Agency Response Letter GRAS Notice No. GRN 000374
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CFSAN/Office of Food Additive Safety
August 16, 2011
Dock Road, Mostyn, Holywell
Flintshire, CH8 9HE
Re: GRAS Notice No. GRN 000374
Dear Ms. Sheane:
The Food and Drug Administration (FDA) is responding to the notice, dated February 7, 2011, that you submitted 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 March 2, 2011, filed it on March 8, 2011, and designated it as GRAS Notice No. GRN 000374.
The subject of the notice is maleated isoprenyl polymer with methoxy-polyethylene glycol (MIP-MPEG). The notice informs FDA of the view of Revolymer Limited (Revolymer) that MIP-MPEG is GRAS, through scientific procedures, for use as a gum base polymer additive in chewing gum formulations at levels up to 15% of gum base. MIP-MPEG is added to improve gum removability from a variety of surfaces.
Our use of “MIP-MPEG” in this letter should not be considered an endorsement or recommendation of that term as an appropriate common or usual name for the purpose of declaring the substance in the ingredient statement of foods that contain that ingredient. Title 21 CFR 101.4 states that each ingredient must be declared by its common or usual name. In addition, 21 CFR 102.5 outlines general principles to use when establishing common or usual names for nonstandardized foods. Issues associated with labeling and the appropriate common or usual name of a food are the responsibility of the Office of Nutrition, Labeling, and Dietary Supplements in the Center for Food Safety and Applied Nutrition.
As part of its notice, Revolymer includes the report of a panel of individuals (Revolymer’s GRAS panel) who evaluated the data and information that are the basis for Revolymer’s GRAS determination. Revolymer considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Revolymer’s GRAS panel evaluated estimates of dietary exposure, method of manufacture, and product specifications as well as published safety studies. Based on this review, Revolymer’s GRAS panel concluded that MIP-MPEG, meeting food grade specifications, is GRAS under the conditions of its intended use.
Revolymer provides information about the identity, composition, and method of manufacture for MIP-MPEG. Revolymer states that the full chemical name of MIP-MPEG is 1,3-butadiene, 2-methyl-homopolymer, maleated esters with polyethylene glycol mono-methyl ether (CAS Number: 1246080-53-4). MIP-MPEG contains approximately 65% MIP-MPEG with up to 35% free methoxy-polyethylene glycol (MPEG2000). Starting materials, maleated polyisoprene and MPEG2000, are mixed in a set ratio under controlled conditions for a specified length of time. Revolymer notes that the temperature of the reaction is not higher than the temperatures used to produce either starting material; therefore, thermal instability is not anticipated.
Revolymer provides specifications for MIP-MPEG, free MPEG, and possible residues carried over from the starting materials. Limits for microbial contamination are also included; however, Revolymer states that the water content of MIP-MPEG is low and that the manufacturing temperature is sufficiently high that microbial proliferation is not expected. Revolymer provides the results of analyses of four batches MIP-MPEG which show conformity with the specifications. Finally, Revolymer states that, based on stability studies, MIP-MPEG has a shelf-life of 3 years.
Revolymer calculates a worst-case estimated daily intake (EDI) for MIP-MPEG by using a consumption value of 30 milligram (mg) chewing gum per kilogram (kg) body weight (bw) per day (d) in the United States (reported by Leatherhead Food International). To account for upper percentile consumers, Revolymer used guidelines issued by the Joint FAO/WHO Expert Committee on Food Additives to extrapolate a consumption value of 90 mg/kg bw/d. Using this information, Revolymer calculates the EDI for MIP-MPEG from the consumption of chewing gum as 7 mg/kg bw/d when the ingredient is present at 8% and as 13 mg/kg bw/d when the ingredient is present at 15%.
Revolymer discusses information about the absorption of MIP-MPEG as well as published studies that demonstrate the safety of MIP-MPEG consumption. Revolymer states that because the average molecular weights of the MIP-MPEG (32,000 Daltons (Da)) and MPEG2000 (2,000 Da) are greater than 1,000 Da (above which polymers are not expected to cross the epithelial layer of the gastrointestinal tract), no bodily absorption or toxicological effects are expected from possible ingestion. Revolymer discusses published studies including bacterial reverse mutation (Ames) assay, mouse lymphoma thymidine kinase gene mutation assay, and a mammalian erythrocyte micronucleus test. The result of the tests showed that MIP-MPEG is not genotoxic. Finally, Revolymer discusses a published 28-day rodent study, which showed that, up to the maximum test concentration (80,000 mg/kg), no changes in mortality, body weight, body weight gain, food consumption, food efficiency, or functional observational battery/motor activity findings related to MIP-MPEG exposure in any of the Sprague Dawley SD rats (10/sex/dose). The no observed effect level was the highest dose tested, 80,000 mg/kg, which is equal to 6.88 g/kg bw/d for males and 6.84 g/kg bw/d for females.
Section 301(ll) of the Federal Food, Drug, and Cosmetic Act (FFDCA)
The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the FFDCA to, among other things, add section 301(ll). Section 301(ll) of the FFDCA prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FFDCA, a biological product licensed under section 351 of the Public Health Service Act, or a drug or a biological product for which substantial clinical investigations have been instituted and their existence made public, unless one of the exemptions in section 301(ll)(1)-(4) applies. In its review of Revolymer’s notice that MIP-MPEG is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to food containing MIP-MPEG. Accordingly, this response should not be construed to be a statement that foods that contain MIP-MPEG, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Revolymer, as well as other information available to FDA, the agency has no questions at this time regarding Revolymer’s conclusion that MIP-MPEG is 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 MIP-MPEG. As always, it is the continuing responsibility of Revolymer 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 000374, as well as a copy of the information in this notice that conforms to the information in the GRAS exemption claim (proposed 21 CFR 170.36(c)(1)), is available for public review and copying at www.fda.gov/grasnoticeinventory.
Mitchell A. Cheeseman, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition