[Federal Register: June 9, 2003 (Volume 68, Number 110)]
[Rules and Regulations]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 310, 350, and 369
[Docket No. 78N-0064]
Antiperspirant Drug Products For Over-the-Counter Human Use;
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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.
Table of Contents
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
X. Section 369.20 Revision
Monograph (Part 350)
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
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,
The agency addressed this issue and reaffirms its conclusions as
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
(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
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
products could remain in the marketplace after relabeling occurred. The
economic impact of this final rule is discussed in section VI of this
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.
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
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
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
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
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
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
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
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
their degree of effectiveness. One comment requested a hearing on this
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
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
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
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
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
(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
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
stick) and, thus, the enhanced duration effect is not limited to
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
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
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
(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
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
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''
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
(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
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
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-
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
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
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
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
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:
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
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
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,
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
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
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
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
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
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
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
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
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
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
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.)
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
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
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
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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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
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
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
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
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
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
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
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.
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)
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,
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.
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
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
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.,
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
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,
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,
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,
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,
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.
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
1. The authority citation for 21 CFR part 310 continues to read as
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,
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
* * * * *
3. Part 350 is added to read as follows:
PART 350--ANTIPERSPIRANT DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN
Subpart A--General Provisions
Subpart B--Active Ingredients
350.10 Antiperspirant active ingredients.
350.50 Labeling of antiperspirant drug products.
Subpart D--Guidelines for Effectiveness Testing
350.60 Guidelines for effectiveness testing of antiperspirant drug
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
PART 350--ANTIPERSPIRANT DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN
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
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
(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.
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
(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
\1\ See Sec. 201.66(b)(4) of this chapter for definition of
(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
Subpart D--Guidelines for Effectiveness Testing
Sec. 350.60 Guidelines for effectiveness testing of antiperspirant
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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/
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
4. The authority citation for 21 CFR part 369 continues to read as
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 371.
Sec. 369.20 [Amended]
5. Section 369.20 Drugs; recommended warning and caution statements is
amended by removing the entry for ``ANTIPERSPIRANTS.''
Dated: May 16, 2003.
Assistant Commissioner for Policy.
[FR Doc. 03-14140 Filed 6-6-03; 8:45 am]
BILLING CODE 4160-01-S