Toxicity of Sucralose in Humans: A Review

Abstract

Sucralose is a non-nutritive artificial sweetener, 600 times sweeter than sucrose, and is very stable at high temperatures, among other characteristics. It was approved by the FDA, in 1999, to be utilized in foods, beverages, pharmaceutical products, diets and vitamin supplements. Studies suggest a diffusion, through the placental barrier, of small doses of sucralose and its metabolites. Its hydrolysis products (4-CG e 1,6-DCF) are more rapidly absorbed than sucralose: 4-CG is excreted intact in the urine, and 1,6-DCF undergoes reduction with elimination by the urine or rapid conjugation with glutathione. Various organs can be affected by ingestion of high doses of sucralose. As a result of the rise in global consumption of sweeteners and light- or diet-type products, studies are necessary to evaluate the action of this substance in the human species. The present study aims to accomplish a review of the literature that involves its indications of use, pharmacodynamics as well as the carcinogenic, teratogenic, neurotoxic, and nephrotoxic potentials of sucralose.

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239
Int. J. Morphol.,
27(1):239-244, 2009.
Toxicity of Sucralose in Humans: A Review
Toxicidad de la Sucralosa en Humanos: Una Revisión
*
Ademir Barianni Rodero;
**
Lucas de Souza Rodero &
***
Reinaldo Azoubel
RODERO, A. B.; RODERO, L. S. & AZOUBEL, R. Toxicity of sucralose in humans: a review. Int. J. Morphol., 27(1):239-244, 2009.
SUMMARY: Sucralose is a non-nutritive artificial sweetener, 600 times sweeter than sucrose, and is very stable at high
temperatures, among other characteristics. It was approved by the FDA, in 1999, to be utilized in foods, beverages, pharmaceutical
products, diets and vitamin supplements. Studies suggest a diffusion, through the placental barrier, of small doses of sucralose and its
metabolites. Its hydrolysis products (4-CG e 1,6-DCF) are more rapidly absorbed than sucralose: 4-CG is excreted intact in the urine, and
1,6-DCF undergoes reduction with elimination by the urine or rapid conjugation with glutathione. Various organs can be affected by
ingestion of high doses of sucralose. As a result of the rise in global consumption of sweeteners and light- or diet-type products, studies
are necessary to evaluate the action of this substance in the human species. The present study aims to accomplish a review of the literature
that involves its indications of use, pharmacodynamics as well as the carcinogenic, teratogenic, neurotoxic, and nephrotoxic potentials of
sucralose.
KEY WORDS: Sucralose; Sweetener; Toxicology.
INTRODUCTION
Sucralose is an edulcorant obtained from
sucrose where three hydroxilic groups, from positions
4, 1 and 6 are replaced by 3 chlorine atoms to form
the compound 4,1’,6’ trichlorogalactosacarose, also
known as 1, 6 -dichloro-1, 6 –dideoxy - b–D-
fructofuranosyl-4 - chloro – 4 – deoxy – a – D –
galactopyranoside, often abbreviated in chemical
nomenclature as 4,1’, 6’-triclorogalactosacarose or
4,1’, 6’ – trichloro - 4,1’, 6’-trideoxi-galacto-sucrose
(Knight, 1994).
Sucralose was discovered accidentally in 1976
by Shashikant Phadnis, a student who had graduated
from King’s College in the UK. Phadnis took part in a
team with researchers from Queen Elizabeth College,
at the University of London, who were seeking to
synthesize halogenated sugars. During one part of the
experiment, due to difficulty in interpreting English,
he erroneously executed a task, chlorinating the sugar,
he tasted it instead (Ophardt, 2003) (Fig. 1).
In 1989, the scientists Leslie Hough and Khan,
*
Unicastelo-Universidade Camilo Castelo Branco, University, School of Health Sciences - Fernandópolis, SP, Brazil.
**
Unifoa - Centro Universitário Volta Redonda. School of Health Sciences - Volta Redonda – RJ. Fernandópolis - SP, Brazil.
***
Post-Graduate Program in Health Sciences-School of Medicine at São José do Rio Preto - SP. São José do Rio Preto - SP, Brazil.
in turn, evaluated the different effects of sweeteners derived from
sucrose, when it was found to be linked with determinate halogens
(Frank, 2002).
Studies indicate the existence of 2 hydrolysis products of
sucralose, 4 –CG and 1,6 – DCF, and that these products are more
rapidly absorbed after oral administration than the original sucralose
compound. The hydrolysis product 4 -CG is excreted, essentially
in intact form, in the urine, while 1,6-DCF follows one of two prin-
cipal metabolic pathways: reduction to 1,6 dichloroaminnitol,
rapidly excreted in unaltered form in the urine, or conjugated with
glutathione (Grice & Goldsmith, 2000) (Fig.
2).
Fig. 1. Sucrose and sucralose structures.

240
Indications of use. Sucralose consumption has increased
by possessing the following sweetener characteristics: non-
caloric, insipid, stable at high temperatures and in acidic
medium, and not being hydrolyzed even during digestion
or metabolism by virtue of the extreme stability of its
carbon-chlorine bonds (Binns, 2003; Barndt & Jackson,
1990), and being hydrophilic, with 25% solubility (Grice
& Goldsmith). According to Binns, it presents the important
characteristic of not interacting chemically with other foods,
being stable in the presence of ethanol and able to be stored
for more than one year while maintaining 99% of its origi-
nal flavor. Its characteristics are preserved, even during
pasteurization,
sterilization and cooking at high temperatures
(Knight).
Another characteristic of sucralose is non-interference
in the utilization and absorption of glucose, metabolism of
carbohydrates and secretion of insulin. Therefore, it is a safe
substance able to be ingested by diabetes patients (Campos,
2000), and neither stimulates insulin secretion nor reduces
plasma glucose concentration (Candido & Campos, 1995).
Furthermore, clinical studies concluded that sucralose is
neither acidogenic nor cariogenic (Mandel & Grotz, 2002).
At the beginning of 1998, the Food and Drug
Administration (FDA), after evaluating 110 studies in
animals and humans, approved sucralose as a food additive
in 15 varieties of foods and beverages (Whitmore, 1998). In
1999, this approval was extended to its utilization as a
sweetener for general use in all foods, conventional
beverages, dietetic vitamin supplements, medical diets, such
as cooked and baked foods (Department of Health and
Human Services, 1999; McNeil Nutritionals, 2006).
Based on its thermic properties, stability over wide
pH variations, lack of chemical interaction with ingredients
and its solubility – sucralose can be used as a table sweetener
in dry formulations (such as, powdered drinks and instant
desserts), in flavorings, preservatives, seasonings, ready sau-
ces, jams, syrups, breads, dairy desserts, canned vegetables,
pasteurized products and other foods (Campos, 2000, 2002).
Currently, according to MacNeil, its use is permitted in more
than 80 countries and it is present in over three thousand
products (McNeil Nutritionals). In Brazil it is found in the
formulation of more than 500 products and, globally,
consumed by thousands of persons (Pachione, 2003).
Pharmacodynamics. In humans the oral administration of
sucralose, at the dose of 1mg/kg body weight per day, shows
that the digestive tube is the major route of elimination, with
an average of 78.3% (69.4 to 89.6%), while urine eliminates
a mean of 14.5% (8.9 to 21.8%) of this dose. Variations
depend on individual differences in absorption and excretion.
Even with administration of high doses, there was no
corresponding increase in the average urinary elimination,
suggesting the possibility of reduction in sucralose absorption
(Roberts et al., 2000).
When sucralose is administered venously to rats at a
dose of 2 to 20 mg/kg body weight, it is excreted at the
proportion of approximately 80% by the urine and 9% to
16% through the feces; however, when administered orally
at doses from 10 to 1000 mg/kg, urinary excretion is below
5%, showing that sucralose is poorly absorbed in the intesti-
nal tract, and is almost entirely excreted in unaltered form
through the feces, rapidly in the first 24 hours, independent
of dose and the sex of the animals (Sims et al., 2000).
