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[Federal Register: October 8, 2008 (Volume 73, Number 196)]
[Proposed Rules]
[Page 59381-59446]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr08oc08-31]
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Part III
Environmental Protection Agency
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40 CFR Parts 158 and 161
Data Requirements for Antimicrobial Pesticides; Proposed Rule
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ENVIRONMENTAL PROTECTION AGENCY
40 CFR Parts 158 and 161
RIN 2070-AD30
Data Requirements for Antimicrobial Pesticides
AGENCY: Environmental Protection Agency (EPA).
ACTION: Proposed rule.
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SUMMARY: EPA proposes to revise and update the existing data
requirements for antimicrobial pesticides. The proposed revisions are
needed to reflect current scientific knowledge and current Agency
regulatory practices, and to improve protection of the general
population as well as sensitive subpopulations. The proposed
requirements are intended to further enhance the Agency's ability to
make regulatory decisions about the human health and environmental fate
and effects of antimicrobial pesticide products.
DATES: Comments must be received on or before January 6, 2009.
ADDRESSES: Submit your comments, identified by docket identification
(ID) number EPA-HQ-OPP-2008-0110, by one of the following methods:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the on-line instructions for submitting comments.
Mail: Office of Pesticide Programs (OPP) Regulatory Public
Docket (7502P), Environmental Protection Agency, 1200 Pennsylvania
Ave., NW., Washington, DC 20460-0001.
Delivery: OPP Regulatory Public Docket (7502P),
Environmental Protection Agency, Rm. S-4400, One Potomac Yard (South
Bldg.), 2777 S. Crystal Dr., Arlington, VA 22202. Deliveries are only
accepted during the Docket's normal hours of operation (8:30 a.m. to 4
p.m., Monday through Friday, excluding legal holidays). Special
arrangements should be made for deliveries of boxed information. The
Docket Facility telephone number is (703) 305-5805.
Instructions: Direct your comments to docket ID number EPA-HQ-OPP-
2008-0110. EPA's policy is that all comments received will be included
in the docket without change and may be made available on-line at
http://www.regulations.gov, including any personal information
provided, unless the comment includes information claimed to be
Confidential Business Information (CBI) or other information whose
disclosure is restricted by statute. Do not submit information that you
consider to be CBI or otherwise protected through regulations.gov or e-
mail. The regulations.gov website is an ``anonymous access'' system,
which means EPA will not know your identity or contact information
unless you provide it in the body of your comment. If you send an e-
mail comment directly to EPA without going through regulations.gov,
your e-mail address will be automatically captured and included as part
of the comment that is placed in the docket and made available on the
Internet. If you submit an electronic comment, EPA recommends that you
include your name and other contact information in the body of your
comment and with any disk or CD-ROM you submit. If EPA cannot read your
comment due to technical difficulties and cannot contact you for
clarification, EPA may not be able to consider your comment. Electronic
files should avoid the use of special characters, any form of
encryption, and be free of any defects or viruses.
Docket: All documents in the docket are listed in the docket index
available in regulations.gov. To access the electronic docket, go to
http://www.regulations.gov, select ``Advanced Search,'' then ``Docket
Search.'' Insert the docket ID number where indicated and select the
``Submit'' button. Follow the instructions on the regulations.gov
website to view the docket index or access available documents.
Although listed in the index, some information is not publicly
available, e.g., CBI or other information whose disclosure is
restricted by statute. Certain other material, such as copyrighted
material, is not placed on the Internet and will be publicly available
only in hard copy form. Publicly available docket materials are
available either in the electronic docket at http://
www.regulations.gov, or, if only available in hard copy, at the OPP
Regulatory Public Docket in Rm. S-4400, One Potomac Yard (South Bldg.),
2777 S. Crystal Dr., Arlington, VA 22202. The hours of operation of
this Docket Facility are from 8:30 a.m. to 4 p.m., Monday through
Friday, excluding legal holidays. The Docket Facility telephone number
is (703) 305-5805.
FOR FURTHER INFORMATION CONTACT: Kathryn Boyle, Field and External
Affairs Division, Office of Pesticide Programs, Environmental
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460-
0001; mail code 7506P; telephone number: 703-305-6304; fax number: 703-
305-5884; e-mail address: boyle.kathryn@epa.gov.
SUPPLEMENTARY INFORMATION:
I. General Information
A. Does this Action Apply to Me?
You may be affected by this action if you are a producer of
pesticide products (NAICS 32532), antifoulants (NAICS 32551),
antimicrobial pesticides (NAICS 32561) or wood preservatives (NAICS
32519), importers of such products, or any person or company who seeks
to register an antimicrobial, antifoulant coating, ballast water
treatment, or wood preservative pesticide or to obtain a tolerance for
such a pesticide. This listing is not intended to be exhaustive, but
rather provides a guide for readers regarding entities likely to be
affected by this action. Other types of entities not listed above could
also be affected. The North American Industrial Classification System
(NAICS) codes have been provided to assist you and others in
determining whether this action might apply to certain entities. If you
have any questions regarding the applicability of this action to a
particular entity, please contact Norm Cook, Chief of the Risk
Assessment and Science Support Branch in the Antimicrobials Division of
the Office of Pesticide Programs at 703-308-8253 or via email,
cook.norm@epa.gov.
B. What Should I Consider as I Prepare My Comments for EPA?
1. Docket. EPA has established a docket for this action under
docket identification (ID) number EPA-HQ-OPP-2008-0110. Publicly
available docket materials are available either in the electronic
docket at http://www.regulations.gov, or, if only available in hard
copy, at the Office of Pesticide Programs (OPP) Regulatory Public
Docket in Rm. S-4400, One Potomac Yard (South Bldg.), 2777 S. Crystal
Dr., Arlington, VA 22202. The hours of operation of this Docket
Facility are from 8:30 a.m. to 4 p.m., Monday through Friday, excluding
legal holidays. The Docket Facility telephone number is (703) 305-5805.
2. Tips for preparing your comments. When submitting comments,
remember to:
i. Identify the document by docket ID number and other identifying
information (subject heading, Federal Register date and page number).
ii. Follow directions. The Agency may ask you to respond to
specific questions or organize comments by referencing a Code of
Federal Regulations (CFR) part or section number.
iii. Explain why you agree or disagree; suggest alternatives and
substitute language for your requested changes.
[[Page 59383]]
iv. Describe any assumptions and provide any technical information
and/or data that you used.
v. If you estimate potential costs or burdens, explain how you
arrived at your estimate in sufficient detail to allow for it to be
reproduced.
vi. Provide specific examples to illustrate your concerns and
suggest alternatives.
vii. Explain your views as clearly as possible, avoiding the use of
profanity or personal threats.
viii. Make sure to submit your comments by the comment period
deadline identified.
II. Background
A. What Action is the Agency Taking?
The Environmental Protection Agency (EPA or the Agency) is
proposing to establish a separate listing of the data requirements for
antimicrobial pesticides in Title 40 of the Code of Federal Regulations
(CFR) in subpart W of part 158. This proposal sets out use patterns
that are designed to make it easier to determine which requirements
apply to antimicrobial products. In addition to retaining most current
data requirements for antimicrobials, this proposal incorporates nine
new data requirements and revises other existing data requirements.
This rule, once final, is intended to further enhance the Agency's
ability to make regulatory decisions about the human health, and
environmental fate and effects of antimicrobial pesticide products.
The Agency has previously issued updated data requirements for
conventional pesticides, and biochemical and microbial pesticides in
part 158. This proposal is part of a larger effort to update and
improve all of the data requirements for pesticide regulatory purposes.
Data requirements for antimicrobial pesticides, currently contained in
part 161, are proposed to be revised and included in part 158 upon
promulgation.
Generally, antimicrobials are considered to be those chemicals that
disinfect and sanitize. However, within this proposal EPA is using the
term antimicrobials to collectively refer to antimicrobial pesticides,
antifoulant coatings and paints, and wood preservatives.
As discussed in Unit XVIII.A., EPA has prepared a white paper
entitled ``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,'' a copy of which is contained in the docket for this proposed
rule (Ref. 43). The white paper discusses the current level of
information and usage of structure-activity-relationship (SAR)
assessments and Quantitative SAR (QSAR) modeling to fulfill data
requirements in the Pesticide Program. The Agency specifically seeks
comment on this support document.
Since many antimicrobial pesticides are typically rinsed down the
drain, EPA has considered the potential impacts of pesticides that are
discharged into wastewater treatment plants (WWTPs). This proposed rule
addresses the issue of down-the-drain antimicrobials by proposing four
new data requirements for use in a screening-level assessment on the
fate of antimicrobials that reach a WWTP. To assess the impacts of this
screening assessment and utility of the new data requirements for
decision-making, EPA prepared four case studies (Ref. 42). The case
studies, copies of which are contained in the docket for this proposed
rule, are discussed in more detail in Unit XII.D. The Agency
specifically seeks comment on the proposed approach for evaluating the
potential impact of antimicrobial pesticide chemicals on WWTPs and
nontarget organisms in receiving water bodies, and on the case studies,
including the assumptions used in those studies, that were used to
develop the proposed approach. EPA will consider comments specific to
the case studies along with comments on the proposed approach, as the
Agency evaluates the use of the proposed approach for down-the-drain
antimicrobials in the final rule for antimicrobial data requirements.
On October 26, 2007, EPA promulgated final rules establishing data
requirements for conventional pesticides (72 FR 60934), and biochemical
pesticides and microbial pesticides (72 FR 60988). These final rules
were effective on December 24, 2007, and are therefore the current part
158. As part of those actions, on October 24, 2007, (72 FR 60251) EPA
preserved the original part 158 data requirements to provide continued
regulatory coverage for antimicrobial pesticides until the Agency could
promulgate a final regulation. To accomplish this, EPA transferred
intact the original 1984 data requirements of part 158 into a new part
161, entitled ``Data Requirements for Antimicrobial Pesticides.'' Part
161, which applies only to antimicrobial pesticides, contains the
current data requirements for antimicrobial pesticide chemicals.
As explained in the preamble to the conventional pesticide final
rule, EPA intended to preserve the existing data requirements for
antimicrobial pesticides until a new rule tailored specifically to
antimicrobial pesticides could be promulgated. Part 161 is intended to
be transitional. Once subpart W of part 158 is promulgated, there will
be no need for part 161. Accordingly, EPA proposes to revoke part 161
upon the effective date of a final rule arising from today's proposal.
B. Reasons for Today's Action
Since the promulgation of part 158 in 1984, the Agency has
recognized that the tables and test notes promulgated in 1984 failed to
adequately address the unique applications, use patterns, and other
factors germane to antimicrobial pesticides. Part 158 specifies the
types of data and information generally required for making sound
regulatory judgments under the Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA). The types of actions for which these data are
needed include experimental use, registration, amended registration,
reregistration, or registration review (collectively referred to in
this proposal as ``registration''). The information required under
FIFRA for registration of food-use pesticides is also information the
Agency needs in order to grant tolerances or exemptions from the
requirement of tolerances under section 408 of the Federal Food, Drug,
and Cosmetic Act (FFDCA).
Required data are intended to provide information about the
potential adverse effects of uses of pesticides, and to define what is
generally expected from applicants for registration in support of their
products. However, it must be emphasized that each applicant has the
continuing obligation under FIFRA to demonstrate that an individual
product meets the standard for registration under section 3 of FIFRA or
section 408 of FFDCA. Accordingly, as indicated in current Sec. 158.75
and Sec. 161.75, additional data may be needed to reflect the
characteristics and use of specific pesticide products under review.
Since the data requirements now set out in part 161 (formerly part
158) were first published in 1984, every disciplinary area and
requirement has been reconsidered and many have been revised in
practice. These changes have been needed because the state of the
science underlying the data requirements has advanced, and because the
Agency has learned in specific registration actions that additional or
different data are necessary to make sound regulatory decisions. These
case-by-case decisions have been made in accordance with Sec. 158.75,
which allows the Agency to impose additional data requirements
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beyond those specified in part 158 and now part 161.
Use patterns specific to antimicrobial pesticides are not specified
in part 161, as they were not set out separately when originally
promulgated in 1984. As a result, applicants have needed to interpret
the data requirements often via extensive consultation with and
interpretation from the Agency to determine the antimicrobial data
requirements for a particular product. Today, EPA is proposing that the
antimicrobial pesticide requirements be codified in a separate subpart
W to part 158 with use patterns (see Unit IV.I. of this preamble) and
groups of use patterns specific to antimicrobials.
Today's proposed rule is part of a series of rules to update all of
the data requirements for pesticide products. On October 26, 2007, EPA
published in the Federal Register two final rules to promulgate the
data requirements for conventional (72 FR 60934), and biochemical and
microbial (72 FR 60988) pesticide chemicals. These rules and their
proposals (conventional (March 11, 2005) (70 FR 12276) and biochemical
and microbial (March 8, 2006) (71 FR12072)) state the rationales for
requiring and/or revising particular data requirements. With few
exceptions, these rationales are also applicable to antimicrobial
pesticide chemicals, and as such have not been repeated in today's
proposed rule. Today's proposal discusses in detail only those
revisions that are singularly applicable to antimicrobial pesticides,
including antifoulants and wood preservatives.
C. Benefits of this Proposal
Greater detail on the benefits of this proposal is provided in the
document entitled ``Economic Analysis of the Proposed Change in Data
Requirements for Antimicrobial Pesticides'' which is available in the
docket for this rulemaking (Ref. 44). The following briefly highlights
the anticipated benefits:
1. More refined assessments mean less uncertainty and clearer
understanding of actual risks. EPA's current applicator/user exposure
data base is not comprehensive, especially regarding exposures to
antimicrobials in industrial and residential settings. The new data
that would be collected once this proposal becomes final would allow
the Agency to conduct improved pre- and post-application exposure
assessments for applicators/users, and the general public. This will
benefit not only workers (including applicators) and consumers by
helping EPA to make better informed regulatory decisions that are
neither too stringent nor too lenient, but also benefit the regulated
industry by reducing the uncertainty in Agency risk assessments. Thus,
today's proposal will reduce, but not eliminate, uncertainty related to
the risks posed by antimicrobial pesticides.
2. Clarity and transparency to regulated community means savings.
The enhanced clarity and transparency of the information presented in
part 158, subpart W should enhance the ability of industry to
efficiently manage their antimicrobial registration submissions.
Applicants may save time and money by understanding when studies are
needed. Having all required studies available to EPA at the time of
application should halt potential delays in the registration process,
thereby enabling registration of antimicrobial pesticides sooner.
Products would enter the market faster.
3. EPA information assists other communities in assessing pesticide
risks. Scientific, environmental, and health communities find
antimicrobial pesticide toxicity information useful to respond to a
variety of needs. For example, medical professionals are concerned
about the health of patients exposed to antimicrobials; poison control
centers use and distribute information on toxicity and treatment
associated with poisoning; and scientists use toxicity information to
characterize the effects of antimicrobial pesticides and to assess
risks of pesticide exposure. Similarly, those responsible for
protection of nontarget wildlife need reliable information about
antimicrobial pesticides and assurance that pesticides do not pose an
unreasonable threat. The proposed changes will help the scientific,
environmental, and health communities by increasing the breadth,
quality, and reliability of Agency regulatory decisions by improving
their scientific underpinnings.
4. Better informed users mean informed risk-reduction choices.
Better regulatory decisions resulting from the proposed changes should
also mean that the label will provide better information on the use of
the antimicrobial pesticide. A pesticide label is the user's direction
for using pesticides safely and effectively. It contains important
information about where to use (or not use) the product, health and
safety information to be read and understood before using a pesticide
product, and how to dispose of that product. This benefits users by
enhancing their ability to obtain antimicrobial pesticide products
appropriate to their needs, and to use and dispose of products in a
manner that is safe and environmentally sound. Applicators/users may
benefit from label information based on the data submitted to the
extent it helps inform their decisions about whether or how to use
particular pesticides to avoid potential exposure.
D. What is the Agency's Authority for Taking this Action?
This action is issued under the authority of sections 3, 4, 5, 10,
12, and 25 of FIFRA as amended and section 408 of FFDCA. The data
required for a registration, reregistration, experimental use permit,
or tolerance are listed in 40 CFR part 158.
III. Statutory and Historical Framework
A. FIFRA
Under FIFRA section 3, every pesticide product must be registered
with EPA or specifically exempted under FIFRA section 25(b) before
being sold or distributed in the United States. Under FIFRA, an
applicant for a new registration or an existing registrant
(collectively referred to as applicant in this proposal) must
demonstrate to the Agency's satisfaction that, among other things, the
pesticide product, when used in accordance with widespread and commonly
recognized practice, will not cause ``unreasonable adverse effects'' to
humans or the environment. This safety determination requires the
Agency to weigh the risks of the use of the pesticide against any
benefits. EPA must determine that the standard for registration
contained in FIFRA is met before granting a registration.
1. Registration. Section 3 of FIFRA contains the requirements for
registration. Specifically, FIFRA section 3(c)(2) provides EPA broad
authority, before and after registration, to require scientific testing
and submission of the resulting data to the Agency by applicants for
registration of pesticide products. An applicant must furnish EPA with
substantial amounts of data on the pesticide, its composition,
toxicity, potential human exposure, environmental properties, and
ecological effects, as well as information on its product performance
(efficacy) in certain cases. Although the data requirements are imposed
primarily as a part of initial registration, EPA is authorized under
FIFRA section 3(c)(2)(B) to require a registrant to develop and submit
additional data to maintain a registration.
2. Reregistration. FIFRA section 4 requires that EPA reregister
each pesticide product first registered before November 1984. This date
was chosen because pesticides registered after 1984 were subject to the
part 158 requirements of the 1984 regulation.
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EPA has completed the reregistration/tolerance reassessment process for
food-use pesticides and expects to complete all reregistration
activities by the statutory deadline of August 2008.
3. Registration review. FIFRA section 3(g) mandates that the
registrations of all pesticides are to be periodically reviewed.
Changes in science, public policy, and pesticide use practices occur
over time. Through the new registration review program implemented via
a regulation promulgated on August 9, 2006 (71 FR 45719) (40 CFR part
155, subpart C), the Agency is periodically reevaluating all registered
pesticides to assure that they continue to meet the statutory standard
of no unreasonable adverse effects. Starting in 2006, registration
review began to replace EPA's reregistration program as the mechanism
for systematic review of existing pesticides. The registration review
process begins by reviewing the available information in the possession
of the Agency and then determining the specific data needed for
assessing a particular pesticide. Thus, the data needed, and the scope
and depth of the Agency's review will be tailored to the specific
circumstances of a particular pesticide. This means that reviews will
be commensurate with the complexity of the issues associated with each
pesticide.
4. Experimental Use Permits (EUPs). Subject to some exceptions,
FIFRA section 5 requires persons seeking permission for experimental
use of a pesticide under controlled condition to obtain an experimental
use permit. A EUP allows limited use of a pesticide for specified
experimental and data collection purposes intended to support future
registration of the pesticide. Because a EUP is for limited use under
controlled conditions, the data needed to support issuance of the
permit are correspondingly less than those required for full
registration. The regulations governing the issuance of EUPs are found
in 40 CFR part 172. In its final rule ``Data Requirements for
Conventional Pesticides'' EPA promulgated subpart C of part 158 to
contain the data requirements for EUPs, which will be applied on a
case-by-case basis to any EUP applications for an antimicrobial
pesticide.
5. Registration requirements for antimicrobials. FIFRA section 3(h)
requires that EPA evaluate its registration process to identify
improvements and reforms that will reduce historical review times for
antimicrobial applications. This includes defining the classes of
antimicrobial use patterns and the types of application review,
conforming reviews to risks and benefits, ensuring efficacy, and
meeting review time goals. EPA believes that this rule assists in
meeting the section 3(h) mandate. By defining the 12 use patterns for
antimicrobials in relation to the data required for a registration
under FIFRA, EPA is providing clearer and more transparent information
to applicants. This should result in submissions to EPA that contain
the required data and therefore can be reviewed and evaluated more
expeditiously.
B. FFDCA
FFDCA requires EPA to determine that the level of pesticide
chemical residues in food and feed will be safe for human consumption.
The safety standard set under FFDCA section 408(b) and (c) defines safe
as ``a reasonable certainty that no harm'' will result from exposures
to pesticide chemical residues. The combination of aggregate and
cumulative exposure assessments required by FFDCA section 408 increases
the nature and scope of EPA's risk assessment, and potentially
increases the types and amounts of data needed to determine that the
FFDCA safety standard is met.
Under FFDCA section 408, EPA is authorized to establish tolerances
for pesticide residues in food and feed, or to exempt a pesticide from
the requirement of a tolerance, if warranted. In this preamble,
references to tolerances include exemptions from tolerance since the
standards and procedures for both are the same. The safety standard
applies to tolerances in a number of regulatory situations, including:
Tolerances that support registration under FIFRA;
Tolerances for imported products which are established to
allow importation of pesticide-treated commodities, but for which no
U.S. registration is sought;
Time-limited tolerances which are established for FIFRA
section 18 emergency exemptions; and
Temporary tolerances established for experimental use
permits under FIFRA section 5.
C. Linking FIFRA and FFDCA Safety Standards
Under FIFRA section 2(bb), a pesticide that is inconsistent with,
or does not meet, the FFDCA section 408 safety standard poses an
unreasonable adverse effect that precludes new or continued
registration. Given this linkage between registration and tolerances,
it makes sense for EPA to define data requirements for both purposes:
The data required to support a determination of ``reasonable certainty
of no harm'' under FFDCA are an integral part of the data needed for an
``unreasonable adverse effects'' determination under FIFRA.
Consequently, when promulgated, these proposed data requirements would
encompass the basic data requirements for both registration and
tolerance-setting determinations. EPA has authority to require
additional data on a case-by-case basis.
D. Scope of Proposed Subpart W
FIFRA contains a number of provisions specific to ``antimicrobial
pesticides'' as defined in FIFRA section 2(mm). The statutory
definition contains a complex construction of functionality, types of
organisms, and intended use to describe what is encompassed by the term
``antimicrobial pesticide.'' EPA believes that the definition was
primarily intended to be used in conjunction with the provisions of
section 3(h), which contains requirements for process improvements,
timeframes for review purposes, and other regulatory matters, but,
significantly, does not include provisions pertaining to data
requirements. The definition in section 2(mm) as it relates to section
3(h) was discussed fully in a proposed rule issued in the Federal
Register of September 17, 1999 (64 FR 50672).
The statutory definition, however, does not mesh with the Agency's
needs in developing this proposed rule concerning data requirements.
Data requirements depend upon the use pattern, taking into account the
pesticide's hazard and exposure profiles. How well the pesticide kills
or repels particular pests are relevant factors in the determination of
product performance data requirements.
Neither FIFRA section 3(c)(2) nor section 3(h) requires the Agency
to develop data requirements for an ``antimicrobial pesticide'' as
defined specifically in section 2(mm). Therefore, the scope of this
proposal has been expanded beyond ``antimicrobial pesticide'' as
defined by FIFRA section 2(mm) to include related pesticides that are
excluded from the 2(mm) definition. The broader applicability of this
40 CFR part 158, subpart W is intended to ensure that all pesticides
currently considered as antimicrobial products for purposes of FIFRA
section 33 fees and review periods are covered.
Accordingly, this proposal applies to:
Antimicrobial pesticides, as defined in FIFRA section
2(mm).
Pesticide products for antimicrobial uses in/on food or
feed.
Antifoulant paints and coatings.
[[Page 59386]]
Wood preservatives.
Pesticide products intended to be manufactured into any of
the above.
