Theobromine

180.16400

180.16

201-494-2

OBD445WZ5P

757407|5039

DTXSID9026132

Monoclinic needles (/crystalline structure is/ lamellar twining on 001 /axis/) from water|White powder or monoclinic needles

C - Cardiovascular system|R - Respiratory system

2933990090

72.68000

-0.8

Theobromine is an odorless white crystalline powder. Bitter taste. pH (saturated solution in water): 5.5-7. (NTP, 1992)

1.5

357 °C

Sublimes 290-295ºC

290-295ºC

1.737

slightly soluble ,

Keep container closed when not in use. Store in a cool, dry area away from incompatible substances.

1.13X10-11 mm Hg at 25 deg C (est)

Bitter tasting alkaloid

9.9None

Henry's Law constant = 1.63X10-11 atm-cu m/mol at 25 °C (est)

9.9|pKa = 9.90 /imide N/

135.25 Ų [M-H]- [CCS Type: DT, Method: single field calibrated with Agilent tune mix (Agilent)]|134.37 Ų [M+H]+ [CCS Type: DT, Method: stepped-field]|131.2 Ų [M+H]+ [CCS Type: DT, Method: single field calibrated with ESI Low Concentration Tuning Mix (Agilent)]|136.9 Ų [M+H]+ [CCS Type: DT, Method: single field calibrated with ESI Low Concentration Tuning Mix (Agilent)]|131.1 Ų [M+H]+

Kb at 18 °C: 1.3X10-14; Ka 0.9X10-10|Forms salts which are decomposed by water, and compounds with bases which are more stable|White, amorphous powder; slightly saline taste; partly soluble in water. Alkaline solutions are alkaline to phenophthalein /Theobromine calcium salicylate/|White, odorless or almost odorless, hygroscopic powder. Absorbs CO2 from the air becoming completely soluble. Very soluble in water, sparingly soluble in cold alcohol; the solutions are strongly alkaline. pH about 10 /Theobromine sodium acetate/|For more Other Experimental Properties (Complete) data for 3,7-Dimethylxanthine (6 total), please visit the HSDB record page.

Insoluble in water.

Amides and Imides

THEOBROMINE may be sensitive to prolonged exposure to light. This chemical has weakly acidic properties, combining with bases to forms salts. It also has even weaker basic properties, combining with acids to form salts which are decomposed in aqueous solution. (NTP, 1992).

UN1230 - class 3 - PG 2 - Methanol, solution

1

R22

S22-S24/25

XH2275000

Xn

Stable under recommended storage conditions.

P210-P260-P280-P301 + P310-P311

H225-H301 + H311 + H331-H370

SRP: 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 air, soil or water; effects on animal, aquatic and plant life; and conformance with environmental and public health regulations. If it is possible or reasonable use an alternative chemical product with less inherent propensity for occupational harm/injury/toxicity or environmental contamination.|Product: Offer surplus and non-recyclable solutions to a licensed disposal company; Contaminated packaging: Dispose of as unused product.

Incompatible materials: Strong oxidizing agents

Drug products containing certain active ingredients offered over-the-counter (OTC) for certain uses. A number of active ingredients have been present in OTC drug products for various uses, as described below. However, based on evidence currently available, there are inadequate data to establish general recognition of the safety and effectiveness of these ingredients for the specified uses: Theobromine sodium salicylate is included in orally administered menstrual drug products. /Theobromine sodium salicylate/

Flash point data for this chemical are not available; however, it is probably combustible. (NTP, 1992)

|Warning|H302 (97.67%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P264, P270, P280, P281, P301+P312, P305+P351+P338, P308+P313, P330, P337+P313, P405, and P501|Aggregated GHS information provided by 172 companies from 8 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|H302: Harmful if swallowed [Warning Acute toxicity, oral]|P264, P270, P301+P312, P330, and P501|Danger|P201, P202, P260, P264, P270, P281, P301+P312, P307+P311, P308+P313, P321, P330, P405, and P501

SMALL SPILLS AND LEAKAGE: If you spill this chemical, dampen the solid spill material with 5% ammonium hydroxide, then transfer the dampened material to a suitable container. Use absorbent paper dampened with 5% ammonium hydroxide to pick up any remaining material. Your contaminated clothing and the absorbent paper should be sealed in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces with 5% ammonium hydroxide followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned. STORAGE PRECAUTIONS: You should protect this chemical from light and store this it under ambient temperatures. (NTP, 1992)

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)|Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).|Skin protection: Handle with gloves.|Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.|Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator. For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.|Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.|Precautions for safe 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.|Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.|Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.|SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Theobromine has been detected in tobacco and tobacco smoke(1), as a result of cocoa being added as a flavoring(2).

IDENTIFICATION AND USE: Theobromine is a white powder. It is an alkaloid found in cocoa and chocolate products. Theobromine is used principally to make caffeine . Formerly, theobromine and its derivatives were used in diuretics, myocardial stimulants, vasodilators and smooth muscle relaxants. Theobromine salts (calcium salicylate, sodium salicylate and sodium acetate) were used previously to dilate coronary arteries at doses of 300 to 600 mg per day. There is no current therapeutic use of theobromine. HUMAN EXPOSURE AND TOXICITY: It has been stated that "in large doses" theobromine may cause nausea and anorexia and that daily intake of 50-100 g cocoa (0.8-1.5 g theobromine) by humans has been associated with sweating, trembling and severe headache. Theobromine responses differed according to dose; it showed limited subjective effects at 250 mg and negative mood effects at higher doses. It also dose-dependently increased heart rate. In other studies, theobromine increased HDL-cholesterol concentrations by 0.16 mmol/L. Furthermore, there was a significant theobromine effect on increasing apolipoprotein A-I and decreasing apolipoprotein B and LDL-cholesterol concentrations. In human lymphocyte cultures, theobromine did not significantly increase the number of sister chromatid exchanges per cell, but, in another experiment using higher doses, the numbers of sister chromatid exchanges per cell were increased in the absence of an exogenous metabolic system. Theobromine induced breaks in human lymphocytes in culture, contrary to the results with rodent cells. ANIMAL STUDIES: High doses 250-300 mg/kg bw (mature animals) and 500 mg/kg bw (immature animals) have been shown to cause complete thymic atrophy in male and female rats. This effect was seen in hamsters only at a level of 850 mg/kg bw and in mice at levels of 1840-1880 mg/kg bw. Theobromine administration in rabbits resulted in marked changes in thymus and testes and the severity of lesions appeared to be related to the amounts of the ingested methylxanthine. Other experiments in rats also found the toxic effects of theobromine on the testis. In rats fed diets containing theobromine (daily doses, 53 or 99 mg/kg bw) on gestation days 6-19, no maternal toxicity was observed. Although no malformation occurred, slight decreases in fetal body weight were observed with the high dose, and a significant increase was seen in the frequency of skeletal variations. In rabbits, decreased fetal body weight and malformations were seen at doses of 125 or 200 mg/kg; the incidence of skeletal variations was increased with 75 mg/kg and over. Theobromine was mutagenic to Escherichia coli under conditions in which a constant growth rate and cell population density were maintained, but it was not mutagenic to Salmonella typhimurium. Theobromine induced mutations in a lower eukaryote, Euglena gracilis. Theobromine did not induce chromosomal aberrations in plants (Vicia faba). It was reported in an abstract that chromosomal aberrations were not observed in Drosophila melanogaster treated with 0.45% theobromine in feeding experiments. Chromosomal aberrations were not induced by theobromine in Chinese hamster cells.

Several concentrations of theobromine (TB) and (-)-epicatechin (EC) were coadministered to rats, and plasma EC and its metabolites were determined using ultra-high-performance liquid chromatography-tandem mass spectrometry. It has been demonstrated that TB increases the absorption of EC in a dose-dependent manner. Cocoa powder had a similar effect, and the mechanism involved is not thought to depend on tight junctions.|Experiments were designed to determine the effects of feeding the methylxanthines caffeine, theobromine, or theophylline to 4- to 6-week-old males rats at a dietary level of 0.5 % for periods ranging from 14 to 75 weeks. In the first two experiments, Osborne-Mendel rats were fed the test substances alone or in combination with sodium nitrite to test the hypothesis that these amines might nitrosate in vivo to produce toxic nitrosamine compounds. The compounds failed to produce neoplastic or preneoplastic lesions, but a significant positive finding was the occurrence of severe bilateral testicular atrophy with aspermatogenesis or oligospermatogenesis in 85-100 % of the rats fed caffeine or theobromine. ...|The effects of allopurinol on the plasma clearance and metabolism of theobromine have been investigated under multiple-dosing conditions. Allopurinol had no effect on the clearance of theobromine, indicating that the elimination of this compound is dependent on enzyme systems other than xanthine oxidase, presumably the hepatic mixed-function oxidases. The excretion of 3-methylxanthine, 6-amino-5-(N-methylformylamino)-1-methyluracil, and unchanged theobromine were similarly unaffected by the allopurinol treatment. Although allopurinol abolished the formation of 7-methyluric acid (7MU) and increased the excretion of 7-methylxanthine (7MX), the metabolic clearance to (7MX + 7MU) was not significantly different with and without allopurinol. It is proposed that the secondary biotransformation of 7MX to 7MU is mediated by xanthine oxidase.|The compounds identified in bile of phenobarbital-treated rats were 3,7-dimethyluric acid (64-76% of biliary radioactivity), dimethylallantoin (5-8%), 6-amino-5-(N-methylformylamino)- 1-methyluracil (10-17%) and theobromine (8-10%). In 3-methylcholanthrene-treated rats, urinary elimination of unchanged theobromine was reduced from 23-27% to only 2%, while excretion of 6-amino-5-(N-methylformylamino)-1- methyluracil was significantly increased. Only 3,7-dimethyluric acid was produced by liver microsomal incubation in control rats while phenobarbital and 3-methylcholanthrene pretreatment enhanced the biotransformation resulting in the production of all metabolites found in vivo as well as unknown polar compounds.

LD50 Dog oral 300 mg/kg bw|LD50 Rat (acute) oral 950 mg/kg bw

Theobromine is the principal alkaloid of the cacao bean(1). It also occurs in tea and cola nuts and is a purine base closely related to caffeine(2).

Theobromine is a breakdown metabolite of caffeine(1) which may result in its release to the environment through various waste streams(SRC). Its former production and use as a diuretic, bronchodilator, and cardiotonic in human medicine and diuretic, mycocardial stimulant and vasodilator in veterinary medicine(2), may have resulted in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 10(SRC), determined from a structure estimation method(2), indicates that theobromine is expected to have very high mobility in soil(SRC). Volatilization of theobromine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.6X10-11 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Theobromine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.1X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Using an acclimated sewage sludge inoculum, theobromine reached 100% of its Theoretical BOD in 28 days(4), suggesting that biodegradation may be an important environmental fate process in soil previously exposed to this compound(SRC).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 10(SRC), determined from a structure estimation method(2), indicates that theobromine is not 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 1.6X10-11 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 3(SRC), from its log Kow of -0.78(6) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Using an acclimated sewage sludge inoculum, theobromine reached 100% of its Theoretical BOD in 28 days(7), suggesting that biodegradation may be an important environmental fate process in water previously exposed to this compound(SRC).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), theobromine, which has an estimated vapor pressure of 1.1X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase theobromine may be removed from the air by wet and dry deposition(SRC). Theobromine does not absorb light at wavelengths >290 nm(3) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

Theobromine is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Theobromine absorbs light at 272 nm(2) and, therefore, is not expected to be susceptible to direct photolysis by sunlight since sunlight consists of wavelengths above 290 nm(SRC).

An estimated BCF of 3 was calculated in fish for theobromine(SRC), using log Kow of -0.78(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of theobromine can be estimated to be 10(SRC). According to a classification scheme(2), this estimated Koc value suggests that theobromine is expected to have very high mobility in soil. However, aromatic amines are expected to bind strongly to humus or organic matter in soils due to the high reactivity of the aromatic amino group(3,4), suggesting that mobility may be much lower in some soils(SRC).

