Neotame

378.46

378.46

253-404-6

VJ597D52EX

DTXSID50167950

2924299090

105

-0.1

white to off-white powder

1.1±0.1 g/cm3

83-85°C

565.3°C at 760 mmHg

277.9±32.9 °C

1.530

In water, 14.4 mg/L at 25 deg C (est)

-20°C Freezer

2.71X10-11 mm Hg at 25 deg C (est)

D -54.84° (c = 1 in methanol); D20 -39.8° (c = 0.5 in water)

Clean sweet taste without bitter, metallic or off flavors

5,0-7,0 (0,5 % aqueous solution)

Henry's Law constant = 2.29X10-17 atm-cu m/mol at 25 °C (est)

pKa1 = 4.11; pKa2 = 7.70; pKa3 = 6.45

White crystalline powder from ethyl acetate/hexane; mp 80-83 deg ; also reported as mp 80.9-83.4 °C from aqueous methanol. SPecific optical rotation: -58.84 deg at 25 °C/D (c = 1 in methanol); -39.8 deg at 20 °C/D (c = 0.5 in water). pKa1 = 3.01; pKa2 = 8.02. pI: 5.5. Calorie value: <1.2 kH/g. Solubility in water (g/L): 10.6 (15 °C), 12.6 (25 °C), 47.5 (60 °C); in ethyl acetate (g/L): 43.6 (15 °C), 77 (25 °C), >1000 (60 °C); in absolute ethanol (g/L): approximately 950 (25 °C) /Neotame monohydrate/|Hydroxyl radical reaction rate constant = 1.10X10-10 cu cm/molec-sec at 25 °C (est)

NONH for all modes of transport

24/25

The degradation of neotame was assessed at an artificially high concentration of 200 ppm in mock beverages containing phosphate- and citrate-buffered solutions simulating formulations used in commercial cola soft drinks (pH 2.8 and 3.2) lemon-lime soft drink (pH 3.8) and root beer soft drink (pH 4.5), and covered a range of temperatures (5, 20, 30, and 35 deg C) and storage for up to 8 weeks. These conditions simulated typical commercial, as well as extreme, storage conditions for beverages, wit

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational harm/injury/toxicity 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 and plant life; and conformance with environmental and public health regulations.

Neotame is a food additive permitted for direct addition to food for human consumption, as long as 1) the quantity of the substance added to food does not exceed the amount reasonably required to accomplish its intended physical, nutritive, or other technical effect in food, and 2) any substance intended for use in or on food is of appropriate food grade and is prepared and handled as a food ingredient.

SRP: In bulk storage or manufacturing situations where combustible dusts can collect in sufficient concentrations to give rise to an explosion/deflagration, reasonable precautions shall be taken to reduce or eliminate the hazard. Efforts shall be made to control or eliminate the five elements necessary to initiate a dust explosion. These include combustible dust (fuel), ignition source (heat), oxygen in air (oxidizer), and dispersion of dust particles in sufficient quantity and concentration as well as confinement of the dust cloud. General guidance in these efforts can be found in OSHA's "Combustible Dust in Industry; Preventing and Mitigating the Effects of Fire and Explosions", which list measures to control dusts, eliminate ignition sources, and limit the effects of explosions.

Neotame's production and use as a non-nutritive sweetener(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 390(SRC), determined from a structure estimation method(2), indicates that neotame is expected to have moderate mobility in soil(SRC). The estimated pKa values of neotame are 4.11, 7.70, and 6.45(3), indicating that this compound will partially exist in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of neotame from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.3X10-17 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Neotame is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.7X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(6). Biodegradation data were not available(SRC, 2011).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 390(SRC), determined from a structure estimation method(2), indicates that neotame 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 2.3X10-17 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of three(SRC), from an estimated log Kow of 2.88(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data were not available(SRC, 2011).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), neotame, which has an estimated vapor pressure of 2.7X10-11 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 neotame may be removed from the air by wet or dry deposition(SRC). Neotame contains chromophores that absorb at wavelengths >290 nm(4), and therefore may be susceptible to direct photolysis by sunlight(SRC).

A base-catalyzed second-order hydrolysis rate constant of 4.6X10-2 L/mole-sec(SRC) was estimated using a structure estimation method(2); this corresponds to half-lives of 5 years and 170 days at pH values of 7 and 8, respectively(1). Neotame contains chromophores that absorb at wavelengths >290 nm(2), and therefore may be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of three was calculated in fish for neotame(SRC), using an estimated/ log Kow of 2.88(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 neotame can be estimated to be 390(SRC). According to a classification scheme(2), this estimated Koc value suggests that neotame is expected to have moderate mobility in soil. The estimated pKa values of neotame are 4.11, 7.70, and 6.45(3), indicating that this compound will partially exist in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

The Henry's Law constant for neotame is estimated as 2.3X10-9 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that neotame is expected to be essentially nonvolatile from water and moist soil surfaces surfaces(2). Neotame is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.7X10-11 mm Hg(SRC), determined from a fragment constant method(3).

Occupational exposure to neotame may occur through inhalation and dermal contact with this compound at workplaces where neotame is produced or used. Use data indicate that the general population may be exposed to neotame via ingestion of consumer products containing neotame. (SRC)

14(C)-neotame was administered to groups of six male and six female Sprague-Dawley Crl:CDBR rats by gavage or by intravenous injection as a single dose of 15 mg/kg bw. Rats were individually housed in metabolism cages and urine and feces were collected at intervals for 72 hr after dosing. A additional group of three rats received a single oral dose of 120 mg/kg bw. All rats were killed after 72 hr and the carcasses were retained for analysis. Radiolabel was measured in all samples and the metabolites present in the urine and feces were determined. After oral administration, >90% of the radiolabel was recovered in urine and faeces within 48 hr. Within 72 hr after oral administration of (14)C-neotame at a dose of 15 or 120 mg/kg bw, 8.5-10.8% and 84.5-87.2% of the radiolabel was excreted in the urine and feces, respectively. After intravenous administration of (14)C-neotame at dose of 15 mg/kg bw, approximately 35% and 59% of the radiolabel was recovered in urine and feces, respectively. Less than 0.3% of the radiolabel was recovered in the carcasses within 72 hr after either oral or intravenous administration. Unchanged neotame was only detected in urine collected from female rats 0-6 h after intravenous administration and accounted for 3.7% of the administered dose. Unchanged neotame was not detected in the feces of any animal regardless of the dose or route of administration.|Sprague-Dawley Crl:CDBRVAF Plus rats were each given a single oral dose of 15 mg/kg bw of (14)C-neotame by gavage and divided among four groups. In rats in group 1 (three rats of each sex), blood was taken at intervals up to 24 hr after treatment, separated into cell and plasma fractions, and analysed for radiolabel. Rats in group 2 (two rats of each sex) were housed in glass metabolism cages for 72 hr after treatment for collection of urine, feces and expired air. Carcasses were solubilized for analysis of retained radiolabel, and urine and feces were pooled for analysis of metabolites as well as total radiolabel. In group 3 (two rats of each sex), rats were anesthetized 0.5 hr or 2 hr after dosing, and blood was collected and analysed. Rats in group 4 (two males) were anesthetized and the bile ducts and stomach cannulated. Radiolabelled neotame was administered via the stomach cannula, and bile was collected at intervals up to 48 hr after treatment. Urine and feces were collected for 0-24 hr and 24-48 hr and radiolabel was measured. Plasma concentrations of radiolabel after oral dosing with (14)C-neotame peaked at 30 min after dosing in females and 1 h after dosing in males, followed by a rapid decline. The major metabolite identified in plasma, urine, feces and bile was de-esterified neotame. The excretion of (14)C-neotame was examined over 72 hr; 8-10% of the radiolabel was recovered in urine, 90-92% in feces, and 0.01-0.03% in expired air. After 72 hr, 0.11-0.13% of the radiolabel remained in the carcass. In males, urinary excretion was virtually complete within 12 hr, while in females, urinary excretion continued over 24 hr. Most fecal excretion occurred between 6 hr and 24 hr after dosing in both sexes. In males in group 4, urinary excretion was similar to that seen in other groups, with around 5-9% of the administered dose being excreted in the urine. Biliary excretion accounted for approximately 5.7% of the administered dose, while fecal excretion accounted for around 85% of the administered dose. Little radiolabel was retained in the carcass.|In a study designed to examine the distribution and elimination of radioactivity derived from neotame by whole-body autoradiography, eight pregnant and eight non-pregnant Sprague-Dawley rats were each given a single dose of 15 mg/kg bw of (14)C-neotame by gavage. The rats were sacrificed at various times up to 24 hr after dosing and the carcasses treated as in the previous study. The tissue distribution of radiolabel was similar in pregnant and non-pregnant rats. Placental concentrations of radiolabel were low at 0.5 and 2 hr after dosing, similar to those seen in other peripheral tissues and in circulating blood. No radiolabel was detected in the fetus at any time. The highest concentrations of radiolabel were seen shortly after dosing, initially in the stomach contents, gastrointestinal tract, liver, kidneys and bladder, with lower concentrations in the rest of the body. At subsequent time-points, the passage of radiolabel through the excretory organs was seen. No accumulation was seen in tissues, and concentrations were very low after 24 hr. There was no significant difference between pregnant and non-pregnant rats in the time profile with which radiolabel was distributed in the tissues|In a ... study to examine the distribution of neotame in rat tissues, 21 male Lister Hooded rats were given (14)C-neotame in a single oral dose of 15 mg/kg bw by gavage. Pairs of rats (one of each sex) were killed after 0.5, 2, 6, 12 and 24 hr, pinned out, frozen rapidly, and sagittal sections taken through the carcass at six levels were examined by autoradiography. Qualitative assessment of radiolabel present in male and female rats indicated that the highest levels were present in rats killed at the earliest time-points after dosing. Levels decreased rapidly with time. At 0.5 hr and 2 hr after dosing, most radiolabel was found in the stomach, the gastrointestinal tract, liver, kidneys and bladder, with smaller amounts being distributed throughout the rest of the body. Very small amounts were found in the central nervous system, and no binding to pigmented skin or the eye was observed. Levels were consistent with the circulation of radiolabel in the bloodstream. At subsequent time-points (6, 12 and 24 hr), the passage of radiolabel through the excretory organs was seen. By 24 hr after dosing, only very small amounts remained in the animal and there was no evidence of accumulation in any tissue.|For more Absorption, Distribution and Excretion (Complete) data for Neotame (11 total), please visit the HSDB record page.

... Neotame was labelled with Carbon-14 at the 1-position in the dimethylbutyl side chain and with Carbon-13 in the 2 terminal methyl groups of the same side chain. ... Volunteers ingested a single dose of the labelled test substance in water at a level approximately equivalent to 0.25 mg/kg, which corresponds to the amount of neotame needed to sweeten 1 L of beverage. Neotame was rapidly, but incompletely absorbed and rapidly excreted. A mean of 98% of the administered radioactivity was recovered in urine and feces, mostly within 72 hours of dosing. Mean plasma concentrations of neotame peaked at 0.4 hr ... and declined with a half-life of 0.6 hr. The major metabolite of neotame was de-esterified neotame formed by hydrolysis of the methyl ester group. Mean plasma concentrations of this metabolite peaked at 1 hr ... /and/ were approximately 2.5 times higher than neotame concentrations and declined with a half-life of 1.5 hr. De-esterified neotame represented a mean of approximately 80% of the excreted dose. Two other metabolites were detected at greater than 1% of the dose. One, that was a mean of about 4.9% of the dose, was found in the feces and was identified as N-(3, 3 dimethylbutyl)-L aspartic acid. The other metabolite was in urine and was identified by LC/MS/MS, NMR and original synthesis as a carnitine ester of 3, 3-dimethylbutanoic acid. All metabolites of neotame present at 1% or greater of the dose have been shown to occur in the species used in safety studies, confirming the safety of these metabolites.|... As part of the safety testing, studies were conducted to evaluate the absorption, distribution, pharmacokinetics, metabolism and excretion of neotame in laboratory rats and dogs. For this purpose, neotame was labelled with Carbon-14 at the 1-position in the dimethylbutyl side chain and was administered to animals at doses of 15 or 120 mg/kg body weight. In rats and dogs, oral doses of neotame were rapidly, but incompletely absorbed and rapidly excreted with no evidence of potential for accumulation. In rats, absorbed Carbon-14 was mainly associated with the gastrointestinal tract and organs of metabolism and excretion (liver, kidney and bladder). Almost no neotame was detected in (stabilised) plasma or .../excretions/ after oral dosing to rats. This was probably due to high activity of plasma esterases. The major metabolite of neotame was de-esterified neotame formed by hydrolysis of the methyl ester group. In rats, mean plasma concentrations of this metabolite peaked at 0.5 hr ...and declined with a half life of 1 hr. In dogs, which have a lower level of plasma esterase activity, neotame was detected in plasma and ... /excretions/ after oral dosing. Mean plasma concentrations of neotame peaked at 0.5 hr ... and declined with a half-life of 0.4 hr. Deesterified neotame represented a mean of approximately 70-80% of excreted oral doses in both rats and dogs. Other metabolites detected included N-(3, 3 dimethylbutyl)- L aspartic acid (in rats and dogs about 2% of the dose) and a beta-glucuronide conjugate of 3, 3-dimethylbutanoic acid (in rats and dogs about 5% of the dose). In addition the carnitine ester of 3, 3-dimethylbutanoic acid was present in the urine of female rats.|After oral administration, approximately 20-30% of the administered dose is absorbed and rapidly converted to the major metabolite, N-(N-(3,3-dimethylbutyl)-L-alpha-aspartyl)-L-phenylalanine (de-esterified neotame) and a number of minor metabolites. Neotame and its metabolites are rapidly eliminated in the urine and feces. ... The major metabolic pathway is de-esterification of neotame to N-[N-(3,3-dimethylbutyl)-L-alpha-aspartyl]-L-phenylalanine and methanol. Minor metabolites are N-(3,3-dimethylbutyl)-L-aspartic acid, a metabolite formed via peptide or amide hydrolysis of neotame; 3,3-dimethylbutyric acid, also referred to as 3,3-dimethylbutanoic acid; the carnitine conjugate of 3,3-dimethylbutyric acid; and the glucuronide conjugate of 3,3-dimethylbutyric acid.|14(C)-neotame was administered to groups of six male and six female Sprague-Dawley Crl:CDBR rats by gavage or by intravenous injection as a single dose of 15 mg/kg bw. Rats were individually housed in metabolism cages and urine and feces were collected at intervals for 72 hr after dosing. A additional group of three rats received a single oral dose of 120 mg/kg bw. All rats were killed after 72 hr and the carcasses were retained for analysis. Radiolabel was measured in all samples and the metabolites present in the urine and feces were determined. ... The major metabolite found in urine after 48 hr was de-esterified neotame, independent of the route of administration or the dose. N-(3,3-dimethylbutyl)-L-aspartic acid (NC-00754) was detected at lower concentrations (around 10% of the levels of de-esterified neotame after oral dosing). Parent compound was found only in the urine of female rats after intravenous dosing (3.7% of the dose); none was detected in the urine of any other groups. A glucuronide metabolite was also detected at low levels (0.4-0.5% of the administered dose) in the urine, independent of dose or route of administration. Two minor metabolites, each representing <1.6% of the administered dose, were identified. In the feces, de-esterified neotame was the major metabolite (approximately 70-80% of the dose after oral administration). N(3,3dimethylbutyl)Laspartic acid (NC-00754) was detected at lower levels, 0.8-2.5% of the dose. Low concentrations of an unidentified metabolite were also found, representing 0.7-1.2% of the administered dose.|For more Metabolism/Metabolites (Complete) data for Neotame (9 total), please visit the HSDB record page.

