Agency Response Letter GRAS Notice No. GRN 000291
CFSAN/Office of Food Additive Safety
November 6, 2009
Mark L. Itzkoff
Olsson Frank Weeda
1400 Sixteenth Street N.W., Suite 400
Re: GRAS Notice No. GRN 000291
Dear Mr. Itzkoff:
The Food and Drug Administration (FDA) is responding to the notice, dated May 6, 2009, that you submitted on behalf of Industrial Organica S.A. de C.V. (IOSA) 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 May 8, 2009, filed it on May 11, 2009, and designated it as GRAS Notice No. GRN 000291.
The subject of the notice is a mixture of carotenoids lutein and zeaxanthin referred to by IOSA as crystalline lutein. The notice informs FDA of the view of IOSA that crystalline lutein is GRAS, through scientific procedures, for use as an ingredient in baked goods and baking mixes, beverages and beverage bases, breakfast cereals, chewing gum, dairy product analogs, fats and oils, frozen dairy desserts and mixes, gravies and sauces, hard candy, infant and toddler foods, milk products, processed fruits and fruit juices, and soft candy at levels ranging from 0.3 to 3.0 milligrams per reference amount customarily consumed (Table 1).
|Food Category||Intended Food Use|
|* RACC is defined as "reference amounts customarily consumed per eating occasion" (21 CFR 101.12).|
|** IOSA states that the infant food category does not include infant formula.|
|Baked goods and baking mixes||Cereal and energy bars||2.0|
|Crackers and crisp bread||2.0|
|Beverages and beverage bases||Bottled water||0.5|
|Breakfast cereals||Instant & regular hot cereal||2.0|
|Chewing gum||Chewing gum||1.0|
|Dairy product analogs||Imitation milks||2.0|
|Fats and oils||Margarine-like spreads||1.5|
|Frozen dairy desserts and mixes||Frozen yogurts||1.0|
|Gravies and sauces||Tomato-based sauces||0.3|
|Hard candy||Hard candy||1.0|
|Infant** and toddler foods||Junior, strained and toddler type baby foods||1.0|
|Milk products||Dry milk||3.0|
|Fermented milk beverages||0.6|
|Flavored milk & milk drinks||3.0|
|Milk-based meal replacement||3.0|
|Processed fruit and fruit juices||Energy, sport and isotonic drinks||2.0|
|Soft candy||Chewy and nougat candy||1.0|
For clarity, in the remainder of this letter FDA uses the term "crystalline lutein" to denote the mixture of the carotenoids lutein and zeaxanthin that is the subject of the notice and the term "lutein" to denote the principal component of this mixture.
21 CFR 101.4 states that all ingredients must be declared by their common or usual name. In addition, 21 CFR 102.5 outlines general principles to use when establishing common or usual names for nonstandardized foods. Our use of "crystalline lutein" 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. 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 (ONLDS) in the Center for Food Safety and Applied Nutrition.
As part of its notice, IOSA includes the report of two panels of individuals (IOSA's GRAS panel 2006 and IOSA's GRAS panel 2008) who evaluated the data and information that are the basis for IOSA's GRAS determination. IOSA considers the members of its GRAS panels to be qualified by scientific training and experience to evaluate the safety of substances added to food. IOSA's GRAS panels evaluated the method of manufacture, product specifications, estimates of dietary exposure and published studies on crystalline lutein and related compounds. Based on this review, IOSA's GRAS panels concluded that crystalline lutein, that meets food grade specifications and is manufactured in accordance with good manufacturing practice, is GRAS under the conditions of its intended use.
IOSA describes the method of manufacture for crystalline lutein. Marigold oleoresin is treated with diluted alkali solution, followed by diluted acid solutions to eliminate impurities and to remove unwanted fatty acids, waxes, gums and other plant materials from the oleoresin. The oleoresin is then extracted with a basic solution, organic solvent and water yielding a concentrate containing lutein and zeaxanthin. This concentrate is then extracted with hexane to further remove unwanted components. The solvent is separated by filtration, decanting and centrifugation. Lutein crystals are then subjected to high vacuum and temperature to remove the remaining solvent. Lutein crystals are filtered and dried to remove water. The final crystalline lutein product is packed under high vacuum and inert nitrogen atmosphere in food-grade plastic pouches.
