Agency Response Letter GRAS Notice No. GRN 000400
CFSAN/Office of Food Additive Safety
June 18, 2012
Susan Cho, Ph.D.
6309 Morning Dew Court
Clarksville, MD 21029
Re: GRAS Notice No. GRN 000400
Dear Dr. Cho:
The Food and Drug Administration (FDA) is responding to the notice, dated August 18, 2011, 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 24, 2011, filed it on August 25, 2011, and designated it as GRAS Notice No. GRN 000400.
The subject of the notice is D-psicose. The notice informs FDA of the view of Cheiljedang that D-psicose is GRAS, through scientific procedures, for use as a sugar substitute in a variety of food categories, as described in Table 1 (below).
|Food Category||Intended Level of Use |
|Rolls, cakes, pies, pastries, and cookies, dietetic or low calorie||10|
|Fat-based cream used in modified fat/calorie cookies, cakes, and pastries||10|
|Hard candies, low calorie (including pressed candy, mints)||70|
|Frozen dairy desserts (regular ice cream, soft serve, sorbet), low calorie||5|
|Carbonated beverages, low calorie||2.1|
|Non-carbonated beverages, reduced and low calorie||2.1|
|Soft candies, low-calorie (non-chocolate, plain chocolate, chocolate coated)||25|
|Sugar substitutes (carrier)||100|
|Yogurt (regular and frozen), low calorie||5|
|Ready-to-eat cereals (< 5% sugar)||10|
As part of its notice, Cheiljedang includes a statement from 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 Cheiljedang’s GRAS panel discusses estimates of dietary exposure, intended uses, and published and unpublished toxicological safety studies in animals and humans. Based on this review, and the totality of scientific evidence, Cheiljedang’s GRAS panel concluded that D-psicose is GRAS under the conditions of its intended use.
Cheiljedang provides information about the chemical identity and specifications for D-psicose. D-psicose is a C-3 epimer of D-fructose. Its CAS Registry No. is 551-68-8. Cheiljedang provides specifications for D-psicose including D-psicose (> 98.5%), D-fructose and other sugars (≤ 1%), and limits on microbial contaminants, lead, arsenic, and heavy metals. Cheiljedang notes that D-psicose is a white or off-white crystalline powder.
Cheiljedang states that D-psicose is manufactured from fructose by enzymatic epimerization. The starting material is a fructose solution to which manganese chloride has been added. This solution is exposed to an immobilized psicose 3-epimerase (originally derived from Agrobacterium tumefaciens) system that converts fructose to D-psicose. The D-psicose solution is decolorized using activated carbon and then further purified through an ion exchange process. Following purification, the D-psicose solution is concentrated, and the resulting syrup is chromatographed to separate D-psicose from other sugars. The purified D-psicose solution is further concentrated and then crystallized. The crystalline D-psicose is washed with distilled water and then dried.
Cheiljedang provides estimated daily intakes for D-psicose assuming that the ingredient will be used either (1) at the maximum levels in all foods in a particular food category or (2) at the maximum levels in 10% of the foods in a particular food category. This estimate was conducted using data from the National Center for Health Statistics’ National Health and Nutrition Examination Surveys 2005-2008. For the use in all foods in each food category, Cheiljedang estimates the mean intake for all users of D-psicose is 12.6 grams per person per day (g/p/d) and 28.5 g/p/d at the 90th percentile. On a body weight basis, these estimates are equivalent to 167.7 and 358.4 milligrams per kilogram of body weight per day (mg/kg bw/d) respectively. For use in 10% of the foods in a category, Cheiljedang estimates the mean intake for all users of D-psicose to be 1.3 g/p/d and 2.9 g/p/d at the 90th percentile, or 4.3 and 15.4 mg/kg bw/d respectively. The notifier argued that it was more realistic, but still quite conservative, to assume that D-psicose would be used at the maximum levels in 10% of the intended foods.
