Agency Response Letter GRAS Notice No. GRN 000193

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CFSAN/Office of Food Additive Safety

August 3, 2006

Arjan Geerlings, Ph.D.
Puleva Biotech
Camino de Purchil 66
18004 Granada

Re: GRAS Notice No. GRN 000193

Dear Dr. Geerlings:

The Food and Drug Administration (FDA) is responding to the notice, dated January 25, 2006, that you submitted on behalf of Puleva Biotech 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, 2006, filed it on February 7, 2006, and designated it as GRAS Notice No. GRN 000193.

The subjects of the notice are fish oil (predominantly sardine and anchovy) and tuna oil. The notice describes fish oil (predominantly sardine and anchovy) as an eicosapentaenoic acid (EPA)-rich oil and tuna oil as a docosahexaenoic acid (DHA)-rich oil(1). For the purpose of this letter, FDA refers to these ingredients as "fish oils." The notice informs FDA of the view of Puleva Biotech that fish oil (predominantly sardine and anchovy) and tuna oil are GRAS, through scientific procedures, for use as direct food ingredients in the same food categories as those currently listed in 21 CFR 184.1472(a)(3)(menhaden oil) at levels that are 67 percent of the levels specified in that regulation.

Our use of the term "fish oils" in this letter should not be considered an endorsement or recommendation of that term as an appropriate common or usual name for the purpose of declaring the substance in the ingredient statement of foods that contain that ingredient. 21 CFR 101.4 states that all ingredients must be declared by their common or usual name. In addition, 21 CFR 102.5 outlines general principles to use when establishing common or usual names for non-standardized foods. Issues associated with labeling and the appropriate common or usual name of a food are the responsibility of the Office of Nutritional Products, Labeling, and Dietary Supplements.

As with the use of menhaden oil, the maximum use levels of Puleva Biotech's fish oils are designed to assure that the combined daily intake of two fatty acids (i.e., EPA and DHA) that are components of sardine, anchovy, and tuna oil would not exceed 3 grams/person/day (g/p/d). FDA has affirmed the GRAS status of menhaden oil (21 CFR 184.1472(a)(3)) provided that the combined daily intake of EPA and DHA from consumption of menhaden oil does not exceed 3 g/p/d. Similarly, Puleva Biotech concludes that its fish oils are safe for use as a direct ingredient provided that the combined daily intake of EPA and DHA from consumption of foods containing these fish oils does not exceed 3 g/p/d and that these fish oils are added as the sole source of EPA and DHA in any given food category.

As part of its notice, Puleva Biotech includes a summary of conclusions of a panel of individuals (Puleva Biotech's GRAS panel) who evaluated the publicly available data that Puleva Biotech includes in its notice demonstrating the safety of the proposed uses of fish oils. Puleva Biotech considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Puleva Biotech's GRAS panel reviewed all the data and other information presented in the notice regarding source of the fish oils, manufacturing method, specifications, contaminant levels, dietary exposure, and recent published toxicological and human studies. Puleva Biotech's GRAS panel concluded that fish oils, meeting the food grade specifications described in the Puleva Biotech's notice, are GRAS under their intended conditions of use.

Puleva Biotech describes the intended use of its fish oils in foods and provides a table that lists the food categories and intended use level in each food category (Table 1). Puleva Biotech's fish oils are intended to be used as direct food ingredients in food categories listed in 21 CFR 184.1472(a)(3) at maximum use levels that are 67 percent of the levels specified in that regulation. Puleva Biotech estimated that the mean intake of EPA and DHA combined from the proposed uses of its fish oils will not exceed 3 g/p/d.

Table 1
Maximum Intended Use Levels of Fish Oils*

*The food categories correspond to those listed in 21 CFR 170.3(n). The number in parenthesis
following each food category is the paragraph listing of that food category in 21 CFR 170.3(n).

Food CategoryFish Oils
[percent by weight]
Maximum EPA + DHA addition level
[percent by weight]
Baked goods and baking mixes (1)3.31.0
Cereals (4)2.60.8
Cheese products (5)3.31.0
Chewing gum (6)2.00.6
Condiments (8)3.31.0
Confections and frostings (9)3.31.0
Dairy product analogs (10)3.31.0
Egg products (11)3.31.0
Fats and oils (12), not in infant formulas8.02.4
Fish products (13)3.31.0
Frozen dairy desserts (20)3.31.0
Gelatins and puddings (22)0.60.2
Gravies and sauces (24)3.31.0
Hard candy (25)6.62.0
Jams and jellies (28)4.61.4
Meat products (29)3.31.0
Milk products (31)3.31.0
Nonalcoholic beverages (3)0.30.1
Nut products (32)3.31.0
Pastas (23)1.30.4
Plant protein products (33)3.31.0
Poultry products (34)2.00.6
Processed fruit juices (35)0.60.2
Processed vegetable juices (36)0.60.2
Snack foods (37)3.31.0
Soft candy (38)2.60.8
Soup mixes (40)2.00.6
Sugar substitutes (42)6.62.0
Sweet sauces, toppings, and syrups (43)3.31.0
White granulated sugar (41)2.60.8

Puleva Biotech describes generally available information about the identity and composition of fish oil (predominantly sardine and anchovy) and of tuna oil. The fish oils are predominantly triacylglycerides. Puleva Biotech presents typical fatty acid profiles of the fish oils in its notice. The fish oil (predominantly sardine and anchovy) contains EPA at a level of approximately 20 percent (by weight) of total fatty acids and DHA at a level of approximately 10 percent (by weight) of total fatty acids. The tuna oil contains DHA at a level of approximately 20 percent (by weight) of total fatty acids and EPA at a level of approximately 10 percent (by weight) of total fatty acids.

Puleva Biotech also describes the manufacture of its fish oils. Puleva Biotech's EPA-rich fish oil is obtained from sardine and anchovy and its DHA-rich tuna oil is obtained from tuna. Puleva Biotech notes that the manufacturing processes are identical for each oil. Processing of the crude fish oils extracts includes: 1) neutralization; 2) silica treatment; 3) decolorization (bleaching); 4) deodorization; and 5) stabilization with tocopherols and other food-grade antioxidants. Batches of fish oils may be blended to obtain the desired EPA and DHA fatty acid concentrations. Puleva Biotech provides specifications for the food-grade oils including specifications for lead, mercury, and persistent environmental pollutants. The notice includes results of batch analyses to support the ability of the method of manufacture to produce ingredients that meets Puleva Biotech's specifications.

Puleva Biotech acknowledges that FDA has previously raised concerns about the consumption of high levels of two fatty acids (i.e., DHA and EPA), which may increase bleeding time, increase levels of low-density lipoprotein cholesterol, and have an effect on glycemic control in non-insulin dependent diabetics (menhaden oil final rule; 62 FR 30571; June 5, 1997). In affirming the GRAS status of menhaden oil, FDA concluded that the use of menhaden oil as a direct food ingredient is GRAS, provided that the combined daily intake of EPA and DHA from consumption of menhaden oil does not exceed 3 g/p/d. To assure that the combined exposure to EPA and DHA would not exceed 3 g/p/d, FDA established maximum levels of use of menhaden oil that would be permitted in specified food categories (21 CFR 184.1472(a)(3)). Puleva Biotech reviewed literature published since the date of the June 1997 menhaden oil final rule and provides brief summaries of human studies on possible adverse effects. Puleva Biotech concludes from its literature review that the recent published scientific literature is consistent with FDA's conclusion regarding the safety of ingestion of up to 3 g/p/d of EPA and DHA.

In the notice, Puleva Biotech states its intention to use these fish oils 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.

During its evaluation of GRN 000193, FDA consulted with the Labeling and Consumer Protection Staff of the Food Safety and Inspection Service (FSIS) of the United States Department of Agriculture (USDA). Under the Federal Meat Inspection Act and the Poultry Products Inspection Act, FSIS is responsible for determining the efficacy and suitability of food ingredients in meat and poultry products as well as prescribing safe conditions of use. Suitability relates to the effectiveness of the ingredient in performing the intended purpose of use and the assurance that the conditions of use will not result in an adulterated product, or one that misleads consumers. FSIS notes that because the oils are of fish origin and are similar in composition to that of menhaden oil, FSIS has no objection regarding their use in the production of meat and poultry products at the proposed use levels so long as the food standards that apply to the meat and poultry products in which the use of the ingredients is intended allow for such use. FSIS advised that Puleva Biotech seek regulatory guidance about the use of these ingredients in meat and poultry products from Dr. Robert Post, Director for labeling and Consumer Protection Staff, Office of Policy, Program, and Employee Development, Food Safety and Inspection Service, 1400 Independence Avenue, SW, Suite 602-Annex Building, Washington, DC 20250-3700.

Based on the information provided by Puleva Biotech, as well as other information available to FDA, the agency has no questions at this time regarding Puleva Biotech's conclusion that fish oil (primarily sardine and anchovy) and tuna oil 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 these fish oils. As always, it is the continuing responsibility of Puleva Biotech 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 000193, as well as a copy of the information in this notice that conforms to the information in the proposed GRAS exemption claim (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

Laura M. Tarantino, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition

cc: Dr. Robert Post, Director
Labeling and Consumer Protection Staff
Office of Policy, Program and Employee Development
Food Safety and Inspection Service
1400 Independence Ave., SW, Suite 602, Annex
Washington, DC 20250-3700

(1)In the notice, Puleva Biotech uses the trade names Eupoly-EPA and Eupoly-DHA respectively.

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