toxicity to young plants. The antimicrobial is applied to the foliage
to evaluate uptake of the antimicrobial from the exposed green tissue.
The Agency is proposing to require this study for wood preservatives
and aquatic areas. For wood preservatives, this would codify current
practices. For aquatic areas, this would codify the shift from the use
of the Tier I study to a Tier II study and thereby would codify current
practices.
    The Agency is also proposing to conditionally require this study
for the low environmental exposure grouping, and industrial processes
and water systems (once-through). This would expand the number of use
patterns for which this study is conditionally required.

G. Aquatic Plant Growth (Lemna gibba) (Tier II - Dose-Response)

    The Agency is proposing to require the Aquatic Plant Growth (Lemna
gibba) (Tier II - Dose-Response) study for the high environmental
exposure grouping. This would codify the shift from the use of the Tier
I study to a Tier II study and thereby would codify current practices.
    The Agency is also proposing to conditionally require the Tier II
study for low environmental exposures based on the results of the algal
study. This would expand the number of use patterns for which this
study is conditionally required.
    Lemna gibba or duckweed is an important wildfowl food source and is
used in wastewater reclamation. Therefore, it is important to
understand the impact of an antimicrobial on this food source.

H. Aquatic Plant Growth (Tier II - Dose-Response)

    The Agency is proposing to require one or more of the Aquatic Plant
Growth (Tier II - Dose-Response) studies for all antimicrobial use
patterns. As with the aquatic plant study discussed in the previous
section, part 161 requires the Tier I study and conditionally requires
the Tier II study. For the high environmental exposure grouping, this
would codify the shift from the use of the Tier I study to a Tier II
study and thereby would codify current practices. Testing is required
for four species representing green algae, freshwater cyanobacteria, a
freshwater diatom and a marine diatom. These four species are used to
represent hundreds of different species.
    Testing is required in only one species (green algae) for the low
environmental exposure grouping. This would expand the number of use
patterns for which this study is required.
    Green algae produce oxygen, serve as a food source for aquatic
animals, and provide the basic energy needs of any aquatic ecosystem.
The results of the green algae study will allow the Agency to determine
if the other three aquatic plant growth studies are required for the
low environmental exposure grouping.

I. Terrestrial and Aquatic Field Studies

    The Agency is proposing to conditionally require Terrestrial and
Aquatic Field Studies for all antimicrobial use patterns. Field studies
provide more realistic information on a pesticide's impacts than
laboratory studies which focus only on one parameter, because field
studies consider all potential impacts on plant growth. The need for
these higher tier studies would be based on the results of the lower
tier plant protection studies, adverse incident reports, intended use
pattern, and environmental fate characteristics that indicate potential
exposure.
    These two studies are conditionally required in part 161 for three
use patterns. Due to the use patterns currently used in part 161, there
is not sufficient delineation for comparison to the antimicrobial use
patterns proposed today. While EPA routinely considers the need for
these studies in determining the data needed for its risk assessments,
it has required these

studies based on case-by-case circumstances on a very infrequent basis
for antimicrobials.
    Since the testing is proposed to be conditionally required for all
antimicrobial pesticide use patterns, this would expand the number of
use patterns for which these studies are conditionally required.
Additionally, this would harmonize the requirements for antimicrobials
with those of conventional pesticides.

XV. Peer Review

A. National Research Council Recommendations

    The National Academy of Sciences issued a report in 1993 entitled,
``Pesticides in the Diets of Infants and Children'' (Ref. 19). The
study, conducted by the National Research Council (NRC), was initiated
to address the question of whether the current regulatory system
adequately protected infants and children from pesticide residues in
food. The Council reviewed EPA's then-current practices and data
requirements related to dietary risk assessment as well as testing
modifications planned by the Agency. The panel of experts concluded
that, at that time, EPA approaches to data requirements and risk
assessments emphasized the evaluation of the effects of pesticides in
mature animals and, in general, there was a lack of data on pesticide
toxicity in developing organisms.
    The Council's recommendations with respect to regulatory needs for
data development included the following:
     Discussed the need to investigate the effects of pesticide
exposure on immunotoxic responses in infants and children.
     Supported the need for acute and subchronic neurotoxicity
testing and encouraged the Agency to have these studies as part of the
required data for all food-use pesticides.
     Encouraged further work in the area of developmental
neurotoxicity.
    Many of the NRC recommendations were incorporated into the data
requirements that were promulgated for conventional pesticides (72 FR
60933), and for biochemical and microbial pesticides (72 FR 60988). By
deliberately building on the foundation of these promulgated rules, and
harmonizing to the extent practicable considering the differences in
use patterns, many of the NRC recommendations, such as immunotoxicity
testing, are incorporated into this proposed rule for antimicrobial
pesticides.

B. FIFRA Scientific Advisory Panel (SAP)

    1. 1994 meeting. In 1994, EPA held a 2-day meeting of the SAP to
review the Agency's proposed amendments to the data requirements for
pesticide registrations contained in 40 CFR part 158, which covered
antimicrobials. The SAP was asked to comment on each data requirement
and identify, in their scientific opinion, which requirements were
necessary to fully and thoroughly evaluate the potential hazard of a
chemical compound and which were not intrinsically useful in providing
practical scientific information. The revisions presented to the Panel,
i.e., the changes to the data requirements presented in this document,
were generally endorsed. A very complete discussion of the 1994 SAP
meeting was presented in the proposed rule for conventional pesticides
(70 FR 12276).
    2. June 1997 meeting: A set of scientific issues being considered
by the Agency to determine antimicrobial issues. On June 3, 1997, the
Agency presented an early version of the part 158, subpart W proposal
in an open meeting to the SAP. The Agency asked for specific comments
in five areas covered by proposed 158W data requirements: Toxicology;
residue chemistry, ecological effects and environmental fate, human
exposure, and efficacy. The SAP's full comments are found in the docket
for this action (Ref. 29) and are summarized here.
    i. Toxicology. The Agency asked if its division of antimicrobial
pesticide uses into high human exposure and low human exposure groups,
with extensive data requirements for high exposure uses and tiered data
requirements for low exposure uses, was an acceptable approach. The SAP
agreed that the Agency's tiered approach was reasonable, and made
several suggestions to improve the proposal. Two of these suggestions
were ``unambiguous trigger points indicating next Tier level of
toxicity testing,'' and ``to continue dialogue with Canadian
counterparts to harmonize, clearly define trigger points, and improve
the guidelines.''
    The Agency has worked to provide clear, unambiguous triggers in the
test notes to the toxicology data requirements tables. EPA is also
committed to dialogue with its Canadian counterpart. PMRA has routinely
received updates on the status of the draft antimicrobial data
requirements, and has been actively engaged throughout the development
of this proposal.
    ii. Residue chemistry. The Agency asked the SAP if the scientific
approach to obtaining dietary residue information in general, but
specifically for indirect food contact sanitizers, was reasonable. The
SAP agreed that the scientific approach was reasonable, and remarked
extensively on the residue chemistry data requirements for indirect
food uses such as sanitizers. They noted that such products had
generally been of low toxicity or low persistence, and their belief
that a tolerance or tolerance exemption for such uses was unnecessary,
based on FDA's practice with such products. The SAP also suggested the
use of default surface residue values for estimating sanitizer residues
to obviate the need for measured data.
    Although the SAP believes that a tolerance or tolerance exemption
is unnecessary, under FFDCA, EPA is required to establish either a
numerical tolerance, or an exemption from the requirement of a
tolerance for indirect food uses. To obviate the need for measured
data, EPA uses modeling and ``worst-case'' estimates, as appropriate.
As discussed in Unit X. of this preamble, if such estimates when paired
with the toxicity data do not indicate a concern, then it is unlikely
that measured surface residue data would be required.
    iii. Human exposure. The Agency asked the SAP if the approaches
presented were reasonable and if the Agency had adequately accounted
for all antimicrobial use and exposure scenarios. Additionally, the
Agency asked if multiple exposure scenarios for one pesticide product
would be better accounted for by data for all applicable exposure
scenarios or a subset of applicable scenarios.
     The SAP agreed that the Agency's 12 use categories for
antimicrobials were a reasonable approach to organizing exposure data
requirements, and were, in fact, similar to the approaches used by PMRA
and the California EPA. EPA is proposing that these use categories be
codified in Sec.  158.2201 as the antimicrobial use patterns.
     The SAP also advised that initially, all applicable
exposure scenarios should be considered for a single antimicrobial
product. The Agency accepted this recommendation which is now part of
its standard exposure assessment practices.
     The SAP expressed concern that post-application exposure
might be too narrowly defined, and noted some possible exposure
scenarios involving persons not in the 1997 presentation. In response,
the Agency has broadened the scope of post-application exposure to

include persons who may come in contact with materials after treatment.
This includes contact with impregnated materials and children's
exposure to treated wood. In response, the Agency is proposing to
require the indoor surface residue dissipation study and the non-
dietary ingestion exposure study for residential uses to address this
concern.
    iv. Ecological effects and environmental fate. For the 1997
presentation to the SAP, EPA divided the antimicrobial use sites into
two groupings: high expected environmental exposure and low expected
environmental exposure. The Agency asked if a tiered data set to
support an ecological risk assessment for uses with high expected
environmental exposure was appropriate. The SAP agreed that a tiered
data set to support an ecological risk assessment would be appropriate.
    EPA also asked if ecological risk assessments were necessary for
the low expected environmental exposure grouping. In its presentation
EPA stated its intention to require a very reduced data set suitable
for developing precautionary labeling for manufacturing and certain
end-use products. At that time EPA considered that ``indoor'' uses had
minimal environmental exposures or releases of pesticide residues to
the environment. The SAP commented that the reduced data set could be
justified only if data available from other programs within EPA and
elsewhere were adequate to assess ecological risk. As a result of the
SAP's concerns, the Pesticide Program discussed these issues with EPA's
Office of Solid Waste and Office of Water.
    As a result of these discussions in the late 1990s, the Pesticide
Program continued to believe that
     ``Indoor'' residential uses of antimicrobials with the
rinses going down-the-drain had minimal environmental exposures or
releases of pesticide residues to the environment,
     Industrial effluents that could possibly contain
antimicrobials would be adequately regulated via the permitting process
under the National Pollutant Discharge Elimination System Program of
the Clean Water Act and wastes possibly containing antimicrobials would
be adequately regulated under the Resource Conservation and Recovery
Act.
    Therefore, in 1997, the Agency determined not to require
biodegradation or microbial data.
    More recently, as part of its development of this proposed rule,
EPA re-evaluated its belief that ``indoor'' residential uses had
minimal environmental exposures. EPA is now proposing to require the
environmental fate and ecological effects data for conducting an
ecological risk assessment for down-the-drain antimicrobials. The
rationale for this decision is discussed in Unit XII.B. of this
preamble.
    The SAP expressed its concerns about ``the lack of chemical fate
data,'' and also stated that biodegradation data (both aerobic and
anaerobic) should be required.
     In response to the SAP, EPA reexamined the need for
environmental fate data other than hydrolysis, and as a result of this
1997 reexamination, the Agency determined to conditionally require data
on photodegradation in water for these low expected environmental
exposures. EPA is now proposing to require the photodegradation in
water study for all antimicrobial chemicals, including the low
environmental exposure grouping.
     Initially, in 1997, the Agency determined to not require
biodegradation data. EPA has reconsidered this 1997 decision and today
is proposing to require an activated sludge sorption isotherm, a ready
biodegradability test, and a modified activated sludge, respiration
inhibition study for the low environmental exposure grouping.
    The SAP also questioned why microbial data to protect publicly
owned treatment works (POTWs) and other treatment systems which often
rely on microbial treatment processes were not required. The Agency
investigated this possibility, but could not in the early 1990s
determine a satisfactory set of data that would then be useful in
protecting the highly variable conditions of specific POTWs. EPA is
proposing as part of its environmental fate data requirements, to
require the data that would allow EPA to assess the impacts of
antimicrobials on wastewater treatment plants.
    The SAP questioned the use of precautionary labeling to protect
fish and wildlife from improper use of antimicrobials, especially
considering that some use categories would pose exposure via sewage
systems. As a result, EPA prepared sample labeling to reduce this
source of exposure: ``This product is toxic to fish and aquatic
invertebrates. Do not discharge effluent containing this product into
lakes, streams, ponds, estuaries, oceans, or public water unless this
product is specifically identified and addressed in a NPDES permit. Do
not discharge effluent containing this product to sewer systems without
previously notifying the sewage treatment plant authority.'' This type
of labeling is still in use today.
    The SAP cautioned that although wildlife exposure to antimicrobials
via water was the most likely source of exposure, terrestrial exposure
is also possible. The Agency concurred, and is proposing to require for
the aquatic areas use pattern and to conditionally require for all
other use patterns, the avian dietary and avian reproductive studies
for performing such an assessment.
    Finally, the SAP expressed concern that antimicrobial metabolites
may be more toxic than their parent compounds, and therefore may also
need to be tested. The Agency agrees, and has revised many of the test
notes in this proposal to clarify the need for data on metabolites when
the available information demonstrate that the metabolites are more
toxic or otherwise pose environmental risks.
    3. 1998 and 1999 meetings. Data requirements, as related to the
application of the newly mandated FFDCA safety factor (required under
the FQPA amendments) were presented to the SAP in 1998 and 1999. Copies
of documents prepared for the 1998 and 1999 SAP meetings and the final
reports from each of the meetings are in the docket for this action
(Refs. 30, 31, 32, and 33) and can be found on EPA's web site at http:/
/www.epa.gov/scipoly/sap. A summary of the issues specific to the
proposed antimicrobial data requirements follows:
    i. Toxicology. In December 1998, EPA presented the SAP an issues
paper on the use of the FQPA safety factor to address the special
sensitivity of infants and children to pesticides. The discussion on
the developmental neurotoxicity study was specifically discussed in the
context of the appropriateness of using an additional safety factor. At
that time, the SAP did not reach a consensus recommendation on whether
this study should be routinely or conditionally required. The issue of
what is a complete and reliable data set was brought before the SAP
again in May 1999. The majority of the Panel supported the Agency's
approach to applying data requirements but advised the Agency to
revisit the first tier of required toxicity studies every few years to
update data requirements as needed. The Panel also agreed with the
Agency on the need to require the neurotoxicity battery of studies,
including developmental neurotoxicity testing, for high exposure
pesticides such as food-use pesticides. The SAP's recommendations are
reflected in today's proposed antimicrobial data requirements for
developmental neurotoxicity and immunotoxicity. This also harmonizes
the data requirements

for conventional pesticides and for antimicrobials.
    ii. Post-application exposure. Working in collaboration with Health
Canada and the Organization for Economic Cooperation and Development
(OECD), EPA drafted guidelines for post-application exposures studies.
They were internally peer-reviewed and shared with the California
Department of Pesticide Regulation, representatives from academia, and
the American Crop Protection Association. The Agency presented its
post-application exposure guidelines and standard operating procedures
to the SAP in 1998 and again in 1999. In 1999, the SAP commended the
Agency for making significant strides toward developing scenario-based
residential and non-occupational exposure assessments that are
sufficiently conservative as to not underestimate exposures. The data
requirements proposed for post-application exposure to antimicrobials
are drawn from this body of work.
    4. 2000 meeting. In its response to an April 2000 presentation on
certain scientific issues concerning probabilistic ecological risk
assessment, the SAP was asked for recommendations on sediment toxicity
testing. The SAP stated that the extent to which a compound partitions
from the aqueous phase to the sediment is a key consideration in
determining the need for testing benthic organisms. There was a
consensus among SAP members that compounds with high Kocs
(organic carbon-water partition coefficient) or Kows
(octanol-water partition coefficient) required sediment testing for
benthic fish or invertebrates. A copy of the final report is in the
docket for this action (Ref. 34) and can be found on EPA's web site at
http://www.epa.gov/scipoly/sap. Based on this meeting, the guidelines
for sediment testing were developed. For antimicrobials, acute and
chronic sediment testing are proposed to be required or conditionally
required.

XVI. International Activities

    EPA actively works through international and regional organizations
and directly with other countries to develop common or compatible
international approaches to pesticide registration, including data
requirements. Joint reviews and work sharing are two of the approaches
used by EPA to increase the harmonization of pesticide regulatory
programs. EPA believes that making pesticide regulatory programs more
consistent internationally will:
     Maintain high standards for the protection of human health
and the environment.
     Increase the efficiency of the registration process by
lessening the resource burden on governments and the regulatory
community.
     Provide more equal access to pest management tools.
     Strengthen the regulatory process.
     Facilitate the registration of alternative pest control
tools.
     Minimize trade problems.
    Harmonization activities are increasing and evolving as agencies
and applicants build upon their experiences.

A. Joint Data Reviews and Evaluations

    EPA is working closely with other countries toward greater
uniformity in testing, reviewing and evaluating all pesticides. The
benefits of international regulatory cooperation on antimicrobials are
potentially great: Improved science through greater information
exchange, and reduced regulatory and resource burdens on national
governments and regulated parties through harmonized pesticide
regulatory review. Over the last several years, substantial progress
has been made toward international cooperation on pesticide regulatory
review. Member countries of the Organization for Economic Cooperation
and Development (OECD), including the United States, have agreed upon
harmonized guidance for the formats of industry data submissions
(dossiers) and country data review reports (monographs). Countries now
frequently exchange pesticide reviews or consult with one another on
key technical aspects of a review.
    Under the North American Free Trade Act (NAFTA), EPA has worked
cooperatively with Canada and/or Mexico, dividing up detailed
evaluation work on a number of pesticides. The Agency has also entered
into similar information exchange and comparative review arrangements
with other countries. There have been multiple bilateral joint reviews
and/or work sharing with member countries of the European Union.
Trilateral joint reviews and workshares have been performed with Canada
and Australia. A global joint review is being conducted among six
countries (the United States, Australia, New Zealand, Canada, Ireland,
and the United Kingdom.) The peer reviewers will be four other EU
countries. The primary objective of all of these arrangements has been
to use resources in the most efficient way possible.
    Concerning antimicrobials, since 2000, Health Canada's Pest
Management Regulatory Agency (PMRA), the USEPA and California's EPA
have been cooperating on a joint review for the re-evaluation/
reregistration of the following three heavy-duty wood preservatives:
Pentachlorophenol, creosote, and chromated copper arsenate. The review
of submitted data, writing of the risk assessments, and peer review
activities are being shared. Exposure data used in the preliminary risk
assessment were collected from both U.S. and Canadian wood-treatment
facilities. Both PMRA and EPA are contributing to the public comment
process. The cooperative activities continue as both EPA and PMRA work
toward issuance of their decision documents in September 2008.

B. Harmonization of Data Requirements

    As the international regulatory community works toward greater
harmonization on pesticide review, attention has also focused on the
data requirements, how the requirements compare from one country to
another, and what can or should be done to establish common
requirements. To the extent that data requirements for pesticide
registration are similar, sharing reviews and comparing evaluations is
easier and more meaningful. Requirements that differ considerably from
one country to another can mean that applicants who are looking to
register a pesticide in more than one country may have to conduct many
different studies to satisfy all the various national requirements.
Therefore, from the perspective of the applicant, establishing similar
requirements also can reduce the resources that must be spent to
conduct testing.
    OECD Member countries have had discussions about harmonizing
pesticide data requirements within the OECD community. The pesticide
industry took on the complex task of looking at data requirement
differences among Member countries to identify areas that might benefit
from harmonization. Preliminary findings presented to the OECD Working
Group on Pesticides Meeting in June 2001, reported, consistent with the
positions of scientific reviewers in OECD Member countries, that
toxicology data requirements are quite similar across countries. This
does not mean that there is no room for additional harmonization work
on toxicology data requirements, but rather that there are other
testing areas where there is much less consistency on data requirements
across countries.
    Ecotoxicological and environmental fate studies present a
particular

challenge for harmonization. Data requirements in these areas can
differ considerably from one country to another depending upon how
countries' tiered approaches to data requirements are applied. National
data requirements must be tied to national use patterns and
environmental and ecological conditions. A reliable environmental
hazard assessment, for example, must be based on studies that
accurately reflect the climate, soil types and agricultural practices
of the country doing the assessment. Because ecological and
environmental studies must be representative of national conditions to
adequately support national risk assessments, harmonization of data
requirements for these types of studies can be difficult. Harmonization
can require extensive dialogue between scientists to determine which
data requirements can act as common requirements. Such dialogue can
also include discussions of test ``conditionalities,'' that are
reflected in the test notes to the tables for the proposed data
requirements.
    Since 1995, the United States and Canada under the NAFTA Technical
Working Group on Pesticides, Harmonization of the Evaluation of
Antimicrobial Pesticides Project have worked together to harmonize data
requirements for antimicrobials. These harmonization activities
represent two efforts. EPA coordinates with Canada's PMRA on
harmonization activities for all disciplines except efficacy. For
harmonization activities for efficacy requirements EPA coordinates with
Health Canada's Therapeutic Product Directorate (TPD).
    EPA and PMRA approach antimicrobial data requirements differently.
EPA uses a tiered testing strategy, while PMRA bases its data
requirements on a defined use pattern approach. EPA and PMRA's data
requirements have been carefully compared. TPD and EPA recently
completed a crosswalk of EPA and TPD efficacy data requirements, which
is being used for planning purposes to explore future harmonization
activities. The data requirements proposed in this document for
antimicrobials represent U.S. national requirements but they reflect
extensive consultation with Canada. The data requirements are
harmonized to a high degree. The two countries plan to continue to work
together to keep data requirements for all disciplines as similar as
possible.
    OECD has not conducted any activity specifically aimed at
harmonizing data requirements for biocides. In 1997-1998, the OECD
Pesticide Program conducted a survey to collect information on the
existing requirements across countries. The survey served two purposes:
(1) To improve OECD's understanding of how Member countries regulate
biocides, and (2) to provide information that could be used to prepare
the way for future efforts to increase international co-operation in
biocide regulation. The survey shows great variability. At this time
OECD has no plans to work toward harmonizing these data requirements,
but instead has worked at harmonizing tools and methodologies in order
to reduce duplication and harmonize review procedures for possible work
sharing.

C. Protocol/Guideline Harmonization

    Harmonization can also involve protocol/guideline development or
revisions so that the studies produced can meet common data
requirements.
    Issues can arise because the study protocols or guidelines used to
generate the studies to meet the requirements can be different. In
other words, a particular data requirement might be the same from one
country to the next, but the study submitted to meet the requirement
can run into acceptance problems if done according to a protocol that
is acceptable in one country, but not in another. There is significant
commonality in protocol design for toxicology studies among various
countries, but less for ecotoxicology and environmental fate studies.
Information on how to satisfy data requirements is specified in Sec.
158.70. This section provides for both the recommended use of EPA
Guidelines and for the acceptability of OECD protocols with certain
caveats. Section 158.80 allows for the use of data developed in foreign
countries, again with certain caveats to ensure that the data will meet
EPA's needs under FIFRA and FFDCA.

D. Ballast Water Treaty

    Both domestically and internationally, an emerging significant use
of antimicrobials is the treatment of ballast water. Ballast water
provides needed stability for safe operation of marine vessels. It is
the water that is pumped in and out of the ship's ballast tanks to
ensure safe operation, such as compensating for the ship's weight
changes due to loading and unloading of cargo. In recent years there
have been significant concerns about transport of marine species from
one marine environment to another, via ballast water. Ballast water
treatments are intended to kill the marine species prior to discharge.
When discharged into a new environment, a new species may become
invasive and disrupt the native ecology.
    The International Convention for The Control and Management of
Ships' Ballast Water and Sediments, 2004 (also referred to as the
Ballast Water Convention) was adopted by consensus at a diplomatic
conference in London on February 13, 2004. The U. S. delegation was led
by the Coast Guard with participation by EPA and other Federal
agencies. The treaty opened for signature on June 1, 2004, and will
enter into force 12 months after ratification by 30 countries
representing 35% of the world's merchant shipping tonnage. Once in
force, the treaty will require that ships manage their ballast water to
meet discharge standards according to a schedule in the treaty. In
order to meet those discharge standards, ships will need to install
equipment to treat their ballast water, including disinfection. To
date, ten countries representing 3.42% of the world shipping tonnage
have become Parties to the treaty.
    Although the United States has not signed the treaty, ballast water
discharges in U.S. waters are already regulated by the Coast Guard
under the Nonindigenous Aquatic Nuisance Prevention and Control Act, as
amended (16 U.S.C. 4701 et seq.) The existing Coast Guard ballast water
management regulations can be found at 33 CFR part 151, subparts C and
D. At present, the Coast Guard is engaged in further rulemaking that
would set a performance standard for the quality of ballast water
discharged in U.S. waters and which will further foster development of
ballast water treatment technologies.
    The Agency has reviewed few applications for ballast water
treatments, presumably because such treatments and technologies are
relatively new. Therefore, for the purpose of determining data
requirements EPA determined to group ballast water treatments with
antifoulant paints and coatings since both have the potential for
exposure to marine organisms. OECD has not developed data requirements
for ballast water.

