Low Calorie Intense Sweeteners: Safety

Aspects 26
Qurrat ul-Ain, Madiha Sikander, Sohaib Ahmed Khan,
Muhammad Sikander Ghayas Khan, and Rabia Ghayas

Abstract
The safety of low calorie sweeteners (LCS) is always the subject of question.
Artificial sweeteners or intense sweeteners are sugar substitutes that are utilized as
a different option for common sugar. They are commonly sweeter than normal
sugar and as they contain no calories, they can be utilized aptly to control weight
and obesity. Because of this, they are presently utilized by a large number of
individuals worldwide without knowing their potential hazards on the body.
Broad investigative exploration has shown the safety of the six low-calorie
sweeteners at present endorsed for use in foods in the U.S and Europe (stevia,
acesulfame-K, aspartame, neotame, saccharin and sucralose) each with a satis-
factory status. This chapter means to cover the health concerns, highlighting
dangers of consuming artificial sweetener. Artificial sweeteners are added in
food, beverages, medications and hygiene items. The principle explanation

Q. ul-Ain (*)
Shalamar Hospital, Lahore, Pakistan
Dow Medical College DUHS, Civil Hospital Karachi, Karachi, Pakistan
e-mail: [email protected]
M. Sikander
University of Lahore, Lahore, Pakistan
e-mail: [email protected]
S.A. Khan
Civil Hospital, Karachi, Pakistan
e-mail: [email protected]
M.S.G. Khan
Riphah International University, Lahore campus, Lahore, Pakistan
e-mail: [email protected]
R. Ghayas
Arif Memorial Teaching Hospital, Lahore, Pakistan
e-mail: [email protected]

# Springer International Publishing AG 2018 591

J.-M. Mérillon, K.G. Ramawat (eds.), Sweeteners, Reference Series in Phytochemistry,
https://doi.org/10.1007/978-3-319-27027-2_28
592 Q. ul-Ain et al.

behind their overall use is that they don’t raise blood glucose levels, used to
control weight and to treat hypoglycemia. Apart from these advantages, artificial
sweetener can affect the body in several ways for instance leukemia, lymphoma
and others which is supported by researches. Use of artificial sweeteners also
contributes in obesity as well as in diabetes mellitus type 2. To control the above
mentioned complications usage of artificial sweetener must be implied to certain
limitation and use of natural sweeteners must be encouraged.

Keywords
Artificial sweetener • Low calorie sweetener • Aspartame • Saccharin • Non
nutritional sweetener • Intense sweeteners

Abbreviations
Ace-K Asculfame potassium
ADI Acceptable daily intake
AS Artificial sweetener
ATP Adenosine tri phosphate
DNA Deoxy Ribo Nucleic acid
E-Number European number
EU European Union
FDA Food and Drug Administration
JECFA Joint Expert Committee on Food Additives
LCS Low calorie sweetener
MUD Maximum usable dose
NNs Non Nutritional sweeteners
NOAEL No observed adverse effect level
pKa Acid dissociation constant
PKU Phenyl ketone urea
SCF Scientific committee on food
US United States

Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593
2 History of Low Calorie Intense Sweeteners Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 594
3 Criteria for Safety Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 595
3.1 Toxicological Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 595
3.2 Risk Assessment and Acceptable Daily Intake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 596
3.3 Re-Evaluation of Safety of Sweeteners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 596
3.4 Risk Assessment of LCS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597
4 Chemical and Physical Properties of FDA Approved Intense Sweeteners . . . . . . . . . . . . . . . . 597
4.1 Acesulfame Potassium (E950) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597
4.2 Aspartame (951) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599
4.3 Cyclamate E952 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601
4.4 Saccharin (E954) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602
4.5 Sucralose (E955) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602
4.6 Neotame E961 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604
26 Low Calorie Intense Sweeteners: Safety Aspects 593

5 Sweetener Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605

5.1 Metabolism of Artificial Sweeteners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605
6 Safety Aspects of Intense Sweeteners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 606
6.1 Gastrointestinal Tract Disturbance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 606
6.2 Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
6.3 Diabetes Mellitus Type 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
6.4 Coronary Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
6.5 Brain Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608
6.6 Phenylketonuria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608
6.7 Early Menarche . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608
6.8 Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608
6.9 Preterm Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609
7 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609
8 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 610
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 610

1 Introduction

Sweeteners are food additives that are used to improve the taste of everyday foods.
Natural sweeteners are sweet-tasting compounds with some nutritional value the
major ingredient of natural sweeteners is either mono- or disaccharides. Artificial
sweeteners, on the other hand, are compounds that have very little or no nutritional
value. This is possible because artificial sweeteners are synthesized compounds that
have high-intensities of sweetness, meaning less of the compound is necessary to
achieve the same amount of sweetness.
High intensity, low calorie sweeteners is an important class of sweeteners. This
class comprise of compounds which are sweeter than common table sugar. So in
result, small quantities are required to produce the same intensity as that of sugar and
energy input is often low or negligible. Sensation of sweet taste comes after artificial
sweetener is comparatively different than that of table sugar. Therefore to achieve the
natural essence of sugar various blends of ASs are used in food industries. The
beverages containing AS which are labeled as light or diet have different mouth feel.
In Europe and United States six AS have been approved for use yet [1] (Fig. 1).
Intense sweeteners, as their name infers, are commonly sweeter than sugar. For
instance saccharin, aspartame and acesulfame K (pro K) which are up to 200 times
sweeter than sucrose. Sucralose and neotame have been more as of latest endorsed
and are around 600 and 7,000 times sweeter than sugar correspondingly. Artificial
sweeteners are regularly used to give sweetness in an extensive variety of food items
including refreshments, dairy items, confectioneries, pastries and ice cream. Some
artificial sweeteners are metabolized during digestion e.g., aspartame while others
are not metabolized and are discharged unchanged e.g., sucralose.
Low calorie sweeteners are utilized in variety of food and beverage items,
especially in the manufacturing of low calorie forms of foods and beverages. Though
getting good taste by keeping its shelf life long is not an easy and straight away job.
Supplanting sugar with low calorie sweeteners in foods shows some specific chal-
lenges, as sugar has various practical attributes providing sweet taste. Frequently,
594 Q. ul-Ain et al.