John et al. (2000), employing oral administration,
detected in non-pregnant rabbits, sucralose excretion of 22%
by urine and 55% via feces. In pregnant rabbits excretion
was 22% urinary and 65% through the gastrointestinal tract.
The same authors, investigating the excretion and metabolism
of sucralose in mice through both oral and intravenous
administration, found that when receiving 20 mg/kg body
weight/day intravenously, the preferential excretion route was
urinary, being almost 80% in 5 days, while fecal elimination
was 22% of the dose. With oral administration at doses of
1000, 1500 and 3000 mg/kg body weight/day, urinary
elimination averaged, respectively 23%, 15% and 16%,
indicating that 20 to 30% of this oral dose is absorbed. This
study shows that, even with augmented administration of
sucralose, there is no corresponding rise in absorption or
consequent renal elimination. Sucralose was excreted in
unaltered form, and represented more than 80% to 90% in
the urine and feces.
When administered orally to dogs, sucralose is rapidly
absorbed, with urinary excretion in inactive form, with
conjugated glucuronic acid being present with the sucralose,
Fig. 2. Hydrolysis products of sucralose: 4-chloro-4-deoxy-D-
galactose (4-CG) and 1,6-dichloro-1-6-dideoxy-D-fructose (1,6-
DCG).
RODERO, A. B.; RODERO, L. S. & AZOUBEL, R. Toxicity of sucralose in humans: a review. Int. J. Morphol., 27(1):239-244, 2009.

241
at small doses, in proportions of 2% to 8% of the dose
administered. In intravenous administration, unaltered
urinary excretion of sucralose predominates, with glucuronic
acid detected, conjugated with sucralose, in 15% to 20% of
the dose administered (Wood et al., 2000).
According to some studies, the elimination profile in
humans is similar to the profiles found in rats, dogs and mice,
although urinary excretion in rats is half that observed in
humans, while elimination by the feces is higher in those
animals (Roberts et al.; Sham, 2005). Pharmacokinetic
studies concluded that 85% of sucralose is not absorbed, and
is excreted intact in the feces, with absorption limits of
approximately 15% of the dose consumed by passive
diffusion.
DISCUSSION
The ADI (Acceptable Daily Ingestion) of sucralose
in humans is 15 mg/kg body weight/day (Goldsmith &
Meckel, 2001). Based on the studies of MacNeil (McNeil
Specialty Products, 1987) reporting the diffusion of sucralose
or of its metabolites through the placental barrier,
investigations were accomplished to evaluate its possible
teratogenic effects at diverse doses and by different routes
of administration.
Teratological studies of rodent organogenesis (in
pregnant rats), from the 6
th
to 15
th
day of gestation, at doses
of 500, 1000 and 2000 mg/kg body weight/day, and in non-
rodents (pregnant rabbits), from days 6 to 19 of gestation, at
doses of 175, 350 and 700 mg/kg body weight/day), did not
detect alterations in fetal development, confirmed after
necropsy. There was only a slight increase in water
consumption and intestinal disturbances in female rabbits
(Kille et al., 2000).
According to a review by Grice & Godsmith, animals
were treated with an equimolar mixture of hydrolyzed
products of sucralose, demonstrating that, although a focal
increase occurs in the incidence of clear cells in the liver,
there is no significant evidence of progression of this lesion
to neoplasia, when compared to the non-treated group.
Studies on sucralose and its hydrolysis products, did not
reveal significant hematological alterations: the number of
lymphocytes appeared to have diminished in treated dogs.
In rats, sucralose alterations of 2.5 and 5% do not constitute
toxicity and would be secondary to diminution of food
consumption, by decreasing palatability. Studies in rats
indicated an adverse effect of sucralose on the immune
system.
