HERB RESEARCH FOUNDATION

------------------------

 

Supplement To

GRAS Affirmation Petition Number 2G0390

Stevia rebaudiana Bertoni

 

 

INTRODUCTION

 

This document and others previously submitted and incorporated by

reference constitute a complete supplement to Stevia GRAS Affirmation

Petition number 2G0390. This supplement is complete in that it

address all issues raised in FDA's "not-filed" letters of June 24,

1992 and March 31, 1993 from A. Orstan to W.R. Pendergast.

 

This supplement is a submission of additional information to the GRAS

petition filed on behalf of the American Herbal Products Association

(AHPA) by Bill Pendergast of the law firm Arent, Fox. All previous

data submitted including the GRAS petition submitted on April 23,

1992, and request for recognition of GRAS status of October 21, 1991

and all other documents and letters rearding stevia herb submitted to

FDA on behalf of the AHPA are hereby incorporated by reference. The

word petition in this text signifies the Stevia GRAS petition, which

includes the aforementioned documents and this text in that

definition.

 

This document was written by the Herb Research Foundation (HRF),

under contract from the American Herbal Products Association. The

Herb Research Foundation has created this document without the

editorial influence of the AHPA and is solely responsible for its

content.

 

The common name of Stevia rebaudiana Bertoni, is written variously as

stevia, stevia herb, stevia leaf and by common names it was known by

in Paraguay and Brazil. The common names for stevia used by

Paraguayans and Brazilians are quoted from various sources and

spelled in several different ways, such as Kaa-hee, Ka-he-e,

Caa-He-e, Caa-ehe, Caa-hee, Ca-jhe-e, etc.

 

In addition, the text refers to the plant Ilex paraguaiensis, which

is known by the common names mate, yerba mate, matte, and yerba

matte.

 

FORMAT: This document will list points raised, and requests made, by

FDA in their letters of June 24, 1992, and March 31, 1993. It also

addresses issues raised in FDA's record of the meeting on July 28,

1992 between FDA, Bill Pendergast and Timothy Moley.

 

The HRF recognizes that FDA has requested the following data, citing

the authority of title 21 of the Code of Federal Regulations,

especially parts 170.30(c), 170.35(c)(1), 170.30(c)(2), 170.3(i), and

170.3(f). The HRF is familiar with the Food Additive Regulations.

To the best of our knowledge, the data listed below, combined with

data in previous submission, meets the criteria set forth in 21 CFR

parts 170.

 

HRF is also very familiar with data submitted in the previous

petition, in part because some of that data (in particular, the

Stevia rebaudiana Safety Review) was prepared by HRF.

 

This report addresses statements and requests made by FDA in response

to the AHPA GRAS petition for stevia.

 

 

RESPONSE TO FDA LETTER DATED JUNE 24, 1992

A. Orstan to W.R. Pendergast

 

QUALITY AND AVAILABILITY OF INFORMATION

FDA states, "The petition contains mostly anecdotal and speculative

information..."

 

The petition--including this submission--contains articles published

in scientific journals documenting the safe use of stevia. These

articles were written by botanists, chemists, and food technologists

who are experts qualified by training and experience. Over 120

articles about stevia were written prior to 1958. Most of the

articles are written by scientists or government officials. Only

three of the 120 articles referred to were written by or published

for the lay public. All were published in journals and books.

Several more articles written after 1958 reviewed the use of stevia

as food prior to 1958. Over 900 articles have been published on

stevia to date.

 

Some of the articles written about stevia were funded by the United

States Government. Letters on file at USDA chronicle the fact that

the US government had samples of stevia leaf and intended to

investigate it as a crop for the USA as early as 1921 (Van Eseltine,

1921). Articles written by American scholars and published in

American journals prior to 1958 clearly state stevia leaf has been

used in Paraguay for many years and that no adverse effects have ever

been reported from the consumption of stevia leaf. Fletcher 1955,

Jacobs 1955, Bell 1954, Chem + Eng. News. 1956.

 

The stevia documentation is not anecdotal but represents the work of

qualified researchers from distinguished universities and

organizations, published in scientific journals. Almost all of these

documents are readily available in the United States. Stevia was

well known and thoroughly studied by 1958. The petition is based

upon generally available data and information and complies with 21

CFR 170.30(c)(1) and 21 CFR 170.30(c)(2) in that respect.

 

HOW WELL KNOWN WAS STEVIA?

FDA states, "...during most of this century stevia was a very rare

plant in Paraguay"

 

Articles stating stevia is rare were written in 1899 and 1905 by

Bertoni. In Bertoni's 1905 article he says, "Six years after my

first article, I am now able to give a complete description of Kaa

he-e and some additional data. This lapse of time illustrates the

difficulties involved in trying to seriously study a rare of

little-known Paraguayan plant." Bertoni's early usage of this

language certainly does not mean that it could not have been a

frequently used food plant. Bertoni was an Italian botanist, not

living in the region of Paraguay where stevia was grown and used.

His difficulty with the language spoken in, and problems traveling

to, Paraguay, initially limited his knowledge of the area and plant,

but this was later overcome.

 

"This plant, which has probably been known to the Indians since a

hundred years or more and whose secret has as usual been so

faithfully guarded by them,..."

Kew Bull 1901

 

To understand why a plant could be described as rare, when it is not,

let's consider ginseng in USA as an example. Ginseng is a rare plant

in the wild; in fact it is considered a threatened species. If a

foreigner were to try to find wild ginseng in the USA they might

describe it as a rare plant. It is highly unlikely that it could be

found without the assistance of local people, who may not be inclined

to help anyone find the herb, even though they know where it grows.

Its rarity is that it is challenging to find. However, many peopel

who live where ginseng grows could easily find large stands of wild

ginseng. Ginseng is also challenging to cultivate.

 

Despite the appearance and the belief that ginseng is a rare plant,

its use has been, and still is, very common. The same was true for

stevia in Paraguay in the late 1800s with an Italian botanist trying

to find it. The articles describing stevia as a rare plant were

written by foreign botanists. There was no overland method of travel

during that time, and travel to and within Paraguay entailed an

up-river journey of many days by steamship.

 

By the 1913, stevia was no longer considered a rare plant, and by

1920 it was cultivated in plantations.

 

"In 1913, new examinations of the now famous Stevia rebaudiana were

completed in three distinct laboratories, in Antwerp, Wiesbaden and

Hamburg. The most conclusive report seems to be that of the Official

Public Laboratory of Hamburg which reads: 'The specimens received

are of the well known plant which has alarmed sugar producers some

years ago.'" (emphasis added) Bertoni 1918

 

"A plantation of Caa-ehe has been established in Paraguay by Senior

Jimenez, who according to the department of Overseas Trade, is stated

to be in a position to supply plants ready packed to stand a long

journey."

Bulletin Imperial Institute of Kew Gardens Vol. 18, 1920

 

"People living along the frontier of Brazil with Paraguay are

mainly those who has been using stevia since time immemorial as a

natural sweetener for foods and beverages, especially mate. This

plant became well known early in this century." Marques 1993

 

Betoni describes stevia as a rare or little known plant in 1899, but

describes it as famous and well known by the year 1913.

 

 

CULTIVATION

FDA states, "...none of the cultivation attempts prior to 1958 in

Paraguay or elsewhere seems to have achieved commercial success."

 

Stevia is a plant that was native to Paraguay. It was harvested from

the wild, where it grew. Early attempts at cultivation were not

fruitful because those attempting to grow it did not understand its

culture and reproduction. By the 1920s stevia was being cultivated.

 

"A plantation of Caa-ehe has been established in Paraguay by Senior

Jimenez, who according to the department of Overseas Trade, is stated

to be in a position to supply plants ready packed to stand a long

journey."

Bulletin Imperial Institute of Kew Gardens Vol. 18, 1920

 

"Cultivated in England," Western Morning News, June 1, 1942

 

"Cultivation of the plant has been carried out in Paraguay both as

a horticultural curiosity and on a larger scale but the latter is

expensive since the seed is usually sterile and reproduction must be

made by subdivision."

Wood 1955

 

A report from the Ministry of Agriculture for the Republic of

Paraguay states that stevia cultivation was on the average 20

hectares per year from 1930 to the 1970.

 

The amount of cultivation is not a determination of common use. Many

foods grew in the wild and were harvested for personal use or for

commercial trade. Often, households had a small patch of stevia in

their backyard that would supply their needs. It is important to

note that major economic plants have been collected from the wild for

decades with no attempt at, or need for, cultivation. This was

certainly true at the turn of the century.

 

Yerba mate was not cultivated, but harvested from the wild. In 1899

the annual production of yerba mate in South America was estimated at

100,000 tons. (Revisita de Agronomia 1899). Many spice crops today,

such as cinnamon in Indonesia, thyme in Spain, and mushrooms in the

USA are harvested from wild stands rather than cultivated. For some

crops, such as ginseng in the US or truffles in France, the wild crop

is preferred over the cultivated crop. To assume the annual

consumption of apples in the USA is equivalent to the harvest

statistic reported by apple farmers would be seriously flawed without

considering the large number of apple trees present in people's yards

across the country.

 

To state that the use of stevia was low due to a lack of cultivation

is erroneous. Stevia was cultivated, although not on a scale equal

to its consumption. The major souce of stevia was from wild stands

and backyard gardens. The trade in stevia occurred mostly on a local

scale in small farmers' markets and herb stores, and was not a matter

of public record. Food additive regulations do not provide a

criteria for evaluating the safety of a food substance based upon

where and how it was grown, whether it was cultivated or harvested

from the wild.

 

COMMON USE

FDA requests "...additional data to help us establish how a rare

plant could have been in common use by a significant number of

consumers."

 

Several articles in scientific journals and documents from the

Paraguayan and Brazilian governments clearly show a substantial

history of consumption of stevia leaf in beverages by a significant

number of consumers.

 

A report from the Brazilian Department of Health states: "It is

public knowledge that Stevia rebaudiana (Ca'-He-e) is a plant native

to this region ordinarily used as a sweetener by natie gauchos,

indigenous people and the general population. People living along

the frontier of Brazil with Paraguay are mainly those who have been

using stevia since time immemorial as a natural sweetener for foods

and beverages, especially mate. This plant became well known early

in this century."

Marques 1993

 

A report from the Paraguayan Ministry of Agriculture states that

over 50% of the population of Paraguay consumes yerba mate, in which

stevia herb is commonly used. The report states that the use of

stevia is more popular by the native peoples and rural populations.

 

"It is non-toxic, as proved by the experiences made with animals

and its large use by the inhabitants of Paraguay since Pre-Columbian

times."

Schmeling 1967

Pre-Columbian refers to the time prior to the arrival of

Christopher Columbus in the Americas in 1492. Therefore this article

states that stevia had been used for at least 466 years prior to

1958.

 

"Although the human consumption of stevia began before the Spanish

settlement of the country we now know as Paraguay, improved versions

have been developed only recently." "Stevia rebaudiana, the sweet

principle is believed to have been used by the Paraguayan Indians for

centuries."

Phillips 1987

 

"The plant, which has probably been known to the Indians since a

hundred years o r more and whose secret has as usual been so

faithfully guarded by them,"

Kew Bull 1901

 

"Some data found in copies of informative documents that the

Conquistadors sent back to Spain and [others] that are kept in the

National Archives in Asuncion indicate that the Caa'jhe-he plant had

been known by the natives since the dawn of history and that they

used it to sweeten medical drinks and in particular, to impart

sweetness to cooked mate, i.e., the cooking of the mate herb."

Samaneigo 1946

 

Stevia has been consumed by the peoples of Paraguay and southern

Brazil continuously for centuries, before the arrival of the

Conquistadors, that is for more than 466 years prior to 1958. We

believe this substantial history of consumption as a food substance

by a significant number of consumers meets the criteria for common

use in food as defined by 21 CFR 170.3(f).

 

SAFETY

FDA states they require enough information to establish "...whether

the experience with the ingredient in common use establishes that use

of the ingredient is safe."

 

The safety of stevia can be demonstrated by reports from the

Brazilian and Paraguayan government and numerous reports in the

literature of the absence of adverse effects from the consumption of

stevia leaves. All reports in the literature concerning the safety

of stevia leaves are positive. A complete review of all available

literature fails to report a single adverse reaction from the

consumption of stevia leaf or extracts of stevia.

 

A report from the Brazilian department of health states "We

analyzed the literary data, statistics on consumption of medications

and popular knowledge, and were unable to find any parameter on file

for decades which might relate Caa'-He-e to any ill effects on

health, intoxication or pain among the people."

Marques 1993

 

"It is non-toxic, as proved by the experiences made with animals

and its large use by the inhabitants of Paraguay since Pre-Columbian

times."

Schmeling 1967

Pre-Columbian refers to the time prior to the arrival of

Christopher Columbus in the Americas in 1492. Therefore this article

states that stevia had been used for at least 466 years prior to

1958.

 

"Experience of its use in man and data from animal feeding trials

indicate that it is safe for human consumption."

Phillips 1987

 

"a few small leaves are sufficient to sweeten a strong cup of

coffee or tea. To this must be added that the plant does not contain

any noxious substance whatever which might tend to limit it's use,"

Bertoni, 1901

 

"It is not toxic but, on the contrary, it is healthful, as shown by

long experience and according to the studies of Dr. Rebaudi."

Bertoni 1918

 

"Furthermore, there are no recorded reports of ill effects in the

Paraguayan users of the leaves of S. rebaudiana."

Hodge, 1974

 

"While no reports of ill effects in the Paraguayan users of the

leaves have come to us, the long term effects of ingestion of

stevioside would have to be investigated carefully before the

material could be used with confidence as a regular sweetening

agent."

Fletcher 1955 (emphasis added)

 

"A new plant, discovered by me, sweetener almost as powerful as

saccharine and without any of the disadvantages of the latter, it

does not have any other action, except that it is slightly tonic, and

can be used in daily doses much higher than those actually needed."

Bertoni, 1926

 

We concur with FDA that it is impossible in the present state of

scientific knowledge to establish with complete certainty the

absolute harmlessness of any substance. However, in the context of

21 CFR 170.3(i), there is a reasonable certainty in the minds of

competent scientists that stevia leaf is not harmful under the

intended conditions of use. This certainty is based upon reports

from the Governments of Brazil and Paraguay and the absence of any

report of adverse reaction to stevia leaves in the literature. We

can conclude that stevia is safe for use in food as defined by 21 CFR

170.3(i).

 

REGULATIONS ON THE CULTURAL CONTEXT OF USE

 

For requesting some of the following information, FDA cites as their

authority a proposed rule published on July 2, 1985 in 50 FR. 27294.

Some of the data FDA is requesting was part of that proposed rule.

However, it was not codified in the final rule in 1988, and as such,

it is not part of Federal Regulations. HRF is unaware of any

precedent for proposed rules being a requirement for--or having the

force of--regulation or being incorporated as policy. Nor does HRF

wish to, in any way, set a precedent for the same, especially in

reference to the criteria for GRAS petitions. We are providing this

information at the request of the AHPA and in the spirit of

cooperation with FDA, but note that some of FDA's requests are for

data not required by the food additive regulations.

 

Furthermore, HRF believes tha tthe cultural context in which a food

is used has no relevance to its safety, which relates only to the

quantity of a substance consumed and the toxicity of that quantity of

the substance. Cultural context of use was not a consideration when

congressman Delaney proposed the Food Additive amendment.

Ethnocentric bias by FDA in the consideration of the cultural context

of the use of a food was not upheld in Fmali Vs Heckler 715 F2.d 1385

(9th cir. 1983).

 

CULTURAL CONTEXT OF USE OF STEVIA

FDA states, "Based on the FDA's list, we request additional

information on the cultural context of the use of stevia by the

Paraguayan Indians before 1958..."

 

Stevia is used to flavor and sweeten beverages. It was commonly

consumed as a beverage. Beverages in Paraguay, Brazil, and Argentina

were consumed as frequently as beverages are consumed in any culture,

at least 4 times to as many as 11 times a day. (Bertoni, 1899)

 

Stevia was most commonly used in the beverage mate. Mate has the

cultural significance of being a social beverage. Often people

drinking mate share a cup among their friends. Mate is prepared with

a large cup of mixed herbs. Mate is mixed with stevia, and this

mixture is known by the common name as terere and or mate cozido.

Hot water is poured on the herbs and the resulting tea is imbibed

through a special straw called a bombilla that has a strainer on the

end of the straw that rests in the cup. The water is replenished in

the cup of herbs and the cup passed to another person who in turn

drinks. The sharing of beverage terere or cozido is the extent of

the cultural significance of its use. Mate or terere is also

consumed by individuals who will drink and replenish the water and

continue drink in that way. In more modern times, mate and other

stevia containing hot beverages are brewed and consumed just as other

teas or herbal teas.

 

HOW OFTEN WAS STEVIA USED?

FDA would like to know how often stevia was consumed.

 

Stevia was consumed as a beverage and the frequency of beverage

consumption, several times a day.

 

"Eight or ten leaves can sweeten 50-80 grams of tea or coffee,

black or with milk. Once the drink is sweetened the leaves should be

removed. Caa jhe-he can be used three or four times a day."

Samaniego 1946

 

The most common use of stevia was its combination with mate as a tea.

Bertoni reports in Revista De Agronomia, 1899, that the annual

consumption of mate for Paraguay was 8 kilograms per person per year.

Dividing 8000 grams by 365 days per year results in a daily average

per capita consumption of 22 grams of yerba mate. Using the weight

of 2 to 3 grams of yerba mater per cup of tea results in a per capita

consumption of 7 to 11 cups of mate per day.

 

We can conclude from this and other parts of the petition that stevia

was used in beverages, primarily mate. Stevia was consumed three to

four times a day. (Samaneigo 1946) The frequency of mate

consumption in Paraguay was about 7 to 11 cups per day. Therefore

for those consumers who used stevia in their mate, their stevia

consumption was up to 11 times per day.

 

ON WHICH OCCASIONS WAS STEVIA USED?

 

Stevia was used as a common daily beverage and n ot limited to

special occasions. No reference stated that its use was for any

special or unusual occasions or ceremonies. Stevia was consumed as a

beverage several times a day, every day.

 

IN LIEU OF WHAT OTHER FOODS?

 

Stevia was not used in lieu of any other foods. Although the

uninformed would think of stevia being used in lieu of sugar, Stevia

was present and used to flavor beverages prior to the introduction of

sugar cane in Paraguay and Brazil. Sugar was henceforth used in lieu

of stevia.

 

"It has now fallen into disuse due to the cultivation of sugar

can;"

Samaniego 1946

 

DIABETIC USE

 

Stevia is safe for diabetics and was used by them to provide a sweet

flavor to their foods.

 

"This species of sweet plant the Ka'a Hee serves to replace sugar

in the regimen of diabetis,"

Paraguay, Cartilla, 1939

 

WITH WHAT OTHER FOODS

 

Stevia was used to flavor beverages, primarily yerba mate, and also

tea, coffee, and other bitter beverages.

 

Juan B. Aranda J., 1932, states that stevia was used to

manufacture a commercially bottled soft drink which was sold in

Argentina. These beverages were consumed singly and with other food

common to the diet of the people of the region.

 

Stevia was used in varying amounts most commonly cited as two to

four leaves per cup.

 

Stevia was used in various forms, most commonly powdered dried

leaf mixed with dry herbs, tea or coffee, whole leaf added to brewed

beverage, and extracts added to beverages. It was commercially sold

as a mixture with yerba matte and in prepared foods such as soft

drinks. (Juan B. Aranda J. 1932)

 

Stevia was consumed with beverages as frequently as 3 to 11 times

a day, and according to Bertoni (1926) it could be used in excess.

("...can be used in daily doses much higher than those actually

needed.") Statistics indicate that Paraguayans consumed matte in

various preparations and at the rate of 7 to 11 cups per day.

 

DRIED STEVIA MIXED WITH DRIED LEAVES OF MATE

 

A very popular use of stevia is the beverages of yerba mate called

terere and cozido.

 

"Unfortunately it consisted of a few branchlets reduced to

fragments with the Matte. (Leaves of this plant, called Kaa he e are

powdered and mixed in a small proportion of Yerba Mate to sweeten the

bitter mate.)"

Bertoni 1918

 

"People living along the frontier of Brazil with Paraguay are

mainly those who have been using stevia since time immemorial as a

natural sweetener for foods and beverages, especially mate. This

plant became well known early in this century."

Marques 1993

 

"Terere, a tea made with mate brewed in a cup, is often sweetened

with caa-he-e."

Oliveira, 1993

 

"It is reasonable to assume that the local Indians used stevia to

sweeten their food and drink, especially mate, the traditional

Paraguayan beverage prepared by steeping the crushed, dried leaves of

Ilex paraguayensis in water."

Phillips, 1987

 

"[Stevia] is employed in the country where it is found for

sweetening Paraguay tea, (Mate)."

Dietrich 1909

 

"This Species was known by the Guarany Indians under several names

(Caa-jhe-he, Caa-hee, Ca-a-yupe, Azuca-caa, Eria-caa) related to its

sweet leaf taste and to its use in sweet beverages, remedies,

especially the cooked mate' (Ilex paraguariensis)."

Handro 1989

 

The most common use of stevia was mixed with mate. Bertoni reports

in Revista De Agronomia, 1899, that the annual consumption of mate

for Paraguay was 8 kilograms per person per year. Dividing 8000

grams by 365 days per year results in a daily average per capita

consumption of 22 grams of yerba mate. Using the weight of 2 to 3

grams of yerba mater per cup of tea results in a per capita

consumption of 7 to 11 cups of mate per day.

 

STEVIA FOR SWEETENING TEA AND COFFEE

 

"Two or three leaves are enough to sweeten a cup of tea or

coffee.... Stevia leaves can be kept indefinitely in the dried

condition.... They may be added whole or powdered to tea or coffee

and the powdered leaves could be added to stewed fruit and other

dishes without the necessity for separating the sweet principles."

Melville 1941

 

"The leaves are small and the flowers still more diminutive, and

the Indians call it Caa-ehe, meaning sweet herb, because of its

sweetness, a few leaves being sufficient to sweeten a strong cup of

tea or coffee, giving also a pleasant aromatic flavor."

Kew bull. 1901

 

"...three to four little leaves of the plant are sufficient to

sweeten a cup of tea. Forms of utilization: pulverized leaves and

extract."

Paraguay, Cartilla, 1939

 

"Eight or ten leaves can sweeten 50-80 grams of tea or coffee,

black or with milk."

Samaniego 1946

 

STEVIA FOR SWEETENING OTHER BEVERAGES

 

"They can be added to any hot or cold drink without an advance

preparation; the effect is instantaneous and, except for the

sweetness, no flavor or property is altered because of them.

Bertoni 1905

 

"...[Stevia], possessing leaves having such a remarkable sweetness

that the natives used them to sweeten bitter drinks."

Fletcher, 1955

 

"The natives of Paraguay, where the shrub is grown or found, have

used it to sweeten bitter beverages for many years."

Jacobs, 1955

 

"This Species was known by the Guarany Indians under several names

(Caa-jhe-he, Caa-hee, Ca-a-yupe, Azuca-caa, Eria-caa) related to its

sweet leaf taste and to its use in sweet beverages, remedies,

especially the cooked mate' (Ilex paraguariensis)."

Handro 1989

 

STEVIA FOR SWEETENING MANUFACTURED SOFT DRINKS

 

"Encouraged by these first results, an industrial chemist, Mr. C.

Bieneck prepared and marketed in Buenos Aires a gaseous non-alcoholic

beverage [soft drink] for diabetics based on Caa-Hee which was very

well received."

Juan B. Aranda J. 1932

 

FORMS AND AMOUNTS OF STEVIA USED

 

Stevia was used in several forms and in various amounts. Most

commonly it was used dry and mixed with other herbs such as yerba

mate and with other dry plant materials used to brew beverages such

as tea and coffee. It was also used in the form of extract. In some

references, whole leaves were added to coffee or tea and then later

removed. Stevia leaves remained in the cup with the herbs when yerba

mate was prepared. The leaves and herbs were not removed while

drinking the beverage. The range of use cited was 2 leaves minimum

to 4 leaves maximum per cup of tea or coffee.

 

"Two or three leaves are enough to sweeten a cup of tea or coffee."

"Stevia leaves can be kept indefinitely in the dried condition."

"They may be added whole or powdered to tea or coffee and the

powdered leaves could be added to stewed fruit and other dishes

without the necessity for separating the sweet principles."

Melville 1941

 

"The leaves are small and the flowers still more diminutive, and

the Indians call it Caa-ehe, meaning sweet herb, because of its

sweetness, a few leaves being sufficient to sweeten a strong cup of

tea or coffee, giving also a pleasant aromatic flavor."

Kew bull. 1901

 

"a few small leaves are sufficient to sweeten a strong cup of

coffee or tea."

Bertoni 1905

 

"three to four little leaves of the plant are sufficient to sweeten

a cup of tea. Forms of utilization: pulverized leaves and extract."

Paraguay, Ministry of Economy, 1939

 

"Eight to ten leaves can sweeten 50-80 grams of tea or coffee,

black or with milk."

Samaniego 1946

 

DIETARY HABITS OF PARAGUAYAN INDIANS

 

FDA requested general information of Paraguayan Indians dietary

habits. The peoples of the region of Paraguay, southern Brazil and

northern Argentina shared similar diet and customs, in fact so

homogeneous that the region has a name, which is Chaco. A detailed

description of the diet of Brazilians written by Olivera, 1993, is

attached.

 

PUBLIC HEALTH RECORDS

 

FDA's intent is to determine if stevia was safely used as a food.

The food additive regulations do not provide a criteria for

evaluating the safety of a food based upon the presence, absence,

quality or quantity of the public health records or reporting

systems.

 

The safety of stevia can be demonstrated by reports from the

Brazilian and Paraguayan government and numerous reports in the

literature of the absence of adverse effects from the consumption of

stevia leaves. All reports in the literature concerning the safety

of stevia leaves are positive. A complete review of all literature

fails to report a single adverse reaction from the consumption of

stevia leaf or extract of stevia.

 

A report from the Brazilian department of health states, "We

analyzed the literary data, statistics on consumption of medications

and popular knowledge, and were unable to find any parameter on file

for decades which might relate Caa'-He-e to any ill effects on

health, intoxication or pain among the people."

Marques 1993

 

"The pharmacology division of this department has sent us an

opinion stating that the active ingredient, Stevia rebaudiana

Bertoni, commonly known in our country as KA'A HE'E has been

evaluated and no undesirable effects of it have been found."

Paraguayan Ministry of Public Health and Welfare, 1993

 

A report from the Brazilian department of health, and the Paraguayan

department of health and welfare are attached for FDA review.

Additional data regarding safety is contained elsewhere in this text

in the section named SAFETY and in other parts of this text and

petition.

 

USE AS FOOD, NOT DRUG

FDA states, "The requested information must demonstrate that stevia

was in fact used as a food ingredient and not as a drug, tonic or

folk remedy."

 

All references state that stevia was used in beverages such as yerba

matte, tea, coffee, and herbal tea. References on use clearly

establish stevia was used as a food. Refer to the COMMON USE section

and WITH WHAT OTHER FOODS section of this text for details about how

stevia was used as a food.

 

 

RESPONSE TO FDA LETTER DATED MARCH 31, 1993

A. Orstan to Pendergast

 

FDA requested additional data citing as their authority CFR

170.35(c)(1). The results of a review of 21 CFR 170.35(c)(1) and the

requests for data made by FDA indicate that some of the data FDA is

requesting is not required. As in other parts of this text, an

effort is made to provide the exact information FDA is requesting,

when such a request is not unreasonable. In other areas the answer

provided is intended to respond to the section of regulation that FDA

has cited.

