# Topical Antimicrobial Drug Products for Over-the-Counter Human Use; Tentative Final Monograph for Health-Care Antiseptic Drug Products

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## Record

- **Collection:** Federal Register
- **Document type:** Uncategorized Document
- **Published:** June 17, 1994

## Text

SUMMARY: The Food and Drug Administration (FDA) is issuing a notice of
proposed rulemaking in the form of an amended tentative final monograph
that would establish conditions under which over-the-counter (OTC)
topical health-care antiseptic drug products are generally recognized
as safe and effective and not misbranded. FDA is issuing this notice of
proposed rulemaking to amend the previous notice of proposed rulemaking
on topical antimicrobial drug products (see the Federal Register of
January 6, 1978, 43 FR 1210) after considering the public comments on
that notice and other information in the administrative record for this
rulemaking. FDA is also requesting data and information concerning the
safety and effectiveness of topical antimicrobials for use as hand
sanitizers or dips. This proposal is part of the ongoing review of OTC
drug products conducted by FDA.

DATES: Written comments, objections, or requests for an oral hearing on
the proposed regulation before the Commissioner of Food and Drugs by
December 14, 1994. Because of the length and complexity of this
proposed regulation, the agency is allowing a period of 180 days for
comments and objections instead of the normal 60 days. New data by June
19, 1995. Comments on the new data by August 17, 1995. Written comments
on the agency's economic impact determination by December 14, 1994.

ADDRESSES: Written comments, objections, new data, or requests for an
oral hearing to the Dockets Management Branch (HFA-305), Food and Drug
Administration, rm. 1-23, 12420 Parklawn Dr., Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: William E. Gilbertson, Center for Drug
Evaluation and Research (HFD-810), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-594-5000.

SUPPLEMENTARY INFORMATION: In the Federal Register of September 13,
1974 (39 FR 33103), FDA published, under Sec. 330.10(a)(6) (21 CFR
330.10(a)(6)), an advance notice of proposed rulemaking to establish a
monograph for OTC topical antimicrobial drug products, together with
the recommendations of the Advisory Review Panel on OTC Topical
Antimicrobial I Drug Products (Antimicrobial I Panel), which was the
advisory review panel responsible for evaluating data on the active
ingredients in this drug class. Interested persons were invited to
submit comments by November 12, 1974. Reply comments in response to
comments filed in the initial comment period could be submitted by
December 12, 1974. In response to numerous requests, the agency issued
a notice in the Federal Register of October 17, 1974 (39 FR 37066)
granting an extension of the deadline for comments until December 12,
1974, and for reply comments until January 13, 1975.
In the Federal Register of January 6, 1978 (43 FR 1210), FDA
published, under Sec. 330.10(a)(7), a notice of proposed rulemaking to
establish a monograph for OTC topical antimicrobial drug products,
based on the recommendations of the Antimicrobial I Panel and the
agency's response to comments submitted following publication of the
advance notice of proposed rulemaking. Interested persons were invited
to submit objections or requests for oral hearing by February 6, 1978.
In response to numerous requests to extend the time period for
submitting objections or requests for oral hearing, the agency issued a
notice in the Federal Register of February 3, 1978 (43 FR 4637)
granting an extension of the deadline to March 6, 1978. During this
time period, the agency received 6 petitions that requested reopening
the administrative record and 11 requests for an oral hearing. In a
notice published in the Federal Register of March 9, 1979 (44 FR
13041), the agency deferred action on the requests for a hearing, but
granted the petitions to reopen the record to allow interested persons
to submit comments and any new or additional data by June 7, 1979, and
reply comments by July 9, 1979. FDA also stated its intent to publish
an updated (amended) tentative final monograph based on the review and
evaluation of new submissions and a reevaluation of existing data.
In a notice published in the Federal Register of October 26, 1979
(44 FR 61609), the agency again reopened the administrative record for
the submission of new data by March 26, 1980, and for comments on the
new data by May 27, 1980. This action was taken to permit manufacturers
to submit the results of testing to FDA as expeditiously as possible
prior to establishment of a final monograph.
Subsequent to the June 7, 1979, closing date for the submission of
new data, and prior to the October 26, 1979, reopening of the
administrative record, data and information were submitted to FDA. In a
notice published in the Federal Register of March 21, 1980 (45 FR
18398), the agency advised that it had reopened the administrative
record for OTC topical antimicrobial drug products to allow for
consideration of data and information that had been filed in the
Dockets Management Branch after the date the administrative record on
the tentative final monograph had officially closed on March 6, 1978.
The agency concluded that any new data and information filed prior to
March 21, 1980, should be available to the agency in developing a
proposed regulation in the form of a tentative final monograph.
In a notice published in the Federal Register on January 5, 1982
(47 FR 436), the agency advised that it had again reopened the
administrative record for OTC topical antimicrobial drug products to
allow for consideration of the recommendations of the Advisory Review
Panel on OTC Miscellaneous External Drug Products (Miscellaneous
External Panel) on mercury-containing drug products. Interested persons
were invited to submit comments by April 5, 1982, and reply comments by
May 5, 1982. FDA stated that the proceeding to develop a monograph for
mercury-containing drug products would be merged with the general
proceeding to establish a monograph for OTC topical antimicrobial drug
products.
In a notice published in the Federal Register on May 21, 1982 (47
FR 22324), the agency advised that it had again reopened the
administrative record for OTC topical antimicrobial drug products to
allow for consideration of the recommendations of the Miscellaneous
External Panel on alcohol drug products. Interested persons were
invited to submit comments by August 19, 1982, and reply comments by
September 20, 1982. The notice stated that the proceeding to develop a
monograph for alcohol drug products would be merged with the general
proceeding to establish a monograph for OTC topical antimicrobial drug
products.
In the Federal Register of September 7, 1982 (47 FR 39406), FDA
issued a notice to reopen the administrative record for OTC topical
antimicrobial drug products to allow for consideration of the
Miscellaneous External Panel's recommendations on topical antimicrobial
drug products used for the treatment of diaper rash. The agency
discussed topical antimicrobial active ingredients for this use in the
Federal Register of June 20, 1990 (55 FR 25246).
In accordance with Sec. 330.10(a)(10), the data and information
considered by the Panels were put on public display in the Dockets
Management Branch (address above), after deletion of a small amount of
trade secret information. In response to the previous tentative final
monograph and the advance notice of proposed rulemaking for mercury-
containing drug products and the advance notice of proposed rulemaking
for alcohol drug products, 4 drug manufacturers' associations, 44 drug
manufacturers, 1 medical device manufacturer, 1 drug distributor, 2
medical schools, 2 research laboratories, 1 law firm, and 1 consulting
firm submitted comments. Copies of the comments received are also on
public display in the Dockets Management Branch.
The advance notice of proposed rulemaking, which was published in
the Federal Register of September 13, 1974 (39 FR 33103), was
designated as a ``proposed monograph'' in order to conform to
terminology used in the OTC drug review regulations (Sec. 330.10).
Similarly, the notice of proposed rulemaking, which was published in
the Federal Register of January 6, 1978 (43 FR 1210), was designated as
a ``tentative final monograph.'' The present document is also
designated as a ``tentative final monograph.'' The legal status of each
tentative final monograph, however, is that of a proposed rule. The
present document is a reproposal regarding health-care antiseptic drug
products.
This antimicrobial rulemaking is broad in scope, encompassing
products that may contain the same active ingredients, but are labeled
and marketed for different intended uses. For example, one group of
products is primarily used by consumers for ``first aid'' and includes
skin antiseptics, skin wound cleansers, and skin wound protectants.
Another group of products, antiseptic handwashes, are used by consumers
on a more frequent, even daily, basis and includes products for
personal use in the home, such as when caring for invalids and during
family illness. A third group of products is generally intended for use
by health professionals and includes health-care personnel handwashes,
patient preoperative skin preparations, and surgical hand scrubs.
In order to expedite the completion of the first aid section of the
antimicrobial monograph, the agency published a separate tentative
final monograph for these products in the Federal Register of July 22,
1991 (56 FR 33644). The non-first aid uses of topical antimicrobials,
now identified as ``health-care antiseptics,'' are addressed in this
document. Although the amended tentative final monographs for first-aid
antiseptics and health-care antiseptics are being published separately,
both categories will eventually be included under part 333 (21 CFR part
333).
The agency also has decided that OTC topical antimicrobial and
topical antibiotic drug products should be included within the same
monograph. Although an advance notice of proposed rulemaking to
establish a monograph for OTC topical antibiotic drug products was
published under part 342 (21 CFR part 342) on April 1, 1977 (42 FR
17642), the final monograph for those products was issued on December
11, 1987 (52 FR 47312) as a new subpart of the OTC topical
antimicrobial monograph, part 333, subpart B--Topical First Aid
Antibiotic Drug Products. Subpart A will cover first aid antiseptic
drug products; subpart C will cover antifungal drug products; subpart D
covers acne drug products; and new subpart E will cover health-care
antiseptic drug products.
In this tentative final monograph (proposed rule) to establish
subpart E of part 333, FDA states its position on the establishment of
a monograph for OTC health-care antiseptic drug products. This document
addresses only those comments and data concerning the previous
antimicrobial tentative final monograph that are related to ``non-first
aid uses,'' including products for personal use in the home and
products used by health-care professionals.
This proposal constitutes FDA's reevaluation of the January 6, 1978
tentative final monograph based on the comments received and the
agency's independent evaluation of the Miscellaneous External Panel's
reports on OTC alcohol and mercury-containing drug products and the
comments received. The following sections of the January 6, 1978
tentative final monograph for topical antimicrobial drug products are
being addressed in this document: Secs. 333.1, 333.3, 333.30, 333.50,
333.85, 333.87, 333.97, and 333.99. The following sections of the
advance notice of proposed rulemaking for alcohol drug products are
being addressed in this document: Secs. 333.55 and 333.98.
Modifications have been made for clarity and regulatory accuracy and to
reflect new information. Such new information has been placed on file
in the Dockets Management Branch (address above). These modifications
are reflected in the following summary of the comments and FDA's
responses to them. (See section I.)
The OTC drug procedural regulations (21 CFR 330.10) provide that
any testing necessary to resolve the safety or effectiveness issues
that formerly resulted in a Category III classification, and submission
to FDA of the results of that testing or any other data, must be done
during the OTC drug rulemaking process before the establishment of a
final monograph. Accordingly, FDA does not use the terms ``Category I''
(generally recognized as safe and effective and not misbranded),
``Category II'' (not generally recognized as safe and effective or
misbranded), and ``Category III'' (available data are insufficient to
classify as safe and effective, and further testing is required) at the
final monograph stage. In place of Category I, the term ``monograph
conditions'' is used; in place of Categories II and III, the term
``nonmonograph conditions'' is used. This document retains the concepts
of Categories I, II, and III at the tentative final monograph stage.
The agency advises that the conditions under which the drug
products that are subject to this monograph would be generally
recognized as safe and effective and not misbranded (monograph
conditions) will be effective 12 months after the date of publication
of the final monograph in the Federal Register. On or after that date,
no OTC drug product that is subject to the monograph and that contains
a nonmonograph condition, i.e., a condition that would cause the drug
to be not generally recognized as safe and effective or to be
misbranded, may be initially introduced or initially delivered for
introduction into interstate commerce unless it is the subject of an
approved application or abbreviated application (hereinafter called
application). Further, any OTC drug product subject to this monograph
that is repackaged or relabeled after the effective date of the
monograph must be in compliance with the monograph 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 monograph at the earliest possible date.
In the advance notice of proposed rulemaking for OTC topical
antimicrobial drug products (39 FR 33103), the agency suggested that
the conditions included in the monograph (Category I) be effective 30
days after the date of publication of the final monograph in the
Federal Register and that the conditions excluded from the monograph
(Category II) be eliminated from OTC drug products effective 6 months
after the date of publication of the final monograph, regardless of
whether further testing was undertaken to justify their future use.
Experience has shown that relabeling of products covered by the
monograph is necessary in order for manufacturers to comply with the
monograph. New labels containing the monograph labeling have to be
written, ordered, received, and incorporated into the manufacturing
process. The agency has determined that it is impractical to expect new
labeling to be in effect 30 days after the date of publication of the
final monograph. Experience has shown also that if the deadline for
relabeling is too short, the agency is burdened with extension requests
and related paperwork.
In addition, some products will have to be reformulated to comply
with the monograph. Reformulation often involves the need to do
stability testing on the new product. An accelerated aging process may
be used to test a new formulation; however, if the stability testing is
not successful, and if further reformulation is required, there could
be a further delay in having a new product available for manufacture.
The agency wishes to establish a reasonable period of time for
relabeling and reformulation in order to avoid an unnecessary
disruption of the marketplace that could not only result in economic
loss, but also interfere with consumers' access to safe and effective
drug products. Therefore, the agency is proposing that the final
monograph be effective 12 months after the date of its publication in
the Federal Register. The agency believes that within 12 months after
the date of publication most manufacturers can order new labeling and
reformulate their products and have them in compliance in the
marketplace. If the agency determines that any labeling for a condition
included in the final monograph should be implemented sooner than the
12-month effective date, a shorter deadline may be established.
Similarly, if a safety problem is identified for a particular
nonmonograph condition, a shorter deadline may be set for removal of
that condition from OTC drug products.
All ``OTC Volumes'' cited throughout this document refer to the
submissions made by interested persons pursuant to the call-for-data
notice published in the Federal Register of January 7, 1972 (37 FR 235)
or to additional information that has come to the agency's attention
since publication of the advance notice of proposed rulemaking. The
volumes are on public display in the Dockets Management Branch (address
above).

I. The Agency's Tentative Conclusions on the Comments and Reply
Comments

A. General Comments

1. Two comments contended that OTC drug monographs are
interpretive, as opposed to substantive, regulations. One comment
referred to statements on this issue submitted earlier to other OTC
drug rulemaking proceedings.
The agency addressed this issue in paragraphs 85 through 91 of the
preamble to the procedures for classification of OTC drug products,
published in the Federal Register of May 11, 1972 (37 FR 9464 at 9471
to 9472), and in paragraph 3 of the preamble to the tentative final
monograph for OTC antacid drug products, published in the Federal
Register of November 12, 1973 (38 FR 31260). FDA reaffirms the
conclusions stated in those documents. Court decisions have confirmed
the agency's authority to issue substantive regulations by rulemaking.
(See, e.g., National Nutritional Foods Association v. Weinberger, 512
F.2d 688, 696 to 698 (2d Cir. 1975) and National Association of
Pharmaceutical Manufacturers v. FDA, 487 F. Supp. 412 (S.D.N.Y. 1980),
aff'd, 637 F.2d 887 (2d Cir. 1981).)
2. One comment pointed out that under ``Subpart B--Active
Ingredients'' of the tentative final monograph, no CFR part number was
assigned to the category ``skin antiseptic.'' However, part numbers
were assigned to other categories without any Category I ingredients,
with the term ``reserved'' in parentheses. The comment requested that
this omission be corrected in the amended tentative final monograph.
The omission pointed out by the comment was an oversight. However,
it is no longer necessary to assign a CFR part number to the category
``skin antiseptic,'' because skin antiseptics have been included in
broader categories identified as first aid antiseptics in the amended
tentative final monograph for first aid antiseptics (56 FR 33644) and
as health-care antiseptics in this tentative final monograph. (See
section I.B., comment 3.) All Category I first aid antiseptic and
health-care antiseptic active ingredients have been listed in the
amended tentative final monograph under subpart A and subpart E,
respectively.

B. General Comments on Antimicrobials

3. A number of comments objected to the Panel's recommendation for
separate statements of identity in the labeling of products containing
the same antimicrobial active ingredient. As an example, several
comments noted that povidone-iodine has several professional uses
(health-care personnel handwash, skin antiseptic, and surgical hand
scrub) and marketing a product in conformance with two or more product
categories becomes difficult because there are different labeling
requirements for each drug product category. Some comments requested
FDA to combine the drug product category designations or to add a new
multipurpose product category that allows the combining of labeling
indications now included in several product categories. One comment
specifically recommended that the agency consider changing product
class designations and/or adding a new product class ``Multi Purpose
Skin Prep'' or ``Skin Prep,'' with the indications for use including
those listed under Sec. 333.85 (health-care personnel hand wash),
Sec. 333.87 (patient preoperative skin preparation), Sec. 333.90 (skin
antiseptic), and Sec. 333.97 (surgical hand scrub).
Another comment stated that the word ``skin'' was superfluous
because all OTC antiseptics are intended only for use on the skin;
still another comment contended that the statement of identity
``antiseptic'' is preferable to ``skin antiseptic'' because these
products are used on cuts, scratches, and mucous membranes as well as
skin.
In response to the advance notice of proposed rulemaking and
reopening of the administrative record for alcohol drug products for
topical antimicrobial OTC use published in the Federal Register of May
21, 1982 (47 FR 22324), one comment objected to the statement of
identity in proposed Sec. 333.98(a) which read, ``alcohol for topical
antimicrobial use,'' (47 FR 22324 at 22332). The comment stated that
this term would be confusing to the consumer and suggested the term
``antiseptic for the skin.''
The agency agrees that OTC topical antimicrobial drug products need
not have multiple statements of identity. In reviewing the statements
of identity recommended by the Antimicrobial I Panel (39 FR 33103),
i.e., health-care personnel handwash, patient preoperative skin
preparation, skin antiseptic, surgical hand scrub, and the statement of
identity recommended by the Miscellaneous External Panel (47 FR 22324),
i.e., alcohol for topical antimicrobial use, the agency has determined
that the general term ``antiseptic'' broadly describes all proposed
product categories and reflects the basic intended uses of these
products. The agency believes that the statement of identity of
``multiple purpose skin prep'' or ``skin prep'' recommended by one
comment would not as clearly and succinctly describe the use of these
products as the statement of identity ``antiseptic.'' As discussed in
section I.B., comment 5, the agency is also proposing an additional
term ``antiseptic handwash'' as a statement of identity to describe
products for home use.
As discussed in the first aid antiseptic segment of this rulemaking
(56 FR 33644 at 33647), the term ``skin'' has been deleted from the
previously proposed statement of identity ``skin antiseptic.'' Although
several comments felt that the word ``skin'' was superfluous, the
agency has no objection to the statement ``antiseptic for the skin'' or
``skin antiseptic'' appearing elsewhere in the labeling of these
products as additional information to the consumer or health-care
professional, provided it does not appear in any portion of the
labeling required by the monograph and does not detract from such
required information. (See section I.I., comment 19.)
As stated in the first aid antiseptic segment of this rulemaking
(56 FR 33644 at 33647), the agency believes that the term
``antiseptic'' is readily understood by consumers. The agency also
finds this to be true for health professionals. The agency is therefore
proposing the term ``antiseptic'' as the general statement of identity
for all OTC topical antimicrobial ingredients included in this
tentative final monograph. Further, FDA is also proposing that
manufacturers may have an option to provide an alternate statement of
identity describing only the specific intended use(s) of the product.
Specifically, the agency is proposing that the statement of identity
for antiseptic drug products in Sec. 333.450(a) read as follows: ``The
labeling of a single-use product contains the established name of the
drug, if any, and identifies the product as an `antiseptic' and/or with
the appropriate statement of identity described in Secs. 333.455(a),
333.460(a), or 333.465(a). The labeling of a multiple-use product
contains the established name of the drug, if any, and may use the
single statement of identity `antiseptic' and/or the appropriate
statements of identity described in Secs. 333.455(a), 333.460(a), and
333.465(a). When `antiseptic' is used as the only statement of identity
on a single-use or a multiple-use product, the intended use(s), such as
patient preoperative skin preparation, is to be included under the
indications. For multiple-use products, a statement of the intended use
should also precede the specific directions for each use.''
The agency believes that the proposed labeling for these multiple-
use products is flexible and provides manufacturers with a number of
options. However, the agency recognizes that some manufacturers may
wish to label their antiseptic drug products with all of the allowable
indications for a particular active ingredient and that this may give
rise to difficulties in incorporating all of the information on a
product's various uses in the limited space on an OTC label. The agency
wishes to point out that some portions of the proposed indications are
optional, i.e., the examples included in both the antiseptic and
health-care personnel handwash indications, and need not be
incorporated in the labeling at all. In addition, manufacturers are
free to design ways of incorporating all the information on the various
uses of their drug product through the use of flap labels, redesigned
packages, or package inserts.
The agency is providing several examples of labeling for an
antiseptic product containing povidone-iodine when labeled as a single-
use or as a multiple-use product, as follows:
1. When labeled as a single-use product, i.e., patient preoperative
skin preparation.
a. Established name: povidone-iodine.
b. Statement of identity (any of these is acceptable):
(1) ``antiseptic'';
(2) ``patient preoperative skin preparation'';
(3) ``antiseptic/patient preoperative skin preparation.''
c. Indications:
(1) When only ``antiseptic'' is used in the statement of identity:
``Patient preoperative skin preparation:
Helps to reduce bacteria that potentially can cause skin
infection.''
(2) When patient preoperative skin preparation is used as or
included as part of the statement of identity: ``Helps to reduce
bacteria that potentially can cause skin infection.''
d. Directions: (Insert directions in Sec. 333.460(d).)
2. When labeled as a multiple-use product, i.e., patient
preoperative skin preparation, antiseptic handwash or health-care
personnel handwash, and surgical hand scrub.
a. Established name: povidone-iodine.
b. Statement of identity (any of these is acceptable):
(1) ``antiseptic'';
(2) ``patient preoperative skin preparation, antiseptic handwash or
health-care personnel handwash, and surgical hand scrub'';
(3) ``antiseptic/patient preoperative skin preparation, antiseptic
handwash or health-care personnel handwash, and surgical hand scrub.''
c. Indications: Irrespective of which statement of identity is
used, the following is required: ``Patient preoperative skin
preparation: Helps to reduce bacteria that potentially can cause skin
infection. Antiseptic handwash: For handwashing to reduce bacteria on
the skin (which may be followed by one or more of the following: after
changing diapers, after assisting ill persons, or before contact with a
person under medical care or treatment). Health-care personnel
handwash: Handwash to help reduce bacteria that potentially can cause
disease or For handwashing to reduce bacteria on the skin (which may be
followed by one or more of the following: after changing diapers, after
assisting ill persons, or before contact with a person under medical
care or treatment). Surgical hand scrub: Significantly reduces the
number of micro-organisms on the hands and forearms prior to surgery or
patient care.''
d. Directions: The following is required: Patient preoperative skin
preparation: (Insert directions in Sec. 333.460(d).) Antiseptic
handwash or health-care personnel handwash: (Insert directions in
Sec. 333.455(c).) Surgical handscrub: (Insert directions in
Sec. 333.465(c).)
4. One comment requested that scrubbing devices such as brushes or
sponges that are impregnated with approved antimicrobial ingredients be
included in the monograph. Another comment requested clarification of
the agency's views on trays or kits that contain povidone-iodine and
disposable instruments (scissors, forceps, and hemostats) packed in a
sterile package, which are designed to reduce the incidence of cross-
infection in hospitals.
This tentative final monograph does not provide for the use of
devices such as brushes or sponges impregnated with antimicrobials, or
of trays or kits that contain povidone-iodine and disposable
instruments, because the monograph is intended to regulate only OTC
drug active ingredients. Since these comments were submitted, the
agency has established procedures (see 21 CFR part 3) describing how it
determines which agency component has primary jurisdiction for the
premarket review and regulation of products comprised of any
combination of a drug and a device. In addition, interested parties are
encouraged to read the following document (Ref. 1) for guidance:
``Intercenter Agreement Between the Center for Drug Evaluation and
Research and the Center for Devices and Radiological Health.'' (See
Sec. 3.5 (21 CFR 3.5).) This agreement is on file in the Dockets
Management Branch (address above).
(1) Intercenter Agreement Between the Center for Drug Evaluation
and Research and the Center for Devices and Radiological Health in OTC
Vol. 230001, Docket No. 75N-183H, Dockets Management Branch.
5. One comment expressed concern that the tentative final monograph
failed to provide consumers with an antibacterial skin cleanser for
home use. The comment noted that, in addition to professional health
care personnel, many consumers have a need for cleansing products
containing antibacterial agents for the purpose of promoting good
individual and family hygiene. Uses for such products include the
following: (1) To reduce bacteria on the hands and face to a greater
extent than can be accomplished with ordinary soap, and to prevent
accumulation of bacteria from potential sources of contamination. The
following examples were cited: Cleansing oneself after changing a
baby's diaper, or after assisting aged or ill members of the household
with their toilet needs, and before preparing a family meal. (2) The
added benefit of an antibacterial cleanser for the minute cuts and
abrasions from shaving and other minor traumas. (3) The need for an
antibacterial cleanser other than bar soap on local parts of the body
such as the face because soap (alkali salts of fatty acids) can be
irritating or too drying for some individuals' needs. The comment
recommended a new product class under proposed Sec. 333.90(a) (skin
antiseptic) to be identified as ``Antimicrobial (or Antibacterial)
Personal Cleanser'' with claims such as ``decreases bacteria on the
skin'' and ``contains an antibacterial agent.'' The comment also
suggested that the 10-day maximum use limitation would not be
appropriate for this product class, but use could be restricted to 5 or
10 times daily.
Another comment recommended that antimicrobial soaps be allowed to
make claims relating to general health care and personal hygiene
similar to the claims allowed for health-care personnel handwashes. The
comment stated that an antimicrobial soap will reduce bacteria or the
transfer of potentially pathogenic micro-organisms in the home and,
therefore, serves as a preventive health care aid in controlling
diseases.
A third comment requested the addition of a fourth indication for
alcohol active ingredients in proposed Sec. 333.98(b) to allow use as
an antibacterial handwash to avoid cross-contamination from one
individual to another. The comment argued that products containing
alcohols are often used as handwashes by athletic trainers to help
prevent the spread of skin infections from one individual to another in
situations in which soap and water are not available, e.g., on the
playing field.
A fourth comment asserted that numerous other meaningful and
truthful indications can be used which enhance the safe and effective
use of a health-care personnel handwash. For example, the terms
``microbicidal cleanser'' or ``antiseptic germicidal skin cleanser''
are appropriate and meaningful terminology describing this use
indication.
The agency agrees that antibacterial or antiseptic personal
cleanser products are practical for home use, to help prevent cross
contamination from one person to another, especially after diaper
changing and caring for invalids or ill family members. The agency also
agrees with one comment that claims relating to general health-care and
personal hygiene similar to the claims allowed for health-care
personnel handwashes may be suitable because such claims explain the
uses of these products in lay terms.
In the Federal Register of July 22, 1991 (56 FR 33644), the agency
separated the first aid antiseptic uses of OTC topical antimicrobial
drug products from the ``non-first aid uses.'' In that document, the
agency proposed that the following terms and categories be deleted:
skin antiseptics, skin wound protectants, and skin wound cleansers; and
the agency proposed that the appropriate labeling, instead, be included
in a new category called ``first aid antiseptics'' (56 FR 33644 at
33649). Several uses proposed by one comment, i.e., ``minute cuts and
abrasions from shaving and other minor traumas,'' are considered as
describing ``first aid uses'' and are adequately covered by the
labeling provided for ``first aid antiseptics'' in proposed
Sec. 333.50(b) (56 FR 33677), which contains the following: ``First aid
to help'' (select one of the following: ``prevent,'' (``decrease''
(``the risk of'' or ``the chance of'')), (``reduce'' (``the risk of''
or ``the chance of'')), ``guard against,'' or ``protect against'')
(select one of the following: ``infection,'' ``bacterial
contamination,'' or ``skin infection'') ``in minor cuts, scrapes, and
burns.'' The agency believes that the first aid indication is
sufficiently broad to cover minute cuts and abrasions from shaving and
that it is not necessary to include the words ``other minor traumas''
in the indications statement.
Beyond the first aid uses described in the first comment, the
agency recognizes a need for an OTC ``antiseptic handwash'' product for
repeated or daily use over an extended period of time for some of the
other uses described by the comment. The agency agrees with the
comments that health-care personnel handwashes are appropriate for such
use because submitted data from effectiveness studies, for uses subject
to this rulemaking, were derived from handwashing tests similar to or
the same as tests described in the agency's previously proposed testing
guidelines (see 43 FR 1210 at 1240), i.e., ``Modified Cade Procedure,''
``Glove Juice Test,'' and ``Test for Health-Care Personnel Handwash
Effectiveness.'' The agency is proposing in this tentative final
monograph in Sec. 333.455(a) that a health-care personnel handwash can
also bear a statement of identity of ``antiseptic handwash.'' (See
section I.B., comment 3.) For products labeled for multiple uses
including both antiseptic handwash and first aid labeling claims, the
general statement of identity would be ``antiseptic'' as described in
section I.B., comment 3. The product would then need to incorporate the
monograph labeling for both antiseptic handwash as well as first aid
antiseptic.
The term ``cleanser'' included in claims requested by the comments
is not appropriate in this rulemaking because it is considered to be a
cosmetic claim in view of the fact that the Federal Food, Drug, and
Cosmetic Act (the act) defines a cosmetic as ``articles intended to be
* * * applied to the human body * * * for cleansing * * *'' (21 U.S.C.
321(i)(1)) and thus may be misleading to consumers. As discussed in
section I.I., comment 19, the terms ``microbicidal'' and ``germicidal''
may appear in the labeling of OTC antiseptic drug products under
certain conditions.
Accordingly, the agency is proposing as the indication for products
bearing the statement of identity ``antiseptic handwash'' a general
claim similar to one recommended by one of the comments, i.e., ``for
handwashing to decrease bacteria on the skin.'' The agency has
determined that this claim may, at the manufacturer's option, be
followed by one or more of the following examples: ``after changing
diapers,'' ``after assisting ill persons,'' or ``before contact with a
person under medical care or treatment.''
Descriptive statements such as ``contains antibacterial
ingredients'' and ``for the purpose of promoting good individual and
family hygiene'' are considered to be examples of statements not
significantly related to the safe and effective use of the product and
thus are outside the scope of the rulemaking. Such statements may be
included in the labeling of these OTC drug products subject to the
statutory provisions against false or misleading labeling.
The agency has determined that the indication proposed for
antiseptic handwash drug products is also appropriate for health-care
personnel handwashes and is also proposing the following indication for
health-care personnel handwashes. ``For handwashing to decrease
bacteria on the skin'' (which may be followed by one or more of the
following: ``after changing diapers,'' ``after assisting ill persons,''
or ``before contact with a person under medical care or treatment.'')
In addition to the indication proposed above, the agency is proposing
that health-care personnel handwashes may also bear the following
indication: ``Handwash to help reduce bacteria that potentially can
cause disease.'' The agency is proposing the statement ``recommended
for repeated use'' as an ``other allowable indication'' for antiseptic
or health-care personnel handwash drug products (see below).
The agency sees no reason to continue to include ``antimicrobial
soap'' as a separate product category. Soap is considered to be a
dosage form, and specific dosage forms are not being included in the
monograph unless there is a particular safety or efficacy reason for
doing so. Antimicrobial ingredients may be formulated as soaps for some
of the uses discussed in this document, e.g., handwash; however, the
designation ``antimicrobial soap'' is no longer being proposed for
inclusion in the monograph. In addition, the agency considers the other
product categories that are being proposed to be more informative to
the users of these products.
Based upon the comments, the agency is proposing labeling
appropriate for professional or consumer uses as follows:

Section 333.455 Labeling of Antiseptic Handwash or Health-Care
Personnel Handwash Drug Products.

(a) Statement of identity. The labeling of the product contains the
established name of the drug, if any, and identifies the product as an
``antiseptic,'' as stated above under Sec. 333.450(a), and/or
``antiseptic handwash,'' or ``health-care personnel handwash.''
(b) Indications. * * *
(1) For products labeled as a health-care personnel handwash.
``Handwash to help reduce bacteria that potentially can cause disease''
or ``For handwashing to decrease bacteria on the skin'' (which may be
followed by one or more of the following: ``after changing diapers,''
``after assisting ill persons,'' or ``before contact with a person
under medical care or treatment.'')
(2) For products labeled as an antiseptic handwash. ``For
handwashing to decrease bacteria on the skin'' (which may be followed
by one or more of the following: ``after changing diapers,'' ``after
assisting ill persons,'' or ``before contact with a person under
medical care or treatment.'')
(3) Other allowable indications for products labeled as either
antiseptic or health-care personnel handwash. The labeling of the
product may also contain the following phrase: ``Recommended for
repeated use.''
Other labeling claims requested by the comments for first aid
antiseptics are not being included in the tentative final monograph.
The agency believes that the general claim ``for handwashing to
decrease bacteria on the skin'' encompasses the variety of uses for
promoting good individual and family hygiene. The agency tentatively
concludes that the labeling statements proposed above express the same
concepts as the labeling suggested by the comments in language that can
be more readily understood by the consumer.

C. Comments on Definitions

6. One comment objected to a portion of the definition for health-
care personnel handwash in Sec. 333.3(d) of the tentative final
monograph that states that the antimicrobial agent is ``broad-
spectrum'' and ``if possible, persistent.'' The comment argued that,
because these handwashes are used 50 to 100 times daily, persistence of
effect is unnecessary. The comment also questioned the need for a
broad-spectrum antimicrobial, stating that Staphylococcus epidermidis
(S. epidermidis) generally is the only natural resident bacteria on the
skin, and other transient micro-organisms are more likely to be removed
mechanically by washing than by antimicrobial action. The comment
suggested that the choice to use or not to use a broad-spectrum
antimicrobial ingredient should be left to the manufacturer.
Another comment pointed out that the requirement for ``broad
spectrum'' activity is inconsistently applied in the definitions for
health-care personnel handwash, patient preoperative skin preparation,
and surgical hand scrub (Sec. 333.3(d), (e), and (i), respectively)
because ``broad spectrum'' activity is mandatory for the first two
classes and only ``desirable'' for surgical hand scrubs. The comment
cited comment 93 (43 FR 1210 at 1224) and the testing guidelines for
safety and effectiveness of OTC topical antimicrobials (43 FR 1239) to
show the agency's awareness of possible shifts in microbial flora due
to a lack of broad spectrum activity. The comment urged that all three
product classes include the requirement for each product to at least
demonstrate in vitro ``cidal'' activity against gram-negative bacteria,
fungi, and lipophilic and hydrophilic viruses in addition to the gram-
positive activity.
In Sec. 333.3(d) of the previous tentative final monograph, a
health-care personnel handwash was defined as an ``* * * antimicrobial-
containing preparation designed for frequent use; it reduces the number
of transient micro-organisms on intact skin to an initial baseline
level after adequate washing, rinsing, and drying, and it is broad-
spectrum, fast acting, and, if possible, persistent.'' In the tentative
final monograph, the agency agreed with the Panel that persistence,
defined as prolonged activity, is a valuable attribute that assures
antimicrobial activity during the interval between washings and is
important to a safe and effective health-care personnel handwash (43 FR
1215). The Panel explained that a property such as persistence, which
acts to prevent the growth or establishment of transient micro-
organisms as part of the normal baseline or resident flora, would be an
added benefit (39 FR 33103 at 33115). Although the Panel did not
propose persistence as a mandatory requirement for a health-care
personnel handwash, the agency is retaining the words ``if possible,
persistent'' in the definition in this amended tentative final
monograph because this is a desirable trait for these products.
Regarding the comment's objection to the broad-spectrum
requirement, the Panel in its discussion of the normal skin flora
stated that the predominant members of the normal flora are gram
positive cocci and diptheroids and not S. epidermidis, as the comment
indicates. The Panel stated further that a small number of gram
negative species, such as coliforms and related micro-organisms, as
well as higher forms such as yeast may also be residents of the skin of
healthy individuals (39 FR 33103 at 33107). In its discussion of
health-care personnel handwash drug products, the Panel acknowledged
that, in all likelihood, the specified effect of these products (i.e.,
removal of transient micro-organisms) can be achieved with a well
formulated nonantimicrobial soap or detergent product. However, the
Panel concluded that transient micro-organisms may become part of the
established ``resident'' flora with time, and stated that in a health-
care situation, the fast, effective removal of transient micro-
organisms is a requirement because they may be pathogenic (39 FR 33103
at 33115). The Panel recommended that health-care personnel handwash
drug products containing an antimicrobial ingredient should be broad
spectrum. The Panel defined ``broad spectrum'' in reference to
microbiological activity as meaning the antimicrobial has activity
against more than one type of micro-organism, that is, activity against
gram positive and gram negative bacteria, fungi, and viruses (39 FR
33115). Because transient micro-organisms present on the skin may
include widely diverse species, resulting from contact with
contaminated persons and materials, the agency concludes that a greater
reduction of transient micro-organisms on the skin can be achieved if
the antimicrobial containing drug product used as a health-care
personnel handwash provides broad spectrum activity.
In addition, because the principal intended use of these
professional use products is the prevention of nosocomial (hospital
acquired) infections, the agency believes that these drug products
should have demonstrable antimicrobial activity against a microbial
spectrum that includes the micro-organisms associated with these
infections. As discussed in section I.N., comment 28, the agency is
proposing, in Sec. 333.470(a)(1)(ii) of the testing requirements, a
list of micro-organisms that reflects a spectrum of antimicrobial
activity pertinent to the intended use of these drug products and
against which the products must be tested. The agency is proposing the
following definition of broad spectrum activity in Sec. 333.403(b) of
this amended tentative final monograph: ``Broad spectrum activity. A
properly formulated drug product, containing an ingredient included in
the monograph, that possesses in vitro activity against the micro-
organisms listed in Sec. 333.470(a)(1)(ii), as demonstrated by in vitro
minimum inhibitory concentration determinations conducted according to
methodology in Sec. 333.470(a)(1)(ii).'' This methodology has been
developed by the National Committee for Clinical Standards (NCCLS)
(Ref. 1). Although micro-organisms in addition to those listed may also
be used for testing, the agency will use the test micro-organisms
identified in Sec. 333.470(a)(1)(ii) for any necessary compliance
testing.
The agency wants to emphasize that in this amended tentative final
monograph the broad-spectrum criterion applies to final-formulated drug
products used as an antiseptic handwash or health-care personnel
handwash, patient preoperative skin preparation, and surgical hand
scrub. Although the Category I active ingredients currently included in
this amended tentative final monograph are broad spectrum independent
of formulation, some Category III antiseptic ingredients have limited
spectra (activity against only gram positive bacteria; for example,
chloroxylenol (see section I.G., comment 12) and triclosan (see section
I.L., comment 23)), but when properly formulated in a final product the
spectrum can be broadened to include additional activity against the
test micro-organisms, thereby possibly enabling these ingredients to
become Category I. Although the agency agrees with the first comment
that the manufacturer may use or not use a broad-spectrum ingredient in
a particular health-care antiseptic drug product, the finished product
must demonstrate in vitro activity against the specific micro-organisms
listed in proposed Sec. 333.470(a)(1)(ii).
In response to the second comment, that broad spectrum was
inconsistently applied in the definitions of the three product classes,
the agency has reevaluated the issue and believes that all product
classes should be broad spectrum. As stated in the tentative final
monograph (43 FR 1210 at 1212), maintaining the balance among species
of micro-organisms constituting the normal skin flora is more likely to
be threatened by use of antimicrobial products with a limited spectrum.
Also much of the data concerning the spread of infections in hospitals
indicates that the use of an antimicrobial with broad spectrum activity
would help prevent this (see section I.D., comment 9). Based on the
reasons mentioned above, the agency is proposing to include ``broad
spectrum'' in the definitions of the three product classes included in
this tentative final monograph.

Reference

(1) National Committee for Clinical Laboratory Standards,
``Methods for Dilution Antimicrobial Susceptibility Tests for
Bacteria that Grow Aerobically--2d ed.; Approved Standard,'' NCCLS
Document M7-A2, 10:8, 1990.

D. Comments on Labeling

7. Several comments contended that FDA does not have the authority
to restrict OTC labeling claims to exact wording, to the exclusion of
what the comments described as other ``equally truthful claims for the
products.'' One comment pointed out that numerous other meaningful and
truthful statements will provide useful information and will enhance
the safe and effective use of these products. Several comments
maintained that manufacturers have a constitutional right to use any
truthful, nonmisleading labeling under the first amendment. To support
their position, the comments cited Bigelow v. Virginia, 421 U.S. 809
(1975); Virginia State Board of Pharmacy v. Virginia Citizens Consumer
Council, Inc., 425 U.S. 748 (1976); Linmark Associates, Inc. v.
Willingboro, 431 U.S. 85 (1977); Bates v. State Bar of Arizona, 433
U.S. 350 (1977); Federal Trade Commission v. Beneficial Corp., 542 F.2d
611, 97 S. Ct. 1679 (1977); and Warner-Lambert Co. v. Federal Trade
Commission, 562 F.2d 749 at 768 (D.C. Cir. 1977).
In the Federal Register of May 1, 1986 (51 FR 16258), the agency
published a final rule changing its labeling policy for stating the
indications for use of OTC drug products. Under 21 CFR 330.1(c)(2), the
label and labeling of OTC drug products are required to contain in a
prominent and conspicuous location, either (1) the specific wording on
indications for use established under an OTC drug monograph, which may
appear within a boxed area designated ``APPROVED USES''; (2) other
wording describing such indications for use that meets the statutory
prohibitions against false or misleading labeling, which shall neither
appear within a boxed area nor be designated ``APPROVED USES''; or (3)
the approved monograph language on indications, which may appear within
a boxed area designated ``APPROVED USES,'' plus alternative language
describing indications for use that is not false or misleading, which
shall appear elsewhere in the labeling. All other OTC drug labeling
required by a monograph or other regulation (e.g., statement of
identity, warnings, and directions) must appear in the specific wording
established under the OTC drug monograph or other regulation where
exact language has been established and identified by quotation marks,
e.g., 21 CFR 201.63 or 330.1(g).
In the previous tentative final monograph, supplemental language
relating to indications had been proposed and captioned as Other
Allowable Statements in Secs. 333.85, 333.87 and 333.97. Under FDA's
revised labeling policy (51 FR 16258), such statements are included at
the tentative final stage as examples of other truthful and
nonmisleading language that would be allowed elsewhere in the labeling.
In accordance with the revised labeling policy, such statements would
not be included in a final monograph.
In preparing this amended tentative final monograph, the agency has
reevaluated these ``other allowable statements'' to determine whether
they should be incorporated, wherever possible, as part of the
indications developed under the monograph.
The agency has reviewed the ``Other Allowable Statements'' proposed
in the previous tentative final monograph in Sec. 333.85 for health-
care personnel handwash, in Sec. 333.87 for patient preoperative skin
preparation, and in Sec. 333.97 for surgical hand scrub. The statement
``recommended for repeated use'' proposed for a health-care personnel
handwash has been included in this amended tentative final monograph as
an ``other allowable indication'' in proposed Sec. 333.455 for
antiseptic handwash or health-care personnel handwash drug products.
(See section I.B., comment 5.)
The terms ``broad spectrum'' and ``fast-acting'' (if applicable)
were proposed as ``Other Allowable Statements'' for all three of these
product classes in the previous tentative final monograph. As discussed
in section I.C., comment 6, the agency is proposing to include ``broad
spectrum'' in the definition of the three product classes included in
this amended tentative final monograph. Although the term ``broad
spectrum'' is included in the definitions of these product classes, the
agency does not see a need to include this information in the
``indications'' for these products. Likewise, the term ``fast-acting''
is included in the definitions of these product classes, but the agency
does not see a need to include this information in the indications for
these products. This type of information may appear elsewhere in the
labeling of these products as additional information to the health-care
professional, provided it does not appear in any portion of the
labeling required by the monograph and does not detract from such
required information. Other previously proposed ``Other Allowable
Statements,'' i.e., ``contains antibacterial ingredient(s),''
``contains antimicrobial ingredient(s),'' and ``nonirritating,'' are
not related in a significant way to the safe and effective use of these
products. The agency does not believe that statements such as
``contains antibacterial ingredient(s)'' or ``contains antimicrobial
ingredient(s)'' are necessary on products intended primarily for health
professionals, but has no objection to such statements appearing in the
labeling as other information not intertwined with any portion of the
labeling required by the monograph. Likewise, the term
``nonirritating'' may appear as additional information to the health-
care professional, provided it does not appear in any portion of the
labeling required by the monograph and does not detract from such
required information. However, such statements are subject to the
provisions of section 502 of the act (21 U.S.C. 352) relating to
labeling that is false or misleading. Such statements will be evaluated
on a product-by- product basis, under the provisions of section 502 of
the act relating to labeling that is false or misleading.
8. Several comments requested that certain warnings required in the
labeling of OTC drug products marketed for the general public should
not be required on such products distributed only to health
professionals and labeled primarily for use in health-care facilities
as in proposed Sec. 333.99 ``Professional labeling'' (43 FR 1210 at
1248 and 1249). Examples cited were the cautionary statements for
``skin antiseptic'' and ``skin wound protectant'' in proposed
Secs. 333.90(c)(3) and 333.93(c)(3) ``Do not use this product for more
than 10 days. If the infection (condition) worsens or persists, see
your physician,'' and for ``skin wound protectant'' in proposed
Sec. 333.93(c)(7) ``Do not use on chronic skin conditions such as leg
ulcers, diaper rash, or hand eczema.'' The comments stated that the
professional use of these products sometimes differs from consumer use
and that products which are marketed only to health-care institutions
and are dispensed and administered by professionals should only contain
warnings that apply to professional use. One comment concluded that
requiring professional labeling to contain a caution such as in
proposed Sec. 333.93(c)(7) could possibly subject the health-care
facility and the physician to unwarranted product liability claims,
although the particular use of the product under medical supervision is
entirely justified and necessary for proper treatment of the patient.
One of the comments stated that flexibility should be provided so that
manufacturers can utilize only those warnings that are appropriate for
professional personnel when packages are restricted to health-care
facilities or where a topical antimicrobial product is used as part of
a course of treatment selected by the clinician.
In the Federal Register of November 12, 1973 (38 FR 31260), the
agency published the tentative final monograph for OTC antacid drug
products, in which the concept of ethical labeling for OTC drug
products was first discussed in comment 56 at 38 FR 31264. There, the
agency stated that the warning statements appearing on OTC drug
products should be included in ethical (professional) labeling.
Subsequently, in the previous tentative final monograph for OTC
topical antimicrobial drug products, published in the Federal Register
of January 6, 1978 (43 FR 1210), the agency proposed Sec. 333.99
(``Professional labeling'') which stated that the labeling of products
(covered by the monograph) that is provided only to health
professionals and the labeling for those products primarily used in
health-care facilities shall include all of the warnings required in
each subsection of the monograph, e.g., those in Sec. 333.90 for ``skin
antiseptic'' or Sec. 333.93 for ``skin wound protectant.''
As described in the first aid antiseptic segment of the tentative
final monograph for OTC antimicrobial drug products, published in the
Federal Register of July 22, 1991 (56 FR 33644), the agency has
proposed deletion of the categories cited by the comments, i.e., ``skin
antiseptic'' and ``skin wound protectant,'' as separate drug categories
and included them in a single drug product category identified as
``first aid antiseptic.'' The cautionary statements referred to by the
comments are addressed in that document.
In this document, the agency is addressing the uses other than
first-aid, i.e., health-care antiseptic uses, of topical antimicrobial
drug products. These products may contain the same antiseptic active
ingredient(s) as the first aid antiseptic drug products, but they are
labeled and marketed for different uses. The cautionary statements
previously proposed in Secs. 333.90(c)(3) and 333.93(c)(3) addressed
short-term first aid uses of products primarily proposed as ``consumer
products.'' These products were not principally intended to be marketed
for hospital or professional use. Therefore, the agency agrees with the
comments that such cautionary statements do not apply to professional
use of antiseptic drug products and need not appear in the labeling of
antiseptic products marketed as antiseptic handwashes or health-care
personnel handwashes, patient preoperative skin preparations, and
surgical hand scrubs. Likewise the agency believes that health-care
antiseptic drug products, marketed principally to health-care
professionals, do not need to bear a cautionary statement not to use
the product on chronic skin conditions such as leg ulcers, diaper rash,
or hand eczema. As the comment pointed out, professional use of these
products is different than consumer use and, in some instances, use of
the product on the above-mentioned skin conditions under medical
supervision may be justified and necessary for proper treatment of the
patient. Therefore, this cautionary statement is not being included in
this tentative final monograph.
This tentative final monograph addresses specifically the use of
these topical antiseptic drug products by health-care professionals and
in health-care facilities. The labeling proposed for those products in
this document represents that labeling which the agency believes
health-care professionals need to properly use these products.
Therefore, the agency believes that the warnings proposed in
Sec. 333.450(c) of this tentative final monograph should appear in the
labeling of these products that are directed to health-care
professionals and health-care facilities, even if the product is
marketed principally to these sources only. However, the agency
believes that one of these warnings can be modified if the product is
labeled ``For Hospital and Professional Use Only.'' In such cases, the
second sentence of the warning proposed in Sec. 333.450(c)(3),
regarding consulting a doctor, can be deleted. This concept is being
included in this tentative final monograph. (See Sec. 333.450(d).)
In responding to the comments regarding the warnings in the
``Professional labeling'' section (Sec. 333.99) of the previous
tentative final monograph, the agency has determined that these
warnings are no longer necessary. Accordingly, Sec. 333.99 is not being
included in this amended tentative final monograph. (See section I.D.,
comment 9 for discussion of Sec. 333.99(a), and section I.J., comment
21 for discussion of Sec. 333.99(b). Also, see section II.B., paragraph
14 in the first aid antiseptic segment of this tentative final
monograph (56 FR 33644 at 33675) for discussion of Sec. 333.99(c).)
9. Several comments made recommendations regarding the requirement
that professional labeling for all classes of OTC topical antimicrobial
drug products must contain the caution statement in proposed
Sec. 333.99(a), ``Caution: Overuse of this and other antimicrobial
products may result in an overgrowth of gram-negative micro-organisms,
particularly Pseudomonas.'' Some of the comments stated that this
caution statement should be required only for antimicrobials where
there is valid scientific evidence to show that such caution is
appropriate, for example, quaternary ammonium compounds and triclosan,
which have been associated with the overgrowth of gram-negative micro-
organisms, specifically Pseudomonas. Three comments contended that
reports of contamination of benzalkonium chloride solutions with
Pseudomonas and Enterobacteria species were basically the result of
misuse, improper storage and dilution, poor technique, and
contamination with neutralizing chemicals. One comment recommended that
the proposed caution statement in Sec. 333.99(a) should be changed to
read: ``Improper use or overuse * * *.'' and cited the discussion of
the proposed warning for quaternary ammonium compounds by the agency at
43 FR 1237 where the phrase ``misuse or overuse'' was included. Another
comment objected to the caution, arguing that it is based on
theoretical considerations only and there is no published clinical
evidence implicating quaternary ammonium compounds. Still another
comment stated that its quaternary ammonium compound product passed the
commonly used test for Pseudomonas activity.
In defense of triclosan's implication in Pseudomonas overgrowth,
one comment argued that overgrowth was just an unproven hypothesis and
submitted the ``Summary for Basis of Approval'' from an approved new
drug application (NDA) for chlorhexidine gluconate (Ref. 1) which
included data on a skin flora study that indicated an increasing,
continuous gram-negative growth only in the axillary area over a 6-
month period, even though chlorhexidine is active against gram-negative
micro-organisms. The comment referred to FDA's Division of Anti-
Infective Drug Products as having recognized that gram-negative
overgrowth can be adequately controlled by restricting use to
indications provided in the labeling of a product.
Several comments pointed out that data on povidone-iodine have
proven broad spectrum effectiveness, referring to the Centers for
Disease Control and Prevention's (CDC) recommendation (Ref. 2) for
using this ingredient for skin preparation before intravenous catheter
insertion and other procedures to reduce infection. The comments also
noted that in a study by Houang et al. (Ref. 3), in which 20 transfers
of 7 gram-negative micro-organisms (including Pseudomonas aeruginosa
(P. aeruginosa)) were made, the minimum inhibitory concentration did
not change, supporting the fact that repeated use of povidone-iodine
would not result in resistant micro-organisms. For these reasons, these
comments recommended that Sec. 333.99(a) should be revised to exclude
povidone-iodine.
After a thorough review and evaluation of the available data, the
agency concludes that the professional labeling caution that overuse of
an antimicrobial drug product may cause an overgrowth of gram-negative
micro-organisms is not necessary. In the previous tentative final
monograph (43 FR 1210 at 1212), the agency stated its awareness of the
theory that gram-negative bacteria will replace gram-positive bacteria
that are reduced in number or eliminated by use of antimicrobials and
encouraged research to test the validity of the theory. The agency also
recalled the Panel's highlighting the need for research on microbial
ecology of the skin and its concern about the effect of overuse of
antimicrobial drug products, especially products with a limited
spectrum, in hospitals and other closed populations. Therefore, the
agency proposed the professional labeling caution in Sec. 333.99(a)
``for certain antimicrobial ingredients approved for OTC drug use * * *
used in health-care facilities'' (43 FR 1213). However, the agency
concluded that the limited consumer use of these products in the
population at large did not constitute a risk that would warrant such a
label warning. Although benzalkonium chloride has been frequently
implicated in Pseudomonas hospital infections, the agency's review of
numerous reports and studies on quaternary ammonium compounds and other
antimicrobials (Refs. 4 through 10) indicates that specific causes for
contamination, such as lack of aseptic technique when applying
intravenous infusions and sterilization failure of the items used
(bottles, tubing, distilled water used in diluting benzalkonium
chloride), were the problem and not overuse of benzalkonium chloride.
The agency discussed this problem in the previous tentative final
monograph and stated that it appears that practices in the health-care
facility environments where quaternary ammonium compounds are commonly
used often fall short of the minimum necessary to prevent outbreaks of
infection. (See comment 51 43 FR 1210 at 1218.) Benzalkonium chloride
is more prone to become contaminated for several reasons that were
brought out in the studies: (1) Pseudomonas species are among the
bacteria most resistant to surface-active agents like quaternary
ammonium compounds. (2) The usual quaternary ammonium compound
concentration appears to be ineffective against some species, such as
Pseudomonas cepacia, an organism which has been reported to have been
associated with hospital infections. One study showed that this
organism survived 14 years in a salt solution preserved with 0.05
percent benzalkonium chloride. (3) Organic materials (gauze, cotton,
cork in stoppers, soaps), inorganic matter, protein, and anionic
substances inactivate quaternary ammonium compounds. (4) Hospital
personnel are unfamiliar with these problems and with procedures for
using quaternary ammonium compounds safely and effectively. Based on
these reports, the agency agrees with the comments that ``improper''
use, not ``overuse,'' is the cause of benzalkonium chloride being
implicated in Pseudomonas contamination and that there is a lack of
data demonstrating ``overuse'' to be the cause.
The agency also agrees with the comment which stated that it was an
unproven hypothesis that overuse of an antiseptic causes Pseudomonas
overgrowth. The ``Summary for Basis of Approval'' from an approved NDA
for chlorhexidine gluconate (Ref. 1) cites a skin flora study that
indicated that the axilla was an area where gram-negative micro-
organisms continued to be isolated even though chlorhexidine gluconate
has shown gram-negative effectiveness. The comment cited FDA's Division
of Anti-Infective Drug Products' recognition that for health-care uses,
such as surgical scrub and health-care personnel handwash, there would
be no problem with Pseudomonas overgrowth because the hands are an area
of the body not likely to support the growth of Pseudomonas because of
the lack of moisture. In defending triclosan, the comment contended
that this ingredient is bacteriostatic and does not eliminate all gram-
positive bacteria; therefore, it would not predispose for gram-negative
overgrowth. Triclosan has been implicated in Pseudomonas contamination
because it is primarily effective against gram-positive bacteria, has
limited in vitro and in vivo activity against gram-negative bacteria,
and no activity against Pseudomonas (43 FR 1210 at 1232). One report
showed that triclosan was effective against some gram-negative micro-
organisms, but not effective against Serratia and Pseudomonas (Ref.
11). Pseudomonas and Serratia resistance caused the contamination, not
overuse of the antiseptic.
The agency agrees with the comments that quaternary ammonium
compounds and triclosan have been implicated in Pseudomonas hospital
infections more frequently than povidone-iodine, but studies indicate
that `overuse' of these or any antimicrobial has not been the cause.
Pseudomonas species may become dominant because of inherent resistant
factors which enable them to survive the effects of many antibiotics
and antiseptics (Refs. 12, 13, and 14). In addition, this genus is
ubiquitous, found in both soil and water, and can multiply in almost
any moist environment with even a trace of organic material (Ref. 15).
The agency believes that the data and reports have not provided
specific evidence that repeated use of health-care antiseptics,
including benzalkonium chloride and triclosan, have brought about
overgrowth of gram-negative bacteria, particularly Pseudomonas. The
agency agrees with the comments that improper use, failure of hospital
personnel to use according to labeling indications, nonaseptic
technique in diluting and handling, and lack of good quality control to
ensure sterility of items in contact with antiseptics, such as sterile
distilled water, hosing, and receptacles, are responsible.
The study by Houang et al. (Ref. 3) shows that repeated in vitro
exposure of seven gram-negative micro-organisms, including P.
aeruginosa, in povidone-iodine dilutions did not result in the
development of resistance. The agency notes that CDC previously
recommended povidone-iodine for use in intravenous catheter and other
procedures (Ref. 2). However, there has been one report from CDC (Ref.
16) which described Pseudomonas hospital infections caused by
intrinsically contaminated povidone-iodine (contaminated during
manufacture, indicating failure of control of microbiological
contamination). Compliance with the agency's regulations governing
current good manufacturing practice for finished pharmaceuticals (21
CFR part 211) should prevent intrinsic contamination.
Accordingly, the agency concludes that a cautionary statement
against overuse is not needed in the professional labeling of health-
care antiseptic drug products. Therefore, the previously proposed
caution in Sec. 333.99(a) is not being included in this tentative final
monograph. If new information indicates a need for a cautionary
statement, the agency will consider appropriate action at that time.

