Food

Agency Response Letter GRAS Notice No. GRN 000553

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CFSAN/Office of Food Additive Safety

June 19, 2015

Erin Sylvester
DSM Nutritional Products
6480 Dobbin Road
Columbia, MD 21045

Re: GRAS Notice No. GRN 000553

Dear Ms. Sylvester:

The Food and Drug Administration (FDA) is responding to the notice, dated October 6, 2014, 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 October 28, 2014, filed it on December 23, 2014, and designated it as GRAS Notice No. GRN 000553.

The subject of the notice is algal oil derived from Schizochytrium sp. (algal oil). The notice informs FDA of the view of DSM Nutritional Products (DSM) that algal oil is GRAS, through scientific procedures, for use as an ingredient in preterm and term, exempt and non-exempt infant formulas and follow-on formulas at a maximum use level of 1.25% dietary fat, which corresponds to a maximum use level of 0.5% total fat as docosahexaenoic acid (DHA). DSM states that algal oil is intended to be used in combination with a safe and suitable source of arachidonic acid (ARA) and the ratio of DHA to ARA would range from 1:1 to 1:2.

Our use of "algal oil" 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. 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 principals to use when establishing common or usual names for nonstandarized 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 (ONLDS) in the Center for Food Safety and Applied Nutrition (CFSAN).

As part of its notice, DSM includes a statement from a panel of individuals (DSM’s GRAS panel) that evaluated the data and information that are the basis for DSM’s GRAS determination. DSM considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. DSM’s GRAS panel evaluated the identity and composition, method of manufacture, product specifications, and estimates of dietary exposure, as well as published and unpublished studies supporting the safety of algal oil. Based on this review, DSM’s GRAS panel concluded that algal oil that meets its established food grade specifications is GRAS under the conditions of its intended use.

DSM describes the identity and composition of algal oil. Algal oil has a light yellow-orange color and is composed predominantly of triglycerides (91 to 95%), with some monoglycerides (2%), diglycerides (2%), and unsaponifiable material (1% by weight), including sterols (0.8 % of total oil). DSM states that the major fatty acids in algal oil are myristic acid (14:0), palmitic acid (16:0), stearic acid (18:0), oleic acid (18:1 n-9), linoleic acid (18:2 n-6), eicosapentaenoic acid (EPA, 20:5 n-3), and docosapentaenoic acid (22:5 n-6). DSM compares the fatty acid profile of its algal oil with that of other algal and fish oils intended for use in infant formulas, including DHA-rich single cell oil (DHASCO), DHA and EPA oil (DHA-O), oil produced from Schizochytrium sp. (DHA-S), and tuna oil. Based on its comparison, DSM concludes that algal oil has a similar fatty acid composition as these oils.

DSM describes the manufacturing process for algal oil, beginning with the fermentation of a strain of Schizochytrium sp. algae. DSM states that following fermentation, the culture is diluted with water (aqueous extraction) and then centrifuged to separate algal biomass from the broth. The algal biomass is then pasteurized and treated with an approved food grade protease to degrade the algal cells and release algal oil. Sodium chloride is added to the resulting mixture, which is then heated. The mixture is centrifuged to separate the broth and collect the algal oil. The collected algal oil is vacuum-dried, filtered, refined, bleached, and deodorized. DSM states that the manufacturing process is conducted according to current good manufacturing practices and that all raw materials used in the manufacturing process are food grade.

DSM provides specifications for algal oil, including a minimum content of DHA (≥40 %), and limits for EPA (≤10 %), free fatty acids (≤ 0.4%), unsaponifiable matter (≤3.5%), lead (≤0.1 milligrams per kilogram (mg/kg)), arsenic (≤0.1 mg/kg), cadmium (≤0.1 mg/kg), mercury (≤0.04 mg/kg), copper (≤0.1 mg/kg), and iron (≤0.2 mg/kg). DSM also discusses limits for microbial contaminants, including no detectable Cronobacter sakazakii in a 25 gram (g) sample. DSM provides analytical data from five lots of algal oil to demonstrate compliance with these specifications. DSM also discusses stability studies conducted with algal oil and concludes that algal oil is stable for up to 12 months. However, DSM notes that the stability studies will continue and expects algal oil to be stable for at least 36 months.

DSM estimates the daily dietary exposure to algal oil by referencing GRN 000041.(1) DSM notes that algal oil that is the subject of GRN 000041 (DHASCO) contains approximately 40% DHA, and DSM states that the use level corresponds to a maximum of 0.5% of total fat as DHA. DSM states that algal oil may be used as a replacement for DHASCO in infant formulas at the same use level. DSM calculates the daily dietary exposure to algal oil based on the assumption that human infants consume 100 to 120 kilocalories (kcal)/kg body weight per day (bw/d), of which fat comprises about 50%. Therefore, DSM calculates that infants consume about 50 to 60 kcal of fat/kg bw/d which corresponds to approximately 5.5 to 6.7 g of fat/kg bw/d. Based on the maximum use level for algal oil, DSM concludes that an infant would consume approximately 75 mg algal oil/kg bw/d.

DSM describes published and unpublished studies supporting the safety of the source organism for algal oil. DSM cites published studies noting that Schizochytrium sp. algae are frequently associated with animals without evidence of pathogenicity. DSM states that there are no published reports showing that the class of algae to which Schizochytrium sp. belongs produces algal toxins. DSM also discusses the results of unpublished studies showing that Schizochytrium sp. algae do not produce toxins.

DSM describes unpublished and published studies supporting the safety of algal oil. DSM discusses unpublished genotoxicity studies on their algal oil produced utilizing aqueous extraction, as well as published genotoxicity studies conducted on algal oil produced utilizing isopropyl alcohol extraction (algal oil-IPA).(2) DSM states that these studies demonstrate that algal oil is not mutagenic or genotoxic. Additionally, the results of unpublished and published subchronic toxicity studies conducted in rats show that administration of algal oil and algal oil-IPA does not result in adverse effects at the highest levels tested (3279 mg/kg bw/d and 4122 mg/kg bw/d, respectively). Furthermore, the notifier cites a published 3 week bioequivalence study conducted in neonatal piglets consuming either the algal oil that is the subject of GRN 000553 or DHASCO, a similar algal oil currently consumed as part of infant formula. The results showed no adverse effects in the neonatal piglets which consumed up to approximately 290 mg/kg bw/d of either algal oil.

Based on the data and information described above, DSM concludes that algal oil is GRAS for its intended use in food.

Potential Requirement for a Color Additive Petition

In its notice, DSM notes that algal oil may impart color to food. As such, the use of algal in food products may constitute the use of a color additive under section 201(t)(1) of the Federal Food, Drug, and Cosmetic Act (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,(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 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 algal oil 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.(4)

In its notice, DSM states that algal oil has a light yellow-orange color. Importantly, FDA’s response to GRN 000553 does not include any comment by FDA about DSM’s view of this issue. If, after receipt of this letter, DSM has any specific questions about this issue, we recommend that DSM contact the Division of Petition Review in the Office of Food Additive Safety (OFAS).

Potential Labeling Issues

In describing the intended use of algal oil and in describing the information that DSM relies on to conclude that algal oil is GRAS under the conditions of its intended use, DSM raises a potential issue under the labeling provisions of the FD&C Act. Under section 403(a) of the 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 algal oil bear any claims on the label or in labeling, such claims are the purview of the ONLDS in the CFSAN. OFAS 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 algal oil on the label or in labeling.

Intended Use in Infant Formula

Under section 412 of the FD&C Act, a manufacturer of a new infant formula must make a submission to FDA, providing required assurances about the formula, at least 90 days before the formula is marketed. DSM should be aware that FDA’s response to DSM’s GRAS notice does not alleviate the responsibility of any infant formula manufacturer who intends to market an infant formula that contains algal oil to make the submission required by section 412.

Section 301(ll) of the FD&C Act

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 DSM’s notice that algal oil is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing algal oil. Accordingly, this response should not be construed to be a statement that foods that contain algal oil, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).

Conclusions

Based on the information provided by DSM, as well as other information available to FDA, the agency has no questions at this time regarding DSM’s conclusion that algal oil 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 algal oil. As always, it is the continuing responsibility of DSM 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 000553, 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


 

(1)The subjects of GRN 000041 are (docosahexaenoic acid-rich single-cell oil (DHASCO) derived from the microalgal species Crypthecodinium cohnii, and arachidonic acid-rich single-cell oil (ARASCO) derived from the soil fungus Mortierella alpina. Martek Biosciences Corporation (Martek) informed FDA that DHASCO and ARASCO are GRAS for use in term infant formulas at a maximum level of 1.25% each of the total dietary fat and at a ratio ranging from 1:1 to 1:2 (DHASCO:ARASCO). FDA responded in a letter dated March 1, 2000, stating that the agency had no questions at that time regarding Martek’s GRAS determination.

(2)DSM considers these algal oils to be comparable to the algal oil that is the subject of GRN 000553.

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

(4)We 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 a 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 000553 does not constitute a finding of the Secretary within the meaning of section 721(b)(4) of the FD&C Act.

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