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See also Generally Recognized as Safe (GRAS).
CFSAN/Office of Food Additive Safety
June 6, 2016
Alan B. Richards, Ph.D.
Vanguard Regulatory Services, Inc.
1311 Iris Circle
Broomfield, CO 80020
Re: GRAS Notice No. GRN 000610
Dear Dr. Richards:
The Food and Drug Administration (FDA) is responding to the notice, dated November 10, 2015, that you submitted on behalf of Hayashibara Co., Ltd. (Hayashibara) in accordance with the agency’s proposed regulation, proposed 21 Code of Federal Regulations (CFR) 170.36 (62 FR 18938; April 17, 1997; Substances Generally Recognized as Safe (GRAS); the GRAS proposal). FDA received the notice on November 17, 2015, filed it on December 10, 2015, and designated it as GRAS Notice No. GRN 000610.
The subject of the notice is isomaltodextrin. The notice informs FDA of Hayashibara’s view that isomaltodextrin is GRAS, through scientific procedures, for use as an ingredient and as a dietary fiber in milk and milk products; fish and fish mixtures; legumes; meat substitutes, mainly legume protein and cereal protein products; baked products; crackers and salty snacks from grain products; pancakes, waffles, French toast, and other grain products; pastas, cooked cereals, and rice; cereals; grain mixtures, frozen plate meals, sauces, and soups; fruits and fruit products; vegetable products; salad dressings; sugars, sweets, and beverages, selected waters; and in formulated nutrition beverages, energy drinks, sports drinks, and functional beverages at a level of 3.2 to 6.3 grams (g) per serving. Hayashibara states that isomaltodextrin is not intended for use in meat and poultry products under USDA jurisdiction or for uses in foods intended for infants and toddlers.
As part of its notice, Hayashibara includes the report of a panel of individuals (Hayashibara’s GRAS panel) that evaluated the data and information that are the basis for Hayashibara’s GRAS determination. Hayashibara considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Hayashibara’s GRAS panel discusses the identity, composition, manufacturing process, product specifications, intended uses, and dietary exposure estimates for isomaltodextrin, and published and unpublished safety studies and human tolerance studies with resistant dextrin, resistant maltodextrin products, and isomaltodextrin. Based on this review, Hayashibara’s GRAS panel concluded that isomaltodextrin produced in accordance with current good manufacturing practices (cGMP) that meets its established food grade specifications is GRAS under the conditions of its intended use.
Hayashibara describes isomaltodextrin as a white powder that is enzymatically produced from food-grade starch (i.e., derived from corn, tapioca, potato, cassava). Isomaltodextrin is exclusively composed of α-D-glucose units with a degree of polymerization (DP) > 2. The molecular weight (MW) range is 500 – 10,000 Daltons (Da), with an average MW of approximately 5,000 Da. Isomaltodextrin contains 17% α-1 glucosidic linkages, 3% α-1,3 glucosidic linkages, 19% α-1,4 glucosidic linkages, 49% α-1,6 linkages, and 12% multi-branched linkages (7% α-1,3,6 and 5% α-1,4,6). While isomaltodextrin is structurally similar to resistant dextrin, resistant maltodextrin, and polydextrose, it differs from these substances in that it lacks β-linkages, similarly to pullulan, and in its relative proportions of α-1,3, α-1,4, and α-1,6 bonds.
Hayashibara describes the manufacturing process for isomaltodextrin. Food-grade starch is treated with α-amylase to cleave amylose and amylopectin chains into shorter units. The suspension is heated until liquefied, and then the enzyme is inactivated by further heat treatment. The solution is cooled, pH adjusted, and then treated with α-amylase and α-glucosyltransferase to produce isomaltodextrin. Subsequent heat inactivation of the enzymes is followed by pH adjustment, decolorization with activated carbon, and filtration. The solution is concentrated by evaporation, then decolorized, filtered, deionized, and filtered again to remove insoluble substances, salts, and proteins. The final solution is evaporated before spray drying into powder form for packaging. Hayashibara states that isomaltodextrin is produced in accordance with cGMP.