Sweeteners

Sugars Sugar Replacers Intense Sweeteners

Acesulfame
Sucrose Glucose Isomalt Sorbitol Aspartame
K

Fructose Lactose Xylitol Maltitol Saccharin Cyclamate

Maltose ………. Mannitol ……….. Sucralose Neotame

Fig. 1 Brief classification of sweeteners

blends of bulk and intense sweeteners are required to coordinate the taste and texture
of sugar-sweetened items. With a comprehension of the specialized qualities of
various sweeteners, it is conceivable to create lower calorie items that still taste
great and give more customer choice [2].

2 History of Low Calorie Intense Sweeteners Discovery

The novel artificial sweetener, saccharin, was at first created to address sugar
deficiencies in the Second World War. Saccharin was found at first by the physicist
Ira Remsen in 1878 at Johns Hopkins University. Though, it was inadvertently
re-found in 1879 by his post-doctoral student, Constantine Fahlberg, while dealing
with derivatives of coal tar items. Fahlberg’s native origin is itself not as much as
clear, being referenced as American, Russian and German-American in various
sources. Remsen was not inspired by commercializing saccharin, but rather Fahlberg
filed a patent and guaranteed to be the sole pioneer, much to the dismay of Remsen.
Through the end of the 1800s and start of the 1900s, utilization of saccharin started to
develop raising concerns by Harvey Wiley, the principal driver of the 1906 Pure
Food and Drug Act and organizer of the Food and Drug Administration (FDA).
Wiley scrutinized the security of saccharin and in 1908 proposed banning its
utilization in the food supply. He spoke to then president Theodore Roosevelt to
bolster a boycott. Though, Roosevelt was not persuaded of the detrimental effects
and is notably reported as expressing, “Any individual who says saccharin is
damaging to health is an idiot. Dr. Rixey offers it to me consistently” (supposedly
26 Low Calorie Intense Sweeteners: Safety Aspects 595

as a way to deal with moderate his weight). In spite of broad audit by different
administrative bodies and leeway by every one of them, inquiries concerning the
security of LCS continue [3, 4].

3 Criteria for Safety Evaluation

Food added substances that have been assessed and thought to be safe for utilization
by people under the proposed states of utilization are assigned an “E-number”
(E = European). In spite of the fact that this is intended to bring a surety for safe
use, E-numbers are once in a while wrongly seen as speaking to non-natural
constituents or even a danger to human health despite the fact that it is feasible for
a food added substance to be of common starting point or be natural origin or
identical to nature [5].
Regarding LCS manufacturers, LCS use, maximum usable dose (MUD) levels
for every sweetener have been determined for important food and refreshment items
which should not be surpassed. The factual levels utilized in items, nonetheless,
won’t generally equate to the MUD as this will likewise be impacted by extra
variables, for example, the inborn sweetening properties of the sweetener and the
coveted taste of the final product. Moreover, it is feasible for a few LCS to be utilized
as a part of blend as they have been appeared to work synergistically to upgrade the
sweetness power or veil undesirable persistent flavors. All the time, this will bring
about a lower level of LCS being utilized as a part of items than would be required in
the event that they were being utilized separately [6].
Wide range database is required to lead a safety assessment for administrative
purposes of any substance as a food added substance. It ought to incorporate results
from studies on ingestion, circulation and digestion system in testing animals and
human subjects, in vitro and in vivo toxicological testing, regulatory information,
specialized information in connection to identity, purity, strength and potential
breakdown items, production process, technological requirement, worth to cus-
tomers, proposed applications, levels of utilization in various food classifications
and evaluated contact in result of the proposed use [7, 8].

3.1 Toxicological Testing

The point of toxicological testing is to figure out if the substance, when utilized in
various ways and amounts proposed, would represent any apparent danger to the
health of the normal consumer and to those whose food utilization pattern, physio-
logical or health status might make them susceptible, e.g., pregnancy, young age or
diabetes. The toxicological testing project of food added substances incorporates
fundamental and supplementary studies. The annex to direction on compliance for
food added substance assessments by the SCF gives contemplations basic the central
toxicological prerequisites and examinations on the degree and utilization of differ-
ent studies and relevance [9].
596 Q. ul-Ain et al.

3.2 Risk Assessment and Acceptable Daily Intake

The hazard evaluation of sweeteners is performed taking after a general system for
risk appraisal of chemicals in food, an investigative procedure that requires
aptitude in toxicology and nutrition (for the intake evaluation). The strategy
comprises of four stages: hazard identification, hazard characterization, exposure
assessment and risk characterization. As the consequence of risk interpretation
acceptable daily intake (ADI) has been built up for every sweetener. The ADI is the
measure of the food added substance, represented as mg/kg body weight, that can
be ingested day by day over a lifetime without causing any calculable health
hazard. Artificial sweeteners that are as of now all owed for food use in the EU
have been allotted a numerical ADI, with one special case. Bulk sweeteners that are
presently allowed for food use in the EU were observed to be “acceptable” by the
SCF. This shows the normal presentation to the substance, emerging from its
utilization or utilizations in food at the level important to accomplish the preferred
technological impact as known at the period of assessment, does not express to a
hazard to human health [9].

3.3 Re-Evaluation of Safety of Sweeteners

There is at present no procurement for occasional audits of the safety of allowed food
added substances. Nonetheless, the safety evaluation of sweeteners (and other food
added substances) depends on the learning and information accessible at the season
of evaluation. At the point when new toxicology information get to be accessible in
the documented literature, national specialists and worldwide expert boards of
trustees consider them with alert and might embrace a re-assessment of their safety.
Reliant upon the result, three situations are conceivable: the ADI can be managed or
changed, or the utilization of a sweetener as a food added substance can be observed
to be inadmissible. The SCF distributed its first opinion on sweeteners in 1985. The
main re-assessment of the security of a percentage of the sweeteners was directed
in. From that point forward, the safety of a few sweeteners has been re-assessed on a
few events. Nordic specialists talked about the security features of sweeteners in
1989 [10].
In 1999 the Nordic Working Group on Food Toxicology and Risk Assessment
chose to inspect whether the safety assessments, which shaped the premise for states
of utilization, were still substantial and sufficient in the light of standards for security
evaluation sat that time, and whether critical new toxicological studies had been
documented subsequent to past assessments. Thus, a report covering all food added
substances allowed in EU by April 2000 was submitted to the Nordic Council of
Ministers. This report contains monographs of 12 sweeteners. The second part of
every monograph is a concentrate of the background information as reported by the
SCF and JECFA, supplemented by a short depiction of the central studies for their
evaluation of the sweetener and also important studies on that compound
documented after the assessments by the SCF and JECFA [11].
26 Low Calorie Intense Sweeteners: Safety Aspects 597

3.4 Risk Assessment of LCS

The danger evaluation of LCS contains four stages:

1. Hazard identification: recognizes the antagonistic health impacts connected to the

substance being referred to. For this reason, investigative information from
experiences from human exposures, concentrates on in vitro studies are required.
2. Hazard characterization: prompts determination of the basic information set in
which the critical adverse impact is recognized. This information set is utilized to
build up the dosage response effect for the substance. On the other hand, if the
information exhibit that the substance is non-genotoxic the “no observed adverse
effect level” (NOAEL) is resolved from the sensitive study in the most delicate
species tried. The acceptable daily intake (ADI) is built up from the NOAEL by
partitioning it by a security component, which considers species contrasts in
between of people and test animals, and variety within human subjects.
3. Exposure evaluation: in view of data in regards to the levels of a substance
proposed for use in various foodstuff sand estimations of the intake of the
applicable foodstuffs in the nation or area being referred to. The objective is to
decide exposure to the substance (by means of intake of food items) in the
population as such considered and in special population groups, and in people
(maximum/minimum, daily/over time). Data on food utilization might be gotten
from food supply information, family unit reviews, singular dietary overviews,
total diet studies and/or biomarkers. The figures are made accessible for the
hazard characterization process.
4. Risk assessment: coordinates data from exposure appraisal and risk assessment
into advice suitable for use in choice making or hazard administration. The
conclusions might be that the anticipated/present exposure is secure by set up
ADI or that declines in exposure are required to meet the ADI standards [12, 13].

4 Chemical and Physical Properties of FDA Approved Intense

Sweeteners

Under this heading various properties of artificial sweeteners which are approved by
FDA will be discussed (Table 1).

4.1 Acesulfame Potassium (E950)

Acesulfame potassium is a calorie-free artificial sweetener usually known as Sunett

and Sweet One. It was found by a German scientific expert, Karl Clauss, in 1967. It
has a white crystalline structure and is around 180–200 times sweeter than sucrose.
At high dosage, it has a tendency to have a persistent bitter flavor however less so as
lower quantity. Kraft Foods licensed the utilization of sodium ferulate to cover this
bitter sensation. The US FDA affirmed the utilization of Ace-K alongside the Kraft
Table 1 Characteristics of 5 FDA Approved Artificial Sweeteners
598

Year of Times Used

Artificial FDA Year of sweeter than Acceptable Calories Pregnancy Association for Brand
sweetener approval discovery sugar daily intake KCAL/KG status with cancer Side effects baking name
Aspertame 1981 1965 200 50 mg/kg 4 Approved No Headache, No Nutra
dizziness, mood sweet,
changes, skin equal,
reactions sugar
twin
Saccharin 2000 1879 200–700 5 mg/kg 0 Not Listed as Irritability, Muscle Yes Sweet N
approved anticipated Dysfunction, low,
carcinogen Crossess Placenta sweet
in 1981, twin,
removed in necta
2000 sweet
Acesulfame-K 1998 1967 200 15 mg/kg 0 Approved No Bitter taste Yes Ack,
sunett,
sweet N
safe,
sweet
one
Neotame 2002 7,000–13,000 18 mg/kg 0 Approved No As toxic as Yes Neotame
aspertame. Both
substances break
to methanol
Sucralose 1998 1976 500 5 mg/kg 0 Approved No Skin rashes, Yes Splenda
diarrhea, muscle
aches, abdominal
cramping,
headaches, bladder
issues
Q. ul-Ain et al.

FDA Food and drug administration

26 Low Calorie Intense Sweeteners: Safety Aspects 599

Food protected rendition in 2003. Ace-K, not at all like its well-known opponent
sweetener aspartame, is stable in high-warm circumstances and is in this manner
frequently utilized as a part of prepared items. Presently it can be found in numerous
tabletop sweeteners, pastries, puddings, bakery products, soda pops, confections
(counting breath mints, hack drops and lozenges), dairy items, canned foods and
alcoholic beverages. Ace K has unique long time shelf life and due to this is perfect
for use in confections, canned foods and alcoholic drinks.

IUPAC name: potassium 6-methyl-2,2-dioxo-2H-1,2λ6,3-oxathiazin-4-olate.

Common name: Acesulfame potassium (E950)
Ace-K is a white crystalline powder with molecular formula C4H4KNO4S,
molecular weight of 201.24 g/mol, and a density of 1.81 g/cm3. It has a structural
resemblance to that of saccharin. Acesulfame K is obtained by chemical synthesis
and purified through recrystallization. The compound is freely soluble in water and
very slightly soluble in ethanol, and stable in the high temperature, pH and time
ranges. No by-products can be found in beverages under normal usage and storage
conditions. Its stability and solubility in water facilitate its use in foodstuffs. Another
critical part of Ace-K is its capacity to stay stable and hold its sweetness under
purifying conditions which frequently opens dairy items to a wide variety of
temperatures and pH values. Ace- K does not participate in tooth rot making
therefore it is a perfect possibility for “sugar free” confections and light or diet
drinks. Considering Ace-K’s intense bitter prolong flavor impression, it is regularly
utilized along with another sweetener as a part of general items. Ordinarily aspar-
tame or sucralose are utilized to adjust the bitter aftertaste impression. Regular items
which contain exclusively Ace-K or a mix of Ace-K and another sweetener are: Diet
Rite Cola, Pepsi One/Pepsi Max, Coca-Cola Zero, Diet Coke with Splenda, Trident
gum, and without sugar Jell-O [14, 15].

4.2 Aspartame (951)

Aspartame was found unintentionally by scientific expert James M. Schlatter in 1965

when he licked his finger which happened to have become sullied by a compound he
composed while attempting to produce anti-ulcer medication. Aspartame was not
promptly affirmed by the US FDA at the point when an extensive study demon-
strated an immediate association among aspartame and bladder cancer in rats. In
1980 there were no further certain studies connecting aspartame to brain damage or
cancer, furthermore, it was then affirmed as a general sweetener. In 1983 it was
600 Q. ul-Ain et al.

further affirmed for use in carbonated drinks then further again in 1996 when it
was took into account use in different drinks, bakery products and desserts. In 1996,
the FDA expelled all confinements from aspartame use. Between its disclosure
and today, aspartame has gotten to be a standout amongst the most studied
artificial sweeteners worldwide. Aspartame has basically no bitter prolonged flavor
impression permitting it to be utilized as a part of numerous items as a sugar elective.
It is a non-nutritive sweetener which makes it exceptionally prominent among
individuals hoping to watch calories, stay in better general health or basically
enjoy a hefty portion of the low-or lessened calories items accessible today. A few
parts of aspartame make it an exceptionally alluring sweetener in natural product
seasoned items, particularly gum, since aspartame has a capacity to “amplify”
flavors making them appear to be sweeter and given them above all full-bodied
taste. Non-significant part of aspartame is its low working temperature. Since it loses
sweetness in high-heat or high-pressure circumstances, it is fairly constrained for use
in bakery products. This issue can be resolved by utilizing extra sweeteners as a part
of the initial preparing process of bakery products, for example, Ace- K or sucralose
then including aspartame at a later stage. Likewise, aspartame can be utilized for
heating for its flavor while another sweetener can be utilized for its sweetness, (for
example, Ace-K).
Aspartame is frequently used to protect or strengthen taste in an item however
normally depends on another source of sweetness if the item is to boiled or baked.
Aspartame can be found in more than 6,000 items, including carbonated soda pops,
powdered soda pops, chewing gum, sugary confectionaries, gelatins, dessert blends,
puddings and fillings, frozen desserts, yogurt, tabletop sweeteners, and a few
pharmaceuticals, for example, vitamins and sugar free cough syrups..

IUPAC name: Methyl L-α-aspartyl-L-phenylalaninate

Common name: Aspartame (E951)
Aspartame (N-L-alpha-Aspartyl-L-phenylalanine 1-methyl ester) is the methyl
ester of the dipeptide of the normal amino acids L-aspartic acid and L-phenylalanine.
It hydrolyzes, or breaks down, into its amino acids when warmed to high tempera-
tures, subsequently losing its sweetness. Aspartame is made out of 57.1% carbon,
6.2% hydrogen, 9.5% nitrogen, and 27.2% oxygen [5]. It has the concoction
equation C14H18N2O, a molar mass of 294.3 g/mol, and a thickness of 1.3 g/cm3.
Aspartames’ segments, aspartic acid, phenylalanine, and methanol, happen nor-
mally in food items, yet aspartame itself does not present and should be made.
Aspartame is made through fermentation and synthesis procedures. Foods and
drinks that contain aspartame must carry a label demonstrating that the item contains
26 Low Calorie Intense Sweeteners: Safety Aspects 601

phenylalanine. This announcement is for the advantage of people with the inherited
sickness phenylketonuria, who should entirely confine their consumption of this
amino acid. Normal and healthy people don’t have to limit their phenylalanine
consumption [16–19].

