PRODUCTS

FUMARIC ACID

CAS No. : 110-17-8
EC No. : 203-743-0

Synonyms:
(2E)-But-2-enedioic acid; Fumaric acid; FA; trans-1,2-Ethylenedicarboxylic acid; 2-Butenedioic acid; trans-Butenedioic acid; Allomaleic acid; Boletic acid; Donitic acid; Lichenic acid; fümarik asit; fumarik asit; fumarık asıt; fumarıc acid; fumaric asit; fumarik acid; fümarik asid; fumarate; fumarat; fümarat; fumaric acid; 110-17-8; 2-Butenedioic acid; trans-Butenedioic acid; Allomaleic acid; Boletic acid; (2E)-but-2-enedioic acid; Lichenic acid; Tumaric acid; trans-2-Butenedioic acid; trans-1,2-Ethylenedicarboxylic acid; Allomalenic acid; (E)-2-Butenedioic acid; But-2-enedioic acid; 2-Butenedioic acid (2E)-; 2-Butenedioic acid (E)-; Kyselina fumarova; USAF EK-P-583; Butenedioic acid; Butenedioic acid, (E)-; (2E)-2-butenedioic acid; Lichenic acid (VAN); 2-Butenedioic acid, (E)-; Caswell No. 465E; FEMA No. 2488; FEMA Number 2488; 2-(E)-Butenedioic acid; Kyselina fumarova [Czech]; NSC-2752; ammonium fumarate; 1,2-Ethylenedicarboxylic acid, (E); CCRIS 1039; HSDB 710; U-1149; trans-but-2-enedioic acid; 1,2-Ethenedicarboxylic acid, trans-; EPA Pesticide Chemical Code 051201; FA; Fumaric acid (NF); Fumaric acid [NF]; Fumaric acid, 99+%; Futrans-2-Butenedioic Acid; (E)-2-Butenedioate; (E)-Butenedioic acid; C4H4O4; (2E)-but-2-enedioate; Malezid CM; H2male; Fumarsaeure; Fumaricum acidum; CAS-110-17-8; fumarate, 10; cis-but-2-enedioic acid; E-2-Butenedioic acid; Fumaric acid (8CI); FC 33 (acid); Scotchbond Multipurpose Etchant; (2Z)-but-2-enedioate; Allomaleate; Boletate; Lichenate; fumeric acid; Cis-butenedioate; 2-Butenedioate; Modified Gumrosin; (z)-butenedioate; trans-Butenedioate; fumaric acid group; FUMARIC ACID; cis-2-Butenedioate; Fumaric Acid,(S); Maleic Acid (MA); cis-but-2-enedioate; Fumaric acid solution; trans-2-Butenedioate; Fumaric Acid (FA); 2-(E)-Butenedioate; Fumaric acid, 99%; (2Z)-2-Butenedioate; FA; (Trans)-butenedioic acid; (2Z)-Butene-2-dioate; F0067; Fumaric acid, >=99%; FUMARIC ACID; (2Z)-2-Butenedioic acid; EC 203-743-0; Maleic acid [NA2215]; (2Z)-Butene-2-dioic acid; (E)-but-2-enedioate;hydron; 4-02-00-02202 (Beilstein Handbook Reference); FUMARIC ACID; 2-butenedioic acid, (2E)-; (2E)-2-Butenedioic acid #; CHEMBL503160; INS NO.297; Fumaric Acid (Fragrance Grade); trans-1,2-Ethylenedicarboxylate; Pharmakon1600-01301022; Fumaric acid, >=99.0% (T); 2-Butenedioic acid (2E)- (9CI); BBL022974; Fumaric acid, >=99%, FCC, FG; s4952; Fumaric acid, qNMR Standard for DMSO; Fumaric acid, tested according to USP/NF; Fumaric acid, Vetec(TM) reagent grade, 99%; Fumaric acid, BioReagent, suitable for cell culture; Fumaric acid, certified reference material, TraceCERT(R); Fumaric acid, anhydrous, free-flowing, Redi-Dri(TM), >=99%; Fumaric acid, European Pharmacopoeia (EP) Reference Standard; Fumaric acid, United States Pharmacopeia (USP) Reference Standard; Fumaric acid solution, TraceCERT(R), 1H-qNMR Standard, 1 mg/g in D2O; Fumaric Acid, Pharmaceutical Secondary Standard; Certified Reference Material; Fumaric acid, PharmaGrade, USP/NF, Manufactured under appropriate GMP controls for pharma or biopharmaceutical production.

Fumaric Acid

Fumaric 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
4H2O2−4 ion (in solution). The trans isomer possesses a dipole moment.

