Microbial Metabolite; Endogenous Metabolite; Flavoring Agents; Alters several flavor and/or taste characteristics; Food additives; Fragrance Ingredients; Cosmetics -> Buffering; Environmental transformation -> Pesticide transformation products (metabolite, successor)

Fermentation of agricultural carbohydrates yields tromethamine succinate [2].
Succinic acid is considered as an important platform chemical. Succinic acid fermentation with Actinobacillus succinogenes strain BE-1 was optimized by central composite design (CCD) using a response surface methodology (RSM). The optimized production of succinic acid was predicted and the interactive effects between glucose, yeast extract, and magnesium carbonate were investigated. As a result, a model for predicting the concentration of succinic acid production was developed. The accuracy of the model was confirmed by the analysis of variance (ANOVA), and the validity was further proved by verification experiments showing that percentage errors between actual and predicted values varied from 3.02% to 6.38%. In addition, it was observed that the interactive effect between yeast extract and magnesium carbonate was statistically significant. In conclusion, RSM is an effective and useful method for optimizing the medium components and investigating the interactive effects, and can provide valuable information for succinic acid scale-up fermentation using A. succinogenes strain BE-1[1].

Tromethamine succinate (3, 6 mg/kg; oral) increases the percentage of male mice accessing the open arm and the time spent in the open arm [3]. Tromethamine succinate (3, 6, 12 mg/kg; i.p.) significantly enhanced food intake after 5 minutes of delivery, and rectal temperatures were recorded 40 minutes after administration, at doses of 1.5 mg/kg of amber Acid, prevents stress-induced hyperthermia [3].

The putative anxiolytic activity of succinic acid was examined in male mice by using a number of experimental paradigms of anxiety and compared with that of the known anxiolytic compound diazepam. Use of the elevated plus-maze test revealed that diazepam (1.0, 2.0 and 4.0 mg/kg, PO) or succinic acid (3.0 or 6.0 mg/kg, PO) increased the percentage of entries into open arms and of time spent on open arms. In novel food consumption test, succinic acid (3.0, 6.0, and 12.0 mg/kg, IP) caused significant increases in food intake during 5 min when compared with the vehicle. In the stress-induced hyperthermia test, 40 min after drug administration rectal temperature was measured, succinic acid at dose of 1.5 mg/kg, inhibited stress-induced hyperthermia. Thus, these findings indicated that, in contrast with diazepam, succinic acid exhibits anxiolytic-like effect.[3]

Absorption, Distribution, and Excretion
Succinic acid is normally present in human urine (1.9-8.8 mg/L).
Metabolism/Metabolites
Succinic acid is a normal intermediate metabolite and a component of the citric acid cycle. When administered to animals, it is readily metabolized, but in large doses, some succinic acid may be excreted unchanged in the urine.
Succinic acid can be oxidized to fumarate by succinate dehydrogenase.
Pesticide Transformation
Succinic acid is a known environmental transformation product of sulfadiazine.
Succinic acid is a known environmental transformation product of linuron.

Toxicity Overview
Succinate inhibits the activity of α-ketoglutarate-dependent oxygenases (KDMs) and TET family 5-methylcytosine (5mC) hydroxylases. Succinate also mediates allosteric inhibition of hypoxia-inducible factor (HIF) prolyl hydroxylases (PHDs). Inhibition of HIF PHDs activates HIF-mediated pseudohypoxia responses, while inhibition of KDMs and TET family 5mC hydroxylases leads to epigenetic alterations, ultimately resulting in cancer. Succinylation of KEAP1 in FH deficiency leads to constitutive activation of NRF2-mediated antioxidant defense pathways, creating a reducing environment that promotes cell proliferation. Succinylation of the Krebs cycle enzyme Aco2 impairs aconitase activity in Fh1-deficient MEF cells. Succinylation also leads to irreversible inactivation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH).

---

Health Effects
Succinate can irritate the skin at acute doses or exposure. Long-term high doses of succinate can lead to succinylation or succinification of various enzymes. A partial deficiency of succinate dehydrogenase in skeletal muscle (15% to 50% of normal reference enzyme activity) results in elevated succinate levels and causes mitochondrial myopathy, leading to a variety of symptoms such as brain involvement, cardiomyopathy, and/or exercise intolerance.

---

Routes of Exposure
Eye contact, inhalation, ingestion.

---

Symptoms
Acute exposure: Clinical symptoms of acute poisoning include weakness and diarrhea.

---

Adverse Reactions
Neurotoxins - Other Central Nervous System Neurotoxins

---

View More

Toxicity Data
Acute Oral Toxicity (LD50): 2260 mg/kg [Rat].

