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Published by siroplc, 2016-08-13 13:38:14

Metabolism and Toxicology of Saccharin

Metabolism and Toxicology of Saccharin

Infohealth Awareness Article A Publication Series By
SIRONigeria Global Limited
Mini-Review
Vol 1, (1): Jun. 2013, pp 14-19

THE METABOLISM AND TOXICOLOGY OF SACCHARIN

1*S.I.R. Okoduwa; 2G.U. Ebiloma; 1J. Baba and 3 S. Ajide.

1Department of Biochemistry, Ahmadu Bello University, Zaria-Nigeria.
2Department of Biochemistry, Kogi State University, Anyigba, Kogi State Nigeria

3Department of Animal Science, Ahmadu Bello University, Zaria-Nigeria.

Accepted 07 June, 2013

ABSTRACT
Saccharin, one of the sweeteners in the world, is still regarded as a carcinogen and diabetic inducer in some
parts of the world. Concern peaked in 1977, after publication of a study indicating an increased rate of bladder
cancer in rats fed large doses of saccharin. In 1977, Canada banned saccharin while US-FDA also proposed a
ban. In due course, US congress required all saccharin-containing foods to display a warning label indicating
that saccharin may be carcinogenic. This resulted in the carcinogenicity, genotoxicity, hepatotoxicity and
teratological studies of saccharin in animals including humans by the most highly reputable global health and
credible science organizations worldwide. None of these studies ever showed a clear causal relationship between
saccharin consumption and health risks in humans at normal dosage. Ultimately, the influential 1977 study was
later criticized for the high dosages of saccharin that were given to test subject rats. Consequently, the US-FDA
formally withdraws its 1977 proposal to ban the use of saccharin and the National Toxicity Program announced
the delisting of saccharin as a carcinogen. Therefore, use of saccharin can bring about a healthy lifestyle free of
calorie accumulation and the risk of obesity with its associated cardiovascular complications.

Key Words: Saccharin, Carcinogen, Sweetener, Toxicity

INTRODUCTION This happened when he was researching the oxidative
Saccharin, a petroleum derivative is a white crystalline mechanisms of toluenesulfonamide while working on coal
artificial sweetener that is about 200 to 700 times sweeter tar derivatives in the laboratory of Ira Remsen. Accidentally,
than sucrose. It is one of the most studied food ingredients he spilled a chemical on his hand. Later on, while eating
and the foundation of many low-calorie and sugar-free dinner, Fahlberg noticed a more sweetness in the bread he
products around the world. It is one of the oldest of non- was eating, he licked his finger and noticed that the
nutritive sweeteners, whose use is allowed in the US, but substance had a sweet taste [5, 6, 2,7]. Through careful
banned in other countries [1, 2, 3,4]. examination, he traced the sweetness back to the chemical,
later named saccharin, by tasting various residues on his
Origin of Saccharin: Saccharin was serendipitously hands and clothes and finally chemicals in the laboratory. In
discovered in 1879 by Constantine Fahlberg, a chemist of 1879 and 1880, Fahlberg and Remsen published articles on
Johns Hopkins University as one of the first artificial benzoic sulfinide. Fahlberg described the methods of
sweeteners on earth. producing this substance that he named saccharin when he
was in New York City working on his own in 1884 [5].
*Okoduwa, S.I.R. is a Toxicologist/Medical Biochemist; and presently the Since the time of saccharin discovery, a number of
Director of Medical Research at Infohealth Awareness Group, Abuja - compounds have been discovered and used as food additives
Nigeria. for their sweetening properties. Its use has been since 1900,
but obtained FDA approval in 1970 [7]. By 1907, saccharin
CORRESPONDENCE: was used as a replacement for sugar in foods for diabetics.
Tel: (+234) 08055-843-993; 0909-9640-143.
Email: [email protected];
Website: http://sironigeria.com

