December 20, 1999

Gareth Tempelman
Vice President, Regulatory Affairs
ShanStar Biotech, Inc.
P.O. Box 10
Chadwick Bay, NY 14048

Re: GRAS Notice No. GRN 000030

Dear Mr. Tempelman:

The Food and Drug Administration (FDA) is responding to the notice, dated July 13, 1999, that you submitted in accordance with the agency's proposed regulation, proposed 21 CFR 170.36 (62 FR 18938; April 17, 1997; Substances Generally Recognized as Safe (GRAS); the GRAS proposal). FDA received your notice on August 3, 1999 and designated it as GRAS Notice No. GRN 000030.

The subject of your notice is "cranberry extract." The notice informs FDA of the view of ShanStar Biotech, Inc., that "cranberry extract" is GRAS, through scientific procedures, for use as an antioxidant and antimicrobial in foods, beverages and cosmetics, and for use as a cleaning agent in sanitizing solutions. According to your notice, "cranberry extract" is a solid consisting of an extract of cranberries adsorbed to crospovidone (a crosslinked homopolymer of purified vinylpyrrolidone, also known as polyvinyl polypyrrolidone). In FDA's view, your use of the term "cranberry extract" neither adequately describes the substance that is the subject of your notice nor distinguishes this substance from one of its components. Therefore, we are using the term "crospovidone-cranberry juice extract" to describe the subject of your notice.

FDA has evaluated the information in GRAS Notice No. GRN 000030, as well as other available data and information. As discussed in more detail below, your notice does not provide a sufficient basis for a determination that crospovidone-cranberry juice extract is GRAS under the conditions of its intended use.

Data and information that you present to support the GRAS determination

Your notice includes information regarding the production of crospovidone-cranberry juice extract, its composition, and the intended conditions of use. In addition, your notice describes an oral acute toxicity study conducted with crospovidone-cranberry juice extract.

Cranberry juice is obtained from the fruit of Vaccinium macrocarpon. After filtration, it is mixed thoroughly with USP-NF grade crospovidone, which binds (i.e., extracts) certain components of the cranberry juice. After filtration again, the wet cake is dried until it contains about 10% water. The crospovidone that you use conforms to the specifications outlined in the Food Chemicals Codex, 4th edition, pages 309-310.

The composition of the dried cake, i.e., crospovidone-cranberry juice extract, is crospovidone (not more than 60% of the total mass), cranberry juice extract (not less than 30%), and water (not more than 10%). The cranberry juice extract that is one component of crospovidone-cranberry juice extract contains phenolics (such as bioflavonoids and polyphenolics), sugars and acids. According to your notice, 800 mg of crospovidone-cranberry juice extract contains about the same amount of phenolics as 8 ounces of cranberry juice.

You intend to use crospovidone-cranberry juice extract in foods (at a maximum level of 5 mg/g), beverages (at a maximum level of 1 mg/ml), cosmetics (at a maximum level of 50 mg/ml), and in sanitizing solutions (level not specified).

Your notice describes an oral acute toxicity study conducted with crospovidone-cranberry juice extract in Sprague-Dawley rats. Five male rats and five female rats were given a single dose (5,000 mg/kg body weight) of the crospovidone-cranberry juice extract (30% w/w suspension in distilled water) by gavage. The rats were observed for 14 days. All rats survived the treatment. No sign of gross toxicity, adverse pharmacological effects or abnormal behavior were observed. No gross abnormalities were noted for the animals at necropsy. The author of the study concluded that LD₅₀ of crospovidone-cranberry juice extract was greater than 5,000 mg/kg body weight.

Your notice states that crospovidone is "declared GRAS" for use as a clarifying and stabilizing agent in beverage processing as listed in 21 CFR 173.50. In addition, your notice refers to the conclusions of a GRAS panel convened by International Specialty Products regarding the use of a related substance, povidone, as a diluent in color additive formulations. Further, your notice cites a report of the Joint Expert Committee on Food Additives (JECFA; a joint committee of the Food and Agriculture Organization/World Health Organization), which evaluated several studies (including a 90-day feeding study in rats, a 180-day feeding study in dogs, a teratogenicity study, a pharmacokinetic study, and other short-term studies), and concluded that crospovidone does not represent a hazard to health for its use in food.