Two-year carcinogenesis studies of mice even
detected a rise in the incidence of chronic nephropathy,
compared to the control group, but showed statistical
significance only in female rats of the group treated with a
high dose of sucralose. However, no increase was observed
in other renal pathologies in rats, dogs or primates that had
been fed the same diet. Works on oncogenesis showed higher
incidence of pelvic mineralization, accompanied by epithelial
hyperplasia of the renal pelvis, in female rats submitted to
treatment with doses containing 1 to 3% sucralose (Lord &
Newberne, 1990). In relation to reproduction, studies in
female rabbits and rats with sucralose and female rats with
sucralose hydrolysis products yielded no evidence of a
teratogenic effect nor alteration of reproductive capacity. In
studies of female rats using sucralose hydrolysis products at
high doses (250 mg/kg body weight) there are multiple pieces
of evidence of maternal toxicity. Progeny showed little
change in development, but this dose is 40,000 times the
maximum value permitted in the USA (6.6 µ g/kg body
weight/day). However, general toxological studies,
conducted with sucralose and its hydrolysis products, did
not display adverse effects sufficient to compromise human
health
Finn & Lord (2000) addressed the possible
neurotoxicity induced by the utilization of sucralose, its
hydrolysis products and 6-chloro 6-deoxiglucose (6-CG).
Given that these three products possess similarities in their
structures, it is appropriate to verify the neurotoxicity in
species susceptible to 6-CG – proven to be neurotoxic.
Sucralose and its hydrolysis products were administered to
rats and monkeys at the dose of 1000 mg/kg body weight/
day, for 21 and 28 days, for subsequent analysis by electron
or light microscope of histopathological structure and
possible effects in the CNS ultrastructure of male rats, female
rats and male monkeys. This study did not evidence
alterations in the central nervous system induced by sucralose
and its hydrolysis product, 4-CG. Given the impossibility of
sucralose being metabolized to 6-CG, a neurotoxicity simi-
lar to 6-CG should not be expected.
In the same study, as positive control, 6-chloro 6-
deoxiglucose was administered by gavage at the dose of 500
mg/kg body weight/day, predicting that neurotoxic alterations
induced (as symmetric lesions in nuclei deep in the
cerebellum cerebrum and spinal medulla, and profound
neurological lesions including the CNS) would be found.
The potential of formation of 6-chloro-6-deoxifrutose
(6CF) starting from metabolite of sucralose hydrolysis 1-6
DCF exists theoretically. However, if it is produced, its
quantity would be small and negligible. The major metabolite
of 1,6 DCF does not involve the formation of 6-CF or any
RODERO, A. B.; RODERO, L. S. & AZOUBEL, R. Toxicity of sucralose in humans: a review. Int. J. Morphol., 27(1):239-244, 2009.

242
other known neurotoxic component: it consists of the
formation of glutathione conjugated to 1,6 DCF, forming
conjugated glutathione, with no 6-CF being produced
(Houghes et al., 1989).
Goldsmith & Meckel evaluating acute toxicity,
utilized female and male mice (16 g/kg/day) and male rats
(10 g/kg/day), administered for 4-8 weeks, at concentrations
of 1, 2 and 5%. No significant teratological effects were
observed at doses of 1 or 2%. But at 5%, there was diminished
food consumption, weight gain, deficient food conversion
and alterations in absolute and relative weights of various
organs, including the spleen and thymus, as well as
histopathological alterations of the cecum. Furthermore, a
diet containing 5% for 4 weeks produced diminution in the
number of lymphocytes and increase in the excretion of
calcium and magnesium, although these alterations were
without statistical significance. However, the 5% dose
produced a significant drop in the urinary volume at both 4
and 8 weeks. It is believed that many of the effects were
probably secondary to the diminished food consumption or
to large-scale consumption of a non-nutritive diet, of low
absorption and with osmotically active substance.
In the same study, evaluating subchronic toxicity,
doses of 0, 750, 1500 and 3000 mg/Kg body weight/day,
were administered by gavage to male and female rats for 26
weeks, investigating the diets and their respective toxicities.
The diet of 3000 mg/Kg body weight/day for 26 weeks
presented increase in the relative weight of the kidney, as
well as in enlargement and weight of the cecum. In this study,
toxicity was not evidenced, and there was only reduced of
palatability and digestibility in diets containing high
concentrations of sucralose, as the cause for the decreased
food consumption. Under acute administration, for 4 to 8
weeks, at concentrations of 1, 2.5 and 5%, no significant
toxological effects occurred at 1 and 2.5%. However, the
5% concentration produced reduction of food consumption,
body weight gain and weights of some organs (spleen), and
histopathological alterations changes of the thymus in rats
for 4 or 8 weeks.
