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CFSAN/Office of Food Additive Safety
July 21, 2014
Sanni Raju, Ph.D., R.Ph.
2-D Janine Place
New Brunswick, NJ 08901
Re: GRAS Notice No. GRN 000483
Dear Dr. Raju:
This letter corrects our letter in response to GRAS Notice No. GRN 000483 dated April 17, 2014. The purpose of this revised letter is to correct the name that appears in the headers on pages 2 and 3, as well as to include text that was inadvertently omitted.
The Food and Drug Administration (FDA) is responding to the notice, dated July 8, 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 August 30, 2013, filed it on September 18, 2013, and designated it as GRAS Notice No. GRN 000483.
The subject of the notice is aqueous extract of Emblica officinalis Gaertn (E. officinalis extract). The notice informs FDA of the view of Natreon, Inc. (Natreon) that E. officinalis extract is GRAS, through scientific procedures, for use as an ingredient in non-alcoholic beverages, processed fruits and fruit juices, and cereals at levels up to 150 milligrams per serving (mg/serving).
As part of its notice, Natreon includes the report of a panel of individuals (Natreon’s GRAS panel) that evaluated the data and information that are the basis for Natreon’s GRAS determination. Natreon considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Natreon’s GRAS panel evaluated information describing the identity and composition, method of manufacture, product specifications, intended uses, estimates of dietary exposure, as well as published and unpublished studies supporting the safety of E. officinalis extract. Based on this review, Natreon’s GRAS panel concluded that E. officinalis extract produced consistently and in accordance with current good manufacturing practices (cGMP) is GRAS under the intended conditions of use.
Natreon describes the identity and composition of E. officinalis extract. Natreon describes the ingredient as a yellow, free-flowing, spray-dried powder of the juice of the edible fruit of E. officinalis (formerly Phyllanthus emblica; also known as amla, Indian gooseberry, emblic, and myrobalan) with a characteristic odor and astringent flavor. The primary components of the ingredient are low to medium molecular weight hydrolysable tannins, such as Emblicanin A, Emblicanin B, Punigluconin, and Pedunculagin. A typical 100 grams (g) of E. officinalis extract contains 88 g carbohydrate, 0.3 g total fat,
0.2 g saturated fat, 0.05 g monounsaturated fat, 2 g protein, 5 g amino acids, 9 g total dietary fiber, < 6 g water, and < 6 g ash.
Natreon describes the manufacture of E. officinalis extract from E. officinalis fruits, the source material. Harvested fruits are processed to a fine pulp and extracted with aqueous solutions containing 0.1 to 5% various salts. The extraction is performed at 70±5q C to destroy endogenous hydrolytic enzymes. The extracted mass is filtered and refrigerated for up to three days, followed by spray drying or vacuum drying to an amorphous powder with 1.5% silicon dioxide used as an anti-adherent. Natreon states that E. officinalis extract is manufactured according to cGMP, and all reagents used in the manufacturing process are safe and suitable.
Natreon provides specifications for E. officinalis extract. These specifications include identity (Â•60% w/w low molecular weight hydrolysable tannins), gallic acid (Â”4%), sulfated ash, and water. Natreon provides
limits for microbial contaminants and heavy metals including lead (< 3 mg per kilogram (mg/kg)) and arsenic (< 1 mg/kg). Natreon provides data from five batch lots to demonstrate consistency with these specifications.
Natreon states that E. officinalis extract is stable at room temperature for up to 48 months and at 45q C for up to three months.
Natreon calculates dietary exposure to E. officinalis extract based on the United States Department of Agriculture Continuing Survey of Food Intake by Individuals (USDA CSFII) 1994-96 surveys for quantities of food consumed daily and mean portion size. Natreon estimates mean and 90th percentile intakes of 445 mg/person/day (mg/p/d) and 868 mg/p/d, which corresponds to 7.7 mg/kg body weight/d (mg/kg bw/d) and 14.5 mg/kg bw/d, respectively.
Natreon describes published and unpublished studies on the safety of E. officinalis extract in animals and humans. These include a published chronic oral toxicity study and six unpublished studies conducted in humans. Natreon also cites a published in vitro mutagenicity study and discusses the results of a literature search assessing the potential allergenicity of E. officinalis fruit.
Natreon discusses a published chronic oral toxicity study conducted in SD rats administered standardized water extract of E. officinalis fruits (standardized to 20% gallic acid). Natreon notes that hematological analysis and clinical blood chemistry revealed slight changes, but these were within the normal limits and no adverse gross or histopathological findings were observed in the treatment groups. Natreon states that the study authors considered the no-observed-adverse-effect level of the extract to be 1,200 mg/kg bw/d, the highest dose tested. Natreon concludes that these findings are applicable to the present GRAS determination for the use of E. officinalis extract as both products are water extracts of E. officinalis fruit.
Natreon discusses six unpublished, randomized, double-blind, placebo-controlled studies conducted in human subjects. In these studies, subjects with type-2 diabetes or pre-metabolic syndrome, long term smokers, and healthy volunteers were administered E. officinalis extract at dose levels up to 1000 mg/p/d for 12 weeks. Natreon states that the authors of these studies did not report any adverse effects and concluded that the E. officinalis extract was well-tolerated. Natreon also cites the results of several other published efficacy studies conducted in humans demonstrating that consumption of E. officinalis preparations at levels up to 1000 mg/p/d for six months did not result in any adverse effects.
Natreon reports that the Ames test demonstrated that E. officinalis extract is not mutagenic. Natreon states that no reports of allergenicity of the E. officinalis fruit were found in the literature.
Standards of Identity
In the notice, Natreon states its intention to use E. officinalis extract 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 intended use of E. officinalis extract and in describing the information that Natreon relies on to conclude that E. officinalis extract is GRAS under the conditions of its intended use, Natreon raises a potential issue under the labeling provisions of the Federal Food Drug and Cosmetic (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 E. officinalis extract 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 E. officinalis extract 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 Natreon’s notice that E. officinalis extract is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing E. officinalis extract. Accordingly, this response should not be construed to be a statement that foods that contain E. officinalis extract, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Natreon, as well as other information available to FDA, the agency has no questions at this time regarding Natreon’s conclusion that E. officinalis extract 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 E. officinalis extract. As always, it is the continuing responsibility of Natreon 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 000483, 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