Food

Agency Response Letter GRAS Notice No. GRN 000320

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CFSAN/Office of Food Additive Safety

September 3, 2010

Susan S. Cho, Ph.D.
NutraSource, Inc.
6309 Morning Dew Court
Clarksville, MD 21029

Re: GRAS Notice No. GRN 000320

Dear Dr. Cho:

The Food and Drug Administration (FDA) is responding to the notice, dated January 19, 2010, that you submitted on behalf of the Malaysian Palm Oil Board (MPOB) 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 January 21, 2010, filed it on February 1, 2010, and designated it as GRAS Notice No. GRN 000320.

The subject of the notice is palm oil-derived carotenoids with β-carotene, α-carotene, γ-carotene, and lycopene as the principle components (hereafter referred to as palm carotenoids). The notice informs FDA of the view of MPOB that palm carotenoids are GRAS, through scientific procedures, for use as an ingredient in various food categories, excluding meat and poultry products, at the use levels listed in Table 1 and in medical foods at a level of 180 milligrams (mg) β-carotene per day.

Table 1. Food categories and use levels of palm carotenoids
Food Category Maximum Use Levels
(mg total carotenoids per kilogram (kg) food)
Fats and oils, margarine 38.9
Canned green peas, canned mangoes, mayonnaise 155.8
Meatless bouillons and consommé 311.6
Pickled cucumber 467.4
Baked goods, bread, rolls, cakes 15.58
Meatless soups, soup mixes 15.58
Baking mixes, cookies, crackers, salty snacks 15.58
Grain products, such as pastas or rice dishes 15.58
Ready-to-eat cereals 15.58
Frozen dairy desserts and mixes, ice cream and mixes 15.58
Processed fruits, juices, juice drinks, punches 15.58
Meatless meat products (soy-based imitation meat) 15.58
Processed vegetables, juices 15.58
Sweet sauces, toppings, syrups 15.58
Gelatins, puddings, fillings 15.58
Meatless gravies, sauces 15.58
Egg substitute products (imitation egg products) 15.58
Soft drink-orange drink type only 15.58
Granola bars, cereal bars 15.58
Meal replacement shakes/mixes, functional beverages 15.58

As part of its notice, MPOB includes the report of a panel of individuals (MPOB’s GRAS panel) who evaluated the data and information that are the basis for MPOB’s GRAS determination. MPOB considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. MPOB’s GRAS panel evaluated estimates of dietary exposure, method of production, and product specifications as well as published pre-clinical and clinical studies. Based on this review, MPOB’s GRAS panel concluded that palm carotenoids are GRAS under the conditions of their intended use.

MPOB provides information about the identity and composition of palm carotenoids. Palm carotenoids are extracts of palm oil containing various carotenoids, predominantly β-carotene and α-carotene with lesser amounts of γ-carotene and lycopene. Palm carotenoids are manufactured in a variety of ways to produce several formulations of palm carotenoids that differ in carotenoid content, water solubility, and physical form. The total carotenoid content of the formulations ranges from 1 percent to 30 percent, with β-carotene and α-carotene constituting more than 90 percent of total carotenoids. The physical forms include palm oil suspensions, emulsions, beadlets, and a powder.

MPOB describes the method of manufacture for palm carotenoids. The starting raw material for all formulations of palm carotenoids is crude palm oil obtained from the mesocarp of the oil palm fruit (Elaeis guineensis). MPOB notes that crude palm oil contains mixed carotenoids, which give it a reddish color, as well as compounds that possess vitamin E activity (tocotrienols and tocopherols) and other minor components. In the first step of the method of manufacture, the triglycerides of the crude palm oil are converted to methyl esters and glycerol through trans-esterification, facilitating separation from the mixed carotenoids by molecular distillation. MPOB states that the mixed carotenoids are not involved in this reaction and that the ratio, chemical structure, and characteristics remain the same as in the starting crude palm oil. Next, a multi-step molecular distillation process separates the mixed carotenoids from the methyl esters as well as the tocotrienols, tocopherols, and other minor components. Additional molecular distillation of the concentrated mixed carotenoid residue is used to recover various concentrations of mixed carotenoids as palm oil suspensions. The emulsions, beadlets, and powder formulations are produced from the mixed carotenoid oil suspension in combination with safe and suitable ingredients as needed for the desired physical functionality of the particular palm carotenoid formulation.

MPOB provides specifications for the different formulations of palm carotenoids. These specifications include the ranges of the individual carotenoids, total carotenoids, palm oil, and the concentrations of the added ingredients. The notice also provides batch analysis of the different formulations in support of the specifications.

