Truvia™ rebiana Zero-calorie sweetness from the stevia leafBackground briefing: history and safety assessment

Contents

Stevia – unique plant, unique story

From Green to White

Truvia™ rebiana

Overview of research results

Expert reviews and approvals

Summary of conclusions

Implications for consumers

Stevia rebaudiana Bertoni

Stevia: unique plant, unique story

Shrub in the Asteraceae family native to northeastern Paraguay

First discovered by indigenous people who used plant’s leaves to sweeten drinks

By 1800s, stevia consumption established throughout South America, including Brazil and Argentina

Food researchers worldwide have been working with stevia for decades

– In 1931, French food chemists isolated compounds (steviol glycosides) that give stevia its sweet taste

– Japan has been using stevia commercially for over three decades

– Stevia-sweetened food and beverages are now available to consumers on every continent

US market opened in 2008 and France in 2009

Steviol glycosides – the sweet constituents

10+ glycosides in the leaf

2 most predominant stevioside rebaudioside A

CH2CH3

H

H

O

O

OO

H3CHO

OH

OH

HO

O

O

OR

HO

OH

O

OH

OH

HO

HO

O

HO

OH

OH

HO

Stevioside: R=H

Rebaudioside A: R=

From Green to White

Steviol Glycosides

Stevioside

Rebaudioside A

Others

Rebiana

The first fully characterised, high purity form of rebaudioside A

The first fully characterised, high purity form of rebaudioside A

Other components

Stevia rebaudiana Bertoni or

“stevia”

Stevia – the vocabulary

Stevia General term used to refer to the plant and commercially to food uses of Stevia rebaudiana (botanical name)

Stevia extract refers to compounds isolated (extracted) from stevia without regard to purity or identity of the compounds

Steviol glycosides Sweet tasting components in leaves of the stevia plant Leaf contains at least 10 unique steviol glycosides including rebaudioside A, stevioside, rebaudioside C

Rebaudioside A Best tasting steviol glycoside

Also called “reb A” for short

Purified from the leaf, it provides a clean, sweet taste

Rebiana* Ingredient containing high-purity rebaudioside A

Purity assures clean, sweet taste

Rebiana is not less than 97% rebaudioside A* Appears on ingredient labels in the US

Truvia ™ Brand name of leading sweetener derived from Stevia

Attributes of rebiana

Plant derived, high potency, zero calorie, good tasting sweetener

The best tasting part of the stevia leaf – not less than 97% rebaudioside A

200 300 times sweeter than sucrose

Non caloric, non glycemic

Good solubility

Heat and pH stable in food and beverage systems

Introduction to Truvia™ rebiana

Truvia™ rebiana is comprised entirely of purified steviol glycosides, containing not less than 97% rebaudioside A

Truvia™ rebiana (ingredient) and Truvia™ tabletop sweetener launched in the USA in 2008:

– Brand has established leadership position in new category of zero-calorie, plant-derived, high intensity sweeteners

Cargill, maker of Truvia™ rebiana, has applied for European regulatory approval

European Food Safety Authority recently completed a safety assessment; their Scientific Opinion published on 14 April 2010

EFSA Scientific Opinion

EFSA confirmed that steviol glycosides are safe for use in foods and beverages

“Steviol glycosides complying with JECFA specifications are not carcinogenic, genotoxic or associated with any reproductive / developmental toxicity”

EFSA established an Acceptable Daily Intake (ADI) for their safe consumption

−Expert panel established same ADI as previously established by JECFA

EFSA Scientific Opinion is critical milestone in EU approval process; final EU regulatory approval likely to be in 2011

Rebiana safety programme objective

Demonstrate the safety of rebiana for consumption by all consumers, in all foods, for all eating occasions

in all countries

Demonstrate the safety of rebiana for consumption by all consumers, in all foods, for all eating occasions

in all countries

Research on stevia and steviol glycosides

Stevia and its components have been evaluated in a range of studies over the past five decades

Studies varied widely in purpose, design and quality:– Many small studies used a crude extract of stevia, making it

impossible to attribute the observed effects to any part of the leaf

– Others injected steviol glycosides into animals or fed animals very large amounts of steviol (the breakdown product of the steviol glycosides)

Minority of these studies raised questions about potential effects on reproductive health and kidney function

Some human studies suggested beneficial effects on blood pressure and blood sugar

Rebiana safety programme

Cargill and The Coca Cola Company collaborated to develop the ingredient rebiana – high purity rebaudioside A

With guidance from global food safety experts and leading external scientists, Cargill’s research programme set out to:

– Systematically evaluate a fully characterised, high purity form of rebaudioside A

– Ensure stevioside safety data are relevant to rebaudioside A

– Resolve questions raised by regulatory authorities, with further clinical studies where appropriate

Research results overview

Programme Area Findings / Implications

Metabolism studies

Metabolism of rebaudioside A is similar to that of stevioside Extensive toxicology data on stevioside can be applied to rebiana

General toxicology

No signs of toxicity associated with daily consumption of the equivalent of 2,000 250ml servings of a rebiana-sweetened beverage (for a 68kg person)

No treatment-related effects on any organ, including kidneys and male reproductive organs

Multigenerational/reproductive toxicology

No treatment effects on reproductive health or developmental outcomes

Clinical programme

Address JECFA request for additional data pertaining to potential pharmacological effects of steviol glycosides in humans

– Blood pressure lowering effects

– Effects on blood glucose in people with diabetes

Provide definitive data to further support the safety of rebiana

– Hemodynamic effects of rebaudioside A in healthy adults with normal and low-normal blood pressure (Blood pressure study)

– Chronic consumption of rebaudioside A in men and women with type 2 diabetes mellitus (Diabetes study)

– Comparative pharmacokinetics of rebaudioside A and stevioside in humans

Blood pressure study: Changes from baseline to treatment for resting, seated blood pressure

Resting,

Seated Measurements

Rebaudioside A

(n=50)

Placebo

(n=50)p-value*

Mean ±SEM

Baseline SBP (mm Hg) 110.0 ± 1.2 110.7 ± 1.3 0.683

SBP Δ -1.3 ± 0.7 -0.4 ± 0.8 0.237

Baseline DBP (mm Hg) 70.3 ± 0.9 71.2 ± 0.9 0.529

DBP Δ -1.3 ± 0.5 -0.7 ± 0.5 0.154

Baseline MAP (mm Hg) 83.6 ± 0.9 84.3 ± 1.0 0.554

MAP Δ -1.3 ± 0.6 -0.6 ± 0.6 0.192

*ANCOVA; initial model included terms for baseline value, treatment, site, and treatment by site interaction. Values for pre- to post-treatment change in DBP were ranked prior to analysis.•SBP – systolic blood pressure; DBP – diastolic blood pressure; MAP – mean arterial pressureMaki et al. (2008) Food and Chem Toxicol 46:S40-S46

Diabetes study: Glycosylated hemoglobin at baseline to weeks 4, 8, 12, 16

Glycosylated hemoglobin

Rebaudioside A

(n=60)

Placebo

(n=62)p-value*

Mean ±SEM

Baseline (%) 6.71 ± 0.11 6.70 ± 0.10 0.964

Week 4 Δ (%) 0.02 ± 0.03 0.02 ± 0.903 0.982

Week 8 Δ 0.11 ± 0.05 0.04 ± 0.04 0.574

Week 12 Δ 0.11 ± 0.05 0.07 ± 0.05 0.248

Week 16 Δ 0.11 ± 0.06 0.09 ± 0.05 0.355

*P-values for the change from baseline are for the analysis of covariance with baseline value as the covariate. All values were ranked prior to analysis.

Maki et al. (2008) Food and Chem Toxicol. 46:S47-S63

Diabetes study: Results of secondary outcomes

Rebaudioside A

(n=60)

Placebo

(n=62)

p-value

Mean ± SEM

Baseline SBP (mm Hg) 121.6 ± 1.4 126.0 ± 1.6 0.051

Δ (mm Hg) -0.2 ± 1.0 -0.9 ± 1.1 0.775

Baseline DBP 72.5 ± 1.0 71.3 ± 1.1 0.429

Δ 0.2 ± 0.8 -1.1 ± 0.7 0.132

No effect of rebaudioside A on the following outcomes:

Fasting glucose, insulin, C-peptide Body weight Total-C, LDL-C, HDL-C, Non-HDL-C, triglycerides

Maki et al. (2008) Food and Chem Toxicol. 46:S47-S63

Publication of the science supporting safety

12 papers evaluating the safety of rebiana have been published

electronically in the peer-reviewed journal

Food and Chemical Toxicology.

