[Federal Register Volume 77, Number 130 (Friday, July 6, 2012)]
[Rules and Regulations]
[Pages 39921-39923]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2012-16581]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 74
[Docket No. FDA-2011-C-0050]
D&C Red No. 6 and D&C Red No. 7; Change in Specification
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA or the Agency) is
revising its requirements for D&C Red No. 6 and D&C Red No. 7 by
replacing the current specification for ``Ether-soluble matter'' with a
maximum limit of 0.015 percent for the recently identified impurity 1-
[(4-methylphenyl)azo]-2-naphthalenol. This action is in response to a
petition filed by Sun Chemical Corp.
DATES: This rule is effective August 7, 2012, except as to any
provisions that may be stayed by the filing of proper objections.
Submit either electronic or written objections and requests for a
hearing by August 6, 2012. See section XI of this document for
information on the filing of objections.
ADDRESSES: You may submit objections and requests for a hearing,
identified by Docket No. FDA-2011-C-0050, by any of the following
methods:
Electronic Submissions: Submit electronic objections in the
following way:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.
Written Submissions: Submit written objections in the following
ways:
Fax: 301-827-6870.
Mail/Hand delivery/Courier (for paper or CD-ROM
submissions): Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
Instructions: All submissions received must include the Agency name
and Docket No. FDA-2011-C-0050 for this rulemaking. All objections
received may be posted without change to http://www.regulations.gov,
including any personal information provided. For detailed instructions
on submitting objections, see section XI of this document.
Docket: For access to the docket to read background documents or
objections received, go to http://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 Division of
Dockets Management, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Teresa A. Croce, Center for Food
Safety and Applied Nutrition (HFS-265), Food and Drug Administration,
5100 Paint Branch Pkwy., College Park, MD 20740-3835, 240-402-1281.
SUPPLEMENTARY INFORMATION:
I. Background
In a notice published in the Federal Register of April 14, 2011 (76
FR 20992), FDA announced that Sun Chemical Corp., 5020 Spring Grove
Ave., Cincinnati, OH 45232, had filed a color additive petition (CAP
1C0290) requesting that FDA amend its regulations for D&C Red No. 6 and
D&C Red No. 7 by replacing the current specification for ``Ether-
soluble matter'' with a maximum limit of 0.015 percent for the recently
identified impurity 1-[(4-methylphenyl)azo]-2-naphthalenol. As part of
CAP 1C0290, Sun Chemical Corp. also requested that FDA remove Appendix
A in part 74 (21 CFR part 74), which pertains to the ether-soluble
matter specification.
D&C Red No. 6 and D&C Red No. 7 are principally monosulfo monoazo
dyes prepared by the coupling of diazotized 2-amino-5-
methylbenzenesulfonic acid with 3-hydroxy-2-naphthalenecarboxylic acid
in alkaline medium. D&C Red No. 6 is produced as the disodium salt,
whereas D&C Red No. 7 is the corresponding monocalcium salt. D&C Red
No. 6 is listed in Sec. 74.1306 for use in coloring drugs and in Sec.
74.2306 for use in coloring cosmetics. D&C Red No. 7 is listed in Sec.
74.1307 for use in coloring drugs and in Sec. 74.2307 for use in
coloring cosmetics. The identity and specifications in Sec. Sec.
74.1306 and 74.1307 are referenced by Sec. Sec. 74.2306 and 74.2307.
Both color additives are required to be batch certified by FDA before
they may legally be used in drugs and cosmetics marketed in the United
States.
II. Regulatory History
In the Federal Register of December 28, 1982 (47 FR 57681), FDA
published a final rule that permanently listed D&C Red No. 6 and D&C
Red No. 7 for use in coloring drugs and cosmetics. The final rule
described how D&C Red Nos. 6 and 7 contained ether-soluble matter for
which the proponents of the color additives were not able to determine
the chemical identity. FDA's final rule established a specification for
ether-
[[Page 39922]]
soluble matter for both color additives, determined by a pass/fail test
described in Appendix A of part 74. In the specified test, ether-
soluble matter is extracted from each new sample submitted for batch
certification and analyzed by visible spectrophotometry. As explained
in the final rule, FDA determined that spectrophotometric analysis
provided a means of measuring the ether-soluble matter that may be
present in each batch. Appendix A includes a reference spectrum that
was based on the D&C Red No. 6 lot (the D&C No. 6 reference lot) that
was used for toxicology testing in support of the permanent listing of
D&C Red No. 6 and D&C Red No. 7. The sample passes the test if the
absorption spectrum of the analyte does not exceed the reference
spectrum in Appendix A at any wavelength. The reference spectrum
represents 150 percent of the ether-soluble matter in the D&C Red No. 6
reference lot. The test is not capable of further characterizing the
analyte.