MPOB estimates the daily intake of palm carotenoids from the intended food uses of palm carotenoids using data available from the National Center for Health Statistics’ 2005-2006 National Health and Nutrition Examination Survey. In its calculations, the notifier takes into consideration (1) current dietary intake from foods naturally containing β-carotene, α-carotene, and lycopene;(1) and (2) dietary intake from foods containing palm carotenoids at the intended and the maximum use levels. The notifier estimates that, at the maximum use levels, the cumulative estimated daily intake at the 90th percentile level for users aged 1 year and above would be: 0.341 mg per kg bodyweight per day (mg/kg bw/d) for β-carotene, 0.159 mg/kg bw/d for α-carotene, 0.238 mg/kg bw/d for lycopene, and 0.731 mg/kg bw/d for total carotenoids.

MPOB discusses the safety of β-carotene, α-carotene, γ-carotene, and lycopene in general as well as palm carotenoids specifically. The notifier describes a long history of consumption of carotenoids from fruits and vegetables, including carrot, spinach, broccoli, and tomato and tomato products. The notifier discusses the bioavailability and metabolic fates of carotenoids, as well as the bioconversion of the provitamin A carotenoids (β-carotene, α-carotene, γ-carotene) to retinol. MPOB discusses published acute, subchronic, and chronic animal studies; published mutagenicity studies; and published human clinical studies related to β-carotene, α-carotene, and lycopene. In addition, MPOB discusses published animal and human studies on red palm oil and palm carotenoids in relation to γ-carotene safety. In a corroborative subchronic animal study discussed by MPOB, rats received a palm carotenoid formulation containing 25 percent total carotenoids, which provided up to 833 mg/kg bw/d β-carotene, 406 mg/kg bw/d α-carotene, 6.5 mg/kg bw/d γ-carotene, and 6.5 mg/kg bw/d lycopene. MPOB states that no toxicological effects were observed in these studies. In addition, MPOB notes that β-carotene is affirmed GRAS (21 CFR Part 184) and that lycopene has been the subject of two GRAS determinations evaluated by FDA (GRN 000119 for synthetic lycopene and GRN 000173 for lycopene from Blakeslea trispora).(2) Based on the totality of this information, MPOB considers palm carotenoids safe for their intended use as an ingredient in various food categories and in medical food.

Standards of Identity

In the notice, MPOB states its intention to use palm carotenoids 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 pro-vitamin A and antioxidant activities of palm carotenoids and in describing human clinical study information that MPOB relies on to conclude that palm carotenoids are GRAS under the conditions of their intended use, MPOB raises a potential issue under the labeling provisions of the Federal Food, Drug, and Cosmetic Act (FFDCA). Under section 403(a) of the FFDCA, a food is misbranded if its labeling is false or misleading in any particular. Section 403(r) of the FFDCA 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 palm carotenoids 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 palm carotenoids on the label or in labeling.

Potential Requirement for a Color Additive Petition

In its notice, MPOB describes palm carotenoids as containing β-carotene, α-carotene, γ-carotene, and lycopene, which give it a reddish color. As such, the use of palm carotenoids in food products may constitute the use of a color additive under section 201(t)(1) of the FFDCA and FDA’s implementing regulations in 21 CFR Part 70. Under section 201(t)(1) and 21 CFR 70.3(f), the term color additive means a material that is a dye, pigment, or other substance made by a process of synthesis or similar artifice, or extracted, isolated, or otherwise derived from a vegetable, animal, mineral, or other source, and that is capable (alone or through reaction with another substance) of imparting color when added or applied to a food; except that such term does not include any material which the Secretary,(3) by regulation, determines is used (or intended to be used) solely for a purpose or purposes other than coloring. Under 21 CFR 70.3(g), a material that otherwise meets the definition of color additive can be exempt from that definition on the basis that it is used or intended to be used solely for a purpose or purposes other than coloring, as long as the material is used in a way that any color imparted is clearly unimportant insofar as the appearance, value, marketability, or consumer acceptability is concerned. Given the construct of section 201(t)(1) of the FFDCA and 21 CFR 70.3(f) and (g), the use of a substance that is capable of imparting color may constitute use as a color additive in addition to use as a food additive or GRAS substance. For example, β-carotene is both approved for use as a color additive (21 CFR 73.95) and affirmed as GRAS for use as a nutrient supplement (21 CFR 184.1245); in some food products, β-carotene is used for both purposes. Importantly, if the use of palm carotenoids constitutes use as a color additive within the meaning of section 201(t)(1) of the FFDCA and FDA’s implementing regulations in 21 CFR 70.3(f) and (g), section 721(a) of the FFDCA requires premarket review and approval of that use by FDA. Under section 402(c) of the FFDCA, a food product that contains an unapproved color additive would be deemed adulterated.(4)

In an electronic mail sent by FDA to NutraSource, Inc., on March 30, 2010, FDA requested that MPOB present its view on whether any of the intended uses of palm carotenoids would be exempt from the definition of a color additive. In an amendment received May 7, 2010, MPOB stated that the intended use of palm carotenoids is “for a purpose or purposes other than coloring (e.g., where the material is used in a way that any color imparted is clearly unimportant insofar as the appearance, value, marketability, or consumer acceptability is concerned).” In its review of MPOB’s notice that the ingredient palm carotenoids is GRAS for the intended uses, FDA did not consider whether section 201(t)(1) of the FFDCA and FDA’s implementing regulations in 21 CFR Part 70 apply to the use of palm carotenoids in foods. Accordingly, this response should not be construed to be a statement that the use of palm carotenoids in foods is lawful under section 721(a). If, after receipt of this letter, MPOB has any further questions about this issue, we recommend that MPOB contact the Division of Petition Review in the Office of Food Additive Safety.

Medical Foods

In its notice, MPOB informs FDA that one intended use of palm carotenoids is use in medical foods. Section 5(b) of the Orphan Drug Act (ODA) defines a medical food as a food that is formulated to be consumed or administered enterally under the supervision of a physician and that is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation. Section 403(q) of the FFDCA lays out the statutory framework for nutrition labeling of food products. Section 403(r) of the FFDCA lays out the statutory framework for health claims and nutrient content claims. Under section 403(q)(5)(A)(iv) of the FFDCA and FDA's implementing regulations in 21 CFR 101.9(j)(8), the requirements for nutrition labeling do not apply to medical foods as defined in section 5(b) of the ODA. Under section 403(r)(5)(A) of the FFDCA and FDA's implementing regulations in 21 CFR 101.13(q)(4)(ii) and 21 CFR 101.14(f)(2), the requirements for nutrient content claims and health claims, respectively, do not apply to medical foods as defined in section 5(b) of the ODA. For your information, FDA's response to MPOB’s notice that palm carotenoids are GRAS for use in medical foods does not address the question of whether any particular food product that contains palm carotenoids as an ingredient would be a medical food within the meaning of section 5(b) of the ODA and, thus, would be exempt from the requirements for nutrition labeling, nutrient content claims, and health claims.

Section 301(ll) of the FFDCA

The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the FFDCA to, among other things, add section 301(ll). Section 301(ll) of the FFDCA prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FFDCA, 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 MPOB’s notice that the ingredient palm carotenoids is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing palm carotenoids. Accordingly, this response should not be construed to be a statement that foods that contain palm carotenoids, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).

Conclusions

Based on the information provided by MPOB, as well as other information available to FDA, the agency has no questions at this time regarding MPOB’s conclusion that palm carotenoids are 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 palm carotenoids. As always, it is the continuing responsibility of MPOB 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 000320, 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 via the FDA home page at http://www.fda.gov. To view or obtain an electronic copy of the text of the letter, follow the hyperlinks from the “Food” topic to the “Food Ingredients and Packaging” section to the “Generally Recognized as Safe (GRAS)” page where the GRAS Inventory is listed.

Sincerely,

Mitchell A. Cheeseman, Ph.D.
Acting Director
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition


(1)MPOB states that the NHANES and other dietary survey datasets are not designed to calculate the consumption levels of γ-carotene due to its insignificant contribution to the American diet.

(2)FDA notes that β-carotene is affirmed GRAS for use as a nutrient supplement in dairy product analogs, fats and oils, and processed fruits and fruit juices (21 CFR 184.1245) and is approved for use as a color additive in foods generally, except those foods for which standards of identity have been promulgated under section 401 of the FFDCA and for which the use of colors is not authorized (21 CFR 73.95). FDA further notes that the intended use of lycopene, either synthetic or from B. trispora as determined in GRN 000119 and GRN 000173, respectively, is as an ingredient in foods in general, except meat and poultry.

(3)The Secretary of the Department of Health and Human Services

(4)We note that section 721(b)(4) of the FFDCA provides that a color additive shall be deemed to be safe and suitable for the purpose of listing under section 721(b) of the FFDCA while there is in effect a published finding of the Secretary declaring that the substance is exempt from the definition of “food additive” because of its being generally recognized by qualified experts as safe for its intended use as provided in section 201(s) of the FFDCA. Importantly, FDA’s response to GRN 000320 does not constitute a “finding of the Secretary” within the meaning of section 721(b)(4) of the FFDCA.

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