Accordingly, EPA interprets the notice and comment rulemaking portion
of the FFDCA section 408 process as an integral part of the FFDCA
process, inextricably linked to the administrative hearing. The point
of the rulemaking is to resolve the issues that can be resolved, and to
identify and narrow any remaining issues for adjudication. Consequently
the administrative hearing does not represent an unlimited opportunity
to supplement the record, particularly with information that was
available during the comment period, but that commenters have chosen to
withhold. For example, as discussed at greater length in Unit VI.E.2,
both in their comments, and again in their objections, the Petitioners
failed to provide the underlying mathematical modeling that supported
their claim that the appropriate children's safety factor was 1X,
rather than 4X. Instead, they presented only summary results.
Similarly, although the Petitioners claimed in their comments to have
conducted an alternate analysis showing that aggregate carbofuran
exposures to children would be safe, they failed to provide the data
and details of that assessment to the Agency. They also failed to
provide several critical components that served to support key inputs
into that assessment.
    To read the statute otherwise would be to render the rulemaking
portion of the process entirely duplicative of the hearing, and thus,
ultimately meaningless. See, e.g., FDA v. Brown & Williamson Tobacco,
529 U.S. 120, 132-133 (2000) (Court must interpret statute as a
symmetrical and coherent regulatory scheme, and fit, if possible,

all parts into a harmonious whole.) APW, AFL-CIO v. Potter, 343 F.3d
619, 626 (2nd Cir. 2003) (``A basic tenet of statutory construction * *
* [is] that a text should be construed so that effect is given to all
its provisions, so that no part will be inoperative or superfluous,
void or insignificant, and so that one section will not destroy another
* * *''), quoting Silverman v. Eastrich Mulitple Investor Fund, 51 F.3d
28, 31 (3rd Cir. 1995). The equities of this construction are
particularly strong, where, as here, the information was (or should
have been) available during the comment period. See, Kleissler, 183
F.3d at 202 (``[A]dministrative proceedings should not be a game or a
forum to engage in unjustified obstructionism by making cryptic and
obscure reference to matters that `ought to be' considered and then,
after failing to do more to bring the matter to the agency's attention,
seeking to have that agency determination vacated'') citing Vermont
Yankee Nuclear Power Corp. v. NRDC, 435 U.S. 519, 553-54 (1978). For
example, one of Petitioners' exhibits is the drinking water modeling
that served as the basis for the comments submitted on the proposed
rule. The documents are dated well before the close of the comment
period, and were clearly available for submission along with the
comments (Exhibit 15). Yet they were only provided to EPA as part of
the Petitioners' objections.
    Contrary to Petitioners' contention, EPA's interpretation is
entirely consistent with the FFDCA's language and structure. The fact
that the statute and regulations allow ``any person'' to file
objections is immaterial. At issue is not ``who'' may raise objections,
but what issues may be raised as part of the objections to justify a
hearing. And on the relevant question, the statute is clear that only
certain issues--those of material fact--may be raised in objections to
justify a hearing (21 U.S.C. 346a(g)(2)(B)). EPA's regulations expand
on this limitation, providing, among other requirements, that hearings
will not be held on legal or policy issues, nor on the basis of mere
allegations, nor where EPA concludes that the data and information
submitted, even if accurate, would be insufficient to justify the
factual determination urged (See 40 CFR 178.32). It is true that FFDCA
section 408(g)(2)(A) provides little guidance on the objections that a
party may raise, requiring only that parties identify the specific
provisions challenged, and state ``reasonable grounds'' for their
objection. But the relative silence of the statutory provision does not
mean that EPA is required to allow parties to raise any and all
objections; rather it means that Congress left the question of what
constitutes ``reasonable grounds'' for EPA to resolve.
    In construing that requirement, EPA gives weight to the fact that
408(g) is only one part of a larger, multi-stage, administrative
process, and that the statute does not support an interpretation that
this one phase be granted greater significance than the rest of the
process. Also relevant is that Congress delegated broad discretion to
the Agency to determine whether a hearing is ``necessary'' (21 U.S.C.
346a(g)(2)(B)). Accordingly, EPA believes that whether an objection
states ``reasonable grounds'' is to be measured against the context of
the rulemaking, and the provisions applicable to hearing requests.
    Fundamentally, FFDCA section 408 delegates broad discretion to EPA,
both to determine how best to harmonize the statutory process and to
determine what constitutes ``reasonable grounds'' for objections.
Consequently, the relevant question is whether EPA's exercise of
discretion in requiring parties to present all available factual issues
and evidence during the rulemaking is reasonable. It is undeniably a
reasonable exercise of discretion to ensure that the rulemaking is not
an opportunity for one party to waste the time and resources of all
parties--both the government and other rulemaking participants--by
failing to raise all of their issues or withholding information for the
purpose of surprising the government at a later point during the
proceeding. See, e.g., Vt. Yankee, 435 U.S. at 553-554; United States
v. L.A. Tucker Truck Lines, 344 U.S. 33, 37 (1952) (``courts should not
topple over administrative decisions unless the administrative body * *
* has erred against objection made at the time appropriate under its
practice'').
    EPA has consistently interpreted section 408 in this fashion since
the 1996 amendments. For example, EPA previously ruled that a
petitioner could not raise new issues in filing objections to EPA's
denial of its Original petition. See 72 FR 39318, 39324 (July 18, 2007)
(``The FFDCA's tolerance revocation procedures are not some sort of
`game,' whereby a party may petition to revoke a tolerance on one
ground, and then, after the petition is denied, file objections to the
denial based on an entirely new ground not relied upon by EPA in
denying the petition.''). EPA reasoned that new issues were not
cognizable because they ``not an objection to the `provisions of the *
* * order [denying the petition]' '' (Id.). Similarly, in a recent
decision EPA denied NRDC's request for a hearing because they had
failed in their original petition to raise the claim asserted in their
objection (73 FR 42683, 42696 (July 23, 2008)). EPA noted that although
NRDC did argue in its petition that EPA cannot make a safety finding
without completing the endocrine screening program under FFDCA section
408(p), it did not assert claims regarding the endocrine data and the
children's safety factor. Citing its previous decision, EPA denied
NRDC's objections and hearing requests as to the children's safety
factor (Id.). In that same decision, EPA also denied a number of
hearing requests on the ground that requestor failed to proffer
supporting evidence; EPA opined that a failure to offer evidence at an
earlier stage of the administrative proceeding could not be cured by
suddenly submitting such evidence with a hearing request. (See 73 FR
42683, 42710 (July 23, 2008) (``Presumably Congress created a multi-
stage administrative process for resolution of tolerance petitions to
give EPA the opportunity in the first stage of the proceedings to
resolve factual issues, where possible, through a notice-and-comment
process, prior to requiring EPA to hold a full evidentiary hearing,
which can involve a substantial investment of resources by all parties
taking part * * * Accordingly, if a party were to withhold evidence
from the first stage of a tolerance petition proceeding and only
produce it as part of a request for a hearing on an objection, EPA
might very likely determine that such an untimely submission of
supporting evidence constituted an amendment to the Original petition
requiring a return to the first stage of the administrative proceeding
(if, consideration of information that was previously available is
appropriate at all'').
    The two cases Petitioners cite that are specific to section 408(d)
do not alter this assessment. Neither of those cases addressed the
scope of the evidence that could be properly raised as part of
objections to justify a hearing. Nor were the courts examining the
extent of EPA's authority to impose requirements on the filing of
objections under 408(g). Rather these courts were evaluating the scope
of the FFDCA's exclusive review provisions, and whether the plaintiffs
could bring a challenge to EPA policies and individual tolerance
decisions without first exhausting the FFDCA's petition process.
Geertson Farms v. Johanns, 439 F.Supp.2d 1012, 1022-1023 (N.D. Ca
2006); NY v. EPA, 350 F.Supp.2d 429, 442-443 (S.D.N.Y. 2004). This
issue is not identical to the questions at issue here: for example, the

court in Geertson Farms held that the plaintiffs' procedural and policy
decisions were properly raised initially before the Agency through the
petition process. 439 F.Supp2d at 442. Yet it is undeniable that EPA's
regulations preclude the reliance on policy or legal issues as a
justification for an Agency hearing.
    Nor do the Petitioners' other cases compel a different result. The
majority of the Petitioners' cases concern FFDCA section 701(e), which
differs in several significant respects from FFDCA section 408. Section
701(e) imposes no requirements whatsoever on the party submitting the
objection: ``any person may file objections * * * specifying the
provisions of the order deemed objectionable, stating the grounds
therefore * * *'' 21 U.S.C. 371(e)(2). This section also expressly
provides that FDA must hold a hearing upon request: ``As soon as
practicable after such request for a public hearing, the Secretary,
after due notice, shall hold such a public hearing for the purpose of
receiving evidence relevant and material to the issues raised by such
objections.'' 21 U.S.C. 371(e)(3). In the face of this language, it is
unsurprising that the courts held that FDA lacked discretion to deny a
hearing. Further, under FFDCA section 701(e) the mere filing of an
objection automatically stays the effectiveness of the challenged
provisions. ``Until final action is taken upon such objections is taken
by the Secretary under paragraph (3), the filing of such objections
shall operate to stay the effectiveness of those provisions of the
order to which the objections are made.'' 21 U.S.C. 371(e)(3). By
contrast, section 408 grants the Administrator the discretion to stay
the effectiveness of the regulation if objections are filed. 21 U.S.C.
346a(g)(1). Indeed, the Petitioners' own cases specifically distinguish
between section 701(e) and other FFDCA provisions. See Pactra
Industries v. Consumer Product Safety Commission, 555 F.2d 677, 685
(9th Cir. 1977) (rejecting FDA argument that FFDCA section 701 should
be read consistently with FFDCA sections 505 and 507 to allow for
summary judgment procedures).
    Petitioners' second argument is equally incorrect.\6\ As an initial
matter, the parties agree that FFDCA 408 establishes a hybrid
rulemaking procedure, with informal rulemaking initiating, and
frequently ending, the process (74 FR 23070 (May 15, 2009)); Obj at
62). Hybrid rulemaking is not formal rulemaking, which is the only
rulemaking to which APA sections 556 and 557 apply. Nevertheless,
Petitioners contend that once objections are raised, ``Congress
required the use of a formal rulemaking procedure involving an on-the-
record hearing for resolving factual disputes.'' (Obj at 62) Nothing in
the FFDCA section 408 or the APA supports this interpretation. And the
cases cited in support of this argument are inapposite or misconstrued.
---------------------------------------------------------------------------

    \6\ As discussed below, it is not clear that a determination
that a hearing, if held, must be held in accordance with APA
sections 556 and 557 precludes EPA from exercising its discretion to
restrict the issues and evidence that may be raised at this final
stage of the administrative process.
---------------------------------------------------------------------------

    The APA section 553 on its face applies to all rulemakings except
``[w]hen rules are required by statute to be made on the record after
opportunity for an agency hearing'' (5 U.S.C. 553(c)). Under this
language, APA section 553 will apply unless two requirements are met:
(1) The statute requires an opportunity for a hearing as part of the
rulemaking, and (2) the hearing is required to be ``on the record.''
FFDCA section 408 hearings are neither ``required,'' nor mandated to be
``on the record.'' The case law is clear that statutes containing both
characteristics are the hallmark of formal rulemaking, and that formal
rulemaking is the rare exception. AT&T v. FCC, 572 F.2d 17, 21-23 (2d
Cir. 1978) (``The APA requires trial-type hearings only `[w]hen rules
(or adjudications) are required by statute to be made (or determined)
on the record after opportunity for an agency hearing.' '') (citations
omitted); Minden Beef Co v. Cost of Living Council, 362 F.Supp. 298 (D.
Neb. 1973) (examining whether statutory provision that ``[t]o the
maximum extent possible, the President or his delegate shall conduct
formal hearings * * *'' makes hearings mandatory, in determinating
whether formal rulemaking required). See also, e.g., Girard v.
Klopfenstien, 930 F.2d 738, 741 (9th Cir. 1991) (``The APA does not
apply because a debarment hearing is not required by statute. The fact
that the hearing is `on the record' does not trigger an application of
the formal adjudication provisions of section 554 of the APA'');
Smedberg Machine & Tool v. Donovan, 730 F.2d 1089, 1092-93 (7th Cir.
1984) (holding section 554 inapplicable to a proceeding that ``gives
the adminsitrative law judge the discretion, rather than the obligation
to conduct a review hearing.''). As discussed below, in contrast to
other sections of the FFDCA, such as section 701(e), FFDCA section 408
makes clear that a hearing is not mandatory upon request, but that EPA
has broad discretion to determine whether a public hearing is necessary
to receive factual evidence. See, 21 U.S.C. 346a(g)(2)(B),
346a(g)(2)(C). See also, H.R. Rep. No. 104-669, at 49 (1996).
    The Supreme Court made clear in Florida East Coast Railway v. FLRA,
that the circumstances under which rules are ``required to be made on
the record after opportunity for an agency hearing'' are limited to
those where Congress clearly indicates the intent to do so. 410 US 224,
241 (1973). The mere fact that statute offers an opportunity for an
agency hearing is not sufficient to bring rulemaking under scope of
this exemption. Id. See also, U.S. v. Allegheny-Ludlum Steel, 406 U.S.
742 (1972); NRA v. Brady, 914 F.2d 475, 485 (9th Cir. 1990) (No oral
hearing required where statute required Secretary to ``afford
interested parties opportunity for hearing'' and Agency regulations
reserved right to determine whether oral hearing warranted); Wisconsin
Gas Co v. FERC, 770 F.2d 1144, 1165-1168 (DC Cir. 1985) (APA 556
hearing not required when statute only contained provisions requiring
decision ``after a hearing'' and ``substantial evidence'' standard of
judicial review); AT&T v. FCC, 572 F.2d 17, 21-23 (2d Cir. 1978) (APA
556 hearing not required when statute only contained provisions
requiring decision ``after a hearing'' and ``substantial evidence''
standard of judicial review) Philips Petroleum Co v. FPC, 475 F.2d 842,
851-852 (10th Cir. 1973) (formal rulemaking not required even though
statute required ``full hearing'' and Agency traditionally conducted
trial-type adjudicative hearing).
    Unless the statute providing for agency action prescribes
``hearings on the record,'' either in those exact words or by using
similar words to indicate that Congress specifically intended to impose
the full trial-type requirements of sections 556 and 557, the statute
does not fall within section 553's exception. FL East Coast Railway,
410 US at 241. While the absence of those words is not dispositive,
``in the absence of these magic words, Congress must clearly indicate
its intent to trigger the formal, on the record hearing provisions of
the APA.'' City of West Chicago, Illinois v. NRC. 701 F.2d 632, 641
(7th Cir. 1983) (citations omitted). See also, e.g., National
Classification Committee v. ICC. 765 F.2d 1146, 1150-1151 (DC Cir.
1985) (``Thus under Florida East Coast, there is a strong presumption
that the procedural guarantees of section 553 of the APA are sufficient
unless Congress specifically indicates to the contrary'' citing Vermont
Yankee Nuclear Power Corp v. NRC, 435 U.S. 519 (1978)); AT & T v. FCC,
572 F.2d at 21-23 (``The words, `on the record' have become, as the
District of Columbia Circuit has