IOSA provides specifications for crystalline lutein. These specifications include limits on lead, arsenic, pesticides, organic solvents, yeasts and molds, and microbiological contaminants. IOSA also provides specifications on the total carotenoids in crystalline lutein and the percentages of lutein and zeaxanthin. IOSA reports that crystalline lutein contains greater than 74 percent lutein by weight and no more than 6 -- 8 percent zeaxanthin by weight (for a total of greater than 80 percent total carotenoids by weight).
IOSA incorporates by reference, the estimated daily intake (EDI) calculations from GRN 000140. GRN 000140 included an estimate of the current intake of crystalline lutein from the diet and the intended intake of crystalline lutein from the foods summarized in Table 1 along with the food categories, egg products and soup and soup mixes.1 IOSA concludes that, due to the substantial equivalency in composition with the crystalline lutein from GRN 000140 and the fact that the intended use would be substitutional and not additive, the EDI calculations would be considered the same for the uses of crystalline lutein in both GRN 000140 and this notice.The intake of lutein and zeaxanthin from specified foods is estimated to be 7.3 mg/p/d and 0.7 mg/p/d, respectively, at the mean, and 13.4 mg/p/d and 1.2 mg/p/d respectively at the 90th percentile.
GRN 000291 discusses published and unpublished studies in GRN 000140, as well as several published animal and human studies that became available after the agency review of GRN 000140. Based upon the totality of the safety studies, IOSA concludes that crystalline lutein in the diet at the levels estimated above is not considered to pose any safety concerns.
Standards of Identity
In the notice, IOSA states its intention to use crystalline lutein 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
Under section 403(a) of the Federal Food, Drug, and Cosmetic Act (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. In describing the intended use of crystalline lutein and in describing the information that IOSA relies on to conclude that crystalline lutein is GRAS under the conditions of its intended use, IOSA raises a potential issue under these labeling provisions of the FFDCA. If products that contain crystalline lutein bear any claims on the label or in labeling, such claims are the purview of ONLDS. 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 crystalline lutein on the label or in labeling.
Potential Requirement for a Color Additive Petition
In its notice, IOSA describes the concentrate that it uses to prepare its crystalline lutein. As such, the use of crystalline lutein 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,2 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, beta-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, beta-carotene is used for both purposes. Importantly, if the use of crystalline lutein 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.3
In a telephone conference on July 7, 2009, between representatives of FDA and yourself, FDA requested that IOSA present its view on whether any of the intended uses of crystalline lutein would be exempt from the definition of color additive. In an amendment dated August 13, 2009, IOSA presented its reasons for concluding that all of the intended uses of crystalline lutein would be exempt from the definition of color additive under section 201(t) of the FFDCA and FDA's implementing regulations in 21 CFR 70.3(f) and (g). Importantly, FDA's response to GRN 000291 does not include any comment by FDA about IOSA's view on this issue. If, after receipt of this letter, IOSA has any further questions about this issue, we recommend that IOSA contact the Division of Petition Review in the Office of Food Additive Safety.
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 IOSA's notice that crystalline lutein is GRAS for its intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing crystalline lutein. Accordingly, this response should not be construed to be a statement that foods that contain crystalline lutein, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by IOSA, as well as other information available to FDA, the agency has no questions at this time regarding IOSA's conclusion that crystalline lutein 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 crystalline lutein. As always, it is the continuing responsibility of IOSA 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 000291, 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.
Mitchell A. Cheeseman, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
1Unlike GRN 000140, egg products and soup and soup mixes are not food categories in GRN 000291.
2The Secretary of the Department of Health and Human Services
3We 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 000291 does not constitute a “finding of the Secretary” within the meaning of section 721(b)(4) of the FFDCA.