®

STEVIA SAFETY REVIEW

Foreword

The safety of any ingredient is paramount to the benefits it presents.

Stevia, a natural origin sweetener, offers the safety support of hundreds
of years of use plus the rigorous scientific research and evaluation necessary for
an ingredient to be approved for use in foods and beverages today. Stevia
is used across the globe for its no calorie, plant based sweetness in foods and
beverages. We’ve compiled a summary of the extensive database of science
supporting stevia as a safe, no calorie sweetening choice.

Bernadene Magnuson, PhD

Global Stevia Institute Advisory Board Member
Contributors

Bernadene Magnuson, PhD

Dr. Bernadene Magnuson is a scientific consultant specializing in food toxicology, ingredient safety and regulation.
One of her areas of expertise is the safety of low calorie sweeteners. In addition to consulting, Dr. Magnuson
is an Associate Professor in the Dept. of Nutritional Sciences in the Faculty of Medicine, University of Toronto. She
obtained her BSc. degree in food science, MSc degree in toxicology, and a PhD in Food and Nutritional Sciences
from universities in Canada. Dr. Magnuson has published over 50 peer-reviewed articles, book chapters, and
professional articles, and is a Fellow of the Academy of Toxicological Sciences.

Keith Ayoob, EdD, RD

Dr. Keith Ayoob is an internationally known nutritionist and an Associate Clinical Professor of Pediatrics at
the Albert Einstein College of Medicine in New York City, where he has maintained a clinical practice for more
than 20 years. Dr. Ayoob has worked extensively in the areas of obesity, heart health, child nutrition and family
dynamics and specializes in motivational counseling.

Margaret Ashwell, OBE, PhD

Dr. Margaret Ashwell OBE is Director/Owner of Ashwell Associates (Europe) Ltd., a company of independent
scientific consultants who focus on obesity, heart disease and health claims, among other areas of expertise.
She has held positions with the Medical Research Council, Good Housekeeping Institute, British Nutrition
Foundation and served on the UK Government’s Food Advisory Committee. Dr. Ashwell was made an Officer
of the British Empire (OBE) for services to Food.

Jean-Michel Cohen, MD, PhD

Dr. Jean-Michel Cohen is a nutrition specialist in France and an award-winning and best-selling author on the
subjects of nutrition and obesity. Dr. Cohen first introduced the use of triglyceride perfusion in France for intensive
care and created the first inter-departmental consultation center on obesity in France. Many of Dr. Cohen’s books
are considered food analysis references and he is an expert on food component regulation and food display.

Mauro Fisberg, MD, PhD

Dr. Mauro Fisberg is a fellow from Kellogg´s Foundation (Partners of the Americas Leadership program) and United
Nations University (World Hunger Program). Dr. Fisberg is a pediatrician and Associate Professor of Adolescent
Pediatrics at the Universidade Federal de São Paulo (Brazil). He is an expert on Adolescent Nutrition specializing in
childhood obesity, food intake and consumption, anemia and nutritional intervention.
 Contents

I. Introduction

II. Stevia and Purified Stevia Leaf Extract

III. Stevia—A Sweetener with Strong Safety Support

— Ingredient Safety Assessment

— SAFETY Research Summary

— Regulatory Status

IV. Stevia as A tool for calorie reduction

V. Role of Stevia in a Healthful Diet

VI. About the GLOBAL STEVIA INSTITUTE

VII. Appendix
I. Introduction
The management of a healthy weight is challenging for many individuals, as shown
by the increasing prevalence of overweight and obesity worldwide. A balanced diet
with controlled calorie intake and an active lifestyle are essential for successful weight
management.

Low calorie sweeteners can play an important role in calorie control by offering
consumers a choice to enjoy sweet foods or beverages, and reduce calorie intake as part
of a healthy diet approach. Stevia (purified stevia leaf extract) is a unique choice among
non-caloric sweeteners, because its sweetness is plant-based. The stevia plant, though
new to many, has been used for centuries for its natural sweetness. Today, the safety of
purified stevia is widely supported by rigorous scientific research.

The focus of this paper is to summarize the current scientific research supporting the
safety of purified stevia leaf extract for the general population and special subpopulations.

II. Stevia and Purified Stevia Leaf Extract

Stevia is produced from the stevia plant native to South America, where it was
traditionally used as a sweet herb in foods and beverages by indigenous peoples for
centuries. The stevia leaf contains natural, sweet compounds called steviol glycosides,
which are filtered and purified to produce stevia leaf extract that is typically 200 –300
times sweeter than sucrose.

Purified stevia leaf extract (also known as high purity stevia) generally describes stevia
that has 95% or greater steviol glycoside content. This purity specification was set as
part of a thorough safety review by the Joint FAO/WHO Expert Committee on Food
Additives (JECFA) in 2008, and is supported by several regulatory authorities including
the US Food and Drug Administration (FDA) and the European Commission. These
agencies have also established an Acceptable Daily Intake (ADI) for steviol glycosides.

There are crude stevia extracts often sold as dietary supplements in some countries, but it
is important to note that only purified stevia leaf extract has been evaluated and approved
for use as an ingredient in foods and beverages by the leading regulatory agencies.

Extraction and Purification

Extracting and purifying stevia’s steviol glycosides, the sweet compounds of the leaf,
allows stevia producers to reduce off-flavor notes from other naturally occurring
compounds in the plant for better tasting stevia ingredients. Steviol glycosides are
removed from the stevia leaf through water extraction. The water extract then
undergoes filtration to separate the steviol glycosides from plant biomass, and is further
purified with either water or food-grade alcohol, followed by drying. This extraction
and purification process gives purified stevia leaf extract a cleaner, more sugar-like taste
than crude stevia extracts. The extract can then be further purified to an extract that
contains one or more specific steviol glycosides. The steviol glycosides remain intact and
unchanged throughout the process.

GLOBAL STEVIA INSTITUTE |5

 There are many steviol glycosides naturally present in the stevia leaf, but there are
11 main steviol glycosides that are typically focused on due to their abundance. At a
molecular level, steviol glycosides share a common diterpene steviol backbone. The ar-
rangement and number of glucose units bonded to the steviol backbone give each steviol
glycoside a unique sweetness and taste profile. Rebaudioside A and stevioside are the
most abundant steviol glycosides in the leaves. Rebaudioside A is also one of the sweetest
glycosides, and is one of the first steviol glycosides to be purified and commercially
available on a mass scale for use as a sweetener.

Stevia Metabolism
Steviol glycosides pass through the body without any significant caloric impact or ac-
cumulation in the body. Steviol glycosides are not digested and pass through the upper
gastrointestinal tract fully intact. Gut bacteria in the colon hydrolyze steviol glycosides
into steviol by snipping off their glucose units. Steviol is then absorbed via the portal vein
and primarily metabolized by the liver forming steviol glucuronide, and then excreted in
the urine. (Gardana et al., 2003)

III. Stevia—A Sweetener with Strong Safety Support

The safety of purified steviol glycosides has been evaluated through rigorous scientific
research, which supports the safety of purified stevia leaf extracts for use as a sweetener.

The safety of purified stevia leaf extract is supported by:

• Stevia’s historical use dating back centuries in South American
countries and for over four decades in Japan;
• Years of rigorous scientific research on purified steviol glycosides, the sweet
components of the stevia leaf; and
• The positive scientific statements of several food safety and regulatory
authorities, including JECFA and the European Food Safety Authority
(EFSA) which support the safety of purified stevia leaf extract for use in foods
and beverages.

Ingredient Safety Assessment

The safety assessment for food ingredients by regulatory agencies is an extensively
detailed and lengthy process, designed to ensure that a new food ingredient, such as a
non-caloric sweetener, does not pose a risk for any consumers, including children and
pregnant women.

The protocols that must be used for safety studies have been established over many
years, by independent international experts, and are globally accepted. The results from
toxicology or safety studies are used to establish the Acceptable Daily Intake (ADI). The
ADI is defined as the amount of a food ingredient that people can consume on a daily
basis during their lifetime without any appreciable risk to health. The ADI is established
from long-term animal studies, in which animals are fed diets containing increasing
levels of the food ingredient for the majority of their lifetime, through stages of devel-
opment and growth. Detailed assessment of the animals’ health is completed, and the
highest dose that resulted in no adverse effects is called the no observable adverse effect
level (NOAEL). To adjust for any possible individual differences (intra-species) or
6 | STEVIA SAFETY REVIEW
differences between the test species and humans (inter-species), the NOAEL level is
divided by 100 (10X for intra-species and 10X for inter-species). This is called a safety
factor, and is designed to provide even more assurance that the ADI level will be safe
for all consumers.

