Arent Fox Kintner Plotkin & Kahn October 21, 1991 HAND-DELIVERY David A. Kessler, M.D., J.D. Commissioner of Food and Drugs Food and Drug Administration Room 14-71, HF-1 5600 Rishers Lane Rockville, Maryland 20857-1706 Dear Commissioner Kessler: We are counsel to the American Herbal Products Association (AHPA), an association of companies that manufacture and distribute a variety of herbal products, including herbal teas. On behalf of AHPA, and its members, we request the FDA's concurrence and acquiesence, pursuant to 21 C.F.R. 170.30(C)(2), in the marketing, in interstate commerce, of foods and food products containing the flavoring ingredient stevia leaf, Stevia Rebaudiana Bertoni, hereafter stevia or stevia leaf. In a recent Import Alert 45-06 issued May 17, 1991, and elsewhere, FDA has taken the position that stevia leaf is an unapproved food additive within the meaning of Sec. 201(s) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. 321(s), (the Act), which may not be legally incorporated into food products sold in interstate commerce because no food additive petition, filed pursuant to Sec. 409, 21 U.S.C. 348, has been approved for it (1). AHPA believes that FDA's position is incorrect in that stevia leaf is not a food additive within the meaning of Sec. 201(s), 21 U.S.C. 321(s) because it is exempt from that definition by reason of its "common use in food" prior to 1958 (2). For that reason, FDA approval pursuant to Sec. 409, 21 U.S.C. 348 of the Act is not required and, indeed, AHPA does not seek such approval here. Instead, AHPA seeks only FDA's acquiesence in the marketing of stevia-containing foods in interstate commerce, such acquiesence based upon the facts, data, and legal issues as presented herein. FDA has urged petitioners, such as AHPA, to seeks such concurrence, 21 C.F.R. 170.30(C)(2). (1) These references are to exhibits attached hereto. On occasion these exhibits may contain n ot only documents referred to in the text but also additional references to other exhibits or source materials. I. Background - History of Use ------------------------------ Stevia Rebaudiana Bertoni is a perennial shrub of the Asteraceae (Compositae) familiy native to those portions of South America between 22-22 [degrees] S and 53-56 [degrees] W in the Amambay and Iquacu districts on the borders of Paraguay and Brazil (3, 4, 5). It was, and is, known to the Guarany people, native to that region since time immemorial, by several names: Caa-jhe-he, Caa-hee, Ca-a-yupe, Azuca-caa, Eira-caa, Caa-ahe, Kaa He e, Caa-enbem and Ka-a He-e, all of which refer, in one way or another, to the sweet taste of the leaf (3, 4) especially to its use in "mate" tea (Ilex paraguariensis) (3). It is often referred to as the "sweet herb of Paraguay" and, indeed, has even been described as the "sweetest plant in the world" (6). Stevia is exclusively a New World genus and while it has been grown in the United States, Mexico, Central America and down through the Andes (3, 12) by far its predominate history of use and cultivation is in Paraguay and Brazil (4). According to documents at the National Archives in Asuncion, Paraguay, the Spanish Conquistadors of the Sixteenth Century forwarded information to Spain that the indigenous population of that region had used stevia to sweeten their herbal teas since "ancient times," i.e., predating 1500 A.D. (7, 8). It is still used as such by the natives of that region (8, 9). The sweetening properties of stevia were first noted by Bertoni in 1899, and fully described by him in 1905 (3, 4, 5, 7, 8, 10, 11). Over the years stevia continued to be used and studied. For example, during the Second World War attempts were made to cultivate it in England because of the then unavailability of sugar there (11), while the National Institute of Health (NIH), United States Department of Health, Education & Welfare (now Department of Health and Human Services) studied its history and properties in 1955 (6). As near as AHPA can determine the use of stevia leaf in foods first came to the official attention of the United States Government in 1918 when a USDA botanist reported that "many years ago when in Uruguay while drinking mate, or Paraguay tea" he learned of the plant's use by "Indians of Northeastern Paraguay, for sweetening their mate" (13 and references cited therein). Samples of the plant were soon sent to USDA in 1921 with the recommendation that stevia be presented, by USDA, to United States companies because of its "great commercial importance" (14). By 1939, USDA (of which FDA was then a part) was aware that an extract of stevia, stevioside, was "commonly used in South America to sweeten drinks" (15). Over these same decades other studies were confirming the common use in foods of stevia leaf, stating, for example, in 1918, that it was about 180 times as sweet as cane sugar and that "[i]t is not toxic but, on the contrary, it is healthful, as shown by long experience ...." (16). Further, because of its long use and popularity, the cultivation of stevia moved to other countries and it is now grown and used in a number of subtropical countries such as China, Malaysia and South Korea (17, 18). In China it is sold in bags as dry leaves for infusion in a tea. Japan has imported stevia from Paraguay since 1970 (21). The extract is approved as a food ingredient in Brazil, Japan and South Korea where it is widely used today. According to publicly-available trade data, this pattern of use has been increasing. For example, in 1976, one-hundred (metric) tons of stevia leaf were used in Japan and by 1987 that use had grown to 1,700 (metric) tons. In *none* of these countries, despite its widespread use, is there any evidence of *any* adverse health consequences. Until FDA's recent action (1) stevia was widely used in this country without any reports of ill effects. II. Scientific Data -------------------- As we shall see later scientific data of the type needed to obtain FDA approval of a Food Additive Petition (FAP) pursuant to Sec. 409 of the Act, 21 U.S.C. 348, is not legally required to support the marketing of stevia pursuant to the "common use in food" exemption to the definition of a food additive under Sec. 201(s) of the Act, 21 U.S.C. 321(s). (See p. 19, infra.) However, a review of the scientific data there reveals both that it is extensive and that nothing therein contradicts the common use in food experience over the last 500 years that demonstrates stevia's safety. These studies deal with various extracts of stevia. 1. Acute toxicity. The LD50 of an extract containing 50% stevioside was 3.4 g/kg when administered intraperitoneal to rats (4). Most importantly, an oral administration study reveals LD50's ranging from 15 g/kg to 42 g/kg and that a dose of 5 mg/kg produced no adverse effects (22). Acute toxicity was not demonstrated when separate 2 g/kg doses were administered to mice by oral intubation (4), indicating that a concentrated extract of stevia is less than 1/10th as toxic (acute) as caffeine (7). 2. Subacute toxicity. The authors in Exhibit 4 discuss a number of subacute toxicity studies and concluded that when up to 7.0% stevioside was fed to male and female rats over a three-month period there were "no remarkable toxic effects" (p. 23). 3. Chronic toxicity - carcinogenicity. A chronic toxicity study on the ingestion of stevia rebaudiana extracts has been conducted in Japan (19). A hot-water extract of stevia rebaudiana leaves was purified so as to contain the equivalent of about 95% total sweet glycosides. Male and female F344 rats were fed with laboratory chow containing either 0.1%, 0.3% or 1.0% by weight of the purified plant extract. Altogether, 480 rats (240 of each sex) were employed, and divided randomly into four groups that were comprised of control, high- and medium-dosed animals (70 males and 70 females each) and by low-dosed animals (30 males and 30 females). The upper dose employed (1% of the total feed) took into account a calculated daily human intake of stevia rebaudiana sweeteners in Japan (4 mg/kg/day), and allowed a safety factor of 100. The duration of the investigation was 22 months for the male rats and 24 months for the females. After periods of six and 12 months, 10 males and 10 females from each group were sacrificed for clinical and histopathological examination. Individual body weights and food consumption levels were recorded at one-week intervals, with water intake measured weekly for the first 48 weeks of the study and every four weeks thereafter. Rats were checked daily, and moribund animals were sacrificed and subjected to histopathology. Urinalysis, as well as hematological, blood biochemical, and pathological examinations were performed on the control and dosed animals. Statistical methods were used to properly evaluate the test data obtained. While the growth rate of the low-dose (0.1%) group was similar to that of the controls, growth was depressed slightly after week 69 in males and after week 11 in the females in the medium-dose (0.3%) group. Transient growth retardation was observed in the high-dose (1.0%) group between weeks 23 and 50 (males) and between weeks 60 and 75 (females). After week 69 (males) and week 79 (females), the weights of the rats tended to decrease in all groups, including the controls. The general appearance and behavior of the animals were the same in all groups, including the controls. Mortality at the end of the study did not differ significantly for stevia rebaudiana-extract treated animals when compared to the controls. After urinalysis, no dose-related changes were found, except for an increased incidence of proteinuria in females after six months. Also after this time-period, dose-related increases in erythrocyte counts and decreases in mean corpuscular volume and mean corpuscular hemoglobin were observed in male rats, with decreased erythrocyte counts in female rats. However, the differences between the hematological parameters of the dosed and control rats after 12 months were not statistically significant. Administration of the stevia rebaudiana extracts for six months caused an increase in blood glucose for animals of both sexes, and decreases of blood glutamate-oxalacetate transferase, glutamate-pyruvate transaminase, and triglycerides in females. No significant differences in blood biochemical values occurred between any of the four groups of animals either after 12 months or at the end of the experiment. Organ weights of the liver, kidneys, heart, prostate, and testes were significantly increased in males relative to controls in the high-dose group after six months. Analogous (six-month) data obtained for females in the high-dose group indicated significant decreases in ovary weights and increases in liver weights. Again, changes in organ weights for all dosed animals employed in the study were not significantly different from controls after 12 months or at the end of the study. A variety of non-neoplastic histopathological findings were recorded, and, in most cases, both animals dosed with stevia rebaudiana extracts and control animals exhibited similar conditions. Changes more common in rats given stevia rebaudiana extracts than in control animals were reduced spermatogenesis, interstitial cell proliferation in the testes, medullary cell proliferation in the adrenal glands, atrophy of the thymus, inflammatory lesions in the trachea and lungs, age-related changes of the kidneys, such as degeneration of tubular epithelium, hyaline casts, and glomerular sclerosis, and pigmentation and increased hematogenesis of the spleen. A number of neoplasms were observed, both for the control and stevia rebaudiana-dosed animals. The most common neoplasms in the males were interstitial cell adenoma of the testes and pheochromocytoma of the adrenal glands, while in the females they were interstitial polyps of the endometrium and adenoma of the anterior lobe of the pituitary. The incidence of neoplasms was not related to dose. As a result of this protracted and extensive investigation, it was concluded that no significant dose-related changes were found in the growth, general appearance, hematological and blood biochemical findings, organ weights, and macroscopic or microscopic observations, as a result of feeding male and female F344 rats with stevia rebaudiana extracts at levels up to 1% of their feed for about two years. It was also concluded that any neoplasms that occurred were not attributable to the administration of stevia rebaudiana extracts. 4. Effect on Reproduction. It was claimed in 1968 by Planas and Kuc that the Paraguayan Matto Grosso Indians have employed the leaves and stems of stevia rebaudiana in the form of a tea as a contraceptive. These workers also reported an antifertility effect for periods up to two months following the incorporation of a 5% stevia rebaudiana extract (10ml) into the drinking water of both male and female rats (20). Recent field inquiries in various regions of northeastern Paraguay, however, do not confirm the use of stevia rebaudiana extracts for contraceptive purposes (4). Moreover, a number of other laboratories have been unable to confirm an antifertility activity of stevia rebaudiana extracts in rats (4). In one such laboratory study, an extract of stevia rebaudiana leaves containing 53.1% stevioside was mixed with stadard rations to afford various dose levels of stevioside for feeding to groups of rats. After receiving normal ration for several days, 13-week-old male and female SLC-Wistar strain rats were fed a stevioside-containing ration for 21 days. After this period, one male was placed with two females for mating. Female rats were examined daily for evidence of a vaginal plug, which was considered as day 0 of pregnancy. On day 20, half the pregnant animals were laparotomized and the remaining half were allowed to have spontaneous deliveries. At the time of mating, the stevioside-containing rations were removed and substituted with standard laboratory diet. The data obtained showed a lack of antifertility effects for the extracts tested. Furthermore, there was no evidence of any teratogenic activities or other abnormalities in the fetuses or offspring (4). In a later study, it was reported that male and female rats, maintained with up to 3% stevioside in the diet, exhibited no abnormal signs in mating performance and fertility (21). Also, no skeletal or other teratogenic effects attributable to stevioside were observed in fetuses after birth. 5. Mutagenicity Potential. Partially purified extracts and pure compounds from stevia rebaudiana leaves have been extensively tested for their mutagenic activity. Utilizing Salmonella typhimurium strains TA98, TA100, TA1538, and TM677, or Escherichia coli strain WP2, either in the presence or absence of a 9,000 x g supernatant metabolic activating system derived from the rat liver (S-9), one or more of these materials have been reported as nonmutagenic in laboratories in Japan, Brazil, and the United States (4). Mutagenicity tests performed with recombination deficient (rec-) strains of Bacillus subtilis (H17 and M45) also showed several of these substances to be innocuous, both in the presence and absence of S-9, as did host-mediated tests in mice bearing S. typhimurium strain G46. Recent studies have shown that steviol, the aglycone of stevia constituents such as stevioside and rebaudioside A, is mutagenic in a forward mutation assay utilizing S. typhimurium strain TM677 in the presence of a metabolic activating system, derived from a 9,000 x g supernatant fraction obtained from the livers of Aroclor-1254 pretreated rats. Unmetabolized steviol was inactive in this system (the Pezzuto paper, 23). In contrast, however, a Japanese study demonstrated that activated steviol was not mutagenic in the reverse mutation assay (Ames test) using S. typhimurium strains TA97, TA98, TA100 and TA102. M. Matosi, et al., 1489. Mutagenicity of Steviol: An Analytical Approach, Bulletin of the National Institute of Hygienic Sciences, Tokyo, 107, 83-87, 1989. Even more i mportantly a recent evaluation of the Pezzuto Report demonstrated that Pezzuto's conclusion "that 150 xosteviol induces mutations ... is shown to be a consequence of mishandling of data" (23, p. 6). Thus there are no valid data demonstrating that steviol is mutagenic. There is also no evidence that stevia extracts are biotransformed to steviol by ingestion by humans and, as noted, steviol itself has not been found to be mutagenic, and would require further transformation in the body to elicit a mutagenic substance or substances. In addition, by no means all proven mutagens are carcinogenic. The authors in Pezzuto themselves conclude by noting that "no reports have thus far appeared indicating that adverse effects have resulted from human use of stevia ...." (23, p. 2482.) The results of these experiments reveal that stevia is not mutagenic and must be evaluated with the chronic toxicity studies mentioned earlier on stevia where no significant incidence of tumor formation was reported in rats dosed for about two years with stevia rebaudiana extracts (up to 1% of total diet), when compared with control animals. Also, the lack of teratogenic effects noted in the reproduction studies provides further evidence that stevia and its extracts are not mutagenic in mammals. Thus, scientific studies have been carried out in the several major safety categories, including acute toxicity, subacute toxicity, chronic toxicity, and effects on reproduction. These studies show no dose-related abnormalities that are significant from a safety standpoint, and thus are supportive of the safety of stevia for human consumption. These data, while not legally required for a "common use in food" exemption, do show that when one looks not only at stevia's history of common use in foods but also at the extant scientific data, it is safe for human use. No scientific data contradicts that. III. The Legal Standard ------------------------ FDA has asserted that stevia is an unapproved food additive, requiring FDA approval before it can legally be imported into this country or sold here (1). However, if stevia does not meet the statutory definition of a food additive then FDA approval is neither required nor appropriate. AHPA suggests that stevia is not such a food additive. In order to assess this position some review of the relevant law is material. The statutory definition of the term "food additive," provides that a substance used in foods is a "food additive" if it is not generally recognized, by appropriately qualified experts, as having been shown, through scientific procedures, to be safe under the conditions of its intended use (2). If a substance is such an additive, it cannot be used in food until approved by the FDA pursuant to the provisions of [Section] 409 of the Act, 21 U.S.C. [Section] 348, and FDA implementing regulations which specify a complex mechanism for the preclearance of all food additives (21 C.F.R. 171.1-171.6). However, this same definition, Sec. 201(s), excludes certain substances from FDA approval. Excluded are all food substances "commonly used" in foods prior to 1958 if that common usage demonstrated safety. Thus, a finding about the safety of any substance used in food prior to January 1958 does not depend on "scientific procedures"; instead, a pre-1958 substance can also be found safe by experience "based on [its] common use in food" [Sec. 201(s)]. As a result, the safety of pre-1958 substances does not have to be shown by "scientific procedures"; rather, their safety can also be determined by another standard--their common use in food. Safe they must be; as to how that safety must be determined--by "common use in food or by scientific studies is the distinguishing characteristic between pre-1958 and post-1958 substances. The legislative history bears this out. The Legislative History