Agency Response Letter GRAS Notice No. GRN 000124
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CFSAN/Office of Food Additive Safety
August 1, 2003
Mr. Steven J. Anderson
San Joaquin Valley Concentrates
5631 East Olive Avenue
Fresno, CA 93727
Re: GRAS Notice No. GRN 000124
Dear Mr. Anderson:
The Food and Drug Administration (FDA) is responding to the notice, dated January 28, 2003, 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 February 3, 2003, filed it on February 14, 2003, and designated it as GRAS Notice No. GRN 000124.
The subject of the notice is grape seed extract (GSE). The notice informs FDA of the view of San Joaquin Valley Concentrates (San Joaquin) that GSE is GRAS, through scientific procedures, for use in beverages and beverage bases, breakfast cereals, fats and oils, frozen dairy desserts and mixes, grain products, milk (whole and skim), milk products, processed fruits and fruit juices at levels ranging from 0.01 to 0.08 percent. In oil/water systems, GSE functions as an antioxidant and as an emulsifier; in aqueous solutions, GSE functions as an antioxidant. San Joaquin notes that the astringent flavor that is associated with use levels greater than 0.05 percent makes the use of GSE self-limiting.
As part of its notice, San Joaquin includes the report of a panel of individuals (San Joaquin's GRAS panel) who evaluated the data and information that are the basis for San Joaquin's GRAS determination. San Joaquin considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. San Joaquin's GRAS panel evaluated estimates of dietary exposure, method of manufacture, and product specifications as well as published studies on San Joaquin's GSE and other grape seed extract products or components. Based on this review, San Joaquin's GRAS panel concluded that GSE, meeting food grade specifications and produced in compliance with good manufacturing practice, is GRAS, through scientific procedures, as an antioxidant and/or emulsifier in conventional foods under the conditions of its intended use.
San Joaquin describes GSE as a soluble, rose-brown powder that is a complex mixture of polyphenolic compounds, trace amounts of lipids and protein and small amounts of polysaccharides. Polyphenols are commonly found in higher plants, and are a diverse group of polymeric compounds containing multiple phenolic functionalities. Polyphenols are classified according to their repeating monomeric building blocks. In GSE, these monomers generally fall into two classes, i.e., flavonoids and non-flavonoids. The flavonoid polymers that are known as proanthocyanidins contain a specific type of flavonoid (called flavanols) as monomers. The non-flavonoid polymers are composed of esters of the monomers gallic acid or hexahydroxydiphenyl and a polyol (such as D-glucose). Other non-flavonoid polyphenols can be found in GSE and are composed of the monomers caffeic acid, chlorogenic acid and resveratrol.
San Joaquin notes that GSE is composed of approximately 74 to 78 percent proanthocyanidins and less than approximately 6 percent of free flavanol monomers on a dry weight basis. Specifically, San Joaquin states that GSE contains the flavanol monomers (+)-catechin, (-)-epicatechin, (-)-epicatechin gallate (ECG), (-)-epigallocatechin (EGC), and (-)-epigallocatechin gallate (EGCG).
San Joaquin describes the method of manufacture for GSE. Seeds obtained from grapes (Vitis vinifera) are purified, dried, and extracted with deionized water under heat and increased pressure. The aqueous extract is ultrafiltered to remove suspended solids and applied to a chromatographic column that adsorbs the proanthocyanidins. The adsorbed proanthocyanidins are eluted from the column with ethanol and then concentrated by nanofiltration and/or evaporation. The concentrated proanthocyanidin extract is dried to remove residual water and ethanol, ground to particle-sized specifications, blended, and packaged. San Joaquin reports that all materials involved in the manufacturing process are appropriate for food use. San Joaquin provides product specifications for GSE. Specifications include limits on the maximum levels of total phenols (gallic acid equivalents), total monomers, loss on drying, protein, ash, fat, polysaccharides, heavy metals, and microbial contaminants.
Using the United States Department of Agriculture 1994-1996 Continuing Surveys of Food Intakes by Individuals and the 1998 Supplemental Children's Survey, San Joaquin estimates the intake of GSE for the total population from San Joaquin's intended use of GSE would be approximately 150 milligrams per person per day (mg/person/day) at the mean (equivalent to approximately 3 milligrams per kilogram body weight per day (mg/kg body weight/day)) and approximately 300 mg/person/day at the 90th percentile (equivalent to approximately 6 mg/kg body weight/day). San Joaquin also estimates that the current per capita consumption of total proanthocyanidins and total flavanol monomers (from foods including tea, wine, beer, fruits and fruit juices, and chocolate) is approximately 500 mg/person/day and approximately 220 mg/person/day, respectively. San Joaquin concludes that the estimated intake of GSE would be similar to or less than the current dietary intake of total proanthocyanidins and total flavanol monomers from their natural occurrence in food.
