[Federal Register Volume 84, Number 148 (Thursday, August 1, 2019)]
[Rules and Regulations]
[Pages 37573-37576]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-16374]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 73

[Docket No. FDA-2018-C-4464]


Listing of Color Additives Exempt From Certification; Soy 
Leghemoglobin

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA or we) is amending the 
color additive regulations to provide for the safe use of soy 
leghemoglobin as a color additive in ground beef analogue products. We 
are taking this action in response to a color additive petition (CAP) 
submitted by Impossible Foods, Inc. (Impossible Foods or petitioner).

DATES: This rule is effective September 4, 2019. See section X for 
further information on the filing of objections. Submit either 
electronic or written objections and requests for a hearing on the 
final rule by September 3, 2019.

ADDRESSES: You may submit objections and requests for a hearing as 
follows. Please note that late, untimely filed objections will not be 
considered. Electronic objections must be submitted on or before 
September 3, 2019. The https://www.regulations.gov electronic filing 
system will accept comments until 11:59 p.m. Eastern Time at the end of 
September 3, 2019. Objections received by mail/hand delivery/courier 
(for written/paper submissions) will be considered timely if they are 
postmarked or the delivery service acceptance receipt is on or before 
that date.

Electronic Submissions

    Submit electronic objections in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Objections submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your objection will be 
made public, you are solely responsible for ensuring that your 
objection does not include any confidential information that you or a 
third party may not wish to be posted, such as medical information, 
your or anyone else's Social Security number, or confidential business 
information, such as a manufacturing process. Please note that if you 
include your name, contact information, or other information that 
identifies you in the body of your objection, that information will be 
posted on https://www.regulations.gov.
     If you want to submit an objection with confidential 
information that you do not wish to be made available to the public, 
submit the objection as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper objections submitted to the Dockets 
Management Staff, FDA will post your objection, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2018-C-4464 for ``Listing of Color Additives Exempt From 
Certification; Soy Leghemoglobin.'' Received objections, those filed in 
a timely manner (see ADDRESSES), will be placed in the docket and, 
except for those submitted as ``Confidential Submissions,'' publicly 
viewable at https://www.regulations.gov or with the Dockets Management 
Staff between 9 a.m. and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit an objection with 
confidential information that you do not wish to be made publicly 
available, submit your objections only as a written/paper submission. 
You should submit two copies total. One copy will include the 
information you claim to be confidential with a heading or cover note 
that states ``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' We 
will review this copy, including the claimed confidential information, 
in our consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Ellen Anderson, Center for Food Safety 
and Applied Nutrition, Food and Drug Administration, 5001 Campus Dr., 
College Park, MD 20740-3835, 240-402-1309.

SUPPLEMENTARY INFORMATION:

I. Introduction

    In a notice published in the Federal Register of December 13, 2018 
(83 FR 64045), we announced that we filed a color additive petition 
(CAP 9C0314) submitted by Impossible Foods, Inc., c/o Exponent, Inc., 
1150 Connecticut Avenue NW, Suite 1100, Washington, DC 20036. The 
petition proposed to amend the color additive regulations in part 73 
(21 CFR part 73), ``Listing of Color Additives Exempt from 
Certification'' to provide for the safe use of soy leghemoglobin as a 
color additive in ground beef analogue products such that the amount of 
soy leghemoglobin protein does not exceed 0.8 percent by weight of the 
uncooked ground beef analogue product. For the purposes of this final 
rule, the term ``ground beef analogue products'' refers to plant-based 
or other non-animal derived ground beef-like food products. The 
petition describes soy leghemoglobin protein as the principal reddish 
brown coloring component of a stabilized mixture, referred to as soy 
leghemoglobin preparation. We are establishing soy leghemoglobin as the 
common or usual name for this color additive and note

[[Page 37574]]

that the terms ``soy leghemoglobin'' and ``soy leghemoglobin 
preparation'' are used interchangeably when referring to the name of 
the color additive in this final rule and in our review memoranda 
(Refs. 1 and 2).

