Federal Register, Volume 59 Issue 116 (Friday, June 17, 1994)

[Federal Register Volume 59, Number 116 (Friday, June 17, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-14503]

[[Page Unknown]]

[Federal Register: June 17, 1994]

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Part III

Department of Health and Human Services

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Food and Drug Administration

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21 CFR Parts 333 and 369

Tentative Final Monograph for Health-Care Antiseptic Drug Products;
Proposed Rule
DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 333 and 369

[Docket No. 75N-183H]
RIN 0905-AA06

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

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of proposed rulemaking.

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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.

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

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 Dettol^{R
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, ``Dettol^{R 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 Vaseline^{R Petroleum
Jelly and Vaseline^{R 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 Vaseline^{R Petroleum
Jelly and Vaseline^{R 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 Dettol^{R 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 Dettol^{R, 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
Dettol^{R 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 Dettol^{R 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 skin flora is of
public health significance.
Regarding the comment's statement that the data were previously
submitted, the agency has no record of any submission of these data in
1974. Because this hand scrub was not previously reviewed or
categorized as an OTC topical antimicrobial drug product, the agency
reviewed the product's marketing history and considers it appropriate
to include this product in the OTC drug review. The agency has
evaluated the data submitted by the comment (Ref. 1) and determined
that iodine complexed by ammonium ether sulfate and polyoxyethylene
sorbitan monolaurate is safe for use as a surgical hand scrub and
health-care personnel handwash, but that there are insufficient data
available to determine its effectiveness for these uses. Therefore, the
ingredient is being classified in Category III.
The data included several studies on the absorption of the iodine
complex, blood levels of iodine, and the systemic toxicity of the
iodine complex. Protein-bound iodine (PBI) and iodine blood levels in
rabbits were determined following two studies of acute dermal
applications. In the first study, either 2 or 5 mL/kilogram (kg) of the
test iodine complex was applied to the shaved backs of rabbits in one
experiment. The method of occlusion, if any, was not stated, but the
test material was washed off after 24 hours. In another experiment, 2
mL/kg of the test iodine complex was compared with a povidone-iodine
complex and both were applied as in the first experiment. PBI and total
iodine in blood were determined at 0, 24, and 48 hours in both
experiments. In all treated animals, the level of PBI was extremely
high at certain times, primarily at 24 hours. Animals receiving the
higher dose of iodine complex in the first experiment seemed to return
to normal sooner than those receiving the lower dose. All animals
returned to normal by 14 days. For purposes of comparison, the second
experiment showed that serum total iodine increased from 1.4 to 30.7
milligrams/deciliter (mg/dL) in the test iodine complex group compared
to from 1.23 to 37.9 mg/dL in the povidone-iodine group in the 24 hours
that the application remained on. In the second study, 5 mL/kg of the
test iodine complex was applied to the shaved backs of two groups of
five rabbits each. In one group the shaved backs were occluded for 24
hours and in the other group, the shaved backs were scrubbed for 10
minutes followed by rinsing and occlusion. An additional group served
as an untreated control group. Blood samples for iodine determinations
were taken at 0, 24, and 48 hours and at 14 days. All five animals in
the group in which the iodine complex remained occluded on intact skin
for 24 hours had markedly elevated levels of PBI and iodine at both 24
and 48 hours, but were only slightly above normal at 14 days. For the
10-minute scrub animals, the PBI levels were increased in two of five
animals at 24 hours, slightly in all five animals at 48 hours, and were
normal at 14 days.
A study to determine the effect on blood PBI levels of a routine
scrubbing procedure in which exposure to the iodine complex exceeded
normal use showed no alteration in PBI levels in four humans who
scrubbed twice daily (each scrub consisting of two 5 minute hand washes
with 5 mL) for 26 consecutive days. Also, no irritation was observed.
In a similar study in which the subjects wore gloves for 2 hours after
each scrub, PBI levels were not increased, but total iodine was
slightly increased. In two subjects, this increase was greater in the
middle of the study, but the total iodine blood levels were near normal
by the end of the study.
A dermal absorption study in which the shaved backs of four monkeys
were rubbed with 0.17 mL/kg of radioactive iodine complex for 10
minutes, rinsed, wrapped for 2 hours, and the animals sacrificed after
24 hours, revealed that less than 0.1 percent of the application was
recovered in the thyroid, the target organ for iodine.
A 90-day sub-acute dermal toxicity study was conducted in three
groups of monkeys divided into one control group and two test groups.
One test group was scrubbed once for 10 minutes daily with 0.17 mL/kg
of the iodine surgical scrub detergent product and the second group was
scrubbed three times with 0.34 mL/kg (once for 10 minutes and twice for
3 minutes each day). To simulate the wearing of surgical gloves, the
treated area of each animal, which consisted of a shaved area of the
back equivalent to about 10 percent of the body area, was wrapped with
a rubber dam for 30 to 90 minutes. The study lasted 13 weeks during
which the animals were monitored. Neither test group showed any effects
of iodophor treatment except elevated PBI levels in the high dose
group, which peaked at one month. Also, there was no significant effect
on the thyroid in the treated groups.
The agency believes this iodine complex is safe for humans based on
the data from human, rabbit, and monkey studies. Test data showed very
little iodine absorption when the product was used as a scrub,
negligible uptake (following acute dermal application of radioactive
iodine complex) by the thyroid in monkeys, and an unchanged thyroid
weight in test groups of monkeys following 90 days of sub-acute
applications of the iodine complex.
The comment submitted data from one clinical study for evaluating
effectiveness as a surgical hand scrub but did not provide the testing
protocol used. Five subjects scrubbed three times daily for 5 days with
the iodophor formulation (containing 1.1 percent iodine). Four subjects
completed the study. Surgical gloves were worn for 2 hours after the
first wash of the day. Subjects' hands were sampled once each day at
the end of the 2-hour gloved period using a single-basin Cade method.
The initial sampling was used to establish a baseline microbial count
for each subject. Study results were reported as the number of
organisms per mL of basin water and the percent reduction in the number
of organisms recovered. The reduction in the bacterial population
ranged from 89 to 98 percent on the first day. By the fifth day, the
reduction ranged from 99 to 100 percent. Similar results were obtained
in a comparative study on six subjects using povidone-iodine.
Although it is clear that the test used was not the glove juice
test which is described in the antimicrobial tentative final monograph
(43 FR 1210 at 1242), alternative methods may be acceptable. However,
because of the small number of subjects included in the study, the data
are not sufficient to support the Category I classification of this
ingredient for use as a surgical hand scrub. Additional studies, of the
type described in Sec. 333.470(b)(1) of this amended tentative final
monograph, are necessary to support the effectiveness of this
surfactant iodine complex for this use.
In the previous tentative final monograph (43 FR 1235), the agency
recognized that elemental iodine complexed with a surfactant type
``carrier'' molecule reduces the amount of immediate ``free'' iodine,
because most of the formulated iodine is bound in the complex.
Effectiveness of all iodophors is dependent on the release of free
iodine as the active agent from the complexing molecule which acts only
as a carrier. The agency acknowledges that iodine complexed with a
surfactant is an acceptable way of presenting iodine as an
antimicrobial agent to the skin. However, because most of the
formulated iodine may be tied up in the complex and because the
information submitted by the comment to support in vitro efficacy (Ref.
2) dealt only with aqueous and/or tincture solutions of free iodine,
testing of the complete formulation is necessary to judge the
importance of formulation on the release of the active ingredient and,
thus, its influence on aspects of effectiveness.
Based on the data submitted, the agency concludes that iodine
complexed by ammonium ether sulfate and polyoxyethylene sorbitan
monolaurate is safe but additional data from appropriate studies are
needed to establish general recognition of effectiveness for use as a
surgical hand scrub and health-care personnel handwash. The data should
include results obtained from both in vitro and in vivo testing
procedures. (See section I.N., comment 28.)

References

(1) Unpublished Nonclinical and Clinical Studies on V.I.S.,
Vestal Iodine Scrub (iodine complexed by ammonium ether sulfate and
polyoxyethylene sorbitan monolaurate), Comment No. C106, Docket No.
75N-0183, Dockets Management Branch.
(a) Acute Dermal Toxicity in Rabbits.
(b) Acute Dermal Application--Rabbits.
(c) Determination of the Influence of Scrubbing with Vestal
Iodine Surgical Scrub Detergent on the Protein Bound Iodine Level of
the Blood.
(d) Determination of the Influence of Scrubbing with Vestal
Iodine Surgical Scrub Detergent on the Protein Bound Iodine and
Total Serum Iodine Levels in the Blood.
(e) Percutaneous Absorption of Iodine in Monkeys from the Dermal
Application of an Iodine Surgical Scrub Detergent.
(f) Three Month Sub-Acute Dermal Toxicity Study in Monkeys with
Vestal Iodine Scrub Detergent.
(g) Iodine Surgical Scrub Detergent, Surgical Hand Scrub Study
in Five Human Test Subjects.
(2) Gershenfeld, L., ``Iodine,'' in ``Disinfection,
Sterilization, and Preservation'' 1st ed., Lee and Febiger,
Philadelphia, pp. 329-347, 1968.

16. Several comments objected to the warning proposed for the
professional labeling for povidone-iodine and iodophor-surfactant
products: ``Caution: Do not use this product in the presence of starch-
containing products. Starch can adsorb iodophors and the resulting
complex can cause serosal adhesions (abnormal union of the serous
membranes) and other undesirable effects in the body'' (43 FR 1210 at
1221). The comments pointed out that the study by Goodrich, Prine, and
Wilson (Ref. 1) on which the warning is based is not well controlled,
is rudimentary, and lacks rigorous testing that produces evidence which
can be statistically analyzed. The comments contended that this article
is not sufficient basis for the warning. The comments requested that
the impact of the article by Goodrich, Prine, and Wilson on the
labeling of nonsurfactant iodophors be reevaluated and that povidone-
iodine be exempt from the required warning relating to contact of
starch and iodophors. One comment stated that there are numerous papers
in the literature describing the antiadhesive effect of povidone and
povidone-iodine and submitted nine references dealing with humans and
animals that support an antiadhesive effect when povidone or povidone-
iodine is used in intraperitoneal surgery (Ref. 2). Another comment
explained that starch is well known for producing granuloma and that
every package of surgeons' gloves carries a warning statement to the
effect that the outside of the gloves must be cleansed of starch powder
prior to use. The comment concluded that FDA should require a warning
label on the gloves, but not on products containing the drug.
FDA has reevaluated the article by Goodrich et al. (Ref. 1),
considered the additional cited references (Ref. 2), and examined
current policy on the labeling of United States Pharmacopeia (U.S.P.)
Absorbable Dusting Powder (cornstarch). Goodrich, Prine, and Wilson
(Ref. 1) provide data from observations and arbitrary scoring of
adhesions after intraperitoneal injection into 4 groups of 13 adult
female mice with: (1) Powdered starch suspended in 1.5 mL of normal
saline, (2) powdered starch treated with 5 mL of an iodophor and washed
three times in saline before resuspension in 1.5 mL normal saline, (3)
powdered starch treated with 5 mL of a 10-percent solution of
surfactant washed three times in saline and resuspended in 1.5 mL of
normal saline and (4) normal saline (control animals). The data do not
indicate any significant difference between suspensions of the
surfactant mixed with starch and the surfactant-iodophor mixed with
starch. The agency's policy on the labeling of surgical gloves treated
with Absorbable Dusting Powder U.S.P., determined upon evidence
presented during the Drug Efficacy Study Implementation, was published
in the Federal Register of May 25, 1971 (36 FR 9475). The agency
requires the following statement on surgical gloves treated with
Absorbable Dusting Powder U.S.P.: ``Caution: after donning, remove
powder by wiping gloves thoroughly with a sterile wet sponge, sterile
wet towel, or other effective method.'' Products containing Absorbable
Dusting Powder U.S.P. for lubricating surgical gloves were formerly
classified as new drugs, but are now regarded as transitional devices,
for which premarket approval is required under the Medical Device
Amendments to the Federal Food, Drug, and Cosmetic Act (42 FR 63472 at
63474). FDA's Center for Devices and Radiological Health is
establishing categories for all surgical devices, including surgical
gloves lubricated with powdered starch. Any changes in the labeling for
this class of products will be dealt with in a separate rulemaking
procedure and separate Federal Register notice.
The agency believes that the user's removal of dusting powder from
surgical medical devices (rubber goods) treated with Absorbable Dusting
Powder U.S.P. decreases the incidence of adhesions and is not persuaded
that the data in the article by Goodrich, Prine, and Wilson provide a
sufficient scientific basis for a warning label. Therefore, the warning
about the interaction of iodophors and starch-containing products
proposed in comment 66 of the previous tentative final monograph is not
included in this amended tentative final monograph.

References

(1) Goodrich, E. O., J. R. Prine, and J. S. Wilson, ``Iodized
Starch Granules as a Cause of Starch Peritonitis,'' Surgical Forum,
25:372-374, 1974.
(2) Nonclinical and Clinical Safety Studies on Postoperative
Observations of Abrasions, Comment No. C111, vol. 4, tabs 6-14,
Docket No. 75N-0183, Dockets Management Branch.

17. A number of comments submitted new data (Ref. 1) to establish
that povidone-iodine is safe and effective as a topical antimicrobial
drug. The comments requested that povidone-iodine be reclassified from
Category III to Category I as a topical antimicrobial ingredient for
use as an antimicrobial soap, health-care personnel handwash, surgical
hand scrub, patient preoperative skin preparation, skin antiseptic,
skin wound cleanser, and skin wound protectant.
As discussed earlier in this document, this amended tentative final
monograph addresses only topical antiseptics for health-care antiseptic
uses as a surgical hand scrub, antiseptic handwash or health-care
personnel handwash, and patient preoperative skin preparation. As
discussed in section I.B., comment 5, antimicrobial soaps are no longer
included in this rulemaking. The agency addressed the other use
categories mentioned in the comment in a separate Federal Register
notice for OTC first aid antiseptic drug products (56 FR 33644). As
discussed in comment 38 of that document (56 FR 33660), FDA has
tentatively concluded that povidone-iodine should be classified in
Category I for use as a first aid antiseptic (formerly designated skin
antiseptic, skin wound cleanser, and skin wound protectant).
The agency has considered the new data submitted and other
information in support of the request to reclassify povidone-iodine
from Category III to Category I. On the basis of these data and
information, the agency tentatively concludes that povidone-iodine
should be reclassified from Category III to Category I as a topical
antiseptic ingredient for use in surgical hand scrub, patient
preoperative skin preparation, and health-care personnel or antiseptic
handwash drug products.
The general safety aspects of povidone-iodine that concerned the
agency in the previous tentative final monograph (43 FR 1210 at 1234 to
1236) are addressed elsewhere as follows: (1) The effect of povidone-
iodine on wound healing. Based upon submitted data, the agency
concluded in the first aid antiseptic segment of this rulemaking that
non-surfactant iodophor products (povidone-iodine) do not delay wound
healing. See comment 42 of that document (56 FR 33644 at 33662). Also,
the Advisory Review Panel on OTC Antimicrobial II Drug Products
reviewed povidone-iodine's effect on wound healing in its report on
topical antifungal drug products and concluded that the drug did not
affect wound healing (47 FR 12480 at 12545). (2) The effect of
povidone-iodine on thyroid function. In comment 41 of the tentative
final monograph for OTC first aid antiseptic drug products (56 FR 33644
at 33661), the agency discusses studies that indicate that topically
applied povidone-iodine does not cause thyroid dysfunction. (3) The
proposed warning about the interaction of starch-containing products
with iodophors resulting in serosal adhesions and other undesirable
effects, i.e., ``Caution: Do not use this product in the presence of
starch-containing products. Starch can adsorb iodophors and the
resulting complex can cause serosal adhesions (abnormal union of the
serous membranes) and other undesirable effects in the body'' (43 FR
1210 at 1221). The agency has reevaluated the proposal and decided that
the warning is not supported by the data. (See section I.I., comment
16.) (4) The agency's concern regarding molecular weights of povidone-
iodine greater than 35,000 daltons not being excreted by the kidney and
causing lymph node changes. In section I.I., comment 18, the agency
discusses a previously proposed warning regarding this subject and
determines, based on more recent data, that larger povidone-iodine
molecules are not a risk when the product is limited to the topical
uses included in this tentative final monograph.
The agency's concern about the need for expiration dates (not to
exceed 2 years after manufacture) because of the lack of stability data
for several iodophor preparations, which relates to the effectiveness
of the product, can be satisfied by compliance with the current good
manufacturing practices regulations (21 CFR parts 210 and 211). These
regulations include, among other things, requirements regarding
stability testing and expiration dating (see Secs. 211.137 and
211.166). Therefore, as discussed in comment 40 of the tentative final
monograph for OTC first aid antiseptic drug products (56 FR 33644 at
33661), data on the stability of povidone-iodine and the proposed 2-
year expiration date are no longer considered needed in this rulemaking
proceeding.
A second agency concern relating to effectiveness was the rate of
release of ``free'' iodine from the complex and whether there was
evidence of germicidal activity over a period of time in clinical
application (43 FR 1210 at 1235). As discussed in the tentative final
monograph for OTC topical acne drug products (comment 5, 50 FR 2172 at
2173), iodine is released from the povidone-iodine complex within
milliseconds, thus resolving this concern.
With regard to the effectiveness of health-care antiseptic uses
subject to this rulemaking, the agency has reviewed the data and
information on povidone-iodine's germicidal in vitro and antiseptic in
vivo effectiveness (Refs. 1 through 19) and concludes that the data are
sufficient to reclassify this ingredient from Category III to Category
I.
A series of in vitro controlled studies (Ref. 1-C133, Volume 1)
included a broad spectrum of test micro-organisms which were associated
with between 40 to 60 percent of the nosocomial infections in the
urinary tract, surgical wounds, pneumonia, and bloodstream, reported by
the National Nosocomial Infections Surveillance System (NNIS) for the
period from January 1985 to August 1988 (Ref. 2). In most instances,
these test micro-organisms, as proposed in Sec. 333.470(a)(1)(ii) (see
section I.C., comment 6), were killed after 0.5 to 5 minutes exposure
to povidone-iodine. A minimum inhibitory concentration (MIC) study
(Ref. 1-C133) using 30 cultures, both American Type Culture Collection
(ATCC) and recent skin isolates, was also included in this series of in
vitro studies. The results indicated a range for MIC from 87 parts per
million (ppm) to 492 ppm for dilutions of povidone-iodine solution and
83 ppm to 476 ppm for dilutions of povidone-iodine surgical scrub
depending on the test micro-organism. Tests with controls, neutralizer,
and organic load using a serial dilution method were included in the
study.
Gocke, Ponticas, and Pollack (Ref. 3) evaluated the susceptibility
of 230 clinical isolates from blood, urine, sputum, and wound cultures
to the bacteriocidal activity of povidone-iodine. These clinical
isolates contained over half the organisms included in
Sec. 333.470(a)(1)(ii). Results indicated that 106 of the 230 organisms
tested (46 percent) were killed when 1 mL of a standardized suspension
containing 10\8\ organisms was exposed to a 10 percent povidone-iodine
solution for 15 seconds. Povidone-iodine showed its highest activity
against gram-negative isolates, with 72 of the 94 isolates (75 percent)
being killed after a 15-second exposure. Only 34 of the 134 (25
percent) gram-positive isolates were killed under the same conditions.
However, further testing of organisms not killed after a 15-second
exposure indicated that increases in exposure time to 120 seconds
killed all of the previously ``resistant'' isolates. The study design
incorporated the use of a neutralizer and controls.
The effectiveness of a povidone-iodine formulation on micro-
organisms in a clinical setting was demonstrated by Michael (Ref. 4).
The study included 100 subjects with decubitus ulcers following a
spinal cord injury. Cultures of the wounds were taken prior to, during,
and upon completion of a once-a-day povidone-iodine treatment. Prior to
treatment, subjects had positive cultures for the following organisms:
S. aureus (60 subjects), Klebsiella/Enterobacter species (20 subjects),
E. coli (15 subjects), and Pseudomonas species (15 species). Following
an 8-to-10 week period of treatment with povidone-iodine, cultures
revealed that 90 of the 110 subjects no longer had positive cultures
for these organisms.
Pereira, Lee, and Wade (Ref. 5) conducted an in vivo gloved hand
test that is supportive of the effectiveness of povidone-iodine as a
surgical hand scrub. They examined the effects of surgical scrub
duration and type of antiseptic on the reduction of resident microbial
flora. Thirty-four subjects scrubbed with a 7.5 percent povidone-iodine
formulation or another antiseptic formulation using either a 5 minute
initial/3 minute consecutive scrub procedure or a 3 minute initial/30
second scrub procedure. Subjects were assigned to one of four groups,
and each group was assigned to one of the four treatments. Sampling was
done by the glove juice method using a sampling solution containing a
neutralizer. Glove juice samples were taken from both hands immediately
before scrubbing (baseline), from the nondominant hand immediately
after the initial scrub, 2 hours after the initial surgical scrub but
before the consecutive scrub (dominant hand), and 2 hours after one
consecutive surgical scrub (dominant hand). No significant difference
was found between the two durations of scrubbing with povidone-iodine.
Povidone-iodine produced an immediate 1.2 log10 reduction on the
dominant hand after an initial 5 minute scrub and a 1.0 log10
reduction on the dominant hand immediately after the 3 minute initial
scrub. Baseline was not exceeded 2 hours after either the 5 or 3 minute
scrub.
Aly and Maibach (Ref. 6) evaluated the characteristics of two
antimicrobial impregnated surgical hand scrub sponge/brush drug
products. The study, which included a widely used povidone-iodine
impregnated surgical hand scrub sponge/brush, evaluated both the
immediate and persistent effect on the resident bacterial flora of the
hands plus the effect of blood on the persistent antimicrobial activity
of the surgical hand scrub drug products. In the first phase of the
study, 13 subjects with left and right hand baseline counts of
>10^{6 organisms were randomly assigned to perform a total of 11
scrubs with the povidone-iodine impregnated sponge/brush. Glove juice
samples were taken from the right hand of each subject immediately
following the first scrub of the day and from the left hand at either 3
or 6 hours. The entire procedure was repeated on test days 2 and 5. A
similar procedure was used in phase two of the study, except that 2 mL
of bacteriologically sterile blood was spread over the hands of 6
subjects following the initial scrub, and sampling occurred only at 3
and 6 hours. Neutralizers were incorporated into the stripping
solution, diluent, and culture media. On day 1, povidone-iodine
produced an immediate mean log10 reduction of 1.2, and baseline
was not exceeded at 3 hours. On days 2 and 5, povidone-iodine produced
immediate mean log10 reductions of 2.2 and 2.8, respectively, and
bacterial counts did not exceed baseline at 6 hours. While counts for
povidone-iodine approached baseline in the presence of blood, counts
did not exceed baseline at 6 hours on any day.
Another study (Ref. 1-C104), employing a method similar to the
effectiveness testing procedures described in proposed
Sec. 333.470(b)(2) of this amended tentative final monograph,
demonstrated the effectiveness of povidone-iodine 5 percent as a
health-care personnel handwash. Twenty-five consecutive handwashings
were done in 10 human subjects with a 5 minute rest between washings.
Before each washing the hands were dipped in broth culture containing
2.0 x 10^{9 organisms (Bacillus subtilis var. niger ATCC 9372) per
mL; the contaminant was spread up over the wrists to the forearms.
Bacterial counts were done at the completion of every fifth washing by
the glove juice sampling method. Both the dilution fluid and growth
media incorporated a neutralizer. The transient microbial flora of the
hands was reduced by an average of 5.8 logs from baseline.
Dineen (Ref. 7) used a 7.5 percent povidone-iodine formulation as a
reference antiseptic in an open crossover evaluation of a health-care
personnel handwash drug product. Participation in the study followed a
1-week prewash period in which study subjects used only a bland
nonantiseptic soap. On day 1 of the study, samples were taken prior to
contamination and again after a second contamination followed by a 15-
second wash with a bland nonantiseptic soap, using the glove juice
sampling method. Following the post-wash sampling, subjects washed for
5 minutes with povidone-iodine to remove any remaining inoculum. The
hands of the first three subjects were contaminated with a 1 mL
inoculum containing 1 X 10^{14 S. marcescens, E. coli, P.
aeruginosa, and Providentia stuartii (P. stuartii). The hands of the
seven other subjects were contaminated with a 1 mL inoculum containing
8 X 10^{14 to 2 X 10^{15 S. marcescens and P. stuartii. Inocula
concentrations were determined each test day in a parallel experiment.
On days 3 or 4 and 5, the procedure was repeated except that subjects
were randomly assigned to wash with either (1) the reference antiseptic
or the test preparation or (2) were crossed over to the preparation not
used the previous day. In the interim between test days, subjects
followed the wash and sampling procedure using only the nonantiseptic
soap. The number of organisms included in the 1 mL inoculum was taken
as the baseline, and all reductions were calculated on this basis.
Neutralizers were incorporated in both the diluent and the culture
medium. When corrected for the average log reduction produced by the
nonantiseptic soap (4-log10), the reductions produced by povidone-
iodine ranged from 7 to 9 log10.
Studies conducted by Ulrich (Ref. 8) and Newsom and Matthews (Ref.
9) are supportive of the effectiveness of povidone-iodine for this
indication. Ulrich (Ref. 8) conducted a study using povidone-iodine 7.5
percent in 25 subjects. Both hands of each subject were contaminated
with a stock culture of Micrococcus roseus (2.75 x 10^{8 organisms
per hand, the baseline count) and allowed to air dry for 60 seconds.
This artificial hand contamination was followed by a 15-second wash
with 5 mL of the povidone-iodine preparation, and this same procedure
was repeated until 25 contaminations/washes had been performed. Glove
fluid samples were taken after every fifth contamination/wash.
Dilutions of the glove fluid were made in a sterile diluent that
included a neutralizer. A neutralizer was also incorporated into the
culture medium. Based on the average of both hands, the povidone-iodine
preparation produced a 4.9 and a 5.2 log reduction of the transient
micro-organisms from baseline by the 5th and 10th wash, respectively.
By the end of the 25th wash the povidone-iodine preparation
demonstrated a 5.5 log10 reduction from the baseline bacterial
count.
Newsom and Matthews (Ref. 9) studied test solutions containing 5 or
10 percent povidone-iodine on hands artificially contaminated with an
overnight culture of E. coli. The numbers of micro-organisms were
measured before and immediately after hand disinfection with the test
solution in 15 subjects. Sampling of the hands was accomplished by
kneading the fingertips in a ``recovery'' broth that included a
neutralizer. A mean 4.4 log reduction from baseline was reported for
the bacterial counts taken immediately after the antiseptic wash.
Ayliffe, Babb, and Quoraishi (Ref. 10) evaluated the effect of
various detergent and alcoholic antiseptic formulations (including a
7.5 percent povidone-iodine formulation) on the removal of S. aureus,
Staphylococcus saprophyticus (S. saprophyticus), P. aeruginosa, or E.
coli from contaminated fingertips. In one set of experiments, six
subjects performed an initial wash with an unmedicated soap, followed
by the inoculation of the tips of the subjects' fingers and thumbs with
0.02 mL of a broth culture containing either S. aureus or P.
aeruginosa. Following contamination, subjects performed either a 30-
second wash with 5 mL of a detergent or alcoholic antiseptic
preparation, a 30-second wash with an unmedicated soap, or no wash at
all. Bacterial sampling was accomplished by rubbing the fingers and
thumbs on glass beads immersed in 100 mL of nutrient broth containing
neutralizers. All treatments were tested against each organism. Results
were reported as the log of the average number of viable organisms
recovered from each subject. Against S. aureus, povidone-iodine
produced a 3.2 log reduction, which was significantly superior to the
reduction achieved by the unmedicated soap. Against P. aeruginosa,
povidone-iodine produced a 2.7 log reduction. However, this was not
significantly different from the 2.2 log reduction demonstrated by the
unmedicated soap.
In a second set of experiments (Ref. 10), the same authors assessed
the effectiveness of three antiseptic formulations, including povidone-
iodine, and an unmedicated soap in the removal of S. aureus, S.
saprophyticus, or E. coli from contaminated fingertips. Under
conditions similar to those in the previous study, povidone-iodine
demonstrated a 3-log reduction in the baseline number of S. aureus,
which was significantly superior to the log reduction demonstrated by
the unmedicated soap. Povidone-iodine produced an average 2.1 log
reduction in the number of S. saprophyticus and a 2.8 reduction in the
number of E. coli. However, neither of these reductions was
significantly different from the reductions produced by the unmedicated
soap.
Rotter (Ref. 11) evaluated the influence of differences in two
testing methodologies on the demonstration of the effectiveness of
povidone-iodine. One test method used is the standard test method
(Vienna) for the evaluation of drug products for hygienic disinfection
adopted by the Austrian and German Societies for Hygiene and
Microbiology. In this test model, the release of E. coli from the
finger tips of artificially contaminated hands was determined before
and after a 1-minute wash with povidone-iodine. The second model, based
on agency recommendations for the testing of health-care personnel
handwashes, evaluated the release of the E. coli from all surfaces of
artificially contaminated hands by the glove juice sampling method
before and after a 1 minute wash with the ingredient. These comparisons
showed no significant difference in the reduction factor produced by
povidone-iodine when tested with the two methods. Povidone-iodine when
tested by the Vienna test method produced a 3.3 log10 reduction
from the baseline count. When tested by the second method, the
ingredient produced a 3.2 log10 reduction.
Rotter (Ref. 11) also used the Vienna test method to assess the
effectiveness of rubbing antiseptics onto the hands versus washing with
an antiseptic. Two povidone-iodine containing formulations were
included in the assessment. A watery solution of povidone-iodine with 1
percent available free iodine rubbed onto the skin produced a 4
log10 reduction. Washing with a detergent formulation of the
ingredient produced a 3.2 log10 reduction. However, this reduction
was not statistically different from the reduction produced by washing
with a nonantiseptic soap.
Rotter, Koller, and Wewalka (Ref. 12) used the Vienna test model to
assess the effectiveness of a povidone-iodine liquid soap preparation
(containing 0.75 percent available free iodine) for hygienic hand
disinfection. The subjects' hands were contaminated by immersing them
up to the mid-metacarpals in a broth culture of E. coli. The hands were
allowed to air dry for 3 minutes prior to a pretreatment sampling.
Sampling was accomplished by rubbing the finger tips of each hand for 1
minute on the bottom of a Petri dish containing a phosphate buffer
sampling solution with neutralizers. After a 2-minute wash with the
povidone-iodine or liquid soap followed by a 20-second rinse, the hands
were again sampled. Average log values of the counts from the right and
left hands of each subject were calculated, and the difference (log
reduction factor) was determined. The povidone-iodine liquid soap
formulation produced a 3.2 log10 reduction in the transient
organisms.
Wade and Casewell (Ref. 13) evaluated the residual effectiveness of
povidone-iodine against two clinical isolates associated with hospital
outbreaks of infection. An initial determination of the survival of the
test organisms on untreated hands of three subjects was made by
contaminating the subjects' finger tips with either of the test
organisms and sampling the individual fingers immediately after
contamination and at 1, 3, 10, and 30 minutes. The subjects' hands were
then pretreated by performing three 30-second washes at 5 minute
intervals with various alcoholic and aqueous antiseptic test
formulations, including a 7.5 percent povidone-iodine formulation and
an unmedicated bar soap. The contamination and sampling procedure was
repeated as before. All formulations were tested against both
organisms. The median value of the log counts for the three subjects as
each sampling was plotted against time. The survival curves for both
organisms on hands pretreated by washing with an unmedicated soap and
on hands with no pretreatment were similar. Pretreatment with povidone-
iodine resulted in counts that were consistently less than for the
untreated hands and for the hands pretreated by washing with an
unmedicated soap and water for both organisms. After 30 minutes, hands
pretreated with the povidone-iodine formulation demonstrated a 2.5
log10 reduction in the number of viable Enterococcus faecium and a
3.9 reduction in the number of viable Enterobacter cloacae.
The agency concludes that these data demonstrate the effectiveness
of povidone-iodine 5 to 10 percent for use as a health-care personnel
handwash.
Many published studies referenced in the submitted data and in the
published literature (Refs. 1 and 14 through 19) have evaluated the
effectiveness of povidone-iodine for use as a patient preoperative skin
preparation. Although the procedures followed are different from those
in the previous FDA testing procedures (43 FR 1210 at 1244) and from
those proposed in Sec. 333.470 of this amended tentative final
monograph, the essential criteria have been met.
Georgiade et al. (Ref. 15) evaluated the effectiveness of two
povidone-iodine formulations for use in the preoperative skin
preparation of 150 subjects scheduled for elective surgical procedures.
An initial sample for culture was taken from the unbroken skin of the
operation site prior to the use of the formulations, and a baseline
bacterial count was determined. Sampling was by a cup scrubbing method,
using a sterile wash solution that incorporated a neutralizer. The
operative site was then gently treated for 5 minutes with a povidone-
iodine surgical scrub formulation and allowed to dry. Following the
initial disinfection, a povidone-iodine antiseptic solution was evenly
applied to the site and allowed to dry. The sample site was rinsed with
sterile water and a second sample for culture was done. Upon completion
of surgical procedures lasting from 30 to 180 minutes, the sample site
was again cultured and sterile dressings were applied. The reported
mean post-scrub reduction in the baseline number of bacteria of the
sample site was 30,599 (4.5 log10 reduction). This reduction was
maintained through the surgery as evidenced by the reported post-
operative mean reduction of 30,613 organisms.
Vorherr, Vorherr, and Moss (Ref. 16) compared three antiseptic
preparations (including 10 percent povidone-iodine), in 150 female
subjects (50 to each preparation) for effectiveness in reducing the
numbers of bacteria in the perineum and groin. The mean log reductions
in bacteria after skin preparation with povidone-iodine at 10 minutes
and 3 hours, respectively, were reported as 3.65/3.09 for the perineum
and 3.42/2.85 for the groin. Another study by Dzubow et al. (Ref. 17)
evaluated three antiseptic skin preparations frequently used for
dermatologic surgical procedures. A 60-second wipe with 1-percent
povidone- iodine was performed in 14 subjects after which aerobic and
anaerobic cultures were taken at 5 and 60 minutes. The aerobic flora
were reduced by 2.8 and 2.5 log at 5 and 60 minutes, respectively. The
reduction in anaerobic flora was reported to be 1.7 log at 5 minutes
and 1.2 log at 60 minutes.
Leaper, Lewis, and Speller (Ref. 18) compared the effectiveness of
povidone-iodine impregnated drapes, povidone- iodine with a sterile
drape, and conventional preoperative skin preparation with povidone-
iodine for the reduction of skin bacteria. Forty-five subjects
scheduled to undergo elective groin surgery were randomized to one of
the three treatments. Impression plates and skin swabs were taken
immediately before and after surgery, and swabs were taken before and
after skin incision and closure. Conventional preoperative skin
prepping with povidone-iodine produced the greatest reduction of the
bacterial flora (240 colony counts to 34 colony counts, 2.3 log10
reduction).
Duignan and Lowe (Ref. 19) studied the effectiveness of povidone-
iodine for reducing pathogenic bacteria in the vagina. A 1:10 solution
of a povidone-iodine formulation containing 0.75 percent available free
iodine was instilled into the vagina of 35 subjects and left in situ
for 1 to 3 minutes. Aspirate cultures were taken from the vagina before
and after preoperative disinfection and subcultured into thioglycollate
broth containing neutralizers. Povidone-iodine removed 92 percent of
the bacteroides species, anaerobic streptococci, gram negative bacilli,
and Streptococcus pyogenes present prior to the preoperative
disinfection.
A surveillance report (Ref. 1-C132) of hospital infections showed
that the use of povidone-iodine in preparing patients for
catheterization significantly reduced the rate of urinary tract
infections. A 5-year study showed that the rate of urinary tract
infections before October 1977 ranged from 5.2 percent to 11.5 percent
(mean 7.8 percent), but beginning in October 1977 when povidone-iodine
was the antiseptic solution in use, the rate ranged from 1.0 percent to
4.0 percent (mean 2.4 percent). At the 95 percent confidence level this
is statistically significant. No method data accompanied the report
except that the urethral meatus was cleansed with cotton dipped in the
antiseptic solution before catheterization.
The agency believes that these studies and other published and
publicly available medical and scientific data demonstrate that
povidone-iodine is effective for use as a patient preoperative skin
preparation. Although all of the trials were not done the same way, and
thus they are not strictly comparable, the weight of the evidence shows
that povidone-iodine is effective both as a preoperative skin
preparation and surgical hand scrub, reducing the normal microbial
flora by more than 90 percent and not showing any significant
qualitative selection among the normal species found on the skin. In
conclusion, povidone-iodine was effective against a wide spectrum of
pathogenic and normal skin micro-organisms and maintained some
suppressive effect on skin counts after the initial use.
In addition to the data reviewed supporting the safety and
effectiveness of povidone-iodine for these professional uses, the
agency classified povidone-iodine 5 to 10 percent as Category I as a
first aid antiseptic in the tentative final monograph published in the
Federal Register on July 22, 1991 (56 FR 33644). Accordingly, the
agency is reclassifying povidone-iodine 5 to 10 percent from Category
III to Category I for use as a topical antiseptic ingredient for use in
surgical hand scrub, patient preoperative skin preparation, and
antiseptic handwash or health-care personnel handwash drug products.

References

(1) Comments No. C104, C108, C111, C112, C113, C128, C132, and
C133, Docket No. 75N-0183, Dockets Management Branch.
(2) Horan, T. et al., ``Pathogens Causing Nosocomial
Infections,'' The Antimicrobic Newsletter, 5:65-67, 1988.
(3) Gocke, D. J., S. Ponticas, and W. Pollack, ``In Vitro
Studies of the Killing of Clinical Isolates by Povidone-Iodine
Solutions,'' Journal of Hospital Infection, 6:59-66, 1985.
(4) Michael, J., ``Topical Use of PVP-I (Betadine Preparations
in Patients with Spinal Cord Injury,'' Drugs in Experimental
Clinical Research, XI:107-109, 1985.
(5) Pereira, L. J., G. M. Lee, and K. J. Wade, ``The Effect of
Surgical Handwashing Routines on the Microbial Counts of Operating
Room Nurses,'' American Journal of Infection Control, 18:354-364,
1990.
(6) Aly, R. and H. I. Maibach, ``Comparative Evaluation of
Chlorhexidine Gluconate (Hibiclens) and Povidone-iodine
(E-Z Scrub) Sponge/Brushes for Presurgical Scrubbing,''
Current Therapeutic Research, 34:740-745, 1983.
(7) Dineen, P., ``Handwashing Degerming: A Comparison of
Povidone-Iodine and Chlorhexidine,'' Clinical Pharmacology and
Therapeutics, 23:63-67, 1978.
(8) Ulrich, J. A., ``Clinical Study Comparing Hibistat (0.5%
Chlorhexidine Gluconate in 70% Isopropyl Alcohol) and Betadine
Surgical Scrub (7.5% Povidone-Iodine) for Efficacy against
Experimental Contamination of Human Skin,'' Current Therapeutic
Research, 31:27-30, 1982.
(9) Newson, S. W. B., and J. Matthews, ``Studies on the Use of
Povidone-iodine with the `Hygienic Hand Disinfection' Test,''
Journal of Hospital Infection, 6:45-50, 1985.
(10) Ayliffe, G. A. J., J. R. Babb, and A. H. Quoraishi, ``A
Test for `Hygienic' Hand Disinfection,'' Journal of Clinical
Pathology, 31:923-928, 1978.
(11) Rotter, M. L., ``Hygienic Hand Disinfection,'' Infection
Control, 5:18-22, 1984.
(12) Rotter, M., W. Koller, and G. Wewalka, ``Povidone-Iodine
and Chlorhexidine Gluconate-Containing Detergents for Disinfection
of the Hands,'' Journal of Hospital Infection, 1:149-158, 1980.
(13) Wade, J. J., and M. W. Casewell, ``The Evaluation of
Residual Antimicrobial Activity on Hand and its Clinical
Relevance,'' Journal of Hospital Infection, 18:23-28, 1991.
(14) Peterson, A. F., ``Microbiology Efficacy of
Polyvinylpyrrolidone-iodine: A Critical Review,'' unpublished
review, Comment No. C118, Docket No. 75N-0183, Dockets Management
Branch.
(15) Georgiade, G. et al., ``Efficacy of Povidone-Iodine in Pre-
operative Skin Preparation,'' Journal of Hospital Infection, 6:67-
71, 1985.
(16) Vorherr, H., U. F. Vorherr, and J. C. Moss, ``Comparative
Effectiveness of Chlorhexidine, Povidone-iodine, and Hexachlorophene
on the Bacteria of the Perineum and Groin of Pregnant Women,''
American Journal of Infection Control, 16:178-181, 1988.
(17) Dzubow, L. M. et al., ``Comparison of Preoperative Skin
Preparations for the Face,'' Journal of the American Academy of
Dermatology, 19:737-741, 1988.
(18) Leaper, D. J., D. A. Lewis, and D. C. E. Spiller,
``Prophylaxis of Wound Sepsis Using Povidone-Iodine Skin Preparation
or `Ioban' Incise Drapes After Clean Inguinal Surgery,'' Journal of
Hospital Infection, 6(supplement):215-218, 1985.
(19) Duignan, N. M., and P. A. Lowe, ``Pre-operative
Disinfection of the Vagina,'' Journal of Antimicrobial Chemotherapy,
1:117-120, 1975.

18. Several comments objected to the agency's proposal that the
professional labeling of povidone-iodine products containing molecules
greater than 35,000 daltons should include warnings against parenteral
use and against exposure of open surgical wounds or deep wounds to the
product. (See comment 71, 43 FR 1210 at 1221.) Some of the comments
contended that the Panel recommended such warnings because it felt
there was widespread misuse (unapproved use) of povidone-iodine
solution by surgeons bathing the peritoneal cavity with povidone-iodine
during major surgery and then cleansing the area by rinsing. Another
comment stated that because health-care personnel handwashes or
surgical hand scrubs require a surfactant, such products so formulated
would never be considered for peritoneal lavage by surgeons. One
comment argued that labeling to warn against parenteral use is clearly
beyond the scope of the OTC drug review and FDA's regulatory authority.
Another comment stated that it is unnecessary to establish an arbitrary
molecular weight limit for povidone-iodine because no parenteral use of
povidone-iodine is permitted in any of the approved labeling in the new
drug applications for those products.
One comment stated that povidone-iodine is generally recognized as
safe and effective for use in open wounds and a warning against such
use would be contrary to clinical experience with this drug. In support
of this position, the comment submitted a controlled study in which the
surgical incisions of one group were irrigated before closure with 10
percent povidone-iodine solution, and the surgical incisions of the
control group were irrigated before closure with saline solution (Ref.
1). The comment stated that the results of this study showed a
significant decrease in infections when povidone-iodine was used, and
there were no allergic, adverse, or other deleterious effects following
this use of povidone-iodine.
In response to the Commissioner's recommendation for research data
(43 FR 1210 at 1235), one comment submitted an extensive review of the
extent of scavenging of residual povidone-iodine molecules by the
reticuloendothelial system and possible lymph node involvement
following use in the abdominal cavity or in large wounds (Ref. 2). The
comment stated that, based on these data, povidone-iodine with medium
molecular weights should not be limited to use on intact skin, nor
should a warning be required. Another comment stated that the average
molecular weight of povidone in the povidone-iodine that has been used
exclusively in topical antimicrobial products for almost a quarter of a
century is 37,900 daltons, and it presents no risk for any of the
topical antimicrobial uses covered by the tentative final monograph.
The Panel recognized a relationship between molecular size and
nodular lymphatic changes accompanying exposure to povidone-iodine, but
made no decision on limiting the molecular size causing such pathology.
(See 39 FR 33103 at 33130.) In the previous tentative final monograph,
FDA evaluated data provided in a comment (Ref. 3) that contended there
should be restrictions on the use of povidone-iodine according to
molecular size. Published research cited in that comment indicated that
povidone molecules larger than 40,000 daltons cannot be excreted by the
kidneys, can cause nodules to appear in the lymphatic system, and may
induce cosmetic deformities in the area of healing skin wounds. Based
on expert opinion and the data provided in the comment (Ref. 3), the
agency proposed that a molecular weight of 35,000 daltons be
established as the safe upper limit for povidone-iodine products used
parenterally. This calculation assumed that a povidone-iodine molecule
with this molecular weight would be too large to pass through the
kidney. (See comment 71, 43 FR 1210 at 1221.) FDA also noted its
awareness of the inappropriate use of povidone-iodine products in open
wounds and in the abdominal cavity during surgery. (See 43 FR 1235.) To
promote proper use of povidone-iodine products, FDA proposed to
recognize two categories of such products. Products with povidone-
iodine molecular weights less than 35,000 daltons would be permitted
for general use. Appropriate labeling would place each product in its
proper category of use. The professional labeling of povidone-iodine
products containing molecules greater than 35,000 daltons would also
include warnings against parenteral use of, and exposure of open
surgical wounds or deep wounds to, the product.
In this current tentative final monograph, the agency recognizes
that the professional uses of povidone-iodine that are proposed as safe
and effective are limited to a patient preoperative skin preparation,
health-care personnel handwash, and surgical hand scrub. Further
examination of the reference cited in the previous tentative final
monograph (Ref. 3) reveals that the reported adverse effects were due
to intravenous or parenteral use of povidone. Based on the more recent
data and comments, the agency now believes that neither medium nor
larger molecular weight povidone-iodine molecules present risks when
limited to the topical uses included in this tentative final monograph.
Larger molecules of povidone-iodine would not be absorbed if the drug
is used for these professional uses in accordance with the monograph.
Thus, there is no need for the professional labeling to limit the
molecular weight of povidone-iodine products or to require special
warnings related to the molecular weight of povidone-iodine.
Accordingly, such labeling is not being included in this tentative
final monograph.

References

(1) Sindelar, W.F., and Mason, G.R., ``Irrigation of
Subcutaneous Tissue With Povidone-Iodine Solution for Prevention of
Surgical Wound Infections,'' Surgery, Gynecology and Obstetrics,
148:227-231, 1979.
(2) Unpublished review of published and unpublished studies
regarding lymph node changes and effect on the reticuloendothelial
system resulting from use of PVP-iodine on intact skin, mucous
membranes, and open wounds, Comment No. C111 (vol. III A), Docket
No. 75N-0183, Dockets Management Branch.
(3) Unpublished review of published studies regarding
intravenous or parenteral use of polyvinylpyrrolidone (PVP), Comment
No. C40, Docket No. 75N-0183, Dockets Management Branch.

19. Several comments contended that there are numerous professional
uses for povidone-iodine, particularly uses that involve medical
devices, that were not discussed by the Panel or by the agency in the
tentative final monograph. These professional uses include catheter
care, ostomy hygiene, patient skin scrubbing prior to preoperative
prepping, surgical site cleansing after stitching, mouth and throat
swabbing, treatment of the skin before covering a fracture with a cast,
antiseptic treatment of various scalp problems, and intravenous site
preparation. One comment added that a pharmacist or other health
professional may recommend the use of povidone-iodine as a douche,
perianal wash, or whirlpool concentrate. The comments requested that
special labeling be added to the monograph to cover all of these uses,
but did not submit data regarding these uses.
One comment also provided professional labeling for povidone-iodine
used for urinary or intravenous catheter care procedures. The suggested
labeling included the following terms: ``antiseptic,'' ``germicide,''
``microbicidal,'' and ``for hospital and professional use.''
Several of the professional uses mentioned by the comments are not
covered by this rulemaking, but they will be addressed under other OTC
drug rulemakings. For example, the use of povidone-iodine for mouth and
throat swabbing is included in the advance notice of proposed
rulemaking for OTC oral health care drug products, published in the
Federal Register of May 25, 1982 (47 FR 22760). The use of povidone-
iodine for the treatment of scalp problems is addressed in the final
rule for OTC dandruff, seborrheic dermatitis, and psoriasis drug
products, published in the Federal Register of December 4, 1991 (56 FR
63554). The use of povidone-iodine as a douche is addressed in the
advance notice of proposed rulemaking for OTC vaginal drug products,
published in the Federal Register of October 13, 1983 (48 FR 46694).
The Advisory Review Panel on OTC Hemorrhoidal Drug Products stated
that the inclusion of antiseptics in OTC anorectal drug products ``is
useful in concept,'' but ``that proof of any significant clinical
benefit of claimed antiseptic ingredients must be demonstrated in
clinical trials'' (45 FR 35576 at 35659). That Panel believed that,
because of the large numbers of micro-organisms present in feces, there
is little likelihood that effective antisepsis could be obtained in the
anorectal area with antiseptics any more than with soap and water.
Because no data were submitted on povidone-iodine as a perianal wash,
the agency did not address this ingredient in the discussion of
antiseptics in the tentative final monograph for OTC anorectal drug
products when the agency evaluated the Panel's conclusions. Similarly,
the ingredient was not included in the final rule for OTC anorectal
drug products, published in the Federal Register of August 3, 1990 (55
FR 31766). Parties interested in this use of povidone-iodine can submit
data and information as part of a citizen petition to amend the final
rule for OTC anorectal drug products. (See 21 CFR 10.30.)
Several of the uses suggested by the comments are related to the
general category of patient preoperative skin preparation that was
discussed by the Panel. (See the Federal Register of September 13,
1974, 39 FR 33103 and 33114.) One example is the use ``patient skin
scrubbing prior to preoperative prepping.'' The agency believes that
this use can more simply be described by the indication ``for
preparation of the skin prior to surgery,'' which is being proposed in
Sec. 333.460(b)(1)(i) of this tentative final monograph. Other uses are
catheter care, ostomy hygiene, and intravenous site preparation. Some
uses mentioned by the comments involve postoperative situations
(surgical site cleansing after stitching) or do not even involve a
surgical procedure (treatment of skin prior to covering a fracture with
a cast or use as a whirlpool concentrate). The agency believes that
instead of trying to identify in the product's labeling every possible
situation where use of the product would reduce the risk of skin
infection, this use of the product can best be described by the general
indication ``Helps to reduce bacteria that potentially can cause skin
infection,'' which is being proposed in Sec. 333.460(b)(1)(ii).
The agency has considered the term ``for hospital and professional
use only'' suggested by one comment and finds it acceptable for
professional labeling. (See section I.D., comment 8.) Likewise, the
agency has no objection to terms such as ``germicide,'' ``germicidal,''
and ``microbicidal'' being used in professional labeling because health
professionals understand the meaning of these terms. However, the
agency does not believe there is a need to include in the monograph
every one of these terms that might be used in the professional
labeling of these products. These terms will be evaluated by the agency
on a product-by-product basis, under the provision of section 502 of
the act (21 U.S.C. 352) relating to labeling that is false or
misleading.

J. Comments on Quaternary Ammonium Compounds

20. One comment requested that benzalkonium chloride be placed in
Category I as a skin antiseptic, a patient preoperative skin
preparation, and a skin wound protectant, in addition to its present
Category I classification as a skin wound cleanser. In support of its
request, the comment cited several surgery textbooks and other
references that recommend use of benzalkonium chloride at
concentrations ranging from 1:750 to 1:5,000 as a preoperative skin
preparation, surgical scrub, skin antiseptic for venipuncture, and in
urinary tract procedures, especially in catheterized patients (Ref. 1).
The comment also submitted two studies on a product containing
benzalkonium chloride at a concentration of 1:1,000: (1) An in vitro
study to demonstrate that this product formulation acts as a physical
chemical barrier against contamination by micro-organisms, and (2) a
study on induced wounds on the arms of 10 healthy subjects to present
evidence that this product is nonirritating and neither delays healing
nor favors the growth of micro-organisms (Ref. 2).
The agency determined in the tentative final monograph for OTC
first aid antiseptic drug products that the safe and effective
concentration range for using benzalkonium chloride as a first aid
antiseptic has been established as 0.1 percent to 0.13 percent. (See 56
FR 33644 and 33663.) Data submitted to the Antimicrobial I Panel and by
the comment were sufficient to establish safety for products intended
for short-term use, such as a first aid antiseptic drug product. The
data submitted also support safety for use as a patient preoperative
skin preparation, based on the short-term use of the drug for this
purpose. However, the data reviewed by the Panel and supplemented by
the comments to establish the efficacy of benzalkonium chloride for use
as a topical antiseptic ingredient in patient preoperative skin
preparations are not sufficient. The Antimicrobial I Panel placed this
ingredient in Category III for this use. (See 39 FR 33103 and 33115.)
The agency finds that the surgery textbooks and other references cited
by the comment (Ref. 1) do not contain sufficient information about
quantitative and qualitative changes in the microbial flora of the
treated skin areas. Before benzalkonium chloride may be generally
regarded as effective for use as a patient preoperative skin
preparation, additional in vitro and in vivo effectiveness data are
needed. The data should include results obtained from both in vitro and
in vivo testing procedures as described for patient preoperative skin
preparation drug products. (See section I.N., comment 28.)
Accordingly, benzalkonium chloride remains classified in Category
III as a topical antiseptic ingredient for use as a patient
preoperative skin preparation.

References

(1) Comment No. C116, Docket No. 75N-0183, Dockets Management
Branch.
(a) Review of Scientific Literature on the Safety and
Effectiveness of Zephiran Chloridee as a ``Skin Antiseptic'' and
``Patient Preoperative Skin Preparation'' for the Preoperative
Cleansing and Degerming Before Surgery and Use of Medical Devices.
(2) Unpublished Clinical Wound Healing Studies on Medi-Quike,
Comment No. SUP13, Docket No. 75N-0183, Dockets Management Branch.
(a) Statistical Analysis of Data from Efficacy Study of Medi-
Quik as a Skin Wound Protectant in Humans.
(b) Studies on Medi-Quik as a Wound Protectant.

21. Two comments objected to the proposed warning statement in
Sec. 333.92(c)(6) for concentrated products containing quaternary
ammonium compounds, which states, ``Dilute with distilled water before
use because acidic or hard water may render the product inactive.'' One
comment contended that this proposed warning is prejudicial to the
quaternary ammonium products that can act in acidic or hard water and
noted that the existence of quaternary ammonium compounds that can act
as antimicrobials in acidic or hard water was recognized in the
tentative final monograph (43 FR 1210 at 1219). The comment recommended
that the labeling of products containing quaternary ammonium compounds
include a statement, based on appropriate laboratory tests, about the
ability of the product to perform in acidic solutions and the amount of
water hardness (described as parts per million (ppm) calcium carbonate)
in which the product will continue to be effective.
The other comment stated that several concentrated quaternary
ammonium compounds (e.g., 50 percent benzalkonium chloride, U.S.P.)
registered with the Environmental Protection Agency (EPA) conform with
the hard-water tolerance requirements and therefore can maintain
activity at a water-hardness level of 600 ppm. The comment also stated
that pH must be reduced below 3.5 before the effectiveness of
quaternary ammonium compounds is decreased to any significant extent
(Ref. 1). The comment concluded that, because normal potable water
supplies do not approach these levels for either hardness or acidity,
the requirement in proposed Sec. 333.92(c)(6) for diluting only with
distilled water is inappropriate and needless.
In the tentative final monograph, the agency acknowledged that hard
water and acidity reduce the antimicrobial activity of quaternary
ammonium compounds, but that there are some newer synthesized
quaternary ammonium compounds that are not adversely affected by hard
water and acidity (43 FR 1210 at 1218, 1219, and 1236). However, these
newer quaternary ammonium compounds (e.g., a mixture of three
benzalkonium halide compounds with varying chain lengths), while
structurally related to benzalkonium chloride, benzethonium chloride,
and methylbenzethonium chloride (the quaternary ammonium compounds
which the Antimicrobial I Panel reviewed and which the agency proposed
as Category III), were not reviewed or categorized by the Panel or the
agency and are not included in this rulemaking. (See comment 58, 43 FR
1210 at 1219.) Further, the agency notes that the 50 percent quaternary
ammonium concentrates that conform with EPA standards are intended for
germicidal uses and not for the antiseptic uses that are being
considered in this rulemaking.
The agency is aware that studies have shown that effects of acidic
water on quaternary ammonium compounds occur only at dilutions
containing less than the dosage concentration proposed in the tentative
final monograph (Ref. 2). Higher concentrations minimize quaternary
ammonium compound inactivation due to pH change (Ref. 3). However, it
is well known that natural water supplies in different areas differ in
acidity and hardness. As a precautionary measure, FDA believes that
concentrates of the ingredients considered in this rulemaking should be
diluted in distilled water by consumers and health-care professionals,
because information about water pH or hardness in any given area is not
usually known. Diluting the concentrated quaternary ammonium compound
products addressed in this rulemaking with distilled water ensures that
inactivating factors are not encountered. Therefore, the agency
proposes to retain the warning statement, ``Dilute with distilled water
before use because acidic or hard water may render the product
inactive,'' for diluting any Category I quaternary ammonium
concentrate. However, because all the quaternary ammonium compounds
remain in Category III at this time, the warning statement is not being
included in this tentative final monograph.

References

(1) Lawrence, C. A., ``Surface-Active Quaternary Ammonium
Germicides,'' Academic Press Inc., New York, pp. 76-79, 1950.
(2) Kundsin, R. B., ``Investigations on Dynamics of Bactericidal
Action of Two Quaternary Ammonium Salts,'' Archives of Surgery,
81:789-797, 1960.
(3) Soike, K. F., D. D. Miller, and P. R. Ellikerr, ``Effect of
pH of Solution on Germicidal Activity of Quaternary Ammonium
Compounds,'' Journal of Dairy Science, 35:764-771, 1952.

K. Comment on Sodium Oxychlorosene

22. One comment requested that sodium oxychlorosene be included in
the monograph for use as a topical antiseptic for treating localized
infections, to remove necrotic debris in massive infections, as a
patient preoperative skin preparation and postoperative irrigant, and
for the cleansing and disinfection of fistulae, sinus tracts, empyemas,
and wounds. The comment included a number of references that
recommended usage of sodium oxychlorosene (Ref. 1). The comment stated
that ``* * * the 25 years of marketing experience, the almost total
absence of complaints, the number of published articles, the unusual
spectrum of organisms reported on, all attest to the safety and
efficacy of this product.''
The agency has reviewed the data submitted and concludes that the
available information does not contain any well-controlled clinical
studies on the effectiveness of sodium oxychlorosene. In addition, no
meaningful scientific information was presented in regard to safety.
Clinical use for a period of years may provide corroborative evidence
but is inadequate to support safe use. A good example is
hexachlorophene; this drug had been used OTC for many years before more
thorough safety studies in animals showed that the drug was not as safe
as had been assumed. The agency concludes that the data are
insufficient to demonstrate the safety and effectiveness of sodium
oxychlorosene for OTC topical antiseptic use and therefore places this
ingredient in Category III for both safety and effectiveness.
The agency's detailed evaluation of the data and information is on
file in the Dockets Management Branch (Ref. 2).

References

(1) Published in vivo and in vitro studies, submitted by
Guardian Chemical Corporation, Comment No. C126, Docket No. 75N-
0183, Dockets Management Branch.
(2) Letter from W. E. Gilbertson, FDA, to R. Rubinger, Guardian
Chemical Corporation, Comment No. ANS3, Docket No. 75N-0183, Dockets
Management Branch.

L. Comments on Triclosan

23. A number of comments submitted data and information from
microbiological, mutagenicity, metabolism, cross-sensitization, photo-
sensitization, and drug experience studies on triclosan (Ref. 1). The
comments stated that the data and information show that triclosan (up
to 1.0 percent) is safe and effective and that triclosan should be
placed in Category I for use in the categories that were defined in the
previous tentative final monograph, i.e., skin antiseptic, skin wound
cleanser, skin wound protectant, antimicrobial soap, health-care
personnel handwash, patient preoperative skin preparations, and
surgical hand scrub. In addition, one comment submitted information on
triclosan (0.1 percent) for the treatment of diaper rash and on
triclosan (0.1 percent) combined with benzocaine for the treatment of
sunburn (Ref. 2).
One comment from the manufacturer of triclosan objected to the
agency's expressed concern, as stated in the tentative final monograph
(43 FR 1210 at 1231 and 1233), that there is a proliferation of
products containing triclosan marketed to the American consumer (Ref.
3). The comment argued that the agency's concerns were without factual
basis and submitted sales data, held confidential under 21 CFR
10.20(j)(2)(i)(d), showing that overall sales of triclosan in the U.S.
have in fact decreased from 1973 to 1977 and that sales for use in bar
soaps and deodorants have also declined from 1973 to 1977. The comment
pointed out that it has exclusive U.S. patent rights for triclosan and
that no license has been, or will be, granted under these patents. The
comment added that to the best of its knowledge triclosan is not used
in infant clothing, a use mentioned in the tentative final monograph at
43 FR 1231. The comment stated that if triclosan is placed in Category
I for use in antimicrobial soaps, it would limit sales of triclosan to
OTC use in antimicrobial and deodorant soaps, underarm deodorants, and
registered Environmental Protection Agency (EPA) pesticide products. In
the future, sales might be extended to include approved new drug
applications. The comment also pointed out that the statement at 43 FR
1233 about the EPA's Office of Special Pesticide Review preparing a
report on the proliferation of triclosan-containing products is in
error, and that the erroneous statement apparently resulted from a
miscommunication between FDA and EPA staff. The comment concluded that
the concerns about proliferation raised by the agency in the tentative
final monograph should not prevent triclosan from being placed in
Category I.
Another comment from the manufacturer of triclosan submitted
validation reports and raw data from a 2-year chronic oral toxicity
study in rats, and carcinogenicity and reproduction studies conducted
in mice, rats, rabbits, and monkeys by Industrial Bio-Test Laboratories
(IBT) (Refs. 4, 5, and 6) and asserted that its validation of the
studies shows that triclosan is safe.
Several comments objected to the agency's restriction at 43 FR 1229
that antimicrobial soaps containing triclosan can only be formulated in
a bar soap to be used with water (Ref. 1). The comments argued that
such a restriction was not applied to the other Category III uses of
triclosan, i.e., skin antiseptic, skin wound cleanser, and skin wound
protectant, and that such a restriction was not recommended by the
Panel in the advance notice of proposed rulemaking. The comments
suggested that the footnote under ``antimicrobial soaps'' limiting
triclosan to bar soap was probably intended to apply to cloflucarban,
which, like triclocarban, is known for its ``physical and/or chemical
incompatibility.''
With regard to safety, the agency evaluated the validation reports
to support long-term use of the ingredient (Refs. 4, 5, and 6) and
advised the manufacturer of triclosan that the IBT studies were invalid
because of numerous problems. The agency's detailed comments and
evaluation on the data are on file in the Dockets Management Branch
(Ref. 7).
The manufacturer subsequently stated its intent to no longer rely
on the 2-year chronic oral toxicity IBT study (Ref. 8), and submitted a
final report from a new 2-year chronic oral toxicity study in rats
(Ref. 9). The agency has determined that the study data are
unacceptable as the sole evidence of the safety of the long-term use of
triclosan as a health-care personnel handwash or surgical handscrub
based on the marginal survival of the animals in both the control and
treated groups and uncertainties about the dose and study conduct.
Therefore, data from another chronic exposure study are necessary to
assess the safety of the long-term use of triclosan. The agency's
detailed comments and evaluation of the data are on file in the Dockets
Management Branch (Ref. 10). A subsequent submission from the same
manufacturer contained the final report of a two-generation study of
the reproductive toxicity of triclosan in rats (Ref. 11). These data
are currently being reviewed by the agency and will be discussed in the
final rule for these drug products. Triclosan remains classified as
Category III for safety for long-term use.
The agency concluded in the amended tentative final monograph for
OTC first aid antiseptic drug products (56 FR 33644 at 33665) that
triclosan (in concentrations up to 1.0 percent) is safe for short term
use as a first aid antiseptic (formerly designated as skin antiseptic,
skin wound cleanser, and skin wound protectant). The data reviewed
(Ref. 1) also support the safety of triclosan (up to 1.0 percent) for
use as a patient preoperative skin preparation. However, with regard to
safety for use as an antiseptic handwash or health-care personnel
handwash and surgical hand scrub, triclosan remains classified in
Category III for safety for long-term use, as stated above.
With regard to effectiveness, in the previous tentative final
monograph the agency classified triclosan as Category II for use as a
health-care personnel handwash, patient preoperative skin preparation,
and surgical hand scrub because triclosan has limited activity against
gram-negative bacteria. For example, triclosan is the subject of a
patent (patent No. 3,616,256) for use in culture media for isolating
Pseudomonas. Because human skin is regarded as a superb ``culture
medium,'' the possibility was raised (43 FR 1210 at 1232) that
triclosan might selectively promote overgrowth of Pseudomonas on the
hands of health-care personnel. Based upon data reviewed, the agency
advised that in vitro data demonstrate that triclosan's antibacterial
spectrum can be broadened, to be effective against Pseudomonas when
triclosan is properly formulated with anionic surfactants to form a
``synergistic mixture.'' Therefore, FDA reclassified triclosan (up to
1.0 percent, with the lower limit to be determined) from Category II to
Category III for effectiveness. The agency further advised that
additional studies are needed before triclosan can be generally
recognized as effective for specific uses, i.e., surgical hand scrub,
health-care personnel handwash, patient preoperative skin preparation,
and first aid uses (formerly designated as skin antiseptic, skin wound
cleanser, and skin wound protectant). The agency's detailed comments
are on file in the Dockets Management Branch (Ref. 12).
In response to the agency's comments (Ref. 12), the manufacturer of
triclosan requested further guidance, and asserted, ``The overall
antimicrobial effectiveness of a topically applied product is a
function of the total formulation rather than a single ingredient.
Although it is impossible to anticipate and test all possible
formulations, adequate in vivo evaluations of triclosan-containing
formulations for specific end uses are available to fully justify
Category I status for triclosan as an active ingredient in surgical
hand scrubs, health-care personnel handwashes, and antimicrobial
soaps.'' The comment submitted effectiveness data from four in vivo
studies on formulations of triclosan (Ref. 13). These data included
three previously unsubmitted studies (RDP/19/23 (June 24, 1981), RDP/
19/21 (February 2, 1981), and CAB/AVD (February 2, 1982)), and one
previously submitted study (66-D15-W221, OTC Volume 020038) that had
been reviewed by the Panel (39 FR 33128). In study RDP/19/23 (June 24,
1981), following modified glove juice test procedures, a test product
(0.5 percent triclosan in 60 percent n-propyl alcohol) and a control
(60 percent n-propyl alcohol) were compared for reduction of normal
baseline flora and persistence of that reduction for 3 hours on the
hands of 15 test subjects. The test product (0.5 percent triclosan in
60 percent n-propyl alcohol) and the control (60 percent n-propyl
alcohol) immediately reduced approximately 99.5 percent of the baseline
number of bacteria. After 3 hours, 0.5 percent triclosan in 60 percent
n-propyl alcohol suppressed the baseline count better than the vehicle
control; for example the test product allowed about a onefold increase
in bacterial count within 3 hours, while the vehicle control (60
percent n-propyl alcohol) allowed an approximately twelvefold increase.
Although the test used was not the glove juice test described in the
antimicrobial tentative final monograph, alternative methods are
acceptable, provided criteria meet those of the glove juice test
procedures described in the guidelines. (See ``Effectiveness Testing of
Surgical Hand Scrub (Glove Juice Test),'' 43 FR 1210 at 1242.) The
agency has the following comments regarding the protocol for the study:
only 15 subjects (an insufficient number) were tested; a baseline count
from 3 samplings was not established before the test; the log10
reduction in bacteria from baseline was determined after 3 hours, but
not after 6 hours; and the results of the test were not analyzed
statistically.
In study RDP/19/21 (February 2, 1981), 2 percent triclosan in a
liquid soap vehicle reduced baseline counts of test bacteria E. coli
ATCC 11229, P. aeruginosa ATCC 15442, and Staphylococcus species on the
hands of human test subjects by 1 log greater than the water control
after 2 minutes of handwashing. In study CAB/AVD (February 2, 1982),
triclosan (unknown concentrations) in a liquid soap formulation,
compared to a vehicle control, maintained reduction of baseline counts
(within 10, 30, 60, 90, and 120 minutes) after artificial contamination
with K. aerogenes. In study 66-D15-W221 (in OTC Volume 020038), 0.5
percent, 1 percent, and 2 percent triclosan in Ivory^{R soap was
compared to Ivory^{R soap without triclosan, as a control, to show
reduction of baseline counts on the hands of five human test subjects
after 5 days. Using the Quinn Split-Use Modification of the Price-Cade
Method, increased skin-degerming activity was shown after 3 days of
repeated (10) applications of triclosan as compared to the control.
However, the number of test subjects (5) is not adequate to demonstrate
general recognition of effectiveness. (See the ``Modified Cade
Procedure,'' 43 FR 1210 at 1243.)
The agency concludes that the data (Ref. 13) discussed above
indicate that formulations of triclosan significantly reduce the
baseline count of bacterial skin flora. However, before triclosan may
be generally recognized as an effective health-care antiseptic for use
in antiseptic handwash or health-care personnel handwash, patient
preoperative skin preparation, and surgical hand scrub drug products,
additional in vivo data, i.e., glove juice test data, are needed. The
in vivo data should correlate with data obtained from in vitro studies.
Because of the nature of the intended uses of health-care antiseptic
drug products, the agency believes it is essential to assure the
effectiveness of the active ingredient, triclosan, in final
formulations. To demonstrate effectiveness in vitro, information is
needed on the germicidal activity of the vehicle alone, so that the
germicidal contribution of triclosan attributed to the total
effectiveness of the finished formulation can be determined. (See
section I.N., comment 28.)
Accordingly, triclosan (up to 1 percent, with the lower limit to be
determined) is being classified as Category III for use in health-care
antiseptic drug products as a patient preoperative skin preparation,
antiseptic handwash or health-care personnel handwash, and surgical
hand scrub. The agency's conclusions are summarized below:

------------------------------------------------------------------------
Short-term use Long-term (repeated/daily) uses
------------------------------------------------------------------------
Patient Preoperative Skin Antiseptic Handwash or Health-Care
Preparation IIIE. Personnel Handwash IIISE.
Surgical Hand Scrub IIISE.
------------------------------------------------------------------------
S=Safety.
E=Effectiveness.

The agency has communicated further with EPA and has ascertained
that there is no specific report on the proliferation of triclosan
(Ref. 14). Regarding exclusive patent rights, the agency advises that
these are not among the determining criteria to establish general
recognition of safety and effectiveness, and therefore cannot be used
in the evaluation. However, having reviewed the new data along with the
previously submitted data, the agency concludes that there is no
proliferation problem with triclosan.
Finally, the agency did not intend to restrict formulations of
triclosan to bar soap. The agency has reviewed the Panel's
recommendations and the footnotes in the previous tentative final
monograph (43 FR 1210 at 1229) and finds that triclosan under
``antimicrobial soaps'' was erroneously marked with the reference to
the footnote ``Category III only when formulated in a bar soap to be
used with water.''
The use of triclosan in products for the treatment of diaper rash
was discussed in the tentative final monograph for antimicrobial diaper
rash drug products published on June 20, 1990 (55 FR 25246 at 25277 to
25278). The use of triclosan in products for treating sunburn will be
addressed in the Federal Register at a later date in another OTC drug
rulemaking for drug products for this use.

References

(1) Comments No. CP1, SUP19, SUP23, C103, C109, SUP31, SUP39,
and C134, Docket No. 75N-0183, Dockets Management Branch.
(2) Comment No. SUP20, Docket No. 75N-0183, Dockets Management
Branch.
(3) Comment No. OB15, Docket No. 75N-0183, Dockets Management
Branch.
(4) ``Two Year Chronic Oral Toxicity Study With Fat 80' 023/A in
Albino Rats,'' Comment No. C109, vol. 1, appendix E, and Comment No.
C139, vol. 1-8, Docket No. 75N-0183, Dockets Management Branch.
(5) ``Eighteen Month Carcinogenicity Study with Fat 80' 023/A in
Albino Mice,'' Comment No. C109, vol. 3, appendix I, and Comment No.
C139, vol. 9, Docket No. 75N-0183, Dockets Management Branch.
(6) ``Three Phase Reproduction Study Albino Rats and Rabbits,
Bacteriostat CH 3565,'' Comment No. C134, tab 7, and Comment No.
C139, vol. 10-11, Docket No. 75N-0183, Dockets Management Branch.
(7) Letter from W. E. Gilbertson, FDA, to R. Bernegger, Ciba-
Geigy Corp., coded LET28/ANS, Docket No. 75N-0183, Dockets
Management Branch.
(8) Memorandum of meeting between representatives of Ciba-Geigy
Corp. and FDA, Comment No. MM7, Docket No. 75N-0183, Dockets
Management Branch.
(9) ``FAT 80' 023 2-Year Oral Administration in Rats,'' vol.
XLI, XLII, and XLIII and ``Determination of FAT 80' 023 in Blood and
Tissue Samples Taken During a Two-Year Chronic Oral Toxicity/
Oncogenicity Study in Albino Rats,'' vol. XLIV, Comment No. RPT2,
Docket No. 75N-0183, Dockets Management Branch.
(10) Letter from W. E. Gilbertson, FDA, to Per Stensby, Ciba-
Geigy Corp., coded LET100, Docket No. 75N-0183, Dockets Management
Branch.
(11) Comment No. RPT7, Docket No. 75N-0183, Dockets Management
Branch.
(12) Letter from W. E. Gilbertson, FDA, to R. Bernegger, Ciba-
Geigy Corp., coded LET34, Docket No. 75N-0183, Dockets Management
Branch.
(13) Comments No. MM3 and C157, Docket No. 75N-0183, Dockets
Management Branch.
(14) Letter from A. E. Castillo, EPA, to W. E. Gilbertson, FDA,
coded LET33, Docket No. 75N-0183, Dockets Management Branch.

M. Comments on Combinations of Active Ingredients

24. One comment stated that the Panel did not review safety and
effectiveness data submitted to it on mercufenol chloride
(orthohydroxyphenylmercuric chloride) 0.1 percent and secondary
amyltricresols 0.1 percent as single ingredients and in combination for
use as a patient preoperative skin preparation, skin antiseptic, and
skin wound protectant (Ref. 1). The comment added that the agency did
not discuss these ingredients alone or in combination in the previous
tentative final monograph.
The comment asserted that secondary amyltricresols, mentioned in
the previous tentative final monograph under phenol (43 FR 1210 at
1238), is not equivalent to phenol because of chemical differences and
differing antimicrobial properties, formulation concentrations, and
patterns of use. The comment requested the agency to make decisions on
the safety and effectiveness of this ingredient when used alone, or in
combination, as a patient preoperative skin preparation, a skin
antiseptic, or a skin wound protectant.
The agency has previously reviewed data for first aid antiseptic
uses of 0.1 percent mercufenol chloride and 0.1 percent secondary
amyltricresols and found the evidence insufficient to support their
safety and effectiveness either as single ingredients or in combination
(56 FR 33644 at 33668). Only safety data on animals were submitted by
the comment (Ref. 1); in general, these studies were conducted on a
very small number of animals, did not detail methodology, and did not
adequately describe results (physical condition of the animals). The
submitted in vitro studies also lack sufficient detail to establish the
effectiveness of mercufenol chloride.
Secondary amyltricresols is a mixture of isomeric secondary
amyltricresols, which are derivatives of phenol, and has
pharmacological properties similar to phenol. The agency agrees with
the comment that the mixture of secondary amyltricresols is not
equivalent to phenol and should be categorized separately from phenol.
The submitted safety data included a study by Broom (Ref. 2), who
reported that amylmetacresol is relatively nontoxic and less toxic than
hexylresorcinol in rats and mice.
No toxicity studies in humans were included in the information
provided by the comment. However, in the tentative final monograph for
OTC external analgesic drug products, published in the Federal Register
of February 8, 1983 (48 FR 5852 at 5858), the agency proposed that
metacresol up to a 3.6-percent concentration be considered safe when
combined with camphor and that a 3-to-1 ratio of camphor to metacresol
reduces the irritating properties of metacresol. Although cresols may
cause some irritation when applied to minor wounds, the agency believes
that secondary amyltricresols at the concentration requested (0.1
percent) would not present any safety concerns, particularly
considering the short-term use of antiseptics as patient preoperative
skin preparation drug products. The submitted data are, however,
inadequate to establish the efficacy of secondary amyltricresols.
Data are also needed to determine the safety and effectiveness of
the combination of mercufenol chloride and secondary amyltricresols.
Only animal safety data are available, and these studies were limited
to determinations of the minimum lethal dose by various routes of
administration (Ref. 1). The submitted information on marketing history
is not sufficient to provide general recognition of the safety of these
ingredients. The data contained isolated reports of the combination of
mercufenol chloride and secondary amyltricresols causing occasional
skin irritation, such as burning and blistering (Ref. 1), adverse
effects that need to be more fully studied.
Most of the effectiveness work on the combination of mercufenol
chloride and secondary amyltricresols has been in vitro. The
combination is reported to combine the antibacterial activity of the
single ingredients, that is, mercufenol chloride which is primarily
active against gram-negative organisms and secondary amyltricresols
which is primarily active against gram-positive organisms (Ref. 3). One
in vivo study on the effectiveness of the combination as a patient
preoperative skin preparation showed a substantial reduction in the
skin microflora (Ref. 4). However, because neutralizers were not used,
bacteriocidal activity cannot be differentiated from residual
bacteriostatic activity. In addition, the effect of the 50-percent
alcohol in the alcohol-acetone vehicle was not taken into
consideration. Alcohol, 60 to 95 percent, is in Category I for
antiseptic health-care uses.
Under the agency's guidelines for OTC drug combination products
(Ref. 5), Category I active ingredients from the same therapeutic
category that have different mechanisms of action may be combined to
treat the same symptoms or condition if the combination meets the OTC
combination policy in all respects and the combination is on a benefit-
risk basis, equal to or better than each of the active ingredients used
alone at its therapeutic dose. Accordingly, both mercufenol chloride
and secondary amyltricresols and the combination of these ingredients
are placed in Category III. The combination needs further testing of
the combined ingredients compared to each individual active ingredient
to establish effectiveness of the combination as a patient preoperative
skin preparation.
The agency recommends that in vivo and in vitro effectiveness data
be submitted. The data should be based on both in vitro and in vivo
testing procedures as described for patient preoperative skin
preparation drug products. (See section I.N., comment 28.)

References

(1) OTC Vol. 020093.
(2) Broom, W. A., ``A Note on the Toxicity of Amyl-meta-
cresol,'' British Journal of Experimental Pathology, 12:327-331,
1931.
(3) Dunn, C. G., ``Germicidal Properties of Phenolic
Compounds,'' Industrial and Engineering Chemistry, 28:609-612, 1936.
(4) Maddock, W. G., and L. K. Georg, ``Further Experience with
Mercresin,'' American Journal of Surgery, 45:72-75, 1939.
(5) Food and Drug Administration, ``General Guidelines for OTC
Drug Combination Products,'' September 1978, Docket No. 78D-0322,
Dockets Management Branch.

25. One comment submitted data on a combination drug product
containing calomel (mercurous chloride) 30 percent, oxyquinoline
benzoate, and trolamine (triethanolamine) combined with fatty acids to
form a soap compound, plus a phenol derivative that is currently
marketed over-the-counter and is indicated for use in the prevention of
venereal disease (syphilis and gonorrhea) (Ref. 1). The comment
included a historical review and information on in vitro activity of
one of the ingredients. According to the comment, in 1905 the discovery
was made that calomel in combination with fats is an effective
germicide against Treponema pallidum (T. pallidum), the causative
organism of syphilis. Later, calomel was stated to be active against
Neisseria gonorrhoeae (N. gonorrhoeae) (the causative organism of
gonorrhea).
This combination of ingredients and the indication of prevention of
syphilis and gonorrhea have not been reviewed by any OTC advisory
review panel. However, because a claim is made indicating antimicrobial
activity and the product contains calomel, which is already included in
the rulemaking for OTC topical antimicrobial drug products, the agency
believes it is appropriate to review this combination and labeling
claim in this amended tentative final monograph.
The in vitro effectiveness test described in the comment (Ref. 1)
is a zone of inhibition test comparing the germicidal activity of
calomel, phenol, and organic silver salts against S. aureus as an
indicator of activity against syphilis (T. pallidum) and gonorrhea (N.
gonorrhoeae). According to the submission, the causative organisms are
not viable in vitro and were not used in the testing. The agency points
out that it is possible to isolate and subculture isolates of N.
gonorrhoeae for in vitro antimicrobial testing (Ref. 2), but T.
pallidum cannot be grown in vitro (Ref. 3). The agency does not
consider the in vitro test against S. aureus to be adequate to support
a claim of prevention of syphilis and gonorrhea.
In a separate rulemaking for mercury-containing drug products for
topical antimicrobial use, calomel was reviewed by the Miscellaneous
External Panel (47 FR 436 at 440). That Panel did note that calomel
``has been used in the past by inunction (rubbing into the skin) as a
prophylactic against venereal disease * * *'' but placed the ingredient
in Category II because ``calomel may be safe as a topical antimicrobial
agent, but it is not effective for this purpose.''
Although it is apparent that calomel 30 percent would be considered
an active ingredient, it is not clear from the available information
whether the other ingredients in the combination (oxyquinoline
benzoate, trolamine, and phenol derivative) are also considered active
ingredients, nor are the concentrations of these other ingredients
stated in the submission and no data have been submitted to the OTC
drug review on these ingredients in relation to the prevention of
venereal disease. In the absence of any data, none of these ingredients
are considered safe and effective for this use.
The comment did not submit any in vivo data from clinical studies
to demonstrate that the combination of calomel, oxyquinoline benzoate,
trolamine, and phenol derivative is safe and effective for use in the
prevention of syphilis and gonorrhea. Preliminary in vitro testing
against N. gonorrhoeae should be conducted before any human clinical
trials are done. Then, favorable results from two well-controlled
clinical studies in humans conducted by qualified investigators in two
geographic locations (at least one should be within the United States
of America) are needed before any drug product can be recognized to be
safe and effective in preventing syphilis and gonorrhea. Interested
individuals should consult with the agency before initiating any
testing. In conclusion, the agency is proposing that this combination
of ingredients indicated for the prevention of syphilis and gonorrhea
be classified Category II in this amended tentative final monograph.
The agency's detailed comments and evaluation on the data are on
file in the Dockets Management Branch (Ref. 4).

References

(1) Comment No. C158, Docket No. 75N-0183, Dockets Management
Branch.
(2) Morello, J. A., and M. Bohnhoff, ``Neisseria and
Branhamella,'' in ``Manual of Clinical Microbiology,'' 3rd ed.,
edited by E. H. Lennette, American Society for Microbiology,
Washington, pp. 111-122, 1980.
(3) Buchanan, R. E., and N. E. Gibbons, ``Bergey's Manual of
Determinative Bacteriology,'' 8th ed., Williams and Wilkins Co.,
Baltimore, p. 176, 1974.
(4) Letter from W. E. Gilbertson, FDA, to M. Lowenstein, The
Sanitube Co., coded LET68, Docket No. 75N-0183, Dockets Management
Branch.

N. Comments on Testing

26. Numerous comments addressed the agency's modifications in the
Panel's proposed testing guidelines (43 FR 1210 at 1239 to 1240), the
agency's statements on final formulation testing (43 FR 1211, 1224, and
1240), and specific protocols for upgrading an antimicrobial ingredient
from Category III to Category I (43 FR 1242 to 1246). Stating that the
testing guidelines were unclear in some places and pointing out
inconsistencies between the guidelines and the agency's responses to
comments at 43 FR 1211 and 1223 to 1227, a number of comments requested
clarification or proposed modifications of a number of items in the
guidelines.
Several comments requested specific information or submitted
protocols for testing Category III ingredients. One comment requested
that manufacturers be permitted to determine which protocol to follow
to establish safety or effectiveness of an ingredient. A number of
comments objected to the agency's consideration of the testing
guidelines as final, and urged revisions in the guidelines for
publication in the Federal Register.
The agency acknowledges that there were some inconsistencies in the
testing guidelines for safety and effectiveness proposed in the
previous tentative final rule. The agency does not consider the
previous testing guidelines as final. The agency is clarifying in this
amended tentative final monograph that all final formulations will be
required to meet the specifications in the final monograph. As stated
in section I.N., comment 28, the agency is proposing testing procedures
in Sec. 333.470 for evaluating the active ingredient in pure form as
well as in the complete formulation. The agency recommends that
manufacturers use these procedures for testing the final formulations
of products intended for health-care antiseptic use. Manufacturers may
propose other appropriate testing procedures subject to agency
evaluation, as requested. The data from these tests are not required to
be submitted to FDA by the manufacturer. However, the agency intends to
use these procedures for any necessary compliance testing.
27. Two comments pointed out an apparent conflict in the agency's
statements concerning safety factor calculations as follows: At 43 FR
1240, the agency concluded that a minimum of a 100-fold safety factor
should apply to the exposure dose for ingredients labeled for repeated
daily use; at 43 FR 1241, the agency stated that if the safety factor
is extrapolated from an animal species to man, considering surface
area, the highest no-effect dose should be used for the multiplier, and
in the absence of complete data, a 100-fold safety factor should be
applied when translating the animal highest no-effect dose to man; and
at 43 FR 1213 (see comment 19), the agency stated that modifications of
the safety factor will be allowed for specific ingredients where
justified by risk-benefit considerations. One comment suggested that a
safety factor of less than 100-fold be acceptable when scientific
investigation of good quality shows that the test animals used in
establishing the no-effect dose are similar to humans with respect to
metabolism (biotransformation and pharmacokinetics) and/or tissue
susceptibility. Another comment stated that a more reasoned and
practical approach would be to require calculation of certain safety
factors as recommended, and indicate in a general guideline that risk-
benefit ratios based on these factors would determine the relative
merits of the product.
The agency does not find any conflict in the various statements
included in the previous tentative final monograph. The safety factor
calculations were included merely as a general guideline. The agency's
response to comment 19 at 43 FR 1213 indicated that the agency would
retain a minimum of a 100-fold safety factor applied to the exposure
dose for ingredients in products labeled for repeated daily use.
However, the agency will consider modifications of the safety factor
for specific ingredients where justified by risk-benefit considerations
and where requests are based on submitted data. While the 100-fold
safety factor was a general guideline in the previous tentative final
monograph, the agency does not find a need to include a general
guideline in this amended tentative final monograph.
28. Numerous comments requested clarification of the criteria
required to establish effectiveness for each antimicrobial product
class. One comment stated that the ``Testing Guidelines'' section seems
to indicate that it may be necessary to determine the effect of the
vehicle on the active ingredient. The comment contended that this
provision is confusing because the preamble discussion in the tentative
final monograph indicates that vehicle testing will not be necessary
``* * * where adequate data are available on the active ingredients
alone.'' (See 43 FR 1210 at 1224.) Another comment stated that the Cade
handwashing test can only be conducted if the antimicrobial is placed
in a vehicle and noted that the antimicrobial is never used by
consumers in its raw form; therefore, efficacy testing on the raw
antimicrobial ingredient should not be required. A third comment stated
that the overall antimicrobial effectiveness of a topically applied
product is a function of the total formulation rather than a single
ingredient. Another comment added that if an individual product
formulation must be tested, and/or the testing of a product vehicle is
considered essential, then such testing requirements must be
specifically described. Citing the definition of an antiseptic in
section 201(o) of the act (21 U.S.C. 321(o)), one comment asserted that
the definition requires that the antimicrobial product kill or inhibit
the growth of micro-organisms on the skin. The comment proposed that
efficacy can be demonstrated by showing that the preparation produces a
quantitative reduction in the levels of normal skin flora and/or
inhibition of bacterial growth in vitro. Two comments pointed out that
the ``Modified Cade Procedure'' handwashing test (43 FR 1210 at 1243)
specifies a one-log reduction of bacteria, but the procedure fails to
indicate how many uses or days of use of test product should produce
the reduction. Other comments requested that no upper limit be set for
bacterial hand counts, that the lower limit of 1.5 x 10\6\ per hand be
the only criteria for subject selection, and that minimal hand count
reduction be defined in the test protocols for surgical hand scrub and
health-care personnel handwash products. Another comment suggested that
modification of the ``Sampling technique and times'' (paragraph 6) of
the protocol ``Effectiveness Testing of Surgical Hand Scrub (Glove
Juice Test)'' (43 FR 1243) was needed because the protocol did not
indicate the volume of sampling solution but only stated that the
volume * * * should be ``kept constant'' for all tests. The comment
recommended that the agency specify a range of 50 to 100 mL of sampling
solution in order to provide consistent and reproducible results.
The agency has carefully reviewed the comments, existing data, and
other information, and is clarifying the effectiveness criteria for
health-care antiseptics in this tentative final monograph.
In order for an antiseptic ingredient to be generally recognized as
effective for use as an antiseptic handwash or health-care personnel
handwash, patient preoperative skin preparation, and/or surgical hand
scrub, it must have existing data from well designed clinical studies
demonstrating effectiveness. The agency believes that it is important
to correlate effectiveness data from clinical studies with
effectiveness data from in vitro studies on the activity of the vehicle
and active ingredient individually, so that the germicidal contribution
of the antiseptic ingredient to the total formulation can be fully
characterized. As stated in the testing guidelines in the previous
tentative final monograph, at 43 FR 1240, ``* * * there should be
demonstration that the formulated product is better than the vehicle
alone. Testing of the complete formulation of Category III ingredients
* * * is necessary to judge the importance of the vehicle in the
release of the active ingredient as well as the influence of
formulation on aspects of effectiveness * * *.'' The agency believes
that information on the in vitro activity of the active ingredient
alone helps to characterize its antiseptic activity independent of
formulation and helps to further define formulation effects on the
antimicrobial ingredient. Therefore, the agency is proposing that in
vitro studies of the antimicrobial activity of health-care antiseptic
drug products covered by Sec. 333.470(a)(1)(i) and (a)(1)(ii) be
conducted on the active ingredient, the vehicle, and the final
formulation. Manufacturers are to have such data in their files for
products containing ingredients included in the monograph.
In this amended tentative final monograph, the agency is proposing
that the in vitro antimicrobial activity of the antiseptic ingredient,
the vehicle, and the formulated product be characterized by the
determination of their antimicrobial spectrum and by minimal inhibitory
concentration determinations performed against selected organisms using
methodology established by the National Committee for Clinical
Laboratories Standards (NCCLS) (Ref. 1). Because the principal intended
use of these health-care antiseptic drug products is the prevention of
nosocomial or hospital acquired infections, the agency concludes that
these products should be able to demonstrate in vitro activity against
a microbial spectrum that reflects this use. Since 1970, the National
Nosocomial Infection Surveillance System (NNIS) has collected and
analyzed data on nosocomial pathogens reported to the Centers for
Disease Control by a number of hospitals who perform prospective
surveillance on nosocomial infections. These data provide an indication
of the most frequently occurring pathogens at four major sites of
nosocomial infection--the urinary tract, surgical wounds, lungs
(pneumonia), and bloodstream. The agency believes that health-care
personnel handwash, surgical hand scrub, and patient preoperative skin
preparations should be able to demonstrate in vitro effectiveness
against these pathogens as well as the normal resident skin flora.
Therefore, the agency is proposing that micro-organisms associated with
the most commonly occurring nosocomial infections and those found most
often in nosocomial infections of high risk patients as reported by the
NNIS, for the period from January 1985 through August 1988 (Ref. 2), be
included in the list of micro-organisms to be tested in
Sec. 333.470(a)(1)(ii). The agency further concludes that this proposed
list identifies a broad spectrum of antimicrobial activity that is also
appropriate for home use antiseptic handwash products.
The agency notes that neither filamentous dermatophytic fungi or
viruses are included in the NNIS report. More recent studies (Refs. 3
and 4) have reported small numbers of nosocomial infections associated
with both of these organisms. However, the new studies do not provide
sufficient information to assess the relative importance of these
organisms as a cause of nosocomial infection. Therefore, the agency is
not proposing to include filamentous dermatophytic fungi in the list of
micro-organisms to be tested, as proposed in the previous in vitro
effectiveness testing guidelines (43 FR 1210 at 1241) and is continuing
to propose that viruses also not be included. The agency recognizes
that the list of organisms to be tested may need updating to assure
that it remains reflective of current trends in the microbial etiology
of nosocomial infections. The agency intends to update the list as new
information becomes available. Further, the agency invites the
submission of comments and specifically data on the role of other
organisms, particularly viruses and filamentous dermatophytic fungi, in
nosocomial infections.
In addition to the characterization of the in vitro spectrum of
activity, the agency believes that information on how rapidly these
antimicrobial drug products achieve their antimicrobial effect is
necessary. As a means of indicating how quickly these products achieve
their antimicrobial effect, the agency is proposing in vitro time-kill
curves of the formulated drug product as part of the testing
requirements. The agency acknowledges that there is currently no
accepted or standardized method that may be used in conducting this
type of study and invites the submission of proposed methods that may
be considered as applicable to this test. In Sec. 333.470(a)(1)(iv) of
the proposed testing regulations, the agency provides guidance on the
development of such methods. However, any time-kill studies submitted
to the agency are to be conducted on a 10-fold dilution of the
formulated product against the ATCC strains identified in
Sec. 333.470(a)(1)(ii) of the proposed testing regulations and are to
include enumeration at times at 0, 3, 6, 9, 12, 15, and 30 minutes.
With regard to proof of clinical effectiveness, the agency is
proposing specific criteria for final formulations of antiseptic
handwashes or health-care personnel handwashes, patient preoperative
skin preparations, and surgical hand scrubs that are based on the
recommendations of the Panel and agency experience in evaluating the
effectiveness of these types of drug products, as follows.
For antiseptic handwash or health-care personnel handwash products,
the agency is proposing the following criteria: (1) A 2-log10
reduction of the indicator organism on each hand within 5 minutes after
the first wash and (2) a 3-log10 reduction in the indicator
organism on each hand within 5 minutes after the tenth wash, when
tested by a modification of the standard procedure for the evaluation
of health-care personnel handwash formulations published by the
American Society for Testing and Materials (ASTM) (Ref. 5).
For patient preoperative skin preparations, the agency is proposing
the following criteria: (1) A 2-log10 reduction of the microbial
flora per square centimeter of an abdominal test site, (2) a 3-
log10 reduction of the microbial flora per square centimeter of a
groin test site within 10 minutes from a matched control area, and (3)
the suppression of bacterial growth below baseline for 6 hours, when
tested by a modification of the standard procedure for the evaluation
of patient preoperative skin preparations published by the ASTM (Ref.
6). The agency believes that the revised effectiveness criteria more
closely reflect the conditions of product use, i.e., on a number of
different body sites, each supporting different numbers of resident
skin flora. In addition, although persistence of effect was not
recommended by the Panel as a requirement for these drug products, the
agency believes that persistence of antimicrobial effect would suppress
the growth of residual skin flora not removed by preoperative prepping
as well as transient micro-organisms inadvertently added to the
operative field during the course of surgery and reduce the risk of
surgical wound infection. Based on the proposed effectiveness criteria
for this product class, the agency is proposing a revised definition of
a patient preoperative skin preparation drug product in
Sec. 333.403(c)(2) of this amended tentative final monograph as
follows: ``A fast-acting broad-spectrum persistent antiseptic-
containing preparation that significantly reduces the number of micro-
organisms on intact skin.''
As discussed in section I.E., comment 10, the agency is proposing
the indication ``for the preparation of the skin prior to an
injection'' for OTC alcohol and isopropyl alcohol drug products. The
agency is further proposing that products labeled for such use
demonstrate effectiveness by testing according to the same procedure
used to demonstrate the effectiveness of patient preoperative skin
preparation drug products not labeled for this use. Based on this
intended use of alcohol drug products, the agency is proposing a 1-
log10 reduction in the microbial flora per square centimeter of a
dry skin test site within 30 seconds of product use as the
effectiveness criteria for these products.
For surgical hand scrub products, the agency is proposing the
following criteria: (1) A 1-log10 reduction of the microbial flora
of each hand from the baseline count within 1 minute, (2) suppression
of bacterial growth on each hand below baseline for 6 hours on the
first day, (3) a 2-log10 reduction of the microbial flora on each
hand within 1 minute of product use by the end of the second day, and
(4) a 3-log10 reduction of the microbial flora on each hand within
1 minute of product use by the end of the fifth day, when tested by a
modification of the standard procedure for the evaluation of surgical
hand scrub products published by the ASTM (Ref. 7).
Based on glove juice test data for surgical hand scrub use of
povidone-iodine (section I.I., comment 17), alcohol (section I.E.,
comment 10), chloroxylenol (section I.G., comment 12), and triclosan
(section I.L., comment 23), the agency concludes that formulated
products containing certain ingredients, i.e., chloroxylenol and
triclosan, are substantive in their action and do not produce a high
(1-log^{10) initial reduction, but after repeated use for up to 5
days do reduce the baseline count and suppress the count in the user's
glove. In a separate final rule, the agency stated that any product
indicated for use as a surgical scrub should meet a standard for
initial reduction. A one-log reduction was found acceptable as the
minimal level of reduction suitable for a surgical scrub in a
handwashing test. (See ``New Drugs Containing Hexachlorophene,''
published in the Federal Register of December 20, 1977; 42 FR 63771.)
In that same final rule, the agency acknowledged that
hexachlorophene containing surgical scrub drug products are substantive
in their action and do not produce an initial high reduction but with
repeated use are effective in reducing the resident skin flora and
suppressing bacterial growth in the user's glove for up to 6 hours.
Based on a lack of available products capable of producing both an
initial high reduction in the resident skin flora and a prolonged
microbial suppression marketed at the time of the agency's action on
the ingredient in 1972, the agency agreed with the recommendations of
its Antimicrobial I Panel and concluded that the ingredient should
continue to be marketed for use as a surgical scrub and for handwashing
as part of patient care. The agency stated its intention to reconsider
its criteria for evaluating such products in light of risk-benefit
judgments as new products containing both attributes become available
(42 FR 63771).
Since that final rule was issued in 1977, data have been submitted
to the agency demonstrating the effectiveness of surgical hand scrub
formulations capable of producing an initial 1-log10 reduction and
a suppression of microbial growth in the wearer's glove for up to 6
hours. (See section I.E., comment 10 on alcohol and section I.I.,
comment 17 on povidone-iodine.) The agency notes that the persistence
of the antimicrobial effect demonstrated by an alcohol-containing
surgical hand scrub formulation was provided by a preservative agent in
the vehicle. Based on the new data, the agency has concerns about the
risk associated with the initial use of substantive surgical hand scrub
formulations, and with the use of these formulations after extended
lapses in their routine use. Therefore, the agency is proposing that
all surgical hand scrub formulations must demonstrate an initial one-
log reduction in the bacterial flora. The agency invites comment on the
use of substantive antimicrobials in health-care antiseptic drug
products. Based on the revised effectiveness criterion for these drug
products, the agency is proposing a revised definition of a surgical
hand scrub drug product in Sec. 333.403(c)(3) as follows: ``An
antiseptic containing preparation that significantly reduces the number
of micro-organisms on intact skin; it is broad spectrum, fast acting,
and persistent.''
The agency believes that the modified ASTM procedures for the
testing of health-care or antiseptic handwashes, surgical hand scrubs,
and patient preoperative skin preps being proposed for inclusion in the
testing requirements provide protocols that are appropriate for the
final formulation testing of these drug products. The proposed
protocols describe, in detail, study conditions and materials to be
used and address the concerns raised by the comments. For instance, the
proposed protocol for the testing of surgical hand scrub products
includes a baseline criterion for subject selection of equal to, or
greater than, 1.5 x 10^{5 bacteria per hand and specifies that a
50 to 100 mL volume of sampling is to be used. The proposed protocols
also specify requirements for a number of areas not addressed by the
testing guidelines proposed in the previous tentative final monograph.
For example, they address statistical aspects of study design and data
analysis, and the use of neutralizers. A positive control is included
in the protocols as a means of validating the testing procedure,
equipment, and facilities. The agency believes that the proposed
protocols for the testing of these products provide a consistent
approach to the effectiveness testing of health-care personnel
handwashes, surgical hand scrubs, and patient preoperative skin
preparations. The agency is incorporating the above criteria and
testing requirements in proposed Sec. 333.470 of this tentative final
monograph and invites specific comment on them at this time. After
reviewing any submitted comments or data, the agency may revise the
testing requirements and procedures prior to establishing a final
monograph. The agency also recognizes that the test procedures may need
to be revised periodically to reflect new information and newer
techniques that are developed and proven adequate.

References

(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.
(2) Horan, T. et al., ``Pathogens Causing Nosocomial
Infections,'' The Antimicrobic Newsletter, 5:65-67, 1988.
(3) Andersen, L. J., ``Major Trends in Nosocomial Viral
Infections,'' The American Journal of Medicine, 91:107S-111S, 1991.
(4) Jarvis, W. R. et al., ``Nosocomial Outbreaks: The Centers
for Disease Control's Hospital Infections Program Experience,'' The
American Journal of Medicine, 91:101S-106S, 1991.
(5) American Society for Testing and Materials, ``Standard Test
Method for Evaluation of Health Care Personnel Handwash Formulation,
Designation E 1174,'' in ``The Annual Book of ASTM Standards,'' vol.
11.04, American Society for Testing and Materials, Philadelphia, pp.
209-212, 1987.
(6) American Society for Testing and Materials, ``Standard Test
Method for Evaluation of a Preoperative Skin Preparation,
Designation E 1173,'' in ``The Annual Book of ASTM Standards,'' vol.
11.04, American Society for Testing and Materials, Philadelphia, pp.
205-208, 1987.
(7) American Society for Testing and Materials, ``Standard Test
Method for Evaluation of Surgical Hand Scrub Formulation,
Designation 1115,'' in ``The Annual Book of ASTM Standards,'' vol.
11.04, American Society for Testing and Materials, Philadelphia, pp.
201-204, 1986.

II. The Agency's Amended Tentative Final Monograph

A. Summary of Ingredient Categories and Testing of Category II and
Category III Conditions

1. Summary of Ingredient Categories
The agency has carefully reviewed the claimed active ingredients
submitted to this administrative record (Docket No. 75N-0183), which
includes the following: the advance notice of proposed rulemaking (39
FR 33103) and previous tentative final monograph (43 FR 1210) for OTC
topical antimicrobial drug products, the advance notice of proposed
rulemaking for OTC topical alcohol drug products (47 FR 22324), and the
advance notice of proposed rulemaking for OTC topical mercury-
containing drug products (47 FR 436). Based upon the available
information, including clinical and marketing history, as well as the
recommendations of the Miscellaneous External Panel, the agency is
proposing a tentative classification for OTC health-care antiseptic
active ingredients.
Many of the ingredients included in the tabulation below are in
Category II and Category III because of no data or a lack of data on
use as a health-care antiseptic. However, all the ingredients have been
included as a convenience to the reader. The agency specifically
invites comment and additional data on these ingredients.
The advance notice of proposed rulemaking for alcohol drug products
for topical antimicrobial OTC human use (47 FR 22324, May 21, 1982) is
being incorporated into this amended tentative final monograph. In that
proposed monograph, the Miscellaneous External Panel recommended that
alcohol 60 to 95 percent by volume in an aqueous solution denatured
according to Bureau of Alcohol, Tobacco, and Firearms regulations at 27
CFR part 21 and isopropyl alcohol 50 to 91.3 percent by volume in an
aqueous solution be classified as Category I for topical antimicrobial
use. 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.)
Based upon submitted data and the conclusions of the Miscellaneous
External Panel, the agency is including alcohol as a Category I
surgical hand scrub, patient preoperative skin preparation, and
antiseptic handwash or health-care personnel handwash (see section
I.E., comment 10). While no comments submitted data on health-care uses
of isopropyl alcohol, the agency notes that one comment (Ref. 1) from a
manufacturer requested that the OTC alcohol drug products monograph
provide the labeling indication, ``antibacterial handwash.'' The same
manufacturer provided a submission (Ref. 2) to the Miscellaneous
External Panel on a combination product containing isopropyl alcohol 50
percent and oxyquinoline sulfate 0.125 percent for use as a germicidal-
fungicidal wash. However, the Panel disbanded before it was able to
review the submission, which contained labeling for a currently
marketed product and in vitro studies of the product's bacteriocidal
activity. No in vivo effectiveness data were submitted for the use of
isopropyl alcohol as an antiseptic handwash or health-care personnel
handwash, patient preoperative skin preparation, or surgical hand
scrub.
Based on the lack of data for the use of isopropyl alcohol as an
antiseptic handwash or health-care personnel handwash and surgical hand
scrub, the agency is placing the ingredient in Category III for these
uses. The agency invites data on these uses of isopropyl alcohol. As
discussed in section I.E., comment 10, the agency is including the
Panel's recommended indication ``for the preparation of the skin prior
to an injection'' as an additional Category I indication for patient
preoperative skin preparations containing alcohol. Based on the Panel's
recommendations, the agency is also proposing isopropyl alcohol as a
Category I patient preoperative skin preparation for this indication.
However, based on the lack of data on the use of isopropyl alcohol for
more general patient preoperative skin preparation use, the agency is
not proposing isopropyl alcohol as Category I for the other patient
preoperative skin preparation indications included in
Sec. 333.460(b)(1), i.e., ``for the preparation of the skin prior to
surgery'' and ``helps to reduce bacteria that potentially can cause
skin infection.''
The agency has evaluated standard textbooks and published data on
the effectiveness of isopropyl alcohol used topically on the area prior
to an injection (Refs. 3, 4, and 5). The minimum effective
concentration of isopropyl alcohol for this use is 70 percent. Further,
the agency is not aware of any information concerning the use of
isopropyl alcohol below 70 percent for this indication. Therefore, the
agency is proposing to include isopropyl alcohol 70 to 91.3 percent in
Category I for use as a patient preoperative skin preparation for the
limited indication ``for the preparation of the skin prior to an
injection''.
The Miscellaneous External Panel recommended that drug products
containing alcohol and isopropyl alcohol bear the following warning:
``Flammable, keep away from fire or flame,'' (47 FR 22324 at 22330).
The agency concurs with the Panel's recommended warning and is
proposing this warning in Sec. 333.450(c)(4) of this tentative final
monograph. In order to ensure the warning's prominence, the agency is
further proposing that it appear in boldface type and as the first
warning immediately following the heading ``WARNINGS''.
The agency is aware of ten reports (Refs. 6 and 7) of first and
second degree burns occurring in patients undergoing electrocautery
procedures. The burns were caused by the ignition of the isopropyl
alcohol in patient preoperative skin preparations containing
chlorhexidine gluconate or povidone-iodine in 70 percent isopropyl
alcohol. The reports indicate that these incidents have occurred
despite the presence of detailed warnings in the products' labeling
cautioning that the products are flammable until dry and should not be
allowed to pool on body surfaces or should not be used in conjunction
with electrocautery procedures until dry (Refs. 8 and 9). Based on
these reports, the agency tentatively concludes that patient
preoperative skin preparations containing isopropyl alcohol in
concentrations of 70 percent or more cannot be adequately labeled to
allow the safe use of these drug products in conjunction with
electrocautery procedures. Therefore, the agency is proposing that
patient preoperative skin preparations containing isopropyl alcohol in
concentrations of 70 percent or more bear the following label warning:
``Do not use with electrocautery procedures.'' The agency is further
proposing that the proposed warning immediately follow the flammable
warning being proposed in Sec. 333.450(c)(4).
The agency is not currently aware of any similar incidence
occurring with other nonemollient patient preoperative skin
preparations containing alcohol in similar concentrations. Therefore,
at this time the agency is not proposing that patient preoperative skin
preparations containing alcohol identified in Sec. 333.412(a) bear a
warning concerning the use of these products in conjunction with
electrocautery procedures. However, the agency will consider extending
the warning to patient preoperative skin preparations containing
alcohol if new information indicates that this is necessary. The agency
invites specific comment and data on the safety of both alcohol and
isopropyl alcohol containing patient preoperative skin preparations in
conjunction with electrocautery procedures.

References

(1) Comment No. C00148, Docket No. 75N-0183, Dockets Management
Branch.
(2) OTC Vol. 160251.
(3) Lee, S., I. Schoen, and A. Malkin, ``Comparison of Use of
Alcohol with that of Iodine for Skin Antisepsis in Obtaining Blood
Cultures,'' American Journal of Clinical Pathology, 47:646-648,
1967.
(4) Harvey, S.C., ``Isopropanol,'' in ``The Pharmacological
Basis of Therapeutics,'' 7th ed., Macmillan Publishing Co., New
York, p. 962, 1985.
(5) Harvey, S.C., ``Isopropyl Alcohol,'' in ``Remington's
Pharmaceutical Sciences,'' 16th ed., Mack Publishing Co., Easton,
PA, pp. 1103-1104, 1980.
(6) Drug Experience Reports No. 184970, 190547, 190548, 190549,
807471, and 851772 in OTC Vol. 230001, Docket No. 75N-183H, Dockets
Management Branch.
(7) Transcripts of consumer complaints regarding DuraPrep^{TM
Surgical Solution dated January 31, 1991, April 8, 1992, and April
9, 1992 in OTC Vol. 230001, Docket No. 75N-183H, Dockets Management
Branch.
(8) Labeling for DuraPrep Surgical Solution, in OTC Vol. 230001,
Docket No. 75N-183H, Dockets Management Branch.
(9) Physicians' Desk Reference, 38th ed., Medical Economics
Company, Oradell, NJ, p. 1956, 1984.

The Panel also stated that benzyl alcohol and chlorobutanol were
safe, but recommended that the ingredients be categorized as Category
II for effectiveness. However, in the first aid antiseptic segment of
this rulemaking these alcohol ingredients were reclassified from
Category II to Category III for effectiveness as first aid antiseptic
ingredients. (See 56 FR 33644 at 33673.) Because no comments, data, or
information were received, and because the agency is not aware of any
health-care antiseptic uses for these ingredients, benzyl alcohol and
chlorobutanol are not being classified in this rulemaking for health-
care antiseptic drug products.
The agency published an advance notice of proposed rulemaking for
mercury-containing drug products on January 5, 1982 (47 FR 436). That
notice, based upon the recommendations of the Miscellaneous External
Panel, proposed to classify OTC mercury-containing drug products for
topical antimicrobial use as not generally recognized as safe and
effective and as being misbranded. The agency received no comments. The
Panel classified the mercurial ingredients, as a group, in Category II;
some for lack of safety, some for lack of efficacy, and others due to a
lack of both safety and efficacy. However, in the first aid antiseptic
segment of this amended tentative final monograph, several mercury-
containing OTC topical antimicrobials have been reclassified from
Category II to Category III for effectiveness. Mercurial ingredients
placed in Category II for safety were not reclassified. The ingredients
reclassified are calomel, merbromin, mercufenol chloride, and
phenylmercuric nitrate. This change was made in keeping with the
revised effectiveness criteria for the drug product category ``first
aid antiseptic,'' which were not available at the time the
Miscellaneous External Panel evaluated the effectiveness of mercurial
ingredients. (See 56 FR 33644 at 33672.) The agency is unaware of any
clinical data or marketing history for the use of mercury-containing
drug products as health-care antiseptics. Consequently, these drugs
have not been classified as health-care antiseptics. In addition, the
agency has reviewed submitted data on two combinations containing
mercurial ingredients and proposes a Category II classification for
these combinations. (See section I.M., comments 24 and 25.)
In the previous tentative final monograph, the agency concluded
that cloflucarban and triclocarban are not generally recognized as safe
and effective for use as a patient preoperative skin preparation,
surgical hand scrub, and health-care personnel handwash. The Panel
reviewed safety and effectiveness data on these ingredients formulated
as a bar soap and classified them in Category III as a health-care
personnel handwash when formulated as a bar soap (39 FR 33103 at 33124
and 33126). No safety and effectiveness data for the use of clofucarban
in the other health-care antiseptic drug product classes were submitted
to the OTC drug review; no data were reviewed by the Panel; and no data
were received by the agency. Cloflucarban is therefore considered to be
outside this monograph except as a health-care personnel handwash
(formulated as a bar soap). Accordingly, cloflucarban remains Category
II as a health-care antiseptic for use as a patient preoperative skin
preparation and surgical scrub and Category III as an antiseptic
handwash or health-care personnel handwash.
Additional safety data and information were submitted to the agency
on triclocarban formulated as a soap. As discussed in the segment of
this rulemaking covering first aid antiseptics (56 FR 33644 at 33664),
the agency has reviewed a chronic toxicity study and other information
and determined that triclocarban can be recognized as safe for OTC
daily topical use in a concentration of 1.5 percent. However, no
effectiveness data were submitted for any health-care antiseptic uses
of this ingredient and the agency is classifying triclocarban in
Category III as an antiseptic handwash or health-care personnel
handwash, patient preoperative skin preparation, and surgical hand
scrub. In the previous tentative final monograph, the agency placed the
combination of cloflucarban and triclocarban in Category III (43 FR
1210 at 1230) to be ``used in antimicrobial soap * * *''. No additional
data were submitted on this combination. Therefore, the combination of
cloflucarban and triclocarban remains in Category III for antiseptic
handwash or health-care personnel handwash uses.
Based upon the Panel's recommendations on phenol, in the previous
tentative final monograph, the agency classified phenol less than 1.5
percent as Category III and phenol greater than 1.5 percent as Category
II for use as a health-care personnel handwash, patient preoperative
skin preparation, and surgical hand scrub (43 FR 1227 and 1229).
Hexylresorcinol was also classified in Category III for these uses in
the previous tentative final monograph (43 FR 1229). No additional data
were submitted on health-care antiseptic uses of phenol and
hexylresorcinol and their classifications are unchanged in this amended
tentative final monograph. In the previous tentative final monograph,
the agency classified triple dye (a combination of gentian violet,
brilliant green, and proflavine hemisulfate) in Category II as a
health-care personnel handwash, patient preoperative skin preparation,
and surgical hand scrub based on a lack of safety data (43 FR 1239). No
additional data have been submitted and the ingredient remains in
Category II for health-care antiseptic uses.
In comment 85 of the previous tentative final monograph (43 FR
1223), the agency deferred classification of several ingredients to the
Miscellaneous External Panel. All of the ingredients have been
classified with the exception of methyl alcohol and gentian violet 1
and 2 percent solutions. The Miscellaneous External Panel at its 38th
meeting placed methyl alcohol in Category II as an OTC topical
antimicrobial ingredient for both safety and effectiveness (Ref. 1).
However, this classification was not included in the advance notice of
proposed rulemaking for OTC alcohol drug products. The agency agrees
with this classification. Further, the agency is not aware of any use
of methyl alcohol in OTC drug products, except as a denaturant. Gentian
violet was reviewed by the Advisory Review Panel on OTC Oral Cavity
Drug Products and placed in Category III based on the lack of
effectiveness data for use as a topical antimicrobial on the mucous
membranes of the mouth. The agency is not aware of any data on the use
of gentian violet as a health-care antiseptic and places this
ingredient in Category III for this use.

Reference

(1) Transcript of the Proceedings of the 39th Meeting of the
Advisory Review Panel on OTC Miscellaneous External Drug Products,
April 20, 1980, pp. 121-123.

Fluorosalan was not classified as an OTC topical antimicrobial
ingredient in the previous tentative final monograph because the agency
stated that final regulatory action had been taken against ``* * * the
halogenated salicylanilides, particularly * * * fluorosalan (21 CFR
310.508) * * *'' (43 FR 1210 at 1227). Although no comments were
received, the agency notes that fluorosalan was not addressed in the
final rule for halogenated salicylanilides (21 CFR 310.508), published
in the Federal Register of October 30, 1975 (40 FR 5027). In reviewing
the Antimicrobial I Panel's recommendations, the agency has determined
that the Panel did not intend to include fluorosalan in the group of
halogenated salicylanilides which it recommended be handled more
expeditiously by the agency in a separate Federal Register notice. (See
the notice of proposed rulemaking for certain halogenated
salicylanilides as active or inactive ingredients in drug and cosmetic
products (September 13, 1974, 39 FR 33102) and the advance notice of
proposed rulemaking for OTC topical antimicrobial drug products
(September 13, 1974, 39 FR 33103 at 33120).) The agency affirms the
recommendation of the Antimicrobial I Panel (39 FR 33121) that
fluorosalan be classified as Category II for use in antiseptic
handwash, health-care personnel handwash, patient preoperative skin
preparation, and surgical hand scrub drug products.
The following charts are included as a summary of the
categorization of health-care antiseptic active ingredients proposed by
the agency.

Topical Antimicrobial Ingredients\1\ Summary of Health-Care Antiseptic Active Ingredients
----------------------------------------------------------------------------------------------------------------
Antiseptic handwash or
Active ingredient Patient preoperative skin health-care personnel Surgical hand scrub
preparation handwash
----------------------------------------------------------------------------------------------------------------
Alcohol 60 to 95 percent\2\.... I I I
Benzalkonium chloride.......... IIIE IIISE\4\ IIISE
Benzethonium chloride.......... IIIE IIISE IIISE
Chlorhexidine gluconate\2\..... (^{5) (^{5) (^{5)
Chloroxylenol.................. IIIE IIISE IIISE
Cloflucarban................... II IIISE II
Fluorosalan.................... II II II
Hexachlorophene................ II II II
Hexylresorcinol................ IIIE IIIE IIIE
Iodine Active Ingredients:
Iodine complex (ammonium NA IIIE IIIE
ether sulfate and
polyoxyethylene sorbitan
monolaurate)\2\.
Iodine complex (phosphate IIIE IIIE IIIE
ester of alkylaryloxy
polyethylene glycol).
Iodine tincture U.S.P...... I NA NA
Iodine topical solution I NA NA
U.S.P.
Nonylphenoxypoly IIIE IIIE IIIE
(ethyleneoxy)
ethanoliodine.
Poloxamer-iodine complex... IIIE IIIE IIIE
Povidone-iodine 5 to 10 I I I
percent.
Undecoylium chloride iodine IIIE IIIE IIIE
complex.
Isopropyl alcohol 70-91.3 I IIIE IIIE
percent\2\.
Mercufenol chloride\2\..... IIIE NA NA
Methylbenzethonium chloride IIIE IIISE IIISE
Phenol (less than 1.5 IIIE IIISE IIISE
percent).
Phenol (greater than 1.5 II II II
percent).
Secondary amyltricresols\2\ IIISE IIIE IIIE
Sodium oxychlorosene\2\.... IIISE IIISE IIISE
Tribromsalan\3\............ II II II
Triclocarban............... IIIE IIIE IIIE
Triclosan.................. IIIE IIISE IIISE
Combinations
Calomel, oxyquinoline II NA NA
benzoate, triethanolamine,
and phenol derivative\2\.
Mercufenol chloride and IIISE NA NA
secondary amyltricresols
in 50 percent alcohol\2\.
Triple Dye................. II NA NA
----------------------------------------------------------------------------------------------------------------
\1\--All ingredients (unless otherwise noted) in Antimicrobial I Drug Products Advance Notice of Proposed
Rulemaking (39 FR 33103) and Tentative Final Monograph (47 FR 1210).
\2\--Not categorized in previous tentative final monograph, but categorized in this amended tentative final
monograph.
NA=Not Applicable because not evaluated for this use.
\3\--Categorized in Antimicrobial I Drug Products Advance Notice of Proposed Rulemaking (39 FR 33103) and in
Certain Halogenated Salicylanilides as Active or Inactive Ingredients in Drug and Cosmetic Products (40 FR
50527).
\4\--S=safety; E=effectiveness
\5\--Determined by the agency to be a ``new drug''.

Summary of Topical Antimicrobial Active Ingredients Not Addressed in
This Rulemaking
Ingredients not classified as health-care antiseptic ingredients but
generally recognized as safe and effective for OTC first aid use within
the established concentration(s) (see 56 FR 33644).

------------------------------------------------------------------------
Single ingredients

------------------------------------------------------------------------
Alcohol 48 to 59 percent
Hydrogen peroxide topical solution U.S.P.
Isopropyl alcohol 50 to 69 percent

------------------------------------------------------------------------
Combinations

------------------------------------------------------------------------
Eucalyptol 0.091 percent, menthol 0.042 percent, methyl salicylate 0.055
percent, and thymol 0.063 percent in 26.9 percent alcohol.

------------------------------------------------------------------------
Complexes

------------------------------------------------------------------------
Camphorated metacresol (3 to 10.8 percent camphor and 1 to 3.6 percent
metacresol) in a ratio of 3:1
Camphorated phenol (10.8 percent camphor and 4.7 percent phenol) in
light mineral oil, U.S.P. vehicle

------------------------------------------------------------------------
Ingredients not classified as Category I as a health-care antiseptic
because the agency is not aware of any health-care antiseptic uses for
these ingredients.

------------------------------------------------------------------------
Single ingredients

------------------------------------------------------------------------
Ammoniated mercury
Benzyl alcohol
Calomel (Mercurous chloride)
Chlorobutanol
Gentian violet
Merbromin
Mercuric chloride (Mercury chloride)
Mercuric oxide, yellow
Mercuric salicylate
Mercuric sulfide, red
Mercury
Mercury oleate
Mercury sulfide
Methyl alcohol
Nitromersol
Para-chloromercuriphenol
Phenylmercuric nitrate
Thimerosal
Vitromersol
Zyloxin

------------------------------------------------------------------------
Combinations and/or Complexes

------------------------------------------------------------------------
None
------------------------------------------------------------------------

2. Testing of Category II and Category III Conditions
Required testing procedures for evaluating the effectiveness of the
complete formulation of a health-care antiseptic drug product are
included in proposed Sec. 333.470. These effectiveness testing
procedures can also be used to demonstrate the effectiveness of active
ingredients not in a final formulation. Suggested safety testing is
described in the previous tentative final monograph. (See 43 FR 1210 at
1240 to 1242.)
Interested persons may communicate with the agency about the
submission of data and information to demonstrate the safety or
effectiveness of any health-care antiseptic ingredient or condition
included in the review by following the procedures outlined in the
agency's policy statement published in the Federal Register of
September 29, 1981 (46 FR 47740) and clarified April 1, 1983 (48 FR
14050). That policy statement includes procedures for the submission
and review of proposed protocols, agency meetings with industry or
other interested persons, and agency communications on submitted test
data and other information.

B. Summary of the Agency's Conclusions Including Changes in the Panel's
Recommendations and in the Agency's Previous Recommendations

FDA has considered the comments and other relevant information and
is amending the previous tentative final monograph with the changes
described in FDA's responses to the comments above and with other
changes described in the summary below. A summary of the changes made
by the agency in this amended tentative final monograph follows.
1. All of the section numbers for health-care antiseptics in the
previous tentative final monograph have been redesignated in this
amendment. As a convenience to the reader, the following chart is
included to show these redesignations.

Redesignated Section Numbers of the Tentative Final Monograph for
Antimicrobial Drug Products
------------------------------------------------------------------------
New
Old section No. Section name section
No.
------------------------------------------------------------------------
General Provisions:
333.1...................... Scope.......................... 333.401
333.3...................... Definitions Active Ingredients. 333.403
333.20..................... Antimicrobial Soap............. Deleted
333.30..................... Patient Preoperative Skin 333.410
Preparation.
333.50..................... Surgical Hand Scrub Labeling... 333.410
333.80..................... Antimicrobial Soap............. Deleted
333.85..................... Health-Care Personnel Handwash. 333.455
333.87..................... Patient Preoperative Skin 333.460
Preparation.
333.97..................... Surgical Hand Scrub............ 333.465
333.99..................... Professional Labeling.......... Deleted
------------------------------------------------------------------------

In addition, a number of format changes have been made that are
consistent with the format used in recently published tentative final
and final monographs.
2. The agency is proposing the term ``antiseptic'' as the general
statement of identity for the product categories of patient
preoperative skin preparation, surgical hand scrub, and health-care
personnel handwash drug products. The agency is also providing
manufacturers the option to provide alternative statements of identity
describing only the specific intended use of the product, e.g.,
surgical hand scrub. When the term ``antiseptic'' is used as the only
statement of identity on a single-use or a multiple-use product, the
intended use(s) is to be included as part of the indications. For
multiple use products the agency proposes that a statement of the
intended use(s) should also precede the specific directions for each
use. (See section I.B., comment 3.)
3. The agency is proposing that the statement of identity
``antiseptic handwash'' may also be used for a health-care personnel
handwash. The agency is proposing to expand the indications proposed
for health-care personnel handwash drug products in the previous
tentative final monograph to read, ``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.'')
The agency is also proposing ``recommended for repeated use'' as
another allowable indication for this product class. (See section I.B.,
comment 5.)
4. The agency has replaced the previously proposed definition of an
antimicrobial (active) ingredient with a definition of an
``antiseptic'' drug that is consistent with the definition of an
antiseptic in section 201(o) of the Federal Food, Drug, and Cosmetic
Act (21 U.S.C. 321(o)). The agency is also including a definition for a
health-care antiseptic as follows: ``An antiseptic containing drug
product applied topically to the skin to help prevent infection or to
help prevent cross contamination.'' The agency has also proposed
revised definitions for patient preoperative skin preparations and
surgical hand scrubs that reflect the agency's proposed effectiveness
criteria for these products. (See section I.N., comment 28.) In
addition, the agency has made minor revisions in the definitions of a
health-care personnel handwash, patient preoperative skin preparation,
and surgical hand scrub to reflect the revised terminology being used
in this amended tentative final monograph.
5. The agency is adding to this amended tentative final monograph a
definition of broad spectrum activity as follows: 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
established in Sec. 333.470(a)(1)(ii). The agency is proposing to
include ``broad spectrum'' in the definitions of the three product
classes included in this tentative final monograph. (See section I.C,
comment 6.)
6. 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 and determined
that statements such as ``contains antibacterial ingredient(s),''
``contains antimicrobial ingredient(s),'' and ``non-irritating,'' are
not related in a significant way to the safe and effective use of these
products and are not necessary on products intended primarily for
health-care professionals. Therefore, the agency is not including these
statements in this amended tentative final monograph. The statement
``recommended for repeated use,'' proposed for a health-care personnel
handwash, has been included as an ``other allowable indication'' in
proposed Sec. 333.455. The terms ``broad spectrum'' and ``fast acting''
are included in the definitions of all three product classes and the
agency does not see the need to include this information in the
required labeling. (See section I.D., comment 7.)
7. The agency is proposing revised indications for patient
preoperative skin preparations in order to more precisely describe the
intended uses of these products. The previous indications ``kills
micro-organisms,'' ``antibacterial,'' and ``antimicrobial'' are not
being included. Likewise, the indications ``kills micro-organisms,''
``bacteriostatic,'' and ``bactericidal'' previously proposed for
surgical hand scrubs are not being included in this amended tentative
final monograph. The agency believes that these terms are product
attributes and not indications for use and should not be included as
indications in the labeling of these products.
8. Based on the recommendations of the Miscellaneous External Panel
in the advance notice of proposed rulemaking for OTC alcohol drug
products (47 FR 22324 at 22332), the agency is proposing ``for
preparation of the skin prior to an injection'' as an indication for
OTC alcohol and isopropyl alcohol drug products.
9. The agency is proposing in Sec. 333.450(c) of this amended
tentative final monograph the following general warning statements for
all health-care antiseptic drug products:
(1) ``For external use only.''
(2) ``Do not use in the eyes.''
(3) ``Discontinue use if irritation and redness develops. If
condition persists for more than 72 hours consult a doctor.'' The
agency is further proposing that the second sentence of the proposed
warning in (3) above may be deleted for products labeled ``For Hospital
and Professional Use Only.'' (See section I.D., comment 8.) In addition
to the general warnings proposed for OTC health-care antiseptic drug
products, the agency is proposing the following warning for patient
preoperative skin preparations containing isopropyl alcohol identified
in Sec. 333.412(d): ``Do not use this product with electrocautery
procedures.'' The proposed warning is based on reports of burns
associated with the use of isopropyl alcohol containing patient
preoperative skin preparations with electrocautery procedures. (See
section II.A., paragraph 1--Summary of Ingredient Categories.)
10. Based on its review of the published literature (Refs. 1, 2,
and 3), the agency has determined that the way in which health-care
antiseptic drug products are used, e.g., method of application,
duration of scrub or wash, or use in conjunction with a device (such as
a scrub brush), contributes to the effectiveness of these drug
products. Therefore, instead of proposing directions for use of these
products that include fixed scrub or wash durations or methods of
application, the agency is proposing in Secs. 333.455(c), 333.460(d),
and 333.465(c) directions for use that reflect the conditions used when
the antiseptic product was tested according to Sec. 333.470(b). In
addition, based on data indicating that the largest bioburden of the
hands lies in the subungual region (Ref. 4), the agency is proposing
that the directions for use of surgical hand scrub drug products
include the following instructions for the trimming and cleansing of
the nails: ``Clean under nails with a nail pick. Nails should be
maintained with a 1 millimeter free edge.''

References

(1) Ayliffe, G.A.J., ``Surgical Scrub and Skin Disinfection,''
Infection Control, 5:23-27, 1984.
(2) Maki, D.G., ``The Use of Antiseptics for Handwashing by
Medical Personnel,'' Journal of Chemotherapy, 1:3-11, 1989.
(3) Ojajarvi, J., ``Effectiveness of Hand Washing and
Disinfection Methods in Removing Transient Bacteria After Patient
Nursing,'' Cambridge University Journal of Hygiene, 85:193-203,
1980.
(4) Leyden, J. et al., ``Subungual Bacteria of the Hand:
Contribution to the Glove Juice Test; Efficacy of Antimicrobial
Detergents,'' Infection Control Hospital Epidemiology, 10:451-454,
1989.