observed, a `touchstone test' for the applicability of the APA's trial-
type procedures''); Philips Petroleum Co, 475 F.2d at 851-852 (``The
fact, as previously noted, that the Gas Act does not contain the words
`on the record' furnishes a strong argument in support of the
Commission's contention that informal rulemaking satisfies the
requirements of the APA''); Minden Beef Co, 362 F.Supp. at 306-307
(``Requiring `formal hearings' is not identical with requiring that
rules be made on the record after opportunity for agency hearing.'')
What is notable is that, in all cases, the court required clear
expression that Congress specifically intended to impose full trial-
type requirements.
    Thus the question is whether Congress indicated any intent to
entirely remove the FFDCA section 408 process from the requirements of
553. The mere fact that FFDCA section 408 requires some (or even many)
of the procedures applicable under section 556 and 557 does not resolve
the question. See, e.g., National Classification Committee v. U.S., 765
F.2d 1146, 1150-1151 (DC Cir. 1985) (Rejecting argument that formal
rulemaking required on grounds that ``[u]nder Florida East Coast there
is a strong presumption that the procedural guarantees of section 553
of the APA are sufficient unless Congress specifically indicates to the
contrary''); Association of National Advertisers v. FTC, 627 F.2d 1151,
1165-1168 (DC Cir. 1979) (formal rulemaking not required, even though
statute ``did order use of procedures not required in informal
rulemaking'' such as rights to rebuttal and cross-examination at public
hearing.); American Public Gas Association v. FPC, 567 F.2d 1016, 1065-
1067 (DC Cir. 1977) (Formal rulemaking not required by statutory
provisions requiring ``full hearing'' and ``substantial evidence''
standard of judicial review).
    In fact, the language and legislative history of section 408
provide clear indication of Congressional intent not to subject
proceedings under these sections to APA sections 556 and 557. FFDCA
section 408 does not reference APA sections 556 or 557 (see, e.g., 7
U.S.C. 136d(c)(2)). By contrast, the previous version of section 408
did reference APA section 556, and the deletion of this requirement
provides clear evidence of Congressional intent not to exempt FFDCA
from APA 553. Prior to the 1996 amendments, section 408(d)(5) of the
original act, which governed the conduct of hearings, specifically
referenced APA 556. (``Any report, recommendations, underlying data,
and reasons certified to the Secretary by an advisory committee shall
be made part of the record of the hearing, if relevant and material,
subject to the provisions of section [556] of the APA.''). 21 U.S.C.
346(d)(5). Moreover, the previous version of the statute contained
additional language consistent with the requirement of hearings subject
to APA sections 556 and 557; for example, the previous version of
section 408(d)(5) repeatedly makes reference to ``testifying at such
hearing.'' A further consideration is that several other provisions of
the FFDCA do explicitly reference APA sections 554 or 556. Compare, 21
U.S.C. 333(g)(3) (``A civil penalty * * * shall be assessed by the
Secretary by an order made on the record after opportunity for a
hearing provided in accordance with this subparagraph and section 554
of title 5''); 21 U.S.C. 342(f)(1)(C) (requiring the Secretary, upon
any declaration of imminent hazard under this section to ``initiate a
proceeding in accordance with sections 554 and 556 of title 5''). The
fact that Congress chose not to explicitly reference APA sections 556
or 557 provides a strong indication that they did not intend to impose
such a requirement on section 408 proceedings. See, e.g., St Louis Fuel
and Supply Co v. FERC, 890 F.2d 446, 449 (DC Cir. 1989) (holding that
formal hearing under APA 554 not required on that grounds that ``[w]e
consider it significant that, unlike section 7193(c), other
prescriptions in the DOE Organization Act expressly invoke the APA'')
(citations omitted).
    Nor does any provision of FFDCA section 408 include the requirement
that the hearing be ``on the record.'' By contrast, several other
provisions of the FFDCA include that exact phrase. Compare, 21 U.S.C.
335a(i) (``The Secretary may not take action * * * unless the Secretary
has issued an order for such action made on the record after
opportunity for an agency hearing on disputed issues of material
fact.''); 21 U.S.C. 335b(b)(1)(A) (``A civil penalty shall be assessed
* * * by an order made on the record after an opportunity for an agency
hearing * * *''); 21 U.S.C. 335(c)(b) (``The Secretary may not take
action * * * unless the Secretary has issued an order for such action
made on the record after opportunity for an agency hearing on disputed
issues of material fact.'') Under all rules of statutory construction,
those differences are presumed to be intentional. Russello v. United
States, 464 U.S. 16, 23 (1983) (``[W]here Congress includes particular
language in one section of a statute and omits it in another section of
the same Act, it is generally presumed that Congress acts intentionally
and purposely in the disparate inclusion or exclusion'').
    Equally significant is that the language of section 408 explicitly
grants EPA broad discretion to deny a hearing. Section 408(g)(2)(B)
provides that EPA shall ``hold a public evidentiary hearing, if and to
the extent the Administrator determines that such a public hearing is
necessary to receive factual evidence relevant to material issues of
fact raised by the objections'' (21 U.S.C. 346a(g)(2)(B)) (emphasis
added). This language grants EPA the discretion to determine whether
the issues raised in objections are ``material'' issues of fact.
Further, even where evidence relevant to an issue of material fact is
proffered (essentially the standard set forth in 40 CFR 178.32), EPA
construes the statutory language as requiring it to hold a hearing only
where it determines it is necessary to receive proffered evidence. In
other words, the statute grants EPA the discretion to determine that
the issues could be resolved entirely on the basis of the existing
written record. See Philips Petroleum, 475 F.2d at 848-849 (Formal
rulemaking under APA 556 not required even though statute required that
hearing be held, but ``Commission has a very broad discretion in
determining the form of its proceedings'').
    EPA's construction is confirmed by the House Commerce Committee
Report accompanying the final bill, which states:

    New subparagraph (g)(2)(B) allows an objector to request a
public evidentiary hearing. The Administrator would decide whether
[a] hearing were necessary to receive factual evidence relevant to
material issues of fact raised by the objections. The Committee
expects EPA to use this discretion fairly and to grant hearings to
responsible parties on all sides.

    H.R. Rep. No. 104-669, at 49 (1996) (emphasis added). Notably, in
an earlier version of the 1996 amendments, the House bill provided for
a mandatory hearing during the notice-and-comment rulemaking stage of
an EPA-initiated proceeding. [H.R. 1627, 104th Cong. Section 405 (new
FFDCA section 408(e)(2)) (``EPA shall provide an opportunity for a
public hearing * * *'') (emphasis added). This requirement was dropped
prior to enactment but the contrast with section 408(g)(2)(B) confirms
the discretionary character of the latter.
    If this were not sufficient indication of Congressional intent,
further evidence is provided by the fact that in amending section 408,
Congress chose not to adopt the provisions of section 701(e) that
Petitioners cite in their objections. Clearly, Congress could have

adopted the same provisions found in FFDCA 701(e), or in any of the
other comparable FFDCA provisions discussed above, but chose not to do
so.
    EPA agrees that, when a hearing is warranted, the FFDCA requires an
evidentiary hearing that comports with the procedures contemplated by
408(g)(2)(B). But that is not the same as a requirement that section
553 be inapplicable to the proceedings, or that any hearing be held in
accordance with APA sections 556 and 557.\7\ Rather, section 408's
provisions are consistent with APA sections 553 (b) and (c), which
recognize the potential for hearings as part of informal rulemaking:
``Except when notice or hearing is required by statute, * * * the
agency shall give interested persons an opportunity to participate in
the rule making through submission of written data, views, or
arguments, with or without the opportunity for oral presentation.'' 5
U.S.C. Sec.  553(b)(c) (emphasis added).
---------------------------------------------------------------------------

    \7\ EPA's regulations currently provide for a trial-type
adjudicatory hearing. These regulations were adopted under the
preceding statutory provision, and EPA has not yet undertaken any
effort to revise the regulations to take into account the revised
provisions of section 408.
---------------------------------------------------------------------------

    Finally, Petitioners' citation to case law interpreting FFDCA
section 701(e) does not compel a different result. Petitioners claim
that the provisions of FFDCA 701(e) are ``near identical'' to those
under section 408, and on this basis, argue that, ``by analogy'' these
decisions compel an identical interpretation of the requirements of
FFDCA section 408 (Obj at 65). Petitioners are correct that section
701(e) of the FFDCA has been held to be ``one of those statutes, few in
number, that does require rule-making hearings to be on the record in
accordance with APA sections 556.'' Pactra, supra, 555 F.2d 677, 685
(9th Cir. 1977), citing Florida East Coast Railway, 410 U.S. at 237-38,
(dictum). But in all other regards, Petitioners are incorrect.
    As previously discussed, there are several significant differences
between the statutory language of FFDCA sections 701 and 408 that
render Petitioners' citation to these cases inapposite. Hearings are
mandatory upon request under section 701, and the filing of objections
operates to automatically stay the provisions of the rule. Section
701(e)(2) requires only that the objection ``state the grounds
therefore,'' rather than requiring the a statement of ``reasonable
grounds.'' See Pactra at 684 (distinguishing FFDCA section 701(e) from
507(f) because the latter requires hearing applicants to show
`reasonable grounds'). Further, although section 701 does not itself
contain the requirement that the hearing be ``on the record,'' the
legislative history of this provision indicates that Congress intended
such hearings to be ``on the record.'' Pactra, 555 F.2d at 682-684
(detailing FFDCA section 701 legislative history). These
characteristics played a significant role in the court's decision that
FDA lacked the authority to deny hearings under section 701(e) on the
basis of summary judgment proceedings.\8\ However, as shown above, the
legislative history of section 408 provides a clear indication of a
contrary Congressional intent with respect to hearings under this
section.
---------------------------------------------------------------------------

    \8\ Contrary to Petitioners' allegation, the DC Circuit has not
``arrived at the same conclusion'' (Obj at 65). All of the
discussion from Independent Cosmetic Manufacturers and Distributors
v. U.S. Dept of Health, Education, and Welfare presented in their
objections is dicta from a dissenting opinion. 574 F.2d 553, 572 (DC
Cir. 1978).
---------------------------------------------------------------------------

