Fumaric Acid - C4H4O4 - PubChem

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Compound Summary for CID 444972
Fumaric Acid Cite this Record

STRUCTURE VENDORS DRUG INFO PHARMACOLOGY LITERATURE PATENTS BIOACTIVITIES
PubChem CID: 444972

Fumaric acid; 110178; 2Butenedioic acid; TransButenedioic acid; Allomaleic acid; Boletic
Chemical Names:
acid More...
Molecular Formula: C4H4O4 or COOHCH=CHCOOH

Molecular Weight: 116.072 g/mol
InChI Key: VZCYOOQTPOCHFLOWOJBTEDSAN
Drug Information: Therapeutic Uses Clinical Trials FDA UNII
Safety Summary: Laboratory Chemical Safety Summary LCSS
Fumaric acid is a dicarboxylic acid. It is a precursor to Lmalate in the Krebs tricarboxylic acid TCA cycle. It is formed by
the oxidation of succinic acid by succinate dehydrogenase. Fumarate is converted by the enzyme fumarase to malate.
Fumaric acid has recently been identified as an oncometabolite or an endogenous, cancer causing metabolite. High
levels of this organic acid can be found in tumors or biofluids surrounding tumors. Its oncogenic action appears to due
to its ability to inhibit prolyl hydroxylasecontaining enzymes. In many tumours, oxygen availability becomes limited
hypoxia very quickly due to rapid cell proliferation and limited blood vessel growth. The major regulator of the
response to hypoxia is the HIF transcription factor HIFalpha. Under normal oxygen levels, protein levels of HIFalpha
are very low due to constant degradation, mediated by a series of posttranslational modification events catalyzed by
the prolyl hydroxylase domaincontaining enzymes PHD1, 2 and 3, also known as EglN2, 1 and 3 that hydroxylate HIF
alpha and lead to its degradation. All three of the PHD enzymes are inhibited by fumarate.
Metabolite Description from Human Metabolome Database
Fumaric acid is 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.
Physical Description from CAMEO Chemicals
PUBCHEM COMPOUND FUMARIC ACID Create Date: 20040916
https://pubchem.ncbi.nlm.nih.gov/compound/444972 1/72
Contents
1 2D Structure
2 3D Conformer
3 Names and Identifiers
4 Chemical and Physical Properties
5 Related Records
6 Chemical Vendors
7 Drug and Medication Information
8 Food Additives and Ingredients
9 Pharmacology and Biochemistry
10 Use and Manufacturing
11 Identification
12 Safety and Hazards
13 Toxicity
14 Literature
15 Patents
16 Biomolecular Interactions and Pathways
17 Biological Test Results
18 Classification
19 Information Sources
1 2D Structure
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from PubChem
2 3D Conformer
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from PubChem
3 Names and Identifiers
3.1 Computed Descriptors
3.1.1 IUPAC Name
Ebut2enedioic acid
from PubChem
3.1.2 InChI
InChI=1S/C4H4O4/c53612478/h12H,H,5,6H,7,8/b21+
from PubChem
3.1.3 InChI Key
VZCYOOQTPOCHFLOWOJBTEDSAN
from PubChem
3.1.4 Canonical SMILES
C=CC=OOC=OO
from PubChem
3.1.5 Isomeric SMILES
C=C/C=OO\C=OO
from PubChem
3.2 Molecular Formula

C4H4O4
from EU Food Improvement Agents, ILOICSC, PubChem
COOHCH=CHCOOH
from ILOICSC
3.3 Other Identifiers
3.3.1 CAS
110178
from CAMEO Chemicals, ChemIDplus, DrugBank, EPA Chemicals under the TSCA, EPA DSStox, European Che
6915180
from ChemIDplus
110167
from DrugBank
3.3.2 EC Number
2037430
from EU Food Improvement Agents
2037430
from European Chemicals Agency ECHA
3.3.3 FEMA Number
2488
from Flavor & Extract Manufacturers Association FEMA
3.3.4 ICSC Number
1173
from ILOICSC
3.3.5 RTECS Number
LS9625000
from ILOICSC, The National Institute for Occupational Safety and Health NIOSH
3.3.6 UN Number
9126
from NJDOH RTK Hazardous Substance List
3.3.7 UNII
88XHZ13131
from FDA/SPL Indexing Data
3.3.8 Wikipedia
Title fumaric acid
Description chemical compound
Title ammonium fumarate

Title butenedioic acid
from Wikipedia
3.4 Synonyms
3.4.1 MeSH Synonyms
1. ammonium fumarate
2. fumaric acid
3. Furamag
4. magnesium fumarate
5. sodium fumarate
from MeSH
3.4.2 DepositorSupplied Synonyms
1. fumaric acid 11. trans2Butenedioic acid 21. FEMA Number 2488 31. Sodium fumarate
2. 110178 12. Allomalenic acid 22. USAF EKP583 32. NSC2752
3. 2Butenedioic acid 13. trans1,2Ethylenedicarboxylic acid 23. E2Butenedioic acid 33. ammonium fumarate
4. transButenedioic acid 14. But2enedioic acid 24. Lichenic acid VAN 34. 1,2Ethenedicarboxyli
5. Allomaleic acid 15. 2Butenedioic acid E 25. FEMA No. 2488 35. 1,2Ethylenedicarboxy
6. Boletic acid 16. Butenedioic acid, E 26. CCRIS 1039 36. Fumarsaeure
7. Lichenic acid 17. Kyselina fumarova 27. HSDB 710 37. EPA Pesticide Chemic
8. 2Ebut2enedioic acid 18. Caswell No. 465E 28. 2EButenedioic acid 38. U1149
9. Tumaric acid 19. 2Butenedioic acid 2E 29. Kyselina fumarova [Czech] 39. UNII88XHZ13131
10. Butenedioic acid 20. 2Butenedioic acid, E 30. 2E2butenedioic acid 40. AI324236
from PubChem
4 Chemical and Physical Properties
4.1 Computed Properties
Property Name Property Value
Molecular Weight 116.072 g/mol
Hydrogen Bond Donor Count 2
Hydrogen Bond Acceptor Count 4
Rotatable Bond Count 2
Complexity 119
AAADcYBgOAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA
AAAAAAAAAAAAAGgAACAAACACAgAAACAAAAgCIAC
CACTVS Substructure Key Fingerprint
DSCAAAAAAAAAAICAAAAEAABAAAAAAAEAAAAAAAEY
AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA
Topological Polar Surface Area 74.6 A^2
Monoisotopic Mass 116.011 g/mol
Exact Mass 116.011 g/mol
XLogP3 0.3
Compound Is Canonicalized true
Formal Charge 0
Heavy Atom Count 8
Defined Atom Stereocenter Count 0
Undefined Atom Stereocenter Count 0
Defined Bond Stereocenter Count 1
Undefined Bond Stereocenter Count 0
Isotope Atom Count 0
CovalentlyBonded Unit Count 1
from PubChem
4.2 Experimental Properties
4.2.1 Physical Description
Fumaric acid is 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.
from CAMEO Chemicals
1. DryPowder
2. Liquid
3. PelletsLargeCrystals
from EPA Chemicals under the TSCA
White crystalline powder or granules

Solid
from Human Metabolome Database
ODOURLESS COLOURLESS CRYSTALLINE POWDER.

from ILOICSC
4.2.2 Color
Needles, monoclinic prisms or leaflets from water

Lide, D.R. CRC Handbook of Chemistry and Physics 88TH Edition 20072008. CRC Press, Taylor & Francis, Boca Raton, FL 2007, p. 3
264
from HSDB
Colorless crystals
Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 15th Edition. John Wiley & Sons, Inc. New York, NY 2007., p. 586
from HSDB
WHITE CRYSTALLINE POWDER

Merory, J. Food Flavorings: Composition, Manufacture, and Use. 2nd ed. Westport, Conn.: Avi Publishing Co., 1968., p. 343
from HSDB
4.2.3 Odor
Odorless
from HSDB
4.2.4 Taste
Fruit acid
from HSDB
4.2.5 Boiling Point
329 F at 1.7 mm Hg ; sublimes NTP, 1992

522 C
PhysProp
from DrugBank
Sublimes at 200 deg C
Dean, J.A. (ed.). Lange's Handbook of Chemistry. 13 ed. New York, NY: McGrawHill Book Co., 1985., p. 7419
from HSDB
200C 392F Sublimes

from OSHA Chemical Sampling Information
4.2.6 Melting Point
572 to 576 F NTP, 1992

130.5 C
PhysProp
from DrugBank
287 dec C
PhysProp
from DrugBank
286302C closed capillary, rapid heating

287 deg C decomposes

Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p.
V2: 1964
from HSDB
549 C
287C 549F Capillary

4.2.7 Flash Point
273 deg C open cup

European Commission, ESIS; IUCLID Dataset, Fumaric acid (110178) p.15 (2000 CDROM edition). Available from, as of February
25, 2010: http://esis.jrc.ec.europa.eu/
from HSDB
230 deg C closed cup

SigmaAldrich Corp; Safety Data Sheet for Fumaric acid (Product Number: 47900) Version 3.2 (June 19, 2008). Available from, as of
March 19, 2010: http://www.sigmaaldrich.com
from HSDB
273C
from ILOICSC
Ignition Temp. Powder ** All Trademarks are the property of their respective owners.
4.2.8 Solubility
less than 1 mg/mL at 72 F NTP, 1992

Water Solubility
441000 mg/L at 25 C
YALKOWSKY,SH & DANNENFELSER,RM (1992)
from DrugBank
Water Solubility
7000 mg/L at 25 C
US EPA (1981)
from DrugBank
Soluble in ethanol, concentrated sulfuric acid; slightly soluble in ethyl ether, acetone
264
from HSDB
Soluble in alcohol 5.76 g/100 g at 30 deg C. Insoluble in chloroform and benzene

from HSDB
in 100 g 95% alcohol at 30 deg C: 5.76g; in 100 g acetone at 30 deg C: 1.72 g; in 100 g ether at 25 deg C: 0.72 g
O'Neil, M.J. (ed.). The Merck Index An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co.,
Inc., 2006., p. 736
from HSDB
Almost insoluble in olive oil, ... carbon tetrachloride, xylene, ... molten camphor, liquid ammonia.
Inc., 2006., p. 736
from HSDB
In water, 7X103 mg/L at 25 deg C

Yalkowsky, S.H., He, Yan., Handbook of Aqueous Solubility Data: An Extensive Compilation of Aqueous Solubility Data for Organic
Compounds Extracted from the AQUASOL dATAbASE. CRC Press LLC, Boca Raton, FL. 2003., p. 86
from HSDB
7.0 mg/mL
in water, g/100ml at 25C: 0.63 poor

from ILOICSC
4.2.9 Density
1.635 at 68 F USCG, 1999

1.635 g/cu cm at 20 deg C

264
from HSDB
at 20C: 1.64 g/cm

from ILOICSC
4.2.10 Vapor Pressure
1.54X104 mm Hg at 25 deg C
Yaws CL; Handbook of Vapor Pressure. Volume 1 C1 to C4 Compounds. Gulf Publishing Co: Houston, TX (1994)
from HSDB
10 @ 0C 32F
4.2.11 LogP
0.48
SANGSTER (1994)
from DrugBank
0.46
HANSCH,C ET AL. (1995)
from DrugBank, Human Metabolome Database
log Kow = 0.46

Hansch, C., Leo, A., D. Hoekman. Exploring QSAR Hydrophobic, Electronic, and Steric Constants. Washington, DC: American
Chemical Society., 1995., p. 8
from HSDB
0.46 estimated
from ILOICSC
4.2.12 Stability
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 deg C it forms DLmalic acid.
Rowe, R.C., Sheskey, P.J., Quinn, M.E.; (Eds.), Handbook of Pharmaceutical Excipients 6th edition Pharmaceutical Press, London,
England 2009, p. 276
from HSDB
4.2.13 AutoIgnition
1364 F USCG, 1999

1364 deg F powder
U.S. Coast Guard, Department of Transportation. CHRIS Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government
Printing Office, 19845.
from HSDB
375C powder
from ILOICSC
4.2.14 Heat of Combustion
4,970 Btu/lb = 2,760 cal/g = 116X10+5 J/kg

U.S. Coast Guard, Department of Transportation. CHRIS Hazardous Chemical Data. Manual Two. Washington, DC: U.S.
Government Printing Office, Oct., 1978.
from HSDB
4.2.15 pH
3,03,2 0,05% solution at 25C

4.2.16 pKa
1.83
LIDE,DR (1996)
from DrugBank
3.03 at 18 C
LIDE,DR (1996)
from DrugBank
4.2.17 Dissociation Constants
pKa1 = 3.03; pKa2 = 4.44 at 18 deg C

Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 19951996., p. 846
from HSDB
pKa1 = 3.03; pKa2 = 4.54 at 25 deg C

Inc., 2006., p. 736
from HSDB
4.3 Spectral Properties

MAX ABSORPTION WATER: 208 NM LOG E= 4.20; SADTLER REFERENCE NUMBER: 472 IR, PRISM; 127 IR,
GRATING
Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 19881989., p. C280
from HSDB
IR: 1278 Coblentz Society Spectral Collection

V2: 1964
from HSDB
UV: 165 Sadtler Research Laboratories Spectral Collection

V2: 1964
from HSDB
1H NMR: 4407 Sadtler Research Laboratories Spectral Collection

V2: 1964
from HSDB
Raman: 12 Sadtler Research Laboratories Spectral Collection

V2: 1964
from HSDB
MASS: 1989 NIST/EPA/MSDC Mass Spectral Database, 1990 version

V2: 1964
from HSDB
4.3.1 GCMS
1. GCMS Spectrum 360 GCEITOF Pegasus III TOFMS system, Leco; GC 6890, Agilent Technologies Positive 2 TMS
4. GCMS Spectrum 363 GCEITOF Pegasus III TOFMS system, Leco; GC 6890, Agilent Technologies Positive
6. GCMS Spectrum 1063 GCMS 2 TMS
7. GCMS Spectrum 2816
1 of 5
NIST Number 194179
Library Main library
Total Peaks 68
m/z Top Peak 98
m/z 2nd Highest 45
m/z 3rd Highest 27
1 of 5
CLICK TO LOAD...
Thumbnail
from NIST
4.3.2 MSMS
1. MSMS Spectrum 206 Quattro_QQQ 10V Negative delivery=Flow_Injection analyzer=Triple_Quad

4. MSMS Spectrum 3041 EIB HITACHI RMU6L Positive
5. MSMS Spectrum 178911
4.3.3 EIMS
EIMS Spectrum 232

4.3.4 1D NMR
1. 1D NMR Spectrum 1104 Varian 500 MHz 1H NMR

2. 1D NMR Spectrum 1163 Bruker 400 MHz 13C NMR
3. 1D NMR Spectrum 2142 JEOL 400 MHz 1H NMR
4. 1D NMR Spectrum 2830 JEOL 22.53 MHz 13C NMR
5. 1D NMR Spectrum 4764
6. 1D NMR Spectrum 4765
4.3.5 2D NMR
1. 2D NMR Spectrum 966 1H1H TOCSY

2. 2D NMR Spectrum 1162 Bruker 600 MHz 1H13C HSQC
5 Related Records
CLICK TO LOAD...
from NCBI
5.1 Related Compounds with Annotation
CLICK TO LOAD...
from PubChem
5.2 Related Compounds
Same Connectivity 27 records
Same Stereo 15 records
Same Isotope 3 records
Same Parent, Connectivity 554 records
Same Parent, Stereo 267 records
Same Parent, Isotope 523 records
Same Parent, Exact 247 records
Mixtures, Components, and

18003 records
Neutralized Forms
Similar Compounds 432 records
Similar Conformers 1985 records
from PubChem
5.3 Substances
5.3.1 Related Substances
All 42403 records
Same 319 records
Mixture 42084 records
from PubChem
5.3.2 Substances by Category
CLICK TO LOAD...
from PubChem
5.4 Entrez Crosslinks
PubMed 10 records
Protein Structures 26 records
Taxonomy 2 records
OMIM 17 records
Gene 9 records
from PubChem
6 Chemical Vendors
CLICK TO LOAD...
from PubChem
7 Drug and Medication Information
7.1 Clinical Trials
Download
1 to 1 of 1
Record ID Title Status Phase
Economic Evaluation of Systemic Treatments for Moderatetosevere

NCT01812954 Completed
Psoriasis
from ClinicalTrials.gov
7.2 Therapeutic Uses

Fumaric acid is used in oral pharmaceutical formulations and food products, and is generally regarded as a relatively
nontoxic and nonirritant material.
from HSDB
Fumaric acid preparations are used as long term and effective treatment of psoriasis. /Fumaric acid preparation/
Abstract: PubMed
Raschka C, Koch Hj; Hum Exp Toxicol 18 (12): 7389 (1999). Available from, as of January 7, 2009:
from HSDB
/EXPERIMENTAL THERAPY/ Fumaric acid and its esters FAE ... are already in use for treatment of psoriasis and are
known to have an immunomodulatory effect ... A phase II clinical study in relapsingremitting multiple sclerosis
RRMS patients with the modified fumaric acid ester BG12 showed as "proof of principle" in a frequent MRI design
that FAE significantly reduce the number of gadoliniumenhancing lesions after 24 weeks of treatment. Further phase
III studies have been started to explore the longterm efficacy of this substance ... Abstract: PubMed
Stangel M et al; Nervenarzt 79 (2): 2127 (2008). Available from, as of January 7, 2009:
from HSDB
/EXPERIMENTAL THERAPY/ Oral treatment of psoriasis on an outpatient basis, using a preparation containing fumaric
acid derivatives, was evaluated as initial monotherapy 3 months and as longterm basic therapy 1214 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. /Fumaric acid derivatives/
Bayard W et al; Hautarz (5): 27985 (1987)
from HSDB
7.3 Drug Warning
Fumaric acid ...is generally regarded as a relatively nontoxic and nonirritant material. However, acute renal falure and
other adverse reactions have occurred following the topical and systemic therapeutic use of fumaric acid and fumaric
acid derivatives in the treatment of psoriasis or other skin disorders. Other adverse effects of oral therapy have
included disturbances of liver function, gastrointestinal effects, and flushing.
from HSDB
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. Abstract: PubMed
Roodnat JI et al; Schweiz Med Wochenschr 119 (23): 82630 (1989). Available from, as of December 23, 2009:
from HSDB
24 days after starting treatment of psoriasis with fumaric acid derivatives 0.81.0 g orally, plus unknown quantities
locally a 21yearold woman developed acute oliguric renal failure with a rise of serum creatinine levels to 1094
mmol/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
followup examination four months after discharge. /Fumaric acid derivatives/ Abstract: PubMed
Dalhoff K et al; Dtsch Med Wochenschr 115 (26): 10147 (1990). Available from, as of January 7, 2009:
from HSDB
Apart from gastrointestinal, dermatological and hematological sideeffects, 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 preparation/ Abstract: PubMed
Raschka C, Koch Hj; Hum Exp Toxicol 18 (12): 7389 (1999). Available from, as of January 7, 2009:
from HSDB
8 Food Additives and Ingredients
8.1 Food Additive Classes

Flavoring Agents
JECFA Functional Classes

Flavouring Agent: FLAVOURING_AGENT Food Additives: ACIDITY_REGULATOR
from FAO/WHO Food Additive Evaluations JECFA
8.2 Evaluations of the Joint FAO/WHO Expert Committee on Food Additives

JECFA
Chemical Name ALLOMALEIC ACID
ADI NOT SPECIFIED 1989
Evaluation Year 1999
No safety concern at current levels of intake when used as a flavouring agent.

Comments The 1989 group ADI of "not specified" for fumaric acid and its salts was
maintained at the fiftythird meeting 1999.
Report TRS 896JECFA 53/67
9 Pharmacology and Biochemistry
9.1 ATC Code

D05AX01 Fumaric acid < D05AX Other antipsoriatics for topical use < D05A Antipsoriatics for topical use < D05
Antipsoriatics < D Dermatologicals
from WHO ATC
9.2 Absorption, Distribution and Excretion

The total activity of labeled carbon dioxide in the blood entering and leaving the brain was determined following a
single injection of fumarate214C in four normal human subjects. Blood samples were drawn simultaneously from
the femoral artery and the superior bulb of the internal jugular vein. Also, cerebrospinal fluid specimens were
collected. Evidence from the experiments indicates that there was an immmediate formation of 14CO2 by the brain
after injection of the isotope. It suggests that fumarate penetrates the bloodbrain barrier with little difficulty.
European Commission, ESIS; IUCLID Dataset, Fumaric acid (110178) pp.3940 (2000 CDROM edition). Available from, as of
February 25, 2010: http://esis.jrc.ec.europa.eu/
from HSDB
9.3 Human Metabolite Information
9.3.1 Metabolite Description
Fumaric acid is a dicarboxylic acid. It is a precursor to Lmalate in the Krebs tricarboxylic acid TCA cycle. It is formed
by the oxidation of succinic acid by succinate dehydrogenase. Fumarate is converted by the enzyme fumarase to
malate. Fumaric acid has recently been identified as an oncometabolite or an endogenous, cancer causing metabolite.
High levels of this organic acid can be found in tumors or biofluids surrounding tumors. Its oncogenic action appears
to due to its ability to inhibit prolyl hydroxylasecontaining enzymes. In many tumours, oxygen availability becomes
limited hypoxia very quickly due to rapid cell proliferation and limited blood vessel growth. The major regulator of
the response to hypoxia is the HIF transcription factor HIFalpha. Under normal oxygen levels, protein levels of HIF
alpha are very low due to constant degradation, mediated by a series of posttranslational modification events
catalyzed by the prolyl hydroxylase domaincontaining enzymes PHD1, 2 and 3, also known as EglN2, 1 and 3 that
hydroxylate HIFalpha and lead to its degradation. All three of the PHD enzymes are inhibited by fumarate.
9.3.2 Biofluid Locations
1. Blood
2. Breast Milk
3. Cerebrospinal Fluid CSF
4. Feces
5. Saliva
6. Sweat
7. Urine
9.3.3 Tissue Locations

Prostate
9.3.4 Cellular Locations
1. Extracellular
2. Membrane
3. Mitochondria
9.3.5 Metabolite Pathways
1. 2ketoglutarate dehydrogenase complex deficiency 11. Aspartate Metabolism

2. Adenine phosphoribosyltransferase deficiency APRT 12. Azathioprine Pathway
3. Adenosine Deaminase Deficiency 13. Canavan Disease
4. Adenylosuccinate Lyase Deficiency 14. Carbamoyl Phosphate Synthetase Deficiency
5. AICARibosiduria 15. Citric Acid Cycle
6. Alkaptonuria 16. Citrullinemia Type I
7. Arginine and Proline Metabolism 17. Congenital lactic acidosis
8. Arginine: Glycine Amidinotransferase Deficiency AGAT Deficiency 18. Creatine deficiency, guanidinoacetate methyltransfe
9. Argininemia 19. Disulfiram Pathway
10. Argininosuccinic Aciduria 20. Dopamine betahydroxylase deficiency
9.3.6 Associated Disorders and Diseases
Alzheimer's disease
RedjemsBennani N, Jeandel C, Lefebvre E, Blain H, Vidailhet M, Gueant JL: Abnormal substrate levels that depend
upon mitochondrial function in cerebrospinal fluid from Alzheimer patients. Gerontology. 1998;445:3004.
[PMID:9693263]
Raskind MA, Peskind ER, Holmes C, Goldstein DS: Patterns of cerebrospinal fluid catechols support increased central
noradrenergic responsiveness in aging and Alzheimer's disease. Biol Psychiatry. 1999 Sep 15;466:75665.
[PMID:10494443]
Walter A, Korth U, Hilgert M, Hartmann J, Weichel O, Hilgert M, Fassbender K, Schmitt A, Klein J:
Glycerophosphocholine is elevated in cerebrospinal fluid of Alzheimer patients. Neurobiol Aging. 2004 Nov
Dec;2510:1299303.[PMID:15465626]
Selley ML, Close DR, Stern SE: The effect of increased concentrations of homocysteine on the concentration of E4
hydroxy2nonenal in the plasma and cerebrospinal fluid of patients with Alzheimer's disease. Neurobiol Aging. 2002
MayJun;233:3838.[PMID:11959400]
Molina JA, JimenezJimenez FJ, Hernanz A, FernandezVivancos E, Medina S, de Bustos F, GomezEscalonilla C, Sayed
Y: Cerebrospinal fluid levels of thiamine in patients with Alzheimer's disease. J Neural Transm Vienna. 2002 Jul;1097
8:103544.[PMID:12111441]
Serot JM, Barbe F, Arning E, Bottiglieri T, Franck P, Montagne P, Nicolas JP: Homocysteine and methylmalonic acid
concentrations in cerebrospinal fluid: relation with age and Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2005
Nov;7611:15857.[PMID:16227558]
Leoni V, Masterman T, Mousavi FS, Wretlind B, Wahlund LO, Diczfalusy U, Hillert J, Bjorkhem I: Diagnostic use of
cerebral and extracerebral oxysterols. Clin Chem Lab Med. 2004 Feb;422:18691.[PMID:15061359]
Lovell MA, Markesbery WR: Ratio of 8hydroxyguanine in intact DNA to free 8hydroxyguanine is increased in
Alzheimer disease ventricular cerebrospinal fluid. Arch Neurol. 2001 Mar;583:3926.[PMID:11255442]
Shetty HU, Holloway HW, Schapiro MB: Cerebrospinal fluid and plasma distribution of myoinositol and other polyols
in Alzheimer disease. Clin Chem. 1996 Feb;422:298302.[PMID:8595727]
Bar KJ, Franke S, Wenda B, Muller S, KientschEngel R, Stein G, Sauer H: Pentosidine and Nepsiloncarboxymethyl
lysine in Alzheimer's disease and vascular dementia. Neurobiol Aging. 2003 MarApr;242:3338.[PMID:12498967]
Fonteh AN, Harrington RJ, Tsai A, Liao P, Harrington MG: Free amino acid and dipeptide changes in the body fluids
from Alzheimer's disease subjects. Amino Acids. 2007 Feb;322:21324. Epub 2006 Oct 10.[PMID:17031479]
Jia JP, Jia JM, Zhou WD, Xu M, Chu CB, Yan X, Sun YX: Differential acetylcholine and choline concentrations in the
cerebrospinal fluid of patients with Alzheimer's disease and vascular dementia. Chin Med J Engl. 2004
Aug;1178:11614.[PMID:15361288]
Abe T, Tohgi H, Isobe C, Murata T, Sato C: Remarkable increase in the concentration of 8hydroxyguanosine in
cerebrospinal fluid from patients with Alzheimer's disease. J Neurosci Res. 2002 Nov 1;703:44750.[PMID:12391605]
Molina JA, JimenezJimenez FJ, Aguilar MV, Meseguer I, MateosVega CJ, GonzalezMunoz MJ, de Bustos F, Porta J,
OrtiPareja M, Zurdo M, Barrios E, MartinezPara MC: Cerebrospinal fluid levels of transition metals in patients with
Alzheimer's disease. J Neural Transm Vienna. 1998;10545:47988.[PMID:9720975]
Bocca B, Forte G, Petrucci F, Pino A, Marchione F, Bomboi G, Senofonte O, Giubilei F, Alimonti A: Monitoring of
chemical elements and oxidative damage in patients affected by Alzheimer's disease. Ann Ist Super Sanita.
2005;412:197203.[PMID:16244393]
Kristensen MO, Gulmann NC, Christensen JE, Ostergaard K, Rasmussen K: Serum cobalamin and methylmalonic acid in
Alzheimer dementia. Acta Neurol Scand. 1993 Jun;876:47581.[PMID:8356878]
Fumarase deficiency
MetaGene: http://www.metagene.de/program/d.prg?mp=FUMARIC%20ACIDURIA
Lung Cancer
Wishart DS, Knox C, Guo AC, Eisner R, Young N, Gautam B, Hau DD, Psychogios N, Dong E, Bouatra S, Mandal R,
Sinelnikov I, Xia J, Jia L, Cruz JA, Lim E, Sobsey CA, Shrivastava S, Huang P, Liu P, Fang L, Peng J, Fradette R, Cheng D,
Tzur D, Clements M, Lewis A, De Souza A, Zuniga A, Dawe M, Xiong Y, Clive D, Greiner R, Nazyrova A, Shaykhutdinov
R, Li L, Vogel HJ, Forsythe I: HMDB: a knowledgebase for the human metabolome. Nucleic Acids Res. 2009
Jan;37Database issue:D60310. doi: 10.1093/nar/gkn810. Epub 2008 Oct 25.[PMID:18953024]
Stretch C, Eastman T, Mandal R, Eisner R, Wishart DS, Mourtzakis M, Prado CM, Damaraju S, Ball RO, Greiner R,
Baracos VE: Prediction of skeletal muscle and fat mass in patients with advanced cancer using a metabolomic
approach. J Nutr. 2012 Jan;1421:1421. doi: 10.3945/jn.111.147751. Epub 2011 Dec 7.[PMID:22157537]
10 Use and Manufacturing
10.1 Uses
EPA Safer Chemical Functional Use Classes

