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Fumaric acid
Skeletal formula of fumaric acid
Skeletal formula of fumaric acid
Ball-and-stick model of the fumaric acid molecule
Ball-and-stick model of the fumaric acid molecule
Names
Preferred IUPAC name
(2E)-But-2-enedioic acid
Other names
  • Fumaric acid
  • trans-1,2-Ethylenedicarboxylic acid
  • 2-Butenedioic acid
  • trans-Butenedioic acid
  • Allomaleic acid
  • Boletic acid
  • Donitic acid
  • Lichenic acid
Identifiers
3D model (JSmol)
605763
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.003.404 Edit this at Wikidata
EC Number
  • 203-743-0
E number E297 (preservatives)
49855
KEGG
RTECS number
  • LS9625000
UNII
UN number 9126
  • InChI=1S/C4H4O4/c5-3(6)1-2-4(7)8/h1-2H,(H,5,6)(H,7,8)/b2-1+ checkY
    Key: VZCYOOQTPOCHFL-OWOJBTEDSA-N checkY
  • InChI=1/C4H4O4/c5-3(6)1-2-4(7)8/h1-2H,(H,5,6)(H,7,8)/b2-1+
    Key: VZCYOOQTPOCHFL-OWOJBTEDBF
  • C(=C/C(=O)O)\C(=O)O
Properties
C4H4O4
Molar mass 116.072 g·mol−1
Appearance White solid
Density 1.635 g/cm3
Melting point 287 °C (549 °F; 560 K) (decomposes)[2]
6.3 g/L at 25 °C[1]
Acidity (pKa) pka1 = 3.03, pka2 = 4.44 (15 °C, cis isomer)
−49.11·10−6 cm3/mol
non zero
Pharmacology
D05AX01 (WHO)
Hazards
GHS labelling:
GHS07: Exclamation mark
Warning
H319
P264, P280, P305+P351+P338, P313
NFPA 704 (fire diamond)
NFPA 704 four-colored diamondHealth 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g. chloroformFlammability 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
2
1
0
375 °C (707 °F; 648 K)
Related compounds
Related compounds
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

Fumaric acid or trans-butenedioic acid is an organic compound with the formula HO2CCH=CHCO2H. A white solid, fumaric acid occurs widely in nature. It has a fruit-like taste and has been used as a food additive. Its E number is E297.[3] The salts and esters are known as fumarates. Fumarate can also refer to the C
4H
2O2−
4 ion (in solution). Fumaric acid is the trans isomer of butenedioic acid, while maleic acid is the cis isomer.

Biosynthesis and occurrence

[edit]

It is produced in eukaryotic organisms from succinate in complex 2 of the electron transport chain via the enzyme succinate dehydrogenase.

Fumaric acid is found in fumitory (Fumaria officinalis), bolete mushrooms (specifically Boletus fomentarius var. pseudo-igniarius), lichen, and Iceland moss.

Fumarate is an intermediate in the citric acid cycle used by cells to produce energy in the form of adenosine triphosphate (ATP) from food. It is formed by the oxidation of succinate by the enzyme succinate dehydrogenase. Fumarate is then converted by the enzyme fumarase to malate.

Human skin naturally produces fumaric acid when exposed to sunlight.[4][5]

Fumarate is also a product of the urea cycle.

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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TCACycle_WP78Go to articleGo to articleGo to articleGo to articleGo to HMDBGo to articleGo to articleGo to articleGo to HMDBGo to HMDBGo to articleGo to WikiPathwaysGo to articleGo to articleGo to articleGo to WikiPathwaysGo to articleGo to articleGo to articleGo to articleGo to articleGo to articleGo to articleGo to articleGo to articleGo to articleGo to articleGo to articleGo to articleGo to articleGo to articleGo to articleGo to articleGo to articleGo to articleGo to WikiPathwaysGo to articleGo to articleGo to articleGo to HMDBGo to articleGo to articleGo to articleGo to articleGo to articleGo to WikiPathwaysGo to articleGo to WikiPathwaysGo to HMDBGo to articleGo to WikiPathwaysGo to articleGo to HMDBGo to articleGo to articleGo to articleGo to articleGo to articleGo to articleGo to articleGo to articleGo to articleGo to article
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TCACycle_WP78 edit
  1. ^ The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78".

Uses

[edit]

Food

[edit]

Fumaric acid has been used as a food acidulant since 1946. It is approved for use as a food additive in the EU,[6] USA[7] and Australia and New Zealand.[8] As a food additive, it is used as an acidity regulator and can be denoted by the E number E297. It is generally used in beverages and baking powders for which requirements are placed on purity. Fumaric acid is used in the making of wheat tortillas as a food preservative and as the acid in leavening.[9] It is generally used as a substitute for tartaric acid and occasionally in place of citric acid, at a rate of 1 g of fumaric acid to every ~1.5 g of citric acid, in order to add sourness, similarly to the way malic acid is used. As well as being a component of some artificial vinegar flavors, such as "Salt and Vinegar" flavored potato chips,[10] it is also used as a coagulant in stove-top pudding mixes.

The European Commission Scientific Committee on Animal Nutrition, part of DG Health, found in 2014 that fumaric acid is "practically non-toxic" but high doses are probably nephrotoxic after long-term use.[11]

Medicine

[edit]

Fumaric acid was developed as a medicine to treat the autoimmune condition psoriasis in the 1950s in Germany as a tablet containing 3 esters, primarily dimethyl fumarate, and marketed as Fumaderm by Biogen Idec in Europe. Biogen would later go on to develop the main ester, dimethyl fumarate, as a treatment for multiple sclerosis.

In patients with relapsing-remitting multiple sclerosis, the ester dimethyl fumarate (BG-12, Biogen) significantly reduced relapse and disability progression in a phase 3 trial. It activates the Nrf2 antioxidant response pathway, the primary cellular defense against the cytotoxic effects of oxidative stress.[12]

Other uses

[edit]

Fumaric acid is used in the manufacture of polyester resins and polyhydric alcohols and as a mordant for dyes.

Fumaric acid can be used to make 6-methylcoumarin.[13]

When fumaric acid is added to their feed, lambs produce up to 70% less methane during digestion.[14]

Synthesis

[edit]

Fumaric acid is produced based on catalytic isomerisation of maleic acid in aqueous solutions at low pH. It precipitates from the reaction solution. Maleic acid is accessible in large volumes as a hydrolysis product of maleic anhydride, produced by catalytic oxidation of benzene or butane.[3]

Historic and laboratory routes

[edit]

Fumaric acid was first prepared from succinic acid.[15] A traditional synthesis involves oxidation of furfural (from the processing of maize) using chlorate in the presence of a vanadium-based catalyst.[16]

Reactions

[edit]

The chemical properties of fumaric acid can be anticipated from its component functional groups. This weak acid forms a diester, it undergoes bromination across the double bond,[17] and it is a good dienophile.

Safety

[edit]

The oral LD50 is 10 g/kg.[3]

See also

[edit]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Fumaric acid

View on Grokipedia
from Grokipedia
Fumaric acid is an classified as a , with the chemical formula C₄H₄O₄ and a molecular weight of 116.07 g/mol. It exists as the trans (E) isomer of but-2-enedioic acid, appearing as a white crystalline powder that is slightly soluble in water (approximately 5 g/L at 20°C) and more soluble in , with a of 287°C where it decomposes. Naturally occurring in plants such as —from which it derives its name—this acid plays a crucial role as an intermediate in the (citric acid cycle), where it is formed from succinate via and hydrated to malate by , facilitating cellular energy production through aerobic respiration. Industrially, fumaric acid is primarily produced through the catalytic of in aqueous solutions at low , often using mineral acids or peroxy compounds, yielding a product that precipitates directly from the reaction mixture. Alternative biotechnological methods involve using fungi like species on substrates such as glucose or (e.g., ), offering a more sustainable "green" production route amid growing environmental concerns. These processes have scaled up significantly, with global demand driven by its versatility, though routes remain dominant due to cost efficiency. Fumaric acid finds extensive applications across multiple sectors, serving as a (E297 in the ) for acidification, preservation, and flavor enhancement in products like beverages, candies, and baked goods, where it is recognized as GRAS by the FDA and used at levels up to 3,600 ppm. In industry, it is a key raw material for unsaturated resins used in paints, coatings, and composites, as well as in resins, inks, and , where it lowers reaction temperatures and improves product performance. Additionally, it appears in pharmaceuticals as a buffering agent and in as an to promote growth. Safety profiles indicate low (oral LD50 in rats: 9,300–10,700 mg/kg), though it can irritate eyes and skin.

Introduction and Properties

Chemical Structure and Nomenclature

Fumaric acid is an with the molecular formula C₄H₄O₄ (molecular weight 116.07 g/mol) and the HOOC-CH=CH-COOH, featuring a carbon-carbon in the trans () configuration. This trans arrangement positions the two groups on opposite sides of the , contributing to its distinct geometric isomerism. The IUPAC name for fumaric acid is (E)-but-2-enedioic acid, reflecting its systematic nomenclature as a of butenedioic acid with specified . It is commonly known as fumaric acid, a name derived from its historical isolation from the fumitory plant () in the 19th century. Other synonyms include trans-butenedioic acid and allomaleic acid, emphasizing its relation to the broader class of dicarboxylic acids. Fumaric acid exists as the trans of butenedioic acid, in contrast to its cis counterpart, , which has the carboxylic groups on the same side of the . The trans configuration of fumaric acid imparts greater thermodynamic stability compared to , primarily due to a lower dipole moment that minimizes molecular polarity and intramolecular repulsion. This stability difference influences their respective reactivities and applications, with fumaric acid being the preferred form in many industrial and biological contexts.

Physical and Chemical Properties

Fumaric acid appears as a crystalline solid, often in the form of odorless powder or granules. It has a of 287 °C, at which it sublimes without fully liquefying. The of the solid is 1.635 g/cm³ at 20 °C. Fumaric acid exhibits low in , approximately 6.3 g/L at 25 °C, but shows higher solubility in alcohols such as (5.76 g/100 g at 30 °C).
PropertyValueConditions
AppearanceWhite crystalline solid
Melting point287 (sublimes)-
Density1.635 g/cm³20
Solubility in water6.3 g/L25
Solubility in ethanol5.76 g/100 g30
As a , fumaric acid dissociates in two steps with pKa values of 3.03 and 4.44 at 25 , reflecting its moderately weak acidity. Its trans configuration imparts a dipole moment of 0 D due to , and the molecule is achiral, resulting in optical inactivity. Infrared spectroscopy of fumaric acid reveals characteristic absorption peaks for the carbonyl (C=O) stretch at approximately 1700 cm⁻¹ and the (C=C) stretch at 1640 cm⁻¹, confirming the presence of and carbon-carbon double bond functionalities. (¹H NMR) shows the alkene protons as a singlet around 6.6 ppm in typical solvents like DMSO-d₆. Upon heating above 200 °C, fumaric acid undergoes thermal decomposition, primarily forming maleic anhydride through dehydration.

Natural Occurrence and Biosynthesis

Biological Role

Fumaric acid serves as a key intermediate in the tricarboxylic acid (TCA) cycle, also known as the Krebs or citric acid cycle, where it is formed from the oxidation of succinate by the enzyme succinate dehydrogenase (EC 1.3.5.1). This reaction is coupled to the reduction of flavin adenine dinucleotide (FAD) and occurs within the mitochondrial inner membrane as part of complex II of the electron transport chain. The balanced equation for this step is: Succinate+FAD→Fumarate+FADH2\text{Succinate} + \text{FAD} \rightarrow \text{Fumarate} + \text{FADH}_2 Fumarate is then reversibly hydrated to L-malate by fumarase (EC 4.2.1.2), facilitating the cycle's progression toward oxaloacetate regeneration. Through its position in the TCA cycle, fumaric acid contributes to cellular energy production by enabling the generation of reducing equivalents (FADH₂ and NADH) that drive oxidative phosphorylation and ATP synthesis. Additionally, fumarate participates in anaplerotic reactions that replenish TCA cycle intermediates depleted for biosynthetic purposes, such as gluconeogenesis or amino acid synthesis, thereby maintaining metabolic flux and redox balance. Disruptions in fumarate metabolism, particularly deficiencies in fumarase activity, lead to fumarase deficiency syndrome (also known as fumaric aciduria), a rare autosomal recessive disorder characterized by severe neurological impairment, developmental delays, and elevated urinary fumarate levels due to impaired conversion to malate. In plants, fumaric acid is biosynthesized primarily through the mitochondrial TCA cycle via , mirroring its role in other eukaryotes, and accumulates as a storage form of fixed carbon, particularly in the where it supports acclimation to environmental stresses like low temperature. expresses two fumarase isoforms—one mitochondrial and one cytosolic—enabling compartmentalized regulation of fumarate levels for energy provision and osmotic adjustment.

Natural Sources

Fumaric acid occurs naturally in several plants, particularly in high concentrations within , a common European herb from which the compound derives its name. It is also present in , a used traditionally in , as well as in , where it contributes to the acidic profile of these fungi. Additionally, fumaric acid has been identified as a component in , exhibiting antibacterial properties in the plant's gel extracts. In animal sources, fumaric acid exists in trace amounts as a key intermediate in the tricarboxylic acid (TCA) cycle, supporting . In humans, it is detectable in at concentrations of approximately 1-2 μM and in urine, reflecting metabolic turnover. These levels underscore its role in energy production rather than accumulation. The compound was first isolated from natural sources in 1832 by German chemist Friedrich Ludwig Winckler, who extracted it from fumitory plants, establishing its presence in botanical materials.

Production Methods

Industrial Production

The industrial production of fumaric acid has undergone significant evolution, shifting from benzene oxidation processes dominant before the 1970s to more efficient and environmentally preferable n-butane oxidation methods. Early production relied on the catalytic vapor-phase oxidation of to , but this was phased out due to benzene's toxicity and regulatory concerns over carcinogenicity. By the late , the n-butane process became predominant, offering higher yields and lower costs through selective oxidation using vanadium-phosphorus oxide catalysts at temperatures around 400–500°C. The primary commercial method today involves the catalytic isomerization of —derived from n-butane oxidation—to , followed by conversion to fumaric acid. is hydrolyzed to in , then isomerized using catalysts such as , salts (e.g., bromides), or mineral acids at temperatures of 100–150°C, often under pressure to enhance conversion rates exceeding 90%. This route accounts for the majority of production due to its scalability and economic viability. An alternative bio-based approach, gaining traction since the amid demand for sustainable chemicals, utilizes fungal with species (e.g., R. oryzae or R. arrhizus) on glucose or other carbohydrates. In submerged or solid-state systems at 30–35°C and 2–6, yields up to 126 g/L (or higher, e.g., 195 g/L in fed-batch processes) of fumaric acid can be achieved, with productivities up to 1.38 g/L/h, facilitated by neutralization to precipitate the acid as a salt. This method supports renewable feedstocks and reduces reliance on , though it currently represents a smaller share of output compared to . Global production of fumaric acid reached approximately 230,000 tons per year as of 2024, with estimates around 296,000 tons in 2025, and major manufacturing hubs in (over 50% of capacity) and the , driven by demand in , resins, and pharmaceuticals.

Laboratory Synthesis

One early laboratory method for synthesizing fumaric acid involves the of bromomaleic acid, which is prepared from dibromosuccinic acid by elimination of . Dibromosuccinic acid is first obtained by addition of to fumaric or , followed by treatment to form the bromomaleic intermediate, and subsequent with or dilute at elevated temperatures yields fumaric acid after removal of ions. A classic procedure utilizes the oxidation of with in the presence of a vanadium pentoxide catalyst. In this method, 200 g of furfural is dissolved in 1 L of water in a 5-L flask equipped with a mechanical stirrer and reflux condenser, followed by addition of 2 g of vanadium pentoxide and gradual introduction of 450 g of over 70–80 minutes while maintaining the temperature at 70–75°C. The reaction mixture is then heated for an additional 10–11 hours, during which the temperature rises to about 105°C due to the exothermic process. The resulting crude product is filtered, acidified with , and purified by recrystallization from 1 N , affording 155–170 g of crude fumaric acid (65–72% yield based on furfural) that can be further refined to 120–138 g of pure material (50–58% overall yield). This approach provides a reliable small-scale route suitable for educational or research settings. Fumaric acid can also be obtained from malic acid through , typically employing strong dehydrating agents such as fuming or (HI) under controlled heating conditions to eliminate water and favor the trans configuration. With fuming , malic acid undergoes at elevated temperatures, yielding a mixture that includes fumaric acid alongside , requiring separation by recrystallization or fractional precipitation due to solubility differences. Alternatively, using concentrated HI promotes with potential toward the thermodynamically stable fumaric , though yields vary and purification is essential to isolate the product from iodine-containing byproducts. These methods are adapted for benchtop scale but demand careful handling of corrosive reagents. A modern preparation relies on the cis-trans of by heating in as a , leveraging to drive the equilibrium toward the more stable trans-fumaric form without additional catalysts. is dissolved in (typically at a concentration of 10–20% w/v), and the mixture is refluxed at 200–250°C for several hours until completes, monitored by changes or TLC. The fumaric acid precipitates upon cooling due to its lower , and it is isolated by and with a non-polar , achieving high selectivity (up to 90%) in this bionic-inspired process suitable for small-scale synthesis.

Chemical Reactivity

Isomerization and Addition Reactions

Fumaric acid, as a trans-alkene, can undergo to , its , through base-catalyzed or thermal pathways, though the strongly favors the more stable trans configuration of fumaric acid. typically involves organic amines such as , which facilitate proton abstraction and reprotonation to achieve rotation around the C=C bond, allowing interconversion between the geometric isomers. Thermal isomerization occurs at elevated temperatures, often above 150°C, where the energy barrier for bond rotation is overcome without a catalyst. The for the isomerization (K = [fumaric acid]/[maleic acid]) is approximately 99 at 25°C in , reflecting the greater stability of the trans form due to reduced steric repulsion between the carboxylic groups. Addition reactions across the C=C of fumaric acid are facilitated by its electron-deficient nature, owing to the conjugated carboxylic groups, making it susceptible to electrophilic s. with (Br₂) in an aqueous or inert solvent proceeds via anti through a bromonium ion intermediate, yielding meso-2,3-dibromosuccinic acid as the major product due to the trans geometry of the starting , which leads to erythro in the saturated product. Similarly, hydration can occur either enzymatically via , which catalyzes the stereospecific of to form L-malic acid in biological systems, or under acid-catalyzed conditions (e.g., with H₂SO₄), producing racemic malic acid through of the followed by nucleophilic attack by . The enzymatic process is highly efficient and reversible, with an of approximately 4.4 favoring malate formation at physiological and temperature. Fumaric acid serves as an effective dienophile in Diels-Alder cycloadditions due to its activated , reacting with dienes such as 1,3-butadiene under thermal conditions (typically 100–200°C) to form bicyclic or derivatives with retained trans in the product. For example, the reaction with 1,3-butadiene yields trans-4-cyclohexene-1,2-dicarboxylic acid, a key intermediate in synthesis, proceeding via a concerted [4+2] pericyclic mechanism that preserves the endo/exo selectivity influenced by the electron-withdrawing groups. Addition of (HBr) to fumaric acid also exemplifies , producing racemic 2-bromobutanedioic acid (2-bromosuccinic acid). The reaction can be represented as: \ceHOOC−CH=CH−COOH+HBr−>HOOC−CH2−CHBr−COOH\ce{HOOC-CH=CH-COOH + HBr -> HOOC-CH2-CHBr-COOH} This product arises from Markovnikov-oriented addition, though the symmetry of fumaric acid minimizes regioselectivity concerns.

Esterification and Derivative Formation

Fumaric acid readily undergoes esterification at its carboxyl groups through the Fischer esterification process, reacting with alcohols in the presence of an acid catalyst such as sulfuric acid to produce the corresponding dialkyl fumarates. A representative example is the reaction with methanol to form dimethyl fumarate, a colorless crystalline solid with a boiling point of 192–193 °C and melting point of 102–106 °C. This esterification is typically conducted under reflux conditions to drive the equilibrium toward the ester product by removing water. Dimethyl fumarate and related esters serve as key intermediates in pharmaceutical synthesis, particularly for immunomodulatory agents. Upon heating to elevated temperatures, approximately 230 °C, fumaric acid undergoes to followed by to form , often resulting in a that favors the anhydride due to the cis configuration of enabling cyclic formation. , a versatile derivative, is employed in the synthesis of unsaturated resins. This thermal transformation highlights the reactivity of the trans-alkene in fumaric acid under dehydrating conditions. Fumaric acid forms salts by neutralization with bases, yielding compounds such as sodium fumarate (NaOOC-CH=CH-COONa), which acts as an acidity regulator in and has been incorporated into pharmaceutical formulations for its buffering properties. In medical contexts, salts like calcium, magnesium, and fumarates are used in oral therapies for , often in combination with esters to enhance and therapeutic . Furthermore, fumaric acid ligands coordinate with metal ions to form complexes, typically through bidentate binding via the carboxylate groups; examples include octahedral complexes with Cu(II), Ni(II), and Zn(II), which exhibit diverse structural motifs in coordination polymers. Catalytic of fumaric acid under high pressure (e.g., 50–100 atm H₂) and with metal catalysts such as or reduces the carbon-carbon to produce , a saturated used as a precursor in various syntheses. This reaction proceeds selectively without affecting the carboxyl groups, achieving high yields under optimized conditions.