Properties
Chemical formula 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]
Solubility in water 4.9 g/L at 20 °C[1]
Acidity (pKa) pka1 = 3.03, pka2 = 4.44 (15 °C, cis isomer)
Magnetic susceptibility (χ) −49.11·10−6 cm3/mol
Dipole moment non zero

Biosynthesis and occurrence of Fumaric acid
It is produced in eukaryotic organisms from succinate in complex 2 of the electron transport chain via the enzyme succinate dehydrogenase. It is one of two isomeric unsaturated dicarboxylic acids, the other being maleic acid. In fumaric acid the carboxylic acid groups are trans (E) and in maleic acid they are cis (Z).

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.

Fumarate is also a product of the urea cycle.

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

When fumaric acid (FA) is added to their feed, lambs produce up to 70% less methane during digestion.[13]

Safety of Fumaric acid
It is "practically non-toxic" but high doses are probably nephrotoxic after long-term use.[11]

Synthesis and reactions of Fumaric acid
Fumaric acid was first prepared from succinic acid.[14] A traditional synthesis involves oxidation of furfural (from the processing of maize) using chlorate in the presence of a vanadium-based catalyst.[15] Currently, industrial synthesis of fumaric acid is mostly based on catalytic isomerisation of maleic acid in aqueous solutions at low pH. Maleic acid is accessible in large volumes as a hydrolysis product of maleic anhydride, produced by catalytic oxidation of benzene or butane.[3]

The chemical properties of fumaric acid can be anticipated from its component functional groups. This weak acid forms a diester, it undergoes additions across the double bond, and it is an excellent dienophile.

Fumaric acid does not combust in a bomb calorimeter under conditions where maleic acid deflagrates smoothly. For teaching experiments designed to measure the difference in energy between the cis- and trans- isomers, a measured quantity of carbon can be ground with the subject compound and the enthalpy of combustion computed by difference.

See also
Citric acid cycle (TCA cycle)
Dermatology
Photosynthesis
Maleic acid, the cis-isomer of fumaric acid

Fumaric acid appears as a colorless crystalline solid. The primary hazard is the threat to the environment. Immediate steps should be taken to limit spread to the environment. Combustible, though may be difficult to ignite. Used to make paints and plastics, in food processing and preservation, and for other uses.

Fumaric acid is stable although it is subject to degradation by both aerobic and anaerobic microorganisms. When heated in sealed vessels with water at 150 - 170 °C it forms DL-malic acid.

Therapeutic Uses of Fumaric acid
Fumaric acid is used in oral pharmaceutical formulations and food products, and is generally regarded as a relatively nontoxic and nonirritant material.

Fumaric acid preparations are used as long term and effective treatment of psoriasis.

Oral treatment of psoriasis on an outpatient basis, using a preparation containing fumaric acid derivatives, was evaluated as initial monotherapy (3 months) and as long-term basic therapy (12-14 months) in 13 and 11 patients, respectively. The course of the disease was analysed in each individual case. After completion of both parts of the trial, half of the patients that had only responded poorly to conventional antipsoriatic therapy showed a significant improvement which occurred after several weeks of treatment. In 4 patients the medication had to be stopped because of abdominal pain. No severe side effects, particularly of renal, hepatic or hematological nature, could be established. Studies in mice and rats disclosed only a low acute toxicity of the fumaric acid derivatives used. In additional analyses, hypotheses were dealt with concerning the mechanism of action of fumaric acid in psoriasis. To establish fumaric acid derivatives in the treatment of psoriasis, studies on chronic toxicity and pharmacokinetics will have to be conducted. Further clinical trials should evaluate a single fumaric acid derivative instead of mixtures.

Two patients who developed acute renal failure during therapy with fumaric acid esters /are discussed/. Histologic findings after renal biopsy in one patient were compatible with the diagnosis of acute tubular necrosis, and renal function was restored after cessation of the medication. The histologic diagnosis in the other patient was tubulo-interstitial nephritis, possibly reactive to acute tubular necrosis. The recovery of renal function was incomplete after 9 months. Two other patients had deterioration of renal function and proteinuria during therapy with fumaric acid-esters. The symptoms were completely reversible in one patient after discontinuation of the medication, and incompletely reversible in the other.

Apart from gastrointestinal, dermatological and hematological side-effects, transient renal damage was observed during treatment with fumaric acid. The case of a 38 year old woman who was treated with fumaric acid (420 mg bid) for 5 years before she complained of fatigue and weakness. According to clinical laboratory she had developed severe proximal tubular damage. Hypophosphatemia, glycosuria and proteinuria persisted although medication was stopped immediately.

Fumaric acid is used primarily in liquid pharmaceutical preparations as an acidulant and flavoring agent. Fumaric acid may be included as the acid part of effervescent tablet formulations, although this use is limited as the compound has an extremely low solubility in water. It is also used as a chelating agent which exhibits synergism when used in combination with other true antioxidants. In the design of novel pelletized formulations manufactured by extrusion-spheronization, fumaric acid was used to aid spheronization, favoring the production of fine pellets. It has also been investigated as an alternative filler to lactose in pellets. Fumaric acid has been investigated as a lubricant for effervescent tablets, and copolymers of fumaric acid and sebacic acid have been investigated as bioadhesive microspheres. It has also been used in film-coated pellet formulations as an acidifying agent and also to increase drug solubility. Fumaric acid is also used as a food additive at concentrations up to 3600 ppm, and as a therapeutic agent in the treatment of psoriasis and other skin disorders.

