Agency Response Letter GRAS Notice No. GRN 000228
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CFSAN/Office of Food Additive Safety
July 26, 2010
Melvin S. Drozen
Keller and Heckman LLP
1001 G Street NW, Suite 500 West
Washington, DC 20001
Re: GRAS Notice No. GRN 000228
Dear Mr. Drozen:
The Food and Drug Administration (FDA) is responding to the notice, dated July 3, 2007, that you submitted on behalf of Bemis Company, Inc. (Bemis) 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 July 5, 2007, filed it on July 10, 2007, and designated it as GRAS Notice No. GRN 000228. An amendment dated March 24, 2010, which you submitted on behalf of Bemis, contains additional information and considerations to address the total dietary exposure to nitrite, including nitrite that is produced endogenously.
The subject of the notice is sodium nitrite. The notice informs FDA of the view of Bemis that sodium nitrite embedded on one side of a food packaging film at a maximum level of 113 milligrams per square meter (mg/m2, "the film"), is GRAS, through scientific procedures, for use in maintaining the characteristic color of raw ground beef and raw whole muscle cuts of beef when vacuum packaged in the film.
Bemis notes that sodium nitrite is regulated as a food additive for use in some smoked fish and some meats (21 CFR 172.175); in the processing of smoked chub (21 CFR 172.177); and in meat curing premixes (21 CFR 170.60(b)) at levels ranging from 10 to 200 parts per million (ppm). Sodium nitrite is also prior-sanctioned (21 CFR 181.34) for use as a color fixative in the curing of red meat and poultry products.
In its notice, Bemis describes the manufacturing of the film that contains sodium nitrite (NaNO2, CAS No.: 7632-00-0). Bemis states that all other components of the film comply with all applicable FDA regulations under the Federal Food, Drug, and Cosmetic Act (FFDCA) and are permitted for use in food contact applications. Bemis further states that the sodium nitrite is food-grade and conforms to the specifications listed in the Food Chemicals Codex (5th edition).
Bemis states that beef would be packaged in the film using vacuum packaging technology, with the sodium nitrite-containing layer contacting the surface of the beef. Sodium nitrite migrates to the surface of raw ground beef and raw whole muscle cuts of beef from the film. Bemis states that 60 to 100 percent of the nitrite from the film diffuses onto the surface of the beef where it is converted to nitric oxide. The nitric oxide reacts with myoglobin, producing nitrosomyoglobin (nitric oxide myoglobin), fixing the color of the beef while it is in the package. Bemis notes that nitrosomyoglobin present on the surface of the beef is expected to be degraded during cooking, or via digestion, to amino acids and peptides.
Using default assumptions, Bemis calculated an estimated daily intake (EDI) for sodium nitrite in beef from the use of the film.(1) Bemis prepared its estimate based on two additional assumptions: 1) all the film with embedded sodium nitrite would contain 113 mg sodium nitrite/m2; and, 2) a person consumes 300 grams of beef daily. Based on these assumptions, Bemis calculated an EDI of 2.19 mg per person per day (mg/p/d) for sodium nitrite (equivalent to 1.46 mg nitrite ion/p/d) from this application.
In the March 24, 2010, amendment, Bemis reports that no nitrite is detected on beef packaged with the film with a limit of detection of 0.7 parts per million (ppm). Using a nitrite concentration in beef of one-half the limit of detection (i.e., 0.35 ppm) and the beef consumption value of 300 g/p/d (as in the original calculation), Bemis calculates a refined dietary exposure to nitrite from use of the film to be 0.1 mg/p/d. To put their EDI for sodium nitrite into context, Bemis estimated the endogenous nitrite production from the consumption of foods containing nitrate ion. The nitrate ion is present naturally in a variety of food products (mainly vegetables) and is converted to nitrite ions in human saliva. Using published literature values for the amounts of nitrate ion in vegetables, Bemis reported an EDI for nitrate of 75 mg/p/d that is typically consumed. Using an estimated conversion rate of nitrate to nitrite of 5%, Bemis concluded that the endogenous production of nitrite would be 3.75 mg/p/d. Bemis states: "This amount cannot be practicably detected over variable food nitrite background levels in the 4-5 mg/day range and adding this tiny amount effectively leaves the current exposures and current risk from nitrite, if any, unchanged."