Okoduwa,et al., 2013 / Infohealth Awareness Article. Vol 1, No.1: PP 14-19

Since it is not metabolized in the body for energy, saccharin of nectar, do not treat it as a pleasing substance. [2]. The
is classified as a non-caloric sweetener. By the 1960s it was figure 2 below shows the sweetness receptor with saccharin.
used on a massive scale in the "diet" soft drink industry [2].
Consequent upon sugar shortage during the World War I, Figure 2: The structure of saccharin with its sweetness receptor site.
saccharin became widespread and commercialized. Since
saccharin is a calorie-free sweetener, its popularity further The region marked “AH+” has hydrogen available to
increased during the 1960s and 1970s among dieters [2]. In hydrogen bond to oxygen that is part of the sulfur group,
the United States, saccharin is often found in restaurants in whereas, the area marked “B-” has a partially negative
pink packets; the most popular brand is "Sweet 'N Low". oxygen avail.
Saccharin is used to sweeten products such as drinks, Effect of Heat on Saccharin: Saccharin is stable to heat
candies, medicines, and toothpaste, canned fruit, jams, salad unlike the newer artificial sweetener aspartame, but it does
dressing, chewing gum, table top sweeteners, baked goods, not react chemically with other food ingredients. Blends of
jams, and dessert toppings etc [2] saccharin with other sweeteners are often used to
compensate for each sweetener's weaknesses [5, 8].
CHEMISTRY OF SACCHARIN
Structure of Saccharin: The chemical formula of saccharin
is C7H5NO3S and the basic substance in it is benzoic
sulfimide. It has a pKa value of about 2.0. It can be used to
prepare exclusively disubstituted amines from alkyl halides
using Gabriel synthesis. The chemical structure of saccharin
is diagrammatically represented Figure 1.

Figure 1. The Structure of saccharin. Solubility in Water: The solubility of Saccharin in water is
about 1g per 290 ml. In its acidic form it is insoluble in
Nature of Saccharin: Saccharin is a white crystalline solid water. The sodium salt form is usually used as an artificial
with a molecular mass of 183.18g mol-1 and a density of sweetener. The calcium salt is also used at times, particularly
0.828g/cm3. It has a melting point of 228.8 – 229.7oC. Even by people restricting their dietary sodium intake. Both salts
though saccharin has about 200 – 700 times the sweetening are highly water-soluble; usually about 0.67 grams per
power of sucrose, yet it has an unpleasant bitter or metallic milliliter water at room temperature. [5, 8].
aftertaste, especially at high concentrations.
Synthesis of Saccharin: Saccharin can be synthesized
Taste of Saccharin: It is still unclear as to the reason for the through the initial reaction between toluene and
sweet taste of saccharin. However, scientist has proposed chlorosulfonic acid. It is then converted to a sulfonamide
that it might be due to its shape which fit into the specific with ammonia, and oxidized to a benzoic acid then heated to
receptor site in the taste buds. Evidence for this comes from form the cyclic imide [5, 9]. The yield from this method is
the fact that if the shape is modified slightly, say by very low. An improve method was developed in 1950 at the
changing the H on the nitrogen to a methyl, the new Maumee Chemical Company of Toledo. In this production
molecule no longer tastes sweet. Perhaps the specific taste method, anthranilic acid successively reacts with nitrous
receptors it targets are peculiar to humans, in view of the fact acid, sulfur dioxide, chlorine, and then ammonia to produce
that bees or butterflies, which normally crave the sweetness saccharin. Another route begins with o-chlorotoluene. It is
also known as ortho sulfobenzoic acid [10]. A series of
different chemical impurities could find their way to the final
product, hence the most widely used methods for the
production of saccharin are the Remsen-Fahlberg and the
Maumee processes.

