RESPONSE TO COMMENTS to

Part 158 Rule Proposed March 11, 2005

Docket ID:  OPP-2004-0387

SUMMARY:

EPA proposed to limit the applicability of revised part 158 to
conventional chemicals, in anticipation of additional revisions tailored
to biochemical, microbial and antimicrobial pesticides.   EPA is
promulgating a final rule establishing data requirements for biochemical
and microbial pesticides at the same time it is promulgating a final
rule establishing data requirements for conventional pesticides.
However, EPA has not yet issued a proposed rule that would create
separate data requirements tailored to antimicrobial pesticides.

If EPA were to maintain the proposed rule’s exclusive application to
conventional pesticides, the result would be that there would be no data
requirements established by regulation for antimicrobial pesticides.
Registrants of antimicrobial pesticides would have to rely solely on
consultations with EPA to determine the data requirements for their
products without the benefit of regulatory data requirements.  However,
EPA has decided to preserve the current data requirements to provide
regulatory coverage for antimicrobial pesticides until the Agency can
propose and promulgate a final regulation.  To accomplish this, EPA has
transferred intact the current data requirements of part 158 into a new
part 161, entitled “Data Requirements for Antimicrobial Pesticides.”
 New part 161 will only apply to antimicrobial pesticides.  Part 158 as
promulgated will only apply to conventional pesticides.  EPA received no
key comments concerning the proposed limited applicability of part 158,
and accordingly, EPA is adopting its proposal.

	Comments that would be of wide interest were considered key and
summarized in the preamble.  Comments that were tangential or of
marginal interest were not considered key and therefore not summarized
in the preamble; instead, these were addressed in the Response to
Comments document.  In many areas of the preamble, readers were reminded
to access the Response to Comments document for a more complete view of
comments and responses.

	A commenter is identified by the number of his comment document in
Docket ID OPP-2004-0387.

ACRONYMS/INITIALISMS USED IN THIS DOCUMENT

ACSA		Agricultural Chemical Safety Assessment

AHETF	Agricultural Handlers Exposure Task Force

CARB		California Air Resources Board

ChEI		Cholinesterase inhibitors

CNS		Central Nervous System

CFR		Code of Federal Regulations

CR		Conditionally Required

DCI		Data Call-In

DOI		Department of Interior

DFR		Dislodgeable Foliar Residue

DNT		Developmental Neurotoxicity

EDSP		Endocrine Disruptor Screening Program

EP		End-use Product

EPA		Environmental Protection Agency

EU		European Union

EUP		Experimental Use Permit

FDA		Food and Drug Administration

FFDCA	Federal Food, Drug and Cosmetic Act

FHE		Food Handling Establishment

FIFRA		Federal Insecticide, Fungicide, and Rodenticide Act

FIFRA SAP	FIFRA Science Advisory Panel

FQPA		Food Quality Protection Act

FWS		Fish and Wildlife Service

GLP		Good Laboratory Practice

HESI		Health and Environmental Sciences Institute

HSRB	  	Human Subjects Review Board

ICCVAM	Interagency Coordinating Committee on Validation of Alternative
Methods

ILSI		International Life Sciences Institute

ILV		Independent Laboratory Validation

LOAEL	Lowest Observed Adverse Effect Level

MAD		Mutual Acceptance of Data

MBS		Market Basket Survey

MOE		Margin of Exposure

MOR		Magnitude of Residue

MP		Manufacturing Use Product

MRID		Master Record Identification

NAFTA	North American Fair Trade Act

NAS		National Academy of Sciences

NCAP		Northwest Coalition for Alternatives to Pesticides

NDTEF	Non-Dietary Exposure Task Force

NICEATM	National Toxicology Program Interagency Center for the
Evaluation of Alternative Toxicological Methods

NOAEL	No Observed Adverse Effect Level

NRC		National Research Council

NSCEP	National Center for Environmental Publications

NTIS		National Technical Information Services

OECD		Organisation for Economic Co-Operation and Development

OPP		Office of Pesticide Programs

OPPTS	Office of Prevention, Pesticides, and Toxic Substances

ORD		Office of Research and Development

ORETF	Outdoor Residential Exposure Task Force

OSHA		Occupational Safety and Health Administration

PAI		Pure Active Ingredient

PAIRA		Pure Active Ingredient Radio-labeled

PCC		Poison Control Center

PDP		USDA’s Pesticide Data Program

PHED		Pesticide Handlers Exposure Database

PMRA		Pesticide Management Regulatory Agency

PPDC		Pesticide Policy Dialogue Committee

PR		Pesticide Registration

QSAR		Quantitative Structure-Activity Relationship

R		Required

REJV		Residential Exposure Joint Venture

RfD		Reference Dose

RQ		Risk Quotient

SAP		Science Advisory Panel

SAR		Structural-activity Relationships

SOP		Standard Operating Procedures for Residential Exposures

TEP		Typical End-use Product

TGAI		Technical Grade of the Active Ingredient

TSCA		Toxic Substances Control Act

TTR		Turf Transferable Residue

UDS		Unscheduled DNA Synthesis

UV		Ultraviolet

I.	Discussion of Comments on General Provisions of Part 158 (Subpart A)

Changes to Subpart A

	EPA proposed revising subpart A by adding new material, deleting some
portions, and revising the portions that were retained or relocated.
The new material included definitions for “applicant” and
“registration,” with references to definitions in FIFRA and FFDCA
that apply to part 158.  Deletions from subpart A to eliminate
redundancy included:  timing of the imposition of data requirements;
consultation with the Agency; agricultural versus non-agricultural
pesticides; and biochemical and microbial pesticides.  The remaining
sections of the current subpart A were retained and updated or
streamlined.

B.	Format for Data Submissions

	EPA proposed minor revisions to §158.32, which describes how data are
to be formatted for submission to EPA.

COMMENT:  Commenter 48 encouraged EPA to be as flexible as possible in
revising Pesticide Registration (PR) Notice 86-5 (Standard Format for
Data Submitted Under FIFRA and Certain Provisions of FFDCA), by not
rejecting studies due to minor points of presentation.  Commenter 123
asked for regulatory language to ensure data will not be rejected for
formatting reasons.  This commenter urged the Agency to integrate the
formatting recommendations from PR Notice 86-5 with §158.32 and either
include them in 40 CFR part 158 or include them only in a PR notice.
Commenter 120 supported flexibility in determining what data are needed
but wanted the Agency to confirm its willingness to abide by agreements
made during consultation.  This commenter requested a clear set of
required or core data requirements for each use pattern & a clear set of
conditionally required data requirements

RESPONSE:	EPA made no revisions to §158.32 in the final rule. The
Agency intends to update the guidance provided in PR Notice 86-5 to help
further clarify the different elements of the submission process.  The
improved guidance, together with consultation with the Agency, should
help reduce the formatting uncertainties. Linking a set of data
requirements to each use pattern would be misleading since the
conditionalities vary depending on the product under consideration.

Confidential Business Information

FFDCA Sec. 408 information

	EPA proposed to make all information not designated as confidential
eligible for disclosure by operation of FIFRA sec. 10(d)(1), without
prior notice to the submitter.  This was a change from current
regulations, under which information not designated confidential must be
evaluated on a case-by-case basis at the time disclosure is requested.

COMMENT:  A commenter, while not disagreeing generally with the
Agency’s proposal, suggested that certain data, such as market basket
surveys and computer modeling systems, are types of data that are not
within the scope of FIFRA sec 10(d)(1), and thus should continue to be
the subject of case-by-case confidentiality determinations.

RESPONSE:  EPA disagrees that such data are not within the scope of
FIFRA sec. 10(d)(1), as they provide significant exposure information
that affects the risk assessments performed by the Agency.

COMMENT:	This same commenter read FIFRA sec 10(b) and (c) as requiring
the initial non-disclosure of all information submitted by an applicant.
 Thus, he asserted, subsequent notification to the submitter is required
to allow disclosure.

RESPONSE:  FIFRA sec. 10(b) and (c) do not provide for such broad
non-disclosure.  Non-disclosure is limited to information for which a
claim of confidentiality has been made and where the information is
eligible for confidential treatment, not to all information.

Since 1988, current regulations have required that data submitters
assert a claim of  confidentiality at the time of submission of data,
and appropriately mark the information claimed as confidential.  Absent
such a claim, this final rule would consider that no claim of
confidentiality had been made for any data submitted after May 4, 1988.
The current system of post-submission notification and case-by-case
determination is inefficient and cumbersome for the Agency, and
discourages the disclosure of information that FIFRA clearly intends to
be releasable.  EPA believes it should not be perpetuated.

Safety and efficacy information

COMMENT:	One commenter disagreed with the decision of the court in the
case of NCAP v. Browner, cited by EPA as the basis for its proposal.

RESPONSE:  EPA intends to abide by the Court’s decision, which
supports the Agency’s interpretation of FIFRA sec. 10(d).

Information pertaining to unregistered pesticides

	With respect to unregistered pesticides, EPA stated that information
relating to effects of unregistered pesticides would infrequently be
eligible for confidential treatment.

COMMENT:  Commenters were concerned that EPA’s release of such
information could give an advantage to competitors by providing leads
that would allow them to produce similar pesticides, or make marketing
decisions.

RESPONSE:  EPA acknowledges that certain information about unregistered
pesticides may be eligible for confidentiality, but continues to believe
that such instances will be infrequent, and in such cases the Agency
will prevent an unauthorized release of information.  EPA also notes
that it is required under FIFRA sec. 3(c)(4) to make public certain
information concerning new, unregistered pesticides, including identity
and proposed use patterns.

Confidentiality claims for plant-incorporated protectant information.

	There were no comments on confidentiality claims for plant-incorporated
protectant information.

Disclosure of data to multinational entities

COMMENT:  Two commenters were concerned that EPA’s proposal to release
less than complete, or summarized, information about unpublished
studies, or Agency reviews of studies, without a declaration of
non-multinational status, could allow a multi-national company the free
and wholesale use of data to their advantage.

RESPONSE:  Under FIFRA sec. 10(g), a requestor of data from EPA must
declare that he is not a multi-national corporation.  Sec. 10(g) is a
statutory provision intended to ensure that EPA data is not used to
attain marketing rights in other countries without adequate compensation
to the data-producer for use of the data.

Release to state & foreign governments with consent

	There were no comments on releasing information to state and foreign
governments with consent.

D.	Flagging Requirements

COMMENT:	Commenters 48, 120, and 124 commented on the proposed changes
to the flagging criteria.  Commenter 48 also requested clarification
when specific criteria would apply to specific studies.

RESPONSE:  All of the listed flagging criteria for a study need not
apply.  If any of the criteria listed is applicable to the study, then
the corresponding criteria number should be included in the flagging
statement submitted with the study.  In the example provided by the
commenter, the following flagging statement would be included with the
prenatal developmental toxicity study submission:

“I have applied the criteria of 40 CFR 158.34 for flagging studies for
potential adverse effects to the results of the attached study.  This
study meets or exceeds Criterion No. 5.”

COMMENT:	Commenter 120 requested an indication when a positive flagging
statement is appropriate for proposed Criterion No. 7.

RESPONSE:  Proposed Criterion No. 7 simplifies the flagging process with
respect to No Observed Adverse Effect Levels (NOAELs); no calculation or
justification is required by the registrant.  If the study NOAEL is less
than that currently used by the Agency for regulation (i.e., used to
derive the acute and/or chronic reference dose), then Criterion No. 7 is
met and the flagging statement must reflect this (by the use of
Statement No. 2).  The Agency will then evaluate the regulatory impact
of the lower NOAEL.

COMMENT:	Commenter 124 indicated the proposed revisions to flagging
criteria could significantly increase the burden to registrants.

RESPONSE:  In the preamble to the proposed rule, the Agency acknowledged
the revisions could result in more flagging of studies, thus increasing
the burden.  This was the expected result because of the new types of
toxicity studies being proposed.

	E.	Data Waivers

COMMENT:  Six commenters (119, 120, 123, 124, 125, and 133) expressed
their concerns about clarity, timelines for waiver requests, and the
organization of information.  Two commenters asked for more guidance on
when waiver requests would be considered.  Commenter 119 suggested a
transparent and clearly elucidated waiver-granting process and
recommended that EPA grant waivers only under the most stringent and
prescribed circumstances.  Commenter 120 felt that clarification of
table footnotes and use patterns would help knowing when and on what
basis waiver requests would be appropriate.

RESPONSE:  The current 40 CFR part 158 states that “Because of the
wide variety of types and use patterns of pesticides, it is impossible
to spell out all of the circumstances which might serve as a basis for
waiving data requirements.”  Although this language was not carried
over into the proposed regulatory text, EPA tried to refine data
requirements and supply test notes that might help the registrant
determine if a waiver request is in order as Commenter 120 suggested.
Applicants are encouraged to discuss the waiver request with the Agency
before developing and submitting supporting data, information, or other
materials.

Once the discussion has been conducted, waiver requests must be
submitted in writing and include:

the data requirement(s) that the applicant believes should be waived

explanation(s) and supporting rationale(s) why the data requirement(s)
should be waived

any unsuccessful attempt(s) to generate the required data

any other information to support the request

alternative means of obtaining data to address the concern(s) underlying
the data requirement(s)

The Agency will review the waiver request and inform the applicant in
writing of its decision.  The decision will include a rationale for
determination of the waiver.  The Agency may send a notice to all
registrants or publish a notice in the Federal Register announcing its
decision if the decision applies to more than the requested product.
The Agency decision to deny a waiver request is a final Agency action.