---

Treatment
Eyes: Rinse open eyes with running water for several minutes. Ingestion: Do not induce vomiting. Rinse mouth with water (never feed anything to an unconscious person). Seek immediate medical attention. Skin: Immediately rinse affected area with cold water for at least 15 minutes, then wash thoroughly with soap and water. If necessary, the patient should shower and change contaminated clothing and shoes, and must then seek medical attention. Inhalation: Provide fresh air. If necessary, perform artificial respiration.

---

Human Toxicity Excerpt
/Other Toxicity Information/ Many aliphatic dicarboxylic acids have major irritant effects, especially in concentrated solutions or dust—sensitization is rare. /Aliphatic Dicarboxylic Acids/ International Labour Organization. Encyclopedia of Occupational Health and Safety, Volumes 1 and 2. New York: McGraw-Hill Books, 1971, p. 30.

---

Non-Human Toxicity Excerpt/Laboratory Animals: Acute Exposure/Succinic acid is mildly irritating to the skin and strongly irritating to the eyes of rats. A 15% solution of 750 micrograms of succinic acid caused severe damage to the eyes of rabbits. Clinical symptoms of acute poisoning in rats were weakness and diarrhea.
/Laboratory Animals: Acute Exposure/ High-dose intravenous administration of sodium succinate can cause vomiting and diarrhea in cats…
/Experimental Animals: Subchronic or Pre-chronic Exposure/ Rats/Fischer (F344) Males and Females, 10 rats per group/Exposed to/ 13 weeks, free access to/0, 0.3, 0.6, 1.25, 2.5, 5, 10% sodium succinate (100.2% purity). …The weight gain of rats in the 10% group was severely inhibited, and all rats in this group died within the first 4 weeks of the experiment. However, all rats in the other dose groups survived to the end of the experiment. Inhibition of weight gain was observed at concentrations ≥2.5%. Water intake was very low in the highest dose group, although water intake was higher in the 5% group than in the other groups. No dose-related specific changes were observed in any parameters of hematological and biochemical assays. Rats that died during the experiment were severely emaciated. However, despite the observation of organ atrophy, histopathological examination did not reveal any toxic lesions caused by the test substance in any organs of these rats. No specific lesions were observed in histological examination of any other experimental groups. Based on the weight loss inhibition, the maximum tolerated dose of sodium monosuccinate in drinking water was determined to be approximately 2-2.5%.

---

Non-human toxicity values
Oral LD50 in rats: 2260 mg/kg

[1]. Optimization of succinic acid fermentation with Actinobacillus succinogenes by response surface methodology (RSM). J Zhejiang Univ Sci B. 2012 Feb;13(2):103-10.

[2]. The production of propionic acid by decarboxylation of succinic acid in a bacterial fermentation. Biochem J. 1948;42(1):ii.

[3]. Si Wei Chen, Anxiolytic-like effect of succinic acid in mice. Life Sci. 2003 Nov 7;73(25):3257-64.

Succinic acid is a white crystal or a lustrous white, odorless crystalline powder. The pH of a 0.1 mol/L solution is 2.7. It has an extremely sour taste. (NTP, 1992) National Toxicology Program (NTP), Institute of Environmental Health Sciences, National Institutes of Health. 1992. National Toxicology Program Chemical Database. Research Triangle Park, North Carolina. Succinic acid is an α,ω-dicarboxylic acid, produced by the oxidation of the terminal methyl group of butane to the corresponding carboxyl group. It is an intermediate metabolite in the citric acid cycle. It has various uses, including as a nutritional supplement, radiation protectant, anti-ulcer drug, micronutrient, and basic metabolite. It is an α,ω-dicarboxylic acid, and also a C4-dicarboxylic acid. It is the conjugate acid of succinic acid (1-). Succinic acid is a water-soluble, colorless crystal with a sour taste, used as a chemical intermediate, pharmaceutical raw material, paint manufacturing raw material, and fragrance ester raw material. It is also used as a chelating agent, buffer, and neutralizing agent in food. (Hawley's Concise Dictionary of Chemistry, 12th edition, p. 1099; McGraw-Hill Dictionary of Scientific and Technical Terminology, 4th edition, p. 1851)
Succinic acid is a metabolite found or produced in Escherichia coli (K12 strain, MG1655 strain).
Succinic acid has also been reported in tea plants, Pseudomonas aeruginosa, and several other organisms with relevant data.
Succinic acid is a dicarboxylic acid. The succinate anion is a component of the citric acid cycle and can donate electrons to the electron transport chain. Succinic acid is a byproduct of sugar fermentation, giving fermented beverages such as wine and beer a unique salty, bitter, and sour flavor. Succinic acid is commonly used as a chemical intermediate in pharmaceuticals, paint manufacturing, and the production of flavor esters. It is also used as a chelating agent, buffer, and neutralizing agent in food. Succinate plays a role in the citric acid cycle (an energy-producing process) and is metabolized to fumarate by succinate dehydrogenase. Succinate dehydrogenase (SDH) plays a crucial role in cellular mitochondria, serving as both a component of the respiratory chain and the Krebs cycle. Succinate dehydrogenase (SDH) carries a covalently linked FAD prosthetic group that binds to enzyme substrates (succinate and fumarate) as well as physiological regulators (oxaloacetate and ATP). Oxidation of succinate links SDH to the rapidly circulating Krebs cycle portion, participating in the breakdown of acetyl-CoA throughout the Krebs cycle. Succinate can be readily introduced into the mitochondrial matrix via dicarboxylic acid carriers sensitive to n-butylmalonic acid (or phenylsuccinate), exchanging it with inorganic phosphates or other organic acids (such as malic acid). Mutations in the four genes encoding the succinate dehydrogenase subunit (A3509) are associated with a variety of clinical manifestations (e.g., Huntington's disease). (A3510) Succinic acid is also a carcinogenic metabolite. Succinic acid inhibits 2-ketoglutarate-dependent histone and DNA demethylases, leading to epigenetic silencing and thus affecting neuroendocrine differentiation. Succinic acid is a water-soluble, colorless crystal with a sour taste. It can be used as a chemical intermediate, pharmaceutical raw material, paint manufacturing raw material, and flavor ester raw material. It can also be used as a chelating agent, buffer, and neutralizing agent in food.

