Agency Response Letter GRAS Notice No. GRN 000498
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CFSAN/Office of Food Additive Safety
June 6, 2014
Morgan, Lewis & Bockius, LLP
1111 Pennsylvania Avenue, NW
Washington, DC 20004
Re: GRAS Notice No. GRN 000498
Dear Mr. Yingling:
The Food and Drug Administration (FDA) is responding to the notice, dated December 20, 2013, that you submitted on behalf of Matsutani Chemical Industry Company (Matsutani), 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 23, 2013, filed it on January 13, 2014, and designated it as GRAS Notice No. GRN 000498.
The subject of the notice is D-psicose. The notice informs FDA of the view of Matsutani that D-psicose is GRAS, through scientific procedures, for use as a sugar substitute in food applications at use levels ranging from 2% to 100%.
Matsutani describes the identity of D-psicose (also called psicose, D-allulose, or allulose). D-psicose (D-ribo-2-hexulose) is a monosaccharide with a molecular weight of 180.16 and a molecular formula of C6H12O6. The CAS Registry No. is 551-68-8 or 23140-52-5. D-psicose is a C-3 epimer of D-fructose.
Matsutani describes the manufacturing process for three products of D-psicose. D-psicose is manufactured from fructose in aqueous solution by enzymatic epimerization in the presence of magnesium chloride or manganese chloride. The enzyme used is an immobilized D-psicose-3-epimerase, which converts fructose to D-psicose.1 The D-psicose solution is decolorized using activated carbon or ion exchange chromatography. The (c)oncentration of the solution by evaporation results in product 1 in liquid form with a minimum D-psicose content of 1%. Further chromatography and concentration results in product 2, also in liquid form, with a minimum D-psicose content of 10%. Crystallization and drying of product 2 yields product 3 in powder form with a minimum D-psicose content of 10%. Matsutani explains that the three products contain only D-psicose, residual fructose, and water, and that the amounts of these components in a given product can vary according to the requirements of food manufacturers.
Matsutani provides specifications for all three D-psicose products. These include specifications for D-psicose content (minimum 1 or 10%), and limits for lead (<1 milligram per kilogram (mg/kg)) and microbiological contaminants. Matsutani also provides the results of analyses of three batches of each of the products to demonstrate compliance with the specifications, including that the lead level is below the detection limit of 0.1 mg/kg.
Matsutani estimates the dietary exposure levels to D-psicose in all the intended food categories for the U.S. population 2 years of age and older. The calculated exposures at the 90th percentile are 22.5 grams per person per day (g/p/d) (0.31 g per kg body weight per d (g/kg bw/d)) for all persons and 24.8 g/p/d (0.33 g/kg bw/d) for users only. The uses of D-psicose described in GRN 000498 are substitutional for those described in GRN 000400 and no increase in exposure would be expected.
Matsutani states that D-psicose is found in many foods at low levels and that these foods are widely consumed with no known adverse effects attributed to D-psicose. Matsutani also states that orally administered D-psicose is partly excreted unchanged into feces and urine, and partly fermented in the cecum by intestinal microflora. Matsutani incorporates by reference the safety studies described in GRN 000400 and discusses a 90-day study published since the submission of GRN 000400. In the 90-day study, there were no toxicologically relevant effects in clinical pathology parameters in male Wistar rats fed 3% D-psicose in the diet, except for a small increase in liver and kidney weights compared to the sucrose controls. There were no hematological or pathological findings associated with these increased tissue weights. Additionally, serum aspartate aminotransferase, a marker of hepatic damage, was not statistically different between D-psicose and sucrose control groups. Matsutani concludes that 3% D-psicose in the diet did not cause any adverse effects in rats. Matsutani also reports the summary conclusion of human tolerance studies that daily D-psicose intakes of up to 31-33 g are well tolerated.
In summary, Matsutani concludes that D-psicose is GRAS for the intended uses.
Standards of Identity
In the notice, Matsutani states its intention to use D-psicose 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.
Potential Labeling Issues
In describing potential biological effects of dietary D-psicose, Matsutani raises a potential issue under the labeling provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act). Under section 403(a) of the FD&C Act, a food is misbranded if its labeling is false or misleading in any particular. Section 403(r) of the FD&C Act lays out the statutory framework for the use of labeling claims that characterize the level of a nutrient in a food or that characterize the relationship of a nutrient to a disease or health-related condition. If products that contain D-psicose bear any claims on the label or in labeling, such claims are the purview of the Office of Nutrition, Labeling, and Dietary Supplements (ONLDS) in the Center for Food Safety and Applied Nutrition. The Office of Food Additive Safety neither consulted with ONLDS on this labeling issue nor evaluated the information in your notice to determine whether it would support any claims made about D-psicose on the label or in labeling.
Section 301(ll) of the 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 Matsutani’s notice that D-psicose is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing D-psicose. Accordingly, this response should not be construed to be a statement that foods that contain D-psicose, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Matsutani, as well as other information available to FDA, the agency has no questions at this time regarding Matsutani’s conclusion that D-psicose 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 D-psicose. As always, it is the continuing responsibility of Matsutani 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 000498, 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)Matsutani states that the D-psicose-3-epimerase enzyme is produced by either Escherichia coli strain K-12 or strains of Arthrobacter globiformis or Streptomyces violaceoruber, and provides information supporting the safety of each of these production microbes.