Agency Response Letter GRAS Notice No. GRN 000326
CFSAN/Office of Food Additive Safety
February 16, 2011
Phillip L. Casterton, M.S., D.A.B.T.
15407 McGinty Road West, MS-163
Wayzata, MN 55391
Re: GRAS Notice No. GRN 000326
Dear Mr. Casterton:
This letter corrects our letter in response to GRAS Notice No. 000326 dated October 24, 2010. The purpose of this revised letter is to correct the levels of use in infant formula for term and preterm infants. In addition, in an electronic mail message dated November 4, 2010, Cargill noted that GRN 000326 contained a typographical error in the strain name for Mortierella alpina; and, that the correct name is M. alpina strain I49-N18.
The Food and Drug Administration (FDA) is responding to the notice, dated February 24, 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 February 25, 2010, filed it on March 2, 2010, and designated it as GRAS Notice No. GRN 000326.
The subject of the notice is arachidonic acid (ARA)-rich oil from M. alpina strain I49-N18 (hereinafter referred to as ARA-rich oil from M. alpina). The notice informs FDA of the view of Cargill, Incorporated (Cargill) that ARA-rich oil from M. alpina is GRAS, through scientific procedures, for use as an ingredient in infant formula containing docosahexaenoic acid (DHA) at mean concentrations of 0.75 grams (g) per 100 g total fat for term infants, and 0.40 g per 100 g total fat for preterm infants.
Cargill states that the use of ARA-rich oil from M. alpina as a source of ARA in infant formula will be in combination with a GRAS source of DHA at ratios ranging from 1:1 to 2.7:1 ARA to DHA, which is consistent with the ratios documented in GRN 000080 and GRN 000094.
Our use of “ARA-rich oil from M. alpina” 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. Title 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. 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 in the Center for Food Safety and Applied Nutrition.
Cargill describes ARA-rich oil from M. alpina as a clear yellow oil with an ARA content of approximately 40 percent by weight of fatty acids. ARA has the chemical name all-cis-5,8,11,14-eicosatetraenoic acid. Cargill also describes other fatty acids present in triglycerides at greater than 5 percent by weight of fatty acids and their approximate levels including: palmitic (8 percent), stearic (6 percent), oleic (9 percent), linoleic (6 percent), and lignoceric (9 percent).
Cargill states that ARA-rich oil from M. alpina is produced using a non-toxigenic and non-pathogenic fungus M. alpina strain I49-N18. Cargill states that M. alpina is not related to mycotoxin-producing fungi. Cargill notes that M. alpina has not been found to be pathogenic. Cargill describes the production of ARA-rich oil from M. alpina by the fermentation of M. alpina strain I49-N18 under aerobic conditions.
During production, glucose concentration, temperature, agitation, and air flow are controlled, and sodium hydroxide is used to adjust the pH. The resulting biomass is washed and dried. After drying, the crude ARA-rich oil is extracted with butane, filtered, and further refined. Cargill notes that butane is recovered and recycled. The refinement process involves degumming followed by de-acidification to separate the oil from the impurity-containing aqueous phase. The oil is washed with water and filtered, and any remaining impurities are removed by bleaching. Cargill notes that hexane is used as a solvent in the refining and bleaching processes and is removed and recycled. After bleaching, the oil undergoes a solvent removal step and is then deodorized. The resulting oil is mixed with Vitamin C and Vitamin E to increase the oxidative stability of the oil followed by a final filtration step prior to packaging. Cargill notes that if the ARA levels of the oil are greater than 42 percent, sunflower oil is added to dilute the final mixture and standardize the ARA content at 42 percent. Cargill states that ARA-rich oil from M. alpina is produced using manufacturing processes consistent with current good manufacturing practices requirements.
Cargill provides chemical and physical specifications for food-grade ARA-rich oil from M. alpina including: ARA content (≥ 40 percent by weight), lead (≤ 0.1 milligram per kilogram (mg/kg)), arsenic (≤ 0.1 mg/kg), peroxide value (≤ 2.0 milli-equivalents per kilogram), butane (≤ 1.0 mg/kg), and hexane (≤ 1.0 mg/kg). In addition, Cargill also provides specifications for free fatty acids and unsaponifiable material as follows: free fatty acids (≤ 0.2 percent oleic acid) and unsaponifiable material (≤ 1.5 percent by weight).
Cargill compares the subject oil with those that were the subjects of GRN 000041 and GRN 000080 (arachidonic acid-rich single-cell oil) and GRN 000094 (arachidonic acid-rich oil from M. alpina ) to draw conclusions about the safety of ARA-rich oil from M. alpina. Cargill provides tables comparing these oils, noting that there is a natural variability in the fatty acid and sterol profiles. Cargill further notes that the magnitude of the variations in the finished products is within the expected normal concentration range for the biological source when produced under controlled circumstances.
In support of the use of ARA-rich oil from M. alpina in infant formula, Cargill discusses published data on exposure levels of ARA in human milk based on samples from mothers who delivered preterm and term infants throughout the global population. These studies show a range of ARA in human milk of 0.34 to 1.22 percent of total fatty acids across the global population, with the United States having a mean ARA concentration range of 0.40 to 0.67 percent of total fatty acids.
Cargill notes the published recommendations from the Food and Agriculture Organization/World Health Organization, the British Nutrition Foundation (1992), and studies from the National Institutes of Health (1999) for the addition of fatty acids to infant formula. These recommendations for ARA supplementation for preterm and term infants range from 0.5 to 0.9 percent of total fatty acids and 0.4 to 0.7 percent of total fatty acids, respectively.
Cargill reports an ARA-rich oil estimated daily intake (EDI) of 27 and 42 milligrams per kilogram body weight per day (mg/kg bw/day) for preterm and term infants, respectively. Cargill bases their intake estimates on the following assumptions: (1) preterm infants consume 120 kilocalories per kilogram body weight per day (kcal/kg bw/day) and term infants consume 100 kcal/kg bw/day; (2) fatty acids comprise 50 percent of the available energy in breast milk or infant formula; and (3) one gram of fat contains nine kcal. Cargill notes that the methodology used to calculate their EDI is that used by the Food Standards Australia New Zealand.
Cargill discusses several published studies as part of their safety assessment, including a published 90 day study in rats with an in utero phase. This study shows that rats consuming diets containing up to 5 percent ARA-rich oil from M. alpina have no treatment related effects. In addition, Cargill provides results from published genotoxicity tests performed on the ARA-rich oil from M. alpina ingredient, including bacterial reverse mutation assays, a gene mutation study in mouse lymphoma cells and a chromosome aberration study. All of the genotoxicity tests are negative.
Cargill provides an updated literature review regarding ARA-rich oil, including all studies published from 2005 through 2009. These publications include: (1) studies documenting infant exposure to ARA- rich oils; and (2) animal studies (rats, piglets, and baboons). Based on the totality of generally available evidence, Cargill concludes that the intended use of ARA-rich oil from M. alpina is generally recognized as safe.
Potential Labeling Issues
In describing the intended use of ARA-rich oil from M. alpina in infant formula, a food category that often contains health or nutrient content claims, and in describing data and information on clinical studies that Cargill relies on to conclude that ARA-rich oil from M. alpina is GRAS under the conditions of its intended use, Cargill raises a potential issue under the labeling provisions of the Federal Food, Drug, and Cosmetic Act (FFDCA). Under section 403(a) of the 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. If products that contain ARA-rich oil from M. alpina 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 your notice to determine whether it would support any claims made about ARA-rich oil from M. alpina on the label or in labeling.
Intended use in infant formula
Under section 412 of the FFDCA a manufacturer of a new infant formula must make a submission to FDA, providing required assurances about the formula, at least 90 days before the formula is marketed. Cargill should be aware that FDA’s response to Cargill’s GRAS notice does not alleviate the responsibility of any infant formula manufacturer who intends to market an infant formula that contains ARA-rich oil from M. alpina to make the submission required by section 412.
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 Cargill’s notice that ARA-rich oil from M. alpina is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing ARA-rich oil from M. alpina. Accordingly, this response should not be construed to be a statement that foods that contain ARA-rich oil from M. alpina, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Cargill, as well as other information available to FDA, the agency has no questions at this time regarding Cargill’s conclusion that ARA-rich oil from M. alpina 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 ARA-rich oil from M. alpina. As always, it is the continuing responsibility of Cargill 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 000326, 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