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Re: GRAS Notice No. GRN 000352 Dear Dr. Cho: The Food and Drug Administration (FDA) is responding to the notice, dated August 12, 2010, that you submitted on behalf of CJ Cheiljedang, Inc. (Cheiljedang) 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 16, 2010, filed it on August 20, 2010, and designated it as GRAS Notice No. GRN 000352. The subject of the notice is D-tagatose. The notice informs FDA of the view of Cheiljedang that D-tagatose is GRAS, through scientific procedures, for use as a sweetener, texturizer, humectant, and stabilizer in a variety of food categories, as described in Table 1 (below).
As part of its notice, Cheiljedang includes the report of a panel of individuals (Cheiljedang’s GRAS panel) who evaluated the data and information that are the basis for Cheiljedang’s GRAS determination. Cheiljedang considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Cheiljedang’s GRAS panel discusses estimates of dietary exposure, intended uses, and current regulatory status of D-tagatose. According to Cheiljedang’s GRAS panel, D-tagatose is GRAS under the conditions of its intended use. Cheiljedang provides information about the chemical identity and specifications for D-tagatose. D-tagatose, which is also known as tagatose or pseudo-fructose, is an epimer of the common six carbon sugar D-fructose. Its Chemical Abstract Service Registry No. is 87-81-0 and the empirical formula is C6H12O6. Cheiljedang provides specifications for D-tagatose including D-tagatose (>98.0%), D-galactose and other sugars (≤1.5%), microbial limits, and limits on heavy metals (mercury, cadmium, lead, and arsenic). Cheiljedang notes that D-tagatose is a white to off-white crystalline powder and has a sweet taste. Cheiljedang states that D-tagatose is manufactured from lactose through a two-step process where lactose is hydrolyzed to D-galactose and then enzymatically isomerized to D-tagatose. Lactose is first dissolved in water, and is chemically hydrolyzed into D-glucose and D-galactose. After an hour, calcium carbonate is added to remove the precipitants. The remaining syrup is mixed with manganese chloride and subjected to an immobilized L-arabinose isomerase preparation. The enzyme preparation converts D-galactose to D-tagatose. The D-tagatose solution is decolorized using active carbon, filtered, cooled, and purified through an ion exchange process. Following purification, the D-tagatose solution is concentrated, and the resulting concentrated syrup is pumped through a chromatography system to separate D-tagatose from other sugars. The purified D-tagatose solution is concentrated and pumped into a continuous crystallizer. Following crystallization, D-tagatose is washed with water, then dried. Cheiljedang states that all processing aids used in the manufacture of D-tagatose are food grade and are considered safe and suitable. Cheiljedang calculated a mean estimated daily intake (EDI) of 16.2 grams per person per day (g/p/d). Cheiljedang notes that this estimate assumes tagatose would be used in 100% of the foods in each category at the maximum use level. Cheiljedang noted that this assessment is likely to greatly overestimate actual consumption based on market utilization of D-tagatose, which would be expected to be far lower. As an example of this overestimate, Cheiljedang cited a published exposure estimate for all sugar alcohols of 3.43 g/p/d. Cheiljedang notes that it expects actual consumption of D-tagatose to be below any single sugar alcohol. In its notice, Cheiljedang summarizes published and unpublished in vivo and in vitro studies supporting the safe use of D-tagatose in foods. Cheiljedang also discusses a previous GRAS notice for D-tagatose (GRN 000078) as well international regulatory approvals, including the Joint FAO/WHO Expert Committee on Food Additives (JECFA) conclusion regarding the safe use of D-tagatose in foods. Cheiljedang notes that in 2004, JECFA listed D-tagatose as having an acceptable daily intake (ADI) of “not specified.” JECFA assigns an ADI of “not specified” in situations where they conclude that the total dietary intake, including intake from the intended uses of the substance, does not pose a hazard to human health. Cheiljedang summarizes published metabolism data on D-tagatose and describes its typical metabolism. Cheiljedang notes that animal models suggest that the intestinal absorption of D-tagatose is between 20 and 30 percent. Cheiljedang further noted that the majority of unabsorbed D-tagatose is metabolized by microorganisms in the gut. Cheiljedang noted that absorbed tagatose is metabolized to innocuous substances, predominantly in the liver though pathways common to other sugars. Cheiljedang summarizes short- and long-term toxicity studies as well as teratogenicity and genotoxicity studies. Cheiljedang noted that results from these studies were unremarkable with the exception of a dose-dependant increase in liver weights that was observed in rat toxicity studies. Cheiljedang notes that increases in liver weight associated with increased glycogen accumulation are also seen with fructose at similar levels of intake in rats. Cheiljedang further stated that these finding are not toxicologically significant as no histopathological evidence of hepatotoxicity was observed in these animals. Cheiljedang noted no other treatment-related effects. Cheiljedang describes a published clinical study in which adult males were given 45 grams of D-tagatose per day. Liver volume and glycogen levels were not affected by D-tagatose compared to a sucrose control group. D-tagatose was generally well-tolerated and had no significant effects on hematological and blood chemistry parameters. Mild-to-moderate laxation was reported by some subjects receiving D-tagatose in this study. Standards of Identity In the notice, Cheiljedang states its intention to use D-tagatose 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 Cheiljedang’s notice that D-tagatose is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing D-tagatose. Accordingly, this response should not be construed to be a statement that foods that contain D-tagatose, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll). Conclusions Based on the information provided by Cheiljedang, as well as other information available to FDA, the agency has no questions at this time regarding Cheiljedang’s conclusion that D-tagatose 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-tagatose. As always, it is the continuing responsibility of Cheiljedang 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 000352, 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./grasnoticeinventory. Sincerely, |
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