[Federal Register Volume 68, Number 110 (Monday, June 9, 2003)]
[Rules and Regulations]
[Pages 34273-34293]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-14140]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 310, 350, and 369

[Docket No. 78N-0064]
RIN 0910-AA01


Antiperspirant Drug Products For Over-the-Counter Human Use; 
Final Monograph

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule 
in the form of a final monograph establishing conditions under which 
over-the-counter (OTC) antiperspirant drug products are generally 
recognized as safe and effective and not misbranded as part of FDA's 
ongoing review of OTC drug products. FDA is issuing this final rule 
after considering public comments on its proposed regulation, issued as 
a tentative final monograph (TFM), and all new data and information on 
antiperspirant drug products that have come to the agency's attention.

DATES: Effective Date: This rule is effective December 9, 2004.
    Compliance Dates: The compliance date for products with annual 
sales less than $25,000 is June 9, 2005. The compliance date for all 
other products is December 9, 2004.

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

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background
II. The Agency's Conclusions on the Comments
    A. General Comments on OTC Antiperspirant Drug Products
    B. General Comments on Labeling of OTC Antiperspirant Drug Products
    C. Comments on Category III Effectiveness Testing
    D. Comments on Testing Guidelines
    E. Comments on Antiperspirant Active Ingredients
    F. Comments on the Safety of Aluminum Ingredients
III. Agency Changes
IV. Summary of Changes From the Proposed Rule
V. The Agency's Final Conclusions
VI. Analysis of Impacts
VII. Paperwork Reduction Act of 1995
VIII. Environmental Impact
IX. Federalism
X. Section 369.20 Revision
XI. References
Monograph (Part 350)

I. Background

    In the Federal Register of October 10, 1978 (43 FR 46694), FDA 
published an advance notice of proposed rulemaking to establish a 
monograph for OTC antiperspirant drug products, together with the 
recommendations of the Advisory Review Panel on OTC Antiperspirant Drug 
Products (the Panel), which evaluated the data on these products. The 
agency's proposed regulation (TFM) for OTC antiperspirant drug products 
was published in the Federal Register of August 20, 1982 (47 FR 36492).
    In the Federal Register of November 7, 1990 (55 FR 46914), the 
agency issued a final rule establishing that certain active ingredients 
in OTC drug products are not generally recognized as safe and effective 
and are misbranded. These ingredients included seven antiperspirant 
ingredients, which are included in Sec.  310.545(a)(4) (21 CFR 
310.545(a)(4)). In this rulemaking, the agency is adding one additional 
ingredient to this section. (See section III.1 of this document.)
    In the Federal Register of March 23, 1993 (58 FR 15452), the agency 
requested public comment on two citizen petitions, and a response to 
one of the petitions, related to the safety of aluminum compounds in 
OTC antiperspirant drug products. This final monograph completes the 
TFM and provides the substantive response to the citizen petitions.
    Twenty-four months after the date of publication in the Federal 
Register, for products with annual sales less than $25,000, and 18 
months after the date of publication in the Federal Register, for all 
other products, no OTC drug product that is subject to this final rule 
and that contains a nonmonograph condition may be initially introduced 
or initially delivered for introduction into interstate commerce unless 
it is the subject of an approved new drug application (NDA) or 
abbreviated new drug application. Further, any OTC drug product subject 
to this final monograph that is repackaged or relabeled after the 
compliance dates of the final rule 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 as soon as possible.
    In response to the TFM on OTC antiperspirant drug products and the 
request for comment on the citizen petitions, the agency received 20 
comments. One manufacturer requested an oral hearing before the 
Commissioner of Food and Drugs on six different issues. Copies of the 
information considered by the Panel, the comments, and the hearing 
request are on public display in the Dockets Management Branch (HFA-
305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. ``OTC Volumes'' cited in this document refer to 
information on public display.
    The agency received some ``feedback'' communications under the OTC 
drug review procedures (see the Federal Registers of September 29, 1981 
(46 FR 47740) and April 1, 1983 (48 FR 14050)). The agency has included 
these communications in the administrative record and addressed them in 
this document.
    The safety issues raised by the citizen petitions are discussed in 
section II.F of this document. The agency believes it has adequately 
responded to the six issues related to the hearing request; therefore, 
a hearing is not necessary.

II. The Agency's Conclusions on the Comments

A. General Comments on OTC Antiperspirant Drug Products

    (Comment 1) One comment requested that FDA reconsider its position 
that OTC drug monographs are substantive, as opposed to interpretive, 
regulations.
    The agency addressed this issue and reaffirms its conclusions as 
stated in

[[Page 34274]]

paragraphs 85 through 91 of the preamble to the procedures for 
classification of OTC drug products (May 11, 1972, 37 FR 9464 at 9471 
to 9472) and in paragraph 1 of the preamble to the TFM in the present 
proceeding (47 FR 36492 at 36493).
    (Comment 2) Three comments disagreed with the agency's proposed 
definition of an antiperspirant: ``A drug product that, when applied 
topically to the underarm, will reduce the production of perspiration 
(sweat) at that site,'' (47 FR 36492 at 36503). One comment contended 
it was unduly restrictive and unnecessary to limit use only in the 
underarm area because it is not the only area of the body upon which 
these products could potentially be applied. The comment asked the 
agency to modify the definition to parallel the pharmacologic activity 
of the active ingredients and suggested: ``A drug product that, when 
applied topically, will reduce the production of perspiration (sweat) 
at that site.''
    A second comment stated that the definition limiting use to the 
underarm only would adversely affect its products labeled for use on 
the hands and for use with orthotic and prosthetic appliances (to keep 
appliance-skin contact areas dry). Noting that the agency and the Panel 
recognized the similarities and differences between axillary and foot 
perspiration, a third comment stated that ingredients effective in the 
underarm area are probably effective to control foot perspiration.
    The agency agrees with the first comment that it is not necessary 
to specify the area of use on the body in the definition of an 
antiperspirant because that information is included in the product's 
labeling. Accordingly, the agency is deleting the phrase ``to the 
underarm'' from the definition of an antiperspirant in Sec.  350.3 (21 
CFR 350.3) of this final monograph to read: ``Antiperspirant. A drug 
product applied topically that reduces the production of perspiration 
(sweat) at that site.'' The use of an antiperspirant on other areas of 
the body, as mentioned by the second and third comments, is discussed 
in section II.A, comment no. 4 and section II.C, comment 14 of this 
document.
    (Comment 3) One comment stated that the TFM for OTC antiperspirant 
drug products was substantively and procedurally defective because it 
failed to address adequately the Panel's Category III recommendations 
concerning ``enhanced duration of effect'' and ``problem perspiration'' 
and failed to state what testing was required to substantiate these 
claims. The comment requested that FDA issue a new or amended TFM to 
address these issues.
    The agency has determined that there is no need to withdraw, amend, 
or initiate a new TFM. Since the Panel's report was published in 1978, 
the procedural regulations for the OTC drug review were revised to 
comply with the Court ruling in Cutler v. Kennedy, 475 F. Supp. 838 
(D.D.C. 1979). The revised regulations (46 FR 47730, September 29, 
1981) provide that TFMs and final monographs will no longer contain 
recommended testing guidelines. The agency is not required by statute 
or regulation to include testing guidelines as part of OTC panel 
reports or TFMs. The agency stated in proposed Sec.  350.60 of the TFM 
(47 FR 36492 at 36504) and states in Sec.  350.60 of this final 
monograph (21 CFR 350.60) that ``To assure the effectiveness of an 
antiperspirant, the Food and Drug Administration is providing 
guidelines that manufacturers may (emphasis added) use in testing for 
effectiveness.''
    The ``enhanced duration of effect'' and the ``problem 
perspiration'' issues are discussed in section II.C, comments 10 and 12 
of this document. Extended duration of effect claims have been placed 
in Category I based on data submitted by other comments (see also 
comment 12). The agency has determined that claims for problem 
perspiration are outside the scope of this monograph because no data 
were submitted to support such claims (see also comment 10).
    (Comment 4) One comment contended that the proposed monograph would 
have a disastrous economic effect on its company, which markets an 
antiperspirant product first formulated in 1902 and labeled for 
excessive perspiration, including keeping the hands free of 
perspiration (labeled for use on the hands for tennis, racquetball, 
bowling, football, and other sporting uses), and marketed for 
prosthesis and orthotic use (for amputees to keep their appliance 
contact areas dry).
    To qualify for exemption from the ``new drug'' definition under the 
1938 grandfather clause of the act, the drug product must have been 
subject to the Food and Drug Act of 1906, prior to June 25, 1938, and 
at such time its labeling must have contained the same representations 
concerning the conditions of its use (21 U.S.C. 321(p)(1)). Under the 
1962 grandfather clause of the act, a drug product which on October 9, 
1962 was: (1) Commercially used or sold in the United States; (2) not a 
``new drug'' as defined in the 1938 act; and (3) not covered by an 
effective NDA under the 1938 act, would not be subject to the added 
requirement of effectiveness ``when intended solely for use under 
conditions prescribed, recommended, or suggested in labeling with 
respect to such drug on that day.'' (Public Law 87-781, section 
107(c)(4), 76 Stat. 788, note following 21 U.S.C. 321).
    The person seeking to show that a drug comes within a grandfather 
exemption must prove every essential fact necessary for invocation of 
the exemption. See United States v. An Article of Drug * * * ``Bentex 
Ulcerine,'' 469 F.2d 875, 878 (5th Cir. 1972), cert. denied, 412 U.S. 
938 (1973). Furthermore, the grandfather clause will be strictly 
construed against one who invokes it. See id.; United States v. Allan 
Drug Corp., 357 F.2d 713, 718 (10th Cir.), cert. denied, 385 U.S. 899 
(1966). A change in composition or labeling precludes the applicability 
of the grandfather exemption. See USV Pharmaceutical Corp. v. 
Weinberger, 412 U.S. 655, 663 (1973).
    Although the comment stated that its drug products have been 
marketed since 1902 with hand perspiration labeling claims, no evidence 
was submitted to show that the labeling and composition of the products 
have remained unchanged since either 1938 or 1962, so that they qualify 
as grandfathered products. The agency requested product labeling from 
these years on several occasions (Refs. 1, 2, and 3), but none was ever 
provided. Without such evidence, the products do not qualify for either 
grandfather exemption. The burden of proof with respect to the 
grandfather exemption is not on FDA, but on the person seeking the 
exemption. See An Article of Drug * * * ``Bentex Ulcerine,'' supra.
    The 1938 and 1962 grandfather clauses apply only to the new drug 
provisions of the act (see 21 CFR 314.200(e)) and not to the 
adulteration and misbranding provisions. The OTC drug review was 
designed to implement both the misbranding and the new drug provisions 
of the act. (See Sec.  330.10 (21 CFR 330.10), 37 FR 9464 at 9466.) The 
grandfather clauses do not preclude the agency from reviewing any 
currently marketed OTC drug product, regardless of whether it has 
grandfather protection from the new drug provisions, in order to ensure 
that it is not misbranded.
    Although the comment claimed this final rule would have a 
disastrous economic effect on its company if antiperspirants can be 
labeled only for underarm use, it provided no documentation about this 
impact. The agency notes that while the company's products would need 
to be relabeled to bear different indications, as long as the monograph 
conditions are met, the

[[Page 34275]]

products could remain in the marketplace after relabeling occurred. The 
economic impact of this final rule is discussed in section VI of this 
document.

B. General Comments on Labeling of OTC Antiperspirant Drug Products

    (Comment 5) Several comments contended that FDA should not 
incorporate the ``exclusivity policy'' in the final monograph by 
prescribing specific labeling terminology to the exclusion of other 
truthful nonmisleading language.
    After these comments were submitted, in the Federal Registers of 
May 1, 1986 (51 FR 16258) and March 17, 1999 (64 FR 13254), the agency 
published final rules changing its labeling policy for stating the 
indications for use of OTC drug products. Under Sec.  330.1(c)(2) (21 
CFR 330.1(c)(2)), the agency provides options for labeling OTC drug 
products. The final monograph in this document is subject to the 
labeling provisions in Sec.  330.1(c)(2). In addition, the monograph 
labeling follows the format and content requirements of Sec.  201.66 
(21 CFR 201.66).
    (Comment 6) One comment objected to limiting the terms proposed in 
Sec.  350.50(b)(1), (b)(2), and (b)(3) to ``reduces,'' ``decreases,'' 
``diminishes,'' and ``lessens.'' The comment stated that ``lower'' and 
``mitigate'' are synonyms for ``reduce'' and other words and phrases 
state, truthfully and accurately, the effect of antiperspirants.
    Several comments disagreed with the agency that words such as 
``stop,'' ``check,'' ``halt,'' ``end,'' ``eliminate,'' and ``protect'' 
should not be used in the labeling of antiperspirant drug products, 
even if preceded by the word ``helps,'' because these words imply the 
ability to stop underarm perspiration totally and would therefore 
mislead the consumer about the effectiveness of antiperspirant drug 
products. The comments mentioned the minority Panel position that ``The 
Panel did not see scientific data to indicate that a consumer can 
differentiate between such words as `halts,' `checks,' `stops,' and 
`ends,' as disallowable words versus `diminishes' and `reduces' as 
allowable words,'' (43 FR 46694 at 46725). One comment agreed with the 
minority because a review of the entire record of this proceeding found 
no studies or data to support a decision to disallow ``protects,'' 
``halts,'' ``checks,'' and ``stops.'' Another comment requested a 
hearing on this issue.
    One comment disagreed with the Panel's Category II status for the 
following labeling claims (43 FR 46694 at 46724): ``Dry,'' ``dry 
formula,'' ``super dry,'' ``helps stop wetness,'' ``completely guards 
your family,'' ``helps stop embarrassing perspiration wetness,'' 
``complete protection,'' ``really helps keep you dry,'' and ``gentle 
enough for sensitive areas of the body.'' The comment asked the agency 
to allow these claims in the final monograph.
    The agency has re-evaluated these claims in light of the comments' 
arguments and its current policy to provide consumer friendly OTC drug 
product labeling. The agency is deleting one previously proposed word 
(``diminishes'') and adding some more consumer-friendly words 
(``sweat'' and ``sweating'') to antiperspirant product labeling.
    The agency proposed the word ``diminishes'' in Sec.  350.50(b) as 
one of the optional terms that could be used as the first word of the 
indications statement. While the word ``diminish'' means to ``reduce,'' 
the agency does not consider it as consumer-friendly as the other 
optional words ``reduces,'' ``decreases,'' or ``lessens.'' Therefore, 
the agency is not including ``diminishes'' in Sec.  350.50(b) of this 
final monograph as an FDA-approved term. The agency rejected the words 
``mitigate'' and ``lower'' in the TFM (comment 14, 47 FR 36492 at 36496 
to 36497). The agency's position has not changed. While the terms 
``mitigate,'' ``lower,'' and ``diminishes'' are not in the monograph 
and the agency does not favor their use, manufacturers may use these 
terms, or other words or phrases that truthfully and accurately express 
a similar meaning, under the flexible labeling policy in Sec.  
330.1(c)(2).
    The agency is not changing its position on the use of the word 
``helps'' in conjunction with the words ``stop,'' ``halt,'' ``check,'' 
``end,'' and ``eliminate.'' In the TFM (comment 14), the agency stated 
that these words imply the ability to stop underarm perspiration 
totally and would therefore mislead consumers about antiperspirant 
effectiveness. Although neither the Panel nor the agency had any 
consumer comprehension studies to support a decision to disallow this 
information, the comments also did not provide any data to support 
these terms. The agency would consider these terms if data are provided 
to show that consumers would not be misled about the effect of 
antiperspirant drug products. The agency is not including ``helps 
protect'' before ``underarm dampness,'' ``underarm perspiration,'' or 
``underarm wetness,'' because the language is not clear and could 
confuse consumers.
    The agency is not including any ``dry'' or similar claims (``dry,'' 
``dry formula,'' ``super dry,'' ``really helps keep you dry'') in this 
final monograph because no criteria have been established to define 
``dry.'' Thus, what may be ``dry'' for one manufacturer's product may 
not be ``dry'' for another manufacturer's product. The agency would 
consider including ``dry'' claims in the monograph if appropriate 
criteria for such claims are developed.
    The agency is not including claims such as ``complete protection'' 
or ``completely guards your family'' in the monograph because there is 
no evidence that antiperspirant drug products provide ``complete'' 
protection. The agency is not including the claim ``gentle enough for 
sensitive areas of the body'' because the words ``sensitive areas'' may 
imply that the product can be used on other body areas in addition to 
the underarm. The agency is not including the claim ``helps stop 
embarrassing perspiration wetness'' because what is ``embarrassing'' or 
``problem'' perspiration for one individual may not be ``embarrassing'' 
or a ``problem'' for others. (See section II.C, comment 10 of this 
document.)
    The agency is not including both ``perspiration'' and ``wetness'' 
in the same claim because it considers the duplicative wording 
unnecessary. The currently allowed claims are ``* * * underarm 
wetness'' or ``* * * underarm perspiration.'' The agency would have no 
objection to ``* * * underarm perspiration wetness,'' but such would 
have to be done under the flexible labeling provisions of Sec.  
330.1(c)(2). The agency is adding the words ``sweat'' and ``sweating'' 
in Sec.  350.50(b) as other ways to describe ``wetness'' and 
``perspiration,'' because consumers regularly use these terms to 
describe perspiration. Based on the previous discussion, the agency 
concludes that a hearing is not warranted on these issues.
    (Comment 7) Three comments requested that OTC antiperspirant drug 
products be exempted from the keep out of reach of children and 
accidental ingestion warnings in Sec.  330.1(g) because these products 
are not toxic by oral ingestion. One comment noted only one reported 
ingestion in 30 years of marketing antiperspirant products. Another 
comment stated that aerosols, in particular, should be exempt from the 
ingestion warning due to the characteristics of the delivery system and 
the warnings already required for aerosols pressurized by gaseous 
propellants under Sec.  369.21 (21 CFR 369.21).
    Although the comments did not submit any data to show that 
antiperspirant drug products are safe if ingested, the agency believes 
these products should not be toxic by oral

[[Page 34276]]

ingestion for most individuals. However, individuals with renal 
dysfunction or immature renal function (i.e., infants) are at a higher 
risk from any exposure to aluminum. Further, ingestion of the various 
inactive ingredients present in these products may make young children 
ill or cause other undesirable consequences. Without adequate proof of 
safety if accidental ingestion were to occur, the agency has no basis 
to exempt OTC antiperspirant drug products from the accidental 
ingestion warning.
    Although aerosol antiperspirant drug products are unlikely to be 
accidentally ingested by most consumers, the agency notes that the 
product containers are similar to those used for some food products. 
Spraying an aerosol into the mouth and ingesting it could be more 
hazardous than ingesting other dosage forms of the product because of 
the aerosol propellants. The warnings required under Sec.  369.21, for 
those drugs in dispensers pressurized by gaseous propellants, are not 
related to ingestion, but state the following: ``Avoid spraying in the 
eyes. Do not puncture or incinerate. Do not store at temperatures above 
120 [deg]F. Keep out of reach of children.'' The agency does not 
consider these warnings a basis to exempt aerosol antiperspirants from 
the accidental ingestion warning required by Sec.  330.1(g) for topical 
drug products. The last statement of the warning required by Sec.  
369.21 and the first warning required by Sec.  330.1(g) (i.e., ``Keep 
out of reach of children.'') are identical as of March 17, 1999 (64 FR 
13254 at 13294). Section 350.50(c)(4)(ii)) of the final monograph 
requires aerosol antiperspirant drug products to bear the language in 
Sec.  369.21. These products do not have to repeat the first general 
warning required by Sec.  330.1(g) but need to have the accidental 
ingestion warning required by Sec.  330.1(g).
    (Comment 8) Two comments objected to the proposed warning in Sec.  
350.50(c) for aerosol antiperspirants, which states: ``Avoid excessive 
inhalation.'' The comments argued that the warning duplicates and gives 
less information than the current warning required for aerosol drug 
products under Sec.  369.21.
    Section 369.21 requires the following warning statement for a drug 
packaged in a self-pressurized container in which the propellant 
consists in whole or in part of a halocarbon or hydrocarbon: ``Use only 
as directed. Intentional misuse by deliberately concentrating and 
inhaling the contents can be harmful or fatal.'' The agency does not 
consider this warning (which addresses deliberate misuse) as being the 
same as a general statement warning people to avoid excessive 
inhalation. There are many people who would not deliberately misuse the 
product who should be alerted to keep away from their face and mouth 
and to avoid excessive inhalation. The warning appears in the final 
monograph in more consumer friendly language and in the new labeling 
format as follows: ``When using this product [bullet] keep away from 
face and mouth to avoid breathing it.'' (See Sec.  201.66(b)(4) for 
description of a ``bullet.'')

C. Comments on Category III Effectiveness Testing

    (Comment 9) Several comments objected to user perception testing to 
substantiate Category III effectiveness claims. (See comment 24, 47 FR 
36492 at 36499.) The comments contended that the user perception test 
is not reliably indicative of product effectiveness and offers at best 
a crude index of activity that is difficult to employ for precise 
qualitative and quantitative evaluations. The comments considered 
objective gravimetric sweat collection procedures more reliable than 
user perception testing to assess antiperspirant activity levels and 
requested that user perception testing be deleted. Three comments 
submitted data on user perception testing of Category III claims, 
including extra effective, 24-hour duration, emotional sweating, and 
foot perspiration (see section II.C, comments 11 through 14 of this 
document).
    The agency has determined that user-perception test data support 
emotional sweating, 24-hour protection, and extra effective claims. 
Accordingly, the agency concludes that there are sufficient data on 
user perception tests (including both user and independent observer 
perception tests) for use of antiperspirants for the underarm. No 
further user perception tests are necessary if an underarm 
antiperspirant shows at least 20 percent sweat reduction by gravimetric 
tests for emotional sweating and 24-hour protection claims or 30 
percent sweat reduction for extra effective claims. Adequate user 
perception tests have not been conducted for parts of the body other 
than the underarms, such as the hands or feet. The agency will still 
require user perception and other effectiveness data to support use of 
antiperspirants on the hands and feet (see section II.A, comment 4 and 
section II.C, comment 14 of this document).
    (Comment 10) Several comments objected to the Category III status 
of the claims ``problem perspiration'' and ``especially troublesome 
perspiration.'' One comment contended these claims are not inherently 
misleading or untruthful and many people who do not perspire heavily 
may, at times, consider themselves to have ``problem'' or 
``troublesome'' perspiration.
    Other comments objected to the agency's definition of problem 
perspiration as affecting the upper 5 percent of perspirerers, 
contending that a more realistic approach would be to let consumers 
define the meaning of these words by running efficacy studies on people 
who identify themselves as having problem or especially troublesome 
perspiration. One comment objected to the economic consequences of 
testing the top 5 percent of the population to establish a ``problem 
perspiration'' claim, because this could raise the price for one 
efficacy evaluation from the current $5,000 to $10,000 up to $200,000. 
The comment requested a hearing on this issue if FDA did not revise its 
approach.
    No data were submitted to the agency to show that any OTC 
antiperspirant drug product is effective in reducing ``problem'' or 
``especially troublesome'' perspiration. The agency is not aware of any 
products that currently qualify as effective for those conditions. If 
products are found to be effective in the future, the agency will 
include a definition and labeling for ``problem'' or ``especially 
troublesome'' perspiration in the monograph. The agency proposed in the 
tentative final monograph that a 30 percent reduction in sweat 
production in the upper 5 percent of perspirerers is necessary for a 
``problem perspiration claim'' (47 FR 36492 at 36500). As discussed in 
section II.C, comment 9 of this document, gravimetric testing is 
sufficient to prove these claims. The agency would find acceptable an 
antiperspirant effectiveness study on a population of individuals who 
perceive themselves to have ``problem perspiration,'' as one comment 
suggested. Based on changes in the testing to support these claims, the 
agency concludes that a hearing is not needed.
    (Comment 11) Several comments objected to the agency's proposed 
Category II classification of the claims ``extra strength,'' ``extra 
effective,'' or any other comparative effectiveness claims (see comment 
19, 47 FR 36492 at 36498). The comments argued that if manufacturers 
can demonstrate by appropriate testing and methods of statistical 
analysis that one product is more effective than another, they should 
be permitted to so inform consumers. The comments noted that the agency 
had approved an NDA for an acetaminophen ``extra strength'' product and 
allowed sunscreen products to label

[[Page 34277]]

their degree of effectiveness. One comment requested a hearing on this 
subject.
    To prove the validity of comparative claims, two comments submitted 
both gravimetric and perceptual data (Refs. 4 and 5). Another comment 
submitted gravimetric data only (Refs. 6 and 7) and stated that one 
study showed that a 10 percent difference in antiperspirant 
effectiveness can be measured with currently marketed antiperspirant 
products. This comment stated that adequate data (Ref. 8) had been 
submitted to the Panel (43 FR 46694 at 46715) to show that as 
differences in antiperspirant performance levels increase, larger 
numbers of consumers perceive the difference. These data included a 
chart plotting differences in sweat reduction against the percentage of 
subjects who noted variations in axillary wetness. The chart shows that 
at 20 percent sweat reduction, approximately 45 to 50 percent of the 
subjects noticed a difference; at 35 percent sweat reduction, 
approximately 60 percent noticed a difference; and at 50 percent sweat 
reduction, approximately 75 percent noticed a difference. The comment 
contended that this study confirmed the Panel's determination that the 
user can perceive a shift of at least 10 percent in antiperspirant 
effectiveness and that a product providing a 30 percent or greater 
sweat reduction is perceived as more effective than a standard 
antiperspirant. The comments requested monograph status for ``extra 
strength'' and ``extra effective'' claims, as qualified by gravimetric 
studies.
    The agency has determined that some of the studies (Ref. 4) meet 
the Panel's ``guidelines for user perception test to be done for claims 
of `extra-effective' to be classified as Category I'' (43 FR 46694 at 
46730). In these studies, two solid stick antiperspirant products 
(containing either 10 percent or 25 percent aluminum chlorohydrate) 
were compared by both a gravimetric and a user perception test. In the 
gravimetric test, 91 female subjects used the 10-percent product, and 
88 used the 25-percent product. A 17-day conditioning period with no 
antiperspirant use was followed by four daily applications of one of 
the products to a randomly selected axilla (armpit or underarm). The 
opposite axilla received no treatment and served as the control. 
Baseline sweat production was determined the first day of the test. On 
days two and three, the antiperspirant was applied and 1 hour later a 
sweat production sample was collected. On day five, 24 hours after the 
fourth application, a sweat production sample was collected. Both the 
10- and 25-percent products were more effective than the no treatment 
control for all time periods according to the statistical methods 
(Wilcoxon signed rank test) in the agency's guidelines for 
effectiveness testing of OTC antiperspirant drug products (Ref. 9). 
Evaluation of the Z values for the two 1-hour test days and the 24-hour 
test day showed that both products were statistically (Wilcoxon test) 
at least 20 percent better than the control axilla for all time periods 
(p < 0.001 for all three cases). Thus, both products met the 
requirements for standard effectiveness, i.e., a minimum of 20-percent 
reduction in underarm perspiration. Applying the same statistical 
methods to a 30-percent reduction in underarm perspiration on the last 
24-hour data showed that the 25-percent product was more effective than 
no treatment (p < 0.001) and, thus, met one of the extra effective 
criteria.
    The same study design was used in the user perception test except 
that the subjects applied the 10-percent product under one axilla and 
the 25-percent product under the other axilla. On day five, 24 hours 
after the fourth application, the 100 female subjects were asked 
``Under which arm do you feel drier?'' All subjects had a preference: 
33 favored the 10-percent product and 67 favored the 25-percent 
product. A statistically significant number of the subjects were able 
to perceive that the 25-percent product was more effective than the 10-
percent product (p = 0.0005 one-sided). This result exceeded the 
Panel's requirement that 58 out of 100 subjects have a preference for 
the test antiperspirant (43 FR 46694 at 46731). Thus, these studies 
showed that the 25-percent aluminum chlorohydrate met the Panel's 
criteria (gravimetric measurements and user perception) for an extra 
effective claim.
    The agency has determined that the studies indicate that 
gravimetric testing shows an adequate difference between a standard 
antiperspirant (with a 20-percent reduction in sweat) and an 
antiperspirant with at least a 30-percent reduction in sweat, as 
required by the Panel, to support an ``extra effective'' claim. The 
agency stated in the tentative final monograph (47 FR 36492 at 36499) 
that once the level of activity that is perceivable by users has been 
established using the Panel's recommended guidelines, it will not be 
necessary to perform user perception testing on individual products. 
Accordingly, the agency concludes that no further user perception 
testing is necessary for an ``extra effective'' claim, which is being 
included in the monograph for those antiperspirant products that reduce 
underarm perspiration by 30 percent or more using the guidelines for 
effectiveness testing of antiperspirant drug products referred to in 
Sec.  350.60.
    The Panel placed ``extra-strength'' claims in Category II because 
it concluded that ``the presence of more active ingredient in an 
antiperspirant product cannot be used as a basis for a claim of added 
effectiveness because additional amounts of antiperspirant active 
ingredient do not necessarily result in improved product 
effectiveness'' (43 FR 46694 at 46724). The Panel also stated that 
``the term `extra-strength' normally refers to increased concentration 
of the active ingredient which would normally mean added 
effectiveness.'' Several comments agreed that more active ingredient 
may not yield more effectiveness. Thus, a product containing 20 percent 
of an active ingredient (compared to 15 percent) that did not provide 
30 percent or more sweat reduction could not claim ``extra strength'' 
or ``extra effective.''
    The agency does not believe that for antiperspirants the claim 
``extra strength'' is as informative to consumers as the claim ``extra 
effective.'' The agency considers ``extra effective'' to be the key 
information that consumers want to know to select an appropriate 
antiperspirant product. The agency is including this new labeling claim 
in Sec.  350.50(b)(4) of this final monograph. Based on this 
discussion, the agency concludes that a hearing is not needed on this 
subject.
    (Comment 12) Several comments objected to the Panel's Category III 
classification of claims for enhanced duration of effect, such as ``24-
hour protection,'' ``one spray keeps you comfortably dry all day,'' 
``prolonged protection,'' etc. (43 FR 46694 at 46728). One comment 
stated that if an antiperspirant product can be shown to provide the 
required 20-percent reduction in perspiration under hotroom conditions 
for 24, 48, etc. hours after application, then duration claims have 
been substantiated.
    Three manufacturers submitted gravimetric studies (Refs. 4, 7, 10, 
and 11) that used a hotroom to induce sweating and measured sweat 
collected in cotton pads twice over a 24-hour period. The tested 
ingredients showed a 20-percent or more reduction in sweat production 
for both collection times, which the comments contended satisfied 
enhanced duration claims such as ``24 hour protection'' and ``all day 
protection.'' One comment added that its data (Ref. 11) support a 
variety of product forms (cream, roll-on, solid

[[Page 34278]]

stick) and, thus, the enhanced duration effect is not limited to 
product form.
    The agency has determined that the data support a claim of enhanced 
duration for 24 hours according to the Panel's criteria. The protocols 
in seven of the studies (Refs. 7 and 10) varied only slightly from the 
Panel's recommended protocol. Subjects in one study abstained from 
antiperspirant use for 2 weeks prior to the study. Subjects in the 
other six studies stopped using antiperspirants 4 weeks prior to the 
studies. The subjects were pretreated with an antiperspirant for the 5 
days prior to beginning sweat collection procedures. Sweat was 
collected 4 and 24 hours following the last antiperspirant application. 
Five studies included untreated axilla controls, and two studies 
included placebo controls. One product was tested in two different 
studies (one with a placebo and one without), and the results were 
virtually identical. The tests supported enhanced duration efficacy of 
20 percent sweat reduction over the 24-hour period for aluminum 
zirconium tetrachloride (15.5 percent roll-on and 18.2 percent stick), 
zirconium tetrachloride (20 percent roll-on), aluminum chlorohydrate 
(6.8 percent aerosol), and aluminum chloride (20 percent solution).
    Other data (Ref. 4) also supported enhanced duration of 
effectiveness for antiperspirant solid sticks containing 10 and 25 
percent aluminum chlorohydrate. Subjects, who abstained from 
antiperspirant use for 17 days prior to the study, were pretreated with 
an antiperspirant for the 3 days prior to sweat collection, 1 and 24 
hours after the last antiperspirant application. Standard hotroom and 
sweat collection procedures were used. Over the 24-hour period, both 10 
percent and 25 percent aluminum chlorohydrate sticks reduced sweat 
production in the treated axilla by 20 percent compared to the 
untreated axilla. The 25-percent aluminum chlorohydrate product also 
showed a 30-percent reduction in sweat production.
    Six other studies (Ref. 11) support enhanced duration claims. Most 
products showed a 20-percent reduction in sweat production compared to 
an untreated axilla for both the 4- and 24-hour evaluation periods, 
with several products showing a 30-percent sweat reduction. However, 
the studies did not identify the antiperspirant active ingredients.
    The agency is including the following enhanced duration claims in 
Sec.  350.50(b)(3) of this final monograph: ``all day protection,'' 
``lasts all day,'' ``lasts 24 hours,'' or ``24 hour protection.'' In 
order to make such a claim, an antiperspirant product must reduce sweat 
production by at least 20 percent over a 24-hour period after 
application using the guidelines for effectiveness testing referred to 
in Sec.  350.60. Antiperspirant products that meet the extra effective 
criteria (see section II.C, comment 11 of this document) over a 24-hour 
period can be labeled with both extra effective and enhanced duration 
claims (e.g., ``24 hour extra effective protection,'' ``all day extra 
effective protection,'' ``extra effective protection lasts all day,'' 
etc.). Claims of enhanced duration for more than 24 hours are 
nonmonograph because the agency has not received any data to 
demonstrate antiperspirant effectiveness for more than 24 hours 
according to the Panel's criteria.
    (Comment 13) Several comments objected to the Panel's Category III 
classification of claims for control of emotional sweating, e.g., 
induced by tension or stress (43 FR 46694 at 46728). The comments 
contended that a product's antiperspirant activity is the same whether 
the sweat is due to thermal conditions or emotional factors. Some 
comments disagreed with the need for additional testing, especially 
consumer perception testing, to establish these claims. One comment 
requested a hearing.
    One comment submitted clinical data (Refs. 7 and 12) which it 
contended showed: (1) There is a valid scientific protocol that 
combines a gravimetric sweat test with a word-quiz stress test to 
measure reduction in emotionally-induced sweat; (2) an antiperspirant 
is not washed from the axillae during controlled emotional stressing, 
and excessive sweat does not diminish antiperspirant effectiveness; (3) 
an antiperspirant effective in reducing thermally-induced sweat is 
effective in reducing emotionally-induced sweat also; and (4) an 
antiperspirant that reduces emotionally-induced sweat by 20 percent or 
more meets the standard for antiperspirant effectiveness for which user 
perception and benefit has already been accepted and, thus, there is no 
need for additional user perception testing. The studies included 
aerosol, roll-on, and stick products containing aluminum chlorohydrate 
or aluminum zirconium tetrachlorohydrate, the major antiperspirant 
active ingredients.
    The agency has determined that gravimetric sweat tests combined 
with mental stress tests support an emotionally-induced sweating claim. 
The data included 12 studies with the same design of 5 days each on 
panels of approximately 25 female subjects: Pretest-abstention from all 
antiperspirants for at least 4 weeks prior to the study; day one--
pretreatment control sweat collection under no stress; day two--
pretreatment control sweat collection under emotional stressing; days 
two through five--apply test product; and days four and five--
posttreatment sweat collection under emotional stressing. Subjects 
applied the antiperspirant test formulation to one axilla and used 
either a comparative formulation, a control placebo formulation, or no 
treatment on the opposite axilla. A control emotional challenge test, 
which lasted for about 60 minutes, was done on day two and an emotional 
challenge test was done on days four and five of the study.
    Emotional sweating was induced by having subjects do a word 
definition test conducted by a moderator experienced at insuring 
optimum stress. The subjects received monetary rewards for a correct 
definition, but forfeited some of their rewards for incorrect or 
untimely definitions. Subjects had a 5-second time limit to begin a 
response and a 15-second maximum time to give the actual word 
definition. After 60 minutes, sweat was measured gravimetrically from 
the preweighed absorbent pads. Standard sweat collection and 
statistical evaluation procedures were used. The median sweat output 
for the 12 studies was 1,257 milligrams (mg) for the pretreatment 
control under emotional stressing compared to 415 mg for the 
pretreatment control under no stress. This word definition test 
effectively elicited a sweat response.
    In the 12 studies using the word definition test, there was at 
least a 20-percent reduction of sweat production. The top 10 percent of 
heavy sweaters from each study (25 subjects) having the highest 
sweating rates on the untreated axilla had a 36.8 percent average sweat 
reduction compared to 38.2 percent reduction in the remaining 90 
percent of each population (196 subjects), showing no significant 
difference in effectiveness in the two groups. Majors and Wild (Ref. 
13) obtained similar results when comparing individual percent 
reduction in thermal sweating in the antiperspirant-treated axilla to 
rate of sweating from the untreated axilla in 89 subjects. They found 
that heavy sweating did not affect the rate of reduction.
    The products tested under the emotional sweat protocol were also 
evaluated under a standard thermal sweat protocol at 100 [deg]F with 30 
percent relative humidity. The average percent sweat reduction for 
aerosols was 37.0 percent for emotional sweating and 34.0 percent for 
thermal sweating, for sticks it was 46.0 percent for emotional

[[Page 34279]]

sweating and 41.4 percent for thermal sweating, and for roll-ons it was 
51.3 percent for emotional sweating and 53.3 percent for thermal 
sweating. These data show that the same products have similar average 
percent sweat reduction for both emotional and thermal sweating.
    The agency concludes that gravimetric sweat tests combined with 
mental stress tests are sufficient to show effectiveness for control of 
emotionally-induced sweating; the data show antiperspirant drug 
products that are effective for thermal sweating are also effective for 
emotional sweating. The agency has determined that no additional 
testing (e.g., user perception tests) is required for an emotionally-
induced sweating claim for products containing monograph ingredients 
that meet the guidelines for effectiveness testing of antiperspirant 
drug products referred to in Sec.  350.60.
    The agency is including the following emotionally-induced sweating 
claim in Sec.  350.50(b)(2) of this final monograph: ``also [select one 
of the following: `decreases,' `lessens,' or `reduces'] underarm 
[select one of the following: `dampness,' `perspiration,` `sweat,' 
`sweating,' or `wetness'] due to stress''. Based on the previous 
discussion, the agency concludes that a hearing is not needed on this 
subject.
    (Comment 14) One comment requested monograph status for 25 percent 
aluminum chlorohydrate to control foot perspiration based on 
gravimetric and perceptual data from four randomized, double-blind, 
bilateral, paired-comparison trials, each having 12 female subjects 
(Ref. 14). Treatment was randomly assigned; aluminum chlorohydrate was 
used on one foot and placebo on the other foot. A 25 percent aluminum 
chlorohydrate solution in 50 percent ethanol:50 percent water and a 
placebo control consisting of 50 percent ethanol:50 percent water were 
used in the first study. The same solutions in aerosol form were used 
in the other three studies. The procedure in the agency's ``Guidelines 
for Effectiveness Testing of OTC Antiperspirant Drug Products'' (Ref. 
9) was modified for foot testing: (1) A 3-day pre-treatment period 
during which subjects were not to use any foot care products, with each 
subject receiving four daily product applications prior to final 
hotroom posttreatment testing collection; (2) sweat collection media 
were cotton socks rather than absorbent pads; (3) a required 5-minute 
period of mild exercise (walking around the hotroom at the beginning of 
each collection period); and (4) a modified method to calculate 
effectiveness due to the erratic rate of sweat collections for both 
treated and control feet.
    The comment stated that the calculation technique included in the 
agency's guidelines could not be used for the following several 
reasons: (1) The increased number and higher concentration of sweat 
glands in the foot area, (2) the occlusive nature of the foot area, and 
(3) the erratic rate of sweat collections for both treated and control 
feet. The comment contended that by considering the baseline, the 
posttreatment sweat collections, and the preferential subject 
perception data, statistically significant differences could be shown 
between sweat collection values for the treated foot compared to 
baseline values.
    The comment stated that based on at least a 5-percent difference 
between the measured sweat output of each foot, sweat reduction was 
achieved for the treated foot in 25 of 48 subjects (52 percent) 
compared to only 10 of 48 subjects (21 percent) for the control foot. 
The comment added that, based on the user perception questionnaire, 75 
percent of the subjects (29 out of 39 subjects who were able to 
discriminate) were able to perceive after the hotroom exposure that the 
treated foot was drier compared to only 21 percent of the subjects (10 
out of 48) who perceived the control foot to be drier.
    A second comment submitted a proposed clinical protocol (Ref. 15), 
but never submitted any clinical data.
    The agency has found the data are insufficient to support a foot 
antiperspirant claim. In axillary sweating tests submitted to the 
Panel, the range of effectiveness (average percent sweat reduction) of 
antiperspirants was 20 to 40 percent in most tests, with aerosols 
having a reduction range of 20 to 33 percent (43 FR 46694 at 46713). In 
the comment's studies on aluminum chlorohydrate for foot 
antiperspirancy (Ref. 14), the average percent sweat reduction was 
below 10 percent, which is considerably below the 20 percent minimum 
level of sweat reduction recommended by the Panel for efficacy testing 
of OTC antiperspirant drug products on the foot (43 FR 46728). In 
addition, the agency has a number of concerns about the comment's data 
treatment methods: (1) The particular sweat collections selected for 
analysis were not chosen consistently across studies but were based on 
arbitrarily chosen final sweat measurements that varied with the 
different studies, (2) the choice of a 5-percent difference between the 
measured sweat output of each foot as ``clinically significant'' seems 
arbitrary and was not prespecified in the protocol, (3) the efficacy 
criterion used (greater than 15 percent reduction from baseline) was 
apparently defined after the data were collected and the results are 
therefore potentially biased, and (4) comparison with baseline is not 
an adequate basis upon which to conclude product efficacy because it 
ignores placebo and time effects that are accounted for in between 
product comparisons. The agency's analysis of ``across study'' data 
(using the average of the two sweat collections on day four, or average 
of the four collections on day four and five as the baseline, and the 
average of the two final collections as a measure of the final sweat 
product) did not show a statistically significant mean (or mean 
percent) sweat reduction from baseline in treated or control feet.
    The agency does not agree with the comment's evaluation of its user 
perception data, but considers the product as ineffective both in 
subjects who preferred placebo and in subjects with no preference. It 
appears that the comment chose to ignore tied preferences. However, 
when subjects with no preference were included in the analysis, 22 out 
of 48 subjects (45.8 percent) and 29 out of 48 subjects (60.4 percent) 
preferred the treated foot, before entering and after leaving the 
hotroom, respectively. Both proportions are not significantly different 
from 1/2 (two-tailed, p = 0.28 and 0.15, respectively). Furthermore, 
the subjects apparently could not perceive which foot, treated or 
untreated, was drier. More subjects failed to choose the drier foot, 
than chose it correctly, both at baseline and posttreatment. Thus, the 
wetness perception study failed to show that subjects are able to tell 
marginal differences in sweating of the feet.
    The agency has concluded that no statistically significant 
treatment effect was found in sweat reduction or in subject's 
perception of sweat (Ref. 16). Thus, 25 percent aluminum chlorohydrate 
has not been shown to be an effective foot antiperspirant. The agency 
provided the second comment suggestions on its protocol; a revised 
protocol was acceptable (Ref. 17), but no test data were ever 
submitted. The agency is not including foot antiperspirancy claims in 
the final monograph.

D. Comments on Testing Guidelines

    (Comment 15) Several comments requested that the background section 
of the effectiveness testing guidelines include the following: ``FDA 
recognizes that alternative methodologies may be appropriate to qualify 
an antiperspirant drug product as effective. These

[[Page 34280]]

guidelines do not preclude the use of alternative methodologies that 
provide scientifically valid results.''
    The agency is adding this statement (but changing the words 
``alternative methodologies'' to ``alternate methods'') and adding 
``subject to FDA approval'' to provide for alternate methods and 
statistical evaluations of effectiveness test data.
    (Comment 16) Several comments requested that the relative humidity 
of 35 to 40 percent in the effectiveness testing guidelines be lowered 
to 30 percent, the hotroom condition widely used by industry. One 
comment submitted the results of effectiveness studies (Refs. 7, 10, 
and 18) that used a hotroom operated at 30 + 3 percent relative 
humidity. The comment stated that 30 percent relative humidity 
accurately measures antiperspirant effectiveness without causing 
excessive discomfort to test subjects. Two other comments submitted 
effectiveness test data where the relative humidity in the hotroom was 
``about 35 percent'' (Refs. 19 and 20) or ``35 percent +/- 5 percent'' 
(Ref. 21).
    Based on these data, the agency is revising the relative humidity 
range for hotroom conditions in the antiperspirant effectiveness 
testing guidelines from 35 to 40 percent to a range of 30 to 40 
percent. Seven studies (Ref. 10) that showed an enhanced duration of 
effectiveness of 20 percent sweat reduction over a 24-hour period for 
several antiperspirant products (see also section II.C, comment 12 of 
this document) used a protocol (Ref. 18) in which the subjects were 
placed in a controlled environment with the temperature held at 100 +/- 
2 [deg]F and the relative humidity held at 30 +/- 3 percent. Because 
the subjects were able to generate at least 150 mg of sweat per axilla 
per 20 minute period, the agency considers the results of the 
gravimetric tests valid. In other studies (Refs. 20 and 21), sweating 
was induced by having the subjects sit in a hotroom maintained at a 
temperature of 100 +/- 2 [deg]F and at a relative humidity of about 35 
percent or 35 +/- 5 percent. These studies support claims of extra 
effectiveness and enhanced duration (24-hour claims). See section II.C, 
comments 11 and 12 of this document. To assure that test subjects sweat 
adequately during the hotroom test, the agency is adding the following 
baseline perspiration rate condition: ``Baseline perspiration rate. 
Test subjects must produce at least 100 milligrams of sweat from the 
untreated or placebo control axilla in a 20-minute collection in the 
controlled environment.''
    (Comment 17) Two comments requested revision of the part of the 
antiperspirant effectiveness testing guidelines that involves 
application of a control formulation to the alternate axilla during 
testing. Noting that the guidelines state that the control formulation 
is to be ``devoid of any antiperspirant activity * * * determined in a 
test compared to no treatment,'' a comment contended that it should be 
appropriate to compare antiperspirant activity directly against an 
untreated axilla and, thereby, reduce the time, complexity, and cost of 
the testing, especially the cost of developing a control formulation 
``devoid'' of antiperspirant activity. The comment requested that the 
testing guidelines be revised to provide for the application of a 
control formulation or no treatment to the other axilla of each test 
subject. The other comment submitted data from two studies (Refs. 22 
and 23) where one antiperspirant formulation was tested against both a 
placebo control and an untreated axilla control with virtually 
identical results; therefore, a placebo control was unnecessary to 
evaluate product effectiveness.
    The data (Refs. 22 and 23) involved an aerosol spray containing 6.8 
percent aluminum chlorohydrate tested by two gravimetric sweat tests 
under hotroom conditions to substantiate the claim that the product 
provides ``all day wetness protection.'' Both studies had the same 
design: Day one--pretreatment control collection; days two, three, and 
four--application of antiperspirant; and days four and five--
posttreatment sweat collection 4 and 24 hours after application. The 
data were evaluated using one of the statistical methods recommended in 
the antiperspirant testing guidelines. In one study (Ref. 22), the 
product was tested against a placebo aerosol in 44 subjects. The 
placebo was identical to the test formulation and supposedly devoid of 
antiperspirant activity; the formula difference was adjusted with 
aerosol propellant. The results were statistically significant and 
showed that the aluminum chlorohydrate aerosol effectively reduced 
sweat production by at least 20 percent more than the placebo aerosol 
at 4 and 24 hours after application. However, the placebo showed some 
antiperspirant activity. In the second study (Ref. 23), the same 
product was tested against an untreated axilla control in 49 subjects 
with statistically significant results. The aluminum chlorohydrate 
aerosol effectively reduced sweat production by at least 20 percent 
more on the treated axilla than the untreated control axilla at 4 and 
24 hours after application.
    The agency is unable to conclude from these data that an untreated 
comparator is equivalent to use of a placebo. The observed effect of a 
treatment (e.g., antiperspirant) may represent the sum of the 
pharmacological effects of the test drug and other effects associated 
with the intervention effort, which may include psychological effects 
and the effects of the excipients used in a product formulation. 
Although studies have been conducted in the past using no treatment for 
one axilla, the use of a placebo control for that axilla allows for 
assessment of the net treatment effects of the test article. Therefore, 
the agency is retaining the requirement for a placebo/vehicle control 
in the antiperspirant effectiveness testing guidelines.
    The proposed guidelines stated that the control formulation is as 
similar as possible to the test formulation and devoid of any 
antiperspirant activity. As the placebo used in one study (Ref. 22) was 
not completely devoid of antiperspirant activity, the agency is 
revising the guidelines to state:
    Hotroom procedure. (1) For gravimetric and user perception 
testing, treatments consist of the application of the test 
formulation to one axilla and the application of a placebo control 
formulation to the other axilla of each test subject. Except for the 
active ingredient, the placebo control formulation should be as 
similar as possible to the test formulation.
    The agency concludes that this revised testing procedure will 
reduce the time, complexity, and cost of testing because it eliminates 
the cost of developing a control formulation ``devoid'' of 
antiperspirant activity.

E. Comments on Antiperspirant Active Ingredients

    (Comment 18) Several comments noted a discrepancy in a heading in 
an active ingredient table in the Panel's report (43 FR 46694 at 
46697), where ``Metal:Halide'' is used, and in proposed Sec.  350.10 
(47 FR 36492 at 36504), where ``Al:Cl'' is used. Two comments suggested 
that ``Al:Cl'' in the table heading and in Sec.  350.10 should be 
changed to ``Metal:Cl,'' because the ratio range in the table is for 
the ratio of the ``Cl'' to either aluminum (``Al'') or aluminum plus 
zirconium (``Al+Zr'').
    The agency notes that the ratio range designated as ``A1:Cl'' in 
the TFM should have been ``Metal:Halide,'' as it was in the Panel's 
report. The agency is not including the ratio range table in Sec.  
350.10 of this final monograph because this information is now included 
in the U.S. Pharmacopeia-

[[Page 34281]]

National Formulary (USP-NF) monographs for each active ingredient 
included in Sec.  350.10, where applicable. The agency is changing the 
introductory text of Sec.  350.10 to state: ``Where applicable, the 
ingredient must meet the aluminum to chloride, aluminum to zirconium, 
and aluminum plus zirconium to chloride atomic ratios described in the 
United States Pharmacopeia-National Formulary.''
    (Comment 19) Two comments agreed with the agency that buffer 
components present in the compound, such as glycine or glycol, should 
be omitted when calculating the maximum allowable concentration of 
active ingredients in an antiperspirant product (47 FR 36492 at 36495). 
One comment noted a potential source of confusion because the active 
ingredients table in proposed Sec.  350.10 included the buffer names 
along with the active ingredient names. To minimize confusion and to be 
consistent with the agency's policy regarding buffers, the comment 
requested the agency to remove the buffer names from the ``active 
ingredient'' column in Sec.  350.10. The comment proposed a number of 
changes in the active ingredient section.
    When the Panel first discussed terminology for aluminum chloride 
and aluminum chlorohydrate antiperspirant active ingredients, the 
buffer additives were not included (Ref. 24). Subsequently, the 
Cosmetic, Toiletry, and Fragrance Association (CTFA) Antiperspirant 
Task Force developed definitions for aluminum chlorohydrex complexes 
with propylene glycol or polyethylene glycol, and for aluminum 
zirconium chlorohydrex complexes with glycine (Ref. 25). The Panel 
adopted these definitions, including those for ingredients with 
buffered additives, in its report (43 FR 46694 at 46696 and 46697), and 
the agency proposed this nomenclature in the TFM (47 FR 36492). Since 
the comment was submitted, the USP-NF developed names for these 
antiperspirant active ingredients that include the names of the 
buffers, where applicable, and active ingredient names in this final 
monograph include the buffer, where applicable.
    The agency considers calculation of the concentration of an 
antiperspirant ingredient present in a product based on the amount of 
anhydrous ingredient to be appropriate. Buffered antiperspirant 
ingredients contain the same active chemical moiety as the 
corresponding nonbuffered ingredients, and the antiperspirant activity 
of both ingredients is similar.
    (Comment 20) One comment requested the agency allow concentrations 
of antiperspirant active ingredients above those proposed in the 
monograph as long as the amount of ingredient applied to the skin is 
not greater than the amount judged safe by the Panel. The comment noted 
that, in the TFM (comment no. 12, 47 FR 36492 at 36495 to 36496), the 
agency had disagreed with earlier comments on this issue and stated 
that ``the comments included no new data to show that a higher 
concentration of antiperspirant active ingredient marketed in a 
particular container would deliver no more than the amount of active 
ingredient judged safe by the Panel.''
    The comment submitted new data from eight usage studies (Ref. 26) 
to support a higher (up to 35 percent) active ingredient concentration 
for powder roll-on antiperspirant drug products. Fifty male and female 
subjects, between the ages of 18 and 55, participated in each study. 
Subjects were given a preweighed product and instructed to use only 
that product, to keep a record of how many times they used it, and not 
to allow anyone else in the household to use the product. An average of 
43 subjects completed the 1-week studies and returned their product to 
the laboratory where it was reweighed.
    The amount of product applied with each use was calculated. The 
four powder roll-ons, which contained 33 percent aluminum zirconium 
tetrachlorohydrate, were found to deliver between 23 and 44 mg of 
antiperspirant ingredient per axilla per use. The other product forms 
(solid stick, cream, or liquid roll-on), containing 18 to 19 percent of 
either aluminum chlorohydrate or aluminum zirconium tetrachlorohydrate, 
were found to deliver between 54 and 98 mg of antiperspirant ingredient 
per axilla per use. The comment contended these data show that higher 
concentrations of active antiperspirant ingredients, as used in powder 
roll-on systems, deposit no more and, in fact, deposit less active 
ingredient than is deposited in a liquid roll-on, solid stick, or cream 
product containing proposed monograph concentrations of active 
ingredients. Thus, the comment argued that concentrations up to 35 
percent of Category I active ingredients should be allowed in powder 
roll-on antiperspirants.
    This issue was specifically brought before the Panel, which did not 
agree to change the maximum concentration (Ref. 27). The Panel noted 
that aluminum antiperspirants can be irritating, expressed concern that 
a small amount of a concentrated formulation may be more irritating 
than a large amount of a more dilute formulation, and concluded that 
antiperspirant products with a higher concentration would need an NDA 
with additional safety studies. The agency notes that increasing the 
concentration of aluminum antiperspirant ingredients increases the 
acidity of the material and irritation of the skin (Refs. 28, 29, and 
30). The agency concludes that safety data are needed to show that 
powder roll-on dosage forms containing up to 35 percent aluminum 
chlorhydrates or aluminum zirconium chlorhydrates are not irritating.
    Since the TFM was published, several citizen petitions have raised 
concerns about the amount of aluminum absorbed from topical 
antiperspirant drug products. (See section II.F, comment 23 of this 
document.) The agency has no data showing that products containing up 
to 35 percent aluminum chlorhydrates or aluminum zirconium 
chlorhydrates increase aluminum absorption and is not revising the 
monograph to provide for powder roll-on dosage forms containing up to 
35 percent antiperspirant active ingredient, without additional safety 
data being provided.
    (Comment 21) One comment requested monograph status for aluminum 
sesquichlorohydrate prepared by neutralizing aluminum chloride with 
magnesium hydroxide even though the aluminum to chloride (Al:Cl) ratio 
of the ingredient prepared in this manner does not fall within the 
range specified for aluminum sesquichlorohydrate in the TFM. The 
comment stated that during the course of the rulemaking all aluminum 
chlorhydrates placed in Category I were prepared by conventional 
techniques: Either by neutralization of aluminum chloride with aluminum 
monochlorohydrate or by a controlled reaction of aluminum metal with 
hydrochloric acid. Thus, the comment argued that it was both 
appropriate and convenient to characterize the various aluminum 
chlorhydrates in terms of their Al:Cl ratios.
    The comment stated that its data showed that the reaction of 
aluminum chloride with magnesium hydroxide yields aluminum 
sesquichlorohydrate equivalent to that listed in the TFM and the 
neutralizer magnesium hydroxide does not contribute either aluminum or 
chloride ions to the neutralization process; thus, the Al:Cl ratio of 
aluminum sesquichlorohydrate prepared this way will always remain 0.33, 
the same as aluminum chloride alone. The comment was concerned because 
this Al:Cl ratio of 0.33 does not fall within the ratio range of 1.9 
down

[[Page 34282]]

to but not including 1.25:1 proposed for aluminum sesquichlorohydrate 
in the tentative final monograph (47 FR 36492 at 36504). The comment 
contended that if the final product is regarded as a mixture of 
aluminum sesquichlorohydrate and magnesium chloride, and if the amount 
of chloride that serves as counter ions for the magnesium ions were 
subtracted from the total chloride, then the Al:Cl ratio of the 
aluminum sesquichlorohydrate component of the mixture would have the 
Al:Cl ratio specified in the TFM. The comment submitted data (Ref. 31) 
using gel permeation chromatography and elemental analysis of the 
eluates (the substance separated out by washing) to show that aluminum 
sesquichlorohydrate prepared by this neutralization method is 
chromatographically indistinguishable from that prepared by 
conventional methods. The comment suggested designating the ingredient 
prepared by the neutralization method as ``aluminum sesquichlorohydrate 
MAG.''
    The agency does not find these analytical data sufficient to 
support the comment's claim that the ingredient prepared by this 
neutralization method is chemically equivalent in composition to 
aluminum sesquichlorohydrate. The chromatographic indistinguishability 
from aluminum sesquichlorohydrate prepared by conventional methods only 
demonstrates that the chromatographic method in this study is 
insufficient to support the claim. This result perhaps is to be 
expected because the gel permeation chromatographic method used in this 
study is based primarily on a size exclusion principle; however, the 
agency doubts that any chromatographic method will provide such 
support.
    USP 23-NF 18 Fifth Supplement (Ref. 32) added a monograph for 
aluminum sesquichlorohydrate and described it as consisting of complex 
basic aluminum chloride that is polymeric and loosely hydrated and 
encompasses a range of aluminum-to-chloride atomic ratios between 
1.26:1 and 1.90:1. Its chemical formula is stated as: 
Aly(OH)3y-zClz.nH2O.
    According to the method described in the comment, when aluminum 
sesquichlorohydrate is prepared by the reaction of aluminum chloride 
with magnesium hydroxide, the product must be a mixture of aluminum 
sesquichlorohydrate and magnesium chloride. The agency does not 
consider it suitable from a technical point of view to simply designate 
this material as aluminum sesquichlorohydrate. Information provided by 
the comment shows that the alternate process material is not 
``equivalent in composition'' because the aluminum to chloride ratio of 
0.33 is outside the specified range for aluminum sesquichlorohydrate 
and because the material contains measurable amounts of magnesium. 
Also, as discussed in section II.E, comment 18 of this document, 
because the atomic ratio range should be metal to halide, magnesium 
should be counted as a metal in the atomic ratio range of the comment's 
material. Using the name aluminum sesquichlorohydrate for an ingredient 
prepared by neutralization of aluminum chloride with magnesium 
hydroxide would be misleading because this would imply that the drug is 
the same identifiable ingredient as aluminum sesquichlorohydrate 
prepared by neutralization of aluminum chloride with aluminum 
chlorohydrate. The agency believes the material described in the 
comment should be classified as a new ingredient, perhaps an aluminum 
magnesium chlorohydrate, rather than aluminum sesquichlorohydrate.
    The agency concludes that additional information on the chemical 
characterization of the proposed material, particularly its ionic 
structure, is needed to permit a more scientific review. The submitted 
information does not provide a technical basis for allowing the 
substitution of aluminum sesquichlorohydrate manufactured by 
neutralization with magnesium chloride for that neutralized with 
aluminum monochlorohydrate. The USP-NF monograph (Ref. 32) does not 
contain information to characterize or identify an aluminum 
sesquichlorohydrate containing magnesium (e.g., no identification or 
content test, and no assay involving magnesium calculations).
    Further, the agency notes that no clinical efficacy data were 
provided to show that the material proposed in the comment would be 
equally effective as aluminum sesquichlorohydrate prepared in the 
conventional manner. Even minor variations in formulation, such as the 
addition of emollients or buffers, can alter the effectiveness of an 
antiperspirant ingredient. (See comment no. 8 in the TFM (47 FR 36492 
at 36494).) The new mixture may be just as effective. However, whether 
such a finding would apply to equal amounts, or whether an equivalent 
effect could be achieved with a greater or lesser amount of aluminum 
sesquichlorohydrate prepared with magnesium hydroxide, should be 
determined by effectiveness testing that follows the guidelines 
referred to in Sec.  350.60 of the final monograph. The agency needs 
appropriate effectiveness data and an appropriate USP-NF monograph 
amendment (see 21 CFR 330.14(i)) before the ingredient prepared by the 
new method can be generally recognized as safe and effective and 
included in the final monograph.
    (Comment 22) One comment objected to the agency's rejection of its 
earlier request (discussed in comment no. 9 of the TFM, 47 FR 36492 at 
36495) that combinations of two or more Category I antiperspirant 
ingredients should be Category I. The comment stated that the 
combination policy in Sec.  330.10(a)(4)(iv) allows combinations of two 
or more safe and effective active ingredients; thus, the Panel should 
be reversed.
    In the TFM (47 FR 36495), the agency concurred with the Panel (43 
FR 46694 at 46718) that both combinations of antiperspirant active 
ingredients and combinations of antiperspirant active ingredients with 
other types of active ingredients (except for a deferred 
antiperspirant/antifungal combination) are Category II because of no 
information on the existence of any such combinations or any data to 
support their safe and effective use.
    The agency classified antiperspirant/antifungal combination drug 
products in Category III in the TFM for OTC antifungal drug products 
(December 12, 1989, 54 FR 51136 at 51148 and 51149). No additional data 
were submitted to support this combination, and in the final monograph 
for OTC antifungal drug products (September 23, 1993, 58 FR 49890 at 
49891), the agency classified all antifungal combination drug products 
as nonmonograph.
    The comment did not provide any supporting data or specific 
examples of Category I antiperspirant ingredients that would be 
suitable for use in combination with other antiperspirant or 
nonantiperspirant Category I ingredients. Thus, the combination policy 
does not apply. These combinations remain nonmonograph. However, new 
clinical data may be submitted to support safety and effectiveness.

F. Comments on the Safety of Aluminum Ingredients

    (Comment 23) The information and arguments presented by the citizen 
petitions that questioned the safety of aluminum-containing ingredients 
in OTC antiperspirant drug products and the comment that disagreed with 
one of the citizen petitions were discussed in detail in the Federal 
Register of March 23, 1993 (58 FR 15452 at 15453 and 15454). One 
petition was concerned that aluminum can be absorbed and get into the 
blood and that some of the aluminum in the blood enters the brain,

[[Page 34283]]

where it remains and accumulates. The petition cited a study by Perl 
and Good (Ref. 33) that suggested that inhaled aluminum compounds could 
have a direct nasal-olfactory pathway to the brain. The other petition 
contended that two inhalation studies (Refs. 34 and 35) provided by 
industry showed aluminum absorption in the peribronchial lymph nodes, 
brain, and adrenal glands of the animals after 12 and 24 months. Both 
petitions expressed concern about the potential neurotoxicity of 
aluminum upon chronic use, especially a possible link to Alzheimer's 
disease.
    The comment that disagreed with one petition contended that the 
majority of the petitioner's references described findings from in 
vitro studies that did not consider the blood-brain barrier, which is 
the brain's main defense against potentially toxic substances such as 
aluminum. The comment contended that extraordinarily high 
concentrations of aluminum were used in these studies, and that 
aluminum from antiperspirants would never reach a biologically 
significant level to be of concern. The comment stated that the 
majority of researchers investigating the etiology of Alzheimer's 
disease would consider current evidence insufficient to link aluminum 
to Alzheimer's disease. The comment concluded that current scientific 
information does not support the need to reclassify the safety of 
aluminum-containing antiperspirants.
    The agency does not find the current evidence sufficient to 
conclude that aluminum from antiperspirant use results in Alzheimer's 
disease. Both petitions mention the widely quoted study by Perl and 
Good (Ref. 33) as showing that inhaled aluminum compounds may get 
directly into the brain by a nasal-olfactory pathway. The agency does 
not consider this animal study (published as a one-page Letter to the 
Editor in Lancet) as adequate to establish a direct nasal-olfactory 
pathway for aluminum. This study was only a small pilot animal study, 
about which the agency has a number of concerns.
    First, the method of introducing the aluminum to these animals was 
not physiologically relevant. Two strips of Gelfoam (absorbable gelatin 
sponge, USP) saturated with high concentrations of aluminum salts (15 
percent aluminum lactate or 5 percent aluminum chloride) were inserted 
into rabbits' left nasal recess through a hole drilled into the frontal 
bone. While the authors attempted to demonstrate the accessibility of 
aluminum from the nasal recess to the brain, the agency questions 
whether the normal use of antiperspirant aerosols would ever produce a 
high aluminum concentration in this relatively distant anatomic site. 
Second, the size of this study was very small (only three rabbits in 
each group). The agency is concerned that any error in this complicated 
surgical procedure to introduce the aluminum salts or in preparing the 
specimens for analysis could have caused a major difference in the 
final results. Third, the results were not consistent. Of the three 
animals exposed to aluminum lactate, besides the involvement of the 
left olfactory bulb and the cerebral cortex, only one rabbit had a 
lesion in the hippocampus while the other two rabbits had granulomas 
found in the pyriform cortex. In the group exposed to aluminum 
chloride, only one rabbit had a granuloma in the olfactory bulb while 
the other two rabbits were free of lesions. The distribution of lesions 
in this study was fairly random. If a nasal-olfactory pathway exists 
for neuronal aluminum transport, the agency believes that the 
distribution of these lesions should follow a more persistent 
anatomical pattern. In addition, the authors were unable to explain why 
two of the six rabbits were free of lesions. Finally, although some of 
the rabbits had granulomas, these lesions did not resemble the plaques 
or neurofibrillary tangles found in Alzheimer's disease, and none of 
the rabbits had any symptomatic neurologic deficit. While this study 
implied that access to the brain via the nasal recess may be possible 
under nonphysiological conditions, a direct nasal-olfactory pathway and 
any relationship to Alzheimer's disease cannot be established. Several 
other studies, which were not done with aluminum, are of no value in 
establishing a direct nasal-central nervous system pathway for aluminum 
antiperspirants.
    Aluminum lactate, one aluminum salt used in this study (Ref. 33), 
is not included in this final monograph. Sodium aluminum lactate has 
been used as a buffer for aluminum sulfate in a nonaerosol dosage form, 
but that product is nonmonograph.
    In one of the inhalation studies (Ref. 34), the life-span of the 
male hamsters exposed to the aluminum chlorhydrate aerosol was shorter 
(583 days) than that of the controls (661 days). The female hamsters 
exposed to aluminum chlorhydrate had a slightly longer life-span (489 
days) than the controls (481 days). Male hamsters exposed to aluminum 
chlorhydrate coated with a high concentration of isopropyl myristate, 
an emollient frequently used to increase the retention on the skin of 
the aluminum salts used in antiperspirant products, had a life-span 
(646 days) comparable to the controls (661 days). Overall, these 
numbers do not follow a consistent pattern and could be affected by 
other experimental conditions.
    The same petition criticized the other inhalation study (Ref. 35), 
contending that the results showed that the animals had suffered 
significant weight loss and increased terminal brain-to-body weight 
ratios, results it considered consistent with clinical aluminum 
toxicity, and that the increase in brain weight was possibly due to 
cerebral edema. The petition claimed that because aluminum was found to 
be deposited in the animals' brains, peribronchial lymph nodes, and 
adrenal glands, this proved that systemic absorption of aluminum had 
occurred and that aluminum had been transported to the brain. Other 
comments disagreed with the petition's argument that the rats in this 
study were found to have detectable aluminum levels in their brains 
after 12 months, contending that this finding may only be artificial 
considering the analytical methods used. The comments added that if 
aluminum did accumulate in the rats' brains, those rats should have had 
symptoms of neurotoxicity, which they did not have. The comments 
concluded that the artificial finding should be ignored.
    The agency does not concur with the petition's extrapolations. The 
weight loss occurred only in rats and not in guinea pigs that were 
similarly treated. The increase in terminal brain-to-body weight ratio 
occurred only in the female rats at 12 months in the low- and high-dose 
groups. The female rats in the middle-dose group and all the males were 
not affected. At 24 months, this same ratio was found to increase only 
in the high-dose groups of both sexes; however, the increase in the 
female high-dose group was not statistically significant. The agency 
notes that all of these findings did not follow any predictable pattern 
or a pattern that would be expected from a dose-related or cumulative 
toxin exposure.
    The pattern of deposition was not consistent. In the guinea pigs, 
aluminum was found in the peribronchial lymph nodes, but not in the 
adrenal glands and brains (as occurred in the rats). The agency finds 
it possible that aluminum absorption and deposition may be animal 
dependent. If this were the case, then even if the rat data were 
evidence of a problem, the same situation may not apply to humans. The 
agency is not aware of other investigators having similar results.
    The petitions and the comment had different views on a study by 
Rollin,

[[Page 34284]]

Theodorou, and Kilroe-Smith (Ref. 36) in which rabbits were exposed to 
aluminum oxide dust for 8 hours a day, 5 days a week, for 5 months. The 
authors of the study found that the brains of these rabbits had a 
significant increase in aluminum at the end of the study. The first 
petition contended that this study showed that the inhalation of 
aluminum antiperspirants poses a special risk because this route of 
delivery bypasses the blood-brain barrier. The comment calculated that 
this study would be equivalent to a person using spray antiperspirants 
for approximately 10 seconds daily for 789 years to experience the same 
toxicity. The second petition contended that this 10-seconds-exposure 
assumption was incorrect because the aluminum particles in an 
antiperspirant aerosol remain suspended in the air for a long period of 
time, and the exposure will be more than the comment calculated.
    The agency finds this study has a number of limitations: (1) The 
extraordinary high concentrations of aluminum oxide exposure in the 
animals, (2) the small sample size (eight animals in each group), and 
(3) an overlap in the standard deviations of the results obtained 
decreases the power and generalizability of the study. While the study 
shows an accumulation of aluminum in the rabbits' body tissues under 
certain exposure conditions, the agency does not consider the study as 
providing evidence of a direct nasal-olfactory pathway or that normal 
use of aluminum-containing antiperspirants would provide comparable 
results. Further, the second petition's position includes a number of 
assumptions, which might not occur: (1) That the place where the 
product is used is a confined, poor-ventilated airspace, and (2) that 
the user remains in the vicinity of the dispersed aerosol for a period 
of time during which significant inhalation would occur.
    One petition claimed that an epidemiology study by Graves et al. 
(Ref. 37) has shown that Alzheimer's disease was associated with the 
use of aluminum antiperspirants and that a high incidence of 
amyotrophic lateral sclerosis (ALS) and Parkinson's disease in Chamorro 
natives of Guam, as reported by Garruto (Ref. 38), may be related to 
high environmental aluminum. The agency has looked closely at the 
Graves et al. study (Ref. 37) because it explored the association 
between exposure to aluminum through the lifetime use of 
antiperspirants and antacids and Alzheimer's disease. This was a case-
control study of 130 matched pairs, where the controls were friends or 
nonblood relatives of the case. Subjects (cases and controls) were 
matched by age, sex, and the relationship between the case/control and 
his or her surrogate (spouse or child).
    The authors mentioned that, in general, antiperspirants contain 
aluminum and deodorants do not, except for some deodorants marketed for 
women. The authors reported that there was no association between the 
use of ``any'' antiperspirant/deodorant and Alzheimer's disease. 
However, when the data were stratified by aluminum-containing 
antiperspirants the overall odds ratio showed a modest increase in risk 
and a statistically significant trend emerged between increasing 
lifetime use of aluminum-containing antiperspirants and the estimated 
relative risk of Alzheimer's disease.
    The authors commented that, to their knowledge, this was the first 
epidemiological study of this association between antiperspirants and 
Alzheimer's disease, and there were several methodologic limitations 
that made interpretation of their results difficult. First, there were 
missing data because the case surrogate and the control surrogate could 
only recall all variables (frequency and duration of use, and product 
brand name) in about one-half of the matched pairs. Second, there might 
have been some misclassification because the analyses were based on the 
most common brand provided, while some subjects may have used multiple 
brands. Third, the authors considered the validity of the data, 
resulting from difficulty in learning the subjects' exposure using 
telephone interview methods, to be a critical limitation. Despite these 
limitations, the authors considered an association between aluminum-
containing antiperspirants and Alzheimer's disease as biologically 
plausible, but concluded that their findings are provocative and, due 
to methodologic problems, should be considered preliminary.
    Garruto (Ref. 38) described efforts to establish models of chronic 
motor neuron degeneration in a long-term effort to understand the 
cellular and molecular mechanisms of aluminum neurotoxicity. He studied 
foci of dementia (ALS and Parkinson's disease) in western Pacific 
populations. He mentioned experimental models in rabbits and cell 
culture as demonstrating that chronic, rather than acute, toxicity is 
the cause of human neurodegenerative disorders with a long latency and 
slow progression. However, Garruto stated that he and his colleagues 
had been most deficient in the design and implementation of good 
epidemiological studies, particularly of Alzheimer's disease and the 
epidemiology of aluminum intoxication per se, and described what he 
felt was needed for future well-designed studies.
    The petitions/comment also discussed environmental exposure to 
aluminum, percutaneous absorption after topical use, inhaled absorption 
after aerosol use, aluminum neurotoxicity (and a possible relationship 
to Alzheimer's disease), and possible mechanisms of action. Numerous 
references were provided. The agency has reviewed these references and 
other literature published on aluminum since the petitions were 
submitted. Many early references were simply hypotheses and different 
theories that have not been adequately substantiated in humans or any 
animal models. A number of studies were pilot projects in a few 
animals, and the agency is unable to draw any definite conclusions 
based on the small sample sizes.
    The agency notes Priest's (Ref. 39) statement that most 
investigators now agree that aluminum is unlikely to be implicated in 
causing Alzheimer's disease, whereas Rowan (Ref. 40) contended it would 
be considerably more correct to state that the issue is controversial. 
More recently, Savory et al. (Ref. 41) stated that the question whether 
aluminum presents a health hazard to humans as a contributing factor to 
Alzheimer's disease is still subject to debate.
    The agency finds the literature shows the issue of aluminum 
toxicity and Alzheimer's disease remains controversial and is not 
resolved. Scott et al. (Ref. 42) reported that aluminum has been 
detected in Alzheimer neurofibrillary tangles, but the significance of 
its presence is unknown. Kasa, Szerdahelyi, and Wisniewski (Ref. 43) 
reported that histochemical staining showed that aluminum was present 
in brain samples from Alzheimer's disease victims, but the structural 
localization indicated that it is not primarily involved in the 
etiology of the disease. Candy et al. (Ref. 44) reported that data from 
post mortem brain examinations of patients with chronic renal failure 
who did not have dialysis encephalopathy suggest that it is unlikely 
that aluminum plays any major role in neurofibrillary tangle formation 
and that its role in senile plaque formation is likely to be only part 
of a complex cascade of changes. Savory et al. (Ref. 41) stated that 
the lack of agreement on the question whether the brain content of 
aluminum is increased in Alzheimer's disease attests to the complexity 
of the issue.
    Savory et al. (Ref. 41) indicated that most of the data linking 
aluminum

[[Page 34285]]

exposure to Alzheimer's disease have been derived from several 
epidemiological studies of aluminum in drinking water, which represents 
only a small percentage of the total exposure. They concluded that 
quantification of the risk of Alzheimer's disease from other sources of 
aluminum (such as food additives, cosmetics, deodorants, 
antiperspirants, pharmaceuticals, and respiratory dusts) is needed 
before the total risk from all environmental sources of aluminum can be 
fully evaluated.
    Despite Graves et al.'s acknowledgment of the limitations of their 
study (Ref. 37), other authors, e.g., Anane et al. (Ref. 45), report 
that Graves et al. found an increased risk of Alzheimer's disease with 
lifetime use of aluminum-containing antiperspirants after an 
epidemiological study. Anane et al. applied low aqueous concentrations 
(0.025 to 0.1 micrograms (microg)/square centimeter) of aluminum 
chloride (AlCl3.6H2O) to healthy shaved Swiss 
mouse skin for 130 days. They reported that this led to a significant 
increase in urine, serum, and whole brain aluminum, especially in the 
hippocampus area, compared to control animals. They mentioned that this 
percutaneous uptake and accumulation of aluminum in the brain was 
greater than that caused by dietary exposure to 2.3 microg per day in 
feed and water.
    Anane et al. conducted in vitro and in vivo mouse skin studies and 
showed for the first time that aluminum is absorbed through mouse skin 
and this contributes to a greater body burden than does oral uptake. 
They also mentioned that several antiperspirant preparations containing 
AlCl3.6H2O are applied to sensitive regions of 
the skin, which may increase penetration and could be an important 
source of body aluminum burden. Anane et al. recommended that an 
epidemiological study be conducted to ascertain whether use of 
AlCl3.6H2O-containing antiperspirants correlates 
with neurodegenerative disease, because such cannot be excluded based 
on the results of their study.
    Forbes and Agwani (Ref. 46) stated that there is uncertainty about 
how aluminum-containing substances enter the body, but current 
information suggests that the skin and/or the lung are important. They 
mentioned that Priest (Ref. 39) noted that at least some antiperspirant 
sprays contain aluminum compounds of a particle size of about 1 
micrometer (micron) (micro), which is ideally sized for deposition in 
the deep lung, and that such deposition may also be relevant for skin.
    Salib and Hillier (Ref. 47) examined clinically diagnosed 
Alzheimer's disease patients and controls (other dementias and 
nondementias) and collected information to examine the association 
between Alzheimer's disease and aluminum occupation. They reported that 
manual work, such as welding, expected to be in direct contact with 
aluminum dust and fumes does not appear to be significantly associated 
with the risk of Alzheimer's disease. The authors concluded that no 
significant association was shown between developing Alzheimer's 
disease later in life and previous occupational history for all of the 
occupations in the study. This included both manual workers, who would 
be expected to have had a higher exposure opportunity to aluminum dust 
and fumes, and other workers at an aluminum factory. The authors 
concluded that neither Alzheimer's disease nor dementia in general were 
shown to be associated with previous aluminum occupation.
    Salib and Hillier (Ref. 47), in 1996, repeated Doll's (Ref. 48) 
conclusions from 1993 that it is generally accepted that the delayed 
effects of chronic aluminum exposure have not been adequately assessed 
in man. Factors that govern the bioavailability, neurotoxicity, and the 
effect of chronic low dose exposure to aluminum compounds remain 
unclear. Flaten et al. (Ref. 49) stated that the lack of a readily 
available radioactive isotope of aluminum has been a major obstacle 
toward elucidating the mechanisms of absorption, distribution, and 
excretion of the metal.
    Both Doll (Ref. 48) and Salib and Hillier (Ref. 47) stated that the 
possibility of a causal link between aluminum and Alzheimer's disease 
must be kept open until uncertainty about neuropathological evidence is 
resolved and the prognosis of humans exposed to aluminum by inhalation 
is known. Flaten et al. (Ref. 49) stated that multidisciplinary 
collaborative research efforts, involving scientists from many 
different specialities, are needed, with emphasis placed on: (1) 
Increasing knowledge of the chemistry of aluminum in biologic systems 
and determining the cellular and molecular mechanisms of aluminum 
toxicity, and (2) variations in neuropathology from long-term, low-
level exposure to aluminum.
    In summary, the literature shows that at high doses and long-term 
industrial exposures, aluminum can be associated with recognizable, 
specific neurologic effects. However, to date, the agency considers the 
evidence insufficient to link aluminum to Alzheimer's disease, 
Parkinson's disease, or ALS. Although aluminum uptake and transport by 
a ``nasal-olfactory pathway'' has been suggested in a nonphysiologic 
study in an animal model (Ref. 36), the agency is not aware of any 
evidence in humans that supports an olfactory-neuronal transport of 
aluminum to the brain.
    One petition suggested that the agency require that 90 percent of 
the particles of an aerosol aluminum antiperspirant be greater than 50 
micro (currently the requirement is between 10 and 50 micro) to reduce 
exposure to the upper respiratory tract. The agency notes that both 
Priest (Ref. 39) and Forbes and Agwani (Ref. 46) discussed a particle 
size of 1 micro for deposition in the deep lung. Based on current 
knowledge (no proof in humans of an olfactory neuronal transport of 
aluminum to the brain) and the lack of information on a minimum 
particle size to affect the respiratory tract, the agency finds no 
basis to impose a greater than 50micro requirement at this time. Flaten 
et al. (Ref. 49) stated that the possible human toxicity of aluminum 
has been a matter of controversy for well over 100 years. Despite many 
investigators looking at this issue, the agency does not find data from 
topical and inhalation chronic exposure animal and human studies 
submitted to date sufficient to change the monograph status of aluminum 
containing antiperspirants. The agency will continue to monitor the 
scientific literature on aluminum and, if new information appears, will 
reassess the status of aluminum-containing antiperspirants at such 
time.
    The agency acknowledges that small amounts of aluminum can be 
absorbed from the gastrointestinal tract and through the skin. Assuming 
a person has normal renal function, accumulation of aluminum resulting 
from usual exposures to antiperspirant drug products (application to 
the underarms once or twice daily) and subsequent absorption is 
considered minimal. However, people with renal dysfunction have an 
impairment in normal renal excretion of aluminum.
    Flaten et al. (Ref. 49) noted that the first human conditions 
generally accepted to be causally related to aluminum exposure did not 
occur until the 1970's, shortly after the introduction of routine 
dialysis therapy in persons with chronic renal failure. Dialysis 
encephalopathy was perhaps the first disease recognized in this 
population (1972, 1976). Later, fracturing osteomalacia (1977, 1978) 
and a microcytic hypochromic anemia (1980) were related to aluminum 
exposure in dialysis patients. Flaten et al. indicated that aluminum 
can cause encephalopathy, bone disease, and anemia in dialysis patients 
resulting

[[Page 34286]]

from the introduction of aluminum directly into the blood stream via 
high-aluminum dialysate or the consumption of large oral doses of 
aluminum-containing phosphate binders. Reduced urine production (the 
major route for aluminum excretion) contributes to this problem. The 
authors noted that, in the early 1980's, reports began to appear 
describing aluminum neurotoxicity and osteotoxicity in children with 
renal failure who were not on dialysis treatment.
    The agency is concerned that people with renal dysfunction may not 
be aware that the daily use of antiperspirant drug products containing 
aluminum may put them at a higher risk because of exposure to aluminum 
in the product. The agency considers it prudent to alert these people 
to consult a doctor before using or continuing to use these products on 
a regular basis and is including a warning in the final monograph: 
``Ask a doctor before use if you have kidney disease.``
    Flaten et al. (Ref. 49) mentioned several reports of aluminum 
accumulation and toxicity in individuals without chronic renal failure, 
especially preterm infants (primarily fed intravenously), and stated 
that preterm infants are at risk for aluminum loading because of their 
immature kidney function. Term infants with normal renal function may 
also be at risk because of their rapidly growing and immature brain and 
skeleton, and an immature blood-brain barrier. Until they are 1 to 2 
years old, infants have lower glomerular filtration rates than adults, 
which affects their kidney function. The agency is concerned that young 
children and children with immature renal function are at a higher risk 
resulting from any exposure to aluminum. Accordingly, the agency is 
requiring both general warnings in Sec.  330.1(g) on all aluminum-
containing antiperspirant drug products to inform parents and others to 
keep these products away from children, and to seek professional 
assistance if accidental ingestion occurs. (See also section II.B, 
comment 7 of this document.)
    (Comment 24) One comment submitted a research paper (Ref. 50) 
containing the author's theories concerning how antiperspirants and 
aluminum in these products may be associated with breast cancer: The 
secretions of the apocrine sweat glands contain androgens, which are 
blocked by the antiperspirant and thus caused to spread internally. 
These androgens may be converted in the surrounding adipose tissues to 
estrogens, and excess estrogens have been associated with an increase 
in breast cancer. Alternatively, these excess androgens may interfere 
with the normal functioning of the hypothalamic-pituitary axis, thereby 
causing an imbalance of estrogen in the body. About 50 percent of 
breast cancers occur in the upper outer quadrant of the breast, and 
axillary sweat glands are anatomically very close to this site. A 
protein marker called GCDFP-15 (Gross Cystic Disease Fluid Protein), 
which is normally found only in the sweat glands, was found in the 
fluids of many breast cysts. The author postulated that the blocked 
axillary sweat glands would cause GCDFP-15 and other markers to migrate 
to the breast due to its proximity and gravity, and because the fetal 
precursors for apocrine sweat glands and mammary glands are the same, 
these migrated protein markers may stimulate the breast and play a role 
in the carcinogenic process.
    The author also postulated that aluminum may play a role in the 
development of breast cancer because calcification of breast tissues 
(commonly seen in breast cancer) may be caused by a local electrolyte 
imbalance induced by the absorbed aluminum. The author noted that 
breast cancer in Japan was more than five times lower than in the 
United States and postulated this has occurred because Japanese women, 
especially the older population, do not use antiperspirants. The author 
noted that the breast cancer rate is currently on the rise in Japan, 
especially among young premenopausal women, and postulated that this is 
occurring because the young Japanese generation has adopted the western 
habit of using antiperspirants.
    The agency finds these theories lack sufficient evidence. The 
agency notes that the amount of androgens produced by the sweat glands 
is relatively insignificant compared to normal physiologic amounts 
produced by the adrenals and the gonads. The agency is not aware of any 
studies that have shown an ``internal spread'' of androgens or that 
establish that GCDFP-15 or other protein markers are carcinogenic in 
humans.
    The agency considers the author's views about a local electrolyte 
imbalance by absorbed aluminum causing breast tissue calcification 
inconsistent with knowledge about the calcification process. In 
addition, there are many benign calcifications. Finally, many proposals 
(e.g., diet, lifestyle changes) have been made as to why there is an 
increased incidence of breast cancer among Japanese women. However, 
there is no evidence to associate this increase with an increased use 
of antiperspirants. Thus, the agency concludes that there is 
insufficient evidence to support these theories.
    (Comment 25) The agency previously assessed the carcinogenic 
potential of aerosolized aluminum chlorhydrate antiperspirants in 
comment 22 of the TFM (47 FR 36492 at 36498 and 36499). Primary lung 
tumors, granulomatous lesions, and macrophagic activity were evaluated 
in animal studies. No increase in lung tumors was seen in the low- and 
mid-dose rats given doses at least 100 times greater than the expected 
human exposure via aerosolized antiperspirants. Normal macrophage 
response and pulmonary fibrosis were observed at higher doses with 
chronic exposure. No increase in tumors was noted in guinea pigs or 
hamsters at any dose levels in the studies. While the agency removed 
aerosol antiperspirant products containing zirconium from the market 
because of granuloma formation (August 16, 1977, 42 FR 41374), the 
agency is not aware of data that indicate aluminum antiperspirants 
cause foreign body granulomas or pulmonary tumors.

III. Agency Changes

    1. It has been agency policy since April 3, 1989 (54 FR 13480 at 
13486), that before any ingredient is included in a final OTC drug 
monograph, it must have a compendial (USP-NF) monograph. Compendial 
monographs include an ingredient's official name, chemical formula, and 
analytical chemical tests to confirm the quality and purity of the 
ingredient. These monographs establish public standards for the 
strength, quality, purity, and packaging of ingredients and drug 
products available in the United States. Eighteen of the 19 
antiperspirant active ingredients that the agency proposed in Sec.  
350.10 of the antiperspirant TFM (47 FR 36492 at 36504) currently have 
compendial monographs. Nine of the official compendial names are the 
same as those proposed in Sec.  350.10, while 10 of the names have 
changed slightly. (See Table 1 of this document for the previous and 
current ingredient names.)

[[Page 34287]]



               Table 1.--Antiperspirant Active Ingredients
------------------------------------------------------------------------
     Name in Tentative Final Monograph              Current Name
------------------------------------------------------------------------
Aluminum chloride                           Same
------------------------------------------------------------------------
Aluminum chlorohydrate                      Same
------------------------------------------------------------------------
Aluminum chlorohydrex polyethylene glycol   Aluminum chlorohydrex
 complex                                     polyethylene glycol
------------------------------------------------------------------------
Aluminum chlorohydrex propylene glycol      Aluminum chlorohydrex
 complex.                                    propylene glycol
------------------------------------------------------------------------
Aluminum dichlorohydrate                    Same
------------------------------------------------------------------------
Aluminum dichlorohydrex polyethylene        Aluminum dichlorohydrex
 glycol complex                              polyethylene glycol
------------------------------------------------------------------------
Aluminum dichlorohydrex propylene glycol    Aluminum dichlorohydrex
 complex.                                    propylene glycol
------------------------------------------------------------------------
Aluminum sesquichlorohydrate                Same
------------------------------------------------------------------------
Aluminum sesquichlorohydrex polyethylene    Aluminum sesquichloro-hydrex
 glycol complex                              polyethylene glycol
------------------------------------------------------------------------
Aluminum sesquichlorohydrex propylene       Aluminum sesquichloro-hydrex
 glycol complex                              propylene glycol
------------------------------------------------------------------------
Aluminum sulfate buffered\1\                Same
------------------------------------------------------------------------
Aluminum zirconium octachlorohydrate        Same
------------------------------------------------------------------------
Aluminum zirconium octachlorohydrex         Aluminum zirconium
 glycine complex                             octachlorohydrex gly
------------------------------------------------------------------------
Aluminum zirconium pentachlorohydrate       Same
------------------------------------------------------------------------
Aluminum zirconium pentachlorohydrex        Aluminum zirconium
 glycine complex                             pentachlorohydrex gly
------------------------------------------------------------------------
Aluminum zirconium tetrachlorohydrate       Same
------------------------------------------------------------------------
Aluminum zirconium tetrachlorohydrex        Aluminum zirconium
 glycine complex                             tetrachlorohydrex gly
------------------------------------------------------------------------
Aluminum zirconium trichlorohydrate         Same
------------------------------------------------------------------------
Aluminum zirconium trichlorohydrex glycine  Aluminum zirconium
 complex                                     trichlorohydrex gly
------------------------------------------------------------------------
\1\ Aluminum sulfate buffered with sodium aluminum lactate.

    The agency is including in Sec.  350.10 of this final monograph 
those antiperspirant active ingredients that currently have a 
compendial monograph. Only one active ingredient, aluminum sulfate 
buffered, does not have a current or proposed compendial monograph. 
While aluminum sulfate does have a compendial monograph, the buffer 
component, sodium aluminum lactate, does not. This buffer ingredient 
must also have a compendial monograph or there must be a compendial 
monograph for aluminum sulfate buffered in order for aluminum sulfate 
buffered to be included in the antiperspirant final monograph. At the 
present time, this ingredient is being included in Sec.  
310.545(a)(4)(ii) as a nonmonograph ingredient because the agency is 
not aware of any pending compendial monograph being developed. Should a 
compendial monograph eventually be developed, the agency will move this 
ingredient from Sec.  310.545(a)(4)(ii) to Sec.  350.10.
    2. The agency is revising the format for active ingredients in 
Sec.  350.10 for consistency with recent monographs: The proposed chart 
format is now a paragraph format listing ingredients in alphabetical 
order. The amount of active ingredient is stated as ``up to ---------- 
percent'' instead of as ---------- percent or less concentration.'' The 
information about calculating the concentration on an anhydrous basis 
is moved to the preamble of Sec.  350.10. The preamble statement about 
aluminum to chloride and/or aluminum to zirconium ratios is revised to 
state: ``Where applicable, the ingredient must meet the aluminum to 
chloride, aluminum to zirconium, and aluminum plus zirconium to 
chloride atomic ratios described in the United States Pharmacopeia-
National Formulary.'' The proposed ratio range table is not included in 
the final monograph because this information is now included in the 
USP-NF monographs for each active ingredient in Sec.  350.10, where 
applicable.
    3. The agency is expanding the indications proposed in Sec.  
350.50(b) of the TFM to provide additional uses based on new 
effectiveness data. The agency is also revising the uses format to make 
it more concise.
    Because the indications proposed in Sec.  350.50(b)(1), (b)(2), and 
(b)(3) of the TFM are very similar, the agency is combining them as a 
single indication with choices under Sec.  350.50(b)(1): [Select one of 
the following: ``decreases,'' ``lessens,'' or ``reduces''] ``underarm'' 
[select one of the following: ``dampness,'' ``perspiration,'' 
``sweat,'' ``sweating,'' or ``wetness'']. (See section II.B, comment 6 
of this document.) The agency is adding a new additional indication in 
Sec.  350.50(b)(2): ``also [select one of the following: `decreases,' 
`lessens,' or `reduces'] underarm [select one of the following: 
`dampness,' `perspiration,' `sweat,' `sweating,' or `wetness'] due to 
stress''. (See section II.B, comment 6 and section II.C, comment 13 of 
this document.) The agency is adding a new additional indication in 
Sec.  350.50(b)(3): Select one of the following: [``all day 
protection,'' ``lasts all day,'' ``lasts 24 hours,'' or ``24 hour 
protection'']. (See section II.C, comment 12 of this document.) The 
agency is adding a new additional

[[Page 34288]]

indication in Sec.  350.50(b)(4) that states ``extra effective''. This 
claim applies to products that demonstrate 30 percent or more sweat 
reduction using the guidelines for effectiveness testing of 
antiperspirant drug products referred to in Sec.  350.60. (See section 
II.C, comment 11 of this document.) The agency is adding a new 
additional indication in Sec.  350.50(b)(5) for products that 
demonstrate extra effectiveness sustained over a 24-hour period: These 
products may state the claims in Sec. Sec.  350.50(b)(3) and (b)(4) 
either individually or combined, e.g., ``24 hour extra effective 
protection,'' ``all day extra effective protection,'' ``extra effective 
protection lasts 24 hours,'' or ``extra effective protection lasts all 
day''. (See section II.C, comment 12 of this document.)
    4. The agency is revising the ``Do not apply * * *'' warning in 
proposed Sec.  350.50(c)(1) to the new labeling format. The warning now 
reads: ``Do not use on broken skin'' and ``Stop use if rash or 
irritation occurs''.
    5. The agency is including a warning to alert people with renal 
dysfunction to consult a doctor before using antiperspirants containing 
aluminum. The warning appears in the new labeling format and states: 
``Ask a doctor before use if you have kidney disease''. (See section 
II.F, comment 23 of this document.)
    6. The agency has revised the August 1982 Guidelines for 
Effectiveness Testing. The revised guidelines (dated as of the date of 
publication of this document) state that ``FDA recognizes that 
alternate methods may be appropriate to qualify an antiperspirant drug 
product as effective. These guidelines do not preclude the use of 
alternate methods that provide scientifically valid results, subject to 
FDA approval.'' (See section II.D, comment 15 of this document.)
    The agency has revised parts of the test procedures section of the 
guidelines to delete the requirement that the control formulation be 
devoid of ``any'' antiperspirant activity. Therefore, the control 
formulation no longer needs to be compared to no treatment. (See 
section II.D, comment 17 of this document.) The agency has changed the 
permitted relative humidity of the hotroom conditions from 35 to 40 
percent to a range of 30 to 40 percent. (See section II.D, comment 16 
of this document.) The agency has added a requirement for ``baseline 
perspiration rate'' to assure that test subjects sweat adequately 
during a hotroom test: ``Test subjects must produce at least 100 
milligrams of sweat from the placebo control axilla in a 20-minute 
collection in the controlled environment.'' (See comment 16 also.)
    Because the final monograph contains 24-hour duration effectiveness 
claims, the agency has revised section 4(a)(4) of the guidelines to 
state: ``For claims of enhanced duration of effect, the test should be 
conducted at least two times during the period of the claim, such as 1 
hour and 24 hours after the last daily treatment for 24 hour claims.'' 
(See section II.C, comment 12 of this document.) Because the final 
monograph contains ``extra-effective'' claims shown by standard 
gravimetric testing to have a 30-percent or more reduction in sweat, 
the agency has revised the guidelines to include a section on data 
treatment to demonstrate, with high probability, at least 50 percent of 
the target population will obtain a sweat reduction of at least 30 
percent. (See section II.C, comment 11 of this document.)
    The revised ``Guidelines for Effectiveness Testing of OTC 
Antiperspirant Drug Products'' are now dated as of the date of 
publication of this final rule and are on file in the Dockets 
Management Branch (address above) and on FDA's Web site at http://www.fda.gov/cder/otc/index.htm. Persons wishing to obtain a copy of the 
guidelines should submit a Freedom of Information (FOI) request in 
writing to FDA's FOI Staff (HFI-35), 5600 Fishers Lane, Rockville, MD 
20857. The agency has revised Sec.  350.60 to include this information 
about the guidelines.

IV. Summary of Changes from the Proposed Rule

    1. The agency is modifying the definition of an antiperspirant that 
was proposed in Sec.  350.3 of the TFM to delete the phrase ``to the 
underarm.'' (See section II.B, comment 2 of this document.)
    2. The agency is revising the format for listing active ingredients 
in Sec.  350.10. (See section III.2. of this document.)
    3. The agency is expanding the indications for OTC antiperspirant 
drug products based on new data that support these additional uses (see 
section III.3. of this document) and is expanding the ``Guidelines for 
Effectiveness Testing of OTC Antiperspirant Drug Products'' to address 
some of these additional uses (see section III.6. of this document).

V. The Agency's Final Conclusions

    The agency is issuing a final monograph establishing conditions 
under which OTC antiperspirant drug products are generally recognized 
as safe and effective and not misbranded; 18 ingredients listed in 
Sec.  350.10 are a monograph condition. In the Federal Register of 
November 7, 1990 (55 FR 46914), the agency published a final rule in 
part 310 establishing that certain active ingredients that had been 
under consideration in a number of OTC drug rulemaking proceedings were 
not generally recognized as safe and effective. That final rule 
included the antiperspirant ingredients aluminum bromohydrate, aluminum 
chloride (alcoholic solutions), aluminum chloride (aqueous solution) 
(aerosol only), aluminum sulfate, aluminum sulfate buffered (aerosol 
only), potassium alum, and sodium aluminum chlorohydroxy lactate in 
Sec.  310.545(a)(4), and was effective on May 7, 1991. In this final 
rule, the agency is redesignating the text of paragraph (a)(4) as 
paragraph (a)(4)(i), adding new paragraph (a)(4)(i) heading, and adding 
new paragraph (a)(4)(ii) to contain aluminum sulfate buffered with 
sodium aluminum lactate. Any drug product labeled, represented, or 
promoted for use as an OTC antiperspirant drug that contains any of the 
ingredients listed in Sec.  310.545(a)(4)(i) or (a)(4)(ii) or that is 
not in conformance with the monograph (21 CFR part 350) may be 
considered a new drug within the meaning of section 201(p) of the 
Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 321(p)) and 
misbranded under section 502 of the act (21 U.S.C. 352). Such a drug 
product can not be marketed for OTC antiperspirant use unless it is the 
subject of an approved application under section 505 of the act (21 
U.S.C. 355) and 21 CFR part 314. An appropriate citizen petition to 
amend the monograph may also be submitted in accord with 21 CFR 10.30 
and Sec.  330.10(a)(12)(i). Any OTC antiperspirant drug product 
initially introduced or initially delivered for introduction into 
interstate commerce after the effective date of the final rule for 
Sec.  310.545(a)(4)(i) or after the compliance dates of this final rule 
that is not in compliance with the regulations is subject to regulatory 
action.
    Mandating warnings in an OTC drug monograph does not require a 
finding that any or all of the OTC drug products covered by the 
monograph actually caused an adverse event, and FDA does not so find. 
Nor does FDA's requirement of warnings repudiate the prior OTC drug 
monographs and monograph rulemakings under which the affected drug 
products have been lawfully marketed. Rather, as a consumer protection 
agency, FDA has determined that warnings are necessary to ensure that 
these OTC drug products continue

[[Page 34289]]

to be safe and effective for their labeled indications under ordinary 
conditions of use as those terms are defined in the act. This judgment 
balances the benefits of these drug products against their potential 
risks (see Sec.  330.10(a)).
    FDA's decision to act in this instance need not meet the standard 
of proof required to prevail in a private tort action (Glastetter v. 
Novartis Pharmaceuticals, Corp., 252 F.3d 986, 991 (8th Cir. 2001)). To 
mandate warnings, or take similar regulatory action, FDA need not show, 
nor do we allege, actual causation. For an expanded discussion of case 
law supporting FDA's authority to require such warnings, see ``Labeling 
of Diphenhydramine-Containing Drug Products for Over-the-Counter Human 
Use, Final Rule'' (67 FR 72555, December 6, 2002).

VI. Analysis of Impacts

    An analysis of the costs and benefits of this regulation, conducted 
under Executive Order 12291, was discussed in the TFM for OTC 
antiperspirant drug products (47 FR 36492 at 36503). The one comment 
received is addressed in section II.A, comment 4 of this final rule and 
further addressed later in this section.
    FDA has examined the impacts of this final rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
Unfunded Mandates Reform Act of 1995 (2 U.S.C. 1501 et seq.). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). Under the Regulatory 
Flexibility Act, if a rule has a significant economic impact on a 
substantial number of small entities, an agency must analyze regulatory 
options that would minimize any significant impact of the rule on small 
entities. Section 202(a) of the Unfunded Mandates Reform Act of 1995 
requires that agencies prepare a written statement of anticipated costs 
and benefits before proposing any rule that may result in an 
expenditure in any one year by State, local, and tribal governments, in 
the aggregate, or by the private sector, of $100 million (adjusted 
annually for inflation). The proposed rule that has led to the 
development of this final rule was published on August 20, 1982, before 
the Unfunded Mandates Reform Act of 1995 was enacted. This final rule 
will not result in an expenditure in any one year by State, local, and 
tribal governments, in the aggregate, or by the private sector, of $100 
million.
    The agency concludes that this final rule is consistent with the 
principles set out in Executive Order 12866 and in these two statutes. 
Additionally, the final rule is not a significant regulatory action as 
defined by the Executive order. The Unfunded Mandates Reform Act does 
not require FDA to prepare a statement of costs and benefits for this 
final rule, because the final rule will not result in any 1-year 
expenditure that would exceed $100 million adjusted for inflation. The 
current inflation adjusted statutory threshold is about $110 million.
    FDA has determined that this final rule will not have a significant 
economic impact on a substantial number of small entities. While the 
exact number of affected small entities is difficult to determine at 
any given time, the agency received only one comment from a small 
entity, which is discussed later in this section. This discussion 
explains the agency's determination that this final rule will not have 
a significant economic impact on a substantial number of small 
entities.
    The purpose of this final rule is to establish conditions under 
which OTC antiperspirant drug products are generally recognized as safe 
and effective and not misbranded. This includes establishing the 
allowable monograph ingredients and labeling. Eighteen of the 19 active 
ingredients under review are included in the final monograph. The 
remaining ingredient could have been included had a USP-NF monograph 
been developed for this ingredient. If a USP-NF monograph is developed 
before the effective date of this final monograph, products containing 
this ingredient could continue to be marketed without reformulation. 
Without a USP-NF monograph for the ingredient, product reformulations 
to include a monograph antiperspirant active ingredient or 
discontinuation of the products will need to occur. The agency believes 
that this one antiperspirant active ingredient is currently in only a 
few products. Based on the large number of antiperspirant drug products 
in the OTC marketplace and the vast array of products that one known 
affected company currently markets, the agency considers the required 
reformulation or discontinuation of a few products not to be overly 
burdensome or substantial. The one known affected company markets at 
least 30 products not affected by this final rule. Only one of its 
products includes the active ingredient excluded under the final rule. 
Any company using this active ingredient has the option to: (1) 
Reformulate using any of the 18 active ingredients included in this 
final rule, (2) reformulate without this active ingredient and market 
the product as a deodorant, or (3) discontinue the product.
    This final rule establishes the monograph labeling for OTC 
antiperspirant drug products and will require relabeling of all 
products covered by the monograph. The agency's Drug Listing System 
identifies approximately 200 manufacturers and 700 marketers of 1,300 
OTC antiperspirant drug products containing the 19 ingredients covered 
by this final rule. It is likely that there are additional products 
that are not currently included in the agency's system. While it is 
difficult to determine an exact number, the agency estimates that about 
1,500 OTC antiperspirant drug products will need to be relabeled based 
on this final rule.
    The agency has been informed that relabeling costs of the type 
required by a final monograph generally average about $3,000 to $5,000 
per stock keeping unit (SKU) (individual products, packages, and 
sizes). However, some of the relabeling that occurs as a result of this 
specific final monograph will be due to additional indications that the 
agency has included in the final monograph and that manufacturers will 
wish to add to their labeling. Assuming that there are about 1,300 to 
1,500 affected OTC SKUs in the marketplace, total one-time costs of 
relabeling would be $3.9 million ($3,000 per SKU x 1,300 SKUs) to $7.5 
million ($5,000 per SKU x 1,500 SKUs). The agency believes that actual 
costs will be lower for several reasons. First, many of the label 
changes will be made by private label manufacturers that tend to use 
relatively simple and less expensive labeling. Second, the agency has 
finalized a revised labeling format for OTC drug products in Sec.  
201.66. The agency is allowing manufacturers to incorporate the 
labeling changes required by this final rule along with the new general 
OTC drug labeling format. Thus, the relabeling costs resulting from two 
different but related final rules will be individually reduced by 
implementing both required changes at the same time.
    Some relabeling costs will be further reduced because the agency is 
allowing up to 18 months (24 months for products with annual sales less 
than $25,000) for these revisions so they may be done in the normal 
course of business. Thus, manufacturers who

[[Page 34290]]

wish to add additional indications included in this final monograph can 
do so at their next regular printing of product labeling. Among the 
steps the agency is taking to minimize the impact on small entities 
are: (1) To provide enough time to enable entities to use up existing 
labeling stock, and (2) to allow the labeling changes required by this 
final monograph to be done concurrently with the changes required by 
the new OTC drug labeling format. The agency believes that these 
actions provide small entities substantial flexibility and reductions 
in cost.
    The agency considered but rejected several labeling alternatives: 
(1) A shorter or longer implementation period, and (2) an exemption 
from coverage for small entities. While the agency believes that 
consumers would benefit from having this new labeling in place as soon 
as possible, a longer time period would unnecessarily delay the benefit 
of new labeling and a few revised formulations. Conversely, a shorter 
time period was also considered but rejected because it would be 
inflexible and more costly for the affected companies. The agency 
rejected an exemption for small entities because the new labeling and 
revised formulations, where applicable, are also needed by consumers 
who purchase products marketed by those entities. However, a longer 
(24-month) compliance date is being provided for products with annual 
sales less than $25,000.
    One small manufacturer has indicated that it will suffer economic 
consequences because it will no longer be able to make claims for use 
of its antiperspirant products on the hands, and for prosthesis and 
orthotic use. However, the manufacturer did not provide sufficient data 
to show that its products were safe and effective for these uses and 
did not provide documentation to show the economic impact of this final 
rule on its sales. The agency notes that the company could: (1) Relabel 
its products to contain only the monograph indications and then remain 
in the marketplace, or (2) discontinue its products. While revising the 
product labeling may have an economic impact on a company, it will be 
able to continue to market its products and can use the expanded 
indications provided by the final monograph to try to enhance product 
sales.
    The final rule would not require any new reporting and 
recordkeeping activities, and no additional professional skills are 
needed. There are no other Federal rules that duplicate, overlap, or 
conflict with the final rule.
    For the reasons in this section and under the Regulatory 
Flexibility Act (5 U.S.C. 605(b)), the agency certifies that this final 
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.

VII. Paperwork Reduction Act of 1995

    FDA concludes that the labeling requirements in this document are 
not subject to review by the Office of Management and Budget because 
they do not constitute a ``collection of information'' under the 
Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et seq.). Rather, the 
labeling statements are a ``public disclosure of information originally 
supplied by the Federal government to the recipient for the purpose of 
disclosure to the public'' (5 CFR 1320.3(c)(2)).

VIII. Environmental Impact

    The agency has determined under 21 CFR 25.31(a) 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.

IX. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the rule 
does not contain policies that have substantial direct effects on the 
States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, the agency has concluded 
that the rule does not contain policies that have federalism 
implications as defined in the Executive order and, consequently, a 
federalism summary impact statement is not required.

X. Section 369.20 Revision

    Section 369.20 (21 CFR 369.20) contains a recommended warning and 
caution statement for OTC antiperspirant drug products under the 
heading ``ANTIPERSPIRANTS:'' ``Do not apply to broken skin. If a rash 
develops, discontinue use.'' This statement is very similar to, but not 
quite as extensive as, the warnings required by the final monograph: 
``Do not use on broken skin'' and ``Stop use if rash or irritation 
occurs''. The agency is removing the entry for ``ANTIPERSPIRANTS'' 
under Sec.  369.20 because it is superseded by Sec. Sec.  350.50(c)(1) 
and (c)(2).