COMMENT:  Commenters 124, 125, and 133 were concerned about timelines
when waiver requests are denied; they suggested a decision be made well
in advance of application submission.  Commenter 119 also cautioned that
EPA must be diligent in assuring that the required tests be conducted by
the applicant and assessed by the Agency within a reasonable time
period.

RESPONSE: While the Agency understands the concern about timelines, it
indicated in the proposed rule that consideration of waiver requests
must be done when Agency scientists review the application.  While not
intended as a disincentive to submit such requests as perceived by two
of the three commenters, the Agency is committed to timely decisions and
notification of the applicant with anticipated timelines in mind.

COMMENT:  The proposed organization of sections under “Waivers”
preserves the numbering from current 40 CFR part 158 and Commenter 123
suggested abandoning it and grouping closely-related sections instead.
The commenter specifically proposed combining 158.30 (flexibility),
158.45 (waivers) and 158.75 (requirements for additional data) to remove
redundant material and shorten the information.  The commenter also
proposed a reference to FIFRA 3(c)(2)(E) and a definition of “minor
use” from FIFRA under “data waivers.”

RESPONSE:   The Agency proposed deleting 158.30 because it addressed
approval of registration actions and was more properly covered in part
152.  The Agency proposed to reformat the waiver process but retain its
provisions.  The Agency removed a redundant paragraph from the current
158.75 but retained the remaining paragraph.  The Agency proposed
removing redundant material as the commenter suggested but the Agency
believed that retaining the separation would be less confusing for
registrants accustomed to finding information in three separate
sections.  The Agency does not believe it is necessary to duplicate the
information from FIFRA regarding waivers for minor uses because
definitions and policies are largely covered by statutory mandates, not
regulations.

COMMENT:  Commenter 124 suggested that EPA should reinstate language
previously found in §158.101 that directed the user to the data waiver
provisions.

RESPONSE:  EPA accepts this comment and has included in the final rule
(§158.110) a reference to §158.45.   An applicant may avail himself of
the waiver provisions regardless of the designation of the study as R or
CR.

Formulators’ Exemption

	EPA chose to remove or revise provisions in part 158 that directly or
indirectly arise from the statutory formulators’ exemption of FIFRA
section 3(c)(2)(D).  First, EPA proposed to remove language in § 158.50
pertaining to the statutory formulators’ exemption.  Second, EPA
proposed removal of asterisks denoting the application of the
formulators’ exemption to product chemistry data.

COMMENT:  A number of commenters objected to the removal of
formulators’ exemption language, and others were confused by the
removal of the asterisks (which appeared in the product chemistry table
and toxicology table).

RESPONSE:  Commenters appear to have been confused by the distinction
between the array of data that the Agency must have to determine whether
a pesticide may be registered (the data requirements of part 158), and
the means by which those data requirements are satisfied (the data
citation and compensation provisions of part 152, subpart E, including
the formulators’ exemption).  In a nutshell, part 158 specifies the
“what” and part 152 specifies the “how” with respect to some
aspects of addressing data requirements. The primary purpose of part 158
is to specify the data requirements pertaining to a product.  Part 158
was never intended to serve the broader purpose of specifying the
various means though which an individual applicant can legally satisfy
the data requirements; that is the purpose of the data compensation
provisions of part 152.  Part 152 lays out all of the ways of addressing
a data requirement specified in part 158 -- submitting new data, citing
existing data, citing to public literature, obtaining a waiver, or
claiming eligibility for the formulators’ exemption.  EPA believes
that it should reinforce this distinction by removing from part 158 what
is actually incomplete information about the formulators’ exemption.

	Eligibility for the formulators’ exemption is not a function of a
data requirement; eligibility depends on the purchase of a registered
product for incorporation into another product.  The 1984 regulations
erred in attempting to apply the formulators’ exemption to specific
product chemistry and acute toxicology requirements by means of the
asterisk notation.  First, the asterisks were displayed in a misleading
fashion so that it was not clear precisely when the formulators’
exemption did or did not excuse an applicant from the requirement to
submit data.  Furthermore, the asterisks were misleading because they
conveyed the notion that the data requirement need not be satisfied.
The fact that certain data need not be submitted or cited by an
applicant eligible for the formulators’ exemption does not mean that
those data are not necessary to support the registration of his product.
 It means that the data requirement has been satisfied by another means,
usually the submission of data by the producer of the registered TGAI or
MP that the formulator purchases.

	In addition, maintaining information on the formulators’ exemption in
two locations in the Code of Federal Regulations is administratively
cumbersome.  As one commenter noted, the statute has been revised since
both of these regulations were issued, and neither § 152.85 nor

§ 158.50 are accurate or complete.  For this reason, EPA believes it
important to consolidate the formulators’ exemption language in a
single location.

	All commenters pointed out, correctly, that although EPA indicated in
the preamble that the formulators’ exemption text of § 158.50 was to
be relocated to part 152, no proposed regulatory language was included.
EPA did not include in the proposal the actual regulatory text that
would be incorporated into part 152.  In the final rule EPA has included
the revised language, which would incorporate the provisions of §
158.50 into § 152.85 with needed conforming text changes.  EPA has also
corrected § 152.85 to reflect current FIFRA section 3(c)(2)(D), as
amended in 1988.  Except where required as a result of these statutory
amendments, EPA has made no substantive change to the exemption or
EPA’s interpretation of its applicability and it was therefore not
necessary to re-propose the changes discussed in the preamble to the
proposed rule.

	Although EPA believes that the formulators’ exemption should properly
be located in part 152 together with other provisions concerning
submission or citation of data, the Agency recognizes the value of
referring to the provisions of part 152 in part 158.   Accordingly, EPA
has revised § 158.70(a), by including a new paragraph (1) which
explains that the provisions of part 158 are to be read in conjunction
with those of part 152, subpart E.

Minor Uses

	EPA proposed deleting the section on minor uses but, based on the
comments and subsequent review, the Agency retained portions of the
minor use section.

COMMENT:  Commenters 112, 120, 122, 123, 124, 125, 129, 133, and 134
expressed their concerns in various ways about the removal of current
§158.60 on minor use policy.  Five commenters recommended retaining the
section as is.  Three commenters recommended supplementing the current
information by:  adding a reference to FIFRA §3(c)2)(E) and a
definition of “minor use” from FIFRA; adding criteria regarding
minor use; codifying protections that exist outside of the regulations;
and collecting policy in one place in the regulations for Agency staff.
Commenter 112 recommended retention of §158.60(a)(2) and (3).

RESPONSE:  The Agency continues to believe the non-regulatory policies
should not be retained in part 158 so supplementing what it retained
would not serve any useful purpose.  The paragraphs being deleted have
been superseded (the definition in paragraph (a)), are guidance only
(paragraphs (a)(1) and (b)), or are covered by regulations elsewhere
(paragraph (a)(4)).  EPA will in the final rule retain paragraphs (a)(2)
and (3), but has removed the remaining material and re-designated those
paragraphs.

		Weight-of-Evidence Approach

	Some commenters requested clarification of the weight-of-evidence
approach, especially how it is applied for the developmental
neurotoxicity (DNT) data requirement.   It is discussed in detail with
DNT as an example in Unit V.H. of the preamble to the final rule.

Discussion of Comments on the Data Tables (Subpart B)

Use Patterns

	In the preamble to the proposed rule, EPA proposed subdividing the
current nine major use patterns to fifteen use patterns to fully address
nonagricultural uses.  This proposal seemed to create some confusion
among commenters.

COMMENT:  Commenters 111 and 120 wondered why definitions of the
proposed use patterns were not included in the proposed rule for
comment.    Commenter 125 requested definition of “major use
patterns” and “pesticide use site groups.”  Commenters 123 and 125
identified inconsistencies in use patterns between the preamble
discussion and the tables of data requirements in the regulatory text.
In addition, Commenter 114 recommended that EPA include a new category
of uses for “terrestrial nonfood non-crop uses” or “terrestrial
urban uses.”

RESPONSE:  In the proposed rule, EPA subdivided the existing use
patterns to assist registrants in focusing on data requirements for
their particular pesticide use.  EPA also included nonagricultural use
patterns not reflected in the current major use patterns and believed
that the resulting proposed 15 major use patterns were fairly
self-explanatory.  The major use patterns provide a convenient
organization in the data requirement tables to determine the likelihood
the data will be required.  The pesticide use site groups are more
specific to the registrant’s use site for a particular pesticide
product and can provide a starting point for determining which general
use pattern(s) is(are) most appropriate for the product in question.

	The Agency appreciates commenters’ assistance in locating
inconsistencies between the preamble discussion and the regulatory text
and corrected them in the final rule.  One such inconsistency was the
“Indoor medical” general use pattern.  It was included when the rule
was intended to update all of part 158, including antimicrobial
pesticides.  When the proposed rule for antimicrobials was planned as a
separate entity, the “Indoor medical” use pattern was inadvertently
left in the original rule instead of being removed to accompany the
antimicrobial portion that was to be removed.  There were also five
Aquatic nonfood use patterns (Aquatic nonfood crop, Aquatic nonfood use,
Aquatic nonfood outdoor use, Aquatic nonfood residential, and Aquatic
nonfood industrial use) in the different disciplines.  The five were
consolidated into one major use pattern, Aquatic nonfood.  With the
removal of the “Indoor medical” use pattern and the reduction of
aquatic nonfood patterns to one, the final number of general use
patterns for conventional pesticides will be 12, rather than the 15 in
the proposed rule. The Agency appreciates one commenter’s
recommendation to include another major use pattern such as
“terrestrial urban uses” but believes that the patterns already
proposed are sufficient to cover some of the more specialized uses
without increasing the number of use patterns and adding to the
confusion.

In addition, all the major use patterns will not appear in the data
table for each discipline.  Some of the use patterns have been collapsed
under a larger major use pattern for ease of use.  For example, the
major use patterns in the Toxicology Data Requirements table consist of
Food and Nonfood.  The discussion in §158.500 (b) explains that the
general use patterns of terrestrial food crop, terrestrial feed crop,
aquatic food, greenhouse food crop, and indoor food have been placed
under the major use pattern “Food.”  The “Nonfood” use patterns
include products classified under terrestrial nonfood crop, aquatic
nonfood, greenhouse nonfood crop, forestry, residential outdoor and
indoor, and indoor nonfood.  Therefore only two major use patterns
appear in the data requirement table for Toxicology.  Similar
adjustments have been made to other disciplines as appropriate.

	B.  Appendix A

	EPA proposed updating the current Appendix A, which contains a
compendium of pesticide use sites and major use patterns to help
registrants determine data requirements, and removing it from 40 CFR
part 158.  The Agency intends to issue the updated version on the OPP
website and update it periodically as the need arises; this would
provide EPA with the opportunity to correct and update the pesticide use
sites without a complicated and lengthy rulemaking.  Instead of
“Appendix A,” it will be entitled “Pesticide Use Site Index” and
function as a finding aid for those applicants needing help in
determining which major use pattern(s) would apply to their particular
product.

COMMENT:  Commenters 120 and 124 wanted the Agency to retain Appendix A
in 40 CFR part 158 to provide an opportunity to comment on the major use
patterns and the pesticide use sites.  Commenter 123 voiced the same
preference and requested a schedule for revising and republishing
Appendix A since it had not been revised since its original issue in
1984.

RESPONSE:  EPA intended Appendix A to serve as reference for registrants
who could identify the pesticide use sites but not the general use
patterns to which the site would apply.  The use of Appendix A was not
intended to be a requirement for all registrants and thus not
appropriate for codification.  One of the major reasons for placing the
Appendix A information on the website was the ability to update the
index more frequently, as the need arises.  Commenters will still have
the opportunity to suggest changes to the index even though it now
resides on the website and the revisions should occur with more
timeliness.

COMMENT:  Commenter 122 supported the removal of outdated Appendix A
from the regulations and posting it on the EPA website for better
maintenance and frequent updates.  This commenter requested the Agency
establish a specific procedure for correction and revisions to the
index.

RESPONSE:   The Agency believes that providing the index in current
Appendix A in a more flexible format on the website will allow for more
frequent updates and revisions.  As new crops arise and pesticide use
sites evolve, the index will be updated to keep pace with new
terminology.

C.	Data Tables

	EPA proposed to continue its current system of identifying the
applicability of data requirements in the data tables, i.e. the
designations for required, conditionally required, and not required.  In
the proposed rule, EPA requested comment on its R/CR designation and
received no suggestions for alternative means of presenting the data
requirements.  Therefore, the final rule continues this longstanding
practice.

COMMENT:  Commenters 113, 124, 125, and 133 were confused by the
explanations of R and CR in the proposed rule and requested tighter
definitions and clarification of the test notes since the latter
provided insufficient guidance.

RESPONSE:  Some commenters were confused by the explanations of R and CR
in the proposed rule and requested tighter definitions and clarification
of the test notes since the latter provided insufficient guidance.  In
the proposed rule, EPA requested comment on its R/CR designation, and
received no suggestions for alternative means of presenting the data
requirements.  As described in the preamble to the proposed rule, the
R/CR terminology is a general presentation of the likelihood that a data
requirement will apply.    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.  The use of CR means a study is less likely to be
required.   However, both R and CR designations must be read in the
context of the accompanying test notes to provide context for the R/CR
in the table.  An applicant may assume that a data requirement with R
will typically be required all the time.  The test notes accompanying
that R designation may provide supplementary information or identify
some condition(s) when the study is not required.   A CR designation
will generally include more extensive test notes describing the limited
conditionality of the requirement.  The final rule continues this
longstanding practice.  EPA revised some of the test notes to clarify
the conditions under which the data would be required.

COMMENT:   Commenter 124 disagreed with EPA’s explanation of how the
required (R) and conditionally required (CR) designations were used in
the preamble and in proposed §158.110.  Stating that the statements
were contrary to their historical understanding and usage by companies,
the commenter urged EPA to be very clear about when data requirements
are actually required to provide certainty to companies initiating
studies.

RESPONSE:  EPA notes that current part 158 has never been as certain as
the commenter suggests, i.e. that R means that the data are absolutely
required.  Current part 158 contains numerous examples of R-designated
data requirements that are tempered by test notes limiting their actual
applicability.  As EPA explained in the preamble to the proposed rule,
the R and CR designations are perhaps an imperfect means of presenting
complex data requirements with as much certainty as is possible.  The
test notes must be consulted in all cases.  Moreover, because of the
individual chemical and use patterns, even the test notes may not offer
the certainty that the commenter seeks.  In the final analysis,
applicants are encouraged to consult with the Agency.

COMMENT:  Commenter 120 questioned the availability of Pesticide
Assessment Guidelines from the sources in §158.70(c).

RESPONSE:  The Agency agrees with the commenter that it is not clear
that all the guidelines are available from NSCEP or NTIS.  Thus, the
Agency recommends that applicants access the OPP website (  HYPERLINK
"http://www.epa.gov/pesticides"  www.epa.gov/pesticides ) for the test
guidelines or consult their Product Manager.   As the guidelines are
revised, these are the two sources most likely to provide the latest
information.  The information in §158.70(c) will be revised to reflect
the best source.

COMMENT:  Commenter 120 inquired about the Agency’s basis for changing
“Reentry protection” to “Applicator and Post-Application
exposure.”

RESPONSE:   Although the Agency did not discuss the terminology change,
it did propose changing the subpart designation for Subpart D: 158.390
(Reentry protection) to Subpart K: 158.1050 (Post-Application exposure)
in Table 1 – Proposed Changes to Subpart Designations. The Worker
Protection Standard for Agricultural Chemicals (40 CFR parts 156 and
170) avoided the term “reentry” and sought to standardize the
terminology using the term “post-application exposure.”  In addition
the Worker Protection Standard broadened the scope of post-application
requirements for agricultural workers to include greenhouses, nurseries,
and forests.  The Agency is seeking to bring the Guidelines into line
with this key regulation.  In addition, incidental oral and other types
of residential exposures may occur from post-application oral (or
dermal) contact with individual ant, roach, or rodent baits, rather from
“reentering’ a treated area.  The term “post-application
exposure” is an inclusive and descriptive term for the types for
exposure being characterized.  “Application exposure,” on the other
hand, is new Subpart K: 158.1000 in the proposed rule and was not
combined with “Post-Application exposure.”  Both Applicator Exposure
and Post-Application Exposure appear under Subpart K: Human Exposure
Data Requirements.

COMMENT:  Commenter 123 believed that the proposed rule provided
insufficient information on how to obtain timely decisions from EPA on
data requirements and suggested that the rule should clearly state how
such decisions are to be obtained.

RESPONSE:   The rule is intended to describe the types of data needed to
make regulatory decisions, and how to submit justifications for waivers
if the applicant does not believe that the data are needed.  The rule
describes with as much certainty as possible the criteria for data
determinations.  It is not possible for EPA to describe with certainty
on a case-by-case basis in the rule the precise data requirements that
might apply, as there are product and use pattern factors that may be
highly specific to an application.  EPA strongly encourages
pre-registration consultations to assist applicants in properly applying
the data requirements to their particular product and uses.

Purposes of Registration Data Requirements

	As proposed, the material explaining the purposes of the registration
data requirements was removed from subpart D without revision and
relocated in subpart B.  There were no comments on relocating the
material from subpart D to subpart B.

III.      Discussion of Comments on Identifying Data for Experimental
Use Permits (EUPs) (Subpart C)

	EPA requested comment on a better way to identify data requirements for
EUPs besides the current use of brackets around R and CR designations to
make data tables simpler and more understandable.  The Agency suggested
separating EUP data requirements from the main data tables and placing
EUP requirements in a stand-alone data requirement table.

COMMENT:  Commenters 120 and 122 supported the continued use of brackets
because they believed the designation was descriptive and clear.
Commenter 124 believed that using brackets to distinguish EUPs was
adequate but encouraged the Agency to continue searching for
improvements.  In addition, this commenter suggested adding: brackets to
the product chemistry data requirement table to indicate all
requirements are necessary for EUPs; and a note for applicator exposure
and post-application exposure to indicate none of the studies are
required for EUPs. Commenter 125 suggested placing a EUP data
requirements table in part 172 instead of leaving EUP data requirements
in part 158.

RESPONSE:    EPA had requested comment on this practice because it
wondered if the bracketing in the data requirement tables concentrated
too much information in the latter and made them harder to use.  In
§158.310(a)(3) of the proposed rule, there is a statement that all
product chemistry data must be submitted to support a request for a EUP.
 The sections on applicator exposure and post-application exposure in
the proposed rule relied on lack of brackets to indicate that none of
the studies were required for EUPs.  Because the information in part 172
was more procedural and part 158 is focused on data requirements, EPA
decided to keep the EUP data requirements in part 158.

	After examining alternate ways to indicate EUP requirements besides
using brackets, the Agency decided to designate a new subpart within
part 158 for EUPs.  That new subpart is Subpart C and it is placed early
in part 158 for applicants interested in EUPs so they can locate the
information they seek more efficiently.

IV.	Discussion of Comments on Product Chemistry Data Requirements
(Subpart D)

	EPA proposed two additional data requirements and other minor revisions
to clarify the applicability of existing requirements.  For example, the
Agency proposed to revise the definition of an active ingredient and
end-use product to include nitrogen stabilizers, which were added to the
definition of “pesticide” in 1996.

COMMENT:  EPA proposed only a few changes in product chemistry
requirements but the Agency received a number of comments on elements of
the product chemistry data requirements that EPA had not proposed to
change.  Topics included:

1.  Certified limits [Commenter 113]

2.  Preliminary analysis [Commenters 122, 124]

3.  Submittal of samples [Commenter133]

4.  Definition of TGAI vs.  MP [Commenter 120]

5.  Statement of Formula [Commenter 124]

6.  Grouping of products to reduce or consolidate product chemistry
requirements [Commenter 124]

7.  Data on pesticide degradates [Commenter 114]

RESPONSE:  These comments are outside the scope of the Agency’s
proposal.  They may be considered for future revisions of part 158.
Accordingly, EPA has not revised the final rule to address these
comments.  Except for the large number of comments on topics that were
not proposed, the remaining single comments were not considered key and
therefore not discussed in the preamble.  In the preamble, EPA indicated
that the former may be considered for future revisions of part 158.

Test notes

COMMENT:  Commenter 124 suggested that instead of having the test notes
refer the reader to subsequent sections in the regulatory text that the
test notes be replaced with the subsequent paragraphs.  For example, for
“product chemistry and composition,” the last column of the table
would refer the reader directly to §158.320, rather than first to test
note 1 and then to §158.320.

RESPONSE:  EPA does not agree with this suggestion as it believes that
such a practice would create a mix of information in a column entitled
“Test Note No.” and possibly confuse the reader.  Therefore EPA has
not adopted this suggestion.

Disposition of §158.150

COMMENT:  Commenter 120 noted that EPA did not include in its proposed
rule the text of current § 158.150, describing the purpose of various
product chemistry data.  That section contains no data requirements per
se, but describes how EPA uses product chemistry information in
evaluating a product for registration.

RESPONSE:  EPA did include general information in proposed § 158.130 on
the purpose of other types of information.  Accordingly, in the final
rule, EPA has condensed the text of current § 158.150 and located it in
§158.130(b).

Data requirements for Color (830.6302) and Odor (830.6304)

COMMENT:  In the product chemistry table, EPA’s proposal stated that
the color and odor requirements for an EP were to be conducted with the
TGAI.  Commenter 28 pointed out that it makes little sense to use the
TGAI as the test substance for the EP.

RESPONSE:  EPA agrees with the commenter and has changed the test
substance to the EP.

UV/visible light absorption

COMMENT:  EPA proposed to add a new requirement for a UV/visible light
absorption range.  In the preamble, EPA identified this study as
defining the need for a photodegradation study in water if absorption
occurs within a certain range.  Commenters 122 and 124 suggested that
the study should be located within the environmental fate data
requirements, and that the nanometer range be included as a test note to
the study.  Commenter 120 suggested that the test substance (TGAI) is
inconsistent with EPA’s current practice for this requirement, and
should be revised to be the PAI.

RESPONSE:  With respect to the location of the requirement, EPA
disagrees that the requirement should be in the environmental fate data
requirements.  The light absorption study evaluates a basic property of
an ingredient, and thus properly belongs in subpart D together with
other basic physical and chemical properties.  Although identified as
being needed for the photodegradation in water study requirement, the
data may prove useful in other areas not yet identified and thus should
not be associated solely with the environmental fate data requirements.
EPA is therefore retaining the UV/visible light data requirement in
product chemistry.

	With respect to the suggested test note revision, EPA also disagrees
with the commenter.  The study measures only the potential for an
ingredient or product to absorb light and identifies the range of that
absorption.  EPA uses this information to determine whether a
photodegradation study in water is needed: the criterion for the
photodegradation study is properly identified by a test note in the
photodegradation study requirement in subpart N.  The nanometer range
that triggers the photodegradation study is not relevant to the basic
physical property study.  Accordingly EPA has not adopted the
commenter’s suggestion.

	Finally, EPA agrees that the test substance should be the purest
substance generally resulting from the production process.  As a
practical matter, most production processes are not intended to produce
a pure active ingredient, but a high concentration TGAI that may contain
other ingredients present as a result of the production process.  The
PAI is primarily needed for residue chemistry analyses that measure a
pesticide chemical in extremely small amounts.  Nonetheless, if a PAI is
available, EPA believes the study should be conducted with that
ingredient, and has changed the test substance to be used to either the
PAI or the TGAI.

Particle size, fiber length, and diameter distribution

COMMENT:  EPA proposed to add a new requirement for particle/fiber size
and distribution, applicable to the EP, but conducted using the TGAI or
PAI.  EPA identified its need for the data due to spray drift concerns.
Commenters 28, 120, and 122 noted that data on the TGAI are not relevant
to spray drift, and suggested that the test should more appropriately be
conducted using the EP.

RESPONSE:  EPA agrees with the commenters that for spray drift purposes,
the appropriate test substance should be that actually applied (the EP),
and has revised the table accordingly.  In addition to providing
information for determining spray drift, this data requirement may also
contribute to determinations of inhalation toxicity.

0.1 μm).  The data would be useful for inhalation toxicity studies, as
well as for terrestrial exposure assessments.  The Agency believes that
the degree of specificity suggested by commenters need not be included
in the test note; the guideline and consultation with the Agency should
provide the necessary guidance.

Stability to normal and elevated temperatures, metals, and metal ions

COMMENT:  EPA proposed to require this information on a conditional
basis and to add a test note where previously there was none.
Commenters 125 and 123 noted that although the new test note addressed
the conditionality of the requirement with respect to metal
interactions, it did not provide a description of the temperature
conditionality.  Commenters suggested that since all pesticides may be
exposed to “high temperature,” the data requirement was open-ended.

RESPONSE:   EPA agrees with the commenters and has revised the test note
to include an upper limit criterion for a high temperature of >50( C
(>122( F).

COMMENT:  Commenter 125 noted that the test note stated that the
potential metal interactions of concern were in storage, and the test
substance was limited to the TGAI.  He suggested that all products (EP,
MP, etc) could be destabilized by interaction with metals, and that it
could occur at points other than storage of the material.

RESPONSE:  EPA notes that the test for stability to high temperature and
metal/metal ion interaction should be limited to the TGAI.  The purpose
of the testing is to determine the basic stability of the TGAI.  If the
TGAI breaks down at high temperature or because of instability to metals
before being formulated into an EP, potential breakdown products such as
impurities could be carried over into the formulation of subsequent
products.  The potential for formulated, packaged, and stored products
such as MPs and EUPs to break down is captured by the storage stability
test.

Explodability

COMMENT:  Commenter 82 compared the U.S. data requirement with the
Canadian data requirement.  The Agency currently requires this data but
proposed to make it CR.  Canada currently requires the data but
applicants are usually provided with waivers.  Canada may reconsider the
conditionality of its data requirement in the future, pending the
outcome of part 158 final rule in the U.S.

 RESPONSE:  EPA will continue to work with Canada to harmonize data
requirements although U.S. data requirements are harmonized with
Canada’s to a high degree.

