[Federal Register Volume 83, Number 212 (Thursday, November 1, 2018)]
[Rules and Regulations]
[Pages 54869-54872]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-23863]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 73

[Docket No. FDA-2017-C-6238]


Listing of Color Additives Exempt From Certification; Synthetic 
Iron Oxide

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 expanded safe use of 
synthetic iron oxides as color additives to include use in dietary 
supplement tablets and capsules. This action is in response to a color 
additive petition (CAP) filed by Colorcon, Inc.

DATES: This rule is effective December 4, 2018. 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 December 3, 2018.

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 
December 3, 2018. The https://www.regulations.gov electronic filing 
system will accept comments until 11:59 p.m. Eastern Time at the end of 
December 3, 2018. 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

[[Page 54870]]

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-2017-C-6238 for ``Listing of Color Additives Exempt from 
Certification; Synthetic Iron Oxide.'' 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.'' The 
Agency 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: Molly A. Harry, Center for Food Safety 
and Applied Nutrition, Food and Drug Administration, 5001 Campus Dr., 
College Park, MD 20740-3835, 240-402-1075.

SUPPLEMENTARY INFORMATION: 

I. Introduction

    In a document published in the Federal Register on November 9, 2017 
(82 FR 52037), we announced that we filed a color additive petition 
(CAP 7C0308) submitted by Colorcon, Inc., 275 Ruth Rd., Harleysville, 
PA 19438. The petition proposed to amend the color additive regulations 
in Sec.  73.200 Synthetic iron oxide (21 CFR 73.200) by expanding the 
permitted uses of synthetic iron oxides as a color additive to include 
use in dietary supplement tablets and capsules, including coatings and 
printing inks. The petitioner requested that the proposed uses be 
permitted at a maximum use level of 5 milligrams (mg), calculated as 
elemental iron, per day for labeled dosages.

II. Background

    Synthetic iron oxides and their hydrated forms are currently 
approved as color additives for use in human foods and drugs: (1) In 
sausage casings intended for human consumption in an amount not to 
exceed 0.10 percent by weight of the finished food (Sec.  73.200); (2) 
in soft and hard candy, mints, and chewing gum at levels consistent 
with good manufacturing practice (GMP), except that they may not be 
used to color foods for which standards of identity have been issued 
under section 401 of the Federal Food, Drug, and Cosmetic Act (21 
U.S.C. 431) (FD&C Act), unless the use of the added color is authorized 
by such standards (Sec.  73.200); and (3) in ingested or topically 
applied drugs with a limit for ingested drugs of 5 mg, calculated as 
elemental iron, per day for labeled or prescribed dosages (21 CFR 
73.1200). Synthetic iron oxides also are approved for use as color 
additives in cosmetics generally, including cosmetics applied to the 
area of the eye, in amounts consistent with GMP (21 CFR 73.2250).
    Synthetic iron oxides and their hydrated forms include red iron 
oxide (synthetic hematite), yellow iron oxide (synthetic geoethite), 
black iron oxide (synthetic magnetite), and brown iron oxide, which is 
a blend of various iron oxides. For the subject petition, synthetic 
iron oxides are intended for coloring dietary supplement tablets and 
capsules, including coatings for tablets and capsules and printing inks 
applied to dietary supplement tablets and capsules, such that the total 
amount of elemental iron in the dietary supplements does not exceed 5 
mg per day for labeled dosages.

III. Safety Evaluation

    Under section 721(b)(4) of the FD&C Act (21 U.S.C. 379e(b)(4)), a 
color additive cannot be listed for a particular use unless the data 
and information available to FDA establish that the color additive is 
safe for that use. FDA's color additive regulations in 21 CFR 70.3(i) 
define ``safe'' to mean that there is convincing evidence that 
establishes with reasonable certainty that no harm will result from the 
intended use of the color additive.
    To establish with reasonable certainty that a color additive 
intended for use in foods is not harmful under its intended conditions 
of use, we consider the projected human dietary exposure to the color 
additive, the additive's toxicological data, and other relevant 
information (such as published literature) available to us. We compare 
an individual's estimated exposure, or estimated daily intake (EDI), of 
the color additive from all sources to an acceptable daily intake level 
established by toxicological data. The EDI is determined by projections 
based on the amount of the color additive proposed for use in 
particular foods and on data regarding the amount consumed from all 
sources of the color additive. We commonly use the EDI for the 90th 
percentile consumer of a color additive as a measure of high chronic 
exposure.

[[Page 54871]]

IV. Safety of Petitioned Use of Color Additive

A. Estimated Dietary Exposure

    To support the safety of the proposed use of synthetic iron oxides, 
Colorcon proposed a maximum use level of the color additive in dietary 
supplements such that the total amount of elemental iron consumed shall 
not exceed 5 mg per day for labeled dosages. Using 2-day food 
consumption data from the 2009-2010 National Health and Nutrition 
Examination Survey (NHANES) food consumption database, Colorcon 
estimated exposure to elemental iron from the proposed use in dietary 
supplements. From the NHANES data, Colorcon determined that 2 dietary 
supplements are consumed in a 24-hour period at the mean, and 4 at the 
90th percentile. We note that these values could represent 2 or 4 
different dietary supplements, respectively, with each supplement 
containing up to 5 mg elemental iron. Considering this, FDA has 
estimated exposure to elemental iron resulting from the petitioned use 
of synthetic iron oxides in dietary supplements as described below.
    Using more recent NHANES data (2011-2014), FDA determined that the 
U.S. population aged 2 years and older consumes 2 dietary supplements 
per day at the mean and 5 supplements per day at the 90th percentile 
(Ref. 1). In estimating exposure, we presumed that: (1) Each dietary 
supplement could contain up to 5 mg elemental iron for labeled dosages 
from the use of synthetic iron oxides, resulting in an exposure to 
elemental iron of 10 milligrams per person per day (mg/p/d) at the mean 
and 25 mg/p/d at the 90th percentile; (2) all dietary supplements would 
contain added synthetic iron oxides; and (3) the added synthetic iron 
oxides would contain a maximum amount (72 percent) of elemental iron; 
therefore, the use level of 5 mg elemental iron per labeled dosage of 
dietary supplement would result in a use level of 6.9 mg synthetic iron 
oxides per labeled dosage of dietary supplement (Ref. 1).
    We estimated an upper-bound exposure to synthetic iron oxides from 
its use as a color additive in dietary supplement tablets and capsules 
and in coatings applied to dietary supplement tablets and capsules, but 
excluding its use in printing inks applied on tablets and capsules, to 
be 13.8 mg/p/d at the mean and 34.5 mg/p/d at the 90th percentile for 
the U.S. population aged 2 years and older (Ref. 1). The exposure to 
elemental iron from the petitioned use of synthetic iron oxides is 
estimated to be 10 mg/p/d at the mean and 25 mg/p/d at the 90th 
percentile. Regarding exposure to elemental iron resulting from the 
proposed use of synthetic iron oxides in printing inks applied on 
tablets and capsules, we estimated that the amount of elemental iron 
from the use of synthetic iron oxides in inks for use on tablets and 
capsules is no more than 5.4 micrograms ([micro]g) per tablet or 
capsule, which corresponds to 10.8 [micro]g elemental iron/p/d at the 
mean (2 tablets or capsules) and 27 [micro]g elemental iron/p/d at the 
90th percentile level (5 tablets or capsules) (Ref. 1). This exposure 
is negligible compared to that for use of elemental iron as a color 
additive in tablets and capsules and in coatings applied to dietary 
supplements.
    In the final rule approving the use of synthetic iron oxides for 
use in candy, mints, and chewing gum (80 FR 14839, March 20, 2015), FDA 
discussed that elemental iron from synthetic iron oxides is not readily 
bioavailable and is poorly absorbed by the human gastrointestinal tract 
(80 FR 14839 at 14840). Approximately 18 percent of iron from 
conventional foods and dietary supplements is bioavailable and about 1 
percent of iron from synthetic iron oxides is bioavailable (Ref. 1). 
Taking into account the bioavailability of iron from synthetic iron 
oxides, the exposure to elemental iron from the petitioned use of 
synthetic iron oxides for the U.S. population aged 2 years and older is 
estimated to be 0.10 mg/p/d at the mean and 0.25 mg/p/d at the 90th 
percentile (Ref 1).
    We previously estimated the cumulative exposure to bioavailable 
elemental iron for the U.S. population to be 3.48 mg/p/d at the mean 
(Ref. 1). Therefore, considering the exposure of 0.10 mg/p/d for 
elemental iron from the proposed use of synthetic iron oxides, the 
updated cumulative exposure to bioavailable iron from the current and 
proposed sources for the U.S. population aged 2 years and older is 
estimated to be 3.6 mg/p/d at the mean and 7.2 mg/p/d at the pseudo-
90th percentile (Ref. 1).

B. Acceptable Intake Level for Iron

    In 2001, the Institute of Medicine (IOM) published a report on 
dietary reference intakes for vitamins and minerals (Ref. 2). In the 
report, IOM determined dietary reference intakes and upper limits (ULs) 
for iron of 40 mg/d for children (2-13 years of age) and 45 mg/d for 
adolescents and adults (14 years and older) (Ref. 2). The IOM considers 
the UL as the highest daily intake level of a nutrient that poses no 
risk of adverse effects with chronic consumption of the nutrient (Ref. 
2). The UL is determined using a risk assessment model developed 
specifically for nutrients and may consider intake from such sources as 
food, water, nutrient supplements, and pharmacological agents (Ref. 2). 
The dose-response assessment, which concludes with an estimate of the 
UL, is built upon three toxicological concepts commonly used in 
assessing the risk of exposures to chemical substances: No-observed-
adverse-effect level, lowest-observed-effect level, and an uncertainty 
factor (Ref. 2).
    We considered the UL established by IOM for iron (45 mg/d) relative 
to the cumulative exposure for bioavailable elemental iron of 7.2 mg/p/
d (at the 90th percentile for U.S. population 2 years and older) as the 
primary basis for assessing the safety of exposure to elemental iron 
from the proposed use of synthetic iron oxides (Ref. 3). Additionally, 
we reviewed scientific articles and other relevant studies available to 
FDA on the safety of iron (Ref. 3). Because the 90th percentile 
exposure estimate to bioavailable elemental iron from all dietary 
sources, including the proposed use of synthetic iron oxides to color 
dietary supplement tablets and capsules, is significantly below the UL 
determined by IOM, we conclude that there is a reasonable certainty of 
no harm from the proposed use of synthetic iron oxide as a color 
additive in dietary supplement tablets and capsules (Ref. 3).

V. Conclusion

    FDA reviewed the data and information in the petition and other 
available relevant material and determined the petitioned use of 
synthetic iron oxides in dietary supplement tablets and capsules is 
safe. We further conclude that the color additive will achieve its 
intended technical effect and is suitable for the petitioned use. 
Consequently, we are amending the color additive regulations in 21 CFR 
part 73 as set forth in this document. In addition, based upon the 
factors listed in 21 CFR 71.20(b), we continue to conclude that 
certification of synthetic iron oxides is not necessary for the 
protection of public health.

VI. Public Disclosure

    In accordance with Sec.  71.15 (21 CFR 71.15), 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 FOR FURTHER INFORMATION CONTACT). As provided in Sec.  71.15, we 
will delete from the documents any materials that are not available for 
public disclosure.

[[Page 54872]]

VII. Analysis of Environmental Impact

    We previously considered the environmental effects of this rule, as 
stated in the November 9, 2017, Federal Register notification of 
petition for CAP 7C0308 (82 FR 52037). We stated that we had 
determined, under 21 CFR 25.32(k), that this action is of a type that 
does not individually or cumulatively have a significant effect on the 
human environment such that neither an environmental assessment nor an 
environmental impact statement is required. We have not received any 
new information or comments that would affect our previous 
determination.

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 Federal Food, Drug, and Cosmetic 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 
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 marked with an asterisk (*) are on display 
in 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. The reference without an asterisk is not on public 
display at https://www.regulations.gov because it has copyright 
restriction but is available at the website address. The reference 
without an asterisk is available for viewing only at the Dockets 
Management Staff. FDA has verified the website address, as of the date 
this document publishes in the Federal Register, but websites are 
subject to change over time.

*1. Memorandum from D. Doell, Chemistry Review Team, Division of 
Petition Review, Office of Food Additive Safety (OFAS), Center for 
Food Safety and Applied Nutrition (CFSAN), FDA to M. Harry, Division 
of Petition Review, OFAS, CFSAN, FDA, September 17, 2018.
2. Institute of Medicine, ``Dietary Reference Intakes for Vitamin A, 
Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, 
Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc.'' 
Washington, DC: National Academies Press (U.S.); 2001. https://www.ncbi.nlm.nih.gov/books/NBK222310/pdf/Bookshelf_NBK222310.pdf.
*3. Memorandum from T. Thurmond, Toxicology Team, Division of 
Petition Review, OFAS, CFSAN, FDA to M. Harry, Division of Petition 
Review, OFAS, CFSAN, FDA, September 17, 2018.

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 
authority delegated to the Commissioner of 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. Section 73.200 is amended by revising paragraph (c)(1) to read as 
follows:


Sec.  73.200   Synthetic iron oxide.

* * * * *
    (c) * * *
    (1) Synthetic iron oxide may be safely used for human food use 
subject to the following restrictions:
    (i) In sausage casings intended for human consumption in an amount 
not exceeding 0.10 percent by weight of the finished food.
    (ii) In soft and hard candy, mints, and chewing gum at levels 
consistent with good manufacturing practice, except that it may not be 
used to color foods for which standards of identity have been issued 
under section 401 of the Federal Food, Drug, and Cosmetic Act, unless 
the use of the added color is authorized by such standards.
    (iii) In dietary supplement tablets and capsules, including 
coatings and printing inks, such that the total amount of elemental 
iron per day for labeled dosages does not exceed 5 milligrams.
* * * * *

    Dated: October 26, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-23863 Filed 10-31-18; 8:45 am]
 BILLING CODE 4164-01-P