FDA's evaluation of the data and information in your notice

FDA has evaluated the information that you discuss in your notice, as well as other data and information that are available to the agency. For your information, we did not evaluate the intended use in cosmetics because the GRAS proposal does not cover such non-food use of a substance. In addition, we did not evaluate the intended use in sanitizing solutions because such use is regulated by the Environmental Protection Agency.⁽¹⁾

1. Estimated dietary exposure

One practical consequence of the common scientific principle "the dose makes the poison" is that a substance that is safely consumed at low levels in the diet may be unsafe if consumed at a higher level in the diet. For this reason, a GRAS determination requires consideration of the probable consumption and cumulative effect of the substance in the diet. FDA uses the information provided under proposed 21 CFR 170.36(c)(1)(iii) (i.e., information regarding the intended food categories and the maximum level of use in each food category) to estimate dietary exposure (see our guidance documents "Recommendations for Submission of Chemical and Technological Data for Direct Food Additive and GRAS Food Ingredient Petitions," and "Estimating Exposure To Direct Food Additives And Chemical Contaminants in the Diet," copies enclosed).

Your proposed use as an antioxidant and antimicrobial in "foods" and "beverages" is very broad. To evaluate such broad use, we made a conservative assumption that crospovidone-cranberry juice extract would be present in all foods and beverages. Given this assumption, we estimate that a person who eats 1500 grams of food per day and drinks 1500 ml of beverages per day would consume 7.5 grams of crospovidone-cranberry juice extract per day in food and 1.5 grams of crospovidone-cranberry juice extract per day in beverages, for a total of 9 grams crospovidone-cranberry juice extract per day. Although our conservative approach to the estimated dietary exposure grossly overestimates that exposure, your notice neither provides your own estimate of dietary exposure nor provides realistic use information that would be necessary for FDA, or experts generally, to evaluate the basis for your determination that the consumption of crospovidone-cranberry juice extract would be safe in light of its probable dietary intake. We recommend that you consult the enclosed guidance documents regarding estimation of dietary exposure. If you would like to discuss technical issues related to this matter, an initial contact in the Office of Premarket Approval is Dr. Michael DiNovi, who can be reached by telephone at (202)418-3003 or by electronic mail at MDINOVI@BANGATE.FDA.GOV.

2. The crospovidone component of crospovidone-cranberry juice extract

Your statement that crospovidone is "declared GRAS" for use as a clarifying and stabilizing agent in beverage processing as listed in 21 CFR 173.50 is incorrect in several respects. First, the regulation that you cite is a food additive, rather than a GRAS affirmation, regulation and as such, is not based on common knowledge about crospovidone throughout the scientific community knowledgeable about the safety of substances added to food (21 CFR 170.30(a)). Importantly, 21 CFR 173.50 requires that crospovidone be removed by filtration at the end of its application. In contrast, you intend that crospovidone constitute up to 60 per cent of crospovidone-cranberry juice extract, which would be directly added to food. For this reason, FDA's approval of the use of crospovidone as a clarifying and stabilizing agent in beverage processing has no relevance to the evaluation of whether your intended use of crospovidone would be safe.

In addition, your notice provides information that International Specialty Products has concluded that the use of povidone (polyvinylpyrrolidone) as a diluent in color additive formulations is GRAS. Your notice provides no evidence that International Specialty Products has evaluated the GRAS status of crospovidone (which is related to, but distinct from, povidone) for the uses described in your notice.

Further, your notice inappropriately infers that JECFA's conclusion (i.e., that crospovidone does not represent a hazard to health based on its total daily intake; Ref. 1) is evidence that your intended use of crospovidone is GRAS. In its report, JECFA did not specify the type of foods in which crospovidone is used and the type of technical effect for which it is used. We question whether the total daily intake of crospovidone that JECFA evaluated is comparable to that which would result from the proposed use of crospovidone-cranberry juice extract in all foods and beverages.

Moreover, as discussed in the GRAS proposal, a GRAS substance is distinguished from a food additive on the basis of the common knowledge about the safety of the substance for its intended use. There are two aspects to this common knowledge. First, the data and information relied on to establish safety must be generally available. Second, there must be a basis to conclude that there is consensus among qualified experts about the safety of the substance for its intended use. Neither aspect is, by itself, sufficient to satisfy the common knowledge element of the GRAS standard. To our knowledge, the safety studies that JECFA relied on in reaching its conclusion are not generally available to the public, e.g., through publication in the scientific literature. Thus, the generally available JECFA report is an opinion based on data and information that are not generally available. This report does not satisfy both aspects of the common knowledge standard.

The acute oral toxicity study that you describe is inadequate to support the safety of the amount of crospovidone that would be consumed under the conditions of use of crospovidone-cranberry juice extract that you describe in your notice. We suggest that you consult FDA's guidance document "Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food," commonly referred to as "Redbook," to determine the appropriate level of testing that FDA ordinarily recommends for a substance with the chemical features of crospovidone and a dietary exposure that is consistent with your intended use in foods and beverages. We have enclosed a copy of the Redbook for your information.

3. The cranberry component of crospovidone-cranberry juice extract

As discussed in the GRAS proposal, consumption of a component of a commonly consumed food may present a basis for a safety concern if the dietary exposure to the isolated component under its intended conditions of use is significantly greater than its dietary exposure when consumed as a component of food. We question whether the cranberry extract component of crospovidone-cranberry juice extract will be safe under your intended conditions of use. For example, we estimate that the use of crospovidone-cranberry juice extract in "foods and beverages" would increase dietary exposure to mutagenic phenolic compounds that are present in cranberries, including the quercetin component that is mutagenic and is a reported animal carcinogen, by as much as 50-fold.

Conclusions

In accordance with proposed 21 CFR 170.36(f), a copy of the text of this letter, as well as a copy of the information in your notice that conforms to the information in proposed 21 CFR 170.36(c)(1), is available for public review and copying on the Office of Premarket Approval's homepage on the World Wide Web.

Enclosures (4):

Antimicrobial Food Additives

Recommendations for Submission of Chemical and Technological Data for Direct Food Additive and GRAS Food Ingredient Petitions

Estimating Exposure To Direct Food Additives And Chemical Contaminants in the Diet

Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food

References

1. 27th Report of the Joint Expert Committee on Food Additives, WHO Technical Report Series No. 696, 1983.

2. Bilyk, A., and G. M. Sapers, "Varietal Differences in the Quercetin, Kaempferol, and Myricetin Contents of Highbush Blueberry, Cranberry, and Thornless Blackberry Fruits," Journal of Agricultural and Food Chemistry, 34 (4):585-588, 1986.

3. Bjeldanes, L. F., and G. W. Chang, "Mutagenic Activity of Quercetin and Related Compounds," Science, 197:577-578, 1977.

4. Hardigree, A. A., and J. L. Epler, "Comparative Mutagenesis of Plant Flavonoids in Microbial Systems," Mutation Research, 58:231-239, 1978.

5. MacGregor, J. T., and L. Jurd, "Mutagenicity of Plant Flavonoids: Structural Requirements for Mutagenic Activity in Salmonella typhimurium," Mutation Research, 54:297-309, 1978.

6. Meltz, M. L., and J. T. MacGregor, "Activity of the Plant Flavonol Quercetin in the Mouse Lymphoma L5178Y TK^+/- Mutation, DNA Single-Strand Break, and Balb/c 3T3 Chemical Transformation Assays," Mutation Research, 88:317-324, 1981.

7. Pamukcu, A.M., et al, "Quercetin, a Rat intestinal and Bladder Carcinogen Present in Bracken Fern (Pteridium aquilinum)," Cancer Research, 40:3468-3472, 1980.

8. Hatcher, J. F., et al, "Mutagenic and Carcinogenic Activities of Quercetin (Q)," Federation Proceedings, 42:786, 1983.

9. National Toxicology Program, "NTP Technical Report on the Toxicology and Carcinogenesis Studies of Quercetin (CAS No. 117-39-5) in F344/N Rats," NTP TR 409, NIH Publication No. 92-3140, 1992.

⁽¹⁾See our guidance document entitled "Antimicrobial Food Additives," Chapter 5 - Pesticide Chemical Uses of Antimicrobial Substances under FFDCA, as Amended by ARTCA (Antimicrobial Regulation Technical Corrections Act of 1998) (copy enclosed).

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