ArticlePDF Available

The Metabolism and Toxicology of Saccharin

  • Department of Biochemistry, Babcock University, Ilishan-Remo Nigeria

Abstract and Figures

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.
Content may be subject to copyright.
Infohealth Awareness Article
Mini-Review Vol 1, (1): Jun. 2013, pp 14-19
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
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
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 -
Tel: (+234) 08055-843-993; 0909-9640-143.
This happened when he was researching the oxidative
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.
A Publication Series By
SIRONigeria Global Limited
Okoduwa,et al., 2013 / Infohealth Awareness Article. Vol 1, No.1: PP 14-19
InfoHealth Awareness Article Vol 1 No 1 Jun. 2013 15
Since it is not metabolized in the body for energy, saccharin
is classified as a non-caloric sweetener. By the 1960s it was
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]
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.
Nature of Saccharin: Saccharin is a white crystalline solid
with a molecular mass of 183.18g mol-1 and a density of
0.828g/cm3. It has a melting point of 228.8 – 229.7oC. Even
though saccharin has about 200 700 times the sweetening
power of sucrose, yet it has an unpleasant bitter or metallic
aftertaste, especially at high concentrations.
Taste of Saccharin: It is still unclear as to the reason for the
sweet taste of saccharin. However, scientist has proposed
that it might be due to its shape which fit into the specific
receptor site in the taste buds. Evidence for this comes from
the fact that if the shape is modified slightly, say by
changing the H on the nitrogen to a methyl, the new
molecule no longer tastes sweet. Perhaps the specific taste
receptors it targets are peculiar to humans, in view of the fact
that bees or butterflies, which normally crave the sweetness
of nectar, do not treat it as a pleasing substance. [2]. The
figure 2 below shows the sweetness receptor with saccharin.
Figure 2: The structure of saccharin with its sweetness receptor site.
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].
Synthesis of Saccharin: Saccharin can be synthesized
through the initial reaction between toluene and
chlorosulfonic acid. It is then converted to a sulfonamide
with ammonia, and oxidized to a benzoic acid then heated to
form the cyclic imide [5, 9]. The yield from this method is
very low. An improve method was developed in 1950 at the
Maumee Chemical Company of Toledo. In this production
method, anthranilic acid successively reacts with nitrous
acid, sulfur dioxide, chlorine, and then ammonia to produce
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.
Okoduwa,et al., 2013 / Infohealth Awareness Article. Vol 1, No.1: PP 14-19
InfoHealth Awareness Article Vol 1 No 1 Jun. 2013 16
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].
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].
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
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
banning saccharin came in 1911, when a group
of federal scientists categorized
as an
suitable for general use in foods,
though the
same group
later approved its use in
s “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
Okoduwa,et al., 2013 / Infohealth Awareness Article. Vol 1, No.1: PP 14-19
InfoHealth Awareness Article Vol 1 No 1 Jun. 2013 17
studies of saccharin used a two-generation model, as at the
time of Arnold’s 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
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
Okoduwa,et al., 2013 / Infohealth Awareness Article. Vol 1, No.1: PP 14-19
InfoHealth Awareness Article Vol 1 No 1 Jun. 2013 18
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].
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 saccharin’s 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
"Epidemiological studies have also not established any
evidence that bladder cancer in man is associated with
saccharin intake [33, 34].
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
1. Ahmed Z, Banu H, Akhter F, Faruquzzaman KM and
Haque S. Concept of sugar-a review. Online Journal of
Biological Science 2001, 1(9): 883-894
2. Ophardt CE. Saccharin - the oldest Sweetener Sweet 'N
Low, Sugar Twin. V.Chmbook 2003, 549
3. Anderson J and Young L. Sugar and sweeteners. Health,
Food and Nutrition series. 2008, 9: 301
4. National Cancer Institute, NCI. Artificial sweeteners
and Cancer. Fact Sheet. Rev. 2009, 3:19
5. Remsen I and Fahlberg C. "Über die Oxydation des
Orthotoluolsulfamids". Chemische Berichte. 1879, 12:
6. Arnold DL. Toxicology of saccharin. Fundamental and
Applied Toxicology, 1984, 4(5): 674-685.
7. Whitehouse CR, Boullata J and McCauley LA. The
Potential Toxicity of Artificial Sweeteners. AAOHN
Journal, 2008, 56(6): 251-259.
8. Priebem PM and Kauffman GB. Making governmental
policy under conditions of scientific uncertainty: A
century of controversy about saccharin in congress and
the laboratory". Minerva, 1980, 18 (4): 556–574
9. Ager DJ, Pantaleone DP, Henderson SA, Katritzky AR.,
Prakash I and Walters DE. Commercial, Synthetic
Nonnutritive Sweeteners. Angewandte Chemie
International Edition 1998, 37 (13-24): 1802–1817
10. Bungard, G. Die SusStoff Der deut Apotheker, 1967,
Okoduwa,et al., 2013 / Infohealth Awareness Article. Vol 1, No.1: PP 14-19
InfoHealth Awareness Article Vol 1 No 1 Jun. 2013 19
11. Berthoud HR, Trimble ER, Siegel EG, Bereiter DA and
Jeanrenaud B. "Cephalic-phase insulin secretion in
normal and pancreatic islet-transplanted rats". American
Journal of Physiology-Endocrinology and Metabolism,
1980, 238 (4): E336-E340
12. Ionescu E, Rohner-Jeanrenaud F, Proietto J, Rivest RW
and Jeanrenaud B. Taste-induced changes in plasma
insulin and glucose turnover in lean and genetically
obese rats. Diabetes, 1988, 37: 773–779.
13. Just T, Pau HW, Engel U, and Hummel T. Cephalic
phase insulin release in healthy humans after taste
stimulation?. Appetite, 2008, 238 (4): 622–7.
14. Ball LM. The metabolism of saccharin and related
compounds. Report 4, from the Department of
Biochemistry, St Mary's Hospital Medical School,
London, UK. Unpublished report submitted to WHO,
15. Minegishi KI, Asahina M and Yamaha T. The
metabolism of saccharin and the related compounds in
rats and guinea pigs, Chemistry and Pharmaceutical
Bulletin, 1972, 20: 1351
16. Lethco EJ and Wallace WC. The metabolism of
saccharin in animals, Toxicology, 1975, 3: 287
17. Weihrauch MR and Diehl V. Artificial sweetener-do
they bear a carcinogenic risk?. Annals of Oncology.,
2004, 15 (10): 1460-1465
enkel, J.
Sugar Substitutes: Americans
FDA Consumer
, Revised,
2006, 6:3
19. Misner S, Curtis C and Whitmer E. Sugar substitute-Are
they safe? Arizona Cooperative Extension, 2008,
20. ISA, International Sweeteners Association ISA. Fact
sheet on low calorie sweeteners. 2008, Retrieved from
21. CCC. Calorie Control Council. Low calorie sweeteners.
Saccharin, 2007. Retrieved from http://
22. Health Canada, HC. Information Document on the
Proposal to Reinstate Saccharin for Use as a Sweetener
in Foods in Canada, 2007
23. Kumar A, Weatherly, MR and Beaman DC. Sweeteners,
flavouring and dyes in antibiotics preparations.
Paediatrics., 1992, 87: 352-360
24. Francesco N, Alessandra M and Franco P.
Hepatotoxicity of saccharin. New England Journal of
Medicine., 1994, 2: (331) 134-135.
25. Lederer J and pottier-Arnould AM. Influence of
saccharin on embryonal development in the pregnant
rat., le Diabete., 1973, 21:1329
26. Kramers PGN. The mutagenicity of saccharin. Mutation
Research. 1975, 32: 81-92
27. Kristofferson F. The effects of cyclamate and saccharin
on the chromosome of a Chinese hamster cell line.
Hereditas., 1977, 70: 271-282.
28. Ashby J and Ishidate M Jr. Clastogenicity in vitro of the
NA, K, CA and Mg salts of saccahin; and of magnesium
chloride; consideration of significance. Mutation
Research, 1986, 163: 63-73
29. Leonard A and Leonard ED. Mutagenicity test with
saccharin in the male mouse. Journal of Environmental
Pathology and Toxicology., 1979, 2: 1047-1053
30. Chapel CL. A review and biological risk assessment of
sodium saccharin. Regulatory Toxicology and
Pharmacology., 1992, 15: 253-270
31. Elcock M and Morgan RW. Update on artificial
sweeteners and bladder cancer. Regulatory Toxicology
and Pharmacology., 1993, 17: 35-43
32. Commission of the European Communities (CEC).
Report of the Scientific communities for food on
saccharin. Reports of the scientific committee for food,
Luxembourg, 4th series. 1977, Pp 7-23
Noah L
and Merrill RA.
From Scratch?:
Reinventing the Food
78 B.U.
34. International Food Information Council Foundation,
IFICF. Facts about low-calorie sweeteners. Food
Ingredients. online:, 2009.
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.
... White crystalline powders Saccharin can be synthesized through an initial reaction between toluene and chlorosulfonic acid. It is converted to a sulphonamide with ammonia, and oxidized to a benzoic acid then heated to form the cyclic imide (Okoduwa et al., 2013). However, this process is very inefficient resulting in low yields of saccharin and an improved method now tends to be used on an industrial scale. ...
... According to Scheurer et al. (2014) there is common consensus that saccharin does not metabolise in mammals. Most of the saccharin that a person ingests is absorbed from the digestive tract and excreted in the urine and so will make its way to a waste water treatment plant Okoduwa et al., 2013;. Similarly that lost from the use of personal hygiene products, such as toothpaste and mouthwashes, will also find its way to a waste water treatment plant. ...
Full-text available
EFSA is implementing evidence‐based risk assessments for the re‐evaluation of certain sweeteners. The aim of this work was to ensure that, as part of the preparatory work done by EFSA to support its Panel on Food Additives and Flavourings (FAF) in reaching conclusions on the safety of permitted food additives, relevant information on the environmental risks associated with the use of the artificial sweeteners are identified. In the context of this re‐evaluation process the following substances used as sweeteners were considered: acesulfame‐K (E 950), salt of aspartame‐acesulfame (E 962), sucralose (E 955), saccharins (E 954), thaumatin (E 957), neohesperidine DC (E 959), neotame (E 961), cyclamates (E 952) and the polyol sweeteners (sorbitols (E 420); mannitol (E 421); isomalt (E 953); maltitols (E 965); lactitol (E 966); xylitol (E 967) and erythritol (E 968)). Data was collated using a systematic review approach. Generally, the data identified was extremely limited particularly with respect to neohesperidine DC, neotame, thaumatin and the polyol sweeteners. However, there was also limited evidence to suggest their widespread occurrence in the environment. With respect to acesulfame‐K, sucralose, cyclamates and saccharin multiple studies were identified that demonstrate the widespread distribution of these sweeteners in surface waters, groundwaters, coastal and marine waters. There are also studies showing their presence in drinking (tap) water supplies, rainwater and in atmospheric samples. However, these sweeteners do not appear to be highly toxic to aquatic species, at least not at environmental concentrations currently seen. The salt of aspartame‐acesulfame easily dissociates into its two component sweeteners in the human body and the environment and so the review process also considered aspartame despite it not being a specific focus of the regulatory review process. Whilst there is some evidence to suggest aspartame is toxic to aquatic species it is not detected at levels of concern in the environment.
... 2-(Pyridine-4-yldiazonium) isoindoline-1-one-3-sulphoxide (22) resulted from the coupling reaction of 4-(chloridediazeayl) pyridine (21) with sodium saccharin(6a) in DMF, Scheme 5. [57]. Sulfonphthalein can be synthesized in a single pot by treatment of saccharin and phenol through the in-situ preparation of 2-sulfobenzoic anhydride, subsequently its reaction with phenol by using H2SO4 as the condensing agent, in the absence of any solvent, Scheme 6. [58]. Schiff bases (30, 31 and33) can be synthesized by reaction of a compound (29) with NH2NH2.H2O, and glacial acetic acid. ...
