April 2, 2001

Mr. Robert H. Sindt
Attorney At Law
1850 M Street, N.W.
Suite 400
Washington, D.C. 20036

Re: GRAS Notice No. GRN 000064

Dear Mr. Sindt:

The Food and Drug Administration (FDA) is responding to the notice, dated December 15, 2000, that you submitted on behalf of Rhodia, Inc. (Rhodia) 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 December 20, 2000, and designated it as GRAS Notice No. GRN 000064.

The subject of the notice is egg white lysozyme. The notice informs FDA of the view of Rhodia that egg white lysozyme is GRAS, through scientific procedures, for use as an antimicrobial agent in casings for frankfurters and on cooked meat and poultry products. Egg white lysozyme would be used in casings for frankfurters at a concentration of 2.5 milligram (mg) lysozyme per pound (lb) of frankfurter (equivalent to 5.5 mg lysozyme per kilogram (kg) of food) and in cooked meat and poultry products sold as ready-to-eat at a concentration of 2.0 mg of lysozyme per lb of cooked meat or poultry product (equivalent to 4.4 mg of lysozyme per kg of food).

Rhodia's notice describes published information regarding the chemical identity of lysozyme (Chemical Abstract Service Registry Number 9001-63-2). Under a system developed by the Commission on Enzymes of the International Union of Biochemistry, the systematic name of lysozyme is peptidoglycan N-acetylmuramoylhydrolase and its systematic number is EC No. 3.2.1.17. Rhodia describes lysozyme as a natural antimicrobial protein with a molecular weight of approximately 14,300 daltons. The enzyme occurs naturally in many organisms. Hen egg white lysozyme is among the most throughly characterized enzymes, and its three-dimensional structure, mechanism of action, substrate specificity, and other properties have been determined. Lysozyme is inactivated by stomach and intestinal proteolytic enzymes, particularly pepsin.

Rhodia describes the method of manufacture of egg white lysozyme, which is based on generally available and accepted principles of protein purification. Lysozyme is extracted from fresh egg white, where it is present at approximately 0.3 percent of the egg white, and 3.5 percent of the egg white protein. In the processing, a food-grade inert material (a polymer resin) is mixed with egg white where it specifically binds with the lysozyme. The resin carrying the lysozyme is separated from the egg white, and the lysozyme is removed from the resin by addition of salts and a change in the pH. The enzyme is then concentrated, further purified, and dried. Specifications provided for lysozyme are consistent with the general and additional requirements for enzyme preparations in the Food Chemicals Codex (4th ed., 1996). Rhodia's notice provides intake estimates for the proposed uses of lysozyme based on food consumption data collected by the U.S. Department of Agriculture (1998).

As part of its notice, Rhodia includes the report of a panel of individuals (Rhodia's GRAS panel) who evaluated the data and information that are the basis for Rhodia's GRAS determination. Rhodia considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Rhodia's GRAS panel discusses the information and data provided by Rhodia to the panel on the chemical, physical, and antimicrobial properties, manufacture and processing, stability, conditions of anticipated use, and estimates of dietary exposure.

Rhodia's GRAS panel notes that FDA recently evaluated available information on lysozyme and tentatively affirmed that egg white lysozyme, when labeled by the name "egg white lysozyme" to identify its source, is GRAS for use in preventing late blowing of cheese caused by the bacterium Clostridium tyrobutyricum during cheese production (the tentative final rule on lysozyme; 63 FR 12421; March 13, 1998). In that tentative final rule, FDA explained that egg whites are known to be an allergenic food source, particularly in children. FDA referenced a literature report indicating that lysozyme may in fact have been an allergen for some individuals who became sensitive to egg whites. Accordingly, FDA proposed that a condition for the safe use of lysozyme would be labeling to alert such individuals to the presence of egg white lysozyme in cheese. Such labeling also would alert the sensitive population to the possible presence of source-derived proteins other than lysozyme in the enzyme preparation.

In its report, Rhodia's GRAS panel discusses, and concurs with, several of the conclusions drawn by FDA in the tentative final rule on lysozyme. Rhodia's GRAS panel concludes that:

• There will be no long term increase in lysozyme intake by the general population because the egg whites from which lysozyme is extracted will be subsequently consumed (without lysozyme) in other food uses.
• The safety of lysozyme as a component of egg white is supported by a long history of safe consumption by humans as a source of food protein throughout recorded history.
• Proteins derived from egg whites do not raise toxicity concerns, and the methods used for extracting lysozyme from the egg white source should not alter either the chemical identity or the characteristic properties of the enzyme.
• FDA's tentative conclusion that egg white lysozyme is GRAS for use in preventing late blowing of cheese caused by the bacterium Clostridium tyrobutyricum during cheese production is based, in part, on a presumption that the ingredient would be labeled by the name "egg white lysozyme" to identify its source.

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

During its evaluation of GRN 000064, FDA consulted with the Labeling and Consumer Protection Staff of the Food Safety and Inspection Service of the United States Department of Agriculture (FSIS). FSIS requests that Rhodia be advised that it may be necessary to modify regulatory standards where a standard of identity prohibits or limits the use of an ingredient. At this time, FSIS is not initiating any substance-specific rulemaking activities to amend food standards until its ongoing standards modernization activities are completed. However, FSIS will be able to address requests for the use of any antimicrobial formulations containing egg white lysozyme on meat and poultry products with prevailing standards of identity provided they are descriptively labeled to clearly distinguish them from the traditional standardized products. It is our understanding that you will seek regulatory guidance from FSIS concerning the use of these antimicrobial formulations in standardized meat and poultry products. You should direct your inquiry 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 of his office is (202) 205-0279 and the FAX number is (202)205-3625.

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 the notice that conforms to the information in proposed 21 CFR 170.36(c)(1), is available for public review and copying on the Office of Premarket Approval's homepage on the Internet (at http://www.cfsan.fda.gov/~lrd/foodadd.html).

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