U. S. Food and Drug Administration
Center for Food Safety and Applied Nutrition
Office of Food Additive Safety
June 5, 2002

Mr. Edward J. Race
Director of Research
Polyphenolics, Inc.
12667 Road 24
Madera, CA 93637

Re: GRAS Notice No. GRN 000093

Dear Mr. Race:

The Food and Drug Administration (FDA) is responding to the notice, dated December 12, 2001, 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 the notice on December 17, 2001, and designated it as GRAS Notice No. GRN 000093.

The subjects of the notice are grape seed extract (GSE) and grape skin extract (GSKE). The notice informs FDA of the view of Polyphenolics, Inc. (Polyphenolics) that GSE and GSKE are GRAS, through scientific procedures, for use in fruit juice and fruit flavored beverages as antioxidants to retard deterioration. The extracts would be used separately or in combination at a maximum total extract concentration of 210 milligrams per liter (equivalent to 50 milligrams per eight fluid ounces) in the finished beverage products.

FDA has evaluated the information that Polyphenolics discusses in its GRAS notice as well as other data and information that are available to the agency. As discussed more fully below, the notice does not provide a sufficient basis for a determination that GSE and GSKE are GRAS under the conditions of their intended use.

Data and information that Polyphenolics presents to support its GRAS determination

Because GSE and GSKE are mixtures that are comprised predominantly of a class of compounds known as phenolics or polyphenols, Polyphenolics discusses generally available information about phenolic compounds. Polyphenols are the products of plant metabolism and can range from simple molecules to highly polymerized compounds. Flavonoids, a subclass of polyphenols, are the most common polyphenolic compounds found in nature and are further divided into several subclasses including flavones, flavonols, isoflavones, anthocyanins, flavanols, and proanthocyanidins (PACs).

Polyphenolics describes the method of manufacture of GSE and GSKE. The extracts are manufactured from fresh grapes, which are inspected for quality and screened for defects. The grapes are de-stemmed, crushed, and pressed, leaving a pomace residue of seeds and skin. The seeds are separated from the skins (for GSE), and the seeds or the pomace of seeds and skin (for GSKE) are boiled in water to extract the polyphenolic constituents. The seeds are then removed, and the extract is cooled, enzymatically depectinized, and the pH is adjusted. The resulting extract is refrigerated and stored for one to three months. The extract is then filtered with diatomaceous earth and passed through a column of trimethylolpropane trimethacrylate (TMPTMA). Polyphenolics notes that grape phenolic constituents preferentially adsorb to the TMPTMA resin, while other grape constituents such as minerals and organic acids pass through the column and are discarded. The phenolic constituents are eluted from the resin using 75 percent (by volume) beverage-grade ethanol. The ethanol is then removed using a vacuum thermal evaporator, and the concentrate is spray dried to give the final GSE or GSKE product.

Polyphenolics provides product specifications⁽¹⁾ and analyses of several production lots of GSE and GSKE. The specifications for both GSE and GSKE include limits on total phenolics and levels of any residual pesticides. Additional specifications for GSE include ranges for the monomeric, oligomeric, and polymeric content of the phenols and limits on insoluble substances. Additional specifications for GSKE include a limit on total anthocyanins.

Using its proposed use levels and data from the United States Department of Agriculture (USDA) 1994-1996 Continuing Surveys of Food Intakes by Individuals and the 1998 Supplemental Children’s Survey, Polyphenolics estimates the combined intake of GSE and GSKE would be 70 milligrams per person per day (mg/person/day) at the mean (eaters only) and 130 mg/person/day at the 90th percentile (eaters only). Polyphenolics states that this estimate is comparable to exposure to PACs from other foods and beverages such as red wine. Polyphenolics notes, however, that information on exposure to PACs is limited, and large variations exist in the reported concentrations of PACs for a given product or commodity. Polyphenolics explains that these variations in concentration are due to differences in the assays used to measure PAC concentration and the nature of the sample analyzed (i.e., variety, ripeness, part, and processing of the fruit).

Polyphenolics discusses published information about the absorption, distribution, metabolism, and excretion of low molecular weight phenolic and polyphenolic compounds in general and notes that relatively little information exists about the absorption and bioavailability of the high molecular weight PACs, which are polymers and thus are less likely to be absorbed through the gut barrier than the low molecular weight phenolic and polyphenolic compounds. Polyphenolics also discusses published information about various mutagenicity, animal, and human studies conducted with various polyphenolic compounds. Polyphenolics considers that these studies support the dual nature of phenolic compounds in vitro and in vivo (i.e., that phenolic compounds exhibit properties that are both mutagenic and anti-mutagenic, both carcinogenic and anti-carcinogenic, both promoter and anti-promoter, and both clastogenic and anti-clastogenic) . Polyphenolics notes that quercetin or quercetin derivatives are theorized to be the key mutagenic, carcinogenic, and clastogenic compounds within the class of polyphenolic compounds. Polyphenolics discusses toxicity and carcinogenicity studies of quercetin conducted by the National Toxicology Program (NTP), and notes that NTP has concluded that there is some evidence that quercetin is carcinogenic in male rats. Polyphenolics provides quantitative information on the levels of quercetin and quercetin glycosides present in GSE and GSKE, presents a risk assessment based on these levels, and concludes that use of the GSE and GSKE as proposed will not pose a carcinogenic risk to the consuming public. Polyphenolics concludes from its overall review of the literature that GSE and GSKE do not pose a safety concern despite the fact that GSE and GSKE contain a number of polyphenols that cause a variety of responses in different models.⁽²⁾

To corroborate its conclusion from the published literature about phenolic and polyphenolic compounds, Polyphenolics discusses the results of an unpublished mouse micronucleus assay and an unpublished subchronic (13-week) feeding study conducted in rats. Polyphenolics concludes that the results of the mouse micronucleus assay in Crl:CD-1 mice support a conclusion that GSE and GSKE are not mutagenic. Polyphenolics also concludes that the results of the subchronic feeding study support a no-observed-adverse-effect-level (NOAEL) for GSE or GSKE of 2,150 milligrams per kilogram body weight per day (mg/kg bw/day) in female rats and 1,780 mg/kg bw/day in male rats, corresponding to the highest dose exposure over the course of the study. Polyphenolics uses these NOAELs in rats and a safety factor of 100 to calculate an acceptable daily intake of 1,075 mg/person/day of GSE or GSKE for an average 50 kilogram human female and 1,250 mg/person/day of GSE or GSKE for an average 70 kg human male.