XVII. Research Involving Human Subjects

    Research with human subjects which is conducted or supported by the
U. S. government is subject to regulations for the protection of human
subjects referred to as the Common Rule. EPA was one of many federal
departments and agencies who jointly promulgated the Common Rule in
1991. EPA's codification of the Common Rule appears at 40 CFR part 26,
subpart A.

    On February 6, 2006, EPA published in the Federal Register (71 FR
6138) a final rule amending 40 CFR part 26 by adding nine new subparts.
These amendments extend regulatory protection to human subjects of
research involving intentional exposure and intended for submission to
EPA under the pesticide laws, when the research is conducted not by the
Federal government but by private parties with no support from Federal
Common Rule departments or agencies. As subsequently amended effective
August 22, 2006 (71 FR 36171), this rule (1) forbids both EPA and third
parties who intend to submit the research to EPA to conduct new
research involving intentional exposure of pregnant or nursing women or
of children; (2) extends the substantive provisions of the Common Rule
to third-party human research involving intentional exposure of non-
pregnant adults that is intended for submission to EPA under the
pesticide laws; (3) requires submission to EPA of protocols and related
information about covered human research before it is initiated; (4)
establishes an independent Human Studies Review Board to review both
proposals for new research and reports of covered human research on
which EPA proposes to rely under the pesticide laws; and (5) forbids
EPA to rely, in its actions under the pesticide laws, on research
involving intentional exposure of pregnant or nursing women or of
children, or which otherwise fails to meet criteria for acceptance,
except in narrowly defined circumstances.
    The provisions of this amended rule directly affecting third-party
research intended for submission to EPA are 40 CFR part 26, subparts K,
L, and M. Subpart K extends the substantive provisions of the Common
Rule to third-party research involving intentional exposure of non-
pregnant adult subjects that is intended for submission to EPA under
the pesticide laws. Subpart K also requires submission to EPA of
proposals for any covered research for review by EPA staff and the
Human Studies Review Board before it is initiated, and specifies the
range of information required to support any such proposal. Subpart L
prohibits conduct of any new third-party research intended for
submission to EPA involving intentional exposure of pregnant or nursing
women or of children. Subpart M specifies the range of information
required to be submitted with every report of completed research with
human subjects to document its ethical conduct.
    Studies required under proposed 40 CFR part 158, subpart W which
involve intentional exposure of human subjects are also subject to
subparts K, L, and M of 40 CFR part 26. The following data requirements
in proposed Sec.  158.2260 and Sec.  158.2270 call for studies likely
to involve intentional exposure of human subjects:
     Biological monitoring studies.
     Mixer/loader or applicator exposure studies.
     Post-application exposure studies.
    If any studies undertaken to address these requirements involve
intentional exposure of a human subject (as defined at 40 CFR
Sec. 26.1102(i)), then the study must not be initiated before
submission of protocols and supporting documentation for review by EPA
and the Human Studies Review Board. The requirements for protocol
submissions are specified at 40 CFR 26.1125. It may be possible to
design some studies responsive to the proposed data requirements for
antimicrobials so that they do not meet the regulatory definition of
research involving intentional exposure of a human subject. If there is
any question, however, about whether a proposed study intended for
submission to EPA falls within or outside this regulatory definition,
consultation with EPA is recommended before initiating the study. If
EPA did not review the protocol for a study involving intentional
exposure of a human subject, the study if subsequently submitted to the
Agency would not be acceptable under 40 CFR 26.1705.

XVIII. Alternative Testing Paradigms

    As with conventional pesticide chemicals, the Agency is committed
to moving towards a more efficient and refined testing/risk assessment
paradigm for antimicrobial pesticide chemicals.

A. Structure Activity Relationship (SAR)

    EPA must rely upon information of appropriate quality and
reliability for each decision made by the Agency. In the Office of
Pesticide Programs (OPP), the evaluation process for a pesticide
chemical traditionally begins with the applicant's submission of a set
of studies conducted with the specific pesticide chemical of interest.
The use of the results of such testing (measured data) is a logical,
scientifically-rigorous process that identifies the physical, chemical,
and environmental fate properties of the pesticide, as well as the dose
and endpoints at which an adverse effect can occur in various animal
species.
    Today, there is significant interest in determining alternative
testing paradigms that could offer more flexibility in the design of an
integrated approach in which the selection of the required studies as
well as the design of the study protocols is influenced by the
existing, reliable information about the chemical. EPA is committed to
moving towards alternative testing paradigms that are more efficient,
reduce the use of animal testing, take full advantage of advances in
science, and provide a sufficient, credible amount of data for use in a
risk assessment that will support a risk management decision.
    EPA is charged with developing a pesticide regulatory program that
is protective of human health and the environment. Other factors that
also deserve consideration in the implementation of such a program are
efficiency and effectiveness. It would be a poor use of societal
resources to routinely require the submission and governmental review
of a multi-million dollar database for every active ingredient if there
were alternative methods of determining which chemicals could be
evaluated in a scientifically rigorous manner using means other than
measured data. From the Agency's perspective an alternative testing
paradigm may also allow for a stream-lined review process for chemicals
of potential lower toxicity, thus freeing resources for more in-depth,
complex reviews of higher toxicity chemicals.
    An integrated approach would focus on using all relevant, credible
information on the chemical of interest. Applicants are cautioned that
such an approach will require a different type of thought process which
will incorporate significantly more planning and ``data mining'' types
of activities than making arrangements to conduct the required studies.
However, it could also offer a flexibility that is not always present
under the currently-used, guideline-driven (study-by-study) approach.
    Both SAR and QSAR techniques play a critical role in an integrated
approach. In the SAR process, a chemical's molecular structure is
compared to that of other chemicals for which data are available. These
structural similarities are then used to make predictive judgments
about a chemical's physical, chemical, and biological properties. Thus,
the chemical's physical, chemical, and biological properties are a
function of (or directly related to) the chemical's molecular
structure. Quantitative SAR is referred to as QSAR. To develop a QSAR,
a selected set of measured data on a single physical, chemical, or
biological property are used to derive a model (an equation) to predict
the value of that property.

    EPA's Office of Pollution Prevention and Toxics administers two
programs, the Interagency Testing Committee (ITC) and the New Chemicals
Program (NCP) under the Toxic Substances Control Act, that have been
using various forms of SAR and QSAR since the late 1970s. The ITC is an
independent advisory committee that screens chemicals or classes of
chemicals and prioritizes them for testing. The NCP uses an expert
judgment SAR process to assess human health and has developed QSAR
models to evaluate physical, chemical and environmental fate properties
and ecological effects.
    Additionally, other agencies (both U.S. and non-U.S.) are
investigating how to use these alternative techniques. OECD has devoted
a significant amount of time and effort to coordinating model
development and model validation for such an integrated approach. EPA
has participated on these workgroups.
    During the last 6 years, OPP has made increasing use of SAR as part
of its regulatory decision-making process. Documents to establish
tolerance exemptions, documents to support tolerance reassessment, and
Reregistration Eligibility Decision Documents have incorporated the use
of SAR, when appropriate. OPP recognizes the usefulness of
incorporating predictive techniques into its hazard and risk
assessments, and that for certain chemicals SAR assessments and QSAR
modeling could potentially form a scientifically-sound basis for hazard
and risk assessments used for regulatory decisions. Over time, OPP has
progressed from using SAR techniques to support a dataset of guideline
type studies to, for certain assessments, relying on SAR techniques as
an acceptable source of information on the chemical. OPP is now
considering when and how to codify in subpart A of current part 158
that information derived from SAR assessments and/or QSAR modeling
could be acceptable for fulfilling a data requirement. The submitter of
such information would be expected to supply a rationale describing the
utility of the information and provide documentation on the scientific
validity of the information. The determination that the predicted data
fulfills the data requirement would be at the sole discretion of the
Agency. The Agency seeks comment on the use of predictive techniques to
fulfill the part 158 subpart W data requirements, and specifically on
when and if the use of SAR and QSAR should be codified in part 158,
subpart A. Codification in part 158, subpart A means that SAR and QSAR
techniques would be applicable to conventional, biochemical and
microbial, and antimicrobial pesticide chemicals. The Agency
specifically seeks comment on this issue. Comments will be used in the
further development of SAR and QSAR approaches for fulfilling data
requirements, but will not be addressed in the final rule for
antimicrobial data requirements.
    Those applicants considering use of SAR and QSAR as part of a
submission package to OPP should realize SAR and Quantitative SAR
(QSAR) modeling results can sometimes be used instead of measured data,
but modeled data cannot be preferentially substituted for well-
conducted studies (measured data). If measured data are available for a
particular endpoint, then the measured data should carry the greatest
weight for hazard and risk assessment purposes. Applicants are
cautioned that if the Agency determines that the SAR and/or QSAR do not
fulfill the data requirement, then the registration may be delayed
while a study (measured data) is generated according to part 158
requirements.
    At this time, the Agency intends to continue its initial
explorations and begin the process to shift from the current guideline-
driven (study-by-study) approach to a more integrated approach in which
the use of predicted data, generated using validated models, is
considered along with information from open literature and studies
specifically generated under part 158 data requirements. All relevant
information would be considered as part of a weight-of-evidence
evaluation.
    The shift to an integrated approach would occur over some time. OPP
has deliberately chosen to begin this shift with antimicrobial
pesticide chemicals instead of conventional pesticide chemicals for two
reasons: First, most conventional pesticide chemicals are deliberately
created for their biological activity and many require complex risk
assessments. Few conventional pesticides have non-pesticidal uses.
Second, antimicrobials also have biological activity, but are more
likely to have non-pesticidal uses and, in fact, may have been assessed
by other regulatory agencies. The ready availability of published
literature and publicly-available assessments offer a unique
opportunity for the applicant to use the available information as a
starting point for fulfilling data requirements, and offering the
possible option, when appropriate, of SAR and QSAR for those data
requirements that are not yet fulfilled by measured data.
    It should be realized that just as measured data have
uncertainties, predicted data also have uncertainties. Use of different
models (developed using different sets of data) would necessarily have
trade-offs. Therefore, QSAR models must be used with caution. Expert
judgment is required to determine the appropriate model to use and if
the results of the model strike the correct balance of accuracy and
precision, with the potential for few false negatives or false
positives.
    At this time, EPA believes that for certain endpoints, especially
physical/chemical and fate properties, that SAR and QSAR might be
effectively utilized to fulfill these data requirements for many
antimicrobial pesticide chemicals. When considering biological
properties, EPA believes that SAR and QSAR can be most effectively
utilized in the evaluation of chemicals that exhibit lower toxicity for
human health and/or ecotoxicity parameters. This is appropriate because
the risk assessment for lower toxicity chemicals can be streamlined,
i.e., through use of a screening-level assessment procedure rather than
multiple tiers of assessments with progressively more data
requirements.
    As appropriate, OPP will consider the use of SAR and/or QSAR
predictive techniques as part of the hazard assessment, and eventually
the dose and endpoint selection process for antimicrobial chemicals.
Under a QSAR-based approach an applicant could provide the Agency with
an analysis that could frame the actual data required to register the
antimicrobial pesticide chemical. For some antimicrobials, applicants
may have the option of characterizing certain of the active ingredient
properties via predictive techniques. It is the responsibility of the
applicant to provide sufficient information to conduct a risk
assessment that can be used to support a risk management decision. If
the applicant believes that a SAR assessment and/or QSAR model would
provide scientifically credible information that would be useful to
EPA, then it is the responsibility of the applicant to provide to the
Agency a rationale on the appropriateness of SAR or QSAR for that
particular endpoint and sufficient documentation on how the assessment
and/or model is scientifically valid. Without such information OPP
cannot judge the validity of the model and therefore the acceptability
of the results of the model for OPP's decision-making purposes.
    At this time, the use of SAR is not yet a standardized approach in
OPP, and is being handled on a case-by-case basis. Therefore, OPP has
not yet developed a standardized format for submission of such
information. Further information on OPP's current thinking on how SAR

and QSAR modeling can be used as part of an integrated approach to
hazard and risk assessment to support a regulatory decision-making
process and guidance on submission formats is contained in the support
document, ``Use of Structure-Activity Relationship (SAR) Information
and Quantitative SAR (QSAR) Modeling For Fulfilling Data Requirements
for Antimicrobial Pesticide Chemicals and Informing EPA's Risk
Management Process'' which is contained in the docket for this proposed
rule (Ref. 43). The Agency specifically seeks comment on this support
document.