    Petitioner's reliance on the ``substantial evidence'' standard in
FFDCA section 408(i) is equally misplaced. Incorporation of that
standard into judicial review provisions alone has been consistently
held to be insufficient to indicate Congressional intent to impose the
full requirements of APA sections 556 and 557 to a rulemaking.
Wisconsin Gas Co v. FERC, 770 F.2d at 1167 (``The procedures required
to develop this `substantial evidence' are not necessarily the strict
adversary procedures of sections 556 and 557 of the Administrative
Procedures Act''); Public Systems v. FERC, 606 F.2d 973, 979, n. 32 (DC
Cir. 1979) (substantial evidence requirement in Natural Gas Act
``carries no implications for procedures to be followed by the
Commission in compiling the record''); American Public Gas Association
v. FPC, 567 F.2d 1016, 1065-1067 (DC Cir. 1977) (``In our view,
however, this requirement [of the substantial evidence standard] in the
judicial review provision of the Act does not dictate the procedure to
be followed, or the nature of the hearing to be held).
    The specific language of 408(i) defines the standard for the
reviewing court; it does not describe the process by which the agency
hearing is to be conducted. This is quite different from the language
under 501(c) of the CWA, on which the DC Circuit relied in holding that
hearings pursuant to APA section 554 were required. Marathon Oil v.
EPA, 564 F.2d 1253, 1262-1265 (DC Cir. 1977). The CWA section 501(c)
states ``[i]n any judicial proceeding * * * in which review is sought
of a determination under this chapter required to be made on the record
after notice and opportunity for a hearing * * *'' 33 U.S.C. 1369(c)
(emphasis added).\9\ By contrast, FFDCA section 408(i) merely provides
that ``[a]s to orders issued following a public evidentiary hearing,
the findings of the Administrator with respect to questions of fact
shall be sustained if supported by substantial evidence when considered
on the record as a whole'' (21 U.S.C. 346a(i)) (emphasis added). It is
also worth noting that the court expressly distinguished this case,
which dealt exclusively with an adjudicatory proceeding, from those
circumstances in which an agency proceeds through rulemaking. 564 F.2d
at 1262, n. 30.
    In any event, even if section 556 did apply to hearings under
section 408, Petitioners cannot avoid the case law under section 553
and EPA's interpretation of the interrelationship between any hearing
granted under section 408(g)(2) and the rulemaking preceding it.
Petitioners cite to the general evidentiary provision in section 556(d)
that provides that only irrelevant or immaterial evidence may be
excluded and argue that this generic standard necessarily defines the
scope of a hearing regardless of the statutory scheme in which it is
embedded. However, context matters. As the DC Circuit noted, ``the
informal procedures of section 553 of the APA and the more formal
requirements of sections 556 and 557 are not mutually exclusive.''
American Public Gas Association, 567 F.2d at 1067. Even the caselaw
relied upon by Petitioners does not suggest that section 556(d)'s
evidentiary provision trumps all other considerations. Petitioners cite
primarily to Catholic Medical Center, Inc. v. NLRB, 589 F.2d 1166, 1170
(2d Cir. 1978). In that case, the Second Circuit interpreted section
556(d) as specifying that ``an agency thus may not provide for the
exclusion of evidence not protected by a privilege or countervailing
policy . * * *'' Id. (emphasis added). Here, EPA has interpreted its
authority to impose such a countervailing policy. Moreover, EPA's
interpretation is clearly within the broad discretion granted it by the
statute and the policy underlying the interpretation is a reasonable
adaptation of judicial practice with regard to issues not presented in
notice and comment rulemaking proceedings. Thus, Petitioners' technical
and formalistic argument concerning section 556(d), which ignores the
context of the section 408(g)(2) hearing provision, must be rejected.
    Similarly unavailing is Petitioners' argument concerning section
556(e)'s

specification that the ``exclusive record for decision'' after a
hearing is material or testimony submitted in the hearing or hearing
proceeding. Petitioners assert that this provision somehow removes any
limitations on what can be submitted at the hearing because ``that
`exclusive record' is independent of whatever record may exist in the
prior informal rulemaking * * *.'' (Obj at 64). Yet the hearing record
is not ``independent'' of the rulemaking record in that EPA regulations
require that the rulemaking record be included in the record of the
hearing (40 CFR 179.179.83(a)(1)). Once again, Petitioners' argument
fails because it considers section 556 in isolation rather than taking
into account the context of the entire administrative proceeding in
which the hearing is embedded.
    Finally, Petitioners complain that EPA ``raised a host of new
issues and assertions for the first time in the Final [rule],'' and it
would be inequitable for EPA to prevent them from raising objections on
these new assessments. Petitioners identify ten categories of ``new
computations and contentions'' that they claim raise issues that go
beyond those addressed in their prior comments. With one exception, all
of these ``new computations and contentions'' were revisions to
analyses conducted in response to Petitioners' comments. Indeed, some
of these were revisions undertaken in response to Petitioners' specific
request; for example, the ``new'' BMD analyses they identify were: (1)
Corrections made in response to an EPA error identified in their
comments; (2) an extrapolation of BMD50 s, using the dose-
time-response model, to develop a common point of comparison between
all studies, which they had claimed was the appropriate approach; and
(3) a calculation generating a new dose-response model in order to
calculate the BMD50 s for brain and RBC AChE inhibition, in
response to Petitioners' claim that failure to do so was inappropriate
(Refs. 24, 25, 85). Since these analyses were done at their behest,
they can hardly complain that they present new issues on which they had
no opportunity to comment. The Agency's underlying methodologies were
the same as those used for the proposed rule; the analyses were based
on information provided by the Petitioners and/or to address the
revisions requested as part of the Petitioners' comments.
    Regarding the remaining analyses: The ``new exposure estimates for
ground and surface water,'' as well as the ``revised dietary risk and
drinking water assessments'' and ``new assessment of the impact of
buffers and setbacks'' were conducted to accurately reflect the use
under the registration, as modified by FMC's cancellation of uses and
additional mitigation measures. The same is true for the ``new analysis
of the various carbofuran labels;'' the analysis related to the labels
submitted as part of the September 2008 comments. The chlopyrifos
studies were raised in response to the Petitioners' citation to a
subset of chlorpyrifos data. They acknowledge that the ``new literature
citations'' were provided to address one of their contentions (Obj at
56). The sole exception relates to EPA's calculation of carbofuran-
specific half-lives for use in the dietary risk assessment. As
discussed in Unit VI.G.2, EPA does not reject Petitioners' challenge to
EPA's calculation of the 186-minute half-life on the basis that it is
untimely.\10\
---------------------------------------------------------------------------

    \10\ The Petitioners' claim that ``EPA provided new information
concerning the raw data collected and records maintained by ORD in
relation to its toxicology studies'' is inaccurate. EPA provided no
new information on this topic in the final rule.
---------------------------------------------------------------------------

    A fair indication that EPA has not raised a host of new issues in
the final rule is that, with the exception of the revised half-lives,
Petitioners do not challenge the substance of any of the allegedly
``new'' information. Indeed, as discussed in the sections below,
Petitioners have in many instances failed to address any of the
explanations or revised analyses EPA presented in the final rule.
    Ultimately, Petitioners' complaint misses the point. EPA does not
interpret the statute and regulations to preclude the submission of any
new information as part of the objections phase. Such a position would
in fact be inconsistent with EPA's own regulations and past practice,
which require that in order to support a hearing request, a party
submit more than ``mere allegations or denials'' (40 CFR 178.32(b)(2)).
Rather, EPA's interpretation in this regard is analogous to the
determination of whether a final rule is the logical outgrowth of the
proposal and the comments. For example, EPA does not reject
Petitioners' citation to new studies in support of the contention that
RBC AChE data are generally more sensitive than PNS tissues on the
grounds that they are untimely. This is because these studies are
simply more evidence supplementing the issue they fairly raised in
their comments, and are intended to rebut EPA's response in the final
rule. Similarly, the submission of new analyses relating to the ground
water pH in Exhibit 14 is not considered untimely, as the issues they
raise relating to ground water pH were fairly raised in comments and
discussed throughout the rulemaking. Ultimately, EPA's policy is merely
that the objections phase does not present an opportunity for parties
to begin the process entirely anew, by raising issues or information
that could have been fairly presented as comments on the proposed rule.
Nor is the statute's additional procedural step an excuse to withhold
information that was clearly available at the time of the rulemaking.
    2. Implications for FMC's Submission of New Registration Amendments
as Part of their Objections. On June 29, 2009, in conjunction with
their objections on the final rule, FMC Corporation submitted a request
for EPA to amend its registration in several regards. Some of the
requested amendments were further mitigation measures intended to
address carbofuran's dietary risks. The most significant of these was a
proposal intended to ensure that only 2% of any watershed would be
treated with carbofuran. The proposal would require that, within five
days of applying the product, all applicators report to FMC the
following information: The location that the product will be used,
crop, use rate, application method, acreage, and quantity applied.
Based on this information, FMC would track the percentage in each
watershed. ``Whenever it appears that carbofuran has been applied to
1.75% of any watershed,'' the registrant would report that information
immediately to EPA, ``cease further sales in any county that overlaps
with such a watershed for that use season, and shall attempt to recall
all unused carbofuran within such counties by offering to repurchase
such unused product'' (Exhibit 2). Additionally, FMC requested that its
registration be amended to require that ``based on watershed
boundaries, FMC * * * prior to each use season, allocate to its
distributors in a manner which will attempt to ensure that no
distributor receives more carbofuran for sale than can be accommodated
by the 2% watershed area cap in any watershed supplied by that
distributor.''
    In addition, FMC proposed to add geographic restrictions that would
prohibit use in certain parts of the country. Specifically, they
proposed to restrict the use of carbofuran on potatoes to the three
states: Idaho, Oregon, and to select counties in Washington. They
proposed to restrict use on Sunflowers to only Colorado, Kansas,
Nebraska, and South Dakota, as well as limited portions of North Dakota
and Oklahoma. Under this proposal, use on corn would be restricted to
Colorado, Iowa, Illinois, Indiana, Kansas, Missouri, Nebraska, and
limited counties in Wisconsin. Further, they

proposed to add set-backs (i.e., areas where carbofuran could not be
applied) ranging between 100 and 1,000 feet from drinking water wells,
depending on the geographic area. Finally, as part of these amendments,
FMC also requested that EPA revise its registration to permit use of
carbofuran on pumpkins in Ohio, Illinois, and Indiana, and to cancel
the use on pumpkins in the southeastern United States.
    As made clear in Unit VI.C., FMC's newly-proposed registration
amendments are irrelevant to the prior determinations made in the final
tolerance revocation rule. Further, as discussed in Unit VI.D., as a
consequence of the failure to raise these amendments measures as part
of their comments on the proposal, EPA considers that all issues
arising exclusively as a result of these proposed amendments have been
waived. There is no evident reason that FMC could not have offered
these amendments as part of its September 2008 proposals. All of the
information on which they rely was available in September of 2008. All
of the risk concerns that the amendments were intended to address were
discussed at length in EPA's proposed rule. Since 2006, EPA has clearly
stated its determination that carbofuran's potential to leach into
ground water and to runoff into surface water caused unacceptable
dietary risks. EPA's methodologies for evaluating these risks have not
changed since 2006. Indeed, EPA deferred regulatory action for several
months, subsequent to the Agency's determination in 2006 that
carbofuran did not meet either the FIFRA or FFDCA standard, to allow
the Petitioners time to generate data to address the exact same issues
these proposals are intended to address. In their comments on the
proposed rule, Petitioners provided some mitigation measures intended
to address issues relating to the carbofuran's leaching and runoff
potential: Well set-backs, buffers, geographic use restrictions, and
aerial application recommendations.
    As previously discussed, EPA provided clear notice in the proposed
rule that issues that that were not raised during the comment period
would be considered waived in subsequent stages of the administrative
process (73 FR 44,865). Petitioners were well aware of this, as they
commented that ``EPA's requirement to raise all issues in the comments
does not appear to be legally binding'' (Ref. 18 at 118). Indeed they
acknowledged that they ``agree that identifying disputed issues in the
comments is efficient and desirable, and may help to narrow the issues
arising in subsequent objections and an administrative hearing.
Therefore, the commenters have made a good faith attempt to raise in
these comments the principal issues of which they are aware'' (Id.).
    At this stage of the process, the statute requires the Petitioners
to object to the conclusions and provisions in EPA's final rule, not to
propose some new alternate license that they claim would meet the
statutory standards (21 U.S.C. 346a(g)(2)(A) (``any person may file
objections * * * specifying with particularity the provisions of the
regulation * * * deemed objectionable''). In fact, one might fairly
read their proposal as an admission that the existing license fails to
meet the statutory standards.
    A further consideration is that the question of whether these
amendments can be approved depends on whether the Agency eventually
determines the amended registration meets the standards of FIFRA, which
include considerations beyond the dietary risks evaluated under the
FFDCA. Under FIFRA, the Agency's review of the amendments is also
subject to a statutorily mandated schedule (established as part of the
Pesticide Regulatory Improvement Act (PRIA)). These are no small
matters. In terms of timing, FMC explicitly acknowledged in its letter
submitting the proposed amendments that the amendments were subject to
the PRIA review process, requesting that the actions be subject to the
PRIA 8-month statutory deadline (which would establish a statutory
deadline of February 2010 for Agency consideration of FMC's
application). It is not clear whether FMC is arguing that its
application be accorded a higher priority than other applications and
be taken out of turn, or whether FMC is arguing that the consideration
of the objections and request for hearing must be delayed until the
FIFRA review process is completed. EPA rejects either position;
Petitioners cannot use this tolerance proceeding to evade FIFRA's
statutory review scheme, or use that scheme to delay this tolerance
proceeding.
    As noted, although FIFRA incorporates the FFDCA dietary risk
standard, FIFRA also requires the Agency to evaluate a much wider scope
of issues in determining whether to grant new license requirements. For
example, EPA must evaluate the impact this proposal would have on
worker and ecological risks. In addition, EPA must carefully evaluate
the policy implications involved in authorizing Petitioners' scheme. In
this regard, it is worth noting that FMC's scheme is a novel one that
raises significant policy questions that are specific to FIFRA, such as
whether the steps proposed could be adequately enforced, which could
affect the confidence that everybody would, in fact, comply with all
the steps, (e.g., who would investigate whether users have properly
notified FMC of use of the product; would users have to keep records to
demonstrate to inspectors that they had appropriately reported use; how
would further sales in a county be prohibited); and whether the steps
themselves are appropriate tools from a policy perspective for dealing
with risks associated with the use of a pesticide (e.g., is it
appropriate to require users to report use to a pesticide manufacturer;
is such reporting subject to approval under the Paperwork Reduction
Act; is it appropriate public policy to limit sales in a watershed so
that some growers may have preferential access to a product; would the
scheme encourage early and potentially unnecessary purchase of product
by users; under what circumstances, if any, should EPA approve label
and license conditions that require the extra vigilance that would be
required here of users, distributors, and state and federal
regulators). Even if this scheme were determined independently to meet
the FFDCA safety standard, if ultimately EPA were unable to grant the
amendment based on the other considerations that it must evaluate under
FIFRA, the unacceptable dietary risks would still remain. Thus, whether
this scheme could result in a determination that the dietary risks are
acceptable is not ultimately severable from the larger FIFRA process.
Nor would it be appropriate to attempt to resolve FIFRA issues in a
hearing under the FFDCA.
    Indeed it is questionable whether consideration of the proposed
amendments would be appropriate even under Petitioners' position that
all objections made in good faith may be presented at this stage of the
proceeding (Obj at 61). For example, less than six months prior to
their recent submission, the Petitioners proposed voluntarily
cancellation of all use on pumpkins except in the Southeastern United
States, alleging that sales data demonstrated that carbofuran was
needed in the Southeastern U.S. In response to this amendment, which
was submitted as part of their comments on the proposed rule, EPA
analyzed the dietary risks based on this proposed use pattern for the
final rule. A request, mere months later, for additional use on
pumpkins in states with different geographic and weather conditions and

cancellation of the use in the Southeastern U.S., may fairly be
considered suspect--an action intended to delay the revocation process
by forcing the Agency to conduct yet additional analyses, rather than a
good-faith objection.
    For all of these reasons, EPA has determined that reliance on these
proposed amendments as a basis for raising objections to the final
rule, or for requesting a hearing is not appropriate. Nevertheless, EPA
evaluated the individual objections premised on the newly requested
terms and conditions of registration. And in each case, the submitted
materials relating to these objections and hearing requests
independently failed to meet the statutory and regulatory requirements
to justify a hearing, as discussed in the Units below.

E. Response to Specific Issues Raised in Objections and Hearing
Requests Relating to EPA's Children's Safety Factor

    To more fully understand Petitioners' objection and hearing request
with regard to EPA's choice of a 4X children's safety factor and EPA's
responses, a little background is helpful. Section 408 of the FFDCA
imposes a default additional safety factor for the protection of
infants and children, to take into account the fact that children are
frequently more sensitive to a pesticide's effects than adults. This
default 10X safety factor can only be revised if the Agency has
``reliable data'' to demonstrate that the alternative safety factor--or
no safety factor--``will be safe for infants and children'' (21 U.S.C.
346a(b)(2)(C)). In determining whether a different factor is safe for
children, EPA focuses on the three factors listed in section
408(b)(2)(C)--the completeness of the toxicity database, the
completeness of the exposure database, and potential pre- and post-
natal toxicity. In examining these factors, EPA strives to make sure
that its choice of a safety factor, based on a weight-of-the-evidence
evaluation, does not understate the risk to children. (Ref. 79). The
Agency's approach to evaluating whether sufficient ``reliable'' data
exist to support the reduction or removal of the statutory default 10X
is described below in Figure 1.
BILLING CODE 6560-50-P
[GRAPHIC] [TIFF OMITTED] TR18NO09.000

BILLING CODE 6560-50-C
    EPA has consistently required that data comparing the AChE
inhibition in young rat pups (typically PND11) and adult rats be
submitted on AChE-inhibiting pesticides, such as carbofuran, to
determine the extent of children's potential sensitivity. The study
measures the levels of AChE inhibition in both potentially relevant
target tissues: The brain and either the PNS or red blood cell (RBC),
which serves as a surrogate for the PNS. EPA required these data from
FMC for carbofuran, and FMC on two occasions submitted the studies.
Both sets of data, however, were rejected by EPA as scientifically
flawed because they inaccurately measured the levels of RBC AChE.
    Despite the invalidity of the two FMC studies as to RBC AChE, EPA
still has certain, limited RBC AChE data and other PNS-related data on
carbofuran from other studies. These other carbofuran data indicate the
following: (1) PNS-related effects (tremors) occur in pups as a result
of exposure to carbofuran at low doses; (2) juveniles are more
sensitive than adults to carbofuran based on brain measures; (3)
juveniles are more sensitive than adults to carbofuran based on RBC
AChE measures; and (4) the relative sensitivity of juveniles compared
to adults as to RBC AChE is significantly greater the relative
sensitivity of juveniles compared to adults as to brain AChE. It is
also noteworthy that the data in adult rats showed RBC AChE was
generally more sensitive to carbofuran's effects than brain AChE (RBC
AChE inhibition was higher than brain at every dose except the lowest),
although these data are of limited relevance, because they were
conducted on adult animals rather than pups, and adult responses are
frequently not predictive of children's responses. However, because the
available pup RBC AChE data from EPA-ORD did not involve testing at
doses that produced a sufficiently low level of inhibition, the data
were not sufficient to develop a PoD for juveniles based on RBC AChE.
    Accordingly, in making its children's safety factor determination
for carbofuran, EPA was faced with three significant issues: (1)
Sufficient data on carbofuran that are routinely-required for AChE-
inhibiting pesticides to measure PNS effects was not available; (2)
available data measuring the levels of AChE inhibition in brain and RBC
indicated that juveniles were more sensitive than adults to carbofuran
and other carbofuran data indicated that PNS-related effects could
occur in pups at low dose levels; and (3) although the evidence on
carbofuran as to RBC AChE inhibition in juveniles indicated that
effects on juveniles' PNS might be the most sensitive endpoint, there
was not sufficient data to calculate a PoD (for use in determining the
safe dose or PAD) on these effects. Despite the incompleteness of the
toxicity database and the evidence indicating the potential for pre-
and post-natal toxicity at a very sensitive level, which indicate the
need to retain a children's safety factor, EPA nonetheless determined
that, because there was limited reliable data in juveniles, a full
statutory default 10X was not necessary to ensure that children's
exposures would be ``safe.'' EPA undertook a complex comparison of the
brain and RBC AChE data in juveniles and determined that the likely
increased level of sensitivity for RBC AChE inhibition is 4X. EPA thus
concluded that using an additional children's safety factor of 4X
applied to the PoD from data on brain AChE inhibition in juveniles
would protect infants and children.
    1. Challenge to EPA's Scientific Basis for Retention of a 4X
Children's Safety Factor. Petitioners object to EPA's conclusion that
the lack of peripheral tissue data justifies retention of any portion
of the children's safety factor. Petitioners raise two claims in this
regard. First, they allege that a carbofuran PoD based on brain AChE is
adequately protective of PNS effects. Second, they claim that RBC AChE
inhibition data are not the best surrogate for PNS effects when brain
data are available, and therefore, these data are not an ``appropriate
surrogate for PNS effects'' and should not have been relied upon as the
basis for retaining any portion of the safety factor. In support of
these points, Petitioners submit summaries of the testimony they intend
to offer at a hearing, along with copies of published studies that they
allege provide evidence of the points raised in the testimony.
    In essence, these two main issues overlap, particularly with
respect to the evidence submitted. Petitioners rely on the same studies
to support both points. However, they are presented below separately as
discrete issues in the interest of clarity. Supplemental to these two
main points, EPA has identified three separate allegations made by
Petitioners in support of this objection, which are also analyzed
individually in this section.
    a. Objection/hearing request subissue: Whether a carbofuran PoD
based on pup brain AChE inhibition data alone is adequately protective
of PNS effects. Petitioners argue that by establishing the PoD on pup
brain AChE inhibition data, EPA has adequately accounted for all PNS
effects in pups without the need for an additional children's safety
factor. They argue that brain data will adequately protect against PNS
effects, based on the claim that the available data show that the brain
is equally sensitive or more sensitive than PNS tissue. In support of
this objection, Petitioners' submit the evidence contained in Exhibits
4 and 6. Exhibit 4 consists of a report by Kendall Wallace, PhD,
entitled ``Expert Report: Carbofuran FQPA Safety Factor,'' along with
published studies conducted with OP chemicals, and other NMC chemicals
(Ref. 17, 51, 53, 54, 59, 61, 62, 72). Exhibit 6 consists of a report
by Lucio Costa, PhD, entitled, ``Expert Report: Carbofuran's FQPA
Safety Factor and Interspecies Uncertainty Factor,'' as well as
published literature studies conducted with chlorpyrifos and
disulfoton, both OP pesticides, and a single study with propoxur, an
NMC pesticide.
    i. Background. In the proposed tolerance revocation, EPA presented
its rationale for retention of a children's safety factor.
    As explained in Unit IV.A, EPA uses a weight of evidence approach
to determine the toxic effect that will serve as the appropriate PoD
(or regulatory endpoint) for a risk assessment for AChE inhibiting
pesticides, such as carbofuran (Ref. 78). Neurotoxicity resulting from
carbofuran exposures can occur in both the central (brain) and
peripheral nervous systems (PNS). In its weight of the evidence
analysis, EPA reviews data, such as AChE inhibition data from the
brain, peripheral tissues and blood (e.g., RBC or plasma), in addition
to data on clinical signs and other functional effects related to AChE
inhibition. Based on these data, EPA selects the most appropriate
effect on which to regulate; such effects can include clinical signs of
AChE inhibition, central or peripheral nervous tissue measurements of
AChE inhibition or RBC AChE measures (Id). Due to the rapid nature of
NMC pesticide toxicity it is difficult to document effects in the PNS
or even AChE inhibition in the PNS and thus studies measuring AChE
inhibition in the PNS are very rare for NMC pesticides. Although RBC
AChE inhibition is not adverse in itself, EPA's policy is to use it as
a surrogate for inhibition in peripheral tissues when peripheral data
are not available. As such, RBC AChE inhibition provides an indirect
indication of adverse effects on the nervous system (Id.).
    There are laboratory data on carbofuran for cholinesterase activity
in plasma, RBC, and brain from studies in

