Tributyrin

302.36

302.36

1714746

200-451-5

S05LZ624MF

661583

DTXSID4052267

C1260

COLORLESS|Oily liquid

2915900090

78.9

2.54

Clear colorless to yellow Liquid

1.0350 g/cm³ @ Temp: 20 °C

-75 °C

305-310 °C

345 °F

1.448

Not miscible in water.

Store at RT.

1.3X10-3 mm Hg at 25 deg C /Estimated/

Lower flammable limit: 0.5% (by volume) @ 406 deg F (208 deg C)

FRUITY, BUTTERY

Bitter taste

Henry's Law constant = 9.6X10-9 atm cu m/mole at 25 °C /Estimated/

Conversion factor: 12.34 mg/cu m= 1 ppm|Hydroxyl radical reaction rate constant = 1.3X10-11cu cm/molec-sec at 25 °C /Estimated/

765 °F (407 °C)

Lower flammable limit: 0.5% (by volume) @ 406 °F (208 °C)

NONH for all modes of transport

1

24/25

ET7350000

Stable. Incompatible with strong oxidizing agents.

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

Substance added directly to human food affirmed as generally recognized as safe (GRAS).|Synthetic flavoring substances and adjuvants /for animal drugs, feeds, and related products/ that are generally recognized as safe for their intended use, within the meaning of section 409 of the Act. Tributyrin is included on this list.

AEROBIC: Tributyrin is oxidized by activated sludge with a measured oxygen uptake of 300 mg/L in 7 days(1). Activated sludge at a concn of 2,500 mg/L, was exposed to tributyrin using a Warburg constant temperature respirometer; oxygen uptake was used to determine amount of degradation of the tributyrin(1). Nocardia erythropolis, which readily degrades several phthalate esters, has been shown to be twice as active against tributyrin(2).

| 0 - Materials that, under emergency conditions, would offer no hazard beyond that of ordinary combustible materials.| 1 - Materials that must be preheated before ignition can occur. Materials require considerable preheating, under all ambient temperature conditions, before ignition and combustion can occur.| 0 - Materials that in themselves are normally stable, even under fire conditions.

Effect of feeding tributyrin on toxicity of diisopropylfluorophosphate (DFP) in mice. After 36 hr of tributyrin feeding the DFP toxicity is 1.7 time normal & after 14 days of feeding it is only 1.15 times normal. .

LD50 Rat oral 3.2 g/kg|LD50 Mouse oral 12.8 mg/kg

/AQUATIC SPECIES/ Tributyrin did not inhibit amylase activity in /carp/ fingerling but did in adults.

Tributyrin's production and use as a plasticizer and flavoring agent(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 570(SRC), determined from a log Kow of 2.54(2) and a regression-derived equation(3), indicates that tributyrin is expected to have low mobility in soil(SRC). Volatilization of tributyrin from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 9.6X10-9 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Tributyrin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 0.0013 mm Hg(SRC), determined from a fragment constant method(5). Tributyrin is biodegraded by activated sludge with a measured oxygen uptake of 300 mg/L in 7 days(6), indicating that biodegradation may be an important fate process in soil(SRC).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 570(SRC), determined from a log Kow of 2.54(2) and a regression-derived equation(3), indicates that tributyrin is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 9.6X10-9 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 50(SRC), from an estimated log Kow(2) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Tributyrin is biodegraded by activated sludge with a measured oxygen uptake of 300 mg/L in 7 days(7), indicating that biodegradation may be an important fate process in water(SRC).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), tributyrin, which has an estimated vapor pressure of 0.0013 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase tributyrin is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 1.2 days(SRC), calculated from its rate constant of 1.3X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Tributyrin does not contain chromophores that absorb at wavelengths >290 nm and therefore would not be expected to be susceptible to direct photolysis by sunlight(SRC).

The rate constant for the vapor-phase reaction of tributyrin with photochemically-produced hydroxyl radicals has been estimated as 1.3X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 1.2 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). A base-catalyzed second-order hydrolysis rate constant of 3.2X10-1 L/mole-sec(SRC) was estimated using a structure estimation method(2); this corresponds to half-lives of 250 and 25 days at pH values of 7 and 8, respectively(2). Tributyrin does not contain chromophores that absorb at wavelengths >290 nm and therefore would not be expected to be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 50 was calculated for tributyrin(SRC), using a log Kow of 2.54(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is moderate(SRC), provided the compound is not metabolized by the organism(SRP).

The Koc of tributyrin is estimated as 570 (SRC), using a log Kow of 2.54(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that tributyrin is expected to have low mobility in soil.

The Henry's Law constant for tributyrin is estimated as 9.6X10-9 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that tributyrin is expected to be essentially nonvolatile from water surfaces(2). Tributyrin's Henry's Law constant indicates that volatilization from moist soil surfaces will not occur(SRC). Tributyrin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 0.0013 mm Hg(SRC), determined from a fragment constant method(3).

