Agency Response Letter GRAS Notice No. GRN 000386

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CFSAN/Office of Food Additive Safety

December 28, 2011

Melvin S. Drozen
Keller and Heckman, LLP
1001 G Street NW, Suite 500 West
Washington, DC 20001

Re: GRAS Notice No. GRN 000386

Dear Mr. Drozen:

The Food and Drug Administration (FDA) is responding to the notice, dated May 20, 2011, that you submitted on behalf of BioExx Specialty Proteins, Ltd. (BioExx) 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 this notice on May 23, 2011, filed it on June 22, 2011, and designated it as GRAS Notice No. GRN 000386.

The subjects of the notice are canola[1] protein isolate (CPI) and hydrolyzed canola protein isolate (HCPI). The notice informs FDA of the view of BioExx that both CPI and HCPI are GRAS, through scientific procedures, as ingredients in foods such as bakery products, snack foods, beverages, soups, dairy products, dry instant milkshake mixes and protein drinks, instant powdered nutritional beverages, processed meat and poultry products, vegetarian food products/meat analogues, and meal replacement and nutritional bars.

Our use of "CPI" and "HCPI" in this letter should not be considered an endorsement or recommendation of these terms 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 (CFSAN).

As part of its notice, BioExx includes the report of a panel of individuals (BioExx's GRAS panel) who evaluated the data and information that are the basis for BioExx's GRAS determination. BioExx considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. BioExx's GRAS panel evaluated estimated consumption, method of manufacture, and product specifications as well as published and unpublished studies. Based on this review, BioExx's GRAS panel concluded that CPI and HCPI are GRAS under the conditions of intended use.

BioExx describes the manufacturing process for CPI and HCPI. The process begins with the extraction of the oil from the Brassica napus or Brassica juncea seeds, followed by the extraction of defatted canola meal with water. This defatted canola meal fraction, after filtering and drying, becomes the CPI. The remaining water-insoluble solid fraction is treated with food-grade proteases. The end product is filtered and dried to produce HCPI. BioExx reports the amino acid profiles of the two isolates, CPI and HCPI, are substantially similar. BioExx states that CPI and HCPI are manufactured under current good manufacturing practices and meet appropriate food grade specifications.

BioExx provides specifications for CPI including protein content (not less than 90 percent), soluble protein (not less than 85 percent), fat (less than 2 percent), ash (less than 4 percent), total glucosinolates (less than 1 micromole/gram (μmol/g)), and microbial limits; specifications for HCPI include peptides and amino acid content (not less than 80 percent), solubility (not less than 98 percent), fat (less than 2 percent), ash (less than 7 percent), total glucosinolates (less than 1 μmol/g), and microbial limits.

BioExx states that CPI and HCPI are intended for use as ingredients in various food categories at maximum levels of 3 to 30 percent. BioExx states that the 90th percentile daily protein intakes of the combination of CPI and HCPI could possibly exceed the FDA's daily reference value (DRV) and the recommended dietary allowance (RDA) published by the Institute of Medicine.[2] BioExx provides a discussion regarding a conservative exposure estimate for protein for CPI and HCPI, and concludes that it is unlikely that actual exposure would exceed the DVR and RDA for protein.

BioExx discusses the safety of consumption of CPI and HCPI by discussing the traditional safe use of B. napus and B. juncea canola meals in animals, including cattle, swine, poultry and fish. BioExx discusses three published studies in rodents fed protein isolates from rapeseed that has been treated to reduce or eliminate erucic acid and glucosinolates (rapeseed flour for 90 days, rapeseed protein isolate (RPI) and rapeseed extraction residue (RER) for 28 days, or a cruciferin-rich canola protein isolate (CRCP) for 90 days). BioExx concludes that these studies showed no adverse effects in rats fed a standard diet containing a level of 5 percent RPI and/or 2.5 percent RER, and up to 20 percent of dietary protein supplied by CRCP. BioExx also considers the issue of potential allergy to mustard proteins, which are common in canola, by reviewing published and unpublished studies on B. juncea and related mustard proteins. BioExx discusses studies of protein isolates from known allergenic sources in support of their determination that the proposed uses and levels of CPI and HCPI are unlikely to increase the prevalence of allergenicity in the United States.

Standards of Identity

In the notice, BioExx states its intention to use CPI and HCPI 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 CPI and HCPI, BioExx lists meal replacements and nutritional bars, two food categories that often contain health or nutrient content claims. Under section 403(a) of the Federal Food, Drug, and Cosmetic Act (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 CPI or HCPI bear any claims on the label or in labeling, such claims are the purview of ONLDS in CFSAN. 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 CPI or HCPI on the label or in labeling.

Use in Products under USDA Jurisdiction

During its evaluation of GRN 000386, FDA consulted with the Risk, Innovations, and Management Division of the Food Safety and Inspection Service (FSIS) of the United States Department of Agriculture (USDA). Under the Federal Meat Inspection Act, 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 has determined that BioExx has provided sufficient data to support that CPI and HCPI are each suitable as a binder at a level up to 2 percent of the product formulation in ground meat (beef and pork) patties and whole muscle poultry products where binders are permitted. Data were provided for both ground meat and whole muscle poultry products that demonstrated an increase in cooking yield. Furthermore, a summary of the organoleptic testing stated that products containing canola proteins were equivalent to the control formulations with regard to texture and juiciness. With regard to labeling, FSIS states that CPI and HCPI must be listed by common or usual name in the ingredients statement of ground beef and pork patties and whole muscle products.

FSIS requested that FDA advise BioExx to seek regulatory guidance from FSIS, Risk, Innovations, and Management Division, about the use of CPI and HCPI in meat and poultry products. BioExx should direct such an inquiry to Dr. William K. Shaw Jr., Director, Risk, Innovations, and Management Division, Office of Policy and Program Development, Food Safety and Inspection Service, Stop Code 3782, Patriots Plaza III, Cubicle 8-163A, 1400 Independence Avenue SW, Washington, DC 20250-3700.

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 BioExx's notice that CPI and HCPI are GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing CPI and HCPI. Accordingly, this response should not be construed to be a statement that foods that contain CPI and HCPI, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).


Based on the information provided by BioExx, as well as other information available to FDA, the agency has no questions at this time regarding BioExx's conclusion that CPI and HCPI are 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 CPI and HCPI. As always, it is the continuing responsibility of BioExx 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 000386, 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

Sincerely yours,
Dennis M. Keefe, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition

cc: William K. Shaw, Jr., Ph.D.
Stop Code 3782, Patriots Plaza III, Cubicle 8-163A
1400 Independence Avenue SW
Washington, DC 20250-3700

[1] Canola refers to Brassica napus or Brassica juncea, rapeseed or Indian mustard, respectively, cultivated to contain a low erucic acid content.

[2] DRVs and RDAs are sets of standard amounts of certain dietary nutrients considered needed to maintain good health, as opposed to an upper limit for risk.

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