 

FOODS IN WHICH STEVIA USE IS INTENDED

 

FOODS

 

The food in which stevia is to be used would be any beverage brewed

from or composed of primarily plant materials such as but not limited

to herbs, spices, tea, coffee, with the extractives and/or essential

oils of plants and/or other nautral or artificial flavorings. This

definition of use would primarily include, but not to be limited to

dried herbs, herb tea blends, tea, tea blends, coffee, or stevia leaf

as a single ingredient. The form of the food intended for sale is a

dried plant mixture, with or without the addition of natural and or

artificial flavorings designed for brewing beverages.

 

AMOUNT TO USE IN FOODS

 

Typical use in tea would not exceed 5% by weight of stevia leaf in

the blend of the dry material to be sold as tea to be brewed,

percolated or otherwise extracted to make the beverage. This level

is not dictated by safety concerns, but was cited by herbal tea

manufacturers as the maximum level which would impart the desired

flavor.

 

The AHPA is not requesting, nor does it see any need to limit by way

of regulation, the amount or level of use of stevia leaf. Stevia

leaf has been used in the USA, and will be used in the future, as any

other GRAS food substance, in accordance with Current Good

Manufacturing Practices, and in forms and in amounts reasonably

required to accomplish the intended effect. The amount of stevia

used is directly related to the intended effect, namely, imparting

stevia flavor. The amount required to produce the intended effect is

determined by the flavor desired.

 

The amount used would be a very small amount and limited by the

practical consideration that stevia imparts a disagreeable flavor at

anything other than small levels of use. Most consumers would find

the flavor imparted by the use of stevia leaf in a beverage at a

level greater than 5% to be unacceptable. This point is aptly

summarized by Dr. Malone in the "HRF Safety review for Stevia

Rebaudiana, 1992" when he stated, "It is doubtful that these

materials would ever be used in excess of these amounts because of

taste aesthetics. Therefore these materials must be considered as

very safe when used as food/drink additives."

 

PESTICIDE RESIDUE

FDA states, "With regard to manufacture, the petitioner should

address (a) how pesticide residues on stevia leaf would be controlled

and (b) the procedures used to control microbial contamination and

mold growth."

 

Measures used to control pesticides in stevia are the same as those

used for any other raw agricultural commodity. These measures

include but are not limited to:

 

Avoiding application of pesticides unless necessary

Using alternative or integrated pest control measures

Use of the appropriate pesticide for the pest and crop

Application in minimum amount to establish intended effect

Avoiding planting on contaminated group or use of contaminated

irrigation water

Allowing borders at edge of fields to reduce over spray, etc.

 

The cultivation of stevia leaf requires no specific pesticides for

growth. Stevia is used finely chopped and its appearance has no

bearing on its value unlike other crops such as fruits and vegetables

which are scrutinized for insect damage prior to purchase.

 

HRF interviewed two organizations that grow stevia, one in Brazil and

the other in Japan. Both organizations stated that no pesticides are

applied to the stevia crops. Subsequent analysis of sample from both

countries resulted in no pesticide residue detected. The amount of

pesticide residue present on stevia leaf imported into the USA would

by law need to comply with levels set forth in EPA and FDA

regulations for pesticide tolerances, as would any other food.

 

Analysis of pesticides in stevia can be performed by typical methods

used for other herbs and spices, and published by the Association of

Official Analytical Chemists, FDA, EPA, or other reliable sources.

 

CONTROL OF MICROBES

 

Control of Microbial growth is achieved by the same methods as any

other food crop grown in a similar manner. Efforts are made to keep

the crop free of animal waste during cultivation. The crop is cut,

leaving the root (and soil) in the ground. Care is taken to remove

excess dirt from plant materials prior to drying. Drying is done

under controlled conditions to assure prompt and even drying to

sufficient dryness that will no longer support microbial growth.

Stevia is then packaged and stored in closed containers in a clean

dry building to protect it from the elements and prevent microbial

contamination.

 

Since stevia is a leaf crop, and the common form of use is dried

leaves, moisture is removed to a level at which water activity does

not permit microbiological growth.

 

NATURAL TOXICANTS

FDA states, "The petitioner should comment as to whether stevia leaf

contains any natural toxins."

 

There are no compounds of toxicological concern present in stevia

leaf. The chemical composition of stevia leaf was evaluated by

Kinghorn in 1985 and 1992. Upon a thorough review of all literature

available and all chemical compounds cited in the literature, none

were found to be naturally occurring toxicants.

 

"...a few small leaves are suffient to sweeten a strong cup of

coffee or tea. To this must be added that the plant does not contain

any noxious substance whatever which might tend to limits it's use,"

Bertoni, 1901

 

HYBRIDS

FDA states, "The petitioner should clarify the botanical nature of

the 'hybrides' that may be utilized and provide information

concerning pesticide residues and natural toxicants in these

'hybrides.'"

 

This petition is for the approval of Stevia rebaudiana Bertoni.

Stevia hybrids would be handled by FDA as are any other hybridized

food crops.

 

HEAVY METALS

FDA states, "The petitioner should analyze five batches of stevia

leaf representative of different growing regions for lead, cadmium,

arsenic and mercury, and discuss typical ranges expected for these

metals. The petitioner should provide all raw data and a description

of the analytical methodology used, including the limit of detection

for the method."

 

FDA's requests for heavy metals analysis data from 5 batches of

stevia is not relevant to the approval of stevia as a food. FDA has

no authority to request such data. 170.35(c)(1)(f) only requires the

submission of a specification for food grade materials including

arsenic and heavy metals. To the best of oru knowledge, the only

tolerances FDA has set for heavy metals are in pottery and drinking

water. Stevia, like other foods, would be expected to be free of

contaminants and can be tested for heavy metals by atomic absorption

spectroscopy, just as with other foods.

 

A search of regulations and a check for informal guildelines with the

American Spice Trade Association found that no standards have been

set by regulation, no defect action levels exist, and no informal

guidelines exist for levels of heavy metal contamination of herbs and

spices.

 

Stevia leaf will be free of levels of heavy metals that might

constitute a hazardous or deleterious substance in the context of its

intended use.

 

A review of the Food Chemicals Codex (FCC), third supplement to third

edition, 1992, reveals that specifications for heavy metals exist

only for 3 types of heavy metals: total heavy metals (as lead),

arsenic, and lead. For that reason only these substances have been

included in the specification provided in reply to FDA's request.

 

The levels set for stevia herb are based upon levels already approved

in the FCC for substances that would be used in a similar amnner. In

light of the fact that stevia leaf would be used in beverages to

impart a sweet taste, the FCC specification for sucrose was used as a

model for the heavy metals specification for stevia leaf.

Considering that the stevia use level would be one thirtieth (1/30)

that of sucrose for the same application, the specified level is very

appropriate. Based upon the review of monographs in the FCC for

substances similar to stevia, we conclude that the following

specification is appropriate for stevia leaf.

 

Heavy Metals (as Pb) not more than 5.0 mg/kg.

Arsenic not more than 1.0 mg/kg.

Lead not more than 0.5 mg/kg.

 

STEVIOL

FDA states, "The petitioner should address whether steviol (a) is a

component of the leaf itself and (b) could be formed in teas prepared

with dried stevia leaf."

 

Steviol is not a component of stevia leaf (Kinghorn 1985, page 7.)

Stevia rebaudiana leaves have never been found to create or release

steviol No study has shown that steviol occurs as a component of

stevia leaf or that steviol could occur as a result of food

processing. Concern over the presence or absence of steviol in

stevia leaf is without scientific basis.

 

Change (1983), in a stability study of carbonated beverages, showed

steviol is not a degradation product of stevioside and rebaudioside.

 

Steviol has only been shown to occur as a metabolite of purified

stevioside or rebaudioside, and present only after it is

metabolically activated, under laboratory conditions that are not

applicable to the normal use of the stevia leaf or stevia leaf

extracts. The Stevia rebaudiana Safety Review (page 24) documents

the fact that several studies in rats show neither stevia nor

stevioside to be mutagenic.

 

In the discussion of mutagenicity, Pezzutto states that a

precondition for the creation of steviol from radioactively labeled

refined stevioside was dependent upon the pretreatment of rats with

Aroclor 1254 and the addition of NADPH and with four consecutive

daily injections of methylchloanthrene and phenobarbitral at 75 mg/kg

body. The rats were decapitated and a 9000x g supernatant fraction

of the liver of these pretreated rats was applied to a bacterial

mutagenicity assay. The result of this work was clarified in the

same paper, stating that refined stevioside has repeatedly been found

not to be mutagenic.

 

Only work with isolated and purified components of stevia leaf, such

as stevioside and rebaudiasie, have been degraded to steviol in a rat

cecum in vitro and in only one experiment. Kinghorn points out that

there is no evidence that steviol is either a human metabolite or a

metabolite of human microflora.

 

Procinksa (1991) reported an attempt to duplicate Pezzuto's work, and

concluded that Pezzutto had made statistically significant errors in

handling of the data. Procinksa's research failed even to confirm

the mutagenicity of microbially produced and enzymatically altered

steviol.

 

Hooks (1987) showed a-gloucosyl steviol glycoside had no negative

effect on rats.

 

Steviol is a microbial metabolite of refined stevioside and

rebaudiaside and has not been shown to occur in nature or in man.

Numerous studies have found stevioside is not mutagenic, nor is

stevia leaf. Experiments with mutagenicity of steviol have not been

reproducible.

 

INDENTIFICATION METHOD

FDA states, "The petitioner should provide a protocol for microscopic

analysis of stevia leaves in tea.... Reference no. 7 in the petition

reviews the analytical methodology for identifying components of

stevia leaf in foods. To document the sensitivity and

reproducibility of these methods, the petitioner should provide

copies of the original references."

 

Powdered stevia leaf can be identified by microscopic analysis,

comparing the food to authenticated specimens of stevia leaf,

according to standard micromorphological techniques. Stevioside and

other unique stevia compounds can be analyzed by several published

methods reviewed in Kinghorn 1985 and 1992. Attached are two methods

which have been used by FDA for analysis of stevioside in the stevia

leaf and stevioside in herb tea. The FDA method for herb tea is

based upon the article "TLC and LC determination of Stevioside and

Rebaudiaside A in Beverages and Foods Following Reverse Phase Column

Chromatography." JAOAC, vol. 69, no. 5, 1986, p. 799-802. Another

FDA method used for stevia herb is cited as Ann. Chem. 76, (1-2)

1986, 39-44, Ist. Sci. Chim. Univ. of Bologna. See also:

 

Kim, 1983, Lorean J. Food Sci. Technol. vol. 15, no. 3

Hashimoto, 1978, Journal of Chromatography, 161

Tanaka, 1980, Saengyak Hakhoe Chi, vol. 11

Sakamoto, 1977, Chem. Pharm. Bull., 25, (4)

Darise, 1983, Agric Biol. Chem. 47(1) _

 

AMOUNT OF DRIED LEAVES PER CUP

FDA states, "The petitioner should indicate the typical amount of

dried stevia leaves that would be used per cup of tea."

 

A probable maximum of 5% of dried stevia leaf is the expected use

level in herb tea blends, tea, tea blends, coffee or other beverages.

See details under heading AMOUNT TO USE IN FOODS.

 

 

RESPONSE TO ISSUES RAISED AT A METTING WITH FDA

ON July 28, 1992

 

PRECONDITION FOR FILING GRAS PETITION

FDA states, "We informed the visitors that FDA will file a GRAS

petition based on history of common use only after FDA is convinced

that there is a reasonable chance that the petition will result in

the affirmation of the substance in question as GRAS."

 

ADEQUACY OF DATA

FDA stated data filed previously, up to and including the GRAS

petition dated April 23, 1992, was inadequate

 

When AHPA asked FDA how they define adequacy of data, FDA stated that

they did not have a numerical standard for data. FDA stated their

standard for data was a substantial history of consumption of a food

substance by a significant number of consumers. FDA further stated

that if AHPA could meet that standard then FDA would file the

petition.

 

As stated earlier, the petition--including this submission--contains

articles published in scientific journals documenting the safe use of

stevia. These articles were written by botanists, chemists, and food

technologists who are experts qualified by training and experience.

Over 120 articles about stevia were written prior to 1958. Most of

the articles are written by scientists or government officials. Only

three of the 120 articles referred to were written by or published

for the lay public. All were published in journals and books.

Several more articles written after 1958 reviewed the use of stevia

as food prior to 1958. Over 900 articles have been published on

stevia to date.

 

Some of the articles written about stevia were funded by the United

States Government. Letters on file at USDA chronicle the fact that

the US government had samples of stevia leaf and intended to

investigate it as a crop for the USA as early as 1921 (Van Eseltine,

1921). Articles written by American scholars and published in

American journals prior to 1958 clearly state stevia leaf has been

used in Paraguay for many years and that no adverse effects have ever

been reported from the consumption of stevia leaf. Fletcher 1955,

Jacobs 1955, Bell 1954, Chem + Eng. News. 1956.

 

The stevia documentation is not anecdotal but represents the work of

qualified researchers from distinguished universities and

organizations, published in scientific journals. Almost all of these

documents are readily available in the United States. Stevia was

well known and thoroughly studied by 1958. The petition is based

upon generally available data and information and complies with 21

CFR 170.30(c)(1) and 21 CFR 170.30(c)(2) in that respect.

 

Stevia has been consumed by the peoples of Paraguay and southern

Brazil continuously for centuries, before the arrival of the

Conquistadors, that is for more than 466 years prior to 1958. We

believe this substantial history of consumption as a food substance

by a significant number of consumers meets the criteria for common

use in food as defined by 21 CFR 170.3(f). The petition is based

upon generally available data and information and complies with 21

CFR 170.30(c)(1) and 21 CFR 170.30(c)(2) in that respect.

 

The Stevia Rebaudiana Safety Review, incorporated into this GRAS

petition, was written by Douglas Kinghorn, Ph.D., and peer reviewed

by Marvin Malone Ph.D., Andrew Weil MD, and Ryan Huxtable Ph.D. The

views of these experts, along with the views of other authors cited

in this text are those of experts qualified by scientific training

and experience to evaluate the safety of substances directly or

indirectly added to food. Their determination that stevia is safe is

consistent with 21 CFR 170.30(a).

 

We concur with FDA that it is impossible in the present state of

scientific knowledge to establish with complete certainty the

absolute harmlessness of any substance. However, in the context of

21 CFR 170.30(i), there is a reasonable certainty in the minds of

competent scientists that stevia leaf is not harmful under the

intended conditions of use. This certainty is based upon reports

from the Governments of Brazil and Paraguay and the absences of any

report of adverse reaction to stevia leaves in the literature. We

can conclude that stevia is safe for use in food as defined by 21 CFR

170.3(i).

 

CONCLUSION

The data contained within this petition and text clearly complies

with all the applicable requirements of 21 CFR part 170, with the

legal and scientific criteria in order for Stevia Rebaudiana leaf to

be Generally Recognized As Safe, based upon the fact that Stevia was

commonly and safely used in food prior to 1958.

 

 

 

Food Ingredient Specification

Stevia Leaf

 

According to 21 CFR 170.35(c)(1)(i), a GRAS petition needs to include

a specification for food grade materials. This subpart referred to

Food Chemicals Codex (FCC). The Food Chemicals Codex includes

specifications for many chemical food additives, as the name implies,

but does not include specifications for any spices or herbs listed as

GRAS by 21 CFR. However, the specifications in the FCC were used as

a model to develop this food ingredient specification.

 

Substance Stevia herb

 

Description Stevia is the dried above-ground portion of the

plant Stevia rebuadiana Bertoni. The plant is

grown as a leaf crop, but commercial material

may include small amounts of flowers, stems and

seeds.

 

Identification 1) Stevia can be identified botanically

according to the description in Robinson, B.L.

1930. Contributions from the Gray Herbarium

of Harvard University. 90, 79-90.

2) Processed stevia leaf can be identified

microscopically by comparison with authenticated

samples.

3) Stevia contains the unique chemical

compound stevioside. Confirmation of stevioside

in stevia leaves or finished products will

indicate the presence of stevia leaf or its

extracts. Methods for analysis include:

 

JAOAC, vol. 69, no. 5, 1986, p. 799-802.

Ann. Chem. 76, (1-2) 1986, 39-44.

Kim, 1983, Korean J. Food Sci. Technol.

vol. 15, no. 3

Hashimoto, 1978, Journal of

Chromatography, 161

Sakamoto, 1977, Chem. Pharm. Bull., 25,

(4)

 

Heavy metals (as Pb) 5.0 mg/kg

Lead 0.5 mg/kg

Arsenic 1.0 mg/kg

 

Loss on drying 12% maximum

 

Residue on ignition 6% maximum

 

Purity 97%

 

Salmonella negative in 100 grams

 

Funcation use in food Flavor ingredient

 

Packaging and Storage Dried plant material needs no special

packaging or storage. Pack in clean bags

or cartons and store in a cool dry location.

 

 

STEVIA REBAUDIANA BERTONI

JOURNAL and BOOK LISTINGS

Cited in Supplement to Stevia GRAS Affirmation

Petition No. 2G0390

Herb Research Foundation

Submission of September 24, 1993

 

By first author

 

Anonymous. 1901. Caa-ehe or azuca-caa (Note based on communication

from Cecil Gosling). Bull Misc. Inf. Royal Bot. Garden. 173-174

(English) H

 

Anonymous. 1920. The caa-ehe plant as a sweetening agent. Bull Imp

Inst (London). Vol. 18(1) 123-125 H

 

Anonymous. 1939. Ka'a he'e (Stevia Rebaudiana Bert.) In Cartilla

de propaganda agro-pecuaria. 24-25 Asuncion: Ministerio de

economia, Paraguay (Spanish) H

 

Anonymous. 1942. Growing the new sugar plant. Western Morning

News. June 1 1p (English) H

 

Anonymous. 1956. Sweetest of all: Sweetness of the "sweet herb of

Paraguay" -- as well as the chemistry -- is unusual. C & EN, January

9 124-126 (English) HT

 

Anonymous. 1993. Ministry of Agriculture and Animal Husbandry,

Paraguay.