San Joaquin discusses published information related to the absorption, distribution, metabolism, and excretion of proanthocyanidins. Although intact proanthocyanidins are poorly absorbed across the intestinal lumen, they may be hydrolyzed in the upper intestinal tract or degraded by intestinal microflora. When proanthocyanidins are absorbed, they and their metabolites are transported to the liver and other organs (e.g., kidney, lung, spleen, and connective tissue) where they are further metabolized and subsequently eliminated via urine, feces, biliary excretion, and respiration.
San Joaquin discusses published studies conducted with San Joaquin's GSE and other grape seed extract products or components in humans and various animal species and draws the following conclusions:
- Acute, subchronic and chronic oral toxicity studies conducted in animals fed GSE, other grape seed extracts, or substances that are components of GSE showed no relevant compound-related toxicological effects.
- Genotoxicity studies conducted in vivo or in vitro with commercial grape seed extracts or substances that are components of GSE demonstrated no mutagenic effects.
- Reproductive and developmental toxicity studies conducted in animals fed (+)-catechin demonstrated no adverse effects.
- Clinical, epidemiological and nutritional studies conducted with substances that are components of GSE demonstrated no significant adverse effects.
San Joaquin reports that GSE was evaluated by the Flavor and Extract Manufacturer's Association and was found to be acceptable for use as a flavoring agent at levels of 100 to 200 parts per million in fruit based beverages, powdered drink mixes, salad dressings, frozen desserts, cultured dairy products and skimmed milk.
Potential labeling issues
Section 403(a) of the Federal Food, Drug, and Cosmetic Act (FFDCA) provides that a food shall be deemed to be misbranded if its labeling is false or misleading in any particular. Section 403(i)(2) of the FFDCA provides that a food shall be deemed to be misbranded unless its label bears the common or usual name of each ingredient. In addition, section 403(k) of the FFDCA provides that a food shall be deemed to be misbranded if it bears or contains any chemical preservative, unless it bears labeling stating that fact. San Joaquin's use of GSE as an antioxidant constitutes use as a preservative. Therefore, the ingredient statement on labels of food products treated with GSE must comply with 21 CFR 101.22(j), which requires a food to which a chemical preservative is added to bear a label declaration stating both the common or usual name of the ingredient and a separate description of its function. If you have any questions about the appropriate labeling of this food ingredient, you should contact the staff in the Office of Nutritional Products, Labeling and Dietary Supplements (ONPLDS), Division of Food Labeling and Standards, 5100 Paint Branch Parkway, College Park, MD 20740. You can also reach this division by telephone at (301)436-2375.
In addition, Section 403(r) of the FFDCA lays out the statutory framework for a health claim. In describing the intended use of GSE and in describing the information that San Joaquin relies on to conclude that GSE is GRAS under the conditions of its intended use, San Joaquin raises potential labeling issues under these provisions of the FFDCA. These labeling issues consist of San Joaquin's assertion that GSE has physiological effects that San Joaquin views as beneficial. If products that contain GSE bear any claims about such benefits on the label or in labeling, such claims are the purview of ONPLDS. The Office of Food Additive Safety (OFAS) neither consulted with ONPLDS on these labeling issues nor evaluated the information in San Joaquin's notice to determine whether it would support any claims made about GSE on the label or in labeling.
Standards of identity
In its notice, San Joaquin states its intention to use GSE in several food categories, including foods for which standards of identity exist, located in Title 21 of the Code of Federal Regulations. We note that 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. If you have any questions about the use of GSE in standardized foods that would be marketed in the United States, you should contact the staff in ONPLDS, Division of Food Labeling and Standards
Based on the information provided by San Joaquin, as well as other information available to FDA, the agency has no questions at this time regarding San Joaquin's conclusion that GSE is GRAS under the intended conditions of use. The agency has not, however, made its own determination regarding the GRAS status of the subject use of GSE. As always, it is the continuing responsibility of San Joaquin to ensure that food ingredients that the firm markets are safe, and are otherwise in compliance with all applicable legal and regulatory requirements
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).
Laura M. Tarantino, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition