cycle) and in the carry over of the amino-N from aspartate. Succinate (acetyl-CoA and oxaloacetate are synthetised to citrate, which is -by multiple steps - converted to succinate) is oxidised to fumarate. Succinate also enters as succinyl-CoA the TCA-cycle as a conversion product of the glucogenic amino acids methionine, isoleucine and valine. The glucogenic amino acids phenylalanine and tyrosine enter the TCA cycle at the stage of fumarate. Fumarate is further converted to malate (by saturation of the double bond). Hydration of fumaric acid is one means of producing malic acid (consequently some information is used as read-across for the similar fumaric acid). Oxidation of malate produces oxaloacetate. By transamination oxaloacetate is in a reversible equilibirum with aspartate. Malate is also important outside the TCA cycle ((i) as a shuttle of reducing equivalents (NADH) from cytoplasm into mitochondria, (ii) it can be converted in the cytoplasm to pyruvate (NADPH source by malic enzyme) and (iii) as a precursor of cytoplasmic synthesis of fatty acids). Aspartate is used for protein synthesis and as a precursor of the pyrimidine bases (the carbon skeleton is used for Uracil, Thymine and Cytosine) and the purine bases (Adenosine and Guanine contain the N1 from amino-N-aspartate and another amino group from aspartate on the C6 of Adenosine). Fumarate results from the the carry over of the aspartate-amino-N via succinate. By the same kind of reaction fumarate also results from the urea cycle in the (periportal) hepatocytes. Citrulline and aspartate form arginino-succinate, which is in turn converted to arginine and fumarate. This reaction is reversible. Aspartate can again be resynthesised from fumarate via malate and oxaloacetate. The urea cycle leads also to binding and excretion of bicarbonate and takes therefore part in the regulation of the acid-base-equilibrium. Urea formation is reduced if pH and/or the HCO3 - concentration in the extracellular space decrease. The resulting increase in ammonia concentration is compensated by ammonia fixation as glutamin (in perivenous hepatocytes). Fumarate results also from the degradation of the amino acid tyrosine (hydroxyphenylalanine). Tyrosine serves as a precursor of several syntheses (melanine (a pigment in skin and hair), dopamine and the catecholamines (hormones of the perineal glands), thyroid hormones and probably ubiquinone).

Discussion on bioaccumulation potential result:

Fumaric acid is an organic dicarboxylic acid (C4H4O4). Fumaric acid occurs naturally in the metabolism. It plays a role in the tricarboxylic cycle (TCA cycle) and in the carry over of the amino-N from aspartate.

Succinate (acetyl-CoA and oxaloacetate are synthetised to citrate, which is -by multiple steps - converted to succinate) is oxidised to fumarate. Succinate also enters as succinyl-CoA the TCA-cycle as a conversion product of the glucogenic amino acids methionine, isoleucine and valine. The glucogenic amino acids phenylalanine and tyrosine enter the TCA cycle at the stage of fumarate. Fumarate is further converted to malate (by saturation of the double bond). Hydration of fumaric acid is one means of producing malic acid (consequently some information is used as read-across for the similar fumaric acid). Oxidation of malate produces oxaloacetate. By transamination oxaloacetate is in a reversible equilibirum with aspartate. Malate is also important outside the TCA cycle ((i) as a shuttle of reducing equivalents (NADH) from cytoplasm into mitochondria, (ii) it can be converted in the cytoplasm to pyruvate (NADPH source by malic enzyme) and (iii) as a precursor of cytoplasmic synthesis of fatty acids). Aspartate is used for protein synthesis and as a precursor of the pyrimidine bases (the carbon skeleton is used for Uracil, Thymine and Cytosine) and the purine bases (Adenosine and Guanine contain the N1 from amino-N-aspartate and another amino group from aspartate on the C6 of Adenosine). Fumarate results from the the carry over of the aspartate-amino-N via succinate. By the same kind of reaction fumarate also results from the urea cycle in the (periportal) hepatocytes. Citrulline and aspartate form arginino-succinate, which is in turn converted to arginine and fumarate. This reaction is reversible. Aspartate can again be resynthesised from fumarate via malate and oxaloacetate. The urea cycle leads also to binding and excretion of bicarbonate and takes therefore part in the regulation of the acid-base-equilibrium. Urea formation is reduced if pH and/or the HCO3 - concentration in the extracellular space decrease. The resulting increase in ammonia concentration is compensated by ammonia fixation as glutamin (in perivenous hepatocytes). Fumarate results also from the degradation of the amino acid tyrosine (hydroxyphenylalanine). Tyrosine serves as a precursor of several syntheses (melanine (a pigment in skin and hair), dopamine and the catecholamines (hormones of the perineal glands), thyroid hormones and probably ubiquinone).

Information regarding the distribution of fumaric acid is available from an older published study (Marshall et al, 1948). These data, combined with the role of fumaric acid in mammalian metabolism and its long history of safe therapeutic use (SCAN, 2003; JECFA, 1999), provide sufficient toxicological information such that additional testing in animals is not necessary.