IV. Introduction to Subpart W
A. Data Requirements for Registration
First promulgated in 1984, EPA's pesticide data requirements
outline the kinds of data and related information typically needed to
register a pesticide. In this proposal, the data requirements are
organized by scientific discipline (e.g., toxicology), just as the
existing data requirements in part 158 for conventional, and
biochemical and microbial pesticides and those in part 161 for
antimicrobials. A significant change in this proposal from the existing
data requirements in part 161 is the introduction of 12 use patterns
specific to antimicrobials. Since there is much variety in pesticide
chemistry, exposure, and hazard, the requirements are designed to be
flexible. Test notes to the data requirements tables explain the
conditions under which data are typically needed. Essentially, the data
requirements identify the questions that the applicant will need to
answer regarding a pesticide product before the Agency can register it.
Data requirements address both components of a risk assessment, i.e.,
the hazards that the pesticide presents, and the estimated level of
exposure to humans or nontarget species. Having the appropriate
information enables the Agency to understand when those hazards pose
risks. The answer to one question may inform the kind of information
needed to answer other questions. For example, a pesticide that is
persistent and toxicologically potent may require more extensive
exposure data to help establish a safe level of exposure. In addition,
because a number of antimicrobials are used for public health purposes
(for example, disinfectants, sterilants, or sanitizers), there are
product performance data requirements to assure that the antimicrobial
product works as intended.
B. Structure of Part 158
At this time data requirements for conventional, biochemical, and
microbial pesticides are established in 40 CFR part 158. Data
requirements for antimicrobial pesticides are established in 40 CFR
part 161.
Part 158 contains general provisions concerning all pesticide data
(subpart A), instructions on how to use the data tables that follow
(subpart B), and a series of disciplinary data tables that are focused
on conventional pesticides (subparts C - O). Individual subparts are
devoted to biochemical (subpart U) and microbial (subpart V)
pesticides. The revised data requirements for antimicrobial pesticides
would be incorporated into part 158 as subpart W.
C. Subpart W of Part 158
Subpart W is proposed to be a freestanding series of tables and
regulatory text establishing specific data requirements for each
scientific discipline for antimicrobial pesticides. EPA recognizes that
antimicrobial uses are generally different from the uses more typically
associated with conventional pesticides (e.g., agricultural outdoor
uses) and therefore can have different combinations of exposure
considerations. The use patterns and expected exposures typically
determine the data requirements for any pesticide. Antimicrobial
pesticides are no different in this regard from conventional,
biochemical, and microbial pesticides.
The order of proposed subpart W mirrors that of the larger part
158: from product chemistry, to efficacy, to hazard/toxicity
requirements (both human health and ecological toxicity), to exposure
data requirements (application and post-application human exposures,
and exposure to residues in food), and environmental fate requirements,
which overlap human exposure through drinking water. Units V-XIV of
this preamble describe the revisions to the current requirements. The
proposed data requirement tables are comprehensive. Generally, the data
requirements for each discipline are discussed separately, but the
applicator and post-application exposure disciplines are discussed
together in a single unit.
D. Clarifying How to Use the Data Tables
Part 158 subpart B contains a step-wise process to assist the
applicant in determining the data needed to support its particular
product. At this time subpart B is specific to the needs of
conventional, and biochemical and microbial pesticides. The process
needed for antimicrobials is no different. EPA is proposing certain
clarifying changes to subpart B to specify the needs of antimicrobial
pesticides. Specifically, EPA proposes to include antimicrobial use
patterns in Sec. 158.100 and a reference to the antimicrobial use site
index that will be available on the EPA website.
While EPA is attempting to assist the applicant in subpart B, it is
important to emphasize that it is the applicant's obligation under
FIFRA to demonstrate that an individual product meets the standard
under FIFRA and that of FFDCA. Accordingly, applicants are encouraged
to consult with the Agency on the appropriate data requirements, as
proposed here, as related to their specific product prior to and during
the registration process.
EPA is continuing its current system of identifying the
applicability of data requirements in the data tables. In essence, the
data requirements illustrate the questions the registrant will need to
answer about the safety of the pesticide product before the Agency can
register it. Because of the variety of chemicals and use patterns, and
because EPA must retain flexibility to tailor data requirements as
appropriate, only qualitative descriptors are in the tables. Test notes
provide more specific information on the applicability of specific data
requirements.
The table descriptors NR (not required), R (required), and CR
(conditionally required) should be viewed as a general presentation,
indicating the likelihood that the data requirement applies. The use of
R does not necessarily indicate that a study is always required, but
that it is more likely to be required than not. For example, if the
applicant wanted to apply his pesticide to apples, then crop field
trials would be required almost always on apples. However, if the
physical/chemical properties of the chemical did not lend themselves to
the test, such as performing an inhalation test with a chemical that is
a solid and has an extremely low vapor pressure, then a waiver might be
granted. Generally test notes for R studies discuss any particular
circumstances when the testing might not be required.
The use of CR means a study is less likely to be required. Triggers
in the test notes indicate the circumstances under which the Agency has
learned through experience that the information is needed. Although
only an approximation, if percentages were to be assigned to indicate
the need for a particular study, then R could be viewed as representing
the submission of a study 50% to 100% of the time and CR would be up to
50%.
Thus, NR, R, and CR are used for convenience to make the table
format feasible, but serve only as a general indication of the
applicability of a data requirement. In all cases, the test notes
referred to in the table must be consulted to determine the actual need
for the data. Applicants are also encouraged to visit the Agency's
website, entitled ``Data Requirements for Pesticide Registration'' (see
http://www.epa.gov/pesticides/regulating/data_requirements.htm). Since
it is not
[[Page 59387]]
possible to sufficiently delineate all circumstances in test notes,
consultation with EPA is encouraged.
The table format includes a column heading entitled ``Guideline,''
which refers to the OPPTS (Office of Pollution Prevention and Toxic
Substances) Harmonized Test Guidelines. Guideline numbers are provided
as information/guidance to applicants. These Guidelines set forth
recommended instructions and test methods for performing a study to
generate the required data. Since these are guidance documents, the
applicant is not required to use these Guidelines, but may instead seek
to fulfill the data requirement by other appropriate means such as
alternative test methods, submission of an article from open
literature, or use of modeling. The applicant may submit a protocol of
his own devising for the Agency to review. However, the OPPTS
Harmonized Guidelines have been developed through a rigorous scientific
process, including extensive peer review by the FIFRA Scientific
Advisory Panel. Additionally, many of the Guidelines have been
harmonized internationally. As such, they represent the recommended
approach to developing high-quality data that should satisfy EPA's data
needs for risk assessment.
E. The Nature of Changes to Requirements
Proposed subpart W does not differ greatly from the data
requirements for conventional pesticides promulgated in October 2007.
Where this proposal differs is in the explicit adaptation of those data
requirements to antimicrobials. As previously discussed, antimicrobial
uses were covered in the original (1984) part 158. However part 158
(now transitioned for antimicrobials as part 161) was developed
primarily for agricultural pesticides. Since the use patterns which now
appear in tables in part 161 are not specific to antimicrobials, often
it has been difficult to discern directly from such tables the data
requirements for certain antimicrobials. Without extensive consultation
with and interpretation from the Agency, frequently it has been
difficult for applicants to effectively use the tables to determine
which data requirements apply to antimicrobials.
Today's proposal reflects the Agency's current needs for risk
assessment of antimicrobials. Describing the antimicrobial data
requirements in terms of use patterns specific to antimicrobial uses
provides a clarity that should reduce the need for extensive
consultations.
There are nine new data requirements for antimicrobials set out in
this proposal. Two (developmental neurotoxicity and immunotoxicity) are
the same new data requirements as promulgated in the final rule for
conventional chemicals (72 FR 60934) (see Unit VIII). While
photodegradation in soil studies have been routinely required for
conventional chemicals, this study would be a new data requirement for
wood preservatives (see Unit XII). Similarly, two new exposure data
requirements (soil residue dissipation and non-dietary ingestion
exposure) are today proposed for antimicrobials (see Unit IX.D).
Four new data requirements (activated sludge sorption isotherm
study; ready biodegradability study; porous pot study; and modified
activated sludge, respiration inhibition test) are proposed today for
antimicrobials that are not included in the final rule for conventional
pesticides. This is due to the nature of antimicrobial pesticides,
which includes many down-the-drain uses, i.e. those discharged to
public treatment systems, and is discussed in Units XII.B. and C.
Most screening-level environmental fate assessments would be
performed using the hydrolysis, photodegradation in water, activated
sludge sorption isotherm, ready biodegradability, and modified
activated sludge, respiration inhibition tests. For wood preservatives,
the results of the photodegradation in soil study may also be
considered in the screening-level assessment. If the porous pot study
is triggered based on the results of the ready biodegradability study,
then those results would also be considered.
EPA notes that its proposed approach for performing a screening-
level fate assessment could potentially result in the submission of
higher-tiered studies. There are seven higher-tiered environmental fate
studies, that could be triggered based on a weight-of-evidence
evaluation of the results of the screening-level studies. For example,
if the screening-level assessment were to indicate that a down-the-
drain chemical would partition to sludge, soil, or sediment, then
higher-tiered environmental fate studies such as the aerobic and
anaerobic soil metabolism studies may be required. If the chemical
would partition to water then higher-tiered ecotoxicity studies such as
the fish early life stage may be required. Thus, the higher-tiered
studies that could be triggered include both the environmental fate and
ecotoxicity scientific disciplines.
While not a new data requirement, subchronic dermal testing of end-
use products has not been routinely required and therefore would be
considered a new testing requirement. The circumstances for requiring
the testing is the same as for conventional chemicals. (See Unit VIII).
Each data requirement proposed in Units, VIII, IX, X, XII, XIII,
and XIV is described as ``new,'' ``current practices,'' or
``existing.'' ``New'' means that the data requirement has never been
required or has rarely been required on a case-by-case basis, and has
not been routinely considered during the Agency's evaluation of the
data needed for the purpose of risk assessment.
``Current practices'' encompasses the data that is typically
required to register an antimicrobial pesticide product. This would
include existing data requirements that are codified in part 161 as
well as those that are not codified in part 161 and are now being
proposed for codification in part 158, subpart W. It would also include
any study that has been routinely required on a case-by-case basis, or
any study that is routinely considered during the Agency's evaluation
of the data needed for the purpose of risk assessment but is
infrequently required because the triggers for that study are
infrequently met.
``Existing'' requirements are a subset of ``current practices.''
This particular subset means that the data requirement is codified in
part 161 and being transferred to part 158, subpart W either ``as is''
or with specified changes to the test notes, to the Rs, CRs, and NRs,
or to the use patterns for which required. If there are proposed
revisions to an existing data requirement, then clarifications on these
proposed revisions are included in the preamble. Such revisions include
proposing changes 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.
As previously discussed, there are frequently consultations to
discern data requirements for certain of the antimicrobial use
patterns. These consultations have led to general understandings as to
the data required for a particular use pattern. For certain use
patterns, all of the studies are considered to be the Agency's current
practices. As an example, for the wood preservative use patterns, there
is not a good fit to any of the part 161 use patterns in the tables and
therefore the data needed to register a wood preservative is difficult
to interpret from those tables. Given these circumstances,
[[Page 59388]]
EPA developed a series of requirements developed specifically for wood
preservatives. These requirements are not codified in CFR, but the
applicants understand that these are the data needed for wood
preservatives and they routinely provide these studies to EPA.
F. Tiered Data Requirements
The Agency has organized the proposed requirements for
antimicrobial pesticide products to support a tiered testing approach.
Under such an approach the Agency prescribes a specific subset of
``lower tier'' studies that are conducted first. The results of this
first- or lower-tiered testing are then used in conjunction with
exposure data or other information to determine the need for more
complex ``higher tier'' studies. The risk assessment must provide
sufficient information to make the risk management decisions needed to
register the product or establish a tolerance. This is a significant
factor in the tiering process.
Data requirements have been tiered when EPA believes it can
adequately conduct a risk assessment using a tiered approach. The
conditions for ``triggering'' these higher tiered studies are specified
in the test notes to the tables in proposed subpart W. A tiered data
submission process is intended to allow the Agency to assess a
pesticide's risk without requiring the applicant to conduct and submit
studies that may not be needed for the regulatory decision. For certain
chemicals, data from lower tiered requirements may be sufficient in and
of themselves or in combination with other data to address the Agency's
risk concerns without submission of higher tiered data requirements. In
other cases, data from lower tiered requirements may indicate that
higher tiered data need to be provided. The Agency expects applicants
to consult with the Agency, as needed, to determine when submission of
higher tiered data may be required.