Full-text available
Saccharin is firstly synthesized in 1879. It is a very well-known as an inexpensive substitute for sugar as it is a non-caloric sweetener. The article shows the properties, use, metabolism and various synthesis and reactions of saccharine. Moreover, the toxicological reports explain that saccharin is mostly responsible for the bladder tumors observed in the male rats, the relationship between the consumption of saccharin and bladder cancer is afforded by epidemiological studies. The benefit-risk evaluation for saccharin is hardly to indicate. Saccharin is a sugar substitute, frequently used either in food industry, or in pharmaceutical formulations and even in tobacco products. The chemistry of saccharin is interesting because of it suspected carcinogenous character and the possible use as an antidote for metal poisoning. It appears prudent to evaluate their main properties and applications further.
... Saccharin (1,2-benzisothiazol-3(2H)-one-1,1-dioxide) (see Figure 1) is the oldest artificial sweetener, and was discovered in 1879 [3]. The compound is prepared through reacting methyl anthranilate with nitrous acid sulfur dioxide, chlorine, and ammonia [4]. ...
Full-text available
Background and objectives: This study evaluated the effect of chronic consumption of saccharin on important physiological and biochemical parameters in rats. Materials and Methods: Male Wistar rats were used in this study and were divided into four groups: A control group and three experimental groups (groups 1, 2, and 3) were treated with different doses of saccharin at 2.5, 5, and 10 mg/kg, respectively. Each experimental group received sodium saccharin once per day for 120 days while the control group was treated with distilled water only. In addition to the evaluation of body weight, blood samples [total protein, albumin, glucose, lipid profile, alanine transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), creatinine, and uric acid] and urine (isoprostane) were collected in zero time, and after 60 and 120 days for biochemical evaluation. Liver (catalase activity) and brain (8-hydroxy-2’-deoxyguanosine, 8-OHdG) tissues were collected at time zero and after 120 days. Results: The data showed that saccharin at 5 mg/kg increased body weight of treated rats after 60 (59%) and 120 (67%) days of treatment. Increased concentration of serum glucose was observed after treatment with saccharin at 5 (75% and 62%) and 10 mg/kg (43% and 40%) following 60 and 120 days, respectively. The concentration of albumin decreased after treatment with saccharin at 2.5 (34% and 36%), 5 (39% and 34%), and 10 mg/kg (15% and 21%) after 60 and 120 days of treatment, respectively. The activity of LDH and uric acid increased proportionally with dosage levels and consumption period. There was an increased concentration of creatinine after treatment with saccharin at 2.5 (125% and 68%), 5 (114% and 45%), and 10 mg/kg (26% and 31%) following 60 and 120 days, respectively. Catalase activity and 8-OHdG increased by 51% and 49%, respectively, following 120 days of treatment with saccharin at 2.5 mg/kg. Elevation in the concentration of isoprostane was observed after treatment with saccharin at all doses. Conclusions: The administration of saccharin throughout the treatment period was correlated with impaired kidney and liver function. Both hyperglycemic and obesity-inducing side effects were observed. There was an increased oxidative status of the liver, as well as exposure to increased oxidative stress demonstrated through the increased levels of isoprostane, uric acid, 8-OHdG, and activity of catalase. Therefore, it is suggested that saccharin is unsafe to be included in the diet.
... It is excreted via kidneys. 3 Aspartame is a low-calorie sweetener and is 200 times sweeter than sucrose. 4 It is aspartyl-phenylalanine-1-methyl ester (methyl ester of the dipeptide of the amino acids aspartic acid and phenylalanine). ...
Full-text available
The purpose of this study was to develop a new control method for Drosophila using saccharin sodium dihydrate (saccharin), an artificial sweetener that is safe for humans and the environment, and to elucidate its mode of action. In this study, we confirmed that saccharin can dose-dependently inhibit the development of or kill vinegar flies (VFs) and spotted wing Drosophila (SWDs). In addition, we found that low concentrations of saccharin induced a similar effect as starvation in Drosophila, whereas high concentrations of saccharin induced changes in the unfolded protein response (UPR) and autophagy signaling that were unlike starvation and inhibited development or killed the VF and the SWD by performing real-time quantitative polymerase chain reaction analyses. Spinosad is a widely used plant protection agent for SWD control. When saccharin was cotreated with 0.25–1.0 ppm spinosad, an additive insecticidal activity was observed only at high concentrations of saccharin. However, when saccharin was cotreated with 2.0 ppm spinosad, an additive insecticidal activity was observed at low concentrations of saccharin. Taken together, alteration of UPR and autophagy signaling represented the molecular basis underlying saccharin toxicity to Drosophila and concurrent spraying of an insecticide with saccharin could enhance the insecticidal activities. Research Highlights • Saccharin inhibits the development of vinegar fly (VF) and spotted wing Drosophila (SWD) larvae and is toxic to adult Drosophila. • Saccharin induces abnormalities in the autophagy and the unfolded protein response (UPR) signaling of the Drosophila fat body. • The toxicity of saccharin to Drosophila was increased by simultaneous treatment with spinosad.