Animal studies are critical to the safety assessment, as it is not ethical to test a new
ingredient in humans without determining the level that is safe. Animals can be given Research has
very high doses, which are used to increase the likelihood of detecting any adverse effect
the ingredient may cause, and to be able to determine how the body uses the ingredient. also shown that
Lower doses are used to determine the amounts that can be consumed every day with no purified stevia leaf
adverse effect. Once animal studies determine the amount that is safe, additional studies
are done in humans to confirm the validity of the animal studies. extract is safe
for consumption
The next step in the approval process is to estimate the likely consumption of the food
ingredient, by different segments of the population. This includes different age groups by special
and sexes. The consumption estimates are based on consumer surveys on consumption populations including
of the foods and beverages that will contain the ingredient. These data are used to set
limits on the levels of the ingredient allowed in each type of food and beverage, to ensure pregnant women,
that no consumer will be exposed to more than the Acceptable Daily Intake in their diet. lactating mothers,
The ADI is a conservative safe exposure level and does not represent a maximum and children.
allowable daily intake level and should not be regarded as a specific point at which safety
ends and possible health concerns begin. Because the ADI has a built-in safety margin
and is based on a chronic lifetime exposure, occasional consumption in amounts greater
than the ADI would not cause adverse effects or concern.

After approval, regulatory agencies continue to monitor scientific literature for new
studies or reports of adverse effects of ingredients, and will carefully review the results to
ensure on-going safety of the use of the new ingredient.

SAFETY Research Summary

There are over 200 research studies that support the safety of purified steviol glycosides.
These studies present biological, toxicological, and clinical data and have been assessed
by a number of reviewers (Carakostas et al., 2008; Geuns, 2003).

The body of scientific evidence supports that purified stevia leaf extract has no adverse
effects in humans and is safe for the general population at the levels used in foods and
beverages. Research has also shown that purified stevia leaf extract is safe for consump-
tion by special populations including pregnant women, lactating mothers, and children.
Furthermore, long-term carcinogenicity studies show that purified stevia leaf extract
consumption is not associated with increased cancer risk.

Specifically, based on the similar metabolism of glycosides in rats and humans, an

ADI level of 0 to 4 mg/kg body weight (bw), as steviol equivalents, was established by
JECFA, the Food Standards Australia New Zealand (FSANZ), and the European Food
Safety Authority (EFSA). The ADI for steviol glycosides was based on a thorough
review of toxicology and tolerance studies. The specific NOAEL was supported by a piv-
otal two-year study in rats (Toyoda et al., 1997) in which the NOAEL was 388 mg steviol
equivalents/kg bw/day (d). A safety factor of 100 was applied, to result in an ADI of
0 to 4 mg/kg bw as steviol equivalents. This ADI was established for steviol equivalents
GLOBAL STEVIA INSTITUTE |7
 as opposed to steviol glycosides for a consistent unit. It is important to remember that
the ADI is a reference for safe long-term exposure and is defined as the amount of a
substance that people can consume on a daily basis over a lifetime without any appre-
ciable health risk. Consumption estimates (estimated daily intake) are included in the
Appendix. Studies in humans have demonstrated that daily doses of the steviol glyco-
sides up to 1000 mg/person/day were well-tolerated by individuals with normal glucose
metabolism or type-2 diabetes mellitus. This dose is equivalent to 16.6 mg/kg bw/day for
a 60 kg person and (corresponds to approximately 330 mg steviol equivalents/person/day
or to 5.5 mg steviol equivalents/kg bw/day). (Maki et al., 2008)

While crude stevia extracts have not been approved for use as an ingredient, several
researchers have studied its consumption. Some animal research studies on crude
stevia extracts indicate adverse effects associated with its consumption, however several
of these studies report contradictory results. The adequacy of these studies has been
questioned by scientific authorities due to limited data, study design limitations, and
relevancy. Moreover, these effects were not observed with purified stevia leaf extract
approved for food and beverage use. (Mazzei-Planas and Kuc, 1968; Nunes and Pereira,
1988; Oliveira-Filho et al., 1989; Melis, 1999; Shiotsu, 1996; Sinchomi and Marcorities,
1989; Saenphet et al., 2006).

Pivotal Long-term Toxicology Studies in Animals

Study Area Methodology Review Main Findings

Long-Term Carcinogenicity study, Stevioside (95.6% purity) provided to rats in dose levels 0, No observable adverse effects at
Toyoda et al., 1997 2.5 and 5% of the diet for 104 wk, resulting in consumption dosage level of 969 and 1120 mg/kg
levels of 0 to 2387 mg/kg/bw/d. bw/day in males and females
respectively with long-term exposure.
NOAEL (mg/kg bw/d): 969 males and 1120 females

Two-Generation Reproductive Rats received up to 2,273 mg/kg bw/day of rebaudioside No reproductive or developmental
Study on Rebaudioside A (Reb A), A (>97% purity). Reb A 97% given via diet to rats for two effects were observed in any of the
Curry et al., 2008 generations. Body weight, body gain, food consumption generations at highest dose NOAEL.
were monitored. Growth and development, survival,
reproductive performance and sexual maturation were
also assessed.

NOAEL (mg/kg bw/day): 2048 and 2567 for males (F0, F1)
2273 and 2768 during premating, 2322 and 2124 during
gestation, 3811 and 4091 during lactation, for females.

Additional studies have been conducted. More references are listed in appendix.

Human Evidence
Several studies in humans have been conducted to evaluate metabolism, pharmacokinet-
ics, and the safety/tolerability of purified steviol glycosides for people with and without
diabetes. Research shows that steviol glycosides are safe for people with diabetes, and
that purified steviol glycosides have no effect on blood pressure when consumed within
recommended levels.

8 | STEVIA SAFETY REVIEW

Studies with Humans

Study Area Methodology Review Main Findings

Chronic consumption of Randomized, double blind, placebo controlled clinical Chronic intake of Reb A had
Rebaudioside A by men and women trial. Subjects (diabetic adults, n=112) were administered no effect on blood glucose levels
with type 2 diabetes mellitus, 1000 mg/d Reb A (97% purity) in 250 mg capsules or or blood pressure.
Maki et al., 2008 placebo for 16 wks. Fasting glucose, C-peptide, body
weight, blood pressure, fasting lipids, and dietary intake No significant clinical differences in
were measured. serum chemistry and hematological

parameters.

Consumption of steviol glycosides Randomized, double blind, placebo controlled clinical High intake consumption of of up to
by healthy men and women with trial. Subjects were administered 1000 mg Reb A /day for 1000 mg /day Reb A had no clinically
low-normal systolic and diastolic 4 wks (n=100). Blood pressure, diet, serum chemistry, significant effects on blood pressure.
blood pressure Maki et al., 2008 and hematology parameters were measured. No statistically significant differences
in haematology and urinalysis results
between groups.

Additional studies have been conducted with humans. More references are listed in appendix.

Key Points

•Research has shown that purified stevia leaf extract is safe for use in
food and beverages for the general population, pregnant women,
children, and children and adults with diabetes.
•Clinical studies indicate that, at the levels approved for use in foods and
beverages, purified stevia leaf extract has no pharmacological effects.
° Steviol glycosides have no effect on blood pressure in individuals
with normal and low-normal blood pressure.
° Steviol glycosides have no effect on glucose homeostasis.
• Leading independent expert evaluations support the weight of safety
evidence for purified stevia leaf extract.

Regulatory Status
Purified stevia leaf extract is recognized as a safe sweetening ingredient at the estab-
lished ADI level by all global food safety and regulatory authorities. JECFA, Codex
Alimentarius Commission, FDA, FSANZ, French Food Safety Agency (AFSSA),
(EFSA) and Health Canada are just a few of the agencies that have concluded that
stevia is safe for use as a sweetener. In fact, stevia is approved by regulatory authorities
in over 70 countries, including all countries in the North and South America, all major
European countries, Australia, Japan, China, and many more.

