Agency Response Letter GRAS Notice No. GRN 000484
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CFSAN/Office of Food Additive Safety
May 8, 2014
Business Manager, North America
1620 Pinetree Drive
Pittsburg, PA 15241
Re: GRAS Notice No. GRN 000484
Dear Mr. Moore:
The Food and Drug Administration (FDA) is responding to the notice, dated August 28, 2013, 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 September 4, 2013, filed it on September 19, 2013, and designated it as GRAS Notice No. GRN 000484.
The subject of the notice is galacto-oligosaccharides (GOS). The notice informs FDA of the view of Clasado, Inc. (Clasado) that GOS is GRAS, through scientific procedures, for use as an ingredient in baked goods and baking mixes, beverages and beverage bases, breakfast cereals, coffee and tea, dairy product analogs, frozen dairy desserts and mixes, grain products and pastas, milk and milk products, processed fruits and fruit juices, processed vegetables and vegetable juices, snacks, and sweet sauces at levels ranging from 0.8 to 3.0 grams per serving (g/serving).
As part of its notice, Clasado includes the statement of a panel of individuals (Clasado’s GRAS panel) that evaluated the data and information that are the basis for Clasado’s GRAS determination. Clasado considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Clasado’s GRAS panel evaluated information describing the identity and composition, manufacturing process and specifications, and estimated dietary exposure, as well as published studies supporting the safety of GOS. Based on this review, Clasado’s GRAS panel concluded that GOS is GRAS under the conditions of its intended use.
Clasado describes the identity and composition of GOS. Clasado describes GOS as a mixture of galactooligosaccharides produced from lactose. The galacto-oligosaccharides are between 2 and 8 saccharide units in length, with one saccharide unit being a terminal glucose and the remaining saccharide units being galactose. Clasado states that GOS contains α-(1,6)-galactobiose, glucose, galactose, and residual lactose.
Clasado describes the manufacturing process for GOS, which starts by dissolving lactose in water. The solution is heat-sterilized and cooled and a beta-galactosidase enzyme preparation(1) is added to facilitate the synthesis of the galacto-oligosaccharides from lactose. After the synthesis reaction is completed, the solution is cooled, diluted, and filtered to remove the enzyme preparation and residual milk proteins and peptides. The GOS mixture is heat-sterilized, cooled, and evaporated to a concentration in excess of 70% total solids prior to cooling, filtering, and packaging. GOS is manufactured as a syrup and as a spray-dried powder (produced from the syrup). During production of the powder, the syrup is filtered to partially remove monosaccharides before spray-drying with maltodextrin. Clasado notes that calcium phosphate may be added as a free flowing agent.
Clasado provides specifications for GOS. These include minimum levels of dry matter (DM) (≥ 70% in the syrup and ≥ 95% in the powder) and total galacto-oligosaccharides (46 to 60% DM in the syrup and 55 to 80% DM in the powder). The specifications also include limits for moisture (≤ 30% in the syrup and ≤ 5% in the powder), protein (< 0.3% in the syrup and 1 to 1.5% in the powder), lactose (< 19% DM in the syrup and < 25% DM in the powder), total monosaccharides (> 35% DM in the syrup and < 15.3% DM in the powder), and heavy metal specifications for both the syrup and the powder including lead (< 0.1 milligram per kilogram (mg/kg)), cadmium (< 0.1 mg/kg), and mercury (< 0.1 mg/kg). Clasado also provides limits for microbial contaminants for both the syrup and powder. Clasado provides the results of non-consecutive batch analyses to demonstrate that GOS meets specifications. In addition, Clasado states that GOS is stable under ambient and accelerated storage conditions for at least 6 months.
Clasado intends that GOS will be substitutional for other GOS preparations currently used in foods and adds uses in coffee and tea. Clasado discusses the current dietary exposure to GOS from intended uses described in previous GRAS notices for a wide variety of foods and beverages (e.g. GRNs 000236, 000285, and 000334). The highest estimated 90th percentile exposure to GOS from these intended uses is 33 g per person per day (g/p/d) for male teenagers and 25.3 g/p/d for the total population. For infants and children, 90th percentile exposures were estimated to be up to 26.8 and 30.4 g/p/d, respectively. Based on data from the National Health and Nutrition Examination Survey (NHANES, 2007–2010), Clasado estimates the daily exposure to GOS from the intended uses in coffee and tea as 5.0 g/p/d for adult males and 4.4 g/p/d for the total population (users only). Clasado concludes that exposure to GOS from the intended use in coffee and tea will be substitutional for other GOS containing foods, and that the cumulative exposure to multiple GOS containing products at the highest use levels on a chronic basis is unlikely to occur.
Clasado discusses the safety of GOS as an ingredient in food by discussing the chemical nature of GOS and its occurrence in food, the metabolism of GOS, as well as subchronic studies, developmental and reproductive studies, and human tolerance studies conducted with GOS.
Clasado discusses that GOS is produced from lactose, a common sugar that occurs naturally in food. GOS is currently also used in various types of food, including infant formula.
Clasado states that it is well-known that GOS is resistant to hydrolysis by human digestive enzymes, is not fully digested in the gut, nor is it absorbed intact. The ingested GOS undergoes fermentation in the gut by colonic microflora, as would be expected of other oligosaccharides.
Clasado summarizes two published 90-day studies in rats to demonstrate the safety of GOS. In both studies, GOS was administered via gavage. Clasado states that the highest doses used in these studies were identified as the no observed adverse effect levels (NOAELs) by the authors of each study. In one study using Sprague-Dawley Crl:CD IGS BR rats, the NOAEL was determined to be 2250 mg GOS/kg body weight (bw)/d. In the other study using Sprague-Dawley Crj:CD IGS rats, the NOAEL was determined to be 2000 mg GOS/kg bw/d. Clasado notes that no treatment-related adverse effects were observed in either study. Clasado also notes that the only treatment-related effect in these studies was increased absolute and relative cecum weights in the highest-dose GOS treatment groups compared to their respective controls. Clasado states that the increase in cecum weights was not associated with any histopathological findings. Clasado also states that the increase in cecum weights in rats is considered to be a physiological response to the fermentation of the ingested indigestible carbohydrates, an effect that is of no toxicological relevance.
Clasado discusses a published study that demonstrates that GOS does not cause developmental or reproductive toxicity. BALB/cj mice were fed a GOS-inulin-enriched diet (approximately 1620 mg GOS/kg bw/d and 400 mg inulin/kg bw/d) throughout pregnancy, lactation, and until weaning. The GOS-inulin treatment had no adverse effects on pregnancy, pregnant mice, or pups.
Clasado discusses published tolerance studies in human adults and infants which demonstrate that consumption of GOS is well-tolerated. The adverse effects frequently reported with the consumption of high amounts of GOS are flatulence and transient diarrhea. Citing a published review, Clasado states that the amount of GOS that does not induce diarrhea has been estimated to be 0.3 to 0.4 g/kg bw, or about 20 g/p. Clasado also cites published studies in infants and states that large daily intakes of GOS (7.2 g/d) are well-tolerated.
Based on all available data, Clasado concludes that GOS is GRAS under the intended conditions of use.
Standards of Identity
In the notice, Clasado states its intention to use GOS 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 the fiber content of GOS and the data from the published human studies that Clasado relies on to conclude that GOS is GRAS under the intended conditions of use, Clasado 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 GOS 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 (OFAS) 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 GOS on the label or in labeling.
The Food Allergen Labeling and Consumer Protection Act of 2004 (FALCPA) amends the FD&C Act to require that the label of a food that is or contains an ingredient that bears or contains a “major food allergen” declare the presence of the allergen (section 403(w)). FALCPA defines a “major food allergen” as one of eight foods or food groups (i.e., milk, eggs, fish, Crustacean shellfish, tree nuts, peanuts, wheat, and soybeans) or a food ingredient that contains protein derived from one of those foods. GOS derived from milk may require labeling under FALCPA because it may contain protein derived from milk. Although issues associated with labeling food are the responsibility of ONLDS, issues associated with FALCPA exemptions are the responsibility of the Food Allergen Coordinator in OFAS.
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 Clasado’s notice that GOS is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing GOS. Accordingly, this response should not be construed to be a statement that foods that contain GOS, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Clasado, as well as other information available to FDA, the agency has no questions at this time regarding Clasado’s conclusion that GOS 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 GOS. As always, it is the continuing responsibility of Clasado 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 000484, 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) The beta-galactosidase enzyme preparation is the subject of GRN 000485; GRN 000484 and GRN 000485 were reviewed concurrently.