Dentifrices containing fumaric acid or salts are effective in removing stains from dentures.

Methods of Manufacturing of Fumaric acid
Commercially, fumaric acid (FA) may be prepared from glucose by the action of fungi such as Rhizopus nigricans, as a by-product in the manufacture of maleic and phthalic anhydrides, and by the isomerization of maleic acid using heat or a catalyst. On the laboratory scale, fumaric acid can be prepared by the oxidation of furfural with sodium chlorate in the presence of vanadium pentoxide.

Maleic acid or maleic anhydride, especially the maleic acid-containing wash water from the production of maleic anhydride or phthalic anhydride, serves as starting material for the manufacture of fumaric acid. The maleic acid concentration should be at least 30%. Maleic acid is converted almost quantitatively by thermal or catalytic isomerization into the sparingly soluble fumaric acid, which is recovered by filtration. Various substances have been proposed as catalysts: mineral acids (e.g., hydrochloric acid); sulfur compounds such as thiocyanates, thiazoles, thiosemicarbazides, thioureas; or bromine compounds in combination with peroxides (e.g., persulfate). Thiourea is most commonly used in practice. The maleic acid-containing wash water contains impurities that can affect quality and yield. This problem can be largely avoided (1) by thermal pretreatment of the wash water, (2) by adding urea if thiourea is used as catalyst, and (3) by addition of sulfites or passaged of sulfur dioxide and addition of mineral acids. The crude fumaric acid obtained is purified by recrystallization from water, combined with purification by active charcoal. Losses during purification are about 10%.

Allowable Tolerances of Fumaric acid
Unless specifically excluded, residues resulting from the use of the following substances as either an inert or an active ingredient in a pesticide chemical formulation, including antimicrobial pesticide chemicals, are exempted from the requirement of a tolerance under FFDCA section 408, if such use is in accordance with good agricultural or manufacturing practices. Fumaric acid is included on this list.

Atmospheric Standards of Fumaric acid
This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Fumaric acid is produced, as an intermediate or final product, by process units covered under this subpart.

Clean Water Act Requirements
Fumaric acid is designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. This designation includes any isomers and hydrates, as well as any solutions and mixtures containing this substance.

FDA Requirements of Fumaric acid
Fumaric acid and its calcium, ferrous, magnesium, potassium, and sodium salts may be safely used in food in accordance with the following prescribed conditions: (a) The additives meet the following specifications: (1) Fumaric acid contains a minimum of 99.5 percent by weight of fumaric acid, calculated on the anhydrous basis. (2) The calcium, magnesium, potassium, and sodium salts contain a minimum of 99 percent by weight of the respective salt, calculated on the anhydrous basis. Ferrous fumarate contains a minimum of 31.3 percent total iron and not more than 2 percent ferric iron. (b) With the exception of ferrous fumarate, fumaric acid and the named salts are used singly or in combination in food at a level not in excess of the amount reasonably required to accomplish the intended effect. (c) Ferrous fumarate is used as a source of iron in foods for special dietary use, when the use is consistent with good nutrition practice.

CAS # EC Number Hill Formula Chemical Formula Molar Mass Grade Value
110-17-8 203-743-0 C₄H₄O₄ HOOCCHCHCOOH 116.07 g/mol NF,JPE

The liver of mice treated with mitomycin C showed perinuclear irregularity, aggregation of chromatin, and abnormal cytoplasmic organelles. The concurrent admin of fumaric acid reduced the incidence of such deleterious changes. The action of fumaric acid against mitomycin C intoxication was even more apparent in the kidney.

Fumaric acid when reacted with chlorine in an aqueous soln was not mutagenic when tested in the Ames test using Salmonella typhimurium TA 100. When a 50/50 by vol methanol/water mixture was used for chlorination, fumaric acid was mutagenic with a peak at 3 equivalents of chlorine per mole.

In humans, no changes in the blood and urine parameters or in liver function were found after administration of 8 mg fumaric acid/kg bw/day for one year.

Acute Exposure/ The nephrotoxic actions of high single oral doses of fumaric acid monoethylester have been investigated in the rat. 50 mg of this substance produced morphologic lesions of the glomeruli without reducing glomerular filtration rate. Following 100 mg, the lesions were more pronounced and glomerular filtration rate was diminished by about 40%. Despite hemorrhages in kidney cortex, the urines did not contain erythrocytes. Urinary protein was augmented in single cases only. 50 to 100 mg fumaric acid monoethylester induced a marked concentration defect after water deprivation. In parallel fumaric acid monoethylester reduced lactate production from glucose by kidney inner medulla in vitro. After in vivo applications, however, no morphologic lesions were found in this zone of the kidney. Fumaric acid monoethylester had no effect on oxygen consumption of kidney slices despite proximal tubular lesions observed histologically after 100 mg orally. Thus, 100 mg of fumaric acid monoethylester have distinct nephrotoxic effects in the rat.