Partition coefficient (n-octanol/water)

COMMENT:  EPA proposed to change the requirement for the octanol/water
partition coefficient from CR to R, because the majority of pesticides
are organic and non-polar.  EPA did not intend to change the nature of
the requirement; however, in revising the test note associated with the
requirement, EPA described the requirement differently from its existing
note, which Commenters 122 and 124 found confusing.

RESPONSE:  EPA believes that the current test note included in the
proposal adequately captures the requirement and has not revised the
test note.  The octanol/water partition coefficient is required for all
products that are organic and non-polar.

Density/relative density/bulk density

COMMENT:  EPA proposed to add a test note to this requirement,
clarifying when various density measurements were required.   EPA did
not intend to change the applicability or nature of this requirement
except to clarify how the requirement applies.  Commenter 28 raised
technical points about how density measurements might apply to various
types of products, and was confused by EPA’s proposed clarification.

RESPONSE:  EPA has had little difficulty in administering this
requirement, and believes that applicants understand the appropriate
measurement of density of various types of products.  Therefore, no test
note is actually required.  Accordingly EPA is deleting the confusing
test note in the final rule.

Discussion of Data Requirements for Product Performance (Subpart E)

	The proposed rule did not apply to the data requirements for product
performance (efficacy).  The data requirements in current 40 CFR part
158 for product performance were relocated to Subpart E with no changes.
There were no comments on relocating product performance data
requirements to Subpart E.

Discussion of Comments on Toxicology Data Requirements (Subpart F)

	EPA proposed revisions that had been peer-reviewed by the FIFRA SAP and
retained data requirements from the current CFR.  The Agency proposed
to:  impose one new data requirement; codify four data requirements; and
revise six data requirements.

Tiered testing for nonfood pesticides

COMMENT:   Commenter 120 agreed that tiered testing based on exposure is
appropriate but wondered why the examples were so extreme.

RESPONSE:  The examples cited in the preamble to the proposed rule
(XI.B.2.i. and ii.) are intended to represent the extreme ends of the
spectrum: very high exposure which would require toxicity data similar
to that for a food use pesticide; and very low exposure requiring at
most only Tier 1 studies.  The Agency also believes that a tiered
testing approach based on the use pattern and expected exposure
scenario(s) is(are) appropriate for nonfood use pesticides.  The Agency
welcomes an open dialog with registrants and other stakeholders to
ensure clarity on its tiered approach to toxicity testing and specific
data requirements.

COMMENT:   Commenters 125 and 133 wondered why a 90-day feeding study
would be required for a nonfood use product such as household
applications.

RESPONSE:  When it has been determined that significant repeated
exposure could result from the use of a nonfood use pesticide, 90-day
feeding studies would only be required (Tier 2) to serve as
range-finding studies to determine dose levels for Tier 3 studies (e.g.,
carcinogenicity studies).

Open literature

COMMENT:   Commenters 114 and 128 were concerned that the proposed data
requirements would require re-testing even if the information is already
publicly available from reliable sources and suggested that the Agency
require registrants to search the professional published literature
(i.e. scientific journals) and to provide copies of all relevant
publications to EPA.

RESPONSE:  Data from the open literature has been and is still
considered along with submitted data when appropriate and available.
Section 158.32 (Format of data submissions), paragraph (c)(1)(vi) tells
the applicant how to submit a study if it is a reprint of a published
document.

Immunotoxicity

  	EPA proposed requiring functional immunotoxicity testing to evaluate
the potential of a chemical to adversely affect the immune system since
immune system suppression has been associated with increased incidences
of infections and neoplasia.  Studies not specifically conducted to
assess immunotoxic endpoints are inadequate to characterize the
potential immunotoxicity of a pesticide, even if tissues likely to
suffer immunotoxic insult are examined.

COMMENT:  Commenters 49, 116, and 128 strongly supported including the
immunotoxicity testing in the toxicology data requirements for all
pesticides.  Commenter 52 pointed out that the European Union includes
functional immunotoxicity testing and assessment of immune systems in
its 90-day rodent study and the U.S. did not address the use of combined
study in its proposed data requirement.

RESPONSE:  The Agency agrees that the guideline did not specifically
address the issue of combining subchronic and immunotoxicity studies.
However, the studies can be combined as long as there are designated
groups of animals specifically for conducting a routine subchronic study
and an immunotoxicity testing, respectively.

COMMENT:  Commenters 125 and 133 requested clarification of when
immunotoxicity testing would be required.

RESPONSE:  Immunotoxicity testing (Guideline 870.7800) is required (R)
for all pesticides, food and nonfood use.

COMMENT:  Commenter 131 was opposed to codification of immunotoxicity
testing and detailed the reasons for its opposition.  One of the reasons
was the extensive divergence in immunological structure and response
between species that gives animal studies limited predictive power for
immunotoxicity in humans.  The commenter also cited the differences
between animal strains; artifacts in laboratory methodology; laboratory
conditions and stress that can negatively affect the immune system.
Instead, the commenter recommended using the ILSI/HESI paradigm.

RESPONSE:  A discussion of details in the guideline is not appropriate
for inclusion in Part 158 but the commenter’s remarks will be
forwarded to the responsible division in OPP for review and
consideration.  While EPA agrees that the testing protocol needs further
work, discussions on other testing paradigms that may lead to guideline
revisions will continue through the International Life Sciences
Institute (ILSI) and Health and Environmental Sciences Institute (HESI)
cooperative effort as will consultation with stakeholders on the
development and validation of this test guideline.

COMMENT:  Commenters 112, 120, 52, 124, and 134 questioned the validity
of such a data requirement and suggested that the data from other
toxicity studies could be used as a trigger to ask for more information
on immunotoxic effects instead of requiring immunotoxic studies; they
also suggested changing the R to CR for food and nonfood uses.

RESPONSE:  The Agency proposed requiring functional immunotoxicity
testing in response to the NRC review and FIFRA SAP recommendations.  As
explained in the preamble of the proposed rule (page 12293), this study
would be required for all pesticides since it would test endpoints not
identified in other studies.

	Immunotoxicity testing is necessary to evaluate the potential of a
chemical to produce adverse effects (i.e., suppression) on the immune
system. Immunosuppression has been associated with the loss in the
ability of the immune system to respond to a challenge such as HIV/AIDS
infections, tuberculosis (TB), Severe Acquired Respiratory Syndrome
(SARS), or neoplasia.  Because the immune system is highly complex,
current studies not specifically conducted to assess immunotoxic
endpoints are inadequate to characterize a pesticide’s potential
immunotoxicity.  While data from hematology, lymphoid organ weights, and
histopathology of routine chronic or subchronic toxicity studies may
offer useful information on potential immunotoxic effects, but these
endpoints alone are insufficient to predict immunotoxicity.  	Therefore
in the final rule, the Agency is requiring functional immunotoxicity
testing along with the data from endpoints in other studies to more
accurately assess the potential risk of pesticides on the immune system.

COMMENT:  Commenters 120 and 124 had several detailed suggestions on how
to update the guideline (870.7800) because they believed it was
inconsistent with current science and no adequately validated methods
existed for this work.

RESPONSE:  A discussion of details in the guideline is not appropriate
for inclusion in Part 158 but the commenter’s remarks will be
forwarded to the responsible division in OPP for review and
consideration.  While EPA agrees that the testing protocol needs further
work, discussions on other testing paradigms that may lead to guideline
revisions will continue through the International Life Sciences
Institute (ILSI) and Health and Environmental Sciences Institute (HESI)
cooperative effort as will consultation with stakeholders on the
development and validation of this test guideline.

COMMENT:  Commenters 116 and 128 suggested including studies using the
EP to provide useful data.

RESPONSE:  Regarding the issue of requiring studies other than those
included in the acute toxicity testing battery to be conducted with the
EP, it would be cost prohibitive and highly impractical for required
toxicity studies to be conducted with each formulated EP.  EPA is
mindful of the burden on the applicant to conduct studies which may not
yield additional useful information.  Only the studies included in the
acute toxicity test battery are required to be conducted with the EP for
labeling purposes.

COMMENT:  Commenter 134 had many suggestions, including adding
information in test notes and waiver information.  This commenter also
inquired about the details of the guideline.

RESPONSE:  Immunotoxicity studies provide critical scientific
information needed to characterize potential hazard to the human
population on the immune system from pesticide exposure. The
immunotoxicity data can be the most sensitive endpoint and used to
select endpoints and doses for use in risk assessment; they are
considered a primary data source for reliable reference dose
calculation.

	The immunotoxicity test is a new requirement and part of the data
requirements for registration of a pesticide (food and nonfood uses).
The Agency believes that no Test Note is required since the study is
discussed extensively in the preamble.  There are no criteria,
indicators, assay type, or other conditions to warrant a Test Note.  The
Agency will review waiver requests and make case-by case decisions.

	A discussion of details in the guideline is not appropriate for
inclusion in Part 158 but the commenter’s remarks will be forwarded to
the responsible division in OPP for review and consideration.

90-day oral – rodent

COMMENT:   Commenter 52 compared the U.S. data requirement with the
draft data requirement of the European Union.  This commenter noted that
the EU requires only one 90-day rodent study, preferably the rat, while
the U.S. requests a 90-day mouse range-finding study besides the rat
study in case a carcinogenicity study is required.

RESPONSE:  A 90-day range-finding study in both rats and mice is
required to determine dose levels when carcinogenicity studies are
required.  The 90-day mouse range-finding study would not be required if
the mouse carcinogenicity study is not required.

COMMENT:   Commenter 128 suggested including studies using the EP to
provide useful data.

RESPONSE:    It would be cost prohibitive and highly impractical to test
each formulated EP.  EPA is mindful of the burden on the applicant to
conduct studies that may not yield additional useful information.  The
Agency will notify the applicant when additional testing using the EP is
required.  EPA is committed to moving towards a more efficient and
reliable testing/risk assessment paradigm that: is more attuned to risk
assessment needs (i.e. hypothesis-driven); avoids requesting data not
used in risk assessment; and reduces and refines the use of laboratory
animals.

90-day inhalation – rat

COMMENT:  Commenter 52 compared the U.S. data requirement with the draft
data requirement of the European Union and noticed that the EU
conditionally requires a 28-day inhalation rodent study while the U.S.
conditionally requires a 90-day inhalation study in the rat.

RESPONSE:  The 90-day inhalation study is conditionally required for
food and non-food use pesticides but studies of a shorter duration may
be considered as sufficient to satisfy this requirement based on the
frequency, magnitude and/or duration of use.  EPA encourages the
applicant to consult the Agency in such instances.  Inhalation waiver
criteria may be accessed on the EPA website at   HYPERLINK
"http://www.epa.gov/pesticides/ppdc/pria/september05/sept14minutes.pdf"
www.epa.gov/pesticides/ppdc/pria/september05/sept14minutes.pdf .

COMMENT:   Commenters 108, 109, 110, 120, 122, and 124 suggested
shortening the 90-day study based on the magnitude and duration of human
exposure.  Commenter 134 mentioned a 28-day inhalation study and
requested specific guidance for waiver requests.

RESPONSE:  The 90-day inhalation study is conditionally required for
food and nonfood use pesticides.  There is currently no test guideline
for a 28-day inhalation study but studies of a shorter duration may be
considered as sufficient to satisfy this requirement based on the
frequency, magnitude and/or duration of use.  In addition, inhalation
waiver criteria are available on the EPA website (  HYPERLINK
"http://www.epa.gov/pesticides/ppdc/pria/september05/sept14minutes.pdf"
http://www.epa.gov/pesticides/ppdc/pria/september05/sept14minutes.pdf ).

COMMENT:   Commenter 128 suggested including studies using the EP to
provide useful data.

RESPONSE:    It would be cost prohibitive and highly impractical to test
each formulated EP.  EPA is mindful of the burden on the applicant to
conduct studies that may not yield additional useful information.  The
Agency will notify the applicant when additional testing using the EP is
required.  EPA is committed to moving towards a more efficient and
reliable testing/risk assessment paradigm that: is more attuned to risk
assessment needs (i.e. hypothesis-driven); avoids requesting data not
used in risk assessment; and reduces and refines the use of laboratory
animals.

Prenatal developmental toxicity

COMMENT:  	Commenter 48 suggested the requirement be based on the likely
exposure pattern for nonfood uses, rather than a mandatory requirement.

RESPONSE:  Since there is much variety in pesticide chemistry, exposure,
and hazard, part 158 is designed to be flexible and data waivers will be
considered on a case-by-case basis for a pesticide.  The decision to
grant a waiver is based on consideration of the use pattern, exposure
pattern, and chemical characteristics.

COMMENT:	Commenter 48 also suggested that the second species requirement
be based on the likely exposure pattern and conducted a simple survey of
seven materials.  The commenter indicated the results of the survey
implied a two-generation study in the rat and a prenatal developmental
study in a second species might be sufficient for some nonfood
materials.

RESPONSE:  The commenter provided a “simple survey” to suggest that
a rat reproduction study and a developmental study in a second species
would be sufficient to identify pre- and postnatal concerns for some
nonfood use pesticides.  This analysis is not adequate to make such a
conclusion for the Agency’s purposes.  Before considering regulatory
changes, the Agency will need to develop scientific position papers for
internal and external review (including review by the FIFRA SAP) and
public comment.

COMMENT:	Commenters 48, 82, 124, and 133 described the possible
technical and logistical challenges associated with combining the rat
developmental toxicity study with the two-generation reproductive
toxicity test.

RESPONSE:  These comments voice concern that various effects of some
test substances in a reproduction study protocol may interfere with
standard developmental observations if the reproduction study has an
added developmental toxicity component.  These are valid concerns and
laboratories are encouraged to consult with the Agency when developing a
protocol for a combined study.  It is additionally noted that the
combining of these studies is an option available to registrants to
consider and not a requirement by the Agency.

COMMENT:	Commenter 125 inquired about:  the cost increase resulting from
the combination of prenatal developmental toxicity study with the
two-generation reproduction study; the increase in the number of
animals; and whether the combination will provide the desired clarity
and economy.

RESPONSE:  Before a final decision is made to change any test protocol
to combine studies, a comprehensive investigation of costs and
effectiveness will be conducted to decide the feasibility of such a
change.

COMMENT:	Commenter 120 suggested the second prenatal developmental
toxicity study be conditionally required.  The study would be required
if the results of the first developmental toxicity study suggest
developmental effects in combination with evidence from other Tier 1
studies.

RESPONSE:  The Agency proposed requiring the prenatal developmental
study in a second species for nonfood use pesticides because the data
will provide some assurance that EPA is not basing an assessment on a
single species (e.g., rodent) which might be highly sensitive (or the
opposite) when compared to another (e.g., nonrodent).  Therefore, in
order to adequately characterize potential hazards to pregnant women and
their fetuses, the prenatal developmental study is required in two
species for all nonfood pesticides.

COMMENT:	Commenter 128, while approving of the data requirement name
change from “Teratogenicity” to “Prenatal Developmental
Toxicity,” pointed out that the test is not designed to assess effects
from exposures after birth or the postnatal effects of gestational
exposures.  This commenter suggested a test of postnatal developmental
toxicity be performed.

RESPONSE:   The suggestion is made that a postnatal developmental
toxicity study also be performed to assess the effects of gestational
exposures to developmental toxicants after birth.  This type of exposure
is currently routinely assessed in the reproduction and fertility
effects study (870.3800) and also in the developmental neurotoxicity
study (870.6300), when triggered.  The commenter also notes that
“male-mediated developmental effects on offspring are not considered
in the current guidelines for developmental toxicity testing,” which
is true but these effects would be detected and evaluated in the
guideline reproduction and fertility effects study and in the
developmental neurotoxicity study, when triggered.

Neurotoxicity

COMMENT:	Commenters 124, 128, and 134 supported the elimination of the
90-day hen requirement and its replacement with the conditionally
required 28-day delayed neurotoxicity – hen study.   Commenter 124
agreed with the conditional requirement of the 28-day delayed
neurotoxicity study in hens, with the understanding that the requirement
would only apply to organophosphate compounds and recommended adding
Test Note 6 to the 28-day hen study.

RESPONSE:  The Toxicology Data Requirements Table on page 12343 will be
revised to add Test Note 6 to the Test Note No. column for 870.6100 –
28-day Delayed neurotoxicity – Hen.  This data requirement will have
two test notes, Test Note 6 and Test Note 15.

COMMENT:	Commenters 124, 131, and 134 wanted the studies to be
conditionally required while Commenter 128 wanted them required.  Those
who supported the CR designation felt the studies should only be
required when neurotoxic effects are suggested in the standard battery
of acute, subchronic, and chronic toxicity tests.  Commenter 52
indicated the European Union conditionally requires neurotoxicity
studies in its draft proposal of data requirements and recommended the
U.S. also conditionally require this study.  Commenter 128 suggested
including studies using the EP to provide useful data.

RESPONSE:  Since the acute and subchronic neurotoxicity studies in the
rat represent different types of exposure (i.e. a single exposure to the
pesticide versus repeated exposures), it is important to require both
studies to more completely understand the neurotoxic potential of the
pesticide and adequately characterize the potential risk to human
health.  The Agency believes that the existing toxicity testing would
not be sufficient as a condition for requiring further neurotoxicity
testing.  The acute and subchronic neurotoxicity studies include
specific neurotoxicity parameters such as motor activity assessment,
functional observation battery and neuropathy examination that are not
included in traditional toxicity studies but are needed for risk
assessment.  It would be cost prohibitive and highly impractical to test
each formulated EP in the neurotoxicity tests.  The Agency will notify
the applicant when additional testing using the EP is required.  EPA is
committed to moving towards a more efficient and reliable testing/risk
assessment paradigm that:  is more attuned to risk assessment needs
(i.e. hypothesis-driven); avoids requesting data not used in risk
assessment; and reduces and refines the use of laboratory animals.

COMMENT:	Commenters 128 and 131 encouraged the substitution of the
neurotoxicity battery of tests with National Toxicology Program
Interagency Center for the Evaluation of Alternative Toxicological
Methods (NICEATM)-validated non-animal and in vitro tests as they became
available.    Commenter 131 cited information from the open literature
regarding the use of neuroblastoma cell lines and biochemical endpoints
and encouraged the Agency use the ILSI/HESI paradigm.

RESPONSE:  The Agency is committed to avoiding unnecessary animal
testing while taking into consideration principles of sound science and
the requirements of FIFRA to protect humans and   SEQ CHAPTER \h \r 1
the environment.  EPA is working closely with 15 other U.S. agencies to
advance the validation and adoption of alternative test methods through
the Federal Interagency Coordinating Committee on Validation of
Alternative Methods (ICCVAM) (    HYPERLINK
"(http://iccvam.niehs.nih.gov),"  http://iccvam.niehs.nih.gov),
established by the National Institute of Environmental Health Sciences.
EPA agrees that the ILSI/HESI paradigm represents the first
comprehensive effort to scientifically re-design the toxicology
animal-testing framework for agricultural chemicals.  The Agricultural
Chemical Safety Assessment (ACSA) proposal is consistent with EPA’s
direction and goals to develop a more efficient and reliable testing
paradigm.  However, ACSA is only one proposal that EPA needs to consider
in improving the risk assessment process of environmental chemicals.

COMMENT:	Commenters 125 and 133 wondered if the results of the acute and
subchronic neurotoxicity studies were intended to show adverse effects
in the central nervous system (CNS) affecting learning, memory or
performance, or adverse effects on visual, auditory, or somatosensory
senses.

RESPONSE:  The Agency is routinely requiring the acute and subchronic
neurotoxicity studies in adult rats to more completely characterize the
potential for neurotoxicity resulting from single and repeated exposures
to pesticides.

Developmental neurotoxicity (DNT)

COMMENT:	Commenters 120, 124, and 134 identified the requirement
inconsistency between the list of required first tier toxicity studies
and the requirements in the Table of Toxicology Data Requirements on p.
12344 of the proposed rule.

RESPONSE:  EPA received several comments alerting it to an error in the
list of required first tier toxicology studies for nonfood use
pesticides on page 12346; §158.510(b)(1)(iii).  The inclusion of the
developmental neurotoxicity study in the rat (guideline 870.6300) was an
error and this study will be removed from the list.  The developmental
neurotoxicity study in the rat (870.6300) is conditionally required (CR)
for food and nonfood use pesticides as indicated on the Table of
Toxicology Data Requirements on page 12344.

COMMENT:	Commenter 48 believed the discussion in the preamble appeared
to require DNT studies, although it was proposed as a conditional
requirement.

RESPONSE:  The section of the preamble cited in this comment is
referring to the 1998 SAP recommendation to the Agency that the DNT
study be required for all food use pesticides.  However, based on the
experience gained with this study since 1998, EPA is now conditionally
requiring (CR) the DNT study for all food and nonfood use pesticides
based on a weight of approach (refer to Test Note 27, page 12345).

COMMENT:	Commenter 49 appreciated EPA’s increased emphasis on DNT
testing because DNT data are essential to the aggregate and cumulative
risk assessments.  This commenter also supports EPA’s position that
harmonization of guidelines into a single set of OPPTS guidelines would
minimize variation among the testing produces but was concerned such
harmonization might lessen data requirements.

RESPONSE:  The Agency recognizes the importance of the DNT study and
therefore is conditionally requiring this study in the rat (870.6300)
for all food and nonfood use pesticides.  For further information on
current risk assessment policies, please refer to Determination of the
Appropriate FQPA Safety Factor(s) in Tolerance Assessment (February 28,
2002; Docket # OPP-00757) and Application of the 10X Safety Factor in
Cumulative Risk Assessment (February 28, 2002; Docket # OPP-00759).

COMMENT:	Commenter 49 pointed out that the developing brain has been
shown to be the most sensitive health endpoint for many pesticides for
which the Agency has DNT data and found it contrary to have less
stringent requirements for this endpoint to protect children under FQPA.

RESPONSE:  While EPA agrees that effects on the developing brain can be
a sensitive endpoint for risk assessment, in a more recent retrospective
analysis of the DNT studies that have been received and reviewed by the
Agency to date, 8 out of 38 cases “resulted in the selection of a
lower regulatory endpoint for at least one exposure scenario” (Docket
ID OPP-2005-0190-0065).  For the remaining 30 cases, a study other than
the DNT study provided the most sensitive endpoint for human health risk
assessment.

COMMENT:	Commenter 49 believed that the source of developmental effects
to trigger a DNT test could only come from a DNT test and not standard
tests in developing animals.  This commenter also questioned whether the
inhibition of cholinesterase activity (ChEI) would be the most sensitive
effect for organophosphorus and N-methyl carbamate pesticides.

RESPONSE:  In the revised data requirements, the acute and subchronic
neurotoxicity studies are required for all food and nonfood use
pesticides, as are two prenatal developmental studies (in rodent and
nonrodent species) and a two-generation reproduction study in the rat.
These studies provide key data in adult animals and in young animals
following pre- and postnatal exposure which can then be considered using
the criteria listed in Test Note 27 (page 12345) to determine the need
for the developmental neurotoxicity study.

	In response to the August 1999 Data Call-in Notice, OPP received and
completed the review of 20 developmental neurotoxicity studies conducted
with organophosphate pesticides.  In 13 out of 20 studies,
cholinesterase activity (ChEI) was measured in the pups; cholinesterase
was the most sensitive endpoint in these 13.

	Only a limited number of developmental neurotoxicity studies are
available for carbamates (seven studies); for one chemical of the seven,
an endpoint from this study was used to assess acute dietary risk (not
chronic).

COMMENT:	A number of commenters were confused about when the DNT study
would be required and the weight-of-evidence approach and requested
clarification.  Commenters 125 and 133 found the criteria that would
suggest requiring a DNT study contradicted a later sentence indicating
that all neurotoxic pesticides would require a DNT study.

RESPONSE:  The text to which the comments refer reads “The Agency is
proposing to conditionally require developmental neurotoxicity studies
for all neurotoxic pesticides and/or when other criteria are met that
indicated a potential for toxicity to the developing nervous system,
based upon a weight-of-evidence evaluation of the toxicological
database.”  EPA has resolved the implied contradiction resulting from
a typographical error by changing “require” to “conditionally
required.”

COMMENT:  Commenter 116 favored including DNT testing but was concerned
that the criteria listed in the proposed rule for identifying
high-priority chemicals cannot identify every potential neurotoxicant.
This commenter also wondered why the same requirement was not proposed
for all pesticides used in and around homes, schools, and daycare
centers.  The commenter felt that a “knowledge-based” approach
should take account of both chemical-specific and exposure-specific
criteria.

RESPONSE:   The developmental neurotoxicity study in the rat (870.6300)
is conditionally required (CR) for food and nonfood use pesticides as
indicated on the Table of Toxicology Data Requirements on page 12344.
The decision to require this study (and any conditionally required
study) should be informed by both toxicological and exposure data.

COMMENT:	Commenters 125 and 133 both asked for clarification of triggers
for the conditionally required DNT study listed in Table 3 of the
proposed rule.

RESPONSE:  The table that you refer to in this comment (Table 3) is a
summary table of proposed changes to the Part 158 data requirements.
The table that includes the test notes for the developmental
neurotoxicity study (and all other toxicology data requirements) is the
Toxicology Data Requirements Table on page 12343-12344.  Test Note 27
for this study contains the criteria to be considered in the weight of
evidence determination for requiring the study (i.e., “triggers”).

COMMENT:	In reference to §158.510 (Tiered testing options for nonfood
pesticides), Commenter 134 felt the DNT study should be conditional and
only be required when neurotoxic effects are suggested in the standard
battery of acute, subchronic and chronic toxicity tests and requested
clarification and well defined effects that would trigger the study.

RESPONSE:   The inclusion of the DNT study in the rat (870.6300) was an
error and this study will be removed from the list.

COMMENT:	Commenters 49 and 82 were concerned that altered hormone
responses and/or effects on the thyroid seen from the two-generation
study as triggers for the DNT study were absent from Test Note 27.

RESPONSE:  Although thyroid effects were previously included as one of
the criteria considered in the weight of evidence for requiring a DNT
study, this criterion has since been removed based on the experience
gained with the study.  When thyroid effects of concern are observed,
the Agency will require a more specific special study to further
characterize the potential for a pesticide to adversely affect thyroid
hormones, thyroid structure, and/or thyroid hormone homeostasis during
development.

COMMENT:	Commenters 48, 113, and 120 agreed with EPA’s decision to
conditionally require this study based on a weight-of-evidence approach.
 They requested a clarification of Test Note 27 to indicate the effects
are part of the weight-of-evidence approach and not individual triggers.

RESPONSE:   To ensure clarity regarding the use of a weight of evidence
approach when conditionally requiring a DNT study, the first sentence of
Test Note 27 on page 12345 will be revised to read “A DNT would be
required using a weight-of-evidence approach considering...” instead
of “A DNT would be required using a weight-of-evidence approach
when….”  EPA provides additional information on the
weight-of-evidence approach and DNT in the preamble to the final rule.

COMMENT:	Commenter 124 agrees that the DNT study should be conditionally
required on a case-by-case basis and that the endpoints that could
trigger a DNT study not be used in isolation.

RESPONSE:  EPA agrees that the criteria used in the determination of the
need for a developmental neurotoxicity study listed in Test Note 27,
“should not be used individually in isolation”; rather all of the
available toxicology and exposure data would be considered together in a
weight-of-evidence determination.

COMMENT:	Commenter 124 requested further clarification of several terms
used in Test Note 27 to describe toxicity-related findings which could
be used as the basis for requiring a DNT study, specifically:
“functional or behavioral effects”; the differentiation between
“altered” and “adverse”; and the interpretation of “altered
neuroreceptor or neurotransmitter responses.”

RESPONSE:  In interpreting these terms, it is important to emphasize the
context provided by Test Note 27 which is that the effects listed would
be considered as part of a weight-of-evidence approach.  EPA agrees that
weight-of-evidence considerations would include the factors listed by
the commenter (mechanistic data, dose-response information, route of
administration, and robustness of the data set).  In the context of Test
Note 27, the term “functional or behavioral effects” refers to
“neurological effects” in adult or developing animals [Test Note 27,
i and ii].  It is not practicable, in the context of test notes to part
158, to provide definitions for such terms as “altered” or
“adverse.” The terms are explained in greater detail in the document
referenced below. The Agency provides considerable discussion of these
issues in its published Risk Assessment Guidelines, including those on
Neurotoxicity (EPA/630/R-95/001F; April 1998) at
www.epa.gov/ncea/raf/pdfs/neurotox.pdf .  EPA provides additional
information on the weight-of-evidence approach and DNT in the preamble
to the final rule.

COMMENT:	Commenter 49 felt that making DNT testing conditional on
findings from other testing is a futile exercise because no other test
guideline provides information on endpoints relevant to significant
developmental outcomes such as learning disabilities and attention
deficit/hyperactivity disorder.

RESPONSE:   Based on the experience gained with this study, the Agency
stands behind the decision to conditionally require (CR) the DNT study
in the rat (870.6300) for food and nonfood use pesticides.  All
available toxicology data for the pesticide will be considered in the
weight-of-evidence determination of the need for the DNT using the
criteria cited in Test Note 27 on page 12345.  These criteria include
neurological effects seen in adult animal studies as well as
neurobehavioral effects following pre- and postnatal exposure to young
animals.

COMMENT:	Commenter 123 referred to the interim summary table in EDocket
item OPP-2005-0190-0065 and pointed out it lacked a more complete
description of results of DNT tests.  Commenters could determine if the
tests were worthwhile depending on how results affected regulatory
outcomes.

RESPONSE:  The document cited in this comment, OPP-2005-0190-0065,
included the preliminary findings in a more recent retrospective
analysis of DNT studies.  Since use of DNT studies in risk assessment
was relatively rare prior to the passage of FQPA, an assessment was
conducted to examine the outcomes of submitted DNT studies and to
determine the impact of DNT studies in OPP risk assessment decisions.

The analysis demonstrated the utility of the DNT study in risk
assessments for pesticide chemicals.

Results of available DNT studies demonstrated the absence of a single
“most sensitive” parameter, affirming the importance of conducting a
broad assessment of neurobehavioral and neuropathological endpoints,
representing a range of nervous system functions.

Results also demonstrated the importance of conducting assessments at
multiple time points in offspring.

Sole findings (single effects at the LOAEL) occurred at both early and
late assessments

Treatment-related effects would have been missed by elimination of
either assessment time point

For the currently available chemicals, the early assessment was more
likely to detect a “sole finding” than was the late assessment

Several parameters were rarely identified as effects in offspring at the
LOAEL, although they may have been affected at higher doses;

Two parameters never identified effects at the LOAEL

Clinical signs

Qualitative neuropathological assessment

Functional observations, as conducted in the DNT study, detected effects
at the LOAEL for only two chemicals

Changes in brain morphometric measures were seen at the LOAEL more
frequently than were changes in brain weight; simultaneous effects in
both these parameters were seen at the LOAEL for only five chemicals
(out of 22 having an effect on at least one of the two).

Mutagenicity

COMMENT:	Commenter 128 suggested that EPA include studies using the EP
for all the mutagenicity tests (870.5100, 870.5300, 870.5375, 870.5385,
and 870.5395) to provide useful data.

RESPONSE:  It would be cost prohibitive and highly impractical to test
each formulated EP in the required mutagenicity tests.  EPA is mindful
of the burden on the applicant to conduct studies that may not yield
additional useful information.  The Agency will notify the applicant
when additional testing using the EP is required.  EPA is committed to
moving towards a more efficient and reliable testing/risk assessment
paradigm that:  is more attuned to risk assessment needs (i.e.
hypothesis-driven); avoids requesting data not used in risk assessment;
and reduces and refines the use of laboratory animals.

COMMENT:	Commenter 131 suggested OPP limit its data requirements for
genetic toxicity to in vitro studies and called attention to the draft
OECD TG 487 (In Vitro Micronucleus Test).

RESPONSE:  The commenter is directed to § 158.70(d)(2) of the
regulatory text in the proposed rule for the policy regarding OECD
protocols.  EPA will continue to work with OECD to harmonize data
requirements, testing protocols and methodologies.    SEQ CHAPTER \h \r
1 EPA is working closely with 15 other U.S. agencies to advance the
validation and adoption of alternative test methods through the Federal
Interagency Coordinating Committee on Validation of Alternative Methods
(ICCVAM).  As new tests and test batteries are validated, the Agency can
present them to the FIFRA SAP to review their applicability in meeting
regulatory needs and consider them for addition to the Agency’s test
guidelines.

COMMENT:	Commenter 124 asked the following questions about the
mutagenicity testing data requirement in the proposed rule:

(1)  What are the criteria for high or moderately prolonged exposure
that would trigger in vivo testing as part of the initial tier of
studies, if the three in vitro mutagenicity studies are negative, and
these studies are determined to have met the criteria for valid studies?

(2)  Is a second in vivo genotoxicity study (e.g. in vivo hepatocytes
UDS) necessary if the in vitro chromosome aberration study is the only
in vitro test producing a positive response and negative results are
obtained in an adequately conducted in vivo cytogenetics test?

(3)  In the event that the in vitro mammalian-cell gene-mutation assay
produces positive results, which in vivo study(s) does the Agency
consider appropriate?

RESPONSE:   As stated in the preamble to the proposed rule, EPA is
authorized to regulate pesticides under two federal statutes, the
Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the
Federal Food, Drug and Cosmetic Act (FFDCA).

	EPA considers all food uses of pesticides to be high exposure (see Unit
XI. Toxicology Data Requirements; Subpart F).  For example, the criteria
for exposure-based testing from Toxic Substances Control Act (TSCA)
Section 5, provide examples.  TSCA is just one example of existing
criteria for requiring these types of study.  Accordingly, mutagenicity
testing, including an in vivo bone marrow assay for metaphase analysis
or a  micronucleus assay, is required for all general food and nonfood
use patterns of pesticides (e.g., terrestrial, aquatic, greenhouse,
forestry, and residential outdoor and indoor uses) (see Subpart F
-Toxicology, Table - Toxicology Data Requirements).

	Additional in vivo testing is evaluated on a case-by-case basis to
address uncertainties such as target tissue/organ specificity,
structural-activity relationships (SAR) or species differences in
metabolism or distribution.  On the other hand, if the only concern is
related to a positive result from an in vitro cytogenetic assay
indicating that the effect is secondary to clastogenicity, additional
testing may not be necessary.

	In general, positive gene mutation assays (either Salmonella or in
vitro mammalian cell gene mutation assays or both) would trigger the
performance of an assay designed to detect the potential of the test
material to reach germ cells and interact with gonadal DNA.  However,
this decision would be influenced by the results from reproductive
toxicity studies, target tissue/organ specificity, structural-activity
relationship (SAR), exposure data, mechanism of action data,
pharmacokinetic and metabolism information, and subchronic and chronic
effects. As indicated by the statements above, the decision to require
additional testing proceeds on a case-by-case basis and takes into
account the overall weight of the evidence for a mutagenic concern.

Acute oral and dermal toxicity

COMMENT:	Commenters 116 and 128 suggested including testing the EP in
addition to the TGAI to support applications for end-use products and
encouraged a transition to non-animal or in vitro testing as such
testing becomes available and validated.

RESPONSE:  As discussed in the proposed rule, the Agency determined that
studies using the EP provided the most useful data and would require
testing on the diluted form of the EP only if the product met the
conditions under §152.170(b) or §154.7(a)(1).  EPA is mindful of the
burden on the applicant to conduct studies that may not yield additional
useful information. The Agency will notify the applicant when additional
testing using the diluted product is required.  EPA is committed to
moving towards a more efficient and reliable testing/risk assessment
paradigm that:  is more attuned to risk assessment needs (i.e.
hypothesis-driven); avoids requesting data not used in risk assessment;
and reduces and refines the use of laboratory animals.

COMMENT:	Commenter 52 compared the data requirements from the European
Union with those of the U.S.  The EU conditionally requires these
studies; the U.S. requires the studies unless the test material is a gas
or a highly volatile liquid or if the material is corrosive to skin or
has a pH of less than 2 or greater than 11.5.

RESPONSE:  The draft EU requirement is conditional when the applicant
can justify to the satisfaction of the competent authority that Council
Directive 99/45/EEC can be invoked.  The test note to the U.S. data
requirement has three possibilities when the test would not be required.
 There are conditionalities attached to both the U.S. and the EU data
requirements, but only a comparison of the final versions of both data
requirements will supply a definitive answer.

COMMENT:	Commenter 28 pointed out that the asterisk used in current part
158 to designate the EP is needed to support an application under the
formulator’s exemption is missing from the proposed rule.

RESPONSE:   Some commenters were confused by the removal of asterisks in
the proposed rule for the toxicology data requirements table.  By
relocating the formulators’ exemption language to part 152, EPA
believes the consolidation of information in a single location
eliminates the need to consult two different parts in 40 CFR, i.e. parts
152 and 158 for information regarding the formulators’ exemption.  The
relocation rendered the use of asterisks in part 158 unnecessary without
removing the exemption.

Primary eye irritation, primary dermal irritation, and dermal
sensitization

COMMENT:	Commenters 28 and 112  pointed out that the asterisk used in
current part 158 to designate the EP is needed to support an application
under the formulator’s exemption is missing from the proposed rule.
They believed this contravention of the formulator’s exemption was not
intentional and requested clarification to ensure that needless testing
would not be conducted.   RESPONSE:  Some commenters were confused by
the removal of asterisks in the proposed rule for the toxicology data
requirements table.  By relocating the formulators’ exemption language
to part 152, EPA believes the consolidation of information in a single
location eliminates the need to consult two different parts in 40 CFR
for information regarding the formulators’ exemption.  The relocation
rendered the use of asterisks in part 158 unnecessary without removing
the exemption.

COMMENT:	Commenter 52 compared the U.S. data requirements with those of
the European Union.  The data requirements are conditionally required
for the EU if the applicant can justify not conducting this study to the
satisfaction of the competent authority; this data is required in the
U.S. but with conditionalities in the test notes.

RESPONSE:  There are conditionalities attached to both the U.S. and the
EU data requirements, but only a comparison of the final versions of
both data requirements will supply a definitive answer as to the extent
of the differences between the two.

COMMENT:	Commenter 28 wondered if adding a test on the TGAI to support
an end-use application is really necessary or appropriate, especially if
the EP is not produced by an integrated process.  The material coming
into contact with the eye or skin of those handling the formulated
product would not in general be the TGAI alone, but rather the entire
formulated product.  In many cases the “inert” ingredients may have
more of an effect on eye and skin irritation than the “active”
ingredients.  Commenters 125 and 133 believed TGAI data should not be
required to support an EP registration and wondered if the study on the
EP would be used to generate the signal word and precautionary
statements on the label.

RESPONSE:  These are the same data requirements as in the current §
158.340 for the six acute toxicity tests for either a TGAI/MP or EP.
There has been no change to the data requirements, and there are various
methods of data compensation available to registrants, with the
formulators’ exemption as one example.  The Agency is not requiring
any additional data to be performed on the TGAI/MP in order to register
an EP compared to the current requirement.  It has always been a
requirement that studies be performed on the TGAI for the six acute
toxicity tests as part of the overall registration decision for a new
active ingredient. Any EPs will be considered for registration only
after the Agency makes the TGAI registration decision.  The front panel
of every EP pesticide label is developed from the data on the six acute
toxicity tests (i.e., signal word, hazard precautionary statements).

COMMENT:  Commenter 128 supported the additional testing but urged
substitution of the acute toxicity battery of tests with validated
non-animal and in vitro tests as they become available while Commenter
131 opposed the expansion of the testing.

RESPONSE:   EPA is committed to moving towards a more efficient and
reliable testing/risk assessment paradigm that:  is more attuned to risk
assessment needs (i.e. hypothesis-driven); avoids requesting data not
used in risk assessment; and reduces and refines the use of laboratory
animals.

21-day dermal and 90-day dermal

COMMENT:	Commenters 108, 109, and 110 summarized the proposed 21- to
28-day subchronic dermal toxicity test for food uses from CR to R
because of worker risk assessments.  Since not all food use applications
pose worker risk, the requirement will be tailored to the potential for
worker exposure.  If the dermal route is the major route of exposure for
nonfood uses, the 90-day study would be conditionally required instead
of the 21- to 28-day subchronic study.  The latter test would be
insufficient to identify potential hazards.

RESPONSE:  This is an accurate summary of the proposed changes to the
dermal data requirements for food and nonfood use pesticides.

COMMENT:	Commenters 108, 109, 110, 122 and 125 believed that the food
and nonfood differentiations for these tests are not relevant.  They
also believed the use patterns pertaining to the frequency and duration
of exposure are more relevant than whether the product is applied to a
food or nonfood crop.  They proposed placing these requirements along
with the inhalation toxicity requirements in a separate table based on
occupational and residential use patterns.

RESPONSE:  The Agency realizes that the categories for toxicology data
requirements are broad but believes they reflect the reality that much
more toxicity data are necessary for evaluating potential widespread
dietary exposure resulting from a food-use pesticide than for exposure
resulting from a nonfood use pesticide.  Therefore, the food and nonfood
use categories best serve the Agency in requiring toxicology data to
support pesticide registration and re-registration. Section 158.500(b)
lists the general use patterns, occupational and residential, under the
food and nonfood use patterns.  EPA proposed an increased number of
major use patterns but many commenters found the increase more confusing
than useful.

COMMENT:	Commenters 108, 109, 110, 122, 124, 125, 133, and 134
questioned the relevance of a 90-day study when exposures rarely exceed
45 days; considering the low dermal absorption of many active
ingredients, only minimal toxicity is typically seen in repeated dermal
exposure studies.  One of the commenters proposed that the basic
requirement be a conditional 21/28 day dermal study and waive it if the
toxicity endpoint selected for risk assessment is not an endpoint
determinable by the data requirement.

RESPONSE: The Agency considers the 21/28-day dermal study insufficient
for nonfood use pesticide assessment because higher tiered studies
(i.e., chronic or cancer studies) are generally not required for nonfood
use pesticides.  While 45-day exposures are common, EPA believes that
they are not the maximum duration.  For example, professional
applicators may be subjected to repeated exposures during the 3 months
of peak summer infestations.  Since for many pesticides there is
increased toxicity with increased exposure, professional applicators may
not be adequately protected with 45-day studies.  Existing regulations
provide the flexibility to implement alternative studies, on a
case-by-case basis, as appropriate.  Registrants should consult with the
Agency if there is any question regarding the appropriate duration of
the study.  The highest level of hazard evaluation available for a
nonfood use pesticide is satisfied through a subchronic toxicity test,
i.e., a 90-day repeated exposure to the nonfood pesticide.  Therefore,
the final rule will require the 90-day dermal toxicity study for nonfood
uses.

COMMENT:	Commenters 108, 109, 110, and 124 suggested that the
requirement be based on the Tier 1 risk assessment.  If dermal exposure
is low, additional studies and data requirements would not be warranted;
dermal studies for EPs should only be required if the attributes of the
“additives” are known or the attributes are known vehicles for
enhanced dermal penetration.

RESPONSE:  In cases where the potential for dermal exposure is very
limited, in terms of the frequency, magnitude and/or duration of
exposure, the registrant may request a data waiver and perhaps a shorter
duration study could meet this requirement.  Applicants are encouraged
to discuss the request with the Agency before developing and submitting
supporting data, information or other materials.

COMMENT:	Commenters 124, 125, 133, and 134 wondered what the criteria
were for testing on the EP due to toxic effects or increased dermal
absorption.  One commenter requested additional guidance to define
co-formulants and their contents in the EP that are likely to increase
dermal absorption of the active ingredient.  Another commenter suggested
global harmonization of the guideline was highly desirable based on past
experience.

RESPONSE:  Test note 11 (page 12345) explains that a dermal study may be
conditionally required for an end-use product (EP) if the product, or
any component in it, could lead to potentially toxic effects to the user
(handler, applicator, etc.) or if the other components of the product
could increase dermal absorption of the active ingredient.  The
determination whether such a study would be required is the
responsibility of the manufacturer in consultation with the Agency.
EPA will continue to work with Canada and the European Union through
OECD to harmonize data requirements, testing protocols and methodologies
and to promote work-sharing opportunities.  EPA provides additional
guidance to fulfill unique U.S. regulatory requirements.

COMMENT:	Commenter 128 recommended that the 90-day dermal study be
extended to R for food and nonfood uses since worker exposure must be
evaluated in both cases.

RESPONSE:  Since the data requirements for a food use pesticide are
generally more extensive than for a nonfood use pesticide, the 21-day
dermal study is adequate for food use because higher tiered toxicity
studies are routinely received.  The Agency simply needs to determine
whether the dermal route of exposure reveals a different toxicity
profile than the oral route.  The Agency believes 21 days is sufficient
to confirm that unforeseen toxic effects are not expressed via the
dermal route of exposure.

COMMENT:	Commenter 134 recommended accepting the 90-day oral study plus
a dermal penetration study to satisfy the requirement for a 90-day
dermal toxicity study, especially in light of the 21/28-day dermal
requirement.

RESPONSE:   A dermal penetration study in addition to a 90-day oral
study could be acceptable in appropriate cases to support waiving the
90-day dermal study requirement for a nonfood use pesticide.  As
previously stated, part 158 is designed to be flexible and data waivers
will be considered on a case-by-case basis for a pesticide.  The
decision to grant a waiver is based on consideration of the use pattern,
exposure pattern, chemical characteristics, etc.

Carcinogenicity

COMMENT:	Commenter 23 advocated adding more studies, especially
long-term ones, to protect the public from cancer.  Commenter 128
suggested including additional studies using the EP to provide useful
data.

RESPONSE:  EPA requires long-term carcinogenicity studies for all food
use pesticides and other pesticides if the use pattern indicates
significant exposure.  It would be cost prohibitive and highly
impractical to test each formulated EP in the required mutagenicity
tests.  The Agency will notify the applicant when additional testing
using the EP is required.  EPA is committed to moving towards a more
efficient and reliable testing/risk assessment paradigm that:  is more
attuned to risk assessment needs (i.e. hypothesis-driven); avoids
requesting data not used in risk assessment; and reduces and refines the
use of laboratory animals.

COMMENT:	Commenter 52 compared U.S. data requirements with those of the
European Union and pointed out that the latter requires toxicokinetic
data while the U.S. does not.  The EU also allows the use of transgenic
animals as a second rodent species.

RESPONSE:  EPA is aware that toxicokinetic data is useful for dose
selection in long-term studies and the Agency currently uses such data
when available.  Currently, transgenic animals are not required in
Agency testing.  However, if studies using transgenic animals were
submitted, they would be considered along with the standard studies.

COMMENT:  Commenter 82 wondered why the durations in Test Note 19 for
the chronic rodent feeding study (food use) and the chronic rodent
feeding study (nonfood) are different for the same endpoint.

RESPONSE:  Test Note 19 refers to the case when, for a food use, the
registrant opts to combine the required chronic oral toxicity study with
the required carcinogenicity study to simultaneously fulfill the
requirements for both (870.4300).  In this case, the study duration for
the combined chronic oral/carcinogenicity study would be 24 months.

COMMENT:  Commenter 82 did not find it easy to discern from the test
notes that accompany the table in Section 158.500 what conditions are
needed to trigger cancer studies for non-food uses.

RESPONSE:  The conditions needed to trigger the requirement of a cancer
study for a non-food use are described in Test Note 20.  The difference
in the study duration for the chronic oral toxicity study conducted for
a food versus nonfood use are due to the difference in typical exposure
pattern for these uses (i.e. exposure resulting from a food use is
expected to be possible over the span of a lifetime while exposure
resulting from a non-food food use is expected to be of a lesser
duration).

COMMENT:  Commenter 124 thought “Oncogenicity” should be retained
instead of changing the data requirement name to “Carcinogenicity”
because the former refers to benign and malignant tumors while the
latter refers only to malignant tumors—and the EPA guidelines are
designed to detect both types of tumors.

RESPONSE:   The name change for the data requirement from
“Oncogenicity” to “Carcinogenicity,” reflects a harmonization
effort with other Agency carcinogenicity documents (e.g., the new
Guidelines for Carcinogen Risk Assessment; EPA/630/P-03/001F; March
2005).

The title of test guideline 870.4200 is “Carcinogenicity.”
Additionally, the term carcinogenicity is associated with animal testing
as opposed to the human condition.  Although the guideline title change
from "Oncogenicity" to "Carcinogenicity" might lead to the assumption
that only cancerous tumors are being evaluated, it is clear from the
discussion within the guideline that the Agency will evaluate both
benign and malignant tumors in their review.

COMMENT:  Commenter 131, citing from the literature, contended that
results indicated that rodent carcinogenicity assays are much less
reproducible than previously expected and have serious limitations.

RESPONSE:   EPA is participating in efforts by ILSI/HESI, ICCVAM, and
the FDA to improve and refine cancer studies.  In the interim, the
Agency will continue to use them in cancer consideration until more
refined studies are validated for use.  Data from these cancer studies
have other applications.  The two-year study in the rat is a combined
cancer and chronic study that provides critical non-cancer data
applicable to regulatory end-point selection, especially the chronic
reference dose.  The cancer study in the mouse also provides non-cancer
toxicity data that is useful in hazard characterization and some
end-point selection.

Reproduction and fertility effects

COMMENT:	Commenters 48, 125, and 133 requested clarification that the
study will be required for an active ingredient used to formulate
products with significant human exposure through food use.

RESPONSE:  The proposed requirement of a reproduction study for nonfood
use pesticides would be based on a weight-of-evidence consideration of
the toxicology data and potential exposure in terms of the frequency,
magnitude and/or duration.  This is an exposure-based data requirement
and may not always be necessary.

	OPP is currently working with EPA's National Center for Computational
Toxicology (NCCT) to populate a Toxicological Reference Database
(ToxRef). The current priority is to populate ToxRef with data from the
rat 2-generation reproductive study, prenatal toxicity, and systemic
toxicity studies on hundreds of pesticides that represent different
classes, modes of action, and toxicity profiles. EPA will use this
relational database to determine the value of endpoints currently
evaluated in risk assessment (i.e., the F1 versus F2 responses).

COMMENT:	Commenter 52 compared U.S. data requirements with those of the
European Union.  The EU is now proposing to require measurement of TGAI
or metabolites in milk while the U.S. does not.

RESPONSE:  EPA does use toxicokinetic data when it is available.
Although it is not routinely required, the Agency will ask for this data
on a case-by-case basis.  The Agency does not currently require TGAI or
metabolite data in milk.  However, this is an option in the
developmental neurotoxicity study protocol to confirm adequate dosing of
the pups.

COMMENT:	Commenters 125 and 133 wondered if there were any studies that
are predictive or structural relationships that may be indicative of
reproductive effects.  They also wondered whether “constant-release
aerosols” were total release foggers or metered release aerosols.

RESPONSE:   The examples cited in the preamble on page 12297 (section XI
C 3 v) represent types of nonfood use pesticides which require
reproduction studies based on exposure.  The term “constant release
aerosols” refers to those pesticides formulated for uses that may
result in repeated exposure over several months (e.g., metered release
aerosols).

COMMENT:	Commenters 125 and 133 noticed the study in the table is not
indicated to be a two-generation study, as it appears in the current
part 158 table.

RESPONSE:   The text in the Data Requirements column of the Toxicology
Data Requirements table on page 12343 will be revised for 870.3800 to
read “Reproduction and Fertility Effects.”  This change will reflect
the test guideline, which is for a two-generation reproduction study.

Scheduled-controlled operant behavior, Peripheral nerve function, and
Neurophysiology – Sensory evoked potentials

COMMENT:	Commenters 113, 124, 125, 133 and 134 felt the inclusion of
three specialized studies (Scheduled-Controlled Operant Behavior –
Guideline 870.6500, Peripheral Nerve Function – Guideline 870.6850,
and Neurophysiology-Sensory Evoked Potentials – Guideline 870.6855)
was premature.  They questioned whether these studies had undergone
inter-laboratory validation and recommended that EPA provide specific
and scientifically-justifiable triggers for any of the studies.
Commenter 133 wondered if this testing would be commonly required.

RESPONSE:  EPA agrees that these three studies have not undergone
inter-laboratory validation. EPA discovered upon review that these
studies were seldom required during the Reregistration process and were
therefore not likely to be required often in the future.  Thus the
Agency has determined that these studies could be removed from the
toxicology data requirements table of commonly required studies in part
158.  If the need ever arises in the future, the Agency may require any
of these studies on a case-by-case basis since there are validated OPPTS
guidelines in place.

COMMENT:   Commenter 128 suggested including studies using the EP to
provide useful data.