Applications

Food and Beverage Uses

Fumaric acid serves as a key , functioning primarily as an acidulant and to enhance flavor, regulate , and extend in various products. It is approved as (GRAS) by the U.S. (FDA) under 21 CFR 184.1091 for use in at levels not exceeding good manufacturing practices. In the , it is authorized as a with the E297 under Regulation (EC) No 1333/2008, with specific maximum levels in categories such as 1000 mg/kg in sugar confectionery and flavoured drinks, and 4000 mg/kg in fruit-flavoured desserts. As a souring agent, fumaric acid imparts a sharp tartness to beverages, baking powders, and confectionery items, typically incorporated at concentrations of 0.03-0.06% (300-600 mg/kg) in soft drinks and fruit juices to stabilize pH near 3.0, thereby preserving color and flavor while inhibiting microbial growth such as . Its antimicrobial properties stem from hydrophobic characteristics that disrupt bacterial membranes, making it effective as a in processed foods. Compared to , fumaric acid offers about 1.5 times greater acidity per unit weight, allowing for reduced usage while achieving equivalent sourness, which can lower formulation costs in dry mixes like beverage powders. Additionally, its lower in (approximately 6.3 g/L at 25°C) enables controlled release upon heating, providing a unique advantage in applications requiring gradual acidification, such as in tortillas where it inhibits mold growth and extends without premature reaction with leavening agents. Fumaric acid contributes to the production of esters, such as dialkyl fumarates, which are utilized as synthetic flavor enhancers in certain products to mimic fruit-like notes. Globally, its application in the accounts for a substantial portion of production, driven by demand in processed foods and beverages. Sensory-wise, fumaric acid delivers a clean, tart taste without any perceptible odor, enhancing perceived sweetness in low-pH formulations by balancing acidity against other flavors. Its safety profile supports widespread use, with no adverse effects reported at typical dietary intake levels.

Pharmaceutical and Medical Applications

Fumaric acid derivatives, particularly (DMF), have established roles in treating autoimmune conditions such as . DMF, formulated as Fumaderm—a combination of DMF with other fumaric acid esters—was approved in in 1994 for moderate-to-severe plaque and later extended across the . This therapy modulates the immune response primarily by activating the Nrf2 (nuclear factor erythroid 2-related factor 2) pathway, which promotes antioxidant defenses and reduces pro-inflammatory production in and immune cells. Clinical use typically involves gradual dose escalation to minimize gastrointestinal side effects, with maintenance dosing around 120–240 mg of DMF per day. In multiple sclerosis (MS), DMF is marketed as Tecfidera and was approved by the U.S. Food and Drug Administration in 2013 and by the European Medicines Agency in 2014 for relapsing-remitting forms of the disease. Phase 3 clinical trials, such as the DEFINE study, demonstrated that DMF at 240 mg twice daily reduced annualized relapse rates by approximately 53% compared to placebo over two years, alongside decreased lesion activity on MRI. The anti-inflammatory mechanism involves Nrf2 activation, which suppresses nuclear factor-kappa B (NF-κB) signaling and shifts T-cell differentiation toward anti-inflammatory profiles. Common side effects include lymphopenia, affecting up to 20–30% of patients, which necessitates regular monitoring of lymphocyte counts to mitigate infection risks. Beyond these immunomodulatory applications, fumaric acid serves as an in pharmaceutical formulations. It acts as an acidulant in effervescent antacids, where it reacts with to produce for rapid dispersion and neutralization of . Additionally, calcium fumarate is incorporated into and supplements as a bioavailable source of calcium, supporting without the gastrointestinal drawbacks of forms. These uses leverage fumaric acid's stability and solubility properties in oral .