Brown trout, Salmo trutta, were exposed to water containing 0.1 or 10 μgl−1 of 63Ni2+ for 1 or 3 weeks. Additional trout were exposed to 0.1 or 10 μgl−1 of 63Ni2+ during 3 weeks followed by a 1- or 3-week period without exposure to the metal. At termination of the experimental periods the uptake and distribution of the 63Ni2+ in the fishes were determined by whole-body autoradiography and liquid scintillation spectrometry. The average whole-fish concentration of 63Ni2+ in the fishes was about 3 times higher than the concentration of 63Ni2+ in the water after 1 week's exposure and about 7–8 times higher than in the water after three weeks' exposure. There was no evidence of saturation of the uptake of the 63Ni2+ at 10 μgl−1 as compared to 0.1 μgl−1. The distribution pattern of the 63Ni2+ within the fishes included an accumulation in the blood, the head and trunk kidney, the gills, the connective tissues, the cerebrospinal fluid and the contents of the stomach and the intestines. After 3 weeks without 63Ni2+-exposure the average whole-fish concentrations decreased to about 40% of the levels observed immediately after the 3 week exposure. The amounts of 63Ni2+ in the kidneys in relation to other tissues were higher in the groups of fishes exposed to the 63Ni2+ for 3 weeks followed by the 1- or the 3-week period without 63Ni2+ as compared to the fishes killed immediately after the 3-week 63Ni2+-exposure. The same observation was made for the nervous tissues of the brain and spinal cord, although this uptake in all groups of fishes was rather low. In the gills there was a more rapid decrease in the concentration of 63Ni2+ than the average whole-fish-decrease. Our results show that there is a moderate bioaccumulation of nickel by fishes from the water.
Embryotoxicity and fetal toxicity of nickel chloride (NiCl2) and nickel subsulfide (Ni3S2) were studied in Fischer rats. Injection of NiCl2 (16 mg of Ni/kg, im) on Day 8 of gestation reduced the mean number of liver pups per dam and resulted in diminished body weights of fetuses on Day 20 of gestation and of weanlings at 4 to 8 weeks after birth. Injection of Ni3S2 (80 mg of Ni/kg, im) on Day 6 of gestation reduced the mean number of live pups per dam. No congenital anomalies were found in fetuses from any Ni-treated dams, including dams that received 10 im injections of NiCl2 (2 mg of Ni/kg, twice daily, on Days 6–10 of gestation). 63NiCl2 (12 mg of Ni/kg, im) was administered to a group of nonpregnant female rats and to groups of pregnant rats on Day 8 or 18 of gestation. After 24 hr, the relative concentrations of 63Ni in tissues were: kidney > serum > adrenal ⋍ lung ⋍ ovary > spleen ⋍ heart ⋍ liver > skeletal muscle. Pituitary 63Ni concentrations were much higher in pregnant rats than in nonpregnant females. 63Ni concentrations in products of conception (embryos and embryonic membranes) on Day 9 and in placentas on Day 19 were equivalent to 63Ni concentrations in adrenal, lung, and ovary tissues of the dams. Autoradiography of fetuses and placentas on Day 19 of gestation showed 63Ni localization in fetal urinary bladders and in the basal laminae and yolk sacs of the placentas. These studies show (a) that im injection of NiCl2 and Ni3S2 during early gestation causes embryonic mortality at dosages that do not cause maternal mortality, and (b) that 63Ni(II) can cross the feto-maternal barriers and enter the fetuses during late gestation.
