Agency Response Letter GRAS Notice No. GRN 000222
CFSAN/Office of Food Additive Safety
December 20, 2007
James T. Heimbach, Ph.D., F.A.C.N.
923 Water Street
Post Office Box 66
Port Royal, Virginia 22535
Re: GRAS Notice No. GRN 000222
Dear Dr. Heimbach:
The Food and Drug Administration (FDA) is responding to the notice, dated April 20, 2007, that you submitted on behalf of Laboratorios Miret, S.A. (LAMIRSA) 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 the notice on April 25, 2007, filed it on May 1, 2007, and designated it as GRAS Notice No. GRN 000222
The subject of the notice is citric acid esters of mono- and diglycerides, otherwise referred to as citroglycerides. The notice informs FDA of the view of LAMIRSA that citroglycerides are GRAS, through scientific procedures for use as an emulsifier for the antimicrobial substance lauramide arginine ethyl ester (LAE) in carbonated beverages at levels up to 563 milligrams per kilogram (mg/kg) and certain other food categories, including meat and poultry products, at levels up to 1125 mg/kg.(1)
As part of its notice, LAMIRSA includes the report of a panel of individuals (LAMIRSA's GRAS panel) who evaluated the data and information that are the basis for LAMIRSA's GRAS determination. LAMIRSA considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. LAMIRSA's GRAS panel discusses chemical specifications, exposure assessment, as well as the relevant biochemical information and toxicity studies for citroglycerides, and other organic acid esters. Based on this review, LAMIRSA's GRAS panel concluded that citroglycerides that meet established food grade specifications are GRAS under the conditions of their intended use.
Citroglycerides are part of a class of organic acid esters that includes acetic acid esters, lactic acid esters, and tartaric acid esters. The mono- or diglycerides in citroglycerides may include either one or two edible fatty acids with chain lengths ranging most commonly from C12 to C18. There is no single molecular formula for citroglycerides.
LAMIRSA describes the method of manufacture and product specifications that citroglycerides will meet. They are manufactured by esterifying the hydroxyl groups of mono- and diglycerides of fatty acids. This may be accomplished either by the esterification of glycerol with both citric acid and edible fatty acids or by reaction of a mixture of mono- and diglycerides of edible fatty acids with citric acid. Specifications cover total citric acid, total glycerol, free glycerol, total fatty acids (as oleic acid), free fatty acids (as oleic acid), sulfated ash, arsenic, heavy metals as lead, mercury, and cadmium.
LAMIRSA intends to use citroglycerides as an emulsifier as described in 21 CFR 170.3(o)(8) in combination with the antimicrobial substance LAE. The technical effect of citroglycerides is to aid in preventing precipitation of LAE in food products to which it is added. The maximum intended use of citroglycerides is in a 5:1 ratio with LAE.
LAMIRSA estimates the average citroglyceride intake in the United States. Based on their assertion that citroglycerides are present at a concentration of 563 mg/kg in all carbonated beverages and at 1125 mg/kg in all other foods within all food categories for which LAE is GRAS, LAMIRSA estimates that the intake of citroglycerides for individuals 2 years of age and older would be at 15.2 mg/kg body weight per day (bw/day) at the mean and 28.2 mg/kg bw/day at the 90th percentile.
LAMIRSA discusses relevant information and published and unpublished studies for citroglycerides as well as related compounds. Citroglycerides and related compounds will breakdown through well established pathways to components normally found in the diet. Published and unpublished animal studies performed with citroglycerides or closely related organic esters showed no significant treatment related effects.
In its notice, LAMIRSA states its intention to use citroglycerides 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.
During its evaluation of GRN 000222, FDA consulted with the Labeling and Program Delivery Division of the Food Safety and Inspection Service (FSIS) of the United States Department of Agriculture (USDA). Under the Federal Meat Inspection Act and the Poultry Products Inspection Act, FSIS is responsible for determining the efficacy and suitability of food ingredients in meat and poultry 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.
Based on the information submitted in the GRAS notice, FSIS has no objections to the use of citroglycerides to prevent the precipitation of LAE in non-standardized ready-to-eat (RTE) meat products and standardized RTE comminuted meat products. Citroglycerides may also be used as an emulsifier for LAE spray applied to the surface of fresh cuts of meat and poultry, various non-standardized RTE meat and poultry products and standardized RTE meat and poultry products. The maximum amount of LAE in these products may not exceed 200 mg/kg.
FSIS requested that FDA advise LAMIRSA to seek regulatory guidance from FSIS, Labeling and Program Delivery Division, about the use of citroglycerides in meat and poultry products. LAMIRSA should direct such an inquiry to Mr. Bill Jones, Labeling and Program Delivery Division, Office of Policy, Program, and Employee Development, Food Safety and Inspection Service, 1400 Independence Ave., S.W., Room 2925, South Building, Washington, DC 20250-3700. The telephone number for that office is (202) 205-0010 and the telefax number is (202) 720-0582.
Based on the information provided by LAMIRSA, as well as other information available to FDA, the agency has no questions at this time regarding LAMIRSA's conclusion that citroglycerides 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 citroglycerides. As always, it is the continuing responsibility of LAMIRSA 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 000222, as well as a copy of the information in this notice that conforms to the information in the proposed GRAS exemption claim (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 http://www.cfsan.fda.gov/~lrd/foodadd.html).
Laura M. Tarantino, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
cc: Mr. Bill Jones
Labeling and Program Delivery Division
Office of Policy, Program and Employee Development
Food Safety and Inspection Service
1400 Independence Ave., SW, Room 2925, South Building
Washington, DC 20250-3700
(1)LAE is the subject of GRN 000164