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The Metabolism and Toxicology of Saccharin

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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.
1
Department of Biochemistry, Ahmadu Bello University, Zaria-Nigeria.
2
Department of Biochemistry, Kogi State University, Anyigba, Kogi State Nigeria
3
Department 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
artificial sweetener that is about 200 to 700 times sweeter
than sucrose. It is one of the most studied food ingredients
and the foundation of many low-calorie and sugar-free
products around the world. It is one of the oldest of non-
nutritive sweeteners, whose use is allowed in the US, but
banned in other countries [1, 2, 3,4].
Origin of Saccharin: Saccharin was serendipitously
discovered in 1879 by Constantine Fahlberg, a chemist of
Johns Hopkins University as one of the first artificial
sweeteners on earth.
*Okoduwa, S.I.R. is a Toxicologist/Medical Biochemist; and presently the
Director of Medical Research at Infohealth Awareness Group, Abuja -
Nigeria.
CORRESPONDENCE:
Tel: (+234) 08055-843-993; 0909-9640-143.
Email: stanley@sironigeria.com;
Website: http://sironigeria.com
mechanisms of toluenesulfonamide while working on coal
tar derivatives in the laboratory of Ira Remsen. Accidentally,
he spilled a chemical on his hand. Later on, while eating
dinner, Fahlberg noticed a more sweetness in the bread he
was eating, he licked his finger and noticed that the
substance had a sweet taste [5, 6, 2,7]. Through careful
examination, he traced the sweetness back to the chemical,
later named saccharin, by tasting various residues on his
hands and clothes and finally chemicals in the laboratory. In
1879 and 1880, Fahlberg and Remsen published articles on
benzoic sulfinide. Fahlberg described the methods of
producing this substance that he named saccharin when he
was in New York City working on his own in 1884 [5].
Since the time of saccharin discovery, a number of
compounds have been discovered and used as food additives
for their sweetening properties. Its use has been since 1900,
but obtained FDA approval in 1970 [7]. By 1907, saccharin
was used as a replacement for sugar in foods for diabetics.
 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,
saccharin became widespread and commercialized. Since
saccharin is a calorie-free sweetener, its popularity further
increased during the 1960s and 1970s among dieters [2]. In
the United States, saccharin is often found in restaurants in
pink packets; the most popular brand is "Sweet 'N Low".
Saccharin is used to sweeten products such as drinks,
candies, medicines, and toothpaste, canned fruit, jams, salad
dressing, chewing gum, table top sweeteners, baked goods,
jams, and dessert toppings etc [2]

Figure 2: The structure of saccharin with its sweetness receptor site.

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.
The region marked AH+ has hydrogen available to
hydrogen bond to oxygen that is part of the sulfur group,
whereas, the area marked B- has a partially negative
oxygen avail.
Effect of Heat on Saccharin: Saccharin is stable to heat
unlike the newer artificial sweetener aspartame, but it does
not react chemically with other food ingredients. Blends of
saccharin with other sweeteners are often used to
compensate for each sweetener's weaknesses [5, 8].

