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U.S. Department of Health and Human Services

Food

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Agency Response Letter GRAS Notice No. GRN 000077

CFSAN/Office of Food Additive Safety

August 14, 2001

 

Claire L. Kruger, Ph.D., D.A.B.T.
Environ Corporation
4350 North Fairfax Drive
Suite 300
Arlington, VA 22203

Re: GRAS Notice No. GRN 000077

Dear Dr. Kruger:

The Food and Drug Administration (FDA) is responding to the notice, dated May 2, 2001, that you submitted on behalf of DMV International 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 received the notice on May 4, 2001 and designated it as GRAS Notice No. GRN 000077.

The subject of the notice is “bovine lactoferrin.” This notice informs FDA of the view of DMV International that “bovine lactoferrin” is GRAS, through scientific procedures, for use as an ingredient in sports and functional foods at a level of 100 milligrams per product serving. For the reasons discussed below in this letter, FDA is using the term “milk-derived lactoferrin” rather than “bovine lactoferrin.”

GRN 000077 incorporates by reference a notice dated April 6, 2000, that you previously submitted on behalf of DMV International. FDA received that notice on April 19, 2000, designated it as GRN 000042, and responded to it in a letter dated March 26, 2001. In our response to GRN 000042, we concluded that GRN 000042 did not provide a basis for a GRAS determination because the notice was silent with respect to two issues. In a letter dated April 6, 2001, and in GRN 000077, DMV International addressed these issues. As discussed more fully below in this letter, based on the information provided by DMV International, as well as other information available to FDA, the agency has no questions at this time regarding DMV International’s conclusion that milk-derived lactoferrin is GRAS for its intended use as an ingredient in sports and functional foods, provided that the ingredient statement of food products that contain this ingredient includes its source (e.g., milk or cow’s milk).

Data and information that DMV International presents in GRN 000042(1)

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 that is pasteurized or from a pasteurized milk derivative, microfiltrated 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.

DMV International 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, DMV International 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 and milk-derived ingredients and products. Thus, persons who consume milk or milk-derived ingredients already consume lactoferrin. DMV International estimates the that the current per-capita consumption of milk-derived lactoferrin from the consumption of milk or milk-derived ingredients, including whey proteins, is 84 milligrams/person/day (mg/p/d) at the 90th percentile consumption level. DMV International estimates that the additional intake of milk-derived lactoferrin from its proposed uses in sports and functional foods would be up to 196 mg/p/d for consumers of these foods at the 90th percentile consumption level.

In describing the intended use of milk-derived lactoferrin, DMV International asserts that milk-derived lactoferrin is a physiologically active substance. According to DMV International, published studies show that lactoferrin that is derived from cow’s milk or from human milk can (1) modulate immune responses such as inflammation, and (2) affect microflora in the gastrointestinal tract. In DMV International’s view, these activities are beneficial to consumers.

DMV International describes published animal toxicity or genotoxicity studies conducted with milk-derived lactoferrin that has similar specifications to the ingredient that is the subject of this notice. DMV International 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/kilogram/day given for up to 13 weeks. DMV International also concludes that the genotoxicity study provides no evidence of mutagenic potential.

DMV International notes that milk proteins are commonly allergenic, particularly in infants and children. According to DMV International, 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, DMV International 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.

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

FDA’s response to GRN 000042

In our letter dated March 26, 2001, we identified two issues that formed the basis for our conclusion that the notice did not provide a basis for a GRAS determination. These issues were (1) the potential that the increased level and overall exposure to milk-derived lactoferrin would sensitize individuals who are not already allergic, and (2) the potential that this immunologically active food component is correlated with autoimmune disorders. Given that DMV International’s notice did not address the potential that some effects of this immunologically active substance could be adverse, we concluded that the notice did not provide a sufficient basis for a determination that milk-derived lactoferrin is GRAS under the conditions of its intended use.

Data and information that DMV International presents in a supplement to GRN 000042 and in GRN 000077

In a letter of April 6, 2001, you outlined a plan to address two issues that were not addressed in GRN 000042 (i.e., the potential that the increased level and overall exposure to milk-derived lactoferrin would sensitize individuals who are not already allergic (to milk), and the potential that this immunologically active food component is correlated with autoimmune disorders). The notifier intended to convene a panel of scientists qualified by scientific training and experience to evaluate these issues. After this panel met, the notifier would send a summary of the panel’s conclusions to FDA to supplement information already provided to FDA.

Your April 6 letter also included an initial opinion from Dr. Steve Taylor concerning the potential allergenicity of milk-derived lactoferrin and its potential role in the onset of autoimmune disease. Dr. Taylor is a member of the medical advisory board of The Food Allergy & Anaphylaxis Network. Dr. Taylor concludes that lactoferrin is not a documented cows’ milk allergen and that there is no proof to indicate that it will become an allergen. Likewise, Dr. Taylor concludes that the findings are not convincing that ingestion of milk-derived lactoferrin plays a role in the onset of autoimmune disease, especially in adults.

In GRN 000077, DMV International provides a report of a specially convened panel of individuals (DMV International’s allergy and immunology panel) who evaluated the data and information that are the basis for DMV International’s GRAS determination. DMV International considers the members of its panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. DMV International’s allergy and immunology panel considered the two issues that that were not addressed in GRN 000042.

The members of DMV International’s allergy and immunology panel assert that the increased exposure to milk-derived lactoferrin at the levels of exposure specified in GRN 000042 would be highly unlikely to induce allergy or autoimmune disease. The panel concludes that although scientific information exists to suggest that milk-derived lactoferrin can induce IgE antibodies in the Brown Norway rat model, this model is not an adequate, appropriate or validated model for prediction of allergic disease in humans. The panel also concludes that the likelihood of increased consumer exposure to milk-derived lactoferrin causing or exacerbating autoimmune disease is remote. Although there is extensive literature documenting the presence of anti-lactoferrin autoantibodies in various autoimmune diseases, there is no evidence that these antibodies play any role in the pathology of these diseases. The development of a harmful autoimmune response as a result of the ingredient use of lactoferrin would require a combination of circumstances, which DMV International’s allergy and immunology panel considers to be unlikely.

DMV International’s allergy and immunology panel concludes that milk-derived lactoferrin, at the proposed levels and for the uses specified by DMV International, is GRAS, provided that food products containing milk-derived lactoferrin are clearly labeled as containing a milk protein so that existing milk-allergic consumers can avoid these products.

Declaration of the source as a condition of safe use

DMV International’s allergy and immunology panel considered that labeling of food products that contain lactoferrin as containing a milk protein is a condition of safe use. Consistent with this panel’s conclusion, we have used the term milk-derived lactoferrin to describe the subject of DMV International’s notice. Other terms that plainly declare that the source is milk would also satisfy the condition established by DMV International’s allergy and immunology panel. We note that a group of trade organizations (i.e., The Food Allergy Issues Alliance) is taking steps to enhance the labeling of food allergens (Ref. 1). One of these steps includes addressing the prevalence and the identification of major allergens, including milk-derived ingredients, in plain simple language in the food ingredient statement.

Potential labeling issues other than declaration of the source as a condition of safe use

Section 403(a) of the Federal Food, Drug, and Cosmetic Act (FFDCA) provides that a food is misbranded if its labeling is false or misleading in any particular manner. Section 403(r) of the FFDCA lays out the statutory framework for a health claim. In describing the intended use of milk-derived lactoferrin and in describing the information that DMV International relies on to conclude that milk-derived lactoferrin is GRAS under the conditions of its intended use, DMV International raises issues under these labeling provisions of the FFDCA. These issues consist of physiological effects of milk-derived lactoferrin that DMV International views as “beneficial.” These issues are the purview of the Office of Nutritional Products, Labeling and Dietary Supplements (ONPLDS) in CFSAN. The Office of Food Additive Safety (OFAS) neither consulted with ONPLDS on these labeling issues nor evaluated the information in DMV International’s notice to determine whether it would support any claims made about milk-derived lactoferrin on the label or in labeling.

Conclusions

Based on the information provided by DMV International, as well as other information available to FDA, the agency has no questions at this time regarding DMV International’s conclusion that milk-derived lactoferrin is GRAS for its intended use as an ingredient in sports and functional foods, provided that the ingredient statement of food products that contain this ingredient include its source (e.g., milk or cow’s milk). The agency has not, however, made its own determination regarding the GRAS status of this use of milk-derived lactoferrin. As always, it is the continuing responsibility of DMV International 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, as well as a copy of the information in your notice that conforms to the information in proposed 21 CFR 170.36(c)(1), is available for public review and copying on OFAS’ homepage on the Internet (at http://www.cfsan.fda.gov/~lrd/foodadd.html).

 

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



 

References

1. Letter dated May 30, 2001, from Joseph Levitt of FDA to Regina Hildwine. Available at http://www.cfsan.fda.gov/~dms/alrgltr3.html.

 

(1)GRN 000042 also includes the findings of a panel of individuals (DMV International’s GRAS panel) who evaluated the data and information that are the basis for DMV International’s GRAS determination. DMV International considers these individuals to be qualified by scientific training and experience to evaluate the safety of substances added to food.