multiple laboratory animals (rat, mouse, dog, and rabbits). Among these
are three studies that compare the effects of carbofuran on PND11 rats
with those in young adult rats (i.e., `comparative AChE studies')
(Refs. 1, 2, 66). Two of these studies were submitted by FMC and one
was performed by EPA-ORD. An additional study conducted by EPA-ORD
involved PND17 rats (Ref. 63).
    The studies in juvenile rats show a consistent pattern that
juvenile rats are more sensitive than adult rats to the effects of
carbofuran. These effects include inhibition of brain AChE in addition
to the incidence of clinical signs of PNS neurotoxicity, such as
tremors, at lower doses in the young rats. This pattern has also been
observed for other NMC pesticides, which exhibit the same mechanism of
toxicity as carbofuran (Ref. 81). The 2008 SAP, in its review of the
carbofuran draft NOIC, concurred with EPA that the brain AChE data
clearly indicate that the juvenile rat is more sensitive than the adult
rat (Ref. 36).
    The Agency does not have any AChE inhibition data for carbofuran in
the PNS tissue of adult or juvenile animals. There is data on RBC AChE
inhibition, which is a surrogate for PNS tissue AChE inhibition, in
adult animals at both high and low doses, and RBC data in pups, but
only at doses causing greater than 50% AChE inhibition (a very high
level of inhibition). In adults, the data show that RBC is generally
more sensitive to the effects of carbofuran than the brain, but that at
the lowest dose tested, brain and RBC have similar sensitivity. In
pups, the available data at higher doses show that, like adults, RBC is
more sensitive than brain. For example, the EPA-ORD studies showed that
RBC AChE inhibition is more sensitive than brain AChE inhibition in
both PND11 and PND17 pups at the lowest dose tested. However, the
lowest dose (0.1 mg/kg) in both studies missed the lower portion of the
RBC AChE inhibition dose-response curve for pups. At the lowest dose,
PND 11 pups had approximately 40% brain and 53% RBC AChE inhibition
while PND17 pups had approximately 25% brain and 50% RBC AChE
inhibition. Consequently, the Agency does not have RBC AChE inhibition
data in pups at the low doses (i.e., those that cause only 10%
inhibition) that are relevant to risk assessment to serve as a
surrogate for PNS tissue data.
    EPA explained that additional evidence for the sensitivity of the
PNS to carbofuran's effects comes from data in pregnant rats exposed to
carbofuran that showed clinical signs that may be indicative of
peripheral toxicity. Finally, EPA explained that data from other AChE
inhibiting pesticides show that direct measures of peripheral nervous
system (e.g., lung, heart, and liver AChE) can be more sensitive than
brain AChE inhibition. To help illustrate, EPA gave an example of
another chemical for which brain inhibition alone was not at all
predictive of toxicity, to help explain why the lack of carbofuran data
was so significant. The example given was fenamiphos (an OP pesticide),
where cholinergic toxicity (e.g., tremors, miosis, salivation) was
observed following inhibition of RBC, but not brain, even up to
maximally tolerated doses (McDaniel and Moser, Ref. 53).
    Normally, EPA would regulate based on the most sensitive endpoint,
which in this case would appear to be the effects on children's PNS.
However, as discussed above, EPA lacked the information that would
allow it to establish a PoD (or regulatory endpoint) based on the
effects on children's PNS. EPA therefore established its PoD based on
the AChE inhibition in pup brain. Generally, by regulating based on pup
data, EPA would directly account for any additional sensitivity that
children might have, because the safe levels estimated from these data
would be the levels at which infants and children would be affected. In
such circumstances, EPA could reduce the children's safety factor.
    But because EPA lacked the data on the PNS effects in pups at low
doses of carbofuran, which are most analogous to the exposures that
infants and children will receive from eating food with carbofuran
residues, the Agency could not be confident that assessing risk using
brain AChE inhibition would be protective of potential effects in the
PNS for infants and children. Accordingly, EPA determined that, even
though the Agency was relying on pup data, consistent with the
statutory mandate that an additional safety factor be applied to
account for children's increased sensitivity in the absence of
information affirmatively demonstrating that no such safety factor is
necessary, the Agency could not conclude that removal of the statutory
default 10X would be ``safe for infants and children.'' As some
information was available to characterize the effects on infants and
children, EPA concluded that the full default 10X was unnecessary, and
that it could safely reduce the factor to 4X.
    Petitioners raised many of the same assertions in their comments on
EPA's proposed rule that they raise in their objections. For example,
the Petitioners claimed that because EPA relied on pup brain data, no
additional safety factor would be necessary to account for children's
increased sensitivity, because ``brain data are a better surrogate for
the PNS than RBC data.'' The comments also contended that RBC data are
problematic in a number of regards, e.g., they are more variable. They
also argued that EPA had generally relied exclusively on brain data for
other NMC pesticides, and that to require an additional safety factor
for carbofuran based on the lack of RBC AChE data was inconsistent with
those other decisions.
    In the final rule and response to comments EPA responded to all of
the Petitioners' claims, and comprehensively restated its reasoning
that the lack of PNS inhibition data warranted retention of some
portion of the children's safety factor for carbofuran (74 FR 68694-
68695 (May 15, 2009)). In essence, EPA explained that Petitioners had
not presented any information that fundamentally altered the available
risk information before the Agency. Specifically, EPA concluded that,
given that (1) the EPA-ORD data clearly show that a surrogate measure
of the peripheral nervous system (RBC AChE) in juvenile rats is more
sensitive to the effects of carbofuran than brain AChE inhibition; (2)
clinical signs consistent with toxicity to the peripheral nervous
system were seen at very low doses of carbofuran; and (3) data from
other AChE inhibiting pesticides show that direct measures of
peripheral nervous system (e.g., lung, heart, and liver AChE) can be
more sensitive than brain AChE inhibition, the Agency could not be
confident that assessing risk using brain AChE inhibition would be
protective of potential effects in the peripheral nervous system for
infants and children.
    ii. Denial of hearing request. EPA is denying Petitioners' hearing
request on this subissue because the evidence proffered, even if
established, is insufficient to justify the factual determination urged
(40 CFR 178.32(b)(2)). The totality of the evidence submitted fails to
demonstrate a reasonable possibility that exclusive reliance on
carbofuran brain data will be protective, largely because they have
failed to proffer any evidence on several points that are critical to
their argument. As such, the objection rests on speculation and mere
allegation, and a hearing will not be granted on this basis (Id. See,
e.g., 73 FR 42708 (July 23, 2008); 57 FR 6667, 6671 (February 27,
1991)).
    It is important to remember that to obtain a hearing on EPA's
children's safety factor decision, Petitioners must proffer more than
evidence on whether

EPA erred, Petitioners must proffer evidence showing there is
``reliable data'' supporting the children's safety factor they urge.
Without the latter, their objection is immaterial because the default
position is retention of an additional 10X safety factor. Accordingly,
EPA has evaluated Petitioners' proffers on its children's safety factor
claims in terms of whether they are sufficient to provide the
``reliable data'' needed to justify the 1X safety factor that
Petitioners propose.
    For purposes of resolving whether the statute requires the
retention of a children's safety factor, the critical issue is whether
sufficient data exists to determine the effects on children's
peripheral nervous systems from low doses of carbofuran. None of the
evidence submitted affirmatively addresses this question. As discussed
in more detail below, the only evidence proffered in support of this
objection was: (1) A subset of the available carbofuran data from adult
animals; and (2) data, primarily in adult animals, from other chemicals
to demonstrate that generally, reliance on brain data will be
protective of PNS effects, and therefore EPA can assume that the same
will hold true for carbofuran. However, the Petitioners have failed to
submit any data to demonstrate that the effects seen in adults will be
predictive of the effects in juveniles. They have also submitted no
evidence specific to carbofuran that demonstrates the effects of low
doses on children's peripheral nervous systems. This is critical
because the evidence they do proffer on other chemicals fails to
establish that as a general matter, reliance on brain data will always
be protective of the effects on the PNS. The majority of the evidence
in other chemicals actually proves that reliance on brain data is
frequently not protective of the effects on the PNS. And the remainder
of the evidence on this point, taken in the light most favorable to the
Petitioners, provides only equivocal support for Petitioners. Such
evidence, by itself, is insufficient to relieve the uncertainty that
remains with respect to carbofuran, based on the affirmative evidence
in carbofuran-specific data, showing that reliance on brain data may
not be protective. And such evidence, that entirely fail to address the
points that the statute makes central to a determination of the
appropriate children's safety factor, cannot justify a hearing.
    When examined more closely, their overall evidentiary proffer is
even less impressive. As discussed, much of the evidence was conducted
in adult rats. Indeed the only evidence Petitioners submitted in
support of this objection that was specific to carbofuran's effects on
the PNS was data in adult rats. No evidence was submitted to
demonstrate that adult data are generally predictive of responses in
pups. Nor was any evidence submitted to support the assumption that
pups will respond to low doses of carbofuran in the same way as adults.
Thus their evidentiary proffer is effectively based on mere speculation
that adult data will be predictive of pup responses, which cannot
justify a hearing (40 CFR 178.32(b)(2)). As EPA previously explained in
the proposed and final rules, responses in adult rats are not
necessarily predictive of, or relevant to, responses in juveniles since
the metabolic capacity of juveniles is less than that of adults (73 FR
44864, 74 FR 23046). As such, juvenile rats can be more sensitive to
some toxic agents. Simply put, studies that only involve adult animals,
therefore, do not provide information on effects on the young, which is
the focus of the children's safety factor. No matter how much evidence
Petitioners can amass showing that brain AChE is protective of RBC AChE
in adult animals, that does not relieve the uncertainty concerning
potential sensitivity of PNS tissues in juvenile animals, particularly
when all of the existing carbofuran data shows that pups are more
sensitive than adults to the effects of carbofuran, and that clinical
signs consistent with toxicity to the PNS were seen in pups at very low
doses of carbofuran. Accordingly, in the absence of carbofuran data in
pup PNS tissues or a surrogate such as RBC data, the Petitioners'
evidentiary proffer fails to establish a reasonable possibility that
this issue could be resolved in their favor. A hearing is not
appropriate in such cases (40 CFR 178.32(b)(2)).
    The central tenet of this objection is that regulating based on the
effects in the CNS will ensure that the PNS is protected. In this
regard, Petitioners do cite to studies in juvenile animals, but all of
them are conducted with chemicals other than carbofuran.\11\ Moreover,
the Petitioners' evidence fails to demonstrate that the PNS can never
be more sensitive than the CNS, or even that the PNS is typically less
sensitive than the CNS. Rather, the evidence shows only that the CNS
(brain) is sometimes more sensitive, and sometimes less sensitive than
the PNS, depending on the chemical involved. Because the data do not
show a consistent pattern, it indicates only that the relative
sensitivity between the central and peripheral nervous systems varies
depending on the chemical involved, which cannot establish that
exclusive reliance on brain data as a general proposition will always
be protective of PNS effects in pups. Nor can it establish that
reliance on the brain data will be protective of the PNS effects in the
case of carbofuran.
---------------------------------------------------------------------------

    \11\ Most of the studies were conducted on OP chemicals, and
expressly caution against extending the results to NMC chemicals
such as carbofuran; a point also raised by Petitioners' own experts
(Ex 4, 6).
---------------------------------------------------------------------------

    When data are not available for a specific chemical, conclusions
based on other chemicals can only be scientifically supported if it has
been demonstrated that the conclusion is always true. If, ``in some
cases,'' the conclusion is not true, then in the absence of data on the
specific chemical, the conclusion cannot be made for that chemical, and
uncertainty exists regarding the effects of the individual chemical.
Since there are no data on the effects of carbofuran in PNS tissues or
RBC data at low doses in pups, even assuming that they were able to
prove that for the specific chemicals identified, the CNS is sometimes
more sensitive than the PNS, significant uncertainty would remain
regarding carbofuran's effects on the PNS. This is because the only
evidence specific to the effects of carbofuran on the PNS at low dose
levels that can be used as a comparison with the brain AChE levels is
the adult RBC data.
    This also affects the materiality of this objection. If the adult
RBC AChE data are not considered, as Petitioners suggest, no
carbofuran-specific data exists to demonstrate the level of AChE
inhibition in the PNS of either adults or pups at the low dose levels
relevant to risk assessment. Thus, even assuming Petitioners could
successfully establish every point they raise in this regard, the fact
still remains that a decision maker would have no data that provides
any information relating to the potential effects of carbofuran on a
child's PNS. Given that FFDCA section 408(b)(2)(C) compels the
application of a 10X safety factor in the absence of information to
account for the presumptive sensitivity of children, the lack of any
data bearing on carbofuran's PNS effects would require the Agency to
apply a 10X safety factor, rather than the 4X factor applied in the
final rule.
    A further flaw in the Petitioners' evidence is that it is
internally inconsistent. Notwithstanding their allegations (discussed
in subissue b below) that RBC data are inherently unreliable and should
be discounted in favor of brain data, the carbofuran adult RBC data are
one of the primary pieces of evidence proffered to support the claim
that reliance on the carbofuran pup brain data will protect against all

