Agency Response Letter GRAS Notice No. GRN 000397
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CFSAN/Office of Food Additive Safety
December 19, 2011
Véronique Maquet, Ph.D.
Rue Haute Claire, 4
Parc Industriel des Hauts-Sarts, Zone 2
BE-4040 Herstal BELGIUM
Re: GRAS Notice No. GRN 000397
Dear Dr. Maquet:
The Food and Drug Administration (FDA) is responding to the notice, dated July 28, 2011, 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 August 3, 2011, filed it on August 8, 2011, and designated it as GRAS Notice No. GRN 000397.
The subject of the notice is chitosan from Aspergillus niger (chitosan). The notice informs FDA of the view of KitoZyme S.A. (KitoZyme) that chitosan from A. niger is GRAS, through scientific procedures, for use as a secondary direct food ingredient  in alcoholic beverage production at levels between 10 and 500 grams per hectoliter (100 liters).
As part of its notice, KitoZyme includes the report of a panel of individuals (KitoZyme's GRAS Panel) who evaluated the data and information that are the basis for KitoZyme's GRAS determination. KitoZyme considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. KitoZyme's GRAS panel discusses identity, specifications, method of manufacture, dietary exposure, and safety of chitosan, including the history and current regulatory status of A. niger and chitosan in food, and concludes that chitosan is GRAS under the intended conditions of use.
Chitosan is identified by the CAS registry number 9012-76-4. KitoZyme describes chitosan as an insoluble, non-digestible fiber derived from the post-fermentation biomass of non-viable A. niger used to manufacture food-grade citric acid. KitoZyme states that strains of A. niger used in the production of citric acid are nonpathogenic and nontoxigenic, and have a long history of safe use worldwide. Hydrolysis of the raw A. niger material produces chitosan, which is then washed, precipitated, concentrated, and dried. KitoZyme states the degree of acetylation for chitosan to be 0 to 30 mole percent (%). All materials and processing aids used in the manufacture of chitosan are food-grade. The notifier provides product specifications for chitosan, including microbiological limits, heavy metals, and chemical characterization. KitoZyme states that chitosan from A. niger is chemically equivalent to chitosan from shellfish, based on Fourier transform infrared spectroscopy and nuclear magnetic resonance analyses. KitoZyme noted the presence of beta-1,3-D-glucans (present in ~10 to 15% concentration on a weight by weight basis) that is absent from shellfish sources of chitosan.
KitoZyme reported on a published 13-week subchronic toxicity study in Wistar rats. Twenty rats per sex were fed A. niger-sourced chitin and beta-glucan in a 30:70 ratio. KitoZyme reported the No Observable Adverse Effect Level to be the highest dose tested, 6,589 and 7,002 milligrams/kilogram body weight/day for the male and female rats, respectively.
When chitosan is used in the production of alcoholic beverages, it is removed from the wine, must, beer, cider, or spirits at the end of the treatment using physical separation processes, such as racking, centrifugation, or filtering.
KitoZyme notes that chitosan preparations are insoluble in both water and ethanol, and because the material is removed from solution, intake modeling is not considered necessary. In addition, high performance liquid chromatography of wine processed with chitosan indicated that the final product was free from chitosan carry-over products at the limit of detection. In addition, KitoZyme notes that neither chitosan nor beta-1,3-D-glucans are digested by the human gastrointestinal tract, therefore, absorption and systemic exposure to chitosan would not occur.
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 KitoZyme's notice that chitosan is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing chitosan. Accordingly, this response should not be construed to be a statement that foods that contain chitosan if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by KitoZyme, as well as other information available to FDA, the agency has no questions at this time regarding KitoZyme's conclusion that chitosan from A. niger 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 chitosan. As always, it is the continuing responsibility of KitoZyme 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 000397, 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 http://www.fda.gov/grasnoticeinventory.
Dennis M. Keefe, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
 21 CFR 173: A secondary direct food additive has a technical effect in food during processing but not in the finished food (e.g., processing aid). The technical use of chitosan in GRN 000397 is for microbiological stabilization, removal of contaminants, and/or clarification of the alcoholic beverage.