fumaric acid

H319: Causes serious eye irritation [Warning Serious eye damage/eye irritation]

P264+P265, P280, P305+P351+P338, and P337+P317 (click each P-code to see the statement)

This chemical does not meet GHS hazard criteria for 0.4% (13 of 3331) of reports.

H319 (99.6%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]

Aggregated GHS information provided per 3331 reports by companies from 12 notifications to the ECHA C&L Inventory.

Reported as not meeting GHS hazard criteria per 13 of 3331 reports by companies.

There are 11 notifications provided by 3318 of 3331 reports by companies with hazard statement code(s).

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.

H402: Harmful to aquatic life [Hazardous to the aquatic environment, acute hazard]

P273, and P501 (click each P-code to see the statement)

Fresh air, rest.

Rinse skin with plenty of water or shower.

First rinse with plenty of water for several minutes (remove contact lenses if easily possible), then refer for medical attention.

Rinse mouth.

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.

SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment.

INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing.

INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

Use water spray, dry powder, foam, carbon dioxide.

If material on fire or involved in fire: use water in flooding quantities as fog. Solid streams of water may spread fire. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use foam, dry chemicals, or carbon dioxide.

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Special protective equipment for fire-fighters: Wear self contained breathing apparatus for fire fighting if necessary.

Personal protection: particulate filter respirator adapted to the airborne concentration of the substance. Do NOT let this chemical enter the environment. Sweep spilled substance into covered containers. If appropriate, moisten first to prevent dusting. Then store and dispose of according to local regulations.

Environmental considerations - land spill: Dig a pit, lagoon, holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Cover solids with a plastic sheet to prevent dissolving in rain or fiefighting water. Neutralize with agricultural lime (CaO), crushed limestone (CaCO3), or sodium bicarbonate (NaHCO3).

Environmental considerations - water spill: Neutralize with agricultural lime (CaO), crushed limestone (CaCO3), or sodium bicarbonate (NaHCO3). If dissolved, in region of 10 ppm or greater concentration, apply activated carbon at ten times the spilled amount. Adjust pH to neutral (pH = 7). Use mechanical dredges or lifts to remove immobililzed masses of pollutants and precipitates.

Personal precautions: Use personal protective equipment. Avoid dust formation. Avoid breathing dust. Ensure adequate ventilation.

Environmental precautions: Do not let product enter drains.

Methods for cleaning up: Pick up and arrange disposal withour creating dust. Keep in suitable, closed containers for disposal.

SRP: Criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

Observe all federal, state, and local environmental regulations. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber.

SRP: The scientific literature for the use of contact lenses by industrial workers is inconsistent. The benefits or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place.

If material not on fire and not involved in fire: keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary.

Personnel protection: avoid breathing vapors or dusts ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water.

Handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection.

For more Preventive Measures (Complete) data for Fumaric acid (7 total), please visit the HSDB record page.

Separated from oxidizing materials.

The bulk material should be stored in a well-closed container in a cool, dry place.

Store in cool place. Keep container tightly closed in a dry and well-ventilated place.

A nuisance-causing concentration of airborne particles can be reached quickly when dispersed.

The substance is irritating to the eyes.

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.

Dust mask; gloves; safety glasses; dust cap (USCG, 1999)

Wear appropriate chemical protective gloves, boots, and goggles.

Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a dust mask type N95 (US) or type P1 (EN 143) respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Hand protection: The selected protective gloves have to satisfy the specifications of EU Directive 89/689/EEC and the standard EN 374 derived from it. Handle with gloves.

Eye protection: Safety glasses.

Skin and body protection: Choose body protection according to the amount and concentration of the dangerous substance at the work place.

NO open flames. Prevent deposition of dust. Closed system, dust explosion-proof electrical equipment and lighting.

Use local exhaust or breathing protection.

Protective gloves.

Wear safety goggles.

Do not eat, drink, or smoke during work.

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.

Liquid; Other Solid; Dry Powder; CBI; Large Crystals

White crystalline powder or granules

Colorless or white odorless solid; [HSDB] White crystalline solid; [MSDSonline]

ODOURLESS COLOURLESS CRYSTALLINE POWDER.

white odourless granules or leafy crystals; virtually odourless with tart acid taste

Needles, monoclinic prisms or leaflets from water

Colorless crystals

WHITE CRYSTALLINE POWDER

Odorless

Fruit acid

329 °F at 1.7 mmHg ; sublimes (NTP, 1992)

Sublimes at 200 °C

572 to 576 °F (NTP, 1992)

286-302 °C (closed capillary, rapid heating)

287 °C decomposes

273 °C (open cup)

230 °C (closed cup)

less than 1 mg/mL at 72 °F (NTP, 1992)

Soluble in ethanol, concentrated sulfuric acid; slightly soluble in ethyl ether, acetone

Soluble in alcohol 5.76 g/100 g at 30 °C. Insoluble in chloroform and benzene

in 100 g 95% alcohol at 30 °C: 5.76g; in 100 g acetone at 30 °C: 1.72 g; in 100 g ether at 25 °C: 0.72 g

Almost insoluble in olive oil, ... carbon tetrachloride, xylene, ... molten camphor, liquid ammonia.

