Agency Response Letter GRAS Notice No. GRN 000379
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CFSAN/Office of Food Additive Safety
November 8, 2011
James T. Heimbach, Ph.D.
923 Water Street
P.O. Box 66
Port Royal, VA 22535
Re: GRAS Notice No. GRN 000379
Dear Dr. Heimbach:
The Food and Drug Administration (FDA) is responding to the notice, dated April 21, 2011, that you submitted on behalf of Ocean Nutrition Canada Ltd. (ONC) 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 April 27, 2011, filed it on May 12, 2011, and designated it as GRAS Notice No. GRN 000379.
The subject of the notice is tuna oil. The notice informs FDA of the view of ONC that tuna oil is GRAS, through scientific procedures, to provide docosahexaenoic acid (DHA) in term and preterm infant formula, at a maximum level of 0.5 gram (g) per 100 g of total fatty acids, when used in combination with an appropriate source of arachidonic acid (ARA).
As part of its notice, ONC includes the report of a panel of individuals who evaluated the data and information that are the basis for ONC's GRAS determination. ONC considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of tuna oil. The GRAS panel evaluated publicly available information on the methods employed by ONC to extract and refine its tuna oil and on the safety of the addition of fish oils and other sources of n-3 fatty acids to infant formula. In addition, the GRAS panel evaluated information regarding starting materials, production methods, physiological effects of fish oil and its primary n-3 polyunsaturated fatty acids, and the safety of adding refined tuna oil to infant formula as a source of DHA, when used in combination with an appropriate source of ARA. Based on this review, the GRAS panel concluded that ONC's tuna oil produced and used in accordance with current good manufacturing practices and complying with the specifications described in the GRAS notice, is GRAS under the conditions of its intended use.
ONC describes the ingredient as refined tuna oil, which is a mixture of triacylglycerols containing DHA and eicosapentaenoic acid (EPA). The DHA will be present at not less than (NLT) 26% and not more than (NMT) 28% and the EPA NLT 7% and NMT 8%, with a DHA to EPA ratio of NLT 3.3:1. ONC states that the CAS Registry number for generic fish oil is CAS Reg. No. 8016-13-5. The CAS numbers for the primary fatty acid components DHA and EPA are CAS Reg. No. 25167-62-8 and CAS Reg. No. 10417-94-4, respectively.
ONC describes the method of manufacture of its tuna oil, stating that their oil extraction methods are widely used, conforming to industry standards for edible oil manufacturing. ONC's tuna oil is processed using the following steps: 1) crude fish oil extraction; 2) fish oil refining; 3) neutralization; 4) deodorization; 5) decolorization/absorption; 6) antioxidant blending; 7) steam deodorization; 8) filtration, drumming, and oil storage.
ONC provides specifications for tuna oil, including: free fatty acids (NMT 0.5%), moisture (NMT 0.1%), and fatty acid profiles: EPA (NLT 7% and NMT 8%), DHA (NLT 26% and NMT 28%), with a DHA:EPA ratio of NLT 3.3:1. The limits for heavy metals (milligrams/kilogram (mg/kg)) are: lead (NMT 0.1), arsenic (NMT 0.1). The microbial limits are: yeast and mold (colony forming units/g) (NMT 100), Escherichia coli (not detected in 1 g), and Salmonella (not detected in 10 g). As part of their purity and composition assessment ONC also provided specifications for pesticides, polybrominated diphenylethers, polychlorinated biphenyls, furans, and dioxins of its tuna oil. In addition, ONC provided batch analysis for four batches of its product, which demonstrate compliance with these specifications.
ONC estimates the daily intake of tuna oil based on intended use levels in infant formula and consumption data provided by Fomon (1993). ONC estimates the highest intake per kg body weight (bw) for infant boys at ages 14-27 days. The 90th percentile energy intake by this group is estimated to be 141.3 kilocalories (kcal)/kg bw/day. Infant girls within the same age range have an estimated intake of 138.9 kcal/kg bw/day. ONC estimates that approximately 50% of calories in infant formula are provided by fats, this indicates intake of about 70 kcal from fat/kg bw/day, or about 8 g fat/kg bw/day. In infant formulas for which DHA provides 0.5% of the fatty acids, the 90th percentile intake of DHA would be 40 mg/kg bw/day.
ONC states that their tuna oil has a DHA:EPA ratio of at least 3.3:1, the 90th percentile intake of EPA would be no more than a third of that of DHA, or 13 mg/kg bw/day. ONC explains that the DHA amount present in tuna oil is at a minimum of 26%, therefore the 90th percentile intake of tuna oil itself would not exceed four times the intake of DHA, or 160 mg/kg bw/day.
ONC has incorporated by reference all animal and clinical studies previously submitted in GRN 000094 and GRN 000138. ONC's updated literature review provided published information on 10 new clinical trials and 3 follow-up reports. ONC concludes that these infant studies showed no adverse events or tolerance issues of any significance as compared to controls. The data presented by ONC in support of tuna oil safety provided no evidence that would contradict previous safety determinations that support the safe use of DHA, when used in combination with an appropriate source and amount of ARA.
Potential Labeling Issues
In describing data and information on clinical studies that ONC relies on to conclude that tuna oil is GRAS under the conditions of its intended use, ONC raises a potential issue under the labeling provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act). Under section 403(a) of the FD&C Act, a food is misbranded if its labeling is false or misleading in any particular. Section 403(r) of the FD&C Act 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 tuna oil 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 tuna oil on the label or in labeling.
Intended use in infant formula
Under section 412 of the FD&C Act 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. ONC should be aware that FDA's response to ONC's GRAS notice does not alleviate the responsibility of any infant formula manufacturer who intends to market an infant formula that contains tuna oil to make the submission required by section 412.
Section 301(ll) of the FD&C Act
The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the FD&C Act to, among other things, add section 301(ll). Section 301(ll) of the FD&C Act prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FD&C Act, 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 ONC's notice that tuna oil is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing tuna oil. Accordingly, this response should not be construed to be a statement that foods that contain tuna oil, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by ONC, as well as other information available to FDA, the agency has no questions at this time regarding ONC's conclusion that tuna oil 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 tuna oil. As always, it is the continuing responsibility of ONC 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 000379, 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 at http://www.fda.gov/grasnoticeinventory.
Dennis M Keefe, Ph.D.
Office of Food Additive Safety
Center for Food Safety
and Applied Nutrition