11. The agency is aware that some manufacturers provide technical
information relating to the antimicrobial activity of their health-care
antiseptic drug products in the form of technical information
bulletins. The agency considers such bulletins to be labeling under the
provisions of the act. Section 201(m) of the act (21 U.S.C. 321(m))
defines the term ``labeling'' as ``all labels and other written,
printed, or graphic matter (1) upon any article or any of the
containers or wrappers, or (2) accompanying such article.'' As
labeling, technical information bulletins are subject to the OTC drug
review.
The agency has no objection to the inclusion of technical
information relating to the antimicrobial activity of these OTC drug
products in the labeling of products intended for health-care
professionals only. Therefore, in this amended tentative final
monograph the agency is proposing that manufacturers have the option of
including data derived from the in vitro and clinical effectiveness
tests included in Sec. 333.470 of the proposed monograph as additional
labeling for products labeled and marketed ``For Hospital and
Professional Use Only.'' In order that such additional information
provide a standardized comparison of the effectiveness of these OTC
drug products, the agency is further proposing that only data on the
antimicrobial activity of these OTC drug products derived from the
effectiveness tests included in Sec. 333.470 of this proposed monograph
be included in the labeling of these OTC drug products. At the present
time, claims of product effectiveness against organisms other than
those included in Sec. 333.470(a)(1)(ii) will require an NDA containing
information supporting the deviation from the monograph in accord with
Sec. 330.11.
12. Based on the wound healing data from studies of test wounds in
laboratory animals that were discussed in the first aid antiseptic
segment of this amended tentative final monograph (comment 37, 56 FR
33644 at 33662), the agency has reevaluated the labeling for iodine
tincture as a patient preoperative skin preparation and is not
including the warning ``Do not apply this product with a tight bandage,
as a burn may result.''
13. The agency has determined that data and reports have not
provided specific evidence that repeated use of health-care antiseptics
has brought about overgrowth of gram-negative bacteria, particularly
Pseudomonas. Therefore, the previously proposed caution in
Sec. 333.99(a) concerning this overgrowth is not being included in this
amended tentative final monograph. (See section I.D, comment 9.) The
warnings proposed in Sec. 333.99 (b) and (c) of the previous tentative
final monograph are not being included in this amendment because these
warnings apply to quaternary ammonium compounds which currently are not
Category I for health-care antiseptic uses. (See section I.J., comment
20.)
14. The agency is not including the warning proposed by the
Miscellaneous External Panel in Sec. 333.98(c)(2) for products
containing isopropyl alcohol, ``Use only in a well-ventilated area;
fumes may be toxic.'' As discussed in section II.B., paragraph 32 of
the segment of this rulemaking covering first aid antiseptics (56 FR
33644 at 33556), the agency invites comment on the need for such a
warning, including any reports of adverse reactions due to inhalation
that have not yet been brought to the agency's attention.
15. In an effort to simplify OTC drug labeling, the agency proposed
in a number of tentative final monographs to substitute the word
``doctor'' for ``physician'' in OTC drug monographs on the basis that
the word ``doctor'' is more commonly used and better understood by
consumers. Based on comments to these proposals, the agency has
determined that final monographs and any applicable OTC drug
regulations will give manufacturers the option of using the word
``physician'' or the word ``doctor.'' This amended tentative final
monograph proposes that option in Sec. 333.450(e).
16. Based on the withdrawal of the majority of the comments on
chlorhexidine gluconate as a health-care antiseptic, sufficient data
upon which to make a safety and effectiveness determination are no
longer present in the rulemaking. (See section I.F., comment 11.)
17. The agency has reviewed the data submitted on chloroxylenol and
is classifying chloroxylenol 0.24 percent to 3.75 percent as Category I
for safety and Category III for effectiveness for short-term use
(patient preoperative skin preparation) and Category III for both
safety and effectiveness for long-term uses (antiseptic handwash or
health-care personnel handwash and surgical hand scrub). (See section
I.G., comment 12.)
18. In Sec. 333.30(a) of the previous tentative final monograph,
the agency included United States Pharmacopeia (U.S.P.) specifications
for iodine tincture and topical solution. In this amended tentative
final monograph, the agency is identifying these Category I patient
preoperative products as iodine tincture U.S.P. and iodine topical
solution U.S.P.
19. The agency has reviewed the submitted data on hexachlorophene
and concludes that the data do not address the safety concerns
expressed by the Antimicrobial I Panel on this ingredient. Therefore,
the agency is proposing that hexachlorophene remain available by
prescription only. (See section I.H., comment 13.)
20. The agency has evaluated a ``mixed iodophor'' consisting of
iodine complexed by ammonium ether sulfate and polyoxyethylene sorbitan
monolaurate and found it to be safe for use as a surgical hand scrub
and health-care personnel handwash, but there are insufficient data
available to determine its effectiveness for these uses. Therefore, it
is being classified in Category III. (See section I.I., comment 15.)
The other iodine-surfactant complexes classified by the Antimicrobial I
Panel remain in Category III for health-care uses due to a lack of
data.
21. The agency is including povidone-iodine 5 to 10 percent as a
Category I health-care antiseptic ingredient for use as a surgical hand
scrub, patient preoperative skin preparation, and antiseptic handwash
or health-care personnel handwash. (See section I.I., comment 17.) As
discussed in section I.I., comment 16, the agency is not including the
warning about the interaction of iodophors and starch-containing
compounds proposed in comment 66 of the previous tentative final
monograph (43 FR 1221). The agency is also not including professional
labeling to limit the molecular weight of povidone-iodine or special
warnings related to the molecular weight of povidone-iodine. (See
section I.I., comment 18.)
22. The agency has evaluated the data submitted on benzalkonium
chloride and determined that the data are not sufficient to establish
the efficacy of this ingredient as a patient preoperative skin
preparation. (See section I.J., comment 20.) No data were received on
other health-care uses of this ingredient or health-care uses of the
two other quaternary ammonium compounds (benzethonium chloride and
methylbenzethonium chloride) classified by the Antimicrobial I Panel.
Accordingly, quaternary ammonium compounds remain in Category III as
health-care antiseptics.
23. The agency has reviewed data submitted on sodium oxychlorosene,
an ingredient not previously classified for OTC topical antiseptic use,
and is placing this ingredient in Category III for both safety and
effectiveness. (See section I.K., comment 22.)
24. The agency has reclassified triclosan up to 1 percent from
Category II to Category III as a health-care antiseptic for use as a
patient preoperative skin preparation, antiseptic handwash or health-
care personnel handwash, and surgical hand scrub. While submitted data
indicate that triclosan--when properly formulated--may be effective,
data that meet the criteria described in section I.N., comment 28 are
needed to establish effectiveness. In addition, based upon submitted
safety data and other information, the agency has reclassified the
ingredient from Category III to Category I for safety for short-term
use as a patient preoperative skin preparation. Triclosan remains
classified in Category III for long-term use (antiseptic handwash or
health-care personnel handwash and surgical hand scrub). (See section
I.L., comment 23.)
25. The agency is proposing a number of Category I health-care
antiseptic ingredients in this document. All of the ingredients
included in this proposal as Category I health-care antiseptic
ingredients are standardized and characterized for quality and purity
and are included as articles in the current United States Pharmacopeia
or National Formulary (U.S.P./N.F.) (Ref. 1). However, a number of
other ingredients being considered in this rulemaking, e.g., triclosan
and triclocarban are not listed in the U.S.P./N.F. For an active
ingredient to be included in an OTC drug final monograph, in addition
to information demonstrating safety and effectiveness, it is necessary
to have publicly available sufficient chemical information that can be
used by all manufacturers to determine that the ingredient is
appropriate for use in their products.
The agency believes that it would be appropriate for parties
interested in upgrading nonmonograph ingredients to monograph status to
develop with the United States Pharmacopeial Convention appropriate
standards for the quality and purity of health-care antiseptic
ingredients that are not already included in official compendia.
However, should interested parties fail to provide necessary
information so that appropriate standards may be established,
ingredients otherwise eligible for monograph status will not be
included in the final monograph.

Reference

(1) ``United States Pharmacopeia XXII--National Formulary
XVII,'' United States Pharmacopeial Convention, Inc., Rockville, MD,
1989, pp. 34, 703, 731, and 1119.

26. The agency is proposing testing requirements for patient
preoperative skin preparation, antiseptic handwash or health-care
personnel handwash, and surgical hand scrub drug products in
Sec. 333.470 of this tentative final monograph. As part of the
effectiveness criteria for a patient preoperative skin preparation, the
agency is proposing new testing requirements for products labeled with
the proposed indication ``for the preparation of the skin prior to an
injection.'' (See section I.N., comment 28.)
27. The agency acknowledges that deodorancy is considered a
cosmetic claim. However, some deodorant soap products also bear
antimicrobial claims. The agency stated in comment 10 of the tentative
final monograph for OTC first aid antiseptic drug products (56 FR 33644
at 33648) that deodorant soap products making antimicrobial claims are
considered to be drugs and that the testing guidelines for
antimicrobial claims would be addressed in this rulemaking. Any
deodorant soap product containing a monograph ingredient may be labeled
with antimicrobial claims provided the product meets the testing
requirements for health-care antiseptic drug products or surgical hand
scrubs as described under proposed Sec. 333.470.
The agency stated in the previous tentative final monograph for
topical antimicrobial drug products (43 FR 1210 at 1244) that actual
claims of deodorancy should correlate the microbial reduction achieved
in a modified Cade handwashing test to an ``adequately designed and
executed deodorancy test, such as controlled sniff test.'' Several
comments to that proposal objected to such a correlation of deodorancy
and microbial reduction. However, none of the comments provided
satisfactory data to enable the agency to include any test in a
monograph as a standard for deodorancy due to antimicrobial activity.
Specific testing for antimicrobial claims for deodorancy has not yet
been developed. The agency intends to review any comments or methods
submitted for such a purpose in response to this publication and
invites comments and data on this topic.
28. The Panel's evaluation of OTC topical antimicrobial drug
products did not include an evaluation of the use of these products by
the food industry as hand sanitizers or dips. Historically, hand
sanitizers and dips have been marketed as hand cleansers for use by
food handlers in federally inspected meat and poultry processing plants
and in food handling establishments. Regulation of these products has
been under the jurisdiction of the U. S. Department of Agriculture.
However, it has come to the agency's attention that many of these
products include label claims that the agency considers drug claims,
i.e., ``antibacterial handwash,'' ``kills germs and bacteria on
contact,'' or ``effectively reduces bacterial flora of the skin''. (See
comment 10 of the tentative final monograph for OTC first aid
antiseptic drug products (56 FR 33644 at 33648).) Examination of the
labeling of these products (Ref. 1) has led the agency to conclude that
the intended use of these products, i.e., the reduction of micro-
organisms on human skin for the purpose of the prevention of disease
caused by contaminated food, makes them drugs under the provisions of
the act. Section 201(g)(1) of the act (21 U.S.C. 321(g)(1)) defines a
``drug'' as an article ``intended for use in the diagnosis, cure,
mitigation, treatment, or prevention of disease in man * * *.''
The safety and effectiveness of active ingredients in these
products for drug use needs to be demonstrated. Therefore, the agency
is including evaluation of the safety and effectiveness of topical
antimicrobial active ingredients indicated for use as hand sanitizers
or dips in the rulemaking for OTC topical antimicrobial drug products.
Accordingly, the agency invites the submission of data, published or
unpublished, and any other information pertinent to the use of topical
antimicrobial ingredients in hand sanitizers or dips. The agency also
invites comment on applicable effectiveness standards for these
products. These data and information will facilitate the agency's
review and aid in its determination as to whether these OTC drug
products for human use are safe, effective, and not misbranded under
their recommended conditions of use. This evaluation will provide all
interested parties an opportunity to present for consideration the best
data and information available to support the stated claims for these
products. The agency suggests that all submissions be in the format
described in 21 CFR 330.10(a)(2).
In order to be eligible for review under the OTC drug review
procedures, the ingredient must have been marketed in a hand sanitizer
or dip to a material extent and for a material time (21 U.S.C.
321(p)(2)). The submission of data should include information that
demonstrates that the ingredient(s) has been marketed as a hand
sanitizer or dip to a material extent and for a material time. Products
with ingredients under consideration in the OTC drug review may be
marketed (at the same dosage strength and in the same dosage form)
under the manufacturer's good faith belief that the product is
generally recognized as safe and effective and not misbranded and in
accord with FDA's enforcement policies related to the OTC drug review.
(See FDA's Compliance Policy Guides 7132b.15 and 7132b.16.) Such
products are marketed at the risk that the agency may adopt a position
requiring relabeling, recall, or other regulatory action.
The agency notes that antimicrobial hand sanitizers/dips marketed
for use in food handling/processing are typically labeled for a variety
of other antimicrobial uses that may include various animal ``drug''
uses and the disinfection of inanimate objects. These other uses of
hand sanitizer or dips will not be included in the agency's evaluation
as part of this rulemaking.

Reference

(1) Labeling for hand sanitizer products, in OTC Vol. 230001,
Docket No. 75N-183H, Dockets Management Branch.

29. The agency is proposing to remove a portion of Sec. 369.21
applicable to OTC health-care antiseptic drug products when the final
monograph eventually becomes effective because a portion of the
regulations will be superseded by the final monograph. The item
proposed for removal is the entry for ``ALCOHOL RUBBING COMPOUND'' in
Sec. 369.21.

III. Analysis of Impacts

FDA has examined the impacts of this proposed rule under Executive
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354).
Executive Order 12866 directs agencies to assess all costs and benefits
of available regulatory alternatives and, when regulation is necessary,
to select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The agency believes that
this proposed rule is consistent with the regulatory philosophy and
principles identified in the Executive Order. In addition, the proposed
rule is not a significant regulatory action as defined by the Executive
Order and, thus, is not subject to review under the Executive Order.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. This proposed rule increases the number of
ingredients tentatively classified as generally recognized as safe and
effective for use in OTC health-care antiseptic drug products from the
previous proposal and, if finalized as proposed, would reduce the need
for further safety and effectiveness testing for a number of health-
care antiseptic drug products. The detailed testing procedures included
in the proposed rule should assist manufacturers of products containing
ingredients not included in the proposed monograph, due to a lack of
demonstrated effectiveness, in performing the tests that would
demonstrate effectiveness so the ingredients can be included in the
final rule. The testing procedures will also provide manufacturers
guidance on testing requirements for regulatory compliance. Products
that contain ingredients for which safety and effectiveness are not
established will require reformulation. The proposed monograph includes
ingredients that may be used if reformulation becomes necessary. All
products will need some relabeling. One year will be provided from the
date of publication of the final rule for any necessary relabeling or
reformulation. Accordingly, the agency certifies that the proposed rule
will not have a significant economic impact on a substantial number of
small entities. Therefore, under the Regulatory Flexibility Act, no
further analysis is required.
The agency invites public comment regarding any substantial or
significant economic impact that this rulemaking would have on OTC
health-care antiseptic drug products. Types of impact may include, but
are not limited to, costs associated with product testing, relabeling,
repackaging, or reformulation. Comments regarding the impact of this
rulemaking on OTC health-care antiseptic drug products should be
accompanied by appropriate documentation. Because the agency has not
previously invited specific comment on the economic impact of the OTC
drug review on health-care antiseptic drug products, a period of 180
days from the date of publication of this proposed rulemaking in the
Federal Register will be provided for comments on this subject to be
developed and submitted. The agency will evaluate any comments and
supporting data that are received and will reassess the economic impact
of this rulemaking in the preamble to the final rule.
The agency has determined under 21 CFR 25.24(c)(6) that this action
is of a type that does not individually or cumulatively have a
significant effect on the human environment. Therefore, neither an
environmental assessment nor an environmental impact statement is
required.
Interested persons may, on or before December 14, 1994, submit to
the Dockets Management Branch, written comments, objections, or
requests for oral hearing before the Commissioner on the proposed
regulation. A request for an oral hearing must specify points to be
covered and time requested. Written comments on the agency's economic
impact determination may be submitted on or before December 14, 1994.
Three copies of all comments, objections, and requests are to be
submitted, except that individuals may submit one copy. Comments,
objections, and requests are to be identified with the docket number
found in brackets in the heading of this document and may be
accompanied by a supporting memorandum or brief. Comments, objections,
and requests may be seen in the office above between 9 a.m. and 4 p.m.,
Monday through Friday. Any scheduled oral hearing will be announced in
the Federal Register.
Interested persons, on or before June 19, 1995, may also submit in
writing new data demonstrating the safety and effectiveness of those
conditions not classified in Category I. Written comments on the new
data may be submitted on or before August 17, 1995. These dates are
consistent with the time periods specified in the agency's final rule
revising the procedural regulations for reviewing and classifying OTC
drugs, published in the Federal Register of September 29, 1981 (46 FR
47730). Three copies of all data and comments on the data are to be
submitted, except that individuals may submit one copy, and all data
and comments are to be identified with the docket number found in
brackets in the heading of this document. Data and comments should be
addressed to the Dockets Management Branch. Received data and comments
may also be seen in the office above between 9 a.m. and 4 p.m., Monday
through Friday.
In establishing a final monograph, the agency will ordinarily
consider only data submitted prior to the closing of the administrative
record on August 17, 1995. Data submitted after the closing of the
administrative record will be reviewed by the agency only after a final
monograph is published in the Federal Register, unless the Commissioner
finds good cause has been shown that warrants earlier consideration.
Therefore, the agency is proposing to amend 21 CFR part 333 by
adding new subpart E, consisting of Secs. 333.401 through 333.470, and
to amend 21 CFR part 369 by amending Sec. 369.21 in order to establish
conditions under which OTC health-care antiseptic drug products are
generally recognized as safe and effective and not misbranded.

List of Subjects

21 CFR Part 333

Labeling, Over-the-counter drugs, Incorporation by reference.

21 CFR Part 369

Labeling, Medical devices, Over-the-counter drugs.

Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR parts 333 and 369 be amended as follows:

PART 333--TOPICAL ANTIMICROBIAL DRUG PRODUCTS FOR OVER-THE-COUNTER
HUMAN USE

1. The authority citation for 21 CFR part 333 is revised to read as
follows:

Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353,
355, 360, 371).

2. New subpart E, consisting of Secs. 333.401 through 333.470, is
added to read as follows:

Subpart E--Health-Care Antiseptic Drug Products

Sec.
333.401 Scope.
333.403 Definitions.
333.410 Antiseptic handwash or health-care personnel handwash
active ingredients.
333.412 Patient preoperative skin preparation active ingredients.
333.414 Surgical hand scrub active ingredients.
333.420 Permitted combinations of active ingredients. [Reserved]
333.450 Labeling of health-care antiseptic drug products.
333.455 Labeling of antiseptic handwash or health-care personnel
handwash drug products.
333.460 Labeling of patient preoperative skin preparation drug
products.
333.465 Labeling of surgical hand scrub drug products.
333.470 Testing of health-care antiseptic drug products.

Subpart E--Health-Care Antiseptic Drug Products

Sec. 333.401 Scope.

(a) An over-the-counter health-care antiseptic drug product in a
form suitable for topical administration is generally recognized as
safe and effective and is not misbranded if it meets each of the
conditions in this subpart and each of the general conditions
established in Sec. 330.1 of this chapter.
(b) References in this subpart to regulatory sections of the Code
of Federal Regulations are to chapter I of title 21 unless otherwise
noted.

Sec. 333.403 Definitions.

As used in this subpart:
(a) Antiseptic drug. In accordance with section 201(o) of the
Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 321(o)),
``The representation of a drug, in its labeling, as an antiseptic shall
be considered to be a representation that it is a germicide, except in
the case of a drug purporting to be, or represented as, an antiseptic
for inhibitory use as a wet dressing, ointment, dusting powder, or such
other use as involves prolonged contact with the body.''
(b) 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
established in Sec. 333.470(a)(1)(ii).
(c) Health-care antiseptic. An antiseptic containing drug product
applied topically to the skin to help prevent infection or to help
prevent cross contamination.
(1) Antiseptic handwash or health-care personnel handwash drug
product. An antiseptic 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; it is broad spectrum, fast acting and, if possible, persistent.
(2) Patient preoperative skin preparation drug product. A fast
acting, broad spectrum, and persistent antiseptic containing
preparation that significantly reduces the number of micro-organisms on
intact skin.
(3) Surgical hand scrub drug product. An antiseptic containing
preparation that significantly reduces the number of micro-organisms on
intact skin; it is broad spectrum, fast acting, and persistent.

Sec. 333.410 Antiseptic handwash or health-care personnel handwash
active ingredients.

The active ingredient of the product consists of any of the
following within the specified concentration established for each
ingredient properly formulated to meet the test requirements in
Sec. 333.470, and the product is labeled according to Secs. 333.450 and
333.455:
(a) 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; or
(b) Povidone-iodine 5 to 10 percent.

Sec. 333.412 Patient preoperative skin preparation active ingredients.

The active ingredient of the product consists of any of the
following within the specified concentration established for each
ingredient properly formulated to meet the test requirements in
Sec. 333.470, and the product is labeled according to Secs. 333.450 and
333.460:
(a) 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;
(b) Iodine tincture U.S.P.;
(c) Iodine topical solution U.S.P.;
(d) Isopropyl alcohol 70 to 91.3 percent by volume in an aqueous
solution; and
(e) Povidone-iodine 5 to 10 percent.

Sec. 333.414 Surgical hand scrub active ingredients.

The active ingredient of the product consists of any of the
following within the specified concentration established for each
ingredient properly formulated to meet the test requirements in
Sec. 333.470, and the product is labeled according to Secs. 333.450 and
333.465:
(a) 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; or
(b) Povidone-iodine 5 to 10 percent.

Sec. 333.420 Permitted combinations of active ingredients.

[Reserved]

Sec. 333.450 Labeling of health-care antiseptic drug products.

(a) Statement of identity. 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.
(b) Indications. The labeling of a single use antiseptic drug
product contains the labeling identified in Secs. 333.455, 333.460, or
333.465, as appropriate. Multiple-use products contain the labeling
from any two or all three of Secs. 333.455, 333.460, and 333.465.
Indications, warnings, and directions applicable to each intended use
of the product may be combined to eliminate duplicative words or
phrases so that the resulting indications, warnings, and directions are
clear and understandable.
(c) Warnings. The labeling of the product contains the following
warnings under the heading ``Warnings'':
(1) ``For external use only.''
(2) ``Do not use in the eyes.''
(3) ``Discontinue use if irritation and redness develop. If
condition persists for more than 72 hours consult a doctor.''
(4) For products containing any ingredient identified in
Secs. 333.410(a), 333.412(a) and (d), and 333.414(a). The following
statement shall immediately follow the heading ``Warnings'':
``Flammable, keep away from fire or flame.'' [sentence in boldface
type]
(d) The second sentence of the warning in paragraph (c)(3) of this
section may be omitted from the labeling of products labeled ``For
Hospital and Professional Use Only.''
(e) The word ``physician'' may be substituted for the word
``doctor'' in any of the labeling statements in Secs. 333.455, 333.460,
and 333.465.
(f) Optional labeling information. Technical information relating
to the antimicrobial activity of products that is limited to data
derived from the in vitro and clinical effectiveness tests included in
Sec. 333.470 may be included as additional labeling for products
labeled for ``Hospital and Professional Use Only.''

Sec. 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. The labeling of the product states, under the
heading ``Indications,'' any of the phrases listed in this paragraph
that are applicable to the product. Other truthful and nonmisleading
statements, describing only the indications for use that have been
established and listed in paragraph (b) of this section, may also be
used, as provided in Sec. 330.1(c)(2) of this chapter, subject to the
provisions of section 502 of the Federal Food, Drug, and Cosmetic Act
(the act) relating to misbranding and the prohibition in section 301(d)
of the act against the introduction or delivery for introduction into
interstate commerce of unapproved new drugs in violation of section
505(a) of the act.
(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 handwash. The labeling of the product may
also contain the following phrase: ``Recommended for repeated use.''
(c) Directions. The labeling of the product contains the following
statements, under the heading ``Directions,'' that reflect the
conditions used when the product was tested according to
Sec. 333.470(b)(2):
(1) For products to be used with water. ``Wet hands and forearms.
Apply 5 milliliters (teaspoonful) or palmful to hands and forearms.
Scrub thoroughly for'' (insert wash duration used when tested according
to Sec. 333.470(b)(2)). (Insert any applicable statements about also
using a device, such as a scrub brush.) ``Rinse and repeat.''
(2) For products to be used without water. ``Place a `palmful' (5
grams) of product in one hand. Spread on both hands and rub into the
skin until dry (approximately 1 to 2 minutes). Place a smaller amount
(2.5 grams) into one hand, spread over both hands to wrist, and rub
into the skin until dry (approximately 30 seconds)'' or ``Wet hands
thoroughly with product and allow to dry without wiping.''

Sec. 333.460 Labeling of patient preoperative skin preparation 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 under Sec. 333.450(a), and/or ``patient
preoperative skin preparation.''
(b) Indications. The labeling of the product states, under the
heading ``Indications,'' any of the phrases listed in paragraph (b) of
this section. Other truthful and nonmisleading statements, describing
only the indications for use that have been established and listed in
this paragraph, may also be used, as provided in Sec. 330.1(c)(2) of
this chapter, subject to the provisions of section 502 of the Federal
Food, Drug, and Cosmetic Act (the act) relating to misbranding and the
prohibition in section 301(d) of the act against the introduction or
delivery for introduction into interstate commerce of unapproved new
drugs in violation of section 505(a) of the act.
(1) For products containing ingredients identified in Sec. 333.412
(a), (b), (c), and (e). (i) ``For preparation of the skin prior to
surgery.''
(ii) ``Helps reduce bacteria that potentially can cause skin
infection.''
(2) For products containing alcohol identified in Sec. 333.412(a).
In addition to the indications listed in Sec. 333.460(1), the labeling
may also include the statement ``For preparation of the skin prior to
an injection.''
(3) For products containing isopropyl alcohol identified in
Sec. 333.412(d). ``For preparation of the skin prior to an injection.''
(c) Warnings. For products containing 70 percent or more isopropyl
alcohol the following warning shall immediately follow the warning
statement in Sec. 333.450(c)(4): ``Do not use with electrocautery
procedures.''
(d) Directions. The labeling of the product contains the following
statements, under the heading ``Directions,'' that reflect the
conditions used when the product was tested according to
Sec. 333.470(b)(3):
(1) For products containing any ingredient identified in
Sec. 333.412(a), (d), and (e) that are intended to remain on the skin
after application. ``Clean the area. Apply product to the operative
site prior to surgery'' (insert method of application, including any
device used, when tested according to Sec. 333.470 (b)(3).) If
appropriate, insert ``Dry and repeat procedure.''
(2) For products containing any ingredient identified in
Sec. 333.412(b) or (c) that are intended to be removed from the skin
after application. ``Apply product to the operative site prior to
surgery'' (insert method of application, including any device used,
when tested according to Sec. 333.470(b)(3).) ``When product dries,
remove immediately with 70 percent alcohol, or use as directed by a
physician.''

Sec. 333.465 Labeling of surgical hand scrub 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
``surgical hand scrub.''
(b) Indication. The labeling of the product states, under the
heading ``Indication,'' the following: ``Significantly reduces the
number of micro-organisms on the hands and forearms prior to surgery or
patient care.'' Other truthful and nonmisleading statements, describing
only the indications for use that have been established and listed in
paragraph (b) of this section, may also be used, as provided in
Sec. 330.1(c)(2) of this chapter, subject to the provisions of section
502 of the Federal Food, Drug, and Cosmetic Act (the act) relating to
misbranding and the prohibition in section 301(d) of the act against
the introduction or delivery for introduction into interstate commerce
of unapproved new drugs in violation of section 505(a) of the act.
(c) Directions. The labeling of the product contains the following
statements, under the heading ``Directions,'' that reflect the
conditions used when the product was tested according to
Sec. 333.470(b)(1):
(1) For products to be used with water. ``Clean under nails with a
nail pick. Nails should be maintained with a 1 millimeter free edge.
Wet hands and forearms. Apply 5 milliliters (teaspoonful) or palmful to
hands and forearms. Scrub thoroughly for (insert scrub duration used
when tested according to Sec. 333.470(b)(1)) ``with a sterile'' (insert
applicable device), ``paying particular attention to the nails,
cuticles, and interdigital spaces. Rinse and repeat scrub'' (if
applicable, insert instructions for second scrub used when tested
according to Sec. 333.470(b)(1), if different from the first).
(2) For products to be used without water. ``Clean under nails with
a nail pick. Nails should be maintained with a 1 millimeter free edge.
Place a `palmful' (5 grams) of product in one hand. Spread on both
hands, paying particular attention to the nails, cuticles, and
interdigital spaces, and rub into the skin until dry (approximately 1
to 2 minutes). Place a smaller amount (2.5 grams) into one hand, spread
over both hands to wrist, and rub into the skin until dry
(approximately 30 seconds).''

Sec. 333.470 Testing of health-care antiseptic drug products.

