Federal Register / Vol. 63, No. 77 /Wednesday, April 22, 1998 /Rules and Regulations 19799

Issued in Kansas City, Missouri, on April

14, 1998.

Michael Gallagher,

Manager, Small Airplane Directorate, Aircraft

Certfication Service.

[FR Doc. 98–10596 Filed 4–21–98; 8:45 am]

BILLING CODE 4910–13–U

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-theCounter Drug Category II and III Active

Ingredients

AGENCY: Food and Drug Administration,

HHS.

ACTION: Final rule.

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 § 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, orthohydroxyphenylmercuric chloride);

mercuric salicylate; mercuric sulfide

(red mercuric sulfide); mercuric oxide,

yellow; mercury; mercury chloride;

mercury oleate; nitromersol; parachloromercuriphenol; 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.
19800 Federal Register / Vol. 63, No. 77 /Wednesday, April 22, 1998 /Rules and Regulations

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 § 10.30

(21 CFR 10.30).)

TABLE I.—OTC DRUG RULEMAKINGS COVERED BY THIS FINAL RULE

Rulemaking and action Publication date Comment closing date New data closing date

(1) Vaginal contraceptive drug products

(Docket No. 80N–0280)

Advance notice of proposed rulemaking (ANPRM) December 12, 1980 March 12, 1981 Not applicable (N/A)

Notice of proposed rulemaking (NPRM) February 3, 1995 June 5, 1995 February 5, 1996

(2) First aid antiseptic drug products

(Docket No. 75N–0183)

ANPRM January 5, 1982 April 5, 1982 N/A

(Docket No. 75N–183F)

NPRM July 22, 1991 January 2, 1992 July 22, 1992

(3) Antimicrobial diaper rash drug products

(Docket No. 75N–0183)

ANPRM September 7, 1982 December 6, 1982 January 5, 1983

(Docket No. 75N–183D)

NPRM June 20, 1990 December 17, 1990 June 20, 1991

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

Rulemaking and ingredients

Ingredient classification

Advance notice of proposed rulemaking Notice of proposed rulemaking

(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, orthohydroxyphenylmercuric 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
Federal Register / Vol. 63, No. 77 /Wednesday, April 22, 1998 /Rules and Regulations 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 § 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.
19802 Federal Register / Vol. 63, No. 77 /Wednesday, April 22, 1998 /Rules and Regulations

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:

§ 310.545 Drug products containing

certain active ingredients offered over-thecounter (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 (orthochloromercuriphenol, orthohydroxyphenylmercuric 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

DEPARTMENT OF THE INTERIOR

Office of Surface Mining Reclamation

and Enforcement

30 CFR Part 938

[PA–112–FOR]

Pennsylvania Regulatory Program

AGENCY: Office of Surface Mining

Reclamation and Enforcement (OSM),

Interior.

ACTION: Final rule; approval of

amendments.

SUMMARY: OSM is approving, with

certain exceptions, a proposed

amendment to the Pennsylvania

permanent regulatory program

(hereinafter referred to as the

Pennsylvania program) under the

Surface Mining Control and

Reclamation Act of 1977 (SMCRA). The

amendment revises the Pennsylvania

program to incorporate changes made by

Pennsylvania House Bill 1075 and

subsequent Pennsylvania law Act 1994–

114. The amendment is intended to

provide special authorization for coal

refuse disposal in areas previously

affected by mining which contain

pollutional discharges.

EFFECTIVE DATE: April 22, 1998.

FOR FURTHER INFORMATION CONTACT:

Robert J. Biggi, Director, Office of

Surface Mining Reclamation and

Enforcement, Harrisburg Field Office,

Harrisburg Transportation Center, Third

Floor, Suite 3C, 4th and Market Streets,

Harrisburg, Pennsylvania 17101,

Telephone: (717) 782–4036.

SUPPLEMENTARY INFORMATION:

I. Background on the Pennsylvania Program.

II. Submission of the Amendment.

III. Director’s Findings.

IV. Summary and Disposition of Comments.

V. Director’s Decision.

VI. Procedural Determinations.

I. Background on the Pennsylvania

Program

On July 31, 1982, the Secretary of the

Interior conditionally approved the

Pennsylvania program. Background

information on the Pennsylvania

program including the Secretary’s

findings, the disposition of comments,

and a detailed explanation of the

conditions of approval of the

Pennsylvania program can be found in

the July 30, 1982, Federal Register (47

FR 33050). Subsequent actions

concerning the conditions of approval

and program amendments are identified

at 30 CFR 938.11, 938.12, 938.15 and

938.16.

II. Submission of the Amendment

By letter dated September 14, 1995

(Administrative Record Number PA

837.01), Pennsylvania submitted an

amendment to the Pennsylvania

program. The amending language is

contained in Pennsylvania House Bill

1075 and was enacted into Pennsylvania

law as Act 1994–124. The amendments

change Pennsylvania’s Coal Refuse

Disposal Act (of September 24, 1968

(P.L. 1040, No. 318) and amended on

October 10, 1980 (P.L. 807, No. 154)) to

provide for authorization for refuse

disposal in areas previously affected by

mining which contain pollutional