Agency Response Letter GRAS Notice No. GRN 000432
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CFSAN/Office of Food Additive Safety
November 14, 2012
Mr. Mark L. Itzkoff
600 New Hampshire Ave, NW
Washington, D.C. 20037
Re: GRAS Notice No. GRN 000432
Dear Mr. Itzkoff:
The Food and Drug Administration (FDA) is responding to the notice, dated May 4, 2012, that you submitted on behalf of Industrial Organica S.A. de CV (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 14, 2012, filed it on May 22, 2012, and designated it as GRAS Notice No. GRN 000432.
The subject of the notice is lutein diacetate. The notice informs FDA of the view of IOSA that lutein diacetate is GRAS, through scientific procedures, 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 (excluding infant formula), milk products, processed fruits and fruit juices, soft candy, and soups and soup mixes at levels of 0.3 to 3 milligram per serving (mg/serving). IOSA notes that lutein diacetate is not intended for use in foods that have a standard of identity.
IOSA states that the intended uses are in the same foods and at the same levels (on a lutein basis) as those listed in GRN 000140 (Table 1).
|Food Category||Proposed food use|| Use level
|1RACC is defined as “reference amounts customarily consumed per eating occasion” (21 CFR 101.12).|
|2Notifier states that infant formula is not included in their intended uses.|
|3Notifier states that soups and soup mixes that contain meat or poultry are excluded from their intended uses.|
|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 yogurt||1.0|
|Gravies and sauces||Tomato-based sauces||0.3|
|Hard candy||Hard candy||1.0|
|Infant2 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|
|Soups and soup mixes3||Canned soups||0.6|
As part of its notice, IOSA includes a statement from a panel of individuals (IOSA’s GRAS panel) who evaluated the data and information that are the basis for IOSA’s GRAS determination. IOSA considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. IOSA’s GRAS panel considered the identity and source of IOSA’s product and discusses its equivalence to other forms of lutein that were the subjects of prior GRAS notices to FDA. IOSA’s GRAS panel evaluated estimates of dietary exposure, method of production, and product specifications as well as published and unpublished studies. IOSA’s GRAS panel concluded that lutein diacetate that meets its established food grade specifications is GRAS under the conditions of its intended use.
IOSA describes the identity, manufacturing process and composition of lutein diacetate. The process starts with a hexane extraction of dried marigold (Tagetes erecta) flowers to isolate oleoresin. The oleoresin is treated with dilute alkali solution, followed by dilute acid solution to remove impurities. The oleoresin is then subjected to saponification with aqueous potassium hydroxide to free xanthophylls. Following saponification, the mixture is acylated with acetic acid and acetic anhydride. The acylated product is washed with water, and then extracted with hexane. The solvent is removed by filtration and centrifugation. The resulting lutein diacetate crystals are then dried and screened to produce the required crystal size. The concentrated, crystalline form of lutein diacetate contains 70% lutein diacetate. The crystalline product is formulated with excipient (corn oil) to specified concentration and vitamin E is added as an antioxidant, forming a final product described as a red-orange oily suspension with characteristic odor. IOSA states that the processing aids potassium hydroxide, acetic acid, and the hexane solvent used during the manufacturing process are food grade quality as specified in the Food Chemicals Codex (5th Edition). IOSA provides specifications for the oil formulation of lutein diacetate. Specifications include a minimum content of lutein diacetate (≥ 22%) and zeaxanthin diacetate (≥ 1.5%). Specifications also include limits on lead (< 2 mg per kilogram (mg/kg)), arsenic (< 1 mg/kg), mercury (< 1 mg/kg), cadmium (< 1 mg/kg), residual hexane (< 25 mg/kg), and microorganisms.
IOSA provides estimated daily intakes (EDI) of lutein diacetate from the intended uses. IOSA relies on the EDI for the lutein and zeaxanthin provided in GRN 000140. IOSA further states that the intended use of lutein diacetate is substitutional for use at the same levels in the same foods as the subject of GRN 000140. Therefore, IOSA does not expect a discernable increase in dietary intake. These estimates were based on the intended uses provided in GRN 000140 and a food consumption analysis using United States Department of Agriculture's (USDA) 1994-1996 Continuing Survey of Food Intakes by Individuals (CSFII 1994-1996) and the 1998 Supplemental Children's Survey (CSFII 1998) (USDA, 2000). Based on this information, the corresponding mean users-only EDI of lutein and zeaxanthin were 7.3 mg/person/day (0.14 mg/kg body weight/day) and 0.7 mg/person/day (0.01 mg/kg body weight/day), respectively. The 90th percentile users-only EDI of lutein and zeaxanthin were 13.4 mg/person/day (0.28 mg/kg body weight/day) and 1.2 mg/person/day (0.03 mg/kg body weight/day), respectively.
