Absorption, Distribution and Excretion
...Triacetin is more rapidly absorbed from the gastrointestinal tract in 3 hours than the other fats tested. Triacetin has been shown to be a source of liver glycogen and when fed in amounts equal in caloric value to 15% glucose it was utilized as efficiently as was glucose.
Mongrel dogs /were used/ to determine the systemic, hindlimb, gut, hepatic, and renal uptake of acetate during infusion of a 5% v/v aqueous solution of triacetin. A primed, continuous infusion of [1-(14)C]-acetate was continued for 7 hr with 10 animals. Three hours after the start of the tracer infusion, the animals were infused with triacetin at a rate of 47 umol/kg/min for 4 hr. Blood and breath samples were taken at 15-min intervals for the last 30 min. Steady-state conditions were achieved in plasma acetate concentrations and specific activity and in expired [(14)-C02]. Plasma acetate concentrations were 1180, 935, 817, 752, and 473 umol/L /(all values approximate)/ in the aorta, renal vein, portal vein, femoral vein, and hepatic vein, respectively. The acetate turnover rate during triacetin infusion was 2214 umol/min; systemic acetate turnover accounted for 68% of triacetin-derived acetate.

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Metabolism / Metabolites
Triacetin has been administered iv to mongrel dogs. The majority of infused triacetin underwent intravascular hydrolysis, and the majority of the resulting acetate is oxidized. Triacetin was found to be hydrolyzed by human intestinal lipase.
...Triacetin is rapidly hydrolysed in vitro by all tissues of the organism including the gastrointestinal tract.
Groups of female mongrel dogs to study the metabolic effects of isocaloric and hypercaloric infusions of 5% v/v aqueous triacetin. A primed, continuous infusion of 5 umol/kg (0.3 uCi/kg/min) [(13)C]-acetoacetate and 1.0 uCi/kg (0.01 uCi/kg/min) [(3)H]-glucose was continued for 6 hr. Three hours after the start of the isotope infusion, dosing with triacetin was started. Six animals were infused at a rate of 47 umol/kg/min and seven were infused at a rate of 70 umol/kg/min triacetin for 3 hr. Blood and breath samples were taken at 15 to 30-min intervals. A group of four animals was infused with 70 umol/kg/min glycerol and used as the control for the hypercaloric infusion. During isocaloric infusion of triacetin, plasma acetate and free fatty acid concentrations were significantly increased at 30 and 60 min, respectively, and remained elevated. During hypercaloric infusion, plasma acetate concentration increased progressively throughout the study, whereas the plasma free fatty acid concentration did not change. Plasma pyruvate and lactate concentrations were significantly decreased after 30 and 90 min, respectively, and throughout the study with both isocaloric and hypercaloric infusion. The plasma insulin concentrations were modestly increased during both infusions. Plasma glucose concentration was significantly decreased during isocaloric triacetin infusion; a slight but significant increase was observed with hypercaloric infusion. Glucose clearance decreased significantly in both groups during the last hour of triacetin infusion. Plasma ketone body concentrations increased significantly by 60 min, and they remained elevated with isocaloric infusion and increased progressively with hypercaloric infusion of triacetin; the increased concentrations were due to increased ketone body production. During the last hour of infusion, resting energy expenditure was significantly increased with isocaloric triacetin.
Esterases in fungi or in serum act at pH >4 to slowly release acetic acid in situ. Extent of hydrolysis is automatically limited by increased acidity and lowering of pH.
... The fungistatic activity of triacetin (glyceryl triacetate) results from its hydrolysis by fungalesterases to acetic acid.