potential PNS effects (Exhibit 4). As discussed in more detail below,
the Report cites to the carbofuran data with adult rats to conclude
that brain AChE inhibition correlated closely with RBC AChE inhibition.
``This was further substantiated by the study published by McDaniel et
al. (Ref. 54), where they report that the `lowest dose of carbofuran
(0.10 mg/kg) significantly decreased brain ChE activity but not RBC ChE
or motor activity' * * *'' (Id. at 4, 6). Yet having granted scientific
validity to the adult RBC data, they must also concede the relevance of
the EPA-ORD carbofuran pup RBC data, which clearly demonstrate that at
every dose tested, RBC AChE, and therefore the PNS for which it is a
surrogate, is more sensitive than the brain in juvenile rats exposed to
carbofuran. They raise no challenge specific to the scientific validity
of the EPA-ORD data, but rely only on their generic challenge that RBC
data are inherently less reliable than brain data. No hearing is
warranted based on such evidence. See 49 FR 6672 (February 22, 1984)
(challenge to one of five related studies; in the absence of any
additional data bearing on the clinical study, the objection
constitutes nothing more than an allegation); 68 FR 46403 (August 5,
2003) (hearing denied because cited studies only contained equivocal
statements supporting objector's position).
    Accordingly, the sum of their evidence is no more than mere
speculation that the effects of carbofuran exposure in the CNS will be
protective of effects in the PNS. This falls far short of the
``reliable data'' on the safety of infants and children needed to
justify the entire removal of the 10X children's safety factor and thus
cannot justify a hearing (40 CFR 178.21(b)(2)). See, e.g., 73 FR 42697
(July 23, 2008) (denying hearing where the only evidence submitted was
NRDC's claim that if the DDVP two-generation rat reproduction study had
been conducted pursuant to the 1998 guidelines it might have shown
endocrine effects at lower doses than the doses at which DDVP's
cholinesterase effects were seen on grounds that this was mere
speculation); 57 FR 6667 (February 27, 1992) (hearing denied to an
objector who challenged FDA's rejection of a study for only containing
partial histopathological data on the grounds that ``[s]peculation
regarding data that do not exist cannot serve as the basis for a
hearing'').
    A detailed examination of Petitioners' evidence follows below.
    (a) Testimony intended to show that brain is the appropriate
endpoint. Petitioners allege that the ``critical effect of concern due
to carbofuran is nervous system AChE. Brain is a direct measure of such
toxic effects, while RBC not linked to any biological function.'' On
this basis, they conclude that brain represents the most appropriate
endpoint for risk assessment.
    Essentially this testimony fails to prove any dispute of material
fact. EPA relied on the carbofuran pup brain AChE inhibition data to
establish carbofuran's PoD. The Petitioners have not argued that PNS
effects are irrelevant. Indeed, their submissions make clear that
effects on the PNS are appropriate considerations in a risk assessment;
the only point they dispute is whether brain or RBC data best account
for those effects (Exhibits 4, 6).
    Alternatively, if they intend to argue that RBC data entirely lacks
any scientific validity, this is contradicted in several places by
their other objections and their own submissions. As discussed above,
the commenters rely on the adult carbofuran RBC data to support their
claim that reliance on the pup brain data is adequately protective of
PNS effects. Moreover, they explicitly acknowledge that reliance on RBC
data is scientifically valid in the context of the human data (Obj at
13). Consequently, the submitted materials are insufficient to justify
the factual determinations urged, and therefore fail to support a
determination that an evidentiary hearing is warranted (40 CFR
178.32(b)(2)).
    (b) Testimony purporting to show that reliance on brain data is
sufficiently protective of the PNS. The Petitioners raise several
arguments in this regard. First, they allege that, ``brain responds
rapidly to carbofuran, which readily passes blood/brain barrier'' (Obj
at 12-13). Petitioners' primary point, however, is that ``the extent of
brain inhibition by carbofuran more accurately compares with the extent
of PNS inhibition, and therefore brain data are adequately protective''
(Id.). In support of this claim, Petitioners cite to Exhibits 4 and 6,
containing a mixture of ``expert testimony'' and published studies.
None of the information contained in these exhibits is sufficient to
establish a reasonable possibility that this issue could be resolved in
their favor.
    Petitioners' first claim simply reiterates points made in their
comments on the proposed rule. As explained in the final rule, EPA
agrees that the data show that the brain responds rapidly to
carbofuran, and that it readily passes the blood/brain barrier.
However, evidence regarding the speed with which the brain reacts
proves nothing with regard to the relative sensitivity of PNS tissues
(Ref. 85 at 46). Petitioners have presented nothing that challenges the
substance of EPA's response. Consequently, these claims do not present
a live controversy as to a material issue of disputed fact; both
parties agree on the facts at issue, which is that the brain responds
rapidly to carbofuran. Moreover, a simple repetition of comments made
on the proposal without more is insufficient to warrant a hearing. See,
e.g., 73 FR at 42698-42699 (July 23, 2008) (denying several NRDC
hearing requests because the objections were based on EPA's preliminary
DDVP risk assessment, rather than the revised risk assessment published
with the final order); 53 FR 53176 (December 30, 1988) (where FDA
responds to a comment in final rule, repetition of comment in
objections does not present a live controversy unless objector proffers
some evidence calling FDA's conclusion into question); 62 FR 64102,
64105 (December 3, 1997) (objector claimed that addition of ethoxyquin
invalidated studies; hearing denied because objector did ``not dispute
FDA's explanation in the final rule as to why addition of ethoxyquin
did not compromise the CIVO studies, and provided no information that
would have altered the agency's conclusion on this issue'').
    Petitioners' second point--that brain AChE inhibition correlates
closely with PNS inhibition, and demonstrates that reliance on brain
data will be protective of the PNS--is a disputed material issue of
fact that could warrant a hearing, except that none of the evidence
submitted in support of this point presents a reasonable possibility
that the Petitioners could establish the points alleged. Consequently,
they have failed to demonstrate that a hearing is warranted on this
objection (40 CFR 178.32(b)(2)).
    (c) Exhibit 4. This exhibit consists of a report by Kendall
Wallace, PhD, entitled ``Expert Report: Carbofuran FQPA Safety
Factor,'' along with published studies (Ref. 17, 51, 53, 54, 59, 61,
62, 72). The report argues that, ``it is my opinion that for
carbofuran, the evidence indicates that inhibition of brain AChE is an
appropriate surrogate for PNS AChE inhibition and that there is
reasonable certainty that a PoD for carbofuran based on brain AChE
inhibition is protective of any adverse CNS and PNS effects.'' The only
carbofuran evidence directly cited in support of this allegation is
data conducted on adult animals, using RBC AChE data, which they
elsewhere try to discount. This assumes that adults and pups are
similarly sensitive despite the carbofuran-specific evidence to the
contrary. No evidence is discussed or

submitted to support this assumption. This therefore constitutes a mere
allegation, which does not justify a hearing.
    None of the published studies conducted with other chemicals cited
in the Report provide more than equivocal support for the points above;
in fact, in several instances, the study results support EPA rather
than the Petitioners.\12\ The studies contained in this exhibit fall
into two general categories. The first group of studies consists of a
subset of the chlorpyrifos literature--which is generally more relevant
to the subissue discussed in the next objection, arguing that RBC data
are not a good surrogate for the PNS--rather than demonstrating
affirmatively that brain is a protective surrogate for the PNS. The
second category of studies is one paper on physostigmine, a carbamate,
that is discussed in the body of the report. All but one of these
studies was conducted using adult rats.
---------------------------------------------------------------------------

    \12\ It is interesting to note that, in Exhibit 4, the expert
actually faults EPA for comparing OP and NMC pesticides, saying
``Although OP pesticides inhibit AChE, they are completely different
from carbofuran and other N-methylcarbamates * * *:'' (Exhibit 4 at
4). Yet the Exhibit includes papers on effects of chlorpyrifos, an
OP, and these papers are not discussed in the text of the Exhibit.
---------------------------------------------------------------------------

    Marable, et al. (Ref. 51) and Nostrandt et al. (Ref. 59) are two of
the chlorpyrifos studies Petitioners submitted as part of the comments
on the proposed rule, and they contain little evidence to demonstrate
that brain data correlate well with the PNS, and thus are generally
protective of the PNS. Marable et al. involved chronic exposures to
adult dogs; in addition to the fact that adult animals were used, and
therefore provide evidence of little relevance to the question at
issue, there are significant differences between the results of chronic
and acute exposures. As a result of the repeated exposures, blood,
brain and peripheral tissues were at steady state, which cannot occur
from an acute exposure, and therefore this study can provide no
information on the effects from acute exposures. Nostrandt et al.
actually reported that, following a single low dose of chlorpyrifos,
brain inhibition was less (not greater) than the inhibition obtained in
heart which is part of the PNS (although higher inhibition was not seen
in the diaphragm or retina, other parts of the PNS). At higher doses,
the inhibition in brain and peripheral tissues were more similar. Thus,
this study contradicts the Petitioners' claim that brain data will be
protective of all PNS effects. Petitioners offer no explanation of how
the resubmission of these studies addressed EPA's conclusion in the
final rule that the chlorpyrifos data failed to prove their claim.
    Chen, et al. (Ref. 17), another study of chlorpyrifos, discussed
whether plasma or RBC AChE should be used to establish a regulatory
endpoint in humans and compared data from several animal studies, some
of which were conducted with adults and some with pups. This is the
only study in Exhibit 4 that contains data on pups. The results of one
of the studies reported in Chen, et al. shows that at the lowest doses,
inhibition was greater in the heart, which is part of the PNS, than in
the brain (56% and 41% respectively); note that these are the data in
adult rats reported in Nostrandt et al. (described above). Based on
data from a developmental study of chlorpyrifos by Hoberman (Ref. 37),
Chen et al. reported that the doses estimated to produce 50% inhibition
in heart and brain actually show that in 5-day old pups (both males and
females), the heart is 2-3 times more sensitive than brain. Thus, this
study contradicts Petitioners' claim that brain data will be protective
of PNS effects, since the PNS inhibition was greater than brain at the
lowest doses in both adults and pups. And in fact, it supports EPA's
concern that the absence of data at low doses is significant because
the effects at low doses can differ significantly from those at higher
doses. The data from Hoberman showed that at higher doses, ranging from
30-100 mg/kg, the levels of inhibition in the brain were higher than
the levels in the PNS (Ref. 37 at 16)--the exact opposite of what
occurred at the lowest doses.
    The second group of studies consists of data on NMC chemicals.
McDaniel et al. (Ref. 53) and Padilla et al. (Ref. 62) were cited in
support of the claim that the difference in sensitivity between the
brain and RBC is generally less for NMC chemicals. These studies were
conducted with adult animals, and so do nothing to address the question
before the Agency with respect to pups. These studies merely confirm
the existing carbofuran data in adults, which shows that at the lowest
dose tested, brain and RBC are essentially the same.
    Somani et al. (Ref. 72) is a study on another NMC chemical,
physostigmine, in adult animals, cited to support the claim that ``in
adult rats, brain AChE is somewhat more sensitive than RBC or
peripheral AChE to inhibition by acute doses of physostigmine.'' As an
initial matter, it is unclear that this study provides more than
equivocal support for their claim; the study authors claim only that
the brain ``appears'' to have the lowest values. However, even
conceding that this study shows that the CNS tissues in adult rats are
more sensitive to the effects of physostigmine than the PNS tissues,
the data in this study is of limited relevance to the issue at hand,
which is the effects in juveniles. Thus it is ultimately insufficient
to affirmatively support the Petitioners' claim.
    In sum, based on the evidence contained in this exhibit, EPA
concludes that there is not a reasonable probability that the proffered
evidence would resolve the issue in Petitioners' favor, and that
consequently no hearing is warranted on this basis. First, all but one
of the studies discussed in this exhibit were conducted with adult
animals, rather than pups. As such, they provide evidence of little
relevance to the question of whether pups' PNS are more sensitive than
the CNS. In the absence of carbofuran PNS data, or pup RBC data, much
of this evidence is effectively mere speculation about whether adult
data will be predictive of pup responses, which cannot justify a
hearing (40 CFR 178.32(b)(1)).
    (d) Exhibit 6. This exhibit consists of a report by Lucio Costa,
PhD, entitled, ``Expert Report: Carbofuran's FQPA Safety Factor and
Interspecies Uncertainty Factor,'' as well as published literature
studies conducted with chlorpyrifos and disulfoton, both OP pesticides,
and a single study with propoxur, an NMC pesticide (Refs. 71, 19, 20,
21, 61, 52, 41, 64, 16). According to Costa, these studies generally
show that there was similar or greater AChE inhibition in brain than in
the PNS tissues of heart, ileum, or the diaphragm, which Petitioners
claim proves that reliance on carbofuran pup brain AChE inhibition data
will necessarily be protective of all effects in the PNS (Exhibit 6 at
3). The exhibit also references a human incident study (Ref. 50) of
carbamate poisoning in early childhood and in adults, claiming that,
``Lifshitz * * * showed that signs of adverse effects in the CNS,
rather than PNS, prevailed in young children at the low dose levels
covered by the paper.''
    EPA concludes that there is not a reasonable probability that the
evidence contained in this exhibit would resolve the issue in
Petitioners' favor. The results of these studies fail to demonstrate
the point for which Petitioners cite them--that brain AChE is always
equally or more sensitive than PNS AChE, and therefore exclusive
reliance on brain data can be assumed to be protective. Consequently,
the fact that Petitioners can identify examples of other chemicals,
whether OPs or NMCs, that sometimes affect the brain more severely than
the PNS does not prove

that this will be the case with carbofuran. Furthermore, in several of
the cited examples the Petitioners misinterpret the findings, which
actually support EPA's position.
    As explained in EPA's final rule, Petitioners are relying on only a
subset of the chlorpyrifos data. The data, when examined in total, do
not support a conclusion that brain data will always be protective of
PNS effects (74 FR 23054-23055 (May 15, 2009)). But even relying solely
on the studies Petitioners reference in this exhibit, it is clear that
brain is not always inhibited to the same degree as peripheral tissues,
nor is it always protective of peripheral tissues. The data in Padilla
et al. (Ref. 61) are the only chlorpyrifos data that support a
conclusion that reliance on the CNS data will be protective of the PNS.
However, the Padilla study involved chronic dosing of rats via the
feed, and as such, cholinesterase measurements reflected steady-state
conditions. This study cannot provide information relevant to acute
exposure. None of the other chlorpyrifos studies referenced in this
exhibit support this conclusion. In Mattson et al. (Ref. 52), and
Hunter et al. (Ref. 41), following a single dose to pregnant dams,
heart and liver tissues were more inhibited than brain tissues.
Similarly, in Richardson and Chambers (Ref. 64), where repeated doses
were administered to pregnant dams, at both the low and high doses, the
lung tissue was more inhibited than the brain tissue in the one-day old
pups. In Carr et al. (Ref. 16), the results were more equivocal; in a
repeated dosing study using pups of varying ages, whether brain or
peripheral tissues were most inhibited depended on the age of the pups
and the dose. Nevertheless, Carr (2001) showed that brain inhibition
decreased as the age of the pups increased, even though inhibition in
the heart tissues did not. In other words, the submitted material only
supports a conclusion that brain is sometimes inhibited by chlorpyrifos
to the same degree as the peripheral tissues, and in reality, the
studies show that brain is often inhibited to a lesser extent than
peripheral tissues. This cannot support a conclusion that reliance
exclusively on brain data will necessarily be protective in the absence
of some additional carbofuran-specific evidence.
    The results are similar for the disulfoton studies. Schwab et al.
(Ref. 71) shows that after both a single dose and repeated doses, the
brain and peripheral tissues were equally inhibited. However, these
results are contradicted by Costa et al. (Ref. 19) and Costa and Murphy
(1983), where the results varied depending on the dosing and the brain
area examined. In Costa and Murphy (Ref. 21), diaphragm tissues were
more inhibited than brain tissues after a single dose of disulfoton,
while after repeated doses, brain and diaphragm tissues were similarly
inhibited. Thus, the relative sensitivity between CNS and PNS changes
with repeated dosing, and these studies provide no information on RBC
inhibition with which to compare the other tissues.
    Finally, the Lifshitz study does not support the claim for which it
was cited. The study presents no data on the dose levels associated
with the poisoning incidents, and in fact concludes that there was
``insufficient information to compare the doses ingested by [adults and
children].'' However, based on the symptomology reported (comas,
stupor, and severe hypotoxicity) it is likely that the doses were high,
not low, as the Report claims. Also, this study cannot be used to
discount PNS effects in children; a large percentage of the children
clearly showed PNS effects (myosis, diarrhea). In addition, because
this was a retrospective study of patients admitted to a hospital
intensive care unit, given the severity of some of the CNS symptoms,
such as comas, it is not unlikely that even if the subjects also showed
PNS symptoms, they were not reported. Finally, the study authors'
conclusion was that in children, the ``clinical presentation [of
carbamate poisoning] differs from adult poisoning manifestations''
(Ref. 50). Or in other words, that the effects in adults from exposure
to carbamates such as carbofuran are not necessarily predictive of the
effects in children. It is difficult to see how this study could be
fairly argued to support Petitioners' allegations.
    In conclusion, the totality of the evidence in Exhibits 4 and 6
fail to support Petitioners' contention. As shown in Table 1 below, the
majority of the study results demonstrate that the PNS is frequently
more sensitive than the CNS. The remainder, taken in the light most
favorable to the Petitioners, provide merely equivocal support.