III. Petitioned Request
Sun Chemical Corp.'s petition is based on the recent identification
of 1-[(4-methylphenyl)azo]-2-naphthalenol (CAS No. 6756-41-8), the
uncarboxylated-unsulfonated homolog of the dye component, as the major
component of the ether-soluble matter. The identity of the ether-
soluble matter was confirmed by FDA using liquid chromatography/mass
spectrometry (LC/MS) (Ref. 1). As part of this work, FDA chemists
prepared and characterized a reference standard for 1-[(4-
methylphenyl)azo]-2-naphthalenol for LC analysis (Ref. 1). FDA chemists
also determined that the D&C Red No. 6 reference lot, which was used as
the reference for Appendix A, contains 0.0099 percent of 1-[(4-
methylphenyl)azo]-2-naphthalenol (Ref. 1).
In its petition, Sun Chemical Corp. notes that the spectrum in
Appendix A of part 74 represents 150 percent of the ether-soluble
matter in the lot that was used as the reference for the appendix, and
that this lot was found to contain 0.0099 percent of 1-[(4-
methylphenyl)azo]-2-naphthalenol. Based on this finding, the company
notes that the pass test result (150 percent) of 0.0099 percent is
0.015 percent and that 0.015 percent therefore corresponds to the
maximum amount of ether-soluble matter permitted in D&C Red Nos. 6 and
7. Accordingly, Sun Chemical Corp. requests 0.015 percent as the
specification limit for 1-[(4-methylphenyl)azo]-2-naphthalenol. In
addition, Sun Chemical Corp. requests that Appendix A be removed from
part 74 and asks that the specification for ether-soluble matter in
Sec. Sec. 74.1306 and 74.1307 (which refers to the pass test in
Appendix A) be replaced.
IV. Exposure Evaluation
In the final rule permanently listing D&C Red No. 6 and D&C Red No.
7, the acute cumulative exposure to these color additives was
calculated to be 8 milligrams per person per day (mg/p/d), and the
chronic exposure was calculated to be 2 mg/p/d (47 FR 57681 at 57685).
These estimates have not changed as a result of the subject petition
because both D&C Red No. 6 and D&C Red No. 7 are intended to be used in
the same manner as currently permitted. In addition, the maximum
amounts of ether-soluble matter permitted in D&C Red Nos. 6 and 7 have
not changed, as the proposed specification limit, 0.015 percent,
corresponds to the pass test result in Appendix A (150 percent of
0.0099 percent is 0.015 percent). Based on the petitioner's proposed
specification limit of 0.015 percent and the exposure to D&C Red Nos. 6
and 7 from their regulated uses, FDA determined that the short-term
(acute) exposure would be no greater than 1.2 micrograms per person per
day ([mu]g/p/d), and the lifetime average (chronic) exposure to this
impurity would be no greater than 0.3 [mu]g/p/d. FDA concludes that no
increase in exposure to 1-[(4-methylphenyl)azo]-2-naphthalenol is
expected as a result of the proposed changes to Sec. Sec. 74.1306,
74.1307, 74.2306, and 74.2307 because the maximum amount of this
impurity permitted in the color additives has not changed (Ref. 2).
FDA also notes that it conducted a survey of the amounts of 1-[(4-
methylphenyl)azo]-2-naphthalenol in D&C Red No. 6 and D&C Red No. 7
straight colors and lakes. In addition to analyzing the D&C Red No. 6
reference lot discussed earlier, FDA analyzed 25 other lots: 4 other
lots of D&C Red No. 6, 4 lots of D&C Red No. 7, 8 lots of D&C Red No. 6
lake, and 9 lots of D&C Red No. 7 lake. Of these 25 other lots, only 3
contained detectable amounts of the impurity, specifically, 0.0006
percent, 0.0008 percent, and 0.002 percent (Ref. 1). FDA also analyzed
for 1-[(4-methylphenyl)azo]-2-naphthalenol in samples of D&C Red No. 6
and D&C Red No. 7 submitted for batch certification between July 2009
and January 2011. Sixty-four samples of D&C Red Nos. 6 and 7 from eight
domestic and foreign manufacturers were analyzed by LC for the
impurity. All of the results obtained were well below 0.015 percent,
and the average amount found, 0.0016 percent, is nearly an order of
magnitude lower than the petitioned specification limit (Ref. 3).
V. Safety Evaluation
Under section 721(b)(4) of the Federal Food, Drug, and Cosmetic Act
(21 U.S.C. 379e(b)(4)), a color additive may not be listed for a
particular use unless a fair evaluation of the data and information
available to FDA establishes that the color additive is safe for that
use. FDA's color additive regulations at 21 CFR 70.3(i) define safe as
the existence of ``convincing evidence that establishes with reasonable
certainty that no harm will result from the intended use of the color
additive.'' Numerous toxicology studies on D&C Red Nos. 6 and 7 were
performed to support their permanent listing (47 FR 57681). The color
additives tested contained the ether-soluble matter, now identified as
primarily 1-[(4-methylphenyl)azo]-2-naphthalenol. Based on the results
from these studies, the Agency concluded that D&C Red Nos. 6 and 7
(including the ether-soluble matter as determined by the test described
in Appendix A) for use in drugs and cosmetics, excluding use in the
area of the eye (47 FR 57681 at 57686), is safe. Therefore, although
the chemical identity of the principal component of the ether-soluble
matter (i.e., 1-[(4-methylphenyl)azo]-2-naphthalenol) was not known
when D&C Red Nos. 6 and 7 were permanently listed, the safety of the
color additives, which contained the unknown ether-soluble matter, was
assessed by FDA through the results of toxicological testing of the
color additives containing this impurity.
The requested revision would not change the composition of D&C Red
No. 6 or D&C Red No. 7 specified in the applicable color additive
regulations, including the permissible level of the impurity. Nor would
it change the authorized intended use. Therefore, the Agency concludes
that the proposed revision would not affect FDA's safety evaluation in
the final rule listing D&C Red No. 6 or D&C Red No. 7. Because there is
no increase in the intake of the impurity of D&C Red No. 6 and D&C Red
No. 7 beyond a level that has already been established as safe, FDA has
no safety concerns regarding the petitioned revision.
VI. Proposed Removal of Appendix A
FDA will no longer analyze the impurity by visible
spectrophotometry when new samples of the color additive are submitted
for batch certification. Instead, FDA will test the impurity using
reversed-phase high performance liquid chromatography and will continue
to do so for as long as the
[[Page 39923]]
Agency determines that reversed-phase high performance liquid
chromatography is appropriate. Because Appendix A of part 74 describes
the spectrophotometry test for the ether-soluble matter, and because
FDA will no longer analyze the impurity using spectrophotometry, FDA
agrees with Sun Chemical Corp.'s request that Appendix A be removed
from part 74.
VII. Conclusion
FDA reviewed data in the petition from Sun Chemical Corp. and other
relevant data and information to evaluate the safety of revising its
requirements for D&C Red Nos. 6 and 7 by replacing the current
specification for ether-soluble matter with a maximum limit of 0.015
percent for the impurity 1-[(4-methylphenyl)azo]-2-naphthalenol and by
removing Appendix A in part 74, which pertains to the ether-soluble
matter specification. Based on this information, the Agency does not
have any safety concerns with the proposed amendment and concludes that
D&C Red Nos. 6 and 7 will continue to be safe and suitable for their
listed uses in drugs and in cosmetics. Therefore, the regulations in
part 74 should be amended as set forth in this document. In addition,
FDA will no longer analyze the impurity by visible spectrophotometry
when new samples of the color additive are submitted for batch
certification. Instead, FDA will test the impurity using reversed-phase
high performance liquid chromatography.
VIII. Public Disclosure
In accordance with Sec. 71.15 (21 CFR 71.15), the petition and the
documents that FDA considered and relied upon in reaching its decision
to approve the petition will be made available for inspection at the
Center for Food Safety and Applied Nutrition by appointment with the
information contact person (see FOR FURTHER INFORMATION CONTACT). As
provided in Sec. 71.15, the Agency will delete from the documents any
material that is not available for public disclosure before making the
documents available for inspection.
IX. Environmental Impact
The Agency has previously considered the environmental effects of
this rule as announced in the notice of filing for CAP 1C0290 (76 FR
20992). No new information or comments have been received that would
affect the Agency's previous determination that there is no significant
impact on the human environment and that an environmental impact
statement is not required.
X. 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.
XI. Objections
This rule is effective as shown in the DATES section of this
document; except as to any provisions that may be stayed by the filing
of proper objections. Any person who will be adversely affected by this
regulation may file with the Division of Dockets Management (see
ADDRESSES) either electronic or written objections. Each objection
shall be separately numbered, and each numbered objection shall specify
with particularity the provisions of the regulation to which objection
is made and the grounds for the objection. Each numbered objection on
which a hearing is requested shall specifically so state. Failure to
request a hearing for any particular objection shall constitute a
waiver of the right to a hearing on that objection. Each numbered
objection for which a hearing is requested shall include a detailed
description and analysis of the specific factual information intended
to be presented in support of the objection in the event that a hearing
is held. Failure to include such a description and analysis for any
particular objection shall constitute a waiver of the right to a
hearing on the objection. It is only necessary to send one set of
documents. Identify documents with the docket number found in brackets
in the heading of this document. Any objections received in response to
the regulation may be seen in the Division of Dockets Management
between 9 a.m. and 4 p.m., Monday through Friday. FDA will publish
notice of the objections that the Agency has received or lack thereof
in the Federal Register.
XII. References
The following references have been placed on display in the
Division of Dockets Management (see ADDRESSES) and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
1. B.P. Harp, A.L. Scher, H.-H.W. Yang, et al., ``Reversed-Phase LC
Determination of Two Manufacturing Intermediates, the Unsulfonated
Subsidiary Color, and 4-Methyl-Sudan I in D&C Red No. 6, D&C Red No.
7, and Their Lakes,'' Journal of AOAC International, vol. 92, pp.
888-895, 2009.
2. Memorandum to the file, CAP 1C0290 from H. Lee, FDA to T. Croce,
FDA dated February 23, 2011.
3. Memorandum to the file, CAP 1C0290 from B. Harp, FDA to T. Croce,
FDA dated April 18, 2011.
List of Subjects in 21 CFR Part 74
Color additives, Cosmetics, Drugs.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, and
redelegated to the Director, Center for Food Safety and Applied
Nutrition, 21 CFR part 74 is amended as follows:
PART 74--LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION
0
1. The authority citation for 21 CFR part 74 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 74.1306 is amended by removing the entry for ``Ether-soluble
matter'' in paragraph (b) and adding in its place a specification for
``1-[(4-methylphenyl)azo]-2-naphthalenol'' to read as follows:
Sec. 74.1306 D&C Red No. 6.
* * * * *
(b) * * *
1-[(4-methylphenyl)azo]-2-naphthalenol, not more than 0.015
percent.
* * * * *
0
3. Section 74.1307 is amended by removing the entry for ``Ether-soluble
matter'' in paragraph (b) and adding in its place a specification for
``1-[(4-methylphenyl)azo]-2-naphthalenol'' to read as follows:
Sec. 74.1307 D&C Red No. 7.
* * * * *
(b) * * *
1-[(4-methylphenyl)azo]-2-naphthalenol, not more than 0.015
percent.
* * * * *
0
4. Part 74 is amended by removing Appendix A to Part 74--The Procedure
for Determining Ether Soluble Material in D&C Red Nos. 6 and 7.
Dated: June 29, 2012.
Dennis M. Keefe,
Director, Office of Food Additive Safety, Center for Food Safety and
Applied Nutrition.
[FR Doc. 2012-16581 Filed 7-5-12; 8:45 am]
BILLING CODE 4160-01-P