(a) General testing criteria. The procedures in this section are
designed to characterize the effectiveness of antiseptic drug products
formulated for use as an antiseptic handwash or health-care personnel
handwash, patient preoperative skin preparation, and surgical hand
scrub. Requests for any modifications of the testing procedures in this
section or alternative assay methods are to be submitted in accordance
with paragraph (d) of this section.
(1) In vitro testing. The following tests must be performed using
the antiseptic ingredient, the vehicle, and the finished product for
all drug product classes:
(i) Determine the in vitro antimicrobial spectrum of the active
ingredient, the vehicle, and the final formulation using both standard
cultures and recently isolated strains of each species. A series of
recently isolated mesophilic strains, including members of the normal
flora and cutaneous pathogens (50 isolates of each species, half of
which must be fresh clinical isolates), are to be selected.
(ii) Determine the minimal inhibitory concentrations (MIC) using
methodology established by the National Committee for Clinical
Laboratory Standards and entitled ``Methods for Dilution Antimicrobial
Susceptibility Test for Bacteria that Grow Aerobically,'' Document M7-
A2, 2d ed., 10:8, 1990, which is incorporated by reference in
accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies are available
from the National Committee for Clinical Laboratory Standards, 771 East
Lancaster Ave., Villanova, PA 19085, or may be examined at the Center
for Drug Evaluation and Research, 7520 Standish Pl., suite 201,
Rockville, MD, or the Office of the Federal Register, 800 North Capitol
St. NW., suite 700, Washington, DC. Twenty-five fresh clinical isolates
and 25 laboratory strains of the organisms listed in this section are
to be included. All in vitro tests must include the American Type
Culture Collection (ATCC) reference strains (available from American
Type Culture Collection, 12301 Parklawn Dr., Rockville, MD 20852)
specified in paragraphs (a)(1)(ii)(A) and (a)(1)(ii)(B) of this
section. The agency requires that these organisms be used in testing
unless data can be presented to the agency that other organisms are
equally representative of organisms associated with nosocomial
infection. There must be no claims, either direct or by implication,
that a product has any activity against an organism or that it reduces
the number of organisms for which it has not been tested. The following
organisms are to be included (note: special media and environmental
conditions may be required):
(A) Gram negative organisms: Acinetobacter species; Bacteroides
fragilis; Haemophilus influenza; Enterobacter species; Escherichia coli
(ATCC Nos. 11229 and 25922); Klebsiella species, including Klebsiella
pneumonia; Pseudomonas aeruginosa (ATCC Nos. 15442 and 27853); Proteus
mirabilis; and Serratia marcescens (ATCC No. 14756).
(B) Gram positive organisms: Staphylococci: Staphylococcus aureus
(ATCC Nos. 6538 and 29213); Coagulase-negative Staphylococci:
Staphylococcus epidermidis (ATCC No. 12228), Staphylococcus hominis,
Staphylococcus haemolyticus, and Staphylococcus saprophyticus;
Micrococcus luteus (ATCC No. 7468); and Streptococci: Streptococcus
pyogenes, Enterococcus faecalis (ATCC No. 29212), Enterococcus faecium,
and Streptococcus pneumoniae.
(C) Yeast: Candida species and Candida albicans.
(iii) Determine the possible development of resistance to the
chemical. Two approaches to determining the emergence of resistance to
a particular antimicrobial are to be used. The first approach involves
a determination of the evolution of a point mutation by the sequential
passage of an organism through increasing concentrations of the
antimicrobial included in the culture medium. The second approach is a
thorough survey of the published literature to determine whether
resistance has been reported for the antimicrobial ingredient. The
survey is to include information on the microbial contamination of
marketed products containing the antimicrobial ingredient in question
irrespective of drug concentration. The survey is to cover all
countries in which products containing the active ingredient are
marketed. Any information submitted in a foreign language should
include a translation. Alternate approaches to determining the
development of resistance can be submitted as a petition in accord with
Sec. 10.30 of this chapter. The petition is to contain sufficient data
to show that the alternate approach provides a reliable indication of
the development of resistance to a particular antimicrobial ingredient.
(iv) Time-kill studies. (A) The assessment of the in vitro spectrum
of the antimicrobial provides information on the types of genera and
species that may be considered susceptible under the conditions of the
test procedure described in paragraph (a)(1)(ii) of this section.
However, information is also required that allows an assessment of how
rapidly the antimicrobial product produces its effect. Such information
may be derived from in vitro time-kill curve studies using a selected
battery of organisms and a specified drug concentration.
(B) The satisfactory performance of the test product as assessed by
the results of the MIC studies, the time-kill studies, and the
simulated in vivo clinical trials of organisms representing the
resident microbial flora can then be used to assess the effectiveness
of the test product for the transient microbial flora most commonly
encountered in the clinical setting. This procedure is required because
methods, other than the health-care personnel hand test, do not exist
for assessing the in vivo effectiveness of test products versus the
transient microbial flora.
(C) It is recognized that a generally accepted or standardized
method that may be used in conducting in vitro time-kill studies is not
available, but the agency encourages the submission of proposed methods
that may be considered applicable to this test. Many variables that
should be considered in the development of a method have been addressed
for antibiotics and are also applicable to these products. Such
variables are described by Schoenknecht, F. D., L. D. Sabath, and C.
Thornsberry, ``Susceptibility Tests: Special Tests,'' in the ``Manual
of Clinical Microbiology,'' 4th ed., edited by E. H. Lennette et al.,
American Society for Microbiology, Washington, pp. 1,000-1,008, which
is incorporated by reference in accordance with 5 U.S.C. 552(a) and 1
CFR part 51. Copies are available from the American Society for
Microbiology, Washington, DC, or may be examined at the Center for Drug
Evaluation and Research, 7520 Standish Pl., suite 201, Rockville, MD,
or at the Office of the Federal Register, 800 North Capitol St. NW.,
suite 700, Washington, DC.
(D) The procedure to be used is to incorporate the recommendations
described on page 1,004 of the chapter in the ``Manual of Clinical
Microbiology'' cited in paragraph (a)(1)(iv)(C) of this section with
the following modifications. Because the time frames of greatest
interest for antiseptic drug products intended for health-care
personnel handwash, surgical hand scrub, and patient preoperative skin
preparation use are 1 to 30 minutes, the time-kill studies are to focus
on these time frames and are to include enumerations at times 0, 3, 6,
9, 12, 15, 20, and 30 minutes. Enumerate the bacteria in the sampling
solution by a standard plate count procedure such as that described in
``Standard Methods for the Evaluation of Dairy Products'' (available
from American Public Health Association, Inc., 1015 15th St. NW.,
Washington, DC 20005), but using soybean-casein digest agar and a
suitable inactivator for the antimicrobial where necessary. The
suitability of the inactivator is to be demonstrated using a procedure
such as described in E 1054, ``Test Methods for Evaluating Inactivators
of Antimicrobial Agents Used in Disinfectant, Sanitizer, and Antiseptic
Products,'' in ``Annual Book of ASTM Standards,'' vol. 11.04, which is
incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR
part 51. Copies are available from The American Society for Testing and
Materials, 1916 Race St., Philadelphia, PA 19103-1187, or may be
examined at the Center for Drug Evaluation and Research (HFD-810), 5600
Fishers Lane, Rockville, MD, or at the Office of the Federal Register,
800 North Capitol St. NW., suite 700, Washington, DC. The battery of
organisms selected is to represent the resident microbial flora most
commonly encountered under actual use conditions of the test product
and the transient microbial flora most likely to be encountered by
health-care professionals in clinical settings. Therefore, the micro-
organisms to be used in these time-kill studies are to be the standard
ATCC strains identified in paragraph (a)(1)(ii) of this section. The
drug concentration to be tested should be a tenfold dilution of the
finished product.
(2) In vivo testing. The following tests, approximating use
conditions for the clinical evaluation of each label claim of the
finished product, are to be carried out using the finished product for
the product classes specified.
(i) Test method for the evaluation of surgical hand scrub drug
products. The procedure to be used (paragraph (b)(1)(iii) of this
section) is a modification of the standard testing procedure for the
evaluation of surgical hand scrub drug products published by the
American Society for Testing and Materials, ``Standard Method for
Evaluation of Surgical Hand Scrub Formulation, Designation E 1115,'' in
``The Annual Book of ASTM Standards,'' vol. 11.04, American Society for
Testing and Materials, Philadelphia, pp. 201-204, 1986, which is
incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR
part 51. Copies are available from The American Society for Testing and
Materials, 1916 Race St., Philadelphia, PA 19103-1187, or may be
examined at the Center for Drug Evaluation and Research, 7520 Standish
Pl., suite 201, Rockville, MD, or at the Office of the Federal
Register, 800 North Capitol St. NW., suite 700, Washington, DC.
(ii) Test method for the evaluation of health-care antiseptic
handwash or health-care personnel handwash drug products. The procedure
to be used (paragraph (b)(2)(iii) of this section) is a modification of
the standard testing procedure for the evaluation of health-care
antiseptic handwash drug products published by the American Society for
Testing and Materials, ``Standard Method for the Evaluation of Health
Care Handwash Formulation, Designation E1174,'' in ``The Annual Book of
ASTM Standards,'' vol. 11.04, American Society for Testing and
Materials, Philadelphia, pp. 209-212, 1987, which is incorporated by
reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies
are available from The American Society for Testing and Materials, 1916
Race St., Philadelphia, PA 19103-1187, or may be examined at the Center
for Drug Evaluation and Research, 7520 Standish Pl., suite 201,
Rockville, MD, or at the Office of the Federal Register, 800 North
Capitol St. NW., suite 700, Washington, DC.
(iii) Test method for the evaluation of patient preoperative skin
preparation drug products. The procedure to be used (paragraph
(b)(3)(iii) of this section) is a modification of the standard testing
procedure for the evaluation of patient preoperative skin preparations
published by the American Society for Testing and Materials, ``Standard
Test Method for the Evaluation of a Patient Preoperative Skin
Preparation, Designation 1173,'' in ``The Annual Book of ASTM
Standards,'' vol. 11.04, American Society for Testing and Materials,
Philadelphia, pp. 205-208, 1987, which is incorporated by reference in
accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies are available
from The American Society for Testing and Materials, 1916 Race St.,
Philadelphia, PA 19103-1187, or may be examined at the Center for Drug
Evaluation and Research, 7520 Standish Pl., suite 201, Rockville, MD,
or at the Office of the Federal Register, 800 North Capitol St. NW.,
suite 700, Washington, DC.
(b) Specific testing criteria--(1) Effectiveness testing of a
surgical hand scrub. A surgical hand scrub drug product in finished
form suitable for topical application will be recognized as effective
provided that the formulated drug product at its recommended use
concentration:
(i) Contains an ingredient in Sec. 333.414 (a) or (b).
(ii) Demonstrates in vitro activity against organisms as described
in paragraph (a)(1)(ii) of this section.
(iii) When tested, in vivo, by the test procedure for the
evaluation of surgical hand scrub drug products in paragraph
(b)(1)(iii) of this section, reduces the number of bacteria 1-
log10 on each hand within 1 minute and the bacterial cell count on
each hand does not subsequently exceed baseline within 6 hours on the
first day, and produces a 2-log10 reduction of the microbial flora
on each hand within 1 minute of product use by the end of the second
day of enumeration, and a 3-log10 reduction of the microbial flora
on each hand within 1 minute of product use by the end of the fifth day
when compared to the established baseline.
(A) Apparatus--(1) Colony Counter. Any of several types may be
used.
(2) Incubator. Any incubator capable of maintaining a temperature
of 302 deg.C may be used.
(3) Sterilizer. Any suitable steam sterilizer capable of producing
conditions of sterility is acceptable.
(4) Timer (stop clock). A timer that can be read in minutes and
seconds.
(5) Hand washing sink. A sink of sufficient size to permit
panelists to wash without touching hands to sink surface or other
panelists.
(6) Water faucet(s). Water faucets should be located above the sink
at a height that permits the hands to be held higher than the elbows
during the washing procedure. (It is desirable for the height of the
faucets to be adjustable.)
(7) Tap water temperature regulator and temperature monitor.
Device(s) to monitor and regulate water temperature to 402
deg.C.
(B) Materials and reagents--(1) Petri dishes. Petri dishes for
performing standard plate count should be 100 by 15 millimeters.
(2) Bacteriological pipets. Pipets of 10.0 and 2.2 or 1.1
milliliter capacity are recommended.
(3) Water-dilution bottles. Any sterilizable glass container having
a 150 to 200 milliliter capacity and tight closures may be used.
(4) Baseline control soap. A liquid castile soap or other liquid
soap containing no antimicrobial.
(5) Gloves. Sterile loose fitting gloves of latex, unlined, not
possessing antimicrobial properties.
(6) Test formulation. Directions used to demonstrate the
effectiveness of the test formulation are to be the same as those
proposed for the use of the product including the use of a nail cleaner
and/or brush, if indicated. If no directions are available, use
directions provided in paragraph (b)(1)(iii)(J)(3) of this section.
(7) Positive control formulation. Any surgical hand scrub
formulation approved by the Food and Drug Administration is acceptable.
(8) Sampling solution. (i) Dissolve 0.4 gram potassium phosphate,
monobasic, 10.1 gram sodium phosphate, dibasic, and 1 gram Triton X-100
in 1 liter distilled water. Adjust to pH 7.8 with 0.1 Normal
hydrochloric acid or 0.1 Normal sodium hydroxide. Dispense 50 to 100
milliliter volumes into water dilution bottles, or other suitable
containers, and sterilize for 20 minutes at 121 deg.C. Include in the
sampling solution used to collect bacterial samples from the hand
following the final wash with the test formulation an antimicrobial
inactivator specific for the test formulation being evaluated.
(ii) A definitive recommendation regarding the inclusion of an
inactivator prior to the final wash cannot be made. The questions of
whether residual neutralizer on the skin will reduce the effectiveness
of the test formulation in subsequent washes and result in higher than
expected bacterial counts and whether or not samples can be processed
rapidly enough to avoid a decreased bacterial count due to the
continued action of the test formulation should be considered when the
decision concerning the use of a neutralizer in sampling solutions used
for bacterial collection prior to the final wash is made. Whatever the
decision, to facilitate the comparison of results across studies, the
investigator is to indicate whether or not a neutralizer has been
included.
(9) Dilution fluid. Butterfield's phosphate buffered water
adjusted to pH 7.2 and containing an antimicrobial inactivator specific
for the test formulation. Adjust pH with 0.1 Normal hydrochloric acid
or 0.1 Normal sodium hydroxide.
(10) Soybean-casein digest agar. Supplemental polysorbate 80 (0.5
to 10 grams/liter) is to be added to the agar to stimulate the growth
of lipophilic organisms. A suitable antimicrobial inactivator is also
to be added.
(11) Fingernail cleaning sticks.
(12) Sterile hand brushes (required only if specified for use with
test formulation). Products that specify the use of a device in
conjunction with the antimicrobial are to include this information in
the product labeling. The device is an integral part of the study. If
gauze is to be used, then the product labeling is to reflect this
condition of use.
(C) Test panelists. Panelists shall consist of healthy adult male
and female volunteers who have no evidence of dermatosis, have not
received antibiotics or taken oral contraceptives 2 weeks prior to the
test, and who agree to abstain from these materials as described in
paragraph (b)(1)(iii)(D)(2) of this section until the conclusion of the
test.
(D) Preparation of volunteers. (1) At least 2 weeks prior to start
of the test, enroll sufficient subjects per product being tested to
satisfy the statistical criteria of the clinical trial design.
(2) Instruct the volunteers to avoid contact with antimicrobials
(other than the test formulation) for the duration of the test. This
restriction includes antimicrobial containing antiperspirants,
deodorants, shampoos, lotions, soaps, and materials such as acids,
bases, and solvents. Bathing in chlorinated pools and hot tubs is to be
avoided. Volunteers are to be provided with a kit of nonantimicrobial
personal care products for exclusive use during the test and rubber
gloves to be worn when contact with antimicrobials cannot be avoided.
(E) Selection of evaluable subjects. After panelists have refrained
from using antimicrobials for at least 2 weeks, perform wash with
baseline control soap. Subjects are not to have washed their hands 2
hours prior to the baseline count determination. After washing,
determine the first estimate of the baseline population by sampling
both hands and enumerating the bacteria in the sampling solution. This
is day 1 of the ``baseline period.'' Repeat this baseline determination
on days 3 and 7, days 3 and 5, or days 5 and 7 of the ``baseline
period'' to obtain three estimates of the baseline population. Any
subjects exhibiting counts greater than or equal to 1.5X10\5\ after the
first and second estimates of the baseline populations are obtained can
be assigned to products in accordance with the randomization plan
described below. Sufficient evaluable subjects must be enrolled per arm
to satisfy the statistical conditions of adequacy with at least 80
percent power and a test level of 5 percent.
(F) Number of subjects. The number of subjects required per arm of
the study can be estimated from the following equation:
n2S^{2(Za/2+Zb)^{2/D^{2, where:
S\2\ is your estimate of variance;
Za/2 corresponds to the level of the test; for a 5 percent
test level = 1.96;
Zb corresponds to the power of the test; for 80 percent power
= .842; and
D is the clinical difference of significance to be ruled out; say
20 percent of the active control's mean reduction from baseline at a
specific time. For example, data from a number of glove juice studies
submitted over the past few years to the agency as part of applications
under part 314 of this chapter were reviewed to obtain information
relative to the variance of the difference from baseline for count
reduction data. For 128 standard deviations extracted, it was noted
that 50 percent of the values are between .90 and 1.12; 25 percent are
less than .90; and 25 percent are greater than 1.12. The range is from
.49 to 1.73, the 25th percentile standard deviation is 0.86, the median
standard deviation is 1.01, and the 75th percentile standard deviation
is 1.20. The larger the standard deviation, the larger the sample size
required to rule out a difference of clinical importance. Assuming that
the active control surgical hand scrub produces a mean log reduction of
2.5 at hour 3 and the test hand scrub is to be within 20 percent of
this, i.e., D=0.5, and if S^{2= 1.02, then n=64 subjects per arm of
the study. Because blocks of six are recommended, the sample size per
arm is 66. The S2=1.44 corresponds to the 75th percentile in the
data set. This gives a sample size of 90 subjects per arm. The total
number of evaluable subjects required for a successful trial will
depend upon the estimate of variance available and the number of
products that need testing.
(G) Study design. A randomized, blinded, parallel arm design is to
be used to test the products. Due to the nature of their constituents,
some test surgical hand scrubs will require not only the use of an
active control arm but also use of a vehicle control arm and perhaps a
placebo control arm to demonstrate efficacy. The schematic layout of
sampling times is given in Table 1 as follows:

Table 1.--Sampling Times for Surgical Hand Scrub Effectiveness Test
------------------------------------------------------------------------
Hours
-----------------------------------------------
Days Baseline
period \1/60\ 3 6
------------------------------------------------------------------------
Day 0................... X
Day 1................... X X X
Day 3 or 5.............. X X X
Day 5 or 7.............. X X X
------------------------------------------------------------------------

The schematic layout of randomization of subjects in blocks of 6 is
given in Table 2; in Table 2, R refers to right hand and L refers to
left hand as follows:

Table 2.--Randomization of Subjects for Surgical Hand Scrub
Effectiveness Test
------------------------------------------------------------------------
Hours
Subjects -----------------------------------
\1/60\ 3 6
------------------------------------------------------------------------
A................................... R L
B................................... L .......... R
C................................... .......... L R
D................................... L R
E................................... R .......... L
F................................... .......... R L
-----------------------------------
Total Observations............ 4 4 4
------------------------------------------------------------------------