B. International Life Sciences Institute and Health and Environmental
Sciences Institute Approaches

    In both the proposed (70 FR 12276) and final (72 FR 60934) rules
for conventional pesticide chemicals, EPA discussed the relevance and
importance of the ILSI/HESI project. There have been discussions on
alternative testing paradigms with the International Life Sciences
Institute (ILSI) Health and Environmental Sciences Institute (HESI)
under the Agricultural Chemical Safety Assessment (ACSA) Technical
Committee, since 2001 (Ref. 14). The focus of this effort has been
toxicity testing for agricultural chemicals, but the results would also
be applicable to antimicrobial pesticides.
    This project, with the participation of EPA scientists, represents
an evolution of the current paradigm of animal (in vivo) toxicity
testing toward a more integrated tiered testing approach for pesticide
chemicals. Under this integrated approach, both the selection of
studies that would be required, as well as the design of the tests
themselves, could be influenced by other substantive and reliable
information about the pesticide.
    The goals being pursued by EPA for this next generation of toxicity
testing are to:
     Incorporate advances in science and technology in an
expeditious manner.
     Identify cost effective and scientifically sound
alternatives to current animal tests.
     Define a transparent, step wise plan that leads to an
evolution, not revolution, in testing and assessment.
     Define a clear and credible process, with external peer-
review and stakeholder participation.
    All available information would be considered: Not only toxicity
and dose-response data from other guideline or non-guideline studies,
but also structure-activity relationships, data on the mechanism or
mode of action of the chemical, pharmacokinetic data, studies that
examine age-related sensitivity or susceptibility to chemical exposure,
and information on potential or actual exposure to humans. These data
could be used to inform a more targeted testing approach in the design
of studies, or to support a position that the requirement for specific
toxicology tests should be waived (i.e., the studies are not needed)or
fulfilled via a means other than data generation, such as SAR.
    ACSA represents the first comprehensive effort to scientifically
re-design the toxicology animal-testing framework for pesticide
chemicals. A series of reports authored by HESI/ILSI were published in
a special edition of the Journal of Critical Reviews in Toxicology in
January 2006 (Refs. 1, 2, 3, and 6). These four articles summarized the
initial findings and recommendations.
    The ACSA proposal is consistent with EPA's direction and goals to
develop a more efficient and reliable testing paradigm. The ACSA
approach departs significantly from the current standardized list of
hazard studies used by many national and international authorities to
assess pesticides. Some studies could be eliminated while endpoint
coverage might be increased in redesigned studies based on responses
observed in a core set of toxicity tests. Thus, it will be essential to
conduct retrospective and prospective data analyses to determine
whether this new testing paradigm will meet EPA's risk assessment
needs.
    The first retrospective analysis has been completed for the 1-year
chronic dog study. Based on this retrospective analysis, which was
reviewed by the FIFRA SAP, the 1-year chronic dog study is no longer
required for conventional pesticide chemicals and is not proposed as a
data requirement for antimicrobial chemicals. Another retrospective
analysis on the 2-generation reproductive toxicity study is underway.
To this end, the Office of Pesticide Programs is currently working with
EPA's National Center for Computational Toxicology to populate a
Toxicological Reference Database (ToxRef) with data from the rat 2-
generation reproductive study, prenatal developmental toxicity and
systemic toxicity studies on hundreds of pesticides that represent
different classes, modes of action, and toxicity profiles. EPA will use
this relational database to determine the value of endpoints currently
evaluated in risk assessment (i.e., the F1 versus
F2 responses).
    From these analyses the Agency will gain other information critical
for gaining scientific consensus. Such information would be the
triggers, that is, the points at which a concern is indicated and thus
a higher level of testing is needed. The retrospective analyses will
aid the Agency in confirming the proposed ACSA triggers or in
determining new ones. Once the analysis is complete, EPA will be able
to complete draft guidance on testing. EPA plans to request SAP review
and public comment of the analyses and draft guidance in 2008.
    Additionally, there are plans to conduct several case studies using
the ACSA tiered testing proposal. It is essential to test how the ACSA
scheme works in practice. From such case studies, EPA will be able to
assess the feasibility of a testing laboratory's ability to perform
such a complex study, and will have the opportunity to evaluate the
ability of the approach and its parameters to characterize known
toxicants and address risk assessment needs.
    In considering regulatory changes to reflect the results of EPA's
consideration of ACSA, the Agency will develop scientific position
papers on the new approach and recommendations for internal and
external review. Internal review includes review by the FIFRA SAP and
opportunities for public comment. External peer review and
acceptability by other national and international regulatory
authorities are considered before implementation of any new testing
paradigm and data requirements. Harmonization of data requirements with
our NAFTA and OECD partners is also an important factor. International
regulations currently require studies that were omitted in ACSA. If EPA
had requirements that were significantly different from those of the
international community, then there could be significant problems for
applicants in trying to satisfy multiple and different requirements
world-wide.
    Thus, as these analyses and the needed peer reviews are completed,
EPA will have the opportunity to determine if the new testing paradigm
will meet its risk assessment needs. EPA will then be able to determine
what revisions to current data requirements and testing guidelines may
be appropriate.

C. Computational Toxicology

    EPA's Office of Research and Development (ORD) established the
National Center for Computational Toxicology (NCCT) in 2005. The NCCT
is developing computational tools for interpreting data from
computational chemistry, high-throughput screening

(HTS) and genomic technologies as follows:
     Computational chemistry is the integration of modern
computing and information technology with information on molecular
biology and chemistry to predict bioactivity profiles.
     HTS is a system to rapidly and efficiently test large
batches of chemicals for bioactivity utilizing robotics and automation
applied to molecular biology and assay methods.
     Genomics is the study of all the genes of a cell or
tissue, and their function.
    EPA's ToxCastTM Program began in 2006. The underlying
hypothesis for ToxCastTM is that an organism's toxicological
response is driven by interactions between chemicals and biomolecular
targets. ToxCastTM also includes model development to
predict the potential toxicity of environmental chemicals based on
bioactivity profiles. These models will identify predictive signatures,
derived from the bioassay data. This means that EPA under
ToxCastTM will develop methods of prioritizing chemicals for
further screening and testing to assist the Agency's programs in the
management and regulation of environmental contaminants (Ref. 5).
    There are three phases to the development of ToxCastTM:
    1. The proof-of-concept phase of ToxCastTM will examine
more than 300 chemicals, with rich toxicological databases, in over 400
different HTS bioassays. Predictive signatures will be created by
correlating the HTS bioassay data to the known toxicity of the 300
chemicals.
    2. A signature evaluation and expansion phase will focus on testing
and extending the ToxCastTM predictive signatures, through
the generation of HTS data on over 1,000 additional chemicals.
    3. The application phase of ToxCastTM will be expanded
to include a variety of high-priority chemicals that are either
regulated and/or considered for regulation by EPA and potentially
thousands of environmental chemicals requiring prioritization.
ToxCastTM is envisioned as delivering an affordable,
science-based system for categorizing chemicals.
    In 2007 the NCCT awarded nine contracts for the generation of HTS
and genomics data as part of the ToxCastTM chemical
prioritization research program, in order to develop the ability to
predict, or forecast toxicity based on bioactivity profiling. State-of-
the-art HTS and genomic approaches developed by the pharmaceutical
industry provide information on the impact of chemicals on biological
pathways critical for the function of systems such as the heart, lungs,
brain, or reproductive organs quickly and in a cost-efficient manner.
Thus, results from these bioassays will provide a comprehensive and
detailed overview of the potential impact of environmental chemicals
upon key cellular activities.
    As the ToxCastTM database grows so will confidence in
the models developed from that data, as well as the resultant
predictions of toxicity and potential mechanisms of action derived from
the models. This could result in changing and/or reducing the use and
numbers of animals in toxicity testing. This could also result in fewer
in vivo tests being conducted as scientists and regulators learn how to
interpret and use ToxCastTM predictions to then determine
the chemicals that must be tested using traditional toxicity testing.
Results from the first phase of ToxCastTM are anticipated by
the summer of 2008. However, significant effort will be needed as
ToxCastTM transitions from proof-of-concept to a useful
prioritization tool.

D. National Academy of Sciences (NAS) Report Concerning Toxicity
Testing and Assessment of Environmental Agents

    EPA asked NAS to undertake a comprehensive review of established
and emerging toxicity-testing methods and strategies. In response to
this request NAS convened the Committee on Toxicity Testing and
Assessment of Environmental Agents. EPA asked the Committee to conduct
their assessment in two parts. Part I is a review document, discussing
current and near-term methods and strategies for collecting information
for human health risk assessment. Part II is a long-range vision and
strategic plan for changes to human health risk assessment paradigms.
    In June 2006, NAS released Toxicity Testing for Assessment of
Environmental Agents: Interim Report (Ref. 20). This report fulfills
EPA's Part I request. In conducting its research NAS considered
numerous documents and resources such as (1) current toxicity testing
protocols and various testing strategies using these protocols, (2)
impediments to the use of human data, (3) strategies that rank or
screen chemical substances, and (4) human health risk assessment
guidance documents. The Part I report identified four objectives that
EPA should strive to meet as it works to evolve its current paradigm of
toxicity testing:
     Depth, providing the most accurate, relevant information
possible for hazard identification and dose-response assessment.
     Breadth, providing data on the broadest possible universe
of chemicals, endpoints, and life stages.
     Animal welfare, causing the least animal suffering
possible and using the fewest possible animals.
     Conservation, minimizing the expenditure of money and time
on testing and regulatory review.
    The report acknowledged that it was difficult to simultaneously
meet all four objectives.
    In 2007 NAS released its Part II report entitled ``Toxicity Testing
in the 21st Century: A Vision and a Strategy'' (Ref. 21). According to
NAS, toxicity testing is approaching a ``scientific pivot point.''
Today, there are advances in the biological sciences that are already
impacting how toxicity testing is conducted. NAS concluded that a
paradigm shift would be needed to transform the current testing system
but that ``the result will be a more efficient, informative and less
costly system for assessing the hazards posed by industrial chemicals
and pesticides.''

E. Next Steps

    EPA will undertake rule-makings on a timely basis as the science
progresses and changes to the data requirements are appropriate.

XIX. Animal Welfare Concerns

    The Agency understands many people's concern about the use of
animals for research and data development purposes. In both the
proposed rule (70 FR 12276) and in the final rule (72 FR 60934) for
conventional pesticide chemicals, EPA discussed its commitment to the
development and use of alternative approaches to animal testing.
    Taking into consideration principles of sound science and the
requirements of FIFRA to protect humans and the environment, the Agency
is committed to avoiding unnecessary or duplicative animal testing. As
a result, the Agency has invested significant resources to investigate
more integrated testing approaches that include, in silico, in vitro,
and focused in vivo testing. The Agency's long-term goal is to create a
testing paradigm so that chemicals are tested in animals only for those
endpoints most relevant to each chemical's exposure or intended use.
The Agency acknowledges that substantial work remains to achieve this
long-term goal, but the Agency is also working on the important short-
term goal to make the existing animal testing paradigm more efficient,
reliable, and

responsive to its risk assessment and management needs.
    As a result of the Agency's activities to move towards a more
efficient animal paradigm, EPA is proposing to eliminate the existing
requirement for the 1-year chronic dog study for antimicrobial
pesticide chemicals.

XX. Potential Rule-Makings of the Future for Endangered Species

    EPA is charged with protecting endangered and threatened species
from potential harm from pesticide use. Under the Endangered Species
Act, EPA must ensure that the registered uses of pesticides will not
jeopardize the continued existence of endangered or threatened species,
or adversely modify habitat designated as critical by the U.S. Fish and
Wildlife Service or National Marine Fisheries Service. Accordingly, in
its proposed and final rules for both conventional pesticide chemicals,
and biochemical and microbial pesticide chemicals, the Agency discussed
the possibility of future data and information needs to develop and/or
refine risk assessments for endangered and threatened species. As a
result of those proposed rules, EPA received comments. For the present,
EPA will consider those comments in the context of its ongoing risk
assessments, including those for antimicrobials. If EPA finds that it
needs to amend subpart W of part 158 to normalize endangered species
data requirements, it will consider those comments and any comments
submitted in response to this proposed rule in the development of a
future proposed rule.
    For agricultural pesticides, there is generally greater specificity
relative to where a pesticide may be used. If adequate geographic
delineation of the use site is possible, then overlap with the
locations of an endangered or threatened species may also be possible.
    However, antimicrobial pesticides are different from agricultural
pesticides. The Agency expects that most antimicrobial uses with
potential for environmental exposure (e.g., wood preservatives,
antifoulant paints, industrial wastewater discharges, ballast water
discharges) could impact geographic areas of the United States that are
less well defined. For example, vessels treated with antifoulant paints
can occur in freshwater, estuarine, or marine areas within the U.S.
(such as lakes and rivers) and in coastal waters. Wood preservatives
could be used in locations that may result in an impact to terrestrial
and/or aquatic organisms depending on the use of the wood, which could
occur throughout the United States. Antimicrobial use sites will be
much more difficult to delineate, and overlay with endangered or
threatened species locations.
    The Agency seeks comment on:
    1. The types of data that could be useful for conducting the
assessment required.
    2. Projections of how long it would take to generate the needed
data.
    3. Whether antimicrobial use sites can be adequately correlated
with endangered species locations, and suggested methods for doing so.