IOSA discusses published information to support the safety of lutein diacetate. IOSA notes that lutein was the subject of previous GRAS notices for use in various foods and beverages. In GRN 000432, IOSA incorporates by reference the safety studies cited in GRNs 000110, 000140, 000221, and 000291. IOSA notes that the safety of lutein and its esters was demonstrated in these notices based on a number of toxicological studies in animals, mutagenicity studies, and further supported by clinical studies in humans. IOSA considers that lutein diacetate is metabolized to lutein, therefore, studies cited and described in the above notices were used to support the safety of lutein diacetate in GRN 000432.
IOSA discusses additional studies published since the completion of GRN 000291. IOSA discusses additional studies of lutein addressing genotoxicity, bioavailability, absorption, distribution, metabolism and elimination and subchronic and chronic studies conducted in animals. IOSA also discusses additional clinical studies in which lutein was administered orally to adults. IOSA states that these new studies show no adverse effects attributable to lutein. To further support its view that lutein diacetate is safe for the intended use, IOSA notes that the Joint Expert Committee on Food Additives established an acceptable daily intake for lutein and zeaxanthin of 0-2 mg/kg body weight/day (0-120 mg/person/day). Based on the consideration of all these studies, IOSA concludes that lutein diacetate is GRAS for its intended use in foods.
Potential Labeling Issues
In discussing the intake of lutein and zeaxanthin as two of the most abundant carotenoids in the North American diet, IOSA references available evidence indicating that higher dietary intake of lutein and zeaxanthin is related to reduced risk of cataracts and age-related macular degeneration. Under section 403(a) of the Federal Food, Drug, and Cosmetic Act (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 lutein diacetate bear any claims on the label or in labeling, such claims are the purview of the Office of Nutrition Labeling and Dietary Supplements (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 lutein diacetate on the label or in labeling.
Potential Requirement for a Color Additive Petition
In their notice, IOSA notes that lutein diacetate may impart color to food. As such, the use of lutein diacetate in food products may constitute the use of a color additive under section 201(t)(1) of the FD&C Act 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,1 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 FD&C Act 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 lutein diacetate constitutes use as a color additive within the meaning of section 201(t)(1) of the FD&C Act and FDA’s implementing regulations in 21 CFR 70.3(f) and (g), section 721(a) of the FD&C Act requires premarket review and approval of that use by FDA. Under section 402(c) of the FD&C Act, a food product that contains an unapproved color additive would be deemed adulterated.2
IOSA states that lutein diacetate is solely added for its intended technical effect, and, thus may constitute an “unimportant color” [21 CFR 70.3(g)] and it does not relate to any use of the ingredient as a color additive [21 CFR 70.3(0)]. Importantly, FDA’s response to GRN 000432 does not include any comment by FDA about IOSA’s view on this issue. If, after receipt of this letter, IOSA has any specific questions about this issue, we recommend that IOSA contact the Division of Petition Review, Office of Food Additive Safety, Center for Food Safety and Applied Nutrition, Food and Drug Administration, 5100 Paint Branch Parkway, College Park, MD 20740. You can reach this division by telephone at (240) 402-1200.
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 IOSA’s notice that lutein diacetate is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing lutein diacetate. Accordingly, this response should not be construed to be a statement that foods that contain lutein diacetate, 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 lutein diacetate 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 lutein diacetate. 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 000432, 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
1The Secretary of the Department of Health and Human Services.
2We note that section 721(b)(4) of the FD&C Act provides that a color additive shall be deemed to be safe and suitable for the purpose of listing under section 721(b) of the FD&C Act 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 FD&C Act. Importantly, FDA’s response to GRN 000417 does not constitute a “finding of the Secretary” within the meaning of section 721(b)(4) of the FD&C Act.