Hayashibara provides specifications for isomaltodextrin, including assay (≥ 95%), dietary fiber content (> 80%), and limits for arsenic (≤ 0.2 parts per million (ppm)), lead (≤ 0.1 ppm), and microbial contaminants. Hayashibara presents the results of six non-consecutive isomaltodextrin batch analyses to demonstrate conformance with these specifications.
Hayashibara provides dietary exposure estimates for consumers of one or more foods containing isomaltodextrin. The reported estimates were generated using two-day average dietary intake data from the 2009-2010 National Health and Nutrition Examination Survey (NHANES). The total isomaltodextrin dietary exposure estimates for the U.S. population aged 2 years or older are 16 g per person per day (g/p/d) (265 milligrams (mg)/kilograms (kg) bodyweight (bw)/d for a 60 kg individual) at the mean and 33 g/p/d (552 mg/kg bw/d for a 60 kg individual) at the 90th percentile.
Hayashibara describes isomaltodextrin as structurally similar to resistant dextrin, resistant maltodextrin, polydextrose, and pullulan and notes that these substances are listed either in FDA’s GRAS affirmation regulations or are the subject of previous GRAS notices that received “No questions” letters from FDA. Hayashibara notes that the structural differences between isomaltodextrin and these starch-based substances are related to the extent and mechanism of degradation in the human gut. There is no indication that any structural differences between these starch-based substances and isomaltodextrin would impact the safety of isomaltodextrin. Hayashibara discusses the metabolism of isomaltodextrin and states that isomaltodextrin is hydrolyzed mostly to glucose. The proportion of atypical glycosidic bonds found in isomaltodextrin renders it resistant to enzymatic hydrolysis, allowing it to pass into the large intestine and undergo either partial or complete bacterial fermentation.
Hayashibara discusses published safety data on dextrin, resistant dextrin, resistant maltodextrin, polydextrose, and pullulan in rats, mice, dogs, and humans. Hayashibara states that the safety data on these chemically and toxicologically similar substances are directly relevant to and support the safety of isomaltodextrin. These data include studies on acute, subchronic, and chronic oral toxicity, reproductive and developmental toxicity, carcinogenicity, genotoxicity, and human tolerance studies. Hayashibara summarizes unpublished acute oral toxicity, 90-day subchronic oral toxicity, and genotoxicity studies with isomaltodextrin showing its safety and confirming the supporting safety data from similar starch-based substances. Hayashibara discusses four unpublished tolerance studies in humans demonstrating that isomaltodextrin is well tolerated and has the same propensity to cause some gastrointestinal symptoms at relatively high doses as other starch-based substances. Hayashibara reports that no significant, compound-related adverse events were observed in any published or unpublished studies.
Based on the totality of the available data and information, Hayashibara concludes that isomaltodextrin is GRAS under the conditions of its intended use.
Standards of Identity
In the notice, Hayashibara states its intention to use isomaltodextrin in several food categories, including foods for which standards of identity exist, located in Title 21 of the CFR. 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 (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 Hayashibara’s notice that isomaltodextrin is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing isomaltodextrin. Accordingly, this response should not be construed to be a statement that foods that contain isomaltodextrin, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Hayashibara, as well as other information available to FDA, the agency has no questions at this time regarding Hayashibara’s conclusion that isomaltodextrin 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 isomaltodextrin. As always, it is the continuing responsibility of Hayashibara 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 000610, 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
 Hyashibara states that Paenibacillus alginolyticus, the soil bacterium used to produce the α-amylase and α-glucosyltransferase enzymes, is non-toxigenic and non-pathogenic. Both enzyme preparations conform to the specifications established in the Food Chemicals Codex (FCC, 2016). An amino acid sequence homology search against known allergens using the publicly available Food Allergy Research and Resource Program (FARRP) did not reveal any matches to known allergens. Hayashibara notes that both enzymes are manufactured using food grade raw materials in accordance with cGMP and are considered safe for use.
 FDA affirmed the use of dextrin (21 CFR 184.1277), maltodextrin (21 CFR 184.1444), and polydextrose (21 CFR 172.841). FDA evaluated GRAS notices for enzyme-modified dextrins (GRN 000436) and pullulan (GRN 000099) and responded with “No questions” letters.