Industrial and Material Uses

Fumaric acid serves as a critical in the synthesis of unsaturated polyester resins (UPR), where it undergoes copolymerization with styrene to produce durable composites reinforced with . These resins exhibit enhanced rigidity, chemical resistance, and thermal stability, making them suitable for applications in boat hulls, automotive panels, construction materials such as pipes and tanks, and protective coatings. In the paper industry, fumaric acid functions as a component in agents, improving the surface properties of by enhancing resistance, printability, and brightness while reducing absorbency for better ink adhesion. For textiles, it is incorporated into interpolymers as a agent or , aiding in fixation and fabric finishing to achieve uniform coloration and increased durability during processing. Beyond these, fumaric acid finds use as an additive in to regulate levels, thereby supporting microbial control and improving nutrient absorption without posing risks to when used within approved limits. In metal processes, it helps maintain optimal in baths for and deposition, ensuring efficient plating and smooth surface finishes. Recent advancements have leveraged fermentation-derived fumaric acid for bio-based plastics, notably poly(butylene fumarate) (PBF), a biodegradable synthesized via polycondensation of fumaric acid with . PBF offers tunable mechanical properties and environmental degradability, with applications in and biomedical scaffolds developed since the and supported by new bio-based production facilities as of 2025.

Safety and Environmental Aspects

Health and Toxicity Profile

Fumaric acid exhibits low upon ingestion, with an oral LD50 of 9,300 mg/kg in female rats and 10,700 mg/kg in male rats, indicating minimal risk from single high-dose exposure in animal models. It acts as a mild irritant to skin and a moderate irritant to eyes, as demonstrated in studies where ocular exposure resulted in reversible conjunctival redness and without or severe damage. of dust may cause , but systemic effects are limited at acute exposure levels. Chronic exposure to high doses of fumaric acid can lead to gastrointestinal upset, including , , and abdominal discomfort, primarily observed in therapeutic contexts with esters rather than the acid itself. Fumaric acid is not classified as carcinogenic by the International Agency for Research on Cancer (IARC), with no evidence of or tumor promotion in available studies. As a , it is considered safe with an (ADI) designated as "not specified" by the Joint FAO/WHO Expert Committee on Food Additives (JECFA), implying no appreciable health risk at typical dietary levels up to several grams per day for adults. No specific (PEL) has been established by the (OSHA) for fumaric acid; however, as a particulate not otherwise regulated (PNOR), workplace airborne concentrations should not exceed 15 mg/m³ for total dust or 5 mg/m³ for the respirable fraction over an 8-hour time-weighted average. , fumaric acid is rapidly metabolized as an intermediate in the tricarboxylic acid (TCA) cycle, where it is converted to malate and ultimately oxidized to , which is exhaled, with negligible accumulation in healthy individuals.

Regulatory and Environmental Impact

Fumaric acid is approved by the (FDA) as a direct for use at levels not exceeding current , as specified in 21 CFR 172.350. In the , it is approved as a food additive designated E297, with an (ADI) of 6 mg/kg body weight as established by the Scientific Committee on Food (SCF) in 1991. In 2024, the (EFSA) initiated a re-evaluation of fumaric acid (E297) as a food additive. Additionally, fumaric acid is registered under the EU's REACH regulation, ensuring evaluation of its environmental and health risks for industrial handling and use. Regarding environmental fate, fumaric acid exhibits high biodegradability, with studies indicating rapid breakdown in aerobic conditions typical of natural waters and soils due to its role as a natural in the . It shows low bioaccumulation potential, characterized by an experimental log Pow value of approximately 0.33, which limits partitioning into fatty tissues of organisms. In wastewater treatment systems, it is efficiently removed via processes, where microbial consortia readily metabolize it as a carbon source, achieving high degradation rates in conventional municipal facilities. Sustainability efforts for fumaric acid emphasize a shift toward bio-fermentation using renewable feedstocks like agricultural wastes, which can significantly lower the compared to traditional routes by incorporating CO2 fixation during microbial synthesis. However, spills at production sites pose risks of , as evidenced by organic pollutant detection—including volatile organic compounds—at abandoned fumaric acid facilities in industrial brownfields.

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