Bemis discusses published toxicity studies and reports on nitrite. Bemis notes that nitrite is rapidly absorbed into the body when ingested. Bemis cites published reproductive and developmental toxicity studies for two nitrite salts; no reproductive effects were reported at 420 milligrams per kilogram bodyweight per day (mg/kg bw/d) of sodium nitrite in mice; and, no teratogenic effects were reported at 120 mg/kg bw/d potassium nitrite in rats. Additionally, Bemis discusses the results of published mutagenicity studies and the fact that nitrite shows genotoxic potential in in vitro bacterial assays; this may be attributed to the deamination of DNA bases at the high concentrations evaluated in the studies. Bemis notes: "in vivo assays are equivocal and that the mutagenic potential of nitrite is complicated by the potential endogenous transformation to N-nitroso compounds when both nitrite and N-nitrosatable compounds are present at high concentrations. From this use, however, the added nitrite would be destroyed in the production of nitric oxide and nitrosomyoglobin."
Bemis also notes that acceptable daily intakes (ADI) for nitrite exposure have been determined by several scientific bodies worldwide, including the Joint FAO/WHO Expert Committee on Food Additives (JECFA), European Union Scientific Committee for Food and the United States Environmental Protection Agency. Bemis states that the potential nitrite consumption from this use is well below the ADI for nitrite (4.2 mg/p/d) established by JECFA.(2)
Use in Products Under USDA Jurisdiction
During its evaluation of GRN 000228, FDA consulted with the Labeling and Program Delivery Division and the Risk and Innovations Management Division, Office of Policy and Program Development, 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 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 has discussed this use of sodium nitrite with Bemis and its consultants. Based on these discussions, FSIS has no objection to the use of sodium nitrite in the film that is produced in accordance with the process described in GRN 000228 and is used for vacuum packaging raw ground beef and raw whole muscle cuts of beef subject to the following provisions:
- "Use by Date" or "Freeze by Date". A "Use by" or "Freeze by" date of 7 days for ground beef and 30 days for raw whole muscle parts must be applied at the time of packaging in the Federal establishment using the agreed upon parameters in GRN 000228. FSIS will amend FSIS Directive 7,120.1 Safe and Suitable Ingredients Used in the Production of Meat and Poultry Products to include the following condition of use in the labeling requirement column: "Raw ground beef and cuts of beef packaged in a film containing sodium nitrite must be coded with a "Use or Freeze by" date not to exceed 7 days after packaging for ground beef and 30 days for whole muscle beef cuts."
- Principal Display Panel Labeling. Products packaged using Bemis' film must contain a statement similar to "Color maintained with sodium nitrite from packaging," which will be placed contiguous to the product name and appear in a type size that is no smaller than 1/3 the size of the largest type size used elsewhere in the product name. Such labeling will meet FSIS' labeling requirement regarding the disclosure of the presence of sodium nitrite as part of the product name.
- FSIS' listing of 7 and 30 days in FSIS Directive 7,120.1. This listing does not preclude Bemis from submitting additional data to FSIS that may support longer or different use or freeze by dates in the future. FSIS would review any submitted data, and if appropriate, revise FSIS Directive 7,120.1 to reflect dates supported by the data.
Any further questions regarding use in meat and poultry products should be directed to Dr. John M. Hicks, Jr., Risk and Innovations Management Division, Office of Policy and Program Development,(3) 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 Bemis's notice that sodium nitrite is GRAS for use in maintaining the characteristic color of raw ground beef and raw whole muscle cuts of beef when vacuum packaged in the film, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing sodium nitrite. Accordingly, this response should not be construed to be a statement that foods that contain sodium nitrite, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Bemis, as well as other information available to FDA, the Agency has no questions at this time regarding Bemis' conclusion that sodium nitrite 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 sodium nitrite. As always, it is the continuing responsibility of Bemis 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 000228, 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 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
(1)FDA’s Office of Food Additive Safety, Division of Food Contact Notification also uses default values for calculating migration of substances to food: 100% of the substance added to the packaging will migrate to food and 10 grams of food contacts each square inch of packaging material. Bemis has included these assumptions in its calculations.
(2)JECFA established an ADI of 4.2 mg/p/d which is the lowest ADI established. The United States Environmental Protection Agency has established an ADI of 31 mg/p/d (http://www.epa.gov/ncea/iris/subst/0078.htm).
(3)Effective June 1, 2008, the Office of Policy and Program Development of FSIS transferred the review process of ingredient submissions from the Labeling and Program Delivery Division to the Risk Management Division, which is now called the Risk and Innovations Management Division.