Processing Aids and Additives
from EPA Safer Choice
Food additives
Food additives > Flavoring Agents

JECFA Functional Classes

Flavouring Agent: FLAVOURING_AGENT Food Additives: ACIDITY_REGULATOR
10.1.1 Industry Uses
1. Intermediates
2. Paint additives and coating additives not described by other categories
3. Plasticizers
4. Processing aids, specific to petroleum production
10.1.2 Consumer Uses
Plastic and Rubber Products not covered elsewhere

10.2 Methods of Manufacturing

Commercially, fumaric acid 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.
from HSDB
Maleic acid or maleic anhydride, especially the maleic acidcontaining 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 acidcontaining 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%.
Lohbeck K, et al; Ullmann's Encyclopedia of Industrial Chemistry 7th ed. (2008). NY, NY: John Wiley & Sons; Maleic and Fumaric
Acids. Online Posting Date: June 15, 2000.
from HSDB
10.3 Impurities
< 20 ppm of heavy metals; <3 ppm iron; <0.1% maleic acid; <0.1% ash
KirkOthmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 126. New York, NY: John Wiley and Sons, 19781984., p. V14
785
from HSDB
10.4 Formulations/Preparations
Grades: Technical; crystal; FCC /Food Chemicals Codex/.
from HSDB
ASTM D350476 > 99.5%

785
from HSDB
Resin grade: 99.6%

785
from HSDB
FCC /Food Chemicals Codex/; fine granular, fine powders, powder 80 mesh and technical grades.
Kuney, J.H. and J.N. Nullican (eds.) Chemcyclopedia. Washington, DC: American Chemical Society, 1988., p. 80
from HSDB
10.5 Consumption
31% as a fortifier in paper size resins; 26% as a fortifier in unsaturated polyester resins; 12% as a fortifier in alkyd
surface coating resins; 12% as a food acidulant in gelatin desserts and dry beverage powders; 7% as a chemical
intermediate for plasticizers including dibutyl fumarate; 12% in miscellaneous applications 1974
SRI
from HSDB
50% is used to produce paper size resins; 20% for food acidulant; 10% for unsaturated polyester resins; 5% for alkyds;
5% for plasticizers; and 10% for miscellaneous 1983
CHEMICAL PRODUCTS SYNOPSIS: Fumaric Acid, 1984
from HSDB
CHEMICAL PROFILE: Fumaric acid. US Enduse Pattern for Fumaric Acid in 1985.
Enduse Percent
Paper size resins 48
Food acidulant 20
Unsaturated polyester resins 16
Alkyds 5
Exports 5
Miscellaneous 6
Anonymous; Chemical Marketing Reporter 230 (6): 50 (1986); 11 August 1986
from HSDB
CHEMICAL PROFILE: Fumaric Acid. US Enduse Pattern for Fumaric Acid in 1988.
Enduse Percent
Food acidulant 20
Alkyds 5
Exports 9
Miscellaneous 6
Anonymous; Chemical Marketing Reporter 236 (1): 42 (1989); 3 July 1989
from HSDB
Enduse Percent
Food acidulants 20
Alkyd resins 5
Other, including lubricating oils and oil field fluids, organic synthesis of esters, inks, lacquers,
23
carboxylating agent
Anonymous; Chemical Marketing Reporter 241 (26): 38 (1992); 29 June 1992
from HSDB
Enduse Percent
Food acidulant 20
Alkyd resins 5
Miscellaneous, including lubricating oils and oil field fluids, esters, inks, lacquers, carboxylating agent for
20
styrenebutadiene rubber
Anonymous; Chemical Marketing Reporter 247 (13): 37 (1995); 27 March 1995
from HSDB
Enduse Percent
Food acidulant 22
Alkyd resins 6
Plasticizers 5
Miscellaneous, including lubricating oils and oil field fluids, esters, inks, lacquers, and as a carboxylating
17
agent for styrenebutadiene rubber
Anonymous; Chemical Market Reporter 258 (4): 33 (2000); 24 July 2000
from HSDB
CHEMICAL PROFILE: Fumaric acid. US Demand: 1985: 30 million pounds; 1986: 30 million pounds; 1990: 33.2 million
pounds /projected/.
from HSDB
CHEMICAL PROFILE: Fumaric acid. US Demand: 1988: 31 million pounds; 1989: 32 million pounds; 1993: 36 million
pounds /projected/.
from HSDB
CHEMICAL PROFILE: Fumaric acid. US Demand: 1991: 28 million pounds; 1992: 28 million pounds; 1996: 29 million
pounds /projected/.
from HSDB
CHEMICAL PROFILE: Fumaric acid. US Demand: 1994: 38 million pounds; 1995: 38.4 million pounds; 1999: 40 million
pounds /projected/.
from HSDB
CHEMICAL PROFILE: Fumaric acid. US Demand: 1998: 40 million pounds; 1999: 40.7 million pounds; 2003: 43.4 million
pounds /projected/.
from HSDB
10.6 U.S. Production

1972 2.34 X 10+10 g
from HSDB
1975 9.46 X 10+9 g

from HSDB
1984 2.24 X 10+10 g

USITC. Syn Org ChemU.S. Prod/Sales 1984 p.254
from HSDB
2Butenedioic acid 2E is listed as a High Production Volume HPV chemical 65FR81686. Chemicals listed as HPV
were produced in or imported into the U.S. in >1 million pounds in 1990 and/or 1994. The HPV list is based on the
1990 Inventory Update Rule. IUR 40 CFR part 710 subpart B; 51FR21438.
EPA/Office of Pollution Prevention and Toxics; High Production Volume (HPV) Challenge Program. 2Butenedioic acid (2E) (110
178). Available from, as of February 13, 2010: http://www.epa.gov/hpv/pubs/general/opptsrch.htm
from HSDB
Production volumes for nonconfidential chemicals reported under the Inventory Update Rule.
Year Production Range pounds
1986 >50 million 100 million
US EPA; Nonconfidential Production Volume Information Submitted by Companies for Chemicals Under the 19862002 Inventory
Update Rule (IUR). 2Butenedioic acid (2E) (110178). Available from, as of February 12, 2010:
http://www.epa.gov/oppt/iur/tools/data/2002vol.html
from HSDB
Production volume for nonconfidential chemicals reported under the 2006 Inventory Update Rule. Chemical: 2
Butenedioic acid 2E. Aggreated National Production Volume: 1 to < 10 million lbs.
US EPA; NonConfidential 2006 Inventory Update Reporting. National Chemical Information. 2Butenedioic acid (2E) (110178).
Available from, as of February 12, 2010: http://cfpub.epa.gov/iursearch/index.cfm?s=chem&err=t
from HSDB
CHEMICAL PROFILE: Fumaric acid. US Production Capacity: 1989: 39 million pounds.

from HSDB

from HSDB

from HSDB

from HSDB
10.7 U.S. Imports

1971 1.1 X 10+8 g Princpl Custms Dists
from HSDB
1975 3.98 X 10+8 g Princpl Custms Dists

from HSDB
1984 3.04 X 10+8 g

Bureau Of The Census. U.S. Imports For Consumption And General Imports 1984 p.1334
from HSDB
CHEMICAL PROFILE: Fumaric acid. US Imports: 1988: 4 million pounds.

from HSDB
CHEMICAL PROFILE: Fumaric acid. US Imports: 1991: 8.9 million pounds.

from HSDB

from HSDB
CHEMICAL PROFILE: Fumaric acid. US Imports: 1998: 30 million pounds; 1999: 34.3 million pounds.
from HSDB
10.8 U.S. Exports

1984 Negligible
CHEMICAL PRODUCTS SYNOPSIS: Fumaric Acid, 1984
from HSDB

from HSDB

from HSDB
CHEMICAL PROFILE: Fumaric acid. US Imports: 1998: 2.7 million pounds; 1999: 1.9 million pounds.
from HSDB
11 Identification
11.1 Analytic Laboratory Methods

... DETECTED IN AIR BY GAS CHROMATOGRAPHY AFTER METHYLATION WITH BORON TRIFLUORIDE.
WATHNE BM; ANALYST (LONDON) 105 (1249): 4003 (1980)
from HSDB
An HPLC method is described for the determination of organic acids incl fumaric acid in cheese.
Jager H, Tschager E; Milchwirtsch Ber Bundesanst Wolfpassing Rotholz 75: 1058 (1983)
from HSDB
Organic polybasic acids incl fumaric acid were determined in foods by gas liquid chromatography.
Tonogai Y et al; Bunseki Kagaku 31 (2): E6975 (1982)
from HSDB
A method is given for the determination of carboxylic acids incl fumaric acid in fruit juices and wines by high
performance liquid chromatography.
Droz C, Tanner H; Schweiz Z ObstWeinbau 118 (15): 4348 (1982)
from HSDB
An ion chromatographic system was developed for routine measurement of carboxylic acids with carbon numbers up
to C8 in precipitation samples. The system combines online sample preconcentration on a low capacity anion
exchange resin with separation by ion exclusion and subsequent detection by UV absorption. ... Fumaric acid was
found to have a retention time of 22.3 min.
Elbert W et al; Int J Environ Anal Chem 35 (3): 14959 (1989)
from HSDB
11.2 OSHA Chemical Sampling

Fumaric Acid
12 Safety and Hazards
12.1 Hazards Identification
12.1.1 GHS Classification
Signal: Warning
GHS Hazard Statements
Aggregated GHS information from 9 notifications provided by 2176 companies to the ECHA C&L Inventory.
H319 99.95%: Causes serious eye irritation [Warning Serious eye damage/eye irritation Category 2A]
Information may vary between notifications depending on impurities, additives, and other factors. The percentage
value in parenthesis indicates the notified classification ratio from all companies. Only Hazard Codes with percentage
values above 10% are shown.
Precautionary Statement Codes

P264, P280, P305+P351+P338, P33, and P313
The corresponding statement to each Pcode can be found here.
from European Chemicals Agency ECHA
View all 4 GHS Classification entries
12.1.2 EPA Safer Chemical
Fumaric acid Green circle The chemical has been verified to be of low concern based on experimental and modeled
data.
12.1.3 Health Hazard
Inhalation of dust may cause respiratory irritation. Compound is nontoxic when ingested. Prolonged contact with
eyes or skin may cause irritation. USCG, 1999
12.1.4 Fire Hazard
Special Hazards of Combustion Products: Irritating fumes of maleic anhydride may form in fires. Behavior in Fire: Dust
presents explosion hazard; knock down dust with water fog. USCG, 1999
Combustible. Gives off irritating or toxic fumes or gases in a fire.

from ILOICSC
12.1.5 Explosion Hazard
Finely dispersed particles form explosive mixtures in air.

from ILOICSC
12.1.6 Fire Potential
SLIGHT
Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984., p. 778
from HSDB
12.1.7 Skin, Eye, and Respiratory Irritations
It is a mild irritant of skin and mucous membranes ...