Effects of welding fumes in an established human cell line NHIK 3025 have been studied. The welding fume material was collected by air filtration from the welding of stainless steel with a stainless-steel electrode. Addition of the fume particles suspended in 0.9% NaCl to the culture medium reduced cell proliferation and substantially increased the fraction of abnormally large cells. A filtrate of this suspension produced similar effects. Analysis showed that hexavalent chromium constituted 3.5% of the total welding fume material collected. Other metals such as nickel, iron, and manganese were tested at their concentrations in the welding fume particles but displayed only slight toxicity. However, corresponding concentrations of hexavalent chromium alone produced very similar effects of those of the welding fume suspension and filtrate. It is concluded that the toxic effect of the welding fume sample on the bioassay system employed is almost entirely due to hexavalent chromium.
Nickel sulphate was injected into Drosophila melanogaster males at different concentrations in order to test the chemical for the induction of SLRL and SCL in germ cells. Nickel sulphate induced SLRL at concentrations tested, with the peak of activity at premeiotic and postmeiotic stages. It failed to produce SCL except at the highest concentration tested, where induction of XO males was significant for the pooled data.
Nickel is widely used in the metallurgical industry, and although not released extensively into the environment, may represent a hazard to human health. Owing to their low absorption from the gastrointestinal tract, nickel compounds, except nickel carbonyl, are essentially non-toxic after ingestion. Epidemiological investigations and experimental studies have demonstrated that certain nickel compounds are extremely potent carcinogens after inhalation, but also that the carcinogenic risk is limited to conditions of occupational exposure. The relatively small number of mutagenicity studies performed up to now do not yet allow definite conclusions as to whether nickel is mutagenic. Nickel can cross the placenta and has embryotoxic and teratogenic properties. The principal hazard of nickel to man, beside its carcinogenicity, however, is its ability to provoke reactions of sensitization.
Two artificial sweeteners, cyclamate and saccharin, were studied as to their effect on the chromosomes of Chinese hamster cells in vitro. An incidence of chromosome breaks and gaps, significantly increased over the control level, was found in the treated experimental groups. A certain dose relationship of the disturbances induced was indicated. The distribution over the karyotype of the aberrations was nonrandom and the pattern of breaks and gaps in the treated groups coincided largely with that in the controls.
Sugars have a long history of safe use in foods. They are common food ingredients that add taste appeal and perform important functions in foods. Besides its pleasant sweetness, sugar performs a host of less obvious and important functions in cooking, baking, candy making and the like. As carbohydrates, sugars are a contributor of calories for the body. The ability to produce solutions of varying degrees of sweetness is important in many food applications, particularly in beverages and confectionery. Low-calorie sweeteners add a taste that is similar to that of sucrose. Intense sweeteners are generally several times sweeter than sucrose. On the other hand, sugar replacers are the bulk and volume providing sweeteners usually less sweet than and different tasting from sugar, commonly used on a one-for-one replacement basis for sugar in recipes. Sugars have been studied extensively for their impact on a variety of issues.
The ability of saccharin to induce chromosome aberrations in mammals was tested in male mice injected i.p. with 1, 2, or 4 g saccharin per kg body weight or receiving during a 100 day period 20 g of saccharin per liter of drinking water. Two tests on somatic cells, induction of chromosomal aberrations in bone marrow cells and of micronuclei in polychromatic erythrocytes, and two tests on germ cells, the spermatocyte test on treated males and the dominant lethality test, yielded all negative results. It is concluded that the positive findings reported in the literature were probably due to the mutagenic activity of saccharin impurities.
Rats given oral doses of [3-14C] saccharin excreted 56-87% of the labeled dose in the urine and 10-40% in the feces during 7 days. Distribution studies showed that the highest levels of 14C were in the kidneys and bladders. The bile was not a significant route of excretion. The presence of labeled CO2 in expired air indicated that saccharin was decarbosylated to a slight degree. DEAE chromatographic separation and isolation of labeled compounds from urine samples showed that more than 99% of the urinary 14C was unchanged saccharin. Up to 1.0% of the 14C was a metabolite identified as 0-sulfamoylbenzoic acid. Comparative metabolic profiles of a dog, rabbit, guinea pig and hamster indicated that there was little difference in the pattern due to animal species or dose level.