Solubility in Water: The solubility of Saccharin in water is

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

InfoHealth Awareness Article Vol 1 No 1 Jun. 2013 15

 Okoduwa,et al., 2013 / Infohealth Awareness Article. Vol 1, No.1: PP 14-19
METABOLISM OF SACCHARIN
Ingestion: Upon ingestion, saccharin goes through the
human digestive system without being digested, for this
reason it is not absorbed or metabolized. It is excreted,
unchanged, via the kidneys. On this bases that saccharin is
not metabolized, the FDA of the United States considers this
compound safe [7]. Although saccharin has no food energy
value, yet it can trigger the release of insulin in humans and
rats due to its taste [11, 12, 13]
Absorption: The absorption of saccharin depends on
various factors, such as the pH value and the pKa of the
animal. In most animas including man, absorption of
saccharin occur rapidly with a pKa of about 2.0- 2.2.
Saccharin exists in acidic media predominantly in the
unionized form, which is the more readily absorbed form in
a number of animal species. In the stomach of rabbit and
guinea-pig, saccharin is absorbed completely at a pH of 1.9
and 1.4 respectively, when compared with the stomach of rat
at a pH 4.2 [14, 15]. In monkeys, and also most probably in
man, both gastric acidity and degree of absorption are
intermediate between those of the rabbit and guinea-pig on
one side, and the rat on the other [14]. Which means the
degree of absorption of saccharin could be dependent on
food intake which affects the acidity of the gastric contents.
Distribution and Excretion: Notable researcher, including
Lethco and wallace [16] studied the distribution of
radioactivity in organs and tissues of rats at various time
intervals (1, 2, 4, 8, 24, 48 and 72 hours) following a single
oral administration of (3-14C) saccharin (50 mg/kg).
Approximately one hour after dosing, Traces of radioactivity
were found in almost all organs. It was found that brain and
spleen contained only minute quantities of 14C., while
Kidney, urinary bladder and liver contained the highest
amount of 14C, which peaked at 4 and 8 hours. In
subsequent experiments, rinsing the bladders of the treated
rats with 8, 0.5 ml portions of a 0.9% saline solution, they
found that a significant portion of the 14C activity was
retained by or bound to the bladder tissue [16].
TOXICITY STUDY OF SACCHARIN
Carcinogenicity Study: Following the investigation
research report of Harvey W. Wiley that saccharin poses
digestive problem [17], worries arose among man regarding
the safety of saccharin. In responds to the issue by the then
president of the United States of American Theodore
Roosevelt (who was at the time dieting too on orders from
his medical doctor to lower his risk for diabetes) said to
Wiley Harvey that Anyone who thinks saccharin is
dangerous is an idiot [17].
InfoHealth Awareness Article Vol 1 No 1 Jun. 2013
The concern that saccharin might be an animal carcinogen
all through the 60s as suggested by various studies that was
conducted in experimental models peaked up in 1977 [17]
consequent upon the publication that saccharin increases the
rate of bladder cancer in rats fed with large doses of
saccharin. This led to the ban of saccharin in China and its
proposed ban in the United State by the US FDA. At the
time, saccharin was only artificial sweetener available in the
U.S and the proposed ban met with strong public opposition,
mostly by the diabetic persons. In the long run, the U.S.
congress placed a moratorium on the ban, requiring instead
that all saccharin-containing foods display a warning label
indicating that saccharin may be a carcinogen. Series of
experiments have been conducted on saccharin with some
showing a correlation between consumption and increased
bladder cancer and others showing no such correlation. An
obvious relationship between saccharin and health risks in
human subjects at normal doses have never been established
in any study till date, but the correlation between
consumption and cancer have been shown in some studies
[17].
The biological mechanism believed to be responsible for the
rats cancers has been shown to be inappropriate to humans,
as a result of the difference in urine composition between
rats and human. Many of the rat cancer may have been
caused by contamination from the rubber plungers inside
syringes, the rubber seals used may corrode when mixed
with certain fluids and decomposed rubber may have caused
the bad results. Others blame certain types of rats like the
Fischer 344 Rat which became a poor example specimen for
testing cancers when it was found out that these laboratory
animals developed cancer spontaneously, when injected with
pure water only [9]. The FDA of the U.S. in 1991, formally
withdraw its proposed 1977 ban on the use of saccharin. But
in 2000, the U.S congress repealed the law requiring
saccharin products to carry health warning labels.
Toxicological Study: Studies on saccharin exposure reveal
that it has both positive and negative effect, such as the
possibility to induce cancer in rats and dogs, hence the first
attempt at banning saccharin came in 1911, when a group
of federal scientists categorized it as an adulterant not
suitable for general use in foods, though the same group
later approved its use in products for invalids [18]. The
review conducted in 1983 by Arnold provide information on
two-generation saccharin bio-assays. In the researching of
the potential effects of substances, at least two generation
studies are beneficial. With respect to the studies, animals
were exposed to saccharin, at all stages of development (i.e.,
in uteri, during lactation, and in feed as an adult). Only three
16
 Okoduwa,et al., 2013 / Infohealth Awareness Article. Vol 1, No.1: PP 14-19
studies of saccharin used a two-generation model, as at the
time of Arnolds publication. These studies categorically
demonstrated that when rats were exposed to diets
containing 5% or 7.5% saccharin from the time of
conception to death, an increased frequency of urinary
bladder cancers was found, mostly in males. There was an
observation of the fact that saccharin is not metabolized, it is
nucleophilic and does not bind to DNA. But, it does suppress
humoral antibody production in rats. At dosages of 5% or
greater, saccharin does not act as a typical chemical
carcinogen, based on the theory that all carcinogens are
strong electrophilic agents [4]. The finding from the study
above lead to the prohibition of saccharin in Canada and a
proposed ban in the United States [6, 19].
In 1991, the U.S. withdrawn her proposed ban, but foods
containing saccharin were required to carry a warning label
[20, 19]. To indicate that saccharin is a potential cancer
causing agent, a warning label was placed on all products
containing saccharin. Current research showing the safety of
this product led to this decision being overturned in 2000
[21]. Though, a ban on saccharin still exists in Canada,
having considering the fact that series of toxicological
evidence and the lack of a consistent association in
epidemiological studies the Health Canada suggests that
