Agency Response Letter GRAS Notice No. GRN 000475
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CFSAN/Office of Food Additive Safety
May 8, 2014
John Endres, N.D.
AIBMR Life Sciences, Inc.
4117 South Meridian
Puyallup, WA 98373
Re: GRAS Notice No. GRN 000475
Dear Dr. Endres:
The Food and Drug Administration (FDA) is responding to the notice, dated May 30, 2013, that you submitted on behalf of BIOSECUR Lab, Inc. (BIOSECUR) 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 June 4, 2013, filed it on June 17, 2013, and designated it as GRAS Notice No. GRN 000475. An amendment dated September 5, 2013, provided clarifications on the estimates of daily exposure. Additional amendments dated April 3, 2014 and April 14, 2014, provided clarifications on the intended use as well as data on antimicrobial effects.
The subject of the notice is a citrus fruit extract derived from three species of citrus fruits, Citrus aurantium amara (bitter orange or marmalade orange), Citrus reticulata (mandarin orange), and Citrus sinensis (sweet or naval orange) (citrus fruit extract). The notice informs FDA of the view of BIOSECUR that citrus fruit extract is GRAS, through scientific procedures, for use as an antimicrobial and preservative in all nonstandardized food categories, excluding uses in infant formula and in food products regulated by the United States Department of Agriculture (USDA), at levels up to 1500 milligrams (mg) per kilogram (kg) of food.1
Our use of “citrus fruit extract” in this letter should not be considered an endorsement or recommendation of that term as an appropriate common or usual name for the purpose of declaring the substance in the ingredient statement of foods that contain that ingredient. Title 21 CFR 101.4 states that each ingredient must be declared by its common or usual name. In addition, 21 CFR 102.5 outlines general principles to use when establishing common or usual names for nonstandardized foods. Issues associated with labeling and the appropriate common or usual name of a food are the responsibility of the Office of Nutrition, Labeling, and Dietary Supplements in the Center for Food Safety and Applied Nutrition.
BIOSECUR describes citrus fruit extract as a water-soluble extract of citrus fruits, C. aurantium amara, C. reticulata, and C. sinensis. The final product is a non-volatile, honey-colored, clear/transparent liquid with a density of 1.11–1.22 grams per milliliter (g/mL) and a pH range from 2.0 to 3.5. It has a light citrus odor and its taste is slightly acidic, sweet, and astringent. Citrus fruit extract contains ascorbic acid, glycerin, protein, and polyphenols.
BIOSECUR describes the method of manufacture for citrus fruit extract. The starting material is a combination of fruits of C. aurantium amara, C. reticulata, and C. sinensis, with their ratios varying based on the seasonal availability. The fruits are washed and peeled, and only the edible parts, including the mesocarp, are extracted with water and glycerin. The pH is then adjusted, followed by separation of citrus solids. The resulting extract is concentrated and centrifuged. The supernatant is submitted to quality control assessment and citric acid, lactic acid, and additional ascorbic acid may then be added. The final product is tested for compliance with specifications and then packaged.2 BIOSECUR states that all ingredients used to manufacture citrus fruit extract are food grade and GRAS for their intended uses, and that the glycerin is free of diethylene glycol.
BIOSECUR provides specifications for citrus fruit extract, which includes the level of glycerin (57 to 64%), total bioflavonoids (quercetin equivalents, 0.50 to 1.20%), total polyphenols (gallic acid equivalents, 2.7 to 5.0%), and the minimum content of ascorbic acid (≥ 4%). The specifications also include limits for arsenic (< 0.02 mg/kg), cadmium (< 0.01 mg/kg), lead (< 0.02 mg/kg), and mercury (≤ 0.01 mg/kg). BIOSECUR also provides limits for microbial contaminants, including total aerobic bacteria (< 10 colony forming units (cfu) per g), Escherichia coli (negative), Salmonellas (negative), Staphylococcus aureus (negative), and Pseudomonas aeruginosa (negative), total yeasts (< 10 cfu/g), and molds (< 10 cfu/g). BIOSECUR discusses the results of an accelerated shelf-life simulation conducted at 50 °C and 90% relative humidity and concludes that these results demonstrate that citrus fruit extract is stable for a period of up to three months.
BIOSECUR provides the results of analyses of three batches of citrus fruit extract for the presence of polyphenols, bioflavonoids, essential oils, limonoids, synephrine, and other adrenergic amines. BIOSECUR provides analytical data to demonstrate the typical levels of certain citrus polyphenols (rutin, hesperidin, quercetin, and tangeritin) and states that lignans, stilbenes, and phenolic acids may be present as part of the total polyphenol content of their citrus fruit extract. The notifier also demonstrates that citrus essential oils, bitter orange adrenergic amines, and citrus limonoids are not detectable.