XXI. References

    1. Barton, A, Pastoor, TP, Baetcke, K, Chambers, JE, Diliberto, J,
Doerrer, NG, Driver, JH, Hastings, CE, Iyengar, S, Krieger, R, Stahl,
B, and Timchalk, C. 2006. The acquisition and application of
absorption, distribution, metabolism, and excretion (ADME) data in
agricultural chemical safety assessments. Critical Reviews in
Toxicology. 36, 9-35.
    2. Carmichael, NG, Barton, HA, Boobis, AR, Cooper, RL, Dellarco,
VL, Doerrer, NG, Fenner-Crisp, PA, Doe, JE, Lamb, JC, and Pastoor, TP.
2006. Agricultural chemical safety assessment: a multi-sector approach
to the modernization of human safety requirements. Critical Reviews in
Toxicology. 36, 1-7.
    3. Cooper, RL, Lamb, JC, Barlow, SM, Bentley, K, Brady, AM,
Doerrer, NG, Eisenbrandt, DL, Fenner-Crisp, PA, Hines, RN, Irvine, L,
Kimmel, CA, Koeter, H, Li, AA, Makris, SL, Sheets, L, Speijers, GJA,
and Whitby, K. 2006. A tiered approach to life stages testing for
agricultural chemical safety assessment. Critical Reviews in
Toxicology. 36, 69-98.
    4. Dearfield, KL, Auletta, AE, Cimino, MC, and Moore, MM. 1991.
Consideration in the U. S. Environmental Protection Agency's Testing
Approach for Mutagenicity. Mutation Research. 258, 259-283.
    5. Dix, DJ, Houck, KA, Martin, MT, Richard, AM, Setzer, RW,
Kavlock, RJ. 2007. The ToxCast Program for Prioritizing Toxicity
Testing of Environmental Chemicals; Toxicological Sciences 95(1), 5-12
(accessed July 2, 2008) http://toxsci.oxfordjournals.org/cgi/content/
abstract/95/1/5.
    6. Doe, JE, Boobis, AR, Blacker, A, Dellarco, VL, Doerrer, NG,
Franklin, C, Goodman, JI, Kronenberg, JM, Lewis, R, McConnell, EE,
Mercier, T, Moretto, A, Nolan, C, Padilla, S, Phang, W, Solecki, R,
Tilbury, L, van Ravenswaay, B, and Wolf, DC. 2006. A tiered approach to
systemic toxicity testing for agricultural chemical safety assessment.
Critical Reviews in Toxicology. 36, 37-68.
    7. Food and Drug Administration (FDA) (January 1993). Sanitizing
Solutions: Chemistry Guidelines for Food Additive Petitions. (accessed
July 2, 2008) http://www.cfsan.fda.gov/~dms/opa-cg3a.html.
    8. FDA (April 2002a). Guidance for Industry: Preparation of
Premarket Notifications for Food Contact Substances: Toxicology
Recommendations. (accessed July 2, 2008) http://www.cfsan.fda.gov/~dms/
opa2pmnt.html.
    9. FDA (April 2002b). Guidance For Industry: Preparation of Food
Contact Notifications and Food Additive Petitions for Food Contact
Substances: Chemistry Recommendations. Final Guidance. (accessed July
2, 2008) http://www.cfsan.fda.gov/~dms/opa2pmnc.html.
    10. FDA (August 2006) Estimating Dietary Intake of Substances in
Food (accessed July 2, 2008) http://www.cfsan.fda.gov/~dms/opa2cg8.html
    11. FDA (December 2007) Guidance for Industry: Preparation of
Premarket Submissions for Food Contact Substances: Chemistry
Recommendations. (accessed July 2, 2008) http://www.cfsan.fda.gov/~dms/
opa3pmnc.html
    12. Halden, R, and Paull, D. 2005. Co-Occurrence of Triclocarban
and Triclosan in U.S. Water Resources. Environmental Science and
Toxicology. 39: 6, 1420-1426.
    13. Health Canada, Pesticide Management Regulatory Agency:
Memorandum from Don Grant, Director Health Evaluation Division:
Reproductive Toxicity Testing in Proposed 40 CFR 158, Subdivision W -
Data Requirements for Antimicrobial Pesticides. December 1, 1997.
Attachment to Memorandum: The Assessment of Reproductive Toxicity for
Antimicrobial Pesticides: The Tiered Approach of USEPA and Proposals
for Change; November 1997 draft.
    14. International Life Sciences Institute, Health and Environmental
Sciences Institute Developing strategies for agricultural chemical
safety evaluation, a report from an April 22-23, 2001 workshop.
(September 2001)
    15. Luster et al. 1992. Risk Assessment in Immunotoxicology I.
Sensitivity and Predictability of Immune Tests, Fundamental and Applied
Toxicology. 18: 200-210.
    16. Luster et al. 1993. Risk Assessment in Immunotoxicology II.
Relationships Between Immune and Host Resistance Tests, Fundamental and
Applied Toxicology. 21: 71-82.
    17. McAvoy, D, Schatowitz, B, Jacob, M, Hauk, A, and Eckhoff, W.
2002. Measurement of Triclosan in

Wastewater Treatment Systems. Environmental Toxicology and Chemistry,
21: 7, 1323-29.
    18. Marzulli, F. and Maibach, H. Dermatotoxicology (5th ed.). page
284.
    19. National Research Council, ``Pesticides in the Diets of Infants
and Children,'' National Academy Press, Washington, D.C., 1993.
    20. National Research Council 2006. Executive Summary: Toxicity
Testing for Assessment of Environmental Agents: Interim Report. (Note:
click on download free executive summary) (accessed July 1, 2008)
http://www.nap.edu/catalog/11523.html.
    21. National Research Council 2007. Executive Summary: Toxicity
Testing in the 21st Century: A Vision and a Strategy (Note: click on
download free executive summary) (accessed July 1, 2008) http://
www.nap.edu/catalog/11970.html.
    22. Santa Clara Basin Watershed Management Initiative. 2006. White
Paper: Environmental Emergence of Triclosan.(accessed July 2, 2008)
http://www.scbwmi.org/PDFs/WMI_Triclosan_FinalJan06.pdf.
    23. Singer, H, Muller, S. Tixiewr, C., and Pillonel, L. 2002.
Triclosan: Occurrence and Fate of a Widely Used Biocide in the
Environment: Field Measurements in Wastewater Treatment Plants, Surface
Waters, and Lake Sediments. Environmental Science and Toxicology. 36:
23, 4998-5004.
    24. USEPA Federal Register Notice. Toxicology Data Call-In for
Antimicrobial Pesticides (January 7, 1987) (FRL-3136-3).
    25. USEPA (March 9, 1992). Environmental Fate and Effects Division
Policy Note 1-2: Waiver of the Photodegradation in Water Data
Requirement Based on the Electronic Absorption Spectra of the Pesticide
(Henry Jacoby).
    26. USEPA (August 5, 1991). Memorandum: Revised Mutagenicity
Guideline and Requirement - Explanation, from Kerry L. Dearfield,
Science Analysis and Coordination Branch.
    27. USEPA (September 1993). Pesticide Reregistration Rejection Rate
Analysis - Environmental Fate (EPA 738-R-93-010).
    28. USEPA (February 7, 1996). Pesticide Registration (PR) Notice
96-1. Tolerance Enforcement Methods -- Independent Laboratory
Validation by Petitioner. (accessed July 1, 2008) http://www.epa.gov/
opppmsd1/PR_Notices/pr96-1.html.
    29. USEPA Federal Insecticide, Fungicide and Rodenticide Act
(FIFRA) Scientific Advisory Panel (SAP) Meeting of June 1997: A Set of
Scientific Issues Being Considered by the Agency to Determine
Antimicrobials Issues (accessed July 1, 2008) http://www.epa.gov/
scipoly/sap/meetings/1997/june/antimicr.htm.
    30. USEPA FIFRA SAP Meeting of December 1998: A Retrospective
Analysis of Twelve Developmental Neurotoxicity Studies (Draft 11/12/98)
(accessed July 1, 2008) http://www.epa.gov/scipoly/sap/meetings/1998/
december/neuro.pdf.
    31. USEPA FIFRA SAP Report No. 99-01B: II - A Retrospective
Analysis of Twelve Developmental Neurotoxicity Studies (January 22,
1999) (accessed July 1, 2008) http://www.epa.gov/scipoly/sap/meetings/
1998/december/final2.pdf.
    32. USEPA FIFRA SAP Meeting of December 1998: Toxicology Data
Requirements for Assessing Risks of Pesticide Exposure to Children's
Health. (Draft--November 30, 1998). http://www.epa.gov/scipoly/sap/
meetings/1998/december/10xreq.pdf.
    33. USEPA FIFRA SAP Meeting of May 1999: Toxicology Data
Requirements for Assessing Risks of Pesticide Exposure to Children's
Health. (Draft--April 28, 1999). (accessed July 1, 2008) http://
www.epa.gov/scipoly/sap/meetings/1999/may/10xtx428.pdf.
    34. USEPA FIFRA SAP Meeting of April 2000: Implementation Plan for
Probabilistic Ecological Assessment (August 2, 2000). (accessed July 2,
2008) http://www.epa.gov/oscpmont/sap/meetings/2000/april/
freportapril572000.pdf.
    35. USEPA (November 28, 2001). General Principles for Performing
Aggregate Exposure and Risk Assessments (page 16) (accessed July 2,
2008) http://www.epa.gov/oppfead1/trac/science/aggregate.pdf.
    36. USEPA FIFRA SAP Meeting May 2005: A Comparison of the Results
of Studies on Pesticides from 12- or 24-Month Dog Studies with Dog
Studies of Shorter Duration (accessed July 2, 2008) http://www.epa.gov/
scipoly/sap/meetings/2005/may2/dogstudymay05.pdf.
    37. USEPA FIFRA SAP Meeting Minutes No. 2005-03: A Set of
Scientific Issues Being Considered by the Environmental Protection
Agency Regarding: A Comparison of the Results of Studies on Pesticides
from 12- or 24-Month Dog Studies with Dog Studies of Shorter Duration
(accessed June 30, 2008) http://www.epa.gov/scipoly/sap/meetings/2005/
may5/meetingminutesmay5_6_2005.pdf.
    38. USEPA (March 20, 2006). Length of Dog Toxicity Study(ies) that
is Appropriate for Chronic RfD Determinations of Pesticide Chemicals.
Health Effects Division/Office of Pesticide Programs.
    39. USEPA (January 2007) FIFRA SAP Meeting Minutes (accessed June
25, 2008) http://www.epa.gov/scipoly/sap/meetings/2007/january/
january2007finalmeetingminutes.pdf.
    40. USEPA (April 2, 2007) Human Studies Review Board Meeting
Minutes (EPA-HSRB-07-02) (accessed June 25, 2008) http://www.epa.gov/
OSA/hsrb/files/April2007HSRBMtgFinalReport.pdf.
    41. USEPA (February 5, 2007) Appendix B - Antimicrobial Product Use
Sites and Categories Index. USEPA, Antimicrobials Division, Office of
Pesticide Programs.
    42. USEPA (December 31, 2007). Four Case Studies of Antimicrobial
Pesticides in the Down-the-Drain Screening Model, Using the Proposed
Approach for a Screening-Level Environmental Fate Assessment. USEPA,
Antimicrobials Division, Office of Pesticide Programs.
    43. USEPA (December 17, 2007). Use of Structure-Activity
Relationship (SAR) Information and Quantitative SAR (QSAR) Modeling For
Fulfilling Data Requirements for Antimicrobial Pesticide Chemicals and
Informing EPA's Risk Management Process.
    44. USEPA (2008). Economic Analysis of the Proposed Data
Requirements for Antimicrobial Pesticides, EAB/BEAD/OPP.
    45. USEPA (August 26, 2008). Supporting Statement for an
Information Collection Request (ICR), Data Requirements for
Antimicrobial Pesticides (Proposed Rule), EPA ICR No. 2318.01, OMB
Control No. 2070-(new).