The Henry's Law constant for theobromine is estimated as 1.6X10-11 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that theobromine is expected to be essentially nonvolatile from water surfaces(2). Theobromine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.1X10-11 mm Hg(SRC), determined from a fragment constant method(3).

SURFACE WATER: Theobromine was detected at an average concentration of 260.3 ng/L in samples from the Guadalquivir River, province of Jaen, South East Spain. Seven of eleven samples were positive, corresponding to a detection frequency of 63.6%. The compound was not detected in associated wetlands. Sampling was conducted between April 2009 and November 2010. Its presence in regional reservoirs was as follows(1):[Table#6932]

Theobromine levels of 0.15-0.20% have been reported in manufactured tea and 0.3% in dried mate(1). Theobromine has been found in blended black tea at a level of 0.69% dry extractable solids present(1).|Theobromine is the predominant alkaloid in coca and chocolate products(1). The theobromine content of finished chocolate products were reported as follows: baking chocolate, 1.386%; chocolate flavored syrup, 0.242%; cocoa, 15% fat, 2.598%; dark sweet chocolate, 0.474%, and milk chocolate, 0.197%(1). An average level of 1.89% was found in eight commercial brands of cocao powder. Hot chocolate beverages contain average levels of 65 mg/5-oz serving. Chocolate milk samples from instant, cold, sweetened cocoa mixes had an average level of 58 mg theobromine per serving, 62 mg per serving for hot cocoa. Theobromine levels in dark eating chocolate were 0.36 to 0.63% with one 1-oz bar of dark chocolate containing 130 mg theobromine; a one 1-oz bar of milk chocolate contained 44 mg theobromine. Chocolate frostings have a higher theobromine content (0.055-0.213%) than chocolate cakes(2).

Theobromine is readily absorbed from food and evenly distributed in body fluids; the half-times in plasma and saliva are highly correlated. Theobromine has been reported to pass into the breast milk of nursing mothers(1). Following ingestion of 113 g of milk chocolate containing 240 mg theobromine and 16 mg caffeine, theobromine concentration in 6 samples of mother's milk ranged from 3.7 to 7.5 mg/L, mean of 5.3 mg/L, with the concentration max noted at 2.1 to 3.3 hours(2).|Six nursing mothers ingested 113 gm of Hershey's milk chocolate containing 240 mg of theobromine. Samples of plasma, saliva, and breast milk were assayed for theobromine by high pressure liquid chromatography. Peak theobromine concentrations of 3.7 to 8.2 mg/L were found in all fluids at 2 to 3 hour after ingestion of chocolate. ... Body clearance was 65 +/- 20 mL/hour/kilogram ... Theobromine is only slightly bound to plasma and milk proteins and concentrations in milk and saliva matched plasma data closely. The mean concentration ratios were 0.82 +/- 0.17 for milk/plasma and 0.92 +/- 0.17 for saliva/plasma.

Occupational exposure to theobromine may occur through inhalation and dermal contact with this compound at workplaces where theobromine is produced or used. Monitoring and use data indicate that the general population may be exposed to theobromine via ingestion of food, in particular coffee, tea and chocolate, inhalation of tobacco smoke and formerly, administration of medicinal products containing theobromine. (SRC)

Following ingestion of 113 g of milk chocolate containing 240 mg theobromine and 16 mg caffeine, theobromine concentration in 6 samples of mother's milk ranged from 3.7 to 7.5 mg/L, mean of 5.3 mg/L, with the concentration max noted at 2.1 to 3.3 hours(1).

theobromine is used as a vasodilator, a diuretic, and heart stimulant. And similar to caffeine, it may be useful in management of fatigue and orthostatic hypotension.

