demonstrated that high oral doses of iodine can affect blood levels of
thyroid hormones, but rarely did these effects seriously impair thyroid
function. Oral iodine exposure exceeding 200 mg/day (2.8 mg/kg/day)
during pregnancy can result in congenital hypothyroidism (Ref. 122).
Generally, however, adverse effects were only observed following very
high oral doses that caused very high serum iodine concentrations.
    Drawing conclusions from these studies is difficult because the
studies have several limitations. Many of these studies lacked control
groups, used small subject numbers, and/or did not record subjects'
iodine status at baseline (iodine-deficient subjects may be more
susceptible to thyroid effects caused by iodine exposure). The study
results are also difficult to compare because the studies used
different subject age groups, subject types, iodine

formulations and amounts, durations and frequency of iodine treatment,
and methods for measuring absorbed iodine levels or thyroid effects.
Despite these deficiencies, we believe there are adequate data
regarding the potential of iodine to cause changes in thyroid hormone
levels and additional studies are not necessary.
    b. Iodophor safety data gaps. In summary, our administrative record
for the safety of iodophor complexes is incomplete with respect to the
following:

 Human studies of the absorption of iodine following maximal
dermal exposure to the complexes
 Human absorption studies of the carrier molecule for small
molecular weight povidone molecules and the other carriers listed in
this section
 Dermal carcinogenicity studies for each of the iodophor
complexes
 Data from laboratory studies that assess the potential for the
development of resistance to iodine and cross-resistance to antibiotics
in the types of organisms listed in section VII.C.3 of this proposed
rule
3. Triclocarban
    In the 1994 TFM, FDA proposed to classify triclocarban as GRAS for
use as an OTC antiseptic handwash. This determination was based on
safety data and information that were submitted in response to the 1978
TFM on triclocarban formulated as bar soap (Refs. 151 and 152). These
data included blood levels, target organs for toxicity, and no effect
levels and were discussed in the 1991 First Aid TFM (56 FR 33644 at
33664). The existing data, however, are no longer sufficient to fully
evaluate the safety of triclocarban. New information regarding
potential risks from systemic absorption and long-term exposure to
antiseptic active ingredients is leading us to propose additional
safety testing.
    a. Summary of triclocarban safety data.
    Triclocarban human pharmacokinetic data. Some human pharmacokinetic
parameters were reported in a study where six male subjects received a
single oral dose of \14\C-labeled triclocarban: The maximum plasma
concentration (i.e., Cmax) was 3.7 nanomole (nmol)-equivalents of
triclocarban per g of plasma (approximately 1,200 nanograms per
milliliter (ng/mL)) and occurred at 2.8 hours (Tmax) (Ref. 152).
Although human pharmacokinetic parameters were reported in this study,
triclocarban was administered orally. As a result, the exposure when
applied topically under maximal use conditions and when steady-state
levels were reached is unknown.
    We found several studies in humans that examine the absorption of
triclocarban after topical application (Refs. 153 through 156). Most of
these studies evaluated absorption after a single topical exposure and
used a small number of subjects. After a single exposure, blood levels
of triclocarban ranged from below the limit of detection (10 ng/mL) to
a Cmax of 530 nanomolar (nM) (167 ng/mL) (Refs. 153, 154, and 155).
Small amounts of triclocarban were also detectable in the urine and
feces of subjects. The estimated total average recovery ranged between
0.39 and 0.6 percent of the applied dose. Although small, these studies
suggest that very little triclocarban is absorbed after a single
topical exposure; however, steady-state levels were not evaluated.
    Howes and Black (Ref. 156) examined absorption of triclocarban
after repeated daily application in a 28-day bathing study. Twelve
subjects bathed once daily using bar soap that contained 2 percent
triclocarban. Each subject was exposed to approximately 260 mg of
triclocarban per day. Triclocarban was below the limit of detection (25
ng/mL) in all samples at all time points. A manufacturer of
triclocarban has suggested that steady-state levels were achieved in
this study (Ref. 157), but this was not directly demonstrated.
    In addition to systemic exposure as a result of dermal absorption,
consumers may have prolonged exposure to those antiseptic active
ingredients that remain bound to the skin after use (that is,
substantive). Triclocarban has been shown to be substantive. North-Root
et al. (Ref. 158) measured the amount of triclocarban that remained on
the skin after a single application of bar soap in 12 human subjects.
An average of 1.4 percent of the applied triclocarban remained on the
skin. Substantive product remaining on the skin after rinsing may lead
to additional absorption and systemic exposure.
    Overall, the human pharmacokinetic studies are not adequate, and we
propose that human pharmacokinetic studies using dermal administration
under maximal use conditions are still needed to define the level of
systemic exposure following repeated use. In addition, data are needed
to help define the effect of formulation on dermal absorption.
    Triclocarban ADME data. Triclocarban is readily metabolized in both
humans and animals (Refs. 159 through 162). Birch et al. (Ref. 159)
identified the metabolites of triclocarban in plasma and urine after
oral exposure in rats, rhesus monkeys, and humans. The principal
metabolites common to all species were the sulfate and glucuronide
conjugates of 2'-, 3'-, and 6-hydroxy-triclocarban. However, there were
differences in triclocarban metabolism between rats and higher
primates, and the monkey appears to be the more appropriate model for
studying triclocarban pharmacokinetics in humans (Ref. 159).
    Elimination of triclocarban metabolites from the plasma appears to
be biphasic. In adult rhesus monkeys, elimination from the plasma
occurs in two distinct phases: Rapid elimination of parent triclocarban
and glucuronide conjugates, and slower elimination of sulfate
conjugates (Ref. 160). Similarly, in humans, the major plasma
metabolites are glucuronide conjugates, which were eliminated in urine
with a half-life of about 2 hours (Ref. 152). Triclocarban sulfate
conjugates are removed from plasma with a half-life of about 20 hours,
presumably into the bile.
    The majority of triclocarban and its metabolites are eliminated
through the feces, with smaller amounts eliminated through the urine.
In a human study where six male volunteers received a single oral dose
of \14\C-labeled triclocarban in corn oil, 70 percent of the dose was
eliminated in the feces and elimination was complete after 120 hours
(Ref. 152). Twenty-seven percent of the dose was eliminated in urine,
and the urinary excretion of triclocarban and its metabolites was
complete by 80 hours after dosing.
    Although there are some ADME data on triclocarban after oral
exposure, there are little data after topical exposure. Gruenke et al.
(Ref. 163) analyzed plasma and urine samples from human subjects who
used triclocarban-containing bar soap. The major plasma metabolite was
a sulfate of hydroxy-triclocarban, with levels ranging from 0-20 ng/mL.
The major metabolites found in the urine were triclocarban
glucuronides, with typical levels averaging 30 ng/mL. The authors did
not describe the frequency or length of time the subjects bathed with
the soap; consequently, it is not known whether maximal exposure or
steady-state levels were reached. Overall, the animal ADME data are not
adequate and additional pharmacokinetic data (e.g., AUC, Tmax, and
Cmax) at steady-state levels continue to be necessary to bridge animal
data to humans.
    Triclocarban carcinogenicity data. A manufacturer submitted a 2-
year oral carcinogenicity study of triclocarban in rats (Refs. 150 and
151). Based on this study, the no observed adverse effect level (NOAEL)
for triclocarban in the rat

is 25 mg/kg/day. Although no carcinogenicity findings were seen in this
study, some noncarcinogenicity findings were noted. Male rats treated
with 75 and 250 mg/kg/day doses of triclocarban exhibited male sex
organ toxicity, including degeneration of the seminiferous tubules,
enlargement of the epididymal secretory epithelium, and a decrease or
absence of sperm in epididymal ducts.
    No dermal carcinogenicity data have been submitted for
triclocarban. Previously, we considered data from systemic exposure to
represent a worst case scenario for topical products. Now, however, we
recognize that topical products may affect the skin or be metabolized
in the skin, which is not addressed in oral carcinogenicity studies.
    The submitted oral carcinogenicity data are adequate and show that
triclocarban does not pose a risk of cancer after repeated oral
administration under the experimental conditions used; however, data
from a dermal carcinogenicity study are lacking.
    Triclocarban DART data. Our records indicate that a manufacturer
submitted data regarding the reproductive toxicity of triclocarban to a
triclocarban drug master file (Ref. 164). Safety data submitted to drug
master files are not publicly available and, consequently, cannot be
used to support a GRAS classification (Sec.  330.10(a)(4)(i)). For FDA
to include these data in the administrative record for this rulemaking,
they must be submitted to this rulemaking or be otherwise publicly
available.
    Triclocarban data on hormonal effects. Recent studies have
demonstrated that triclocarban may have the ability to alter the
activity of the androgen system (Refs. 41 and 42). Chen et al. (Ref.
42) reported that triclocarban enhanced the testosterone-induced
androgen receptor-mediated response both in cell culture and in an in
vivo rat model although triclocarban by itself had no activity. When
castrated male rats were fed a diet containing 0.25 percent
triclocarban and treated with testosterone propionate (0.2 mg/kg) for
10 days, all male sex accessory organs were significantly increased in
size compared to rats treated with either triclocarban or testosterone
alone. The implications of these findings on human health, especially
for children, are not well understood.
    The testicular effects seen in the 2-year oral carcinogenicity
study (Refs. 150 and 151) also suggest a hormonal disturbance on the
testes as a result of exposure to triclocarban. Our records indicate
that additional studies to address possible testicular effects have
been conducted and submitted to a triclocarban drug master file (Ref.
164). For FDA to include these data in the administrative record for
this rulemaking, they must be submitted to the rulemaking or otherwise
publicly available. Overall, the data submitted to the antiseptic
rulemaking are not adequate to address concerns about hormonal effects
of triclocarban. We propose that additional reproductive and
developmental studies are necessary, which should include an assessment
of any hormonal effects.
    Triclocarban resistance data. We found one study that examined the
potential for development of cross-resistance between triclocarban and
antibiotics. Cole et al. (Ref. 78) described antibiotic and antiseptic
susceptibilities of staphylococci isolated from the skin of consumers
who used nonantibacterial or antiseptic body washes. Subjects were
considered antiseptic body wash users if they used either bar soaps
containing triclocarban (triclocarban group) or liquid bath or shower
products containing triclosan (triclosan group) on a regular basis for
at least 30 days prior to study initiation. From a pool of 450
qualified subjects, 70 were randomly chosen for each treatment arm
(non-user, triclocarban group, or triclosan group).
    Bacterial skin samples were collected using a pre-validated method
and were comprised of the combined samples from both forearms.
Staphylococcus aureus and coagulase-negative Staphylococcus (CNS) were
presumptively identified according to morphology, pigmentation,
hemolysis, and other characteristics from these samples. One
representative of each colony type from each sample was selected for
further testing, for a total of 317 isolates: 16 S. aureus and 301 CNS.
    All 317 Staphylococcus isolates were tested for susceptibility to
10 antibiotics, including the primary and secondary antibiotics of
choice for treatment of Staphylococcus infections, by a commercial lab
using an automated procedure. In addition, all isolates were tested for
MIC of triclocarban and triclosan using a standard broth microdilution
method.
    The percentage of CNS isolates resistant to any of the 10
antibiotics was similar for all three groups (non-user, triclocarban,
or triclosan group). When data from both user groups (triclocarban and
triclosan) were pooled, there was no statistical difference in
bacterial resistance patterns between users and non-users with the
exception of tetracycline, which approached significance (p = 0.052).
The authors did not provide the rationale for pooling triclocarban and
triclosan user data in the analysis. Currently, there is no evidence to
suggest that bacteria would use the same mechanisms of resistance
against these two antiseptic active ingredients. When CNS
susceptibility to antiseptics was examined, the MIC range for
triclocarban was the same among all three groups (maximum MIC value of
0.750 (no units provided)). No patterns emerged when the data were
analyzed for cross-resistance between triclocarban or triclosan and
antibiotics.
    The authors conclude that this study shows no increase in
antibiotic resistance from the regular use of triclocarban body wash.
But, this study was not adequately designed to determine whether use of
antiseptic body washes leads to changes in antibiotic or antiseptic
susceptibilities. Given the limited number of isolates examined, it is
not clear that the study was adequately powered to detect a difference
in resistance patterns. Furthermore, the amount of antiseptic exposure
was not defined. The length of time subjects has used antiseptic body
washes (beyond the specified 30 days), the frequency of bathing, and
the volume of antiseptic wash used per bath or shower was not reported.
Finally, few bacterial isolates were examined. It is reasonable to
examine the susceptibilities of Staphylococcus species; however, an
average of only 1.5 isolates was obtained from each subject. Overall,
the available data are not adequate to characterize triclocarban's
potential to foster the development of cross-resistance with clinically
important antibiotics and we propose that these studies are needed.
    b. Triclocarban safety data gaps. In summary, our administrative
record for the safety of triclocarban is incomplete with respect to the
following:

 Human pharmacokinetic studies under maximal use conditions
when applied topically, including documentation of validation of the
methods used to measure triclocarban and its metabolites
 Animal ADME
 Data to help define the effect of formulation on dermal
absorption
 Dermal carcinogenicity
 DART studies
 Potential hormonal effects
 Data from laboratory studies that assess the potential for the
development of resistance to triclocarban and cross-resistance to
antibiotics in the types of organisms listed in section VII.C.3 of this
proposed rule

4. Benzalkonium Chloride
    In the 1994 TFM, FDA categorized benzalkonium chloride in Category
III because of a lack of adequate safety data for its use as OTC
antiseptic handwash (59 FR 31402 at 31435). Because of its widespread
use as an antimicrobial agent in cosmetics and as a disinfectant for
hard surfaces in agriculture and medical settings, the safety of
benzalkonium chloride has also been reviewed by the Environmental
Protection Agency and an industry review panel (Cosmetic Ingredient
Review (CIR)) (Refs. 165 and 166) and found to be safe for disinfectant
and cosmetic uses, respectively. Both these evaluations have been cited
by the comments in support of the safety of benzalkonium chloride as an
antiseptic wash active ingredient (Ref. 167).
    Each of these evaluations cites findings from the type of studies
necessary to support the safety of benzalkonium chloride for repeated
daily use. However, the data that are the basis of these safety
assessments are proprietary and are publicly available only in the form
of summaries. Consequently, these studies are not available to FDA and
are precluded from a complete evaluation by FDA. In addition, the
submitted safety assessments with study summaries do not constitute an
adequate record on which to base a GRAS classification (Sec.
330.10(a)(4)(i)). For FDA to evaluate the safety of benzalkonium
chloride for this rulemaking, these studies must be submitted to the
rulemaking or otherwise be publicly available.
    a. Summary of benzalkonium chloride safety data.
    Benzalkonium chloride carcinogenicity data. Currently, no oral or
dermal carcinogenicity data are publicly available. We found one short-
term dermal toxicity study (Ref. 168). Mice were treated with a single
topical application of 0.8, 3, 13, or 50 percent benzalkonium chloride
aqueous solution and monitored for 1 month. Treatment with either the
13 or 50 percent solution (concentrations well above the actual use
concentrations of 0.1 to 5 percent) caused death in 9 of 48 and 20 of
48 mice in each group, respectively. The surviving mice developed skin
lesions at the application site. The low-dose groups (0.8 or 3 percent
solutions) showed slightly lower body weights and rates of growth than
the control group, suggesting a slight detrimental effect from dermal
exposure to these low concentrations. The available data are not
adequate to assess the carcinogenic potential of benzalkonium chloride.
We propose that both oral and dermal carcinogenicity studies are needed
for benzalkonium chloride.
    Benzalkonium chloride resistance data. Several gram-negative
bacteria (GNB) (Escherichia coli, Salmonella, and Pseudomonas) have
been shown to readily adapt when grown in the presence of subinhibitory
levels of benzalkonium chloride in laboratory studies (Refs. 60, 68,
70, 72, 169, and 170). These bacteria also displayed reduced
susceptibility to antibiotics compared to the nonadapted parental
strain (Refs. 60, 70, 72, 169, and 170). Four studies showed an
association between reduced susceptibility to benzalkonium chloride and
the antibiotic chloramphenicol (Refs. 70, 72, 79, and 170). This
association was shown in three different bacteria; however, no common
mechanism has been identified to explain this finding. There are data
available suggesting that efflux pumps may not play a major role in the
reduced susceptibility of Salmonella to benzalkonium chloride (Ref.
170).
    In a study by Lambert and colleagues (Ref. 69), human clinical and
industrial isolates and standard culture collection strains of P.
aeruginosa were examined for reduced susceptibility to benzalkonium
chloride, chlorhexidine, and eight antibiotics. No statistically
significant association between benzalkonium chloride and antibiotic
susceptibility (i.e., cross-resistance) was found in the industrial
isolates. In contrast, there was a highly significant correlation
between benzalkonium chloride and gentamycin resistance in the clinical
isolates. In other words, strains that were resistant to gentamycin
also tended to have reduced benzalkonium chloride susceptibility.
Although the authors suggest that the clinical environment is
responsible for cross-resistance, this study is not large enough to
provide sufficient support for this theory.
    In a second study, Lambert and colleagues found a positive
correlation between benzalkonium chloride and six antibiotics
(ciprofloxacin, erythromycin, oxacillin, clindamycin, amoxicillin/
clavulanic acid, and sodium cefazolin) in MRSA clinical isolates.
However, most of the statistically significant correlations found in
this study were between two antiseptics or two antibiotics, rather than
between an antiseptic and an antibiotic. In addition, there was also a
negative correlation between benzalkonium chloride and ciprofloxacin in
P. aeruginosa. The authors suggest that there are no correlations in
resistance to benzalkonium chloride and resistance to antibiotics but
believe a larger study is needed to confirm or change that conclusion.
    Similar to what has been observed with triclosan, exposure to
benzalkonium chloride in the laboratory has resulted in changes to the
antibiotic susceptibility profiles of some bacteria (Refs. 60, 70, 72,
79, 169, and 170). However, the data are limited in scope. The
available studies have examined few bacterial species, provide no
information on exposure levels, and are not adequate to define the
potential for the development of resistance or cross-resistance.
Additional laboratory studies are necessary to more clearly define the
potential for the development of resistance to benzalkonium chloride.
Depending on the results of the laboratory studies, additional data of
the type described in section VII.C of this proposed rule may also be
needed to assess the level of risk posed by benzalkonium chloride.
    b. Benzalkonium chloride safety data gaps. In summary, our
administrative record for the safety of benzalkonium chloride is
incomplete with respect to the following:

 Human pharmacokinetic studies under maximal use conditions
when applied topically, including documentation of validation of the
methods used to measure benzalkonium chloride and its metabolites
 Animal ADME
 Data to help define the effect of formulation on dermal
absorption
 Oral carcinogenicity
 Dermal carcinogenicity
 DART studies
 Potential hormonal effects
 Data from laboratory studies that assess the potential for the
development of resistance to benzalkonium chloride and cross-resistance
to antibiotics in the types of organisms listed in section VII.C.3 of
this proposed rule
5. Benzethonium Chloride
    In the 1994 TFM, FDA classified benzethonium chloride as lacking
sufficient evidence of safety for use as an antiseptic handwash (59 FR
31402 at 31435). Since FDA's proposed classification, two industry
review panels (CIR and a second industry panel identified in a comment
only as an ``industry expert panel'') and a European regulatory
advisory board (Scientific Committee on Cosmetic Products and Non-food
Products Intended for Consumers) have evaluated the safety of
benzethonium chloride when used as a preservative in cosmetic
preparations and as an active ingredient

in consumer hand soaps (Refs. 171, 172, and 173). These advisory bodies
found benzethonium chloride to be safe for these uses. However, all of
these safety determinations have largely relied on the findings of
proprietary studies that are not publicly available. One of these
evaluations, the findings of the unidentified industry expert panel,
was submitted to the rulemaking to support the safety of benzethonium
chloride (Ref. 174).
    Some of the safety data reviewed by the unidentified industry
expert panel represent the type of data that are needed to evaluate the
safety of benzethonium chloride for use in consumer antiseptic wash
products, e.g., ADME, DART, and oral carcinogenicity studies. The
safety assessments used to support the unidentified industry expert
panel's finding of safety, however, are publicly available only in the
form of summaries. Consequently, these studies are not available to FDA
and are precluded from a complete evaluation by FDA. Further, the
submitted safety assessments with study summaries do not constitute an
adequate record on which to base a GRAS classification (Sec.
330.10(a)(4)(i)). For FDA to include these studies in the
administrative record for this rulemaking, they must be submitted to
the rulemaking or otherwise publicly available.
    a. Summary of benzethonium chloride safety data.
    Benzethonium chloride ADME data. In 1988, NTP studied the extent of
absorption following single and repeated once-daily dermal doses of
benzethonium chloride and determined the pattern of tissue distribution
and route of elimination of \14\C-labeled benzethonium chloride in rats
(Ref. 175). They also determined the kinetics of distribution and
excretion following intravenous administration. Under the conditions of
the dermal studies, benzethonium chloride was readily absorbed
following single or repeated dermal applications.
    After a single application of \14\C-labeled benzethonium chloride
in ethanol to skin that was covered by a nonocclusive patch, total
urinary excretion was 1 to 2 percent of the applied dose, and fecal
excretion accounted for about 45 percent of the dose. The radiolabel
was below the detection limit in blood and most tissues during the
study, but low levels were measured in the liver. Some residual
radiolabel could be accounted for in the epidermis at the site of
application. When similar studies were performed with repeated once-
daily dermal dosing, the total amount of radiolabel excreted up to 10
days following the last dose was about 25 percent, suggesting some
accumulation with repeated dermal administration.
    More recent data submitted to support the safety of benzethonium
chloride have shown a much lower level of absorption. In response to
the 1994 TFM, a manufacturer provided data from a preliminary rat
dermal absorption study and an in vitro dermal absorption study (Ref.
176). In the rat study, an aqueous 1 percent solution of \14\C-
benzethonium chloride was applied to the shaved back of rats and
covered with a nonocclusive patch. Blood, urine, and feces were
collected for 48 hours after dosing. Little or no radioactivity was
detected in blood or urine samples. Approximately 7 percent of the
administered radioactivity was detected in the fecal samples. The
remaining radioactivity was not accounted for.
    The in vitro dermal absorption study compared the absorption of
benzethonium chloride through rat and human skin (Ref. 176). Pieces of
skin were obtained from rats and human plastic surgery patients. Total
absorption was higher in rat compared to human skin. Under the
conditions of this study, the total amount of benzethonium chloride
maximally absorbed by human skin during 24 hours was 4.14 percent.
Accumulation of benzethonium chloride in the skin was less than 1
percent in human skin but was about 5 percent in rat skin.
    The available data demonstrate that there is absorption of
benzethonium chloride following dermal exposure. However, the level of
absorption is not clearly defined. These data also suggest that the
amount of dermal absorption varies by species and with formulation. The
currently available animal data also lack other pharmacokinetic
determinations, i.e., distribution and metabolism. Subsequent to the
1994 TFM, FDA had numerous discussions with a manufacturer interested
in attaining a GRAS classification for benzethonium chloride (Refs.
174, 177, and 178). Topics covered in these discussions included the
need for pharmacokinetic studies in animals following dermal exposure
(Refs. 177 and 178). The available data are not adequate and data from
ADME studies in animals continue to be necessary because of highly
variable results in the submitted studies, the need to clearly define
the level of dermal absorption, the effect of formulation on dermal
absorption, and the distribution and metabolism of benzethonium
chloride in animals. In addition, we lack human pharmacokinetic studies
under maximal use conditions, which are needed to define the level of
systemic exposure following repeated use.
    Benzethonium chloride carcinogenicity data. In 1995, the NTP
conducted dermal carcinogenicity studies of benzethonium chloride in an
ethanol vehicle in rats and mice (Ref. 175). There were no treatment-
related differences from control animals in survival, clinical signs
(e.g., reddening or crusting of the skin), body weights, organ weights,
or neoplastic lesions in either rats or mice. Histological evaluation
revealed dose-related (minimal in low dose, moderate in high dose)
epithelial hyperplasia in both rats and mice at doses greater than 0.15
mg/kg/day. In rats, epidermal ulceration was frequent in high dose
females and in one high dose male.
    There was no systemic toxicity or carcinogenicity at any dose level
in either species. The no observed effect level (NOEL) for systemic
toxicity was 1.5 mg/kg/day based on systemic toxicity and
carcinogenicity. While we agree with NTP's analysis of the systemic
toxicity, we disagree with the NOEL for dermal toxicity because
epithelial hyperplasia and reddening of the skin were noted at all
doses greater than 0.15 mg/kg/day. Therefore, we consider the NOEL for
dermal toxicity to be 0.15 mg/kg/day.
    The submitted dermal carcinogenicity data are adequate and show
that benzethonium chloride does not pose a risk of cancer after
repeated dermal administration under the experimental conditions used;
however, data from an oral carcinogenicity study are lacking.
    Benzethonium chloride DART data. A manufacturer submitted summaries
of four teratology studies (three rat and one rabbit) and one perinatal
and postnatal study in rats (Ref. 174). In two of the rat teratology
studies, the rats showed delayed bone tissue formation (ossification)
and soft tissue and skeletal malformation at the high dose. Only
delayed ossification was noted in the third rat study and in the rabbit
study. These findings suggest that benzethonium chloride is a teratogen
at high doses when administered orally. However, without the complete
study reports, we are unable to fully assess the significance of these
findings.
    An embryo-fetal rat study with sufficient detail for evaluation was
submitted (Ref. 174). In this study, pregnant female rats were
administered benzethonium chloride on gestational days 6 through 15.
Maternal toxicity was noted among the high dose-treated females. In the
other dose groups, toxicity findings were sporadic and not dose-
related. There were no treatment-related gross necropsy findings or

reproductive endpoint changes caused by the treatment. The incidence of
delayed sternal ossification and/or nonossified sternal centrae was
noted in all treatment groups and was statistically significant.
However, this finding is not considered biologically significant as the
incidence was not dose-related, the litter incidence values did not
differ significantly, and the values were within the range of
historical values. The maternal NOAEL is 100 mg/kg/day based on body
weight changes and deaths at the dose of 170 mg/kg/day.
    Overall, the DART data are not adequate to characterize all aspects
of reproductive toxicity and we propose that studies are needed to
assess the effect of benzethonium chloride on male and female fertility
and on pre- and postnatal endpoints (e.g., the number of live or dead
offspring, body weight at birth, physical growth and development,
neurodevelopmental effects, and fertility of the pups).
    Benzethonium chloride resistance data. We found two studies that
examined bacterial susceptibility profiles for both benzethonium
chloride and antibiotics. One study (Ref. 179) provided the data
collectively, so no associations between reduced susceptibility to
benzethonium chloride and specific antibiotics could be determined. The
second study (Ref. 180) found a positive correlation between reduced
susceptibility to benzethonium chloride and ciprofloxacin or oxacillin
in clinical isolates of MRSA. There were no associations between
benzethonium chloride and antibiotic resistance in the other tested
organisms (methicillin-sensitive S. aureus or P. aeruginosa).
    Overall, the available studies are limited in scope. They examine
few bacterial species, provide no information on the level of
benzethonium chloride exposure, and are not adequate to define the
potential for the development of resistance and cross-resistance to
antibiotics. Additional laboratory studies are necessary to more
clearly define the potential for the development of resistance to
benzethonium chloride. Depending on the results of the laboratory
studies, additional data of the type described in section VII.C of this
proposed rule may also be needed to assess the level of risk posed by
benzethonium chloride.
    b. Benzethonium chloride safety data gaps. In summary, our
administrative record for the safety of benzethonium chloride is
incomplete with respect to the following:

 Human pharmacokinetic studies under maximal use conditions
when applied topically, including documentation of validation of the
methods used to measure benzethonium chloride and its metabolites
 Animal ADME
 Data to help define the effect of formulation on dermal
absorption
 Oral carcinogenicity
 DART studies (fertility and embryo-fetal testing)
 Potential hormonal effects
 Data from laboratory studies that assess the potential for the
development of resistance to benzethonium chloride and cross-resistance
to antibiotics in the types of organisms listed in section VII.C.3 of
this proposed rule
6. Chloroxylenol
    There are limited safety data to support the long-term use of
chloroxylenol in OTC consumer antiseptic hand and body wash products.
Chloroxylenol is absorbed after topical application in both humans and
animals. However, studies conducted in humans and animals are
inadequate to fully characterize the extent of systemic absorption
after repeated topical use or to demonstrate the effect of formulation
on dermal absorption. The administrative record also lacks other
important data to support a GRAS determination for this antiseptic
active ingredient.
    a. Summary of chloroxylenol safety data.
    Chloroxylenol human pharmacokinetic data. The dermal absorption of
chloroxylenol has been studied in humans following single and repeated
bathing (10 minutes daily for 1 to 10 days) and following a single 30-
minute percutaneous application to the back of one subject (Refs. 181
and 182). The studies were conducted with few subjects and a single
formulation, and as shown in table 7 of this proposed rule, produced
inconsistent results.

                          Table 7--Results of Human Absorption Studies of Chloroxylenol
----------------------------------------------------------------------------------------------------------------
                                                                                Absorption \1\
              Study                  Number of            Bath         -----------------------------------------
                                     subjects                                Milligrams            Percent
----------------------------------------------------------------------------------------------------------------
Jordan, Nichols, and Rance,                    1  1st.................  5.74...............  0.5.
 Preliminary Bathing Study (Ref.
 181).
Jordan, B. J., et. al., Repeat                 4  1st.................  2.4 to 4.4.........  0.2 to 0.37.
 Bathing Study (Ref. 182).
                                  ..............  10th................  2.4 to 6.4.........  0.2 to 0.5.
Jordan, B. J., et. al., Dermal                 1  N/A.................  7.2................  15.7.
 ADME under Occlusion Study
 (Ref. 182).
----------------------------------------------------------------------------------------------------------------
\1\ Based on amounts in urine.

    The wide variation in the study findings may be due to the much
lower concentration of chloroxylenol used in bathing studies (1:4,000
and 1:4,800 dilution of a 4.8 percent product versus 1 mL of the same
product undiluted). However, the small sample size and disparate study
results make it difficult to draw any meaningful conclusions on the
level of dermal absorption following single or repeated use.
    The percutaneous absorption study (Ref. 182) also provides some
limited information on the elimination of chloroxylenol in humans.
Assays of urine samples revealed that all chloroxylenol was excreted as
conjugated metabolites. No unchanged chloroxylenol was found in the
urine at any time point, and most of the drug was excreted in the first
8 hours after application.
    Overall, the human pharmacokinetic studies are not adequate and we
propose that human pharmacokinetic studies using dermal administration
under maximal use conditions are still needed to define the level of
systemic exposure following repeated use. In addition, data is needed
to help define the effect of formulation on dermal absorption.
    Chloroxylenol animal ADME data. Dermal ADME studies in rats and
mice are available (Refs. 183 and 184). In a study conducted by Sved
(Ref. 184), increasing doses of \14\C-labeled chloroxylenol were
applied to the shaved backs of mice as a single or repeated dose (once
daily for 14 or 28 days). Absorption was apparent at all time points
and increased with increasing length of exposure. Approximately 50
percent of the applied dose was absorbed at 24 hours

after a single dose and approximately 65 percent at 24 hours after 14
and 28 days of daily dosing. The amount of chloroxylenol absorbed was
proportional to the administered dose. The plasma half-life for
chloroxylenol was 18, 22, and 12 hours for low, mid, and high dose
males, respectively, and 70, 9, and 12 hours for low to high dose
females, respectively. The half-life in skin was longer at lower doses
of chloroxylenol.
    After dermal application chloroxylenol has been found in the
following tissues: Kidney, lung, liver, adrenal glands, skin, heart,
ovary, ovarian fat, skeletal muscle, skull, spinal cord, spleen, eyes,
femur, and brain (Refs. 183 and 184). Tissue concentrations increased
with repeated dosing, up to 1.8-fold in the kidney, up to 3.8-fold in
the liver, and up to 8.9-fold in the brain (Ref. 183). Concentrations
in tissue also increased with dose. Unlike the concentrations in the
liver and kidney, chloroxylenol levels in the brain did not appear to
reach steady-state concentrations after 28 days of dosing, particularly
at the lower chloroxylenol concentrations (Ref. 183). The relevance of
these findings from a chronic use perspective cannot be evaluated
without long-term animal studies.
    The majority of chloroxylenol is excreted in the urine, and this is
largely as polar conjugated metabolites. Only traces of unchanged
chloroxylenol are present in urine. Havler identified a minor
metabolite of chloroxylenol, hydroxylated chloroxylenol, which
represents 10 to 15 percent of the metabolites found in urine (Ref.
183). Both chloroxylenol and the minor metabolite are excreted as a
mixture of glucuronide and sulfate conjugates (Ref. 183). Excretion is
largely complete 24 hours after a single dermal application.
    Overall, these data demonstrate that absorption of chloroxylenol
occurs after dermal application in humans and animals. However, the
extent of this absorption and the resulting systemic exposure has not
been adequately characterized. In the 1994 TFM, FDA stated that data
from human studies characterizing the absorption, distribution, and
metabolism of chloroxylenol conducted under maximal exposure conditions
were needed (59 FR 31402 at 31415). The administrative record for this
active ingredient still lacks data to characterize the rate and extent
of systemic absorption, the similarities and differences between animal
and human metabolism of chloroxylenol under maximal use conditions, and
data to help establish the relevance of findings observed in animal
toxicity studies to humans.
    Chloroxylenol carcinogenicity data. In the 1994 TFM, FDA stated
that a lifetime dermal carcinogenicity study (up to 2 years) in mice
was needed to assess the dermal toxicity of chloroxylenol (59 FR 31402
at 31415). In response to this request, data from a 13-week dose
ranging dermal toxicity study in mice were submitted (Ref. 185).
    The study results show dose-related dermal adverse effects that may
be indicative of dermal toxicity, such as erythema (skin redness),
edema (swelling), and exfoliation (skin peeling). Microscopic changes
consistent with a mild dermal irritant were also noted. These changes
included hyperplasia (abnormal multiplication of skin cells) and
hyperkeratosis of the epidermis (overgrowth of outermost layer of the
skin) in all dosed animals, inflammation of the superficial dermis (a
deeper layer of the skin) in most treated animals, crust formation, and
necrosis (degradation) of epidermal cells. There were also dose-
dependent lesions that increased in significance with dose. Hyperplasia
of bone marrow and increased extramedullary hematopoiesis (formation of
red blood cells outside the bone barrow) in the spleen consistent with
an increasing inflammatory reaction were observed in the high dose
group. The NOEL was 15 percent chloroxylenol and the NOAEL was less
than 30 percent.
    To adequately assess the significance of these study findings, a
long-term dermal carcinogenicity study is needed. In addition, because
of potential systemic exposure, an oral carcinogenicity study is also
necessary to characterize the systemic effects from long-term exposure.
    Chloroxylenol DART data. Data are available from a teratology study
in rats that adequately characterizes chloroxylenol's potential effects
on embryo and fetal development (Ref. 186). The maternal NOEL in this
study was 100 mg/kg/day. The maternal lowest observed effect level was
500 mg/kg/day based on decreased food consumption and decreased body
weight gain. The NOEL for developmental toxicity was 1,000 mg/kg/day.
However, this study is not sufficient to characterize effects on other
aspects of reproduction. Additional studies are necessary to assess the
effect of chloroxylenol on fertility and early embryonic development
and on pre- and postnatal development.
    Chloroxylenol resistance data. We found no published studies that
examine the changes in bacterial susceptibilities that may occur after
exposure to nonlethal amounts of chloroxylenol. The few studies that
are available assess antibiotic susceptibility in chloroxylenol-
tolerant bacteria. In one study Lambert and colleagues determined the
MICs of 8 antiseptics and at least 7 antibiotics for 256 clinical
isolates of S. aureus (including MRSA) and 111 clinical isolates of P.
aeruginosa (Ref. 180). Although most of the statistically significant
correlations were between two antiseptics or between two antibiotics
rather than between an antiseptic and an antibiotic, the authors found
a significant positive correlation between chloroxylenol and gentamycin
resistance in P. aeruginosa, but a negative correlation between
chloroxylenol and ciprofloxacin resistance. They found no correlations
between chloroxylenol and antibiotic resistance for S. aureus.
    In a pair of studies (Refs. 79 and 80), Lear and colleagues
collected, identified, and measured antimicrobial susceptibilities of
bacteria from industrial sources. The authors saw no difference in the
antibiotic susceptibility patterns of the industrial and standard
strains of P. aeruginosa. Overall, there were few changes in antibiotic
resistance patterns between the standard and industrial strains.
    While these studies provide little evidence of cross-resistance to
antibiotics, they are limited in scope. They examine few bacterial
species, provide no information on the level of chloroxylenol exposure,
and are not adequate to define the potential for the development of
resistance to chloroxylenol and cross-resistance to antibiotics. If the
data from initial laboratory studies indicate a potential for the
development of chloroxylenol resistance and antibiotic cross-
resistance, additional data such as the type described in section VII.C
of this proposed rule will be necessary to assess the level of risk
posed by chloroxylenol.
    b. Chloroxylenol safety data gaps. In summary, our administrative
record for the safety of chloroxylenol is incomplete with respect to
the following:

 Human pharmacokinetic studies under maximal use conditions
when applied topically that includes documentation of validation of the
methods used to measure chloroxylenol and its metabolites
 Animal ADME at toxic exposure levels
 Data to help define the effect of formulation on dermal
absorption
 Dermal carcinogenicity

 Oral carcinogenicity
 DART studies defining the effects of chloroxylenol on
fertility and pre- and postnatal development
 Potential hormonal effects
 Data from laboratory studies that assess the potential for the
development of resistance to chloroxylenol and cross-resistance to
antibiotics in the types of organisms listed in section VII.C.3 of this
proposed rule.
7. Triclosan
    A large number of studies have been conducted to characterize the
toxicological and metabolic profile of triclosan using animal models.
Most of these studies have focused on understanding the fate of
triclosan following exposure to a single source of triclosan via the
oral route of administration. However, dermal studies in both humans
and animals are also available. These studies show that triclosan is
absorbed through the skin, but to a lesser extent than oral absorption.
    a. Summary of triclosan safety data.
    Triclosan human pharmacokinetics data. Although much of the human
data relates to oral exposure, there are some human studies that
examine triclosan pharmacokinetics after dermal exposure on the hands
or body (Refs. 187, 188, and 189). The dermal absorption of triclosan
has been estimated or characterized using a variety of formulations and
techniques, as described in this subsection. The available data show
that dermal absorption of triclosan is low. Consequently, additional
human pharmacokinetic studies are not necessary.
    In one multiple exposure handwash study (Ref. 187), 13 human
subjects washed their hands 6 times a day with 1 percent triclosan
liquid soap for 20 days. Dermal absorption of triclosan was
demonstrated by an increase in the levels of triclosan in plasma after
handwash use; however, the percentage of the applied dose that was
absorbed through the skin was not provided or estimated. Steady-state
levels of free and total triclosan were achieved within approximately 1
week (days 6-8). The highest plasma concentrations achieved by any
subject during the study were 69.9 ng/mL for free triclosan and 229 ng/
mL for total triclosan. Although this study provides a picture of the
steady-state levels of triclosan from repeated handwash use, it does
not provide Cmax, Tmax or AUC values for humans.
    Despite the lack of individual concentration-time data, this study
provides a basis on which to estimate the mean steady-state
concentrations that would result if a multiple-application body wash
study were to be conducted. From the reported study results, it is
possible to calculate the cumulative amount of product used by each
subject, and to relate this amount to the amount that would be used as
a body wash. Assuming a concentration of 1 g triclosan/mL of soap, the
mean of all subjects in the handwash study was 3.6 mL/wash. Multiplying
this value by six washes per day gives a total mean volume of 21.6 mL/
day.
    Using a reported industry estimate (Ref. 190) that a 10 ounce
(295.5 mL) bottle contains enough body wash for 29 washes, the
estimated amount of body wash per use would be 10.2 mL (295.5 mL/29
washes = 10.2 mL/wash). Assuming that an individual bathes twice a day
with a 1 percent triclosan-containing body wash, the total mean volume
estimate would be approximately 20.4 mL. This is less than the mean
amount used in the handwash study (21.6 mL/day). Based on the
pharmacokinetic data provided, steady-state was achieved during the
study, indicating that the study was of sufficient length to evaluate
the pharmacokinetics of chronically administered triclosan.
    Another of the available studies (Ref. 188) addresses triclosan
exposure as a result of multiple product use. Two groups of 84 subjects
were enrolled in this 13-week study. One group used triclosan
toothpaste twice a day plus triclosan bar soap for face and handwashing
twice a day plus triclosan deodorant once a day. The other group used
triclosan toothpaste twice a day plus placebo soap and deodorant. Blood
was drawn before product usage and at 3, 6, and 13 weeks.
    At baseline, there was no significant difference in the mean
triclosan plasma concentrations between groups. After product use,
however, the mean triclosan plasma concentrations were significantly
higher in the multiple triclosan-containing product group (highest
achieved concentration: 31.04 ng/mL) than in the toothpaste only group
(highest achieved concentration: 22.47 ng/mL) for all three time
points. This suggests that the use of multiple triclosan-containing
products can lead to higher triclosan exposure than from use of a
single product. The concentrations observed in this study are
substantially lower than the range of concentrations at steady-state
that were observed in the handwashing study (Ref. 187). The substantial
increase in triclosan concentration from baseline to 3 weeks indicates
that the majority of the absorbed triclosan in this study was due to
the use of the triclosan-containing toothpaste.
    There have been several studies that attempted to estimate the
absorption of triclosan following topical application in a variety of
different formulations (Refs. 189, 191, 192, and 193). In theses
studies triclosan was delivered as a solution, in toothpaste, as a
mouthwash, or in a cream. Despite the different properties of the
dosage forms and vehicles used, the estimated absorption was
approximately in the range of 5 to 15 percent of the applied dose.
Based on these data, the impact of different formulations on the dermal
absorption of triclosan appears to be minimal.
    In summary, human absorption of triclosan has been adequately
characterized and no further human pharmacokinetic studies are needed.
    Triclosan ADME data. Triclosan is readily metabolized in both
humans and animals to two main parent conjugates, triclosan glucuronide
and triclosan sulfate. Several other minor metabolites have been
detected in animal studies (Refs. 194 through 197); however, the
relevance of these minor metabolites to humans is unknown. In humans
after oral or oral plus dermal triclosan exposure, triclosan
glucuronide is the primary circulating metabolite in plasma (Ref. 188).
After a single oral exposure to 4 mg of triclosan, the triclosan levels
in human plasma increased rapidly and reached maximum concentration
within 1 to 3 hours (Ref. 198). In this study, the majority of the
triclosan in plasma was conjugated; the unconjugated fraction of
triclosan in plasma was 30 to 35 percent. Triclosan was cleared from
the plasma at a rate of 2.9 L/hour.
    There also are some data to suggest that triclosan is metabolized
during passage through the skin. Moss, Howes, and Williams (Ref. 191)
examined dermal metabolism of triclosan in vivo in the rat and in vitro
using rat or human skin in flow-through diffusion cells. In both
species, triclosan was metabolized during passage through the skin to
triclosan glucuronide and triclosan sulfate. Triclosan was more readily
metabolized to the glucuronide conjugate, which was also more readily
removed from the skin than the sulfate conjugate.
    The elimination pattern of triclosan varies depending on the
species. Triclosan is excreted mainly via urine in humans (Ref. 198)
and hamsters (Ref. 195), while it is eliminated mainly through feces in
mice (Ref. 196) and rats (Ref. 199). After a single oral administration
of 4 mg of triclosan to human subjects, the majority of the triclosan
was excreted in urine within

the first 24 hours (Ref. 198). There was considerable variability among
subjects; between 24 and 83 percent of the dose was excreted within 4
days after exposure. The urinary excretion half-life ranged from 7 to
17 hours, and excretion approached baseline levels by 8 days after
exposure.
    In the multiple exposure handwash study (previously described in
this section (Ref. 187)), the mean elimination half-life for total
triclosan after multiple dermal exposures was 33 hours. This is longer
than the elimination half-life calculated after a single oral exposure
(12 hours). The authors suggest the reason for this difference is that
absorption through the skin takes longer than absorption from the
gastrointestinal tract.
    It is well documented that triclosan in aqueous solution can be
degraded into 2,8-dichlorodibenzo-p-dioxin and other degradation
products by heat or ultraviolet irradiation (i.e., photodegradation)
(Refs. 200 through 206). Although the data support photodegradation in
aqueous solution, we found no data regarding whether photodegradation
of triclosan can occur on human skin. It is not known whether
photodegradation products would be formed on human skin after topical
application of triclosan-containing antiseptics and, if so, whether
they would be absorbed or affect the skin. Because of this new
information regarding photodegradation of triclosan, we propose that
data are needed regarding the potential for formation of triclosan
photodegradation products on human skin as a result of consumer
antiseptic use and, if present, their effects on the skin.
    Overall, the animal ADME data are not adequate and additional
pharmacokinetic data (e.g., AUC, Tmax, and Cmax) at steady-state levels
continue to be necessary to bridge animal data to humans. In addition,
data regarding the potential for formation of photodegradation products
on human skin and their effects on the skin are needed.
    New triclosan findings. A recent study evaluated the physiological
effects of triclosan treatment on muscle function in mice and fish
(Ref. 207). The authors observed a negative effect on both cardiac and
skeletal muscle function as a result of a single triclosan treatment
and identified a mechanism to explain the observed effect. While this
finding suggests a previously unidentified toxicity of triclosan, it is
a preliminary finding that has not been duplicated. Further, the mice
were treated by injecting triclosan into the abdomen (i.e.,
intraperitoneal administration), rather than through a more relevant
route of administration, such as the oral or dermal route. We invite
comment on what these findings tell us about triclosan's potential
impact on human health and the submission of additional data on this
subject.
    Triclosan carcinogenicity data. A 2-year oral carcinogenicity study
in hamsters was submitted to the rulemaking (Ref. 208). The study was
conducted in Syrian hamsters because the elimination pattern of
triclosan is similar in hamsters and humans. Although some treatment-
related noncancerous lesions were seen in the kidneys, epididymides,
testes, and stomach, there were no tumor findings in any of the organs
examined. The NOAEL for triclosan in this hamster study is 75 mg/kg/
day. The study included additional (satellite) groups to assess
triclosan plasma levels at week 53 and at study termination (Ref. 209).
At both time points, plasma levels increased with increasing doses and
significantly higher triclosan plasma levels were seen in males
compared to females (p < 0.001). This increase over time suggests that
triclosan is accumulating in the animals; however, the effect of this
accumulation is unknown.
    In contrast to the oral data, there are little data regarding
dermal toxicity of triclosan. Short-term dermal toxicity studies in
rats (Ref. 210) and mice (Refs. 211 and 212) show dose-related dermal
adverse effects following a 14-day treatment period. Similar dermal
effects were seen in a 90-day subchronic dermal toxicity study in rats
(Ref. 213). A long-term dermal carcinogenicity study could be used to
assess the relevance of the short-term dermal toxicity findings to a
chronic use situation; however, currently no long-term dermal
carcinogenicity data are available. Because these data are not
available but are needed to fully evaluate the safety of triclosan, FDA
nominated triclosan to NTP for toxicological evaluation (Ref. 214). The
NTP studies will evaluate the dermal carcinogenicity potential
following chronic dermal exposure to triclosan (Refs. 215 and 216).
These studies are ongoing; however, results of these studies are not
expected to be available for several years, and we do not intend to
delay the antiseptic rulemaking to wait for these study results.
    The submitted oral carcinogenicity data are adequate and show that
triclosan does not pose a risk of cancer after repeated oral
administration under the experimental conditions used; however, data
from a dermal carcinogenicity study are still needed.
    Triclosan DART data. In the 1994 TFM, we stated that we were
evaluating the data from a two-generation study of the reproductive
toxicity of triclosan in rats (Ref. 217). In this study, rats that were
exposed to a high dose (3,000 ppm) of triclosan in utero showed lower
neonatal survival and lower mean body weights compared to untreated
controls. The offspring of these rats (i.e., F2 pups) had a lower rate
of survival to weaning compared to untreated controls. Based on the
findings from this two-generation study, we recommended that a segment
II study should be conducted to address the decreased survival among
the high dose-treated litters.
    Since that time, additional segment II reproductive toxicity
studies have been submitted showing that triclosan is not teratogenic
in mice, rats, or rabbits (Ref. 218). No treatment-related mortality
was observed, and pregnancy rates and the number of litters for treated
animals were comparable to controls. The oral NOAELs from these studies
are listed in table 8 of this proposed rule.

      Table 8--Oral No Observed Adverse Effect Levels (NOAEL) From
               Reproductive Toxicity Studies of Triclosan
------------------------------------------------------------------------
                                              Oral NOAEL (mg/kg/day)
                                         -------------------------------
                 Species                     Maternal      Developmental
                                             toxicity        toxicity
------------------------------------------------------------------------
Mouse...................................              25              25
Rat.....................................              50              50
Rabbit..................................              50             150
------------------------------------------------------------------------

    Overall, the triclosan DART data are adequate and additional
traditional DART studies are not necessary. However, as discussed in
the subsection of this proposed rule on drug-induced hormonal effects,
we propose that additional reproductive and developmental testing will
be needed to address concerns about these effects.
    Triclosan data on hormonal effects. Recent studies have
demonstrated that triclosan has effects on the thyroid, estrogen, and
testosterone systems in several animal species, including mammals
(Refs. 41, 43 through 47, 50, and 219). In addition, effects were also
seen in the hamster carcinogenicity study (e.g., a reduction or absence
of spermatozoa, abnormal spermatogenic cells, and partial depletion of
one or more generations of germ cells in male testes in the high dose-
treated group) (Ref. 220). The implications of these findings on human
health, especially for children, are still not well understood.
    At this time, no adequate long-term (i.e., more than 30 days) in
vivo animal

studies have been conducted to address the consequences of these
hormonal effects on functional endpoints of growth and development
(e.g., link of preputial separation to sexual differentiation and
fertility, link of decreased thyroxine/triiodothyronine to growth and
neurobehavioral development) in exposed fetuses or pups. Studies in
juvenile animals (of the type described in section VII.C.2 of this
proposed rule) could address the consequences of short-term thyroid and
reproductive findings on the fertility, growth, and development of
triclosan-exposed litters.
    Triclosan resistance data. Much of the recent data looking at
cross-resistance between antiseptic active ingredients and antibiotics
involve an evaluation of triclosan. Several bacterial species that
showed reduced susceptibility to triclosan were also resistant to one
or more of the tested antibiotics (Refs. 60 through 66, 71, and 73
through 77). This trend was seen for both gram-negative (E. coli,
Pseudomonas aeruginosa, Salmonella enterica, Stenotrophomonas
maltophilia, Acinetobacter, and Campylobacter) and gram-positive
(Staphylococcus aureus, including MRSA) organisms. Although the
clinical relevance of these studies is not clear, the possibility that
triclosan contributes to changes in antibiotic susceptibility warrants
further evaluation.
    One of our concerns stems from the observation that triclosan
exposure can lead to changes in bacterial efflux pump activity. Several
studies (Refs. 62, 64, 66, and 102) suggest that an efflux mechanism is
responsible for the observed reduced triclosan susceptibility. In
addition, overexpression of efflux pump regulatory genes also leads to
reduced triclosan susceptibility in E. coli (Ref. 101).
    In addition to bacterial efflux activity, other mechanisms have
been documented that may also contribute to reduced antiseptic
susceptibility and cross-resistance, e.g., changes in bacterial
membrane (Ref. 67). This type of nonspecific mechanism, in theory,
could work against multiple antibiotics or antiseptics.
    Other data suggest that different mechanisms of action may occur at
different triclosan concentrations. In the laboratory, at low
concentrations triclosan has a specific action against a bacterial
enzyme (FabI), while high concentrations act against less specific
targets, such as the cell membrane (Ref. 109). Currently, there is not
enough information to know which scenarios, if any, could occur under
actual use conditions.
    Although numerous studies have evaluated the antiseptic and
antibiotic susceptibility profiles of clinical or culture collection
strains, there are few studies that evaluate the susceptibility
profiles of bacterial isolates from nonhospital or consumer settings.
In a pair of studies (Refs. 79 and 80), Lear and colleagues collected,
identified, and measured antimicrobial susceptibilities of bacteria
from industrial sources. Samples were taken from a factory and
laboratories of companies that manufacture products containing
triclosan, where it was likely that the organisms were exposed to this
ingredient. Of approximately 100 industrial isolates, two triclosan-
tolerant isolates were chosen for further study (Acinetobacter
johnsonii and Citrobacter freundii).
    The authors then determined the antibiotic susceptibility profiles
of the two industrial isolates compared to standard culture collection
strains (Ref. 79). The authors saw no difference in the antibiotic
susceptibility patterns of the industrial and standard strains of A.
johnsonii. In contrast, the C. freundii industrial isolate was more
resistant to 12 of 14 antibiotics tested. These changes in antibiotic
susceptibility were quite modest, however. While this industrial
isolate showed only modest changes in susceptibility for most of the
tested antibiotics, it still demonstrates a change in the antibiotic
susceptibility pattern after triclosan exposure. Unfortunately, the
number of sites that were sampled was low (50 total sites), only two
isolates were studied, and the time and extent of triclosan exposure is
unknown.
    In addition to laboratory data, there are also a few studies that
examined the potential for development of cross-resistance in bacterial
isolates taken from the skin of consumer antiseptic users. Cole et al.
(Ref. 78) described antibiotic and antiseptic susceptibilities of
staphylococci isolated from the skin of consumers who used antiseptic
or nonantibacterial body washes. This study also evaluated triclocarban
and is described in detail in section VII.D.3.a of this proposed rule.
    When CNS susceptibility to antiseptics was examined, the maximum
MIC value was the same for all three groups (2.020 (no units
provided)); however, the minimum MIC value differed between triclosan
users (0.008) and non-users (0.120). Because antiseptic MICs do not
correlate with clinical endpoints, it is not clear what this difference
in MIC means. No patterns emerged when the data were analyzed for
cross-resistance between triclosan or triclocarban and antibiotics.
    The authors conclude that this study shows no increase in
antibiotic resistance from the regular use of antiseptic body washes.
But, this study was not adequately designed to determine whether use of
antiseptic body washes leads to changes in antibiotic or antiseptic
susceptibilities. Given the limited number of isolates examined, it is
not clear that the study was adequately powered to detect a difference
in resistance patterns. Furthermore, the amount of antiseptic exposure
was not defined. The length of time subjects had used antiseptic body
washes (beyond the specified 30 days), the frequency of bathing, and
the volume of antiseptic wash used per bath or shower was not reported.
Finally, few bacterial isolates were examined. It is reasonable to
examine the susceptibilities of Staphylococcus species; however, an
average of only 1.5 isolates was obtained from each subject.
    Aiello et al. (Ref. 81) looked for a possible association between
antibiotic and triclosan susceptibilities among staphylococci and GNB
isolated from the hands of consumers who used nonantibacterial or 0.2
percent triclosan-containing antiseptic handwashes for 1 year. Two
hundred twenty-four inner city households were randomized to use soap
and cleaning products with or without antibacterial ingredients. The
products were blinded and were delivered to each household monthly.
During the study period, the households were required to use only the
assigned home hygiene products and were asked not to change any of
their other normal hygiene practices. To assess prior exposure to
antimicrobials, including antiseptics, a survey of the antibacterial
cleaning and hygiene products used within the home was conducted at
baseline.
    The hands of the primary caregiver in the home were sampled for
bacteria at baseline and 1 year later. Only the most commonly isolated
bacterial species, defined as at least 38 isolates of a single species
from all samples, were analyzed further. A total of 628 isolates were
examined for their triclosan MICs and susceptibilities to selected
antibiotics. Staphylococci were tested against oxacillin to determine
methicillin resistance. The GNB were tested against three to six
antibiotics, based on clinical relevance. There were no significant
differences in the observed proportions of isolates that were
antibiotic resistant at baseline versus the end of the year except for
Enterobacter cloacae, which was significantly higher at baseline (36
percent) than at the end of the year (0 percent) (p = 0.016).

    The MICs of triclosan ranged from 0.03 to 4.00 [mu]g/mL; however,
two thirds of the isolates had triclosan MICs over 1 [mu]g/mL. The
median triclosan MICs for the gram negative species varied widely. In
contrast, the staphylococcus median values were very similar, except
for S. aureus, which was 2 [mu]g/mL at baseline and 0.03 [mu]g/mL at
the end of the year. There was no statistically significant association
between triclosan MICs and susceptibility to antibiotics.
    A randomly chosen subset of seven GNB organisms with triclosan MICs
of at least 32 [mu]g/mL was retested with agar containing triclosan
concentrations in the range of 64 to 1,024 [mu]g/mL. The subset
contained Klebsiella pneumoniae, Acinetobacter baumannii, Enterobacter
cloacae, and P. fluorescens isolates. All of the isolates grew on agar
containing 1,024 [mu]g/mL triclosan, suggesting that they may survive
the triclosan concentrations used in some consumer products.
    This study did not show an association between high triclosan MICs
and antibiotic resistance after 1 year of triclosan handwash use.
However, the authors note that the triclosan MICs seen for many of the
isolates in this study are higher than those reported previously. They
suggest that general levels of decreased susceptibility to triclosan
seem to be increasing in the community, regardless of whether
triclosan-containing products are used in the home or not. The authors
also concluded that the absence of a statistically significant
association between elevated triclosan MICs and reduced antibiotic
susceptibility may indicate that such a correlation does not exist or
that it is relatively small among the isolates that were studied.
Still, they theorized that a relationship may emerge after longer term
or higher dose exposure of bacteria to triclosan in the community
setting.
    Overall, the administrative record for triclosan is complete on the
following aspects of the resistance issue:

 Laboratory studies demonstrate triclosan's ability to alter
antibiotic susceptibilities (Refs. 60 through 66, 71, and 73 through
77)
 Data define triclosan's mechanisms of action and demonstrate
that these mechanisms are dose dependent (Ref. 109)
 Data demonstrate that exposure to triclosan changes efflux
pump activity, a common nonspecific bacterial resistance mechanism
(Refs. 62, 64, 66, and 102)
 Data show that low levels of triclosan may persist in the
environment (Refs. 85, 113, 114, 115, and 221 through 224)

    However, the administrative record is not complete with respect to
data that would clarify the potential public health impact of the
currently available data. Examples of the type of information that
could be submitted to complete the record include the following:

 Data to characterize the concentrations and antimicrobial
activity of triclosan in various biological and environmental
compartments (e.g., on the skin, in the gut, and in environmental
matrices)
 Data to characterize the antiseptic and antibiotic
susceptibility levels of environmental isolates in areas of prevalent
antiseptic use, e.g., in the home, health care, food handler, and
veterinary settings and
 Data to characterize the potential for the reduced antiseptic
susceptibility caused by triclosan to be transferred to other bacteria
that are still sensitive to triclosan

    b. Triclosan safety data gaps. In summary, our administrative
record for the safety of triclosan is incomplete with respect to the
following:

 Animal ADME
 Dermal carcinogenicity
 Data regarding the potential for formation of photodegradation
products on human skin and their effects on the skin
 Potential hormonal effects
 Data to clarify the relevance of antimicrobial resistance
laboratory findings to the consumer setting

VIII. Proposed Effective Date

    Based on the currently available data, this proposed rule finds
that consumer antiseptic wash active ingredients can be considered
neither safe nor effective for use in OTC consumer antiseptic wash drug
products. Accordingly, consumer antiseptic wash active ingredients
would be nonmonograph in any final rule based on this proposed rule. We
recognize, based on the scope of products subject to this monograph,
that manufacturers will need time to comply with a final rule based on
this proposed rule. However, because of the potential safety
considerations raised by the data for some antiseptic active
ingredients evaluated, we believe that an effective date later than 1
year after publication of the final rule would not be appropriate or
necessary. Consequently, any final rule that results from this proposed
rule will be effective 1 year after the date of the final rule's
publication in the Federal Register. On or after that date, any OTC
consumer antiseptic wash drug product that is subject to the monograph
and that contains a nonmonograph condition, i.e., a condition that
would cause the drug to be not GRAS/GRAE or to be misbranded, could not
be initially introduced or initially delivered for introduction into
interstate commerce unless it is the subject of an approved new drug
application or abbreviated new drug application. Any OTC consumer
antiseptic wash drug product subject to the final rule that is
repackaged or relabeled after the effective date of the final rule
would be required to be in compliance with the final rule, regardless
of the date the product was initially introduced or initially delivered
for introduction into interstate commerce.

IX. Summary of Preliminary Regulatory Impact Analysis

    The summary analysis of benefits and costs included in this
proposed rule is drawn from the detailed Preliminary Regulatory Impact
Analysis (PRIA) that is available at http://www.regulations.gov, Docket
No. FDA-1975-N-0012 (formerly Docket No. 1975N-0183H).

A. Introduction

    FDA has examined the impacts of the proposed rule under Executive
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L.
104-4). Executive Orders 12866 and 13563 direct 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). This proposed rule would be an economically significant
regulatory action as defined by Executive Order 12866.
    The Regulatory Flexibility Act requires Agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. This proposed rule would have a significant economic
impact on a substantial number of small entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that Agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $141

million, using the most current (2012) Implicit Price Deflator for the
Gross Domestic Product. FDA expects this proposed rule to result in a
1-year expenditure that would meet or exceed this amount.

B. Summary of Costs and Benefits

    The costs and benefits of the proposed rule are summarized in table
9 of this proposed rule entitled ``Economic Data: Costs and Benefits
Statement.'' As table 9 shows, the primary estimated benefits come from
reduced exposure to antiseptic active ingredients by 2.2 million pounds
per year. Using the primary estimates, the combined total consists of a
reduction in triclosan exposure by 799,426 pounds per year,
triclocarban exposure by 1.4 million pounds per year, chloroxylenol
exposure by 231.9 pounds per year, and benzalkonium chloride by 63.8
pounds per year. Limitations in the available data characterizing the
health effects resulting from widespread long-term exposure to such
ingredients prevent us from translating the estimated reduced exposure
into monetary equivalents of health effects.
    The primary estimate of costs annualized over 10 years is
approximately $23.6 million at a 3 percent discount rate and $28.6
million at a 7 percent discount rate. These costs consist of total one-
time costs of relabeling and reformulation ranging from $112.2 to
$368.8 million. Estimates of the cost of relabeling and reformulating
may be overstated if manufacturers produce data consistent with the
monograph changes in this proposed rule and do not need to relabel or
reformulate. In such a scenario, the costs of producing the data would
be incurred instead. Under the proposed rule, we estimate that each
pound of reduced exposure to antiseptic active ingredients would cost
$3.86 to $43.67 at a 3 percent discount rate and $4.69 to $53.04 at a 7
percent discount rate.
    Manufacturers are expected to incur most product reformulation and
relabeling costs with the impact to relabelers, repackers, and
distributors being considerably less. The impact on a manufacturer can
vary considerably depending on the number and type of products it
produces. For the estimated 707 affected establishments that would
qualify as small,\1\ our estimate of the average one-time cost of
compliance ranges from $0.10 million to $0.33 million, which would be
approximately 0.33 percent to 1.10 percent of the average annual value
of shipments for a small business. In its Initial Regulatory
Flexibility Analysis, the Agency assesses a pair of regulatory options
that would reduce the proposed rule's burden on small entities: (1)
Exempting small businesses from the rule and (2) longer compliance
period, allowing 18 months (rather than 12 months).
---------------------------------------------------------------------------

    \1\ FDA notes that the analysis was conducted using data at the
establishment level rather than at the firm level. This makes the
implicit assumption that the typical manufacturing establishment is
roughly equivalent to the typical small manufacturing firm. However,
if market is dominated by a few large firms with a large number of
small establishments, our estimated number of small entities, may be
an overestimate of the actual number of businesses with fewer than
750 employees.