4.3 Cyclamate E952

Cyclamate, similar to aspartame, was found incidentally. In 1937, Michael Sveda

recklessly set a cigarette into a white powder and when he set the cigarette once again
into his mouth, he found a sweet and charming taste holding up. Cyclamate was
endorsed by the FDA in 1958 however then banned in 1969 after various studies
connecting cyclamate to malignancy. As of date, a wild battle is being driven by
cyclamate makers to reapprove the sweetener in the United States. A few people find
that cyclamate has a bitter aftertaste sensation yet not as much as that of Ace-K. Every
now and again cyclamate is utilized alongside different sweeteners, especially sucra-
lose in a proportion of 10 sections cyclamate to 1 section sucralose, to cover its “off-
taste” and lingering flavor. This synergistic impact frequently shocks specialists in that
the resultant sweetness is fundamentally higher than what might be anticipated from
two sweeteners joined. Cyclamate has a long time span of usability and a wide
working temperature taking into consideration it to be heated and frozen with no
impact on sweetness or stability. It is utilized as a tabletop sweetener, in diet drinks,
and in other low-calorie foods. Additionally, cyclamate is helpful as a flavor enhancer
and in addition a good seasoning ingredient for some pharmaceuticals and toiletries.
Cyclamate (Cyclohexylsulfamic acid) is the sodium or calcium salt of cyclamic acid.

IUPAC name: N-cyclohexylsulfamate

Common name: Cyclamate (E952)
Cyclamate is 30–50 times sweeter than sugar making it the slightest strong of the
industrially utilized artificial sweeteners. It is frequently utilized synergistically with
other simulated sweeteners, particularly saccharin; the blend of 10 sections cycla-
mate to 1 section saccharin is basic and veils the off-tastes of both sweeteners.
Cyclamate is stable under high temperature, making it perfect for baking. Cyclamic
acid is sparingly solvent in water, and is gradually hydrolyzed in boiling hot water.
Sodium cyclamate and calcium cyclamate are both unreservedly solvent in water.
The allowed levels of utilization shift from 250 to 1,500 mg/kg relying upon food
classification. It takes around 1.5 l of soda containing 250 mg/l cyclamates to
accomplish the ADI built up by the SCF [20–22].
602 Q. ul-Ain et al.

4.4 Saccharin (E954)

Saccharin is one of the oldest artificial sweeteners. It was created by a John Hopkins
University graduate understudy in 1879. It was initially utilized as an additive and
germ-free yet turned into an extremely prevalent sweetener amid the first and second
World Wars. It found an extremely tumultuous association with the FDA yet
categorically was banned in 1977. Saccharin is temperamental when warmed yet it
doesn’t respond artificially with different foods. This limits it altogether in cooking
applications however some sweetness is held and no health hazards have been seen
upon saccharin’s breakdown. Saccharin has an extremely observable metallic lin-
gering flavor which numerous individuals find not pleasant. Saccharin had innumer-
able regular uses in drinks and foods. In times of sugar deficiencies, saccharin was
regularly apportioned in tablet structure thinking of it as is 200–700 times sweeter
than sugar. Today it is vigorously controlled because of its disputable health impacts.
In the United States, the FDA requires that any items delivered with or using
saccharin as a sweetener have unclearly obvious cautioning name. Saccharin
(benzoic sulfimide) is an extremely stable natural acid with a pKa of 1.6 and
concoction recipe C7H5NO3S. Its’ synthetic arrangement is 45.9% carbon, 2.7%
hydrogen, 7.7% nitrogen, 26.2% oxygen, and 17.5% sulfur. It has a molar mass of
183.2 g/mol and a thickness of 0.83 g/cm3. In acid structure saccharin is not water
solvent. Along these lines, the structure utilized as a artificial sweetener is its sodium
salt. Saccharin can be produced utilizing the Remsen-Fahlberg and Maumee or
Sherwin-Williams technique

IUPAC name: 2H-1λ6,2-Benzothiazol-1,1,3-trione

Common name: Saccharin (E954)
Saccharin is allowed in an extensive variety of food items and drinks, including
table-top sweeteners, pastries, yogurt, frozen yogurt, prepared bakery products, jam,
jelly, sodas, desserts, mustard and sauces. The allowed levels of utilization fluctuate
from 100 to 500 mg/kg relying upon the food classification. It takes around 0.5 kg of
desserts containing 500 mg/kg or 3.5 l of soda containing 500 mg/l saccharin to
accomplish the ADI built up by the SCF [23–25].

4.5 Sucralose (E955)

Sucralose was found in 1976 and got FDA endorsement in 1998. It is one of the fresher
sweeteners accessible in today’s business sector which makers are discovering hard to
26 Low Calorie Intense Sweeteners: Safety Aspects 603

satisfy. The demand for sucralose, generally known as Splenda, is high while the
assembling of sucralose is moderately tedious and costly creating costs of sucralose to
be essentially higher than those of its rivals. Sucralose is a standout amongst the most
stable artificial sweeteners accessible in today’s business sector and can be utilized as a
part of about each application sugar is utilized. Sucralose is gotten from sugar and is
thusly fundamentally the same to it in its synthetic structure and reactivity. Sucralose is
altogether more stable than aspartame accordingly permitting it an essentially more
time span of usability without loss of sweetness.
Sucralose is otherwise called trichlorosucrose. Sucralose is gotten from sucrose
by the particular substitution of three hydroxyl bunches by chlorine particles.
Sucralose is promptly dissolvable in water, lower alcohols and other polar solvents,
giving arrangements of impartial ph. In corrosive arrangements, e.g., in some soda
pops, sucralose hydrolyses gradually to its constituent monosaccharides, 4-chloro-4-
deoxygalactose (4-CG) and 1,6-dichloro-1,6-dideoxyfructose (1,6DCF). Sucralose
is not metabolized or put away in the body. After it is ingested, it is immediately
retained and after that quickly discharged unaltered. The SCF communicated its first
feeling on sucralose in 1989. Around then the SCF considered sucralose to be
toxicologically unsuitable as a few exceptional inquiries rose up out of the assess-
ment of the accessible information. In 2000, the SCF considered further studies and
built up the ADI of 015 mg/kg body weight. Sucralose is allowed in an extensive
variety of food items and drinks. Among these are soda pops, pastries, frozen yogurt,
ice cream, jam and sandwich spreads. The allowed levels of utilization shift from
10 mg/l to 1,000 mg/kg relying upon the food classification. It takes around 2 kg of a
pastry containing 400 mg/kg or 3 l of soda pop containing 300 mg/l sucralose to
accomplish the ADI built up by the SCF.

IUPAC name: 1,6-Dichloro-1,6-dideoxy-β-D-fructofuranosyl-4-chloro-4-deoxy-α-D-

galactopyranoside
Common name: Sucralose (E955)
Basically, sucralose is utilized all alone on account of its similitude to sugar yet in
a few events is utilized to enhance the taste or properties of a specific food or drink
containing other artificial sweeteners. Sucralose can likewise be utilized alongside
sugar alcohols which are frequently in fluid structure. Sucralose is exceptionally
solvent in a wide range of sorts of fluids making it a standout amongst the most
adaptable synthetic sweeteners today. Sucralose (10 , 4, 60 - Trichloro-galactosucrose)
is a chlorinated sugar with substance equation C12H19Cl3O8 and a molar mass of
397.64 g/mol. Sucralose is a steady particle that keeps up its sweetness property
when presented to high temperatures, making it suitable for use in baking [26–28].
604 Q. ul-Ain et al.

4.6 Neotame E961

Neotame is chemically the same to aspartame however is considerably more stable

and more powerful. Aspartame is around 200 times sweeter than sucrose sugar while
Neotame is somewhere around 7,000 and 13,000 times sweeter than sucrose sugar.
Neotame is utilized as a part of foods and drinks, including chewing gum, carbon-
ated soda pops, ready to-drink drinks, tabletop sweeteners, frozen pastries and
novelties, puddings and fillings, dairy items, (for example, yogurt), bakery products
and confections. It can likewise be utilized as a part of both cooking and preparing
applications as a result of its great heat resistance. Neotame, alongside numerous
other artificial sweeteners, is frequently utilized as a part of mix with different
sweeteners. It doesn’t have an especially solid persistent flavor and in light of its
high strength, is frequently utilized alone or with sweeteners, for example, aspartame
or Ace-K. Likewise, due to its strength, it is extremely alluring by mass makers of
food items since extensive sums can be created, inexpensively and not substantial
sums are required for adequate sweetening purposes. Its’ compound equation is
C20H24N2O5 and it has a molar mass of 378.46 g/mol. Neotame is delivered by
including a 6-carbon (neohexyl) gathering to the amine nitrogen of aspartame.
Peptidases, which would regularly break the peptide bond between the aspartic
corrosive and phenylalanine moieties, are adequately obstructed by the vicinity of
the 3, 3dimethylbutyl moiety, in this manner diminishing the creation of phenylal-
anine, along these lines making its utilization by the individuals who experience the
ill effects of phenylketonuria safe.

IUPAC name: (3S)-3-(3,3-Dimethylbutylamino)-4-[[(2S)-1-methoxy-1-oxo-3-

phenylpropan-2-yl]amino]-4-oxobutanoic acid
Common name: Neotame (E961)
Neotame has a perfect, sweet have an aftertaste like sucrose, and flavor-
improving properties. It is modestly heat stable. Neotame is quickly metabolized
and totally dispensed with, and does not gather in the body. The major metabolic
pathway is hydrolysis of the methyl ester, which yields de-esterified neotame and
methanol in equimolar sums. Since just little measures of neotame are expected to
26 Low Calorie Intense Sweeteners: Safety Aspects 605

Fig. 2 Available brands of various artificial sweeteners

sweeten nourishments, the exposure of methanol that might come about because of
ingestion of neotame-containing food and refreshments is viewed as irrelevant
contrasted and that from other dietary sources [29–31] (Fig. 2).

5 Sweetener Metabolism

The digestion system of sweeteners can be isolated into two primary classes – the
digestion system of natural sweeteners and the digestion system of artificial sweet-
eners. The real distinction that isolates these two classes originates from the way that
natural sweeteners contain some type of starch (sugar) while artificial sweeteners
don’t. Thus, natural sweeteners, for example, table sugar (sucrose), nectar, and
organic product sugar (fructose) prompt pathways that outcome in the generation
of ATP. Then again, artificial sweeteners have almost no healthful worth to the
human body. Research demonstrates that for most artificial sweeteners, more than
90% of the starting compound can be found in excrement and pee natural. This area
gives data on the two noteworthy metabolic pathways that regular sweeteners are
prepared by alongside information from exploratory trials that demonstrate the
destiny of various artificial sweeteners once they are ingested [32].

5.1 Metabolism of Artificial Sweeteners

Generally, artificial sweeteners go through the body naturally. Numerous tests have
been performed attempting to recoup ingested artificial sweeteners from excrement
606 Q. ul-Ain et al.

and pee of animals and people and found that the greater part of expended artificial
sweetener can be recuperated [33].

6 Safety Aspects of Intense Sweeteners

Numerous medical concerns are connected with artificial sweeteners. This is the
fundamental explanation behind their worldwide prevalence. By, Phyllis Roxland,
“it empowers individuals that are carb, sugar or calorie conscious to take in a wider
variety of food that they would either not be permitted to eat or could just eat in such
modest sums that they were not satisfying.” They are utilized as a part of diabetes
mellitus, as a different option for sugar since they don’t raise blood glucose levels.
As they contain no calories, they can likewise be appropriately utilized for weight
control. Various diabetics face trouble in adjusting to non-sugary food items. Arti-
ficial sweeteners make these troublesome move simpler, permitting individuals with
diabetes to eat their most loved foods. They can likewise be utilized as a part of
receptive hypoglycemia, dental consideration to stay away from caries and help
improving flavors. Articulation from American Heart Association and American
Diabetes Association in 2011 spelled out those non-nutritive sweeteners might be
useful for health by decreasing or controlling weight and can have other useful
metabolic impacts too [34].

6.1 Gastrointestinal Tract Disturbance

Episodic proof of bloating and unpredictable bowel movement is common in the

utilization of artificial sweeteners. The impact that artificial sweeteners have on the
gastrointestinal tract for the most part needs to do with their association with the
microbial verdure. The human gut harbors an extremely various group of microbial
living beings which assume imperative parts in the assimilation of food. The human
digestive system, for instance, harbors a rough of 100 trillion micro flora forms of no
less than 1,000 distinctive species [35]. Sucralose is a high-intensity sweetening
exacerbate that is basically a chlorinated disaccharide. In a trial done by the Duke
University Medical Center [36], Sprague–Dawley rats were given the artificial
sweetener Splenda (principle component sucralose) at various time periods. In
conclusion the aftereffects of this study demonstrate that sucralose oppresses some
valuable micro flora. Additionally, sucralose affects raised expression of P-gp and
CYP proteins which basically assume the part of letting medications and toxicants
bypass the body’s digestion system framework and render them less bioavailable.
Aspartame hydrolyzes into its part atoms (L-aspartic acid, L-phenylalanine, and
methanol) inside of the gut and the expansion of these segments inside of the gut
were viewed as a probability for gastrointestinal issues created by aspartame.
Manufactured sweeteners, while they are low caloric and are not metabolized
much inside of the human body; do appear to appreciably affect the micro flora
inside of the gastrointestinal tract.
26 Low Calorie Intense Sweeteners: Safety Aspects 607

6.2 Obesity

Obesity is one of the most serious problems that Americans face today. An obese
lifestyle leads to many other health complications such as diabetes, high blood
pressure, cancer, gallbladder disease, metabolic syndrome, osteoarthritis, heart dis-
ease, and depression [37]. Larger part of the studies surveying the relationship of
NNSs with the body weight include the substitution of caloric sweeteners with NNSs
in drinks, yet meager information is accessible with respect to substitution in food.
San Antonio Heart Study, reported huge weight pick up and danger of stoutness in
ordinary weight or overweight persons at benchmark who expending misleadingly
sweetened drinks as contrasted with nonconsumers [38]. Sweetness decoupled from
caloric substance offers incomplete, however not finish, actuation of the food reward
pathways. Actuation of the hedonic part might add to expanded craving. Animals
look for food to fulfill the inborn longing for sweetness, even without vitality need.
Absence of complete fulfillment, likely in light of the inability to enact the
postingestive part, development energizes the nourishment looking for manner.
Decrease in reward reaction might add to heftiness. Disabled actuation of the
mesolimbic pathways taking after milkshake ingestion was seen in hefty pre-adult
young ladies [39]. Ordinarily, an orosensory boost is noiselessly created by sweet
food items, educating the body concerning exposure of calories. This is trailed by a
few GI reflexes that set up the body for intake. However, when sugar substitutes are
utilized alone, the association between sweet sensation and caloric admission is lost
and capacity of the body in controlling intake of food changes. This prompts disarray
of the body and ultimately weight pick up [34]. The utilization of simulated
sweeteners decreases the caloric intake of a consumer, yet it impedes the mind’s
capacity to evaluate caloric intake in light of sweetness [37].

6.3 Diabetes Mellitus Type 2

In spite of the fact that artificially sweetened drinks and organic product too showed
positive relationship with frequency of type 2 diabetes [40]. Utilization of artificial
sweeteners can expand the risk of type 2 diabetes mellitus. In 2014, an Israeli
research introduced test prove that AS might irritate, as opposed to put a stop to,
metabolic scatters, for example, type 2 diabetes. Another exploration led in 2013
showed that weight control plans sweetened with either common or artificial sugars
are connected with an expansion in type 2 diabetes. However, more exploration is
required [34].

6.4 Coronary Heart Disease

Numerous researchers attempt to discover out the relationship between the utiliza-
tion of NNSs and the cardio‑metabolic and glycemic variables. Utilization of 2 diet
soft drink day by day was significantly connected with the improvement of coronary
608 Q. ul-Ain et al.

heart disease and chronic kidney problem when contrasted with diet soda utilization
of <1 serving month to month when tracked for 11–12 years [38].

6.5 Brain Damage

Anecdotal evidence suggests that artificial sweeteners have negative effects on the
central nervous system, causing difficulty to concentrate and carry out mental
operations. Aspartame is most broadly utilized NNS however it is likewise most
dubious among the NNSs. It is connected with intense symptoms, for example,
queasiness, spewing, migraine particularly headache, and dry mouth.
Mukhopadhyay et al., built up that aspartame is connected with a huge expansion
of up to 2.5–4.2‑fold in chromosomal aberration. Long‑term utilization of aspartame
can cause hepatocellular harm, adjust the hepatic cell reinforcement equalization.
Aspartame present in food jars put away at high temperatures and at pH >6, it can
break into its metabolite deketopiperazine which is a central nervous system cancer-
causing agent and is under dynamic research [38].