II. Background

    The color additive that is the subject of this petition is the 
stabilized product of controlled fermentation of a non-pathogenic and 
non-toxicogenic strain of the yeast, Pichia pastoris (P. pastoris), 
genetically engineered to express soy leghemoglobin protein, the 
principal coloring component. Soy leghemoglobin gets its name from its 
source, the soybean root; it is a hemeprotein present in the nitrogen-
fixing root nodules of leguminous plants. The color additive is 
manufactured by construction of the P. pastoris production strain, 
expression of soy leghemoglobin protein via fermentation, followed by 
concentration and stabilization of the expressed protein. Based on 
information in the petition, soy leghemoglobin preparation contains not 
more than 9 percent soy leghemoglobin protein, minor quantities of P. 
pastoris yeast proteins, and optional stabilizers sodium chloride and 
sodium ascorbate. The color additive is stored either as a frozen 
liquid or in a spray dried form. FDA concurs with the petitioner that 
the genetic modifications made to generate the non-toxigenic and non-
pathogenic production strain are well-characterized and the production 
process conforms to good manufacturing practice (Ref. 1). In addition 
to specification limits for lead, arsenic, mercury, and cadmium, we are 
requiring a specification for the minimum purity of soy leghemoglobin 
protein as a percent of the total protein in the color additive.
    We have previously considered the safety of soy leghemoglobin 
preparation as the result of a submission from Impossible Foods who 
made its own determination, to which we had no questions, that the use 
of soy leghemoglobin preparation to optimize flavor in ground beef 
analogue products intended to be cooked is generally recognized as safe 
(GRAS). Under section 201(s) of the Federal Food, Drug, and Cosmetic 
Act (FD&C Act) (21 U.S.C. 321(s)), a substance is GRAS if it is 
generally recognized, among experts qualified by scientific training 
and experience to evaluate its safety, as having been adequately shown 
through scientific procedures (or, in the case of a substance used in 
food before January 1, 1958, through either scientific procedures or 
experience based on common use in food) to be safe under the conditions 
of its intended use. Under section 201(s) of the FD&C Act, a substance 
that is GRAS for a particular use in food is not a food additive and 
may lawfully be utilized for that use without our review and approval. 
There is no GRAS exemption, however, to the definition of a color 
additive in section 201(t) of the FD&C Act. Therefore, we must approve 
the use of a color additive in food before it is marketed; otherwise, 
the food containing the color additive is adulterated under section 
402(c) of the FD&C Act (21 U.S.C. 342(c)).
    A firm may voluntarily submit to FDA information supporting the 
firm's own conclusion that a substance is GRAS for its intended use in 
food through our GRAS notification program (see 81 FR 54960 (August 17, 
2016)). Through this program, a GRAS notification (GRN) was submitted 
on behalf of Impossible Foods on October 3, 2017 (GRN 737). This GRN 
informed FDA that Impossible Foods concluded that the use of soy 
leghemoglobin preparation to deliver up to 0.8 percent soy 
leghemoglobin protein by weight in the final food was GRAS for 
optimizing flavor in ground beef analogue products intended to be 
cooked. Based on our evaluation of the information provided in GRN 737, 
as well as other available information, we issued a letter on July 23, 
2018, to Impossible Foods stating that we had no questions regarding 
its conclusion that soy leghemoglobin preparation is GRAS for its 
intended conditions of use.
    Importantly, in our response letter to Impossible Foods, we stated 
that because soy leghemoglobin preparation is reddish-brown, its use 
may constitute a color additive use under section 201(t)(1) of the FD&C 
Act and FDA's implementing regulations in 21 CFR part 70. In the case 
of the soy leghemoglobin preparation, the reddish color imparted to the 
uncooked ground beef analogue product is lost when the product is 
heated, and the soy leghemoglobin protein responsible for imparting the 
reddish color in the food is denatured by the cooking process. 
Impossible Foods' GRAS conclusion in GRN 737 was for the use of soy 
leghemoglobin preparation to optimize flavor in ground beef analogue 
products intended to be cooked. When soy leghemoglobin preparation is 
used in ground beef analogue products sold directly to consumers in an 
uncooked form, the reddish color imparted by the soy leghemoglobin 
preparation gives the appearance of uncooked ground beef to the ground 
beef analogue product. This specific use of soy leghemoglobin 
preparation to impart a reddish color to a food is important to the 
appearance and marketability of the food. Therefore, FDA determined 
that this use of soy leghemoglobin preparation requires premarket 
approval as a color additive (see Sec.  70.3(g) (21 CFR 70.3(g))).

III. Safety Evaluation

    Under section 721(b)(4) of the FD&C Act (21 U.S.C. 379e(b)(4)), a 
color additive may not be listed for a proposed use unless the data and 
information available to FDA establish that the color additive is safe 
for that use. Our color additive regulations at Sec.  70.3(i) define 
``safe'' to mean that there is convincing evidence establishing with 
reasonable certainty that no harm will result from the intended use of 
the color additive.
    As part of our safety evaluation to establish with reasonable 
certainty that a color additive is not harmful under its intended 
conditions of use, we consider the additive's manufacturing and 
stability; the projected human dietary exposure to the additive and any 
impurities resulting from the petitioned use of the additive; the 
additive's toxicological data; and other relevant information (such as 
published literature) available to us.

IV. Safety of Petitioned Use of the Color Additive

A. Exposure Estimate

    Soy leghemoglobin preparation is composed mainly of soy 
leghemoglobin protein, minor quantities of P. pastoris proteins, water, 
fat, carbohydrates, and any stabilizers that are used. During our 
safety review of this petition (CAP 9C0314), we evaluated the 
petitioner's dietary exposure estimates for the soy leghemoglobin 
preparation and for the soy leghemoglobin protein component of the 
preparation. To estimate dietary exposure, the petitioner used 
nationwide ground beef consumption data collected from 2003 to 2014 as 
part of the National Health and Nutrition Examination Survey and 
assumed a 1-to-1 substitution of conventional ground beef with ground 
beef analogue product containing soy leghemoglobin preparation at its 
maximum use level. The petitioner estimated the dietary exposure to soy 
leghemoglobin preparation for the U.S. population (aged 2 years or 
more) to be 3,556 milligrams/person/day (mg/p/d) at the mean and 7,911 
mg/p/d at the 90th percentile. For soy leghemoglobin protein only, the 
estimated dietary exposure for the U.S population was 320 mg/p/d at the 
mean and 712 mg/p/d at the 90th percentile. FDA confirmed the 
petitioner's exposure estimates for soy leghemoglobin protein and soy 
leghemoglobin preparation and notes

[[Page 37575]]

that the estimates assume that all conventional ground beef and ground 
beef-containing foods are replaced with ground beef analogue product 
(Ref. 1). FDA estimated the dietary exposure to total protein (soy 
leghemoglobin protein plus P. pastoris proteins) from the petitioned 
use of the color additive to be 871 mg/p/d (Ref. 1). We also considered 
U.S. consumers' dietary exposure to iron from the petitioned use of the 
color additive and determined that no significant change in exposure to 
dietary iron would occur since the amount of iron from the petitioned 
use of soy leghemoglobin in ground beef analogue products is similar to 
the amount of iron found in traditional ground beef (Ref. 1).

B. Toxicological Considerations

    To establish that soy leghemoglobin is safe for use as a color 
additive that provides up to 0.8 percent soy leghemoglobin protein in 
ground beef analogue products, the petitioner used a weight-of-evidence 
approach based on: (1) The history of consumption of soy, soy 
leghemoglobin protein, and P. pastoris; (2) the safety of P. pastoris 
as a production strain; (3) 14-day and 28-day feeding studies with soy 
leghemoglobin preparation in rats; (4) mutagenicity and genotoxicity 
studies of soy leghemoglobin preparation; and (5) an allergenicity 
assessment of soy leghemoglobin and P. pastoris proteins in the soy 
leghemoglobin preparation.
    Based on our review of this petition (CAP 9C0314), we conclude that 
the proteins in the soy leghemoglobin preparation are well defined, 
non-toxic, and that the contribution of total proteins (soy 
leghemoglobin protein plus P. pastoris proteins) from the petitioned 
use of the color additive to total daily dietary protein would be only 
1.7 percent, assuming a daily dietary intake of 50 grams of protein per 
person per day (Ref. 2). Regarding the P. pastoris strain developed by 
the petitioner for the production of soy leghemoglobin preparation, we 
conclude that it is non-toxicogenic and non-pathogenic. We evaluated 
the results from the 14-day dose range finding study and two 28-day 
toxicity studies in rats fed soy leghemoglobin preparation and conclude 
that they did not show any toxicologically relevant effects. We also 
determined that the mutagenicity and genotoxicity studies provided in 
the petition showed no evidence of mutagenic activity or increased 
chromosomal aberrations in cells exposed to soy leghemoglobin 
preparation.
    To address the allergenicity potential of soy leghemoglobin 
preparation, the petition provided results from a study on the 
digestibility of soy leghemoglobin preparation, bioinformatic analyses 
of soy leghemoglobin protein and of P. pastoris proteins identified in 
the soy leghemoglobin preparation, and a memorandum from an expert in 
the field of food allergies on the potential allergenicity of soy 
leghemoglobin. We conclude that soy leghemoglobin and P. pastoris 
proteins in the soy leghemoglobin preparation are readily digested at 
acidic pH conditions found in the stomach and denatured at normal 
cooking temperatures. We also agree with the petitioner that the 
totality of evidence supports the conclusion that soy leghemoglobin 
protein and P. pastoris proteins present in soy leghemoglobin 
preparation do not pose risks of allergenicity when consumed, even for 
people who are allergic to foods containing soybean protein (Ref. 2).

