Agency Response Letter GRAS Notice No. GRN 000415
CFSAN/Office of Food Additive Safety
December 26, 2012
Business Promotion Team 2
International Business Unit
Meiji Co., Ltd.
1-2-10, Shinsuna, Koto-ku, Tokyo 136-8908
Re: GRAS Notice No. GRN 000415
Dear Mr. Seki:
The Food and Drug Administration (FDA) is responding to the notice, dated January 9, 2012, 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 12, 2012, filed it on January 19, 2012, and designated it as GRAS Notice No. GRN 000415.
The subject of the notice is heat-killed Propionibacterium freudenreichii ET-3 culture (powder) (HK-P. freudenreichii ET-3). The notice informs FDA of the view of Meiji Co. Ltd. (Meiji) that HK-P. freudenreichii ET-3 is GRAS, through scientific procedures, for use as an ingredient in beverages and beverage bases, breakfast cereals, cheeses, coffee and tea, fats and oils, frozen dairy desserts and mixes, gelatins, puddings, and fillings, grain products and pastas, milk products, processed fruits and fruit juices, processed vegetables and vegetable juices, and soft candy at levels ranging from 0.2 to 0.6 grams (g) per serving.
Our use of HK-P. freudenreichii ET-3 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. 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 (ONLDS) in the Center for Food Safety and Applied Nutrition.
As part of its notice, Meiji includes the report of a panel of individuals (Meiji’s GRAS Panel) that evaluated the data and information that are the basis for Meiji’s GRAS determination. Meiji considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Meiji’s GRAS panel discusses identity, specifications, method of manufacture, dietary exposure, and safety of HK-P. freudenreichii ET-3, including the history and current regulatory status of P. freudenreichii ET-3 in food. Based on this review, Meiji’s GRAS Panel concluded that HK-P. freudenreichii ET-3 is GRAS under the conditions of its intended use.
Meiji discusses generally available information about the microorganism P. freudenreichii ET-3. Meiji describes P. freudenreichii ET-3 as non-pathogenic, non-toxigenic, and provides information on its long history of safe use in food production. Meiji states that P. freudenreichii ET-3 was isolated from Emmental cheese, that it is well characterized and taxonomically identified, and that it has been deposited in the NITE Patent Microorganisms depository as FERM BP-8115.
Meiji provides information about the method of manufacture and specifications of HK-P. freudenreichii ET-3. The fermentation medium, containing protease-treated whey powder, yeast extract and ammonium sulfate is filtered and sterilized prior to the addition of P. freudenreichii ET-3. Four serial fermentations are performed under controlled pH and temperature, and the P. freudenreichii ET-3 cells are heat-killed at the end of fermentation. During fermentation, 1, 4-dihydroxy-2-naphthoic acid (DHNA) is produced by P. freudenreichii ET-3 and remains in the final product, HK-P. freudenreichii ET-3. The resulting solution is freeze-dried, milled, sieved, and analyzed for contaminants. The final product is yellow-brown to reddish-brown in color with no remarkable taste or odor. All raw materials used in the manufacture of HK-P. freudenreichii ET-3 are food-grade. HK-P. freudenreichii ET-3 is produced in accordance with current good manufacturing practices. Meiji provides food-grade specifications for the final product, including physical and chemical parameters (appearance, protein, ash, and DHNA (20-90 micrograms per gram [μg/g], with limits for moisture and lead (≤ 1 milligram/kilogram)) and microbiological parameters (limits for total viable bacterial count, fungi and yeast, and negative for coliforms, Staphlococcus aureus, and Salmonella sp.).
Meiji calculates the mean and 90th percentile estimated daily intake (EDI) of HK-P. freudenreichii ET-3 to be 27 milligrams per kilogram bodyweight per day (mg/kg bw/d) and 50 mg/kg bw/d, respectively, using consumption data from the National Health and Nutrition Examination Survey (NHANES 2005-2006) and the intended use levels. Meiji calculates the mean and 90th percentile EDI of DHNA present in the HK-P. freudenreichii ET-3 to be 0.0024 mg/kg bw/d and 0.0042 mg/kg bw/d, respectively.
The notifier addresses the safety of HK-P. freudenreichii ET-3 by discussing the use of P. freudenreichii strains in human food, and published and unpublished animal and human studies. Meiji notes that P. freudenreichii is permitted for food use in Japan, Europe, and the United States. HK-P. freudenreichii ET-3 is not expected to be absorbed from the gastrointestinal tract and would be excreted in the feces.
Meiji summarizes two published rodent studies evaluating the effects of the P. freudenreichii ET-3 test article and reports that no adverse effects were attributed to administration of P. freudenreichii ET-3 test article to rats for nine days (2000 or 6000 mg/kg bw/d) or 28 days (6000 mg/kg bw/d containing 0.576 mg DHNA/kg bw/d). Meiji reports that published studies conclude HK-P. freudenreichii ET-3 is not mutagenic. The notifier also cites supportive published evidence that the consumption of HK-P. freudenreichii ET-3 is well tolerated by healthy human subjects.
The notifier considered the issue of vitamin K and in particular vitamin K2 compounds in assessing the safety of its product because DHNA is a precursor to vitamin K2 compounds, specifically, menaquinone-9 (MK-9). The notifier reports that in analyses of four non-consecutive lots of HK-P. freudenreichii ET-3 for vitamin K compounds, little or no vitamin K compounds were detected.1 These levels are lower than published levels reported for various cheeses (0.020 to 0.650 mg/g). Therefore, given the low reported levels of vitamin K in HK-P. freudenreichii ET-3 compared to the levels in cheeses, and the low estimated intakes in relation to overall dietary intake of vitamin K, the notifier concluded that there is no safety issue with respect to vitamin K in HK-P. freudenreichii ET-3.
Based on data and information discussed above, Meiji concludes that the intended use of P. freudenreichii ET-3 in food is GRAS.
Standards of Identity
In the notice, Meiji states its intention to use HK-P. freudenreichii ET-3 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
In describing the intended use of HK-P. freudenreichii ET-3 and the information that Meiji relies on to conclude that HK-P. freudenreichii ET-3 is GRAS under the conditions of its intended use, Meiji raises a potential issue under the labeling provisions of the Food Drug and Cosmetic (FD&C) Act. This issue consists of the effects of HK-P. freudenreichii ET-3 consumption on gastrointestinal health or function. Meiji considers DHNA to have a stimulatory effect on the growth of bifidobacteria. 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 HK-P. freudenreichii ET-3 bear any claims on the label or in labeling, such claims are the purview of ONLDS. The Office of Food Additive Safety (OFAS) 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 HK-P. freudenreichii ET-3 on the label or in labeling.
The Food Allergen Labeling and Consumer Protection Act of 2004 (FALCPA) amends the FD&C Act to require that the label of a food that is or contains an ingredient that bears or contains a “major food allergen” to 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. HK-P. freudenreichii ET-3 may require labeling under FALCPA, because it may contain protein derived from milk (possible residual whey components in the fermentation medium). Although issues associated with labeling food are the responsibility of ONLDS, issues associated with FALCPA exemptions are the responsibility of the Food Allergen Coordinator in OFAS.
Potential Requirement for a Color Additive Petition
In its notice, Meiji describes HK-P. freudenreichii ET-3 as yellow-brown to reddish-brown in color. As such, the use of HK-P. freudenreichii ET-3 in food products may constitute the use of a color additive under section 201(t)(1) of the FD&C Act 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,2 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 can 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 FD&C Act 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, ß-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, β-carotene is used for both purposes. Importantly, if the use of HK-P. freudenreichii ET-3 constitutes use as a color additive within the meaning of section 201(t)(1) of the FD&C Act and FDA's implementing regulations in 21 CFR 70.3(f) and (g), section 721(a) of the FD&C Act requires premarket review and approval of that use by FDA. Under section 402(c) of the FD&C Act, a food product that contains an unapproved color additive would be deemed adulterated.3
In its notice, Meiji states that the addition of its HK-P. freudenreichii ET-3 to the various food products does not impart color to the foods to which it is added and that the subject ingredient is not intended to function as a color additive. Importantly, FDA’s response to GRN 000415 does not include any comment by FDA about Meiji’s view of this issue. If, after receipt of this letter, Meiji has any specific questions about this issue, we recommend that Meiji contact the Division of Petition Review in OFAS.
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 Meiji’s notice that HK-P. freudenreichii ET-3 is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing HK-P. freudenreichii ET-3. Accordingly, this response should not be construed to be a statement that foods that contain HK-P. freudenreichii ET-3 if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Meiji, as well as other information available to FDA, the agency has no questions at this time regarding Meiji’s conclusion that HK-P. freudenreichii ET-3 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 HK-P. freudenreichii ET-3. As always, it is the continuing responsibility of Meiji 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 000415, 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
1Phylloquillone (vitamin K1), MK-7, and MK-9 were not detected (limit of detection = 0.001 mg/100 g), and MK-4 was detected at levels of only 0.002 to 0.003 mg/100 g.
2The Secretary of the Department of Health and Human Services.
3We note that section 721(b)(4) of the FD&C Act provides that a color additive shall be deemed to be safe and suitable for the purpose of listing under section 721(b) of the FD&C Act 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 FD&C Act. Importantly, FDA’s response to GRN 000415 does not constitute a “finding of the Secretary” within the meaning of section 721(b)(4) of the FD&C Act.