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Agency Response Letter GRAS Notice No. GRN 000067

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CFSAN/Office of Food Additive Safety

October 23, 2001

James T. Heimbach, Ph.D., F.A.C.N.
Environ Corporation
4350 North Fairfax Drive, Suite 300
Arlington, Virginia 22203

Re: GRAS Notice No. GRN 000067

Dear Dr. Heimbach:

The Food and Drug Administration (FDA) is responding to the notice, dated January 4, 2001, that you submitted on behalf of Farmland National Beef Packaging Company, L.P. (National Beef) 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)). FDA's Office of Premarket Approval (now the Office of Food Additive Safety (OFAS)) received your notice on January 9, 2001, and designated it as GRAS Notice No. GRN 000067.

The subject of the notice is milk-derived lactoferrin.(1) The notice informs FDA of the view of National Beef that milk-derived lactoferrin is GRAS, through scientific procedures, for use as a component of an antimicrobial spray that contains up to 2 percent lactoferrin that would be applied to uncooked beef. The maximum concentration to be used is 3.26 milliliters spray per kilogram beef (or 65.2 milligrams lactoferrin per kilogram beef).

Data and information that National Beef presents to support its GRAS determination

Lactoferrin is an iron-binding glycoprotein consisting of a single polypeptide chain with a molecular weight of 75,000 - 80,000 Daltons. Milk-derived lactoferrin is isolated from raw bovine milk or a milk derivative, subjected to microfiltration and purified by column chromatography, desalted, subjected to ultra- and micro-filtration, and spray dried. The notice includes food grade specifications for milk-derived lactoferrin, including a specification for lead of less than 0.5 parts per million.

National Beef discusses publications that describe characteristic properties of milk-derived lactoferrin, such as its amino acid sequence, isoelectric point, glycosylation pattern, and ability to bind iron. In describing these properties, National Beef highlights similarities and differences between lactoferrin derived from cow's milk and lactoferrin derived from human milk. For example, the iron content of lactoferrin derived from cow's milk is four times higher than that of human lactoferrin.

Lactoferrin occurs naturally in milk, milk-derived ingredients and products and, to a lesser extent, in beef tissue.(2) Thus, persons who consume milk or milk-derived ingredients or beef already consume lactoferrin. Using consumption data from the USDA Continuing Surveys of Food Intake by Individuals, National Beef reports mean and 90th percentile intake estimates of milk-derived lactoferrin from the consumption of milk or milk-derived ingredients for (1) children 1 year to 12 years of age, (2) teenagers 13 years to 19 years of age, and (3) adults 20 years and older. National Beef reports that 90th percentile intakes of lactoferrin from its natural occurrence in milk and milk products ranges from 75 milligrams per person per day (mg/p/d) for teenagers 13 years to 19 years of age to 50 mg/p/d for adults 20 years and older. National Beef estimates that the additional intake of milk-derived lactoferrin from its proposed use in an antimicrobial spray for uncooked beef would be up to 9.1 mg/p/d for consumers at the 90th percentile consumption level.

National Beef describes the general digestive process for proteins and reviews published studies that examine the fate of lactoferrin in the gastrointestinal tract of infants and adults. National Beef describes published and unpublished animal toxicity and genotoxicity studies conducted with milk-derived lactoferrin that has similar specifications to the ingredient that is the subject of this notice. National Beef concludes that the animal toxicity studies demonstrate that there are no adverse effects related to consumption of milk-derived lactoferrin at levels up to 2,000 milligrams per kilogram per day given for up to 13 weeks. National Beef also concludes that the genotoxicity study provides no evidence of mutagenic potential.

National Beef describes information from clinical trials designed to study effects of milk-derived lactoferrin on iron absorption or on modulation of microflora or infection. In National Beef's view, these clinical studies provide information that demonstrate that food products that are supplemented with milk-derived lactoferrin are well tolerated.

National Beef notes that milk proteins are commonly allergenic, particularly in infants and children. According to National Beef, the proteins in milk that are known to be allergens include beta-lactoglobulin, alpha-lactalbumin, caseins, bovine immunoglobulins, and bovine serum albumin. A few patients who are allergic to milk proteins exhibit IgE antibodies to other milk proteins, including lactoferrin. Because IgE antibodies are associated with an allergic response, National Beef concludes that milk-derived lactoferrin is allergenic for some of the population and that individuals who are already allergic to milk would be aware of this allergenicity.

In addition, National Beef's notice includes the findings of a panel of individuals who evaluated the data and information that are the basis for their GRAS determination. National Beef considers these individuals to be qualified by scientific training and experience to evaluate the safety of substances added to food. National Beef's panel concludes that (1) there is no evidence in the available information on milk-derived lactoferrin that demonstrates, or suggests, reasonable grounds to suspect a hazard to the public health when it is used at levels that are now current or that might reasonably be expected from the proposed application.

FDA's response to National Beef's GRAS determination

Based on the information provided by National Beef, as well as other information available to FDA, the agency has no questions at this time regarding National Beef's conclusion that milk-derived lactoferrin is GRAS under the intended conditions of use, provided that the ingredient statement of food products that contain milk-derived lactoferrin identifies the source of the protein. The agency has not, however, made its own determination regarding the GRAS status of the subject use of milk-derived lactoferrin. As always, it is the continuing responsibility of National Beef to ensure that food ingredients that the firm markets are safe, and are otherwise in compliance with all applicable legal and regulatory requirements.