Diuretic, bronchodilator, cardiotonic. /Former use/|Formerly, theobromine and its derivatives were used in diuretics, myocardial stimulants, vasodilators and smooth muscle relaxants. Theobromine salts (calcium salicylate, sodium salicylate and sodium acetate) were used previously to dilate coronary arteries at doses of 300 to 600 mg per day. There is no current therapeutic use of theobromine. /Former use/|VET: Diuretic, myocardial stimulant, vasodilator. /Former use/|/EXPL THER/ Cough is a common and protective reflex, but persistent coughing is debilitating and impairs quality of life. Antitussive treatment using opioids is limited by unacceptable side effects, and there is a great need for more effective remedies. The present study demonstrates that theobromine, a methylxanthine derivative present in cocoa, effectively inhibits citric acid-induced cough in guinea-pigs in vivo. Furthermore, in a randomized, double-blind, placebo-controlled study in man, theobromine suppresses capsaicin-induced cough with no adverse effects. We also demonstrate that theobromine directly inhibits capsaicin-induced sensory nerve depolarization of guinea-pig and human vagus nerve suggestive of an inhibitory effect on afferent nerve activation. These data indicate the actions of theobromine appear to be peripherally mediated. We conclude theobromine is a novel and promising treatment, which may form the basis for a new class of antitussive drugs.

Theobromine, a xanthine derivative like caffeine and the bronchodilator theophylline, is used as a CNS stimulant, mild diuretic, and respiratory stimulant (in neonates with apnea of prematurity).

Drugs used to cause dilation of the blood vessels. (See all compounds classified as Vasodilator Agents.)|Agents that cause an increase in the expansion of a bronchus or bronchial tubes. (See all compounds classified as Bronchodilator Agents.)

The ratio of brain:blood theobromine concentrations decreased continuously from 0.96 at birth to 0.60 in 30-day-old rats. After 24 hr, no organ accumulation of theobromine or its metabolites could be seen in adult animals.|Theobromine is absorbed and distributed rapidly after oral administration to rats and equilibrates freely between plasma and testicular fluid.|Similar kinetic parameters were observed in male and female rabbits when theobromine was administered intravenously or orally at doses of 1 and 5 mg/kg bw, with complete gastrointestinal absorption. A reduction in the absorption rate constant was seen in rabbits when the dose was increased from 10 to 100 mg/kg bw. In spite of delayed gastrointestinal absorption at high doses, probably due to the low solubility of the compound, the absolute bioavailability of theobromine approached 100%. Labelled theobromine was almost completely absorbed after oral administration (1-6 mg/kg); the peak blood level tended to appear later with larger doses.|When theobromine was given as a single oral dose of 15-50 mg/kg bw to male dogs, peak plasma concentrations, with considerable individual variations, were observed within 3 hr. With a higher dose (150 mg/kg bw), the peak plasma concentrations were attained 14-16 hr later, showing delayed intestinal absorption. In rats, plasma protein binding was very low (8-17%) after oral administration of 1-100 mg/kg bw theobromine.|For more Absorption, Distribution and Excretion (Complete) data for 3,7-Dimethylxanthine (17 total), please visit the HSDB record page.

Pregnancy and increased doses of theobromine were shown to modify theobromine metabolism. At a dose of 50 mg/kg bw, pregnant rabbits excreted more unchanged theobromine in the urine (51% versus 35%). Pregnant rats excreted a higher percentage of a 5 mg/kg dose as unchanged theobromine (53%) than non-pregnant rats (39%); this difference disappeared at the saturation dose (100 mg/kg), when unchanged theobromine corresponded to about 60% of the dose in the urine of both pregnant and non-pregnant animals. Rats given 100 mg/kg excreted more unchanged theobromine than those given 1 mg/kg (73% versus 51%), and showed a corresponding relative decrease in excretion of its uracil metabolite, 6-amino-5-(N-methylformylamino)-1-methyluracil (16% versus 28%).|The compounds identified in bile of phenobarbital-treated rats were 3,7-dimethyluric acid (64-76% of biliary radioactivity), dimethylallantoin (5-8%), 6-amino-5-(N-methylformylamino)- 1-methyluracil (10-17%) and theobromine (8-10%). In 3-methylcholanthrene-treated rats, urinary elimination of unchanged theobromine was reduced from 23-27% to only 2%, while excretion of 6-amino-5-(N-methylformylamino)-1- methyluracil was significantly increased. Only 3,7-dimethyluric acid was produced by liver microsomal incubation in control rats while phenobarbital and 3-methylcholanthrene pretreatment enhanced the biotransformation resulting in the production of all metabolites found in vivo as well as unknown polar compounds.|6-Amino-5-(N-methylformylamino)-1-methyluracil is quantitatively the most important theobromine metabolite in rats, accounting for 20-35% of urinary metabolites. The majority of theobromine-derived radioactivity in the feces of rats could be accounted for by 3,7-dimethyluric acid. The most extensive metabolism of theobromine was observed in rabbits and mice; male mice converted theobromine more extensively into this metabolite than did female mice. In contrast, oxidation of theobromine to 3,7-dimethyluric acid was significantly greater in female than in male rats. Rabbits and dogs metabolized theobromine primarily to 7-methylxanthine and 3-methylxanthine, respectively, and dogs excreted small quantities of an unidentified metabolite.|As a metabolite of caffeine, theobromine has been detected in variable amounts in plasma and urine of humans and different animal species.|For more Metabolism/Metabolites (Complete) data for 3,7-Dimethylxanthine (11 total), please visit the HSDB record page.|Theobromine has known human metabolites that include 3,7-Dimethyluric acid, 3-Methylxanthine, and 7-Methylxanthine.

