Food

Agency Response Letter GRAS Notice no. GRN 000483

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CFSAN/Office of Food Additive Safety

April 17, 2014

Sanni Raju, Ph.D., R.Ph.
2-D Janine Place
New Brunswick, NJ  08901

Re: GRAS Notice No. GRN 000483

Dear Dr. Raju:

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) who 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method of manufacture, product specifications, intended uses, estimates of dietary exposure, as well as published and unpublished studies supporting the safety of E. officinalis extract.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 ±5° 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 (> 60% w/w low molecular weight hydrolysable tannins), gallic acid (≤ 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 45° 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.

Section 301(ll) of the Federal Food, Drug, and Cosmetic Act (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 insection 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). 

Conclusions

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.

 

Sincerely,

Dennis M. Keefe, Ph.D.
Director
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition

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