XI. References

    The following references are on display in the Dockets Management 
Branch (see section I of this document) under Docket No. 78N-0064 
unless otherwise stated and may be seen by interested persons between 9 
a.m. and 4 p.m., Monday through Friday.
    1. Memorandum of telephone conversation between R. Bolger, C. 
Holland, and K. Holland, Perspi-Cura Co., and V. Miguele, FDA, in 
OTC vol. 1400FR, dated November 20, 1995.
    2. Memorandum of fax from V. Miguele, FDA, to R. Bolger and C. 
Holland, Perspi-Cura Co., in OTC Vol. 1400FR, dated February 8, 
1996.
    3. Memorandum of telephone message from R. Bolger, Perspi-Cura 
Co., to V. Miguele, FDA, in OTC Vol. 1400FR, dated March 25, 1996.
    4. Studies 83-0768-70 and 83-0769-70 in Comment RPT.
    5. Studies S-1367, S-1617, and ST-2280/2376) in Comment No. 
C00039.
    6. ``Antiperspirant Efficacy Study of AP10016 (Currently 
Marketed Roll-on Antiperspirant With Aluminum Zirconium 
Tetrachlorohydrate) Against AP10021 (Currently Marketed Roll-on 
Antiperspirant With Aluminum Chlorohydrate),'' Exhibit 24 in Comment 
No. C00040.
    7. Comment No. LET006.
    8. Majors, P. A., and F. B. Carabello, ``Presentation to the OTC 
Panel for Antiperspirants of the Hill Top Research Method of 
Antiperspirant Evaluations and General Discussion of Results 
Obtained,'' in OTC Vol. 140065, August 1975.
    9. FDA, ``Guidelines for Effectiveness Testing of OTC 
Antiperspirant Drug Products,'' in OTC Vol. 140065, August 1982.
    10. Exhibits 1 through 7 in Comment No. C00040.
    11. ``Claim for `Twenty Four Hour Protection' etc., 
Antiperspirant Tests,'' studies S-825, S-1434, S-1473, S-1518, S-
1546, and S-1604, in Comment No. C00039.
    12. Exhibits 9 through 20 and 22, in Comment No. C00040.
    13. Majors, P. A., and J. E. Wild, ``The Evaluation of 
Antiperspirant Efficacy--Influence of Certain Variables,'' Journal 
of the Society of Cosmetic Chemists, 25:139-152, 1974.
    14. ``New Data on Pedal Antiperspirant Activity,'' studies in 
Comment C00041.
    15. Pedal Antiperspirant Efficacy Evaluation, protocol in 
Comments PR1 and PR2.
    16. Letter from W. E. Gilbertson, FDA, to K. R. Johannes, 
Scholl, Inc., coded LET11.
    17. Letters from W. E. Gilbertson, FDA, to R. C. Stites, Numark 
Laboratories, Inc., coded LET12 and LET13.
    18. ``Protocol for the Clinical Evaluation of Antiperspirant 
Efficacy Against Thermally Induced Sweating,'' exhibit 21, in 
Comment No. C00040.
    19. Study 83-0769-70 in Comment No. RPT.
    20. ``Claim for `Twenty Four Hour Protection' etc., 
Antiperspirant Tests,''

[[Page 34291]]

studies No. S-825, S-1367, S-1434, S-1473, S-1518, and S-1546, in 
Comment No. C00039.
    21. Studies ST-2280/2376 in Comment No. C00039.
    22. ``Twenty-Four Hour Enhanced Duration AP Efficacy Evaluation 
Under Thermal Stress of: A = AP10001 (Currently Marketed Aerosol 
Antiperspirant With aluminum chlorohydrate) Against B = AP10008, 
Placebo Aerosol Antiperspirant,'' Exhibit 6, in Comment No. C00040.
    23. ``AP Efficacy 24 Hour Absolute Sweat Reduction Study of: 
AP10001 (Marketed Aerosol Antiperspirant With Aluminum 
Chlorohydrate),'' Exhibit 5, in Comment No. C00040.
    24. Summary Minutes of the 18th Meeting of the Advisory Review 
Panel on OTC Antiperspirant Drug Products, in OTC Vol. 1400FR, 
February 26 and 27, 1976.
    25. OTC Vol. 140059.
    26. Comment No. C00039.
    27. Transcript of the 27th Meeting of the Advisory Review Panel 
on OTC Antiperspirant Drug Products, pp. 75-85, included in OTC Vol. 
1400FM, January 26, 1978.
    28. Lansdown, A. B. G., ``Production of Epidermal Damage in 
Mammalian Skins by Some Simple Aluminum Compounds,'' British Journal 
of Dermatology, 89:67-76, 1973.
    29. Govett, T., and M. G. DeNavarre, ``Aluminum Chlorohydrate, 
New Antiperspirant Ingredient,'' The American Perfumer and Essential 
Oil Review, 49:365-368, 1947.
    30. ``Zirconyl Hy+droxy Chloride Antiperspirant Combinations,'' 
Patent No. 2,854,382, U.S. Patent Office, included in Appendix B in 
OTC Vol. 140037, September 30, 1958.
    31. ``Characterization of Category I Aluminum Chlorhydrates and 
Comparison to an Aluminum Chlorhydrate Prepared With an Alternate 
Neutralization Agent,'' report in Comment No. C00038.
    32. Fifth Supplement, USP 23-NF 18, U.S. Pharmacopeial 
Convention, Inc., Rockville, MD, p. 3363, 1996.
    33. Perl, D. P., and P. F. Good, ``Uptake of Aluminum into 
Central Nervous System Along Nasal-Olfactory Pathways,'' Lancet, 
1:1028, May 2, 1987.
    34. Inhalation Toxicology Research Institute, Lovelace 
Biomedical and Environmental Research Institute, ``Inhalation 
Toxicology Studies of Aerosolized Products, Final Report,'' in 
Comment SUP.
    35. Becton, Dickinson Research Center, ``Final Report on 
Aluminum Chlorhydrate Study,'' in Comment SUP.
    36. Rollin, H. B., P. Theodorou, and T. A. Kilroe-Smith, 
``Deposition of Aluminum in Tissues of Rabbits Exposed to Inhalation 
of Low Concentrations of A1203 Dust,'' British Journal of Industrial 
Medicine, 48:389-391, 1991.
    37. Graves, A. B. et al., ``The Association Between Aluminum-
Containing Products and Alzheimer's Disease,'' Journal of Clinical 
Epidemiology, 43:35-44, 1990.
    38. Garruto, R. M., ``Pacific Paradigms of Environmentally 
Induce Neurological Disorders: Clinical, Epidemiological and 
Molecular Perspectives,'' Neurotoxicology, 12:347-377, 1991.
    39. Priest, N. D., Satellite Symposium on `Alzheimer's Disease 
and Dietary Aluminum', ``The Bioavailability and Metabolism of 
Aluminum Compounds in Man,'' Proceedings of the Nutrition Society, 
52:231-240, 1993.
    40. Rowan, M. J., ``Recent Research on the Causes of Alzheimer's 
Disease,'' Proceedings of the Nutrition Society, 52:255-262, 1993.
    41. Savory, J. et al., ``Can the Controversy of the Role of 
Aluminum in Alzheimer's Disease be Resolved? What are the Suggested 
Approaches to This Controversy and Methodological Issues to be 
Considered?,'' Journal of Toxicology and Environmental Health, 
48:615-635, 1996.
    42. Scott, C. W. et al., ``Aggregation of Tau Protein by 
Aluminum,'' Brain Research, 628:77-84, 1993.
    43. Kasa, P., P. Szerdahelyi, and H. M. Wisniewski, ``Lack of 
Topographical Relationship Between Sites of Aluminum Deposition and 
Senile Plaques in the Alzheimer's Disease Brain,'' Acta 
Neuropathologica, 90:526-531, 1995.
    44. Candy, J. M. et al., ``Aluminum Accumulation in Relation to 
Senile Plaque and Neurofibrillary Tangle Formation in the Brains of 
Patients With Renal Failure,'' Journal of the Neurological Sciences, 
107:210-218, 1992.
    45. Anane, R. et al., ``Bioaccumulation of Water Soluble 
Aluminum Chloride in the Hippocampus After Transdermal Uptake in 
Mice,'' Archives of Toxicology, 69:568-571, 1995.
    46. Forbes, W. F., and N. Agwani, ``A Suggested Mechanism for 
Aluminum Biotoxicity,'' Journal of Theoretical Biology, 171:207-214, 
1994.
    47. Salib, E., and V. Hillier, ``A Case-Control Study of 
Alzheimer's Disease and Aluminum Occupation,'' British Journal of 
Psychiatry, 168:244-249, 1996.
    48. Doll, R., ``Review: Alzheimer's Disease and Environmental 
Aluminum,'' Age and Ageing, 22:138-153, 1993.
    49. Flaten, T. P. et al., ``Status and Future Concerns of 
Clinical and Environmental Aluminum Toxicology,'' Journal of 
Toxicology and Environmental Health, 48:527-541, 1996.
    50. Comments No. C46, RPT2, and RPT3.

List of Subjects

21 CFR Part 310

    Administrative practice and procedure, Drugs, Labeling, Medical 
devices, Reporting and recordkeeping requirements.

21 CFR Part 350

    Labeling, Over-the-counter drugs.

21 CFR Part 369

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

0
Therefore, under the Federal Food, Drug, and Cosmetic Act, and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR 
Chapter I is amended as follows:

PART 310--NEW DRUGS

0
1. The authority citation for 21 CFR part 310 continues to read as 
follows:

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

0
2. Section 310.545 is amended by redesignating the text of paragraph 
(a)(4) as paragraph (a)(4)(i), by adding new paragraph (a)(4)(i) 
heading and paragraphs (a)(4)(ii) and (d)(34), and by revising 
paragraph (d)(1) to read as follows:


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

    (a) * * *
    (4) * * *
    (i) Ingredients--Approved as of May 7, 1991. * * *
    (ii) Approved as of December 9, 2004; June 9, 2005, for products 
with annual sales less than $25,000.
Aluminum sulfate buffered with sodium aluminum lactate
* * * * *
    (d) * * *
    (1) May 7, 1991, for products subject to paragraphs (a)(1) through 
(a)(2)(i), (a)(3)(i), (a)(4)(i), (a)(6)(i)(A), (a)(6)(ii)(A), (a)(7) 
(except as covered by paragraph (d)(3) of this section), (a)(8)(i), 
(a)(10)(i) through (a)(10)(iii), (a)(12)(i) through (a)(12)(iv)(A), 
(a)(14) through (a)(15)(i), (a)(16) through (a)(18)(i)(A), (a)(18)(ii) 
(except as covered by paragraph (d)(22) of this section), (a)(18)(iii), 
(a)(18)(iv), (a)(18)(v)(A), and (a)(18)(vi)(A) of this section.
* * * * *
    (34) December 9, 2004, for products subject to paragraph (a)(4)(ii) 
of this section. June 9, 2005, for products with annual sales less than 
$25,000.
* * * * *

0
3. Part 350 is added to read as follows:

PART 350--ANTIPERSPIRANT DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN 
USE

Subpart A--General Provisions
Sec.
350.1 Scope.
350.3 Definition.
Subpart B--Active Ingredients
350.10 Antiperspirant active ingredients.
Subpart C--Labeling
350.50 Labeling of antiperspirant drug products.

[[Page 34292]]

Subpart D--Guidelines for Effectiveness Testing
350.60 Guidelines for effectiveness testing of antiperspirant drug 
products.

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

PART 350--ANTIPERSPIRANT DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN 
USE

Subpart A--General Provisions


Sec.  350.1  Scope.

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


Sec.  350.3  Definition.

    As used in this part:
    Antiperspirant. A drug product applied topically that reduces the 
production of perspiration (sweat) at that site.

Subpart B--Active Ingredients


Sec.  350.10  Antiperspirant active ingredients.

    The active ingredient of the product consists of any of the 
following within the established concentration and dosage formulation. 
Where applicable, the ingredient must meet the aluminum to chloride, 
aluminum to zirconium, and aluminum plus zirconium to chloride atomic 
ratios described in the U.S. Pharmacopeia-National Formulary. The 
concentration of ingredients in paragraphs (b) through (j) of this 
section is calculated on an anhydrous basis, omitting from the 
calculation any buffer component present in the compound, in an aerosol 
or nonaerosol dosage form. The concentration of ingredients in 
paragraphs (k) through (r) of this section is calculated on an 
anhydrous basis, omitting from the calculation any buffer component 
present in the compound, in a nonaerosol dosage form. The labeled 
declaration of the percentage of the active ingredient should exclude 
any water, buffer components, or propellant.
    (a) Aluminum chloride up to 15 percent, calculated on the 
hexahydrate form, in an aqueous solution nonaerosol dosage form.
    (b) Aluminum chlorohydrate up to 25 percent.
    (c) Aluminum chlorohydrex polyethylene glycol up to 25 percent.
    (d) Aluminum chlorohydrex propylene glycol up to 25 percent.
    (e) Aluminum dichlorohydrate up to 25 percent.
    (f) Aluminum dichlorohydrex polyethylene glycol up to 25 percent.
    (g) Aluminum dichlorohydrex propylene glycol up to 25 percent.
    (h) Aluminum sesquichlorohydrate up to 25 percent.
    (i) Aluminum sesquichlorohydrex polyethylene glycol up to 25 
percent.
    (j) Aluminum sesquichlorohydrex propylene glycol up to 25 percent.
    (k) Aluminum zirconium octachlorohydrate up to 20 percent.
    (l) Aluminum zirconium octachlorohydrex gly up to 20 percent.
    (m) Aluminum zirconium pentachlorohydrate up to 20 percent.
    (n) Aluminum zirconium pentachlorohydrex gly up to 20 percent.
    (o) Aluminum zirconium tetrachlorohydrate up to 20 percent.
    (p) Aluminum zirconium tetrachlorohydrex gly up to 20 percent.
    (q) Aluminum zirconium trichlorohydrate up to 20 percent.
    (r) Aluminum zirconium trichlorohydrex gly up to 20 percent.

Subpart C--Labeling


Sec.  350.50  Labeling of antiperspirant 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 
``antiperspirant.''
    (b) Indications. The labeling of the product states, under the 
heading ``Uses,'' the phrase listed in paragraph (b)(1) of this section 
and may contain any additional phrases listed in paragraphs (b)(2) 
through (b)(5) of this section, as appropriate. Other truthful and 
nonmisleading statements, describing only the uses that have been 
established and listed in paragraphs (b)(1) through (b)(5) 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 any product, the labeling states [select one of the 
following: ``decreases,'' ``lessens,'' or ``reduces''] ``underarm'' 
[select one of the following: ``dampness,'' ``perspiration,'' 
``sweat,'' ``sweating,'' or ``wetness''].
    (2) The labeling may state ``also [select one of the following: 
`decreases,' `lessens,' or `reduces'] underarm [select one of the 
following: `dampness,' `perspiration,' `sweat,' `sweating,' or 
`wetness'] due to stress''.
    (3) For products that demonstrate standard effectiveness (20 
percent sweat reduction) over a 24-hour period, the labeling may state 
[select one of the following: ``all day protection,'' ``lasts all 
day,'' ``lasts 24 hours,'' or ``24 hour protection''].
    (4) For products that demonstrate extra effectiveness (30 percent 
sweat reduction), the labeling may state ``extra effective''.
    (5) Products that demonstrate extra effectiveness (30 percent sweat 
reduction) sustained over a 24-hour period may state the claims in 
paragraphs (b)(3) and (b)(4) of this section either individually or 
combined, e.g., ``24 hour extra effective protection'', ``all day extra 
effective protection,'' ``extra effective protection lasts 24 hours,'' 
or ``extra effective protection lasts all day''.
    (c) Warnings. The labeling of the product contains the following 
statements under the heading ``Warnings'':
    (1) ``Do not use on broken skin''.
    (2) ``Stop use if rash or irritation occurs''.
    (3) ``Ask a doctor before use if you have kidney disease''.
    (4) For products in an aerosolized dosage form. (i) ``When using 
this product [bullet]\1\ keep away from face and mouth to avoid 
breathing it''.
---------------------------------------------------------------------------

    \1\ See Sec.  201.66(b)(4) of this chapter for definition of 
bullet.
---------------------------------------------------------------------------

    (ii) The warning required by Sec.  369.21 of this chapter for drugs 
in dispensers pressurized by gaseous propellants.
    (d) Directions. The labeling of the product contains the following 
statement under the heading ``Directions'': ``apply to underarms 
only''.

Subpart D--Guidelines for Effectiveness Testing


Sec.  350.60  Guidelines for effectiveness testing of antiperspirant 
drug products.

    An antiperspirant in finished dosage form may vary in degree of 
effectiveness because of minor variations in formulation. To assure the 
effectiveness of an antiperspirant, the Food and Drug Administration is 
providing guidelines that manufacturers may use in testing for 
effectiveness. These guidelines are on file in the Dockets Management 
Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 
1061, Rockville, MD 20852. These guidelines are available on the FDA's 
Web site at http://www.fda.gov/cder/

[[Page 34293]]

otc/index.htm or on request for a nominal charge by submitting a 
Freedom of Information (FOI) request in writing to FDA's FOI Staff 
(HFI-35), 5600 Fishers Lane, rm. 12A-16, Rockville, MD 20857.

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

0
4. The authority citation for 21 CFR part 369 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 371.


Sec.  369.20  [Amended]

0
5. Section 369.20 Drugs; recommended warning and caution statements is 
amended by removing the entry for ``ANTIPERSPIRANTS.''

    Dated: May 16, 2003.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 03-14140 Filed 6-6-03; 8:45 am]
BILLING CODE 4160-01-S