XXII. FIFRA Review Requirements

    Under FIFRA section 25(a), EPA has submitted a draft of the
proposed rule to the Secretary of the Department of Agriculture and the
appropriate Congressional Committees. There were no comments in
response to these submissions.
    Under FIFRA section 21(b) EPA submitted a draft of the proposed
rule to the Secretary of Health and Human Services (HHS). Their
comments on this proposed rule included requests for (1) clarification
on the application of these new testing requirements to current
registrants, (2) information about prions, (3) the possible effects of
antimicrobial residues present in food on intestinal flora, and (4) the
potential for antimicrobial resistance.
    EPA agrees with HHS that both current antimicrobial pesticide
registrants and applicants seeking an antimicrobial registration should
understand the applicability of the proposed data requirements, once

promulgated. Once effective, EPA would use the promulgated data
requirements as the standard for reviewing new applications. These same
promulgated data requirements, once effective, would also be used
during Registration Review, when the Agency's scientists prepare the
publicly available documentation on the data needed during Registration
Review to complete the needed risk assessments.
    EPA also agrees that the criteria for determining the efficacy of
proposed anti-prion agents have not yet been established.
    Concerning HHS's Center for Veterinary Medicine's (CVM) comment on
intestinal flora, EPA believes that the studies proposed in this rule
for use in a pesticide risk assessment are protective of human health.
EPA has no specific information on effects on antimicrobial residues
that would not be captured by the required health effects studies.
    HHS's CVM is correct that this proposed rule does not address
potential antimicrobial resistance as a result of the use of a
pesticide product. While the Pesticide Program is aware of this issue,
we have neither determined the extent of the problem nor how data
requirements could be developed to address the issue. The Pesticide
Program will continue to monitor efforts such as those of the CODEX ad
hoc Intergovernmental Task Force on Antimicrobial Resistance and the
Interagency Task Force on Antimicrobial Resistance, on which EPA is a
participant (see http://www.cdc.gov/drugresistance/actionplan/). The
research being conducted by the collaborating federal agencies, which
is primarily focused on antibiotics, may eventually form the basis for
the Pesticide Programs' approach to potential resistance as a result of
the use of pesticide products. We have the authority to require studies
on a case-by-case basis and to revise our data requirements in the
future, if appropriate.
    EPA requested that the SAP waive its review of this proposal based
on the SAP's 1997 review. The SAP waived its review of this proposal on
February 19, 2008.

XXIII. Statutory and Executive Order Reviews

A. Executive Order 12866

    Pursuant to Executive Order 12866, entitled Regulatory Planning and
Review (58 FR 51735, October 4, 1993), the Office of Management and
Budget (OMB) has determined that this proposed rule is a ``significant
regulatory action'' because this action might raise novel legal or
policy issues arising out of legal mandates, the President's
priorities, or the principles set forth in the Executive Order.
Accordingly, as a result of this OMB determination, EPA submitted this
proposed rulemaking to OMB for review under Executive Order 12866. Any
changes made in response to OMB comments have been documented in the
public docket for this rulemaking as required by section 6(a)(3)(E) of
the Executive Order.
    EPA has prepared an economic analysis of the potential costs
associated with this proposed action, entitled ``Economic Analysis of
the Proposed Change in Data Requirements for Antimicrobial
Pesticides.'' It is noted that this analysis applies only to new
antimicrobial pesticides submitted for registration, and to new uses of
currently registered antimicrobial pesticides. For conducting its
economic analysis, EPA considered a registration action as referring to
an application for registration of a new product that contains an
active ingredient that is not included in any currently registered
product, an application for a new product that includes the addition of
a use pattern that is not currently registered for one or more active
ingredients contained in the product, and an amendment of a
registration of a product that includes the addition of a use pattern
that is not currently registered for one or more active ingredients
contained in the product.
    A copy of the economic analysis (Ref. 44) can be found in the
public docket for this action, and is briefly summarized here.
    In the proposed rule, EPA is:
     Proposing newly codified data requirements, which are not
currently established in part 161, but are routinely considered in
current practice.
     Proposing changes to some of the existing data
requirements such as a change from conditionally-required to required,
a change in the number of test species, or expanding the number of use
patterns for which the test is required.
     Proposing new data requirements, which have never been
required or have rarely been required on a case-by-case basis, and have
not been routinely considered during the Agency's evaluation of the
data needed for the purpose of risk assessment.
     Proposing to eliminate the requirement for the chronic
nonrodent study currently established in part 161.
    To calculate the potential costs associated with this proposal, EPA
first identified the studies that would generate the data to fulfill
the proposed data requirements, and then gathered information on the
price that laboratories might charge to conduct that study. To the
extent possible, several cost estimates were compiled for each study.
The low and high cost estimates provided by the various laboratories
were averaged to account for price variations related to differences in
the assumptions about the study performed (e.g., protocol, species
used), and differences in the price charged by different laboratories.
    EPA assumed that each data requirement would always be fulfilled
and therefore data would always need to be generated for each
requirement. This assumption could lead to an overestimate of the
burden of the proposal, because sometimes the data are already
available because the firm generated it for their own use. In such
cases, the firm would simply need to submit those data to EPA, which
involves less burden and cost than generating it. Some firms may have
surrogate data that could be used, while others may qualify for a
waiver. Some firms may share the cost of generating the data. All of
these would involve lower costs than generating the data anew.
    EPA then used historical data on antimicrobial pesticide
registration actions that occurred from 2000 to 2005 to identify the
entities that sought pesticide registration actions in the past. The
data required for each registration action depends on several factors,
including the type of registration action (e.g., registration of a new
active ingredient food-use, registration of a new active ingredient
nonfood-use, registration and amendments to registrations involving a
major new use); scientific discipline (e.g., toxicology, residue
chemistry, human exposure), and use pattern. The percentage of time a
particular test would be required was estimated from this information.
For the new data requirements, the percentage of time was estimated by
EPA scientists, based on their past experience in the program and their
understanding of the need for and the use of the new data requirements.
    The Agency prepared an industry profile using the same historical
data on pesticide registration actions to identify the companies
involved in those actions, and based it on public information gathered
about those companies. EPA also used this industry profile to analyze
the potential impacts of the proposed rule on small businesses, the
results of which are summarized in Unit XXIII.B below.
    Overall the potential impact of this proposal on businesses is
small, and

therefore the Agency believes that a negative effect on the
availability of antimicrobial pesticide products to users is unlikely.
On balance, the Agency believes that the costs of the proposed rule are
justified by the benefits from enhanced protection of human health and
the environment.

          Table 2.--Total Antimicrobial Industry Cost per Year
------------------------------------------------------------------------
                                            Total Industry Cost per Year
                                                       ($1000)
------------------------------------------------------------------------
Baseline (BL)                                                     11,080
------------------------------------------------------------------------
Current Practices (CP)                                            11,726
------------------------------------------------------------------------
Proposed Rule (PR)                                                14,961
------------------------------------------------------------------------
Incremental Costs (PR - BL)                                        3,882
------------------------------------------------------------------------
Newly Imposed Costs (PR-CP)                                        3,236
------------------------------------------------------------------------

    Thus, the difference between the baseline (the existing data
requirements that were codified in 1984) and the Agency's current
practices in requiring data is $646,000 annually. The difference
between the proposed data requirements and current practices is $3.2
million annually. The difference between the proposed data requirements
and the existing data requirements is $3.9 million annually. The
average cost per registration action of a new antimicrobial active
ingredient is approximately $1 million to $4.5 million. It is noted
that this analysis applies only to new antimicrobial pesticides
submitted for registration, and to new uses of currently registered
antimicrobial pesticides.
    For existing chemicals, the proposed part 158 subpart W data
requirements would be relevant to the registration review program which
began to replace the reregistration program in 2006 as a means of
systematically reviewing existing registrations against the standards
of FIFRA. Data needs identified under registration review for existing
chemicals must be imposed under the Agency's Data Call-In (DCI)
program.
    EPA has not evaluated the potential burden of the proposed data
requirements on registrants of existing chemicals in this proposal.
However, EPA anticipates that there will be additional costs associated
with the proposed studies under Registration Review. For each chemical,
EPA will evaluate the specific need for additional data, including
studies proposed today. Stakeholders and the public have opportunities
for input, consultation and involvement concerning individual pesticide
cases throughout the registration review process. Although EPA has
identified the schedule for which chemicals will be reviewed over the
next few years, the evaluation of data needs has not been done. Thus,
the costs are unknown. EPA will articulate the specific burden and
costs associated with each DCI pursuant to the appropriate Information
Collection Request (ICR) approvals under the Paperwork Reduction Act
(PRA).

B. Regulatory Flexibility Act

    Pursuant to section 605(b) of the Regulatory Flexibility Act (RFA),
5 USC 601 et seq., the Agency hereby certifies that this action will
not have a significant adverse economic impact on a substantial number
of small entities. The factual basis for the Agency's determination is
presented in the small entity impact analysis prepared as part of the
economic analysis for this proposed rule (Ref. 44), which is summarized
in Unit XXIII.A., and a copy of which is available in the docket for
this rulemaking. The following is a brief summary of the factual basis
for this certification.
    Under the RFA, small entities include small businesses, small
organizations, and small governmental jurisdictions. For purposes of
assessing the impacts of today's proposed rule on small entities, small
entity is defined in accordance with the RFA as: (1) a small business
as defined by the Small Business Administration's (SBA) regulations at
13 CFR 121.201, which is based on either the maximum number of
employees or on the sales for small businesses in each industry sector,
as defined by a 6-digit NAICS code; (2) a small governmental
jurisdiction that is a government of a city, county, town, school
district or special district with a population of less than 50,000; and
(3) a small organization that is any not-for-profit enterprise which is
independently owned and operated and is not dominant in its field. EPA
has determined that this rulemaking does not impact any small
governmental jurisdictions or any small not-for-profit enterprise
because these entities are rarely pesticide applicants or registrants.
    Some of the small entities directly regulated by this rulemaking
are in the pesticide and other agricultural chemical manufacturing
industry sector (NAICS code 325320). Firms in this sector are
considered small under the RFA definition if they employ 500 or fewer
people. The economic analysis for this proposed rule specifies the
NAICS code used for each of the firms analyzed.
    As detailed in the Economic Analysis, EPA estimates that 750 unique
parent companies constitute the total universe of pesticide
antimicrobial registrants. Of these, based on the SBA definition of a
small business and the available sales data for these firms, EPA
estimates that 500, or approximately 67%, qualify as a small business.
The available antimicrobial pesticide registration data for 2000-2005
indicates that only a small portion of the 500 registrants are likely
to be impacted by the proposed regulation. Specifically, 64 firms with
antimicrobial registrations would have incurred additional costs under
the proposed rule. Of the 64 firms, EPA estimates that a total of 25
small pesticide registrants would have incurred additional costs under
the proposed rule.
    The impacts to small antimicrobial registrants are measured as the
per firm incremental cost, which is the difference between the existing
data requirements in part 161 (the baseline) and those proposed in this
rule. The impact of the regulation is expressed as the proportion of
the average annual per firm incremental costs to the average annual
firm sales.
    The Agency's analysis of impacts on small businesses indicates
that:
     About 25 (5%) of the 500 small firms subject to the
proposal are likely to experience some impact (greater than 0%).

     About 22 (4.4%) of the 500 small firms are likely to
experience an economic impact of 1% or more of gross sales.
     About 14 (2.8%) of the 500 small firms are likely to
experience an economic impact of 3% or more of gross sales.
    Based on the Agency's small business impact analysis, the Agency
does not anticipate that the additional costs to industry resulting
from this proposed rule will cause a significant adverse economic
impact on a substantial number of small entities because the additional
costs are a small share of gross revenues for most firms and less than
5% of small firms are likely to experience some impact.
    EPA is particularly interested in receiving comment from small
businesses as to the benefits, costs and impacts of this rule. Any
comments should be submitted to the Agency in the manner specified
under ADDRESSES.