---

View MoreSources/Uses
Found in fossils, fungi, and lichens; [Merck Index] Found in almost all plant and animal tissues; used in the manufacture of varnishes, dyes, perfume esters, alkyd resins, pharmaceuticals, plasticizers, lubricants, and pesticides; also used in photography, as a food chelating agent, buffer and neutralizer, radiation dosimetry, and to promote plant growth and increase crop yields.
Succinic acid has a wide range of uses, from scientific applications such as radiation dosimetry and standard buffer solutions to agriculture, food, medicine, plastics, cosmetics, textiles, electroplating, and waste gas scrubbing. Kirk-Osmer Encyclopedia of Chemical Technology, 3rd Edition, Volumes 1-26. New York: John Wiley & Son, 1978-1984, Vol. 21 Page 848.
Succinic acid is used as a starting material for the manufacture of alkyd resins and dyes. Succinic acid can be used in the fields of medicine and pesticides. It reacts with ethylene glycol to produce polyester; the esters produced by reacting with monools are important plasticizers and lubricants.
In grain cultivation, succinic acid is a biostimulant that can promote rapid plant growth and increase yield.
Succinic acid is a precursor of some special polyesters and a component of some alkyd resins. Succinic acid is mainly used as an acidity regulator in the food and beverage industry. It is also sold as a food additive and dietary supplement and is generally considered safe by the US FDA.

---

Production method
Succinic acid can be produced in high yield by the hydrogenation reaction of maleic acid, maleic anhydride or fumaric acid.
1,4-Butanediol can be oxidized to succinic acid in a variety of ways: (1) Oxidation with O₂ in an aqueous solution of alkaline earth metal hydroxide at 90-110℃, and the addition of… (2) via a Pd-C catalyst; or (3) by ozone decomposition in an aqueous acetic acid solution; or (4) by reaction with N₂O₄ at low temperature. Succinic acid can be obtained by: phase-transfer catalytic reactions of 2-haloacetic acid esters, electrolytic dimerization of bromoacetic acid or its esters, oxidation of 3-cyanopropanal, and fermentation of n-alkanes.

C4H6O4.2[C4H11NO3]

360.35812

360.174

84540-64-7

Succinic acid;110-15-6; 84540-64-7 (Succinic acid tromethamine); 150-90-3 (Disodium succinate); 26776-24-9;14047-56-4 (Succinic acid sodium)

3086186

Typically exists as solid at room temperature

633.5ºC at 760 mmHg

138-141ºC

336.9ºC

10

12

9

24

147

0

C(CC(=O)O)C(=O)O.C(C(CO)(CO)N)O.C(C(CO)(CO)N)O

CFJZQNZZGQDONE-UHFFFAOYSA-N

InChI=1S/2C4H11NO3.C4H6O4/c2*5-4(1-6,2-7)3-8;5-3(6)1-2-4(7)8/h2*6-8H,1-3,5H2;1-2H2,(H,5,6)(H,7,8)

2-amino-2-(hydroxymethyl)propane-1,3-diol;butanedioic acid

Tris succinate; 85169-32-0; 84540-64-7; Di(tris[hydroxymethyl]aminomethane) succinate; Succinic acid, compound with 2-amino-2-(hydroxymethyl)propane-1,3-diol (1:2); 2-amino-2-(hydroxymethyl)propane-1,3-diol;butanedioic acid; EINECS 285-975-2; EINECS 283-159-0;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

---

Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

View More

Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

---

Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

View More

Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

---

Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

---

 (Please use freshly prepared in vivo formulations for optimal results.)