Dietary sodium saccharin is associated with bladder tumors when fed at high levels to the male rat. Under these conditions urinary pH, sodium concentration, and volume are elevated and proliferative changes are present in the urothelium. Extensive epidemiological studies have shown that saccharin does not increase the risk of bladder cancer in humans and laboratory investigations have shown that sodium saccharin is not mutagenic and does not bind to DNA. Recent research indicates that the urothelium in male rats is damaged under conditions of high urinary pH and sodium levels by a mechanism that involves alpha 2u-globulin and possibly silicate crystalluria. These studies and their implications for human health risk are reviewed.
Even though a variety of adverse effects caused by sweeteners, flavorings, and dyes in susceptible individuals have been reported, there is no good single reference with information about these substances in pediatric antimicrobials. Data on sweeteners, flavorings, and dyes in 91 antimicrobial preparations were collected. Sucrose was present in 74 (85%) of 87 preparations, followed by saccharin in 30 (34%) preparations. Mannitol, lactose, and sorbitol were each present in 7 preparations. None of the preparations were free of sweeteners. Thirty-four (37%) of 91 preparations did not specify the flavoring content. While cherry was the most common flavoring used, there were 25 other flavorings. Thirteen different dyes and coloring agents were used in these antimicrobials. Red dye no. 40 was present in 45% of preparations. Tables detailing sweeteners, flavorings, and dyes in different groups of antimicrobials (amoxicillin, ampicillin, cephalosporins, erythromycin, penicillins, sulfonamides, and others) and adverse effects reported with these inert ingredients are presented. These tables should be helpful to physicians in selecting an antimicrobial containing a different sweetener and/or dye when an adverse reaction occurs.
Cephalic-phase insulin release (CPIR) and the changes in glucose turnover induced by saccharin ingestion were studied in freely moving lean and genetically obese fa/fa rats equipped with chronic catheters for blood sampling. Six-hour-fasted lean and obese rats were trained to drink 1 ml sodium saccharin (0.15%) or 1 ml glucose (70%), and blood samples were taken before and after the stimuli. As early as 1-1.5 min poststimulus, there was a significant increase in CPIR in lean and obese rats. The amplitude of the CPIR induced either by saccharin or by glucose in the obese rats was significantly higher than it was in the lean rats. The effect of saccharin ingestion on the hepatic glucose production (HGP) and the rate of glucose disappearance (Rd) was studied in 6-h-fasted lean and obese rats, under non-steady-state conditions, according to a method previously validated. Saccharin ingestion produced a significant increase in HGP and Rd in lean and obese rats compared with basal values. The saccharin-induced increments in HGP and Rd were higher in the obese than in the lean animals. We conclude that saccharin (through taste) appears to elicit parasympathetic (insulin release) and sympathetic (HGP increase) reflexes in lean and obese rats. These taste-induced changes in plasma insulin and glucose turnover are exaggerated in the obese rats and may participate in obesity and in insulin resistance of the overall syndrome.
The sodium, potassium, calcium and magnesium salts of saccharin, and magnesium chloride, have been shown to be clastogenic to Chinese hamster lung (CHL) fibroblasts in vitro, but only at elevated dose levels (8-16 mg/ml). Saccharin acid was inactive to the limits of its solubility (4 mg/ml). When the data are expressed in terms of ionic concentration, each salt showed a similar clastogenic potency. This suggests that ionic effects induced by these salts in the assay medium may be the critical determinant of the clastogenic effects seen, rather than that the saccharin moiety presents a genotoxic insult to the chromosomes of the cells. The metal-chelating agents EDTA and EGTA were non-clastogenic, but the disodium salt of EDTA showed weak activity prior to toxicity at 0.5 mg/ml. The absence of a clastogenic response for the salts of saccharin at dose levels lower than 4 mg/ml is discussed within the context of the threshold-dependent tumour-promoting activity of high dose levels of sodium saccharin to the bladder of male rats. The doubtful value of conducting in vitro clastogenicity studies at dose levels greater than 10(-2) M is discussed.