Pyraclostrobin; Order Denying Objections to Issuance of Tolerances, 52108-52125 [E7-18025]
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52108
Federal Register / Vol. 72, No. 176 / Wednesday, September 12, 2007 / Notices
ENVIRONMENTAL PROTECTION
AGENCY
C. How and to Whom Do I Submit
Comments?
and inert ingredients of such pesticide.’’
(21 U.S.C. 321(q)(1)).
[EPA–HQ–OPPT–2004–0109; FRL–8146–3]
To submit comments, or access the
public docket, please follow the detailed
instructions as provided in Unit I.B.3. of
the SUPPLEMENTARY INFORMATION of the
June 18, 2007 Federal Register notice. If
you have questions, consult the person
listed under FOR FURTHER INFORMATION
CONTACT.
List of Subjects
Environmental protection, Chemicals,
Endocrine Disruptors, Pesticides
Draft List of Initial Pesticide Active
Ingredients and Pesticide Inerts to be
Considered for Screening under the
Federal Food, Drug, and Cosmetic Act;
Extension of Comment Period
Environmental Protection
Agency (EPA).
ACTION: Notice; extension of comment
period.
AGENCY:
II. What Action Is EPA Taking?
EPA issued a notice in the
Federal Register of June 18, 2007,
concerning the draft list of the first
group of chemicals that will be screened
in the Agency’s Endocrine Disruptor
Screening Program (EDSP). The draft list
was produced using the approach
described in the September 2005 notice,
and includes chemicals that the Agency,
in its discretion, has decided should be
tested first, based upon exposure
potential. This document is extending
the comment period for 60 days, from
September 17, 2007, to November 16,
2007.
SUMMARY:
Comments, identified by docket
identification (ID) number EPA–HQ–
OPPT–2004–0109 must be received on
or before November 16, 2007.
ADDRESSES: Follow the detailed
instructions as provided under
ADDRESSES in the Federal Register
document of June 18, 2007.
FOR FURTHER INFORMATION CONTACT:
Linda Phillips, Office of Science
Coordination and Policy (7203M), Office
of Prevention, Pesticides, and Toxic
Substances, Environmental Protection
Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC 20460–0001; telephone
number: (202) 564–1264; e-mail address:
Phillips.linda@epa.gov.
SUPPLEMENTARY INFORMATION:
DATES:
I. General Information
A. Does this Action Apply to Me?
The Agency included in the June 18,
2007 notice a list of those who may be
potentially affected by this action. If you
have questions regarding the
applicability of this action to a
particular entity, consult the person
listed under FOR FURTHER INFORMATION
CONTACT.
jlentini on PROD1PC65 with NOTICES
B. What Should I Consider as I Prepare
My Comments for EPA?
When preparing comments follow the
procedures and suggestions given in
Unit I.B. of the SUPPLEMENTARY
INFORMATION of the June 18, 2007
Federal Register notice.
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This document extends the public
comment period established in the
Federal Register of June 18, 2007 (72 FR
33486) (FRL–8129–3). In that document,
EPA announced the draft list of the first
group of chemicals that will be screened
in the Agency’s EDSP. The draft list was
developed using the approach described
in the Federal Register notice of
September 27, 2005 (70 FR 56449)
(FRL–7716–9). As required by the
Federal Food, Drug, and Cosmetic Act
(FFDCA), all pesticides must eventually
be screened under the EDSP, and this
first group is simply a starting point.
Because EPA developed this draft list of
chemicals based upon exposure
potential, it should not be construed as
a list of known or likely endocrine
disruptors, and it would be
inappropriate to do so. Following
consideration of comments on this draft
list of chemicals, EPA will issue a
second Federal Register notice
containing the final list of chemicals.
EPA is hereby extending the comment
period, which was set to end on
September 17, 2007, to November 16,
2007.
III. What Is the Agency’s Authority for
Taking this Action?
Section 408(p) of FFDCA requires
EPA to ‘‘develop a screening program,
using appropriate validated test systems
and other scientifically relevant
information, to determine whether
certain substances may have an effect in
humans that is similar to an effect
produced by a naturally occurring
estrogen, or such other endocrine effect
as [EPA] may designate.’’ (21 U.S.C.
346a(p)). The statute generally requires
EPA to ‘‘provide for the testing of all
pesticide chemicals.’’ (21 U.S.C.
346a(p)(3)). However, EPA is authorized
to exempt a chemical, by order upon a
determination that ‘‘the substance is
anticipated not to produce any effect in
humans similar to an effect produced by
a naturally occurring estrogen.’’ (21
U.S.C. 346a(p)(4)). ‘‘Pesticide chemical’’
is defined as ‘‘any substance that is a
pesticide within the meaning of the
Federal Insecticide, Fungicide, and
Rodenticide Act, including all active
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Dated: September 4, 2007.
James B. Gulliford,
Assistant Administrator, Office of Prevention,
Pesticides and Toxic Substances.
[FR Doc. E7–17984 Filed 9–11–07; 8:45 am]
BILLING CODE 6560–50–S
ENVIRONMENTAL PROTECTION
AGENCY
[OPP-2004–0292; FRL–8144–4]
Pyraclostrobin; Order Denying
Objections to Issuance of Tolerances
Environmental Protection
Agency (EPA).
ACTION: Order.
AGENCY:
SUMMARY: The Natural Resource Defense
Council (‘‘NRDC’’) filed objections with
EPA to a final rule under section 408 of
the Federal Food, Drug, and Cosmetic
Act (‘‘FFDCA’’), (21 U.S.C. 346a),
establishing tolerances for the pesticide
pyraclostrobin on various food
commodities. NRDC argues that EPA
has unlawfully removed the additional
safety factor for the protection of infants
and children required by Food Quality
Protection Act of 1996. This order
denies the objections for the reasons
stated herein.
FOR FURTHER INFORMATION CONTACT:
Tony Kish, Registration Division
(7505P), Office of Pesticide Programs,
Environmental Protection Agency, 1200
Pennsylvania Ave., NW., Washington,
DC 20460–0001; telephone number:
(703) 308-9443; e-mail address:
kish.tony@epa.gov.
SUPPLEMENTARY INFORMATION:
Response to NRDC Objections
Table of Contents
I. General Information
A. Does This Action Apply to Me?
B. How Can I Get Additional
Information, Including Copies of
this Document and Other Related
Documents?
II. Introduction
A. What Action Is the Agency Taking?
B. What Is the Agency’s Authority for
Taking This Action?
III. Statutory and Regulatory
Background
A. Statutory Background
B. Setting Tolerances Under the FFDCA
1. In general
2. Choosing a tolerance value
3. The safety determination—risk
assessment
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a. Levels of concern and risk
assessment
(i) Threshold Effects
(ii) Non-threshold effects
b. Estimating human exposure
C. Children’s Safety Factor Policy
IV. The Challenged Tolerance Decision
V. NRDC Objections
A. Children’s Safety Factor
1. Legal Requirements for Imposing
the Children’s Safety Factor and the
Standard for Choosing a Different
Safety Factor
2. Pre-natal Sensitivity
3. Inadequate and Missing Data
a. Immunotoxicity Data
b. Two-generation Reproduction
Study
c. Other Data Deficiencies
B. Arbitrary and Capricious
VI. Public Comment
A. In General
B. BASF Corporation
C. NRDC
VII. Response to Objections
A. Children’s Safety Factor
1. Legal Interpretation of the
Children’s Safety Factor Provision
a. Children’s Safety Factor
Provision
b. Operation of the Children’s
Safety Factor Provision
i. Data Gaps
ii. Increased Sensitivity in the
Young
c. The Standard for Choosing a
Different Safety Factor
2. Individual Factual Findings
Bearing on the Children’s Safety
Factor
a. Pre-Natal Sensitivity
i. Rat Developmental Study
ii. Rabbit Developmental Study
b. Immunotoxicity
c. Two-generation Reproduction
Study
d. Other Data Deficiencies
e. Conclusion With Regard to
NRDC’s Factual Allegations
B. NRDC’s Claim that EPA’s Tolerance
Decision was Arbitrary and
Capricious
C. Conclusion on Objections
VIII. Response to Comments
IX. Regulatory Assessment
Requirements
X. Submission to Congress and the
Comptroller General
I. General Information
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A. Does This Action Apply to Me?
In this document EPA denies
objections to a tolerance actions filed by
the Natural Resources Defense Council
(‘‘NRDC’’). This action may also be of
interest to agricultural producers, food
manufacturers, or other pesticide
manufacturers. Potentially affected
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categories and entities may include, but
are not limited to:
• Crop Production (NAICS code 111).
• Animal Production (NAICS code
112).
• Food Manufacturing (NAICS code
311).
• Pesticide Manufacturing (NAICS
code 32532).
This listing is not intended to be
exhaustive, but rather provides a guide
for readers regarding entities who may
be interested in today’s action.
B. How Can I Get Additional
Information, Including Copies of this
Document and Other Related
Documents?
An electronic copy of this Federal
Register document and all other
documents included in the rulemaking
docket for this action may be accessed
through the EPA’s electronic docket.
EPA has established a docket for this
action under docket identification (ID)
number EPA-HQ-OPP-2004-0292. To
access the electronic docket, go to
https://www.regulations.gov, select
‘‘Advanced Search,’’ then ‘‘Docket
Search.’’ Insert the docket ID number
where indicated and select the
‘‘Submit’’ button. Follow the
instructions on the regulations.gov web
site to view the docket index or access
available documents. All documents in
the docket are listed in the docket index
available in regulations.gov. Although
listed in the index, some information is
not publicly available, e.g., Confidential
Business Information (CBI) or other
information whose disclosure is
restricted by statute. Certain other
material, such as copyrighted material,
is not placed on the Internet and will be
publicly available only in hard copy
form. Publicly available docket
materials are available in the electronic
docket at https://www.regulations.gov,or,
if only available in hard copy, at the
OPP Regulatory Public Docket in Rm. S4400, One Potomac Yard (South
Building), 2777 S. Crystal Drive,
Arlington, VA. The Docket Facility is
open from 8:30 a.m. to 4 p.m., Monday
through Friday, excluding legal
holidays. The Docket telephone number
is (703) 305–5805.You may also access
this Federal Register document
electronically through the EPA Internet
under the Federal Register’’ listings at
https://www.epa.gov/fedrgstr.
II. Introduction
A. What Action Is the Agency Taking?
On June 5, 2006, the Natural Resource
Defense Council (‘‘NRDC’’) filed
objections with EPA to a final rule
under section 408 of the Federal Food,
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Drug, and Cosmetic Act (‘‘FFDCA’’), (21
U.S.C. 346a), establishing tolerances for
the pesticide pyraclostrobin on various
food commodities. (Ref. 1). NRDC makes
two main claims in its objections: (1)
that EPA has unlawfully removed the
additional safety factor for the
protection of infants and children; and
(2) that EPA’s decision to promulgate
the tolerances was arbitrary and
capricious because EPA made its
decision in the absence of data that EPA
had determined were necessary to
evaluate pyraclostrobin’s safety. NRDC
did not exercise the option provided in
section 408(g)(2) to request a hearing on
its objections. This Order responds to
those objections.
EPA published notice of the
objections in the Federal Register, (71
FR 41015 (July 19, 2006)), and held a
60–day public comment period.
The body of this document contains
the following sections. First, there is a
background section which explains the
applicable statutory and regulatory
provisions, EPA risk assessment
practices, and the relevant EPA science
policy documents. Second, EPA
describes the objected-to tolerance
action. Third, there is a section setting
forth in greater detail the substance of
the objections. Fourth, a summary of the
public comment is presented. Finally,
EPA’s announces its response to the
objections.
B. What Is the Agency’s Authority for
Taking This Action?
The procedure for filing objections to
tolerance actions and EPA’s authority
for acting on such objections is
contained in section 408(g) of the
FFDCA and regulations at 40 CFR Part
178. (21 U.S.C. 346a(g)).
III. Statutory and Regulatory
Background
A. Statutory Background
EPA establishes maximum residue
limits, or ‘‘tolerances,’’ for pesticide
residues in food under section 408 of
the FFDCA. (21 U.S.C. 346a). Without
such a tolerance or an exemption from
the requirement of a tolerance, a food
containing a pesticide residue is
‘‘adulterated’’ under section 402 of the
FFDCA and may not be legally moved
in interstate commerce. (21 U.S.C. 331,
342). Monitoring and enforcement of
pesticide tolerances are carried out by
the U.S. Food and Drug Administration
(‘‘FDA’’) and the U. S. Department of
Agriculture (‘‘USDA’’).
A pesticide tolerance may only be
promulgated by EPA if the tolerance is
‘‘safe.’’ (21 U.S.C. 346a(b)(2)(A)(i)).
‘‘Safe’’ is defined by the statute to mean
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that ‘‘there is a reasonable certainty that
no harm will result from aggregate
exposure to the pesticide chemical
residue, including all anticipated
dietary exposures and all other
exposures for which there is reliable
information.’’ (21 U.S.C.
346a(b)(2)(A)(ii)). Section 408 directs
EPA, in making a safety determination,
to ‘‘consider, among other relevant
factors– . . . .available information
concerning the aggregate exposure
levels of consumers (and major
identifiable subgroups of consumers) to
the pesticide chemical residue and to
other related substances, including
dietary exposure under the tolerance
and all other tolerances in effect for the
pesticide chemical residue, and
exposure from other non-occupational
sources.’’ (21 U.S.C. 346a(b)(2)(D)(vi)).
Other provisions address in greater
detail exposure considerations
involving ‘‘anticipated and actual
residue levels’’ and ‘‘percent of crop
actually treated.’’ (See 21 U.S.C.
346a(b)(2)(E) and (F)). Section
408(b)(2)(C) requires EPA to give special
consideration to risks posed to infants
and children. This provision directs that
‘‘an additional tenfold margin of safety
for the pesticide chemical residue and
other sources of exposure shall be
applied for infants and children to take
into account potential pre- and postnatal toxicity and completeness of the
data with respect to exposure and
toxicity to infants and children.’’ (21
U.S.C. 346a(b)(2)(C)). EPA is permitted
to ‘‘use a different margin of safety for
the pesticide chemical residue only if,
on the basis of reliable data, such
margin will be safe for infants and
children.’’ (Id.) [The additional safety
margin for infants and children is
referred to throughout this notice as the
‘‘children’s safety factor.’’] These
provisions establishing the detailed
safety standard for pesticides were
added to section 408 by the Food
Quality Protection Act of 1996
(‘‘FQPA’’), an act that substantially
rewrote this section of the statute.
Tolerances are established by
rulemaking under the unique
procedural framework set forth in the
FFDCA. Generally, the rulemaking is
initiated by the party seeking the
tolerance by means of filing a petition
with EPA. (See 21 U.S.C. 346a(d)(1)).
EPA publishes in the Federal Register a
notice of the petition filing along with
a summary of the petition, prepared by
the petitioner. (21 U.S.C. 346a(d)(3)).
After reviewing the petition, and any
comments received on it, EPA may issue
a final rule establishing the tolerance,
issue a proposed rule, or deny the
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petition. (21 U.S.C. 346a(d)(4)). Once
EPA takes final action on the petition by
either establishing the tolerance or
denying the petition, any affected party
has 60 days to file objections with EPA
and seek an evidentiary hearing on
those objections. (21 U.S.C. 346a(g)(2)).
Objections must state with
‘‘particularity’’ their basis. (40 C.F.R.
178.25(a)(2)). EPA’s final order on the
objections is subject to judicial review.
(21 U.S.C. 346a(h)(1)).
EPA also regulates pesticides under
the Federal Insecticide, Fungicide, and
Rodenticide Act (‘‘FIFRA’’), (7 U.S.C.
136 et seq). While the FFDCA authorizes
the establishment of legal limits for
pesticide residues in food, FIFRA
requires the approval of pesticides prior
to their sale and distribution, (7 U.S.C.
136a(a)), and establishes a registration
regime for regulating the use of
pesticides. FIFRA regulates pesticide
use in conjunction with its registration
scheme by requiring EPA review and
approval of pesticide labels and
specifying that use of a pesticide
inconsistent with its label is a violation
of federal law. (7 U.S.C. 136j(a)(2)(G)).
In the FQPA, Congress integrated action
under the two statutes by requiring that
the safety standard under the FFDCA be
used as a criterion in FIFRA registration
actions as to pesticide uses which result
in dietary risk from residues in or on
food, (7 U.S.C. 136(bb)), and directing
that EPA coordinate, to the extent
practicable, revocations of tolerances
with pesticide cancellations under
FIFRA. (21 U.S.C. 346a(l)(1)).
B. Setting Tolerances Under the FFDCA
1. In general. The process EPA
follows in setting tolerances under the
FFDCA includes two steps. First, EPA
determines an appropriate residue level
value for the tolerance taking into
account data on levels that can be
expected in food. Second, EPA
evaluates the safety of the tolerance
relying on toxicity and exposure data
and guided by the statutory definition of
‘‘safe’’ and requirements concerning risk
assessment. Only on completion of the
second step can EPA make a decision on
whether a tolerance may be established.
Below, EPA explains in detail, the
reasons for this approach.
2. Choosing a tolerance value. In the
first step of the tolerance setting process
(choosing a tolerance value), EPA
evaluates data from experimental crop
field trials in which the pesticide has
been used in a manner, consistent with
the draft FIFRA label, that is likely to
produce the highest residue in the crop
in question (e.g., maximum application
rate, maximum number of applications,
minimum pre-harvest interval between
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last pesticide application and harvest).
(Refs. 2 and 3). These crop field trials
are generally conducted in several fields
at several geographical locations. (Ref. 3
at 5, 7 and Tables 1 and 5). Several
samples are then gathered from each
field and analyzed. (Id. at 53).
Generally, the results from such field
trials show that the residue levels for a
given pesticide use will vary from as
low as non-detectable to measurable
values in the parts per million (‘‘ppm’’)
range with the majority of the values
falling at the lower part of the range.
EPA uses a statistical procedure to
analyze the field trial results and
identify the upper bound of expected
residue values. This upper bound value
is used as the tolerance value. (Ref. 4).
(As discussed below, the safety of the
tolerance value chosen is separately
evaluated.)
There are three main reasons for
closely linking tolerance values to the
maximum value that could be present
from maximum label usage of the
pesticide. First, EPA believes it is
important to coordinate its actions
under the two statutory frameworks
governing pesticides. (See The Pesticide
Coordination Policy; Response to
Petitions, (61 FR 2378, 2379; January 25,
1996)). It would be illogical for EPA to
set a pesticide tolerance under the
FFDCA without considering what action
is being taken under FIFRA with regard
to registration of that pesticide use. (Cf.
40 CFR 152.112(g) (requiring all
necessary tolerances to be in place
before a FIFRA registration may be
granted)). In coordinating its actions,
one basic tenet that EPA follows is that
a grower who applies a pesticide
consistent with the FIFRA label
directions should not run the risk that
his or her crops will be adulterated
under the FFDCA because the residues
from that legal application exceed the
tolerance associated with that use. To
prevent such an outcome, crop field
trials require application of the
pesticide in the manner most likely to
produce maximum residues. Second,
choosing tolerance values based on
FIFRA label rates helps to ensure that
tolerance levels are established no
higher than necessary. If tolerance
values were selected solely in
consideration of health risks, in some
circumstances, tolerance values might
be set so as to allow much greater
application rates than necessary for
effective use of the pesticide. This could
encourage misuse of the pesticide.
Finally, closely linking tolerance values
to FIFRA labels helps EPA to police
compliance with label directions by
growers because detection of an
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overtolerance residue is indicative of
use of a pesticide at levels, or in a
manner, not permitted on the label.
3. The safety determination - risk
assessment. Once a tolerance value is
chosen, EPA then evaluates the safety of
the pesticide tolerance using the process
of risk assessment. To assess risk of a
pesticide, EPA combines information on
pesticide toxicity with information
regarding the route, magnitude, and
duration of exposure to the pesticide.
In evaluating a pesticide’s potential
hazards (e.g., liver effects,
carcinogenicity), EPA examines both
short-term (e.g., ‘‘acute’’) and longerterm (e.g., ‘‘chronic’’) adverse effects
from pesticide exposure. (Ref. 2 at 8–
10). EPA also considers whether the
‘‘effect’’ has a threshold - a level below
which exposure has no appreciable
chance of causing the adverse effect. For
non-threshold effects, EPA assumes that
any exposure to the substance increases
the risk that the adverse effect may
occur. At present, EPA only considers
one adverse effect, the chronic effect of
cancer, to potentially be a non-threshold
effect. (Ref. 2 at 8–9). Not all
carcinogens, however, pose a risk at any
exposure level (i.e., ‘‘a non-threshold
effect or risk’’). Advances in the
understanding of carcinogenesis have
increasingly led EPA to conclude that
some pesticides that cause carcinogenic
effects only cause such effects above a
certain threshold of exposure. EPA has
traditionally considered adverse effects
on the endocrine system to be a
threshold effect; that determination is
being reexamined in conjunction with
the endocrine disruptor screening
program.
Once EPA identifies a hazard for a
durational scenario, EPA must
determine the toxicological level of
concern and then compare estimated
human exposure to this level of
concern. This comparison is done
through either calculating a safe dose in
humans (incorporating all appropriate
safety factors) and expressing exposure
as a percentage of this safe dose (the
reference dose (‘‘RfD’’) approach) or
dividing estimated human exposure into
an appropriately protective dose from
the relevant studies (the margin of
exposure (‘‘MOE’’) approach). How EPA
determines the level of concern and
assesses risk under these two
approaches is explained in more detail
below. EPA’s general approach to
estimating exposure is also briefly
discussed.
a. Levels of concern and risk
assessment—i. Threshold effects. In
assessing the risk from a pesticide’s
threshold effects, EPA evaluates an
array of toxicological studies on the
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pesticide. In each of these studies, EPA
attempts to identify the lowest observed
adverse effect level (‘‘LOAEL’’) and the
next lower dose at which there are no
observed adverse affect levels
(‘‘NOAEL’’). Generally, EPA will use the
lowest NOAEL from the available
studies, taking into account the route
and duration of exposure, as a starting
point in estimating the level of concern
for humans for a given exposure
scenario (e.g., acute oral exposure). This
selected NOAEL is usually referred to as
the Point of Departure. In estimating
and describing the level of concern,
however, the Point of Departure is at
times manipulated differently
depending on whether the risk
assessment addresses dietary or nondietary exposures. (Refs. 2 at 3–8; 5 at
8, 52–52; and 6).
For dietary risks, EPA uses the Point
of Departure to calculate a safe dose or
RfD. The RfD is calculated by dividing
the Point of Departure by applicable
safety or uncertainty factors. Typically,
a combination of safety or uncertainty
factors providing a hundredfold (100X)
margin of safety is used: 10X to account
for uncertainties inherent in the
extrapolation from laboratory animal
data to humans and 10X for variations
in sensitivity among members of the
human population as well as other
unknowns. Further, to account for
deficiencies in the database or the
results seen in the database, EPA has
traditionally applied additional safety
factors on a case-by-case basis. The
FQPA amendments to FFDCA section
408 require an additional safety factor of
10X to protect infants and children (to
address data completeness and pre- and
post-natal toxicity concerns), unless
reliable data support selection of a
different factor.
In implementing FFDCA section 408,
EPA’s Office of Pesticide Programs, also
calculates a variant of the RfD referred
to as a Population Adjusted Dose
(‘‘PAD’’). A PAD is the RfD divided by
any portion of the FQPA children’s
safety factor that does not correspond to
one of the traditional additional safety
factors used in general Agency risk
assessment. (Ref. 5 at 13–16). The
reason for calculating PADs is so that
other parts of the Agency, which are not
governed by FFDCA section 408, can,
when evaluating the same or similar
substances, easily identify which
aspects of a pesticide risk assessment
are a function of the particular statutory
commands in FFDCA section 408.
Today, RfDs and PADs are generally
calculated for both acute and chronic
dietary risks although traditionally a
RfD or PAD was only calculated for
chronic dietary risks. Throughout this
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document general references to EPA’s
calculated safe dose are denoted as a
RfD/PAD.
To quantitatively describe risk using
the RfD/PAD approach, estimated
exposure is expressed as a percentage of
the RfD/PAD. Dietary exposures lower
than 100 percent of the RfD/PAD are
generally not of concern.
For non-dietary, and often for
combined dietary and non-dietary, risk
assessments of threshold effects, the
toxicological level of concern is not
expressed as a safe dose or RfD/PAD but
rather as the margin of exposure (MOE)
that is necessary to be sure that
exposure to a pesticide is safe. To
calculate the MOE for a pesticide for a
given exposure scenario, the expected
human exposure to the pesticide is
divided into the dose identified as the
Point of Departure. A safe MOE is
generally considered to be a margin at
least as high as the product of all
applicable safety factors for a pesticide.
For example, if a pesticide needs a 10X
factor to account for interspecies
differences, a 10X factor for intraspecies
differences, and a 10X FQPA children’s
safety factor, the safe or target MOE
would be a value of at least 1,000. In
contrast to the RfD/PAD approach, the
higher the MOE, the safer the pesticide.
Accordingly, if the target MOE is 1,000,
MOEs exceeding 1,000 would generally
not be of concern. Like RfD/PADs,
specific MOEs are calculated for
exposures of different durations. For
non-dietary exposures, EPA typically
examines short-term, intermediate-term,
and long-term exposures. Additionally,
non-dietary exposure often involves
exposures by various routes including
dermal, inhalation, and oral.
The RfD/PAD and MOE approaches
are fundamentally equivalent. For a
given risk and given exposure of a
pesticide, if the pesticide were found to
be safe under a RfD/PAD analysis it
would also pass under the MOE
approach, and vice-versa.
ii. Non-threshold effects. For risk
assessments for non-threshold effects,
EPA does not use the RfD/PAD or MOE
approach. Rather, EPA calculates the
slope of the dose-response curve for the
non-threshold effects from relevant
studies using a model that assumes that
any amount of exposure will lead to
some degree of risk. The slope of the
dose-response curve can then be used to
estimate the probability of occurrence of
additional adverse effects as a result of
exposure to the pesticide. For nonthreshold cancer risks, EPA generally is
concerned if the probability of increased
cancer cases exceed the range of 1 in 1
million. Because NRDC’s petition
concerns the children’s safety factor and
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the children’s safety factor is only
applicable to threshold risks, no further
discussion of non-threshold risk
assessment is included here.
b. Estimating human exposure.
Equally important to the risk assessment
process as identifying hazards and
determining the toxicological level of
concern is estimating human exposure.
Under FFDCA section 408, EPA is
concerned not only with exposure to
pesticide residues in food but also
exposure resulting from pesticide
contamination of drinking water
supplies and from use of pesticides in
the home or other non-occupational
settings. (See 21 U.S.C.
346a(b)(2)(D)(vi)). There are two critical
variables in estimating exposure in food:
(1) The types and amount of food that
is consumed; and (2) the residue levels
in those foods. Consumption is
estimated by EPA based on scientific
surveys of individuals’ food
consumption in the United States
conducted by the U.S. Department of
Agriculture. (Ref. 2 at 12). Information
on residue levels comes from a range of
sources including crop field trials, data
on pesticide reduction due to processing
and other practices, information on the
extent of usage of the pesticide, and
monitoring of the food supply. (Id. at
17).
In assessing exposure from pesticide
residues in food, EPA, for efficiency’s
sake, follows a tiered approach in which
it, in the first instance, conducts an
initial, screening-level exposure
assessment using the worst case
assumptions that 100 percent of the
crop in question is treated with the
pesticide and 100 percent of the food
from that crop contains pesticide
residues at the tolerance level. (Id. at
11). When such an assessment shows no
risks of concern, EPA’s resources are
conserved because a more complex risk
assessment is avoided and regulated
parties are spared the cost of any
additional studies that may be needed.
If, however, a first tier assessment
suggests there could be a risk of
concern, EPA then attempts to refine its
exposure assumptions to yield a more
realistic picture of residue values
through use of data on the percent of the
crop actually treated with the pesticide
and data on the level of residues that
may be present on the treated crop.
These latter data are used to estimate
what has been traditionally referred to
by EPA as ‘‘anticipated residues.’’ Use
of percent crop treated data and
anticipated residue information is
appropriate because EPA’s worst case
assumptions of 100 percent treatment
and residues at tolerance value
significantly overstate residue values.
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(71 FR 43906, 43909–43910 (August 2,
2006)).
In estimating pesticide exposure
levels in drinking water, EPA most
frequently uses mathematical water
exposure models rather than pesticidespecific monitoring data. (69 FR 30042,
30058 (May 26, 2004). EPA’s models are
based on extensive monitoring data and
detailed information on soil properties,
crop characteristics, and weather
patterns. These models calculate
estimated environmental concentrations
of pesticides using laboratory data that
describe how quickly the pesticide
breaks down to other chemicals and
how it moves in the environment (i.e.,
does it bind to the soil or is it highly
water soluble). Although computer
modeling provides an indirect estimate
of pesticide concentrations, these
concentrations can be estimated
continuously over long periods of time,
and for places that are of most interest
for any particular pesticide. Modeling is
a useful tool for characterizing
vulnerable sites, and can be used to
estimate peak concentrations from
infrequent, large storms. Whether EPA
assesses pesticide exposure in drinking
water through monitoring data or
modeling, EPA uses the higher of the
two values from surface and ground
water in assessing overall exposure to
the pesticide. In most cases, pesticide
residues in surface water are
significantly higher than in ground
water.
Generally, in assessing residential
exposure to pesticides, EPA relies on its
Residential Standard Operating
Procedures (‘‘SOPs’’)(Ref. 7). The SOPs
establish models for estimating
application and post-application
exposures in a residential setting where
pesticide-specific monitoring data is not
available. SOPs have been developed for
many common exposure scenarios
including pesticide treatment of lawns,
garden plants, trees, swimming pools,
pets, and indoor surfaces including
crack and crevice treatments. The SOPs
are based on existing monitoring and
survey data including information on
activity patterns, particularly for
children. Where available, EPA relies on
pesticide-specific data in estimating
residential exposures.
C. Children’s Safety Factor Policy
As part of implementation of the
major changes to FFDCA section 408
included in the FQPA, EPA has issued
a number of policy guidance documents
addressing critical science issues. On
January 31, 2002, EPA released its
science policy guidance on the
children’s safety factor. (Ref. 5) [This
policy is hereinafter referred to as the
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‘‘Children’s Safety Factor Policy’’]. The
Children’s Safety Factor Policy
emphasizes throughout that EPA
interprets the children’s safety factor
provision as establishing a presumption
in favor of application of an additional
10X safety factor for the protection of
infants and children. (Id. at 4, 11, 47, A6). Further, the policy notes that the
children’s safety factor provision
permits a different safety factor to be
substituted for this default 10X factor
only if reliable data are available to
show that the different factor will
protect the safety of infants and
children. (Id.). Given the wealth of data
available on pesticides, however, the
policy indicates a preference for making
an individualized determination of a
protective safety factor if possible. (Id. at
11). The policy states that use of the
default factor could under- or overprotect infants and children due to the
wide variety of issues addressed by the
children’s safety factor. (Id.). Further,
the policy notes that ‘‘[i]ndividual
assessments may result in the use of
additional factors greater or less than, or
equal to 10X, or no additional factor at
all.’’ (Id.).
In making pesticide-specific
assessments regarding the magnitude of
the children’s safety factor, the policy
stresses the importance of focusing on
the statutory language that ties the
children’s safety factor to concerns
regarding potential pre- and post-natal
toxicity and the completeness of the
toxicity and exposure databases. (Id. at
11–12). As to the completeness of the
toxicity database, the policy
recommends use of a weight-of-theevidence approach which considers not
only the presence or absence of data
generally required under EPA
regulations and guidelines but also the
availability of ‘‘any other data needed to
evaluate potential risks to children.’’ (Id.
at 20). The policy indicates that the
principal inquiry concerning missing
data should center on whether the
missing data would significantly affect
calculation of a safe exposure level. (Id.
at 22; accord 67 FR 60950, 60955
(September 27, 2002) (finding no
additional safety factor necessary for
triticonazole despite lack of
developmental neurotoxicity (‘‘DNT’’)
study because the ‘‘DNT [study] is
unlikely to affect the manner in which
triticonazole is regulated.’’)). When the
missing data are data above and beyond
general regulatory requirements, the
policy states that the weight of evidence
would generally only support the need
for an additional safety factor where the
data ‘‘is being required for ‘cause,’ that
is, if a significant concern is raised
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based upon a review of existing
information, not simply because a data
requirement has been levied to expand
OPP’s general knowledge.’’ (Ref. 5 at
23).
As to potential pre- and post-natal
toxicity, the Children’s Safety Factor
Policy lists a variety of factors that
should be considered in evaluating the
degree of concern regarding any
identified pre- or post-natal toxicity. (Id.
at 27–31). As with the completeness of
the toxicity database, the policy
emphasizes that the analysis should
focus on whether any identified pre- or
post-natal toxicity raises uncertainty as
to whether the RfD/PAD is protective of
infants and children. (Id. at 31). Once
again, the presence of pre- or post-natal
toxicity, by itself, is not regarded as
determinative as to the children’s safety
factor. Rather, the policy stresses the
importance of evaluating all of the data
under a weight of evidence approach
focusing on the safety of infants and
children. (Id.).
In evaluating the completeness of the
exposure database, the policy explains
that a weight-of-the-evidence approach
should be used to determine the
confidence level EPA has as to whether
the exposure assessment ‘‘is either
highly accurate or based upon
sufficiently conservative input that it
does not underestimate those exposures
that are critical for assessing the risks to
infants and children.’’ (Id. at 32). EPA
describes why its methods for
calculating exposure through various
routes and aggregating exposure over
those routes generally produce
conservative exposure estimates – i.e.
health-protective estimates due to
overestimation of exposure. (Id. at 40–
43). Nonetheless, EPA emphasizes the
importance of verifying that the
tendency for its methods to overestimate
exposure in fact were adequately
protective in each individual
assessment. (Id. at 44).
IV. The Challenged Tolerance Decision
On April 5, 2006, EPA promulgated a
final rule establishing tolerances for the
fungicide pyraclostrobin on shelled
succulent beans; foliage in the legume
crop group; mangoes; and papayas. (71
FR 17014 (April 5, 2006)).
Pyraclostrobin is a synthetic analog of a
natural antifungal substance which
inhibits spore germination, mycelial
growth, and sporulation of the fungus
on the leaf surface. (Ref. 8 at 4). The
tolerances were requested in petitions
from the pyraclostrobin registrant, BASF
Corporation, and the Interregional
Research Project Number 4 (‘‘IR-4’’). The
IR-4 is a program sponsored by the U.S.
Department of Agriculture and land
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grant universities and directed toward
obtaining regulatory approval for
pesticide uses on minor and speciality
food crops that are not likely to be
supported by private sector companies.
EPA evaluated the petitions in a joint
effort with the Pest Management
Regulatory Agency of Canada.
Given pyraclostrobin’s exposure
pattern and toxicological characteristics,
EPA determined that pyraclostrobin
potentially presented acute, chronic,
short-term, and cancer risks and EPA
quantitatively assessed these risks in
making its safety determination. (71 FR
at 17018–17019; 69 FR 63083, 93093–
63095 (October 29, 2004); Ref. 8 at 31–
32). All of these risks were found to be
below the Agency’s level of concern.
(Id.). EPA concluded that there were
reliable data supporting its
determination that the additional
children’s safety factor was not needed
to protect the safety of children. In
making this determination EPA
considered the completeness of the
toxicity and exposure database and data
bearing on pre- and post-natal toxicity.
(71 FR at 17018; 69 FR 63092–63093).
EPA found that there was adequate
toxicity and exposure data. Although
there was some evidence of qualitative
and quantitative increased sensitivity in
the young from the developmental study
in rabbits and reproduction study in
rats, respectively, EPA concluded using
a weight-of-the-evidence test that
residual concerns for increased
sensitivity in the young were low. (69
FR at 63093); (Ref. 9 at 8).
V. NRDC Objections
In its objections, NRDC cites various
allegedly inadequate studies and prenatal toxic effects of pyraclostrobin as
grounds for claiming it was unlawful for
EPA to remove the children’s safety
factor and EPA’s overall decision was
arbitrary and capricious.
A. Children’s Safety Factor
NRDC argues that EPA should have
retained the children’s safety factor for
two separate reasons: (1) pyraclostrobin
demonstrated pre-natal toxicity; and (2)
there were inadequacies in the
submitted toxicity data on
pyraclostrobin and additional toxicity
and exposure data are needed. NRDC
claims that EPA’s decision to remove
the children’s safety factor violates the
FFDCA; however, NRDC does not allege
that retention of the children’s safety
factor would result in the pyraclostrobin
tolerances exceeding the FFDCA section
408 safety standard. NRDC expanded on
its objections in comments it submitted
on its own objections. These comments
principally argued that EPA had
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wrongly interpreted the children’s
safety factor provision. (Ref. 10).
1. Legal requirements for imposing the
children’s safety factor and the standard
for choosing a different safety factor.
NRDC describes the children’s safety
factor provision as requiring that the
additional children’s safety factor ‘‘shall
be applied’’ to ‘‘take into account’’ (1)
‘‘potential pre- and post-natal toxicity;’’
(2) ‘‘completeness’’ of toxicity data; and
(3) ‘‘completeness’’ of the exposure data.
With regard to the reference to pre- and
post-natal toxicity, NRDC argues that
this statutory language ‘‘mandates
application of the safety factor to
account for any potential for pre- or
post-natal toxicity.’’ (Ref. 10 at 2). As to
completeness of the data, NRDC takes a
similarly rigid position: ‘‘Where studies
identified by EPA as necessary to ensure
safety have never been conducted or
reviewed – or have been determined to
be inadequate – EPA by definition
cannot find that there is a ‘reasonable
certainty’ that ‘no harm will result’ to
children, as required by law[,]’’ and
therefore, cannot modify the children’s
safety factor. (Id.).
NRDC acknowledges that EPA may
apply a factor different than
presumptive tenfold children’s safety
factor but stresses that a different factor
may be applied only if there is reliable
data showing the different factor is safe.
EPA, NRDC claims, has applied a
different standard in the pyraclostrobin
tolerance decision – requiring that there
be merely adequate data on
pyraclostrobin toxicity and exposure
and that there be no substantial
evidence of increased sensitivity of
infants and children to the pesticide.
(Id.).
2. Pre-natal sensitivity. In discussing
evidence on pre-natal sensitivity, NRDC
references both the developmental
studies in rats and in rabbits. NRDC
asserts that the developmental rat study
shows qualitative increased sensitivity
in the rat fetuses because the effects in
the rat fetuses (dilated renal pelvis and
cervical ribs with no cartilage) were
more severe than the effects in adults
(reduced body weight, body weight
gain, food intake, and food efficiency).
(Ref. 1 at 7). Qualitative increased
sensitivity is seen in the rabbit
developmental study, according to
NRDC, again because the effects in the
fetuses were more severe than the
effects in the adults (increased
resorption and post-implantation loss
versus reduced body weight, body
weight gain, food intake, and food
efficiency). (Id.). NRDC argues that EPA
erred by looking beyond the question of
whether the animal studies show fetuses
to be qualitatively more sensitive than
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maternal animals to examine whether it
was safe to remove or reduce the factor
despite a finding of qualitative
increased sensitivity. According to
NRDC, because the studies show
qualitative increased sensitivity in prenatal animals as compared to adult
animals, ‘‘EPA must retain the full
tenfold safety factor . . . .’’ (Id. at 5).
3. Inadequate and missing data—a.
Immunotoxicity data. NRDC argues that,
because EPA has not required
immunotoxicity data on pyraclostrobin,
EPA cannot explain the differential
immunotoxic results between males and
females in the pyraclostrobin studies.
Due to this lack of understanding, NRDC
claims that immunotoxicity ‘‘should be
considered a serious potential risk of
pyraclostrobin . . . [and] EPA must
retain the full tenfold safety factor as a
result.’’ (Id. at 6–7). NRDC cites four
studies in support of this argument.
First, it references a 90–day oral toxicity
mouse study in which females allegedly
showed immunotoxic effects at a dose at
which males only showed more
generalized toxicity (e.g., reduced body
weight). Second, NRDC points to a 90–
day oral toxicity study in dogs in which
NRDC claims females suffered body
weight loss, reduced food intake, and
reduced food efficiency in addition to
the gastrointestinal effects that occurred
in both sexes. Third, NRDC cites two
neurotoxicity studies in which males
were shown to be significantly more
sensitive than females. NRDC claims
that these studies demonstrate that
males and females respond differently
to pyraclostrobin and that EPA should
be particularly concerned about the
immunotoxic effects in females because
there is ‘‘substantial data demonstrating
that females are more likely than males
to develop autoimmune diseases in
response to environmental stressors.’’
(Id. at 6).
b. Two-generation reproduction study.
NRDC asserts that the two-generation rat
reproduction study with pyraclostrobin
relied upon by EPA is ‘‘invalid’’ and
that EPA cannot rehabilitate it by
combining it with a one-generation rat
reproduction study because that study
produced results which contradict the
two-generation study. (Id. at 7–8). The
two-generation study is invalid,
according to NRDC, because it showed
no adverse effects at any of the doses
tested. NRDC states that such a study
‘‘must be considered invalid because it
is unknown whether the study failed to
find an effect because there really was
no effect, or if it was due to a lack of
statistical power, poor study design, or
an endless number of potential fatal
weaknesses (e.g., the test agent could
have degraded through poor storage
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conditions; the endpoint measurements
could have been reported in error;
treated and control animals could have
been mis-categorized, etc.).’’ (Id. at 8).
NRDC argues that the one-generation
study contradicts the two-generation
study because the former identified
adverse effects at a dose lower than a
dose in the two-generation study that
showed no effects. NRDC concludes that
‘‘EPA must retain the full tenfold safety
factor in light of these invalid and
deficient studies.’’ (Id.)
c. Other data deficiencies. NRDC
briefly mentions several other alleged
data gaps or deficiencies: (1) data on
anticipated pyraclostrobin residues
which EPA has required to be
submitted; (2) a missing 28–day
inhalation toxicity study; (3) a deficient
chronic toxicity study in rats due to
failure to show adverse effects; (4) a
deficient mouse cancer study due to
failure to show adverse effects; and (5)
an unacceptable dermal penetration
study due to problems in administration
of the test dose. Categorizing these
deficiencies as ‘‘significant,’’ NRDC
argues EPA must retain the children’s
safety factor to address them. (Id. at 8–
10).
B. Arbitrary and Capricious
NRDC also argues that the tolerance
decision was arbitrary and capricious
‘‘because EPA never received or
reviewed information that the agency
considered necessary to review the
pesticides’ safety (listed above), and
because EPA failed to explain
adequately its departure from the
required children’s safety factor.’’ (Id. at
10).
VI. Public Comment
A. In General
On July 19, 2006, EPA published a
notice in the Federal Register calling
attention to and requesting comments
on the NRDC Objections. (71 FR 41015
(July 19, 2006)). The notice included a
short summary of the objections and
referenced readers to EPA’s electronic
docket for a full copy of the objections.
EPA received three comments on the
objections. Other than NRDC’s
comments on its own objections, the
only significant comment EPA received
was from BASF Corporation, the
registrant under FIFRA for
pyraclostrobin.
B. BASF Corporation
BASF Corporation has registered
pyraclostrobin for use as a pesticide
under FIFRA and petitioned for several
of the tolerances that are subject to the
present objections. As to the potential
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for pyraclostrobin to impact differently
on males and females, BASF argues in
its comments that differential effects on
the sexes are noted in toxicology studies
and taken into account in setting the
RfD. (Ref. 11). Any uncertainty
regarding the sensitivities of these two
groups is addressed, according to BASF,
by the tenfold uncertainty factor used to
account for variable sensitivities in
humans. Further, BASF argues that the
‘‘issue of differential sensitivity between
sexes is not relevant for evaluating the
need to apply the FQPA safety factor’’
because that safety factor only addresses
potential differences in sensitivities
between adults and children. (Id. at 1).
BASF challenges NRDC’s assertion
that qualitative sensitivity was
demonstrated in the rat and rabbit
developmental studies. BASF claims
that the fetal effects seen in the rat study
(dilated renal pelvis and cervical ribs
with no cartilage) were not due to
treatment. This is evidenced, according
to BASF, by the fact that the incidence
of these effects was within the historical
control range for the experimental
animal. As to the effects on rabbit
fetuses (increased resorption and postimplantation loss), BASF argues these
effects are a result of the severe effects
that pyraclostrobin had on the maternal
animals as opposed to any direct toxic
effect on the fetuses. According to
BASF, ‘‘maternal body weight gain
during the treatment period was
reduced by a dramatic 77% at the high
dose and 39% at the mid dose compared
to controls. This substantial effect to the
maternal animals would be expected to
affect the dam’s ability to deliver fullterm fetuses and does not reflect a direct
action of the test material on the fetus.’’
(Id. at 2).
With regard to the two-generation
reproduction study in rats, BASF
contends that the results from this study
are not inconsistent with the onegeneration reproduction study. BASF
claims that body weight changes were
seen in the highest dose tested in the
two-generation reproduction study.
Although the body weight changes in
the two-generation study were small,
BASF argues that ‘‘the effects at this
dose fits along a dose-response curve
with the two doses in the range-finding
[one-generation] study.’’ (Id. at 3).
BASF disputes NRDC’s claims
regarding data gaps and deficiencies.
First, BASF asserts that a 28–day
inhalation study has been submitted to
EPA. Second, BASF contends that
subsequent data submitted to EPA led
EPA to conclude that the rat and mouse
carcinogenicity studies were conducted
at sufficiently high doses. Finally, BASF
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states that a repeat dermal penetration
study was conducted. (Id. at 4).
C. NRDC
In its comments, NRDC expands on its
legal argument that EPA must retain the
children’s safety factor when data are
absent. According to NRDC, when data
EPA has determined are ‘‘necessary to
evaluate safety’’ are not available, EPA
‘‘by definition’’ may not remove the 10X
children’s safety factor. (Ref. 10 at 2).
NRDC also cites general statements that
children can be more vulnerable than
adults to pesticides and that children
may have greater relative exposure to
pesticides than adults and argues that
this means that the children’s safety
factor must be retained for
pyraclostrobin. (Id. at 3). Finally, NRDC
listed various documents that it claims
support its objections. (Id. at 4).
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VII. Response to Objections
As summarized above, NRDC’s
objections pertain primarily to EPA’s
decision on the children’s safety factor
– in brief, NRDC’s argument is that, due
to evidence on pre-natal toxicity and
immunotoxicity, and data deficiencies,
EPA erred in removing the children’s
safety factor. NRDC also recasts these
same allegations to claim that EPA acted
arbitrarily and capriciously in
promulgating the pyraclostrobin
tolerances. These arguments are
addressed separately below.
A. Children’s Safety Factor
NRDC objects to the pyraclostrobin
tolerances on the ground that it was
unlawful for EPA to remove the
children’s safety factor. Although not
stated, presumably NRDC believes that
EPA should have denied the petition
seeking the pyraclostrobin tolerances for
this reason. A decision on the children’s
safety factor, however, is not outcome
determinative with regard to whether a
petitioned-for tolerance meets the safety
standard for establishing tolerances.
Retention of the children’s safety
standard would generally result in a
tenfold lowering of the pesticide’s RfD/
PAD, thus decreasing by a factor of ten
the amount of aggregate exposure to the
pesticide that would not exceed the
RfD/PAD; it would not, however, bar the
establishment of the tolerance. EPA has
established many tolerances for which
the children’s safety factor has been
retained. (See, e.g., 71 FR 56369, 56372
(September 27, 2006); 70 FR 14535,
14541–14542 (March 23, 2005)).
Similarly, EPA has recently denied a
petition to revoke tolerances which
claimed that EPA should have retained
the children’s safety factor where it was
clear that EPA could make the
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reasonable certainty of no harm finding
with or without retention of the
additional safety factor. (72 FR 39318,
39323–39324 (July 18, 2007)). For
pyraclostrobin, EPA’s exposure
assessment, which is partially refined,
suggests that retention of the children’s
safety factor may raise safety concerns
for the pesticide. Because it is unclear
whether further refinement of the
exposure assessment would render the
decision on the children’s safety factor
irrelevant to the ultimate safety
decision, EPA has chosen to address the
merits of the argument presented by
NRDC.
NRDC makes two different types of
arguments as to why the children’s
safety factor should be retained. First,
citing various issues regarding pre-natal
toxicity and data completeness, NRDC
essentially argues that the overall
weight-of-evidence does not support
EPA’s conclusion that there is reliable
data showing it will be safe for children
to use a hundredfold margin of safety
rather than a thousand-fold margin.
Second, NRDC argues that each of the
individual issues it raises ‘‘compel’’
EPA to retain the children’s safety
factor. This second argument is more
fully made in the legal contentions
presented in NRDC’s comments on its
objections.
In responding to NRDC’s arguments,
EPA first addresses the legal contention
that various findings ‘‘compel’’ the
retention of the children’s safety factor.
In this section, EPA explains why it
fundamentally disagrees with NRDC’s
approach to the safety factor provision.
Second, EPA examines the merits of the
various factual allegations made by
NRDC concerning pre-natal toxicity and
data deficiencies. As EPA makes clear
below, in most instances NRDC is
mistaken in its factual allegations.
Finally, EPA addresses whether the
totality of the claims raised by NRDC
alter EPA’s conclusion regarding
removal of the children’s safety factor.
1. Legal interpretation of the
children’s safety factor provision. In its
objections and its comments on its
objections, NRDC claims that (1) EPA is
legally compelled to retain the
children’s safety factor when there is a
data gap; (2) EPA is legally compelled
to retain the children’s safety factor
when there is evidence showing that the
young are more sensitive to the effects
of a pesticide or a pesticide causes preor post-natal toxicity; and (3) EPA has
applied an incorrect standard in
evaluating whether the presumptive
tenfold children’s safety factor may be
modified. Following a summary of the
statutory language on the children’s
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safety provision, EPA explains why
each of these assertions are incorrect.
a. Children’s safety factor provision.
The statutory requirements pertaining to
the children’s safety factor are contained
in two sentences in section 408(b)(2)(C).
The first sentence commands that as to
‘‘threshold effects, for the purposes of
[making the reasonable certainty of no
harm finding], an additional tenfold
margin of safety for the pesticide
chemical residue and other sources of
exposure shall be applied for infants
and children.’’ (21 U.S.C. 346a(b)(2)(C)).
This sentence also explains that the
purpose for this additional safety factor
is ‘‘to take into account potential preand post-natal toxicity and
completeness of the data with respect to
exposure and toxicity to infants and
children.’’ (Id.). Switching course, the
second sentence then countermands the
mandatory language in the first sentence
(‘‘shall be applied’’) and makes clear
that EPA has the authority to deviate
from the requirement to apply an
additional 10X safety factor. The second
sentence reads ‘‘[n]othwithstanding
such requirement for an additional
margin of safety, the Administrator may
use a different margin of safety for the
pesticide chemical residue only if, on
the basis of reliable data, such a margin
will be safe for children.’’ (Id.).
b. Operation of the children’s safety
factor provision. EPA has interpreted
the children’s safety factor provision as
containing a presumption in favor of
retaining an additional tenfold safety
factor for the protection of infants and
children. That presumption may be
overcome, however, when EPA has
reliable data showing that use of a
different safety factor will protect the
safety of infants and children. Such a
different safety factor may be lower or
higher than the default 10X value. In
making decisions about whether it has
reliable data supporting a different
safety factor, EPA has looked at the
totality of the evidence bearing on the
safety of infants and children and
carefully weighed the strength of that
evidence in determining whether a
different safety factor would be safe.
That was the approach followed with
pyraclostrobin.
NRDC appears to interpret the
children’s safety factor provision quite
differently. Repeatedly in its objections,
NRDC argues that EPA ‘‘must’’ retain
the children’s safety factor due to some
data deficiency or because of the
identification of increased sensitivity in
the young. NRDC affirms this view in its
comments stating that the statute
‘‘mandates application of the safety
factor to account for any potential for
pre- or post-natal toxicity’’ and, that
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where necessary studies are missing,
‘‘EPA, by definition’’ cannot make the
safety finding needed to choose a
different safety factor. Under NRDC’s
interpretation, the children’s safety
factor operates in a rigid and automatic
fashion: upon identification of a data
gap or of sensitivity in the young, EPA
loses all discretion to choose a different
safety factor.
i. Data gaps. EPA has previously
rejected NRDC’s interpretation as it
applies to data gaps noting that the
interpretation fails to take into account
the entire children’s safety factor
provision. In responding to other
tolerance objections filed by NRDC, EPA
stated its disagreement with the view
‘‘that the mere absence of a required
[developmental neurotoxicity] study
should, by itself, conclusively bar EPA
from applying a different additional
safety factor than the 10X default
value.’’ (70 FR at 46723). EPA pointed
out that the statute ‘‘expressly
authorizes’’ EPA to choose a different
safety factor based solely on whether
EPA determined that a different factor
was safe and that EPA’s policy of
making children’s safety factor
decisions on a case-by-case basis
examination of all of the data on a
pesticide is in accord with this statutory
provision. (Id.). EPA concluded that
NRDC’s outcome-determinative
approach to data gaps and the children’s
safety factor simply did not address the
statute’s grant of discretion to EPA to
choose a different safety factor.
In its comments on its objections,
NRDC now offers the following
argument as to why, when data on
pesticide safety are lacking, EPA does
not have the authority to choose a
different safety factor. NRDC claims
that, when needed safety data are
missing, EPA, ‘‘by definition,’’ cannot
make the reasonable certainty of no
harm (i.e. safety) finding necessary to
choose a different safety factor. NRDC’s
logic seems to be as follows: if EPA
determines it needs additional data on
safety, EPA has necessarily concluded
that such data are ‘‘necessary to ensure
safety,’’ and if data that are ‘‘necessary
to ensure safety’’ are lacking, EPA
cannot make the safety finding required
to apply a different children’s safety
factor.
The main problem with this argument
is that it ignores the plain language of
the statute. As noted above, section
408(b)(2)(C) contains two sentences
regarding application of an additional
safety factor for the protection of infants
and children. The first sentence requires
EPA to apply an additional 10X safety
factor to address, among other things,
data completeness issues. Importantly,
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the data completeness issue mentioned
by the statute is data bearing on toxicity
and exposure – i.e., data on safety. In
the very next sentence, however, the
statute provides that ‘‘notwithstanding
such requirement’’ to apply a safety
factor to address safety data
completeness issues, EPA may choose a
different factor so long as that factor is
safe for children. If there is any
definitional reading of this language, it
is that EPA has the authority to choose
a different safety factor when safety data
are incomplete. NRDC’s interpretation
would read EPA’s grant of authority to
choose a different factor when there are
safety data completeness issues out of
the statute.
In addition to ignoring the plain
language of the children’s safety
provision, NRDC’s argument also is
inconsistent with the statutory structure
in at least two ways. First, NRDC’s
interpretation renders the children’s
safety factor provision, itself, mere
surplusage if data completeness issues
arise. If, as NRDC has argued, a request
for data means that the data are
necessary to ensure safety, then EPA, in
those circumstances, not only cannot
make the safety (reasonable certainty of
no harm) finding necessary to remove
the children’s safety factor but EPA
cannot make the safety (reasonable
certainty of no harm) finding necessary
to grant the tolerance. In other words,
under NRDC’s argument, the entire
children’s safety provision becomes
irrelevant if EPA has requested data,
because that request, by itself,
conclusively bars EPA from establishing
the tolerance. NRDC has not explained
why it is rational to assume that
Congress drafted a provision addressing
data completeness issues but made the
provision inoperative if data
completeness issues arise.
Second, NRDC’s elevation of an EPA
requirement for additional safety data to
a determination that a tolerance is
unsafe (i.e. that a safety determination
cannot be made) is inconsistent with the
structure of section 408 that permits
EPA to require additional safety data on
existing tolerances while at the same
time commanding that tolerances that
do not meet the safety standard be
revoked. Under section 408(f), EPA is
authorized to require the submission of
data ‘‘to support the continuation of a
tolerance . . . .’’ (21 U.S.C. 346a(f)). The
sole criterion for the continuation of a
tolerance is whether it continues to
meet the reasonable certainty of no
harm standard. (21 U.S.C.
346a(b)(2)(A)(i)). Thus, Congress
contemplated that EPA could require
safety data on existing tolerances. Yet,
under NRDC’s interpretation it is
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difficult to see how EPA could ever
require submission of safety data on
existing tolerances. NRDC has argued
that if data bearing on the reasonable
certainty of no harm finding are needed
(which is the finding necessary to
request data under section 408(f)), then
the reasonable certainty of no harm
finding cannot be made. Thus, if EPA
were to determine that additional safety
data are needed on an existing
tolerance, it would also be concluding
that that tolerance is unsafe. The statute,
however, commands EPA to revoke
unsafe tolerances, not request more
safety data concerning them. (21 U.S.C.
346a(b)(a)(2)(A)(ii)). In other words,
under NRDC’s approach, if EPA
determines that data were needed to
support the continuation of a tolerance,
EPA would have to revoke the tolerance
rendering moot any decision to require
submission of additional data to support
the tolerance. Presumably, Congress
would not have enacted such a selfdefeating provision.
The underlying flaw in NRDC’s
argument is that it equates an EPA
decision to seek additional safety data
with the proposition that EPA has
necessarily determined that a safety
finding cannot be made in the absence
of such data. NRDC does not take into
account that there are many types of
safety data and that the varying types of
safety data have varying degrees of
importance to the ultimate reasonable
certainty of no harm finding. For
example, the five core required
toxicology studies would generally be of
greater importance to the children safety
factor determination than conditionallyrequired toxicology studies or special
studies, for instance, to determine
mechanism of toxicity. Similarly, as to
pesticide exposure data, residue data on
major crops will be of more significance
than data on minor crops, and even for
major crops the importance of the first
15 geographically-distributed residue
studies will be of more value than the
next five such studies. Further, not only
are some studies more important or
necessary to the safety determination
than others, but, in the absence of a
study, information from one study, or a
group of studies, or the assumptions
made to compensate for the missing
study, may significantly diminish any
uncertainty raised by the study’s
absence. For example, in the absence of
dermal absorption data, EPA generally
assumes 100 percent of a pesticide is
dermally absorbed. Given all of these
considerations and the range of data that
can be required, it is apparent that a
request for additional data is not
synonymous with a determination that
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a safety finding cannot be me made.
Thus, it is reasonable not to adopt
NRDC’s absolutist approach but to
evaluate on a case-by-case basis whether
the safety data that are available on a
pesticide show that a different safety
factor is safe.
At bottom, the decision on the
children’s safety factor turns on whether
a safety finding can be made, not on
whether any particular study is
available. If data are absent, EPA may
still examine the existing reliable data to
determine if a factor different than 10X
is safe. NRDC is incorrect to the extent
it argues that EPA is statutorily barred
from making this inquiry.
ii. Increased sensitivity in the young.
In the current objections, NRDC also
argues that EPA ‘‘must’’ retain the
children’s safety factor because
‘‘[j]uveniles are qualitatively more
sensitive than adults to pyraclostrobin
toxicity.’’ (Ref. 1 at 7). NRDC criticizes
EPA for examining whether there is
‘‘substantial evidence’’ of sensitivity.
(Id. at 5). Presumably, NRDC’s view is
that any evidence of sensitivity
automatically requires EPA to retain the
children’s safety factor.
This rigid interpretation of the
children’s safety provision, however,
fails for the same reason NRDC’s
argument for automatic retention of the
children’s safety factor for data
deficiencies fails – it is not in accord
with the plain language of the statute.
The statute does direct EPA to consider
‘‘susceptibility of infants and children’’
to pesticides. (21 U.S.C.
346a(b)(2)(C)(i)(II)). It also states that an
additional safety factor to protect infants
and children shall be applied ‘‘to take
into account potential pre- and postnatal toxicity . . . .’’ (21 U.S.C.
346a(b)(2)(C)). Nonetheless, in clear and
unmistakable language, Congress
decreed that, ‘‘[n]otwithstanding such
requirement for an additional margin of
safety’’ to take into account potential
pre- and post-natal toxicity, EPA is
authorized to choose a different safety
factor if EPA has reliable data showing
a different factor is safe. (Id.).
Interpreting the statute as creating a
rigid, per se rule that the identification
of sensitivity in the young removes
EPA’s discretion to choose a different
safety factor is inconsistent with this
language and the flexibility granted to
the Agency. On the other hand, EPA’s
policy, and the approach it followed
with pyraclostrobin, of examining the
entire database to determine if, despite
a finding of sensitivity, there are reliable
data showing a different factor to be
safe, is in full accord with the statutory
provision.
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c. The standard for choosing a
different safety factor. Alternatively,
NRDC argues that even if the statutory
language does not compel EPA to retain
the children’s safety factor whenever
there is a data gap or evidence of
sensitivity in the young, EPA’s
interpretation of the standard for
choosing a different safety factor
‘‘frustrates congressional policy.’’ (Ref.
10 at 2). NRDC asserts that the language
EPA offered in summarizing its decision
to remove the children’s safety factor
demonstrates the unlawfulness of EPA’s
interpretation: ‘‘[EPA] has concluded
that there are reliable data to support
reducing the FQPA SF [safety factor] to
1X for all potential pyraclostrobin
exposure scenarios because the toxicity
and exposure databases are adequate,
there are no residual uncertainties for
pre- or postnatal toxicity, and there is
no substantial evidence of increased
sensitivity of infants and children to
pyraclostrobin.’’ (Id.). NRDC claims that
‘‘requiring ‘substantial evidence’ of
‘increased sensitivity of infants and
children,’ along with merely ‘adequate’
data regarding toxicity and exposure’’ is
not true to the reasonable certainty of no
harm standard. (Id.).
NRDC’s view here is not wellfounded. Contrary to NRDC’s argument,
EPA does not apply the reasonable
certainty of no harm standard in some
sort of formalistic fashion using fixed
rules that provide minimal protection to
children. Rather, EPA applies the
reasonable certainty of no harm
standard in the children’s safety factor
provision, just as it does with the
overall reasonable certainty of no harm
provision for tolerances, using a
comprehensive, weight-of-the-evidence
approach that is designed to protect
fully the safety of children.
EPA, as well as FDA, has applied a
reasonable certainty of no harm
standard in administering various
provisions of the FFDCA for many
years. Since its enactment in 1958, the
‘‘safety’’ standard in FFDCA section 409
has been interpreted by FDA as
imposing a reasonable certainty of no
harm standard. (21 C.F.R. 170.3(i)). EPA
was governed by this standard in
implementing section 409 as to
pesticides in processed foods for the
period between 1970 and 1996. In 1996,
when Congress enacted the FQPA, the
reasonable certainty of no harm safety
standard was codified in section 408. (7
U.S.C. 346a(b)(2)(A)(ii)). In brief, EPA
has applied that standard using a
complex risk assessment process which
involves careful weighing of scientific
evidence at each step along the way. (62
FR 62961, 62962–62963 (November 26,
1997)). First, a thorough evaluation of
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hazard and exposure data is conducted
to determine the adequacy of that data
to address the potential risks posed by
a pesticide and the significance of any
data gaps that are identified. Hazard
data are examined using a weight-of-theevidence approach for the purpose of
identifying a safe dose for humans.
Derivation of a safe dose generally
requires use of safety factors to address
any uncertainties in knowledge.
Exposure data are carefully weighed in
estimating potential human exposure.
Finally, human exposure estimates are
compared to the safe dose to determine
if there is a reason for concern. (Ref. 2;
5; and 6).
A similar, if slightly more narrowly
focused, inquiry is involved in
determining if there are reliable data
showing that a safety factor different
than the presumptive 10X factor will
ensure that there is a reasonable
certainty of no harm to children. (Ref. 5
at 8–18; 50–53). This inquiry examines
the risks to children guided by the three
factors mentioned in the statute –
completeness of the toxicity database;
completeness of the exposure database;
and the potential for pre- and post-natal
toxicity. (21 U.S.C. 346a(b)(2)(C)). In
other words, EPA focuses on the
completeness or adequacy of the
databases regarding the hazard a
pesticide poses to children and
children’s potential exposure to that
pesticide. This completeness inquiry
identifies and evaluates the significance
of any data gaps. It also examines
evidence bearing on pre- and post-natal
toxicity with particular emphasis on
whether there is evidence indicating
that children may be more sensitive
than adults to the toxic effects of a
pesticide. (21 U.S.C. 346a(b)(2)(C)(i)(II)).
As in the broader reasonable certainty of
no harm evaluation, the children’s
safety factor determination involves an
examination of uncertainties and a
determination as to whether these
uncertainties are addressed by adequate
safety factors or other aspects of the risk
assessment such as the levels that
adverse effects occur in adults. Each
step involves a careful weighing of the
scientific evidence and a
characterization of what the data show.
That is precisely what was done with
pyraclostrobin – examining the
adequacy of the hazard and exposure
data; and evaluating the evidence on
pre- and post-natal toxicity, the
evidence on increased sensitivity in the
young, and the degree to which any preor post-natal toxicity was addressed by
basing safety determinations on effects
seen at similar or lower doses in adults.
EPA did not apply any rigid tests in
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determining if there was reasonable
certainty of no harm supporting the
removal of the additional safety factor
for pyraclostrobin but rather considered
all of the relevant data and weighed its
significance to the safety of children.
This approach is consistent with (1) the
statutory language itself – reasonable
certainty of no harm; (2) EPA’s historic
interpretation and implementation of
that language; and (3) protection of
infants and children.
The language from the pyraclostrobin
decision cited by NRDC (adequate safety
data and no substantial evidence of
sensitivity) was intended as a summary
of EPA’s weight-of-the-evidence
evaluation in making its reasonable
certainty of no harm finding on the
children’s safety factor. Considerations
of data adequacy and the substantiality
of evidence on harmful effects are a
routine part of the weight-of-theevidence analysis used to make
reasonable certainly of no harm
determinations. Surely, Congress did
not intend to remove EPA’s discretion to
choose a different safety factor when
data on infants and children are
adequate to evaluate safety and
evidence of sensitivity in the young is
insubstantial.
Accordingly, EPA denies NRDC’s
objection to the extent they rely on these
flawed interpretations of the statute or
a misreading of EPA’s tolerance
decision.
2. Individual factual findings bearing
on the children’s safety factor—a. Prenatal sensitivity. As indicated above,
NRDC relies on evidence of qualitative
pre-natal sensitivity (i.e., effects more
severe in the young as compared to
adults) as grounds for retaining the
children’s safety factor for
pyraclostrobin. NRDC’s objections
appear to argue that the mere indication
of increased qualitative sensitivity
requires EPA, as a legal matter, to retain
the children’s safety factor. That legal
interpretation is without merit as
explained above. NRDC may, however,
have been asserting that the evidence
bearing on pre-natal sensitivity for
pyraclostrobin is so significant to the
evaluation of the safety of
pyraclostrobin that EPA erred in
concluding that there was reliable data
to determine that removing the
children’s safety factor would be
protective of the safety of children.
NRDC claims two pyraclostrobin
studies show that pyraclostrobin causes
increased qualitative pre-natal
sensitivity: the developmental study in
rats and the developmental study in
rabbits. The developmental study in rats
found that pre-natally exposed fetuses
had adverse effects at 50 milligrams/
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kilogram of body weight/day (mg/kg/
day) and that the maternal animals had
adverse effects at the lower dose of 25
mg/kg/day. The NOAELS in fetuses and
maternal animals respectively were 25
mg/kg/day and 10 mg/kg/day. (Refs. 9 at
4; and 12 ). NRDC contends that the
study showed qualitative pre-natal
sensitivity because the effects in the
fetuses (incidences of dilated renal
pelvis and cervical ribs with no
cartilage) were more severe than the
effects in the maternal animals (reduced
body weight, reduced body weight gain,
food intake, and food efficiency). The
developmental study in rabbits showed
adverse effects in fetuses and the
maternal animals at the same level
(LOAEL – 10 mg/kg/day; NOAEL – 5
mg/kg/day). (Refs. 9 at 5–6; and 13).
NRDC asserts that effects in the fetuses
(increased resorption and postimplantation loss) however, are more
severe than in the maternal animals.
(Ref. 1 at 7).
BASF in its comments disputes
NRDC’s claims of qualitative sensitivity.
First, BASF claims that effects seen in
the rat fetuses were not caused by
exposure to pyraclostrobin. To support
this assertion BASF argues that adverse
effects were within the level to be
expected based on historical
information on this species of rat.
Second, BASF claims that the rabbit
developmental study does not evidence
qualitative sensitivity because the
effects in the fetuses were derivative of
the effects on the maternal animals.
Noting that decreased weight gain in the
maternal animals was dramatic (39% at
the LOAEL and 77% and the next
higher dose), BASF argues that it is to
be expected that ‘‘the dam’s ability to
deliver full-term fetuses [would be
affected] and does not reflect a direct
action of the test material on the fetus.’’
(Ref. 11 at 2).
In the pyraclostrobin rulemaking, EPA
characterized the effects in the rabbit,
but not the rat, study as evidencing
qualitative sensitivity in the young. EPA
further determined that there was a low
degree of concern as to the sensitivity
seen in the rabbit study because the
effects in the rabbit fetuses occurred at
the same dose that adverse effects
occurred in the maternal animals and a
clear NOAEL for the effects seen in the
fetuses was identified and taken into
account in assessing potential risk to
humans. In light of NRDC’s objections
and BASF’s comments, however, EPA
has re-examined its earlier conclusions
both as to the presence or absence of
qualitative sensitivity in the rat and
rabbit fetuses and the degree of concern
raised by the studies regarding the
protection of infants and children.
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i. Rat developmental study. To recap,
in the rat developmental study,
pyraclostrobin exposure resulted in
dilated renal pelvis and cervical ribs
with no cartilage in the rat fetuses at 50
mg/kg/day (with a NOAEL of 25 mg/kg/
day) and reduced body weight in the
maternal animals at the lower dose of 25
mg/kg/day (with a NOAEL of 10 mg/kg/
day). EPA does not believe that these
findings support retention of the
children’s safety factor for four reasons.
First, there is substantial evidence
indicating that the effects seen at the
high dose in the fetuses (dilated renal
pelvis and cervical ribs with no cartilage
present) were not treatment-related.
These effects occur with some frequency
in rats. Historical data from the lab
conducting the study showed that, for
rat controls in other studies, dilated
renal pelvis was seen in between 8.8
and 28.8 percent of rat fetuses, and
cervical ribs with no cartilage present
was seen in between 0.5 and 6.6 percent
of rat fetuses. (Ref. 14 at 2–3). In the
pyraclostrobin rat study, dilated renal
pelvis was detected in 18.8 percent of
the fetuses and cervical ribs with no
cartilage present was found in 5.1
percent. (Id.). Because these effects
appeared at a rate consistent with those
seen in control groups, this study
outcome carries little weight.
Second, the effects in fetuses are not
more severe than the reduced body
weight seen in maternal animals.
Dilated renal pelvis and cervical ribs
with no cartilage present are relatively
common effects in rat fetuses and are
regarded as reversible developmental
variations in that they often disappear
as the animal matures. Dilated renal
pelvis involves an enlargement of the
portion of the kidney referred to as the
pelvis. The renal pelvis is a funnelshaped region that collects urine before
it is discharged through the ureter.
When the renal pelvis becomes dilated
or enlarged there may be difficulties in
discharging urine. As the historical
control data cited above shows, this is
a fairly common event in rats. The
enlargement is related to rapid renal
growth late in the gestation period and
it generally is resolved following birth
so long as no other abnormalities are
present in the kidney. (Ref. 15). A
cervical rib without cartilage is a
supernumerary (or extra) rib that
commonly disappears after birth as
ossification of the bone is unlikely to
occur in the absence of cartilage.
Because these effects are generally
reversible post-natally, were seen with
pyraclostrobin at the high dose only,
and were within the range of historical
controls, it was reasonable for EPA not
to treat them as a severe effect. On the
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other hand, reduced body weight, while
not one of the more severe effects seen
in animal studies, is nonetheless a sign
of generalized toxicity that merits
concern. Thus, the effects in the fetuses
are not properly characterized as more
severe than the effects in maternal
animals.
Third, reduced body weight in the
maternal animals was found at a lower
dose than the dose which resulted in
dilated renal pelvis and cervical ribs
with no cartilage present in the fetuses.
Thus, on a quantitative basis, adult
animals proved more sensitive than the
fetuses.
Fourth, and probably most important,
a clear NOAEL was identified for the
effects seen in the fetuses. That NOAEL
was taken into consideration in setting
the RfD/PAD for pyraclostrobin as EPA
examined all of the NOAELs from
relevant studies to identify the lowest
NOAEL. Accordingly, the RfD/PAD for
pyraclostrobin was set at least 100–fold
(10X for inter-species sensitivity and
10X for intra-species variability) below
the safe level (NOAEL) for rat fetuses in
the rat developmental study. In fact, as
to the NOAEL for the fetal effects seen
in the rat developmental study, there
was a greater than 100–fold margin
because the NOAEL in the rat
developmental study for maternal
animals was lower than the fetal
NOAEL, and a still lower NOAEL from
another study was used to set the RfD/
PAD. (Ref. 8 at 12–13).
Accordingly, after re-evaluating the
rat developmental study, EPA concludes
that (1) the study does not show
increased qualitative sensitivity in rat
fetuses; and (2) given the results of the
study and the manner in which those
results were incorporated into EPA’s
risk assessment for infants and children,
there is reliable data to show, with
regard to developmental effects in rats,
that it is safe to remove the children’s
safety factor.
ii. Rabbit developmental study. As
noted above, the findings in the rabbit
developmental study were that, at the
same dose level, pyraclostrobin caused
reduced body weight and reduced body
weight gain in maternal animals, and
increased resorption of fetuses. EPA
concluded that, because fetal
resorptions were more serious than
body weight effects, this study shows
increased qualitative sensitivity in
rabbit fetuses; however, EPA concluded
that the traditional safety factors
provide sufficient protection for infants
and children. (Ref. 9 at 7). NRDC argues
that because the study shows qualitative
sensitivity the children’s safety factor
must be retained. Taking a different
tack, BASF does not contend that fetal
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resorptions are not more serious than
body weight effects but instead claims
that the resorptions are derivative of the
effects on the maternal animals and thus
not evidence of qualitative sensitivity.
EPA disagrees with BASF that the
fetal resorptions are derivative of the
body weight effects. To the extent either
effect is derivative of the other, it is the
decreased body weights in maternal
animals that is the result of the fetal
resorptions, not the other way around.
Body weight decreases in the maternal
animals were due, in large part, to
decreases in the weight of the gravid
uterus (a uterus containing a fetus or
fetuses). In turn, weight loss in the
gravid uterus was a result of the fetal
resorptions. (Ref. 14 at 7). In light of this
finding, as well as the other evidence of
gestational effects (e.g. blood in the
bedding), EPA concludes there is
insufficient evidence to classify the
resorptions as a derivative effect.
EPA, however, also disagrees with
NRDC regarding the significance of the
finding of qualitative sensitivity based
on fetal resorptions and reaffirms its
conclusion that there is low concern
that traditional safety factors are not
protective of the fetal effects seen in the
rabbit developmental study. Not only
were the fetal effects seen at the same
quantitative levels as the maternal
effects but clear NOAELs were
identified for both the fetal and
maternal effects in that study. These
NOAELs (which were identical) formed
the basis for the RfD/PAD for
pyraclostrobin. Specifically, EPA used
the NOAELs in establishing the RfD/
PAD by dividing the NOAELs by 10X
safety factors for inter- and intra-species
variability (total of 100X). Having
clearly defined the threshold for the
qualitatively more sensitive effects in
the young, and applied a 100X safety
factor to the NOAEL below the
threshold, EPA concludes it is safe for
infants and children not to retain an
additional 10X factor.
b. Immunotoxicity . NRDC claims
various studies show that males and
females have different levels of
sensitivity to pyraclostrobin. According
to NRDC, some of the studies indicated
males were more sensitive and others
indicated females were more sensitive.
NRDC calls particular attention to
alleged heightened female sensitivity to
immunotoxic effects in the 90–day oral
toxicity study in the mouse and claims
that this sensitivity ‘‘is supported by
substantial data demonstrating that
females are more likely than males to
develop autoimmune diseases in
response to environmental stressors.’’
(Ref. 1 at 6). Based on this alleged
sensitivity of females to immunotoxic
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results, NRDC then argues that
‘‘[b]ecause EPA does not routinely test
pesticides for immunotoxicity, the full
repercussions of these results for female
mortality and morbidity (i.e.
autoimmune disease, compromised
immune response, etc.) should be
considered a serious potential risk of
pyraclostrobin’’ and merits retention of
the children’s safety factor. EPA
interprets this argument as essentially a
claim that EPA cannot remove the
children’s safety factor because it has
inadequate data on the immunotoxic
effects of pyraclostrobin.
BASF responds to NRDC by asserting
that the children’s safety factor was not
intended to address differential
sensitivities between males and females.
Further, BASF asserts that any
differences in sensitivity are taken into
account in the risk assessment because
the lowest NOAEL from male or female
is used in selecting a safe dose and, in
addition, a tenfold safety factor is
applied to this NOAEL to address any
lingering uncertainty as to differential
male/female sensitivity.
While EPA agrees generally with
BASF’s comments, EPA does not believe
that they address NRDC’s core concern
here which is the adequacy of the data
pertaining to pyraclostrobin’s
immunotoxic potential. EPA has
identified the immune system as a target
of pyraclostrobin; however, EPA
believes that pyraclostrobin’s
immunotoxic effects have been wellcharacterized and that no additional
data is needed to protect against
immunotoxic risks.
Currently, EPA does not routinely
require that pesticides be tested
specifically for immunotoxicity.
Toxicology data requirements for a fooduse pesticide, however, typically
contain data that provide information
for evaluating potential hazard to the
immune system. For example,
examination (in varying degrees) of the
macro- and/or microscopic structural
anatomy of immune system organs and
tissues is performed in a number of
toxicity studies, including the 90–day
subchronic studies in multiple species,
the chronic and carcinogenicity studies,
the prenatal developmental toxicity
studies (rats and rabbits), acute
inhalation toxicity study, and the twogeneration reproduction and fertility
effects study. Additionally, non-specific
indicators of a diseased state in the
animal (e.g., clinical behavior which is
evaluated by detailed observations
throughout the conduct of all guideline
animal studies) can also be useful in
discerning perturbations in immune
system function. If these toxicity studies
show findings indicative of possible
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immunotoxicity, they are given due
consideration in the risk assessment.
(Ref. 16 at 3).
EPA is considering requiring specific
immunotoxicity testing for pesticides in
the future. If the toxicity studies are
inconclusive regarding immunotoxicity,
there is concern, depending on the
pesticide, that potential immunotoxic
effects may not have been identified.
Accordingly, the Agency has proposed
that the pesticide toxicity data
requirements be amended to require
adult immunotoxicity testing for all
pesticides. (70 FR 12277 (March 11,
2005). The proposed immunotoxicity
testing would improve the likelihood
that pesticides which have potential
immunotoxic effects will be identified.
If these proposed amendments are
adopted, EPA will have to make
determinations as to the timing of
requiring these tests for existing
pesticides and what the implications are
for application of the children’s safety
factor of this new data requirement. The
Children’s Safety Factor policy
recommends that this safety factor is
more appropriate in situations when a
study is requested ‘‘for cause’’ as
opposed to a request based on more
general considerations. EPA is likely to
apply a similar approach to broadlyimposed new data requirements for
immunotoxicity testing: although the
requirements may apply to all
pesticides, only those pesticides for
which immunotoxicity is a specific
concern would require retention of the
children’s safety factor. Important
considerations in this analysis are likely
to be the sensitivity of any
immunotoxicity effects seen in the
existing database (i.e., is the RfD/PAD
based on the immunotoxic responses or
do such effects only occur at higher
doses), the degree to which any
immunotoxicity effects are seen across
studies and across species, and the
nature and severity of the immunotoxic
effects.
For pyraclostrobin, EPA’s analysis of
the existing data identified the immune
system as a target organ but not the
primary target. Effects were seen in the
thymus, an important gland in the
immune system, in terms of thymus
atrophy and lymph node apoptosis. The
thymus effects were seen in the 90–day
study in mice at high doses (NOAEL/
LOAEL of 30.4/119 mg/kg/day in males
and NOAEL/LOAEL of 12.9/40.4 mg/kg/
day in females). In a chronic/
carcinogenicity study in mice, these
effects were not seen at the highest dose
tested (17.2 mg/kg/day for males and
32.8 mg/kg/day for females). Similar
findings were not seen in available data
with rats and dogs. Although decreased
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thymus weights were found at the
highest dose (29–36 mg/kg/day) in the
pups in the two-generation rat
reproduction study, EPA does not
interpret this effect as an immunotoxic
response because total pup weights
were reduced and ‘‘relative’’ thymus
weights (the ratio of thymus weight/
body weight) was normal. (Ref. 16 at 2).
Similarly, in a recently submitted
inhalation study, apparent thymus
weight effects were seen, but again EPA
concluded this was not an immunotoxic
response given the lack of any
confirming histopathological findings in
the thymus and the excessively toxic
level of the dose at which the thymus
effects were seen. (Refs. 16 at 2 and 17).
EPA believes that the immunotoxic
potential of pyraclostrobin has been
well-characterized; that no additional
data is needed taking into account all of
the evidence bearing on potential
immunotoxic effects; and that
identification of immunotoxic effects in
the 90–day mouse study does not
support retention of the children’s
safety factor to protect the safety of
infants and children. Most important to
these findings are the facts that (1)
immunotoxic effects were only seen at
high doses in one study in the mouse –
no immunotoxic effects were seen in
other mouse studies or in studies in
other species; and (2) combining the
data from the 90–day mouse study and
the chronic/cancer study in mice shows
a NOAEL for immunotoxic effects for
both male and female mice (30.4 mg/kg/
day for males from the 90–day mouse
study and 32.8 mg/kg/day for females in
the chronic/cancer study) that is
approximately 10X higher than the
NOAEL used to set the RfD/PAD (3.4
mg/kg/day from the rat chronic study).
Although EPA has required the
submission of developmental
immunotoxicity data for two pesticides,
those pesticides have a markedly
different toxicological profile than
pyraclostrobin. The two pesticides in
question, clothianidin and dinotefuran,
caused immunotoxic effects in multiple
studies and species, and rat pups in the
two generation rat reproduction study
appeared to be more sensitive to these
immunotoxic effects than adult animals.
Further, the immunotoxic effects for
these pesticides were the most sensitive
effects seen in the database and were
used to set the RfD/PAD for the
pesticides. These circumstances are
markedly different from pyraclostrobin
where an immunotoxic effect was seen
at a high dose in only one study.
c. Two-generation reproduction study.
NRDC claims that the two-generation
reproduction study in rats is invalid
because it did not show adverse effects
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at any dose and that it cannot be
rehabilitated by reference to the onegeneration reproduction study because
that study is contradictory in that it
showed adverse effects at levels below
levels tested in the two-generation
study. BASF disputes NRDC’s
contention, arguing that the twogeneration study did show some adverse
effects at the highest dose tested and
these effects were consistent with the
one-generation study and ‘‘fit along a
dose-response curve with the two doses
in the [one-generation] range-finding
[reproduction] study.’’ (Ref. 11 at 3.)
EPA disagrees with NRDC. An
examination of all of the data from the
two reproduction studies indicates that
the reproduction effects of
pyraclostrobin have been adequately
characterized and no further data is
needed.
The two-generation reproduction
study and the one-generation
reproduction study both tested the same
strain of male and female Wistar rats
from the same source. Using the same
batch and purity of pyraclostrobin (BAS
500 F; Batch No. J.-No. 27882/199/b or
/c; 98.7%), the two-generation study
tested 0, 25, 75 or 300 ppm and the onegeneration study tested 200, 400 and
600 ppm of Pyraclostrobin. This
corresponds to 0, 2.5/2.6, 7.4/7.8 and
29.0/30.4 mg/kg/day (males/females
(‘‘M/F’’)) for the two-generation
reproduction study and 0, 20.5/21.3,
39.9/42.5 and 59.1/60.4 mg/kg/day (M/
F) for the one-generation reproduction
study. (Ref. 14 at 7–8).
In evaluating the results of these
studies, EPA concluded that the onegeneration reproduction study resulted
in statistically significant, adverse body
weight effects in parental animals at the
mid (39.9/42.5 mg/kg/day) and high
(59.1/60.4 mg/kg/day) doses and in
pups at the low (20.5/21.3 mg/kg/day)
as well as the mid and high doses. On
the other hand, EPA determined that
none of the doses used in the twogeneration reproduction study (2.5/2.6,
7.4/7.8 and 29.0/30.4 mg/kg/day) caused
statistically significant adverse effects in
the parental animals or the offspring.
Further, EPA initially classified the twogeneration reproduction study as
unacceptable due to its failure to
identify statistically significant adverse
effects and indicated that the study
should be repeated at higher doses.
Upon reevaluation, EPA concluded
that, when taken together, the two
reproduction studies fulfilled the
requirement for a two-generation
reproduction study and a second
reproduction study did not have to be
conducted. Importantly, the twogeneration study did show treatment-
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related effects on body weight; these
effects, however, were not judged
significant enough to be considered
adverse. Body weight decrements of 5
percent or less were consistently seen in
both maternal and paternal animals at
the high dose in the two-generation
study and slightly greater weight
decrements were seen in the first and
second generation pups. (Refs. 14 at 8;
18). Specifically, the first and second
generation pups of the high dose group
(29.0/30.4 mg/kg/day) had decreased
body weights on days 14 and 21 and on
day 7 as well in second generation pups.
The decreases were slightly more
pronounced in the second generation (9
to 13%) than in the first (4 to 10%). In
the one-generation study, the body
weight decrease in pups between days
7 and 21 for the low (20.5/21.3 mg/kg/
day), mid (39.9/42.5 mg/kg/day), and
high (59.1/60.4 mg/kg/day) doses groups
pups were 7 to 14 percent, 11 to 20
percent, and 24 to 37 percent,
respectively. (Ref. 14 at 8). As Table 1
indicates, a comparison of the
percentage weight loss from the pups in
the two studies shows that the studies
are complementary because the dose
response curve when comparing the
lowest two doses in the one-generation
study with the highest dose in the twogeneration study only slightly deviates
from what might be expected. EPA
concludes that this slight deviation in
the dose response curve is likely due to
normal variability in mammalian
response and variability in human and
instrumental measurements rather than
any defect in the two-generation study.
TABLE 1.—BODY WEIGHT LOSS IN
PUPS IN THE ONE- AND TWO-GENERATION RAT REPRODUCTION STUDIES
Dose (mg/
kg/day) for
Males/Females
Weight Loss
(days 7–12)
Study
20/21
One-generation
7–14%
29/30
Two-generation
4–10% (first
generation)*
9–13% (second generation)
40/42
One-generation
11–20%
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*Days 14 - 21 only.
The consistency of effect and
response from the two studies refute
NRDC’s claims regarding the
contradictory nature of the findings
from the two studies.
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Moreover, although the body weight
effects seen at the highest dose in the
two-generation reproduction study were
not significant enough to be judged
adverse, a new study would not provide
any additional data for risk assessment
purposes. The concern with that study
is not that it did not test at a low enough
dose, but the opposite. Repeating the
two-generation study at doses similar to
and above 29 mg/kg/day (the highest
dose tested in the two-generation study)
is very unlikely to change the Point of
Departure for pyraclostrobin which is
currently a NOAEL of 3.4 mg/kg/day
from the rat chronic/carcinogenicity
study. The conclusion not to request a
repeat study is in accord with the
decisions made by the Agency’s
Pesticide Rejection Rate Analysis Toxicology which states that a study
should not be rejected provided that
NOAELs are established in other studies
that can be used to estimate a reference
dose. (Ref. 19). In the case of
pyraclostrobin, acute and chronic
reference doses for dietary risks as well
as doses for non-dietary risks were
based on other studies.
d. Other data deficiencies. NRDC also
claims there are several other significant
data deficiencies which necessitate
retention of the children’s safety factor.
For the reasons explained below, EPA
does not find merit in this contention.
i. Anticipated residue data. NRDC
notes that EPA is issuing a data call-in
for information bearing on anticipated
residues and asserts that this means
there is a database deficiency. NRDC
cites to page 17016 of the Federal
Register to support this assertion. In
fact, however, there is no data
deficiency. If EPA relies on anticipated
residue information in establishing a
tolerance, it must require, pursuant to
section 408(f)(1), that data be provided
five years after the tolerance is
established demonstrating that the
residue levels in food are not above the
levels anticipated. 21 U.S.C.
346a(b)(2)(E). Page 17016 of the
pyraclostrobin Federal Register notice
merely notes that EPA is subject to this
obligation with regard to pyraclostrobin
because it did rely on anticipated
residue data in setting the tolerance.
ii. 28–day inhalation study. NRDC
notes that in 2004 a 28–day inhalation
study in rats was outstanding and
argues that this is a significant data gap.
The 28–day inhalation study, however,
is used to assess worker risk in
connection with application of
pyraclostrobin. Inhalation is not a
significant exposure pathway for
residential post-application exposure
due to pyraclostrobin’s very low
volatility. In any event, this study has
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now been submitted and reviewed. The
study established a NOAEL of 0.001
milligrams/liter (mg/L) based on
hyperplasia of the duodenum, alveolar
histiocytosis in the lungs, and olfactory
atrophy/necrosis in the nasal tissues at
0.030 mg/L (LOAEL). (Ref. 17). This
endpoint will be taken into account in
the future in an updated occupational
risk assessment for pyraclostrobin.
iii. Rat chronic toxicity study. NRDC
claims the chronic toxicity study in rats
was unacceptable due to failure to test
at a dose high enough to produce
significant toxicity. NRDC cites an
October 2004 rulemaking for
pyraclostrobin, (67 FR 63083, 63086
(October 29, 2004)), in support of this
claim. The October 2004 Federal
Register statement, however, was an
error because EPA had determined in
2003 that the dosing in the rat chronic
study was adequate. Specifically, EPA
concluded in an October 2003
memorandum that ‘‘[u]pon reevaluation
at the September 10, 2003 meeting, the
[Cancer Assessment Review Committee]
concluded that female rats were tested
adequately at the top dose of 200 ppm.’’
(Ref. 20 at 23). The re-evaluation was
based on additional data and statistical
analysis bearing on the rat chronic
study. EPA found that ‘‘[t]here was a
statistically significant decrease in
cumulative body weight gain compared
to controls across study intervals from
Day 147 to study termination in the 200
ppm group females.’’ (Id.). It had been
previously determined that male rats
were tested at a high enough dose. (Id.
at 22).
iv. Mouse carcinogenicity study.
NRDC claims the mouse carcinogenicity
study was unacceptable due to failure to
test at a dose high enough to produce
significant toxicity. EPA originally
concluded that this study had to be reconducted at a higher dose; however,
based on interim reports from a second
study, using a higher dose, EPA found
the dosing in the first mouse
carcinogenicity study to be adequate.
(Ref. 21). The second study involved a
dose of 360 ppm which is double the
high dose in the first study. Within a
short period the study evidenced severe
reductions in body weight and body
weight gain at the 360 ppm dose. (Ref.
22). After 6 months of the study, EPA
agreed that the 360 ppm dose was
excessive and permitted the study to be
terminated concluding that based on
both studies, it had sufficient
information to determine that the dosing
in the first study was high enough to
adequately characterize any cancer
potential of pyraclostrobin. Following
formal submission of the data, EPA
confirmed that, compared to control
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animals, there was a large decrease in
the body weight/ body weight gain of
female mice at 360 ppm up to the end
of the study. Mean body weight of
treated females was significantly
decreased by 4–24% compared with
that of controls during the study and
was 21% less than that of controls when
the study was terminated at 7 months.
Weight gain, relative to controls, was
reduced by 37% (p≤0.01) during the
first 91 days of the study and by 40%
(p≤0.01) over the entire study. (Ref. 23).
v. Dermal absorption study. NRDC
claims the dermal absorption study was
inadequate. NRDC notes that EPA
described the study as unacceptable but
nonetheless used it to calculate the
percentage of dermal absorption by
pyraclostrobin. EPA acknowledges that
there were difficulties with the dermal
absorption study; however, EPA was
ultimately able to use the data obtained
from this study to calculate
pyraclostrobin’s dermal absorption rate.
(Ref. 9 at 15–16). The difficulty with the
study was that most of the
pyraclostrobin intended to be applied to
the skin of the animal, remained in the
dressing used to cover the skin where
pyraclostrobin was applied. Because,
however, the amount of pyraclostrobin
that remained in the dressing was
measured, it was possible to calculate
what amount of pyraclostrobin was
applied to the skin and hence, by
comparing this amount to the amount
absorbed by the animal, to derive the
dermal absorption rate. In the
underlying science memorandum, EPA
initially characterized the study as
unacceptable without expressly noting
that its ability to derive a dermal
absorption rate despite the flaws in the
study made the study acceptable. EPA’s
initial characterization of the study was
mistakenly cited in the 2004 Federal
Register notice relied upon by NRDC.
EPA notes that BASF claims to have
submitted a new dermal absorption
study but EPA has not received such a
study from BASF.
e. Conclusion with regard to NRDC’s
factual allegations. For the reasons
described above, EPA rejects each of
NRDC’s claims regarding the need for
additional data or alleged deficiencies
in submitted data.
B. NRDC’s Claim that EPA’s Tolerance
Decision was Arbitrary and Capricious
NRDC also claims that it was arbitrary
and capricious for EPA to establish the
challenged pyraclostrobin tolerances
because EPA did not review needed
safety data and because ‘‘EPA failed to
explain adequately its departure from
the required children’s safety factor.’’
(Ref. 1 at 10). As to the first contention,
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NRDC relies on its prior allegations
regarding missing or deficient data.
Because EPA has above rejected each of
these claims regarding missing or
deficient data, EPA also disagrees that
its tolerance decision was arbitrary or
capricious due to a failure to consider
needed data.
NRDC provides no further elaboration
with regard to its claim that EPA did not
provide an adequate explanation of its
decision on the children’s safety factor.
EPA explained its reasoning in both the
preamble to the final rule promulgating
the challenged pyraclostrobin
tolerances, (71 FR at 17018), and in an
earlier tolerance rulemaking on
pyraclostrobin, (69 FR at 63092–63093),
that was cross-referenced in the later
action. EPA’s regulations require that
the basis for objections be stated with
‘‘particularity,’’ (40 C.F.R. 178.25(a)(2)),
and NRDC’s failure to provide any basis
for its lack of explanation contention is
alone grounds for denial of this
objection. Nonetheless, EPA reiterates
below its reasoning for removal of the
children’s safety factor.
In determining whether there are
reliable data showing that a different
safety factor would be safe for
evaluating the risks of pyraclostrobin to
infants and children, EPA has focused
primarily on three issues: (1) The
completeness of the toxicity database;
(2) the completeness of the exposure
database; and (3) what the data show
with regard to pre- and post-natal
toxicity.
This analysis did not occur in
isolation but in the context of the
overall risk assessment for
pyraclostrobin. Before it makes any
children’s safety factor decision, EPA
analyzes the toxicity and exposure
databases. EPA’s process with regard to
toxicity data is described in its
Children’s Safety Factor policy:
Before any decisions are made on the
appropriate FQPA safety factor applied to
ensure the safety of infants and children from
the use of a particular pesticide, all of the
relevant submitted data for the pesticide
should be assembled and reviewed by
Agency scientists. The toxicology database is
evaluated to identify potential adverse
effects, to determine the adequacy of the
available data to characterize potential
human risks, and to analyze the relationship
between dose and response, that is, the levels
at which the chemical causes adverse effects
in test animals. The assessment of the
potential for adverse health effects in infants
and children is part of the overall hazard and
dose-response assessment for a chemical.
Available data pertinent to children’s health
risks are evaluated along with data on adults
and the NOAEL (no-observed-adverse-effectlevel) or benchmark dose (BMD) for the most
sensitive critical effect(s) based on
consideration of all health effects. By doing
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this, protection of the health of children will
be considered along with that of other
sensitive populations. (Ref. 5 at 7).
A similar process is undertaken to
estimate exposure for all exposed
population subgroups. Once these
toxicity and exposure analyses are
complete, EPA turns to the three critical
factors pertaining to the children’s
safety factor described above and
conducts a weight-of-the-evidence
analysis to identify any concerns
regarding the safety of infants and
children. Finally, each of these factors
are considered together in ‘‘an
integration step wherein the weight-ofevidence analyses for the completeness
of the toxicity database, the degree of
concern for pre- and postnatal toxicity,
and results of the exposure assessments
are combined by decisionmakers in
evaluating whether the presumptive
10X safety factor should be retained or
reliable data justify a different factor
that could range from a level of 1X to
10X, and possibility greater than 10X.’’
(Id. at 50).
In assessing the completeness of the
toxicity database, EPA considers first
whether the core five toxicology studies
are available (chronic toxicity study in
two species, two-generation
reproduction study, and developmental
toxicity study in two species) and next
whether there are data gaps for any
other studies, ‘‘particularly those that
pertain to evaluating risk to children
and other sensitive subpopulations.’’
(Id. at 24.) If data gaps are identified,
then ‘‘the risk assessor should consider
the general, overall value of the
particular type of study to the risk
assessment.’’ For pyraclostrobin, the
toxicity database was adequate because
no data gaps pertaining to infants and
children have been identified. As
explained in Unit VII.A.2., EPA
disagrees with each of NRDC’s claims
regarding the existence of data gaps or
data deficiencies.
In assessing the completeness of the
exposure database, EPA uses a weightof-the-evidence approach to ‘‘address all
important sources, routes, and pathways
of exposure for the pesticide and
include both the expected exposure
duration as a consequence of each use
and the expected pathway(s) of
exposure.’’ (Id. at 36). The object of this
analysis is to determine the level of
confidence that ‘‘the assessment is
either highly accurate or based upon
sufficiently conservative input that it
does not underestimate those exposures
that are critical for assessing the risks to
infants and children.’’ (Id.). For
pyraclostrobin, there is high confidence
that the exposure assessment does not
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underestimate exposure. EPA examined
three pathways of exposure: food,
drinking water, and exposure from use
on residential turf. As explained in Unit
III.B.3.b., EPA follows a tiered approach
in estimating pesticide residues in food,
first conducting a simple, very
conservative assessment (assuming all
registered crops contain tolerance level
residues) that grossly overestimates
exposure from residues in food and then
refining that analysis in steps if needed.
For pyraclostrobin, EPA conducted a
slightly refined analysis. For the acute
exposure assessment, EPA assumed all
pyraclostrobin-registered crops were
treated with pyraclostrobin and that 65
of 73 crops had residues at the tolerance
level. For the other crops (various leafy
greens and dried beans), EPA assumed
residues would be at the highest average
value from residue field trials designed
to produce maximum residues. For the
chronic exposure assessment, EPA used
data on percent crop treated for most of
the registered crops and assumed
tolerance level residues for all registered
crops other than apple and pear. For
apple and pear, EPA used the average
value from residue field trials designed
to produce maximum residues.
Although these exposure assessments
are somewhat refined, they remain very
conservative in comparison to estimates
based on monitoring data gathered from
food distribution channels. To estimate
exposure to pyraclostrobin through
residues in drinking water and from
treated residential turf EPA used
exposure models that incorporate
pesticide specific information and are
designed to produce high-end estimates
of exposure. (Ref. 8 at 30; 69 FR at
30058–30064). Because of this
conservative approach to estimating
exposure, EPA has very high confidence
that its exposure assessment does not
underestimate exposure to
pyraclostrobin. In all likelihood, it
substantially overestimates exposure.
Finally, in examining a pesticide’s
potential pre- and post-natal toxicity,
EPA also conducts a weight-of-theevidence analysis focusing on whether
data show increased sensitivity in the
young, how well the dose-response
relationship of any pre- or post-natal
effects are understood, and, to the extent
available, information on a pesticide’s
toxicokinetics and mode of action. For
pyraclostrobin, the key studies on preand post-natal toxicity were the rat and
rabbit developmental toxicity studies
and the one and two generation rat
reproduction studies. The rat
developmental study showed no
increased sensitivity in the rat fetuses
(see discussion in Unit VII.A.2.a.i.) and,
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in any event, the effects seen in the
fetuses occurred at higher doses than
the effects in maternal animals.
Qualitatively more severe effects were
seen in the fetuses in the rabbit
developmental study (fetal resorptions
compared to body weight effects);
however, these effects occurred at the
same dose as the adverse effects in the
maternal animals and a clear NOAEL
level was identified for both the
maternal and fetal effects. Finally, the
one generation rat reproduction study
indicated that rat pups may be
quantitatively more sensitive than
parental animals in that marginal body
weight effects were seen at a lower dose
in pups than in parental animals. The
two generation rat reproduction study,
however, failed to replicate this
quantitative sensitivity instead showing
that marginal body weight effects
occurred in both pups and parental
animals at the same dose (see discussion
in Unit VII.A.2.c.). Moreover, the two
generation study established a clear
NOAEL for the body weight effects in
both pups and parental animals. Based
on this evidence, EPA concluded that
the effects on the young were well
understood/characterized and that there
were no residual concerns that reliance
on the traditional 10X intra-species
safety factor, when applied to the
NOAELs for effects in fetuses and pups,
would not be protective of infants and
children. (71 FR 17014, 17018 (April 5,
2006); 69 FR 63083, 63092–63093
(October 29, 2004)).
Taking into account that (1) there is
a complete toxicity database; (2) the
exposure estimate is a likely
overestimate of pyraclostrobin exposure;
and (3) pyraclostrobin’s pre- and postnatal effects are well-defined by the
database and there are no residual
concerns regarding potential increased
sensitivity – EPA concludes that it has
reliable data showing that it is safe for
infants children to conduct its risk
assessment using a 100–fold safety
factor without use of the additional 10X
children’s safety factor.
C. Conclusion on Objections
For the reasons stated above, all of the
NRDC’s objections are hereby denied.
VIII. Response to Comments on NRDC’s
Objections
In comments on its own objections,
NRDC made two additional arguments.
First, NRDC cited general statements
that children can be more vulnerable
than adults to pesticides and that
children may have greater relative
exposure to pesticides than adults.
These two points, according to NRDC,
make it ‘‘especially important that EPA
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52123
apply the required FQPA safety factor
for pyraclostrobin.’’ (Ref. 10 at 3). EPA
does not believe that this general
information is particularly helpful in
making the specific determination for
pyraclostrobin under the children’s
safety provision. Concerns about
children’s vulnerability and exposure
led to passage of the children’s safety
factor provision; yet that provision
expressly allows EPA to choose a factor
different than the presumptive
additional 10X safety factor if such
different factor is safe for children.
NRDC’s argument here essentially reads
EPA’s authority to choose a different
factor out of the statute not just for
pyraclostrobin but for all pesticides.
Further, EPA would note that it has
taken into account, in making a decision
on the children’s safety factor for
pyraclostrobin, data estimating
children’s exposure to pyraclostrobin
and data evaluating the relative
sensitivity of the young vis-a-vis adults
to pyraclostrobin.
An additional claim included in
NRDC’s comments is that its objections
are supported by six documents
referenced in the objections. These
documents include a letter to EPA, a
report from EPA’s Office of Inspector
General, several law review articles, and
the National Academy of Sciences’ 1993
report on pesticides and children. Other
than listing the documents, NRDC did
not explain how these documents
support its objections. All of the
documents address, at least in part,
application of an additional safety factor
for the protection of children. None of
the documents, however, mentions
pyraclostrobin. EPA does not believe
that the mere listing of documents,
particularly such general documents as
these, trigger any obligation upon the
Agency to respond to the substance of
the documents. Further, the failure of
NRDC to offer any substantive
explanation as to why these documents
were included in its comments means
that NRDC has not presented or
exhausted any issues, questions, or
conclusions contained in these
documents before the Agency. The
reason for the exhaustion requirement
in section 408 as to tolerance issues is
so that EPA may make a full record on
an issue and bring its experience to bear
on it. (Nader v. EPA, 859 F.2d 747, 754
(9th Cir. 1988)). Because NRDC has not
presented any issues, questions, or
conclusions contained in these
documents to EPA, it cannot, should it
challenge this Order in court, cite
matters in these documents to the court
as supporting its objections. For the
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Federal Register / Vol. 72, No. 176 / Wednesday, September 12, 2007 / Notices
same reason, EPA will not include these
documents in the record for this action.
IX. Regulatory Assessment
Requirements
As indicated previously, this action
announces the Agency’s final order
regarding objections filed under section
408 of FFDCA. As such, this action is an
adjudication and not a rule. The
regulatory assessment requirements
imposed on rulemaking do not,
therefore, apply to this action.
X. Submission to Congress and the
Comptroller General
The Congressional Review Act, (5
U.S.C. 801 et seq.), as added by the
Small Business Regulatory Enforcement
Fairness Act of 1996, does not apply
because this action is not a rule for
purposes of 5 U.S.C. 804(3).
jlentini on PROD1PC65 with NOTICES
XII. References
1. Natural Resources Defense Council,
‘‘Objection to the Establishment of
Tolerances for the Pesticide Chemical
Residues of Pyraclostrobin’’ Docket Id
No. EPA-HQ-OPP-2004-0292 (June 5,
2006).
2. Office of Pesticide Programs, U.S.
EPA, Available Information on
Assessing Pesticide Exposure From
Food: A User’s Guide (June 21, 2000).
3. U.S. EPA, Residue Chemistry Test
Guidelines: OPPTS 860.1500 Crop Field
Trials (August 1996).
4. Office of Pesticide Programs, U.S.
EPA and Pest Management Regulatory
Agency, ‘‘Health Canada, NAFTA
Guidance Document for Guidance for
Setting Pesticide Tolerances Based on
Field Trial Data’’ (September 28, 2005).
5. Office of Pesticide Programs, U.S.
EPA, ‘‘Determination of the Appropriate
FQPA Safety Factor(s) in Tolerance
Assessment’’ (January 31, 2002).
6. Office of Pesticide Programs, U.S.
EPA, ‘‘The Use of Data on
Cholinesterase Inhibition for Risk
Assessments of Organophosphorous and
Carbamate Pesticides’’ (August 18,
2000).
7. Office of Pesticide Programs, U.S.
EPA, Versar Corporation, ‘‘Standard
Operating Procedures (SOPs) for
Residential Exposure Assessments’’
(Draft, December 19, 1997).
8. Office of Prevention, Pesticides,
and Toxic Substances, U.S. EPA,
Memorandum from Barry O’Keefe to
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18:43 Sep 11, 2007
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John Bazuin/Cynthia Giles-Parker,
‘‘Pyraclostrobin Human Health Risk
Assessment to Account for Revised
Tolerances on Succulent Beans, Dried
Shelled Peas and Beans, and
Strawberries, and to Establish
Tolerances on Mangos and Papayas’’
(November 30, 2005).
9. Office of Prevention, Pesticides,
and Toxic Substances, U.S. EPA,
Memorandum from Ghazi Dannan to
William Wassell, ‘‘PYRACLOSTROBIN 3rd Report of the Hazard Identification
Assessment Review Committee’’
(February 10, 2003).
10. Natural Resources Defense
Council, Re: ‘‘Objection to the
Establishment of Tolerances for
Pesticide Chemical Residues of
Pyraclostrobin,’’ Docket ID No. EPA-HQOPP-2004-0292 (September 9, 2006).
11. BASF Corporation, Docket ID
[EPA-HQ-OPP-2004-0292; FRL-8076-81
‘‘Pyraclostrobin; Objections to Pesticide
Tolerances; Notice of Availability;’’
Federal Register, Vol 71, No. 138, July
19, 2006 (September 12, 2006).
12. Health Effects Division, Office of
Pesticide Programs, U.S. EPA, Data
Evaluation Record (TXR#: 0051615):
‘‘Prenatal Developmental Toxicity
Study’’ (Teratology); Species: Rat;
Guideline: OPPTS 870.3700; OPP 83-3a;
‘‘Pyraclostrobin’’ (April 29, 2003).
13. Health Effects Division, Office of
Pesticide Programs, US EPA, ‘‘Data
Evaluation Record (TXR#: 0051615):
Prenatal Developmental Toxicity Study’’
(Teratology); Species: Rabbit; Guideline:
OPPTS 870.3700; OPP 83-3b;
‘‘Pyraclostrobin’’ (April 29, 2003).
14. Office of Prevention, Pesticides,
and Toxic Substances, U.S. EPA,
Memorandum from Ghazi Dannan to
Cynthia Giles-Parker/Tony Kish, ‘‘HED
Response to NRDC Objection to the
Establishment of Tolerances for
Pesticide Chemical Residues of
Pyraclostrobin.’’ Docket ID No. EPA-HQOPP-2004-0292. (PC Code 099100) (July
16, 2007).
15. Woo, David C. and Hoar, Richard
M., ‘‘‘Apparent Hydronephrosis’ as a
Normal Aspect of Renal Development in
the Late Gestation of Rats: The Effect of
Methyl Salicylate’’ (Teratology; 1972
Oct;6(2):191-6).
16. Office of Prevention, Pesticides,
and Toxic Substances, U.S. EPA,
Memorandum from Yung Yang to
Cynthia Giles-Parker/Tony Kish,‘‘HED
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Fmt 4703
Sfmt 4703
Response to NRDC Objection to the
Establishment of Tolerances for
Pesticide Chemical Residues of
Pyraclostrobin.’’ Docket ID No. EPA-HQOPP-2004-0292. TXR # 0054635, DP
Barcode: D341293, PC Code: 099100.
(July 24, 2007).
17. Health Effects Division, Office of
Pesticide Programs, US EPA, Data
Evaluation Record: Subchronic
Inhalation Toxicity - [rat]; OPPTS
870.3465 [82-4]; OECD 413.
‘‘Pyraclostrobin; methyl [2-[[[1-(4chlorophenyl)-1H-pyrazol-3-yl]methyl]
phenyl]methoxycarbamate’’ (August 21,
2007).
18. Office of Pesticide Programs, U.S.
EPA, Data Evaluation Record,
Multigeneration Reproductive Toxicity
Species: Rat; Guideline: OPPTS
870.3800; OPP 83-4; EPA MRID No.
45118327, EPA Pesticide Chemical
Code: 099100, EPA DP Barcode
D269669, D267732, EPA Submission
No. S583112, HED TXR#:0051615, Test
Material: BAS 500 F (January 16, 2003).
19. Office of Pesticide Programs, U.S.
EPA, ‘‘Pesticide Rejection Rate Analysis
Toxicology,’’ 738-R-93-005, pp. 82-83,
(July 1993).
20. Office of Prevention, Pesticides,
and Toxic Substances, U.S. EPA,
Memorandum from Jessica Kidwell to
Ghazi Dannan and Barry O’Keefe,
‘‘PYRACLOSTROBIN: Report of the
Cancer Assessment Review Committee
(Second Evaluation);’’ PC Code: 099100
(October 22, 2003).
21. Office of Prevention, Pesticides,
and Toxic Substances, U.S. EPA,
Memorandum from Jessica Kidwell to
Ghazi Dannan and Paula Deschamp,
‘‘PYRACLOSTROB IN: Third Report of
the Dose Adequacy Review Team
(DART)’’ (July 19, 2005).
22. Office of Prevention, Pesticides,
and Toxic Substances, U.S. EPA,
Memorandum from Jessica Kidwell to
Ghazi Dannan, ‘‘PYRACLOSTROBIN:
Second Report of the Dose Adequacy
Review Team (DART)’’ (March 7, 2005).
23. Office of Prevention, Pesticides,
and Toxic Substances, U.S. EPA,
Memorandum from Jessica Kidwell to
Ghazi Dannan and Barry O’Keefe,
PYRACLOSTROBIN: Report of the
Cancer Assessment Review Committee
(Third Evaluation); PC Code: 099100
(February 15, 2007).
E:\FR\FM\12SEN1.SGM
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Federal Register / Vol. 72, No. 176 / Wednesday, September 12, 2007 / Notices
List of Subjects
Environmental protection, Pesticides
and pests.
Dated: September 4, 2007.
Debra Edwards,
Director, Office of Pesticide Programs.
[FR Doc. E7–18025 Filed 9–11–07; 8:45 am]
BILLING CODE 6560–50–S
ENVIRONMENTAL PROTECTION
AGENCY
[EPA–HQ–OPP–2007–0675; FRL–8145–3]
Pesticide Registration Review; New
Docket Opened for Review and
Comment
Environmental Protection
Agency (EPA).
ACTION: Notice.
jlentini on PROD1PC65 with NOTICES
AGENCY:
SUMMARY: EPA has established a
registration review docket for the
following pesticide: Zinc Borate
(3ZnO•2BO3•3.5H2O; mw 434.66), PC
Code 128859, Case number 5025. With
this document, EPA is opening the
public comment period for this
registration review. Registration review
is EPA’s periodic review of pesticide
registrations to ensure that each
pesticide continues to satisfy the
statutory standard for registration, that
is, the pesticide can perform its
intended function without unreasonable
adverse effects on human health or the
environment. Registration review
dockets contain information that will
assist the public in understanding the
types of information and issues that the
Agency may consider during the course
of registration reviews. Through this
program, EPA is ensuring that each
pesticide’s registration is based on
current scientific and other knowledge,
including its effects on human health
and the environment.
DATES: Comments must be received on
or before December 11, 2007.
ADDRESSES: Submit your comments
identified by the docket identification
(ID) number for the specific pesticide of
interest provided in the table in Unit
III.A., by one of the following methods:
• Federal eRulemaking Portal: https://
www.regulations.gov. Follow the on-line
instructions for submitting comments.
• Mail: Office of Pesticide Programs
(OPP) Regulatory Public Docket (7502P),
Environmental Protection Agency, 1200
Pennsylvania Ave., NW., Washington,
DC 20460–0001.
• Delivery: OPP Regulatory Public
Docket (7502P), Environmental
Protection Agency, Rm. S–4400, One
Potomac Yard (South Bldg.), 2777 S.
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Jkt 211001
Crystal Dr., Arlington, VA. Deliveries
are only accepted during the Docket’s
normal hours of operation (8:30 a.m. to
4 p.m., Monday through Friday,
excluding legal holidays). Special
arrangements should be made for
deliveries of boxed information. The
Docket Facility telephone number is
(703) 305–5805.
Instructions: Direct your comments to
the docket ID numbers listed in the table
in Unit III.A. for the pesticide you are
commenting on. EPA’s policy is that all
comments received will be included in
the docket without change and may be
made available on-line at https://
www.regulations.gov, including any
personal information provided, unless
the comment includes information
claimed to be Confidential Business
Information (CBI) or other information
whose disclosure is restricted by statute.
Do not submit information that you
consider to be CBI or otherwise
protected through regulations.gov or email. The regulations.gov website is an
‘‘anonymous access’’ system, which
means EPA will not know your identity
or contact information unless you
provide it in the body of your comment.
If you send an e-mail comment directly
to EPA without going through
regulations.gov, your e-mail address
will be automatically captured and
included as part of the comment that is
placed in the docket and made available
on the Internet. If you submit an
electronic comment, EPA recommends
that you include your name and other
contact information in the body of your
comment and with any disk or CD-ROM
you submit. If EPA cannot read your
comment due to technical difficulties
and cannot contact you for clarification,
EPA may not be able to consider your
comment. Electronic files should avoid
the use of special characters, any form
of encryption, and be free of any defects
or viruses.
