Agency Response Letter GRAS Notice No. GRN 000302
CFSAN/Office of Food Additive Safety
March 5, 2010
DuPont Tate & Lyle Bio Products
198 Blair Bend Road
Loudon, TN 37774
Re: GRAS Notice No. GRN 000302
Dear Mr. Wood:
The Food and Drug Administration (FDA) is responding to the notice, dated August 28, 2009, 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 September 8, 2009, filed it on September 8, 2009, and designated it as GRAS Notice No. GRN 000302.
The subject of the notice is 1,3-propanediol. The notice informs FDA of the view of DuPont Tate & Lyle Bio Products (DuPont Tate & Lyle) that 1,3-propanediol is GRAS, through scientific procedures, for the same uses for 1,2-propanediol as specified in 21 CFR 184.1666(c), excluding infant formula, fish, meat, and poultry. Specifically, DuPont Tate & Lyle intends 1,3-propanediol to be used in place of 1,2-propanediol at levels not to exceed current good manufacturing practice maximum levels of 5 percent for alcoholic beverages, 24 percent for confections and frostings, 2.5 percent for frozen dairy products, 97 percent for seasonings and flavorings, 5 percent for nuts and nut products and 2 percent for all other food categories (excluding infant formula, fish, meat, and poultry). DuPont Tate and Lyle notes that these are the same levels listed in 21 CFR 184.1666(c) for 1,2-propanediol.
As part of its notice, DuPont Tate & Lyle includes the report of a panel of individuals (DuPont Tate & Lyle’s GRAS panel) who evaluated the data and information that are the basis for DuPont Tate & Lyle’s GRAS determination. DuPont Tate & Lyle considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. DuPont Tate & Lyle’s GRAS panel evaluated estimates of dietary exposure, method of production, and product specifications as well as published and unpublished safety studies. Based on this review, DuPont Tate & Lyle’s GRAS panel concluded that 1,3-propanediol that meets its established food grade specifications is GRAS under the conditions of its intended use.
DuPont Tate & Lyle describes the method of manufacture for 1,3-propanediol. DuPont Tate & Lyle manufactures 1,3-propanediol through a multi-step fermentation, separation and distillation process using a genetically modified non-pathogenic and non-toxigenic strain of Escherichia coli K-12. The production begins with fermentation of corn sugar by E. coli. At the end of fermentation, the biomass is deactivated at a high temperature and removed. 1,3-Propanediol is separated from the fermentation broth by a three-step process involving ion exchange to remove charged impurities, evaporation to remove water, and distillation to remove impurities. DuPont Tate & Lyle states that no solvents are used in the separation process. The final 1,3-propanediol is a flammable, colorless and water soluble liquid.
DuPont Tate & Lyle provides specifications for 1,3-propanediol. The final product is specified to contain 99.8 to 100% 1,3-propanediol. Analyses of five lots of the product demonstrate that it complies with DuPont Tate & Lyle’s specifications.
DuPont Tate & Lyle estimates the exposure to 1,3-propanediol from the intended uses to be approximately 34 milligram per kilogram body weight per day (mg/kg bw/day). This estimate was obtained from the National Toxicology Program's (NTP) evaluation of 1,2-propanediol, in which it was estimated that adults are exposed to approximately 34 mg of 1,2-propanediol/kg bw/day through food products. DuPont Tate & Lyle explained that the ultimate source of the data used in NTP’s exposure estimate was a survey conducted by the Flavor and Extract Manufacturers’ Association (FEMA). The FEMA survey obtained the poundage of 1,2-propanediol used in 2005. DuPont Tate & Lyle states that the production volume of 1,3-propanediol will represent only a fraction of that of 1,2-propanediol and, as a result, complete replacement and penetration into the market in all foods in all of the approved categories for 1,2-propanediol at the maximum incorporation rate is not expected.
DuPont Tate & Lyle discusses metabolism as well as toxicity studies on 1,3-propanediol. Based on published studies the notifier notes that 1,3-propanediol is rapidly metabolized to malonic acid. The notifier states that the safety of 1,3-propanediol is supported by published acute, subacute, subchronic, and developmental toxicity studies conducted in rats. Other published data the notifier considered were mutagenicity studies conducted using Salmonella typhimurium, an in vivo mouse micronucleus study, and an in vitro chromosome aberration study. The notifier also corroborates the safety of 1,3-propanediol with an unpublished study on chromosomal aberration assays in Chinese hamster fibroblast cells. Given the published and unpublished studies on 1,3-propanediol, DuPont Tate & Lyle states that 1,3-propanediol is safe under the intended conditions of use.
Standards of Identity
In the notice, DuPont Tate & Lyle states its intention to use 1,3-propanediol 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 (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 DuPont Tate & Lyle’s notice that 1,3-propanediol is GRAS for use as specified in 21 CFR 184.1666 (c), excluding infant formula, fish, meat, and poultry, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing 1,3-propanediol. Accordingly, this response should not be construed to be a statement that foods that contain 1,3-propanediol, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by DuPont Tate & Lyle, as well as other information available to FDA, the agency has no questions at this time regarding DuPont Tate & Lyle’s conclusion that 1,3-propanediol 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 1,3-propanediol. As always, it is the continuing responsibility of DuPont Tate & Lyle 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 000302, 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 via the FDA home page at http://www.fda.gov. To view or obtain an electronic copy of the text of the letter, follow the hyperlinks from the “Food” topic to the “Food Ingredients and Packaging” section to the “Generally Recognized as Safe (GRAS)” page where the GRAS Inventory is listed.
Mitchell A. Cheeseman
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition