[Federal Register Volume 63, Number 77 (Wednesday, April 22, 1998)]
[Rules and Regulations]
[Pages 19799-19802]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-10578]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 310

[Docket Nos. 75N-183F, 75N-183D, and 80N-0280]
RIN 0910-AA01


Status of Certain Additional Over-the-Counter Drug Category II 
and III Active Ingredients

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule 
stating that certain ingredients in over-the-counter (OTC) drug 
products are not generally recognized as safe and effective or are 
misbranded. FDA is issuing this final rule after considering the 
reports and recommendations of various OTC drug advisory review panels 
and public comments on proposed agency regulations, which were issued 
in the form of a tentative final monograph (proposed rule). Based on 
the absence of substantive comments in opposition to the agency's 
proposed nonmonograph status for these ingredients, as well as the 
failure of interested parties to submit new data or information to FDA 
under the regulation, the agency has determined that the presence of 
these ingredients in an OTC drug product would result in that drug 
product not being generally recognized as safe and effective or would 
result in misbranding. This final rule is part of the ongoing review of 
OTC drug products conducted by FDA.

DATES: Effective October 19, 1998.

FOR FURTHER INFORMATION CONTACT: Gerald M. Rachanow, Center for Drug 
Evaluation and Research (HFD-560), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-2307.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of November 7, 1990 (55 FR 46914), FDA 
published under Sec. 330.10(a)(7)(ii) (21 CFR 330.10(a)(7)(ii)), a 
final rule on the status of certain OTC drug Category II and III active 
ingredients. That final rule declared as not generally recognized as 
safe and effective certain active ingredients that had been proposed as 
nonmonograph (Category II or Category III) under the agency's OTC drug 
review. The periods for submission of comments and new data following 
the publication of a notice of proposed rulemaking (NPRM) had closed 
and no significant comments or new data had been submitted to upgrade 
the status of these ingredients. In each instance, a final rule for the 
class of ingredients involved had not been published to date.
    In the Federal Register of May 10, 1993 (58 FR 27636), FDA 
published a final rule establishing that certain additional active 
ingredients in OTC drug products are not generally recognized as safe 
and effective or are misbranded. That final rule included active 
ingredients from a number of OTC drug rulemakings that were not covered 
by the November 7, 1990, final rule. (See Table I (58 FR 27636 at 27639 
to 27641) for a list of OTC drug rulemakings and active ingredients 
covered by that final rule.)
    At that time, there were other OTC drug review rulemakings for 
which the period for submission of comments and/or new data was still 
pending. Those periods have now closed, and there are a number of 
active ingredients for which no significant comments or new data were 
submitted. In each instance, a final rule for the class of ingredients 
involved has not been published to date. This final rule addresses some 
of the Category II and Category III active ingredients in those classes 
of ingredients, specifically active ingredients considered in the 
rulemakings for OTC vaginal contraceptive, first aid antiseptic, and 
antimicrobial diaper rash drug products.
    In the advance notice of proposed rulemaking (ANPRM) for OTC 
vaginal contraceptive drug products (45 FR 82014, December 12, 1980), 
the Advisory Review Panel on OTC Contraceptives and Other Vaginal Drug 
Products placed phenylmercuric acetate and phenylmercuric nitrate in 
Category II for safety and placed dodecaethylene glycol monolaurate 
(polyethylene glycol 600 monolaurate), laureth 10S, and 
methoxypolyoxyethyleneglycol 550 laurate in Category III for efficacy. 
In the tentative final monograph (TFM) for OTC vaginal contraceptive 
drug products (60 FR 6892, February 3, 1995), the agency proposed that 
all of these ingredients be nonmonograph. In response to this TFM 
(NPRM), the agency received no comments or data relating to the safety 
and effectiveness of these ingredients.
    In the ANPRM for mercury-containing drug products for OTC topical 
antimicrobial use (47 FR 436, January 5, 1982), the Advisory Review 
Panel on OTC Miscellaneous External Drug Products placed all mercury 
compounds in Category II for topical antimicrobial use. This included 
the following ingredients: Ammoniated mercury; calomel (mercurous 
chloride); merbromin (mercurochrome); mercuric chloride (bichloride of 
mercury, mercury chloride); mercufenol chloride (ortho-
chloromercuriphenol, ortho-hydroxyphenylmercuric chloride); mercuric 
salicylate; mercuric sulfide (red mercuric sulfide); mercuric oxide, 
yellow; mercury; mercury chloride; mercury oleate; nitromersol; para-
chloromercuriphenol; phenylmercuric nitrate; thimerosal; vitromersol; 
and zyloxin. In the NPRM for OTC first aid antiseptic drug products (56 
FR 33644, July 22, 1991), the agency proposed that all of these 
ingredients were either Category II or Category III. In response to 
this NPRM, the agency received no comments or data relating to the 
safety and effectiveness of these ingredients.
    In an amendment to the proposed rulemaking for OTC topical 
antimicrobial drug products (55 FR 25246, June 20, 1990), the agency 
proposed that p-chloromercuriphenol and all other ingredients 
containing mercury were Category II for the treatment and prevention of 
diaper rash. In response to this NPRM, the agency received no comments 
or data relating to the safety and effectiveness of these ingredients.

II. Affected Rulemakings and Category II and III Ingredients

    Table I of this document lists the titles and docket numbers of the 
specific rulemakings containing active ingredients that are addressed 
in this document, together with the publication dates of the ANPRM and 
the NPRM, as well as the closing dates for comments and submission of 
new data for each rulemaking. FDA advises that the active ingredients 
discussed in this document (see Table II of section II of this 
document) will not be included in the relevant final monographs because 
they have not been shown to be generally recognized as safe and 
effective for their intended use. The agency further advises that these 
ingredients should be eliminated from OTC drug products 6 months after 
the date of publication in the Federal Register of this final rule 
regardless of whether further testing is undertaken to justify future 
use.

[[Page 19800]]

    The agency points out that publication of a final rule does not 
preclude a manufacturer's testing an ingredient. New, relevant data can 
be submitted to the agency at a later date as the subject of a new drug 
application that may provide for prescription or OTC marketing status. 
(See part 314 (21 CFR part 314).) As an alternative, where there are 
adequate data establishing general recognition of safety and 
effectiveness, such data may be submitted in an appropriate citizen 
petition to amend or establish a monograph, as appropriate. (See 
Sec. 10.30 (21 CFR 10.30).)

        Table I.--OTC Drug Rulemakings Covered by This Final Rule       
------------------------------------------------------------------------
                                Publication      Comment      New data  
    Rulemaking and action          date       closing date  closing date
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(1) Vaginal contraceptive                                               
 drug products                                                          
  (Docket No. 80N-0280)                                                 
    Advance notice of         December 12,    March 12,     Not         
     proposed rulemaking       1980            1981          applicable 
     (ANPRM)                                                 (N/A)      
    Notice of proposed        February 3,     June 5, 1995  February 5, 
     rulemaking (NPRM)         1995                          1996       
(2) First aid antiseptic                                                
 drug products                                                          
  (Docket No. 75N-0183)                                                 
    ANPRM                     January 5,      April 5,      N/A         
                               1982            1982                     
  (Docket No. 75N-183F)                                                 
    NPRM                      July 22, 1991   January 2,    July 22,    
                                               1992          1992       
(3) Antimicrobial diaper                                                
 rash drug products                                                     
  (Docket No. 75N-0183)                                                 
    ANPRM                     September 7,    December 6,   January 5,  
                               1982            1982          1983       
  (Docket No. 75N-183D)                                                 
    NPRM                      June 20, 1990   December 17,  June 20,    
                                               1990          1991       
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    Based on the criteria discussed above, FDA concludes that the 
following ingredients are not generally recognized as safe and 
effective and are misbranded when labeled as OTC drugs for the 
following uses:

                                Table II.--Ingredients Covered by This Final Rule                               
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                                                              Ingredient classification                         
    Rulemaking and ingredients     -----------------------------------------------------------------------------
                                    Advance notice of proposed rulemaking      Notice of proposed rulemaking    
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(1) First aid antiseptic drug                                                                                   
 products:                                                                                                      
  (Docket No. 75N-183F)                                                                                         
    Ammoniated mercury                                              II                                     II   
    Calomel (mercurous chloride)                                    II                                    III   
    Merbromin (mercurochrome)                                       II                                    III   
    Mercufenol chloride (ortho-                                                                                 
     chloromercuriphenol, ortho-                                                                                
     hydroxyphenylmercuric                                                                                      
     chloride)                                                      II                                    III   
    Mercuric chloride (bichloride                                                                               
     of mercury, mercury chloride)                                  II                                     II   
    Mercuric oxide, yellow                                          II                                     II   
    Mercuric salicylate                                             II                                     II   
    Mercuric sulfide, red                                           II                                     II   
    Mercury                                                         II                                     II   
    Mercury oleate                                                  II                                     II   
    Mercury sulfide                                                 II                                     II   
    Nitromersol                                                     II                                     II   
    Para-chloromercuriphenol                                        II                                     II   
    Phenylmercuric nitrate                                          II                                    III   
    Thimerosal                                                      II                                     II   
    Vitromersol                                                     II                                     II   
    Zyloxin                                                         II                                     II   
(2) Vaginal contraceptive drug                                                                                  
 products:                                                                                                      
  (Docket No. 80N-0280)                                                                                         
    Dodecaethylene glycol                                                                                       
     monolaurate) (polyethylene                                                                                 
     glycol 600 monolaurate)                                       III                                    III   
    Laureth 10S                                                    III                                    III   
    Methoxypolyoxyethyleneglycol                                                                                
     550 laurate                                                   III                                    III   
    Phenylmercuric acetate                                          II                                     II   
    Phenylmercuric nitrate                                          II                                     II   
(3) Antimicrobial diaper rash drug                                                                              
 products:                                                                                                      
  (Docket No. 75N-183D)                                                                                         
    Para-chloromercuriphenol                                        NA                                     II   
    Any other ingredient                                                                                        
     containing mercury                                             NA                                     II   
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[[Page 19801]]