Polyphenolics acknowledges that NTP has recommended that additional toxicity data be generated for a different grape seed extract product that is currently marketed for use as a dietary supplement. Polyphenolics considers that this recommendation by NTP is not inconsistent with its view that the intended use of GSE and GSKE as antioxidants in juice is GRAS because the specific charge to NTP is to evaluate a grape seed extract that has widespread consumer use as a dietary supplement.

Polyphenolics provides the report of a panel of individuals (Polyphenolics’ GRAS panel) who evaluated the data and information that are the basis for Polyphenolics’ GRAS determination. Polyphenolics considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Polyphenolics’ GRAS panel evaluated published data and information about phenolic and polyphenolic compounds in general and unpublished data from the two studies conducted with GSE and GSKE (i.e., the mouse micronucleus assay and the 13-week rat feeding study). Based on this review, Polyphenolics’ GRAS panel concluded that GSE and GSKE that meet the appropriate food grade specifications are GRAS, through scientific procedures, under the conditions of their intended use in accordance with limitations of current good manufacturing practice. However, in reaching this conclusion, Polyphenolics’ GRAS panel assigned primary importance to the unpublished studies conducted with GSE and GSKE.

FDA’s evaluation of the data and information in Polyphenolics’ notice

Polyphenolics provides insufficient information about the composition of GSE and GSKE to evaluate safety. For example, although Polyphenolics asserts that the content of PACs in various foods compares well with the estimate of intake of GSE and GSKE, Polyphenolics does not provide the PAC content of GSE and GSKE so that no direct comparison is apparent. Likewise, although Polyphenolics discusses average daily flavonoid intake from currently consumed foods, Polyphenolics does not provide the flavonoid content of GSE and GSKE.

Based on its evaluation of the data and information in Polyphenolics’ notice, FDA agrees with Polyphenolics’ GRAS panel that the most relevant studies are the unpublished studies conducted with GSE and GSKE. Given that these studies are not generally available to the expert scientific community, these studies cannot provide a basis to determine that GSE and GSKE are GRAS, through scientific procedures, for their intended use in fruit juice and fruit flavored beverages. Moreover, the recommendation by NTP that another grape seed extract product be subjected to substantial toxicity tests raises questions about whether Polyphenolics’ two studies, even if they became generally available, could provide a basis to conclude, at this time, that there is consensus within the scientific community about the safety of chronic consumption in food of GSE and GSKE.

For your information, an ingredient that is lawfully added to food products may be used in a standardized food only if it is permitted by the applicable standard of identity. Standards of identity for individual fruit juices are described in 21 CFR Part 146. With the exception of lemon juice, the standards of identity for fruit juices do not permit the addition of antioxidants as an optional ingredient in these standardized foods.

Conclusions

FDA has evaluated the data and information in GRN 000093 as well as other available information. Your notice does not provide a sufficient basis for a determination that GSE and GSKE are GRAS under the conditions of their intended use.

FDA recommends that you review the agency’s discussion in the GRAS proposal of the scientific, legal, and regulatory underpinnings of the GRAS notification program. In particular, we recommend that you review the agency’s discussion of the differences between a food additive and a GRAS substance. As discussed in that proposal (62 FR 18940), a determination that a particular use of a substance is GRAS requires technical evidence of safety and a basis to conclude that this technical evidence of safety is generally known. There are two aspects to this common knowledge. First, the data and information relied on to establish safety must be generally available to the public. 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, by itself, is sufficient to satisfy the common knowledge element of the GRAS standard. In contrast, authorization of a particular use of a substance as a food additive requires technical evidence of safety and review and approval by FDA. For this reason, we also recommend that you review the information on the home page of the Office of Food Additive Safety regarding the food additive petition process. (Ref. 1).

This letter describes in general terms the reason for FDA’s conclusion that the information in your notice does not provide a sufficient basis to conclude that GSE and GSKE are GRAS under their intended conditions of use. If you would like to discuss these issues in more detail, you may contact Dr. Linda Kahl by telephone at (202) 418-3101, by telefax at (202) 418-3131, or by electronic mail at linda.kahl@cfsan.fda.gov.

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 homepage of the Office of Food Additive Safety (on the Internet at http://www.cfsan.fda.gov/~lrd/foodadd.html).

References

1. A series of guidance documents are available at http://vm.cfsan.fda.gov/~lrd/foodadd.html

⁽¹⁾FDA notes that a different preparation of grape skin extract (enocianina), with different specifications, is regulated under 21 CFR 73.170 for use as a color additive in still and carbonated drinks and ades, beverage bases, and alcoholic beverages. Specifications for grape skin extract (enocianina) are also listed in the Food Chemicals Codex, 4th Edition (1996).

⁽²⁾As part of its overall conclusion, Polyphenolics cites several human studies that evaluated the potential that various phenolic compounds have certain pharmacological effects.

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