Occupational exposure to tributyrin may occur through inhalation and dermal contact with this compound at workplaces where tributyrin is produced or used. (SRC)

... Enrolled in this study were 20 patients with advanced solid tumors for whom no other therapy was available, had life expectancy greater than 12 weeks, and normal organ function. They were treated with tributyrin at doses from 150 to 200 mg/kg three times daily. Blood was sampled for pharmacokinetic analysis prior to dosing and at 15 and 30 min and 1, 1.5, 2, 2.5, 3, 3.5 and 4 hr thereafter. The patients entered comprised 15 men and 5 women with a median age of 61 years (range 30-74 years). Prior therapy regimens included: chemotherapy (median two prior regimens, range none to five), radiation therapy (one), no prior therapy (one). There was no dose-limiting toxicity. Escalation was halted at the 200 mg/kg three times daily level due to the number of capsules required. A median butyrate concentration of 52 microM was obtained but there was considerable interpatient variability. No objective responses were seen. There were four patients with prolonged disease stabilization ranging from 3 to 23 months; median progression-free survival was 55 days. Two patients with chemotherapy-refractory non-small-cell lung cancer had survived for >1 year at the time of this report without evidence of progression.

Tributyrin is absorbed by the intestinal mucosa of the rat and is not absorbed cutaneously in guinea pigs.|In humans administered once daily oral injections of 50-400 mg/kg tributyrin for 3 weeks, peak plasma concentrations occurred 0.25-3 hr after dosing. The peak plasma concentration of those administered 200 mg/kg ranged from 0.1-0.45 mM. Higher plasma concentrations were not observed in those given higher doses.|In mice and rats given 10.3 g/kg tributyrin orally, plasma butyrate concentrations peaked at 1.75 and 3.07 mM, respectively. They were >/= 1 mM from 10-60 min after dosing in mice and 30-90 min in rats.|... Female CD2F1 mice were treated with tributyrin by oral gavage or with sodium butyrate by i.v. bolus or oral gavage. Oral tributyrin doses delivered to mice were 3.1, 5.2, 7.8, and 10.3 g/kg. Intravenous sodium butyrate doses were 0.31, 0.62, 0.94, and 1.25 g/kg. Oral sodium butyrate was given to mice at 5 g/kg. Subsequently, similar studies were performed in female Sprague-Dawley rats. Rats were given tributyrin by oral gavage at doses of 3.6, 5.2, or 10.3 g/kg or sodium butyrate i.v. at a dose of 500 mg/kg. Plasma butyrate concentrations were determined by gas chromatography. RESULTS: In mice, oral dosing with tributyrin resulted in detectable plasma butyrate concentrations as early as at 5 min after treatment and produced peak plasma butyrate concentrations at between 15 and 60 min after dosing. Peak plasma butyrate concentrations increased proportionally with increasing tributyrin dose, but as the oral tributyrin dose increased there was a greater than proportional increase in the area under the curve of plasma butyrate concentrations versus time (AUC). At a tributyrin dose of 10.3 g/kg, plasma butyrate concentrations peaked at approximately 1.75 mM and remained >1 mM for between 10 and 60 min after dosing. However, approximately 10% of mice treated with this dose died acutely. At a tributyrin dose of 7.8 g/kg, plasma butyrate concentrations reached approximately 1 mM by 15 min after dosing and remained between 0.8 and 1 mM until 60 min after dosing. No mouse treated with this dose died acutely. Mice given tributyrin doses of 5.2 and 3.1 g/kg achieved peak plasma butyrate concentrations of approximately 0.9 and 0.5 mM, respectively, by 45 min after dosing. Plasma butyrate concentrations in these mice remained above 0.1 mM until 120 and 90 min after dosing, respectively. The four i.v. doses of sodium butyrate resulted in plasma concentration-time profiles that also indicated nonlinear pharmacokinetics and were well described by a one-compartment model with saturable elimination. Values recorded for the Michaelis-Menten constant (Km) and the maximal velocity of the process (Vmax) ranged between 1.02 and 5.65 mM and 0.60 and 1.82 mmol/min, respectively. Values noted for the volume of the central compartment (Vc) varied between 0.48 and 0.72 l/kg. At 1.25 g/kg, i.v. sodium butyrate produced peak plasma butyrate concentrations of 10.5-17.7 mM, and plasma butyrate concentrations remained above 1 mM for 20-30 min. Sodium butyrate delivered orally to mice at 5 g/kg produced peak plasma butyrate concentrations of approximately 9 mM at 15 min after dosing and plasma butyrate concentrations exceeding 1 mM for 90 min after dosing. In rats the 10.3-g/kg oral dose of tributyrin produced peak plasma butyrate concentrations of approximately 3 mM by 75 min after dosing and butyrate concentrations exceeding 1 mM from 30 to 90 min after dosing. The plasma butyrate concentrations produced in rats by 5.2- and 3.6-g/kg doses were appropriately lower than those produced by the 10.3-g/kg dose, and there was no evidence of nonlinearity. The 500-mg/kg i.v. dose of sodium butyrate produced peak plasma butyrate concentrations in rats of approximately 11 mM, and the decline in plasma butyrate concentrations with time after dosing was consistent with saturable clearance.|... Peak plasma butyrate concentrations occurred between 0.25 and 3 h after dose, increased with dose, and ranged from 0 to 0.45 mM. Peak concentrations did not increase in three patients who had dose escalation. Butyrate pharmacokinetics were not different on days 1 and 15. Because peak plasma concentrations near those effective in vitro (0.5-1 mM) were achieved, but butyrate disappeared from plasma by 5 h after dose, we are now pursuing dose escalation with dosing three times daily, beginning at a dose of 450 mg/kg/day.

...Tributyrinase.../is/ an enzyme specific for the hydrolysis of tributyrins. This enzyme is inhibited by some organic compounds, particularly selected fluorophosphates. ...A fluoride-sensitive tributyrinase has been isolated from rat adipose tissue, which liberates butyric acid from 1-mono-, 1,2-di-, or tributyrin.|Porcine liver and kidney microsomes most actively hydrolyzed tributyrin. Liver microsomes from frogs, pigs, rats, cats, rabbits, guinea pigs, sheep, doves, dogs but not fish, also possessed esterase activity against tributyrin.|Studies of the hydrolysis of the glycerol fatty acid esters (/including/ tributyrin...) showed complete hydrolysis to glycerol and the corresponding fatty acids, butyric acid, 5-hydroxy-decanoic acid, and 5-hydroxydodecanoic acid, respectively.

... Human gastric cancer SGC-7901 cells were exposed to tributyrin at 0.5, 1, 2, 5, 10 and 50 mmol/L(-1) for 24-72 h. MTT /2H-Tetrazolium,2-(4,5-Dimethyl-2-thiazolyl-3)/ assay was applied to detect the cell proliferation. [(3)H]-TdR uptake was measured to determine DNA synthesis. Apoptotic morphology was observed by electron microscopy and Hoechst-33258 staining. Flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were performed to detect tributyrin-triggered apoptosis. The expressions of PARP /Poly-ADP Ribose Polymerase/, Bcl-2 and Bax were examined by Western blot assay. Tributyrin could initiate growth inhibition of SGC-7901 cell in a dose- and time-dependent manner. [(3)H]-TdR uptake by SGC-7901 cells was reduced to 33.6 % after 48 h treatment with 2 mmol/L(-1) tributyrin, compared with the control (P<0.05). Apoptotic morphology was detected by TUNEL assay. Flow cytometry revealed that tributyrin could induce apoptosis of SGC-7901 cells in dose-dependent manner. After 48 hours incubation with tributyrin at 2 mmol/L(-1), the level of Bcl-2 protein was lowered, and the level of Bax protein was increased in SGC-7901, accompanied by PARP cleavage.|... HT-29 colon cancer cells exposed to PB /phenylbutyrate/ and TB /tributyrin/ result in growth inhibition associated with an induction of apoptosis mediated through the activation of caspase-3 activity. A block in the G1/S cell cycle traverse associated with a decrease in CDK2 (cyclin dependent kinase) protein levels and retinoblastoma protein hypophosphorylation was also noted after PB and TB exposure.|We investigated the effects of tributyrin establishing induction of growth arrest and apoptosis of MCF-7 human mammary carcinoma cells. Transient increased mitochondria-associated bax, dissipation of the mitochondrial membrane potential (delta(psi)m), and caspase-3-independent cleavage of poly(ADP-ribose) polymerase are evident as early as 4 h after treatment of cells with tributyrin. These events are followed by the transient accumulation of mitochondrial cytochrome c in the cytosol and, finally, the generation and accumulation of cells with subdiploid DNA content. During the period in which mitochondria-associated bax levels are elevated, the delta(psi)m is disrupted, and cytochrome c is detected in the cytosol, we show induction of p21WAF1/Cip1 in the absence of increased p53 and arrest of cells in G2-M.

/HUMAN EXPOSURE STUDIES/ ... We treated 13 patients with escalating doses of tributyrin from 50 to 400 mg/kg/day. Doses were administered p.o. after an overnight fast, once daily for 3 weeks, followed by a 1-week rest. Intrapatient dose escalation occurred after two courses without toxicity greater than grade 2. The time course of butyrate in plasma was assessed on days 1 and 15 and after any dose escalation. Grade 3 toxicities consisted of nausea, vomiting, and myalgia. Grades 1 and 2 toxicities included diarrhea, headache, abdominal cramping, nausea, anemia, constipation, azotemia, lightheadedness, fatigue, rash, alopecia, odor, dysphoria, and clumsiness. There was no consistent increase in hemoglobin F with tributyrin treatment.

glyceryl tributyrate

PURITY: Not less than 99% of C15H26O6.|GRADES: Technical; FCC.

Butanoic acid, 1,2,3-propanetriyl ester: ACTIVE|...Useful in butter, margarine /as flavor/, solvent for flavors.|FEMA NUMBER 2223|Irradiation of tributyrin produces various compounds, among them butanetriol triesters, erythritol tetraesters, and polyglycol polyesters.

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