Agency Response Letter
GRAS Notice No. GRN 000200

Edward A. Steele
AAC Consulting Group
7361 Calhoun Place, Suite 500
Rockville, MD 20855-2765

Re: GRAS Notice No. GRN 000200

Dear Mr. Steele:

The Food and Drug Administration (FDA) is responding to the notice, dated May 26, 2006, that you submitted on behalf of Twin Rivers Technologies 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 May 30, 2006, filed it on June 1, 2006, and designated it as GRAS Notice No. GRN 000200. FDA received an amendment, dated September 25, 2006, containing revised specifications.

The subject of the notice is tailored triglycerides enriched in omega-3 fatty acids from fish oil. For the purpose of this letter, FDA refers to the subject as the tailored triglycerides ingredient. The notice describes the tailored triglycerides ingredient as containing a higher proportion (approximately 55 percent by weight) of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) than that found in naturally-occurring fish oils. ⁽¹⁾ The notice informs FDA of the view of Twin Rivers Technologies that the tailored triglycerides ingredient is GRAS, through scientific procedures, for use as a direct food ingredient in the same food categories as those currently listed in 21 CFR 184.1472(a)(3) (menhaden oil) at levels that are 36 percent of the levels specified in that regulation (Table 1).

Our use of the terms "tailored triglycerides enriched in omega-3 fatty acids from fish oil" and "tailored triglycerides ingredient" in this letter should not be considered an endorsement or recommendation of either 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. According to 21 CFR 101.4, 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 in the Center for Food Safety and Applied Nutrition.

FDA has affirmed the GRAS status of menhaden oil (21 CFR 184.1472) provided that the combined intake of EPA and DHA from consumption of menhaden oil does not exceed 3 grams per person per day (g/p/d). Similarly, Twin Rivers Technologies concludes that its tailored triglycerides ingredient is GRAS for use as an ingredient in the same food categories as menhaden oil provided that the combined daily intake of EPA and DHA from consumption of foods containing the ingredient does not exceed 3 g/p/d and that the tailored triglycerides ingredient is the sole added source of EPA and DHA in any given food category.

As part of its notice, Twin Rivers Technologies includes a summary of conclusions of a panel of individuals (Twin Rivers Technologies' GRAS panel) who evaluated the publicly available data and information summarized in Twin Rivers Technologies' GRAS notice. Specifically, this GRAS panel evaluated (1) previously filed GRAS notices for fish oils; (2) FDA's Proposed, Tentative Final, and Final Rules affirming the GRAS status of menhaden oil; (3) published clinical studies of omega-3 fatty acids; and (4) information about the product itself, including the source of the product, production process, nature and quantity of impurities, product specifications, and identity and positional distributions of EPA and DHA within the glycerides of the ingredient. On the basis of its evaluation of this information, Twin Rivers Technologies' GRAS panel concluded that its tailored triglycerides ingredient, meeting the specifications cited in the GRAS panel statement and manufactured as described in the GRAS panel statement, is GRAS when used as a direct food ingredient at the levels listed in Table 1.

Twin Rivers Technologies describes generally available information about the identity and composition of the tailored triglycerides ingredient. The EPA and DHA levels of this tailored triglycerides ingredient are increased above levels found in naturally-occurring fish oils by a selective process of separating long chain fatty acids from short chain fatty acids in fish oil and then re-esterifying the long chain fatty acids with glycerin to form (predominantly) triglycerides, with lesser amounts of diglycerides (less than 10 percent) and monoglycerides (less than 2 percent).

According to the food-grade specifications for the tailored triglycerides ingredient provided by the notifier, the triglyceride content is not less than 90 percent and the diglyceride content is not more than 10 percent. The glycerides contain a high proportion of the omega-3 fatty acids EPA (typically 32 percent) and DHA (typically 23 percent), for a total EPA+DHA content of approximately 55 percent.⁽²⁾ Twin Rivers Technologies provides representative fatty acid profiles for the tailored triglycerides ingredient and menhaden oil in its notice. In comparison to menhaden oil, the tailored triglycerides ingredient has a higher concentration of long chain polyunsaturated fatty acids (e.g. EPA and DHA) and a lower concentration of shorter chain fatty acids.

Twin Rivers Technologies describes the manufacture of its tailored triglycerides ingredient. The product is manufactured using starting material (crude or refined fish oil) obtained from several edible fish species including salmon, menhaden, anchovy, sardine, jack mackerel, mackerel, and tuna. Fish oil undergoes transesterification by use of methanol or ethanol in the presence of sodium methoxide, resulting in the formation of fatty acid methyl or ethyl esters and free glycerin. Unreacted methanol or ethanol and glycerin are removed by flash evaporation and washing steps. Fractional distillation is used to remove the low-boiling (shorter chain) methyl or ethyl esters and wiped film evaporation is used to distill high-boiling (longer chain) methyl or ethyl esters. The high-boiling esters are reacted with glycerin in the presence of either potassium carbonate or sodium methoxide to produce triglycerides enriched in long chain fatty acids. This product then undergoes refining, bleaching, evaporation and steam stripping steps before addition of mixed tocopherols to retard oxidation. Twin Rivers Technologies concludes that extraction and refining processes described in the method of manufacture are similar to standard industry practices for processing of fish oils and to processes described in GRAS notices previously submitted to FDA.⁽³⁾

Twin Rivers Technologies provides specifications for the food-grade tailored triglycerides ingredient, including specifications for lead, mercury, polychlorinated biphenyls (PCBs), and dioxins. The notice includes the results of batch analyses for potential environmental contaminants, including PCBs, dioxins, polycyclic aromatic hydrocarbons, and organochlorine and organophosphate pesticides. Furthermore, in the amendment dated September 25, 2006, Twin Rivers Technologies states that internal specifications have been established for the presence of methanol and low level methyl esters, which are removed to low milligram per kilogram levels by the wiped film evaporation and stream stripping processes.

Twin Rivers Technologies describes the intended use of its tailored triglycerides ingredient in foods and provides a table that lists the food categories and intended use level in each food category (Table 1). Twin Rivers Technologies' tailored triglycerides ingredient is intended to be used as an ingredient in food categories listed in 21 CFR 184.1472(a)(3) at maximum use levels that are 36 percent of the levels specified in that regulation. The notifier estimates that the mean intake of EPA and DHA combined from the intended uses of its tailored triglycerides ingredient will not exceed 3 g/p/d.

Table 1
Intended maximum use levels in food (as served) of the tailored triglycerides ingredient^*

Category of food	Maximum Use Levels [percent by weight]
Baked goods and baking mixes (1)	1.8
Cereals (4)	1.4
Cheese products (5)	1.8
Chewing gum (6)	1.1
Condiments (8)	1.8
Confections and frostings (9)	1.8
Dairy product analogs (10)	1.8
Egg products (11)	1.8
Fats and oils (12), not in infant formulas	4.3
Fish products (13)	1.8
Frozen dairy desserts (20)	1.8
Gelatins and puddings (22)	0.36
Gravies and sauces (24)	1.8
Hard candy (25)	3.6
Jams and jellies (28)	2.5
Meat products (29)	1.8
Milk products (31)	1.8
Nonalcoholic beverages (3)	0.18
Nut products (32)	1.8
Pastas (23)	0.7
Plant protein products (33)	1.8
Poultry products (34)	1.1
Processed fruit juices (35)	0.36
Processed vegetable juices (36)	0.36
Snack foods (37)	1.8
Soft candy (38)	1.4
Soup mixes (40)	1.1
Sugar substitutes (42)	3.6
Sweet sauces, toppings, and syrups (43)	1.8
White granulated sugar (41)	1.4
* The food categories correspond to those listed in 21 CFR 170.3(n) and the number in parentheses following each food category corresponds to the paragraph number in the regulation.

Twin Rivers Technologies acknowledges that FDA had previously raised concerns about the consumption of high levels of EPA and DHA and possible adverse effects of consumption on bleeding time, glycemic control, and low-density lipoprotein cholesterol levels (62 FR 30751 at 30757; 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. FDA subsequently revised the menhaden oil rule to reallocate the uses of menhaden oil in conventional food, while maintaining the total daily intake of EPA and DHA from menhaden oil at a level not exceeding 3.0 g/p/d (67 FR 8744; February 26, 2002) and to require that menhaden oil not be used as an ingredient in foods in combination with another added oil that is a significant source of EPA and DHA (70 FR 14530; March 23, 2005). Twin Rivers Technologies reviewed (1) rulemaking decisions of FDA on the GRAS affirmation of menhaden oil and of EPA and DHA, (2) several GRAS notices for fish oils and one for fish oil concentrate, and (3) scientific literature published since the menhaden oil final rule appeared in the Federal Register on March 23, 2005. On the basis of this information, Twin Rivers Technologies concludes that its tailored triglycerides ingredient is GRAS for the intended uses as described in Table 1.

In the notice, Twin Rivers Technologies states its intention to use its tailored triglycerides ingredient 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 lawfully added to food products may be used in a standardized food only if it is permitted by the applicable standard of identity.

The Food Allergen Labeling and Consumer Protection Act of 2004 (FALCPA) amends the Federal Food, Drug, and Cosmetic Act to require that the label of a food that is or contains an ingredient that bears or contains a "major food allergen" declare the presence of the allergen (section 403(w)). FALCPA defines a "major food allergen" as one of eight foods or food groups (i.e., milk, eggs, fish, Crustacean shellfish, tree nuts, peanuts, wheat, and soybeans) or a food ingredient that contains protein derived from one of those foods. Issues associated with labeling food are the responsibility of the Office of Nutritional Products, Labeling, and Dietary Supplements in the Center for Food Safety and Applied Nutrition.

During its evaluation of GRN 000200, 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 requested that FDA advise Twin Rivers Technologies to seek regulatory guidance from FSIS, Labeling and Consumer Protection Staff, about the use of the tailored triglycerides ingredient in meat and poultry products. Twin Rivers Technologies should direct such an inquiry to Dr. Robert Post, Director, Labeling and Consumer Protection Staff, Office of Policy, Program, and Employee Development, Food Safety and Inspection Service, 1400 Independence Ave., S.W., Suite 602, Annex, Washington, DC 20250-3700. The telephone number for that office is (202) 205 0279 and the telefax number is (202) 205 3625.

Based on the information provided by Twin Rivers Technologies, as well as other information available to FDA, the agency has no questions at this time regarding Twin Rivers Technologies' conclusion that the tailored triglycerides ingredient 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 this ingredient. As always, it is the continuing responsibility of Twin Rivers Technologies 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 000200, 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 http://www.cfsan.fda.gov/~lrd/foodadd.html).

Sincerely,

Laura M. Tarantino, Ph.D.
Director
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

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⁽¹⁾ In its notice, Twin Rivers Technologies refers to the ingredient as "omega-3 triglyceride concentrate" and "N3-TG-3020."

⁽²⁾The notifier specifies that the range of EPA+DHA content is from 500 milligrams per gram (mg/g) to 600 mg/g of ingredient.

⁽³⁾In its notice, Twin Rivers Technologies references GRAS Notices 000102, 000105, 000109, 000138, and 000146.