GLOBAL STEVIA INSTITUTE |9

 IV. Stevia as a Tool for Calorie Reduction
Recently, leading health and nutrition organizations around the world have published
position papers and recommendations on sweeteners, including stevia as a safe, accept-
able choice. International Food Information Council Foundation (IFIC) concluded that
non-nutritive, or low-calorie, sweeteners such as stevia offer a way to reduce calories in
foods and beverages and help manage weight. IFIC assures that the zero calorie sweet-
Leading health and ener stevia does not cause increased appetite or preference for sweet tasting foods and
that stevia offers a way for people with diabetes to decrease overall carbohydrate intake.
nutrition organizations
around the world The European Food Information Council (EUFIC) cites support of EFSA’s thorough
regulatory framework for assessment and approval of low calories sweeteners, indi-
have published cating that sweeteners such as stevia are a safe and, in many cases, beneficial dietary
positions and component. EFSA states that foods and drinks with low calorie sweeteners are likely to
continue to be a growing part of the European diet, helping to provide choice for people
recommendations on who wish to consume fewer calories and maintain a healthy weight.
sweeteners, including
North American based organizations have also released position papers on sweeteners.
stevia as a safe, In 2012, The Academy of Nutrition and Dietetics (AND) released their position that
acceptable choice. consumers can safely enjoy a range of nonnutritive sweeteners (NNS) if they follow
current federal nutrition recommendations. AND highlights stevia among seven NNS
approved for use in the United States. The National Cancer Institute also purports that
there is no clear evidence that the NNS available commercially in the United States, in-
cluding stevia, are associated with cancer risk in human beings, and that several studies
have been conducted, which support the safety of sweeteners as food ingredients.

In 2012, the American Diabetes Association (ADA) and the American Heart Association
released a joint position paper that maintains sugar alcohols and nonnutritive sweeteners
are safe when consumed within the FDA-established daily intake levels, and may help
people reach and maintain a healthy body weight. They also recognize choosing NNS,
such as stevia, is an effective method to assist with glucose control, an important focus
for diabetics. We may see other health organizations publish their position on low calorie
sweeteners as their use continues to grow in foods and beverages around the world.

V. Role of Stevia in a Healthful Diet

People have an innate preference for sweet tastes, which is thought to confer an evolu-
tionary advantage. Sweet foods tend to be a source of carbohydrates needed for energy.
For centuries, people satisfied this taste preference with sweet foods found in nature.

Today, the consumption of sugars in excess may contribute to an energy imbalance in

the diet. Dietary imbalance is often accompanied with sedentary lifestyle and limited
physical activity. A positive energy balance may contribute to overweight or obesity and
related chronic diseases such as diabetes.

Diet and lifestyle modifications are necessary for the prevention of these conditions.
These modifications may be challenging, but simple changes to diet and lifestyle

10 | STEVIA SAFETY REVIEW

can be an effective and sustainable way to help manage weight. It may be beneficial
to reduce excess added sugars for improved energy balance and weight management.
Purified stevia leaf extract is safe for people of all ages. Including stevia as part of a
healthful, balanced diet in addition to regular physical activity can help people reach
their weight loss or weight management goals.

Stevia IN FOODS AND DRINKS

Purified stevia leaf extract can be found in hundreds of foods and beverage
products around the world. People may find stevia-sweetened teas, soft drinks,
juices, yogurt, soymilk, granola and snack bars, and baked goods. Stevia is
also found in snacks, cereals, salad dressings, savory sauces, alcoholic
beverages, chewing gum, canned fruit and jams, confections, and as a
table top sweetener.

Stevia can be the sole sweetener in a product or blended with other natural
caloric sweeteners or other non-caloric sweeteners.

VI. About the Global Stevia Institute

The Global Stevia Institute (GSI) is an educational resource dedicated to providing
science-based information on stevia and its safety to consumers, healthcare professionals,
public policymakers, and the food industry. The GSI is led by an Advisory Board of
internationally recognized nutritionists, medical doctors and health educators. This
group counsels on current and future stevia scientific research; applicability to health and
nutrition in consumers of all ages; and provides the GSI with a solid backbone rooted
in science.

PureCircle, a leader in purified stevia leaf extract production, established the GSI in 2010
in order to support the education and awareness of stevia as a safe, naturally sourced,
sweet ingredient for consumers by sharing accurate and consistent science-based infor-
mation around the world. PureCircle continues to fully fund the Global Stevia Institute.

GLOBAL STEVIA INSTITUTE | 11

 VII. Appendix
Toxicological Studies in Animals with PURIFIED Steviol Glycosides

REFERENCE STUDY DOSE NOAEL

Curry & Roberts, Dosage study in 1, 12 500, 50 000, 100 000 mg/kg 100 000 mg/kg diet (equals 9938 and 11 728
2008 4 wk-old rats diet (consumption levels up to 9938 mg/kg bw/d for males and females)
and 11,728 mg/kg bw/d for males
and females.)

Curry & Roberts 13-wk rat study with 97% 1,12 500, 50 000 mg/kg diet at wks. 50 000 mg/kg diet (4161 mg/kg bw/d for
2008 Reb A prep 1 and 13. males and 4645 mg/kg bw/d for females)

Nikiforov & Eapen, 13-wk rat study with 97% 0, 500,1000, 2000 mg/ kg bw/d. 2000 mg/kg bw/d
2008 Reb A prep

Aze et al., 1991 13-wk rat study with 0, 155, 310, 625, 1250, and 2500 mg/kg bw/d
stevioside (95.6% SG) 2500 mg/kg bw/d

Curry et al., 2008 Preliminary reprod. Rat 0, 4711, 8021, 9484 mg /kg bw/d Dosage study with NOAEL not established.
study; 97% Reb A for first 4 days, or 0, 6291, 10 045, Authors state issues with food palatability.
11 386 mg/kg bw/d at day 17– 20
in lactation

Curry et al., 2008 Two-gen. repro/devep rat 0, 586, 975, 2048 mg/kg bw/d in 2 048 and 2 567 mg/kg bw/d in males F0 –
study; >97% Reb A males; 0, 669, 1115, 2273 mg/kg F1; 2273 & 2768 mg /kg bw/d F0, F1 during
bw/d in pre-mating females; 0, 648 – premating, 2322 & 2124 mg /kg bw/d in F0,
713, 1119–1169, 2263–2381 mg /kg F1 during gestation, 3811 & 4091 mg/kg bw/d
bw/d in gestation; & 0, 715–1379, F0, F1 during lactation, females
1204–2388, and 2602– 5019 mg/kg
bw/d during lactation.

Charles Rivers Teratology study in 0, 350, 700 and 1400 mg /kg bw/d 1400 mg/kg bw/d*
Laboratories, rabbits with steviol
2008 glycosides preparation (*Adverse effects observed. NOAEL concluded
(Reb A ≥ 97%) from day by authorities due to known high susceptibility
6 to 28 of gestation. of rabbits to alimentary tract disturbances.
These disturbances are commonly observed in
sweetener studies with rabbits.)

Mori et al., 1981 Fertility study in rats with 0, 100, 480, 2100 mg /kg bw/d in 2100 mg/kg bw/day (3%)
stevioside (95.98%) before males; 0,120, 530, 2100 mg /kg
and during mating for a bw/d in females
60 day period (m) and for
14 days before mating and
7 days during gestation (f).

Usami et al., 1995, Repro/Develop. Toxicity 0, 25, 500, or 1000 mg /kg bw/d 1000 mg /kg bw/d
Tanaka et al., 1991 study in rats with stevioside
(unpub) (95.6%) between day
6 to 15 of gestation

12 | STEVIA SAFETY REVIEW

 Human Studies: In Vivo, Metabolic Studies with Purified Steviol Glycosides

REFERENCE STUDY DOSE RESULTS CONCLUSIONS

Maki et al., 2007 Randomized, 500, 750, 1000 mg in No significant Acute consumption of
double blind, placebo- meal tolerance tests differences in pre-meal rebaudioside A has no
controlled clinical trial or placebo blood glucose, insulin, clinically important acute effects
with healthy and C-peptide, glucagon, on glucose homeostasis or
diabetic men and BP blood pressure; Reb A was
women (n=45, n=48) well-tolerated

Maki et al., 2008 Randomized, 1000 mg Reb A 97% No significant differences No significant adverse effects
double blind, placebo- in 250 mg capsules in fasting glucose, insulin, reported; Chronic intake
controlled clinical for 16 wks. or placebo C-peptide, BW, blood of Reb A does not alter blood
trial on chronic 0, 350, 700 and 1400 pressure, fasting lipids, glucose levels or blood pressure
consumption in mg/kg bw/d dietary intake; No changes; Reb A is overall
diabetic men and significant clinical well-tolerated
women with diabetes differences in serum
(n=122) chemistry and
hematological parameters

Maki et al., 2008

Randomized, double 1000 mg Reb A for No significant clinical No significant adverse effects
blind, placebo- 4 wks. or placebo differences in reported; High intake
controlled clinical trial blood pressure, diet, consumption well-tolerated
with healthy and men serum chemistry and with no clinically significant
and women with low- hematology parameters effects on BP
normal systolic and
diastolic BP (n=100)

Gregerson et al., 2004 Paired, cross-over 1 g capsule of Post-prandial glucose Authors stated stevioside
study with diabetic 91% stevioside and levels significantly may potentiate insulin secretion
men and women 4% Reb A decreased in stevia- in individuals with type 2
(n=12) treated group; Significant diabetes mellitus
increase in insulinogenic
index after ingestion;
NSD in AUCs fir glucose,
glucagon response or
urine output

Temme et al., 2004 Intake study with 750 mg total 97% No significant differences No significant differences
healthy males (n=9) stevioside in 250 mg in pre and post-prandial compared to control group
for 3 days capsules for 3 days plasma glucose,
insulin, blood pressure,
serum chemistry
and hematological
parameters, or urine
output and analysis
compared to baseline

GLOBAL STEVIA INSTITUTE | 13

 Estimated Daily Intake of Steviol Glycosides

AGENCY Estimated Daily Intake (EDI) METHOD

(in steviol equivalents)

JECFA (2008A) 0.9–3.5 mg/kg bw/day ( Average-intake consumers) For general population, all ages (GEMS*) of Europe, Latin America,
3.0–5.8 (high-intake consumers) Africa & Asia

High level ( 90th percentile) intakes for Japan and the US

Based on per capita replacement of all dietary sugars for general

population results in very conservative estimates. Generally,
20–30% replacement is a more accurate replacement model.

*WHO Global Environment Monitoring System Food database.

Renwick (2008) 0.4 and 0.7 mg/kg bw/day (Average intake general High intake consumption of of up to 1000 mg /day Reb A had
population and Children) no clinically significant effects on blood pressure. No statistically
significant differences in haematology and urinalysis results
1.1 and 1.7 mg/kg bw/day ( High-intake Adult between groups.
and Children)

1.5 mg/kg bw/day (High-intake Diabetic Children)

14 | STEVIA SAFETY REVIEW

References

1. Anton SD et al (1997). Effects of stevia, aspartame, and sucrose on food intake, satiety, and
postprandial glucose and insulin levels. Appetite. 55(1), 37–43.
2. Aze Y., Toyoda K., Imaida K., Hayashi S., Imazawa T., Hayashi Y., Takahashi M. (1991)
3. [Subchronic oral toxicity study of stevioside in F344 rats]. Eisei Shikenjo hokoku.
4. Bulletin of National Institute of Hygienic Sciences: 48–54.
5. Carakostas M.C., Curry L.L., Boileau A.C., Brusick D.J. (2008) Overview: the history,technical
function and safety of rebaudioside A, a naturally occurring steviol glycoside, for use in food and
beverages. Food and chemical toxicology : an international journal published for the British Industrial
Biological Research Association 46 Suppl 7:S1–S10. DOI: 10.1016/j.fct.2008.05.003.
6. Curry L.L., Roberts A. (2008) Subchronic toxicity of rebaudioside A. Food and chemical toxicology :
an international journal published for the British Industrial Biological Research Association
46 Suppl 7:S11–20. DOI: 10.1016/j.fct.2008.04.042.
7. Curry L.L., Roberts A., Brown N. (2008) Rebaudioside A: two-generation reproductive toxicity study
in rats. Food and chemical toxicology : an international journal published for the British Industrial
Biological Research Association 46 Suppl 7:S21–30. DOI: 10.1016/j.fct.2008.05.005.
8. EFSA. (2010) EFSA Panel on Food Additives and Nutrient Sources scientific opinion on safety of
steviol glycosides for the proposed uses as a food additive. (Question number: EFSA-Q-2007-071;
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