Agency Response Letter GRAS Notice No. GRN 000319
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CFSAN/Office of Food Additive Safety
August 4, 2010
Rene Blum, Ph.D.
Re: GRAS Notice No. GRN 000319
Dear Dr. Blum:
The Food and Drug Administration (FDA) is responding to the notice, dated January 6, 2010, 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 January 11, 2010, filed it on January 21, 2010, and designated it as GRAS Notice No. GRN 000319.
The subject of the notice is micro-algal oil derived from Ulkenia sp. SAM2179 (hereafter referred to as micro-algal oil (Ulkenia sp. SAM2179)). The notice informs FDA of the view of Lonza Ltd. (Lonza) that micro-algal oil (Ulkenia sp. SAM2179) is GRAS, through scientific procedures, for use as an ingredient in the food categories listed in 21 CFR 184.1472(a)(3) at levels up to 40 percent of the levels specified in 21 CFR 184.1472(a)(3) and not to be combined with any other added oil that is a significant source of eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA).
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 nonstandardized foods. Our use of “micro-algal oil (Ulkenia sp. SAM2179)” 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. Issues associated with labeling and the appropriate common or usual name of a food are the responsibility of the Office of Nutrition, Labeling, and Dietary Supplements (ONLDS) in the Center for Food Safety and Applied Nutrition.
As part of its notice, Lonza includes the report of a panel of individuals (Lonza’s GRAS panel) who evaluated the data and information that are the basis for Lonza’s GRAS determination. Lonza considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of micro-algal oil (Ulkenia sp. SAM2179). The GRAS panel evaluated published and unpublished documentation on micro-algal oil (Ulkenia sp. SAM2179), including the safety of the source organism, method of manufacture, product specifications, estimates of dietary exposure and safety studies. Based on this review, the GRAS panel concluded that micro-algal oil (Ulkenia sp. SAM2179), manufactured in accordance with current good manufacturing practices (cGMP), and meeting established food grade specifications, is GRAS under the conditions of its intended use.
Lonza describes the chemical identity and quantitative composition of micro-algal oil (Ulkenia sp. SAM2179). Lonza describes the ingredient as a refined oil, consisting predominantly of triglycerides (greater than 95 percent), and containing approximately 38 to 50 percent DHA. Lonza provides the chemical name (all-cis-4,7, 10, 13, 16, 19-docosahexaenoic acid (22:6)) and Chemical Abstracts Service Registry number (CAS Reg No. 6217-54-5) for the major fatty acid DHA. The remaining major fatty acids are palmitic acid (16:0) and the omega 6 fatty acid docosapentaenoic acid (DPA, 22:5), which comprise 28 to 37 percent and 8 to 14 percent, respectively of the micro-algal oil (Ulkenia sp. SAM2179).
Lonza describes the method of manufacture of micro-algal oil (Ulkenia sp. SAM2179). The ingredient is manufactured in accordance with cGMPs through a multi-step fermentation and refining process, using a genetically-stable, wild-type pure culture of the marine protist, Ulkenia sp. SAM2179. Lonza discusses the safety of the source organism, noting that Ulkenia sp. SAM2179 is a non-toxigenic and non-pathogenic organism. Lonza conducted analyses of micro-algal oil (Ulkenia sp. SAM2179) and Ulkenia sp. SAM2179 dried biomass for the presence of algal and cyanobacterial toxins; no toxins were detected in any samples. Although there are no data demonstrating consumption of Ulkenia spp., Lonza notes that these organisms are part of the diet of filter-feeders (e.g., clams and mussels) and are thus indirectly consumed in the human diet.
Throughout the fermentation process, Lonza maintains the cultural purity, sterility, and integrity of the microalgae, Ulkenia sp. SAM2179. Further, Lonza uses food-grade ingredients as components of the culture medium (based on glucose and corn steep). Safe and suitable defoamers and flocculants may also be added during fermentation. The oil is extracted from Ulkenia sp. SAM2179 by one of three processes: pressing of dried biomass, cell rupture and oil separation of wet biomass, or extraction with a food-grade solvent such as hexane (subsequently removed by vacuum distillation). The crude Ulkenia oil is refined by standard edible oil refining processes of degumming, deacidification, bleaching (including activated carbon), steam deodorization, and winterization. Refined micro-algal oil (Ulkenia sp. SAM2179) is stabilized by the addition of safe and suitable antioxidants and the final product may be mixed with other edible oils (e.g., sunflower) to adjust the DHA concentration to a specified level (38 to 50 percent DHA).
Lonza provides specifications for micro-algal oil (Ulkenia sp. SAM2179), which is described as having a slightly waxy to liquid consistency, pale yellow to orange color, neutral pH, and 0.95 grams per milliliter relative density (25 degrees Celsius). Specifications for the final ingredient are stated as follows: DHA (38 to 50 percent); trans fatty acids (≤1 percent); peroxide value (≤5 milliequivalents per kilogram); acid value (≤0.5 milligrams KOH per gram); non-saponifiables (≤2.0 percent); arsenic, lead, and mercury (each ≤0.1 milligrams per kilogram (mg/kg)); cadmium (<0.1 mg/kg); hexane (<1 mg/kg), and microbiological specifications.
Lonza discusses the sterol content of the micro-algal oil (Ulkenia sp. SAM2179), noting that sterols are generally present at levels below 1 percent. The three main sterols in micro-algal oil (Ulkenia sp. SAM2179) are cholesterol, 4-methyl-chondrillasterol, and 7-dehydrostigmasterol. Lonza discusses the occurrence of these sterols in algae and certain plants, noting that these sterols, or closely related sterols, are normal components of the human diet.
Lonza states that the use of micro-algal oil (Ulkenia sp. SAM2179) will be based on the maximum use levels of menhaden oil in specific food categories established by FDA in the menhaden oil regulation (21 CFR 184.1472) such that the intake would not exceed 3.0 grams of omega 3 fatty acid (i.e., EPA + DHA) per person per day (g/p/d). Lonza estimates the intake of micro-algal oil (Ulkenia sp. SAM2179) to be 7.9 g/p/d, which would be equivalent to 3 g/p/d DHA intake (based on 38 percent DHA in micro-algal oil (Ulkenia sp. SAM2179)). Assuming a total sterol content of 1 percent (and 30 percent of sterols as cholesterol), Lonza estimates the maximum daily intake of cholesterol and other sterols from the Ulkenia oil would be approximately 24 mg and 55 milligrams per day, respectively.
Lonza discusses several published studies as part of their safety assessment. Lonza discusses a 90-day study in which rats receiving micro-algal oil (Ulkenia sp. SAM2179) up to 2,000 milligrams per kilogram body weight per day (mg/kg bw/d) showed no difference with regard to clinical observations, food and water consumption, mortality, gross pathology and histopathology, compared to the control groups receiving water or 2,000 mg/kg bw/d of fish oil. Lonza also reports that a one-generation reproductive toxicity study in rats receiving up to 7.5 percent micro-algal oil (Ulkenia sp. SAM2179) in the diet (approximately 75,000 mg micro-algal oil/kg rat chow) showed that clinical observations, mortality, fertility and reproductive performance, were unaffected by treatment in parental animals, and there were no adverse effects of treatment on the numbers of pups, pups per litter, pup mortality, sex ratio, or pup weight. There was also no evidence of a compound-related effect on the incidence of malformations. In addition, Lonza discusses published and unpublished studies of DHA-rich oils in humans, comparing the composition and DHA content of fish and marine algal-derived oils to micro-algal oil (Ulkenia sp. SAM2179), and stating that the available scientific literature on the safety of these oils also supports the safety of micro-algal oil (Ulkenia sp. SAM2179).
In discussing the metabolic fate of micro-algal oil (Ulkenia sp. SAM2179), Lonza states that the DHA present in micro-algal oil (Ulkenia sp. SAM2179), like other edible oils, is in triglyceride form, and that available evidence indicates that the absorption, distribution, and metabolism of DHA from micro-algal oil (Ulkenia sp. SAM2179) are similar to that of other dietary fatty acids.
Lonza emphasizes that the general recognition of safety of micro-algal oil (Ulkenia sp. SAM2179) is further supported through the knowledge that micro-algal oil (Ulkenia sp. SAM2179) has been evaluated by international regulatory authorities and approved for use as a novel food in Europe, Australia, New Zealand, and China in food categories similar to those outlined in this GRAS notice.
Standards of Identity
In the notice, Lonza states its intention to use micro-algal oil (Ulkenia sp. SAM2179) 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 use of micro-algal oil (Ulkenia sp. SAM2179) and in describing the information that Lonza relies on to conclude that micro-algal oil (Ulkenia sp. SAM2179) is GRAS under the conditions of its intended use, Lonza raises a potential issue under these labeling provisions of the FFDCA. If products that contain micro-algal oil (Ulkenia sp. SAM2179) bear any claims on the label or in labeling, such claims are the purview of ONLDS. The Office of Food Additive Safety neither consulted with ONLDS on this labeling issue nor evaluated the information in your notice to determine whether it would support any claims made about micro-algal oil (Ulkenia sp. SAM2179) on the label or in labeling.
Potential Requirement for a Color Additive Petition
In GRN 000319, Lonza describes the micro-algal oil (Ulkenia sp. SAM2179) as pale yellow to orange in color. As such, the use of micro-algal oil (Ulkenia sp. SAM2179) in food products may constitute the use of a color additive under section 201(t)(1) of the FFDCA and FDA's implementing regulations in 21 CFR Part 70. Under section 201(t)(1) and 21 CFR 70.3(f), the term color additive means a material that is a dye, pigment, or other substance made by a process of synthesis or similar artifice, or extracted, isolated, or otherwise derived from a vegetable, animal, mineral, or other source, and that is capable (alone or through reaction with another substance) of imparting color when added or applied to a food; except that such term does not include any material which the Secretary,1 by regulation, determines is used (or intended to be used) solely for a purpose or purposes other than coloring. Under 21 CFR 70.3(g), a material that otherwise meets the definition of color additive may be exempt from that definition on the basis that it is used or intended to be used solely for a purpose or purposes other than coloring, as long as the material is used in a way that any color imparted is clearly unimportant insofar as the appearance, value, marketability, or consumer acceptability is concerned. Given the construct of section 201(t)(1) of the FFDCA and 21 CFR 70.3(f) and (g), the use of a substance that is capable of imparting color may constitute use as a color additive in addition to use as a food additive or GRAS substance. For example, beta-carotene is both approved for use as a color additive (21 CFR 73.95) and affirmed as GRAS for use as a nutrient supplement (21 CFR 184.1245); in some food products, beta-carotene is used for both purposes. Importantly, if the use of micro-algal oil (Ulkenia sp. SAM2179) constitutes use as a color additive within the meaning of section 201(t)(1) of the FFDCA and FDA's implementing regulations in 21 CFR 70.3(f) and (g), section 721(a) of the FFDCA requires premarket review and approval of that use by FDA. Under section 402(c) of the FFDCA, a food product that contains an unapproved color additive would be deemed adulterated.2
In an email sent July 9, 2010, FDA requested that Lonza present its view on whether any of the intended uses of micro-algal oil (Ulkenia sp. SAM2179) would be exempt from the definition of a color additive. In an amendment dated July 12, 2010, Lonza presented its reason for concluding that all of the intended uses of micro-algal oil (Ulkenia sp. SAM2179) would be exempt from the definition of color additive under section 201(t) of the FFDCA and FDA's implementing regulations in 21 CFR 70.3(f) and (g). Importantly, FDA's response to GRN 000319 does not include any comment by FDA about Lonza’s view on this issue. If, after receipt of this letter, Lonza has any further questions about this issue, we recommend that Lonza contact the Division of Petition Review in the Office of Food Additive Safety.
Use in Products under USDA Jurisdiction
During its evaluation of GRN 000319, FDA consulted with the Risk and Innovations Management Division of the Food Safety and Inspection Service (FSIS) of the United States Department of Agriculture. Under the Federal Meat Inspection Act, the Poultry Products Inspection Act, and the Egg Products Inspection Act, FSIS is responsible for determining the efficacy and suitability of food ingredients in meat, poultry, and egg 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 Lonza to seek regulatory guidance from FSIS about the use of micro-algal oil (Ulkenia sp. SAM2179) in meat and poultry products. Lonza should direct such an inquiry to Dr. John M. Hicks, Jr., Risk and Innovations Management Division, Office of Policy and Program Development, Food Safety and Inspection Service, United States Department of Agriculture, George Washington Carver Center (GWCC), 5601 Sunnyside Ave., Mailstop 5271, Beltsville, MD 20705-5271. The telephone number for that office is (301) 504-0884 and the telefax number is (301) 504-0876.
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 Lonza’s notice that micro-algal oil (Ulkenia sp. SAM2179) is GRAS for use in certain foods, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing micro-algal oil (Ulkenia sp. SAM2179). Accordingly, this response should not be construed to be a statement that foods that contain micro-algal oil (Ulkenia sp. SAM2179), if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Lonza, as well as other information available to FDA, the agency has no questions at this time regarding Lonza’s conclusion that micro-algal oil (Ulkenia sp. SAM2179) 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 micro-algal oil (Ulkenia sp. SAM2179). As always, it is the continuing responsibility of Lonza 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 000319, 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
cc: John M. Hicks, Jr. DVM, MPH
Risk and Innovations Management Division
Office of Policy and Program Development
Food Safety and Inspection Service
United States Department of Agriculture
George Washington Carver Center (GWCC)
5601 Sunnyside Ave., Mailstop 5271
Beltsville, MD 20705-5271
1The Secretary of the Department of Health and Human Services.
2We note that section 721(b)(4) of the FFDCA provides that a color additive shall be deemed to be safe and suitable for the purpose of listing under section 721(b) of the FFDCA while there is in effect a published finding of the Secretary declaring that the substance is exempt from the definition of “food additive” because of its being generally recognized by qualified experts as safe for its intended use as provided in section 201(s) of the FFDCA. Importantly, FDA’s response to GRN 000319 does not constitute a “finding of the Secretary” within the meaning of section 721(b)(4) of the FFDCA.