Agency Response Letter GRAS Notice No. GRN 000470
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CFSAN/Office of Food Additive Safety
December 16, 2013
Jeffrey Pitt, Ph.D.
Senior Product Steward Manager
Dow Wolff Cellulosics
The Dow Chemical Company
1691 N. Swede Road
Midland, MI 48674
Re: GRAS Notice No. GRN 000470
Dear Dr. Pitt:
The Food and Drug Administration (FDA) is responding to the notice, dated February 6, 2013, 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 May 7, 2013, filed it on May 15, 2013, and designated it as GRAS Notice No. GRN 000470.
The subject of the notice is ethyl cellulose. The notice informs FDA of the view of Dow Wolff Cellulosics (Dow) that ethyl cellulose is GRAS, through scientific procedures, for uses as a viscosity modifier, thickener, film-former, stabilizer, filler, and for use in thermal gelation. Dow intends to use ethyl cellulose in grain products, vegetables, fruits, milk and milk products, legumes, nuts and seeds (i.e., peanut butter), fats and oils, sugars and sweets, and beverages at levels ranging from 0.0075 to 5%.
As part of its notice, Dow includes a report from a panel of individuals (Dow’s GRAS panel) that 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 evaluated information describing the identity, method of manufacture and specifications, and estimated dietary exposure, as well as published data and information supporting the safety of ethyl cellulose. Based on this review, Dow’s GRAS panel concluded that ethyl cellulose produced in accordance with current good manufacturing practices (cGMP) and used as described is GRAS.
Dow describes the identity of ethyl cellulose. Ethyl cellulose has the polymeric backbone of the carbohydrate cellulose, and each molecule contains 44 to 51% ethoxyl groups. Ethyl cellulose has an average molecular weight ranging from 44,900 to 223,200 Daltons. Dow states that ethyl cellulose is a free-flowing powder that is white to light tan in color and is insoluble in water.
Dow describes the manufacturing process for ethyl cellulose. Pulp from wood or cotton is immersed in a caustic soda solution to produce alkali cellulose material. The material is reacted with ethyl chloride. The mixture is then cooled and filtered before treatment with water and steam to precipitate the ethyl cellulose and form an aqueous slurry containing ethyl cellulose granules. The granules are then neutralized with hydrochloric acid, washed with deionized water, and dewatered by centrifugation. The granules are sprayed with propyl gallate (an antioxidant) and then dried under controlled conditions. The dried granules are milled and ground to the desired particle size before homogenization and packaging. Dow states that ethyl cellulose is manufactured according to cGMP using appropriate food grade ingredients, and all processing aids used in its manufacture have a history of safe use in food processing.
Dow states that ethyl cellulose complies with the specifications described in the Food Chemicals Codex (7th edition) and those described by the FAO/WHO Joint Committee on Food Additives (JECFA). Dow provides specifications for ethyl cellulose, including identity, viscosity, loss on drying (2% weight maximum), pH (pass), residue on ignition (0.40% maximum), residual solvent (pass), and ethoxyl content (48.0 to 49.5% by weight). Dow also provides limits for heavy metals (lead (2 milligrams per kilogram (mg/kg)), arsenic (2 mg/kg), cadmium (1 mg/kg), and mercury (1 mg/kg)) and microbial contaminants.
Dow estimates the total dietary exposure to ethyl cellulose from the current uses described in 21 CFR 172.868 (as a binder and filler in vitamins, for tablet coatings, and as a fixative in flavorings) and in 21 CFR 182.90 (as a substance migrating to food from paper and paper board) to be 1.2 grams per person per day (g/p/d). Dow used data from the United States Department of Agriculture’s 1994-1996 Continuing Survey of Food Intakes by Individuals to estimate the dietary exposure to ethyl cellulose from the intended uses. Dow estimates a mean intake of 4.95 g/p/d and a 90th percentile consumption of 9.90 g/p/d. Based on the current and intended uses of ethyl cellulose, Dow estimates a > 99th percentile intake of 11.10 g/p/d (185 mg/kg body weight per day (mg/kg bw/d) for a 60 kg individual).
Dow discusses the results of published in vivo studies supporting the safety of ethyl cellulose. The results of a single dose study conducted using rats demonstrated the low oral toxicity of ethyl cellulose when consumed at levels exceeding 5000 mg/kg bw. The results of a repeated dose study in which a total of 80 male and female rats were fed diets containing 600 mg/kg bw/d ethyl cellulose for eight months showed no adverse effects.(1) The results of a subchronic study in which rats (20/sex/group) were fed a formulation containing up to 1250 mg/kg bw/d ethyl cellulose for 90 days showed no adverse effects. The results of another subchronic study in which rats (20/sex/group) were fed a formulation containing up to 1355 mg/kg bw/d ethyl cellulose for 90 days also showed no significant ethyl cellulose-related adverse effects.(2) The results of a developmental toxicity study in which 25 female rats received up to 1355 mg/kg bw/d ethyl cellulose showed no biologically significant effects.
Dow also cites the findings of authoritative bodies to support the safety of ethyl cellulose. Both JECFA and a European Food Safety Authority Expert Panel evaluated the food uses of ethyl cellulose and assigned an acceptable daily intake of “not specified” for ethyl cellulose.(3)
Standards of Identity
In the notice, Dow states its intention to use ethyl cellulose 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.
Section 301(ll) of the Federal Food, Drug, and Cosmetic Act (FD&C Act)
The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the FD&C Act to, among other things, add section 301(ll). Section 301(ll) of the FD&C Act prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FD&C Act, 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 Dow’s notice that ethyl cellulose is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing ethyl cellulose. Accordingly, this response should not be construed to be a statement that foods that contain ethyl cellulose, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
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 ethyl cellulose 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 ethyl cellulose. 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 000470, 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.
Dennis M. Keefe, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
(1)FDA previously evaluated this study during its review of the data and information supporting the GRAS status of ethyl cellulose as described under 21 CFR 182.90.
(2)Dow cites the study authors’ observation that blood levels of alanine aminotransferase (ALT) and aspartame aminotransferase (AST) were significantly elevated in male rats that received the middle and high doses of the formulation. Dow concurs with the study authors’ conclusion that the increases in ALT and AST were not associated with any indicators of liver toxicity.
(3)In their GRAS notice, Dow cites a report from the EFSA Scientific Panel on Food Additives, Flavorings, Processing Aids and Materials in Contact with Food.