The published studies clearly establish the safety of rebiana for

use as a sweetener in food and beverages.

12 papers evaluating the safety of rebiana have been published

electronically in the peer-reviewed journal

Food and Chemical Toxicology.

The published studies clearly establish the safety of rebiana for

use as a sweetener in food and beverages.

Ref: Food and Chemical Toxicology, Vol 46:7 S1-S92 (2008)

EFSA Scientific Opinion (14 April 2010)

“Steviol glycosides complying with JECFA specifications are not carcinogenic, genotoxic or associated with any reproductive / developmental toxicity”

“The Panel considers that there is no need to further test the potential of carcinogenicity of steviol glycosides in other species (e.g. mouse)”

Expert reviews - 2008

Food and Chemical Toxicology Published safety studies

Joint FAO/WHO Expert Committee on Food Additives (JECFA)

Comprehensively examined the safety data and set a permanent ADI

GRAS (Generally Recognised As Safe) Independent Expert Panel

Critically reviewed Truvia ™ rebiana database of studies

Determined its safety for general purpose use as a sweetener

Food and Drug Administration (FDA) Issued no-objection letterRebiana affirmed as Generally Recognised as Safe (GRAS)

Toxicology Forum Panel multi-stakeholder symposium

Reviewed safety of rebaudioside A

Expert reviews - 2009/10

French Food Safety Agency AFSSA Assessed safety of rebaudioside A

Temporary legal approval of ≥97% rebaudioside A for up to a maximum of 2 years, for use in certain food and beverages in France, published on 6 September 2009

First market in EU to approve

European Food Safety Authority (EFSA) Reviewed safety of steviol glycosides, including rebaudioside A

Expert panel’s Scientific Opinion officially published on 14 April 2010

Acceptable Daily Intake (ADI)

Definition of ADI – Estimate of the amount of a food additive that can be consumed daily

over an entire lifetime without appreciable health risk

ADI for steviol glycosides is 4 mg/kg bw/day on a steviol basis – Established by JECFA and EFSA

Translated for rebiana is 12 mg/kg bw/day– Approximately equivalent to 23 teaspoons of Truvia™ tabletop

sweetener every day over the course of a lifetime

EFSA said ADI could be exceeded at max. proposed usage level– Projected uses were based on provisional industry estimates and may

need to be adjusted before final EU regulation

Summary of conclusions

Truvia™ rebiana is safe for use in food and beverages

High purity rebaudioside A (rebiana) is fully differentiated from crude stevia

Truvia™ rebiana is reproducibly purified to specifications that exceed regulatory requirements

Clinical studies indicate lack of pharmacological action of steviol glycosides– No effect on blood pressure in individuals with normal and

low-normal blood pressure

– No effect on glucose homeostasis

Successive independent expert assessments have validated the weight of safety evidence

EFSA is the latest and most relevant to European regulatory approval

Implications for consumers

Truvia™ sweetener provides a zero-calorie sweetening choice for consumers

Truvia™ sweetener is already in use in France following French regulatory approval of rebaudioside A

Once approved for EU-wide use, it will be available as a tabletop sweetener and as an ingredient in foods and beverages

As research and safety assessments show, it can safely be used by all consumers, whether watching weight or managing diabetes

Key references

Food and Chemical Toxicology 46 (2008) S1-S92Peer-reviewed published papers; available on request from Cargill

EFSA Journal 2010;8(4):1537

http//www.efsa.europa.eu/en/scdocs/scdoc/1537

Joint FAO/WHO Expert Committee on Food Additives. 69th Meeting, 2008. JECFA/69/SC, 4 July 2008. Steviol glycosides ADI

Food and Drug Administration (FDA), 2008. http://www.fda.gov/Food/FoodIngredientsPackaging/GenerallyRecognizedasSafeGRAS/GRASListings/ucm154989.htm

Journal officiel de la République Française, 6 September 2009, éd. no. 206 http://textes.droit.org/JORF/2009/09/06/0206 - item 6

For further information or to request Food and Chemical Toxicology reprints contact:

Amy Boileau, Ph.D, R.D.Manager, Regulatory & Scientific AffairsFood Ingredients & Systems, Cargillamy_boileau@cargill.com

Truvia™ sweetenerZero-calorie sweetness from the stevia leaf