ArticlePDF Available

Artificial sweeteners

  • Young Researchers and Elite Club, Quchan Branch, Islamic Azad University, Quchan, (Iran)


Low-calorie sweeteners are authorised food additives in the European Union (EU). The safety of these sweeteners has been evaluated in accordance with internationally agreed principles for the safety evaluation of food additives. So food industry uses various artificial sweeteners which are low in calorie content instead of high calorie sugar. U.S. Food and Drug Administration has approved aspartame, acesulfamek, neotame, cyclamate and alitame for use as per acceptable daily intake (ADI) value. The ADI is the amount of the food additive, expressed on a milligram per kilogram of body weight (bw) basis, that can be ingested daily over a lifetime without any appreciable health risk. The main reasons to use substitutes for sucrose are: to help weight loss (the majority of the sweeteners are virtually calorie free); to diminish the risk of dental disorders, namely cavities; to provide palatable food for some patients such as diabetics; to produce less expensive food items (artificial sweeteners are often cheaper than sucrose and are employed in minute quantities due to their potency in providing a sweet taste); and to avoid post-prandial hyperglycaemia in dietary regimens aimed at controlling insulin response (though this effect is debatable).
Artificial sweeteners
Maryam Sardarodiyan1, Vahid Hakimzadeh2٭
1Young Researchers and Elite Club, Quchan Branch, Islamic Azad University,
Quchan, (Iran)
2Department of Food Science and Technology, Quchan Branch, Islamic Azad
University, Quchan, Iran
Abstract: Low-calorie sweeteners are authorised food additives in the European Union (EU).
The safety of these sweeteners has been evaluated in accordance with internationally agreed
principles for the safety evaluation of food additives. So food industry uses various artificial
sweeteners which are low in calorie content instead of high calorie sugar. U.S. Food and Drug
Administration has approved aspartame, acesulfamek, neotame, cyclamate and alitame for use
as per acceptable daily intake (ADI) value. The ADI is the amount of the food additive,
expressed on a milligram per kilogram of body weight (bw) basis, that can be ingested daily
over a lifetime without any appreciable health risk. The main reasons to use substitutes for
sucrose are: to help weight loss (the majority of the sweeteners are virtually calorie free); to
diminish the risk of dental disorders, namely cavities; to provide palatable food for some
patients such as diabetics; to produce less expensive food items (artificial sweeteners are often
cheaper than sucr ose and are employed in minute quantities due to their potency in providing a
sweet taste); and to avoid post-prandial hyperglycaemia in dietary regimens aimed at
controlling insulin response (though this effect is debatable).
Key words: Artificial sweeteners, Low calorie sweetener, Acceptable daily intake (ADI),
1. Introduction
Sweeteners may be used separately or in combination with other sweeteners, as socalled blends.
Nowadays, the common trend in food industry is to use sweetener blends, because some of the sweeteners
impart side tastes and aftertastes that can limit their applications in foods and beverages1. It was found that
mixing such a problematic sweetener with another frequent ly yields a blend not only lacking unwanted side or
aftertastes but also sweeter than the algebraic sum of the components. A very well-known example of such a
mixture is saccharin-cyclamate (1:10) blend. The bitter aftertaste of saccharin is masked by cyclamate and the
unpleasant aftertaste of cycla mate, sensed by some people, is masked by saccharin. Simultaneously (due to
synergistic effect), the sweetening power of the mixture increases. Properly formulated sweetener blends can
precisely reproduce the texture and the sweetness profile of traditional sugar-containing products, create new
products characterized by an original sweetness profile and improve taste stability2. Artificial high-intensity
sweeteners, intensely promoted by the food industry are among the most controversial food additives due to
suspicions of adverse health effects3. These allegations include causing dermatological problems, headaches,
mood variations, behavior changes, respiratory difficulties, seizures, allergies and cancer.
Artificial sweeteners are used worldwide as sugar substitutes in remarkable amounts in food, beverages,
and also in drugs and sanitary products, such as mouthwashes. They provide no or negligible energy and thus
are ingredients of dietary products4. The structures of the artificial sweeteners treated in this review are depicted
International Journal of PharmTech
CODEN (USA): IJPRIF, ISSN: 0974-4304
Vol.9, No.4, pp 357-363, 2016
Vahid Hakimzadeh
et al
/International Journal of PharmTech Research,2016,9(4),pp 357-363. 358
in Table 1 together with additional data on physicochemical properties, intensity figures for their sweetness
(sugar equivalents), and their acceptable daily intake values that a person can safely consume on average every
day without risk to health. Owing to their use as food additives, artificial sweeteners are extensively tested for
potential adverse health effects on humans4,5,6. Although the measured concentrations of some artificial
sweeteners range up to microgram per liter levels in surface water, groundwater, and drinking water, there is a
huge safety margin regarding potential adverse health effects. Acceptable daily intake values of artificial
sweeteners are in the range from 5 to 50 mg/kg of body weight per day and are thus three to four orders of
magnitude above the maximum possible daily human intake by drinking water4,7. However, their
ecotoxicological profiles have only been scarcely investigated. Therefore, the purpose of the current review is to
summarize the new studies published between 2009 and 2016, and to provide an updated review to guide future
research and public health recommendations.
Table 1. Structures and properties of the seven artificial sweeteners8.
