Agency Response Letter GRAS Notice No. GRN 000616

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 000616

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 000616.

The subject of the notice is high-amylose cornstarch acetate. The notice informs FDA of the view of Yale University (Yale) that high-amylose cornstarch acetate 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 acetate” 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evaluated estimates of dietary exposure, method of production, and product specifications as well as published and unpublished studies supporting the safety of high-amylose corn starch acetate. Based on this review, Yale’s GRAS panel concluded that high-amylose corn starch acetate that meets its established food grade specifications is GRAS under the conditions of its intended use.

Yale describes high-amylose cornstarch acetate as high-amylose cornstarch that has been subjected to acetylation. Cornstarch is a mixture of the glucose polymers amylose and amylopectin. Cornstarch normally contains 25 to 30 percent amylose. The high-amylose cornstarch used in the manufacture of high-amylose cornstarch acetate is obtained from corn varieties with amylose content ranging from 50 to 80 percent. The proportion of glucose residues modified by acetylation does not exceed 2.5%. ^[1]The CAS registry number provided by the notifier for starch acetate is 9045-28-7.

Yale describes the manufacturing process for high-amylose cornstarch acetate. Corn kernels are dehulled and then undergo a wet-milling process to produce a starch slurry. The slurry is acidified, esterified using acetic acid, and sterilized for microbial control. After neutralization, the slurry is dried, screened, packaged, and subjected to quality control. All processes are conducted in accordance with current good manufacturing practices (cGMP).

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

Yale estimates total dietary exposure to high-amylose cornstarch acetate 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 acetate 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 during the initial, 4-hour rehydration phase and the subsequent maintenance phase.

Yale notes that acetylated and non-acetylated forms of native food starches have a long history of safe use in food. According to 21 CFR §172.892, acetylated food starches with not more than 2.5% acetyl groups are approved direct food additives. Starch acetate is also permitted for use in foods without restrictions, aside from adherence to cGMP, in countries including Canada, Europe, Australia, and New Zealand. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) has concluded that the acceptable daily intake level for starch acetate is “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.

Yale notes that the safety of various chemically modified starches, including acetylated starch, has been assessed in a series of evaluations conducted by JECFA and the Select Committee on GRAS Substances (SCOGS). The toxicological data reviewed by both JECFA and SCOGS included several short term animal studies ranging from 4 to 13 weeks in duration, an 89-week study in mice, a 2-year study in rats, and a 3-generation reproductive/developmental study in rats. No toxicologically relevant adverse effects were noted in these studies.

Yale discusses two unpublished animal studies where high-amylose cornstarch acetate was administered at up to 10 milligrams per kilogram bodyweight per day for 1 and for 4 weeks, respectively. No abnormal pathology or significant adverse effects were noted in these studies. Yale summarizes two published studies conducted in healthy humans. In these studies, the consumption of up to 40 g of high-amylose cornstarch acetate (6% acetylation) per day for 2 weeks or 60 g of starch acetate (1.98% acetylation) per day for 4 days did not result in any adverse effects. Yale summarizes multiple human clinical studies where oral rehydration solutions containing high-amylose cornstarch and high-amylose cornstarch acetate were administered to human subjects with diarrhea and dehydration. None of the studies reported adverse effects related to the consumption of high-amylose cornstarch or high-amylose cornstarch acetate.

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

Medical Foods

In its notice, Yale informs FDA that one intended use of high-amylose cornstarch acetate 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 acetate is GRAS for use in medical foods does not address the question of whether any particular food product that contains high-amylose cornstarch acetate 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 acetate 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 acetate. Accordingly, this response should not be construed to be a statement that foods that contain high-amylose cornstarch acetate, 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 acetate 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 acetate. 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 000616, 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. Acetylation may also increase the resistance of starch to digestion.