International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I&II. Geneva, Switzerland: International Labour
Office, 1983., p. 45
from HSDB
Dust: Irritating to eyes, nose and throat. If inhaled will cause coughing or difficult breathing. Solid: Irritating to skin
and eyes.
from HSDB
May cause respiratory tract irritation. May cause skin irritation. Causes eye irritation.
from HSDB
12.2 Safety and Hazard Properties
12.2.1 Physical Dangers
Dust explosion possible if in powder or granular form, mixed with air.

from ILOICSC
12.2.2 Chemical Dangers
Decomposes on heating and on burning. This produces corrosive fumes. Reacts violently with strong oxidants. This
produces toxic and flammable gases. This generates fire and explosion hazard.
from ILOICSC
12.2.3 Explosive Limits and Potential
Dust presents explosion hazard; knock down dust with water fog.
from HSDB
Lower explosive limit: 3% by volume; Upper explosive limit: 40% by volume

from HSDB
12.3 First Aid Measures
12.3.1 First Aid
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,
SelfContained 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
12.3.2 Inhalation First Aid
Fresh air, rest.

from ILOICSC
12.3.3 Skin First Aid
Rinse skin with plenty of water or shower.

from ILOICSC
12.3.4 Eye First Aid
First rinse with plenty of water for several minutes remove contact lenses if easily possible, then refer for medical
attention.
from ILOICSC
12.3.5 Ingestion First Aid
Rinse mouth.
from ILOICSC
12.4 Fire Fighting Measures

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.
Association of American Railroads; Bureau of Explosives. Emergency Handling of Hazardous Materials in Surface Transportation.
Association of American Railroads, Pueblo, CO. 2005, p. 444
from HSDB
Suitable extinguishing media: Use water spray, alcoholresistant foam, dry chemical or carbon dioxide.
from HSDB
Special protective equipment for firefighters: Wear self contained breathing apparatus for fire fighting if necessary.
March 19, 2010: https://www.sigmaaldrich.com
from HSDB
12.4.1 Fire Fighting
Use water spray, dry powder, foam, carbon dioxide.

from ILOICSC
12.5 Accidental Release Measures
12.5.1 Spillage Disposal
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.
from ILOICSC
12.5.2 Cleanup Methods
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.
from HSDB
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.
from HSDB
Personal precautions: Use personal protective equipment. Avoid dust formation. Avoid breathing dust. Ensure
adequate ventilation.
from HSDB
Environmental precautions: Do not let product enter drains.

from HSDB
Methods for cleaning up: Pick up and arrange disposal withour creating dust. Keep in suitable, closed containers for
disposal.
from HSDB
12.5.3 Disposal Methods
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.
from HSDB
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.
from HSDB
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.
from HSDB
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.
from HSDB
12.5.4 Other Preventative Measures
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.
from HSDB
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.
from HSDB
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.
from HSDB
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.
from HSDB
In case of skin contact: Wash off with soap and plenty of water. Consult a physician.
from HSDB
In case of eye contact: Rinse thoroughly with plenty of water for at least 15 minutes and consult a physician.
from HSDB
Hygiene measures: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks
and at the end of workday.
from HSDB
12.6 Handling and Storage
12.6.1 Safe Storage
Separated from oxidizing materials.

from ILOICSC
12.6.2 Storage Conditions
The bulk material should be stored in a wellclosed container in a cool, dry place.
from HSDB
Store in cool place. Keep container tightly closed in a dry and wellventilated place.
from HSDB
12.7 Exposure Control and Personal Protection
12.7.1 Occupational Exposure Limits
TLV NOTESTABLISHED:. MAK not established:. EU OEL:.

from ILOICSC
12.7.2 Inhalation Risk
A nuisancecausing concentration of airborne particles can be reached quickly when dispersed.

from ILOICSC
12.7.3 Effects of Short Term Exposure
The substance is irritating to the eyes.

from ILOICSC
12.7.4 Acceptable Daily Intakes
JECFA: ADI: Not specified. No safety concern when used at current levels of intake as a flavoring agent.
Burdock, G.A. (ed.). Fenaroli's Handbook of Flavor Ingredients. 6th ed.Boca Raton, FL 2010, p. 704
from HSDB
12.7.5 Allowable Tolerances
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.
40 CFR 180.950 (USEPA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available
from, as of February 7, 2010: http://www.ecfr.gov
from HSDB
12.7.6 Fire Prevention
NO open flames.
from ILOICSC
12.7.7 Explosion Prevention
PREVENT DISPERSION OF DUST. Closed system, dust explosionproof electrical equipment and lighting.
from ILOICSC
12.7.8 Inhalation Prevention
Use local exhaust or breathing protection.

from ILOICSC
12.7.9 Skin Prevention
Protective gloves.
from ILOICSC
12.7.10 Eye Prevention
Wear safety goggles.

from ILOICSC
12.7.11 Ingestion Prevention
Do not eat, drink, or smoke during work.

from ILOICSC
12.7.12 Protective Equipment and Clothing
Dust mask; gloves; safety glasses; dust cap USCG, 1999

Wear appropriate chemical protective gloves, boots, and goggles.

from HSDB
Respiratory protection: Where risk assessment shows airpurifying 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.
from HSDB
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.
from HSDB
Eye protection: Safety glasses.

from HSDB
Skin and body protection: Choose body protection according to the amount and concentration of the dangerous
substance at the work place.
from HSDB
12.8 Stability and Reactivity
12.8.1 Air and Water Reactions
Slightly soluble in water.

12.8.2 Reactive Group
Acids, Carboxylic
Hydrocarbons, Aliphatic Unsaturated
12.8.3 Reactivity Profile
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
12.8.4 Reactivities and Incompatibilities

Fumaric acid undergoes reactions typical of an organic acid.

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

from HSDB
12.9 Transport Information
12.9.1 EC Classification
Symbol: Xi; R: 36; S: 226

from ILOICSC
12.10 Regulatory Information
12.10.1 Clean Water Act Requirements
Fumaric acid is designated as a hazardous substance under section 311b2A 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.
40 CFR 116.4 (USEPA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from,
as of February 7, 2010: http://www.ecfr.gov
from HSDB
12.10.2 CERCLA Reportable Quantities
Persons in charge of vessels or facilities are required to notify the National Response Center NRC immediately, when
there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable
quantity of 5000 lb or 2270 kg. The toll free number of the NRC is 800 4248802. The rule for determining when
notification is required is stated in 40 CFR 302.4 section IV.D.3.b.
40 CFR 302.4 (USEPA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from,
as of February 7, 2010: http://www.ecfr.gov
from HSDB
12.10.3 FIFRA Requirements
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.
40 CFR 180.950 (USEPA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available
from HSDB
12.10.4 FDA Requirements
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.
21 CFR 172.350 (USFDA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available
from HSDB
Fumaric acid is an indirect food additive for use only as a component of adhesives.
21 CFR 175.105 (USFDA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available
from HSDB
12.11 Other Safety Information
12.11.1 Toxic Combustion Products
Irritating fumes of maleic anhydride may form in fires.

from HSDB
Hazardous decomposition products formed under fire conditions: Carbon oxides.

from HSDB
13 Toxicity
13.1 Toxicological Information
13.1.1 NIOSH Toxicity Data
Download
1 to 4 of 20 View More
Measurement Count
Skin and Eye Irritation 2
Mutation Data 1
Acute Toxicity Data 12
Other Multiple Dose Data 5
from The National Institute for Occupational Safety and Health NIOSH
13.1.2 Inhalation Symptoms
Cough. Sore throat.

from ILOICSC
13.1.3 Skin Symptoms
Redness.
from ILOICSC
13.1.4 Eye Symptoms
Redness. Pain.
from ILOICSC
13.1.5 Interactions
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.
Abstract: PubMed
Akao M, Kuroda K; Chem Pharm Bull (Tokyo) 38 (7): 20124 (1990). Available from, as of January 7, 2009:
from HSDB
The ability of a substance to reduce the yield of azoxymethane AOMinduced foci in the colon of male Fischer 344
rats, was evaluated as a screening assay for chemopreventive agents. Twentyeight 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 bluestained 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 AOMinduced foci while the acidic salts of lactate and phosphate did not inhibit the
formation of foci. Dimethylfumarate, fumaric acid, genistein, piroxicam, simethicone, sodium suramin and sulindac
reduced the yield of AOMinduced foci of aberrant crypts, with genistein being the most potent ... Abstract: PubMed
Pereira MA et al; Carcinogenesis 15 (5): 104954 (1994). Available from, as of January 7, 2009:
from HSDB
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. Abstract: PubMed
Kuroda K et al; Gann 73 (4): 65660 (1982). Available from, as of December 23, 2009:
from HSDB
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. Abstract: PubMed
Nazar MA et al; Mutat Res 89: 4555 (1981). Available from, as of December 23, 2009:
from HSDB
The effect of fumaric acid was examined on DNA synthesis in hepatocytes or hepatoma cells from rats treated with
toxic agents. Male Donryu rats were injected with mitomycin C or aflatoxin B1, singly or in combination with fumaric
acid. After a specified period, hepatocytes were isolated from the liver by the collagenase perfusion method and
placed in culture, and their activities for DNA synthesis were measured. The iv injection of rats with mitomycin C 0.5
mg/kg reduced the semiconservative DNA synthesis of the hepatocytes, but simultaneous dosing of fumaric acid 40
mg/kg enhanced the recovery of the DNA synthesis. The DNA synthesis of hepatoma cells, a 3'methyl4
dimethylamino azobenzeneinduced transplantable cell line growing in the abdominal ascites of rats, was also
reduced by the iv injection of mitomycin C but, in contrast to that of the hepatocytes, was little influenced by the
simultaneous dosing of fumaric acid. The ip injection of fumaric acid also reduced the toxicity of aflatoxin B1 0.25
mg/kg, ip, preventing the reduction of DNA synthesis as well as the occurrence of nuclear degenerative changes in
the aflatoxin B1exposed hepatocytes. Abstract: PubMed
Kuroda K et al; Jpn J Cancer Res 77 (8): 7508 (1986). Available from, as of December 23, 2009:
from HSDB
Anticarcinogenic effects of the fumaric acid were studied in two rat models of carcinogenesis. Tumors of the
esophagus, forestomach, tongue and throat were induced by peroral instillation of 35 mg/kg bw NmethylN
benzylnitrosamine, and neurogenic and renal ones by transplacental injection of 75 mg/kg bw NethylNnitrosourea.
The fumaric acid given in drinking water in the dose of 1 g/L at the postinitiation stage of the carcinogenesis was
shown to inhibit the development of esophageal papilloma, brain glioma and mesenchymal tumors of the kidney.
Abstract: PubMed
Bespalov VG et al; Vopr Onkol 38 (8): 95661 (1992). Available from, as of January 7, 2009:
from HSDB
Four agents, fumaric acid FA, Nacetylcysteine NAC, N4hydroxyphenyl retinamide 4HPR, and betacarotene
betaCT, were evaluated for potential chemopreventive activity using the tobaccospecific carcinogen 4
methylnitrosamino13pyridyl1butanone NNKinduced lung tumor model in female A/J mice. The agents were
evaluated in both 16week and 52week bioassays at two dose levels corresponding to 0.8 maximum tolerated dose
MTD and 0.4 MTD administered throughout the bioassay either in the diet FA, 160 and 80 mmol/kg diet; NAC, 160
and 80 mmol/kg diet; 4HPR, 4 and 2 mmol/kg diet or by subcutaneous injection twice a week betaCT, 32 and 16
mg/kg b.w.. Mice were treated with a single ip dose of 10 umol NNK in saline 1 week after administration of test
agent. Lung adenomas were evaluated in the 16week bioassay, whereas both adenomas and adenocarcinomas of the
lung were determined in the 52week bioassay. Both bioassays showed that all four agents did not significantly inhibit
the total tumor incidence and multiplicity of the lung. However, the incidence of adenocarcinomas was reduced P <
0.01 at 52 weeks in NNK groups given either 0.8 MTD NAC or 0.8 MTD betaCT compared with the NNK control
group. The decreases in adenocarcinomas were accompanied by corresponding increases in adenomas in these
treatment groups. Thus, this study showed that FA, NAC, 4HPR and betaCT did not inhibit the total tumor formation,
however, at the higher doses both NAC and betaCT significantly retarded the malignant progression in the lung of
NNKtreated A/J mice. Abstract: PubMed
Conaway CC et al; Cancer Lett 124 (1): 8593 (1998). Available from, as of January 7, 2009:
from HSDB
The inhibitory effect of fumaric acid FA on carcinogenesis by potassium 1methyl7[25nitro2furylvinyl]4oxo

1,4dihydro1,8naphthyridine3carbo xylate trans, NFN was examined histologically with male ICR/JCL mice. NFN
was fed to mice at a dose level of 0.012% in the diet for 14 weeks. These mice were then divided into 2 groups. One
group was given a basal diet, and the other group was given a diet containing 1% FA in the subsequent 39 weeks. In
the group of 30 mice fed NFN alone, squamous cell carcinomas were found in the stomachs of 7 mice, multiple
papillomas in the stomachs of 13 mice, and multiple and large papillary adenocarcinomas in the lungs of 27 animals.
The administration of FA suppressed the NFNinduced stomach and lung carcinogenesis. In the group of 32 mice fed
NFN and FA, no stomach tumors developed except 1 earlystage of squamous cell carcinoma. In the lungs, only a
small focus of mild atypical hyperplasia and a few earlystage adenocarcinomas were noted in 7 and 11 animals,
respectively. Abstract: PubMed
Kuroda K et al; J Natl Cancer Inst 69 (6): 131720 (1982). Available from, as of January 7, 2009:
from HSDB
Fumaric acid suppressed the carcinogenesis in the liver of rats fed 3'methyl4dimethylaminoazobenzene, and a
study was performed to examine the effect of fumaric acid on deoxyribonucleic acid DNA synthesis and subcellular
structures of hepatocytes under the anticarcinogenic regimens. Male Donryu strain rats were given 3'methyl4
dimethylaminoazobenzene by being fed a diet containing 0.6% 3'methyl4dimethylaminoazobenzene for 50
days. They were then given a diet containing 1% fumaric acid and drinking water containing 0.025% fumaric acid for
53 to 69 weeks. Hepatocytes were isolated from the liver by the collagenase perfusion method and placed in culture,
and their activity for DNA synthesis was measured in terms of the incorporation of 3HdThd into DNA. An enhanced
DNA synthesis of hepatocytes was noted in the rats given fumaric acid, indicating that fumaric acid enhanced the
proliferation of hepatocytes to counteract the carcinogenic effect of 3'methyl4dimethylaminoazobenzene. An
electron microscopic examination indicated that the distribution of subcellular organella was almost normal in the
fumaric acidtreated hepatocytes. Abstract: PubMed
Kuroda K, Akao M; Chem Pharm Bull (Tokyo) 37 (5): 13456 (1989). Available from, as of December 23, 2009:
from HSDB
13.1.6 Antidote and Emergency Treatment
Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start
artificial respiration, preferably with a demandvalve resuscitator, bagvalvemask 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 headdown 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/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby,
St. Louis, MO 2005, p. 176
from HSDB
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/
St. Louis, MO 2005, p. 1767
from HSDB
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. Positivepressure 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/
St. Louis, MO 2005, p. 177
from HSDB
13.1.7 Human Toxicity Excerpts
/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.
from HSDB
/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.
from HSDB
/SIGNS AND SYMPTOMS/ It is a mild irritant of skin and mucous membranes ...
Office, 1983., p. 45
from HSDB
/CASE REPORTS/ 24 days after starting treatment of psoriasis with fumaric acid derivatives 0.81.0 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 followup examination four months after discharge. Abstract: PubMed
Dalhoff K et al; Dtsch Med Wochenschr 115 (26): 10147 (1990). Available from, as of December 23, 2009:
from HSDB
/CASE REPORTS/ 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 tubulointerstitial 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 acidesters. The symptoms were completely reversible in one patient after discontinuation of the medication,
and incompletely reversible in the other. The literature is reviewed and a comparison is drawn with the maleic acid
model in the rat. Abstract: PubMed
Roodnat JI et al; Schweiz Med Wochenschr 119 (23): 82630 (1989). Available from, as of December 23, 2009:
from HSDB
/ALTERNATIVE and IN VITRO TESTS/ Electron spin resonance investigations of the effect of various dicarboxylic acid
compounds on the physical state of membrane proteins in human erythrocytes were performed. The results indicate
that these aliphatic dicarboxylic acids, including fumaric acid, produce highly significant alteration in the physical state
of membrane proteins.
from HSDB
/OTHER TOXICITY INFORMATION/ Humans tolerate 500 mg/day for a year without ill effect ... No problems of
industrial handling are known.
Office, 1983., p. 45
from HSDB
13.1.8 NonHuman Toxicity Excerpts
/LABORATORY ANIMALS: Acute Exposure/ Guinea pig maximization test: not sensitizing
from HSDB
/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.
Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974., p. 509
from HSDB
/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. Abstract: PubMed
Hohenegger M et al; Adv Exp Med Biol 252: 26572 (1989). Available from, as of December 23, 2009:
from HSDB
/LABORATORY ANIMALS: Acute Exposure/ Rangefinding toxicity tests were conducted in which five nonfasted
/SpragueDawley/ 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 720015800 mg/kg for
males and 630013800 mg/kg for females.
EPA/Office of Pollution Prevention and Toxics; High Production Volume Information System (HPVIS) on Fumaric Acid (110178).
Available from, as of January 12, 2009: http://www.epa.gov/hpvis/index.html
from HSDB
/LABORATORY ANIMALS: Acute Exposure/ A dose of 10 mg/kg injected intraperitoneally in /Wistar/ rats causes
hepatotoxicity, tremors, and hypothermia. Larger doses produced extreme hypothermia, decrease in motor activity,
diuresis, and gross evidence of severe hepatotoxicity.
from HSDB
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Male New Zealand white rabbits, 15 animals/group,
were fed fumaric acid sodium salt in the daily diet in a concentration of 6.9%, being equivalent to 5.0% of the
organic acid, for 150 days. A control group was fed ground Rockland Rabbit Diet. Gross pathologic examinations were
performed on 2 animals from each group after 30 days of feeding and on 1 animal from each group after 60 days.
Organs were weighed, and the testes were subjected to histologic study. After 100 days, similar studies were
performed on one half of the surviving rabbits, the liver and kidney being examined histologically in addition to the
testes. After 150 days all surviving animals were sacrificed and gross and histologic studies were carried out. No
effects on body weight, blood chemistry, and organ weights were observed. Gross and microscopic examination
revealed no substancerelated findings. No signs of testicular toxicity were observed. /Fumaric acid, sodium salt/
from HSDB
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Each of five rabbits received iv injections of 50500
mg/kg sodium fumarate every second or third day for 1032 days without any injurious effect on blood levels of non
protein nitrogen or creatinine, phensulfolphthalein excretion, or kidney and liver histology. /Sodium fumarate/
FAO/WHO Joint Expert Committee on Food Additives; WHO Food Additives Series 9: Fumaric acid (1975). Available from, as of
February 25, 2010: http://www.inchem.org/pages/jecfa.html
from HSDB
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Six rabbits received twice weekly ip injections of 60
mg/kg bw of sodium fumarate over 1729 weeks. Swelling and congestion of the thyroids and atrophy of testes, with
low hyaluronidase content, were found ... A further nine male rabbits received 60 mg/kg bw sodium fumarate every
second day by ip injection for 150 days. By the end of the test period, gonadotropic activity of the serum, as well as
estrogenic activity was detected. There was progressive testicular atrophy in all animals, resulting in disappearance of
seminiferous epithelium and survival of Sertoli cells only. Chromophobe cells were increased in the pituitary. /Sodium
fumarate/
from HSDB
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Fourteen rabbits were fed 3202080 mg/kg bw of
disodium fumarate daily for 28 days without any deaths. A further six rabbits received 28803680 mg/kg bw for 17
days with three deaths. Two rabbits were fed a daily diet containing 640 mg/kg bw for 36 days without consistent
adverse effect on body weight, hematology, nonprotein nitrogen or creatinine levels, or histopathological findings.
/Disodium fumarate/
from HSDB
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ ... Four groups of 15 rabbits were fed diets containing 0
or 6.9% sodium fumarate equivalent to 5% fumaric acid for 150 days. There were no significant differences from
controls in body weight gain, food consumption, mortality rate, blood counts, blood sugar, nonprotein nitrogen
level, and urine. Organ weights were not significantly different between the groups and histologic examination
showed no adverse findings attributable to the diet. In particular, spermatogenesis and testicular structure were
unaffected. /Sodium fumarate/
from HSDB
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In the first experiment 12 groups of 24 rats, equally
divided between sexes, were fed /for 2 years/ on diets containing 0.1, 0.5, 0.8, and 1.2% fumaric acid. In the second
experiment 6 groups of 12 male rats were fed /for 2 years/ on diets containing 0.5, 1.0, and 1.5% fumaric acid. Both
experiments involved control groups. The animals weight and food consumption were measured at weekly intervals.
Slightly increased mortality and increased incidence of testes degeneration were observed in rats fed 1.5% fumaric
acid approximately 750 mg/kg bw/day. Two rats receiving 1% or 0.5% had stomach inflammation. Microscopic
pathological examination of the rats showed no major visceral damage at any level and only minor differences
between control and treated animals.
from HSDB
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Groups of 24 male and female OsborneMendel rats
were fed 0.1, 0.5, 0.8, or 1.2% fumaric acid, and groups of 12 rats were fed 1.0 or 1.5% in the diet daily free access to
food for 2 yr. A control group received commercial rat biscuits with 1% cod liver oil. Increased mortality 10/12
animals died; control 6/12 and testes atrophy details not reported were seen at 1.5% fumaric acid in the diet
approx. 750 mg/kg bw/day. Two rats receiving diets with 1.0% or 0.5% fumaric acid showed phlegmonous gastritis, a
condition not seen in any other group. Tumor incidence was not different among the various animal groups.
from HSDB
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ 8 /guinea pigs/ were maintained on a diet containing
0%, 1% and 10% fumaric acid for one year without any adverse effect on growth.
from HSDB
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Fumaric acid was fed to four groups of six young dogs
at 0, 1, 3, and 5% of the diet for two years without adverse effect on body weight gain, development, hematology,
blood sugar and urea levels, hemoglobin and urine. Organ weights and gross and histopathological examination of all
principal organs and tissues revealed no effects attributable to the treatment.
from HSDB
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Eight groups of 14 weanling rats were kept on diets
containing 0, 0.1 and 1.0% fumaric acid and 1.38% sodium fumarate for one year half the groups or two years. No
adverse effect was noted on rate of weight gain, hemoglobin, blood picture, calcium balance as shown by bone
histology, or on the histology of liver, kidney, spleen, and stomach. /Sodium fumarate/
from HSDB
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Fumaric acid FA was examined for its effect on
hepatocarcinogenesis in rats fed 3methyl4'dimethylaminoazobenzene 3MeDAB. Male DONRYU rats were given
approximately 0.5 g 3MeDAB by being fed a diet containing 0.06% 3MeDAB for 50 days; they were then given a
diet containing 1% FA and drinking water containing 0.025% FA for 51 weeks. The administration of FA effectively
suppressed the development of hepatocellular carcinoma, hyperplastic nodules, and hyperplastic areas in the livers of
rats fed 3MeDAB. Abstract: PubMed
from HSDB
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ An inhibitory effect of fumaric acid FA on

hepatocarcinogenesis was examined in rats fed thioacetamide TAA. A group of male DONRYU rats were fed TAA at a
level of 0.035% in the diet for 40 weeks and then fed a basal diet for 40 weeks. Hepatic carcinomas developed in 9 of
41 animals of this group fed TAA alone. The effect of FA on the carcinogenesis was examined in 2 groups fed both
TAA and FA; one group of rats were fed FA at 1% in a basal diet after ingestion of TAA, and another group of rats
were fed TAA plus a supplement of 1% FA in the diet. The inhibitory effect of FA on TAA carcinogenesis was so
marked that no hepatic carcinomas were found in both groups fed FA in combination with TAA. Abstract: PubMed
from HSDB
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ The inhibitory effect of fumaric acid FA on
carcinogenesis by potassium 1methyl7[25nitro2furylvinyl]4oxo1,4dihydro1,8naphthyridine3carbo xylate
trans, NFN was examined histologically with male ICR/JCL mice. NFN was fed to mice at a dose level of 0.012% in the
diet for 14 weeks. These mice were then divided into 2 groups. One group was given a basal diet, and the other group
was given a diet containing 1% FA in the subsequent 39 weeks. In the group of 30 mice fed NFN alone, squamous cell
carcinomas were found in the stomachs of 7 mice, multiple papillomas in the stomachs of 13 mice, and multiple and
large papillary adenocarcinomas in the lungs of 27 animals. The administration of FA suppressed the NFNinduced
stomach and lung carcinogenesis. In the group of 32 mice fed NFN and FA, no stomach tumors developed except 1
earlystage of squamous cell carcinoma. In the lungs, only a small focus of mild atypical hyperplasia and a few early
stage adenocarcinomas were noted in 7 and 11 animals, respectively. Abstract: PubMed
from HSDB
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ 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. Abstract: PubMed
Akao M, Kuroda K; Chem Pharm Bull (Tokyo) 38 (7): 20124 (1990). Available from, as of January 7, 2009:
from HSDB
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Anticarcinogenic effects of the fumaric acid were
studied in two rat models of carcinogenesis. Tumors of the esophagus, forestomach, tongue and throat were induced
by peroral instillation of 35 mg/kg bw NmethylNbenzylnitrosamine, and neurogenic and renal ones by
transplacental injection of 75 mg/kg bw NethylNnitrosourea. The fumaric acid given in drinking water in the dose
of 1 g/L at the postinitiation stage of the carcinogenesis was shown to inhibit the development of esophageal
papilloma, brain glioma and mesenchymal tumors of the kidney. Abstract: PubMed
Bespalov VG et al; Vopr Onkol 38 (8): 95661 (1992). Available from, as of January 7, 2009:
from HSDB
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ The ability of a substance to reduce the yield of
azoxymethane AOMinduced foci in the colon of male Fischer 344 rats, was evaluated as a screening assay for
chemopreventive agents. Twentyeight 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 bluestained 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. Dimethylfumarate,
fumaric acid, genistein, piroxicam, simethicone, sodium suramin and sulindac reduced the yield of AOMinduced foci
of aberrant crypts, with genistein being the most potent ... Abstract: PubMed
Pereira MA et al; Carcinogenesis 15 (5): 104954 (1994). Available from, as of January 7, 2009:
from HSDB
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Four agents, fumaric acid FA, Nacetylcysteine NAC,
N4hydroxyphenyl retinamide 4HPR, and betacarotene betaCT, were evaluated for potential chemopreventive
activity using the tobaccospecific carcinogen 4methylnitrosamino13pyridyl1butanone NNKinduced lung
tumor model in female A/J mice. The agents were evaluated in both 16week and 52week bioassays at two dose
levels corresponding to 0.8 maximum tolerated dose MTD and 0.4 MTD administered throughout the bioassay either
in the diet FA, 160 and 80 mmol/kg diet; NAC, 160 and 80 mmol/kg diet; 4HPR, 4 and 2 mmol/kg diet or by
subcutaneous injection twice a week betaCT, 32 and 16 mg/kg b.w.. Mice were treated with a single ip dose of 10
umol NNK in saline 1 week after administration of test agent. Lung adenomas were evaluated in the 16week
bioassay, whereas both adenomas and adenocarcinomas of the lung were determined in the 52week bioassay. Both
bioassays showed that all four agents did not significantly inhibit the total tumor incidence and multiplicity of the
lung. However, the incidence of adenocarcinomas was reduced P < 0.01 at 52 weeks in NNK groups given either 0.8
MTD NAC or 0.8 MTD betaCT compared with the NNK control group. The decreases in adenocarcinomas were
accompanied by corresponding increases in adenomas in these treatment groups. Thus, this study showed that FA,
NAC, 4HPR and betaCT did not inhibit the total tumor formation, however, at the higher doses both NAC and beta
CT significantly retarded the malignant progression in the lung of NNKtreated A/J mice. Abstract: PubMed
Conaway CC et al; Cancer Lett 124 (1): 8593 (1998). Available from, as of January 7, 2009:
from HSDB
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ One generation reproductive toxicity study. Two
pregnant guinea pig females received fumaric acid in their diet. Combined, they produced 12 offspring. The males
were also fed fumaric acid in the diet. Dose: 1% about 400 mg/kg bw/day. NOEL Parental: 400 mg/kg bw/ day. NOEL
F1 Offspring: 400 mg/kg bw/ day. There were no detectable toxic effects on growth, reproduction or lactation.
from HSDB
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ 8 /guinea pigs/ were maintained on a diet
containing 0%, 1% and 10% fumaric acid for one year without any adverse effect on growth. The second generation
from four mated animals was treated similarly without any adverse effect noted regarding growth, fertility or lactation.
from HSDB
/GENOTOXICITY/ Bacterial reverse mutation assay Ames. Strains: S. tymphimurium TA97, TA98, TA100, TA1535,
TA1537, with and without metabolic activation. Genotoxic effect: negative.
from HSDB
/GENOTOXICITY/ Bacterial reverse mutation assay Ames. Strain: S. typhimuium TA100 without metabolic activation.
Genotoxic effect: negative. This study was part of a larger study in which compounds associated with pulp mill effluent
were tested individually. A single replicate was tested with a single Salmonella strain.
from HSDB
/GENOTOXICITY/ In vitro mammalian chromosome aberration test. Chinese hamster fibroblast cell line without
metabolic activation. Maximum dose of 0.5 mg/mL. Genotoxic effect: negative. Substance was tested in a
physiological saline solvent. Three different concentrations maximum 0.5 mg/mL were tested and cells were exposed
to each concentration for 48 hours.
from HSDB
/GENOTOXICITY/ Mouse lymphoma assay, L5178Y TK+/ with and without metabolic activation. Fumaric acid purity
99.7% was tested at concentrations of 2,8568,000 ug/mL in the medium. It was mutagenic in the absence and
presence of Aroclor 1254 induced rat liver S9 mix.
from HSDB
/GENOTOXICITY/ 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. Abstract: PubMed
Nazar MA et al; Mutat Res 89: 4555 (1981). Available from, as of December 23, 2009:
from HSDB
/ALTERNATIVE and IN VITRO TESTS/ ... Male Donryu rats were injected with mitomycin C or aflatoxin B1, singly or in
combination with fumaric acid. After a specified period, hepatocytes were isolated from the liver by the collagenase
perfusion method and placed in culture, and their activities for DNA synthesis were measured. The iv injection of rats
with mitomycin C 0.5 mg/kg reduced the semiconservative DNA synthesis of the hepatocytes, but simultaneous
dosing of fumaric acid 40 mg/kg enhanced the recovery of the DNA synthesis. The DNA synthesis of hepatoma cells,
a 3'methyl4dimethylaminoazobenzeneinduced transplantable cell line growing in the abdominal ascites of rats,
was also reduced by the iv injection of mitomycin C but, in contrast to that of the hepatocytes, was little influenced by
the simultaneous dosing of fumaric acid. The ip injection of fumaric acid also reduced the toxicity of aflatoxin B1 0.25
mg/kg, ip, preventing the reduction of DNA synthesis as well as the occurrence of nuclear degenerative changes in
the aflatoxin B1exposed hepatocytes. Abstract: PubMed
Kuroda K et al; Jpn J Cancer Res 77 (8): 7508 (1986). Available from, as of January 7, 2009:
from HSDB
/ALTERNATIVE and IN VITRO TESTS/ ... Male Donryu strain rats were given 3'methyl4dimethylaminoazobenzene
3'MeDAB by being fed a diet containing 0.06% 3'MeDAB for 50 days. They were then given a diet containing 1%
fumaric acid FA and drinking water containing 0.025% FA for 53 to 69 weeks. Hepatocytes were isolated from the
liver by the collagenase perfusion method and placed in culture, and their activity for DNA synthesis was measured in
terms of the incorporation of [3H]dThd into DNA. An enhanced DNA synthesis of hepatocytes was noted in the rats
given FA, indicating that FA enhanced the proliferation of hepatocytes to counteract the carcinogenic effect of 3'Me
DAB. An electron microscopic examination indicated that the distribution of subcellular organella was almost normal
in the FAtreated hepatocytes. Abstract: PubMed
Kuroda K, Akao M; Chem Pharm Bull (Tokyo) 37 (5): 13456 (1989). Available from, as of January 7, 2009:
from HSDB
/ALTERNATIVE and IN VITRO TESTS/ Fumaric acid was found to reduce markedly the growth and viability of Ehrlich,
MH134, and L1210 mouse tumor cells in culture at concentrations of 0.31.2 mg/mL. In contrast, fumaric acid at these
concentrations in the culture medium had no deleterious effect on the monolayer development of mouse and chick
embryo cells. Abstract: PubMed
Kuroda K, Akao M; Gann 72 (5): 77782 (1981). Available from, as of December 23, 2009:
from HSDB
/ALTERNATIVE and IN VITRO TESTS/ Fumaric acid was tested in an in vitro assay for teratogenesis using Drosophila
embryo cell cultures from strains Oregon R, Canton S, and Canton S 109. The number of ganglia and myotubes
serving as endpoint indicated normal differentiation of neurons and muscle. Fumaric acid produced 88% of control
ganglia and 95% of control myotubes at a concn of 103 M. This was judged as a negative result. Abstract: PubMed
BourniasVardiabasis N et al; Teratology 28: 10922 (1983). Available from, as of December 23, 2009:
from HSDB
/ALTERNATIVE and IN VITRO TESTS/ Fumaric acid suppressed the carcinogenesis in the liver of rats fed 3'methyl4
dimethylaminoazobenzene, and a study was performed to examine the effect of fumaric acid on deoxyribonucleic
acid DNA synthesis and subcellular structures of hepatocytes under the anticarcinogenic regimens. Male Donryu
strain rats were given 3'methyl4dimethylaminoazobenzene by being fed a diet containing 0.6% 3'methyl4
dimethylaminoazobenzene for 50 days. They were then given a diet containing 1% fumaric acid and drinking water
containing 0.025% fumaric acid for 53 to 69 weeks. Hepatocytes were isolated from the liver by the collagenase
perfusion method and placed in culture, and their activity for DNA synthesis was measured in terms of the
incorporation of 3HdThd into DNA. An enhanced DNA synthesis of hepatocytes was noted in the rats given fumaric
acid, indicating that fumaric acid enhanced the proliferation of hepatocytes to counteract the carcinogenic effect of
3'methyl4dimethylaminoazobenzene. An electron microscopic examination indicated that the distribution of
subcellular organella was almost normal in the fumaric acidtreated hepatocytes. Abstract: PubMed
Kuroda K, Akao M; Chem Pharm Bull (Tokyo) 37 (5): 13456 (1989). Available from, as of December 23, 2009:
from HSDB
/IMMUNOTOXICITY/ The skin sensitization potential of eight unsaturated and one saturated lipid biochemicals was
tested in both the murine local lymph node assay LLNA and the guinea pig maximization test GPMT... Fumaric acid
... gave clearly negative results /in both assays/ . Abstract: PubMed
Kreiling R et al; Food Chem Toxicol 46 (6): 1896904 (2008). Available from, as of January 7, 2009:
from HSDB
/OTHER TOXICITY INFORMATION/ Studies ... show that rats tolerate about 3 times as much in the diet as in case of
maleic acid. /Fumaric acid and fumaric sodium/ ... were found to be less toxic orally than tartaric acid.
Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963., p. 1816
from HSDB
13.1.9 NonHuman Toxicity Values
LD50 Mouse ip 100 mg/kg

Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. WileyInterscience, Wiley & Sons, Inc. Hoboken,
NJ. 2004., p. 1828
from HSDB
LD50 Rat female oral 9300 mg/kg

from HSDB
LD50 Rat male oral 10,700 mg/kg.

from HSDB
LD50 Rabbit skin 20,000 mg/kg bw No mortality was observed at the high dose of 20,000 mg/kg bw
from HSDB
13.1.10 Ecotoxicity Values
LC50; Species: Brachydanio rerio Zebrafish; Conditions: static; Concentration: 245 mg/L for 48 hr
from HSDB
EC50; Species: Daphnia magna Water flea, age <24 hr larvae, 1st instar; Conditions: freshwater, static, 22 deg C, pH
7.7 7.08.2, hardness 154.5 mg/L CaCO3 89.5180 mg/L CaCO3, alkalinity 137.7 mg/L CaCO3 95156 mg/L CaCO3;
Concentration: 212000 ug/L for 48 hr 95% confidence interval: 204000220000 ug/L; Effect: intoxication,
immobilization
Randall TL, Knopp PV; J Water Pollut Control Fed 52 (8): 211730 (1980) as cited in the ECOTOX database. Available from, as of
December 24, 2009: http://cfpub.epa.gov/ecotox/quick_query.htm
from HSDB
EC50; Species: Daphnia magna water flea, first instar <24 hr old; Conditions: static; Concentration: 212 mg/L for 48 hr
95% confidence level 204220 mg/L; Effect: immobilization
from HSDB
EC50; Species: Scenedesmus subspicatus green algae; Conditions: UBA algal growth inhibition test; Concentration: 41
mg/L for 72 hr; Effect: Growth rate
from HSDB
13.2 Ecological Information
13.2.1 ICSC Environmental Data
The substance is harmful to aquatic organisms.