In its notice, Cheiljedang summarizes published safety data on D-psicose including metabolism, acute, subchronic, and chronic oral toxicity studies, and in vitro genotoxicity studies as well as human clinical studies. Cheiljedang states that these studies support the safety of the intended uses of D-psicose in food.
Cheiljedang summarizes published metabolism data on D-psicose. Cheiljedang cites studies in rats indicating that, when orally administered as a bolus dose of 5 g/kg bw, D-psicose is partially absorbed in the digestive tract and rapidly excreted unchanged in the urine (11-15% of orally ingested D-psicose) within the first 24 hours. Serum D-psicose concentration and contents of D-psicose in the stomach (26-37%) and small intestine (6-10%) decreased progressively with time. The unfermented D-psicose excreted in the feces was 8-13% of the ingested dose. D-psicose was detected in the caecum (11-18%) after 3 and 7 hours. In a separate study where rats were fed diets containing D-psicose at concentrations up to 30%, D-psicose was fermented to short chain fatty acids by the intestinal microflora in the caecum. In this study, the authors report that the average intake of D-psicose was up to 2.3 g/d.
Cheiljedang discusses the results of a published chronic toxicity study conducted in male Wistar rats fed diets containing 3% (1.28 g/kg bw/d) D-psicose or sucrose for 12-18 months. Body weight gain and intra-abdominal adipose tissue weight in rats fed the D-psicose diet for 18 months were significantly lower than those in rats fed the sucrose diet. The relative weights of liver and kidney were significantly higher (about 25%) in the D-psicose group than in the sucrose group. No significant changes in the hematological and serum chemistry tests were observed between the treated and the control groups, indicating no changes in liver or kidney function. Further, no gross pathological findings were evident at dietary doses of 3% D-psicose or correlated with hypertrophy of liver and kidney. Cheiljedang notes that increased liver weight was also observed in rats fed other types of sugars such as fructose and sucrose at similar levels of intake and may be associated with increased glycogen accumulation and therefore not considered to be of toxicological concern. The authors concluded that no adverse effects were seen in rats fed 3% D-psicose in the diet. Cheiljedang provides additional information, including published studies with similar effects using other carbohydrates (erythritol and fructose), where increased kidney weight was observed. Cheiljedang suggests that the increase in kidney weight may be due to the increased workload associated with the increased urinary excretion similar to that observed in chronic toxicity studies (104-107 weeks) where rats were fed diets containing up to 10% erythritol, with an average intake of 4.6 and 5.4 g/kg bw/d in male and female rats respectively, in the 10% erythritol group.
Cheiljedang describes published human clinical studies investigating the effects of D-psicose on postprandial blood glucose, insulin concentrations, glycemic responses, and states that no adverse effects were observed. Cheiljedang states that gastrointestinal disturbances ranging from diarrhea, borborygmi, lower abdominal pain, nausea, and distention were reported at doses above 0.5 g/kg bw/d. These effects are also seen with other poorly digested carbohydrates. The authors of the clinical study concluded that the maximum tolerable levels in humans were 0.5 g/kg bw/d in men and 0.6 g/kg bw/d in women, which corresponds to 33.3 g/d in men and 31.0 g/d in women, calculated based on the mean body weights.
Standards of Identity
In the notice, Cheiljedang 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, Cheiljedang 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 (CFSAN). The Office of Food Additive Safety neither consulted with ONLDS on this labeling issue nor evaluated the information in Cheiljedang’s notice to determine whether it would support any claims made about D-psicose on the label or in labeling.
In its notice, Cheiljedang informs FDA that one intended use of D-psicose is 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 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 Cheiljedang’s notice that D-psicose is GRAS for use in medical foods does not address the question of whether any particular food product that contains D-psicose 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 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 Cheiljedang’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 Cheiljedang, as well as other information available to FDA, the agency has no questions at this time regarding Cheiljedang’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 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 000400, 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