ACE CYC SAC SUC Aspartame Neotame NHDC
33665-90-6 100-88-9 81-07-2 56038-13-2 22839-47-0 165450-17-
13NO3S C
C12H19Cl3O8 C14H18N2O5C20H30N2O
163.15 179.24 183.19 397.63 294.31 378.47 612.58
20093010 30011 60012 160-220 11 7,000-
up to
1,800 14
270 (20 °C)91.00010,
412 283 (20 °C) 15 ~10 (25
12.617 0.4-0.514
a2.018 1.919 2.219 11.8c20 3.19 and
3.01 and
-1.3312 -1.6112 0.9112 -1.0012
0.0712 2.39
species )20
species )20
100 %
>92 %
ne, and
<2 % 13
ation major
m by
n is
9 (potassium
5 (sodium
salt), 3.8
1529 4025 230 526
Vahid Hakimzadeh
et al
/International Journal of PharmTech Research,2016,9(4),pp 357-363. 359
ACE acesulfame, ADI acceptable daily intake, CAS Chemical Abstracts Service, CYC cyclamate, NHDC
neohesperidine dihydrochalcone, SAC saccharin, SUC sucralose
apKa is the negative logarithm of the dissociation constant
blog KOW is the logarithm of the octanol–water partition coefficient
cCalculated pH where 50% of the neutral molecules are dissociated into several corresponding bases
2.1. Aspartame
Aspartame is a dipeptide that is used as an artificial sweetener. It is completely hydrolysed in the
gastrointestinal tract to methanol, aspartic acid, and phenylalanine31. Aspartame appears to be a safe sweetener,
and despite numerous studies of its safety during the past three decades, the incidence of serious adverse effects
has been difficult to determine in controlled studies. Since one of the metabolic products of aspartame is
phenylalanine, excessive use of aspartame should be avoided by patients with phenylketonuria32. Toxicity of
another possible metabolic product, methanol, is unlikely, even when aspartame is used in extraordinary
amounts33. Aspartame has reportedly caused angioedema and urticaria34.
It is sold under the brand names Equal , NutraSweet , and Natra Taste . Because it is made from
amino acids, it provides 4 kcal/g. Aspartame is 200 times sweeter than sucrose and therefore very small
amounts are required for sweetening foods, thus making its caloric contribution insignificant. According to the
FDA, the acceptable daily intake of aspartame for humans is 50 mg/kg body weight, for both adults and
children35. Aspartame is used as a sweetener in many products including chewing gu m, diet soda, dry drink
mixtures, yogurt and pudding, and instant tea and coffee. The flavor profile of aspartame is found to be highly
acceptable. In a study on the effects of artificial sweeteners on food intake and satiety, aspartame was found by
participants to have a more pleasant taste compared with stevia or sucrose36. Furthermore, aspartame does not
elicit the same response as sugar does in the brain or the pancreas. A magnetic resonance imaging study showed
a decline in activity of the hypothalamus part of the brain after ingestion of sucrose, whereas aspartame does not
show similar response. It is suggested that for a hypothalamic reaction to occur there should be the combined
stimuli of sweet taste and energy content, as found in sweetened caloric beverages. In the pancreas, aspartame
does not stimulate an insulin response as sugar does37.
2.2. Cyclamates
Sodium cyclamate is a potent sweetening agent. It has been subjected to numerous safety and
carcinogenicity studies. Animal data led to warning against excessive and indiscriminate use a long time ago,
causing the World Health Organization in 1967 to adopt a safety limit of 50 mg/kg. However, in 1982 a joint
FAO/WHO expert committee on food additives revised this recommendation to allow for a maximum daily
intake of up to 11 mg/kg of sodium or calcium cyclamate (as cyclamic acid)38. Nevertheless, since in certain
climates and populations the amount of cyclamates in soft drinks and other beverages can exceed these limits,
more epidemiological data are needed to evaluate, for example, a possible association with cancer of the
uropoietic system39 and with histological and radiological abnormalities of the small intestine and
malabsorption40. Cyclamate is commercially available in the sodium and calcium salt forms. Both of these are
colourless and odourless solids. Cyclamate in its acid form is a strong acid with pKa of 1.7141. Interestingly, the
acid form of cyclamate has been demonstrated by X-ray crystallography to exist in the zwitterionic state42.
Cyclamates exhibit excellent solubility characteristics for use in essentially all imaginable applications.
Although the acid form is sufficiently water-soluble (133 g/L), its high acidity results in preference for the very
soluble sodium (200 g/L) or calcium (250g/L) salts43. To illustrate the more than adequate solubility of sodium
cyclamate, consider an application in which cyclamate is used in a binary blend with a sweetener such as
saccharin. In such a situation, it is generally desired that cyclamate should provide half of the total sweetness
desired that would typically be, allowing for sweetness synergy, sweetness equivalent to approximately 4%
sucrose. Hydrolytic degradation of cyclamate salts yields cyclohexylamine and inorganic sulfate. As a
consequence of the adverse biological activity of cyclohexylamine, FDA scientists conducted a comprehensive
evaluation of cyclohexylamine levels in a range of food products44.
Vahid Hakimzadeh
et al
/International Journal of PharmTech Research,2016,9(4),pp 357-363. 360
2.3. Acesulfame
The studies on the basis of which acesulfame gained approval showed no evidence in animals of
mutagenicity, teratogenicity, or adverse reproductive effects; a 2-year toxicology study in beagles showed no
untoward adverse effects. The incidence of lymphocytic leukemia was slightly increased in high-dosed female
mice, but not beyond the spontaneous variation with this strain. No other evidence of potential carcinogenicity
was obtained, and it has been concluded that at the estimated level of exposure, acesulfame and its metabolites
are not a health hazard45.
2.4. Neotame
In the year 2000, a number of new studies on the parent molecule and its hydrolysis products had
become available and the no observed adverse effect level (NOAEL) was determined at 1500 mg/kg bw/day,
translating into an ADI of 15 mg/kg bw using a safety factor of 100 46. In 2007, the European Food Safety
Authoriy (EFSA) allocated an ADI of 2 mg/kg bw to neotame, based on studies in dogs. No effects were seen in
rats, but in dogs two different studies recorded an increase in serum alkaline phosphatase, indicative of liver
toxicity at 600 mg/kg bw/day. The toxicological relevance of this effect has been debated, but EFSA decided to
take these data into consideration and used them to set the NOAEL at 200 mg/kg bw/day47.
2.5. Saccharin
Saccharin has been considered to be a possible human carcinogen on the basis of animal experiments.
This suspicion has now been discr edited. There is no evidence that people with diabetes, who consume larger
quantities of saccharin than non-diabetics, are at greater risk of developing bladder cancer48 or other
malignancies. However, in the USA, saccharin-containing medicines are required to carry the following
warning: “Use of this product may be hazardous to your health. This product contains saccharin which has been
determined to cause cancer in laboratory animals”49.
Saccharin is commercially available in acid form as well as in sodium and calcium salt forms. All of
these are white odourless solids. Saccharin in acid form is a strong acid with pKa of 2.3250. To be used in foods
and beverages, a non-caloric sweetener must be sufficiently soluble and many non-caloric sweeteners do not
meet this requirement. Commonly, sweetness intensity levels at least equivalent to 10% sucrose are required
and in some systems (e.g. frozen desserts), sweetener levels matching the sweetness of 15–20% sucrose are
needed. In addition, for many food systems, rapid dissolution is critical to comply with manufacturing
requirements. For example, in carbonated soft drinks, concentrates of the sweetener-flavour system complex are
prepared and it is important that all components rapidly dissolve. Thus, high solubilities and rapid dissolution
rates are very desirable properties for non-nutritive sweeteners. In addition, a commercially viable non-caloric
sweetener must be sufficiently stable to hydrolysis as well as to thermal and photochemical breakdown to be
used in beverages, baked goods and confectionery.
To be commercially viable, a non-caloric sweetener must be stable to degradation from hydrolytic,
pyrolytic or photochemical processes that may be encountered in food or beverage applications. Stability is
critical for thr ee reasons. First, the rate of degradation must not be such that product shelf life is affected.
Second, degradation must not cause any ‘off’ taste or odour. And third, since non-caloric sweeteners are food
additives, any degradation products formed must also be safe. In the United States, for any food or beverage
application, if exposure to the degradation product may reach or exceed 12.5 μg/kg, then safety assess ment
studies equivalent to those requir ed for the sweetener itself must be conducted before regulatory approval is
granted51. Saccharin is very stable to all the conditions to which it may be exposed in food and beverage
applications. Accelerated stability studies on saccharin as a function of pH and temperature (100C, 125C and
150C) were first reported in 1952 by DeGarmo and coworkers (Monsanto Chemical Company)52. Later,
accelerated studies at a single temperature (120C) were carried out at the Sherwin Williams Company53.
Interestingly, the degradation pathway was fou nd to be pH dependent. At acidic pH, the exclusive hydrolysis
product is 2-sulfobenzoic acid, while under alkaline conditions, the sole degradation product is 2-
sulfonamidobenzoic acid. Both of these compounds are sometimes found as trace contaminants in commercial
samples of saccharin. As a consequence of saccharin’s high stability, neither loss of sweetness during food or
beverage product lifetime nor degradation product safety is a significant concern.
Vahid Hakimzadeh
et al
/International Journal of PharmTech Research,2016,9(4),pp 357-363. 361
2.6. Sucralose
This nonnutritive sweetener is made from sucrose by a process that substitutes 3 chloride atoms for 3
hydroxyl groups on the sucrose molecule54. Sucralose is 450–650 times sweeter than sucrose, has a pleasant
sweet taste and its quality and time intensity profile is very close to that of sucrose 55. It has a moderate synergy
with other nutritive and non-nutritive sweeteners56. It is very much soluble in water and is stable over a wide
range of pH and temperature. It does liberate HCl when stored at high temperature and produce some kind of
discoloration56. The synthesis of sucralose involves a series of selective protection and deprotection steps so that
the 4-hydroxyl group can be converted to a chloro atom with inversion of configuration. Treatment of the free
hydroxyl groups with sulfuryl chloride produce trichlorodisaccharide which is then deprotected to give the
sucralose57. The use of enzymes or microbial cultures to augment synthetic or ganic chemistry and carry our
selected functionalization of complex molecule has been widely documented in the growing field of
biocatalysis58. Metabolism and health aspect although sucralose is made from sugar, the human body does not
recognize it as a sugar and does not metabolize it therefore it provides no calories. The bulk of sucralose
ingested does not leave the gastrointestinal tract and is directly excreted in the feces while 11–27% of it is
absorbed59. The amount that is absorbed from the gastro intestinal tract is largely removed from the blood
stream by the kidneys and eliminated in the urine. As it is an organo chloride and some of which are known to
have significant toxicity60 but sucralose is not known to be toxic. In addition sucralose does not breakdown or
dechlorinate. In determining the safety of sucralose, the FDA reviewed data from more than 110 studies in
human and animals. Many of the studies were designed to identify possible toxic effects including carcinogenic
reproductive and neurological effects but no such effects were found. Food and Drug Administration (FDA)
approval is based on the findings that sucralose is safe for human consumption. U.S. Food and Drug
Administration (USFDA) approved sucralose as a generalpurpose sweetener. The acceptable daily intake (ADI)
for sucralose in US is 5mg/kg body weight/day. The estimated daily intake for percentile consumers as
calculated by USFDA is 1.6mg/kg body weight/day61.