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METABOLISM OF SACCHARIN The concern that saccharin might be an animal carcinogen
Ingestion: Upon ingestion, saccharin goes through the all through the “60s as suggested by various studies that was
human digestive system without being digested, for this conducted in experimental models peaked up in 1977 [17]
reason it is not absorbed or metabolized. It is excreted, consequent upon the publication that saccharin increases the
unchanged, via the kidneys. On this bases that saccharin is rate of bladder cancer in rats fed with large doses of
not metabolized, the FDA of the United States considers this saccharin. This led to the ban of saccharin in China and its
compound safe [7]. Although saccharin has no food energy proposed ban in the United State by the US FDA. At the
value, yet it can trigger the release of insulin in humans and time, saccharin was only artificial sweetener available in the
rats due to its taste [11, 12, 13] U.S and the proposed ban met with strong public opposition,
mostly by the diabetic persons. In the long run, the U.S.
Absorption: The absorption of saccharin depends on congress placed a moratorium on the ban, requiring instead
various factors, such as the pH value and the pKa of the that all saccharin-containing foods display a warning label
animal. In most animas including man, absorption of indicating that saccharin may be a carcinogen. Series of
saccharin occur rapidly with a pKa of about 2.0- 2.2. experiments have been conducted on saccharin with some
Saccharin exists in acidic media predominantly in the showing a correlation between consumption and increased
unionized form, which is the more readily absorbed form in bladder cancer and others showing no such correlation. An
a number of animal species. In the stomach of rabbit and obvious relationship between saccharin and health risks in
guinea-pig, saccharin is absorbed completely at a pH of 1.9 human subjects at normal doses have never been established
and 1.4 respectively, when compared with the stomach of rat in any study till date, but the correlation between
at a pH 4.2 [14, 15]. In monkeys, and also most probably in consumption and cancer have been shown in some studies
man, both gastric acidity and degree of absorption are [17].
intermediate between those of the rabbit and guinea-pig on
one side, and the rat on the other [14]. Which means the The biological mechanism believed to be responsible for the
degree of absorption of saccharin could be dependent on rats’ cancers has been shown to be inappropriate to humans,
food intake which affects the acidity of the gastric contents. as a result of the difference in urine composition between
rats and human. Many of the rat cancer may have been
Distribution and Excretion: Notable researcher, including caused by contamination from the rubber plungers inside
Lethco and wallace [16] studied the distribution of syringes, the rubber seals used may corrode when mixed
radioactivity in organs and tissues of rats at various time with certain fluids and decomposed rubber may have caused
intervals (1, 2, 4, 8, 24, 48 and 72 hours) following a single the bad results. Others blame certain types of rats like the
oral administration of (3-14C) saccharin (50 mg/kg). Fischer 344 Rat which became a poor example specimen for
Approximately one hour after dosing, Traces of radioactivity testing cancers when it was found out that these laboratory
were found in almost all organs. It was found that brain and animals developed cancer spontaneously, when injected with
spleen contained only minute quantities of 14C., while pure water only [9]. The FDA of the U.S. in 1991, formally
Kidney, urinary bladder and liver contained the highest withdraw its proposed 1977 ban on the use of saccharin. But
amount of 14C, which peaked at 4 and 8 hours. In in 2000, the U.S congress repealed the law requiring
subsequent experiments, rinsing the bladders of the treated saccharin products to carry health warning labels.
rats with 8, 0.5 ml portions of a 0.9% saline solution, they
found that a significant portion of the 14C activity was Toxicological Study: Studies on saccharin exposure reveal
retained by or bound to the bladder tissue [16]. that it has both positive and negative effect, such as the
possibility to induce cancer in rats and dogs, hence the first
TOXICITY STUDY OF SACCHARIN attempt at banning saccharin came in 1911, when a group
Carcinogenicity Study: Following the investigation of federal scientists categorized it as an “adulterant” not
research report of Harvey W. Wiley that saccharin poses suitable for general use in foods, though the same group
digestive problem [17], worries arose among man regarding later approved its use in products “for invalids [18]. The
the safety of saccharin. In responds to the issue by the then review conducted in 1983 by Arnold provide information on
president of the United States of American Theodore two-generation saccharin bio-assays. In the researching of
Roosevelt (who was at the time dieting too on orders from the potential effects of substances, at least two generation
his medical doctor to lower his risk for diabetes) said to studies are beneficial. With respect to the studies, animals
Wiley Harvey that “Anyone who thinks saccharin is were exposed to saccharin, at all stages of development (i.e.,
dangerous is an idiot” [17]. in uteri, during lactation, and in feed as an adult). Only three

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studies of saccharin used a two-generation model, as at the a 37.9% incidence of lens anomalies versus 12.4% incidence
time of Arnold’s publication. These studies categorically for the control animals [25].
demonstrated that when rats were exposed to diets
containing 5% or 7.5% saccharin from the time of Genotoxicity Study: Several in-vitro and in vivo studies
conception to death, an increased frequency of urinary have shown clastogenicity, specifically at high
bladder cancers was found, mostly in males. There was an concentrations in in-vitro studies [26, 27]. In several in-vitro
observation of the fact that saccharin is not metabolized, it is studies for induction of chromosomal aberrations in Chinese
nucleophilic and does not bind to DNA. But, it does suppress hamster cells and in human lymphocytes, sodium saccharin
humoral antibody production in rats. At dosages of 5% or was found weakly positive [27, 28]. By and large weak
greater, saccharin does not act as a typical chemical responses were observed in some in-vitro assays at the
carcinogen, based on the theory that all carcinogens are chromosomal level. However, these were only seen in high
strong electrophilic agents [4]. The finding from the study concentrations and it is possible that they are attributable to
above lead to the prohibition of saccharin in Canada and a ionic imbalances which are known to cause non-specific
proposed ban in the United States [6, 19]. effects. There are also conflicting reports from in vitro
studies, but some cases the materials use was found or
In 1991, the U.S. withdrawn her proposed ban, but foods known to contain impurities or contaminants from the
containing saccharin were required to carry a warning label manufacture of saccharin [29].
[20, 19]. To indicate that “saccharin is a potential cancer
causing agent,” a warning label was placed on all products Epidemiological Study: Series of evidence comes from the
containing saccharin. Current research showing the safety of now numerous epidemiological studies on saccharin which
this product led to this decision being overturned in 2000 have included studies of groups consuming relatively high
[21]. Though, a ban on saccharin still exists in Canada, levels of saccharin. In a reviews by Chappel, [30]; Elock and
having considering the fact that series of toxicological Morgan, [31], it was indicated that there is no detectable
evidence and the lack of a consistent association in association between artificial sweetener consumption most in
epidemiological studies the Health Canada suggests that particular saccharin and bladder cancer in humans. Various
carcinogenic effects of saccharin noted in rats are not epidemiological studies indicates no increase in the
relevant to humans. Hence, they are considering re-listing occurrence of bladder tumours in human from the ingestion
saccharin as a food additive in the Canadian Food and Drug of saccharin, including in individuals with the highest
Regulations for use as a sweetener in the proposed food consumption rate of artificial sweetened beverages and those
categories [22, 19]. using saccharin as a table-top sweetener.