                                    Table 1--Summary of Petitioners' Studies
----------------------------------------------------------------------------------------------------------------
                                                                                Is CNS protective of
                                             Study design         Relative inhibition              PNS?
----------------------------------------------------------------------------------------------------------------
                                              Chlorpyrifos Studies
----------------------------------------------------------------------------------------------------------------
Padilla et al. 2005..................  Single dose, adults....  RBC > brain [ap]         Yes (same sensitivity).
                                                                 diaphragm.
Mattsson et al. 2000.................  Single dose, pregnant    RBC > heart > brain....  No.
                                        dams.
Hunter et al. 1999...................  Single dose, pregnant    Liver > brain..........  No.
                                        dams.
                                                                Blood not measured.....
Richardson and Chambers 2003.........  Repeated doses to        Low dose, lung > serum   No.
                                        pregnant dams,           [ap] brain > heart.
                                        measured pups at 1 day  High dose, lung > brain
                                        old (not direct dose).   [ap] heart > serum.
                                                                Note, serum has only
                                                                 [ap] 50% AChE, not
                                                                 true measure of AChE.
Carr et al. 2001.....................  Repeated doses to pups.  PND6: brain [ap]         Not always, depending
                                                                 diaphragm > heart [ap]   on age, dose, and
                                                                 lung > skeletal muscle   brain region.
                                                                 [ap] serum.
                                                                PND10: heart [ap]
                                                                 hindbrain [ap]
                                                                 diaphragm [ap] lung >
                                                                 skeletal muscle >
                                                                 forebrain [ap] serum.
                                                                PND16: heart [ap] lung
                                                                 > brain..
                                                                PND20: heart > lung >
                                                                 brain..
                                                                PND25: brain > PNS.....
                                                                Brain inhibition
                                                                 decreased with age,
                                                                 heart did not.

Nostrandt et al. 1997 (also cited in   Acute dose, adults.....  RBC > heart > brain >    No.
 Chen et al. 1999).                                              diaphragm.
Hoberman 1998 as cited in Chen et al.  Repeated doses to        RBC > heart > brain....  No.
 1999.                                  pregnant dams,
                                        measured in pups at 5
                                        days old (not direct
                                        dose).
----------------------------------------------------------------------------------------------------------------
                                               Disulfoton Studies
----------------------------------------------------------------------------------------------------------------
Schwab et al. 1981...................  Single dose............  heart [ap] ileum [ap]    Yes, similar
                                       Repeated doses.........   brain.                   sensitivity.
                                                                brain [ap] ileum >
                                                                 heart.
                                                                No blood measured......
Costa et al. 1981....................  Single dose............  Brain > ileum..........  Not always, depends on
                                       Repeated doses.........  Forebrain > ileum >       dosing paradigm and
                                                                 hindbrain.               brain region.
                                                                Brain [ap] ileum.......  Not consistent within
                                                                                same study.
                                       Repeated doses.........  No blood measured......
Costa and Murphy 1983................  Single dose............  Diaphragm > brain......  Not always, depends on
                                       Repeated doses.........  Brain [ap] diaphragm      dosing paradigm.
                                                                 [ap] plasma..
                                                                Note, plasma has only
                                                                 [ap] 50% AChE, not
                                                                 true measure of AChE.
----------------------------------------------------------------------------------------------------------------

Accordingly, Petitioners' proffer is facially insufficient because
there is no reasonable possibility that it can establish a necessary
element of Petitioners' objection--that there are ``reliable data''
that show it would be safe for infants and children to remove entirely
the 10X children's safety factor.
    iii. Denial of objection. The objections do not address the
fundamental issue that EPA is required by the statute to resolve: Are
there `reliable' data to support reduction or removal of the statutory
10X for protection of infants and children? The statute compels that
EPA may only revise the 10X default safety factor if, ``on the basis of
reliable data'' EPA can conclude that the alternative safety factor
will be ``safe'' (21 U.S.C. 346a(b)(2)(C)). The statute also requires
EPA to account for the ``completeness of the toxicity data'' in making
this determination (Id). In this case, the Agency concluded that there
are sufficient data to reduce the 10X safety factor but there is
insufficient information to justify removing the factor entirely.
    Similar to other AChE inhibiting pesticides, carbofuran can affect
both the central and peripheral nervous system. Because the relative
sensitivity of the central and peripheral nervous system varies among
pesticides and the children's safety factor should account for the most
sensitive toxicity endpoint, the Agency considers the availability of
data in both the central and peripheral nervous systems important in
its safety factor evaluation.
    As shown in Figure 1, above, there are several datasets that
evaluate the effects of carbofuran on the central nervous system (e.g.,
brain AChE inhibition) in juvenile rats. There are no AChE data from
peripheral tissues. Lack of peripheral AChE data is typical of NMCs due
to the rapid reactivation of AChE. As a matter of science policy, the
Agency typically uses AChE data from blood, particularly RBCs, as a
surrogate measure for the peripheral nervous system (Refs. 76, 87). In
the case of carbofuran, RBC AChE data from two separate studies
submitted by FMC are considered unreliable and unusable in human health
risk assessment (Ref. 83). Data from EPA's ORD includes high quality
RBC AChE data, but only high doses were used in the ORD studies. Data
at the low end of the dose response curve are not available for
assessing the effects in juvenile rats, which are the doses relevant
for human health risk assessment. Thus, because reliable data are
available to assess affects on the CNS and some surrogate data are
available to assess the PNS, the Agency believes that the children's
safety factor can be reduced. However, this factor cannot be completely
removed since the available carbofuran data show that RBC AChE
inhibition in pups is more sensitive than brain AChE inhibition.
    Given that (1) data from other AChE inhibiting pesticides show that
direct measures of peripheral nervous system (e.g., lung, heart, and
liver AChE) can be more sensitive than brain AChE inhibition; (2) a
surrogate measure of the peripheral nervous system (RBC AChE) is more
sensitive in juvenile rats to carbofuran; and (3) clinical signs
consistent with toxicity to the peripheral nervous system were seen at
very low doses, the Agency can not be confident that assessing risk
using brain AChE inhibition is protective of potential effects in the
peripheral nervous system for infants and children. For example, in the
first FMC-sponsored comparative ChE studies (Ref. 4) every pup at the
0.3 mg/kg dose group exhibited tremors. The range-finding portion of
the second FMC-sponsored comparative ChE study (Ref. 1) resulted in
tremors in rats exposed to 0.3 mg/kg carbofuran (\2/5\ males and \2/5\
females) within 15 minutes post-dosing.
    Additional evidence for sensitivity of the PNS comes from
carbofuran data in pregnant rats that showed clinical signs that may be
indicative of peripheral toxicity. The California Department of
Pesticide Regulation (CDPR) has calculated a BMD10 and
BMDL10 of 0.04 and 0.03 mg/kg/day, respectively, for mouth
smacking and chewing in pregnant rats exposed to carbofuran. These
signs are early indicators of toxicity from some cholinesterase
inhibitors (Ref. 56). This is notable for two reasons. First,
cholinergic toxicity (e.g., tremors, miosis, salivation) may be
observed following inhibition of blood, but not brain, cholinesterase.
This was the case with fenamiphos (an OP pesticide), even up to
maximally tolerated doses (Ref. 53). Second, the BMDL10 from
the mouth smacking and chewing in pregnant rats is similar to that
being used by EPA for brain AChE in juveniles. The similarity of the
CDPR BMD in adults and EPA's BMD in juveniles is striking because all
of the available data show that pups are more sensitive than adults to
carbofuran toxicity. This therefore suggests that behavioral effects
and/or clinical signs may be occurring in juvenile animals at lower
doses, but which cannot be detected, in part due to the challenges

with assessing clinical signs in juvenile rats. As noted by the SAP,
this ``limitation reflects the limited range of toxic signs detectable
in very young pups (p. 54).'' This provides further support that the
lack of pup data at lower doses is significant, because the Agency
cannot fully evaluate the behavioral effects on juvenile animals.
    Further support for the Agency's concern comes from other clinical
reports of the effects of carbamate poisoning in children. For example,
Lifshitz reported that all children presented with CNS symptoms (coma,
stupor), but CNS symptoms were observed in only 54% and 23% of children
as reported by Zweiner and Ginsburg (1988) and El-Naggar et al. 2009
(Refs. 91, 26). Peripheral muscarinic symptoms were the most commonly
reported (73% and 100%) signs of toxicity in these latter two reports.
These markedly different findings emphasize that conclusions cannot be
unequivocally drawn from only one study.
    In addition, Petitioners' own data show that effects can differ
significantly between high and low doses. In Chen, for example, the
data from Hoberman showed that at the lowest doses the levels of
inhibition were higher in the PNS than in the brain, but at higher
doses, the levels were higher in the brain.
    Thus, for a number of reasons, the Agency has concerns that
children's PNS may be more sensitive to the effects of carbofuran than
the CNS. This concern is the basis for retention of a portion of the
children's safety factor.
    The carbofuran RBC data in adult animals does not resolve this
question. There can be substantial differences in response between pups
and adults, and, as noted, the data show clearly that pups are more
sensitive to the effects of carbofuran. It is not unusual for juvenile
rats, or indeed, for infants or young children, to be more sensitive to
chemical exposures as metabolic detoxification processes in the young
are still developing. Because pups are more sensitive than adult rats,
data from pups provide the most relevant information for evaluating
risk to infants and young children and are thus used to derive the PoD.
In addition, typically (and this is the case for carbofuran) young
children (ages 0-5) tend to be the most exposed age groups because they
tend to eat larger amounts of food per their body weight than do
teenagers or adults.
    b. Objection/hearing request subissue: Reliance on RBC AChE
inhibition data as a surrogate for PNS effects. This objection also
challenges EPA's decision to retain some portion of the presumptive 10X
children's safety factor, rather than remove it entirely. As explained
above, EPA retained a portion of the presumptive 10X children's safety
factor because of the absence of sufficient data on PNS effects in
juveniles and the uncertainty created by the limited data relevant to
the PNS that showed greater sensitivity in juveniles. In the previous
subissue, Petitioners argued that in fact there is no uncertainty
created by the lack of low dose RBC data and the finding of sensitivity
in the RBC AChE data because brain AChE data is protective of PNS
effects. In this subissue, Petitioners attempt to buttress their first
argument by claiming that RBC AChE data are not an ``appropriate
surrogate'' for PNS effects, and should not have formed the basis for
retention of any portion of the children's safety factor.
    Petitioners do not argue that RBC data are entirely irrelevant, but
rather that brain data are ``preferred.'' They raise several points in
support of this contention; first, that ``RBC AChE inhibition data are
only preferred for risk assessment purposes in two circumstances: (1)
Where the PoD is set using data from human studies where only RBC data
are available or (2) where data from the relevant target tissues are
unavailable.'' They allege that, despite the absence of carbofuran data
in the PNS tissues, brain is preferred in this case because the brain
is ``target tissue'' from the nervous system, and because brain data
are a ``better predictor'' of PNS effects than RBC. As further
evidentiary support, they cite to evidence from OP studies that RBC
AChE can ``in some cases'' be inhibited to a greater degree than either
PNS or brain AChE, and therefore reliance on RBC AChE data can
overstate potential PNS effects. They also argue that RBC AChE is more
variable and less reliably measured at low response levels, such as 10%
AChE inhibition. The evidence in Exhibits 4 and 6 is also proffered in
support of this objection.
    i. Background. EPA's well-established policy when evaluating
cholinesterase-inhibiting compounds is to rely on data in the target
tissue where it is available (Ref. 76). As noted in the preceding
section, measures of AChE inhibition in the PNS are rarely collected
for NMC pesticides. And in fact, there are no carbofuran data measuring
effects in PNS tissues. But in the absence of target tissue data, as a
matter of science policy, EPA typically uses RBC AChE inhibition data
as an indicator of possible effects on AChE in the PNS for number of
reasons. (Ref. 76 at 32). Although RBC AChE inhibition is not adverse
in itself, it is a surrogate for inhibition in peripheral tissues. As
such, RBC AChE inhibition provides an indirect indication of adverse
effects on the nervous system (Id.).
    Petitioners raised many of the same issues raised in the objections
in their comments on the proposed rule. For example, they argued that,
``as a matter of science policy, brain AChE inhibition is the preferred
endpoint over RBC AChE inhibition.'' They also argued that no
physiological function has been demonstrated for RBC, and RBC AChE
inhibition is not itself an adverse effect.
    In the final rule, EPA responded to each of their comments, but
concluded that no information had been submitted to justify altering
the Agency's general policy that reliance on RBC is appropriate as a
surrogate for PNS effects in the absence of direct measurements in PNS
tissues.
    ii. Denial of hearing request. This subissue does not raise a
dispute of material fact. There is no dispute regarding many of the
facts raised in this objection: When data in the target tissue are
available, it is preferred over a surrogate. RBC AChE can be more
variable and less reliably measured at low response levels than brain
AChE. RBC AChE inhibition can, in some cases, be more extensive than
PNS AChE inhibition. Equally, there is no dispute that no physiological
function has been demonstrated for RBC, and RBC AChE inhibition is not
itself an adverse effect. All of these points are explicitly recognized
in EPA's Cholinesterase policy and in the tolerance revocation
rulemaking record, and relate purely to the ease or wisdom of relying
on these measures rather than others, as opposed to the scientific
invalidity of such data. The only point on which there is a dispute is,
given that there is no data in the target tissues of the PNS, which
data--brain or RBC--is ``preferred.'' The Petitioners expressly
acknowledge this to be the issue: ``There are other surrogate measures
of PNS AChE that could have been selected by OPP, such as brain AChE''
(Exhibit 4 at 5). This is clearly a question of scientific policy,
since both EPA and the Petitioners agree on the scientific validity and
relevance of RBC AChE inhibition data. As they expressly acknowledged
in their comments, the choice of which surrogate to use is a matter of
``science policy'' (Ref. 18). Indeed, Petitioners explicitly concede
the propriety of relying on RBC data ``where data from the relevant
target tissues are unavailable, or when relying on human data, where
RBC AChE inhibition data are the only data available (Obj at 13).
Hearings are not