III. The Agency's Final Conclusions on Certain OTC Drug Category II 
and III Ingredients

    No substantive comments or additional data have been submitted to 
the OTC drug review to support any of the ingredients listed in Table 
II of this document as being generally recognized as safe and effective 
for the specified OTC uses. The agency has determined that these 
ingredients should be deemed not generally recognized as safe and 
effective for OTC use before a final monograph for each respective drug 
category is established. Accordingly, any drug product containing any 
of these ingredients and labeled for the OTC use identified in Table II 
of this document will be considered nonmonograph and misbranded under 
section 502 of the Federal Food, Drug, and Cosmetic Act (the act) (21 
U.S.C. 352) and a new drug under section 201(p) of the act (21 U.S.C. 
321(p)) for which an approved application under section 505 of the act 
(21 U.S.C. 355) and part 314 of the regulations is required for 
marketing. As an alternative, where there are adequate data 
establishing general recognition of safety and effectiveness, such data 
may be submitted in a citizen petition to amend the appropriate 
monograph to include any of the above ingredients in OTC drug products 
in Table II of this document. (See Sec. 10.30.) Any OTC drug product 
containing any of the ingredients in Table II of this document and 
labeled for the use identified in Table II of this document initially 
introduced or initially delivered for introduction into interstate 
commerce after the effective date of this final rule that is not the 
subject of an approved application will be in violation of sections 502 
and 505 of the act and, therefore, subject to regulatory action. 
Further, any OTC drug product subject to this final rule that is 
repackaged or relabeled after the effective date of the rule would be 
required to be in compliance with the rule regardless of the date the 
product was initially introduced or initially delivered for 
introduction into interstate commerce. Manufacturers are encouraged to 
comply voluntarily with the rule at the earliest possible date.

IV. Analysis of Impacts

    FDA has examined the impacts of the final rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612). 
Executive Order 12866 directs agencies to assess all costs and benefits 
of available regulatory alternatives and, when regulation is necessary, 
to select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). Under the Regulatory 
Flexibility Act, if a rule has a significant impact on a substantial 
number of small entities, an agency must analyze significant regulatory 
options that would minimize any significant impact of the rule on small 
entities.
    Title II of the Unfunded Mandates Reform Act (2 U.S.C. 1501 et 
seq.) requires that agencies prepare a written statement and economic 
analysis before proposing any rule that may result in an expenditure in 
any 1 year by State, local, and tribal governments, in the aggregate, 
or by the private sector, of $100 million (adjusted annually for 
inflation).
    The agency believes that this final rule is consistent with the 
principles set out in the Executive Order and in these two statutes. 
The purpose of this final rule is to act on the proposed nonmonograph 
status of certain ingredients in advance of finalization of other 
monograph conditions in order to expedite completion of the OTC drug 
review. There are a limited number of products currently marketed that 
will be affected by this rule. Of the 17 mercury active ingredients 
included in the final rule, the agency is aware of 12 OTC drug products 
containing merbromin, 1 product containing phenylmercuric nitrate, and 
7 products containing thimerosal. These products are marketed by eight 
different manufacturers, most of which are considered small entities, 
using the U.S. Small Business Administration designation for this 
industry (750 employees). The agency is not aware of any topical 
antimicrobial diaper rash or vaginal contraceptive drug products 
containing any of the active ingredients included in this final rule.
    Manufacturers of these products will no longer be able to market 
products containing the ingredients included in this final rule after 
its effective date. While the manufacturers will incur a loss of 
revenue for these products, the agency believes the economic impact 
will be minimal for several reasons. A. C. Nielsen (Nielsen), a 
recognized provider of market research business information and 
analysis, maintains product data from a sample of 4,000 retail outlets 
selected to represent the geographical and retail characteristics of 
the U.S. OTC market. Based on these Nielsen data, the agency estimates 
that total sales for these products represent less than 0.1 percent of 
all sales of OTC first aid drug products. For the affected companies, 
these product sales comprised less than 1 percent of OTC drug revenues. 
The industry has been aware of the status of these products since 1982, 
and all of the manufacturers identified by FDA also produce products 
containing ingredients proposed for inclusion in the monograph. The 
lost sales from the nonmonograph products are expected to be offset by 
increased sales of the substitute products.
    The agency considered, but rejected, not acting on these 
ingredients in advance of the finalization of other monograph 
conditions. The final monographs for OTC topical antimicrobial and 
vaginal contraceptive drug products are not expected to be completed 
for a period of time. The agency also considered publishing an 
additional notice specifying that the determinations on the ingredients 
in this final rule would be included in a final rule prior to 
publication of a final rule including the determinations on ingredients 
for which new data and information have been submitted. However, safety 
and effectiveness have not been established for the ingredients 
included in this current final rule and manufacturers have not 
submitted the necessary data in response to earlier opportunities. The 
agency's experience has been that under these circumstances companies 
have not submitted data in response to yet another opportunity. 
Consumers will benefit from the early removal from the marketplace of 
products containing ingredients for which safety and effectiveness have 
not been established. Consumers can then purchase products containing 
only ingredients proposed for monograph status. Manufacturers who 
choose to reformulate or replace affected products will be able to use 
alternative ingredients that are proposed as monograph conditions 
without incurring any additional expense of clinical testing for those 
ingredients. As noted previously, FDA believes that most manufacturers 
currently produce such products.
    While this final rule may cause manufacturers to discontinue 
marketing or to reformulate some products prior to issuance of the 
applicable final monograph, these manufacturers have known for some 
time that if adequate data were not submitted to support safety and 
effectiveness, cessation of marketing of the current products would be 
required, in any event, when the final monographs are published. 
Because this rule imposes no additional reporting or recordkeeping 
requirements, no additional professional skills are necessary to 
comply.