References

(1) ``Summary for Basis of Approval, Chlorhexidine Gluconate,''
NDA 17-768, Comment No. SUP022, Docket No. 75N-0183, Dockets
Management Branch.
(2) ``Recommendations for the Insertion and Maintenance of
Plastic Intravenous Catheters,'' Paper for Training Purpose,
Hospital Infections and Microbiological Control Sections, Bacterial
Diseases Branch, Epidemiology Program, Centers for Disease Control,
1972.
(3) Houang, E.T. et al., ``Absence of Bacterial Resistance to
Povidone Iodine,'' Journal of Clinical Pathology, 29:752-755, 1976.
(4) Mitchell, R.G., and A.C. Hayward, ``Postoperative Urinary-
Tract Infections Caused by Contaminated Irrigating Fluid,'' The
Lancet, 1:793-795, 1966.
(5) Geftic, S.G., H. Heymann, and F. W. Adair, ``Fourteen-Year
Survival of Pseudomonas cepacia in a Salts Solution Preserved with
Benzalkonium Chloride.'' Applied and Environmental Microbiology,
37:505-510, 1979.
(6) Rapkin, R.H., ``Pseudomonas cepacia in an Intensive Care
Nursery,'' Pediatrics, 57:239-243, 1976.
(7) Plotkin, S.A., and R. Austrian, ``Bacteremia Caused by
Pseudomonas Sp. Following the Use of Materials Stored in Solutions
of a Cationic Surface-Active Agent,'' The American Journal of the
Medical Sciences, 235:621-627, 1958.
(8) Frank, M.J., and W. Schaffner, ``Contaminated Aqueous
Benzalkonium Chloride. An Unnecessary Hospital Infection Hazard,''
Journal of the American Medical Association, 236:2418-2419, 1976.
(9) Kaslow, R.A., D.C. Mackel, and G.F. Maillison, ``Nosocomial
Pseudobacteremia. Positive Blood Cultures Due to Contaminated
Benzalkonium Antiseptic,'' Journal of the American Medical
Association, 236:2407-2409, 1976.
(10) Burdon, D.W., and J.L. Whitby, ``Contamination of Hospital
Disinfectants with Pseudomonas Species,'' British Medical Journal,
2:153-155, 1967.
(11) Barry, M.A. et al., ``Serratia marcescens Contamination of
Antiseptic Soap Containing Triclosan: Implications for Nosocomial
Infection,'' Infection Control, 5:427-430, 1984.
(12) Dailey, R.H., and E.J. Benner, ``Necrotizing Pneumonitis
Due to the Pseudomonad `Eugonic Oxidizer-Group I','' New England
Journal of Medicine, 279:361-2, 1968.
(13) Weinstein, A.J. et al., ``Case Report: Pseudomonas cepacia
Pneumonia,'' American Journal of the Medical Sciences, 265:491-494,
1973.
(14) Richards, R.M.E., and J.M. Richards, ``Pseudomonas cepacia
Resistance to Antibacterials,'' Journal of Pharmaceutical Sciences,
68:1436-1438, 1979.
(15) Sonnenwirth, A.C., ``Pseudomonas,'' in ``Microbiology,'' 2d
ed., edited by Davis, B.D. et al, Harper and Row, Hagerstown, MD,
New York, Evanston, San Francisco, London, p. 783, 1973.
(16) ``Contaminated Povidone-Iodine Solution--Northeastern
United States,'' Morbidity and Mortality Weekly Report, Public
Health Service, Centers for Disease Control, HHS Publication No.
(CDC) 81-8017, 29:553-555, 1980.

E. Comment on Alcohol

10. One comment submitted data on the safety and effectiveness of
62 percent alcohol formulated in an emolliented vehicle and dispensed
as a foam (Ref. 1) and requested that alcohol be included in the
topical antimicrobial monograph as a surgical hand scrub, health-care
personnel handwash, and hand degermer.
Data on the safety and effectiveness of alcohol formulated in an
emolliented vehicle for use as a surgical hand scrub, health-care
personnel handwash, and hand degermer were submitted to the
Miscellaneous External Panel (Refs. 2 and 3). However, the data were
not reviewed or categorized for these uses during that rulemaking. In
reviewing alcohol for short-term uses, that Panel stated, ``ethyl
alcohol acts relatively quickly to decrease the number of micro-
organisms on the skin surface. Each minute that scrubbed hands and arms
were immersed in approximately 77 percent ethyl alcohol by volume was
found to be equivalent to 6.5 minutes of scrubbing in water; if the
skin was scrubbed with the alcohol, the rate was further increased''
(47 FR 22324 at 22328). The Panel found ethyl alcohol safe and
effective for use as a topical antimicrobial preparation in
concentrations of 60 to 95 percent by volume in an aqueous solution.
The following indications were proposed:
(1) ``For first aid use to decrease germs in minor cuts and
scrapes.''
(2) ``To decrease germs on the skin prior to removing a splinter or
other foreign object.''
(3) ``For preparation of the skin prior to an injection.'' (See the
advance notice of proposed rulemaking for OTC alcohol drug products for
topical antimicrobial use, in the Federal Register of May 21, 1982, 47
FR 22324.)
The submissions (Refs. 1 and 2) included effectiveness data and
labeling for a currently marketed product containing 62 percent ethyl
alcohol formulated in an emolliented vehicle and dispensed as a foam
used ``* * * to degerm hands * * *.'' The agency has reviewed these
data, derived from effectiveness testing as a surgical hand scrub
(glove juice test) and health-care personnel handwash, and finds that
they meet the procedures in the testing guidelines in the previous
tentative final monograph (43 FR 1210 at 1242). Statistical analyses
showed microbial reduction to be highly significant. A glove juice test
showed that alcohol foam reduced the baseline number of bacteria
present in normal skin flora, after first use, by 1.87 logs, and, after
continued use for 5 days, by 2.36 logs. The reduction of the baseline
number of bacteria was maintained for up to 6 hours under surgical
gloves. A health-care personnel handwash effectiveness test showed
microbial reduction on test subjects' hands, artificially contaminated
with Serratia marcescens (S. marcescens). Microbial reduction averaged
3.3 logs after 5 treatments and 3.63 logs after 25 treatments. In vitro
data, derived from studies using S. marcescens as the test bacteria,
showed that alcohol properly formulated in an emolliented vehicle and
dispensed as a foam, significantly reduced the number of test bacteria,
in 10 percent serum, within 15 seconds.
Based on these data and the conclusions of the Miscellaneous
External Panel (47 FR 22324), the agency concludes that alcohol, when
properly formulated, is effective for use as a surgical hand scrub and
antiseptic handwash or health-care personnel handwash. Because it is
well established that alcohol alone does not provide persistence, the
agency notes that a preservative agent in the vehicle provided the
persistent effect to maintain reduction in the baseline number of
bacteria for 6 hours as required to demonstrate efficacy as a surgical
hand scrub drug product.
The agency is including alcohol in proposed Sec. 333.410(a)
(antiseptic handwash or health-care personnel handwash),
Sec. 333.412(a) (patient preoperative skin preparation), and
Sec. 333.414(a) (surgical hand scrub), as follows: ``Alcohol 60 to 95
percent by volume in an aqueous solution denatured according to Bureau
of Alcohol, Tobacco and Firearms regulations in 27 CFR part 20.''
Further, the agency finds the Miscellaneous External Panel's proposed
Category I indication for OTC alcohol drug products, i.e., ``for
preparation of the skin prior to an injection'' to be an appropriate
indication for patient preoperative skin preparation drug products.
Based on that Panel's recommendations, the agency is including this
indication as an additional claim for alcohol drug products in
Sec. 333.460(b)(2) of the proposed monograph. In addition, based on
that Panel's similar recommendations for isopropyl alcohol (47 FR 22324
at 22329 and 22332), the agency is proposing this indication for OTC
isopropyl alcohol drug products in Sec. 333.460(b)(3). As discussed in
section I.N., comment 28, the agency is proposing new effectiveness
criteria for drug products labeled for this use.
The monograph will also state that an alcohol drug product must be
properly formulated, such as the product in an emolliented vehicle
dispensed as a foam discussed above, to meet the test requirements in
Sec. 333.470. This means that alcohol when intended for certain uses
must be able to demonstrate effectiveness by certain tests proposed in
this tentative final monograph, as follows: (1) Antiseptic or health-
care personnel handwash--Sec. 333.470(b)(2), (2) patient preoperative
skin preparation--Sec. 333.470(b) (3), and (3) surgical hand scrub--
Sec. 333.470(b)(1). As discussed in section I.B., comment 5, the term
``antiseptic handwash'' in lieu of ``hand degermer'' is being proposed
in the monograph as the statement of identity for this type of product.
The labeling for the alcohol product (Ref. 1) provides directions
for use without water rinsing, where water is not readily available, as
follows: ``A `palmful' (5 grams) is dispensed in one hand. It is spread
on both hands and rubbed into the skin until dry (approximately 1 to 2
minutes). A smaller amount (2.5 grams) is then dispensed into one hand,
spread over both hands to wrist, and rubbed into the skin until dry
(approximately 30 seconds).'' The agency concurs with these directions
and is incorporating them into its proposed directions for use for OTC
topical antiseptic drug products, including alcohol, formulated for use
without water in this tentative final monograph. See proposed
Sec. 333.455(c) and Sec. 333.465(c).