 

Aranda J[imenez], Juan B., 1932. La yerba dulce (caa-hee) (Stevia

Rebaudiana Bert.). 6p [Asuncion]: Ministerio de Agricultura y

Ganaderia (Spanish) H

 

Bell, F., 1954. Stevioside: A unique sweetening agent. Chemistry

and Industry, Vol. 32 897-898 (English) HT

 

Benitez, E.G. de. 1993. Department of Health Statistics and

Information, Paraguay.

 

Bertoni, M.S., 1899. El caa-ehe (Eupatorium rebaudianum, species

nova): Una nueva planta sacarifera. Rev Agron (Asuncion). Vol. 1

35-37 (Spanish) H

 

Bertoni, M.S., 1901. Caa-ehe; Eupatorium Rebaudianum (species

nova) a new sacchariferous plant. The Paraguay Monthly Review. June

Vol. Iere annee (6) 149-151 (English and Spanish) H

 

Bertoni, M.S., 1905. Anales Cient Paraguayos. Vol. Ser I, 5(1)

 

Bertoni, M.S., 1918. Stevia rebaudiana Bertoni; Stevina and

rebaudina, new sweetening substances. Anales Cient Paraguayos.

Enero Vol II (2) 1-4 (English) (English tras. of Spanish original)

HT

 

Bertoni, M.S., 1926. Agenda & mentor agricola. Guia del agricultr &

colono con el calendario de todos los trabajos rurales. 3a edicion

(ed.) 46-47 Puerto Bertoni, Paraguay: Imp renta y edicion "Ex

Sylvis" (Spanish) H

 

Caffarena, J.C.M., Ph.D. 1993. Ministry of Public Health and

Welfare, Paraguay.

 

Chang, Shin S.; Joanne M. Cook. 1983. Stability studies of

stevioside and rebaudioside A in carbonated beverages. J. Agric.

Food Chem., Vol. 31 409-412 HT

 

Darise, Muchsin; Hiroshi Kohda, Kenji Mizutani, et. 1983. Chemical

constituents of flowers of Stevia rebaudiana Bertoni. Ag Biol Chem.

Vol. 47(1) 133-135 (English) HT

 

Dieterich. 1909. Composition of Eupatorium rebaudianum. Chemist &

Druggist, June 5 1p (English) H

 

FDA, Methods for Analysis of Stevia, 89-453-341.

 

FDA, Methods for Analysis of Stevia in Food, 89-453-342.

 

Fletcher, Hewitt G., Jr., 1955. The sweet herb of Paraguay.

Chemurgic Digest. Vol. 14 (7-8) 7, 18 (English) HT

 

Handro, Walter, 1989. Stevia rebaudiana (Bert.) Bertoni: production

of natural sweeteners. Biotecnol Agric For, Berlin. Vol. 7 468-487.

 

Hashimoto, Yohei, 1978. Determination of sweet components in Stevia

rebaudiana by high-performance liquid chromatography. Ultraviolet

detection. Shoyakugaku Zasshi. Vol. 32 209-211 (English) A

 

Hodge, J.E., 1974. Structural aspects of glycosidic sweeteners

containing (1'2)-linked dissacharides. In Inglett, Symposium:

Sweeteners. 216-234 Avi Publishing Co. Connecticut

 

Hooks, William N., 1987. Alpha-glucosyl steviol glycoside toxicity

to rats by repeated dietary administration for 13 weeks. 5p Tokyo &

Huntingdon: Toyo Seito K.K. & Huntingdon Research Centre Ltd

(English) T

 

Jacobs, M.B., 1955. Sweetening power of stevioside. American

Perfumer. December Vol. 66 44,46 H S3

 

Kim, Nam Soo, 1983. Comparative studies on the assay methods of

stevia sweeteners. Han'guk sikp'um kwahakhoe chi. Vol. 15(3)

209-214 (English) AT

 

Kinghorn, 1985. Current status of stevioside as a sweetening agent

for human use. In Wagner, Economic and Medicinal Plant Research,

vol. 1. 1-52 NY: Academic (English) HT

 

Kinghorn, 1992. Food ingredient safety review: Stevia rebaudiana

leaves. 46 Chicago: Prepared for Herb Research Foundation

[unpublished] (English) T

 

Marques, L.C., 1993. State of Parana, State Secretary of Health,

Brazil.

 

Melville, R. 1941. Stevia rebaudiana as a substitute for sugar &

saccharin (Memo to the director). 1p Kew, England: Royal Botanic

Gardens (English) H

 

Oliveira, E.R.N. de, 1993. State University Foundation of Maringa,

Parana, Brazil.

 

Phillips, 1987. Stevia: Steps in developing a new sweetener. In

Grenby, Developments in Sweeteners, vol. 3. 1-43 Amsterdam:

Elsevier H S5

 

Procinska, E.; B.A. Bridges, J.R. Hanson, 1991. Interpretation of

results with the 8-azaguanine resistance system in Salmonella

typhimurium: No evidence for direct-acting mutagenesis by

15-oxosteviol, a possible metabolite of stevio. Mutagenesis. Vol. 6

165-167 (English) HT S40

 

Sakamoto, Ikunori. 1977. Application of 13C NMR spectroscopy to

chemistry of natural glycosides: Rebaudioside-C, a new sweet

diterpene glycoside of Stevia rebaudiana. Chem Pharm Bull. Vol. 25

844-846 AT

 

Sakamoto, Ikunori. 1977. Application of carbon-13 NMR spectroscopy

to chemistry of plant glycosides: Rebaudiosides-D and E, new sweet

diterpene glucosides of Stevia rebaudiana Bertoni. Chem Pharm Bull.

Vol. 25 (12) 3437-3439 (English) AT

 

Samaniego, Cesar C., 1946. Stevia rebaudiana -- "caa-jhe-he" (Herba

dulce). Revista Farmaceutica, Buenos Aries. Vol. 88 199-202

(Spanish) AT

 

Schmeling, G.A. von, 1967. Caa-Hee. Edulcorante ano calorico

(Stevia rebaudiana Bertoni). Boletim do Sanatorio Sao Lucas. Vol.

XCIV (5) 67-78 (Portuguese)

 

Tanaka, Osamu, 1980. Chemistry of Stevia rebaudiana Bertoni. New

source of natural sweeteners. Saengyak Hakhoe Chi (Hanguk Saengyak

Hakhoe). Vol. 11 (3-4) 219-227 (English) AT

 

Van Eseltine, G.P., 1921. USDA correspondence to Jiminez, Paraguay.

 

Wood, 1955. III Stevioside. The anomeric

2,3,4,6-Tetra-0-aeyl-1-0-mesitoyl-D-glucopyranoses and their

behaviour with alkali. J American Chemical Society. Vol. 70 (207)

207-210 H
HERB RESEARCH FOUNDATION

------------------------

 

Supplement To

GRAS Affirmation Petition Number 2G0390

Stevia rebaudiana Bertoni

 

 

INTRODUCTION

 

This document and others previously submitted and incorporated by

reference constitute a complete supplement to Stevia GRAS Affirmation

Petition number 2G0390. This supplement is complete in that it

address all issues raised in FDA's "not-filed" letters of June 24,

1992 and March 31, 1993 from A. Orstan to W.R. Pendergast.

 

This supplement is a submission of additional information to the GRAS

petition filed on behalf of the American Herbal Products Association

(AHPA) by Bill Pendergast of the law firm Arent, Fox. All previous

data submitted including the GRAS petition submitted on April 23,

1992, and request for recognition of GRAS status of October 21, 1991

and all other documents and letters rearding stevia herb submitted to

FDA on behalf of the AHPA are hereby incorporated by reference. The

word petition in this text signifies the Stevia GRAS petition, which

includes the aforementioned documents and this text in that

definition.

 

This document was written by the Herb Research Foundation (HRF),

under contract from the American Herbal Products Association. The

Herb Research Foundation has created this document without the

editorial influence of the AHPA and is solely responsible for its

content.

 

The common name of Stevia rebaudiana Bertoni, is written variously as

stevia, stevia herb, stevia leaf and by common names it was known by

in Paraguay and Brazil. The common names for stevia used by

Paraguayans and Brazilians are quoted from various sources and

spelled in several different ways, such as Kaa-hee, Ka-he-e,

Caa-He-e, Caa-ehe, Caa-hee, Ca-jhe-e, etc.

 

In addition, the text refers to the plant Ilex paraguaiensis, which

is known by the common names mate, yerba mate, matte, and yerba

matte.

 

FORMAT: This document will list points raised, and requests made, by

FDA in their letters of June 24, 1992, and March 31, 1993. It also

addresses issues raised in FDA's record of the meeting on July 28,

1992 between FDA, Bill Pendergast and Timothy Moley.

 

The HRF recognizes that FDA has requested the following data, citing

the authority of title 21 of the Code of Federal Regulations,

especially parts 170.30(c), 170.35(c)(1), 170.30(c)(2), 170.3(i), and

170.3(f). The HRF is familiar with the Food Additive Regulations.

To the best of our knowledge, the data listed below, combined with

data in previous submission, meets the criteria set forth in 21 CFR

parts 170.

 

HRF is also very familiar with data submitted in the previous

petition, in part because some of that data (in particular, the

Stevia rebaudiana Safety Review) was prepared by HRF.

 

This report addresses statements and requests made by FDA in response

to the AHPA GRAS petition for stevia.

 

 

RESPONSE TO FDA LETTER DATED JUNE 24, 1992

A. Orstan to W.R. Pendergast

 

QUALITY AND AVAILABILITY OF INFORMATION

FDA states, "The petition contains mostly anecdotal and speculative

information..."

 

The petition--including this submission--contains articles published

in scientific journals documenting the safe use of stevia. These

articles were written by botanists, chemists, and food technologists

who are experts qualified by training and experience. Over 120

articles about stevia were written prior to 1958. Most of the

articles are written by scientists or government officials. Only

three of the 120 articles referred to were written by or published

for the lay public. All were published in journals and books.

Several more articles written after 1958 reviewed the use of stevia

as food prior to 1958. Over 900 articles have been published on

stevia to date.

 

Some of the articles written about stevia were funded by the United

States Government. Letters on file at USDA chronicle the fact that

the US government had samples of stevia leaf and intended to

investigate it as a crop for the USA as early as 1921 (Van Eseltine,

1921). Articles written by American scholars and published in

American journals prior to 1958 clearly state stevia leaf has been

used in Paraguay for many years and that no adverse effects have ever

been reported from the consumption of stevia leaf. Fletcher 1955,

Jacobs 1955, Bell 1954, Chem + Eng. News. 1956.

 

The stevia documentation is not anecdotal but represents the work of

qualified researchers from distinguished universities and

organizations, published in scientific journals. Almost all of these

documents are readily available in the United States. Stevia was

well known and thoroughly studied by 1958. The petition is based

upon generally available data and information and complies with 21

CFR 170.30(c)(1) and 21 CFR 170.30(c)(2) in that respect.

 

HOW WELL KNOWN WAS STEVIA?

FDA states, "...during most of this century stevia was a very rare

plant in Paraguay"

 

Articles stating stevia is rare were written in 1899 and 1905 by

Bertoni. In Bertoni's 1905 article he says, "Six years after my

first article, I am now able to give a complete description of Kaa

he-e and some additional data. This lapse of time illustrates the

difficulties involved in trying to seriously study a rare of

little-known Paraguayan plant." Bertoni's early usage of this

language certainly does not mean that it could not have been a

frequently used food plant. Bertoni was an Italian botanist, not

living in the region of Paraguay where stevia was grown and used.

His difficulty with the language spoken in, and problems traveling

to, Paraguay, initially limited his knowledge of the area and plant,

but this was later overcome.

 

"This plant, which has probably been known to the Indians since a

hundred years or more and whose secret has as usual been so

faithfully guarded by them,..."

Kew Bull 1901

 

To understand why a plant could be described as rare, when it is not,

let's consider ginseng in USA as an example. Ginseng is a rare plant

in the wild; in fact it is considered a threatened species. If a

foreigner were to try to find wild ginseng in the USA they might

describe it as a rare plant. It is highly unlikely that it could be

found without the assistance of local people, who may not be inclined

to help anyone find the herb, even though they know where it grows.

Its rarity is that it is challenging to find. However, many peopel

who live where ginseng grows could easily find large stands of wild

ginseng. Ginseng is also challenging to cultivate.

 

Despite the appearance and the belief that ginseng is a rare plant,

its use has been, and still is, very common. The same was true for

stevia in Paraguay in the late 1800s with an Italian botanist trying

to find it. The articles describing stevia as a rare plant were

written by foreign botanists. There was no overland method of travel

during that time, and travel to and within Paraguay entailed an

up-river journey of many days by steamship.

 

By the 1913, stevia was no longer considered a rare plant, and by

1920 it was cultivated in plantations.

 

"In 1913, new examinations of the now famous Stevia rebaudiana were

completed in three distinct laboratories, in Antwerp, Wiesbaden and

Hamburg. The most conclusive report seems to be that of the Official

Public Laboratory of Hamburg which reads: 'The specimens received

are of the well known plant which has alarmed sugar producers some

years ago.'" (emphasis added) Bertoni 1918

 

"A plantation of Caa-ehe has been established in Paraguay by Senior

Jimenez, who according to the department of Overseas Trade, is stated

to be in a position to supply plants ready packed to stand a long

journey."

Bulletin Imperial Institute of Kew Gardens Vol. 18, 1920

 

"People living along the frontier of Brazil with Paraguay are

mainly those who has been using stevia since time immemorial as a

natural sweetener for foods and beverages, especially mate. This

plant became well known early in this century." Marques 1993

 

Betoni describes stevia as a rare or little known plant in 1899, but

describes it as famous and well known by the year 1913.

 

 

CULTIVATION

FDA states, "...none of the cultivation attempts prior to 1958 in

Paraguay or elsewhere seems to have achieved commercial success."

 

Stevia is a plant that was native to Paraguay. It was harvested from

the wild, where it grew. Early attempts at cultivation were not

fruitful because those attempting to grow it did not understand its

culture and reproduction. By the 1920s stevia was being cultivated.

 

"A plantation of Caa-ehe has been established in Paraguay by Senior

Jimenez, who according to the department of Overseas Trade, is stated

to be in a position to supply plants ready packed to stand a long

journey."

Bulletin Imperial Institute of Kew Gardens Vol. 18, 1920

 

"Cultivated in England," Western Morning News, June 1, 1942

 

"Cultivation of the plant has been carried out in Paraguay both as

a horticultural curiosity and on a larger scale but the latter is

expensive since the seed is usually sterile and reproduction must be

made by subdivision."

Wood 1955

 

A report from the Ministry of Agriculture for the Republic of

Paraguay states that stevia cultivation was on the average 20

hectares per year from 1930 to the 1970.

 

The amount of cultivation is not a determination of common use. Many

foods grew in the wild and were harvested for personal use or for

commercial trade. Often, households had a small patch of stevia in

their backyard that would supply their needs. It is important to

note that major economic plants have been collected from the wild for

decades with no attempt at, or need for, cultivation. This was

certainly true at the turn of the century.

 

Yerba mate was not cultivated, but harvested from the wild. In 1899

the annual production of yerba mate in South America was estimated at

100,000 tons. (Revisita de Agronomia 1899). Many spice crops today,

such as cinnamon in Indonesia, thyme in Spain, and mushrooms in the

USA are harvested from wild stands rather than cultivated. For some

crops, such as ginseng in the US or truffles in France, the wild crop

is preferred over the cultivated crop. To assume the annual

consumption of apples in the USA is equivalent to the harvest

statistic reported by apple farmers would be seriously flawed without

considering the large number of apple trees present in people's yards

across the country.

 

To state that the use of stevia was low due to a lack of cultivation

is erroneous. Stevia was cultivated, although not on a scale equal

to its consumption. The major souce of stevia was from wild stands

and backyard gardens. The trade in stevia occurred mostly on a local

scale in small farmers' markets and herb stores, and was not a matter

of public record. Food additive regulations do not provide a

criteria for evaluating the safety of a food substance based upon

where and how it was grown, whether it was cultivated or harvested

from the wild.

 

COMMON USE

FDA requests "...additional data to help us establish how a rare

plant could have been in common use by a significant number of

consumers."

 

Several articles in scientific journals and documents from the

Paraguayan and Brazilian governments clearly show a substantial

history of consumption of stevia leaf in beverages by a significant

number of consumers.

 

A report from the Brazilian Department of Health states: "It is

public knowledge that Stevia rebaudiana (Ca'-He-e) is a plant native

to this region ordinarily used as a sweetener by natie gauchos,

indigenous people and the general population. People living along

the frontier of Brazil with Paraguay are mainly those who have been

using stevia since time immemorial as a natural sweetener for foods

and beverages, especially mate. This plant became well known early

in this century."

Marques 1993

 

A report from the Paraguayan Ministry of Agriculture states that

over 50% of the population of Paraguay consumes yerba mate, in which

stevia herb is commonly used. The report states that the use of

stevia is more popular by the native peoples and rural populations.

 

"It is non-toxic, as proved by the experiences made with animals

and its large use by the inhabitants of Paraguay since Pre-Columbian

times."

Schmeling 1967

Pre-Columbian refers to the time prior to the arrival of

Christopher Columbus in the Americas in 1492. Therefore this article

states that stevia had been used for at least 466 years prior to

1958.

 

"Although the human consumption of stevia began before the Spanish

settlement of the country we now know as Paraguay, improved versions

have been developed only recently." "Stevia rebaudiana, the sweet

principle is believed to have been used by the Paraguayan Indians for

centuries."

Phillips 1987

 

"The plant, which has probably been known to the Indians since a

hundred years o r more and whose secret has as usual been so

faithfully guarded by them,"

Kew Bull 1901

 

"Some data found in copies of informative documents that the

Conquistadors sent back to Spain and [others] that are kept in the

National Archives in Asuncion indicate that the Caa'jhe-he plant had

been known by the natives since the dawn of history and that they

used it to sweeten medical drinks and in particular, to impart

sweetness to cooked mate, i.e., the cooking of the mate herb."

Samaneigo 1946

 

Stevia has been consumed by the peoples of Paraguay and southern

Brazil continuously for centuries, before the arrival of the

Conquistadors, that is for more than 466 years prior to 1958. We

believe this substantial history of consumption as a food substance

by a significant number of consumers meets the criteria for common

use in food as defined by 21 CFR 170.3(f).

 

SAFETY

FDA states they require enough information to establish "...whether

the experience with the ingredient in common use establishes that use

of the ingredient is safe."

 

The safety of stevia can be demonstrated by reports from the

Brazilian and Paraguayan government and numerous reports in the

literature of the absence of adverse effects from the consumption of

stevia leaves. All reports in the literature concerning the safety

of stevia leaves are positive. A complete review of all available

literature fails to report a single adverse reaction from the

consumption of stevia leaf or extracts of stevia.

 

A report from the Brazilian department of health states "We

analyzed the literary data, statistics on consumption of medications

and popular knowledge, and were unable to find any parameter on file

for decades which might relate Caa'-He-e to any ill effects on

health, intoxication or pain among the people."

Marques 1993

 

"It is non-toxic, as proved by the experiences made with animals

and its large use by the inhabitants of Paraguay since Pre-Columbian

times."

Schmeling 1967

Pre-Columbian refers to the time prior to the arrival of

Christopher Columbus in the Americas in 1492. Therefore this article

states that stevia had been used for at least 466 years prior to

1958.

 

"Experience of its use in man and data from animal feeding trials

indicate that it is safe for human consumption."

Phillips 1987

 

"a few small leaves are sufficient to sweeten a strong cup of

coffee or tea. To this must be added that the plant does not contain

any noxious substance whatever which might tend to limit it's use,"

Bertoni, 1901

 

"It is not toxic but, on the contrary, it is healthful, as shown by

long experience and according to the studies of Dr. Rebaudi."

Bertoni 1918

 

"Furthermore, there are no recorded reports of ill effects in the

Paraguayan users of the leaves of S. rebaudiana."

Hodge, 1974

 

"While no reports of ill effects in the Paraguayan users of the

leaves have come to us, the long term effects of ingestion of

stevioside would have to be investigated carefully before the

material could be used with confidence as a regular sweetening

agent."

Fletcher 1955 (emphasis added)

 

"A new plant, discovered by me, sweetener almost as powerful as

saccharine and without any of the disadvantages of the latter, it

does not have any other action, except that it is slightly tonic, and

can be used in daily doses much higher than those actually needed."

Bertoni, 1926

 

We concur with FDA that it is impossible in the present state of

scientific knowledge to establish with complete certainty the

absolute harmlessness of any substance. However, in the context of

21 CFR 170.3(i), there is a reasonable certainty in the minds of

competent scientists that stevia leaf is not harmful under the

intended conditions of use. This certainty is based upon reports

from the Governments of Brazil and Paraguay and the absence of any

report of adverse reaction to stevia leaves in the literature. We

can conclude that stevia is safe for use in food as defined by 21 CFR

170.3(i).

 

REGULATIONS ON THE CULTURAL CONTEXT OF USE

 

For requesting some of the following information, FDA cites as their

authority a proposed rule published on July 2, 1985 in 50 FR. 27294.

Some of the data FDA is requesting was part of that proposed rule.

However, it was not codified in the final rule in 1988, and as such,

it is not part of Federal Regulations. HRF is unaware of any

precedent for proposed rules being a requirement for--or having the

force of--regulation or being incorporated as policy. Nor does HRF

wish to, in any way, set a precedent for the same, especially in

reference to the criteria for GRAS petitions. We are providing this

information at the request of the AHPA and in the spirit of

cooperation with FDA, but note that some of FDA's requests are for

data not required by the food additive regulations.

 

Furthermore, HRF believes tha tthe cultural context in which a food

is used has no relevance to its safety, which relates only to the

quantity of a substance consumed and the toxicity of that quantity of

the substance. Cultural context of use was not a consideration when

congressman Delaney proposed the Food Additive amendment.

Ethnocentric bias by FDA in the consideration of the cultural context

of the use of a food was not upheld in Fmali Vs Heckler 715 F2.d 1385

(9th cir. 1983).

 

CULTURAL CONTEXT OF USE OF STEVIA

FDA states, "Based on the FDA's list, we request additional

information on the cultural context of the use of stevia by the

Paraguayan Indians before 1958..."

 

Stevia is used to flavor and sweeten beverages. It was commonly

consumed as a beverage. Beverages in Paraguay, Brazil, and Argentina

were consumed as frequently as beverages are consumed in any culture,

at least 4 times to as many as 11 times a day. (Bertoni, 1899)

 

Stevia was most commonly used in the beverage mate. Mate has the

cultural significance of being a social beverage. Often people

drinking mate share a cup among their friends. Mate is prepared with

a large cup of mixed herbs. Mate is mixed with stevia, and this

mixture is known by the common name as terere and or mate cozido.

Hot water is poured on the herbs and the resulting tea is imbibed

through a special straw called a bombilla that has a strainer on the

end of the straw that rests in the cup. The water is replenished in

the cup of herbs and the cup passed to another person who in turn

drinks. The sharing of beverage terere or cozido is the extent of

the cultural significance of its use. Mate or terere is also

consumed by individuals who will drink and replenish the water and

continue drink in that way. In more modern times, mate and other

stevia containing hot beverages are brewed and consumed just as other

teas or herbal teas.

 

HOW OFTEN WAS STEVIA USED?

FDA would like to know how often stevia was consumed.

 

Stevia was consumed as a beverage and the frequency of beverage

consumption, several times a day.

 

"Eight or ten leaves can sweeten 50-80 grams of tea or coffee,

black or with milk. Once the drink is sweetened the leaves should be

removed. Caa jhe-he can be used three or four times a day."

Samaniego 1946

 

The most common use of stevia was its combination with mate as a tea.

Bertoni reports in Revista De Agronomia, 1899, that the annual

consumption of mate for Paraguay was 8 kilograms per person per year.

Dividing 8000 grams by 365 days per year results in a daily average

per capita consumption of 22 grams of yerba mate. Using the weight

of 2 to 3 grams of yerba mater per cup of tea results in a per capita

consumption of 7 to 11 cups of mate per day.

 

We can conclude from this and other parts of the petition that stevia

was used in beverages, primarily mate. Stevia was consumed three to

four times a day. (Samaneigo 1946) The frequency of mate

consumption in Paraguay was about 7 to 11 cups per day. Therefore

for those consumers who used stevia in their mate, their stevia

consumption was up to 11 times per day.

 

ON WHICH OCCASIONS WAS STEVIA USED?

 

Stevia was used as a common daily beverage and n ot limited to

special occasions. No reference stated that its use was for any

special or unusual occasions or ceremonies. Stevia was consumed as a

beverage several times a day, every day.

 

IN LIEU OF WHAT OTHER FOODS?

 

Stevia was not used in lieu of any other foods. Although the

uninformed would think of stevia being used in lieu of sugar, Stevia

was present and used to flavor beverages prior to the introduction of

sugar cane in Paraguay and Brazil. Sugar was henceforth used in lieu

of stevia.

 

"It has now fallen into disuse due to the cultivation of sugar

can;"

Samaniego 1946

 

DIABETIC USE

 

Stevia is safe for diabetics and was used by them to provide a sweet

flavor to their foods.

 

"This species of sweet plant the Ka'a Hee serves to replace sugar

in the regimen of diabetis,"

Paraguay, Cartilla, 1939

 

WITH WHAT OTHER FOODS

 

Stevia was used to flavor beverages, primarily yerba mate, and also

tea, coffee, and other bitter beverages.

 

Juan B. Aranda J., 1932, states that stevia was used to

manufacture a commercially bottled soft drink which was sold in

Argentina. These beverages were consumed singly and with other food

common to the diet of the people of the region.

 

Stevia was used in varying amounts most commonly cited as two to

four leaves per cup.

 

Stevia was used in various forms, most commonly powdered dried

leaf mixed with dry herbs, tea or coffee, whole leaf added to brewed

beverage, and extracts added to beverages. It was commercially sold

as a mixture with yerba matte and in prepared foods such as soft

drinks. (Juan B. Aranda J. 1932)

 

Stevia was consumed with beverages as frequently as 3 to 11 times

a day, and according to Bertoni (1926) it could be used in excess.

("...can be used in daily doses much higher than those actually

needed.") Statistics indicate that Paraguayans consumed matte in

various preparations and at the rate of 7 to 11 cups per day.

 

DRIED STEVIA MIXED WITH DRIED LEAVES OF MATE

 

A very popular use of stevia is the beverages of yerba mate called

terere and cozido.

 

"Unfortunately it consisted of a few branchlets reduced to

fragments with the Matte. (Leaves of this plant, called Kaa he e are

powdered and mixed in a small proportion of Yerba Mate to sweeten the

bitter mate.)"

Bertoni 1918

 

"People living along the frontier of Brazil with Paraguay are

mainly those who have been using stevia since time immemorial as a

natural sweetener for foods and beverages, especially mate. This

plant became well known early in this century."

Marques 1993

 

"Terere, a tea made with mate brewed in a cup, is often sweetened

with caa-he-e."

Oliveira, 1993

 

"It is reasonable to assume that the local Indians used stevia to

sweeten their food and drink, especially mate, the traditional

Paraguayan beverage prepared by steeping the crushed, dried leaves of

Ilex paraguayensis in water."

Phillips, 1987

 

"[Stevia] is employed in the country where it is found for

sweetening Paraguay tea, (Mate)."

Dietrich 1909

 

"This Species was known by the Guarany Indians under several names

(Caa-jhe-he, Caa-hee, Ca-a-yupe, Azuca-c