Consultation with the Food Safety and Inspection Service, US Department of Agriculture

OFAS consulted with the Food Safety and Inspection Service (FSIS), US Department of Agriculture (USDA), Labeling and Consumer Protection Staff. FSIS is responsible for determining the efficacy and suitability of food ingredients and additives in meat and poultry products as well as prescribing safe conditions of use. FSIS advises that, to adequately assess the efficacy and suitability of the lactoferrin spray as an antimicrobial agent on uncooked beef, FSIS will need additional information. This includes identification of all components of the spray, data that establish the lowest level of the blend (and the amounts of each ingredient in the blend) necessary to achieve the intended functional effect (i.e., inhibition of the growth of microorganisms), and data regarding the actual concentrations of each component of the spray that will remain in the beef that will be available to the consumer. FSIS advises that National Beef also must address whether the appearance of the treated product would mislead the consumer into perceiving the product as "fresher" when compared to untreated beef and whether the use of this spray extends the shelf-life beyond actual microbial shelf-life. FSIS also advises that use of the lactoferrin spray on beef may involve issues relating to standards of identity or composition. FSIS requested that FDA advise National Beef to seek regulatory guidance from FSIS about the use of lactoferrin in an antimicrobial spray applied to uncooked beef. Inquiries should be directed to Dr. Robert Post, Director, Labeling and Consumer Protection Staff, Office of Policy, Program Development and Evaluation, Food Safety and Inspection Service, 300 12th Street, SW, Room 602, Washington, DC 20250-3700. The telephone number for Dr. Post is (202) 205-0279 and the FAX number is (202) 205-3625.

As part of the consultation with FSIS, OFAS and FSIS discussed labeling issues that are associated with the use of lactoferrin on uncooked beef. In a meeting held on May 22, 2001, OFAS and FSIS met with representatives of National Beef to discuss the implications of National Beef's view that milk-derived lactoferrin is an allergen. Specifically, OFAS, FSIS and representatives of National Beef discussed practical aspects associated with tracking the presence of lactoferrin from the point of application to the consumer, so that consumers who are allergic to milk would be aware of the presence of this milk-derived ingredient.

Following the meeting, representatives from National Beef met with FSIS to review National Beef's labeling plans and to determine whether current regulatory procedures are adequate to assure that required labeling will appear on treated products offered to consumers. National Beef then submitted an amendment to GRN 000067(3) that describes the controls that would be put in place to ensure that all lactoferrin-treated beef, from slaughter to retail, would be properly labeled as to the presence of a milk protein. In that amendment, National Beef proposed to label all lactoferrin-treated beef products with a statement such as "treated with lactoferrin from milk" or "treated with lactoferrin, a milk protein." National Beef also noted that it is possible that this statement would be followed by a phrase such as "for your protection" or "for your added safety."

National Beef considers that there will be an economic incentive for retailers purchasing these products to display the required labeling because lactoferrin-treated beef products will command a premium price in the market. National Beef reports that much of the beef product treated with lactoferrin will be produced as "case-ready beef." That is, the product will be shipped directly by National Beef to the retailer in its finished form, including the final package with the final consumer label.

For treated beef products that are sold directly to the retailer in a pre-finished form that may require additional cutting, trimming, and portioning, the retailer will be responsible for the final packaging. The treated product shipped from National Beef will contain a complete label on the outside of the shipping carton and the retailer will receive accompanying instructions regarding labeling of the retail product. Thus, National Beef expects that every package shipped from National Beef will contain production information that can be tracked to the individual retailer.

Beef products that are shipped by National Beef to other processors for further processing into products such as hot dogs and sausages will contain the appropriate label with instructions to the processor regarding consumer labeling. According to National Beef, products produced by these processors contain standard ingredient labeling to which the lactoferrin label will be added.

OFAS has discussed National Beef's labeling plan with FSIS. FSIS has advised OFAS that National Beef's labeling plan is both practical and enforceable. For your information, because label statements on beef products are the purview of FSIS, FDA neither evaluated data and information to determine whether it would substantiate a label statement that lactoferrin is effective as an antimicrobial agent nor evaluated the suitability of the potential label statements "for your protection" and "for your added safety."

In accordance with proposed 21 CFR 170.36(f), a copy of the text of this letter, as well as a copy of the information in National Beef's notice that conforms to the information in proposed 21 CFR 170.36(c)(1), is available for public review and copying on the homepage of the Office of Food Additive Safety (on the Internet at

Alan M. Rulis, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition

cc: Dr. Robert Post, Director
Labeling and Consumer Protection Staff
Office of Policy, Program Development and Evaluation
Food Safety and Inspection Service
300 12th Street, SW, Room 602
Washington, DC 20250-3700

(1)In its notice, National Beef uses the term "bovine lactoferrin" to describe the subject of the notice. As discussed more fully in the body of this letter, FDA is using the term "milk-derived lactoferrin" to describe the subject of the notice.

(2)National Beef reports that, while a small amount of lactoferrin is present naturally in beef due to residual blood, it is an insignificant source of lactoferrin intake.

(3)Letter from J. Heimbach (Environ Corporation) to J. Kidwell (FDA, OFAS), August 1, 2001.

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