References

(1) Unpublished studies on emolliented alcohol foam (62 percent
alcohol), Comments No. C105, C144, and CR7, Docket No. 75N-0183,
Dockets Management Branch.
(a) Microbiological evaluation of ``Alcare Hand Degermer'' on
personnel in a newborn intensive care unit, May 12, 1977.
(b) Results of a study of efficacy against experimental
contamination of human skin, June 20, 1978.
(c) Efficacy study with Vestal Foam results of a glove fluid
study, January 27, 1975.
(d) Serratia marcescens efficacy data for Alcare, February 20,
1978.
(e) Amended labeling for Alcare Foamed Alcohol, August 19, 1982.
(2) OTC Vol. 160377.
(3) OTC Vol. 160382.

F. Comments on Chlorhexidine Gluconate

11. Several comments requested that the agency include
chlorhexidine gluconate as a Category I ingredient in any amended
tentative final monograph. The comments submitted references and data
to establish general recognition of safety and effectiveness (Ref. 1),
and stated that chlorhexidine gluconate solution is recognized in the
``British Pharmacopeia'' (Ref. 2) and is formulated in a wide range of
products that have been successfully marketed to a material extent and
for a material length of time in other countries. The comments asserted
that when formulated in compliance with FDA's current good
manufacturing practice regulations (21 CFR part 211), chlorhexidine
products are safe and effective for use as skin wound cleansers, skin
wound protectants, patient preoperative skin preparations, skin
antiseptics, surgical hand scrubs, and health-care personnel
handwashes.
A reply comment argued that chlorhexidine gluconate, currently
marketed in the United States under approved new drug applications
(NDA's), is not eligible for an OTC drug monograph because the
ingredient has not been marketed within this country to a material
extent and for a material length of time. The comment added that
variations in final formulations may alter the safety and effectiveness
of the ingredient. The comment submitted data (Ref. 3) to support this
viewpoint and requested that chlorhexidine gluconate be classified in
Category II.
In the previous tentative final monograph (43 FR 1210),
chlorhexidine gluconate (4 percent solution) was neither addressed nor
categorized as Category I, II, or III. However, subsequent to the
tentative final monograph, the agency granted a petition (Ref. 4) and
in the Federal Register of March 9, 1979, reopened the administrative
record to allow interested persons an opportunity to submit data and
information (44 FR 13041). The comments (Ref. 1) and reply comment
(Ref. 2) were submitted in response to that notice. However, since that
time a majority of the comments on chlorhexidine submitted in response
to the notice have been withdrawn (Ref. 5). While the withdrawn
comments remain on public display as part of the administrative record,
they are no longer being considered in this rulemaking.
The agency has reviewed the marketing history of chlorhexidine
gluconate and finds that although it has been marketed for professional
or hospital use under NDA's, insufficient data remain in the public
administrative record for this rulemaking to support general
recognition of safety and effectiveness for OTC use. Accordingly,
chlorhexidine gluconate 4 percent aqueous solution as a health-care
antiseptic is a new drug and is not included in this tentative final
monograph.

References

(1) Comments No. C110, C116, C120, C130, C131, C136, C137,
EXT18, RC2, RC5, CP3, LET12, LET14, LET16, SUP30, SUP33, SUP38, and
SUP40, Docket No. 75N-0183, Dockets Management Branch.
(2) ``British Pharmacopeia,'' Vol. I, Her Majesty's Stationery
Office, London, pp. 100-101, 1980.
(3) Comments No. RC1 and RC4, Docket No. 75N-0183, Dockets
Management Branch.
(4) Comment No. CP3, Docket No. 75N-0183, Dockets Management
Branch.
(5) Comments No. WDL3, WDL4, and WDL5, Docket No. 75N-0183,
Dockets Management Branch.

G. Comments on Chloroxylenol

12. A number of comments disagreed with the agency's Category III
classification of chloroxylenol in the tentative final monograph. They
argued that a reevaluation of the data previously submitted to the
agency along with new data that have been submitted (Refs. 1 through
16) would provide adequate justification for classifying chloroxylenol
in Category I for safety and effectiveness for use in antimicrobial
soaps, health-care personnel handwashes, patient preoperative skin
preparations, skin antiseptics, skin wound cleansers, skin wound
protectants, and surgical hand scrubs. Several comments pointed out
that the Antimicrobial II Panel unanimously concluded that
chloroxylenol is generally recognized as safe for topical use in
athlete's foot and jock-itch preparations.
Based upon the submitted data (Refs. 1 through 16) and other
information reviewed by the Antimicrobial Panels, the agency concluded
in the amended tentative final monograph for OTC first aid antiseptic
drug products that chloroxylenol (0.24 percent to 3.75 percent) was
safe but not effective for short-term use as an OTC topical first aid
antiseptic (54 FR 33644 at 33658). These data (Refs. 1 through 16) and
new data submitted under the agency's ``feedback'' procedures (Refs. 17
through 30) are insufficient to support a Category I classification of
the safety and effectiveness of the ingredient for other long-term
uses, e.g., antiseptic handwash or health-care personnel handwash and
surgical hand scrub. The agency concludes that chloroxylenol remains
classified in Category III as an active ingredient for these uses.
However, the ingredient would be considered safe for short-term use as
a patient preoperative skin preparation but remains in Category III due
to a lack of effectiveness data for this use.
In the previous tentative final monograph (43 FR 1210 at 1222 and
1238), the agency stated that the data were insufficient to reclassify
chloroxylenol into Category I, and the ingredient remained in Category
III for safety and effectiveness. Indicating concern about the
absorption of topically applied antimicrobial drug products used
repeatedly by consumers over a number of years, the agency stated the
following regarding the safety of the ingredient:

Only the most superficial toxicity data in animals were
submitted to and reviewed by the Panel. The Commissioner concurs
with the Panel that toxicity in rodent and nonrodent species,
substantivity, blood levels, distribution and metabolism, as well as
any subsequent systemic absorption studies must be characterized * *
*. The degree of absorption of PCMX following topical administration
has not been established. The target organ for PCMX toxicity in
animals also remains unidentified and should be shown in a long-term
animal toxicity study.

While safety data (Refs. 1, 2, 6, and 7) are sufficient to
establish safety for short-term use such as for a patient preoperative
skin preparation drug product, these data do not resolve concerns about
long-term chronic toxicity. Conclusions on these data, which were also
reviewed by the Advisory Review Panel on OTC Antimicrobial II Drug
Products (Antimicrobial II Panel) in conjunction with its review of OTC
topical antifungal drug products, were published in the Federal
Register of March 23, 1982 (47 FR 12480). That Panel, which evaluated
the safety of the ingredient for use in OTC topical antifungal drug
products, categorized chloroxylenol (0.5 to 3.75 percent) as safe
(Category I) for short-term use (up to 13 weeks) and advised, ``* * *
relatively low doses of chloroxylenol can be systemically tolerated, at
least over a 13-week period. The Panel is concerned about the effect of
chronic administration on the liver, but does not consider that topical
application of chloroxylenol to small areas of the skin over short
periods of time would result in liver damage.'' (47 FR 12480 at 12534).
The agency subsequently agreed with the Panel's conclusions concerning
the safety of using the ingredient in OTC topical antifungal drug
products for the treatment of athlete's foot, jock itch, and ringworm
(maximum treatment duration 4 weeks) in its tentative final monograph
for these OTC drug products, published in the Federal Register of
December 12, 1989 (54 FR 51136 at 51139). The agency subsequently
finalized these conclusions in the final rule for OTC topical
antifungal drug products published in the Federal Register of September
23, 1993 (58 FR 49890).
Regarding long-term chronic toxicity, data and information provided
by one manufacturer included final reports of completed studies and
interim reports of incomplete studies (Ref. 2). The information also
contained a protocol of a planned preclinical study (projected starting
and completion dates for experiments) which identified a 2-year rat
feeding study. Because this study might resolve concerns about long-
term chronic toxicity, the agency requested the raw data (Ref. 31);
however, the manufacturer declined to submit the data, explaining that
it is no longer interested in marketing chloroxylenol, that its study
had not been completed, and that the study was conducted prior to
establishment of the Good Laboratory Practices regulations (Ref. 32).
In response to the agency's determination that data from a 2-year
rat feeding study were essential (Ref. 33), another manufacturer
submitted additional information along with copies of already available
safety data (Ref. 34). The manufacturer explained that it believes that
long-term safety data, i.e., 2-year oral feeding study, while not
currently available, may not be a necessity. Citing statements made by
the Panel, that its recommended guidelines for the safety testing of
these drug products were developed primarily for antimicrobial agents
applied to the entire body surface and that appropriate tests should be
chosen to reflect the intended use of the antimicrobial drug product
(39 FR 33103 at 33135), the manufacturer contended that the guidelines
were developed to address the most extreme exposure to an antimicrobial
ingredient rather than to describe the minimal requirements for safety
data that the Panel would find acceptable. Noting the contrast between
the use of surgical hand scrub drug products (products used by adults
in a limited area of the body for a specified time span) with lifetime
application to the entire body in bar soaps, the manufacturer contended
that while the use of a surgical hand scrub is considered chronic use,
the exposure to the antimicrobial ingredient during such use is limited
to the hand and half the distance to the elbow. The manufacturer
further suggested that one might simply regard the use of health-care
antiseptic ingredients in handwashes and surgical scrubs as repeated
daily use in a limited area of the body.
The manufacturer contended that data from a 2-year feeding study
would not contribute any information on the long-term safety of
chloroxylenol that is not already available from subchronic studies
(Ref. 35). In support of its contention, the manufacturer submitted
data from subchronic animal toxicity and human bathing studies (Ref.
18) previously submitted in response to the tentative final monograph
for OTC topical antimicrobial drug products and to the Antimicrobial II
Panel. The data also included computer simulation models (Ref. 36) of
plasma levels of chloroxylenol that might occur after dermal
applications of varying concentrations of the ingredient. The
simulations, based on urinary excretion data from human bathing
studies, predict a lack of potential for accumulation of the ingredient
in humans. Subsequent submissions from the same manufacturer included a
review article on the toxicity of chloroxylenol (Ref. 19), a
retrospective analysis of the value of chronic animal toxicology
studies of pharmaceutical compounds (Ref. 20), and copies of all
available toxicity data for chloroxylenol (Ref. 21). Included in the
toxicity data was a kinetic analysis (Ref. 37) of data from human and
animal studies of the ingredient previously submitted to the agency
that also predicts that accumulation in humans is not likely to occur
at reasonable exposure levels. Based on the above data and information,
the manufacturer requested that the agency reconsider the necessity of
a long-term animal study. In response to the manufacturer's request, a
public meeting was held to discuss the available toxicity data for
chloroxylenol. At that meeting, the agency noted that many of the
subchronic studies of the ingredient are of limited usefulness because
they were conducted using a formulated product that contained isopropyl
alcohol, turpineols, and castor oil soap in addition to chloroxylenol.
The kinetic model used in the studies was considered inappropriate. A
one-compartment model, as used in the analysis, is not relevant to
chloroxylenol due to its lipophilic nature. The agency's detailed
comments are on file in the Dockets Management Branch (Refs. 38 and
39).
After considering the manufacturer's comments and evaluating the
data available at the time, the agency concluded that the information
was not adequate to characterize the level of absorption, the
distribution, the metabolism, and the excretion of chloroxylenol
following topical administration. In a 1988 letter to the manufacturer
(Ref. 40), the agency stated: (1) That data from the human bathing
studies reviewed are highly variable (absorption 0.5 to 15.7 percent),
(2) the analytical methodology used in the studies had not been
validated and (3) that the small number of subjects included in the
studies made it difficult to draw meaningful conclusions from the
reported results. The agency commented further that submitted
accumulation predictions were not adequate to define the toxicity that
might occur with repeated exposure to the ingredient because no data
have been submitted to support or validate the model's assumptions in
characterizing exposure and stated that additional data are needed to
justify, support, and verify the assumptions and data used in the
predictions. Pointing out that accumulation is not the sole issue of
long-term toxicity, the agency asserted that long-term toxicity may be
related to repeated daily exposure to low levels of the ingredient over
a lifetime.
In that same letter, the agency stated that it had reexamined the
necessity for a long-term animal study based on the manufacturer's
assertion that use of the ingredient as an antiseptic handwash and
surgical scrub should be regarded as repeated use to a limited area of
the body, and had concluded that data from additional short-term
studies conducted under actual use conditions (i.e., where abrasion is
followed by occlusion, with the level of absorption, distribution,
metabolism, and elimination of the ingredient being shown under these
conditions) could provide adequate information to determine whether or
not a long-term animal study is necessary. Protocols for a
pharmacokinetic surgical scrub study to develop such data were
submitted to the agency (Refs. 41 and 42); however, to date the agency
has not received any data from such a study. The agency's detailed
comments are on file in the Dockets Management Branch (Refs. 43 and
44).
More recently, the agency received additional data pertaining to
the safety of chloroxylenol from another manufacturer (Ref. 30). The
data included an assessment of the ingredient's mutagenic potential by
a series of in vitro and in vivo assays (Ames test, unscheduled DNA
synthesis in rat primary hepatocytes, chromosomal aberrations in
Chinese hamster ovary cells, and an in vivo mouse micronucleus assay).
The data also included a dose range-finding study for a teratology
study of the ingredient in rats and the subsequent teratology study.
Two of the four mutagenicity assays included in the submission
yielded suspect or equivocal results. The in vitro administration of
19, 38, 75, and 150 micrograms per milliliter (g/mL) doses of
chloroxylenol to Chinese hamster ovary cells produced a statistically
significant increase relative to the solvent control in the mean number
of chromosome aberrations per cell at the 75 and 150 g/mL dose
level both in the presence and absence of metabolic activation.
Statistically significant increases in the percent of aberrant cells
were also seen at the 75 g/mL dose in the absence of metabolic
activation and at the 75 and 150 g/mL doses in the presence of
metabolic activation. No dose response was apparent in either the
activated or nonactivated systems. The investigator concluded that the
results were equivocal in the nonactivated test system and suspect in
the activated test system.
The results of the in vivo mouse micronucleus assay demonstrated a
statistically significant increase in micronucleated polychromatic
erythrocytes in female mice 24 and 72 hours after oral dosing with 250
and 833 milligrams per kilogram (mg/kg) doses of chloroxylenol.
However, no dose response was apparent. The investigator considered the
results to be a statistical anomaly based on unusually low mean
micronucleus values in the negative control group and the lack of a
dose response. However, the agency believes that because the observed
increases were significantly elevated over those of the negative
controls (p 0.01) and were reproducible at two dose levels,
these results should be considered equivocal. The manufacturer has
provided additional information (Ref. 45) in response to the agency's
interpretation of the results of the mouse micronucleus assay. However,
the agency continues to believe that reliance on data from historical
controls is inappropriate and has not changed its position on the data.
The agency's detailed comments are on file in the Dockets Management
Branch (Refs. 46 and 47).
In light of the new data (Ref. 30) and the issues that they raise,
the agency has again reexamined the data requirements necessary to
support the safe chronic use of this ingredient. The agency finds it
necessary to broaden the additional testing requirements in order to
clearly assess potential risks associated with chronic use of
chloroxylenol. Therefore, data obtained from the following are
necessary: (1) Human studies conducted under maximal use conditions,
i.e., repeated use as a surgical scrub use where abrasion is followed
by occlusion, characterizing the level of absorption, the distribution,
metabolism, and elimination of the ingredient, (2) a lifetime dermal
carcinogenicity study (up to 2 years) in mice, and (3) an appropriate
human epidemiological study performed to determine the effects on
health-care professionals in countries, such as England, where the
ingredient has been used extensively for a long period of time are
necessary. Further, in order to relate the data derived from the
chronic animal study to humans, the lifetime dermal carcinogenicity
study should also include concomitant absorption, distribution,
metabolism, and excretion studies. A protocol for an 18-month dermal
carcinogenicity study has been submitted to the agency (Ref. 48). The
agency's detailed comments and evaluation of the data and protocol are
on file in the Dockets Management Branch (Ref. 47).
Regarding the effectiveness of chloroxylenol, the agency stated the
following in the previous tentative final monograph: ``Claims for broad
spectrum activity have been made * * *; however, the Commissioner finds
that inadequate effectiveness data were submitted. Many studies were
old and not performed with modern antiseptic testing procedures. * * *
effectiveness testing both in vitro and in vivo should be done in
accordance with the Guidelines'' (43 FR 1238).
The applicable effectiveness data submitted by the comments were
derived from in vivo and in vitro studies (Refs. 1 through 7 and 13
through 16), along with data subsequently submitted under the
``feedback'' procedures (Refs. 22 through 28 and 50).
Data from in vivo glove juice studies (Refs. 1, 2, 19, and 50)
demonstrated the antiseptic activity of chloroxylenol in a range of 3
to 3.75 percent when formulated in an aqueous surfactant vehicle.
Chloroxylenol formulations are substantive in their activity, i.e.,
they do not produce an initial high reduction in the number of bacteria
but after repeated use (routine use), they reduce the baseline number
of bacteria and suppress bacterial growth for 6 hours. In vivo data for
surgical hand scrub products containing chloroxylenol at concentrations
lower than 3 percent are insufficient. Aqueous solutions of
chloroxylenol in a pine oil vehicle (1:40 dilution of Dettol)
consistently reduced more than 99 percent Staphylococcus aureus (S.
aureus) from the hands of test subjects (Ref. 25).
In vivo cup scrubbing and other appropriate data (Refs. 22, 23, and
24) indicate that chloroxylenol, in 70 percent alcohol, is fast acting
as a patient preoperative skin preparation. However, alcohol itself
meets the criteria for a preoperative skin preparation and is a
significant contributor for fast acting contaminant reduction. The data
are not sufficient to demonstrate that chloroxylenol in this
formulation contributes to the total antimicrobial effect.
In vitro study data (Refs. 1, 3, 4, 5, 13, 14, 16, and 26) show
that chloroxylenol in various vehicles is effective against gram-
negative bacteria, i.e., Escherichia coli (E. coli), P. aeruginosa,
Proteus vulgaris, and Klebsiella aerogenes (K. aerogenes). This anti-
gram-negative activity is formulation dependent. Tested aqueous
solutions of pure chloroxylenol with no other additives show that low
concentrations (0.3 mg/mL) reduced 95 percent of some Pseudomonas in 10
minutes.
Data regarding the antiseptic activity of chloroxylenol itself are
not adequate. While the data are considered sufficient to support in
vitro effectiveness for the finished products, the available data are
inadequate to show the contribution of the chloroxylenol. Because these
finished products contain several additional ingredients, e.g.,
surfactants, isopropanol, pine oil, or ethylenediaminetetraacetic acid
(EDTA), which contributed substantial germicidal activity, conclusions
regarding chloroxylenol's active contribution to the product's efficacy
cannot be supported. The agency's detailed comments and evaluations of
the submitted data are on file in the Dockets Management Branch (Refs.
51 and 52). One manufacturer has responded to FDA's concern and
provided additional data (Ref. 53). These data are currently being
reviewed by the agency and will be discussed in the final rule for
these drug products. In summary, the data are sufficient to support the
in vitro and in vivo effectiveness of the formulations tested. However,
additional data are needed to demonstrate that chloroxylenol
contributes to the activity of these formulations. In addition, data
from glove juice studies indicate that the antimicrobial activity of
chloroxylenol is substantive in nature and does not produce an initial
high reduction of bacteria, but that repeated use of the ingredient
will produce a reduction in bacteria as well as a suppression of the
baseline number of bacteria of the normal skin flora for 6 hours. As
discussed in section I.N., comment 28, the agency is proposing that all
antimicrobial products indicated for use as a surgical scrub or health-
care personnel handwash be able to demonstrate an immediate reduction
in bacteria and is inviting comment on the use of substantive
antimicrobials in health-care antiseptic drug products.
The agency, therefore, is proposing that chloroxylenol at the
concentrations evaluated (0.24 percent to 3.75 percent) be classified
as Category I for safety and Category III for effectiveness for short-
term use as a patient preoperative skin preparation and in Category III
for safety and effectiveness for long-term uses, i.e., antiseptic
handwash or health-care personnel handwash and surgical hand scrub. The
existing data are not adequate to extrapolate and assess the chronic
toxicity of chloroxylenol for long-term use. Before chloroxylenol may
be generally recognized as effective, the agency recommends that
appropriate in vitro and in vivo effectiveness data be submitted. The
data should include results obtained from both in vitro and in vivo
tests as described in the testing procedures below. (See section I.N.,
comment 28.)