In water, 7X10-3 mg/L at 25 °C

7.0 mg/mL

Solubility in water, g/100ml at 25 °C: 0.63 (poor)

insoluble to slightly soluble in water; soluble in alcohol; slightly soluble in oils.

(in ethanol)

1.635 at 68 °F (USCG, 1999) - Denser than water; will sink

1.635 g/cu cm at 20 °C

IT HAS AN EXTREMELY LOW RATE OF MOISTURE ABSORPTION; BULK DENSITY: 32.6 LB/CU FT; STANDARD FREE ENERGY OF ANION FORMATION: -144.41 @ 25 °C; BUFFERING INDEX 3.46

Density (at 20 °C): 1.64 g/cm³

0.000154 [mmHg]

1.54X10-4 mm Hg at 25 °C

log Kow = 0.46

0.46 (estimated)

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.

1364 °F (USCG, 1999)

1364 °F (powder)

375 °C (powder)

Slightly soluble in water.

Acids, Carboxylic

Hydrocarbons, Aliphatic Unsaturated

FUMARIC ACID is a carboxylic acid. Carboxylic acids donate hydrogen ions if a base is present to accept them. They react in this way with all bases, both organic (for example, the amines) and inorganic. Their reactions with bases, called "neutralizations", are accompanied by the evolution of substantial amounts of heat. Neutralization between an acid and a base produces water plus a salt. Carboxylic acids with six or fewer carbon atoms are freely or moderately soluble in water; those with more than six carbons are slightly soluble in water. Soluble carboxylic acid dissociate to an extent in water to yield hydrogen ions. The pH of solutions of carboxylic acids is therefore less than 7.0. Many insoluble carboxylic acids react rapidly with aqueous solutions containing a chemical base and dissolve as the neutralization generates a soluble salt. Carboxylic acids in aqueous solution and liquid or molten carboxylic acids can react with active metals to form gaseous hydrogen and a metal salt. Such reactions occur in principle for solid carboxylic acids as well, but are slow if the solid acid remains dry. Even "insoluble" carboxylic acids may absorb enough water from the air and dissolve sufficiently in it to corrode or dissolve iron, steel, and aluminum parts and containers. Carboxylic acids, like other acids, react with cyanide salts to generate gaseous hydrogen cyanide. The reaction is slower for dry, solid carboxylic acids. Insoluble carboxylic acids react with solutions of cyanides to cause the release of gaseous hydrogen cyanide. Flammable and/or toxic gases and heat are generated by the reaction of carboxylic acids with diazo compounds, dithiocarbamates, isocyanates, mercaptans, nitrides, and sulfides. Carboxylic acids, especially in aqueous solution, also react with sulfites, nitrites, thiosulfates (to give H2S and SO3), dithionites (SO2), to generate flammable and/or toxic gases and heat. Their reaction with carbonates and bicarbonates generates a harmless gas (carbon dioxide) but still heat. Like other organic compounds, carboxylic acids can be oxidized by strong oxidizing agents and reduced by strong reducing agents. These reactions generate heat. A wide variety of products is possible. Like other acids, carboxylic acids may initiate polymerization reactions; like other acids, they often catalyze (increase the rate of) chemical reactions. Partial carbonization and formation of maleic anhydride occur at 446 °F (open vessel). (NTP, 1992)

Fumaric acid undergoes reactions typical of an organic acid.

Materials to avoid: Oxidizing agents, amines, strong bases.

Safe in the present practices of use and concentration. Ingredient, concentration, and use information are available in documents discoverable at https://cir-reports.cir-safety.org

Acute Toxicity: Fumarate is also an endogenous electrophile and reacts spontaneously with cysteine residues in proteins by a Michael addition reaction to form S-(2-succinyl) cysteine, a process termed succination. Lachrymators such as fumarate are thought to act by attacking sulfhydryl functional groups in enzymes. One of the most probable protein targets is the TRPA1 ion channel that is expressed in sensory nerves (trigeminal nerve) of the eyes, nose, mouth and lungs.