The Agency has tiered the data requirements based on an
understanding of the potential exposure for a specific use pattern. As
an example, for toxicology studies used to support human health risk
assessments, the high human exposure grouping specifies 19 toxicology
studies as required at the lower tier. The low human exposure grouping
specifies 13 toxicology studies as required. The Agency considered the
frequency, duration, and/or magnitude of the exposure to determine the
lower tier of toxicology testing requirements for both the high and low
human exposure groupings.
For ecotoxicity data requirements, the Agency requires a first tier
of required data for all antimicrobials regardless of the use pattern.
The need for higher tiered data depends not only on the frequency,
duration, or magnitude of the exposure, but also on the results of the
first tier of the data.
Such a flexible approach allows EPA to require enough data, but not
more than enough, to make the required safety finding. Such an approach
is the same as that used for other pesticides; however, for
antimicrobials the progression from lower to higher tier requirements
may differ from that of conventional pesticides because the uses and
expected exposures are different.
G. Impact of this Proposal on Future and Existing Registrations
This proposal concerns prospective data requirements for future
registrations of antimicrobial pesticides. That is, these proposed data
requirements, once final, would apply to all new applications for
registration of antimicrobial pesticides submitted after the effective
date of the rule. The new data requirements would also apply to
applications of antimicrobial pesticides that are undergoing Agency
review when the new regulation goes into effect. EPA believes that
there may be a need for some type of a limited transition ``window''
for certain antimicrobial registration applications. EPA anticipates
applicants of applications that were submitted, but not yet approved
when the new regulations go into effect, may need to discuss with EPA
the specifics of their application and whether additional time may be
needed to complete generation of certain studies that may then be
required to fulfill new data requirements. The Agency specifically
requests comment on implementing the effective date of the final rule
for antimicrobials with regards to future registrations of
antimicrobials.
The Agency does not intend to apply these requirements
automatically or routinely to all existing pesticide registrations.
While EPA intends a flexible approach to imposing the new requirements
upon existing products, the Agency may find it necessary to call-in
data on certain existing registrations, for example, as warranted by
emerging risks of concern for particular pesticides or as a result of
possible future programmatic changes and priorities on existing
pesticides, or during registration review.
However, EPA notes that issuance of this proposed rule provides
notice to applicants of potential new data requirements and of
potential expansion of existing data requirements to additional
antimicrobial use patterns. Applicants and potential applicants for new
registrations as well as registrants of existing products may wish to
evaluate their products in light of the proposed requirements. As
always, the Agency encourages applicants to consult with EPA, if they
have any questions regarding data requirements.
H. Weight-of-Evidence Approach
The weight-of-evidence (WOE) approach is referenced in several
subpart W test notes. Such an approach requires a critical analysis of
the entire body of available data for consistency and biological
plausibility. Some considerations in this approach are listed below:
Sufficiency of data. Studies that completely characterize
both the effects and exposure of the agent have more credibility and
support than studies that contain data gaps.
Quality of the data. Potentially relevant studies are
judged for quality and studies of higher quality are given more weight
than those of lower quality.
Evidence of causality. The degree of correlation between
the presence of an agent and some adverse effect is an important
consideration.
Corroborative information. Supplementary information
relevant to the conclusions reached in the assessment is incorporated,
e.g., studies demonstrating agreement between model predictions and
observed effects.
WOE considers the kinds of evidence available, how that evidence
fits together in drawing conclusions, and significant issues/strengths/
limitations of the data and conclusions. WOE is not simply tallying the
number of positive or negative studies.
I. Use Patterns in Subpart W
The general use pattern groups described in subpart B of part 158
are not used as the bases for describing antimicrobial data
requirements. Those general use patterns were developed for and are
appropriate to conventional pesticide chemicals.
Some years ago, 12 use categories were developed specifically for
antimicrobials. At that time the Agency's data requirements for all
pesticide chemicals were specified by use patterns developed for and
appropriate to conventional pesticide chemicals. To fit antimicrobial
uses into this agricultural scheme, the antimicrobial use categories
referred back to the then-existing use patterns. With the Agency's
intention to establish specific data requirements for
[[Page 59389]]
antimicrobials in subpart W, this referral is no longer needed.
Therefore, the Agency is proposing that the use categories employed
in recent years to generalize the range of uses for individual
antimicrobial pesticide chemicals, now constitute the use patterns for
specifying the antimicrobials data requirements in the tables in
proposed subpart W. Additionally, EPA is proposing to codify in Sec.
158.2201 the specific use patterns for antimicrobials.
FIFRA section 3(h)(3)(A)(ii)(I) requires that EPA ``define the
various classes of antimicrobial use patterns.'' For antimicrobial
pesticides, the Agency proposes to structure its requirements by using
a system of 12 use patterns based on similarity of use, purpose,
pesticidal function, the nature of the exposure, and, in some cases,
application methods. Today's proposal meshes with the statutory mandate
to identify classes of antimicrobial use patterns by defining for each
use pattern the data requirements that apply. EPA requests comment not
only on the 12 antimicrobial use patterns described in this Unit, but
also on the usefulness of these use patterns. EPA also requests comment
on whether or not any different/additional use patterns should be
codified by splitting or recombining the existing use patterns to make
separate and distinct use patterns.
Antimicrobial use patterns also reflect environmental concerns for
indoor versus outdoor use, as well as food versus nonfood-use, and high
versus low human exposure. The 12 general use patterns for
antimicrobial pesticides are described below. Examples within each use
pattern are provided:
1. Agricultural premises and equipment. This use pattern includes
many indirect food uses with mostly indoor use sites.
Farm and farm animal premises such as animal houses and
pens (including milk houses), parlors, stalls, and barns.
Transportation vehicles used to transport animals.
Equipment such as forks, shovels, scrapers; halters,
ropes, other restraining equipment; racks, mangers, feeders, waterers,
troughs, and fountains.
Food-handling equipment such as milking equipment.
2. Food-handling/storage establishments, premises, and equipment.
This use pattern also includes many indirect food uses due to the
treatment of food contact surfaces and the resultant human exposures.
All use sites are indoor.
Food or feed processing plants.
Eating establishments such as restaurants and cafeterias.
Food storage or distribution facilities.
Commercial transportation vehicles, shipping, and storage
containers.
Food or feed stores and markets.
Vending machines.
3. Commercial, institutional and industrial premises and equipment.
This use pattern includes nonfood contact areas of commercial sites.
Typically, antimicrobial pesticides would be applied to ceilings,
doors, doorknobs, fixtures, floors, light switches, stairs, walls,
windows, and woodwork as part of routine cleaning practices. Included
within this use pattern are residential school and daycare
institutions.
This use pattern includes both indoor and outdoor uses. Some of the
uses have the potential for significant exposure due to the repetitive
nature of certain exposures and therefore may be considered as high
human exposure.
4. Residential and public access premises. This use pattern
includes mostly nonfood areas, although it includes food-handling areas
in homes. Some of the uses have the potential for significant exposure
due to the repetitive nature of certain exposures and therefore may be
considered as high human exposure. Most uses are indoor.
Premises, contents, and equipment of homes, apartments,
mobile homes and shelters, including home-based daycare.
Public areas, public buildings, and public rooms.
Commercial kennels, or living quarters of pets, zoo
animals, race horses, or laboratory animals.
5. Medical premises and equipment. Medical waste is defined as any
solid waste that is generated in the diagnosis, treatment, or
immunization of human beings or animals, in research pertaining
thereto, or in the production of biologicals including, but not limited
to, culture and stocks, pathological wastes, human blood and blood
products, and sharps. This use pattern is considered to be indoor
nonfood. Some of the uses have the potential for repeated exposure and
therefore may be considered as high human exposure.
Hospital or medical environments such as clinics, dental
offices, nursing homes, sick rooms, morgues, and veterinary clinics.
Non-critical medical equipment such as bedpans, basins,
and furniture.
6. Human drinking water systems. Human drinking water systems
include any methods used to provide potable water from raw water
supplies. This use pattern is considered to be high human exposure due
to the potential for human exposures via drinking water, as well as
dermal exposures to the treated water.
Public water systems.
Individual water systems.
Emergency water systems.
Water purifier units.
Private water systems of individual homes, farms,
institutions, camps, resorts, and industrial plants.
Emergency water systems for the public, campers,
travelers, military, and fishermen.
7. Materials preservatives. Materials preservatives are
antimicrobial chemicals added during industrial processes to prevent
the growth of microorganisms. Examples of such uses include paints,
coatings, adhesives, textiles, and paper. This use pattern includes
food and nonfood, and mostly indoor uses.
8. Industrial processes and water systems. Certain antimicrobial
chemicals, known as microbiocides, are used to control the growth of
bacteria, fungi, and algae in circulating water systems. There are two
types of systems: ``once-through'' and ``recirculating.''
For ``once-through'' systems, the water is not re-used and is
therefore released into the aquatic environment or a wastewater
treatment plant after a single cycle through the system. Once-through
uses have the potential for significant environmental exposure when the
treated water is released to the environment. Large volumes of water
(as much as millions of gallons per minute) may be released directly to
a river, estuary, or marine environment within minutes or hours of
adding the antimicrobial to the system. In addition to the potential
for environmental exposure after release, there is the potential for
high human exposure via drinking water if the intake pipe for a
drinking water treatment plant is downstream. Also, the water could be
used in crop and/or livestock production thus providing for additional
human exposure.
However, for many uses of water in industrial plants the treated
water is re-used repeatedly within the system, ``recirculating'' in the
system multiple times until released into the aquatic environment or a
wastewater treatment plant. EPA has assumed that the releases are
scheduled as the antimicrobial has been ``used-up.'' Given the lower
frequency of release, resulting in lower volumes released to the
environment, recirculating uses are likely to have less environmental
exposure than that of once-through systems.
As will be explained later in Unit XI, for the purposes of
determining data requirements for environmental fate and
[[Page 59390]]
ecological effects, the industrial processes and water systems use
pattern will be subdivided. Because of the distinct differences between
the once-through and recirculating water systems, the once-through
water system will be grouped with those use patterns with potential for
higher environmental exposures and the recirculating water system with
those use patterns with the potential for lower environmental
exposures.
9. Antifoulant paints and coatings. Antifoulants are coatings and
paints applied to boat hulls and bottoms, crab and lobster pots, and
underwater structures or equipment to control the growth of freshwater
or marine fouling organisms. Antifoulant coatings have the potential
for high environmental exposure most particularly for marine (both
freshwater and saltwater) environments.
Also included within this use pattern is ballast water, that is,
the water that is pumped in and out of ballast tanks as a ship's weight
changes due to loading and unloading of cargo. Ballast water provides
needed stability for safe operation of marine vessels. In recent years
there have been significant concerns about transport of marine species
from one marine environment to another in ballast water. When
discharged into a new environment, the new species may become invasive
and disrupt the native ecology. Ballast water treatments (such as
adding an antimicrobial to the ballast water before discharge) are
intended to prevent this. The Agency has reviewed few applications for
ballast water treatments, presumably because treatment of ballast water
to prevent the transfer of microorganisms from one marine environment
to another is relatively new. Since ballast water treatments also have
the potential for high exposure to the aquatic (both freshwater and
seawater) environment, EPA has grouped the ballast water treatment
pesticide chemicals with the antifoulant coating pesticide chemicals.
10. Wood preservatives. Wood preservative products are those which
claim to control wood degradation problems due to fungal rot or decay,
sapstain, molds, or wood-destroying insects. This use pattern has the
potential for high exposure for both humans and the environment with
mostly outdoor use sites. Certain uses can be food-uses. The types of
wood and the products that can be manufactured with this treated wood
are:
Freshly cut logs or lumber.
Seasoned building materials.
Utility poles, fence posts and rails.
Structural members.
Structures and dwellings.
Transportation vehicles (truck beds and support
structures).
