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

Abstract

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...

The artificial sweetener neotame negatively regulates the intestinal epithelium directly through T1R3-signaling and indirectly through pathogenic changes to model gut bacteria

“…In the present study, we investigated the effect of neotame at concentrations ranging from 0.1 to 50 mM but noted intestinal epithelial cell death at 0.1 mM and intestinal barrier disruption at 1 µM. Furthermore, co-culture studies with E. coli or E. faecalis demonstrated pathogenic effects at 100 µM, which is lower than the expected concentration in many food and drink, and the acceptable daily intake (2,8). It is worth noting, however, that studies were performed following 24 h exposure to neotame whereas transit time in the intestine is 5 h therefore it is possible that the epithelium and gut microbiota would not be exposed to sustained sweetener for as long as was studied (51).…”

“…Our previous studies have demonstrated that artificial sweeteners, sucralose, saccharin and aspartame, significantly reduce viability of intestinal epithelial cells ( 23 ) therefore our first experiments in this study assessed the impact of neotame on the intestinal epithelium in vitro at a range of physiological concentrations. Given that the ADI for neotame is approximately equivalent to 10 mM, we used up to this concentration for initial studies ( 8 ). There was a significant increase in Caco-2 cell viability at 1,000 μM neotame concentration exposure with higher concentrations showing very little cell viability (0.025 ± 0.005 a.u.…”

“…Previous in vivo studies used a range of concentrations of neotame from 0.75 mg/kg body weight in mice to a range of 10–500 mg/kg body weight in pigs ( 26 , 50 ). The acceptable daily intake in humans is up to 2 mg/kg body weight which, considering the average adult weight and gastric fluid volume is equivalent to 40 mg/L ( 8 , 51 , 52 ). There is little evidence around the accumulation concentration of artificial sweeteners in the intestine however, given known concentrations of sweeteners in commercial products, it is possible that following consumption of a diet soft drink, for example, the intestine could be exposed to up to 2 mM sweetener ( 2 ).…”

“…Neotame is one such new sweetener which was developed in the 1990′s with the commercial benefits of greater sweetness potential and improved stability compared to existing sweeteners ( 6 , 7 ). Whilst neotame is a non-nutritive additive, it is rapidly metabolized and eliminated with no apparent physiological accumulation in the body ( 8 ). Feeding studies with neotame in mice and other test animals did not show adverse physical symptoms, water consumption, or clinical pathology evaluations, therefore the sweetener is considered safe for consumption and was approved by FDA in 2002 and EFSA in 2010( 8 ) The acceptable daily intake (ADI) of neotame is 2 mg/kg body weight per day which is no more than 10 mM per day in an individual with average weight ( 8 ) Given the different available forms of neotame, such as agglomerated, encapsulated, co-crystallized with sugar and cyclodextrin complexes, the sweetener is easy and cost-effective to use for food manufacturing and, as such, is found in a range of drinks, sauces, savory and sweet foods, and chewing gums ( 7 , 9 ).…”