appropriate for debating questions of policy (40 CFR 178.32(b)(1)).
    Nor does the proffered evidence present any other issue that would
warrant a hearing. The evidence submitted in Exhibits 4 and 6 on this
point only relates to the question of whether brain data can sometimes
correspond more closely with PNS effects than RBC AChE data, rather
than the question of whether the RBC data are scientifically invalid.
Or in other words, the submitted materials relate only to the point
that reliance on RBC data is unnecessarily conservative, because
sometimes it overestimates the potential PNS effects, rather than to
the factual question of whether RBC data bears no relation whatsoever
to PNS effects. Unless Petitioners can show that RBC AChE is not
related to CNS effects generally or specifically for carbofuran, or
that brain AChE is protective of CNS effects generally or specifically
for carbofuran, then the mere fact that RBC AChE may be a conservative,
or even very conservative, indicator of PNS effects is simply
immaterial to the question of whether there are ``reliable data'' to
justify removing the presumptive 10X children's safety factor in the
absence of sufficient RBC AChE data. As shown in the discussion of
subissue 1, the Petitioners' evidence does not demonstrate that
reliance on juvenile brain data as a surrogate for effects in the
juvenile PNS will guarantee that the levels chosen on that basis will
be predictive of all PNS effects from carbofuran, because the PNS
effects occur only at the same or higher doses than those that produce
effects on the brain AChE--i.e., that the brain data ``bound'' all
potential PNS effects. Nor, as discussed below, does any of
Petitioners' evidence support a conclusion that RBC AChE is unrelated
to PNS effects.
    Indeed, much of the evidence in the Exhibit 4 and 6 Reports is
ultimately an irrelevance, and thus fails to present a material factual
dispute. Instead of focusing the stated objection--RBC AChE is
inappropriate marker for CNS effects--the Reports attempt to link EPA's
children's safety factor decision to findings concerning chlorpyrifos
(Exhibit 4 at 4). In fact, a fair portion of the Report in Exhibit 6 is
dedicated to a rebuttal of EPA's conclusion that the majority of the
more recent and more relevant chlorpyrifos evidence did not support
Petitioners' contention. EPA, however, has been clear throughout the
rulemaking that the basis for retention of a children's safety factor
has been the absence of carbofuran data to determine the levels of
exposure that will be protective of children's PNS, in the context of a
statutory provision that expressly requires EPA to account for missing
data. EPA's point in discussing the chlorpyrifos data--which
Petitioners initially raised as relevant--was simply that it showed
that because peripheral tissues can be more sensitive than central
nervous system tissues, the absence of data addressing carbofuran's
effects on the PNS is highly relevant. Whatever the chlorpyrifos data
show cannot resolve the extent of carbofuran's risks. As the
Petitioners' experts themselves point out, ``Even conceding that [EPA's
conclusion in the final rule that peripheral tissues are often shown to
be more sensitive than brain tissue following exposure to chlorpyrifos]
may be true, it is still unclear how this would be relevant to
carbofuran * * *'' (Exhibit 6 at 3). Accordingly, this evidentiary
submission fails to demonstrate that a dispute exists on a question of
material fact.
    Finally, their submission provides an inadequate basis on which to
grant a hearing; because evidence is not proffered on critical points,
the objection ultimately rests on allegation, speculation, and general
denials (40 CFR 178.32(b)(2)). As discussed in preceding section, the
majority of the evidence comes from adult data, which are of limited
relevance. Further, and more significantly, the evidence fails to
demonstrate that brain data always--or even more frequently than not--
correlates more closely with PNS effects than RBC AChE data. Instead,
the proffered evidence only demonstrates that whether brain or RBC data
correlate better with actual PNS effects can vary depending on the
chemical. This, therefore, cannot resolve the question as to whether,
in the case of carbofuran, brain AChE data will necessarily correspond
more closely with the PNS. Finally, as also discussed in the preceding
section, Petitioners' argument is internally inconsistent, because they
rely on carbofuran adult RBC AChE data to support their argument that
exclusive reliance on the brain data will be protective of potential
PNS effects in pups. No hearing is appropriate where the proffered
evidence fails to prove the points for which it is offered, or offers
merely equivocal support (See, 73 FR 42705 (July 23, 2008) (hearing
denied because published articles focus on an issue not applicable to
the facts of the case at hand); 68 FR 46405-46406 (August 5, 2003) (a
hearing was denied because the cited studies only contained equivocal
statements)).

A detailed examination of Petitioners' evidence follows below:

    (a) Exhibit 4. As discussed in the previous objection, this exhibit
consists of a report, along with published studies. The Report
criticizes EPA for assuming that RBC AChE inhibition provides ``a
stronger and more quantitative concordance with the sensitivity of AChE
of the PNS to inhibition by carbofuran,'' on the ground that EPA failed
to cite to evidence to support this inference (Exhibit 4 at 5). In the
absence of such evidence, the report concludes that, ``one cannot
discount the plausibility that brain AChE may be a more quantitative
and representative surrogate measure of PNS sensitivity'' (Id). To
support this allegation, the report argues that the cited NMC data show
that the difference in sensitivity between brain and RBC shown with NMC
chemicals is less than the differences seen with OP chemicals, citing
studies by Padilla et al. (Ref. 62) and McDaniel et al. (Ref. 54). In
this regard, the Report actually misquotes McDaniel et al. The Report
claims that the paper concluded that there was a stronger correlation
between brain AChE inhibition and motor activity. The study actually
concluded that there was little difference between brain AChE
inhibition and RBC AChE inhibitions (``higher correlation for brain and
motor activity compared to RBC were not significantly different.'')
(Ref. 54). In any event, the Report's equivocal conclusion that ``one
cannot discount the plausibility'' that brain AChE might be the most
representative measure of PNS effect is, on its face, insufficient
grounds to overcome the statutory presumption for retention of the
additional 10X children's safety factor in the face of the evidence of
children's additional sensitivity to carbofuran, and the lack of
carbofuran data in PNS tissues or in a surrogate for such tissues, RBC
AChE.
    Chen et al. (Ref. 17), which was discussed at length in the earlier
objection, evaluated whether plasma or RBC AChE should be used to
establish a regulatory endpoint; it did not evaluate whether brain AChE
would be an appropriate surrogate for PNS effects. It is true that the
authors conclude that ``[i]nhibition of RBC AChE activity is
consistently exhibited at lower dosages of chlorpyrifos than those
required to result in clinical symptoms of OP toxicity, or alterations
in cognitive functional responses.'' However, since the study authors
ultimately concluded that, ``inhibition of RBC AChE activity is an
appropriate surrogate for measurement of chlorpyrifos exposure and
provides a conservative endpoint for establishing appropriate margins
of

safety for both adults and infants,'' it is difficult to see how this
could be argued to provide unequivocal support for Petitioners'
objections.
    Exhibit 6. This exhibit consists of a report by Lucio Costa, PhD,
entitled, ``Expert Report: Carbofuran's FQPA Safety Factor and
Interspecies Uncertainty Factor,'' as well as published literature
studies. The report discussed the results of several published studies
that they claim demonstrate that ``where available, brain AChE
inhibition data provide a superior surrogate'' to RBC data because ``in
some cases RBC AChE may overestimate PNS AChE inhibition, while in
other cases * * * RBC AChE inhibition may underestimate actual AChE
inhibition in the PNS.'' In support of this allegation, the report
references data from several studies conducted with chlorpyrifos and
disulfoton, both OP pesticides, and a single study with propoxur, an
NMC pesticide (Refs. 16, 19, 20, 21, 41, 52, 61, 64, and 71). According
to the Report, these studies generally show that there was similar or
greater AChE inhibition in brain than in the PNS tissues of heart,
ileum, or the diaphragm, which Petitioners claim proves that reliance
on carbofuran pup brain AChE inhibition data is more predictive of all
effects in the PNS. The exhibit also references a human incident study
(Ref. 50) of carbamate poisoning in early childhood and in adults,
claiming that, ``Lifshitz * * * showed that signs of adverse effects in
the CNS, rather than PNS, prevailed in young children at the low dose
levels covered by the paper.''
    In its denial of the hearing request on the previous issue, EPA
examined the results of the studies in this exhibit at length, and
demonstrated that the results of the studies failed to support a
conclusion that brain data correlate more closely to PNS effects than
RBC data. Indeed, in most of these studies, brain AChE inhibition
poorly reflected the AChE inhibition in PNS tissues. For example, the
Carr et al. study results, reproduced in Table 1 of Exhibit 6, showed
that for PND 10, 16, and 20 rat pups, the heart tissue had the greatest
levels of inhibition, and that PND 16 and 20 rat pups had greater
levels of inhibition in lung tissue than in the brain (Ref. 16 at 3).
Further, since the study was conducted with serum, which contains no
RBC, it is unclear how this study could prove that brain data are a
better indicator of PNS effects than RBC data.
    The remainder of the report consists of criticisms of EPA's
conclusions, and contentions that EPA was inconsistent, without
citation to biological evidence to support these claims. For example,
the Report addresses EPA's rejection of the Bretaud study in goldfish
on the grounds that the ``distribution of carbofuran across fish and
mammalian tissues may be quite different,'' by criticizing EPA for
failing to provide ``evidence or a citation to support this point''
(Exhibit 6 at 1). But they cite to nothing demonstrating the similarity
of fish and mammalian tissues or otherwise supporting their proposed
extrapolation across taxa; at this stage of the administrative process
the obligation is on the Petitioners to come forward with evidence to
call EPA's conclusions into question. See, 73 FR 42683, 42706, July 23,
2008 (``NRDC does no more than state `we are aware of no statistical
test' which would support EPA's use of the Gledhill data. As EPA's
regulations make clear, a mere `denial' of an EPA position is not
enough to satisfy the standard for granting a hearing.''); 53 FR 53176,
53199, December 10, 1982 (``Rather than presenting evidence, [the
objector] asserts that FDA did not adequately justify its conclusions.
Such an assertion will not justify a hearing.''). The report also
attempts to dismiss EPA's conclusions by complaining that EPA's
assessment fails to include ``any analysis of the relationship between
RBC AChE and PNS AChE.'' This also, cannot justify a hearing. As has
been previously noted, FMC, who bears the statutory burden for
producing such data, has failed to provide data in the PNS that would
allow EPA to make the suggested comparison (See, 73 FR 42683, 42699,
July 23, 2008 (hearing denied where NRDC made no evidentiary proffer
supporting its claim that each of the factors cited in EPA's risk
assessment ``poses a serious risk of understating the risks''); 70 FR
21619, April 27, 2005 (objector questioned exposure assessment and
studies relied on for assessment; hearing denied because no information
presented); 72 FR 39557, 39560, July 19, 2007 (``Although Public
Citizen alleged that the studies that FDA evaluated do not support the
safety of x-rays of 10 MeV or lower used for inspection of cargo
containers that may contain food, Public Citizen did not present any
evidence that would have led to a different conclusion concerning the
safety of the subject additive.'').
    iii. Denial of Objection. EPA's well-established policy when
evaluating blood cholinesterase inhibition is to use RBC AChE data as
an indicator of possible effects on AChE in the PNS; EPA adopted this
policy for a number of reasons (Ref. 76 at 32). EPA's reasoning here is
straightforward. As a biomarker of exposure, blood AChE inhibition can
be correlated with the extent of exposure. There is often a direct