5. Conclusion
Food additive approval is based on a robust hazard and risk characterization, leading to the
establishment of an ADI and often a maximum permitted level (MPL) in foods. They must be subjected to a
wide range of tests, devised to assess potential risks to the consumer, before they are allowed in food. Tests
assess how the additive reacts in the body and also look for any toxic effects at and above the levels the additive
is to be used in food. This includes testing to see if there is any chance of genetic damage or cancers being
caused by the long-term use of the additive. A formal process for safety evaluation exists at national and
international levels for analysing the test data on food additives, setting the ADIs and publishing the results. In
Europe, food additives permitted before 20 January 2009 must go through a new risk assessment by EFSA;
furthermor e, at any time, the authority can revise its decision on the basis of new data reporting toxicological
effects. With reference to epidemiologic data, evidence on low-calorie sweeteners – and specifically aspartame
– does not support the existence of a consistent association with hematopoietic neoplasms, brain cancer,
digestive sites, breast, prostate and several other neoplasms; similarly, low-calorie sweeteners are not related to
vascular events and preterm deliveries.
1. Zhao L, Tepper BJ. Food Qual. Prefer., 2007, 18; 531.
2. Furia TE. CRC Handbook of Food Additives, CRC Press, BocamRaton, FL, USA, 1980.
3. Kroger M, Meister K, Kava R. Comp. Rev. Food Sci. Food Safety., 2006, 5: 35.
4. Kroger M, Meister K, Kava R Compr Rev Food Sci Food Saf., 2006, 5:35–47.
5. Renwick AG .Xenobiotica. 1986, 16:1057–1071
6. Schiffman SS, Gatlin CA. Neurosci Biobehav Rev., 1993, 17:313– 345
7. Bundesinstitut für Risikobewertung (BfR). Bewertung von Süßstoffen - Information des BfR vom 21.
August 2003. Accessed 23 Nov 2011
8. Lange FT., Scheurer M., Brauch H-J. Artificial sweetenersa recently recognized class of emerging
environmental contaminants: a review. Anal Bioanal Chem., 2012, 403: 2503–251
Vahid Hakimzadeh
et al
/International Journal of PharmTech Research,2016,9(4),pp 357-363. 362
9. Haber B, von Rymon Lipinski GE, Rathjen S. In: Mitchell H (ed) Sweeteners and sugar alternatives in
food technology. Blackwell, Oxford., 2006.
10. Hunt F, Bopp BA, Price P. In: O’Brien-Nabors L (ed) Alternative sweeteners, 4th edn. CRC, Boca
Raton., 2011.
11. Sardesai VM, Waldshan TH. J Nutr Biochem., 1991, 2: 236–244
12. United States National Library of Medicine .ChemIDplus Advanced.
/chemidplus/. Accessed 23 Nov 2011
13. EFSA Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Foods
(AFC) 2007, EFSA J 581:1–43
14. Borrego F. In: O’Brien-Nabors L (ed) Alternative sweeteners, 4th edn. CRC, Boca Raton., 2011.
15. Jenner MR, Smithson A. J Food Sci., 1989, 54:1646–1649
16. The Nutra Sweet Company. Nutra Sweet brand sweetener -ingredient overview bulletin no. AG-TB-03-
001. The Nutra Sweet Company, Chicago.
Id0130&filename0AG-TB-03-001.pdf. Accessed 5 Jun 2010
17. Mayhew DA, Meyers BI, Stargel WW, Comer CP, Andress SE, Butchko HH. In: O’Brien-Nabors L
(ed) Alternative sweeteners, 4th edn. CRC, Boca Raton., 2011.
18. Froloff N, Lloret E, Martinez JM, Faurion A. Chem Senses., 1998, 23:197–206
19. Kojima S, IchibagaH, Iguchi S. Chem Pharm Bull., 1966, 14: 965–971
20. ChemAxon Ltd. New & improved ClogP calculator. Accessed 2 Feb 2012
21. Skwierczynski RD, Connors KA. Pharm Res., 1993, 10:1174–1180.
22. Nofre C, Tinti JM. Food Chem., 2000, 69:245–257.
23. European Commission - Scientific Committee on Food (SCF) (2000) Revised opinion on cyclamic acid
and its sodium and calcium salts-SCF/CS/EDUL/192 final. Accessed 9 Feb 2012.
24. Roberts A, Renwick AG, Sims J, Snodin DJ. Food Chem Toxicol., 2000, 38: 31–41.
25. EFSA Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Foods
(AFC) EFSA J., 2006, 356:1–44
26. EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF) (2010)
EFSA J 8(9):1065. doi:10.2903/j.efsa.2010.1065
27. European Commission - Scientific Committee on Food (SCF) (2000) Opinion-Re-evaluation of
acesulfame K with reference to the previous SCF opinion of 1991- SCF/CS/ADD/EDUL/194 final. Accessed 28 Nov2011
28. European Commission - Scientific Committee on Food (SCF) (1997) Opinion on saccharin and its
sodium, potassium and calcium salts - annex III to document III/5157/97, CS/ADD/EDUL/148 final. Accessed 28 Nov 2011
29. WHO (1991) Evaluation of certain food additives and contaminants. WHO technical report series 806. WHO_TRS_806.pdf. Accessed 28 Nov 2011
30. Joint FAO/WHO Expert Committee on Food Additives (JECFA) (2003) Summary and conclusions of
the sixty-first meeting -JECFA/61/SC. Accessed 28 Nov
31. Trefz F, de Sonneville L, Matthis P, Benninger C, Lanz- Englert B, Bickel H. Neuropsychological and
biochemical investigations in heterozygotes for phenylketonuria during ingestion of high dose
aspartame (a sweetener containing phenylalanine). Hum Genet., 1994, 93(4): 369–74.
32. Stegink LD, Filer LJ Jr, Baker GL. Repeated ingestion of aspartame-sweetened beverage: effect on
plasma amino acid concentrations in normal adults. Metabolism 1988; 37(3): 246–51.
33. Stegink LD, Filer LJ, Baker GL, Brummel MC, Tephly TR. Aspartame metabolism in human subjects.
In: Guggenheim B (editor). Health and Sugar Substitutes. Proceedings of ERGOB Conference. Basel:
Karger, 1979: 160–5.
34. Kumar A, Aitas AT, Hunter AG, Beamer DC. Sweeteners, dyes and other excipients in vitamin and
mineral preparations. Clin Pediatr 1996; 35: 443–50.
35. Learn about cancer. Aspartame. Available at
OtherCarcinogens/AtHome/aspartame. Accessed October 4, 2012.
36. Anton SD, Martin CK, Han H, Coulon S, CefaluWT, Geiselman P, et al. Effects of stevia, aspartame,
and sucrose on food intake, satiety, and postprandial glucose and insulin levels. Appetite., 2010; 55:
Vahid Hakimzadeh
et al
/International Journal of PharmTech Research,2016,9(4),pp 357-363. 363
37. Smeets PAM, De Graaf C, Stafleu A, Van Osch MJP, Van der Grond J. Functional magnetic resonance
imaging of human hypothalamic responses to sweet taste and calories 1’2’3. Am J Clin Nutr., 2005;
38. FAO/WHO. Evaluation of certain food additives and contaminants. Thirty-s eventh report of the Joint
FAO/WHO Expert Committee on Food Additives. World Health Organ Tech Rep Ser., 1991, 806: 1–
39. Barkin M, Comisarow RH, Taranger LA, Canada A. Three cases of human bladder cancer following
high dose cyclamate ingestion. J Urol., 1977, 118(2): 258–9.
40. Derfler K, Meryn S, Herold C, Neuhold N, Mostbeck G, Gangl A. Reversible malabsorption caused by
high doses of cyclamate. Am J Med 1988, 85(3): 446–7.
41. Spillane WJ, Thomson JB. Studies of the protonation equilibria of sulphamates using 13C and 1H
nuclear magnetic resonance spectroscopic, potent iometric, and conductimetric methods. Journal of
Chemical Society, Perkin Transactions 2., 1977, 580–584.
42. Leban I, Rudan-Tasiˇc D, Lah N, Klofutar C. Structures of artificial sweeteners– cyclamic acid and
sodium cyclamate with other cyclamates. Acta Crystallographica., 2007, B63: 418–425.
43. Beck KM. Nonnutritive sweeteners: saccharin and cyclamate. In: T.E. Furia (ed). CRC Handbook of
Food Additives, Vol. 11, 2nd edn, CRC Press, Boca Raton, FL; 1980, p. 125.
44. Fazio T, Howard JW, Haenni EO. Survey of cyclohexylamine content of food products containing
cyclamates. Journal of the Association of Official Analytical Chemists., 1970, 3: 1120–1128.
45. FAO/WHO. Evaluation of certain food additives and contamina nts. Twenty-sixth report of t he Joint
FAO/WHO Expert Committee on Food Additives. World Health Organ Tech Rep Ser., 1982; 683: 7–
46. Scientific Committee for Food (SCF) (2000) Opinion of the Scientific Committee on Food on sucralose
(adopted on 7 September 2000)., 14th february 2012
47. European Food Safety Authority (EFSA). Scientific opinion of the Panel on Food Additives,
Flavourings, Processing Aids and Materials in Contact with Food (AFC) on the request from the
European Commission on neotame as a sweetener and flavour enhancer. EFSA J., 2007, 581:1–43
48. Walker AM, Dreyer NA, Friedlander E, Loughlin J, Rothman KJ, Kohn HI. An independent analysis of
the National Cancer Institute study on non-nutritive sweeteners and bladder cancer. Am J Public
Health., 1982, 72(4): 376–81.
49. US Food and Drug Administration. Saccharin. FDA Talk Paper T87-38, 1 September 1987.
50. Dean JA. Lange’s Handbook of Chemistry, 13th edn, McGraw-Hill Book Company, New York; 1985,
5: 56.
51. Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used
in Food, US Food and Drug Administration, Bureau of Foods; 1982, 1–19.
52. DeGarmo O, Ashworth GW, Eaker CM, Munch RH. Hydrolytic stabilit y of saccharin. Journal of
America n Pharmacists Ass ociation., 1952, 41:17–18.
53. Mitchell ML. Unpublished Results. PMC Specialties Group, Cincinnati, OH.
54. [FDA] Food and Drug Administration, Food labeling: health claims; dietary noncariogenic
carbohydrate sweeteners and dental caries. Fed Reg 2006, 71:15559-15564.
55. Arora S, Singh VP, Sharma V, Wadhwa BK, George V, Singh AK, Sharma GS. Analysis of sucralose
and its storage stability in barfi. J Food Sci Technol., 2009, 46:114–117
56. Beyts P K, Lillard D W, Batterman C K (1995) A sucralose compositon. PatentstromUS patent
5380541. 5380541/fulltext.html. Accessed 21 August 2009
57. Ager DJ, Pantaleone DP, Henderson SA, Katritzky AR, Prakash I, Walters DE. Commercial, Synthetic
Nonnutritive Sweeteners. Angew Chem Int Edit 1998, 37:1802–1817
58. Wong CH, Whitesides GM. Enzymes in Synthetic Organic Chemistry. Elsevier, Oxford. 1994
59. Knight I. The development a nd applications of sucralose, a new high-int ensity sweetener. Can J Physiol
Pharmacol 1993, 72: 435–439
60. Patel RM, Sharma R, Grimsley E. Popular Sweetener Sucralose as a Migraine Trigger. J Head Face
Pain., 2006, 46: 1303–1304
61. [USFDA] US Food and Drug Administration (1999) Food additives permitted for direct addition to
food for human consumption: sucralose. Fed Reg 64:43908–43909.
/dockets/98fr/081299b.txt. Accessed 7 March 2009.
... The sweetness level of different NSSs also differs [93,94]. They do not all have the same physiological effect [95], and quantities of NSS intake are largely unknown. Worldwide, only two countries (Chile [7] and very recently Saudi Arabia [96]) include quantities of each type of NSS on the NIP. ...
Full-text available
South Africa (SA) is facing a rising prevalence of obesity and diet-related chronic diseases. The government is seeking to develop effective, evidence-based policy measures to address this. A well-designed, fit-for-purpose nutrient profiling model (NPM) can aid policy development. The aim of this study was to develop a fit-for-purpose NPM in SA. Steps included: (1) determining the purpose and target population; (2) selecting appropriate nutrients and other food components to include; (3) selecting a suitable NPM type, criteria and base; and (4) selecting appropriate numbers and thresholds. As part of the evaluation, the nutritional composition of packaged foods containing nutritional information (n = 6747) in the SA food supply chain was analyzed, a literature review was undertaken and various NPMs were evaluated. Our findings indicated that it is most appropriate to adapt an NPM and underpin regulation with a restrictive NPM that limits unhealthy food components. The Chile 2019 NPM was identified as suitable to adapt, and total sugar, saturated fat, sodium and non-sugar sweetener were identified as appropriate to restrict. This NPM has the potential to underpin restrictive policies, such as front-of-package labelling and child-directed marketing regulations in SA. These policies will support the fight against obesity and NCDs in the country.
... These substances are common in beverages, but they need to be evaluated since the beneficial health effects of these beverages could be inhibited in the presence of some sweeteners. High-intensity artificial sweeteners, heavily promoted by the food industry, are among the most controversial food additives for suspected adverse effects such as dermatological problems, headaches, mood variations, behavior changes, respiratory difficulties, seizures, allergies, and cancer [33]. ...
Full-text available
Although physiologically pain has a protective function, in many diseases, it is one of the most prominent symptoms. Today, new trends are focused on finding more natural alternatives to conventional treatments to alleviate it. Thereby, the purpose of this investigation was to obtain preclinical data of the antinociceptive properties of a lyophilized obtained from a newly designed maqui–citrus beverage alone and added with different sweeteners. To achieve this objective, maqui berry and citrus pharmacological activity were studied separately, as well as the interaction of both ingredients. In addition, due to the controversy generated regarding the intake of sugars, related to different metabolic diseases, the influence of different sweeteners (stevia, sucralose, or sucrose) was studied to determine their possible influence on the bioactive compounds of this product. For the attainment of our goals, a pharmacological evaluation, using the 1% formalin test, a nociceptive pain model in mice, was performed by using a sub-efficacious dosage of Maqui (25 mg/kg, i.p.) alone and combined with citrus, and then compared with the effects obtained in the presence of the different sweeteners. As a result, the antinociceptive response of the maqui was synergized in the presence of citrus in the neurogenic and inflammatory phases of the formalin test. However, this response was partially or totally reduced in the presence of the sweeteners. Our study gives preclinical evidence that a combination of maqui and citrus might exert beneficial actions to relieve pain, whereas the presence of sweeteners could reduce or avoid it.
... Currently the non-nutritive sweeteners are more preferred over nutritive sweetener. Drawbacks of artificial sweeteners include the development of lipid dysregulation, visceral adiposity, hypertension, inflammation and clinical coronary heart disease (Chattopadhyay et al., 2014;Raben, 2012;Sardarodiyan and Hakimzadeh, 2016). ...
... Currently the non-nutritive sweeteners are more preferred over nutritive sweetener. Drawbacks like development of lipid dysregulation, visceral adiposity, hypertension, inflammation and clinical coronary heart disease because of this functional food manufacture are utilizing the artificial sweetener to reduce these consequences (Chattopadhyay et al., 2014;Raben, 2012;Sardarodiyan and Hakimzadeh, 2016). ...
... Most NSSs so far have been synthesised, but through research and development in food chemistry and processing, the number of natural NSS compounds is increasing. 8 NSSs differ from sugars not only in their taste properties, but also in how the body metabolises them 9 and how they in turn affect physiological processes. 10 NSSs are generally sweeter than sucrose, but contain far fewer or no calories. ...
Full-text available
Objective To assess the association between intake of non-sugar sweeteners (NSS) and important health outcomes in generally healthy or overweight/obese adults and children. Design Systematic review following standard Cochrane review methodology. Data sources Medline (Ovid), Embase, Cochrane CENTRAL, WHO International Clinical Trials Registry Platform,, and reference lists of relevant publications. Eligibility criteria for selecting studies Studies including generally healthy adults or children with or without overweight or obesity were eligible. Included study designs allowed for a direct comparison of no intake or lower intake of NSS with higher NSS intake. NSSs had to be clearly named, the dose had to be within the acceptable daily intake, and the intervention duration had to be at least seven days. Main outcome measures Body weight or body mass index, glycaemic control, oral health, eating behaviour, preference for sweet taste, cancer, cardiovascular disease, kidney disease, mood, behaviour, neurocognition, and adverse effects. Results The search resulted in 13 941 unique records. Of 56 individual studies that provided data for this review, 35 were observational studies. In adults, evidence of very low and low certainty from a limited number of small studies indicated a small beneficial effect of NSSs on body mass index (mean difference −0.6, 95% confidence interval −1.19 to −0.01; two studies, n=174) and fasting blood glucose (−0.16 mmol/L, −0.26 to −0.06; two, n=52). Lower doses of NSSs were associated with lower weight gain (−0.09 kg, −0.13 to −0.05; one, n=17 934) compared with higher doses of NSSs (very low certainty of evidence). For all other outcomes, no differences were detected between the use and non-use of NSSs, or between different doses of NSSs. No evidence of any effect of NSSs was seen on overweight or obese adults or children actively trying to lose weight (very low to moderate certainty). In children, a smaller increase in body mass index z score was observed with NSS intake compared with sugar intake (−0.15, −0.17 to −0.12; two, n=528, moderate certainty of evidence), but no significant differences were observed in body weight (−0.60 kg, −1.33 to 0.14; two, n=467, low certainty of evidence), or between different doses of NSSs (very low to moderate certainty). Conclusions Most health outcomes did not seem to have differences between the NSS exposed and unexposed groups. Of the few studies identified for each outcome, most had few participants, were of short duration, and their methodological and reporting quality was limited; therefore, confidence in the reported results is limited. Future studies should assess the effects of NSSs with an appropriate intervention duration. Detailed descriptions of interventions, comparators, and outcomes should be included in all reports. Systematic review registration Prospero CRD42017047668.
... Sweeteners may be used separately or in combination with other sweeteners, as socalled blends 53,54,55 . Numerous studies to improve biotechnological production of sugar alcohols have been reported. ...
Sugar alcohols are extensively used as sweetening agents. They sometimes possess advantages over the parent sugars in sweetness, caloric reduction and non-cariogenicity. The physical status of carbohydrates in food and confectionery affects both the properties of the product during production and the quality of the final product. Sugar alcohols, such as xylitol, mannitol, sorbitol, and erythritol are emerging food ingredients that provide similar or better sweetness/sensory properties of sucrose, but are less calorigenic. Also, sugar alcohols can be converted into commodity chemicals through chemical catalysis. Biotechnological production offers the safe and sustainable supply of sugar alcohols from renewable biomass. These compounds are usually produced by a catalytic hydrogenation of carbohydrates, but they can be also found in nature in fruits, vegetables or mushrooms as well as in human organism. Due to their properties, sugar alcohols are widely used in food, beverage, confectionery and pharmaceutical industries throughout the world. They have found use as bulk sweeteners that promote dental health and exert prebiotic effect. They are added to foods as alternative sweeteners what might be helpful in the control of calories intake. Consumption of low-calorie foods by the worldwide population has dramatically increased, as well as health concerns associated with the consequent high intake of sweeteners.
Artificial sweeteners (ASs) have been recently included in the group of contaminants of emerging concern, since monitoring studies revealed their widespread occurrence in the environment, as a result of their high production and their environmental persistence. The technique of choice for the determination of ASs should be taken into consideration during the sample extraction and clean‐up step for selecting compatible solvents and pre‐concentration factors to be in line with the sensitivity of the method. The most prevalent extraction technique for water samples is solid‐phase extraction, both off‐ and on‐line, whereas solid‐phase microextraction was also tested as an alternative. Based on their increasing use and detection in environmental samples, and due to their persistence, ASs should be integrated in future water monitoring and risk assessment programs.
