Food consumption and body weight changes with neotame, a new sweetener with intense taste: differentiating effects of palatability from toxicity in dietary safety studies

Mayhew, Dale A.; Comer, C. Phil; Stargel, W. Wayne

doi:10.1016/s0273-2300(03)00074-6

Cited by 36 publications

(18 citation statements)

References 30 publications

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“…Decrease in body weight/body weight gain after feeding laboratory animals with high doses of intense sweeteners is a phenomenon associated with poor palatability and/or lower nutritional value of the diets containing high concentrations of the test material (Chowaniec and Hicks, 1979;Grice and Goldsmith, 2000;Flamm et al, 2003;Mahew et al, 2003). The lower body weight/body weight gain of variable severity were seen at dietary concentration of 50 000 mg advantame/kg diet in some of the subchronic toxicity studies (apart from 13-week study in rats and 1-year study in dogs), in the carcinogenicity study in mice and in the combined chronic toxicity and carcinogenicity study in rats.…”

Section: Discussionmentioning

confidence: 99%

“…Decrease in body weight/body weight gain after feeding laboratory animals with high doses of intense sweeteners is a known phenomenon (Chowaniec and Hicks, 1979;Grice and Goldsmith, 2000;Flamm et al, 2003;Mahew et al, 2003) associated with poor palatability and/or lower nutritional value of the diets containing high concentrations of sweeteners. In the 13-week study in mice the lower body weight gain (89% of the control) was additionally recorded in the low-dose female group.…”

Section: Subacute and Subchronic Toxicitymentioning

confidence: 99%

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Scientific Opinion on the safety of advantame for the proposed uses as a food additive

2013

EFS2

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The Panel on Food Additives and Nutrient Sources added to Food (ANS) provides a scientific opinion on the safety of advantame as a sweetener for use in the food categories specified in the dossier. Advantame is stable under normal storage conditions. The Panel noted that there is an indication of advantame instability in acidic beverages and thermally treated foods. Metabolism and toxicokinetics of advantame and its main metabolite, ANS9801-acid, have been studied in mice, rats, rabbits, dogs and humans. Advantame is rapidly but poorly absorbed and the main excretion route is via faeces. The Panel concluded that advantame does not raised concern with regards to genotoxicity and carcinogenicity. The critical effect observed in animal studies was maternal toxicity (gastrointestinal disturbances) in the prenatal developmental toxicity study in rabbits. The NOAEL for this effect was 500 mg advantame/kg bw/day. Advantame was well tolerated in single or repeated doses up to 0.5 mg/kg bw/day by normo-glycemic or diabetic subjects. The Panel established an ADI of 5 mg/kg bw/day based on the application of a 100-fold uncertainty factor to the NOAEL of 500 mg/kg bw/day for maternal toxicity from the prenatal developmental toxicity study in the rabbit. Conservative estimates of advantame exposure for high level adults and children consumers were below the ADI for the proposed use levels

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Section: Discussionmentioning

confidence: 99%

Section: Subacute and Subchronic Toxicitymentioning

confidence: 99%

Scientific Opinion on the safety of advantame for the proposed uses as a food additive

2013

EFS2

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“…Reduced body weight and body weight gain were the only consistent finding in neotame safety studies. The authors concluded, that these changes were adequately explained by the small decrements in feed consumption, and that consideration of the objective criteria proposed in the first study (Flamm et al, 2003) supported the conclusion that reduced body weight and body weight gain observed in neotame studies were neither adverse nor a manifestation of toxicity, and that they were not appropriate endpoints for setting NOEL and ADI for neotame (Mahew et al, 2003) …”

Section: 3mentioning

confidence: 91%

“…Two studies, submitted by the petitioner, investigated whether the changes in body weight gain in sub-chronic, chronic and carcinogenicity studies with neotame were adverse or secondary to decrements in feed consumption (Flamm et al, 2003, Mahew et al, 2003.…”

Section: 3mentioning

confidence: 99%

Neotame as a sweetener and flavour enhancer - Scientific Opinion of the Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food