Crop containers.
Lawn furniture and decks.
Playground equipment.
Garden/landscape timbers.
Log homes.
11. Swimming pools. Products in this use pattern are used to
prevent/control the growth of bacteria or algae in the water systems of
swimming pools, Jacuzzis, and hot tubs. This use pattern is considered
to be high human exposure. Under routine use little or no environmental
exposure is expected, as the water in swimming pools, Jacuzzis, or hot
tubs is considered to be separated from the natural environment.
However, when draining is needed, depending on the volume of water and
the location of the pool or hot tub, it is most likely that discharge
would be down-the-drain to a wastewater treatment plant, to a storm
drain that discharges to a stream, or directly to soil.
12. Aquatic areas. Products in this use pattern are designed to
control or kill slime-forming bacteria, fungi, or algae in lakes,
ponds, streams, drainage ditches, and other bodies of water. In
addition to the potential for environmental exposure, there is the
potential for high human exposure via drinking water if the intake pipe
for a drinking water treatment plant is in a lake or downstream, or
through recreational activities such as swimming. Also, the water could
be used in crop and/or livestock production thus providing for
additional human exposure.
J. Use Site Index
As part of this action, the Agency is proposing to place on its
website an Antimicrobial Use Site Index similar to the existing
Pesticide Use Site Index at http://www.epa.gov/pesticides/regulating/
usesite/index.htm. Information similar to that which would be included
on the Antimicrobial Use Site Index is included in the docket for this
action (Ref. 41). The existing Pesticide Use Site Index will be re-
titled, the Pesticide Use Site Index for Conventional, Biochemical, and
Microbial Pesticides to distinguish it from the Antimicrobial Use Site
Index.
K. Request for Comments
The Agency invites the public to provide its views and suggestions
for changes on all of the various proposals in this document.
Specifically included within the Agency's request for comments are the
following proposals:
SAR white paper.
Four case studies.
12 general use patterns, suggestions for different/
additional use patterns, and their utility.
Proposed new down-the-drain requirements.
Additionally, in other parts of this proposed rule, EPA is
specifically requesting comments on certain issues.
As appropriate during the development of this proposal, EPA has
occasionally shared information with the regulated community on the
data requirements that were under consideration. Commenters are
encouraged to comment on such sharing of information as part of the
administrative process of developing this proposed rule.
The Agency welcomes comments on the following topics of particular
interest to the Agency:
All aspects of the administrative process used to develop
this proposed rule including outreach activities.
The need for, value of, and any alternatives to, the data
requirements described in this document.
The scientific basis of this proposed rule.
The clarity of the proposed data requirements for
antimicrobial pesticides and the relationship between the proposed data
requirements and EPA's statutory determinations.
The economic analysis of the proposed rule, as well as on
its underlying assumptions, economic data, and high- and low-cost
options and alternatives.
Commenters are encouraged to present any data or information that
should be considered by EPA during the development of the final rule.
Describe any assumptions and provide any technical information and data
used in preparing your comments. Explain estimates in sufficient detail
to allow for them to be reproduced for validation. EPA's underlying
principle in developing the proposed revisions has been to strike an
appropriate balance between the need for adequate data to make the
statutorily mandated determinations and informed risk management
decisions, while minimizing data collection burdens on applicants.
V. Product Chemistry
The Agency proposes to apply the product chemistry data
requirements for conventional pesticide chemicals, in subpart D, to
antimicrobial products. These requirements were promulgated in the
final rule on October 26, 2007, (72 FR 60934). Product chemistry
requirements identify the basic identity, and chemical and physical
characteristics of a pesticide chemical.
[[Page 59391]]
These data, to a limited extent, are used to determine if a pesticide
contains contaminants which are of toxicological or environmental
concern and are necessary to determine proper label precautions.
Product chemistry requirements are generally not dependent on a
pesticide's intended use pattern, and therefore it is appropriate to
apply the same requirements to antimicrobial pesticides as required for
conventional pesticides. If circumstances particular to antimicrobial
pesticides should arise, then the Agency has the authority to require
the appropriate product chemistry data on a case-by-case basis.
VI. Product Performance Data Requirements
EPA is not proposing to revise product performance data
requirements (Sec. 158.2220) at this time. At this time there are
nearly identical product performance data requirements for
antimicrobial chemicals in both Sec. 158.400 and part 161. EPA
proposes to transfer the contents of the existing product performance
data requirements for antimicrobial pesticides into subpart W,
specifically Sec. 158.2220. The table is transferred essentially
unchanged. EPA is also proposing to delete the duplicative data
requirements for antimicrobials from the table in Sec. 158.400. After
the publication of the final rule, all product performance data
requirements for antimicrobials will be contained in Sec. 158.2220.
In the Federal Register of September 17, 1999, (64 FR 50726), EPA
published a proposed rule entitled, ``Registration Requirements for
Antimicrobial Pesticide Products and Other Pesticide Regulatory
Changes.'' In that proposed rule, EPA proposed various definitions for
public health pesticides. Today, the Agency is re-proposing definitions
for the following terms: disinfectant, fungicide, microbiological water
purifier, sanitizer, sterilant, tuberculocide, and virucide. These
proposed definitions are identical to those in the 1999 proposal. The
Agency is also re-proposing the 1999 criteria that EPA would use to
consider whether a product makes a public health claim. The comments
that were received on the 1999 proposed rule were considered for
today's proposed rule.
The current regulations in part 161 require that each applicant
must ensure through testing that its products are efficacious when used
in accordance with label directions and commonly accepted practices.
The requirement to submit product performance data is directly linked
to making a public health claim. Today's proposal makes explicit what
antimicrobial claims would be considered public health claims for
purposes of product performance data submission.
At the time of application, EPA requires the submission of product
performance data for products making a public health claim. An
application will not be approved in the absence of acceptable data
substantiating a public health claim. EPA requires the development of
product performance data for all other (non-public-health) products,
but does not review or approve such data as part of a new or amended
registration. If, after the product has been registered, EPA has reason
to review such data (for example, there are indications that the
product does not perform as claimed), then EPA will require the
registrant to submit such data within a reasonable time. A request for
submission of product performance data after product registration is
not required to be done under the Data Call-In provisions of FIFRA
section 3(c)(2)(B), but is instead authorized by regulation.
Accordingly, if an antimicrobial product makes a claim to control
microorganisms that pose a threat to human health, the applicant is
then required to submit product performance data to support its
registration. The types of product performance data required by the
Agency to support registration of an antimicrobial are determined by
the types of claims made on the product's label (e.g., sanitizer,
disinfectant) and the intended use site for the product (e.g., hard
surface, fabric).
VII. Human Health Risk Assessment
The data needed to conduct a human health risk assessment include
both toxicology and exposure data. Toxicology studies are used to
assess hazards of pesticides to humans and domestic animals, and
include a variety of acute, subchronic, and chronic toxicity studies;
developmental/reproductive tests; and tests to assess mutagenicity and
pesticide metabolism. To assess human health risk, there must be
sufficient information to select the appropriate doses and end-points,
i.e., the Agency must know the level of exposure at which an adverse
effect is observed. This requires a toxicological database that is not
only complete in the endpoints it covers, but is also of acceptable
quality. The duration of the toxicity study approximates the estimated
duration of the human exposure, while considering species differences
in maturational milestones and overall life span. The toxicology data
requirements are discussed in Unit VIII of this preamble.
For EPA to assess the potential risks that antimicrobial products
pose to humans, it is necessary not only to assess the hazard of the
antimicrobial active ingredient based on toxicology information, but
also to estimate human exposures to the antimicrobial based on the
product use patterns. For antimicrobials, three types of exposure data
are required: applicator, post-application, and residue chemistry
(which includes exposure via food and water).
Applicator and post-application exposure data are used to evaluate
exposures to persons in occupational and non-occupational settings,
including residential, commercial, institutional, and recreational
sites. Exposure data include: dermal and inhalation exposure data for
applicators, post-application residue data, post-application monitoring
data, use information, and human activity information. Applicator and
post-application data requirements are discussed in Unit IX of this
preamble.
Residue chemistry information is used to establish tolerances for
residues of pesticide chemicals (and any metabolites of concern) in/on
food crops, processed foods, and animal products consumed by humans
when the animal consumes a feed item derived from these crops. The
Agency estimates the dietary exposure of the general population and
various population subgroups to pesticide residues in food by using the
residue data as inputs to the dietary modeling. The dietary exposure is
then used in conjunction with toxicity data to determine risk. Residue
chemistry data requirements are discussed in Unit X.
VIII. Toxicology Data Requirements
A. Toxicology Data Requirements for Antimicrobials
EPA proposes to adapt the basic toxicology data types as listed in
subpart F of current part 158 to support applications for antimicrobial
products. However, EPA also proposes to modify the applicability of
those requirements to reflect the differing risks of and levels of
exposure to antimicrobials.
As with conventional pesticides, the types of toxicology studies
required for antimicrobials can include acute, subchronic, and chronic
toxicity studies, as well as carcinogenicity, prenatal developmental
toxicity, reproductive toxicity, mutagenicity, neurotoxicity,
immunotoxicity, and other studies.
[[Page 59392]]
1. Acute toxicity studies provide information that serves as a
basis for classification and precautionary labeling and the need for
child resistant packaging.
2. Subchronic toxicity studies provide information that can be used
to assess human health hazards that may result from repeated exposures
to a pesticide over a limited period of time. These data also provide
information for selecting proper dose levels for chronic/
carcinogenicity studies.
3. Chronic toxicity studies are used to assess potential hazards
resulting from prolonged and repeated exposures to a pesticide over a
significant portion of the life span.
4. Prenatal developmental toxicity studies are designed to assess
the potential of a pesticide to induce effects in offspring as the
result of exposure of the mother during pregnancy.
5. Multigeneration reproduction studies are designed to provide
information concerning the general effects of a pesticide on overall
reproductive capability.
6. Mutagenicity studies assess the ability of the pesticide to
interact directly or indirectly with cellular DNA, RNA, proteins, or
chromosomes and the potential for adverse effects on cellular genetic
material.
7. Neurotoxicity studies evaluate the potential of the pesticide to
adversely affect the structure and functions of the nervous system.
8. Immunotoxicity studies evaluate the potential of the pesticide
to adversely impact the immune system.
9. Metabolism studies evaluate the absorption, distribution,
biotransformation, and excretion of the pesticide.
B. The History of Toxicology Requirements for Antimicrobials
By 1984, the Agency had reconsidered its toxicology data
requirements for all pesticides, including antimicrobials. For
instance, it had become clear that exposure to antimicrobial pesticides
might well be long-term and frequent since many antimicrobials were
used indoors in close proximity to humans. Occupational users often
were exposed to concentrated antimicrobial products while mixing and
diluting the product for use, and might be exposed to an antimicrobial
pesticide for large portions of their working lifetimes. In response to
the reregistration program initiated under the 1988 amendments to
FIFRA, EPA concluded that additional data were needed to properly
evaluate the potential hazards associated with antimicrobial
pesticides. Consequently, the Agency began to require more toxicity
data for antimicrobials. In 1987, based on its evolving understanding
of antimicrobial uses, the Agency issued an Antimicrobial Toxicology
Data Call-In (DCI) Notice (52 FR 595, January 7, 1987) (Ref. 24), which
specified a tiered approach for submission of toxicology and human
exposure data.
The 1987 Antimicrobial Toxicology DCI divided antimicrobial
pesticides into three exposure categories: low, medium, and high. The
toxicology data required was tiered according the amount of exposure.
The first tier toxicology data requirements (low exposure) were the
standard acute studies, a 90-day dermal or inhalation study, a prenatal
developmental toxicity study in one species, and a battery of
mutagenicity studies. The second tier (medium exposure) included the
first-tier toxicology studies and a subchronic feeding study, a
prenatal developmental study in a second species, and a dermal
absorption study. The third tier (high exposure) included the first-
and second-tier studies and the chronic feeding, carcinogenicity,
reproduction, and metabolism studies. All food-use antimicrobials were
considered high exposure.
Applicants could fulfill the toxicology data requirements by
submitting the appropriate toxicity studies or by submitting a
combination of toxicity studies and exposure data. The Agency used the
exposure data and submitted toxicology data to determine whether and
which additional toxicology studies were needed to assess the hazard of
the antimicrobial.
In proposing part 158, subpart W, the Agency is specifying the
toxicology data requirements it believes are appropriate for specific
antimicrobial use categories, drawing upon EPA's experience since 1987.
EPA is now proposing two groupings: Low- and high-exposure. In
practice, the submission, review, and evaluation of toxicity data
merged the low- and medium-exposure categories. Therefore, the low- and
medium-exposure categories from the 1987 DCI were combined to create
what is today the low exposure category.
Today's proposed approach conceptually follows the tiering approach
used in 1987. Generally, data requirements proceed in a tiered manner
from simpler to more complex studies considering the frequency,
duration, and magnitude of exposure as well as the dermal absorption of
the pesticide. Knowledge gained from results of assessments performed
using these lower tiered studies is used to indicate if any higher
tiered studies are required. The Agency does not prescribe a required
sequence of toxicological testing. There are many factors that could
affect the testing progression. Rather, decisions regarding the
sequence in which the tests are conducted are left up to the applicant.
Thus, the applicant has flexibility to determine the sequence of
testing, as best suited for their particular chemical. Early
consultation with the Agency is recommended to attain a common
understanding of the sequencing that should be used.
C. Groupings for Antimicrobial Toxicology Data Requirements
1. Overview. This proposal divides the antimicrobial uses into two
groups, high human exposure and low human exposure uses. Because high
human exposure uses may pose higher risks, more toxicology studies are
required than for uses with less exposure. For the purpose of
determining toxicology data requirements, high human exposure is
defined as that resulting in human exposures over a considerable
portion of the human lifespan. Exposure to food and water, which occurs
throughout the human life span, is therefore a high human exposure. For
other exposures such as occupational and residential, the Agency has
considered the frequency, duration, or magnitude of the exposure to
determine in its best professional judgment if the exposure is high.
One or a combination of these parameters led the Agency to make the
determination that the exposure is high. As an example, swimmers may
swim daily or weekly, from several minutes to several hours with almost
their entire body in the water. There are workers who manually pour
concentrates into vessels for mixing (with water or other chemicals) in
order to prepare dilute solutions for use. Such exposures can occur
daily, weekly, monthly, or episodically as dictated by the
circumstances of the job. Particularly in the absence of personal
protective equipment, these workers have the potential for high dermal
and inhalation exposures. Accordingly, for the purposes of defining
data requirements, EPA proposes to categorize food and feed uses and
certain nonfood-uses as high human exposure.
As discussed, the Agency considers high human exposure uses to be
those that could result in pesticide residues occurring in food or
feed, or in drinking water. These would include, but are not limited
to:
Human or animal drinking water.
Fruit and vegetable rinses.
Egg washes.
Outdoor aquatic uses in lakes, rivers, or streams which
have the potential to contaminate potable water.
[[Page 59393]]
Indirect food uses with residues equal to or greater than
200 parts per billion (ppb).
Any use that 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).
EPA also considers high human exposure uses to be those uses that
could result in high exposure to applicators, and any other
antimicrobial uses which could result in high exposure to humans. These
would include but are not limited to:
Wood preservatives.
Metal cutting (metalworking) fluids.
Swimming pools.
This list is not exhaustive. There may be other uses that the
Agency would consider high human exposure uses based on their potential
for human exposure. Low human exposure uses are defined as those that
are not high human exposure uses.
The Agency is proposing an approach that might allow an applicant
for registration of a pesticide with low human exposure uses to
generate fewer studies in total than would be required for high human
exposure uses. Under this proposal, applicants with low human exposure
antimicrobials may perform tests in a tiered fashion. As previously
explained, for toxicology studies the high human exposure grouping
specifies 19 toxicology studies as required, and for the low human
exposure grouping, 13 toxicology studies as required. After the 13
required studies for low human exposure are reviewed by the Agency,
additional testing may be required for low-exposure uses based on the
result(s) of the lower-tiered studies. These 13 studies could indicate
a low risk potential or could trigger the need for additional data.
The table in proposed Sec. 158.2230 presents the toxicology data
requirements. The proposed toxicology data requirements for the two
groupings (high human exposure and low human exposure) are separated
into two columns showing test by test whether it is typically required
(shown as R) or conditionally required (shown as CR).
The Agency recognizes that toxicology testing can represent a large
burden on applicants and can involve significant animal testing.
Consequently, the Agency works with applicants, the scientific
community, and other stakeholders to ensure that data requirements
produce the information needed to enable the Agency to make the safety
findings required under FIFRA and FFDCA. The tiering process proposed
within the toxicology data requirements requires fewer studies for
lower exposures. The Agency also works to design study protocols that
minimize the development burden and limit uses of test animals.
Toxicity testing requirements may be satisfied in a combined study,
such as combining the prenatal developmental and reproductive toxicity
testing requirements in a single study. However, if this option is
chosen, the protocol must be approved by the Agency prior to the
initiation of the study. Details for developing protocols are available
from the Agency.
2. Data requirements for high human exposure uses. For high human
exposure uses, EPA is proposing to require the following studies: Acute
oral, dermal, and inhalation toxicity; primary eye and dermal
irritation; dermal sensitization; subchronic studies in two species;
mutagenicity studies; acute and subchronic neurotoxicity testing;
prenatal developmental toxicity studies in two species; a two-
generation reproduction study; a chronic feeding study in one species;
carcinogenicity studies in two species; a mammalian metabolism study;
and an immunotoxicity study. Based on a weight-of-evidence evaluation,
a developmental neurotoxicity study may be required. If the Agency
determines, based on use information that dermal exposure is the major
route of exposure, then EPA may require dermal absorption testing or
toxicological studies conducted by the dermal route.
i. Wood preservatives. For wood preservatives, the Agency may
require toxicity data on both the active ingredient which is
incorporated into the wood and on transformation/degradation products
which occur in wood post-treatment. Such transformation/degradation
products would include dislodgeable residues (i.e., residues that occur
from hand contact with treated wood) or leachate residues (i.e.,
residues that occur in soil or water in contact with treated wood).
ii. Metal working fluids (MWFs). While both ``open'' and ``closed''
MWF systems are high human exposure uses, under the appropriate
circumstances, the Agency distinguishes between ``open'' and ``closed''
systems. Fewer toxicity data may be required for a ``closed'' system.
If the use of the MWF is limited to ``closed'' systems only, the
applicant clearly identifies the use as such, and the Agency agrees,
then fewer toxicity studies would be required for that ``closed''
system. Based upon review and evaluation of the submitted toxicity
studies and exposure data, EPA may determine that fewer additional
toxicity studies than would generally be submitted are required. Upon
request the Agency will provide written guidance concerning exposure,
toxicity, and other data requirements for ``open'' and ``closed'' MWF
systems.
3. Data requirements for low human exposure uses. As previously
discussed, the Agency proposes to apply a tiered system to toxicology
testing requirements for low human exposure antimicrobials. The
required data are: Acute oral, dermal, and inhalation toxicity; primary
eye and dermal irritation; dermal sensitization; a subchronic toxicity
study in the rodent; prenatal developmental toxicity studies in two
species; a two-generation reproduction study; mutagenicity studies; and
immunotoxicity testing.
Based on the review of these studies, additional studies may be
required if there is evidence of significant toxicity in the submitted
studies. Evidence that could trigger concerns may include data
indicating neurotoxicity, immunotoxicity, developmental, reproductive,
or other systemic toxicity such as the presence of neoplastic growth or
significant target organ toxicity. In such cases, appropriate studies
to address the Agency's hazard or risk concern would be required. The
table in proposed Sec. 158.2230 contains test notes that explain how
these toxicology requirements are proposed to be applied to low human
exposure antimicrobials.
4. Data requirements for indirect food uses. For the purpose of
determining toxicology data requirements, an antimicrobial use is
considered an indirect food use when the antimicrobial pesticide is
applied to a surface or incorporated into a material that may contact
food, but is not applied directly to food. Residues of the pesticide or
its degradates can be transferred to the food when it comes into
contact with these treated surfaces and articles. Examples of
antimicrobial uses which may result in residues in food, through normal
use, are sanitizers and disinfectants, which may be used in food-
handling areas, but not directly applied to the food.
With the passage of the Food Quality Protection Act of 1996 (FQPA),
as later modified by the Antimicrobial Regulation Technical Corrections
Act of 1998 (ARTCA), EPA currently has the responsibility for
establishing tolerances or tolerance exemptions for all pesticide uses
that result in residues in or on food, except for:
Residues that result from the use of antimicrobial
substances on food or in water that comes into contact with food, if
such substances are used where food
[[Page 59394]]
is prepared, packed, or held for commercial purposes. (For raw food
commodities, this exclusion does not apply if the antimicrobial is
applied in a facility where only such foods are treated and the
treatment of the foods does not constitute food processing.)
Antimicrobial substances used as food contact substances
in or on food, such as those used in the manufacture of food contact
packaging. This exclusion does not apply to objects impregnated with a
food contact substance (other than food packaging material) if the
inclusion of the substance is intended to have an antimicrobial effect
on the food contact surface of the object.
FDA has the responsibility for regulating these antimicrobial
substances as food additives under section 409 of the FFDCA. However,
under the provisions of FIFRA section 2(bb) prior to registration of a
pesticide that may result in residues of that pesticide in or on food
(including sanitizers, disinfectants, and slimicides), EPA must make a
safety finding that the pesticide residue meets the standard set forth
in section 408 of FFDCA. This applies even if FDA will establish a food
additive regulation for the use of the antimicrobial substance under
section 409 of the FFDCA.
Since publication in 2002 of its final guidance for toxicology
recommendations for food contact substances, FDA has used an approach
with several tiers: residues less than 0.5 ppb, between 0.5 and 50 ppb,
between 50 ppb and 1,000 ppb, and greater than 1,000 ppb. EPA
recognizes the historic usefulness of the FDA's tiered approach and
proposes to adopt it conceptually, but with a modification appropriate
to antimicrobials (biocides). FDA's guidance (Ref. 8) specifically
recommends that a factor of 5 be used to account for the toxicity of
biocides. Further modifications to this approach are needed for EPA to
perform an assessment of risk that conforms to the FFDCA section 408
safety finding which now requires consideration of the ``... special
susceptibility of infants and children to the pesticide chemical
residues....''. Thus, additional studies are needed even for the lower
exposures for which FDA historically would not have required data.
Accordingly, EPA proposes to classify indirect food uses of
antimicrobials which result in residues in or on food of less than 200
ppb as low human exposure uses for purposes of subpart W. Given FDA's
historical experience with biocides, EPA believes that the 200 ppb
(1,000 ppb divided by 5) benchmark is a reasonable delineation between
high and low human exposures. Antimicrobials used in a manner which
results in residues in food from an indirect use that are equal to or
greater than 200 ppb would be considered high exposure uses. The Agency
specifically requests comment on the use of 200 ppb residues in food as
the differentiation between the high and low human exposure for the
purposes of subpart W.
For indirect food uses, the applicant should begin the process by
collecting all available information. Since many indirect food uses
were previously evaluated by FDA, there may be a petition that was
submitted to FDA. For some chemicals, toxicity testing may have been
conducted and reviewed in the open literature. After identifying the
available reliable information, the applicant should compare this
information to the data requirements in the appropriate column in the
table in Sec. 158.2230. If the applicant believes that an existing
study satisfies the data requirement, then this should be discussed
with EPA.
The applicant is also encouraged to review the approach discussed
in Unit XVIII.A. of this preamble on the use of Structure-Activity-
Relationship (SAR) assessments to ascertain if such techniques could
provide useful information in preparing a submission to EPA.
D. Acute Toxicity Studies for End-Use Products
EPA proposes to add a test note to clarify that the currently
required six acute toxicity studies are to be conducted on the product
as formulated for sale and distribution. These six acute studies may
also be needed for the product as diluted for use. Many antimicrobial
products are diluted at the point of use, but can still lead to
significant exposure. The applicant has the option of also conducting
certain studies using the highest diluted concentration (i.e., the
least diluted product) permitted by the labeling. This test note
codifies EPA's current practices. Consultation with the Agency is
highly suggested to assure that the appropriate product and any
appropriate dilutions are tested.
E. Neurotoxicity
EPA promulgated toxicity requirements for conventional pesticide
chemicals, in which the data requirements for neurotoxicity were
revised. The former test battery of three studies was revised to
include only two studies. The rationale for those revisions was
discussed in Unit XI of that proposed rule (March 11, 2005) (70 FR
12276), and in the final rule preamble (October 26, 2007) (72 FR
60934). That rationale is also applicable to antimicrobial pesticide
chemicals.
EPA proposes to adopt the current conventional pesticide data
requirements for neurotoxicity testing to antimicrobials. Adopting the
battery of two neurotoxicity studies would codify the Agency's current
practices.
The current adult neurotoxicity test battery for antimicrobials in
part 161 consists of three studies: Acute delayed neurotoxicity (hen),
90-day neurotoxicity (hen), and 90-day neurotoxicity (mammal). The
mammal subchronic neurotoxicity study is required if the acute oral,
dermal, or inhalation toxicity studies show neurotoxicity or
neuropathy. The existing required data are inadequate for evaluating
neurotoxic effects of some chemicals.
The proposed battery of two studies in the rat is more sensitive
than the neurotoxicity tests currently required in part 161. The
objective of the proposed acute and subchronic neurotoxicity battery is
to evaluate the incidence and severity of the functional and behavioral
effects, the level of motor activity, and the histopathology of the
nervous system following exposure to a pesticide chemical.
Under this proposal, an adult neurotoxicity test battery of two
studies would replace the current battery of three studies. The two
studies are an acute and a subchronic 90-day neurotoxicity study in
rats. The acute study would detect possible neurotoxic effects
resulting from a single exposure. The subchronic study would detect
possible effects resulting from repeated exposures. These studies were
presented to the FIFRA SAP in 1994, which endorsed them, and the Agency
has generally required them on a case-by-case basis since 1992 for all
pesticides, including antimicrobial pesticides.
The required parameters for a subchronic neurotoxicity study may be
incorporated into the standard 90-day subchronic feeding study in rats.
The acute and subchronic neurotoxicity studies in adult rats, in
addition to providing data on the potential for adverse neurotoxic
effects, may also provide a basis for comparing the potential for age-
related differences in impacts on the nervous system if a developmental
neurotoxicity study is triggered for the same chemical.
For high human exposure uses, EPA proposes to require both the
acute neurotoxicity and subchronic neurotoxicity studies in the rat.
For low human exposure uses, both
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neurotoxicity studies are proposed to be conditionally required (CR)
and would be triggered if there is evidence of neurotoxic effects in
the 90-day oral study in rodents or if other data show evidence of
neurotoxicity.
F. 90-Day Oral Studies
EPA proposes to adopt the current conventional pesticide data
requirements for subchronic (90-day) studies to antimicrobials. Oral
90-day toxicity studies in two species are currently required in part
161 for high human exposure uses and conditionally required in part 161
for low human exposure uses. The Agency is proposing to continue this
existing requirement for high human exposure uses in part 158, subpart
W. The Agency is proposing to require an oral 90-day study in one
species (rodent) for low human exposure uses and to conditionally
require testing in a second species (non-rodent). For low human
exposure uses, this change from two conditionally required studies to
one required and one conditionally required study would codify current
practices.
Often, range-finding studies of at least 90 days are needed to
select the appropriate dose levels for the mouse carcinogenicity study.
Thus, 90-day studies are often performed routinely by most
investigators prior to the initiation of the carcinogenicity study.
Often the range-finding studies have been submitted to the Agency for
review. Because of their utility in determining the dose levels in the
mouse carcinogenicity study, in the test notes, the Agency encourages
the use of range-finding studies in the mouse.
Additionally, all 90-day subchronic studies in the rodent can be
designed to simultaneously fulfill the requirements of the 90-day
neurotoxicity study by adding separate groups of animals for testing.
Although the subchronic guidelines include the measurement of certain
neurological endpoints, they do not meet the requirement for a 90-day
neurotoxicity study.
G. 21/28-day Dermal and 90-day Dermal Testing with End-Use Product
Currently in part 161 there is a conditional requirement for 21-day
and/or 90-day dermal toxicity studies for all use patterns. The Agency
is proposing to continue to conditionally require 21/28-day and/or 90-
day dermal toxicity studies for all antimicrobials. As determined by
the Agency, based on the use pattern, frequency of exposure, and
magnitude of exposure, the 21/28 day study may provide the appropriate
information for risk assessment purposes.
Just as with conventional pesticides, the Agency is proposing to
require subchronic dermal testing of the end-use product if the product
or any component of the product may increase dermal absorption of the
active ingredient(s) or could potentiate toxic or pharmacologic
effects. Testing of an end-use (formulated) product in either of these
studies has not been routinely required and therefore would be a new
testing requirement for antimicrobials. A test note has been added to
both of these existing data requirements to describe the triggers for
end-use product testing.
Currently, end-use products are required to be tested for acute
dermal toxicity and dermal irritation. Without additional subchronic
testing of the end-use product, risk from dermal exposure to an end-use
product may be underestimated for those products that contain an inert
ingredient that increases the dermal absorption of the active
ingredient. An example of such an inert ingredient would be dimethyl
sulfoxide.
H. 90-day Dermal and 90-day Inhalation Testing for HVAC&R Uses
Heating, ventilation, air conditioning, and refrigeration systems
(collectively referred to as HVAC&R) refer to systems which
refrigerate, exclusively air condition, or exclusively heat, as well as
those in which one system provides both heating and cooling. HVAC&R
systems are present in industrial, institutional, commercial, and
residential establishments, and include, but are not limited to: air
ducts, duct fittings, duct liners, fans, supply ducts, return ducts,
exhaust ducts, intakes, outlets, louvers, diffusers, dampers, plenums,
outdoor air intakes, air handling units, and any other ductwork and
similar components. The Agency is concerned with potential exposures
and risks from application of antimicrobial pesticide products used to
treat the surfaces of HVAC&'s system components. An example of such
treatment would be use of an antimicrobial as part of air duct
cleaning.
HVAC&R is a unique use site which must be specifically identified
on the label of the antimicrobial product. The application of an
antimicrobial product to an HVAC&R system represents a use pattern
substantially different from other hard surface disinfection or
sanitizer treatments. Application to HVAC&R systems may require that
larger volumes of the antimicrobial be applied to both internal and
external system components than would typically be used as a
disinfection/sanitizer application to a hard surface such as a desktop.
Thus, there is a greater potential for the applicator to be exposed to
large amounts of pesticide. In addition, many of the components of
HVAC&R systems are typically inaccessible and could create unique
exposure scenarios for applicators. Post-application exposure to
building occupants is also a concern. When the treated system resumes
operation, the potential exists for the pesticide to be readily spread
throughout the building.
For these reasons, the Agency is proposing to modify the
requirement for 90-day subchronic studies to address HVAC&R uses.
Specifically, the Agency is proposing to replace the 90-day oral
toxicity test with two 90-day toxicity tests, one by the dermal route,
and one by the inhalation route. These are the primary routes of
exposure from HVAC&R uses, and such route-specific studies are intended
to provide the Agency with the information needed to characterize the
hazard for the risk assessment for HVAC&R uses of antimicrobial
pesticides.
I. Chronic Studies
Currently in part 161 a chronic toxicity study in two species is
required for all food-uses and conditionally required for all other use
patterns. Today the Agency is proposing to continue this existing
requirement by requiring a chronic study in the rodent for high human
exposures and conditionally requiring the study for low human
exposures.
In its final rule for conventional pesticide chemicals, the Agency
eliminated the requirement for an oral chronic study in a second, non-
rodent species, usually the dog. Similarly, EPA is proposing to
eliminate the 1-year dog study as a data requirement for antimicrobial
pesticides. EPA's reasoning is fully explained in the final rule (Unit
X) for conventional pesticides (Refs. 36, 37, and 38). For
antimicrobials EPA would adopt the same criteria (as set out in the
applicable test note to the table in proposed Sec. 158.2230) for the
rare circumstances when a 1-year dog study might be required.
J. Carcinogenicity Studies
Currently in part 161 two carcinogenicity studies are required for
all food-uses and conditionally required for all other use patterns.
Today the Agency is proposing to continue this existing requirement by
requiring carcinogenicity studies in two species for high human
exposures and conditionally requiring the studies for low human
exposures.
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K. Prenatal Developmental Toxicity
The Agency proposes to require two oral prenatal developmental
toxicity studies (one in rodents and one in a non-rodent species) to
support the registration of every antimicrobial pesticide product. This
not only codifies the Agency's current practices, but also harmonizes
the requirements for antimicrobials with those of conventional
pesticides.
The Agency encourages applicants for registration to consider the
use of combined study protocols in satisfying this requirement. A
prenatal developmental toxicity study segment could be added to a two-
generation reproduction study in rodents. By combining protocols, a
single study could satisfy the requirement for both prenatal
developmental and reproductive toxicity in the rodent. While it is
recognized that the cost of the reproduction study would increase
somewhat due to the additional work scope, the total cost of the
combined study would be substantially less than that incurred by
conducting the two studies separately. Moreover, a combined
reproduction/developmental protocol should not require the use of
additional animals and would increase the efficient utilization of the
animals being studied. The second required prenatal developmental
toxicity study in the non-rodent would then be performed separately.
The Agency may require an additional prenatal developmental study
by another route of exposure (usually dermal) if there is evidence of
developmental toxicity in any of the available studies and the other
route of exposure is, in the Agency's judgment, a significant route of
exposure (Refs. 3, 18, and 35). Submission of such a study is an
infrequent occurrence: only one dermal prenatal developmental toxicity
study has been submitted for an antimicrobial.
L. Reproduction
The Agency proposes to require a reproductive toxicity study to
support the registration of every antimicrobial pesticide product. This
codifies the Agency's current practices.
For many years, for nonfood-uses, the Agency did not require a
reproductive toxicity study for low human exposure antimicrobials.
However, in 1997, it was suggested that, without a reproductive
toxicity study, the Agency could be missing reproductive risks of
concern. For example, the Pest Management Regulatory Agency (PMRA) of
Canada, presented the results of a retrospective analysis during the
public comment portion of the FIFRA SAP in June 1997 (Ref. 13).
Although the SAP did not comment on this analysis, the Agency
determined that a reproductive toxicity study would ensure that it did
not miss potential reproductive risks of concern.
In making the safety finding under FFDCA, the Agency is required to
consider the special susceptibility/sensitivity of infants and children
to pesticide chemical residues. EPA cannot adequately characterize the
susceptibility of infants and children without a reproduction and
fertility effects study that assesses the occurrence of biologically
adverse effects on the male and female reproductive system, as well as
on the developing organisms from exposure prior to conception (either
parent), during prenatal development, or post-natally in the offspring
up to the time of sexual maturation. Thus, to make the safety finding
requires reproduction testing, since reproductive toxicity testing
endpoints are not adequately assessed in the other required toxicity
studies. Therefore, these other studies do not provide adequate
``triggers'' which would indicate the potential for reproductive
toxicity.
Today's proposal harmonizes the requirements for antimicrobials
with those of conventional pesticides. EPA has been requiring a
reproductive toxicity study for all antimicrobials for the last several
years.
As noted in Unit VIII.K. of this preamble, the prenatal
developmental and reproductive toxicity testing requirements may be
combined in a single study. If the applicant does not choose this
option, then separate developmental and reproductive toxicity studies
must be conducted.
M. Developmental Neurotoxicity (DNT)
In practice, EPA evaluates each pesticide using all available
toxicological information that might indicate a need for a
developmental neurotoxicity study. The DNT study has been required on a
case-by-case basis for certain conventional chemicals for food-use and
nonfood-use registrations since 1991.