Sucralose used at 0.025% level in burfi scored highest in sweetness perception and resembled control with sucrose. A simple method was developed for the isolation of sucralose from burfi for HPTLC analysis. Methods were also standardized for qualitative detection (semi-quantification) of sucralose over amino HPTLC plates and quantitative analysis over silica gel HPTLC plates. Sucralose sweetened burfi (SSB) possessed the same desirable sweetness, colour, body and texture even after 7 days of storage at 6-8°C. Titratable acidity was higher in sucralose sweetened burfi than in control sample. Hunter, colour lightness was lower in control with sucrose than in SSB. Total plate counts were higher in SSB than in control. Total plate counts increased linearly for both SSB and control during storage. Analysis over HPTLC plates established the stability of sucralose and hence, its sweetness on storage of burfi.
A national survey was conducted to ascertain the relationship of the cyclohexylamine content of cyclamate-containing products to their composition, processing, and storage conditions. Cyclohexylamine was found in 174 of the 232 samples examined. The cyclohexylamine content range for each major type of food product was as follows: 0.0–8.2 ppm for carbonated beverages; 0.0–5.8 ppm for dry beverage bases; 0.0–1.5 ppm for fruit juices; 0.0–0.8 ppm for weight control foods; and 0.3–66 ppm for food sweetener preparations (liquid and dry base). No correlation between the cyclamate content of products and the cyclohexylamine present was evident. However, the findings indicate that significant hydrolysis of cyclamate can occur.
pKa Values are determined for the ionization R[graphic omitted]H2SO3 RNHSO3–+ H+ for sulphamates with R = Bun, Prn Bu8, and cyclohexyl using 13C and 1H n.m.r. spectroscopic, potentiometric, and conductimetric methods. These compounds have pKa values in the range 1–1.9 and they are thus less acidic than sulphamic acid. Intramolecular standards were used in the n.m.r. measurements. The similarity in the pKa values determined by the two n.m.r. methods suggests that solvation effects are small.
Nonnutritive sweeteners represent a large commercial market, and both in terms of volume and value of sales they fall between the majority of pharmaceutical compounds and bulk chemicals. The synthesis of these sweeteners can offer some unique challenges. The current large-scale methods used for the preparation of sweeteners that are currently allowed for usage in North America and Europe have been highlighted. The elegance of some of these syntheses is the simplicity of the methodology and is a reflection the amount of resources that have been expended to discover the approach and then reduce it to practical scale. Alternative approaches to some of the sweeteners, in particular biochemical methods, have been included as these could supercede total chemical synthesis.
An overview is given of existing trace analytical methods for the determination of seven popular artificial sweeteners [acesulfame (ACE), aspartame, cyclamate (CYC), neotame, neohesperidine dihydrochalcone, saccharin (SAC), and sucralose (SUC)] from aqueous environmental samples. Liquid chromatography-electrospray ionization tandem mass spectrometry and liquid chromatography-electrospray ionization high-resolution mass spectrometry are the methods most widely applied, either directly or after solid-phase extraction. Limits of detection and limits of quantification down to the low nanogram per liter range can be achieved. ACE, CYC, SAC, and SUC were detected in wastewater treatment plants in high microgram per liter concentrations. Per capita loads of individual sweeteners can vary within a wide range depending on their use in different countries. Whereas CYC and SAC are usually degraded by more than 90% during wastewater treatment, ACE and SUC pass through wastewater treatment plants mainly unchanged. This suggests their use as virtually perfect markers for the study of the impact of wastewater on source waters and drinking waters. In finished water of drinking water treatment plants using surface-water-influenced source water, ACE and SUC were detected in concentrations up to 7 and 2.4 μg/L, respectively. ACE was identified as a precursor of oxidation byproducts during ozonation, resulting in an aldehyde intermediate and acetic acid. Although the concentrations of ACE and SUC are among the highest measured for anthropogenic trace pollutants found in surface water, groundwater, and drinking water, the levels are at least three orders of magnitude lower than organoleptic threshold values. However, ecotoxicology studies are scarce and have focused on SUC. Thus, further research is needed both on identification of transformation products and on the ecotoxicological impact of artificial sweeteners and their transformation products.
Unlabelled: Consumption of sugar-sweetened beverages may be one of the dietary causes of metabolic disorders, such as obesity. Therefore, substituting sugar with low calorie sweeteners may be an efficacious weight management strategy. We tested the effect of preloads containing stevia, aspartame, or sucrose on food intake, satiety, and postprandial glucose and insulin levels. Design: 19 healthy lean (BMI=20.0-24.9) and 12 obese (BMI=30.0-39.9) individuals 18-50 years old completed three separate food test days during which they received preloads containing stevia (290kcal), aspartame (290kcal), or sucrose (493kcal) before the lunch and dinner meal. The preload order was balanced, and food intake (kcal) was directly calculated. Hunger and satiety levels were reported before and after meals, and every hour throughout the afternoon. Participants provided blood samples immediately before and 20min after the lunch preload. Despite the caloric difference in preloads (290kcal vs. 493kcal), participants did not compensate by eating more at their lunch and dinner meals when they consumed stevia and aspartame versus sucrose in preloads (mean differences in food intake over entire day between sucrose and stevia=301kcal, p<.01; aspartame=330kcal, p<.01). Self-reported hunger and satiety levels did not differ by condition. Stevia preloads significantly reduced postprandial glucose levels compared to sucrose preloads (p<.01), and postprandial insulin levels compared to both aspartame and sucrose preloads (p<.05). When consuming stevia and aspartame preloads, participants did not compensate by eating more at either their lunch or dinner meal and reported similar levels of satiety compared to when they consumed the higher calorie sucrose preload.