2007

EFSA Journal

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SUMMARYFollowing a request from the European Commission, the Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food (AFC) was asked to deliver a scientific opinion on the safety of neotame as a sweetener and flavour enhancer.Neotame is a dipeptide methyl ester derivate. Its chemical structure is N-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester. It is intended for use in food as a sweetener and flavour enhancer. Neotame has a sweetness factor approximately 7000 to 13000 times greater than that of sucrose and approximately 30 to 60 times greater than that of aspartame, depending upon the food application.Neotame is manufactured by the reaction of aspartame and 3,3-dimethylbutyraldehyde, followed by purification, drying, and milling. Neotame is generally stable under conditions of intended use as a sweetener across a wide range of food and beverage applications. Neotame as a sweetener and flavour enhancerThe EFSA Journal (2007) 581, are not detected at the anticipated concentrations and conditions of neotame use in carbonated soft drinks.At least 30% of neotame ingested is rapidly absorbed in all species. The major metabolic pathway is de-esterification by non-specific esterases to NC-00751, which accounts for approximately 80% of the neotame dose as NC-00751 in all species tested. Peak plasma concentrations of neotame and NC-00751 are observed at approximately 0.5 hours and within 1 hour, respectively. Neotame is completely eliminated from the body with recovery in urine and faeces exceeding 98% in the human and greater than 93% in the rat and the dog within 72 hours. The majority of radioactivity is excreted in faeces in all species. The major component in the faeces is NC-00751.Studies with radiolabelled neotame given orally to rats indicate no accumulation in tissues. The highest radioactivity is associated with the contents of the gastrointestinal tract and organs of metabolism and excretion (liver, kidney, urinary bladder). In whole body autoradiography studies with pregnant rats no radioactivity has been reported in the fetus.The safety of neotame has been investigated in in vitro studies and in short and long-term studies in mice, rats, rabbits and dogs. The results indicate that neotame is not genotoxic, carcinogenic, teratogenic or associated with any reproductive/developmental toxicity. The consistent findings in animal studies were reduced feed consumption, body weight and body weight gain relative to that of controls, with no clear dose response. These effects are considered not adverse or indicative of toxicity but a consequence of reduced palatability of the neotame-containing diets. Therefore body weight parameters were not considered appropriate endpoints for setting no-observed-adverse-effect levels (NOAELs) in these studies.A consistent finding was an increased activity of alkaline phosphatase (AP) of hepatic origin in dogs in the 13-week study at doses of 600 and 1200 mg/kg bw and in the 52-week study at 800 mg/kg bw. In the lat...

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“…The safety of neotame has been investigated and the results indicate that neotame is not carcinogenic, genotoxic, teratogenic, or associated with any reproductive toxicity (Scientific Opinion 2007). However, 3,3-dimethylbutyraldehyde, a highly flammable component used in the synthesis of neotame, may cause minor side effects such as irritation to the skin, eyes, respiratory, and reproductive systems after prolonged consumption (Mayhew, Comer, and Stargel 2003;Tomasik 2004).…”

Section: Introductionmentioning

confidence: 99%

Determination of Neotame by High-Performance Capillary Electrophoresis Using ß-cyclodextrin as a Chiral Selector

et al. 2014

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An electrokinetic chromatographic method was developed for the chiral separation of neotame, a new high intensity artificial sweetener, using a chiral separating agent heptakis 2,3,6-tri-o-methylbetacyclodextrin. The purpose of this study was to better understand diastereomer-resolution interactions between neotame and the chiral separating agent. Molecular docking studies were performed to elucidate the mechanism of the separation. The optimum conditions were 50 mM phosphate buffer, pH 5.5, applied voltage 20 kV, cassette temperature of 30 C, and a 4 s sample injection time. The calibration curve showed good linearity (r 2 > 0.99) with recoveries for both diastereomers, ranging from 95.66-99.00% and the limits of detection for L,L-neotame and D,D-neotame were 0.01857 and 0.08214 mM, respectively. The developed method showed analytical precision with relative standard deviations (n ¼ 5) of 1.20% and 1.17% with respect to migration time and peak area, respectively. A large difference in the interaction energies observed between the diastereomers represents a significant differentiation. The results showed that both electrostatic and hydrophobic interactions played a significant role in stabilizing their inclusion complexes and consequently supported the elution order based on their differential stabilities.

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Food consumption and body weight changes with neotame, a new sweetener with intense taste: differentiating effects of palatability from toxicity in dietary safety studies

Cited by 36 publications

References 30 publications

Scientific Opinion on the safety of advantame for the proposed uses as a food additive

Scientific Opinion on the safety of advantame for the proposed uses as a food additive

Neotame as a sweetener and flavour enhancer - Scientific Opinion of the Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food

Determination of Neotame by High-Performance Capillary Electrophoresis Using ß-cyclodextrin as a Chiral Selector

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