C. Paperwork Reduction Act

    The information collection requirements contained in this proposed
rule have been submitted for approval to the Office of Management and
Budget (OMB) under the Paperwork Reduction Act (PRA), 44 U.S.C. 3501 et
seq. EPA has prepared a new Information Collection Request (ICR)
document identified by EPA ICR No. 2318.01, a copy of which has also
been placed in the docket for this proposed rule. (Ref. 45).
    Under the PRA, ``burden'' is defined at 5 CFR 1320.3(b). In
addition, an agency may not conduct or sponsor, and a person is not
required to respond to an information collection request unless it
displays a currently valid OMB control number, or is otherwise required
to submit the specific information by a statute. The OMB control
numbers for certain EPA regulations in 40 CFR, after appearing in the
preamble of the final rule, are listed in 40 CFR part 9 and, if
applicable, included with the related collection instrument (e.g., form
or survey).
    The information collection activities related to the submission of
data to EPA in order to register, amend or retain a new or existing
pesticide product or obtain a tolerance for that product are already
approved by OMB under the PRA. As such, this ICR only addresses the
proposed changes to the data requirements that impact the information
collection activities related to antimicrobial pesticides. The
procedures for submitting data to EPA under FIFRA and the FFDCA are not
changed in this proposal, and are already approved by OMB as follows:
    1. The data submission activities associated with the establishment
of a tolerance are currently approved under OMB Control No. 2070-0024
(EPA ICR No. 0597);
    2. The data submission activities associated with the application
for a new or amended registration of a pesticide are currently approved
under OMB Control No. 2070-0060 (EPA ICR No. 0277);
    3. The data submission activities associated with the generation of
data for reregistration are currently approved under OMB Control No.
2070-0107 (EPA ICR No. 1504); and
    4. The data submission activities associated with the generation of
data for special review or registration review are currently approved
under OMB Control No. 2070-0057 (EPA ICR No. 0922).
    These program activities are an integral part of the Agency
pesticide program and the corresponding ICRs are regularly renewed
every three years as required by the PRA. The total estimated average
annual public reporting burden currently approved by OMB for these
various activities range from 8 hours to approximately 3,000 hours per
respondent, depending on the activity and other factors surrounding the
particular pesticide product.
    In the new ICR for this proposed rule, which is based on the
Economic Analysis (Ref. 44), EPA estimates that the typical current
annual paperwork burden for registrants per antimicrobial pesticide
registration is 194 burden hours and $12,631. This represents the
baseline antimicrobial pesticide registration burden and costs. When
considering the potential increase in this estimated annual burden and
cost resulting from the new data requirements in this proposed rule,
the Agency estimated the incremental burden and cost to be 35% of the
baseline burden and costs, i.e., 68 burden hours and $4,421. Assuming
an annual number of 15 antimicrobial pesticide registrations, the total
annual registrant paperwork burden and costs for antimicrobial
pesticide registrations are estimated to be approximately 3,929 hours
and $255,773.25, of which 1,019 hours and $66,150 represent burden
related to new data requirements, and $158.25 represents estimated
delivery costs.
    Any comments on the Agency's need for this information, the
accuracy of the provided burden estimates, and any suggested methods
for minimizing respondent burden, should be directed to the docket for
this proposed rule, under Docket ID number EPA-HQ-OPP-2008-0110. See
ADDRESSES section at the beginning of this document for where to submit
comments to EPA.
    You may also submit a copy of your comments on the ICR directly to
OMB. Comments to OMB should be sent to the Office of Information and
Regulatory Affairs, Office of Management and Budget (OMB), 725 17th
Street, NW, Washington, DC 20503, Attention: Desk Office for EPA. Since
OMB is required to make a decision concerning the ICR between 30 and 60
days after October 8, 2008, a comment to OMB is best assured of having
its full effect if OMB receives it by November 7, 2008.
    In the final rule, the Agency will address any comments received
regarding the information collection requirements contained in this
proposal. In addition, after the ICR for the final rule is approved,
EPA will incorporate the increased burden into the existing ICRs as
appropriate.

D. Unfunded Mandates Reform Act

    Under Title II of the Unfunded Mandates Reform Act of 1995 (UMRA)
(Public Law 104- 4), EPA has determined that this action does not
contain a Federal mandate that may result in expenditures of $100
million or more for State, local, and tribal governments, in the
aggregate, or the private sector in any one year. As described in this
document, the incremental costs for the proposed part 158 subpart W
data requirement changes for antimicrobial pesticides is estimated at
nearly $3.9 million per year for the private sector, which is below the
$100 million threshold. Since State, local, and tribal governments are
rarely pesticide applicants, the proposed rule is not expected to
significantly or uniquely affect small governments. Accordingly, this
action is not subject to the requirements of sections 202 and 205 of
UMRA.

E. Executive Order 13132

    Pursuant to Executive Order 13132, entitled Federalism (64 FR
43255, August 10, 1999), EPA has determined that this proposed rule
does not have ``federalism implications,'' because it will not 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, as
specified in the Order. As indicated above, instances where a state is
a registrant are extremely rare. Therefore, this proposed rule may
seldom affect a state government. Thus, Executive Order 13132 does not
apply to this proposed rule. In the spirit of the Order,

and consistent with EPA policy to promote communications between the
Agency and State and local governments, EPA specifically solicits
comment on this proposed rule from State and local officials.

F. Executive Order 13175

    As required by Executive Order 13175, entitled Consultation and
Coordination with Indian Tribal Governments (65 FR 67249, November 6,
2000), EPA has determined that this proposed rule does not have tribal
implications because it will not have substantial direct effects on
tribal governments, on the relationship between the Federal government
and the Indian tribes, or on the distribution of power and
responsibilities between the Federal government and Indian tribes, as
specified in the Order. As indicated above, at present, no tribal
governments hold, or have applied for, a pesticide registration. Thus,
Executive Order 13175 does not apply to this proposed rule. In the
spirit of the Order, and consistent with EPA policy to promote
communications between the Agency and State and local governments, EPA
specifically solicits comment on this proposed rule from tribal
officials.

G. Executive Order 13045

    This section is not subject to Executive Order 13045, entitled
Protection of Children from Environmental Health Risks and Safety Risks
(62 FR 19885, April 23, 1997) because it does not propose an
environmental standard that is intended to have a negatively
disproportionate effect on children. To the contrary, this action will
provide added protection for children from pesticide risk. The proposed
data requirements are intended to address risks that, if not addressed,
could have a disproportionate negative impact on children. EPA will use
the data and information obtained by this proposed rule to carry out
its mandate under FFDCA to give special attention to the risks of
pesticides to sensitive subpopulations, especially infants and
children.

H. Executive Order 12898

    This proposed rule does not have an adverse impact on the
environmental and health conditions in low-income and minority
communities because this proposed rule only impacts entities that
intend to register or currently hold a registration for an
antimicrobial pesticide. Therefore, under Executive Order 12898,
entitled Federal Actions to Address Environmental Justice in Minority
Populations and Low-Income Populations (59 FR 7629, February 16, 1994),
the Agency does not need to consider environmental justice-related
issues.

I. National Technology Transfer and Advancement Act

    Section 12(d) of the National Technology Transfer and Advancement
Act of 1995 (NTTAA), 15 U.S.C. 272 note) directs EPA to use voluntary
consensus standards in its regulatory activities unless to do so would
be inconsistent with applicable law or impractical. Voluntary consensus
standards are technical standards (e.g., materials specifications, test
methods, sampling procedures, etc.) that are developed or adopted by
voluntary consensus standards bodies. NTTAA directs EPA to provide
Congress, through OMB, explanations when the Agency decides not to use
available and applicable voluntary consensus standards. This regulation
proposes the types of data to be required to support antimicrobial
pesticide registration but does not propose to require specific methods
or standards to generate those data.
    This proposed regulation does not impose any technical standards
that would require Agency consideration of voluntary consensus
standards. The Agency invites comment on its conclusion regarding the
applicability of voluntary consensus standards to this rulemaking.

J. Executive Order 12630

    EPA has complied with Executive Order 12630, entitled Governmental
Actions and Interference with Constitutionally Protected Property
Rights (53 FR 8859, March 15, 1988), by examining the takings
implications of this rule in accordance with the ``Attorney General's
Supplemental Guidelines for the Evaluation of Risk and Avoidance of
Unanticipated Takings'' issued under the Executive Order.

K. Executive Order 12988

    In issuing this rule, EPA has taken the necessary steps to
eliminate drafting errors and ambiguity, minimize potential litigation,
and provide a clear legal standard for affected conduct, as required by
section 3 of Executive Order 12988, entitled Civil Justice Reform (61
FR 4729, February 7, 1996).

L. Executive Order 13211

    This rule is not subject to Executive Order 13211, entitled
``Actions concerning Regulations that Significantly Affect Energy
Supply, Distribution, or Use'' (66 FR 28355, May 22, 2001) because it
is not likely to have any adverse effect on the supply, distribution,
or use of energy.

Lists of Subjects in 40 CFR Part 158

    Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Reporting and record
keeping requirements.

Lists of Subjects in 40 CFR Part 161

    Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Reporting and record
keeping requirements.

    Dated: September 24, 2008.
Stephen L. Johnson,
Administrator.

    Therefore, it is proposed that 40 CFR part 158 and part 161 be
amended as follows:
    1. The authority citation for part 158 continues to read as
follows:

    Authority: 7 U.S.C. 136-136y and 21 U.S.C. 346a.

    2. Section 158.1(c)(4) is revised to read as follows:

Sec.  158.1  Purpose and scope.

* * * * *
    (c) * * *
    (4) Antimicrobial pesticides. Subparts A, B, C, D, and W apply to
antimicrobial pesticides.
    3. Section 158.100 is amended by revising the heading of paragraph
(a); by revising paragraph (b); by redesignating paragraph (c) as
paragraph (e); and by adding new paragraphs (c) and (d) to read as
follows:

Sec.  158.100  Pesticide use patterns.

    (a). General use patterns for conventional, biochemical, and
microbial pesticides. * * *
    (b) Pesticide use site index for conventional, biochemical, and
microbial pesticides. The Pesticide Use Site Index for Conventional,
Biochemical, and Microbial Pesticides is a comprehensive list of
specific pesticide use sites. The index is alphabetized separately by
site for all agricultural and all nonagricultural uses. The Pesticide
Use Site Index associates each pesticide use site with one or more of
the 12 general use patterns. It may be used in conjunction with the
data tables to determine the applicability of data requirements to
specific uses. The Pesticide Use Site Index for Conventional,
Biochemical, and Microbial Pesticides, which will be updated
periodically, is available from

the Agency or may be obtained from the Agency's website at http://
www.epa.gov/pesticides.
    (c) Antimicrobial pesticide use patterns. The general use patterns
for antimicrobial pesticides are described in Sec.  158.2201.
    (d) Pesticide use site index for antimicrobial pesticides. The
Pesticide Use Site Index for Antimicrobial Pesticides is a
comprehensive list of specific antimicrobial use sites. The index is
alphabetized by antimicrobial use sites, and associates each
antimicrobial use site with one or more of the antimicrobial use
patterns. It may be used in conjunction with the data tables to
determine the applicability of data requirements to specific uses. The
Pesticide Use Site Index for Antimicrobial Pesticides, which will be
updated periodically, is available from the Agency or may be obtained
from the Agency's website at http://www.epa.gov/pesticides/regulating/
usesite/.
    (e) * * *

Sec.  158.400  [Amended]

    4. The table in Sec.  158.400(d) is amended by removing the
category ``Efficacy of antimicrobial agents'' and all of the entries
under that category.
    5. Part 158 is amended by adding subpart W to read as follows:

Subpart W--Antimicrobial Pesticide Data Requirements

Sec
Sec.  158.2200 Applicability.
Sec.  158.2201 Antimicrobial use patterns.
Sec.  158.2203 Definitions.
Sec.  158.2210 Product chemistry.
Sec.  158.2220 Product performance.
Sec.  158.2230 Toxicology data.
Sec.  158.2240 Nontarget organisms.
Sec.  158.2250 Nontarget plant protection.
Sec.  158.2260 Applicator exposure.
Sec.  158.2270 Post-application exposure.
Sec.  158.2280 Environmental fate.
Sec.  158.2290 Residue chemistry.

Subpart W--Antimicrobial Pesticide Data Requirements

Sec.  158.2200  Applicability.