A similar study was accomplished by Mann et al.
(2000) to evaluate chronic toxicity and carcinogenic potential
in Sprague Dawley rats, who were administered sucralose
at doses of 0.3, 1 and 3%, during pregnancy and in the
subsequent 104 weeks. To assess chronic toxicity, rats were
sacrificed at 52 weeks and 78 weeks, and to evaluate
carcinogenesis, at 104 weeks. Among the effects found, at
doses of 1% and 3%, there occurred body weight loss from
lesser food consumption due to reduction in palatability in
the diet and a physiological response provoked by high
sucralose concentration, not digested in the diet. In relation
to non-neoplastic findings, epithelial hyperplasia of the re-
nal pelvis was observed in all females of the treated group,
mineralization of the renal pelvis in females treated with
intermediate and high doses of sucralose (1% and 3%) and
hemorrhagic degeneration in the adrenal cortex, in males
and females treated with high doses of the sweetener.
According to Ono et al. (2005) and Lopes & Drager
(2006), the global population is presenting rises in
overweight, obesity, diabetes, hypertension, cardiovascular
diseases, hyperlipidemia and hypercholesterolemia, a
situation which has created concern about changes in lifestyle
and balanced diet. As a result, there is an acceleration in the
use of light or diet products, and in the consequent
consumption of sweeteners. Given that the use of sucralose,
one of the newest sweeteners of high sweetening power, has
been gradually increasing, new studies are necessary to attest
to its safe consumption. Recent studies have proven an
association between ingestion of sweeteners and
nephrotoxicity, hepatoxicity or retardation of placental and
fetal development (Arruda et al., 2003; Portela & Azoubel,
2004; Martins et al., 2005; De Matos et al., 2006; Portela et
al., 2007).
RODERO, A. B.; RODERO, L. S. & AZOUBEL, R. Toxicidad de la sucralosa en humanos: Una revisión. Int. J. Morphol., 27(1):239-
244, 2009.
RESUMEN: La sucralosa es un edulcorante artificial no nutritivo, 600 veces más dulce que la sacarosa, y es muy estable a altas
temperaturas, entre otras características. Fue aprobado por la FDA, en 1999, para ser utilizada en los alimentos, bebidas, productos
farmacéuticos, dietéticos y suplementos vitamínicos. Los estudios sugieren una difusión a través de la barrera placentaria, de pequeñas
dosis de la sucralosa y sus metabolitos. Sus productos de hidrólisis (4-CG e 1,6-DCF) se absorben más rápidamente que la sucralosa: 4-
CG se excreta intacta en la orina, y el 1,6-DCF sufre reducción con la eliminación por la orina o la rápida conjugación con glutatión.
Diversos órganos pueden verse afectados por la ingestión de altas dosis de sucralosa. Como resultado del aumento en el consumo
mundial de los edulcorantes y productos de tipo light o diet, son necesarias investigaciones para evaluar la acción de esta sustancia en la
especie humana. El presente estudio tiene como objetivo realizar una revisión de la literatura que trata de las indicaciones de uso, la
farmacodinamia, así como los potencialidades cancerígenas, teratogénicas, neurotóxicas y nefrotóxicas de la sucralosa.
PALABRAS CLAVE: Sucralosa; Edulcorante; Toxicología.
RODERO, A. B.; RODERO, L. S. & AZOUBEL, R. Toxicity of sucralose in humans: a review. Int. J. Morphol., 27(1):239-244, 2009.

243
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Correspondence to:
Ademir Barianni Rodero
Unicastelo – Universidade Camilo Castelo Branco
University, School of Health Sciences
Fernandópolis - SP
Av. Projetada, s/n
Zip Code – 15600-000
Fernandópolis – SP
BRAZIL
Email: coordgeralmedicina@unicastelo.br
Received: 01-07-2008
Accepted: 04-10-2008
RODERO, A. B.; RODERO, L. S. & AZOUBEL, R. Toxicity of sucralose in humans: a review. Int. J. Morphol., 27(1):239-244, 2009.