                                                  Table 9--Economic Data: Costs and Benefits Statement
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                Units
                                           Primary       Low        High    -------------------------------------------------
                Category                  estimate    estimate    estimate      Year      Discount                                       Notes
                                                                               dollars      rate         Period  covered
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                        Benefits
--------------------------------------------------------------------------------------------------------------------------------------------------------
    Annualized Monetized $millions/year  ..........  ..........  ..........  ..........          7%  Annual.
                                                                                3%  Annual.................
    Annualized Quantified..............   2,198,033     989,922   3,406,145  ..........          7%  Annual.                  Reduced antiseptic active
                                          2,198,033     989,922   3,406,145                      3%  Annual.................   ingredient exposure (in
                                                                                pounds).
--------------------------------------------------------------------------------------------------------------------------------------------------------
Qualitative
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                          Costs
--------------------------------------------------------------------------------------------------------------------------------------------------------
    Annualized Monetized $millions/year       $28.6       $16.0       $52.5        2010          7%  Annual.                  Annualized costs of
                                              $23.6       $13.2       $43.2        2010          3%  Annual.................   relabeling and
                                                                                reformulation. Range of
                                                                                estimates captures
                                                                                uncertainty.
    Annualized Quantified..............  ..........  ..........  ..........  ..........          7%
                                                                                3%
--------------------------------------------------------------------------------------------------------------------------------------------------------
Qualitative
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                        Transfers
--------------------------------------------------------------------------------------------------------------------------------------------------------
Federal Annualized Monetized $millions/  ..........  ..........  ..........  ..........          7%  .......................  None.
 year.                                                                                3%
                                        ----------------------------------------------------------------------------------------------------------------
From/To................................  From:
                                         To:
--------------------------------------------------------------------------------------------------------------------------------------------------------
Other Annualized Monetized $millions/    ..........  ..........  ..........  ..........          7%
 year.                                                                                3%
--------------------------------------------------------------------------------------------------------------------------------------------------------
From/To................................  From:
                                         To:
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects
    State, Local, or Tribal Government: Not applicable......................................................................
----------------------------------------             ------------------------------------------------------------------------
Small Business
    Annual cost per affected small entity estimated as $0.01-$0.04 million, which would represent 0.04-0.13 percent of
     annual shipments.
----------------------------------------             ------------------------------------------------------------------------
Wages: No estimated effect.
----------------------------------------             ------------------------------------------------------------------------
Growth: No estimated effect.
--------------------------------------------------------------------------------------------------------------------------------------------------------

X. Paperwork Reduction Act of 1995

    This proposed rule contains no collections of information.
Therefore, clearance by the Office of Management and Budget under the
Paperwork Reduction Act of 1995 is not required.

XI. Environmental Impact

    We have 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.

XII. Federalism

    FDA has analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. FDA has determined that
the proposed rule, if finalized, would have a preemptive effect on
State law. Section 4(a) of the Executive order requires Agencies to
``construe * * * a Federal statute to preempt State law only where the
statute contains an express preemption provision or there is some other
clear evidence that the Congress intended preemption of State law, or
where the exercise of State authority conflicts with the exercise of
Federal authority under the Federal statute.'' Section 751 of the
Federal Food, Drug and Cosmetic Act (the FD&C Act) (21 U.S.C. 379r) is
an express preemption provision. Section 751(a) of the FD&C Act (21
U.S.C. 379r(a)) provides that ``no State or political subdivision of a
State may establish or continue in effect any requirement--(1) that
relates to the regulation of a drug that is not subject to the
requirements of section 503(b)(1) or 503(f)(1)(A); and (2) that is
different from or in addition to, or that is otherwise not identical
with, a requirement under this Act, the Poison Prevention Packaging Act
of 1970 (15 U.S.C. 1471 et seq.), or the Fair Packaging and Labeling
Act (15 U.S.C. 1451 et seq.).'' Currently, this provision operates to
preempt States from imposing requirements related to the regulation of
nonprescription drug products. (See section 751(b) through (e) of the
FD&C Act for the scope of the express preemption provision, the
exemption procedures, and the exceptions to the provision.)
    This proposed rule, if finalized as proposed, would require data
from clinical outcome studies to demonstrate the effectiveness of
consumer antiseptic active ingredients. Any final rule would have a
preemptive effect in that it would preclude States from issuing
requirements related to OTC consumer antiseptics that are different
from, in addition to, or not otherwise identical with a requirement in
the final rule. This preemptive effect is consistent with what Congress
set forth in section 751 of the FD&C Act. Section 751(a) of the FD&C
Act displaces both State legislative requirements and State common law
duties. We also note that even where the express preemption provision
is not applicable, implied preemption may arise (see Geier v. American
Honda Co., 529 U.S. 861 (2000)).
    FDA believes that the preemptive effect of the proposed rule, if
finalized, would be consistent with Executive Order 13132. Section 4(e)
of the Executive order provides that ``when an agency proposed to act
through adjudication or rulemaking to preempt State law, the agency
shall provide all affected State and local officials notice and an
opportunity for appropriate participation in the proceedings.'' FDA is
providing an opportunity for State and local officials to comment on
this rulemaking.

XIII. References

    The following references are on display in the Division of Dockets
Management (see ADDRESSES) under Docket No. FDA-1975-N-0012 (formerly
1975N-0183H) and may be seen by interested persons between 9 a.m. and 4
p.m., Monday through Friday, and are available electronically at http://www.regulations.gov. (FDA has verified all Web site addresses in this
reference section, but we are not responsible for any subsequent
changes to the Web sites after this proposed rule publishes in the
Federal Register.)

1. Comment No. C12 in Docket No. 1975N-0183H.
2. Transcript of the January 22, 1997, Meeting of the Joint
Nonprescription Drugs and Anti-Infective Drugs Advisory Committees,
OTC Vol. 02CAWASHTFM.
3. Transcript of the March 23, 2005, Meeting of the Nonprescription
Drugs Advisory Committee, http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4098T1.pdf, 2005.
4. Transcript of the October 20, 2005, Meeting of the
Nonprescription Drugs Advisory Committee, http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4184T1.pdf, 2005.
5. Summary Minutes of the November 14, 2008, Feedback Meeting with
Personal Care Products Council and Soap and Detergent Association,
OTC Vol. 02CAWASHTFM.
6. Comment Nos. C7, C10, C11, C12, C14, C18, C22, C25, C32, C34,
C35, C36, C40, C43, C44, C45, C47, C48, C53, C54, C55, C56, C57,
C60, C61, C63, C64, C77, C80, C81, C82, C83, C85, C89, CP3, CP4,
CP6, CP7, CP11, CP14, CP15, CP16, LET11, LET13, LET15, LET18, LET43,
RPT3, RPT5, SUP1, SUP2, SUP3, SUP5, SUP6, and SUP7 in Docket No.
1975N-0183H.
7. Comment Nos. C1, C8, C11, C14, C18, C19, C20, C23, C32, C34, C35,
C36, C38, C42, C43, C45, C48, C50, C51, C52, C58, C60, C61, C70,
C76, C79, C82, C84, C85, C89, C93, CP1, CP3, CP4, CP7, CP9, CP12,
CP14, CP17, LET1, LET12, LET13, LET16, LET17, LET43, PR1, PR3, PR4,
PR5, PR6, PR7, PR9, RPT4, SUP3, SUP4, SUP5, SUP7, SUP12, and SUP13
in Docket No. 1975N-0183H.
8. Comment Nos. C171, C172, C173, LET98, LET99, PR2, and SUP47 in
Docket No. 1975N-0183H.
9. Comment Nos. DRAFT-1044, DRAFT-1045, DRAFT-1046, DRAFT-1047,
DRAFT-1048 in Docket No. FDA-1975-N-0012.
10. Comment No. CP1 in Docket No. 2005P-0432.
11. Comment No. C4 in Docket No. 1975N-0183H.
12. Comment No. C42 in Docket No. 1975N-0183H.
13. Comment No. C20 in Docket No. 1975N-0183H.
14. Comment No. CP8 in Docket No. 1975N-0183H.
15. Comment No. CP1 in Docket No. 1996P-0312.
16. Comment No. CP1 in Docket No. 1975N-0183H.
17. Comment No. C30 in Docket No. 1975N-0183H.
18. Comment No. LET23 in Docket No. 1975N-0183H.
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