of the "Common Use in Food" Exemption ------------------------------------------------------------- Because of the availability of new technologies, after World War II, and the impact of an expanding population, the food industry began to use more chemicals in the fabrication of foods. These chemicals performed a myriad of technical effects needed in order to mass produce palatable (and nutritious) foods that would remain so for long periods of time. Soon Congress addressed the consequence of this technological change. In 1950, a Select Committee of the House of Representatives began an investigation of the use of chemicals in foods. This Committee, directed to investigate the "nature, extent, and effect of the use of chemicals, compounds, and synthetics in the production, processing, preparation and packing of food products to determine the effect of [such] use ... upon the health and welfare of the Nation ..." [H.R. Res. 323, 81st Cong., 2d Sess., 1950], heard the views of approximately 350 witnesses and organizations, including the FDA, the California Department of Health, the AMA, and virtually every food trade association then in existence. The subjects discussed ranged from the merits of fluoridation to the benefits of organic fertilizers. But always the focus was on chemicals in foods--not foods themselves, or their natural constituents, and always on the "new" chemicals. For example, an attorney defined the substances under consideration as those "industrially created by applying the science of chemistry; and I will refer to the addition of such a chemical to fabricated food, in its production, and to the natural food, through a pesticidal residue," [Chemicals in Food Products: Hearings Before The House Select Committee to Investigate the Use of Chemicals in Food Products, 81st Cong., 2d Sess. 654 (1950) (statement of Charles Wesley Dunn)], while legislation offered by the Deputy FDA Commissioner tracked the same thinking. [Id. at 346 (statement of C.W. Crawford, Deputy Commissioner, FDA, and accompanying proposed bill).] These hearings were thus restricted to the role of new chemicals in our food supply, and there is no indication that the Committee (or any witness before it) intended anything other than that. Because of this, when legislative hearings began, Congress was careful to exempt from any proposed legislation (over chemicals) those natural substances mankind had long enjoyed. The first bill introduced (by Congressman Delaney) applied to "chemical additives," a term defined as any substance intended to be used as a food, or in a food, if such substance is not generally recognized, by experts, as having been "adequately tested" to demonstrate its safety [H.R. 2245, 83rd Cong., 1st Sess. (1953)]. Any substance, no matter how long in use meeting this definition could be marketed only with FDA approval. Congressman Delaney would thus exempt none of the older constituents commonly used in foods unless they were generally recognized as safe. A later version used the term "new chemical additive" and, instead of the phrase "adequately tested," introduced the concept that adequate testing to determine the safety of a food substance could be shown either through "scientific procedures" or by its "prolonged use in food." [H.R. 8418, H.R. 9166, 83d Cong., 2d Sess. (1954).] This concept, of "prolonged use in food," rather than strict scientific testing as demonstrating safety for the older food constituents first proposed here, is the genesis of the "common use in food" exemption. These bills lapsed, but the first relevant bill introduced in the next Congress defined a new chemical additive as any substance likely to be a component of any food if it is not generally recognized as having been shown, by either "scientific procedures" or by "prolonged use in food" to not be a "hazard to man." [H.R. 4099, 84th Cong., 1st Sess. (1955), and see H.R. 4100, Id..] Still more variations were proposed, although the term "new food additive" began to replace "chemical additive." [H.R. 7605 and 7606, 84th Cong., 1st Sess. (1955).] Then, just before adjournment, more substantial revisions were proposed. Under these bills the law would have included within the term "new food additives" any substance intended to be "newly" used in foods if that substance was not genearlly recognized as safe (with no reference to the scientific procedures or prolonged use concepts), but excluded any substance which, prior to the effective date of the Act, was "used in the United States," without reference to whether such United States use demonstrated that the substance was safe. [H.R. 7607, H.R. 7764, 84th Cong., 1st Sess. (1955).] The exception was a blanket one excluding from the new law anything in use in the United States before the law was passed. Such a blanket exception was unreasonable and it soon disappeared. In later bills the only substances not generally recognized as safe to be excluded from the law would be those in use "in the United States" prior to the enactment of the law if such use had been "authorized or approved" by any federal agency or official [H.R. 8271 and 8275, 84th Cong., 2d Sess. (1956)]. The concept that "prolonged use" anywhere might constitute valid evidence of safety for the older constituents in foods was not then included. The approval of some federal agency-on whatever basis--was required. Then, in a final version proposed just before legislative hearings began, the exempt substances would be in use, provided such use "presents no reasonable probability of injury to health." [H.R. 8748, 84th Cong., 2d Sess. (1956).] The next Congress saw a variety of proposals which, so far as the issue of the "common use in food" exclusion is concerned, can be groups as follows: (1) No exclusion. H.R.'s 4014, 4432, 7700, 7798, and 7938, and S. 1895 [85th Cong., 1st Sess. (1957)]. (2) Excludes Substances Authorized Prior to Enactment Date. H.R.'s 366, 8390, and 8629 [Ibid]. (3) Excludes substances whose safety is demonstrated by prolonged use. No geographical limitation. H.R.'s 6747 and 8112 [Id,]. (4) Exempts all pre-enactment substances. H.R. 10404 [85th Cong., 2d Sess. (1958).] Doubtless because other matters were more controversial, little was subsequently said about the thrust of the phrase "prolonged use." For example, Congressman Haselton said that "prolonged use" was "long use without harm which is the strongest piece of evidence they could present." [1958 Hearings at 126.] Similarly, Elliot Richardson, then Secretary of HEW, testified that the substances entitled to have their safety determined by their "common use in food" would be those in use "over a long period." [Id., at 419.] And the then FDA Commissioner had this to say in a colloquy with Congressman Dingell: MR. DINGELL: To go along with these things that are more or less scientifically accepted by reason of testing and approval by the Food and Drug Administration, would that include long periods of use? MR. LARRICK: Yes. We can't stop the food industry short in its tracks. If they have been using, let us say, salt to preserve food for centuries, I would guess that salt has never gone through this modern-day testing technique. Yet everybody recognized that salt not only is safe, but it is necessary. There are literally thousands of substances in that category. Finally, even Congressman Delaney, who opposed all exemptions, saw some merit in the "prolonged use" concept: The FDA bill, H.R. 6747, has a provision which seems to have some grandfather possibilities. It would exempt an additive if it has been shown to be safe through "prolonged use" in food. However, it does not define "prolonged use." [Id. at 497.] As Congressman Delaney intimated, the "prolonged use" exemption was an FDA proposal [See H.R. 6747, Sec. 2, 85th Cong., 1st Sess. (1957).] The legislative markups kept the FDA prolonged use concept but moved it to the parenthetical exemption where it now appears. The word "common" replaced "prolonged" and this is the varsion ultimately introduced and debated on the floor of Congress. [H.R. 13254, 85th Cong., 2d Sess. (1958).] FDA recognized the merit of the common-prolonged-use concept. In a letter to Congressman Delaney, a Deputy FDA Commissioner said: Another provision of H.R. 13254 that has sometimes been regarded as a grandfather clause is the one that would exempt from the definition of food additive substances used in food prior to January 1, 1958, that have been adequately shown through experience based on common use in food to be safe under the conditions of intended use. *** Our Department believes that it is not necessary to good public health protection to have chronic toxicity studies conducted of common food chemicals, such as salt, sugar, vinegar, baking soda, and a great many other materials that have been in common use for a long time.*** As a matter of fact, these substances have been established as suitable food ingredients through feeding to generations of human beings. [104 Cong. Rec. 17420 (1958). Emphasis added.] ... An additive may be shown to be safe either by means of scientific procedures (including a review of the existing scientific literature) or, in the case of substances in use prior to January 1, 1958, also by means of experience based on common use in food. [H.R. Rep. No. 2284, 85th Cong., 2d Sess. 3 (1958).] In 1983 the United States Court of Appeals for the Ninth Circuit held that FDA's attempt by regulation to limit this "common use in food" exemption to useage in the United States invalid. Fmali Herb Inc. v. Heckler, 715 F.2d 1385 (9th Cir., 1983). The Court, in doing so, did note that if "the foreign experience cited by [a] proponent does not clearly demonstrate safety, because doubts about cultural comparability or the adequacy of public health data, then the substance must be deemed a food additive," 715 F.2d 1385, 1390-91. FDA did not appeal that decision and has issued a regulation implementing it, 21 C.F.R. 170.30(c) (1991 ed.). That regulation acknowledges that the "common use in food" exemption permits a safety determination" without the quantity or quality of scientific procedures required for approval of a food additive regulation." 