Toxicity Summary
IDENTIFICATION AND USE: Triacetin, also known as glyceryl triacetate (GTA), is a colorless liquid. It is reported to function as a cosmetic biocide, plasticizer, and solvent in cosmetic formulations. Triacetin is also used as a cellulose plasticizer in the manufacture of cigarette filters, as a carrier in fungicidal compositions, and to remove carbon dioxide from natural gas. Triacetin was affirmed as a GRAS (generally recognized as safe) human food ingredient by FDA. Triacetin has been used experimentally for the treatment of Canavan disease, a fatal dysmyelinating genetic disorder associated with aspartoacylase deficiency, resulting in decreased brain acetate levels and reduced myelin lipid synthesis in the developing brain. HUMAN EXPOSURE AND TOXICITY: In humans, commercial Triacetin has caused ocular irritation but no injury. Triacetin was not an irritant or a sensitizer in a clinical maximization study, and only very mild reactions were seen in a Duhring-chamber test using a 50% dilution. In sensitive individuals, it may cause slight irritation. ANIMAL STUDIES: Triacetin is moderately toxic by intraperitoneal, subcutaneous, and intravenous routes. The symptoms of toxicity with triacetin are primarily weakness and ataxia. Animals near death exhibit severe dyspnea, muscular tremors, and occasional convulsions, usually 2-22 min after the injection. Also various degrees of hemorrhage in the lung have been observed. It does not appear to affect the liver, spleen, heart, or kidneys. In short-term feeding studies, triacetin affected weight gain. Rats that were fed diets containing 30% triacetin as a starch substitute for 3 to 4 or 12 to 13 weeks, showed relatively poor growth. Liver enlargement was observed in all animals. Triacetin was not toxic in short-term studies when administered via inhalation or parenterally or in subchronic studies when administered via feed or inhalation. Triacetin was, at most, slightly irritating to guinea pig skin. However, in one study, it caused erythema, slight edema, alopecia, and desquamation. Triacetin was not sensitizing in guinea pigs. Triacetin caused some irritation in rabbit eyes. In a study performed on dogs, it was found that intra-gastric infusion of 1.0%-2.0% triacetin delays gastric emptying by increasing proximal stomach receptive volume, temporarily inhibiting gastric antral contractions and facilitating duodenal contractions. In a study using triacetin as a method of delivering metabolizable acetate to the brain of rats suffering traumatic brain injury, it was found that triacetin administration significantly increased the levels of both NAA (N-acetylaspartate) and ATP in the injured hemisphere 4 and 6 days after injury, and also resulted in significantly improved motor performance in rats 3 days after injury. Triacetin, with and without metabolic activation, was not mutagenic in the Ames assay using Salmonella typhimurium strains TA98, TA100, TA1535, TA153 with or without activation. It was also not mutagenic in an in vivo assay using Drosophila.

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Toxicity Data
LC50 (rat) > 1,721 mg/m3/4h

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Interactions
The present studies investigated the effects of intravenous administration of the short-chain triglyceride triacetin on leucine metabolism in dogs. Animals received infusions of triacetin at 1.0 x estimated resting energy expenditure (REE), hyperenergetic triacetin at 1.5 x REE, glycerol, or saline during infusion of [(1-14)C]leucine. During both triacetin infusions, plasma alpha-ketoisocaproate concentrations increased (p < 0.05). During triacetin infusion at 1.5 REE, the plasma leucine concentration decreased (p < 0.05) and leucine rate of appearance decreased by approximately 19% (p < 0.05); this was significantly greater than the changes that occurred during triacetin at 1.0 x REE and glycerol (p < 0.05). There was no difference in leucine oxidation between the dogs given triacetin at 1.0 x REE and control groups, whereas leucine oxidation decreased by 53% during triacetin infusion at 1.5 x REE (p < 0.05). Nonoxidative leucine disappearance, an indicator of protein synthesis, did not change in any of the studies.

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Non-Human Toxicity Values
LD50 Rabbit iv 750 mg/kg
LD50 Dog iv 1500 mg/kg
LD50 Mouse sc 2300 mg/kg
LD50 Mouse ip 1400 mg/kg
For more Non-Human Toxicity Values (Complete) data for TRIACETIN (13 total), please visit the HSDB record page.

Triacetin is a triglyceride obtained by acetylation of the three hydroxy groups of glycerol. It has fungistatic properties (based on release of acetic acid) and has been used in the topical treatment of minor dermatophyte infections. It has a role as a plant metabolite, a solvent, a fuel additive, an adjuvant, a food additive carrier, a food emulsifier, a food humectant and an antifungal drug. It is functionally related to an acetic acid.
Triacetin has been reported in Vitis vinifera with data available.
A triglyceride that is used as an antifungal agent.
See also: Tobacco Leaf (part of).

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Therapeutic Uses
/EXPL THER/ Canavan disease (CD) is a fatal dysmyelinating genetic disorder associated with aspartoacylase deficiency, resulting in decreased brain acetate levels and reduced myelin lipid synthesis in the developing brain. Here we tested tolerability of a potent acetate precursor, glyceryl triacetate (GTA), at low doses in two infants diagnosed with CD, aged 8 and 13 months. Much higher doses of GTA were evaluated for toxicity in the tremor rat model of CD. GTA was given orally to the infants for up to 4.5 and 6 months, starting at 25 mg/kg twice daily, doubling the dose weekly until a maximum of 250 mg/kg reached. GTA treatment caused no detectable toxicity and the patients showed no deterioration in clinical status. Lack of GTA toxicity in two CD patients in low-dose trials suggests that higher, effective dose studies in human CD patients are warranted.
Antifungal Agents; Solvents
/EXPL THER/ The FDA approved food additive Triacetin (glyceryl triacetate, GTA) has been safely used for acetate supplementation therapy in Canavan disease, a leukodystrophy due to aspartoacylase (ASPA) mutation. This study characterized the effects of GTA on the proliferation and differentiation of six primary glioblastoma (GBM)-derived glioma stem-like cells (GSCs) relative to established U87 and U251 GBM cell lines, normal human cerebral cortical astrocytes, and murine neural stem cells. GTA reduced proliferation of GSCs greater than established GBM lines. Moreover, GTA reduced growth of the more aggressive mesenchymal GSCs greater than proneural GSCs. Although sodium acetate induced a dose-dependent reduction of GSC growth, it also reduced cell viability. GTA-mediated growth inhibition was not associated with differentiation, but increased protein acetylation. These data suggest that GTA-mediated acetate supplementation is a novel therapeutic strategy to inhibit GSC growth.
/EXPL THER/ Canavan disease (CD) is a rare autosomal recessive neurodegenerative disorder presenting in early infancy. The course of the disease is variable, but it is always fatal. CD is caused by mutations in the ASPA gene, which codes for the enzyme aspartoacylase (ASPA), which breaks down N-acetylaspartate (NAA) to acetate and aspartic acid. The lack of NAA-degrading enzyme activity leads to excess accumulation of NAA in the brain and deficiency of acetate, which is necessary for myelin lipid synthesis. Glyceryltriacetate (GTA) is a short-chain triglyceride with three acetate moieties on a glycerol backbone and has proven an effective acetate precursor. Intragastric administration of GTA to tremor mice results in greatly increased brain acetate levels, and improved motor functions. GTA given to infants with CD at a low dose (up to 0.25 g/kg/d) resulted in no improvement in their clinical status, but also no detectable toxicity. We present for the first time the safety profile of high dose GTA (4.5 g/kg/d) in 2 patients with CD. We treated 2 infants with CD at ages 8 months and 1 year with high dose GTA, for 4.5 and 6 months respectively. No significant side effects and no toxicity were observed. Although the treatment resulted in no motor improvement, it was well tolerated. The lack of clinical improvement might be explained mainly by the late onset of treatment, when significant brain damage was already present. Further larger studies of CD patients below age 3 months are required in order to test the long-term efficacy of this drug.
For more Therapeutic Uses (Complete) data for TRIACETIN (9 total), please visit the HSDB record page.

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Drug Warnings
For external use only: Not for ophthalmic use.
Irritation or sensitivity: Discontinue treatment and notify physician.
Diabetics or patients with impaired blood circulation: Use spray with caution.

C9H14O6

218.2039

218.079

102-76-1

Triacetin-d5;159510-46-0;Glyceryl Triacetate-d9

5541

Colorless to light yellow liquid

1.2±0.1 g/cm3

258.0±0.0 °C at 760 mmHg

3 °C(lit.)

148.9±0.0 °C

0.0±0.5 mmHg at 25°C

1.435

-0.24

0

6

8

15

229

0

O(C(C([H])([H])[H])=O)C([H])(C([H])([H])OC(C([H])([H])[H])=O)C([H])([H])OC(C([H])([H])[H])=O

URAYPUMNDPQOKB-UHFFFAOYSA-N

InChI=1S/C9H14O6/c1-6(10)13-4-9(15-8(3)12)5-14-7(2)11/h9H,4-5H2,1-3H3

2,3-diacetyloxypropyl acetate

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)

DMSO : ≥ 2.3 mg/mL (~10.54 mM)

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.

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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).

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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)

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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).

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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

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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.

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