Hepatotoxicity Study: In 1992, Kumar, et al. reported that Beneficial Usage of Saccharin: All over the world, Food
saccharin posed no threat to liver function [23]. It was also and beverages industries have over the century found the use
reported that in a patients who had elevated serum of saccharin imperative due to its absence of carbohydrate
concentrations of liver enzymes after the oral administration and no calorie value. For example, in Europe, the use of
of three different drugs, of which saccharin was the only saccharin became more considerable after the two world
common constituents, re-exposure to pure saccharin wars. Several generations of Americans has made the use
supported its role in the pathogenesis of liver damage in the saccharin an integral part of their daily lifestyle in the United
patients. The pathogenesis of saccharin hepatotoxicity in State. Most in particular, the diabetic individuals whose diets
these patients is unclear. Symptoms suggestive of require a restriction of caloric or carbohydrate intake. A
hypersensitivity were absent. Saccharin is not metabolized in good number of health practitioners support the use of a non-
vivo, being in an almost unmodified form in the urine, and it caloric sweetener like saccharin in weight reduction and for
does not accumulate in the liver. The small amount of people with diabetes [21].
saccharin (never exceeding 16 mg daily) taken by patients
underscores the idiosyncratic nature of the reaction [23, 24]. According to the Calorie Control Council Research (CCC),
Health professionals believe saccharin is especially
Teratology Study: Till date, the teratogenic study of beneficial to persons with diabetes and the obese, and helps
saccharin with mice has always been negative. In an reduce dental cavities. According to opinion research, people
experiment conducted on feeding pregnant female rats with use saccharin to stay in better overall health, control weight
diets containing 0.3% saccharin throughout the gestation or maintain an attractive physical appearance. In another
period shown that the pups from saccharin treated dams had report of the CCC, No low-calorie sweetener is perfect for
all uses. But, a range of sweeteners enables the development
of a much wider range of new, good-tasting, low-calorie

InfoHealth Awareness Article Vol 1 No 1 Jun. 2013 17

Okoduwa,et al., 2013 / Infohealth Awareness Article. Vol 1, No.1: PP 14-19

products to meet consumer demand. Also, an array of low- "Epidemiological studies have also not established any
calorie sweeteners provides products with increased stability, evidence that bladder cancer in man is associated with
improved taste, lower production costs and more choices for saccharin intake [33, 34].
the consumer [21].
CONCLUSION
Saccharin is important for a wide range of low-calorie and The Joint Expert Committee on Food Additives (JECFA) of
sugar-free food and beverage applications. It is used in such the World Health Organization and the Scientific Committee
products like soft drinks, tabletop sweeteners, baked goods, for Food of the European Union has reviewed and certified
jams, chewing gum, canned fruit, candy, dessert toppings the safety of saccharin. As of today, saccharin is approved in
and salad dressings. It is also used in cosmetic products, more than 100 countries around the world. It can therefore
vitamins and pharmaceuticals. One of the most popular uses be recommended as one of the very best choice for diabetic
of saccharin is in the production of the product called “Sweet patients and those dieting. Therefore, use of saccharin can
'N Low®”, a tabletop sweetener in the United State [21,30]. bring about a healthy lifestyle free of calorie accumulation
and the risk of obesity with its associated cardiovascular
GLOBAL REPORTS ON THE SAFETY OF complications.
SACCHARIN
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This article is a postgraduate research seminar presented by the first author to the Department of Biochemistry, Ahmadu Bello University, Zaria-
Nigeria, in partial fulfillment for the assessment of Nutritional and Environmental Toxicology in 2010. Infohealth Awareness Article is a Copyright of
InfoHealth Awareness Group, a Non-Profit Organisation aimed at eradicating preventable diseases and hereditary disorders in Nigeria in order to have

a Society of people living a healthier life. © 2013 Infohealth Awareness Article. Alrights Reserved, Published By SIRONigeria Global Limited.

InfoHealth Awareness Article Vol 1 No 1 Jun. 2013 19


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