Agency Response Letter GRAS Notice No. GRN 000615

Recently Published GRAS Notices and FDA Letters

CFSAN/Office of Food Additive Safety

June 24, 2016

Henry J. Binder, M.D.
Yale School of Medicine
LMP 1080
New Haven, CT 06519

Re: GRAS Notice No. GRN 000615

Dear Dr. Binder:

The Food and Drug Administration (FDA) is responding to the notice, dated December 7, 2015, 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 December 18, 2015, filed it on January 4, 2016, and designated it as GRAS Notice No. GRN 000615.

The subject of the notice is high-amylose cornstarch. The notice informs FDA of the view of Yale University (Yale) that high-amylose cornstarch is GRAS, through scientific procedures, for use as an ingredient in oral rehydration solutions for adults and children over two years of age at a level of 50 grams (g) per liter.

Our use of “high-amylose cornstarch” 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 and Food Labeling in the Center for Food Safety and Applied Nutrition.

As part of its notice, Yale includes the statement of a panel of individuals (Yale’s GRAS panel) that evaluated the data and information that are the basis for Yale’s GRAS determination. Yale considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Yale’s GRAS panel evaluated estimates of dietary exposure, method of production, and product specifications as well as published and unpublished studies supporting the safety of high-amylose cornstarch. Based on this review, Yale’s GRAS panel concluded that high-amylose cornstarch that meets its established food grade specifications is GRAS under the conditions of its intended use.

Yale describes high-amylose cornstarch as a mixture of the polysaccharides amylose and amylopectin obtained from corn varieties with amylose content ranging from 55 to over 90 percent.^[1] Cornstarch normally contains 25 to 30 percent amylose. The CAS registry number provided by the notifier for starches is 9005-25-8.

Yale describes the manufacturing process for high-amylose cornstarch. Corn kernels are dehulled and undergo wet-milling to obtain a starch slurry. The slurry is acidified and treated with a sterilizing agent for microbial control. The slurry is then adjusted to neutral pH, dried, screened, packaged, and subjected to quality control. All processes are conducted in accordance with current good manufacturing practices.

Yale provides specifications for high-amylose cornstarch, including limits for lead, sulfur dioxide, and microbial contaminants. Yale provides analytical data from four non-consecutive batches of high-amylose cornstarch demonstrating the product complies with the specifications.

Yale estimates total dietary exposure to high-amylose cornstarch based on its proposed use as an ingredient in oral rehydration solutions. Yale bases its estimates on the volume of oral rehydration solution recommended by the Centers for Disease Control and Prevention, World Health Organization, and World Gastroenterology Organization. The maximum exposures to high-amylose cornstarch are in the range of 105 to 250 grams per person per day (g/p/d) for consumers 2 to 15 years of age and 300 g/p/d for consumers older than 15 years. These estimates represent cumulative 24-hour exposure including the initial, 4-hour rehydration phase and the subsequent maintenance phase.

Yale notes that food starches, including high-amylose cornstarch, have a long history of safe use in the food supply. The Joint FAO/WHO Expert Committee on Food Additives set the acceptable daily intake level for native food starches as “not specified,” a designation given to substances considered to be of very low toxicity that do not represent a hazard to health based on available data and on dietary exposure. The Select Committee on GRAS Substances also evaluated the safety of starches, including high-amylose cornstarch, and concluded that there is no evidence that demonstrates or suggests reasonable grounds to suspect that high-amylose cornstarch poses a hazard to the public when used at the then current levels or at levels that might be expected in the future.

According to Yale, given that high-amylose cornstarch is a macronutrient with a long history of safe use in food, toxicological studies have not been conducted. Nonetheless, many published repeated-dose studies have been conducted in rats (at dietary levels of up to 40%) and pigs (at dietary levels of up to 51.5%) to evaluate the physiological effects of high-amylose cornstarch, including changes in mineral absorption, lipid metabolism, cecal microflora, and other cecal variables. Yale states that the general lack of adverse effects observed in these studies supports the safety of high-amylose cornstarch.

Yale summarizes published studies with high-amylose cornstarch in adults and children. High-amylose cornstarch was well tolerated in healthy subjects who consumed up to 60 g/p/d for up to 4 weeks. Yale summarizes five studies where oral rehydration solutions containing high-amylose cornstarch were administered to human subjects with diarrhea and dehydration. In one study, patients with severe diarrhea were estimated to have consumed an average of 330 g of high-amylose cornstarch in the first 24 hours without adverse effects related to consumption of high-amylose cornstarch. Yale concludes that multiple studies in adults and in children support the safe use of high-amylose cornstarch in oral rehydration solutions.

Based on the totality of evidence, Yale concludes that the intended use of high-amylose cornstarch is GRAS.

Medical Foods

In its notice, Yale informs FDA that high-amylose cornstarch is intended for use in medical foods. Section 5(b) of the Orphan Drug Act (ODA) defines a medical food as a food that is formulated to be consumed or administered enterally under the supervision of a physician and that is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation. Section 403(q) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) lays out the statutory framework for nutrition labeling of food products. Section 403(r) of the FD&C Act lays out the statutory framework for health claims and nutrient content claims. Under section 403(q)(5)(A)(iv) of the FD&C Act and FDA's implementing regulations in 21 CFR 101.9(j)(8), the requirements for nutrition labeling do not apply to medical foods as defined in section 5(b) of the ODA. Under section 403(r)(5)(A) of the FD&C Act and FDA's implementing regulations in 21 CFR 101.13(q)(4)(ii) and 21 CFR 101.14(f)(2), the requirements for nutrient content claims and health claims, respectively, do not apply to medical foods as defined in section 5(b) of the ODA. For your information, FDA's response to Yale’s notice that high-amylose cornstarch is GRAS for use in medical foods does not address the question of whether any particular food product that contains high-amylose cornstarch as an ingredient would be a medical food within the meaning of section 5(b) of the ODA and, thus, would be exempt from the requirements for nutrition labeling, nutrient content claims, and health claims.

Section 301(ll) of the Federal Food, Drug, and Cosmetic Act (FD&C Act)

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 Yale’s notice that high-amylose cornstarch is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing high-amylose cornstarch. Accordingly, this response should not be construed to be a statement that foods that contain high-amylose cornstarch, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).

Conclusions

Based on the information provided by Yale, as well as other information available to FDA, the agency has no questions at this time regarding Yale’s conclusion that high-amylose cornstarch 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 high-amylose cornstarch. As always, it is the continuing responsibility of Yale University 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 000615, 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.

Sincerely,

Dennis M. Keefe, Ph.D.
Director
Office of Food Additive Safety
Center for Food Safety
and Applied Nutrition

^[1] High-amylose cornstarch is more resistant to digestion in the upper gastrointestinal tract, resulting in a greater proportion of starch reaching the large intestine, where it undergoes fermentation.