[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