Agency Response Letter GRAS Notice No. GRN 000213
CFSAN/Office of Food Additive Safety
March 27, 2007
Melvin S. Drozen and Devon Wm. Hill
Keller and Heckman
1001 G Street, N.W.
Suite 500 West
Washington, D.C. 20001
Re: GRAS Notice No. GRN 000213
Dear Mr. Drozen and Mr. Hill:
The Food and Drug Administration (FDA) is responding to the notice, dated September 20, 2006, that you submitted on behalf of the Dow Chemical Company (Dow) 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 September 22, 2006, filed it on September 27, 2006, and designated it as GRAS Notice No. GRN 000213.
The subject of the notice is hydroxypropyl methylcellulose (HPMC), a propylene glycol ether of methylcellulose containing 16-31.5 percent methyl groups and 2-32 percent hydroxypropyl groups. For the purpose of this letter, FDA refers to the subject of the notice as "HPMC - expanded substitution pattern" (HPMC-ESP). The notice informs FDA of the view of Dow that HPMC-ESP is GRAS, through scientific procedures, for use in food in general, including meat and poultry products, at intake levels up to 20 grams per person per day (g/p/d).
As part of its notice, Dow includes a report of a panel of individuals (Dow's GRAS panel) who evaluated the data and information that are the basis for Dow's GRAS determination. Dow considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Dow's GRAS Panel discusses the identity, specifications, method of manufacture and proposed dietary intake of HPMC-ESP. Dow's GRAS Panel also discusses published safety studies on HPMC with a range of substitution ratios. Based on this review, Dow's GRAS panel concluded that HPMC-ESP, meeting the specifications described in the notice and used in accordance with good manufacturing practices (GMPs), is GRAS under the conditions of its intended use.
Dow notes that the subject of the notice is similar, though not identical, to food-grade HPMC as defined by the specifications of the Joint FAO/WHO Expert Committee on Food Additives (JECFA) (FAO Food and Nutrition Paper 52 (1992)) and the Food Chemicals Codex (FCC) (5th edition (2003)) or by those of the United States Pharmacopeia - National Formulary (USP-NF) (29th edition (2006)). Both JECFA and FCC monographs specify that HPMC contains 19 to 30 percent methyl groups and 3 to 12 percent hydroxypropyl groups(1). The current USP-NF monograph includes specifications for four distinct substitution types(2), each with stated minimum and maximum values for methyl and hydroxypropyl substitution. As specified in its notice, HPMC-ESP has a broader substitution range (16-31.5 percent methyl substitution and 2-32 percent hydroxypropyl substitution) and includes more substitution combinations within that range than does HPMC as specified by the JECFA, FCC, and USP-NF monographs.
Dow describes generally available information about the identity and composition of HPMC-ESP. HPMC-ESP is a powder typically composed of 85-99 percent hydroxypropyl methylcellulose, 1-10 percent water, and 0.5-5 percent sodium chloride. Dow states that its product has a substitution range for methyl groups of 16-31.5 percent and for hydroxypropyl groups of 2-32 percent.
Dow describes the manufacture of HPMC-ESP, which is produced in accordance with GMPs. The product is manufactured from raw materials suitable for their intended use. The materials include pulp (cellulose fibers), methyl chloride, propylene oxide, caustic soda solution, acid, buffering agent, and water. The cellulose fibers are heated along with a caustic solution to produce alkali cellulose, which is then treated with methyl chloride (to obtain methyl substitution) and propylene oxide (to obtain hydroxypropyl substitution). To produce low viscosity products, additional steps of acid addition and subsequent neutralization are performed. The reaction product is (1) purified by filtration and washed with hot water to remove by-products and unreacted materials, (2) dried, (3) ground to a powder, and (4) blended to achieve homogeneity.
Dow provides specifications for its food-grade HPMC-ESP, including specifications for solubility, loss on drying, pH, residue on ignition, substituents, arsenic, lead, and propylene chlorohydrins. The notice includes the results of several batch analyses to demonstrate compliance with specifications.
Dow discusses possible residual impurities from the manufacturing process and provides results of analyses of several lots (n=11) of HPMC-ESP for propylene oxide and propylene chlorohydrin isomers. The notifier reports that neither propylene oxide nor the propylene chlorohydrin isomers (1-chloro-2-propanol and 2-chloro-1-propanol) were present in any of the samples analyzed(3). Dow states that process variables are monitored to ensure proper removal of salt and organics and concludes that propylene chlorohydrins and other residuals are not expected to be present in its food-grade HPMC-ESP.
Dow describes the intended use of HPMC-ESP in foods. Dow intends to use HPMC-ESP for multiple technical effects, including use as film former, stabilizer, and thickener. The notifier lists examples of potential foods to which HPMC-ESP could be added, including: white breads, breakfast cereals, pasta, tortillas, cakes, cookies, biscuits and granola bars, fruit juices, fish sticks, frozen dinners and canned pastas, omelets and egg white substitutes, veggie burgers and meat substitutes, peanut butter, sugar substitutes, candy bars, and fruit roll-up type snacks. Dow notes that the self-limiting level of use for HPMC-ESP generally occurs at 2- percent, on the basis of undesirable mouth feel, undesirable texture, and off flavor, depending on the specific food and the HPMC-ESP viscosity. Dow provides an estimate of intake of HPMC-ESP of approximately 18 g/p/d, based on the intended uses of HPMC-ESP.
In its notice, Dow summarizes published, publicly available toxicology literature. The published toxicology literature includes various study types (acute oral, repeated dose, genetic toxicity, carcinogenicity, reproductive, developmental, pharmacokinetic, and metabolism studies) for both HPMC and for HPMC analogues. The notifier summarizes the results of published studies on mice, rats, dogs, and humans and indicates the substitution ranges and viscosities of the HPMC or analogue studied, when available. Dow states that "no frank toxic effects were observed, except at feeding levels that interfered with the ability of test animals to consume adequate nutrients and calories." Dow states that the data are consistent among all cellulose types, including unmodified celluloses, all molecular weights and viscosities, and all types of modifications, including cross-linking. Dow further asserts that toxicology of the class of modified cellulose, and HPMC specifically, is determined by the absence of absorption from the gastrointestinal system and, therefore, the absence of systemic bioavailability. Dow concludes that the substitution range for HPMC-ESP, as defined in its notice, is supported by the scientific literature and the toxicology of the class of modified cellulose.
Dow also cites the findings of the JECFA toxicological evaluation (35th meeting of JECFA, as published in WHO Food Additives Series 26), which is based on published literature. JECFA concluded that modified celluloses, as a group (including HPMC), are of very low toxicity. However, the evaluation notes the observance of adverse gastrointestinal effects (e.g., laxation) in clinical studies at high doses and recommends an upper safe level of 30 g/p/d of dietary fiber in general. On the basis of the summarized toxicology literature as well as the JECFA toxicological evaluation of modified celluloses, including HPMC, Dow concludes that HPMC-ESP is GRAS for general use in food of at intake levels up to 20 g/p/d.
In the notice, Dow states its intention to use HPMC-ESP in food in general, including foods for which standards of identity exist, located in Title 21 of the Code of Federal Regulations. We note that an ingredient 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 000213, FDA consulted with the Labeling and Consumer Protection Staff 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 products 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. FSIS requested that FDA advise Dow to seek regulatory guidance from FSIS, Labeling and Consumer Protection Staff, about the use of HPMC-ESP in meat and poultry products. Dow should direct such an inquiry to Dr. Robert Post, Director, Labeling and Consumer Protection Staff, Office of Policy, Program, and Employee Development, Food Safety and Inspection Service, 1400 Independence Ave., S.W., Suite 602, Annex, Washington, DC 20250-3700. The telephone number for that office is (202) 205 0279 and the telefax number is (202) 205 3625.
Based on the information provided by Dow, as well as other information available to FDA, the agency has no questions at this time regarding Dow's conclusion that HPMC-ESP 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 this ingredient. As always, it is the continuing responsibility of Dow 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 000213, 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: Dr. Robert Post, Director
Labeling and Consumer Protection Staff
Office of Policy, Program and Employee Development
Food Safety and Inspection Service
1400 Independence Ave., SW, Suite 602, Annex
Washington, DC 20250-3700
(1)FDA notes that HPMC is regulated as a food additive in 21 CFR 172.874. FDA further notes that this regulation cites the definition and specifications for HPMC prescribed by the National Formulary, 12th edition (1965). These specifications include ranges for methyl content and hydroxypropyl content that are in agreement with current JECFA and FCC specifications.
(2) In the USP monograph, HPMC is referred to as "Hypromellose."
(3)Dow calculated the limit of detection of propylene oxide to be 21 micrograms per kilogram (µg/kg) of HPMC-ESP, of 1-chloro-2-propanol to be 17 µg/kg of HPMC-ESP, and of 2-chloro-1-propanol to be 38 µg/kg of HPMC-ESP.