RESPONSE:    It would be cost prohibitive and highly impractical to test
each formulated EP. EPA is mindful of the burden on the applicant to
conduct studies which may not yield additional useful information. The
Agency will notify the applicant when additional testing using the EP is
required.  EPA is committed to moving towards a more efficient and
reliable testing/risk assessment paradigm that: is more attuned to risk
assessment needs (i.e. hypothesis-driven); avoids requesting data not
used in risk assessment; and reduces and refines the use of laboratory
animals.

Dermal penetration

COMMENT:   Commenters 120 and 124 wondered why EPA did not incorporate
the best available science in its OPPTS harmonized test guideline
(870.7600).  They observed the OECD test guideline for in vitro testing
has been developed.

RESPONSE:  OPP does not currently accept in vitro dermal penetration
studies since this methodology has not yet been validated as a
replacement for in vivo dermal penetration studies.  Currently the
Agency prefers to have chemical-specific dermal absorption study data
for risk assessment.  However, in the absence of chemical-specific
dermal absorption data, it is possible that a value for risk assessment
could be calculated from available oral and dermal studies.  Once the in
vitro dermal penetration methodology has been validated, OPP will accept
this as an alternative to in vivo dermal penetration studies.

COMMENT:  Commenters 52 and 124 requested clarification of Test Note 34.

RESPONSE:  Test Note no. 34 in the Toxicology Data Requirements table on
page 12345 has been revised for further clarification.  The revised
note, now re-numbered as Test Note 35, reads as follows:  “A risk
assessment, assuming that dermal absorption is equal to oral absorption,
must be performed to determine if the study is required, and to identify
the doses and duration of exposure for which dermal absorption is to be
quantified.”  This risk assessment should consider all available oral
studies.  If this “worst case” assessment indicates that there is no
risk concern, then the study would not be required.

COMMENT:   Commenter 128 suggested including studies using the EP to
provide useful data.

RESPONSE:    It would be cost prohibitive and highly impractical to test
each formulated EP.  EPA is mindful of the burden on the applicant to
conduct studies which may not yield additional useful information.  The
Agency will notify the applicant when additional testing using the EP is
required.  EPA is committed to moving towards a more efficient and
reliable testing/risk assessment paradigm that: is more attuned to risk
assessment needs (i.e. hypothesis-driven); avoids requesting data not
used in risk assessment; and reduces and refines the use of laboratory
animals.

Metabolism and pharmacokinetics

COMMENT:  Commenter 52 requested clarification whether Test Note 32
applies to both food and nonfood use or only to nonfood use.

RESPONSE:  The test notes included in the Toxicology Data Requirements
table on page 12343-12344 are applicable to those data requirements
which are required (R) and those which are conditionally required (CR).
For example, in the case of guideline 870.7485, Test Note 32 would be
applicable to both the nonfood use as well as to the food use.  In the
case of the food use, this study would be required. In the case of the
nonfood use, this study requirement would only be considered if the
long-term studies had been required.  Additionally, as stated in the
Test Note, it may be required if significant adverse effects are seen in
other studies which could be elucidated by these studies.

Companion animal safety

COMMENT:   Commenter 128 suggested including studies using the EP to
provide useful data.

RESPONSE:    It would be cost prohibitive and highly impractical to test
each formulated EP. EPA is mindful of the burden on the applicant to
conduct studies which may not yield additional useful information.  The
Agency will notify the applicant when additional testing using the EP is
required.  EPA is committed to moving towards a more efficient and
reliable testing/risk assessment paradigm that: is more attuned to risk
assessment needs (i.e. hypothesis-driven); avoids requesting data not
used in risk assessment; and reduces and refines the use of laboratory
animals.

Non-rodent chronic studies (one-year dog study)

	EPA currently requires a 90-day dog study and a one-year dog study for
all food and nonfood uses to fulfill the non-rodent data requirements.
EPA referenced published literature that suggested that the one-year dog
study may not be necessary.  Based on analysis of a large body of
one-year dog studies in its toxicology database, EPA proposed to
eliminate the one-year dog study but retain the 90-day study.  EPA
solicited review and comment by the FIFRA SAP on the results of the
preliminary analysis for RfD derivation on May 5-6, 2005.

COMMENT:	Ten commenters addressed the elimination of the one-year dog
study.  Commenter 52, in comparing European Union and U.S. data
requirements, indicated the EU requires a one-year dog study but not a
90-day study; the commenter also correctly pointed out that the one-year
study should be considered a subchronic study since 1 year does not
cover the majority of the lifespan of the species.  The EU also requires
toxicokinetic and mechanistic data, which the U.S. does not.  Commenters
113, 124, 125, 130, 131, 133, and 134 strongly supported elimination of
the one-year dog study.

RESPONSE:	The FIFRA SAP reviewed the Agency’s retrospective analysis
of the toxicity studies and encouraged the Agency to continue its
analyses with a larger database.  The FIFRA SAP made the following
recommendations:  (1) increase the robustness of data analysis by
including dog study datasets that were not used for the RfD
determination; (2) conduct an analysis more representative of a
prospective comparison through delineating the 13-week No Observed
Adverse Effect Levels (NOAELs) and Lowest Observed Adverse Effect Levels
(LOAELs) independent of the one-year study and establish data review
criteria; (3) consider data analysis for separate classes of pesticides;
(4) include additional background information on RfD that provides
better perspectives for reviewing the Agency position paper; and (5)
revise the title of the Agency position paper to reflect the purpose of
the data analysis.  The FIFRA SAP specified that “if the results of
the analyses continue to indicate little added value from the one-year
studies, the Agency could move toward eliminating them on a stronger
basis.”

EPA has completed a more extensive analysis of dog toxicity studies on
110 chemicals representing over 50 different classes of pesticides
(USEPA 2006).  EPA concluded from this analysis that extending a dog
toxicity study beyond a thirteen-week duration does not provide
additional essential toxicity information and eliminating the one-year
dog toxicity study does not compromise the data needed for the
determination of chronic RfDs and margins of exposure (MOE).  Thus,
reliance on the required chronic rodent studies, two-generation rat
reproductive study, and the thirteen-week dog toxicity study is
generally expected to provide an adequate basis for chronic RfD
derivation in pesticide risk assessment.

	EPA acknowledges that there may be situations where a longer duration
dog toxicity study may be warranted when a pesticide chemical is highly
bioaccumulating (e.g. builds up in body fat) and is eliminated so slowly
that it does not achieve steady state or sufficient tissue
concentrations to elicit an effect during a 90-day study.  EPA
anticipates that this situation will be infrequent since current
pesticides are not usually designed to be highly persistent and
bioaccumulating.  If such a chemical is encountered, EP would require
the appropriate tier 2 metabolism and pharmacokinetic studies to more
precisely evaluate bioavailability, half life, and steady state and
determine if a longer duration dog toxicity study is needed.

Endocrine disruptors

COMMENT:	Commenters 116, 119, and 128 introduced the Endocrine Disruptor
Screening Program (EDSP) in the context of the thyroid testing protocols
(p. 12296).  They acknowledged that developing protocols to screen
endocrine disruptors has taken more time than initially expected and
that the required testing cannot yet be specified.  Nevertheless,
Commenter 119 felt EPA should include endocrine disruptor effects
testing in the data requirements to allow registrants to plan for the
future and EPA could avoid another rulemaking by doing this.  This
commenter also recommended EPA consider requiring registrants to conduct
the testing.  Commenter 128 expressed concerns about the activity of
endocrine disrupting chemicals at concentrations far below those being
tested in toxicity studies and referenced several studies from the
literature.

RESPONSE:  EPA does not agree with the recommendation to include a data
requirement for endocrine disruptor screening in the final part 158
rule.  As the comment notes, because of the state of scientific
understanding of endocrine disruptor testing, such a provision would
need to indicate that currently such testing is "not required," except
on a case by case basis.  In fact, EPA is still working to identify and
validate appropriate assays to include in an endocrine disruptor
screening battery
(www.epa.gov/scipoly/oscpendo/pubs/assayvalidation/index.htm).  Thus, a
"requirement" for endocrine disruptor testing in the final rule would
not only fail to identify any criteria for requiring endocrine disruptor
testing, but also could not specify the types of studies that might
potentially be required.  Such a "requirement" would provide no
meaningful guidance for pesticide applicants or registrants.  Since EPA
in general intended its proposed and final versions of part 158 to
codify current data requirements, the Agency has decided not to accept
the commenter's recommendation.

	EPA, however, does agree with the comment that pesticide companies, not
EPA, should conduct any studies required by the endocrine disruptor
screening program.  Accordingly, EPA notes that, when the endocrine
disruptor program reaches the stage of full implementation, the Agency
will use its authority to impose testing requirements on pesticide
companies and others who produce pesticide chemicals to generate data to
assess endocrine disrupting effects.  There is no need to modify the
proposed rule to reflect this position.

B.	Test Guidelines Under Development

	EPA listed six studies for which guidelines are under development; they
may be required on a case-by-case basis to support the registration of
particular pesticide products.  As the Agency’s experience with these
studies increases and if the studies are imposed with regularity, EPA
may propose to include them in future revisions to part 158.

COMMENT:	Commenters 133 and 125 pointed out a mistake in the wording of
one of the studies listed:  direct dosing of neonates prior to weaning
for exposure through the maternal route.  This mistake led to some
confusion.  Both commenters had technical and cost concerns with the
wording as it was proposed and pointed out that neonates were already
exposed through the maternal route in the two-generation reproduction
and chronic feeding studies.

RESPONSE:  EPA agrees that the wording should read:  “direct dosing of
neonates prior to weaning rather than exposure through the maternal
route.”  Neonates are routinely exposed through the maternal route (as
opposed to directly dosed) in the current guidelines for developmental
and reproduction studies.

COMMENT:	Commenter 48 said it seemed reasonable to request additional
studies where the results might help assess safe exposure levels but be
individually designed to answer the necessary end-points.  They should
not be routinely required but when knowledge has advanced, a guideline
for these studies would then be appropriate.

RESPONSE:  EPA appreciates this comment on the circumstances under which
such data should be required and will integrate these comments in the
Agency’s continuing discussions on other testing paradigms that may
lead to guideline revisions.

C.	Alternative Testing Paradigms

ILSI/HESI and the ACSA testing paradigm

COMMENT:  Eleven commenters commented on the tiered-testing approach
discussed in the preamble to the proposed rule.  Six commenters
(Commenters 83, 86, 87, 88, 101, and 104) commented on the Health and
Environmental Sciences Institute (HESI)/International Life Sciences
Institute (ILSI) project, “Agricultural Chemical Safety Assessment
(ACSA): a Tiered Approach” and urged EPA to consider the
tiered-testing approach.

Five commenters (120, 124, 128, 130/131, and 134) also suggested that
EPA incorporate the ACSA into the final rule.  Commenter 120 pointed out
that the use of structure-activity relationships (SAR) and predictive
modeling has developed exponentially over the last decade and that
modeling for nontarget organisms and environmental exposure should be
incorporated whenever possible.  Commenter 124 commended EPA for its
significant participation in ACSA and felt that a number of the concepts
developed in ACSA were ripe for incorporation into pesticide testing
requirements at this time and thus requested a delay in finalizing the
rule to allow this to happen.  Commenter 128 called for termination of
EPA’s role in ACSA because of an absence of public interest
representation in the ACSA project; this commenter also asked for
“transparency that has formed the focus for discussion on the
Scientific Advisory Panels (SAP) and Pesticide Policy Dialogue Committee
(PPDC).”  Commenter 130/131 felt that a number of ACSA recommendations
could be incorporated into part 158 to eliminate wasteful redundancies.
Commenter 134 also recommended incorporation of the ACSA paradigm; this
commenter also offered more detailed comments on toxicity studies.

RESPONSE:  ACSA represents the first comprehensive effort to
scientifically redesign the toxicology animal-testing framework for
agricultural chemicals. The ACSA proposal is consistent with EPA's
direction and goals to develop a more efficient and reliable testing
paradigm. Under the ACSA scheme, some studies would be eliminated while
endpoint coverage would be increased in redesigned studies based on
responses observed in a core set of toxicity tests. The value of the
scheme is that animals are more fully utilized and the need for some
tests can be eliminated if the core set of tests or existing knowledge
does not indicate a concern. Decisions on next steps must be made
throughout the course of the study as a thorough evaluation of all
available information, including data on the pharmacokinetics and mode
of action of the pesticide (if such data exist), could lead to different
conclusions regarding the appropriate way to approach testing.

EPA has multiple activities underway to address the remaining science
and policy issues associated with the ASCA proposal.  One essential step
towards adopting the ASCA proposal will be conducting retrospective and
prospective data analyses to determine whether this new testing paradigm
will meet EPA's risk assessment needs as defined by statute.  To this
end, the Office of Pesticide Programs is currently working with EPA's
National Center for Computational Toxicology (NCCT) to populate a
Toxicological Reference Database (ToxRef). The current priority is to
populate ToxRef with data from the rat 2-generation reproductive study,
prenatal toxicity, and systemic toxicity studies on hundreds of
pesticides that represent different classes, modes of action, and
toxicity profiles. EPA will use this relational database to determine
the value of endpoints currently evaluated in risk assessment (i.e., the
F1 versus F2 responses). This analysis will provide scientific support
for EPA's adoption of the proposal as the analysis will subject the ASCA
proposal to a much broader set of chemicals than that used to develop
the proposal.