Assume N evaluable subjects are enrolled (the issue of determining
N, the sample size, is discussed in paragraph (b)(1)(iii)(F) of this
section). First, randomly divide the N subjects into as many treatment
groups as there are products to be tested (nt). Secondly,
randomize the nt subjects within each treatment group in blocks of
six subjects in accordance with the subject allocation scheme in Table
2 of paragraph (b)(iii)(G) of this section until all nt patients
are randomized to 6 hours. Repeat this process for each of the other
treatment groups.
(H) Count determinations. No sooner than 12 hours, nor longer than
4 days after completion of their baseline determination, subjects
perform the initial scrub with the test formulations. Determine the
bacterial population on the randomly designated hand of all subjects
assigned to hour \1/60\ in Table 2 of paragraph (b)(iii)(G) of this
section immediately (within 1 minute) after scrub with the appropriate
scrub formulation. Determine the bacterial counts on the designated
hands at 3 and 6 hours after scrub. Determine bacterial population by
sampling hands and enumerating the bacteria in the sampling solution as
specified in paragraphs (b)(1)(iii)(K) and (b)(1)(iii)(L) of this
section. Repeat this scrubbing and sampling procedure the next day (day
2). On day 5, repeat the sampling procedure after scrubbing with the
formulations two additional times on day 2 and three times per day on
day 3 and day 4, with at least a 1-hour interval between scrubs.
Perform one scrub on day 5, prior to sampling. In summary, the subjects
scrub a total of 11 times with each formulation, once on days 1 and 5
and 3 times per day on days 2, 3, and 4. Collect bacterial samples
following the single scrubs of days 1 and 5 and following the first
scrub on day 2. This procedure mimics typical usage and permits
determination of both immediate and longer-term reductions.
(I) Washing technique for baseline determinations. (1) Volunteers
clean under fingernails with nail stick and clip fingernails to less
than or equal to 2 millimeter free edge. Remove all jewelry from hands
and arms.
(2) Rinse hands including two thirds of forearm under running tap
water 38 to 42 deg.C for 30 seconds. Maintain hands higher than elbows
during this procedure and steps outlined in paragraphs
(b)(1)(iii)(I)(3), (b)(1)(iii)(I)(4), and (b)(1)(iii)(I)(5) of this
section.
(3) Wash hands and forearms with baseline control soap for 30
seconds using water as required to develop lather.
(4) Rinse hands and forearms for 30 seconds under tap water to
thoroughly remove all lather.
(5) Don rubber gloves used in sampling hands and secure gloves at
wrist.
(J) Surgical scrub technique to be used prior to bacterial
sampling. (1) Repeat procedure outlined in paragraphs (b)(1)(iii)(I)(1)
and (b)(1)(iii)(I)(2) of this section.
(2) Perform surgical scrub with test formulation in accordance with
directions furnished with the test formulation. If no instructions are
provided with the test formulation, use the 10-minute scrub procedure
described in paragraph (b)(1)(iii)(J)(3) of this section.
(3) Perform 10-minute scrub procedure as follows:
(i) Dispense formulation into hands.
(ii) Set and start timer for 5 minutes (time required for the steps
described in paragraphs (b)(1)(iii)(J)(3)(iii) through
(b)(1)(iii)(J)(3)(vii) of this section.
(iii) With hands, distribute formulation over hands and lower two-
thirds of forearms.
(iv) If scrub brush is to be used, pick up with finger tips and
pass under tap to wet without rinsing formulation from hands.
(v) Alternatively, scrub right hand and lower two-thirds of forearm
and left hand and lower two-thirds of forearm.
(vi) Rinse both hands, the lower two-thirds of forearms, and the
brush for 30 seconds.
(vii) Place brush in sterile dish within easy reach.
(viii) Repeat the timed 5 minute scrub in paragraphs
(b)(1)(iii)(J)(3)(iii) through (b)(1)(iii)(J)(3)(vii) of this section
so that each hand and forearm is washed twice. The second wash and
rinse should be limited to the lower one-third of the forearms and the
hands.
(ix) Perform final rinse. Rinse each hand and forearm separately
for 1 minute per hand.
(x) Don rubber gloves used in sampling hands and secure at wrist.
(K) Sampling techniques. (1) At specified sampling times,
aseptically add 50 to 100 milliliters of sampling solution to glove and
hand to be sampled, and fasten glove securely above wrist.
(2) After adding sampling solution, uniformly massage all surfaces
of hand for 1 minute, paying particular attention to the area under the
nails.
(3) After massaging, aseptically sample the fluid of the glove.
Transfer immediately a measured volume of the sample to a serial
dilution tube containing a suitable antimicrobial inactivator.
(L) Enumeration of bacteria in sampling solution. Enumerate the
bacteria in the sampling solution by a standard plate count procedure
such as that described in ``Standard Methods for the Evaluation of
Dairy Products'' (available from American Public Health Association,
Inc., 1015 15th St. NW., Washington, DC 20005) but using soybean-casein
digest agar and a suitable inactivator for the antimicrobial where
necessary. The suitability of the inactivator is to be demonstrated
using a procedure such as described in E 1054, ``Test Methods for
Evaluating Inactivators of Antimicrobial Agents Used in Disinfectant,
Sanitizer, and Antiseptic Products,'' in ``Annual Book of ASTM
Standards,'' vol. 11.04, which is incorporated by reference in
accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies are available
from The American Society for Testing and Materials, 1916 Race St.,
Philadelphia, PA 19103-1187, or may be examined at the Center for Drug
Evaluation and Research, 7520 Standish Pl., suite 201, Rockville, MD,
or at the Office of the Federal Register, 800 North Capitol St. NW.,
suite 700, Washington, DC. Prepare sample dilutions in dilution fluid.
Plate in duplicate. Incubate plated sample at 30 2 deg.C
for 48 hours before reading.
(M) Determination of reduction obtained. (1) At each sampling
interval, determine changes from baseline counts obtained with test
material.
(2) For a more realistic appraisal of the activity of products, all
raw data should be converted to common (base 10) logarithms. Reductions
should be calculated from average of the logarithms. This will also
facilitate statistical analysis of data.
(N) Comparison of test materials with a positive control material.
(1) In order to validate the testing procedure, equipment, and
facilities, it is required that the test formulation be compared with
an active control formulation. This will require an equivalent number
of panelists to be assigned to the control formulation on a random
basis. All test parameters will be equivalent for both formulations,
except that the scrub procedure for the established formulation may be
different from that of the test formulation. Both test and control
formulations are to be run concurrently. Identity of the formulations
used by panelists are to be blinded from those individuals counting
plates and analyzing data.
(2) To validate the assay, compare changes from baseline counts
obtained with control material at each sampling interval.
(O) Statistical analyses. Either of the statistical approaches to
the evaluation of the data detailed in paragraph (b)(1)(iii)(O) of this
section is acceptable.
(1) Treat data as a binomial response. That is, if a subject
achieves the target reduction, it is judged a success; if not, it is a
failure. A potential problem to this approach is that information may
be lost. For example, if at the 1 minute time frame, a large number of
subjects using one skin scrub achieve a 2-log reduction and those on
the other scrub attain only a 1-log reduction, the binomial procedure
will indicate both scrubs achieve the same degree of reduction. If it
is believed that the binomial approach causes loss of information by
not including numerical response data, then the alternate statistical
analysis described in paragraph (b)(1)(iii)(0)(2) of this section is
applicable. If the success rate is in the 90 percent range, then the
variance is relatively small, sample size requirements are relatively
small, and confidence intervals are reasonable. However, if the success
rates drop to the 70 percent range, then relatively large sample sizes
are required to obtain the same power as one gets for 90 percent
success rates.
(2) Another option is to treat the log counts as numerical data and
evaluate using the Student's t-test or similar procedure. The large
variance that usually occurs with this type of data may cause problems
with tests of significance and construction of confidence intervals.
However, Monte Carlo techniques indicate that if entry is limited to
subjects that exhibit 1.5x10^{5 to 10^{6 counts, then the
reductions are rather homogeneous and the large variance problem is
alleviated. If the variances are large, the sample size must be
increased considerably to retain the same level of the test, same
power, and same difference to be ruled out.
(2) Effectiveness testing of an antiseptic handwash or health-care
personnel handwash. An antiseptic handwash or health-care personnel
handwash drug product in finished form suitable for topical application
will be recognized as effective provided that the formulated drug
product at its recommended use concentration:
(i) Contains an ingredient in Sec. 333.410 (a) or (b).
(ii) Demonstrates in vitro activity against organisms as described
in paragraph (a)(1)(ii) of this section.
(iii) When tested, in vivo, by the test method for the evaluation
of antiseptic or health-care personnel handwash drug products described
in paragraph (b)(2)(iii) of this section, reduces the number of the
indicator organism on each hand 2 log10 within 5 minutes after the
first wash and demonstrates a 3-log10 reduction of the indicator
organism on each hand within 5 minutes after the tenth wash.
(A) Apparatus.--(1) Colony Counter. Any of several types may be
used.
(2) Incubator. Any incubator capable of maintaining a temperature
of 252 deg.C may be used. This temperature is required to
assure pigment production by the Serratia marcescens.
(3) Sterilizer. Any suitable steam sterilizer capable of producing
conditions of sterility is acceptable.
(4) Timer (stop clock). A timer that can be read in minutes and
seconds.
(5) Hand washing sink. A sink of sufficient size to permit
panelists to wash without touching hands to sink surface or other
panelists.
(6) Water faucet(s). Water faucet(s) should be located above the
sink at a height that permits the hands to be held higher than the
elbows during the washing procedure. (It is desirable for the height of
the faucet(s) to be adjustable.)
(7) Tap water temperature regulator and temperature monitor.
Device(s) to monitor and regulate water temperature to 402
deg.C.
(B) Materials and reagents.--(1) Bacteriological pipets. Pipets of
10.0 and 2.2 or 1.1 milliliter capacity are recommended.
(2) Water-dilution bottles. Any sterilizable glass container having
a 150 to 200 milliliter capacity and tight closures may be used.
(3) Erlenmeyer flask. A 2-liter capacity for culturing test
organism is recommended.
(4) Baseline control soap. A liquid castile soap or other liquid
soap containing no antimicrobial.
(5) Test formulation. Directions used to demonstrate the
effectiveness of the test formulation are to be the same as those
proposed for the use of the product. If no directions are available,
use directions provided in paragraph (b)(2)(iii)(H)(5) of this section.
(6) Positive control formulation. Any health-care personnel
handwash formulation approved by the Food and Drug Administration is
acceptable.
(7) Gloves/bags. Sterile loose fitting gloves of latex, unlined,
possessing non-antimicrobial properties or sterile polyethylene bags
are to be used.
(8) Sampling solution. Dissolve 0.4 gram potassium phosphate,
monobasic, 10.1 gram sodium phosphate, dibasic, and 1 gram Triton X-100
in 1 liter distilled water. Adjust to ph 7.8 with 0.1 Normal
hydrochloric acid or 0.1 Normal sodium hydroxide. Dispense 50 to 100
milliliter volumes into water dilution bottles, or other suitable
containers, and sterilize for 20 minutes at 121 deg.C.
(9) Dilution fluid. Butterfield's phosphate buffered water adjusted
to pH 7.2 and containing an antimicrobial inactivator specific for the
test formulation. Adjust pH with 0.1 Normal hydrochloric acid or 0.1
Normal sodium hydroxide.
(10) Plating medium. Soybean-casein digest agar plus a suitable
inactivator.
(11) Broth. Soybean-casein digest: 1,000 milliliters per 2-liter
flask is recommended.
(C) Test Organism. (1) Serratia marcescens ATCC No. 14756
(available from American Type Culture Collection, 12301 Parklawn Dr.,
Rockville, MD 20852) is to be used as a marker organism. This is a
strain having stable pigmentation.
(2) The application of micro-organisms to the skin may involve a
health risk. Prior to applying the Serratia marcescens strain to the
skin, the antimicrobial sensitivity profile of the strain should be
determined. If the strain is not sensitive to Gentamicin, do not use
it. If an infection occurs, the antibiotic sensitivity profile should
be made available to the attending clinician.
(3) Following the last contamination and wash with the test
formulation, the panelists' hands are to be sanitized by scrubbing with
a 70 percent ethanol solution. The purpose of this alcohol scrub is to
destroy any residual Serratia marcescens.
(4) Preparation of marker culture suspension. From stock culture
inoculate Serratia marcescens ATCC No. 14756 in a 2-liter flask
containing 1,000 milliliters of Soybean-casein digest broth. Incubate
for 24 4 hours at 25 deg.C. Stir or shake the suspension
before each aliquot withdrawal. Assay the suspension for number of
organisms by membrane filtration technique or surface inoculation at
the beginning and end of the use period. Do not use a suspension for
more than 8 hours.
(D) Test panelists. Recruit a sufficient number of healthy adult
male and female human volunteers who have no clinical evidence of
dermatosis, open wounds, hangnail, or other skin disorders that may
affect the integrity of the test, and enroll sufficient subjects per
product being tested to satisfy the statistical criteria of the
clinical trial design.
(E) Preparation of volunteers. Instruct the volunteers to avoid
contact with antimicrobials (other than the test formulation) for the
duration of the test. This restriction includes antimicrobial
containing antiperspirants, deodorants, shampoos, lotions, soaps, and
materials such as acids, bases, and solvents. Bathing in chlorinated
pools and hot tubs is to be avoided. Volunteers are to be provided with
a kit of nonantimicrobial personal care products for exclusive use
during the test and rubber gloves to be worn when contact with
antimicrobials cannot be avoided.
(F) Number of subjects required. The standard deviations for
antiseptic handwash or health-care personnel handwash obtained when an
inoculant such as Serratia marcescens is used are more homogeneous than
those for surgical hand scrub products discussed in paragraph
(b)(1)(iii)(F) of this section. The standard deviations extracted from
data submitted to the agency as part of applications under part 314 of
this chapter for these drug products range from 0.31 to 0.92; the
median standard deviation is 0.71. The sample size estimation equation
in paragraph (b)(1)(iii)(F) of this section may be used to estimate
sample sizes required. For example, assume the active control hand
scrub produces an immediate mean log reduction of 2.0 and the test hand
scrub is to be within 20 percent of this, i.e., D=0.4. If S^{2=0.71,
then n=50 subjects per arm of the study. Because blocks of 6 are
recommended, the sample size per treatment arm is 54 subjects.
(G) Study design. Randomization of subjects to time periods and
treatment to hands will be accomplished in accordance with the plan
presented previously.
(H) Procedure. (1) Initial wash. After panelists have refrained
from using antimicrobials for at least 7 days, perform a 30-second
practice wash in the same manner as is described for the test and
control formulations, except that a solution of nonantimicrobial bland
soap is used. This procedure removes oil and dirt and familiarizes the
panelists with the washing technique.
(2) Contaminant suspension and hand contamination. The contaminant
is a liquid suspension of Serratia marcescens containing at least
10^{8 organisms per milliliter. Five milliliters of the contaminant
culture are dispensed onto the hands then rubbed over the surfaces of
the hands, not reaching above the wrist. Application and spreading
should involve about 45 seconds. The hands are then held still away
from the body and allowed to air dry for 2 minutes.
(3) Contamination schedule. The panelists' hands are contaminated
with the marker organism according to the following schedule:
(i) Prior to the baseline bacterial sample collection.
(ii) Prior to all 10 washes with the test material.
(4) Baseline recovery. Baseline sample is taken after contamination
of the hands to determine the number of marker organisms surviving on
the hands after washing with a baseline control soap as described in
paragraph (b)(2)(iii)(H)(1) of this section. Bacterial sampling will
follow the procedures outlined in paragraph (b)(2)(iii)(H)(6) of this
section.
(5) Wash and rinse procedure. The wash and rinse procedure
described as follows is for all washes with the test formulation. A
specified volume of the test formulation is dispensed onto the hands
and rubbed over all surfaces, taking caution not to lose or dilute the
substance. After the material is spread, a small amount of water is
added from the tap and the hands are completely lathered for a
specified time period. The lower third of the forearm is also washed.
After completion of the wash, hands and forearms are rinsed under tap
water at 40 ^{plus-minuse>2 deg.C for 30 seconds. A total of 10
washes with the test formulation is involved. Bacterial samples are
taken following the 1st, 3rd, 7th, and 10th washes.
(6) Bacterial sampling. After the 1st, 3rd, 7th, and 10th washes,
place rubber gloves or polyethylene bags used for sampling on the right
and left hand. Sampling should occur within 5 minutes after each of
these washes. Add 50 to 100 milliliters of sampling solution to each
glove and secure gloves above the wrist. After adding sampling
solution, uniformly massage all surfaces of the hand for 1 minute,
paying particular attention to the area under the nails. After
massaging aseptically, sample the fluid of the glove. Transfer
immediately a measured volume of the sampling fluid to a test tube
containing a suitable antimicrobial inactivator.
(i) Because contamination, product use, and enumeration are
conducted sequentially within a time period of less than a day, an
inactivator included in the sampling solution prior to the final wash
may affect the test results. Therefore, no inactivator for the
antimicrobial in the handwash formulation is to be included in the
sampling solution prior to the final wash. The 50 to 100 milliliters of
sampling fluid may be sufficient to dilute out the activity of the
antimicrobial; however, this should be demonstrated using a procedure
such as the one described in E 1054, ``Test Methods for Evaluation
Inactivators of Antimicrobial Agents Used in Disinfectants, Sanitizer,
and Antiseptic Products,'' in ``Annual Book of ASTM Standards,'' vol.
11.04, which is incorporated by reference in accordance with 5 U.S.C.
552(a) and 1 CFR part 51. Copies may be obtained from The American
Society of Testing and Materials, 1916 Race St., Philadelphia, PA
19103-1187, or may be examined at the Center for Drug Evaluation and
Research, 7520 Standish Pl., suite 201, Rockville, MD, or at the Office
of the Federal Register, 800 North Capitol St. NW., suite 700,
Washington, DC.
(ii) If neutralization is not accomplished by dilution, include in
the sampling solution used to collect the bacterial samples from the
hand following the final wash with the test formulation an
antimicrobial inactivator specific for the test formulation being
evaluated.
(I) Enumeration of bacteria in sampling solution. (1) Enumerate the
Serratia marcescens in the sampling solution using standard
microbiological techniques, such as membrane filter technique or
surface inoculation technique. Prepare sample dilutions in dilution
fluid. Use Soybean-casein digest agar with suitable inactivator as
recovery medium. The suitability of the inactivator for the
antimicrobial should be demonstrated using a procedure such as
described in E 1054, ``Test Methods for Evaluating Inactivators of
Antimicrobial Agents Used in Disinfectant, Sanitizer, and Antiseptic
Products,'' in ``Annual Book of ASTM Standards,'' vol. 11.04, which is
incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR
part 51. Copies are available from The American Society of Testing and
Materials, 1916 Race St., Philadelphia, PA 19103-1187, or may be
examined at the Center for Drug Evaluation and Research, 7520 Standish
Pl., suite 201, Rockville, MD, or at the Office of the Federal
Register, 800 North Capitol St. NW., suite 700, Washington, DC.
Incubate prepared plates 48 hours at 25^{plus-minuse>2 deg.C.
Standard plate counting procedures are used to count only the red
pigmented Serratia marcescens.
(2) [Reserved]
(J) Determination of reduction. Determine at each sampling interval
changes from baseline counts obtained with test material.
(K) Comparison with a positive control material. (1) In order to
validate the testing procedure, equipment, and facilities, it is
required that the test formulation be compared with an active control
formulation. This will require an equivalent number of panelists to be
assigned to the control formulation on a random basis. All test
parameters will be equivalent for both formulations, although the
handwash procedure for the established formulation may be different
from that of the test formulation. Both test and control formulations
are to be run concurrently. The identity of the formulations used by
panelists is to be blinded from those individuals counting plates and
analyzing data.
(2) To validate the assay, compare, at each sampling interval,
changes from baseline counts obtained with test material to changes
obtained with control material.
(L) Statistical analysis. Because the hands are inoculated prior to
sampling it is possible to generate counts of 1.5x10\5\ to 10\6\
organisms. Therefore, reductions are less variable and evaluation of
the log counts using the Student's t- test or similar procedure is
recommended.
(3) Effectiveness testing of a patient preoperative skin
preparation. A patient preoperative skin preparation drug product in
finished form suitable for topical applications will be recognized as
effective provided that the formulated drug product at its recommended
use concentration:
(i) Contains an ingredient in Sec. 333.412 (a), (b), (c), (d), or
(e).
(ii) Demonstrates in vitro activity against organisms as described
in paragraph (a)(1)(ii) of this section.
(iii) When tested, in vivo, by the standard testing procedure for
the evaluation of patient preoperative skin preparation drug products
described in paragraph (b)(3)(iii) of this section and labeled
according to Sec. 333.460(b)(1) of this section, reduces the number of
bacteria 2 log10 per square centimeter on an abdomen test site and
3 log10 per square centimeter on a groin test site within 10
minutes after product use and the bacterial cell count for each test
site does not subsequently exceed baseline 6 hours after product use.
When labeled according to Sec. 333.460(b)(2) and tested, in vivo, by
the standard testing procedure described in paragraph (b)(3)(iii) of
this section, reduces the number of bacteria 1 log10 per
centimeter squared on a dry skin test site within 30 seconds of product
use.
(A) Apparatus.--(1) Colony Counter. Any of several types may be
used.
(2) Incubator. Any incubator capable of maintaining a temperature
of 30^{plus-minuse>2 deg.C may be used.
(3) Sterilizer. Any suitable steam sterilizer capable of producing
conditions of sterility is acceptable.
(4) Timer (stop clock). A timer that can be read in hours and
minutes.
(5) Examining table. Any elevated surface such as a 3-by- 6-foot
table with mattress or similar padding to allow subject to recline.
(B) Materials and reagents.--(1) Bacteriological pipets. Pipets of
10.0 and 2.2 or 1.1 milliliter capacity are recommended.
(2) Water-dilution bottles. Any sterilizable glass container having
a 150 to 200 milliliter capacity and tight closures may be used.
(3) Scrubbing cups. Sterile glass cylinders, height approximately
2.5 centimeter, inside diameter of convenient size to place on
anatomical area to be sampled. Useful sizes range from approximately
2.5 to 4.0 centimeters. Sampling should be conducted as described in
paragraph (b)(3)(iii)(J) of this section.
(4) Rubber policeman. These can be fashioned in the laboratory or
purchased from most laboratory supply houses.
(5) Test formulation. Directions used to demonstrate the
effectiveness of the test formulation are to be the same as those
proposed for the use of the product.
(6) Positive control formulation. Any patient preoperative skin
preparation formulation approved by the Food and Drug Administration is
acceptable.
(7) Sterile Drape or dressing. A sterile drape or dressing should
be used to cover treated skin sites.
(8) Sampling solution. Dissolve 0.4 gram potassium phosphate,
monobasic, 0.1 gram sodium phosphate, dibasic and 1 gram Triton X-100
in 1 liter distilled water. Include in this formulation an inactivator
specific for the antimicrobial in the test formulation. Adjust to pH
7.8 with 0.1 Normal hydrochloric acid or 0.1 Normal sodium hydroxide.
Dispense 50 to 100-milliliter volumes into water dilution bottles, or
other suitable containers, and sterilize for 20 minutes at 121 deg.C.
(9) Dilution fluid. Butterfield's phosphate buffered water adjusted
to pH 7.2 and containing an antimicrobial inactivator specific for the
test formulation. Adjust pH with 0.1 Normal hydrochloric acid or 0.1
Normal sodium hydroxide.
(10) Plating medium. Soybean-casein digest agar plus a suitable
inactivator.
(C) Test and control skin sites. (1) The skin sites selected for
use in evaluating the effectiveness of the pre-operative skin
preparation are to represent body areas that are common surgical sites
and are to include both dry and moist skin areas. The sites are to
possess bacterial populations large enough to allow demonstrations of
bacterial reduction of up to 2 log10 per square centimeter on dry
skin sites and up to 3 log10 per square centimeter on moist sites.
A suitable dry skin area is the abdomen and a suitable moist area is
the groin. For the effectiveness testing of patient preoperative skin
preparation antiseptic drug products labeled according to
Sec. 333.460(b)(2), a dry skin site such as the arm, from the shoulder
to the elbow, or the posterior surface of the hand below the wrist is
to be selected. The sites to be tested are to have a bacterial
population of 3 log10 organisms per square centimeter of skin.
(2) Treatment and control sites are to be located contralateral to
each other. Each site is to be 5 by 5 centimeters.
(D) Test panelists. Recruit healthy adult male and female human
volunteers who have no clinical evidence of dermatosis, open wounds, or
other skin disorders that may affect the integrity of the study, and in
sufficient numbers per formulation being tested to satisfy the
statistical criteria of the clinical trial design.
(E) Preparation of volunteers. (1) Instruct the volunteers to avoid
contact with antimicrobials (other than the test formulation) for the
duration of the test. This restriction includes antimicrobial
containing antiperspirants, deodorants, shampoos, lotions, soaps, and
materials such as acids, bases, solvents. Bathing in chlorinated pools
and hot tubs should be avoided.
(2) Volunteers are to be provided with a kit of nonantimicrobial
personal care products for exclusive use during the test. Volunteers
are not to shower or tub bathe in the 24-hour period prior to the
application of test material or microbial sampling. Sponge baths may be
taken but the skin sites to be used in the study are to be excluded.
(3) If the skin sites to be used include areas that would require
shaving prior to surgery, for example, the groin site, these sites
should be shaved no later than 48 hours prior to the application of
test formulation or microbial sampling.
(4) After volunteers have refrained from using antimicrobials for
at least 2 weeks, obtain an estimate of baseline bacterial population
from one groin and one abdominal site at least 72 hours prior to
entering subjects into the study. Sampling and enumeration techniques
described in paragraphs (b)(3)(iii)(J) and (b)(3)(iii)(K) of this
section are to be used.
(5) Based on the initial estimate of baseline bacterial population,
select sufficient numbers of subjects with high bacterial counts per
formulation being tested to satisfy the statistical criteria of the
clinical trial design.
(F) Study design and randomization. Subjects admitted to the study
are to be identified as to whether they meet the groin portion or
abdomen portion of the study, or both. Once a subject is admitted to
the study, treatments are to be randomly assigned to one contralateral
groin site, for subjects identified as belonging to this study group
and similar treatments are to be randomly assigned to left or right
side of the abdominal area, for subjects identified as belonging to the
abdominal study group. This method of choosing subjects and sampling
sites fits the paired comparison statistical design. Randomization of
subjects to time periods and treatment to left or right side is to be
accomplished in accordance with the plan similar to that presented for
surgical hand scrub products.
(G) Number of subjects required and statistical analysis of data.
(1) Two ways to statistically evaluate effectiveness of a preoperative
scrub product are presented. The first depends upon calculating the
average log10 reduction from baseline. This is accomplished by
obtaining the difference in log counts for each paired sample for each
subject in the appropriate sampling time frame. This will facilitate
subsequent statistical evaluation of resulting data. It is usually
fairly easy to enroll subjects with counts 1 x 10^{5 or greater when
working with the groin areas. It is anticipated this method will
primarily be used to evaluate data collected from the groin areas. The
sample size estimation equation given earlier may be used to estimate
sample sizes required for this case. Standard deviations for
preoperative scrub products are relatively homogeneous when inclusion
criterion require counts of 1 x 10^{5 or greater. The standard
deviations extracted from files range from 0.82 to 1.72; the median
standard deviation was 0.98. When counts in the range of 1 x 10^{5
to 1 x 10^{6 were used, the standard deviation ranged from 0.78 to
1.22, with a median value of 0.99. Using the sample size estimation
equation given in paragraph (b)(1)(iii)(F) of this section and assuming
the active control preoperative scrub produces an immediate mean log
reduction of 2.0 and test scrub is to be within 20 percent of this,
i.e., D=0.4, and S^{2=0.98, gives n=97 subjects per arm of the
study. Because blocks of 6 are recommended, the sample size per
treatment arm is 96 subjects.
(2) The second method for evaluating the data depends upon
establishing an entry target bacterial population of greater than 250
colony forming units per square centimeter and a target reduction
criterion that a successful scrub reduces bacterial counts to below 25
colony forming units per square centimeter. A successful scrub product
is to provide this degree of reduction in at least 90 percent of the
subjects tested. Using the normal binomial confidence interval
approach, it can be shown that if the standard preoperative scrub
product achieves a 90 percent success rate and it is desired to rule
out success rates less than 85 percent for the new product with power
of 80 percent then 340 subjects per arm are required. If it is desired
to rule out success rates less than 80 percent, then the sample size is
only 100 per arm. Again, since blocks of 6 or some multiple thereof,
are recommended, the sample size is 102 subjects per study arm.
(3) In both cases described in paragraphs (b)(3)(iii)(G)(1) and
(b)(3)(iii)(G)(2) of this section, effectiveness is judged based on
calculation of 95 percent confidence intervals on the difference of the
``success rate for standard scrub product minus success rate for test
scrub product.''
(H) Treatment application procedure. Apply treatment according to
label directions or as stated in the proposed directions for test
formulation. The control product is to be used according to the
labeling directions.
(I) Sampling schedule. (1) For patient preoperative skin
preparation antiseptic drug products labeled according to
Sec. 333.460(b)(1), the treatment is randomly assigned to one
contralateral groin site and one contralateral abdominal site on each
of the subjects. The assignment is to be balanced such that an equal
number of right and left sites in each anatomical area receive
treatment. The untreated contralateral sites serve as control sites to
establish baseline populations. Collect a baseline bacterial sample
from one untreated groin site and from one abdominal site on each
subject using the scrub cup technique just prior to application of the
preoperative skin treatment to the corresponding contralateral site.
Ten minutes after treatment, sample one treated groin site and one
treated abdominal site on one-third of the subjects using the same
sampling technique. Thirty minutes posttreatment, sample another one-
third of the subjects as before, and 6 hours posttreatment, sample the
remaining one-third of the subjects.
(2) Between the time of treatment allocation and the 6-hour
sampling interval, the subjects movements should be restricted.
Subjects treated in the groin area should avoid activities or positions
that would cause untreated skin sites to contact treated sites or
clothing. Positions that might be appropriate are lying on the back or
sitting with the legs extended without flexing from the trunk. To allow
subjects some degree of mobility between the time of treatment and the
4-hour posttreatment sampling, the treated skin areas should be loosely
draped with a sterile nonocclusive dressing. This material is to be
applied in such a manner as to protect the treated skin sites from
contact with untreated skin.
(3) For patient preoperative skin preparation antiseptic drug
products labeled according to Sec. 333.460(b)(2), the treatment is
randomly assigned to contralateral dry skin sites on each of the
subjects. The assignment is to be balanced such that an equal number of
right and left sites in each anatomical area receive treatment. The
untreated contralateral site serves as a control site to establish
baseline populations. Collect a baseline bacterial sample from an
untreated site on each subject using the scrub cup technique just prior
to application of the preoperative skin preparation to the
corresponding contralateral site. Thirty seconds after application,
sample the treated site using the same sampling technique.
(J) Microbiological methods. Samples for bacterial enumeration are
obtained by the detergent scrub cup technique. Hold a sterile scrubbing
cup firmly to the skin. Aseptically pipet 2.5 milliliters of sterile
sampling solution into the scrubbing cup and rub the skin with a
sterile rubber policeman for 1 minute using moderate pressure. Aspirate
the wash fluid and place in a sterile test tube. Place a second 2.5-
milliliter aliquot of sampling solution in the scrub cup and rub the
skin again for 1 minute with the rubber policeman. Pool the two washes
and enumerate the bacteria.
(K) Enumeration of bacteria in sampling solution. (1) Enumerate the
bacteria in the sampling solution by a standard plate count procedure
such as that described in ``Standard Methods for the Evaluation of
Dairy Products'' (available from American Public Health Association,
Inc., 1015 15th St. NW., Washington, DC 20005) but using soybean-casein
digest agar and a suitable inactivator for the antimicrobial where
necessary. The suitability of the inactivator is to be demonstrated
using a procedure such as described in E 1054, ``Test Methods for
Evaluating Inactivators of Antimicrobial Agents Used in Disinfectant,
Sanitizer, and Antiseptic Products,'' in ``Annual Book of ASTM
Standards,'' vol. 11.04, which is incorporated by reference in
accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies are available
from The American Society for Testing and Materials, 1916 Race St.,
Philadelphia, PA 19103-1187, or may be examined at the Center for Drug
Evaluation and Research, 7520 Standish Pl., suite 201, Rockville, MD,
or at the Office of the Federal Register, 800 North Capitol St. NW.,
suite 700, Washington, DC. Prepare sample dilutions in dilution fluid.
Plate in duplicate. Incubate plated sample at 30 2 deg.C
for 48 hours before reading.
(2) Determine changes from baseline counts obtained with the test
material at each sampling interval for each anatomical site. For a more
realistic appraisal of the activity of products, all raw data should be
converted to common (base 10) logarithms. Reduction should be
calculated from the average of the logarithms. This will also
facilitate statistical analysis of data.
(L) Comparison of test material with control material. (1) In order
to validate the testing procedure, equipment, and facilities, it is
required that the test material be compared with an active control
material. The number of test subjects will depend upon the number of
control posttreatment sampling intervals chosen and the level of
statistical significance desired for the test results. The identity of
the formulations used by panelists should be blinded from those
individuals counting plates and analyzing data.
(2) To validate the assay, compare, at each sampling interval,
changes from baseline counts obtained with the test material to changes
obtained with the control materials.
(c) Effects on microbial flora. The agency notes that, if there is
some reasonable scientific indication that the activity of an
ingredient will affect the microbial flora, and thereby cause a shift
in the composition of this flora, e.g., an increase in the fungus or
virus level that might result in greater harm, then further safety and
effectiveness testing will be required.
(d) Test modifications. The formulation or mode of administration
of certain products may require modifications of the testing procedures
in this section. In addition, alternative assay methods (including
automated procedures) employing the same basic chemistry and
microbiology as the methods included in this section may be used. Any
proposed modification or alternative assay method shall be submitted as
a petition under the rules established in Sec. 10.30 of this chapter.
The petition should contain data to support the modification or data
demonstrating that an alternative assay method provides results of
equivalent accuracy. All information submitted will be subject to the
disclosure rules in part 20 of this chapter.

PART 369--INTERPRETATIVE STATEMENTS RE WARNINGS ON DRUGS AND
DEVICES FOR OVER-THE-COUNTER SALE

3. The authority citation for 21 CFR part 369 continues to read as
follows:

Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701 of
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351,
352, 353, 355, 356, 357, 371).

Sec. 369.21 [Amended]

4. Section Sec. 369.21 Drugs; warning and caution statements
required by regulations is amended by removing the entry for ``Alcohol
Rubbing Compound.''

Dated: May 24, 1994.
Michael R. Taylor,
Deputy Commissioner for Policy.
[FR Doc. 94-14503 Filed 6-16-94; 8:45 am]
BILLING CODE 4160-01-P}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}