    Subpart W establishes data requirements for any pesticide product
that is:
    (a) A pesticide that is intended for use as an ``antimicrobial
pesticide'' within the meaning of FIFRA section 2(mm)(1)(A), regardless
of whether it also meets the criterion of FIFRA section 2(mm)(1)(B).
That criterion excludes from the definition any antimicrobial product
that is intended for a food-use requiring a tolerance or exemption
under FFDCA section 408 or a food additive regulation under FFDCA
section 409. EPA will apply this subpart to all products intended for
an antimicrobial use, purpose or function; the exclusion in FIFRA
section 2(mm)(1)(B) does not exclude products from the data
requirements of this subpart.
    (b) A product that bears both antimicrobial and non-antimicrobial
uses or claims is subject to the data requirements for pesticides in
subparts C - O, and U or V of this part with respect to its non-
antimicrobial uses and claims, and to the requirements of this subpart
W with respect to its antimicrobial uses and claims.
    (c) A wood preservative, including a product that is intended to
prevent wood degradation problems due to fungal rot or decay, sapstain,
or molds.
    (d) An antifoulant, including a product that is intended to kill or
repel organisms that can attach to underwater surfaces, such as boat
bottoms.

Sec.  158.2201  Antimicrobial use patterns.

    (a) Antimicrobial use patterns. The 12 general use patterns used in
the data tables in this subpart are:
    (1) Agricultural premises and equipment.
    (2) Food-handling/storage establishments, premises and equipment.
    (3) Commercial, institutional and industrial premises and
equipment.
    (4) Residential and public access premises.
    (5) Medical premises and equipment.
    (6) Human drinking water systems.
    (7) Materials preservatives.
    (8) Industrial processes and water systems.
    (9) Antifoulant paints and coatings.
    (10) Wood preservatives.
    (11) Swimming pools.
    (12) Aquatic areas.
    (b) Use site index. The Antimicrobial Use Site Index is a
comprehensive list of specific antimicrobial use sites. The Index
associates antimicrobial use sites with one or more of the 12
antimicrobial use patterns. It is to be used in conjunction with the
data tables in this subpart to determine the applicability of data
requirements to specific uses. The Antimicrobial Pesticide Use Site
Index, which will be updated periodically, is available from the Agency
or may be obtained from the Agency's website at http://www.epa.gov/
pesticides/regulating/usesite/.
    (c) An applicant unsure of the correct use pattern(s) for his
product should consult the Agency.

Sec.  158.2203  Definitions.

    (a) Definitions. The following terms are defined for the purposes
of this subpart:
    (1) Disinfectant means a substance that destroys or eliminates a
specific species of infectious or other public health microorganism,
but not necessarily bacterial spores, in the inanimate environment.
    (2) Fungicide means a substance that destroys fungi (including
yeasts) and fungal spores pathogenic to man or other animals in the
inanimate environment.
    (3) Microbiological water purifier means any unit, water treatment
product or system that removes, kills or inactivates all types of
disease-causing microorganisms from the water, including bacteria,
viruses and protozoan cysts, so as to render the treated water safe for
drinking.
    (4) Sanitizer means a substance that reduces the bacterial
population in the inanimate environment by significant numbers, but
does not destroy or eliminate all bacteria or other microorganisms.
    (5) Sterilant means a substance that destroys or eliminates all
forms of microbial life in the inanimate environment, including all
forms of vegetative bacteria, bacterial spores, fungi, fungal spores,
and viruses. For purposes of this subpart, ``sporicide'' and
``sterilant'' are synonymous.
    (6) Tuberculocide means a substance that destroys or irreversibly
inactivates tubercle bacilli in the inanimate environment.
    (7) Virucide means a substance that destroys or inactivates viruses
in the inanimate environment.
    (b) Public health claim. An antimicrobial pesticide is considered
to make a public health claim if the pesticide product bears a claim to
control pest microorganisms that pose a threat to human health, and
whose presence cannot readily be observed by the user, including but
not limited to, microorganisms infectious to man in any area of the
inanimate environment. A product makes a public health claim if one or
more of the following apply:
    (1) A claim is made for control of specific microorganisms or
classes of microorganisms that are directly or indirectly infectious or
pathogenic to man (or both man and animals). Examples of specific
microorganisms include, but are not limited to, Mycobacterium
tuberculosis, Pseudomonas aeruginosa, Eschericha coli (E. coli), human
immunodeficiency virus (HIV), Streptococcus, and Staphylococcus aureus.
Claims for control of microorganisms infectious or pathogenic only to
animals (such as canine distemper virus or hog cholera virus) are not
considered public health claims.

    (2) A claim is made for the pesticide product as a sterilant,
disinfectant, virucide, sanitizer, or tuberculocide regardless of the
site of use of the product, and regardless of whether specific
microorganisms are identified.
    (3) A claim is made for the pesticide product as a fungicide
against fungi infectious or pathogenic to man, or the product does not
clearly state that it is intended for use only against non-public
health fungi.
    (4) A claim is made for the pesticide product as a microbiological
water purifier or microbial purification system.
    (5) A non-specific claim is made that the pesticide product will
beneficially impact or affect public health at the site of use or in
the environment in which applied (such as a `sanitary' claim), and:
    (i) The pesticide product contains one or more ingredients that,
under the criteria in 40 CFR 153.125(a), is an active ingredient with
respect to a public health microorganism and there is no other
functional purpose for the ingredient in the product; or
    (ii) The pesticide product is similar in composition to a
registered pesticide product that makes explicit antimicrobial public
health claims.

Sec.  158.2210  Product chemistry.

    The product chemistry data requirements of subpart D of this part
apply to antimicrobial products covered by this subpart.

Sec.  158.2220  Product performance.

    (a) General. (1) Product performance requirement for all
antimicrobial pesticides. Each applicant must ensure through testing
that his product is efficacious when used in accordance with label
directions and commonly accepted pest control practices. The Agency may
require, on a case-by-case basis, submission of product performance
data for any pesticide product registered or proposed for registration.
    (2) Product performance data for each product that bears a public
health claim. Each product that bears a public health claim, as
described in Sec.  158.2203(b), must be supported by product
performance data, as listed in the table in this paragraph. Product
performance data must be submitted with the application for
registration or amended registration.
    (3) Determination of data requirements. Subpart B of this part and
Sec.  158.2201 describe how to use the table in paragraph (c) of this
section to determine the product performance data requirements for
antimicrobial pesticide products.
    (b) Key. R = Required; EP = End-use product;
    (c) Table. The following table shows the data requirements for
product performance.

                          Table -- Antimicrobial Product Performance Data Requirements
----------------------------------------------------------------------------------------------------------------
           Guideline Number                Data Requirement         All Use Patterns          Test Substance
----------------------------------------------------------------------------------------------------------------
91-2                                   Products for use on      R                        EP
                                        hard surfaces
----------------------------------------------------------------------------------------------------------------
91-3                                   Products requiring       R                        EP
                                        confirmatory data
----------------------------------------------------------------------------------------------------------------
91-4                                   Products for use on      R                        EP
                                        fabrics and textiles
----------------------------------------------------------------------------------------------------------------
91-5                                   Air sanitizers           R                        EP
----------------------------------------------------------------------------------------------------------------
91-7                                   Products for control of  R                        EP
                                        microbial pests
                                        associated with human
                                        and animal wastes
----------------------------------------------------------------------------------------------------------------
91-8                                   Products for treating    R                        EP
                                        water systems
----------------------------------------------------------------------------------------------------------------

Sec.  158.2230  Toxicology data.

    (a) General. Subpart B of this part and Sec.  158.2201 describe how
to use the table in paragraph (d) of this section to determine the
toxicology data requirements for an antimicrobial pesticide product.
Notes that apply to an individual test including specific conditions,
qualifications, or exceptions are listed in paragraph (e) of this
section.
    (b) Uses. The applicant for registration must first determine
whether the use is a high human exposure use or a low human exposure
use. If an applicant is not sure if a specific use is a high human
exposure or a low human exposure use, the applicant should consult the
Agency.
    (1) High human exposure uses. For the purpose of determining data
requirements, high human exposure includes those uses which are likely
to result in human exposure over a considerable portion of the human
lifespan, and which are significant in terms of frequency, duration, or
magnitude of exposure, i.e., uses for which there is an expectation of
high, prolonged, or repeated exposure. High human exposure uses of
antimicrobials include but are not limited to:
    (i) Any use which requires a tolerance or tolerance exemption
(except for indirect food uses requiring a tolerance or tolerance
exemption in which residues are less than 200 ppb).
    (ii) Indirect food uses with residues equal to or greater than 200
ppb.
    (iii) Use in human or animal drinking water.
    (iv) Fruit and vegetable rinses.
    (v) Egg washes.
    (vi) Swimming pools.
    (vii) Outdoor aquatic uses in lakes, rivers or streams which have
the potential to contaminate potable water.
    (viii) Wood preservatives.
    (ix) Metalworking fluids.
    (2) Low human exposure nonfood and low human exposure indirect food
uses. Generally, low exposure uses are those not listed in paragraph
(b)(1) of this section as high exposure uses.
    (3) Tiering of data requirements. Applicants for registration of
antimicrobials may perform tests in a tiered fashion. After the
initially required tests are conducted, additional testing may be
required if results of the initial tests trigger the need for
additional data. Conditions that trigger the need for additional data
are given in the test notes in paragraph (e) of this section.

    (c) Key. R = Required; CR = Conditionally required; NR = Not
required; MP = Manufacturing-use product; EP = End-use product; TGAI =
Technical grade of the active ingredient; TEP = Typical end-use
product; PAI = Pure active ingredient; PAIRA = Pure active ingredient,
radiolabeled; Choice = choice of several test substances depending on
studies required.
    (d) Table. The following table shows the data requirements for
toxicology. The test notes appear in paragraph (e) of this section.

                                                   Table -- Antimicrobial Toxicology Data Requirements
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                Use Pattern           Test Substance to Support
                                                                           ---------------------------------------------------------
              Guideline Number                      Data Requirement              High        Low Human                                 Test Note No.
                                                                            Human20Exposure   Exposure        MP            EP
                                                                                Uses          Uses
--------------------------------------------------------------------------------------------------------------------------------------------------------
 Acute Testing..........................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.1100                                     Acute oral toxicity - rat                 R             R   MP and TGAI   EP and TGAI                 1, 2
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.1200                                     Acute dermal toxicity                     R             R   MP and TGAI   EP and TGAI              1, 2, 3
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.1300                                     Acute inhalation toxicity -               R             R   MP and TGAI   EP and TGAI                    4
                                              rat
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.2400                                     Primary eye irritation -                  R             R   MP and TGAI   EP and TGAI              1, 2, 3
                                              rabbit
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.2500                                     Primary dermal irritation                 R             R   MP and TGAI   EP and TGAI              1, 2, 3
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.2600                                     Dermal sensitization                      R             R   MP and TGAI   EP and TGAI           1, 2, 3, 5
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.6200                                     Acute neurotoxicity - rat                 R              CR        TGAI          TGAI                    6
--------------------------------------------------------------------------------------------------------------------------------------------------------
 Subchronic Testing.....................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.3100                                     90-Day oral toxicity - rodent             R             R          TGAI          TGAI          7, 8, 9, 15
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.3150                                     90-Day oral toxicity -                    R              CR        TGAI          TGAI        7, 10, 11, 15
                                              nonrodent
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.3250                                     21/28-Day dermal toxicity                  CR            CR        TGAI   EP and TGAI               12, 13
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.2500                                     90-Day dermal toxicity                     CR            CR        TGAI   EP and TGAI        7, 13, 14, 15
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.3465                                     90-Day inhalation - toxicity -             CR            CR        TGAI          TGAI        7, 15, 16, 17
                                               rat
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.6200                                     90-Day neurotoxicity - rat                R              CR        TGAI          TGAI                 6, 8
--------------------------------------------------------------------------------------------------------------------------------------------------------
 Chronic Testing........................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.4100                                     Chronic oral toxicity -                   R              CR        TGAI          TGAI           18, 19, 20
                                              rodent
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.4200                                     Carcinogenicity - two rodent              R              CR        TGAI          TGAI           19, 21, 22
                                              species - rat and mouse
                                              preferred
--------------------------------------------------------------------------------------------------------------------------------------------------------
 Developmental Toxicity and Reproduction................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.3700                                     Prenatal developmental                    R             R          TGAI          TGAI       23, 24, 25, 26
                                              toxicity - rat and rabbit
                                              preferred
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.3800                                     Reproduction and fertility                R             R          TGAI          TGAI       26, 27, 28, 29
                                              effects
--------------------------------------------------------------------------------------------------------------------------------------------------------
870.6300                                     Developmental neurotoxicity                CR            CR        TGAI          TGAI           28, 29, 30