from ILOICSC
13.2.2 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, papersizing 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 1.54X104 mm Hg at 25 deg C
indicates fumaric acid will exist in both the vapor and particulate phases in the atmosphere. Vaporphase fumaric acid
will be degraded in the atmosphere by reaction with photochemicallyproduced hydroxyl radicals and ozone; the half
lives for these reactions in air are estimated to be 7 hours and 6 days, respectively. Particulatephase 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, 5day Theoretical BODs of 5770% 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 halflife
of fumaric acid in various natural waters ranged from 115 days using river dieaway 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 halflife 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
from HSDB
13.2.3 Natural Occurring Sources
Fumaric acid is commonly produced by organisms1; its presence in soils, dusts and plants can result from biogenic
sources1. Fumaric acid is found in many plants and is named after Fumaria officinalis, a climbing annual plant from
which it was initially isolated2. It has been quantified in star fruit and shepard's purse3.
(1) Kawamura K, Kaplan IR; Environ Sci Technol 21: 10510 (1987) (2) Felthouse TR et al; KirkOthmer Encyclopedia of Chemical
Technology. (2001). New York, NY: John Wiley & Sons; Maleic Anhydride, Maleic Acid, and Fumaric Acid. Online Posting Date:Oct
18, 2001. (3) USDA; Dr. Duke's Phytochemical and Ethnobotanical Databases. Plants with a chosen chemical. Fumaric Acid.
Washington, DC: US Dept Agric, Agric Res Service. Available from, as of August 20, 2010: http://www.arsgrin.gov/duke/
from HSDB
13.2.4 Artificial Sources
Fumaric acid's production and use in liquid pharmaceutical preparations as an acidulent and flavoring agent1; as a
modifier for polyester; in alkyd and phenolic resins, papersizing resins, plasticizers, rosin esters and adducts, alkyd
resin coating, and in upgrading natural drying oils especially tall oil to improve drying characteristics2 may result in
its release to the environment through various waste streamsSRC.
(1) Rowe RC et al, eds; Handbook of Pharmaceutical Excipients 6th ed., London, England: Pharmaceutical Press(2009) (2) Lewis RJ Sr;
Hawley's Condensed Chemical Dictionary. 15th ed., New York, NY: John Wiley & Sons, Inc. p. 586 (2007)
from HSDB
13.2.5 Environmental Fate
TERRESTRIAL FATE: Based on a classification scheme1, an estimated Koc value of 7SRC, determined from a
structure estimation method2, indicates that fumaric acid is expected to have very high mobility in soilSRC. The pKa
values of fumaric acid are 3.03 and 4.543, 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 counterparts4. Volatilization of fumaric acid from moist soil surfaces is not expected to be an important fate
processSRC given its pKa3. Fumaric acid is not expected to volatilize from dry soil surfacesSRC based upon a
vapor pressure of 1.54X104 mm Hg5. Using a Warburg respirometer and a sewage inoculum, 5 day Theoretical
BODs of 5770% were reported6, suggesting that biodegradation may be an important environmental fate process
in soilSRC.
(1) Swann RL et al; Res Rev 85: 1728 (1983) (2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.0. Jan, 2009. Available at
http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm as of Feb 19, 2010. (3) O'Neil MJ; The Merck Index. 14th ed., Whitehouse
Station, NJ: Merck and Co, Inc, pp 736 (2006) (4) Doucette WJ; pp. 141188 in Handbook of Property Estimation Methods for
Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000) (5) Yaws CL; Handbook of Vapor Pressure. Volume 1
C1 to C4 Compounds. Gulf Publishing Co: Houston, TX (1994) (6) Heukelekian H, Rand MD; J Water Pollut Control Assoc 27: 1040
53 (1955)
from HSDB
AQUATIC FATE: Based on a classification scheme1, an estimated Koc value of 7SRC, determined from a structure
estimation method2, indicates that fumaric acid is not expected to adsorb to suspended solids and sedimentSRC. A
pKa values of 3.03 and 4.543 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 process4. According to a
classification scheme5, an estimated BCF of 3SRC, from its log Kow of 0.466 and a regressionderived equation7,
suggests the potential for bioconcentration in aquatic organisms is lowSRC. Fumaric acid is not expected to undergo
hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions8.
The rate constant for the aqueous reaction of fumaric acid with photochemically produced hydroxyl radicals pH 4.5
10 is 6.0X10+9/Msec9; using a hydroxyl radical concentration of 3X1017 M in brightly sunlit natural water10, the
halflife would be 45 daysSRC. The halflife of fumaric acid in various natural waters ranged from 115 days using
river dieaway studies, indicating that biodegradation is an important environmental fate process in water11.
(1) Swann RL et al; Res Rev 85: 1728 (1983) (2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.0. Jan, 2009. Available at
http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm as of Feb 19, 2010. (3) O'Neil MJ; The Merck Index. 14th ed., Whitehouse
Station, NJ: Merck and Co, Inc, pp 736 (2006) (4) Doucette WJ; pp. 141188 in Handbook of Property Estimation Methods for
Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000) (5) Franke C et al; Chemosphere 29: 150114 (1994) (6)
Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed.,
Washington, DC: Amer Chem Soc p. 8 (1995) (7) Meylan WM et al; Environ Toxicol Chem 18: 66472 (1999) (8) Lyman WJ et al;
Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 74, 75 (1990) (9) Buxton GC et al; J
Phys Chem Ref Data 17: 722 (1988) (10) Mill T, Mabey W; pp. 20711 in Environmental Exposure From Chemicals Vol 1 Boca Raton,
FL: CRC Press (1985) (11) Saito N, Nagao M; OkayamaKen Kankyo Hoken Senta Nempo 2: 2746 (1978)
from HSDB
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the
atmosphere1, fumaric acid, which has a vapor pressure of 1.54X104 mm Hg at 25 deg C2, will exist in both the
vapor and particulate phases in the ambient atmosphere. Vaporphase fumaric acid is degraded in the atmosphere by
reaction with photochemicallyproduced hydroxyl radicals and ozoneSRC; the halflives for these reactions in air are
estimated to be 7 hours and 6 daysSRC, calculated from rate constants of 5.3X1011 cu cm/moleculesec3 and
1.8X1018 cu cm/moleculesec4, respectively. Particulatephase fumaric acid may be removed from the air by wet or
dry depositionSRC. Fumaric acid does not absorb UV light above 290 nm in methanol, acidic methanol, or basic
methanol solution5 and therefore is not expected to be susceptible to direct photolysis by sunlightSRC.
(1) Bidleman TF; Environ Sci Technol 22: 361367 (1988) (2) Yaws CL; Handbook of Vapor Pressure. Volume 1 C1 to C4
Compounds. Gulf Publishing Co: Houston, TX (1994) (3) Atkinson R; J Inter Chem Kinet 19: 799828 (1987) (4) Meylan WM, Howard
PH; Chemosphere 26: 229399 (1993) (5) Sadtler Research Lab; UV 165 (1966)
from HSDB
13.2.6 Biodegredation
AEROBIC: In river dieaway studies using various natural waters, the degradation halflife of fumaric acid ranged from
115 days with faster degradation occurring in more polluted waters1; degradation halflife in distilled water controls
was 55 days1. Using a microbe inoculum taken from three polluted surface waters, a 5 day Theoretical BOD of 34%
was measured2. Using a Warburg respirometer and a sewage inoculum, 5 day Theoretical BODs of 5770% were
measured at concentrations of 3.757.5 ppm3. Fumaric acid, present at 500 ppm, had a Theoretical BOD of 1.7%
after a 24hr incubation period in a Warburg respirometer using an activated sludge inoculum4. Using an activated
sludge adapted to phenol, a theoretical BOD of 41% was measured after a 12 hr incubation period in a Warburg
respirometer5.
(1) Saito N, Nagao M; OkayamaKen Kankyo Hoken Senta Nempo 2: 2746 (1978) (2) Dore M et al; Trib Cebedeau 28: 311 (1975)
(3) Heukelekian H, Rand MD; J Water Pollut Control Assoc 27: 104053 (1955) (4) Malaney GW, Gerhold RM; J Water Pollut Control
Fed 41: R18R33 (1969) (5) McKinney RE et al; Sewage Ind Wastes 28: 54757 (1956)
from HSDB
13.2.7 Abiotic Degredation
The rate constant for the vaporphase reaction of fumaric acid with photochemicallyproduced hydroxyl radicals has
been estimated as 5.3X1011 cu cm/moleculesec at 25 deg C1. This corresponds to an atmospheric halflife of
about 7 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm2. The rate constant for the
vaporphase reaction of fumaric acid with ozone has been estimated as 1.8X1018 cu cm/moleculesec at 25 deg
CSRC that was derived using a structure estimation method2. This corresponds to an atmospheric halflife of about
6 days at an atmospheric concentration of 7X10+11 ozone molecules per cu cm3. The rate constant for the aqueous
reaction of fumaric acid with photochemically produced hydroxyl radicals pH 4.510 is 6.0X10+9/Msec4; using a
hydroxyl radical concentration of 3X1017 M in brightly sunlit natural water5, the halflife would be 45 daysSRC.
Since fumaric acid is a substituted olefin, reaction with sunlightformed singlet oxygen in water may be just as fast or
faster than reaction with OH radicals5. Fumaric acid is not expected to undergo hydrolysis in the environment due to
the lack of functional groups that hydrolyze under environmental conditions6. Fumaric acid does not absorb UV light
above 290 nm in methanol, acidic methanol, or basic methanol solution7 and therefore is not expected to be
susceptible to direct photolysis by sunlightSRC.
(1) Atkinson R; J Inter Chem Kinet 19: 799828 (1987) (2) Meylan WM, Howard PH; Chemosphere 26: 229399 (1993) (3) Atkinson R,
Carter WPL; Chem Rev 84: 43770 (1984) (4) Buxton GC et al; J Phys Chem Ref Data 17: 722 (1988) (5) Mill T, Mabey W; pp. 20711
in Environmental Exposure From Chemicals Vol 1 Boca Raton, FL: CRC Press (1985) (6) Lyman WJ et al; Handbook of Chemical
Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 74, 75 (1990) (7) Sadtler Research Lab; UV 165 (1966)
from HSDB
13.2.8 Bioconcentration
An estimated BCF of 3 was calculated in fish for fumaric acidSRC, using a log Kow of 0.461 and a regressionderived
equation2. According to a classification scheme3, this BCF suggests the potential for bioconcentration in aquatic
organisms is lowSRC.
(1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed.,
Washington, DC: Amer Chem Soc p. 8 (1995) (2) Meylan WM et al; Environ Toxicol Chem 18: 66472 (1999) (3) Franke C et al;
Chemosphere 29: 150114 (1994)
from HSDB
13.2.9 Soil Adsorption/Mobility
Using a structure estimation method based on molecular connectivity indices1, the Koc of fumaric acid can be
estimated to be 7SRC. According to a classification scheme2, 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 4.543, 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 counterparts4.
(1) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.0. Jan, 2009. Available at
http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm as of Feb 19, 2010. (2) Swann RL et al; Res Rev 85: 1728 (1983) (3) O'Neil
MJ; The Merck Index.14th ed., Whitehouse Station, NJ: Merck and Co, Inc, pp 736 (2006) (4) Doucette WJ; pp. 141188 in Handbook
of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)
from HSDB
13.2.10 Volatilization from Water/Soil
The pKa values of 3.03 and 4.541 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 process2.
Fumaric acid is not expected to volatilize from dry soil surfacesSRC based upon a vapor pressure of 1.54X104 mm
Hg3.
(1) O'Neil MJ; The Merck Index. 14th ed., Whitehouse Station, NJ: Merck and Co, Inc, pp 736 (2006) (2) Doucette WJ; pp. 141188 in
Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds, Boca Raton, FL: Lewis Publ (2000) (3) Yaws
CL; Handbook of Vapor Pressure. Volume 1 C1 to C4 Compounds. Gulf Publishing Co: Houston, TX (1994)
from HSDB
13.2.11 Water Concentrations
GROUNDWATER: Fumaric acid was not detected in 2 samples and detected at <5 ng/L in 1 groundwater sample taken
from wells in Barcelona, Spain1.
(1) Guardiola J et al; Water Supply 7: 116 (1989)
from HSDB
DRINKING WATER: Fumaric acid was not detected in all 3 filtered samples taken from wells in Barcelona, Spain1.
(1) Guardiola J et al; Water Supply 7: 116 (1989)
from HSDB
RAIN/SNOW: Rain and snow water collected from rural areas near Hubbard Brook, NH and semirural areas near
Ithaca, NY between June 1976 and May 1977 was found to contain fumaric acid1. Fumaric acid was detected at
0.0270.36 uM in precipitation samples from Southern CA, taken Nov 1982 to June 1984 and at 0.012.08 uM in
precipitation samples from west Los Angeles, CA, taken Mar 1982 to Dec 19832.
(1) Mazurek MA, Simoneit BR; CRC Critical Reviews in Environmental Control 16: 74 (1986) (2) Kawamura K et al; Atmos Environ 30:
103552 (1996)
from HSDB
13.2.12 Effluents Concentrations
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, respectively1.
(1) Kawamura K, Kaplan IR; Environ Sci Technol 21: 10510 (1987)
from HSDB
13.2.13 Sediment/Soil Concentrations
SEDIMENT: Bog sediments collected in the foothills of the Sierra Nevada Mountains contained fumaric acid levels of
4.76 mg/kg1.
from HSDB
SOIL: Soil samples collected on the campus of UCLA in Los Angeles, CA contained fumaric acid levels of 0.20.6
mg/kg1.
from HSDB
13.2.14 Atmospheric Concentrations
URBAN/SUBURBAN: Air samples collected in west and downtown Los Angeles, CA during June and Oct 1984
contained fumaric acid concentrations of 3.5147.4 ng/cu m1; the fumaric acid detected was associated primarily
with atmospheric particles rather than the vaporphase1. Samples taken from Tokyo Metropolitan University, Japan,
April 1988 to Feb 1989, contained 0.71.5 ng/cu m of fumaric acid2. Samples taken Feb and July 1992 in Tokyo,
Japan contained 1044 ng/cu m of fumaric acid3. Fumaric acid was detected at 2.934.7 ng/cu m in 27 samples taken
from 7 locations in Hong Kong, in samples taken Oct to Dec 20034. Fumaric acid was detected in daytime air
samples at 1.4613.0 and 7.4715.6 ng/cu m on July 2004 and Jan 2005 and in nighttime air samples at 5.7221.4 and
1.6830.4 ng/cu m on the same dates5.
(1) Kawamura K, Kaplan IR; Environ Sci Technol 21: 10510 (1987) (2) Kawamura K, Ikushima K; Environ Sci Technol 27: 222735
(1993) (3) Sempere R, Kawamura K; Atmos Environ 28: 44959 (1994) (4) Li YC, Yu JZ; Environ Sci Technol 39: 761624 (2005) (5)
Wang G, Kawamura K; Environ Sci Technol 39: 74308 (2005)
from HSDB
RURAL/REMOTE: Atomospheric samples taken from Alert, Canada, July 1987 to June 1988, contained 0.0171.1 ng/cu
m of fumaric acid1.
(1) Kawamura K et al; Atmos Environ 30: 170922 (1996)
from HSDB
SOURCE DOMINATED: Fumaric acid was detected in the Shing Mun Tunnel, Hong Kong at 2.713.5 and 5.816.4 ng/cu
m in samples taken Aug 2003 and Feb 2004, respectively1.
(1) Wang H et al; Environ Sci Technol 40: 625560 (2006)
from HSDB
13.2.15 Food Survey Values
REPORTED USES: NONALCOHOLIC BEVERAGES: 50 PPM; BAKED GOODS: 1300 PPM; GELATINS & PUDDINGS: 3600
PPM.
Fenaroli's Handbook of Flavor Ingredients. Volume 2. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed.
Cleveland: The Chemical Rubber Co., 1975., p. 206
from HSDB
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 drinks1.
(1) O'Neil MJ; The Merck Index. 14th ed., Whitehouse Station, NJ: Merck and Co, Inc, pp 736 (2006)
from HSDB
13.2.16 Plant Concentrations
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, 11.6475.16; Gyroporus castaneus 74.65 ;
Lactarius deliciosus, 13.18237.56; Suillus collintus, 49.49397.16; Xerocomus chrysenteron, 12.77. Samples were
collected in 20031.
(1) Valentao P et al; J Agric Food Chem 53: 362630 (2005)
from HSDB
Plants with the highest amount of Fumaric Acid1.

Genus species Common names Concentration Area of Plant
Averrhoa carambola L. Carambola, Star Fruit 0 3,100 ppm Fruit
Capsella bursapastoris L. MEDICUS Shepard's Purse 1,400 ppm Plant
(1) USDA; Dr. Duke's Phytochemical and Ethnobotanical Databases. Plants with a chosen chemical. Fumaric Acid. Washington, DC:
US Dept Agric, Agric Res Service. Available from, as of August 20, 2010: http://www.arsgrin.gov/duke/
from HSDB
13.2.17 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/kg1.
from HSDB
13.2.18 Probable Routes of Human Exposure
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
underestimated1.
(1) US EPA; Inventory Update Reporting (IUR). Nonconfidential 2006 IUR Records by Chemical, including Manufacturing, Processing
and Use Information. Washington, DC http://cfpub.epa.gov/iursearch/index.cfm
from HSDB
NIOSH NOES Survey 19811983 has statistically estimated that 136,448 workers 48,919 of these were female were
potentially exposed to fumaric acid in the US1. 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 acidSRC.
(1) NIOSH; NOES. National Occupational Exposure Survey conducted from 19811983. Estimated numbers of employees potentially
exposed to specific agents by 2digit standard industrial classification (SIC). Available from, as of Feb 19, 2010:
http://www.cdc.gov/noes/
from HSDB
14 Literature
14.1 Depositor Provided PubMed Citations
CLICK TO LOAD...
from PubChem
14.2 NLM Curated PubMed Citations
CLICK TO LOAD...
from PubChem
14.3 Synthesis References

