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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).

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).

/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

/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.

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).

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).

/LABORATORY ANIMALS: Acute Exposure/ An assessment of the possible effects of orally administered neotame on hexobarbital-induced sleeping time was conducted. Groups of five Sprague-Dawley rats of each sex were given orally administered (1) neotame, at 5 or 15 mg /kg bw per day; or (2) chlorpromazine hydrochloride, at 15 mg /kg bw per day as a positive control; or (3) vehicle alone (0.5% (w/v) methylcellulose and 0.1% (v/v) polysorbate 80). These treatments were administered approximately 30 min before an intraperitoneal injection of sodium hexobarbital at 150 and 100 mg/kg bw per day, in males and females respectively. Sleep onset and duration of sleeping time were recorded, based on loss and reappearance of the righting reflex. Administration of the positive control significantly increased the sleeping times in males and females, while neotame had no effect on hexobarbital-induced sleeping time in rats. Thus, neotame does not interfere with the metabolism of hexobarbital or its pharmacodynamic effects on the central nervous system.

/LABORATORY ANIMALS: Acute Exposure/ The effects of neotame and de-esterified neotame on responses of the autonomic nervous system to acetylcholine, histamine, 5-hydroxytryptamine (5-HT) and barium chloride were examined. The ileum was removed from Dunkin-Hartley guinea-pigs and suspended in an organ bath. The concentrations tested in the organ bath were: neotame, 0 (vehicle only), 20, 60, and 200 mg/mL; and de-esterified neotame, 60, 200, and 600 ng/mL. The effect of neotame and de-esterified neotame on agonist responses was evaluated in separate tissues. Neotame and de-esterified neotame did not affect autonomic responses to agonist-induced spasmogenic effects in the guinea-pig ileum. In addition, neotame and de-esterified did not affect the basal tone of the isolated ileum. Thus, neotame and de-esterified neotame had no agonistic, synergistic, or antagonistic effects on the receptor systems evaluated.

/LABORATORY ANIMALS: Acute Exposure/ The possible effects of neotame on gastrointestinal motility were studied in male Sprague-Dawley rats using the charcoal propulsion test. Rats were assigned randomly to groups (10 rats per group) and given, by gavage, a single dose of (1) neotame, at 5 or 15 mg/kg bw per day; or (2) morphine sulfate, at 100 mg/kg bw per day as a positive control; or (3) vehicle alone (0.5% w/v methylcellulose and 0.1% v/v polysorbate 80). An oral suspension of 5% (w/v) charcoal in water was administered approximately 30 min after dosing. The rats were killed, their gastrointestinal tracts removed, and the distance travelled by the charcoal meal between pyloric sphincter and cecum was measured. The positive control significantly decreased gut, while neotame did not affect gastrointestinal motility at either dose.

/LABORATORY ANIMALS: Acute Exposure/ Cardiovascular, respiratory and renal parameters were evaluated in dogs after intraduodenal administration of neotame. Twelve male beagle dogs were anaesthetized with alpha-chloralose/sodium pentobarbitone, and baseline cardiovascular and respiratory parameters were recorded. Baseline urinary electrolyte and protein concentrations were also measured. After a stabilization period, each dog was given a single intraduodenal dose of vehicle (0.5% methylcellulose/0.1% (v/v) polysorbate 80), followed by neotame at a dose of 5 or 15 mg/kg bw. Blood pressure, heart rate, left ventricular systolic pressure, left ventricular cardiac output (dp/dt max), lead II electrocardiogram, respiratory rate, tidal volume and urinary concentrations of sodium, protein, potassium and chloride were recorded after doses of the vehicle and neotame. There were no treatment-related effects on any of the cardiovascular or respiratory parameters, or on urinary excretion of protein or electrolytes, at either dose.

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).

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)

Neotame's production and use as a non-nutritive sweetener may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 2.7X10-11 mm Hg at 25 °C indicates neotame will exist solely in the particulate phase in the atmosphere. Particulate-phase neotame will be removed from the atmosphere by wet or dry deposition. Neotame contains chromophores that absorb at wavelengths >290 nm, and therefore may be susceptible to direct photolysis by sunlight. If released to soil, neotame is expected to have moderate mobility based upon an estimated Koc of 390. The estimated pKa values are 4.11, 7.70, and 6.45, indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 2.3X10-17 atm-cu m/mole. Neotame may not volatilize from dry soil surfaces based upon its vapor pressure. Biodegradation data were not available. If released into water, neotame is expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. Base-catalyzed second-order hydrolysis half-lives of 5 years and 170 days at pH values of 7 and 8, respectively, have been estimated. 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)

/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/

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.

Neotame is manufactured by the reaction of aspartame and 3,3-dimethylbutyraldehyde, followed by purification, drying and milling.

Preparation: C. Nofre, J.-M. Tinti, FR 2697844; eidem, US 5480668 (1994, 1996)

Food additives

Fragrance Ingredients

Food Additives -> FLAVOUR_ENHANCER; SWEETENER -> JECFA Functional Classes

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.