BIOSECUR estimates the dietary exposure to citrus fruit extract using published food consumption data with maximum intended use levels. Using EPA’s 2011 Exposure Factors Handbook data on total food intake from major food groups (edible and uncooked), BIOSECUR estimates that at the mean, 1050 g of food per day (15 g/kg body weight (bw)/day (d)) treated at 1500 mg/kg with citrus fruit extract (maximum level) results in a mean dietary exposure of 1.6 g/person (p)/d (0.023 g/kg bw/d). At the 95th percentile, exposure would be approximately 3 g/p/d (0.042 g/kg bw/d). For children aged 3–6 years, dietary exposure at the 95th percentile would also be approximately 3 g/p/d (0.153 g/kg bw/d) (based on 102 g food/kg bw/d). BIOSECUR provides a second dietary exposure estimate using food consumption data from the 2012 Statistical Abstract published by the U.S. Census Bureau. Using these data, the estimated daily exposure to citrus fruit extract would be approximately 2.7 to 3.1 g/p/d (0.039 to 0.044 g/kg bw/d).
BIOSECUR suggests that citrus fruit extract is not expected to be used regularly at 1500 mg/kg, but will more typically be used at a level of 500 mg/kg. BIOSECUR concludes that a more realistic estimate of exposure would be to assume that a maximum of 25% of the diet could contain citrus fruit extract at the maximum intended use level. This would result in exposure of approximately 775 mg/p/d (11 mg/kg bw/d). Approximately 60% of citrus fruit extract is glycerin; therefore the maximum estimated daily exposure to citrus and other non-glycerin components is approximately 310 mg/p/d (4 mg/kg bw/d). In an amendment dated September 5, 2013, BIOSECUR provides estimates of daily exposure to rutin, hesperidin, and quercetin. These were 2.6 mg/p/d (0.037 mg/kg bw/d), 5.8 micrograms (μg)/p/d (8.3x10-5 mg/kg bw/d), and 2.9 mg/p/d (0.041 mg/kg bw/d), respectively. In comparison, BIOSECUR states that the background exposure to flavonols (e.g., quercetin) from the diet of the U.S. population is estimated to range from 20 to 50 mg/p/d (0.29 to 0.71 mg/kg bw/d).
BIOSECUR discusses the safety of citrus fruit extract by describing the safety of consumption of the three citrus fruit species as well as their components. BIOSECUR states that historically no safety concerns have been associated with the consumption of the fruits of C. aurantium amara, C. reticulata, and C. sinensis and as a result, safety assessments are not presented for these species. BIOSECUR notes that all three citrus species are mentioned within the standards of identity for orange juice in 21 CFR 146.135 and 21 CFR 146.146. BIOSECUR states that the bioflavonoids rutin, hesperidin, and quercetin derived from these three citrus species are not expected to raise any safety concerns in citrus fruit extract.
BIOSECUR summarizes a preliminary study demonstrating that citrus fruit extract reduces counts of pathogenic and spoilage microbes in vitro at a minimum use level of 20 mg/kg. BIOSECUR also summarizes a preliminary study demonstrating that citrus fruit extract reduces counts of pathogenic microbes in mixed salad at a minimum use level of 100 mg/kg.
BIOSECUR discusses the safety of quercetin and the glycoside rutin and incorporates this information by reference to GRN 000341. BIOSECUR states that hesperidin is a glycoside of the flavanone hesperetin, and is present in citrus fruits and their juices. A peeled orange weighing 140 g contains up to 66 mg hesperetin. BIOSECUR estimates that the highest exposure to hesperidin from the citrus fruit extract is in microgram amounts and will not raise any safety concerns. BIOSECUR notes that the combined estimated maximum exposure (5.5 mg) of quercetin, rutin, and hesperidin falls far below the level of 500 mg per serving that has been determined as GRAS for quercetin uses as stated in GRN 000341. BIOSECUR states that citrus fruit extract is not expected to lead to adverse drug interactions at the intended use level. BIOSECUR concludes that the GRAS status of natural extractives of C. aurantium, C. reticulata, and C. sinensis, precludes the need for further safety analysis of naturally occurring compounds contained in these extractives in the context of the low level of the conservative maximum estimated exposure.
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 BIOSECUR’s notice that citrus fruit extract is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing citrus fruit extract. Accordingly, this response should not be construed to be a statement that foods that contain citrus fruit extract, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by BIOSECUR, as well as other information available to FDA, the agency has no questions at this time regarding BIOSECUR’s conclusion that citrus fruit 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 citrus fruit extract. As always, it is the continuing responsibility of BIOSECUR 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 000475, 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
1FDA did not assess citrus fruit extract’s use in combination with other antimicrobial/preservative products.
2 Biosecur states that the final product is standardized based on total polyphenol specifications