[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.

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

C. Comments on Definitions

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

Reference

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

D. Comments on Labeling

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

References

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

E. Comment on Alcohol

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

References

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

F. Comments on Chlorhexidine Gluconate

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

References

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

G. Comments on Chloroxylenol

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

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

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

References

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

H. Comment on Hexachlorophene

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

References

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

I. Comments on Iodine and Iodophors

    14. One comment pointed out that poloxamer-iodine complex appeared 
to be incorrectly included in the Category II list under ``health-care 
personnel handwash'' (43 FR 1210 at 1227), while it is properly listed 
in Category III for use as a ``health-care personnel handwash'' (43 FR 
1210 at 1229). The comment stated that deletion from the Category II 
list would correct the error.
    The agency concurs with the comment that poloxamer-iodine complex 
for use as a health-care personnel handwash was incorrectly listed as 
Category II (43 FR 1227) and that the listing as Category III (43 FR 
1229) was correct.
    15. One comment submitted data on the safety and effectiveness of a 
``mixed iodophor'' consisting of iodine complexed by ammonium ether 
sulfate and polyoxyethylene sorbitan monolaurate (Ref. 1). The comment 
stated that this information had been previously submitted in May 1974, 
but that the ingredient had not been mentioned in the Panel's report or 
in the agency's proposed monograph and requested that the agency 
include it in the monograph. The comment pointed out that the iodophor, 
formulated as a liquid hand scrub, is intended for use by surgeons, 
food handlers, and others for whom reduced bacterial 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 
>106 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 109 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 1014 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 1014 to 2 X 1015 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  108 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 IvoryR soap was 
compared to IvoryR 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-log10) 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  105 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 DuraPrepTM 
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: 
n2S2(Za/2+Zb)2/D2, 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 S2= 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 1.5x105 to 106 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 S2=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 
108 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 25plus-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 30plus-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 105 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 105 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 105 
to 1 x 106 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 S2=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