Chronic Toxicity: Fumarate is increasingly being identified as an oncometabolite. Fumarase or fumarate hydratase (FH) is a tumor suppressor, whose mutation is associated with the development of leiomyomata, renal cysts, and tumors. Loss of FH enzymatic activity results in accumulation of intracellular fumarate which has been proposed to act as a competitive inhibitor of 2-oxoglutarate-dependent oxygenases including the hypoxia-inducible factor (HIF) hydroxylases, thus activating oncogenic HIF pathways. Mitochondrial dysfunction is also associated with FH deficiency. Fumarate hydratase-deficient cells and tumors have been shown to accumulate fumarate to very high levels with multiple consequences including the activation of oncogenic pathways (A15199). Fumarate (and succinate) inhibit the activity or function of other members of the 2-oxoglutarate-dependent oxygenase superfamily, including histone demethylase enzymes (HDMs) and the TET family of 5-methlycytosine (5mC) hydroxylases which are critical in epigenetic regulation of gene expression.. Fumarate accumulation may also affect cytosolic pathways by inhibiting the reactions involved in the biosynthesis of arginine and purine. More recently it has been found that fumarate promotes p65 phosphorylation and p65 accumulation at the HIF-1α promoter through non-canonical signaling via the upstream Tank Binding Kinase 1 (TBK1). Fumarate is also an endogenous electrophile and reacts spontaneously with cysteine residues in proteins by a Michael addition reaction to form S-(2-succinyl) cysteine, a process termed succination. Accumulation of cellular fumarate has been shown to correlate directly with an increase in succinated proteins. Targets for succination include the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase, adiponectin, cytoskeletal proteins, and endoplasmic reticulum chaperone proteins. Furthermore, evidence suggests that succination of these proteins in cells may impair their functions.

Not listed by IARC. Has been implicated in oncogenesis (A15088, A15092).

Acute exposure to fumaric acid can cause skin redness (skin contact), cough or sore throat (inhalation), abdominal cramps, nausea and diarrhea (ingestion). Chronically high levels of fumaric acid are associated with at least 3 inborn errors of metabolism including: 2-Ketoglutarate dehydrogenase complex deficiency, Fumarase deficiency and Pyruvate carboxylase deficiency. Fumarase deficiency causes encephalopathy, severe mental retardation, unusual facial features, brain malformation, and epileptic seizures. High intracellular fumaric acid levels are associated with the development of renal cancer, leiomyomata, renal cysts, and tumors.

Endogenous, ingestion, contact (skin and eyes)

Cough. Sore throat.

Redness.

Redness. Pain.

Acute exposure to fumaric acid can cause eye and skin irritation, cough or sore throat (inhalation), abdominal cramps, nausea and diarrhea (ingestion).

JECFA: ADI: Not specified. No safety concern when used at current levels of intake as a flavoring agent.

LD50 Mouse ip 100 mg/kg

LD50 Rat (female) oral 9300 mg/kg

LD50 Rat (male) oral 10,700 mg/kg.

LD50 Rabbit skin 20,000 mg/kg bw (No mortality was observed at the high dose of 20,000 mg/kg bw)

Acute exposure: EYES: irrigate opened eyes for several minutes under running water. INGESTION: do not induce vomiting. Rinse mouth with water (never give anything by mouth to an unconscious person). Seek immediate medical advice. SKIN: should be treated immediately by rinsing the affected parts in cold running water for at least 15 minutes, followed by thorough washing with soap and water. If necessary, the person should shower and change contaminated clothing and shoes, and then must seek medical attention.

Chronic Exposure: There is no treatment for fumarase deficiencies. Only palliative care is possible. For cancers caused by intracellular fumarate excess, there are a wide variety of cancer treatments including drugs and surgery.

The inhibitory effect of fumaric acid (FA) on hepatocarcinogenesis was examined in mice fed thioacetamide (TAA). A group of male ICR mice was fed TAA at a level of 0.035% in the diet for 40 weeks and then fed a basal diet for 48 weeks. Hepatic tumors developed in 11 of the 24 animals of this group and they were diagnosed as hepatocellular carcinomas. However, cirrhotic lesions and the enlargement of hepatocyte nucleoli were not as marked in mice as in previous findings in rats fed TAA. The effect of FA on the carcinogenesis was examined in a group of mice fed this compound at a level of 1% in a basal diet after ingestion of TAA. The inhibitory effect of FA on TAA carcinogenesis was so marked that no hepatic carcinomas were found in any of the 15 animals fed FA in combination with TAA.

The ability of a substance to reduce the yield of azoxymethane (AOM)-induced foci in the colon of male Fischer 344 rats, was evaluated as a screening assay for chemopreventive agents. Twenty-eight test agents were administered continuously in the diet from the start of the experiments until the animals were killed 35 days later. AOM was sc administered either as 15 mg/kg bw on days 7 and 14 or as 30 mg/kg bw on day 7 of the experiment. Foci of aberrant crypts were evaluated in whole mounts of methylene blue-stained colons. AOM induced twice as many foci when administered between 8.40 and 11.00 a.m. than between 2.45 and 5.55 p.m. Calcium salts of carbonate, chloride and glucarate decreased the yield of AOM-induced foci while the acidic salts of lactate and phosphate did not inhibit the formation of foci. Dimethyl-fumarate, fumaric acid, genistein, piroxicam, simethicone, sodium suramin and sulindac reduced the yield of AOM-induced foci of aberrant crypts, with genistein being the most potent ...

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.

For more Interactions (Complete) data for Fumaric acid (9 total), please visit the HSDB record page.

Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand-valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR as necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Organic acids and related compounds/

Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist respirations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Activated charcoal is not effective ... . Do not attempt to neutralize because of exothermic reaction. Cover skin burns with dry, sterile dressings after decontamination ... . /Organic acids and related compounds/

Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Early intubation, at the first sign of upper airway obstruction, may be necessary. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if patient is hypotensive with a normal fluid volume. Watch for signs of fluid overload ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Organic acids and related compounds/

/HUMAN EXPOSURE STUDIES/ 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.

/HUMAN EXPOSURE STUDIES/ 75 hospitalized patients (42 females, 33 males, age 20 to 91) were dosed with 500 mg fumaric acid/day for one year. No effects on various blood and urine parameters and no change in liver function were observed.

/SIGNS AND SYMPTOMS/ It is a mild irritant of skin and mucous membranes ...

/CASE REPORTS/ 24 days after starting treatment of psoriasis with fumaric acid derivatives (0.8-1.0 g orally, plus unknown quantities locally) a 21 yr old woman developed acute oliguric renal failure with a rise of serum creatinine levels to 1094 umol/L (12.4 mg/dL). Deterioration of renal function had been preceded by severe abdominal symptoms with nausea, vomiting, and colicky pain. On admission to hospital she was dehydrated with hyponatremia and hypokalemia. There was glomerular microhematuria, increased excretion of renal epithelia, and tubular proteinuria. Renal biopsy demonstrated acute tubular damage with vacuolization of proximal epithelia, dilated tubules and scattered necroses. After intermittent hemodialysis (13 courses over two weeks) renal function gradually recovered, as demonstrated at a follow-up examination four months after discharge.

For more Human Toxicity Excerpts (Complete) data for Fumaric acid (7 total), please visit the HSDB record page.

/LABORATORY ANIMALS: Acute Exposure/ Guinea pig maximization test: not sensitizing

/LABORATORY ANIMALS: Acute Exposure/ ... Has been tested by application of a drop of 10% solution to the eyes of rabbits after mechanical removal of corneal epithelium to facilitate penetration, but it appeared to do no damage, and healing was similar to that in control eyes without fumaric acid.

/LABORATORY ANIMALS: 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.

/LABORATORY ANIMALS: Acute Exposure/ Range-finding toxicity tests were conducted in which five non-fasted /Sprague-Dawley/ male and female rats were given a single oral dose by gastric intubation of 100,000 mg/L (0.100 g/mL) of fumaric acid water. Rats were observed for 14 days and the number of mortalities counted. LD50 = 10,700 mg/kg bw (male rats), LD50 = 9,300 mg/kg bw (female rats). The 95% confidence limits were 7200-15800 mg/kg for males and 6300-13800 mg/kg for females.

For more Non-Human Toxicity Excerpts (Complete) data for Fumaric acid (36 total), please visit the HSDB record page.

LC50; Species: Brachydanio rerio (Zebrafish); Conditions: static; Concentration: 245 mg/L for 48 hr

EC50; Species: Daphnia magna (Water flea, age <24 hr larvae, 1st instar); Conditions: freshwater, static, 22 °C, pH 7.7 (7.0-8.2), hardness 154.5 mg/L CaCO3 (89.5-180 mg/L CaCO3), alkalinity 137.7 mg/L CaCO3 (95-156 mg/L CaCO3); Concentration: 212000 ug/L for 48 hr (95% confidence interval: 204000-220000 ug/L); Effect: intoxication, immobilization

EC50; Species: Daphnia magna (water flea, first instar <24 hr old); Conditions: static; Concentration: 212 mg/L for 48 hr (95% confidence level 204-220 mg/L); Effect: immobilization

EC50; Species: Scenedesmus subspicatus (green algae); Conditions: UBA algal growth inhibition test; Concentration: 41 mg/L for 72 hr; Effect: Growth rate

The substance is harmful to aquatic organisms.