carcinogenic effects of saccharin noted in rats are not
relevant to humans. Hence, they are considering re-listing
saccharin as a food additive in the Canadian Food and Drug
Regulations for use as a sweetener in the proposed food
categories [22, 19].
Hepatotoxicity Study: In 1992, Kumar, et al. reported that
saccharin posed no threat to liver function [23]. It was also
reported that in a patients who had elevated serum
concentrations of liver enzymes after the oral administration
of three different drugs, of which saccharin was the only
common constituents, re-exposure to pure saccharin
supported its role in the pathogenesis of liver damage in the
patients. The pathogenesis of saccharin hepatotoxicity in
these patients is unclear. Symptoms suggestive of
hypersensitivity were absent. Saccharin is not metabolized in
vivo, being in an almost unmodified form in the urine, and it
does not accumulate in the liver. The small amount of
saccharin (never exceeding 16 mg daily) taken by patients
underscores the idiosyncratic nature of the reaction [23, 24].
Teratology Study: Till date, the teratogenic study of
saccharin with mice has always been negative. In an
experiment conducted on feeding pregnant female rats with
diets containing 0.3% saccharin throughout the gestation
period shown that the pups from saccharin treated dams had
InfoHealth Awareness Article Vol 1 No 1 Jun. 2013
a 37.9% incidence of lens anomalies versus 12.4% incidence
for the control animals [25].
Genotoxicity Study: Several in-vitro and in vivo studies
have shown clastogenicity, specifically at high
concentrations in in-vitro studies [26, 27]. In several in-vitro
studies for induction of chromosomal aberrations in Chinese
hamster cells and in human lymphocytes, sodium saccharin
was found weakly positive [27, 28]. By and large weak
responses were observed in some in-vitro assays at the
chromosomal level. However, these were only seen in high
concentrations and it is possible that they are attributable to
ionic imbalances which are known to cause non-specific
effects. There are also conflicting reports from in vitro
studies, but some cases the materials use was found or
known to contain impurities or contaminants from the
manufacture of saccharin [29].
Epidemiological Study: Series of evidence comes from the
now numerous epidemiological studies on saccharin which
have included studies of groups consuming relatively high
levels of saccharin. In a reviews by Chappel, [30]; Elock and
Morgan, [31], it was indicated that there is no detectable
association between artificial sweetener consumption most in
particular saccharin and bladder cancer in humans. Various
epidemiological studies indicates no increase in the
occurrence of bladder tumours in human from the ingestion
of saccharin, including in individuals with the highest
consumption rate of artificial sweetened beverages and those
using saccharin as a table-top sweetener.
Beneficial Usage of Saccharin: All over the world, Food
and beverages industries have over the century found the use
of saccharin imperative due to its absence of carbohydrate
and no calorie value. For example, in Europe, the use of
saccharin became more considerable after the two world
wars. Several generations of Americans has made the use
saccharin an integral part of their daily lifestyle in the United
State. Most in particular, the diabetic individuals whose diets
require a restriction of caloric or carbohydrate intake. A
good number of health practitioners support the use of a non-
caloric sweetener like saccharin in weight reduction and for
people with diabetes [21].
According to the Calorie Control Council Research (CCC),
Health professionals believe saccharin is especially
beneficial to persons with diabetes and the obese, and helps
reduce dental cavities. According to opinion research, people
use saccharin to stay in better overall health, control weight
or maintain an attractive physical appearance. In another
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
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-
calorie sweeteners provides products with increased stability,
improved taste, lower production costs and more choices for
the consumer [21].
Saccharin is important for a wide range of low-calorie and
sugar-free food and beverage applications. It is used in such
products like soft drinks, tabletop sweeteners, baked goods,
jams, chewing gum, canned fruit, candy, dessert toppings
and salad dressings. It is also used in cosmetic products,
vitamins and pharmaceuticals. One of the most popular uses
of saccharin is in the production of the product called Sweet
'N Low, a tabletop sweetener in the United State [21,30].
GLOBAL REPORTS ON THE SAFETY OF
SACCHARIN
Over the years, series of researchers, corporate bodies and
individuals have worked on saccharin. The most highly
reputable global health and credible science organizations
have these comments to say with respect to the evaluation
and confirmation on the safety of saccharin as it relate to
human subjects.
The National Cancer Institute in its "Cancer Facts"
documents reviewed in 2009 stated that epidemiological
studies do not provide clear evidence of saccharins link to
human cancer.
The World Cancer Research Fund Stated in the American
Institute for Cancer Research 2007 reported on page 143 that
the evidence from epidemiological studies does not suggest
that artificial sweeteners have a detectable effect on the risk
of any cancer [32].
The American Dietetic Association "Use of Nutritive and
Non-nutritive Sweeteners" position statement, on July 1993.
States that "Evidence gathered from the numerous animal
and human studies of saccharin does not suggest that there is
any significant risk to the human population from the normal
use of saccharin.
Members of the British Medical Association Advised in
the British Medical Journal, that "The major benefits of
saccharin are; an improved quality of life, low cost, and
stability at warm temperatures. A small risk for bladder
cancer continues to be found in male rats exposed to high
doses of saccharin. However, epidemiologic studies show no
evidence of a carcinogenic effect in man [33].
The Health Protection Branch of the Health and Welfare
Canada, on December 5, 1991 declared that
InfoHealth Awareness Article Vol 1 No 1 Jun. 2013
"Epidemiological studies have also not established any
evidence that bladder cancer in man is associated with
saccharin intake [33, 34].
CONCLUSION
The Joint Expert Committee on Food Additives (JECFA) of
the World Health Organization and the Scientific Committee
for Food of the European Union has reviewed and certified
the safety of saccharin. As of today, saccharin is approved in
more than 100 countries around the world. It can therefore
be recommended as one of the very best choice for diabetic
patients and those dieting. Therefore, use of saccharin can
bring about a healthy lifestyle free of calorie accumulation
and the risk of obesity with its associated cardiovascular
complications.
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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.
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