[Federal Register Volume 77, Number 130 (Friday, July 6, 2012)]
[Rules and Regulations]
[Pages 39921-39923]
From the Federal Register Online via the Government Printing 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