V. Conclusion

    Based on the data and information in the petition and other 
available relevant information, we conclude that the petitioned use of 
soy leghemoglobin as a color additive in ground beef analogue products 
is safe, provided the amount of soy leghemoglobin protein does not 
exceed 0.8 percent by weight of the uncooked product. We further 
conclude that this color additive will achieve its intended technical 
effect and is suitable for the petitioned use. Therefore, we are 
amending the color additive regulations in part 73 to provide for the 
safe use of this color additive as set forth in this document. In 
addition, based on the factors in 21 CFR 71.20(b), we conclude that 
batch certification of soy leghemoglobin is not necessary to protect 
the public health.

VI. Public Disclosure

    In accordance with Sec.  71.15(a) (21 CFR 71.15(a)), the petition 
and the documents that we considered and relied upon in reaching our 
decision to approve the petition will be made available for public 
disclosure (see ADDRESSES). As provided in Sec.  71.15(b), we will 
delete from the documents any materials that are not available for 
public disclosure.

VII. Analysis of Environmental Impact

    As stated in the December 13, 2018, Federal Register notice of 
filing, the petitioner claimed that this action is categorically 
excluded under Sec.  25.32(k) (21 CFR 25.32(k)) because soy 
leghemoglobin would be added directly to food and is intended to remain 
in the food through ingestion by consumers and is not intended to 
replace macronutrients in food. We further stated that if FDA 
determines a categorical exclusion applies, neither an environmental 
assessment nor an environmental impact statement is required. We have 
not received any new information or comments regarding this claim of 
categorical exclusion. We have considered the petitioner's claim of 
categorical exclusion and have determined that this action is 
categorically excluded under Sec.  25.32(k). Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

VIII. Paperwork Reduction Act of 1995

    This final rule contains no collection of information. Therefore, 
clearance by the Office of Management and Budget under the Paperwork 
Reduction Act of 1995 is not required.

IX. Section 301(ll) of the FD&C Act

    Our review of this petition was limited to section 721 of the FD&C 
Act. This final rule is not a statement regarding compliance with other 
sections of the FD&C Act. For example, 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 (21 U.S.C. 355), a biological product licensed under 
section 351 of the Public Health Service Act (42 U.S.C. 262), or a drug 
or biological product for which substantial clinical investigations 
have been instituted and their existence has been made public, unless 
one of the exemptions in section 301(ll)(1) to (4) of the FD&C Act 
applies. In our review of this petition, we did not consider whether 
section 301(ll) of the FD&C Act or any of its exemptions apply to food 
containing this color additive. Accordingly, this final rule should not 
be construed to be a statement that a food containing this color 
additive, if introduced or delivered for introduction into interstate 
commerce, would not violate section 301(ll) of the FD&C Act. 
Furthermore, this language is included in all color additive final 
rules that pertain to food and therefore should not be construed to be 
a statement of the likelihood that section 301(ll) of the FD&C Act 
applies.

X. Objections

    This rule is effective as shown in the DATES section, except as to 
any provisions that may be stayed by the filing of proper objections. 
If you will be adversely affected by one or more provisions of this 
regulation, you may file with the Dockets Management Staff (see 
ADDRESSES) either electronic or written objections. You must separately

[[Page 37576]]

number each objection, and within each numbered objection you must 
specify with particularity the provision(s) to which you object, and 
the grounds for your objection. Within each numbered objection, you 
must specifically state whether you are requesting a hearing on the 
particular provision that you specify in that numbered objection. If 
you do not request a hearing for any particular objection, you waive 
the right to a hearing on that objection. If you request a hearing, 
your objection must include a detailed description and analysis of the 
specific factual information you intend to present in support of the 
objection in the event that a hearing is held. If you do not include 
such a description and analysis for any particular objection, you waive 
the right to a hearing on the objection.
    Any objections received in response to the regulation may be seen 
in the Dockets Management Staff between 9 a.m. and 4 p.m., Monday 
through Friday, and will be posted to the docket at https://www.regulations.gov. We will publish notice of the objections that we 
have received or lack thereof in the Federal Register.

XI. References

    The following references are on display at the Dockets Management 
Staff (see ADDRESSES) and are available for viewing by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also 
available electronically at https://www.regulations.gov.
    1. Memorandum from J.R. Srinivasan, Chemistry Review Team, Division 
of Food Ingredients (DFI), Office of Food Additive Safety (OFAS), 
Center for Food Safety and Applied Nutrition (CFSAN), FDA to E. 
Anderson, DFI, OFAS, CFSAN, FDA, June 20, 2019.
    2. Memorandum from S. Choudhuri, Toxicology Review Team, DFI, OFAS, 
CFSAN, FDA to E. Anderson, DFI, OFAS, CFSAN, FDA, June 21, 2019.

List of Subjects in 21 CFR Part 73

    Color additives, Cosmetics, Drugs, Foods, Medical devices.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
the authority delegated to the Commissioner of the Food and Drugs, 21 
CFR part 73 is amended as follows:

PART 73--LISTING OF COLOR ADDITIVES EXEMPT FROM CERTIFICATION

0
1. The authority citation for part 73 continues to read as follows:

    Authority: 21 U.S.C. 321, 341, 342, 343, 348, 351, 352, 355, 
361, 362, 371, 379e.


0
2. Add Sec.  73.520 to read as follows:


Sec.  73.520  Soy leghemoglobin.

    (a) Identity. (1) The color additive soy leghemoglobin is a 
stabilized product of controlled fermentation of a non-pathogenic and 
non-toxicogenic strain of the yeast, Pichia pastoris, genetically 
engineered to express soy leghemoglobin protein. Soy leghemoglobin 
protein is the principal coloring component of the color additive and 
imparts a reddish-brown color.
    (2) Color additive mixtures made with soy leghemoglobin may contain 
only those diluents that are suitable and are listed in this subpart as 
safe for use in color additive mixtures for coloring foods.
    (b) Specifications. Soy leghemoglobin shall conform to the 
following specifications and shall be free from impurities, other than 
those named, to the extent that such impurities may be avoided by good 
manufacturing practice:
    (1) Soy leghemoglobin protein purity on protein basis (weight/
weight), not less than 65 percent, as determined by sodium dodecyl 
sulfate-polyacrylamide gel electrophoresis.
    (2) Lead, not more than 0.4 milligrams per kilogram (mg/kg) (0.4 
parts per million (ppm)).
    (3) Arsenic, not more than 0.05 mg/kg (0.05 ppm).
    (4) Mercury, not more than 0.05 mg/kg (0.05 ppm).
    (5) Cadmium, not more than 0.2 mg/kg (0.2 ppm).
    (c) Uses and restrictions. Soy leghemoglobin may be safely used in 
ground beef analogue products such that the amount of soy leghemoglobin 
protein does not exceed 0.8 percent by weight of the uncooked ground 
beef analogue product.
    (d) Labeling. The label of the color additive and of any mixture 
prepared therefrom intended solely or in part for coloring purposes 
must conform to Sec.  70.25 of this chapter.
    (e) Exemption from certification. Certification of this color 
additive is not necessary for the protection of the public health, and 
therefore batches thereof are exempt from the certification 
requirements of section 721(c) of the Federal Food, Drug, and Cosmetic 
Act.

    Dated: July 26, 2019.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2019-16374 Filed 7-31-19; 8:45 am]
BILLING CODE 4164-01-P