Maryam Sardarodiyan1, Vahid Hakimzadeh2٭
1Young Researchers and Elite Club, Quchan Branch, Islamic Azad University,
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),
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
/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-
163.15 179.24 183.19 397.63 294.31 378.47 612.58
20093010 30011 60012 160-220 11 7,000-
270 (20 °C)91.00010,
412 283 (20 °C) 15 ~10 (25
a2.018 1.919 2.219 11.8c20 3.19 and
-1.3312 -1.6112 0.9112 -1.0012
<2 % 13
1529 4025 230 526
/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
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.
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.
/International Journal of PharmTech Research,2016,9(4),pp 357-363. 360
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.
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.
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 (100◦C, 125◦C and
150◦C) were first reported in 1952 by DeGarmo and coworkers (Monsanto Chemical Company)52. Later,
accelerated studies at a single temperature (120◦C) 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.
/International Journal of PharmTech Research,2016,9(4),pp 357-363. 361
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.
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.
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