Just as with conventional pesticide chemicals, the Agency is now
proposing that DNT testing be conditionally required for all
antimicrobial pesticides. This would be a new requirement for
antimicrobial pesticides. The study is triggered based upon a weight-
of-evidence evaluation of the toxicological database. The criteria
involved in this weight-of-evidence evaluation are the same as those
for conventional pesticide chemicals and are presented below:
1. The antimicrobial pesticide causes treatment-related
neurological effects in adult animal studies, such as:
Clinical signs of neurotoxicity.
Neuropathology.
Functional or behavioral effects.
2. The antimicrobial pesticide causes treatment-related
neurological effects in developing animals, following pre- or post-
natal exposure such as:
Nervous system malformations or neuropathy.
Brain weight changes in offspring.
Functional or behavioral changes in the offspring.
3. The antimicrobial pesticide elicits a causative association
between exposures and adverse neurological effects in human
epidemiological studies.
4. The antimicrobial pesticide evokes a mechanism that is
associated with adverse effects on the development of the nervous
system, such as:
SAR relationship to known neurotoxicants.
Altered neuroreceptor or neurotransmitter responses.
EPA proposes the addition of the developmental neurotoxicity study
to the toxicology testing requirements as a conditional requirement.
The two required developmental toxicity studies do not include an in-
depth assessment of the development of the nervous system and therefore
do not provide the same information as the DNT. In implementing this
conditional requirement, applicants are encouraged to apply what is
known about the chemical and its toxicity to develop a rational,
science-based approach to this testing.
N. Mutagenicity
Mutagenicity testing is required in part 161; however, just as with
conventional pesticide chemicals, the Agency is proposing to change the
specific types of tests to be performed to satisfy the mutagenicity
testing requirement (Refs. 4 and 26). A battery of mutagenicity tests
is currently required in part 161 to assess the potential of the test
chemical to adversely affect the genetic material in the cell and
subsequently serve as part of the Agency's weight-of-evidence approach
for classifying potential human carcinogens. Mutagenicity data are also
used to evaluate potential heritable effects in humans. Mutagenicity
testing would no longer be subdivided into the categories of gene
mutation, structural chromosomal aberrations, and other genotoxic
effects, with selection from a wide range of mutagenicity tests
satisfying these categories.
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For conventional pesticides, the Agency requires in Sec. 158.500
an initial battery for mutagenicity testing that consists of a
bacterial reverse mutation assay with Salmonella typhimurium and
Escherichia coli, an assay with mammalian cells in culture, and an in
vivo cytogenetics assay. The Agency has selected the bacterial assay
because it is a primary test for detecting intrinsic mutagenicity of
many classes of biologically active chemicals. The genetics of each
test strain of Salmonella and select strains of E. coli have been well-
validated, and the assay is easy to perform, is used routinely
throughout the world, and has an extensive data base of tested
chemicals. The mammalian cells in culture assay will detect a wider
spectrum of possible genetic endpoints not assayed in the bacterial
test. The in vivo cytogenetics assay provides an important examination
of the potential effect a test compound may have on an intact mammalian
system. Data from this study provide information on in vivo metabolism,
repair capabilities, pharmacokinetic factors (e.g., biological half-
life, absorption, distribution, excretion) and target organ/tissue
effects.
EPA is proposing to modify the requirement for a bacterial reverse
mutation assay conducted with Salmonella typhimurium and Escherichia
coli. For antimicrobials, it is not always practical to test
antimicrobials for mutagenicity in bacterial test systems such as the
bacterial reverse mutation assay. Most antimicrobial pesticides are
toxic to bacteria, and therefore can only be tested at very low doses
in bacterial assays. This means that, for antimicrobials, negative
results in studies done in bacterial test systems do not necessarily
demonstrate non-mutagenicity. Given this limitation of bacterial
reverse mutation assays such as the Ames test, EPA must carefully
review Ames studies conducted using antimicrobials. Cytotoxicity and
the test levels used in the study are critical factors to consider when
determining if the results of an Ames test is acceptable or not, that
is, whether the test fulfills the data requirement. However, the Agency
has previously accepted Ames tests for antimicrobials after review and
evaluation indicates the validity of the results. If the results of the
Ames tests are not valid, then the applicant would need to discuss
other mutagenicity testing with the Agency, such as a forward mutation
assay conducted using mouse lymphoma L5178Y cells. The test notes to
the proposed mutagenicity requirements have been modified accordingly.
Since there are many different mutagenicity tests available besides
those in the initial battery, other types of testing may have been
performed in the course of product research and development. In
addition to the initial battery, data from such mutagenicity tests must
be submitted to the Agency, along with a reference list of all studies
and papers known to the applicant concerning the mutagenicity of the
test chemical. Having this information at the beginning of a
mutagenicity assessment will greatly facilitate EPA's effort to provide
a more accurate assessment of the mutagenicity of the antimicrobial
pesticide in question.
O. Immunotoxicity
Just as with conventional pesticide chemicals, the Agency proposes
to require immunotoxicity testing for all antimicrobial pesticides.
This would be a new data requirement. Immunotoxicity testing is
necessary to evaluate the potential of a chemical to produce adverse
effects on the immune system. Immune system suppression has been
associated with increased incidences of infections and neoplasia
(abnormal and uncontrolled cell growth). In 1993, the National Research
Council reviewed the technical literature and found that some
pesticides are immunosuppressive (Ref. 19).
Because the immune system is highly complex, studies not
specifically conducted to assess immunotoxic function are inadequate to
characterize a pesticide's potential immunotoxicity, even if some
tissues subject to immunotoxic insult are examined. While data from
hematology, lymphoid organ weights, and histopathology of routine
chronic or subchronic toxicity studies may offer useful information on
potential immunotoxic effects, these endpoints alone are insufficient
to predict effects on immunotoxic function (Refs. 15 and 16).
Therefore, the Agency is proposing to require functional immunotoxicity
testing along with the data from immunotoxicity endpoints in other
studies to predict the potential risk of pesticides on the immune
system more accurately.
P. Metabolism and Pharmacokinetics
Currently in part 161 a metabolism study is required for all food-
uses and conditionally required for all other use patterns. Today the
Agency is proposing to continue this existing requirement by requiring
a metabolism and pharmacokinetics study for high human exposures and
conditionally requiring the study for low human exposures.
Q. Companion Animal Safety
Currently in part 161 a domestic animal safety study is
conditionally required. According to the test note in Sec. 161.340
this study would be required on a case-by-case basis. Today the Agency
is proposing to continue this existing requirement by conditionally
requiring the study for all antimicrobial use patterns. The test note
specifies that the study would be triggered if the product's use would
result in exposure to domestic animals.
R. Dermal Penetration
Currently in part 161 a dermal penetration study is conditionally
required for all antimicrobial use patterns. Today the Agency is
proposing to continue this existing requirement by conditionally
requiring a dermal penetration study for all antimicrobial use
patterns.
IX. Handler and Post-Application Exposure Data Requirements
A. General
Exposure data are used in the evaluation of the exposures to
persons in occupational and non-occupational settings (Sec. 158.2260
and Sec. 158.2270). For antimicrobials this includes residential,
commercial and industrial, institutional, agricultural premises, and
recreational sites. Data include dermal, inhalation, and non-dietary
oral exposures.
Most past exposure research with antimicrobial products has studied
either handler exposure (i.e., exposure of people who mix, load, or
apply antimicrobial pesticides in the course of the application process
or through other work-related tasks) or post-application exposure of
people to residues of antimicrobial pesticides after application, in
treated areas or on treated surfaces.
Handler exposure research may measure exposure to undiluted
antimicrobial products as the products are mixed for application, or it
may measure exposure to antimicrobial products diluted for use.
Antimicrobial pesticide applicators may be industrial or other workers,
professional applicators, or consumers using the product in or around
their homes.
EPA considers handler exposure data essential for fulfilling its
mandate to protect human health from pesticide risk, including
aggregate and cumulative risk, and is therefore proposing to require
handler exposure studies for all antimicrobial products, when the
toxicity and exposure criteria are
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triggered. Codifying this requirement would assist applicants for
registration of antimicrobial pesticides to determine which studies are
required and then to design and conduct acceptable studies measuring
handler exposure.
Post-application exposure research measures exposures of people to
residues of antimicrobial pesticides after their use or application,
and thus does not involve the direct exposure that occurs during use.
Of particular concern to EPA is the potential exposure of infants and
children to post-application residues of products used in and around
homes, daycare centers, or schools.
The data requirements proposed here are based on the Agency's
current practice of requiring exposure data when certain toxicity and
exposure criteria are met. These criteria are described in proposed
Sec. 158.2260 and Sec. 158.2270. Today's proposal seeks to harmonize
the exposure requirements for antimicrobials with those of conventional
pesticides. The applicator (handler) exposure data requirements are the
same as those codified for conventional pesticides. The post-
application data requirements are the same as conventionals, with the
exception of one study (Dislodgeable Foliar Residue and Turf
Transferable Residues) that is not needed for antimicrobials.
The proposed requirement of such data for antimicrobial products
when the toxicity and exposure criteria are triggered would allow the
Agency to conduct more thorough exposure assessments for residential as
well as occupational sites, and to cover all use and exposure scenarios
for such sites. EPA presented the need for additional handler exposure
data to the SAP in January 2007 (Ref. 39) and to the Human Studies
Review Board (HSRB) in April 2007 (Ref. 40). Both groups agreed that
additional data are warranted.
Research undertaken to address the proposed handler and post-
application data requirements may involve intentional exposure of human
subjects as those terms are defined in EPA's rules at 40 CFR 26.1102,
and if they do, protocols and supporting documentation as specified in
that rule must be submitted for review by EPA and the HSRB before any
subjects are enrolled in the research. If research involving
intentional exposure of human subjects is initiated without EPA's prior
review, the resulting data will not be accepted in support of
registration. Parties who are unsure whether proposed research involves
intentional exposure are encouraged to consult with EPA before
proceeding with the research.
B. Use of Surrogate Data
To support registration of an antimicrobial pesticide product,
according to the proposed tables in Sec. 158.2260 and Sec. 158.2270,
applicants would generate needed exposure data with a typical end-use
product. However, the Agency recognizes the need to minimize the
economic burden of generating data to meet human exposure data
requirements while obtaining sufficient data and information for
exposure and risk assessments. Whenever appropriate, surrogate data may
be used for the assessment of antimicrobial pesticides. The Agency is
currently working with several industry Task Forces that are generating
exposure monitoring data that may be able to be used as surrogate data
sources. The Antimicrobial Exposure Assessment Task Force (AEATF-II) is
developing handler exposure data for antimicrobial applications (such
as mopping, wiping, aerosol sprays, painting, etc.). Task Force members
can consider using this surrogate data, if determined by the Agency to
be suitable, to assess antimicrobial handler risk instead of generating
their own data. If surrogate data are inadequate for the Agency to
adequately predict likely exposures and the resultant risks, then
applicants would need to submit chemical-specific and/or product-
specific data.
C. Handler Exposure
The Agency proposes to require data addressing handler exposure for
antimicrobials when the toxicity and exposure criteria are triggered.
As discussed in Unit IX.A., this not only codifies the Agency's current
practices, but also harmonizes the requirements for antimicrobials with
those of conventional pesticides. EPA now proposes to codify these
requirements in proposed Sec. 158.2260 and set out explicitly in Sec.
158.2260(b) the triggers describing the circumstances under which such
data must be submitted.
For handler exposure, the proposed data requirements are as
follows:
1. Dermal exposure studies. EPA proposes to require data for both
outdoor and indoor dermal exposures to estimate the dermal exposure to
persons directly handling pesticides. The number of exposure studies
that may be required depends on the variety of use sites, their
similarities, and whether the uses are indoor or outdoor. In the
absence of surrogate data, generally, the selection of the appropriate
testing site(s) is based on the exposure sites with the highest
potential for exposure. Generally, this is determined based on the
label uses and use rates. Consultation with the Agency is recommended
for determining the appropriate use site(s) for testing. Studies of
dermal exposure are often designed to |
