March 26, 2001

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

Re: GRAS Notice No. GRN 000042

Dear Dr. Kruger:

The Food and Drug Administration (FDA) is responding to the notice, dated April 6, 2000, 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)). The Office of Premarket Approval (OPA) received the notice on April 10, 2000 and designated it as GRAS Notice No. GRN 000042.

The subject of the notice is milk-derived lactoferrin.⁽¹⁾ The notice includes the findings of a panel of individuals 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.

The notice dated April 6, 2000, informed FDA of the view of DMV International that milk-derived lactoferrin is GRAS, through scientific procedures, for use as a nutrient supplement in infant formulas, and in sports and functional foods. In a letter dated September 11, 2000, you informed FDA that DMV International requested that FDA cease to evaluate the use of milk-derived lactoferrin in infant formulas. You also informed FDA of DMV International's intent to resubmit a notice for the use of milk-derived lactoferrin in infant formulas at a future time.

FDA has evaluated the information that DMV International discusses in its GRAS notice as well as other data and information that are available to the agency. As discussed more fully below, the notice does 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 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,⁽²⁾ 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 evaluation of the data and information in DMV International's notice

On October 30, 2000, FDA representatives met with you and other representatives of DMV International concerning the use of milk-derived lactoferrin in sports and functional foods. At that meeting we discussed three issues pertinent to DMV International's notice: (1) the intended use level and dietary exposure, (2) the potential that the increased level and overall exposure to milk-derived lactoferrin would sensitize individuals who are not already allergic, and (3) the potential that this immunologically active food component is correlated with autoimmune disorders.⁽³⁾ We particularly cautioned DMV International to describe their basis to conclude that experts had considered these issues and would agree that the available data and information demonstrate that the potential for allergenicity or autoimmune problems does not raise a safety concern.

In letters dated January 12 and 15, 2001, you provided a revised description of the intended use level of milk-derived lactoferrin and a revised dietary exposure estimate. Those submissions were silent regarding the potential for allergenicity or autoimmune problems. Thus, the notice is silent with respect to the potential that the increased dietary exposure to milk-derived lactoferrin among individuals who are not already sensitized could cause those individuals to become allergic to this substance. Likewise, the notice is silent with respect to potential autoimmune effects of milk-derived lactoferrin.

Conclusions

FDA has evaluated the information in GRAS Notice No. GRN 000042, as well as other available data and information. Given that DMV International's notice does not address the potential that some effects of this immunologically active substance could be adverse, the notice does not provide a sufficient basis for a determination that milk-derived lactoferrin is GRAS under the conditions of its intended use.

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 OPA's homepage on the Internet (at http://vm.cfsan.fda.gov/~lrd/foodadd.html).

⁽¹⁾The notice used the term "bovine lactoferrin." For the purpose of this letter, we are using the term "milk-derived lactoferrin."

⁽²⁾In telephone conversations on July 18, 2000, you clarified that the cheese whey that is used as a starting material for lactoferrin is pasteurized. According to the notice, the raw bovine milk is pasteurized before the microfiltration step.

⁽³⁾At the October 30th meeting, we also discussed issues concerning the use of milk-derived lactoferrin in infant formula. Because use in infant formula is no longer the subject of this notice, we are not discussing those issues in this letter.

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