Environmental Fate/Exposure Summary
Fumaric acid's production and use in liquid pharmaceutical preparations as an acidulent and flavoring agent; as a modifier for polyester; in alkyd and phenolic resins, paper-sizing resins, plasticizers, rosin esters and adducts, alkyd resin coating, and in upgrading natural drying oils may result in its release to the environment through various waste streams. Fumaric acid is found in many plants. If released to air, a vapor pressure of 1.54X10-4 mm Hg at 25 °C indicates fumaric acid will exist in both the vapor and particulate phases in the atmosphere. Vapor-phase fumaric acid will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals and ozone; the half-lives for these reactions in air are estimated to be 7 hours and 6 days, respectively. Particulate-phase fumaric acid will be removed from the atmosphere by wet or dry deposition. Fumaric acid does not contain chromophores that absorb at wavelengths >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight. If released to soil, fumaric acid is expected to have very high mobility based upon an estimated Koc of 7. The pKa values of fumaric acid are 3.03 and 4.54, indicating that this compound will exist almost entirely in anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts. Volatilization from moist soil is not expected because the acid exists as an anion and anions do not volatilize. Using a Warburg respirometer and a sewage inoculum, 5-day Theoretical BODs of 57-70% were reported, suggesting that biodegradation may be an important environmental fate process in soil.

If released into water, fumaric acid is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. The half-life of fumaric acid in various natural waters ranged from 1-15 days using river die-away studies, indicating that biodegradation is an important environmental fate process in water. Fumaric acid's pKa values indicate it will exist almost entirely in the anion form at pH values of 5 to 9 and therefore volatilization from water surfaces is not expected to be an important fate process. An estimated BCF of 3 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions. Fumaric acid will be degraded in brightly sunlit natural waters by reaction with photochemically produced hydroxyl radicals with a half-life of 45 days. Occupational exposure to fumaric acid may occur through inhalation and dermal contact with this compound at workplaces where fumaric acid is produced or used. Monitoring and use data indicate that the general population may be exposed to fumaric acid via inhalation of ambient air, ingestion of food and drinking water, and dermal contact with consumer products containing fumaric acid.

Natural Pollution Sources
Fumaric acid is commonly produced by organisms(1); its presence in soils, dusts and plants can result from biogenic sources(1). Fumaric acid is found in many plants and is named after Fumaria officinalis, a climbing annual plant from which it was initially isolated(2). It has been quantified in star fruit and shepard's purse(3).

Based on a classification scheme(1), an estimated Koc value of 7(SRC), determined from a structure estimation method(2), indicates that fumaric acid is expected to have very high mobility in soil(SRC). The pKa values of fumaric acid are 3.03 and 4.54(3), indicating that this compound will exist almost entirely in anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of fumaric acid from moist soil surfaces is not expected to be an important fate process(SRC) given its pKa(3). Fumaric acid is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 1.54X10-4 mm Hg(5). Using a Warburg respirometer and a sewage inoculum, 5 day Theoretical BODs of 57-70% were reported(6), suggesting that biodegradation may be an important environmental fate process in soil(SRC).

According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), fumaric acid, which has a vapor pressure of 1.54X10-4 mm Hg at 25 °C(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase fumaric acid is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals and ozone(SRC); the half-lives for these reactions in air are estimated to be 7 hours and 6 days(SRC), calculated from rate constants of 5.3X10-11 cu cm/molecule-sec(3) and 1.8X10-18 cu cm/molecule-sec(4), respectively. Particulate-phase fumaric acid may be removed from the air by wet or dry deposition(SRC). Fumaric acid does not absorb UV light above 290 nm in methanol, acidic methanol, or basic methanol solution(5) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

Environmental Biodegradation
AEROBIC: In river die-away studies using various natural waters, the degradation half-life of fumaric acid ranged from 1-15 days with faster degradation occurring in more polluted waters(1); degradation half-life in distilled water controls was 55 days(1). Using a microbe inoculum taken from three polluted surface waters, a 5 day Theoretical BOD of 34% was measured(2). Using a Warburg respirometer and a sewage inoculum, 5 day Theoretical BODs of 57-70% were measured at concentrations of 3.75-7.5 ppm(3). Fumaric acid, present at 500 ppm, had a Theoretical BOD of 1.7% after a 24-hr incubation period in a Warburg respirometer using an activated sludge inoculum(4). Using an activated sludge adapted to phenol, a theoretical BOD of 41% was measured after a 12 hr incubation period in a Warburg respirometer(5).

Environmental Abiotic Degradation
The rate constant for the vapor-phase reaction of fumaric acid with photochemically-produced hydroxyl radicals has been estimated as 5.3X10-11 cu cm/molecule-sec at 25 °C(1). This corresponds to an atmospheric half-life of about 7 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(2). The rate constant for the vapor-phase reaction of fumaric acid with ozone has been estimated as 1.8X10-18 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). This corresponds to an atmospheric half-life of about 6 days at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(3). The rate constant for the aqueous reaction of fumaric acid with photochemically produced hydroxyl radicals (pH 4.5-10) is 6.0X10+9/M-sec(4); using a hydroxyl radical concentration of 3X10-17 M in brightly sunlit natural water(5), the half-life would be 45 days(SRC). Since fumaric acid is a substituted olefin, reaction with sunlight-formed singlet oxygen in water may be just as fast or faster than reaction with OH radicals(5). Fumaric acid is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(6). Fumaric acid does not absorb UV light above 290 nm in methanol, acidic methanol, or basic methanol solution(7) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

CAS number   110-17-8
EC index number   607-146-00-X
EC number   203-743-0
Grade   NF,JPE
Hill Formula   C₄H₄O₄
Chemical formula   HOOCCHCHCOOH
Molar Mass   116.07 g/mol
HS Code   2917 19 80

An estimated BCF of 3 was calculated in fish for fumaric acid(SRC), using a log Kow of 0.46(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of fumaric acid can be estimated to be 7(SRC). According to a classification scheme(2), this estimated Koc value suggests that fumaric acid is expected to have very high mobility in soil. The pKa values of fumaric acid are 3.03 and 4.54(3), indicating that this compound will exist almost entirely in anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

Effluent Concentrations of fumaric acid
Fumaric acid concentrations of 0.94 and 3.2 ug/cu m were detected in the motor exhaust from a 1982 Toyota Corolla and a diesel engine 1971 Mercedes Benz, respectively(1).

Atmospheric Concentrations
URBAN/SUBURBAN: Air samples collected in west and downtown Los Angeles, CA during June and Oct 1984 contained fumaric acid concentrations of 3.5-147.4 ng/cu m(1); the fumaric acid detected was associated primarily with atmospheric particles rather than the vapor-phase(1). Samples taken from Tokyo Metropolitan University, Japan, April 1988 to Feb 1989, contained 0.7-1.5 ng/cu m of fumaric acid(2). Samples taken Feb and July 1992 in Tokyo, Japan contained 10-44 ng/cu m of fumaric acid(3). Fumaric acid was detected at 2.9-34.7 ng/cu m in 27 samples taken from 7 locations in Hong Kong, in samples taken Oct to Dec 2003(4). Fumaric acid was detected in daytime air samples at 1.46-13.0 and 7.47-15.6 ng/cu m on July 2004 and Jan 2005 and in nighttime air samples at 5.72-21.4 and 1.68-30.4 ng/cu m on the same dates(5).

Fumaric acid is used as a substitute for tartaric acid in beverages and baking powders and as a replacement or partial replacement for citric acid in fruit drinks(1).

Other Environmental Concentrations
Dust collected from the outside window ledge and balcony of two buildings in Los Angeles, CA contained fumaric acid levels that ranged from 2.65 to 6.67 mg/kg(1).

Probable Routes of Human Exposure of fumaric acid
According to the 2006 TSCA Inventory Update Report, the number of persons reasonably likely to be exposed in the industrial manufacturing, processing, and use for fumaric acid is 1000 or greater; the data may be greatly underestimated(1).

NIOSH (NOES Survey 1981-1983) has statistically estimated that 136,448 workers (48,919 of these were female) were potentially exposed to fumaric acid in the US(1). Occupational exposure to fumaric acid may occur through inhalation and dermal contact with this compound at workplaces where fumaric acid is produced or used. Monitoring and use data indicate that the general population may be exposed to fumaric acid via inhalation of ambient air, ingestion of food and drinking water, and dermal contact with consumer products containing fumaric acid(SRC).

Fumaric acid increases the gel strength of gelatines and acts as a calcium ion liberator when incorporated in alginate preparations.

Fumaric acid (2-butenedioic acid trans, C4H4O4) (Figure 14) derives its name from the fact that the acid is found in plants that belong to the genus Fumaria, a common European herb. Fumaric acid is the trans-isomer of symmetric, unsaturated dicarboxylic acid; the cis-isomer is maleic acid. It is produced as a colorless, crystalline powder with a fruit-like taste (a fruit acid), and it is a weak acid which forms diesters, has low solubility in water, and it undergoes additions across the double bond.

Fumaric and maleic acids were discovered in 1817 by Braconnet and independently by Vauquelin during dry distillation of malic acid.

Fumaric acid is widely used in the food industry as an acidulant because it is nontoxic and is the least expensive of the food-grade acids. Fumaric acid solubility in water is low (0.6 g per 100 g at 25 °C), and, therefore, in order to increase its application in various foods a cold water-soluble (CWS) fumaric acid, which contains a wetting agent, for example 0.3% w/w dioctyl sodium sulfosuccinate, is used. Fumaric acid is used for the industrial preparation of l-malic acid catalyzed by the enzyme fumarase (see ‘Malic acid’) and l-aspartic acid, a component of aspartame, by the enzyme aspartase. Other industrial uses of fumaric acid are in jet printing inks, plastics surface coating and paper sizing, and as an intermediate in the preparation of unsaturated polyester and alkyd resins. Fumaric acid is used by the pharmaceutical industry to produce alexipharmic sodium dimercaptosuccinate and ferrous fumarate, as an optical bleaching agent, in formulations for alternative medicine or as fumaric acid esters monoethylfumarate and dimethylfumarate to treat psoriasis.

Fumaric acid does not accumulate under normal growth conditions of microorganisms and its synthesis is carried out through succinic acid by the mitochondrial oxidative TCA cycle (Figure 2). Various species of the filamentous fungus Rhizopus (such as Rhizopus nigricans and Rhizopus oryzae) produce high concentrations of this acid, which is excreted to the medium. In Rhizopus, most of the fumaric acid is formed from pyruvic acid via a carboxylation reaction, yielding oxaloacetic acid, which is converted directly to l-malic acid and then to fumaric acid. These reactions, which are catalyzed by pyruvate carboxylase, malate dehydrogenase, and fumarase, respectively, are localized in the cytosol and are part of the reductive TCA cycle (Figure 3), carried out under aerobic conditions. The production of fumaric acid from glucose through the reductive reactions of the TCA cycle does not provide net energy and is balanced for carbon, oxygen, and hydrogen. Therefore, part of the pyruvic acid must be utilized through the oxidative TCA cycle to provide energy, mainly for maintenance requirements. It should be noted that, in general, pyruvate carboxylase in eukaryotic organisms is localized in mitochondria, while in certain acid producing filamentous fungi (e.g., Rhizopus and Aspergillus), the enzyme is situated exclusively in the cytosol and in some cases in both compartments. The cytosolic localization of this enzyme appears to be important for the ability of these organisms to accumulate high concentrations of organic acids.

In the 1940s, fumaric acid was made by fermentation on a commercial scale (about 4000 tonnes per year) using a strain of the fungus Rhizopus arrhizus (later named R. oryzae). It was the first submerged fermentation process with molds and served as a model for implementing and scaling up the techniques used for submerged fermentations. The biological production of fumaric acid was terminated when the chemical synthesis became economically more attractive. Fumaric acid is a symmetrical molecule having no isomers and, therefore, the biological process offers no specific advantage over the chemical process. Fumaric acid is presently produced by a chemical process through the isomerization of maleic acid (or maleic anhydride), obtained from a catalytic vapor-phase oxidation of benzene or C4 hydrocarbons.

The accumulation and excretion of fumaric acid from glucose by R. oryzae (about 100 g l−1 of fumaric acid) occurs under aerobic conditions in a high-glucose (an initial concentration of 120 g l−1) medium containing a limited amount of nitrogen and a neutralizing agent (CaCO3). Fumaric acid (molar yield of approximately 100%; moles acid produced per mole of glucose utilized × 100), l-malic acid (15 mol%), and succinic acid (5 mol%) are the major acids formed during fermentation. C4 acid (fumaric, l-malic, and succinic acid) molar yields of 120–145% are obtained after 4–5 days. The high fumaric acid molar yield and C4 acid molar yield confirm that these acids are produced via a carboxylation reaction of pyruvic acid.

General description of fumaric acid
Fumaric acid can be prepared by fermentation by employing Rhizopus species.[4][1] Recently, industrial-scale synthesis of fumaric acid from renewable feedstocks[5] and lignocellulosic biomass[6] has been proposed

Application of fumaric acid
Fumaric acid has been used as a standard for the quantitative determination of phenolic compounds in nettle samples by HPLC.[3]
Fumaric acid may be used in the preparation of L-Lysine-fumaric acid crystals.[2] It may also be employed for the industrial manufacture of synthetic resins and eco-friendly/biodegradable polymers.

USES of fumaric acid
Fumaric acid or trans-butenedioic acid, is a white crystalline chemical compound widely found in nature. Fumaric acid is a key intermediate in the tricarboxylic acid cycle for organic acid biosynthesis in humans and other mammals. Fumaric acid is also an essential ingredient in plant life.

Fumaric acid is found in bolete mushrooms, lichen and Iceland moss. Human skin naturally produces fumaric acid when exposed to sunlight. Fumaric acid is used in the manufacture of medicines, drinks, food, animal feed, cleansing agents, unsaturated polyester, alkyd resins, and printing inks, and is the strongest organic food acid in titratable acidity and sourness.

When used as a food additive, the hydrophobic nature of fumaric acid results in persistent, long lasting sourness and flavor impact. The versatile compound also decreases the pH with minimal added sourness in products with pHs greater than 4.5. Its low molecular weight gives fumaric acid more buffering capacity than other food acids at pHs near 3.O.

Because of its strength, less fumaric acid is required when compared to other organic food acids, therefore reducing costs per unit weight.

Specifications
Product   Fumaric Acid, Food Grade
Chemical Formula   C4H4O4
Description   Specification
Appearance   White Crystalline Powder
Odor   None
Assay on dry basis, wt. %   99.5 min.
Maleic Acid, wt. %   0.05 max.
Residue on ignition, wt. %   0.05 max.
Moisture, wt. %   0.3 max.
Color – 5% alcohol solution, APHA   20 max.
Heavy Metals (as Pb), ppm   10 max.
Lead (as Pb), ppm 2 max.
Arsenic (as As), ppm   1 max
Solubility in Water @ 30°C, (g/100ml)   0.7

History
Fumaric Acid has been used as a food acidulent since 1946. Fumaric Acid esters were first introduced in the late 1950’s by the German chemist Schweckendiek in the treatment of psoriasis. A standardized “Fumaric Acid” protocol for psoriasis was developed and used FAEs both orally and topically. Applications for the chemical compound then expanded to industrial uses.

Fumaric Acid in food
Fumaric Acid is a non-toxic food additive generally used in beverages and baking powders for which requirements are based on purity. It is a substitute for tartaric acid and occasionally takes the place of citric acid, at a rate of 1.36 gram of citric acid to every 0.91 grams of Fumaric Acid for the same taste. It is also an essential ingredient in the manufacturing of candy to add sourness, similar to the way malic acid is used.

Applications of Fumaric Acid
Fumaric acid has been used in food and beverage products since 1946. It is currently used in wheat and corn tortillas, sour dough and rye breads, refrigerated biscuit doughs, fruit juice and nutraceutical drinks, gelatin desserts, gelling aids, pie fillings and wine. Food research shows that Fumaric acid improves quality and reduces costs of many food and beverage products. It is also used in animal feed.

Bakery

Tacos
Fumaric Acid lowers the pH of tortilla dough, thereby improving a mold inhibitor’s effectiveness. Shelf life of dry tortilla mixes is extended because Fumaric Acid does not absorb moisture during storage and distribution. In wheat flour tortillas, fumaric acid accelerates the cleavage of disulphide bonds between gluten protein molecules during dough kneading. The result is more easily machined dough and faster production rates. Added cost savings are realized since leavening acids can be replaced with fumaric acid.

Breads
Fumaric acid acts as an instant flavoring agent for rye and sourdough breads. Fumaric acid is added to dough ingredients during the dry blending step. Flavor intensity is easily controlled by the amount of Fumaric acid added to the recipe. In English muffins, Fumaric acid significantly increases porosity. Dough machinability is improved and more sourness is provided per unit weight.

Beverages

Fruit Juice Drinks
Fumaric acid provides more sourness per unit weight than other acidulants used in fruit juice drinks. This substantially reduces the acidulant cost. In fruit juice drinks, Fumaric acid provides more buffering capacity than other acidulants when the pH is near 3.0. Using fumaric acid helps to stabilize the pH of a fruit juice drink, which in turn stabilizes color and flavor.

Fumaric Acid in combination with Sodium Benzoate was shown to have a bactericidal effect against E.Coli O157:H7 in apple cider at pHs 3.2-3.4.

Fumaric Acid would help juice processors achieve the mandated 5-log pathogen reduction.

Wine
Fumaric Acid can economically acidify wine with no detectable difference in flavor. The replacement ratio of three pounds of fumaric acid to five pounds of Citric acid can significantly reduce acidulant cost. Fumaric acid also prevents secondary fermentation after bottling and can act as a clarifier when low concentrations of copper and iron are present.

Confectioneries
Fumaric acid extends the shelf life of acid coated candies because it does not absorb moisture during storage and distribution. Maintaining a low moisture level retards sucrose inversion. Acidulant cost is also reduced as fumaric acid provides more sourness per unit weight than other acidulants used in dry form.

Jellies and Jams
Fumaric acid can cut food acid costs when used as an acidulant for jams, jellies and preserves. As little as two pounds of fumaric acid can be used to replace every three pounds of Citric, Malic or Tartaric acid. At the 2:3 replacement ratio, fumaric acid does not produce significant differences in gel strength or pH.

Desserts

Alginate Based Desserts
Fumaric acid is an economical acidulant that liberates calcium. It improves smoothness and optimizes setting times. Also, the non-hygroscopicity of fumaric acid means that dry dessert mixes remain free flowing, even in high humidity. Fumaric acid can be added directly to dry dessert mixes during the manufacturing process without causing degradation of flavor ingredients because of its non-hygroscopic nature.

Gelatin Desserts
Fumaric acid significantly reduces acidulant costs in gelatin desserts. Depending on the product recipe, each pound of Citric acid can be replaced with 0.6 to 0.7 pounds of fumaric acid. Reducing moisture pick-up improves flavor stability and lengthens shelf life. Fumaric acid maintains non-caking and free-flowing qualities. By keeping the moisture content low, fumaric acid helps to maintain the stability of flavor components and markedly decreases inversion of sucrose in the packaged dry mix. It may also be possible to use less expensive packaging if other moisture-sensitive ingredients are not being used in the product formulation. Fumaric acid also increases gel strength, so food processors may reduce normal gelatin content by about 2%.

Pie Fillings
In pie fillings, Fumaric acid can be mixed directly with the starch and sugar ingredients, as it is non-hygroscopic. Fumaric acid lowers costs by reducing the quantity of food acid needed in product formulations. Fumaric acid also improves smoothness and extends the critical cook times for optimum gelation.

Egg White Foams
Fumaric acid can promote maximum volume in both egg-white foams and end products based on egg-white foams. Fumaric acid can replace the more expensive cream of tartar to control egg-white volume. With Fumaric acid, egg whites can be overbeaten for as much as double the customary optimum time. Well suited for continuous flow processes, fumaric acid can be added to both liquid and dried egg whites.

Cleaning Agents for Dentures/Bath Salts

The carbon dioxide generating compounds containing NaHCO3, K2CO3 and powdered Fumaric acid can be tableted with other ingredients to make cleaning agents for dentures and bath salts.

Animal Feed

Fumaric acid has proven to be a particularly effective additive to piglet feed during the post-weaning period. The inclusion of Fumaric acid and the resultant adjustment of the pH value demonstrate improved weight gain, food consumption and feed conversion ratio.

Industrial Uses

Industrial uses of Fumaric acid include:

Unsaturated Polyester
Alkyd Resins
Printing Inks
Paper Sizing

Abstract
Fumaric acid is an important specialty chemical with wide industrial applications ranging from its use as feedstock for the synthesis of polymeric resins to acidulant in foods and pharmaceuticals. Currently, fumaric acid is mainly produced by petroleum-based chemical synthesis. Limited petroleum resources, rising oil prices, and heightened environmental concern of chemical synthesis have prompted interest in the development of bio-based fumaric acid from renewable resources. Filamentous fungal fermentation with Rhizopus spp. can produce fumaric acid from glucose via a reductive tricarboxylic acid (TCA) pathway and was once used commercially before the rising of the petrochemical industry. However, conventional fumaric acid fermentation is expensive because of its low product yield and productivity. Filamentous fungal fermentation is also difficult to operate because of its morphology. Methods to control cell growth in the pellet form and to immobilize the mycelia in biofilm have been developed to improve fermentation performance. In this chapter, we provide detailed discussions on fumaric acid producing microorganisms (mainly Rhizopus oryzae); the metabolic pathway and key enzymes involved in fumaric acid overproduction; other genetically modified organisms developed for fumaric acid production; fermentation process conditions including alternative feedstock, nutrients, and methods to control cell morphology, fermentation pH, and dissolved oxygen; and separation methods for fumaric acid recovery from the fermentation broth. We conclude that future research aiming at understanding the metabolic pathway and regulatory network associated with fumaric acid biosynthesis, and searching for low-cost feedstock and more efficient fermentation and separation processes should pave the way leading to the development of an economical bioprocess for industrial production of fumaric acid from renewable biomass.

Fumaric acid is currently produced via isomerization of maleic acid, which is produced from maleic anhydride. The fermentative production of fumaric acid has a high theoretical glucose to fumaric acid production yield (1.29 g g−1) when CO2 is provided. Fermentative production of fumaric acid has been investigated using various fungal strains of Rhizopus sp. R. oryzae and R. arrhizus are the two most widely studied fungi for fumaric acid production using mainly glucose and starch hydrolysates. Koutinas et al.1 reported that fumaric acid concentrations up to 130 g L−1 and productivities up to 4.25 g L−1 h have been achieved. Fumaric acid is currently mainly used in the food industry as acidulant and the chemical industry for the production of plasticisers and resins among other products.

Fumaric acid is an acidulant that possesses a fruitlike flavor. It occurs naturally, albeit in limited amounts, in such fruits as papayas, pears, and plums. Fumaric acid has FDA GRAS status in the United States, but its application is not permitted in Europe. In the United States, fumaric acid is used principally in fruit juices, gelatin desserts, tortillas, and pie fillings. It is relatively cheap, but it has the great disadvantage of a stronger taste than citric acid and is difficult to dissolve in water. The solubility of fumaric acid, in fact, is only ∼6 g l−1 (i.e., 0.6%), which is further complicated by the extended times necessary for solubility concentrations to go into solution. For this reason, solubility often is hastened by heating the solvent, which frequently precludes its use for many food industry applications.

Fumaric and maleic acids were discovered in 1817 by Braconnet and independently by Vauquelin during dry distillation of malic acid.