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. (SRC)

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).

LC50; Species: Brachydanio rerio (Zebrafish); Conditions: static; Concentration: 245 mg/L for 48 hr

EC50; Species: Daphnia magna (Water flea, age <24 hr larvae, 1st instar); Conditions: freshwater, static, 22 °C, pH 7.7 (7.0-8.2), hardness 154.5 mg/L CaCO3 (89.5-180 mg/L CaCO3), alkalinity 137.7 mg/L CaCO3 (95-156 mg/L CaCO3); Concentration: 212000 ug/L for 48 hr (95% confidence interval: 204000-220000 ug/L); Effect: intoxication, immobilization

EC50; Species: Daphnia magna (water flea, first instar <24 hr old); Conditions: static; Concentration: 212 mg/L for 48 hr (95% confidence level 204-220 mg/L); Effect: immobilization

EC50; Species: Scenedesmus subspicatus (green algae); Conditions: UBA algal growth inhibition test; Concentration: 41 mg/L for 72 hr; Effect: Growth rate

The substance is harmful to aquatic organisms.

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. (SRC)

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).

Fumaric acid's production and use in liquid pharmaceutical preparations as an acidulent and flavoring agent(1); 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 (especially tall oil) to improve drying characteristics(2) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: 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).

AQUATIC FATE: 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 not expected to adsorb to suspended solids and sediment(SRC). A pKa values of 3.03 and 4.54(3) indicate fumaric acid 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(4). According to a classification scheme(5), an estimated BCF of 3(SRC), from its log Kow of 0.46(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Fumaric acid is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(8). 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(9); using a hydroxyl radical concentration of 3X10-17 M in brightly sunlit natural water(10), the half-life would be 45 days(SRC). 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(11).

ATMOSPHERIC FATE: 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).

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).

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).

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).

The pKa values of 3.03 and 4.54(1) indicate fumaric acid will exist almost entirely in the anion form at pH values of 5 to 9 and therefore volatilization from water surfaces and moist soil is not expected to be an important fate process(2). Fumaric acid is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 1.54X10-4 mm Hg(3).

GROUNDWATER: Fumaric acid was not detected in 2 samples and detected at <5 ng/L in 1 groundwater sample taken from wells in Barcelona, Spain(1).

DRINKING WATER: Fumaric acid was not detected in all 3 filtered samples taken from wells in Barcelona, Spain(1).

RAIN/SNOW: Rain and snow water collected from rural areas near Hubbard Brook, NH and semi-rural areas near Ithaca, NY between June 1976 and May 1977 was found to contain fumaric acid(1). Fumaric acid was detected at 0.027-0.36 uM in precipitation samples from Southern CA, taken Nov 1982 to June 1984 and at 0.01-2.08 uM in precipitation samples from west Los Angeles, CA, taken Mar 1982 to Dec 1983(2).

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).

SEDIMENT: Bog sediments collected in the foothills of the Sierra Nevada Mountains contained fumaric acid levels of 4.76 mg/kg(1).

SOIL: Soil samples collected on the campus of UCLA in Los Angeles, CA contained fumaric acid levels of 0.2-0.6 mg/kg(1).

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).

RURAL/REMOTE: Atomospheric samples taken from Alert, Canada, July 1987 to June 1988, contained 0.017-1.1 ng/cu m of fumaric acid(1).

SOURCE DOMINATED: Fumaric acid was detected in the Shing Mun Tunnel, Hong Kong at 2.7-13.5 and 5.8-16.4 ng/cu m in samples taken Aug 2003 and Feb 2004, respectively(1).

REPORTED USES: NON-ALCOHOLIC BEVERAGES: 50 PPM; BAKED GOODS: 1300 PPM; GELATINS & PUDDINGS: 3600 PPM.

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).

Fumaric acid levels in six wild mushroom species, common to the Northeast and Beira Interior regions of Portugal, were as follows (mg/kg): Amanita caesarea and 43.19; Boletus edulis, 11.64-75.16; Gyroporus castaneus 74.65 ; Lactarius deliciosus, 13.18-237.56; Suillus collintus, 49.49-397.16; Xerocomus chrysenteron, 12.77. Samples were collected in 2003(1).

Plants with the highest amount of Fumaric Acid(1). [Table#2020]

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).

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).

SRP: Criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

Observe all federal, state, and local environmental regulations. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber.

49 663 52; Fumaric acid

Symbol: Xi; R: 36; S: (2)-26