Yasuhisha Fukumoto, Noboru Moriyama, Takashi Itoi, "Maleic acid copolymer, production thereof and scale
preventing agent containing the same." U.S. Patent US4589995, issued August, 1933.
from DrugBank
Chung Kun Shih, Craig W. Gleason, Edmund H. Braun, II, "Solventless process for producing dialkyl fumaratevinyl
acetate copolymers." U.S. Patent US4772674, issued September, 1980.
from DrugBank
Dong, Changsheng; Ma, Xinming. Method for preparation of fumaric acid from the tail gas acid spray solution from
oxidation of phthalic anhydride. Faming Zhuanli Shenqing Gongkai Shuomingshu 2007, 5pp.
14.4 Metabolite References
Download
1 to 5 of 5
PMID Reference
Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, Laxman B, Mehra R, Lonigro RJ, Li Y,
Nyati MK, Ahsan A, KalyanaSundaram S, Han B, Cao X, Byun J, Omenn GS, Ghosh D, Pennathur S,
19212411 Alexander DC, Berger A, Shuster JR, Wei JT, Varambally S, Beecher C, Chinnaiyan AM: Metabolomic
profiles delineate potential role for sarcosine in prostate cancer progression. Nature. 2009 Feb
12;4577231:9104. doi: 10.1038/nature07762.
Shoemaker JD, Elliott WH: Automated screening of urine samples for carbohydrates, organic and amino
2026685
acids after treatment with urease. J Chromatogr. 1991 Jan 2;56212:12538.
Guneral F, Bachmann C: Agerelated reference values for urinary organic acids in a healthy Turkish
8087979
pediatric population. Clin Chem. 1994 Jun;406:8626.
Hoffmann GF, MeierAugenstein W, Stockler S, Surtees R, Rating D, Nyhan WL: Physiology and
8412012
pathophysiology of organic acids in cerebrospinal fluid. J Inherit Metab Dis. 1993;164:64869.
RedjemsBennani N, Jeandel C, Lefebvre E, Blain H, Vidailhet M, Gueant JL: Abnormal substrate levels
9693263 that depend upon mitochondrial function in cerebrospinal fluid from Alzheimer patients. Gerontology.
1998;445:3004.
15 Patents
15.1 DepositorSupplied Patent Identifiers
CLICK TO LOAD...
from PubChem
16 Biomolecular Interactions and Pathways
16.1 Protein Bound 3D Structures
CLICK TO LOAD...
from PubChem
16.2 Biosystems and Pathways
CLICK TO LOAD...
from PubChem
16.3 DrugBank Interactions
Target Fumarylacetoacetase
General
Metal ion binding
Function
Gene
FAH
Name
Overington JP, AlLazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006
Reference
Dec;512:9936. Pubmed
Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev
Reference
Drug Discov. 2006 Oct;510:82134. Pubmed
Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The
Reference
Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;281:23542. Pubmed
from DrugBank
Target Aromaticaminoacid aminotransferase
General Pyridoxal phosphate binding

Function
Specific
Shows activities toward both dicarboxylic and aromatic substrates.
Function
Gene
tyrB
Name
GenBank
Y08272
Gene
GenBank
1806263
Protein
Overington JP, AlLazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov.
Reference
2006 Dec;512:9936. Pubmed
Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat
Reference
Rev Drug Discov. 2006 Oct;510:82134. Pubmed
from DrugBank
Target Trypanothione reductase
General
Trypanothionedisulfide reductase activity
Function
Specific Trypanothione is the parasite analog of glutathione; this enzyme is the equivalent of glutathione
Function reductase.
Gene
TPR
Name
GenBank
M38051
Gene
GenBank
162317
Protein
Overington JP, AlLazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov.
Reference
2006 Dec;512:9936. Pubmed
Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat
Reference
Rev Drug Discov. 2006 Oct;510:82134. Pubmed
from DrugBank
View all 10 DrugBank Interactions entries
17 Biological Test Results
17.1 BioAssay Results
CLICK TO LOAD...
from PubChem
18 Classification
18.1 Ontologies
18.1.1 MeSH Tree
CLICK TO LOAD...
from MeSH
18.1.2 ChEBI Ontology
CLICK TO LOAD...
from ChEBI
18.1.3 KEGG: ATC
CLICK TO LOAD...
from KEGG
18.1.4 KEGG: Additive
CLICK TO LOAD...
from KEGG
18.1.5 WHO ATC Classification System
CLICK TO LOAD...
from WHO ATC
18.1.6 WIPO IPC
CLICK TO LOAD...
from WIPO
18.1.7 EPA Safer Choice
CLICK TO LOAD...
19 Information Sources
1. CAMEO Chemicals /source/CAMEO Chemicals
Fumaric acid
https://cameochemicals.noaa.gov/chemical/3517 https://cameochemicals.noaa.gov/chemical/3517
2. ChemIDplus /source/ChemIDplus
Fumaric acid [NF]
https://chem.nlm.nih.gov/chemidplus/sid/0000110178 https://chem.nlm.nih.gov/chemidplus/sid/0000110178
2Butenedioic acid
https://chem.nlm.nih.gov/chemidplus/sid/0006915180 https://chem.nlm.nih.gov/chemidplus/sid/0006915180
3. DrugBank /source/DrugBank
Maleic Acid
http://www.drugbank.ca/drugs/DB04299 http://www.drugbank.ca/drugs/DB04299
Fumarate
http://www.drugbank.ca/drugs/DB01677 http://www.drugbank.ca/drugs/DB01677
http://www.drugbank.ca/drugs/DB01677#targets http://www.drugbank.ca/drugs/DB01677#targets
http://www.drugbank.ca/drugs/DB04299#targets http://www.drugbank.ca/drugs/DB04299#targets
4. EPA Chemicals under the TSCA /source/EPA Chemicals under the TSCA
2Butenedioic acid (2E)
http://www.epa.gov/chemicaldatareporting http://www.epa.gov/chemicaldatareporting
5. EPA DSStox /source/EPA DSStox

Fumaric acid
https://comptox.epa.gov/dashboard/dsstoxdb/results?search=DTXSID3021518
https://comptox.epa.gov/dashboard/dsstoxdb/results?search=DTXSID3021518
6. European Chemicals Agency ECHA /source/European Chemicals Agency ECHA

Fumaric acid
https://echa.europa.eu/ https://echa.europa.eu/
Fumaric acid
https://echa.europa.eu/informationonchemicals/clinventorydatabase//discli/details/27136
https://echa.europa.eu/informationonchemicals/clinventorydatabase//discli/details/27136
7. Human Metabolome Database /source/Human Metabolome Database

Fumaric acid
http://www.hmdb.ca/metabolites/HMDB00134 http://www.hmdb.ca/metabolites/HMDB00134
8. ILOICSC /source/ILOICSC
FUMARIC ACID
http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=1173 http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=1173
9. The National Institute for Occupational Safety and Health NIOSH /source/The National
Institute for Occupational Safety and Health NIOSH
Fumaric acid
https://www.cdc.gov/nioshrtecs/LS92DDA8.html https://www.cdc.gov/nioshrtecs/LS92DDA8.html
10. EU Food Improvement Agents /source/EU Food Improvement Agents

FUMARIC ACID
http://eurlex.europa.eu/legalcontent/EN/ALL/?uri=CELEX%3A32012R0231 http://eurlex.europa.eu/legalcontent/EN/ALL/?
uri=CELEX%3A32012R0231
Fumaric acid
http://eurlex.europa.eu/legalcontent/EN/TXT/?uri=CELEX:32012R0872 http://eurlex.europa.eu/legalcontent/EN/TXT/?
uri=CELEX:32012R0872
11. HSDB /source/HSDB

Fumaric acid
http://toxnet.nlm.nih.gov/cgibin/sis/search/r?dbs+hsdb:@term+@rn+@rel+110178 http://toxnet.nlm.nih.gov/cgi
bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+110178
12. OSHA Chemical Sampling Information /source/OSHA Chemical Sampling Information

Fumaric Acid
https://www.osha.gov/dts/chemicalsampling/data/CH_242870.html
https://www.osha.gov/dts/chemicalsampling/data/CH_242870.html
13. ClinicalTrials.gov /source/ClinicalTrials.gov

fumaric acid
https://clinicaltrials.gov/ https://clinicaltrials.gov/
14. EPA Safer Choice /source/EPA Safer Choice

Fumaric acid
https://www.epa.gov/saferchoice/saferingredients https://www.epa.gov/saferchoice/saferingredients
EPA Safer Chemical Ingredients Classification
https://www.epa.gov/saferchoice https://www.epa.gov/saferchoice
15. FAO/WHO Food Additive Evaluations JECFA /source/FAO/WHO Food Additive Evaluations
JECFA
ALLOMALEIC ACID
http://apps.who.int/foodadditivescontaminantsjecfadatabase/chemical.aspx?chemID=2360 http://apps.who.int/food
additivescontaminantsjecfadatabase/chemical.aspx?chemID=2360
16. EU REGULATION EC No 1272/2008 /source/EU REGULATION EC No 1272/2008

fumaric acid
http://ec.europa.eu/growth/sectors/chemicals/classificationlabelling/index_en.htm
http://ec.europa.eu/growth/sectors/chemicals/classificationlabelling/index_en.htm
17. NITECMC /source/NITECMC

Fumaric acid
http://www.safe.nite.go.jp/english/ghs/09mhlw2103e.html http://www.safe.nite.go.jp/english/ghs/09mhlw2103e.html
18. Safe Work Australia HCIS /source/Safe Work Australia HCIS

110178
http://hcis.safeworkaustralia.gov.au/ http://hcis.safeworkaustralia.gov.au/
19. FDA/SPL Indexing Data /source/FDA/SPL Indexing Data

88XHZ13131
https://www.fda.gov/ForIndustry/DataStandards/SubstanceRegistrationSystemUniqueIngredientIdentifierUNII/
https://www.fda.gov/ForIndustry/DataStandards/SubstanceRegistrationSystemUniqueIngredientIdentifierUNII/
20. Flavor & Extract Manufacturers Association FEMA /source/Flavor & Extract Manufacturers
Association FEMA
FUMARIC ACID
https://www.femaflavor.org/flavor/library/fumaricacid https://www.femaflavor.org/flavor/library/fumaricacid
21. NIST /source/NIST

But2enedioic acid
http://www.nist.gov/srd/nist1a.cfm http://www.nist.gov/srd/nist1a.cfm
22. NJDOH RTK Hazardous Substance List /source/NJDOH RTK Hazardous Substance List
fumaric acid
http://nj.gov/health/eoh/rtkweb/documents/fs/0949.pdf http://nj.gov/health/eoh/rtkweb/documents/fs/0949.pdf
23. WHO ATC /source/WHO ATC

http://www.whocc.no/atc/ http://www.whocc.no/atc/
ATC Code
https://www.whocc.no/atc_ddd_index/ https://www.whocc.no/atc_ddd_index/
24. Wikipedia /source/Wikipedia

fumaric acid
https://en.wikipedia.org/wiki/Fumaric_acid https://en.wikipedia.org/wiki/Fumaric_acid
ammonium fumarate
https://en.wikipedia.org/wiki/Ammonium_fumarate https://en.wikipedia.org/wiki/Ammonium_fumarate
butenedioic acid
https://www.wikidata.org/wiki/Q27109609 https://www.wikidata.org/wiki/Q27109609
25. PubChem
Data deposited in or computed by PubChem
https://pubchem.ncbi.nlm.nih.gov https://pubchem.ncbi.nlm.nih.gov
26. MeSH /source/MeSH

fumaric acid
https://www.ncbi.nlm.nih.gov/mesh/67032005 https://www.ncbi.nlm.nih.gov/mesh/67032005
MeSH Tree
http://www.nlm.nih.gov/mesh/meshhome.html http://www.nlm.nih.gov/mesh/meshhome.html
27. ChEBI /source/ChEBI

ChEBI Ontology
http://www.ebi.ac.uk/chebi/userManualForward.do#ChEBI%20Ontology
http://www.ebi.ac.uk/chebi/userManualForward.do#ChEBI%20Ontology
28. KEGG /source/KEGG

ATC
http://www.genome.jp/dbgetbin/www_bget?brite:br08303 http://www.genome.jp/dbgetbin/www_bget?brite:br08303
Additive
http://www.genome.jp/dbgetbin/www_bget?brite:br08316 http://www.genome.jp/dbgetbin/www_bget?brite:br08316
29. WIPO /source/WIPO

International Patent Classification
http://www.wipo.int/classifications/ipc/ http://www.wipo.int/classifications/ipc/
30. NCBI
LinkOut is a service that allows one to link directly from NCBI databases to a wide range of information and services beyond
NCBI systems.
https://www.ncbi.nlm.nih.gov/projects/linkout https://www.ncbi.nlm.nih.gov/projects/linkout

Fumaric Acid - C4H4O4 - PubChem

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2017618 fumaricacid|C4H4O4PubChem

Compound Summary for CID 444972

Fumaric Acid Cite this Record

PubChem CID: 444972

Molecular Formula: C4H4O4 or COOHCH=CHCOOH

Drug Information: Therapeutic Uses Clinical Trials FDA UNII

Safety Summary: Laboratory Chemical Safety Summary LCSS

PUBCHEM COMPOUND FUMARIC ACID Create Date: 20040916

3 Names and Identifiers

4 Chemical and Physical Properties

7 Drug and Medication Information

8 Food Additives and Ingredients

9 Pharmacology and Biochemistry

10 Use and Manufacturing

12 Safety and Hazards

16 Biomolecular Interactions and Pathways

17 Biological Test Results

Show Hydrogens Show Atoms Animate

3 Names and Identifiers

3.1 Computed Descriptors

3.1.1 IUPAC Name

3.1.3 InChI Key

3.1.4 Canonical SMILES

3.1.5 Isomeric SMILES

3.2 Molecular Formula

3.3 Other Identifiers

3.3.3 FEMA Number

3.3.4 ICSC Number

3.3.5 RTECS Number

Title fumaric acid

Description chemical compound

Title ammonium fumarate

Description chemical compound

Title butenedioic acid

Description chemical compound

3.4.1 MeSH Synonyms

3.4.2 DepositorSupplied Synonyms

4 Chemical and Physical Properties

4.1 Computed Properties

Property Name Property Value

Molecular Weight 116.072 g/mol

Hydrogen Bond Donor Count 2

Hydrogen Bond Acceptor Count 4

Rotatable Bond Count 2

Topological Polar Surface Area 74.6 A^2

Monoisotopic Mass 116.011 g/mol

Exact Mass 116.011 g/mol

Compound Is Canonicalized true

Heavy Atom Count 8

Defined Atom Stereocenter Count 0

Undefined Atom Stereocenter Count 0

Defined Bond Stereocenter Count 1

Undefined Bond Stereocenter Count 0

Isotope Atom Count 0

CovalentlyBonded Unit Count 1

4.2 Experimental Properties

4.2.1 Physical Description

from EPA Chemicals under the TSCA

White crystalline powder or granules

ODOURLESS COLOURLESS CRYSTALLINE POWDER.

Needles, monoclinic prisms or leaflets from water

WHITE CRYSTALLINE POWDER

4.2.5 Boiling Point