The mean half-time of theobromine in human serum ranged from 6.1 to 10 hr.|The disposition half-life of theobromine averaged 7.1 +/- 2.1 hours ...|In dogs, an average plasma half-time of 17.5 hr was reported after single oral doses of theobromine ranging from 15 to 150 mg/kg bw. In rabbits, the mean elimination half-time was 4.3-5.6 hr for doses ranging from 1 to 100 mg/kg bw.

Theobromine stimulates medullary, vagal, vasomotor, and respiratory centers, promoting bradycardia, vasoconstriction, and increased respiratory rate. This action was previously believed to be due primarily to increased intracellular cyclic 3′,5′-adenosine monophosphate (cyclic AMP) following inhibition of phosphodiesterase, the enzyme that degrades cyclic AMP. It is now thought that xanthines such as caffeine and theobromine act as antagonist at adenosine-receptors within the plasma membrane of virtually every cell. As adenosine acts as an autocoid, inhibiting the release of neurotransmitters from presynaptic sites but augmenting the actions of norepinephrine or angiotensin, antagonism of adenosine receptors promotes neurotransmitter release. This explains the stimulatory effects of xanthine derivatives such as theobromine and caffeine. Blockade of the adenosine A1 receptor in the heart leads to the accelerated, pronounced "pounding" of the heart upon caffeine intake.

SYMPTOMS: Ingestion of large doses of this compound may cause nausea and vomiting. Loss of appetite may also occur. Other symptoms may include central nervous system and gastrointestinal changes. ACUTE/CHRONIC HAZARDS: When heated to decomposition this compound emits toxic fumes of nitrogen oxides. (NTP, 1992)

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

Emergency and supportive measures. Maintain an open airway and assist ventilation if necessary. Treat seizures and hypotension if they occur. Extreme anxiety or agitation may respond to benzodiazepines such as IV lorazepam. Hypokalemia usually resolves without aggressive treatment. Monitor ECG and vital signs for at least 6 hr after ingestion or until the serum level is documented to be decreasing. Specific drugs and antidotes. Beta-blockers effectively reverse cardiotoxic effects mediated by excessive beta-adrenergic stimulation. Treat tachyarrhythmias or hypotension with intravenous propranolol ... or esmolol ... beginning with low doses and titrating to effect. Because of its short half-life and cardioselectivity, esmolol is preferred. Decontamination. Prehospital. Administer activated charcoal if available. Hospital. Administer activated charcoal can be given promptly, although gastric lavage should be considered for massive ingestion. Enhanced elimination. Repeat-dose activated charcoal may enhance caffeine elimination. Seriously intoxicated patients (with multiple seizures, significant tachyarrhythmias, or intractable hypotension) may require hemodialysis or charcoal hemoperfusion. /Caffeine/|/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. 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 ... . Anticipate seizures 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 ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ 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. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /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. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/HUMAN EXPOSURE STUDIES/ Theobromine, a methylxanthine-related to caffeine and present in high levels in cocoa, may contribute to the appeal of chocolate. However, current evidence for this is limited. We conducted a within-subjects placebo-controlled study of a wide range of oral theobromine doses (250, 500, and 1,000 mg) using an active control dose of caffeine (200 mg) in 80 healthy participants. Caffeine had the expected effects on mood including feelings of alertness and cardiovascular parameters. Theobromine responses differed according to dose; it showed limited subjective effects at 250 mg and negative mood effects at higher doses. It also dose-dependently increased heart rate. In secondary analyses, we also examined individual differences in the drug's effects in relation to genes related to their target receptors, but few associations were detected. This study represents the highest dose of theobromine studied in humans. We conclude that theobromine at normal intake ranges may contribute to the positive effects of chocolate, but at higher intakes, effects become negative.|/HUMAN EXPOSURE STUDIES/ Evidence from clinical studies has suggested that cocoa may increase high-density lipoprotein (HDL)-cholesterol concentrations. However, it is unclear whether this effect is attributable to flavonoids or theobromine, both of which are major cocoa components. We investigated whether pure theobromine increases serum HDL cholesterol and whether there is an interaction effect between theobromine and cocoa. The study had a 2-center, double-blind, randomized, placebo-controlled, full factorial parallel design. After a 2-wk run-in period, 152 healthy men and women (aged 40-70 yr) were randomly allocated to consume one 200-mL drink/d for 4 wk that contained 1) cocoa, which naturally provided 150 mg theobromine and 325 mg flavonoids [cocoa intervention (CC)], 2) 850 mg pure theobromine [theobromine intervention (TB)], 3) cocoa and added theobromine, which provided 1000 mg theobromine and 325 mg flavonoids [theobromine and cocoa intervention (TB+CC)], or 4) neither cocoa nor theobromine (placebo). Blood lipids and apolipoproteins were measured at the start and end of interventions. In a 2-factor analysis, there was a significant main effect of the TB (P < 0.0001) but not CC (P = 0.1288) on HDL cholesterol but no significant interaction (P = 0.3735). The TB increased HDL-cholesterol concentrations by 0.16 mmol/L (P < 0.0001). Furthermore, there was a significant main effect of the TB on increasing apolipoprotein A-I (P < 0.0001) and decreasing apolipoprotein B and LDL-cholesterol concentrations (P < 0.02). Theobromine independently increased serum HDL-cholesterol concentrations by 0.16 mmol/L. The lack of significant cocoa and interaction effects suggested that theobromine may be the main ingredient responsible for the HDL cholesterol-raising effect. This trial was registered at clinicaltrials.gov as NCT01481389.|/HUMAN EXPOSURE STUDIES/ Like caffeine, theobromine crosses the blood-brain barrier and binds to adenosine receptors, suggesting it might share caffeine's beneficial effects on mood and vigilance. Therefore, the purpose of this study was to assess the effect of theobromine doses commonly found in foods on mood and vigilance parameters sensitive to caffeine. Caffeine was tested as a positive control. Twenty-four men (age, 23 [3] years) completed 6 double-blind trials during which they consumed experimental beverages, assessed their mood using standardized self-report questionnaires, and completed a 2-hour visual vigilance task. Three experimental doses (100, 200, and 400 mg theobromine) were delivered in a cocoa-based beverage; 3 matched control treatments (0 mg theobromine, 400 mg theobromine, and 100 mg caffeine) were delivered in a non-cocoa beverage. Mean salivary concentrations of theobromine exhibited significant dose-dependent differences (400 mg trials > 200 mg trial > 100 mg trial > 0 mg trials; P < 0.005). At every dose tested, theobromine failed to consistently affect mood state or vigilance (P > 0.05), but 100-mg caffeine significantly decreased lethargy/fatigue and increased vigor (P = 0.006 and 0.011, respectively). These findings indicate theobromine does not influence mood and vigilance when administered in nutritionally relevant doses, despite sharing many of caffeine's structural characteristics.|/SIGNS AND SYMPTOMS/ It has been stated that "in large doses" theobromine may cause nausea and anorexia and that daily intake of 50-100 g cocoa (0.8-1.5 g theobromine) by humans has been associated with sweating, trembling and severe headache.|For more Human Toxicity Excerpts (Complete) data for 3,7-Dimethylxanthine (7 total), please visit the HSDB record page.

Theobromine

Double salt or mixture of calcium theobromine and calcium salicylate. Contains no less than 44% theobromine. /Calcium salicyclate/|Equimolar mixture of sodium theobromine and sodium acetate, containing 1 H2O. Theobromine 59.6%, anhydrous sodium acetate 27.1%. /Sodium acetate/|Equimolar mixture of sodium theobromine and sodium salicylate, containing 1H2O. Theobromine 47.3%, sodium salicylate 42.1%. /Sodium salicylate/

1H-Purine-2,6-dione, 3,7-dihydro-3,7-dimethyl-: ACTIVE|Alkaloid found in cocoa and chocolate products.

Accurate quantitative measurement of drugs and their metabolites is important as this can be used to establish long-term abuse of illicit materials as well as establish accurate drug dosing for legal therapeutics. However, the levels of drugs and xenometabolites found in human body fluids necessitate methods that are highly sensitive as well as reproducible with the potential for portability. Raman spectroscopy does offer excellent reproducibility, portability and chemical specificity, but unfortunately, the Raman effect is generally too weak unless it is enhanced. We therefore developed surface-enhanced Raman scattering (SERS) and combined it with the powerful machine learning technique of artificial neural networks to enable rapid quantification of caffeine and its two major metabolites theobromine and paraxanthine. We established a three-way mixture analysis from 10(-5) to 10(-7) mol/cu dm, and excellent predictions were generated for all three analytes in tertiary mixtures. The range we selected reflects the levels found in human body fluids, and the typical errors for our portable SERS analysis were 1.7x10(-6) mol/cu dm for caffeine, 8.8x10(-7) mol/cu dm for theobromine and 9.6x10(-7) mol/cu dm for paraxanthine. We believe this demonstrates the exciting prospect of using SERS for the quantitative analysis of multiple analytes simultaneously without recourse to lengthy and time-consuming chromatography, a method that often has to be combined with mass spectrometry.|Method: AOAC 980.14; Procedure: liquid chromatographic method; Analyte: theobromine and caffeine; Matrix: cacao products; Detection Limit: not provided.

Rapid, selective and sensitive methods were developed and validated to determine procyanidins, anthocyanins and alkaloids in different biological tissues, such as liver, brain, the aorta vein and adipose tissue. For this purpose, standards of procyanidins (catechin, epicatechin, and dimer B(2)), anthocyanins (cyanidin-3-glucoside and malvidin-3-glucoside) and alkaloids (theobromine, caffeine and theophylline) were used. The methods included the extraction of homogenized tissues by off-line liquid-solid extraction, and then solid-phase extraction to analyze alkaloids, or microelution solid-phase extraction plate for the analysis of procyanidins and anthocyanins. The eluted extracts were then analyzed by ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry, using a triple quadrupole as the analyzer. The optimum extraction solution was water/methanol/phosphoric acid 4% (94/4.5/1.5, v/v/v). The extraction recoveries were higher than 81% for all the studied compounds in all the tissues, except the anthocyanins, which were between 50 and 65% in the liver and brain. In order to show the applicability of the developed methods, different rat tissues were analyzed to determine the procyanidins, anthocyanins and alkaloids and their generated metabolites. The rats had previously consumed 1 g of a grape pomace extract (to analyze procyanidins and anthocyanins) or a cocoa extract (to analyze alkaloids) per kilogram of body weight. Different tissues were extracted 4 hr after administration of the respective extracts. The analysis of the metabolites revealed a hepatic metabolism of procyanidins. The liver was the tissue which produced a greater accumulation of these metabolites.|Method: AOAC 949.16; Procedure spectrophotometric method; Analyte: phenobarbital and theobromine; Matrix: drugs; Detection Limit: not provided.

Food additives -> Flavoring Agents|Pharmaceuticals|Cosmetics -> Skin conditioning

Flavoring Agents