[[Page 19802]]

    The analysis shows that this final rule is not economically 
significant under Executive Order 12866 and that the agency has 
considered the burden to small entities. Based on the above analysis, 
the agency does not believe that the majority of manufacturers will 
incur a significant economic impact. However, there may be a few that 
could incur significant reformulation costs or inventory losses. Thus, 
this economic analysis, together with other relevant sections of this 
document, serves as the agency's final regulatory flexibility analysis, 
as required under the Regulatory Flexibility Act. Finally, this 
analysis shows that the Unfunded Mandates Reform Act does not apply to 
the final rule because it would not result in an expenditure in any 1 
year by State, local, and tribal governments, in the aggregate, or by 
the private sector, of $100 million.

V. Environmental Impact

    The agency has determined under 21 CFR 25.31(c) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

List of Subjects in 21 CFR Part 310

    Administrative practice and procedure, Drugs, Labeling, Medical 
devices, Reporting and recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
310 is amended as follows:

PART 310--NEW DRUGS

    1. The authority citation for 21 CFR part 310 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 
360b-360f, 360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 
242(a), 262, 263b-263n.

    2. Section 310.545 is amended by adding paragraphs (a)(27) and 
(a)(28), by revising paragraph (d) introductory text, by reserving 
paragraphs (d)(26) and (d)(27), and by adding paragraph (d)(28) to read 
as follows:

Sec.  310.545  Drug products containing certain active ingredients 
offered over-the-counter (OTC) for certain uses.

    (a) * * *
    (27) Topical antimicrobial drug products--(i) First aid antiseptic 
drug products.
Ammoniated mercury
Calomel (mercurous chloride)
Merbromin (mercurochrome)
Mercufenol chloride (ortho-chloromercuriphenol, ortho-
hydroxyphenylmercuric chloride)
Mercuric chloride (bichloride of mercury, mercury chloride)
Mercuric oxide, yellow
Mercuric salicylate
Mercuric sulfide, red
Mercury
Mercury oleate
Mercury sulfide
Nitromersol
Para-chloromercuriphenol
Phenylmercuric nitrate
Thimerosal
Vitromersol
Zyloxin
    (ii) Diaper rash drug products.
Para-chloromercuriphenol
Any other ingredient containing mercury
    (28) Vaginal contraceptive drug products.
Dodecaethylene glycol monolaurate (polyethylene glycol 600 monolaurate)
Laureth 10S
Methoxypolyoxyethyleneglycol 550 laurate
Phenylmercuric acetate
Phenylmercuric nitrate
Any other ingredient containing mercury
* * * * *
    (d) Any OTC drug product that is not in compliance with this 
section is subject to regulatory action if initially introduced or 
initially delivered for introduction to interstate commerce after the 
dates specified in paragraphs (d)(1) through (d)(28) of this section.
* * * * *
    (28) October 22, 1998, for products subject to paragraphs (a)(27) 
and (a)(28) of this section.

    Dated: April 8, 1998.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 98-10578 Filed 4-21-98; 8:45 am]
BILLING CODE 4160-01-F