6.6 Phenylketonuria

Phenylalanine, a vital amino acid, is shaped from aspartame digestion system.

However, patients with phenylketonuria (PKU), an inalienable error of digestion
system. Elevated amounts of phenylalanine in youngsters can bring about a number
of conceivably exceptionally negative health impacts, for example, obstructed
mental health. Thus, the ADI is not applicable to PKU patients and as such, items
containing aspartame must carry a label that they are a source of phenylalanine. This
notice, however, does not identify with any potential threat of aspartame to those in
normal community [41].

6.7 Early Menarche

In African American and Caucasian young ladies from the United States, more
prominent utilization of energized and artificially sweetened diet drinks at 9–10
years of age is tentatively connected with a higher danger of ahead of early
menarche, independent of adiposity. Utilization of artificial sweetened beverages
was likewise connected with a higher risk of early menarche [42].

6.8 Cancer

Artificial sweeteners might affect the body effectively. They can bring about variety
of risks including cancer. In 1970, a study was done which demonstrated the
relationship of saccharin with bladder disease in research center rats. They are
26 Low Calorie Intense Sweeteners: Safety Aspects 609

additionally connected with malignancies such as leukemia, lymphoma and various

myelomas (in men). In another study which surveyed the conceivable impacts of five
nonnutritive sweeteners on cell aberration, morphology and cells’ DNA by using
Caco2, HT-29 (colon) and HEK-293 (renal) cell lines. DNA harm, if any, prompted
by AS, was concentrated on. Results demonstrated that cells turned out to be less
which are very much characterized and compliment at higher AS dosage. Colon cells
were observed to be more influenced than renal cells. It was likewise seen that
sodium saccharin and sucralose created more DNA aberrations in all cell lines than
other ASs [34].

6.9 Preterm Delivery

Although many AS are considered safe during pregnancy, women with any form of
diabetes (gestational or diabetes mellitus) and insulin resistance must limit their use of
these substitutes. Saccharin has been shown to cause effects as anemia, iron and vitamin
A deficiency, depressed growth and elevated vitamin E in rats. They are also linked
with premature deliveries prompted by two observational studies published in 2010 and
2012. Therefore pregnant women must be advised to avoid these sweeteners [34].

7 Conclusion

The health impacts of sugar sweetened drinks, artificially sweetened drinks, and
natural product juice have gotten impressive consideration from experimental and
open groups. Artificial sweeteners are generally new and their utilizations are being
investigated and augmented each day. Much debate encompasses artificial sweet-
eners and their health impacts as synthetic sweeteners might separate into unsafe and
safe blends. New artificial sweeteners are continually being investigated and because
of their minimal effort and simplicity of creation, they will probably turn into the
essential sweetening mixes later on. It can be for the most part presumed that the
sweeteners themselves are not made out of any unsafe chemicals and are unrealistic
to represent a noteworthy danger to human health. In any case, the assembling and
generation forms that these sweeteners experience should be precisely directed. As
artificial sweeteners are utilized as a part of a huge number of regular items, the
security of people in general is at danger to conceivable health risks that might
happen as an aftereffect of free assessments of the assembling process. Last items
should be completely tried all the time and creation strategies should be assessed and
kept up to regulation benchmarks.
Aspartame, has been thought to bring about cerebrum harm as a result of one of
its segment atoms, phenylalanine. Phenylalanine causes brain damage in individuals
who have a hereditary disorder (homozygous phenylketonuria) that renders them not
able to metabolize phenylalanine. Aspartame’s joining into the overall population’s
eating routine raised the issue that the populace would be presented to expending
superfluously high dosages of phenylalanine, bringing about conceivable brain harm
610 Q. ul-Ain et al.

even in people who don’t have homozygous phenylketonuria. While the normal
individual will most likely be unable to expend unreasonably high measures of
aspartame – enough to bring about cerebrum harm, a few people with a more inactive,
diet drink subordinate way of life, or people who depend vigorously on simulated
sweeteners in any capacity might expend overabundance phenylalanine and experi-
ence neurological disorientation. Through the examination of overview results with
distributed writing, any reasonable person would agree that the open need more
intensive instruction with respect to artificial sweeteners and their health impacts.
The consistent media buildup must be taken incredulously and concerned people
must attempt to take in the genuine certainties behind sweeteners safety through
substantial experimental examination. Also, the intake of sweeteners must be pre-
cisely checked on an individual premise as was prescribed by the specialists met.
While attempting new items, consumers must be careful about any unexpected
responses and must ensure that they are not expending sweeteners or sweetener
containing items in abundance. As a rule, artificial sweeteners, when utilized as a
part of balance are a satisfactory substitute to normal sweeteners. They have all the
earmarks of being a solid and charming approach to advance food sweetness, taste,
and composition while keeping significant safety chances low.

8 Cross-References

▶ Analytical Strategies to Determine Artificial Sweeteners By Liquid Chromatog-

raphy-Mass Spectrometry
▶ Characterization of Artificial Sweeteners Using Raman Spectroscopy
▶ Health Implications of Fructose Consumption in Humans
▶ Nonnutritive Sweeteners and Their Role in the Gastrointestinal Tract
▶ Sugar Alcohols as Sugar Substitutes in Food Industry
▶ Sweet-Taste Receptor Signaling Network and Low-Calorie Sweeteners
▶ Sweeteners: Regulatory Aspects
▶ Tagatose Stability Issues in Food Systems
▶ The Role of Dietary Sugars and Sweeteners in Metabolic Disorders and Diabetes
▶ Xylitol: One Name, Numerous Benefits
▶ Xylitol as Sweetener

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