References

(1) Unpublished Clinical Safety and Effectiveness Studies on
Aqueous Soap Formulations, Comment No. 0B7, Docket No. 75N-0183,
Dockets Management Branch.
(a) Controlled Clinical Study Comparing the Activity of Fresh,
Camay Soap, and Phisohex Against the Natural Bacterial Flora of the
Hand.
(b) Antimicrobial Activity of PCMX, Triclosan, and TCC.
(c) Repeated Insult Patch Testing of Fresh Soap.
(2) Unpublished Nonclinical and Clinical Studies, and Protocols,
Comment No. C96, Docket No. 75N-0183, Dockets Management Branch.
(a) Part I: PCMX Toxicosis, final reports of completed studies,
interim reports of incomplete studies, and Preclinical Testing
Protocol.
(b) Part II: Complete Reports on Clinical Safety and Efficacy
and In Vitro Efficacy Studies.
(3) Unpublished Clinical Effectiveness Studies on Aqueous Soap
Formulations, Comment No. C122, Docket No. 75N-0183, Dockets
Management Branch.
(a) Protocol and Results of a Glove Juice Hand Washing Test
Performed with PHLO Antimicrobial Skin Cleanser.
(b) Results of a Zone of Inhibition and Assay Performed on Aged
Samples of PHLO Antimicrobial Skin Cleanser.
(4) Unpublished Clinical Safety and Effectiveness Studies on
Aqueous Soap Formulations, Comment No. C123, Docket No. 75N-0183,
Dockets Management Branch.
(a) Bactericidal Activity of Envair Antiseptic Hand Soap.
(b) Dermal Irritation Study.
(c) Insult Patch Test.
(d) Bacterial Kill Test.
(e) Hand-wash Effectiveness Test.
(5) Unpublished In Vitro Effectiveness Studies Performed on
Aqueous Soap Solutions, Comment No. C125, Docket No. 75N-0183,
Dockets Management Branch.
(a) AOAC Available Chlorine Germicidal Equivalent Concentration
Test.
(b) The Antimicrobial Activity of a Sample.
(6) Published and Unpublished Nonclinical and Clinical Safety
Studies, Comment No. SUP11, Docket No. 75N-0183, Dockets Management
Branch.
(7) Comment No. SUP12, Docket No. 75N-0183, Dockets Management
Branch.
(8) Unpublished Clinical Safety an Effectiveness Studies,
Comment No. SUP10, Docket No. 75N-0183, Dockets Management Branch.
(a) The Effects of Vaseline Petroleum Jelly and Vaseline First
Aid Carbolated Petroleum Jelly on Epidermal Wound Healing--A
Controlled Clinical Laboratory Study, April 29, 1976.
(b) The Effect of Vaseline Petroleum Jelly and Vaseline First
Aid Carbolated Petroleum Jelly on Healing of Experimental Skin
Wounds, January 13, 1977.
(9) Bradbury, S. J., and J. Hayden, ``Effect of DettolR
Wound Healing in Rats,'' Report No. RC 76132, unpublished study,
Comment No. SUP5, Docket No. 75N-0183, Dockets Management Branch.
(10) Bradbury, S.J., and E.J. Hayden, ``DettolR Wound
Healing,'' unpublished study, Project No. RC 1081, 1978, Comment No.
SUP12, Docket No. 75N-0183, Dockets Management Branch.
(11) Maibach, H.I., ``The Effects of VaselineR Petroleum
Jelly and VaselineR First Aid Carbolated Petroleum Jelly on
Epidermal Wound Healing--A Controlled Clinical Laboratory Study,''
unpublished study, Comment No. SUP10, Docket No. 75N-0183, Dockets
Management Branch.
(12) Maibach, H.I., ``The Effect of VaselineR Petroleum
Jelly and VaselineR First Aid Carbolated Petroleum Jelly on
Healing of Experimental Skin Wounds,'' unpublished study, Comment
No. SUP10, Docket No. 75N-0183, Dockets Management Branch.
(13) Munton, T.J., and J. Prince, ``The Bacteriostatic and
Bactericidal Activity of DettolR Against a Range of Recently
Isolated Mesophilic Strains Including Members of the Normal Flora
and Cutaneous Pathogens of the Skin,'' unpublished study, No. BL 75/
4, 1975, Comment No. SUP3, Docket No. 75N-0183, Dockets Management
Branch.
(14) Prince, J., and K.A. Barker, ``A Comparison of the In-Vitro
Activity of DettolR, Hexylresorcinol, and Benzalkonium
Chloride,'' unpublished study, No. BL 76/28, 1976, Comment No. SUP3,
Docket No. 75N-0183, Dockets Management Branch.
(15) Munton, T.J., and J. Prince, ``The Bactericidal Activity of
DettolR on Skin Artificially Contaminated with Micro-organisms
Using the Replica Plating Technique,'' unpublished study, No. BL 75/
14, RC 7565, 1975, Comment No. SUP3, Docket No. 75N-0183, Dockets
Management Branch.
(16) ``Scientific Information on the `In-vitro' and `In-vivo'
Antimicrobial Activity of DettolR as Determined in the
Bacteriological Laboratories of Reckitt and Colman, Hull,''
unpublished report, Comment No. C62, Docket No. 75N-0183, Dockets
Management Branch.
(17) Comment No. LET65, Docket No. 75N-0183, Dockets Management
Branch.
(18) Comment No. SUP47, Docket No. 75N-0183, Dockets Management
Branch.
(19) Guess, W.L., and M.K. Bruch, ``A Review of Available
Toxicity Data on the Topical Antimicrobial Chloroxylenol,'' Journal
of Toxicology Cutaneous and Ocular Toxicology, 5:233-262, 1986.
(20) Lumley, C.E., and S.R. Walker, ``The Value of Chronic
Animal Toxicology Studies of Pharmaceutical Compounds: A
Retrospective Analysis,'' Fundamental and Applied Toxicology,
5:1007-1024, 1985.
(21) Comment No. RPT6, Docket No. 75N-0183, Dockets Management
Branch.
(22) Davies, J. et al., ``Disinfection of the Skin of the
Abdomen,'' British Journal of Surgery, 65:855-858, 1978.
(23) Frazer, J., ``The Effect of Two Alcohol Based Antiseptics
on Artificially Contaminated Skin,'' Microbios Letters, 3: (10) 119-
122, 1976.
(24) Byatt, M.E., and A. Henderson, ``Preoperative Sterilization
of the Perineum: A Comparison of Six Antiseptics,'' Journal of
Clinical Pathology, 26:921-924, 1973.
(25) Lowbury, E.J.L., H.A. Lilly, and J. P. Bull, ``Disinfection
of Hands: Removal of Transient Organisms,'' British Medical Journal,
2:230-233, 1964.
(26) Caplin, H., and D.C. Chapman, ``A Comparison of Three
Commercially Available Antiseptics Against Opportunist Gram-Negative
Pathogens,'' Microbios, 16:133-138, 1976.
(27) Comment No. SUP48, Docket No. 75N-0183, Dockets Management
Branch.
(28) Comment No. RPT3, Docket No. 75N-0183, Dockets Management
Branch.
(29) Comment No. RC6, Docket No. 75N-0183, Dockets Management
Branch.
(30) Comment No. C171, Docket No. 75N-0183, Dockets Management
Branch.
(31) Letter from W.E. Gilbertson, FDA, to C. Rose, Pennwalt
Corp., coded LET54, Docket No. 75N-0183, Dockets Management Branch.
(32) Letter from C. Rose, Pennwalt Corporation, to W.E.
Gilbertson, FDA, coded LET59, Docket No. 75N-0183, Dockets
Management Branch.
(33) Letters from W.E. Gilbertson, FDA, to J. Nalls, Ferro
Corp., C. Rose, Pennwalt Corp., M.E. Garabedian, Dexide, Inc., M.
Berdick, Chesebrough-Ponds, Inc., W.F. Stephen, Scientific and
Regulatory Services, H.S. Chapman, Chemical Specialties, Inc., C.A.
Wiseman, Sani-Fresh, Division of Envair, Inc., J. Rowan, Seagull
Chemical, Inc., coded LET70, LET71, LET72, LET73, LET74, LET75,
LET76, and LET77, respectively, in Docket No. 75N-0183, Dockets
Management Branch.
(34) Comment No. LET65, volumes 1 through 3, Docket No. 75N-
0183, Dockets Management Branch.
(35) Memorandum of meeting between representatives of Dexide,
Inc., Ferro Corp., and FDA, coded MM8, Docket No. 75N-0183, Dockets
Management Branch.
(36) Stavchansky, ``Computer Simulations of Chloroxylenol,''
unpublished report, Comment No. SUP47, Docket No. 75N-0183, Dockets
Management Branch.
(37) Cabana, B.E., and E.D. Purich,''Comparative Metabolism and
Pharmacokinetics of Chloroxylenol (PCMX) in Animals and Man,''
unpublished report, Comment No. RPT6, Volume 7, Docket No. 75N-0183,
Dockets Management Branch.
(38) Letter from W. E. Gilbertson, FDA, to M. K. Bruch, Dexide,
Inc., coded LET79, Docket No. 75N-0183, Dockets Management Branch.
(39) Memorandum of meeting between representatives of Dexide,
Inc., Ferro Corp., and FDA, coded MM11, Docket No. 75N-0183, Dockets
Management Branch.
(40) Letter from W. E. Gilbertson, FDA, to M. K. Bruch, Dexide,
Inc., coded LET89, Docket No. 75N-0183, Dockets Management Branch.
(41) Comment No. C165, Docket No. 75N-0183, Dockets Management
Branch.
(42) Comment No. SUP51, Docket No. 75N-0183, Dockets Management
Branch.
(43) Letter from W. E. Gilbertson, FDA, to M. K. Bruch, Dexide,
Inc., coded LET93, Docket No. 75N-0183, Dockets Management Branch.
(44) Memorandum of meeting between representatives of Dexide,
Inc., Ferro Corp., and FDA, coded MM15, Docket No. 75N-0183, Dockets
Management Branch.
(45) Comment No. C172, Docket No. 75N-0183, Dockets Management
Branch.
(46) Letter from W. E. Gilbertson, FDA, to G. R. Kramzar, NIPA
Laboratories, Inc., coded LET97, Docket No. 75N-0183, Dockets
Management Branch.
(47) Letter from W. E. Gilbertson, FDA to G. R. Kramzar, NIPA
Laboratories, Inc., coded C174, Docket No. 75N-0183, Dockets
Management Branch.
(48) Comment No. C173, Docket No. 75N- 0183, Dockets Management
Branch.
(49) Comment No. LET65, vol. 4, 5, and 6, Docket No. 75N-0183,
Dockets Management Branch.
(50) McCracken, A., ``Effectiveness of Ultradex Scrub Sponge
Determined in a Clinical Setting,'' unpublished study, coded LET65,
vol. 6, Docket No. 75N-0183, Dockets Management Branch.
(51) Letter from W. E. Gilbertson, FDA, to M. K. Bruch, Dexide,
Inc., coded LET87, Docket No. 75N-0183, Dockets Management Branch.
(52) Letter from W. E. Gilbertson, FDA, to M. K. Bruch, Dexide,
Inc., coded LET90, Docket No. 75N-0183, Dockets Management Branch.
(53) Letter from M. K. Bruch, Dexide, Inc., to W. E. Gilbertson,
FDA, coded LET91, Docket No. 75N-0183, Dockets Management Branch.

H. Comment on Hexachlorophene

13. One comment urged reconsideration of hexachlorophene as an OTC
``handwashing agent and antimicrobial skin cleanser for use in the
hospital, doctor's office, and by adult consumers.'' The comment stated
that adequate data to support Category I status were submitted in
response to the advance notice of proposed rulemaking, but were only
superficially discussed by the agency in comment 61 of the tentative
final monograph. (See the Federal Register of January 6, 1978, 43 FR
1210 at 1220.) The comment submitted additional data to support the
safety of hexachlorophene, including a retrospective study on 3 percent
hexachlorophene in baby bathing (Ref. 1) and a study of hexachlorophene
blood levels in infants receiving routine antiseptic skin care (Ref.
2). The comment also included a comprehensive review article on the
safety and effectiveness of hexachlorophene (Ref. 3).
The agency has reevaluated the data discussed in comment 61 in the
tentative final monograph (43 FR 1220) and evaluated the new data, and
has determined that the data do not warrant changing the classification
of hexachlorophene as a prescription drug. The infant data (Refs. 1 and
2) were discussed in detail in the tentative final monograph for OTC
antimicrobial diaper rash drug products (55 FR 25246 at 25261 to
25263).
Summaries of handwash studies were also submitted, but no data were
included. In one study, 3 percent hexachlorophene was tested as a
surgical scrub under exaggerated use conditions (Ref. 4). Subjects
(number not specified) washed their hands and forearms in 20 mL
hexachlorophene for 10 minutes, 5 times daily, 6 days a week for a
total of 58 days. No signs of toxicity were reported. The blood levels
of hexachlorophene reached a plateau within 3 days at mean levels of
0.07 g/mL.
The agency believes that it would be necessary to test a very large
group of subjects (the number of subjects required to obtain a
statistically significant result) with a variety of skin conditions to
determine the true degree of absorption. A similar study reviewed by
the Panel (39 FR 33103 at 33118) reported blood levels of 0.5
g/mL or higher.
In the other study, subjects washed their hands and face three
times daily for 3 weeks with either 2 or 5 mL of 3 percent
hexachlorophene (Ref. 4). Blood concentrations reached a plateau within
7 days at mean levels of 0.21 g/mL for the 2-mL group and 0.22
g/mL for the 5-mL group.
Other additional data contained only a brief summary of the
historical use of hexachlorophene and primarily cited publications in
the medical literature (Ref. 5). The references provided no new
information. Consequently, the agency has determined that
hexachlorophene will continue on prescription status subject to the
existing regulation in 21 CFR 250.250.
In order for hexachlorophene to be switched to OTC status, the
concerns expressed by the Antimicrobial I Panel that hexachlorophene
does not have an adequate margin of safety for OTC use (39 FR 33103 at
33117) should be addressed. After reviewing the submitted data, the
agency concludes that the safety of this ingredient for OTC use on
infants has not been demonstrated. For OTC status for use by adults,
any further submission of data should specifically address the safe OTC
use of hexachlorophene in adults.
Based upon the discussion above, the agency is proposing that
hexachlorophene remain available by prescription only, except when used
as a preservative at concentrations of 0.1 percent or less.
The agency's detailed comments and evaluation of the data are on
file in the Dockets Management Branch (Ref. 6).

References

(1) Plueckhahn, V. D., and R. B. Collins, ``Hexachlorophene
Emulsions and Antiseptic Skin Care of Newborn Infants,'' Medical
Journal of Australia, 1:815-819, 1976.
(2) Plueckhahn, V. D., ``Blood Hexachlorophene Concentrations in
New-Born Infants Undergoing Routine Antiseptic Skin Care with a 3%
Hexachlorophene Emulsion,'' unpublished study contained in SUP13,
Docket No. 75N-0183, Dockets Management Branch.
(3) Plueckhahn, V. D., ``Infant Antiseptic Skin Care with
Hexachlorophene Emulsions and Powders,'' unpublished study contained
in SUP28, Docket No. 75N-0183, Dockets Management Branch.
(4) Comment No. SUP13, Docket No. 75N-0183, Dockets Management
Branch.
(5) Comment No. C116, Docket No. 75N-0183, Dockets Management
Branch.
(6) Letter from W. E. Gilbertson, FDA, to G. S. Goldstein,
Sterling Drug Inc., coded LET63, Docket No. 75N-0183, Dockets
Management Branch.

I. Comments on Iodine and Iodophors

14. One comment pointed out that poloxamer-iodine complex appeared
to be incorrectly included in the Category II list under ``health-care
personnel handwash'' (43 FR 1210 at 1227), while it is properly listed
in Category III for use as a ``health-care personnel handwash'' (43 FR
1210 at 1229). The comment stated that deletion from the Category II
list would correct the error.
The agency concurs with the comment that poloxamer-iodine complex
for use as a health-care personnel handwash was incorrectly listed as
Category II (43 FR 1227) and that the listing as Category III (43 FR
1229) was correct.
15. One comment submitted data on the safety and effectiveness of a
``mixed iodophor'' consisting of iodine complexed by ammonium ether
sulfate and polyoxyethylene sorbitan monolaurate (Ref. 1). The comment
stated that this information had been previously submitted in May 1974,
but that the ingredient had not been mentioned in the Panel's report or
in the agency's proposed monograph and requested that the agency
include it in the monograph. The comment pointed out that the iodophor,
formulated as a liquid hand scrub, is intended for use by surgeons,
food handlers, and others for whom reduced bacterial ski

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Source: Frix Law Library, https://www.frixlaw.com/law-library/documents/fr%3A94-14503. Public record. Not legal advice.