Healthy men (mean age + or - standard deviation (SD), 28 + or - 6 years) were each given a single dose of neotame in solution at 0.10, 0.25 or 0.50 mg/kg bw (n =7, 6, and 6 men per dose, respectively), after an overnight fast. Eighteen men completed the study. Clinical evaluations and laboratory tests were done immediately before dosing and approximately 48 hr after dosing. ... Neotame was rapidly eliminated with a half-life ranging from 0.61 hr to 0.75 hr. The short half life was supported by the rapid disappearance of neotame from the urine (neotame was not detectable after 8 hr). ... The calculated half life of de-esterified neotame in plasma was approximately 2 hr.

The sweet taste receptor is a heterodimer of two G protein coupled receptors, T1R2 and T1R3. Previous experimental studies using sweet receptor chimeras and mutants show that there are at least three potential binding sites in this heterodimeric receptor. Receptor activity toward the artificial sweeteners aspartame and neotame depends on residues in the amino terminal domain of human T1R2. In contrast, receptor activity toward the sweetener cyclamate and the sweet taste inhibitor lactisole depends on residues within the transmembrane domain of human T1R3. Furthermore, receptor activity toward the sweet protein brazzein depends on the cysteine rich domain of human T1R3.|The sweet protein brazzein [recombinant protein with sequence identical with the native protein lacking the N-terminal pyroglutamate (the numbering system used has Asp2 as the N-terminal residue)] activates the human sweet receptor, a heterodimeric G-protein-coupled receptor composed of subunits Taste type 1 Receptor 2 (T1R2) and Taste type 1 Receptor 3 (T1R3). In order to elucidate the key amino acid(s) responsible for this interaction, we mutated residues in brazzein and each of the two subunits of the receptor. The effects of brazzein mutations were assayed by a human taste panel and by an in vitro assay involving receptor subunits expressed recombinantly in human embryonic kidney cells; the effects of the receptor mutations were assayed by in vitro assay. We mutated surface residues of brazzein at three putative interaction sites: site 1 (Loop43), site 2 (N- and C-termini and adjacent Glu36, Loop33), and site 3 (Loop9-19). Basic residues in site 1 and acidic residues in site 2 were essential for positive responses from each assay. Mutation of Y39A (site 1) greatly reduced positive responses. A bulky side chain at position 54 (site 2), rather than a side chain with hydrogen-bonding potential, was required for positive responses, as was the presence of the native disulfide bond in Loop9-19 (site 3). Results from mutagenesis and chimeras of the receptor indicated that brazzein interacts with both T1R2 and T1R3 and that the Venus flytrap module of T1R2 is important for brazzein agonism. With one exception, all mutations of receptor residues at putative interaction sites predicted by wedge models failed to yield the expected decrease in brazzein response. The exception, hT1R2 (human T1R2 subunit of the sweet receptor):R217A/hT1R3 (human T1R3 subunit of the sweet receptor), which contained a substitution in lobe 2 at the interface between the two subunits, exhibited a small selective decrease in brazzein activity. However, because the mutation was found to increase the positive cooperativity of binding by multiple ligands proposed to bind both T1R subunits (brazzein, monellin, and sucralose) but not those that bind to a single subunit (neotame and cyclamate), we suggest that this site is involved in subunit-subunit interaction rather than in direct brazzein binding. Results from this study support a multi-point interaction between brazzein and the sweet receptor by some mechanism other than the proposed wedge models.

/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 /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's 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/ In a two-week study of tolerance in men and women, neotame was administered to 74 healthy adults (mean age +/ - SD, 32 +/ - 10 years). The study was randomized, double-blind, and placebo-controlled, and inclusion and exclusion criteria were used to select appropriate subjects. Seventy-two healthy men and women were randomized into three groups of 24 subjects (12 male and 12 female). Two subjects were dropped for reasons unrelated to administration of the test article and were replaced by subjects of the same sex. The groups received neotame at a dose of 0, 0.5 mg/kg bw per day, or 1.5 mg/kg bw per day in capsules, as three divided doses (given at 07:00, 12:00 and 17:00). The men and women attended the clinic to receive each dose and to eat a standardized meal. The first morning dose followed an overnight fast of at least 8 hr. Body weight was determined before the first dose. The sitting blood pressure, temperature, pulse rate and respiratory rate were determined before the morning dose on days 1, 3, 5, 7, 9, 11 and 14. Blood for clinical pathology was taken before dosing on days 1, 3 and 7. Blood samples were taken to determine concentrations of neotame and de-esterified neotame on days 1, 2, 3, 4, 7, 11 and 15. Plasma was separated and stored frozen for later analysis. A screen for drugs in urine was done before dosing on days 1 and 7. An electrocardiogram (ECG) was performed before dosing on days 1 and 3, and a physical examination (including measurement of body weight) was carried out on day 7. Men and women were monitored for adverse experiences or unusual symptoms. A physical examination was done after treatment. Vital signs and body weight were measured, and an ophthalmological examination, ECG and clinical laboratory tests were performed after the last blood sample had been collected. Of the 74 (70 Caucasian, 1 Hispanic, 1 Middle-Eastern and 2 Asian) persons starting the study, 72 successfully completed the study. The failure of two subjects to complete the study was unrelated to administration of neotame. The mean age was 33 (range, 20-53) years for women, and 31 (range, 20-53) years for men. A range of clinical symptoms was documented throughout the study. The most common finding was headache, namely, eight headaches in five men in the control group, 16 headaches in seven men at 0.5 mg/kg bw per day and 10 headaches in four men at 1.5 mg/kg bw per day. Diarrhea was reported in controls and at 0.5 mg/kg bw per day, but was not reported at 1.5 mg/kg bw per day. Abdominal pain was reported in one man at 0.5 mg/kg bw per day and two men at 1.5 mg/kg bw per day. None of these clinical symptoms required medical intervention, and most were considered mild to moderate, although four headaches were documented as severe. These clinical symptoms could not be linked to ingestion of neotame. There were no treatment-related changes in clinical pathology parameters, heart rate, blood pressure, respiratory rate, temperature, body weight or ECG. On analysis of blood samples, concentrations of neotame were below the level of quantification at all time periods. Plasma concentrations of de-esterified neotame were approximately proportional to administered dose. In men and women, plasma concentrations of de-esterified neotame reached steady state after 24 hr and 72 hr, respectively. On the basis of this study, neotame was well tolerated in humans when administered at a dose of up to 1.5 mg/kg bw for a period of 2 weeks.|/HUMAN EXPOSURE STUDIES/ A study was conducted to evaluate tolerance of a single dose of neotame ingested in solution by healthy men. The safety of neotame was evaluated in a stepwise fashion, starting with the lowest dose, followed by the intermediate dose and then the high dose only after safety at lower doses had been confirmed. Nineteen healthy men (mean age +/ - SD, 28 +/ - 6 years) were given single doses of 0.10, 0.25, or 0.50 mg/kg bw (seven, six, six men per dose, repectively) of neotame in solution. The study was randomized, single dose and not double-blinded. Each man received only one treatment regimen after an overnight fast. Eighteen men completed the study; one man was excluded due to poor venous access. Clinical evaluations and laboratory tests were done immediately before dosing and approximately 48 hr after dosing. There were no treatment-related changes in pulse rate or blood pressure, and no changes in haematology, clinical chemistry or urine analysis parameters. Two men experienced mild headaches, one before dosing and one after a dose of 0.1 mg/kg bw per day. At 0.5 mg/kg bw per day, another two men had mild headaches, one before dosing and one after, and one had lower back pain. These signs resolved without further treatment and were not attributed to dosing with neotame.|/EPIDEMIOLOGY STUDIES/ In a 3-month study of tolerance, 151 healthy men and women (mean age +/ - SD, 35 +/ - 11 years) were enrolled in a two site, randomized, double-blind, placebo-controlled, parallel study, consisting of three treatment groups. Inclusion and exclusion criteria were used to select appropriate subjects. A total of 144 men and women (24 of each sex per group) participated. Neotame was provided in a blister pack of four gelatine capsules containing 10 mg of neotame or placebo per capsule. A mixture of placebo and treatment capsules was eaten to yield the appropriate dose of neotame of 0, 0.5 or 1.5 mg/kg bw per day. Average body weight was 70 kg for women and 80 kg for men, therefore, the doses administered were 0, 30 or 110 mg/day for women and 0, 40 or 120 mg/day for men. The test material was self-administered in divided doses, three times daily (07:00, 12:00 and 17:00). The first morning dose followed an overnight fast of at least 8 hr. The dates and times of administration were recorded in a daily logbook. Subjects attended the clinic on a weekly basis to receive test material for 7 days; test material for 3 additional days was also supplied to allow flexibility in attendance at the clinic. On day 1, before the first dose, the sitting blood pressure, temperature, pulse rate and respiratory rate, ECG and body weight were measured, analysis of urine, hematological and clinical chemistry parameters was performed and screening for alcohol or drugs of abuse, and pregnancy was undertaken. On the mornings of study days 7, 14, 28, 42, 56, 84 and 92, subjects were instructed not to take the morning dose or to eat until after attendance at the clinic and blood sampling. Hematology, clinical chemistry and urine analysis, as well as a physical examination, were done at these times. Vital signs were determined before the morning dose weekly throughout the study (on attendance at the clinic to obtain additional test material). On the morning of day 92, blood was taken for clinical pathology tests, clotting times, thyroxine, pregnancy test and possible analysis of concentrations of compound in the plasma. Urine was collected for urine analysis and screening for alcohol and drugs. A physical examination, including vital signs, body weight, ophthalmology and ECG was also done. The majority of men and women in the study were Caucasian, with a small number being American Indian, persons of African origin, European/Middle Eastern and Hispanic. The mean age was 35 (range, 19-65) years for women and 34 (range, 19-54) years for men. With respect to clinical symptoms, 82 persons reported at least one adverse reaction during the study. Most of these were determined to be of mild or moderate severity, and were reported in all three treatment groups, with no dose-response relationship or statistically significant differences between groups. Headache was the most common adverse experience, occurring in 16, 15 and 13 persons at 0, 0.5 and 1.5 mg/kg bw per day, respectively. There were no serious adverse reactions during treatment. There were no treatment-related changes throughout the study in pulse rate, blood pressure, respiratory rate, temperature, body weight, ophthalmological or hematological parameters. The sporadic changes observed in clinical chemistry parameters were not considered to be of biological significance or to be treatment-related. On the basis of the results of this study, neotame was well tolerated at a dose of up to 1.5 mg/kg bw per day for 91 days, with no treatment-related adverse effects

N-(N-(3,3-dimethylbutyl)-L-alpha-aspartyl)-L-phenylalanine 1-methyl ester

The most potent commercial sweetener to date (approximately 2005). It is approximately 8000 times sweeter than sucrose or approximately 40 times sweeter than its analogue, aspartame. ... Approved by FDA as a general purpose sweetener in 2002. ... more commonly used as a partial substitution of sugar or high fructose corn syrup, and in blends with other high potency sweeteners, instead of a stand alone sweetener.|Add sweetness with or without the extra calories ... /in/ beverages, baked goods, confections, table-top sugar, substitutes, many processed foods|Reported to be 6000 to 10000 times sweeter than sucrose.

Food additives