21 C.F. R. 170.30(c)(1). Thus, FDA acknowldges the intent and thrust of the legislative history to exempt food ingredients commonly used in foods prior to 1958 from the requirements of producing the scientific data required by Sec. 409, 21 U.S.C. 348. Indeed, as noted earlier (p. 30, supra) a Deputy Commissioner unequivocally stated, in 1958, that such studies as chronic toxicity testing were *not* needed for pre-1958 food substances. The FDA regulation goes on to say that for such common use in food experience outside the United States to be controlling here it must be "documented by published or other information and shall be corroborated by information from a second, independent source" and the submitted information must be "widely available in the country in which the history of use has occurred and readily available to interested qualified experts in this country." 21 C.F.R. 170.30(c)(2). IV. Stevia Leaf is Entitled to the "Common Use in Food" Exemption and the Data in Support of it Conforms to 21 C. F. R. 170.30(c). In preparing this Peition, AHPA representatives canvassed the world literature, both scientific and non-scientific, concerning the history of the use of stevia leaf in Paraguay and in other countries. All of the documents attached hereto as Exhibits are publicly available to anyone who wishes to make the effort to obtain them. In large part they were obtained from the Library of Congress, University Library Retrieval Systems, and from libraries and trade publications throughout the world. Exhibit 24 is a partial bibliography of additional articles and references obtained but not used in this Petition, either because they were not directly relevant, or because they were no more than cumulative. None of this mass of documentation indicates any safety or public health problem associated with the long use of stevia leaf throughout the world. This documentary evidence demonstrates conclusively the following facts: 1. Stevia leaf is a natural product that has been used for at least 400 years as a food product principally as a sweetener or other flavoring agent. It is a natural product of Paraguay and Brazil but it is now cultivated in many other parts of the world including the People's Republic of China, Japan and other sub-tropical countries in the Pacific Basin. It has been successfully grown in the United States and in England. 2. None of this common usage in foods has indicated any evidence of a safety problem. There are *no* reports of any government agency in any of the above countries indicating any public health concern *whatsoever* in connection with the use of stevia in foods. 3. In addition to all this various extract forms of stevia have been extensively studied and tested. These tests include acute, sub-acute, carcinogenic evaluation and mutagenicity studies. These scientific data, while not directly relevant or required for exemption under the common use in food proviso, nevertheless demonstrate cumulatively that there is no safety problem associated with the use of an extract of stevia. It appears to be extraordinarily safe. 4. Based upon this wealth of data, stevia is specifically approved for food use in a number of industrialized countries, including Japan, South Korea and Brazil. 5. The usage of stevia throughout the world is widespread and growing and none of this widespread usage have so far revealed any evidence of public health concern. The data thus available is all publicly available data corroborating each other in one way or another, and thus what AHPA submits here either directly, as Exhibits, or incorporating by reference, more than complies with the statutory requirements and with FDA's own implementing regulation, 21 C.F.R. 170.30(c). V. Conclusion -------------- Stevia is clearly a food substance that was commonly used in foods prior to 1958. Just as clearly, that common use demonstrates that over literally hundreds of years and in usage by millions of people, stevia is safe for human use. AHPA, therefore, requests FDA's acquiesence and concurrence that stevia leaf is exempt from the food additive provisions of the law by reason of the common use in food exemption, and that stevia leaf may accordingly be imported into the United States, shipped in interstate commerce, and incorporated in food products in the United States without any required approval under Section 409 of the Act, U.S.C. 348. AHPA is prepared to work with the Agency in this process and as AHPA develops further data and information it will be submitted to the Agency as a further amendment to this request for acquiesence. Respectfully submitted, ARENT, FOX, KINTNER, PLOTKIN & KAHN By: William R. Pendergast Attorneys for American Herbal Products Association