Agency Response Letter GRAS Notice No. GRN 000280
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CFSAN/Office of Food Additive Safety
August 24, 2009
James Heimbach, Ph.D.
923 Water Street
PO Box 66
Port Royal, VA 22535
Re: GRAS Notice No. GRN 000280
Dear Dr. Heimbach:
The Food and Drug Administration (FDA) is responding to the notice, dated January 20, 2009, that you submitted on behalf of Flax Canada 2015 (Flax Canada) 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 January 30, 2009, filed it on February 4, 2009, and designated it as GRAS Notice No. GRN 000280. In a letter dated July 7, 2009, Flax Canada limited the intended use to those foods described in the following paragraph.
The subjects of the notice are whole and milled flaxseed. The notice informs FDA of the view of Flax Canada that whole and milled flaxseed are GRAS, through scientific procedures, for use as ingredients in conventional foods, excluding meat and poultry products, limited only by current good manufacturing practices (cGMPs).
As part of its notice, Flax Canada includes the report of a panel of individuals (Flax Canada’s GRAS panel) who evaluated the data and information that are the basis for Flax Canada’s GRAS determination. Flax Canada considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Flax Canada’s GRAS panel evaluated potential human exposure to flaxseed and intake of alpha-linolenic acid (ALA), fiber, and other constituents, as well as the identity and physical-chemical properties of whole and milled flaxseed, including production methods and composition. Based on this review, Flax Canada’s GRAS panel concludes that, whole and milled flaxseed, meeting food grade specifications and produced in accordance with cGMP used as ingredients in conventional foods are GRAS under the conditions of their intended use.
Flax Canada describes the identity of whole and milled flaxseed. Flaxseed is the seed of Linum usitatissimum L, which is marketed and used as whole seed or milled to a powder. Milled flaxseed may be referred to as ground flaxseed or crushed flaxseed as well as milled flax, ground flax, or crushed flax.
Flax Canada notes that dried flaxseed contains about 40 percent (%) to 45% lipid, 30% to 35% carbohydrate, and 20% to 30% protein. The lipid content typically is 70% to 75% polyunsaturated fatty acids (PUFAs) and about 15% to 20% oleic acid. Approximately 80% of PUFAs are ALA, which corresponds to about 25% by weight of the whole seed. ALA, an n-3 fatty acid, constitutes over 50% of the total fatty acid content of flaxseed. Ninety percent of the carbohydrate in flaxseed is in the form of non-digestible fiber, including both insoluble cellulose and soluble mucilage.
Flax Canada reports that flaxseed also contains approximately 1.3% lignans, or approximately 13 milligrams per gram (g) of the seed. The primary lignan is 2,3-bis(3-methoxy-4-hydroxybenzyl)butane-1,4-diol, also known as secoisolariciresinol (SECO). SECO makes up over 95% of the total lignan content of flaxseed.(1) In flaxseed, SECO is bound to two glucose residues, referred to as secoisolariciresinol diglucoside (SDG). Following ingestion, approximately 90% of the lignans SECO and matairesinol are converted by colonic microbiota to the mammalian lignans enterodiol and enterolactone.
Flax Canada notes that flaxseed contains cyanogenic glycosides, which release hydrogen cyanide on hydrolysis. When flaxseed is crushed in water, enzymatic actions releases hydrogen cyanide, which is then washed away. Flax Canada concludes that the large body of animal and human research does not indicate any cyanide-produced adverse effects from consumption of flaxseed. Additionally, flaxseed contains linatine, a pro-antivitamin B6 antagonist. Flax Canada concludes that vitamin B6 deficiency through ingestion of linatine in flaxseed is not expected to be an issue at the intended use levels due to adequate exposure to vitamin B6 in the human diet.
Flax Canada describes the harvesting and milling processes for whole and milled flaxseed. The mature fruit of the flax plant is a dry boll or capsule that contains seeds. Harvesting flax crops is accomplished either by straight combining or cutting with a swather followed by threshing. Once harvested, flaxseed is subjected to a variety of separations based on differences in length, width, and bulk density to remove dirt and other extraneous material. Flaxseed is milled to cut rather than crush the flaxseed, so that oil-rich cellular structures are not damaged, resulting in a free-flowing granular product. Permitted anti-caking agents, such as silica, may be used to improve flowability of the milled product. Flax Canada provides specifications for whole and milled flaxseed, including specifications for total carbohydrates (between 25% and 38%), protein (between 15% and 30%), fat (between 32% and 45%), fiber (between 20% and 37%), moisture (between 3% and 10%), heavy metals, and microbiological limits.
Flax Canada also reports results from analyses for polychlorinated biphenyls and polycyclic aromatic hydrocarbons in seed and dioxins and furans in the oil from these samples. Flax Canada concludes that no contaminants were present at levels exceeding acceptable limits, based on World Health Organization toxic equivalent values for these contaminants.
Flax Canada considers 12% to be a representative maximum addition level for most foods. Flax Canada notes, however, that for many products, 12% flaxseed is likely to be unattainable because of technological and organoleptic issues. Flax Canada determines that intake based on a maximum of 12% flaxseed provides a conservative basis for estimating exposure. Using FDA’s Reference Amounts Customarily Consumed, the average intake of flax from one serving of flaxseed-containing food (at 12% flaxseed) will not exceed 4 g; daily consumption will not exceed 4 servings of foods that provide flaxseed. Thus, the notifier estimates that the estimated daily intake (EDI) of flaxseed from its intended use is 16 g per day.
Flaxseed contains about 25% ALA and 25% fiber; the EDI for ALA and for fiber each is 4 g/day. The National Academies’ Institute of Medicine (IOM) has established an Adequate Intake (AI) for ALA at 1.6 g/day for adult males and 1.1 g/day for adult females. The AI is the average consumption in the US population where there is no obvious sign of deficiency. Flax Canada reports that the IOM has concluded that intake of fiber at levels in excess of 40 g/day does not result in significant increases in adverse effects in healthy individuals and concludes that an EDI of 4 g fiber/day from consumption of flaxseed is safe. Flax Canada notes that other national and international scientific bodies recommend up to 3 g ALA/day and concludes that an EDI of 4 g ALA/day is safe.
Flax Canada summarizes numerous published animal and human studies, including subchronic oral toxicity studies in rats, piglets, and rabbits in which whole flaxseed or its components (e.g., SDG, ALA) were administered. Flax Canada also summarizes more than 30 studies in which flaxseed or SDG was consumed by human participants. Flax Canada discusses details of these studies and results on glycemic response, blood lipids, laxation, hormonal effects, cancer progression, bone metabolism, immune function, vascular stress response, kidney function, and cyanide accumulation. Flax Canada concludes that no adverse effects were observed in the studies, including a number of studies in which human participants consumed flaxseed at levels up to 50 g/day.
Flax Canada summarizes published genotoxicity and mutagenicity studies on flaxseed oil and on mammalian lignans, enterolactone and enterodiol, and plant lignans, matairesinol and secoisolariciresinol. Flax Canada concludes that there was no indication of genotoxicity or mutagenicity.
Flax Canada notes that most studies on hormonal effects involved women and found increased levels of the lignans, enterodiol and enterolactone, and 2-hydroxyestrogen, an estrogen metabolite. Flax Canada notes that weak estrogenic effects were observed at high consumption levels; however, there was variability across studies and no consistent effects were noted at lower levels. Flax Canada concludes that, while these studies found changes in serum hormones, significant hormonal effects were not observed in either males or females, even at levels as high as 50 g flaxseed/day.
Standards of Identity
In the notice, Flax Canada states its intention to use milled and whole flaxseed 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.
Potential Labeling Issues
Under section 403(a) of the Federal Food, Drug, and Cosmetic Act (FFDCA), a food is misbranded if its labeling is false or misleading in any particular. Section 403 (r) of the FFDCA lays out the statutory framework for the use of labeling claims that characterize the level of a nutrient in a food or that characterize the relationship of a nutrient to a disease or health-related condition. In describing the intended uses of whole and milled flaxseed and in describing the information that Flax Canada relies on to conclude that whole and milled flaxseed are GRAS under the conditions of their intended use, Flax Canada raises a potential nutrient content claims issue under these labeling provisions of the FFDCA. If products that contain whole or milled flaxseed bear any claims on the label or in labeling, such claims are the purview of the Office of Nutrition, Labeling, and Dietary Supplements (ONLDS) in the Center for Food Safety and Applied Nutrition. The Office of Food Additive Safety neither consulted with ONLDS on this labeling issue nor evaluated the information in Flax Canada’s notice to determine whether it would support any claims made about flaxseed on the label or in labeling.
Section 301(ll) of the FFDCA
The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the FFDCA to, among other things, add section 301(ll). Section 301(ll) of the FFDCA prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FFDCA, a biological product licensed under section 351 of the Public Health Service Act, or a drug or a biological product for which substantial clinical investigations have been instituted and their existence made public, unless one of the exemptions in section 301(ll)(1)-(4) applies. In its review of Flax Canada’s notice that whole and milled flaxseed are GRAS for use conventional foods, excluding meat and poultry products, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing whole or milled flaxseed. Accordingly, this response should not be construed to be a statement that foods containing whole or milled flaxseed, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Flax Canada, as well as other information available to FDA, the agency has no questions at this time regarding Flax Canada’s conclusion that whole and milled flaxseed are 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 whole and milled flaxseed. As always, it is the continuing responsibility of Flax Canada 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 responding to GRN 000280, as well as a copy of the information in this notice that conforms to the information in the GRAS exemption claim (proposed 21 CFR 170.36(c)(1)), is available for public review and copying via the FDA home page at http://www.fda.gov. To view or obtain an electronic copy of the text of the letter, follow the hyperlinks from the “Food” topic to the “Food Ingredients and Packaging” section to the “Generally Recognized as Safe (GRAS)” page where the GRAS Inventory is listed.
Mitchell A. Cheeseman, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
(1)Lignan content includes matairesinol and trace amounts of pinoresinol and isolariciresinol.