Cooking With Stevia and Stevia Recipes

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.

"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

"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

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

"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.

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

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