Docket: All documents in the docket
are listed in the docket index available
at regulations.gov. To access the
electronic docket, go to https://
www.regulations.gov, select ‘‘Advanced
Search,’’ then ‘‘Docket Search.’’ Insert
the docket ID number where indicated
and select the ‘‘Submit’’ button. Follow
the instructions on the regulations.gov
web site to view the docket index or
access available documents. Although
listed in the index, some information is
not publicly available, e.g., CBI or other
information whose disclosure is
restricted by statute. Certain other
material, such as copyrighted material,
is not placed on the Internet and will be
publicly available only in hard copy
form. Publicly available docket
materials are available electronically at
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52125
https://www.regulations.gov, or, if only
available in hard copy, at the OPP
Regulatory Public Docket in Rm. S–
4400, One Potomac Yard (South Bldg.),
2777 S. Crystal Dr., Arlington, VA. The
hours of operation of this Docket
Facility are from 8:30 a.m. to 4 p.m.,
Monday through Friday, excluding legal
holidays. The Docket Facility telephone
number is (703) 305–5805.
FOR FURTHER INFORMATION CONTACT: For
information about the pesticide
included in this document, contact the
specific Chemical Review Manager for
this pesticide as identified in the table
in Unit III.A.
For general questions on the
registration review program, contact
Kennan Garvey, Antimicrobials Division
(7510P), Office of Pesticide Programs,
Environmental Protection Agency, 1200
Pennsylvania Ave., NW., Washington,
DC 20460–0001; telephone number:
(703) 305–7106; fax number: (703) 308–
8090; e-mail address:
garvey.kennan@epa.gov.
SUPPLEMENTARY INFORMATION:
I. General Information
A. Does this Action Apply to Me?
This action is directed to the public
in general, and may be of interest to a
wide range of stakeholders including
environmental, human health,
farmworker, and agricultural advocates;
the chemical industry; pesticide users;
and members of the public interested in
the sale, distribution, or use of
pesticides. Since others also may be
interested, the Agency has not
attempted to describe all the specific
entities that may be affected by this
action. If you have any questions
regarding the applicability of this action
to a particular entity, consult the person
listed under FOR FURTHER INFORMATION
CONTACT.
B. What Should I Consider as I Prepare
My Comments for EPA?
1. Submitting CBI. Do not submit this
information to EPA through
regulations.gov or e-mail. Clearly mark
the part or all of the information that
you claim to be CBI. For CBI
information in a disk or CD-ROM that
you mail to EPA, mark the outside of the
disk or CD-ROM as CBI and then
identify electronically within the disk or
CD-ROM the specific information that is
claimed as CBI. In addition to one
complete version of the comment that
includes information claimed as CBI, a
copy of the comment that does not
contain the information claimed as CBI
must be submitted for inclusion in the
public docket. Information so marked
will not be disclosed except in
E:\FR\FM\12SEN1.SGM
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Agencies
[Federal Register Volume 72, Number 176 (Wednesday, September 12, 2007)]
[Notices]
[Pages 52108-52125]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E7-18025]
-----------------------------------------------------------------------
ENVIRONMENTAL PROTECTION AGENCY
[OPP-2004-0292; FRL-8144-4]
Pyraclostrobin; Order Denying Objections to Issuance of
Tolerances
AGENCY: Environmental Protection Agency (EPA).
ACTION: Order.
-----------------------------------------------------------------------
SUMMARY: The Natural Resource Defense Council (``NRDC'') filed
objections with EPA to a final rule under section 408 of the Federal
Food, Drug, and Cosmetic Act (``FFDCA''), (21 U.S.C. 346a),
establishing tolerances for the pesticide pyraclostrobin on various
food commodities. NRDC argues that EPA has unlawfully removed the
additional safety factor for the protection of infants and children
required by Food Quality Protection Act of 1996. This order denies the
objections for the reasons stated herein.
FOR FURTHER INFORMATION CONTACT: Tony Kish, Registration Division
(7505P), Office of Pesticide Programs, Environmental Protection Agency,
1200 Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone
number: (703) 308-9443; e-mail address: kish.tony@epa.gov.
SUPPLEMENTARY INFORMATION:
Response to NRDC Objections
Table of Contents
I. General Information
A. Does This Action Apply to Me?
B. How Can I Get Additional Information, Including Copies of this
Document and Other Related Documents?
II. Introduction
A. What Action Is the Agency Taking?
B. What Is the Agency's Authority for Taking This Action?
III. Statutory and Regulatory Background
A. Statutory Background
B. Setting Tolerances Under the FFDCA
1. In general
2. Choosing a tolerance value
3. The safety determination--risk assessment
[[Page 52109]]
a. Levels of concern and risk assessment
(i) Threshold Effects
(ii) Non-threshold effects
b. Estimating human exposure
C. Children's Safety Factor Policy
IV. The Challenged Tolerance Decision
V. NRDC Objections
A. Children's Safety Factor
1. Legal Requirements for Imposing the Children's Safety Factor and
the Standard for Choosing a Different Safety Factor
2. Pre-natal Sensitivity
3. Inadequate and Missing Data
a. Immunotoxicity Data
b. Two-generation Reproduction Study
c. Other Data Deficiencies
B. Arbitrary and Capricious
VI. Public Comment
A. In General
B. BASF Corporation
C. NRDC
VII. Response to Objections
A. Children's Safety Factor
1. Legal Interpretation of the Children's Safety Factor Provision
a. Children's Safety Factor Provision
b. Operation of the Children's Safety Factor Provision
i. Data Gaps
ii. Increased Sensitivity in the Young
c. The Standard for Choosing a Different Safety Factor
2. Individual Factual Findings Bearing on the Children's Safety Factor
a. Pre-Natal Sensitivity
i. Rat Developmental Study
ii. Rabbit Developmental Study
b. Immunotoxicity
c. Two-generation Reproduction Study
d. Other Data Deficiencies
e. Conclusion With Regard to NRDC's Factual Allegations
B. NRDC's Claim that EPA's Tolerance Decision was Arbitrary and
Capricious
C. Conclusion on Objections
VIII. Response to Comments
IX. Regulatory Assessment Requirements
X. Submission to Congress and the Comptroller General
I. General Information
A. Does This Action Apply to Me?
In this document EPA denies objections to a tolerance actions filed
by the Natural Resources Defense Council (``NRDC''). This action may
also be of interest to agricultural producers, food manufacturers, or
other pesticide manufacturers. Potentially affected categories and
entities may include, but are not limited to:
Crop Production (NAICS code 111).
Animal Production (NAICS code 112).
Food Manufacturing (NAICS code 311).
Pesticide Manufacturing (NAICS code 32532).
This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities who may be interested in today's
action.
B. How Can I Get Additional Information, Including Copies of this
Document and Other Related Documents?
An electronic copy of this Federal Register document and all other
documents included in the rulemaking docket for this action may be
accessed through the EPA's electronic docket. EPA has established a
docket for this action under docket identification (ID) number EPA-HQ-
OPP-2004-0292. To access the electronic docket, go to https://
www.regulations.gov, select ``Advanced Search,'' then ``Docket
Search.'' Insert the docket ID number where indicated and select the
``Submit'' button. Follow the instructions on the regulations.gov web
site to view the docket index or access available documents. All
documents in the docket are listed in the docket index available in
regulations.gov. Although listed in the index, some information is not
publicly available, e.g., Confidential Business Information (CBI) or
other information whose disclosure is restricted by statute. Certain
other material, such as copyrighted material, is not placed on the
Internet and will be publicly available only in hard copy form.
Publicly available docket materials are available in the electronic
docket at https://www.regulations.gov,or, if only available in hard
copy, at the OPP Regulatory Public Docket in Rm. S-4400, One Potomac
Yard (South Building), 2777 S. Crystal Drive, Arlington, VA. The Docket
Facility is open from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays. The Docket telephone number is (703) 305-
5805.You may also access this Federal Register document electronically
through the EPA Internet under the Federal Register'' listings at
https://www.epa.gov/fedrgstr.
II. Introduction
A. What Action Is the Agency Taking?
On June 5, 2006, the Natural Resource Defense Council (``NRDC'')
filed objections with EPA to a final rule under section 408 of the
Federal Food, Drug, and Cosmetic Act (``FFDCA''), (21 U.S.C. 346a),
establishing tolerances for the pesticide pyraclostrobin on various
food commodities. (Ref. 1). NRDC makes two main claims in its
objections: (1) that EPA has unlawfully removed the additional safety
factor for the protection of infants and children; and (2) that EPA's
decision to promulgate the tolerances was arbitrary and capricious
because EPA made its decision in the absence of data that EPA had
determined were necessary to evaluate pyraclostrobin's safety. NRDC did
not exercise the option provided in section 408(g)(2) to request a
hearing on its objections. This Order responds to those objections.
EPA published notice of the objections in the Federal Register, (71
FR 41015 (July 19, 2006)), and held a 60-day public comment period.
The body of this document contains the following sections. First,
there is a background section which explains the applicable statutory
and regulatory provisions, EPA risk assessment practices, and the
relevant EPA science policy documents. Second, EPA describes the
objected-to tolerance action. Third, there is a section setting forth
in greater detail the substance of the objections. Fourth, a summary of
the public comment is presented. Finally, EPA's announces its response
to the objections.
B. What Is the Agency's Authority for Taking This Action?
The procedure for filing objections to tolerance actions and EPA's
authority for acting on such objections is contained in section 408(g)
of the FFDCA and regulations at 40 CFR Part 178. (21 U.S.C. 346a(g)).
III. Statutory and Regulatory Background
A. Statutory Background
EPA establishes maximum residue limits, or ``tolerances,'' for
pesticide residues in food under section 408 of the FFDCA. (21 U.S.C.
346a). Without such a tolerance or an exemption from the requirement of
a tolerance, a food containing a pesticide residue is ``adulterated''
under section 402 of the FFDCA and may not be legally moved in
interstate commerce. (21 U.S.C. 331, 342). Monitoring and enforcement
of pesticide tolerances are carried out by the U.S. Food and Drug
Administration (``FDA'') and the U. S. Department of Agriculture
(``USDA'').
A pesticide tolerance may only be promulgated by EPA if the
tolerance is ``safe.'' (21 U.S.C. 346a(b)(2)(A)(i)). ``Safe'' is
defined by the statute to mean
[[Page 52110]]
that ``there is a reasonable certainty that no harm will result from
aggregate exposure to the pesticide chemical residue, including all
anticipated dietary exposures and all other exposures for which there
is reliable information.'' (21 U.S.C. 346a(b)(2)(A)(ii)). Section 408
directs EPA, in making a safety determination, to ``consider, among
other relevant factors- . . . .available information concerning the
aggregate exposure levels of consumers (and major identifiable
subgroups of consumers) to the pesticide chemical residue and to other
related substances, including dietary exposure under the tolerance and
all other tolerances in effect for the pesticide chemical residue, and
exposure from other non-occupational sources.'' (21 U.S.C.
346a(b)(2)(D)(vi)). Other provisions address in greater detail exposure
considerations involving ``anticipated and actual residue levels'' and
``percent of crop actually treated.'' (See 21 U.S.C. 346a(b)(2)(E) and
(F)). Section 408(b)(2)(C) requires EPA to give special consideration
to risks posed to infants and children. This provision directs that
``an additional tenfold margin of safety for the pesticide chemical
residue and other sources of exposure shall be applied for infants and
children to take into account potential pre- and post-natal toxicity
and completeness of the data with respect to exposure and toxicity to
infants and children.'' (21 U.S.C. 346a(b)(2)(C)). EPA is permitted to
``use a different margin of safety for the pesticide chemical residue
only if, on the basis of reliable data, such margin will be safe for
infants and children.'' (Id.) [The additional safety margin for infants
and children is referred to throughout this notice as the ``children's
safety factor.''] These provisions establishing the detailed safety
standard for pesticides were added to section 408 by the Food Quality
Protection Act of 1996 (``FQPA''), an act that substantially rewrote
this section of the statute.
Tolerances are established by rulemaking under the unique
procedural framework set forth in the FFDCA. Generally, the rulemaking
is initiated by the party seeking the tolerance by means of filing a
petition with EPA. (See 21 U.S.C. 346a(d)(1)). EPA publishes in the
Federal Register a notice of the petition filing along with a summary
of the petition, prepared by the petitioner. (21 U.S.C. 346a(d)(3)).
After reviewing the petition, and any comments received on it, EPA may
issue a final rule establishing the tolerance, issue a proposed rule,
or deny the petition. (21 U.S.C. 346a(d)(4)). Once EPA takes final
action on the petition by either establishing the tolerance or denying
the petition, any affected party has 60 days to file objections with
EPA and seek an evidentiary hearing on those objections. (21 U.S.C.
346a(g)(2)). Objections must state with ``particularity'' their basis.
(40 C.F.R. 178.25(a)(2)). EPA's final order on the objections is
subject to judicial review. (21 U.S.C. 346a(h)(1)).
EPA also regulates pesticides under the Federal Insecticide,
Fungicide, and Rodenticide Act (``FIFRA''), (7 U.S.C. 136 et seq).
While the FFDCA authorizes the establishment of legal limits for
pesticide residues in food, FIFRA requires the approval of pesticides
prior to their sale and distribution, (7 U.S.C. 136a(a)), and
establishes a registration regime for regulating the use of pesticides.
FIFRA regulates pesticide use in conjunction with its registration
scheme by requiring EPA review and approval of pesticide labels and
specifying that use of a pesticide inconsistent with its label is a
violation of federal law. (7 U.S.C. 136j(a)(2)(G)). In the FQPA,
Congress integrated action under the two statutes by requiring that the
safety standard under the FFDCA be used as a criterion in FIFRA
registration actions as to pesticide uses which result in dietary risk
from residues in or on food, (7 U.S.C. 136(bb)), and directing that EPA
coordinate, to the extent practicable, revocations of tolerances with
pesticide cancellations under FIFRA. (21 U.S.C. 346a(l)(1)).
B. Setting Tolerances Under the FFDCA
1. In general. The process EPA follows in setting tolerances under
the FFDCA includes two steps. First, EPA determines an appropriate
residue level value for the tolerance taking into account data on
levels that can be expected in food. Second, EPA evaluates the safety
of the tolerance relying on toxicity and exposure data and guided by
the statutory definition of ``safe'' and requirements concerning risk
assessment. Only on completion of the second step can EPA make a
decision on whether a tolerance may be established. Below, EPA explains
in detail, the reasons for this approach.
2. Choosing a tolerance value. In the first step of the tolerance
setting process (choosing a tolerance value), EPA evaluates data from
experimental crop field trials in which the pesticide has been used in
a manner, consistent with the draft FIFRA label, that is likely to
produce the highest residue in the crop in question (e.g., maximum
application rate, maximum number of applications, minimum pre-harvest
interval between last pesticide application and harvest). (Refs. 2 and
3). These crop field trials are generally conducted in several fields
at several geographical locations. (Ref. 3 at 5, 7 and Tables 1 and 5).
Several samples are then gathered from each field and analyzed. (Id. at
53). Generally, the results from such field trials show that the
residue levels for a given pesticide use will vary from as low as non-
detectable to measurable values in the parts per million (``ppm'')
range with the majority of the values falling at the lower part of the
range. EPA uses a statistical procedure to analyze the field trial
results and identify the upper bound of expected residue values. This
upper bound value is used as the tolerance value. (Ref. 4). (As
discussed below, the safety of the tolerance value chosen is separately
evaluated.)
There are three main reasons for closely linking tolerance values
to the maximum value that could be present from maximum label usage of
the pesticide. First, EPA believes it is important to coordinate its
actions under the two statutory frameworks governing pesticides. (See
The Pesticide Coordination Policy; Response to Petitions, (61 FR 2378,
2379; January 25, 1996)). It would be illogical for EPA to set a
pesticide tolerance under the FFDCA without considering what action is
being taken under FIFRA with regard to registration of that pesticide
use. (Cf. 40 CFR 152.112(g) (requiring all necessary tolerances to be
in place before a FIFRA registration may be granted)). In coordinating
its actions, one basic tenet that EPA follows is that a grower who
applies a pesticide consistent with the FIFRA label directions should
not run the risk that his or her crops will be adulterated under the
FFDCA because the residues from that legal application exceed the
tolerance associated with that use. To prevent such an outcome, crop
field trials require application of the pesticide in the manner most
likely to produce maximum residues. Second, choosing tolerance values
based on FIFRA label rates helps to ensure that tolerance levels are
established no higher than necessary. If tolerance values were selected
solely in consideration of health risks, in some circumstances,
tolerance values might be set so as to allow much greater application
rates than necessary for effective use of the pesticide. This could
encourage misuse of the pesticide. Finally, closely linking tolerance
values to FIFRA labels helps EPA to police compliance with label
directions by growers because detection of an
[[Page 52111]]
overtolerance residue is indicative of use of a pesticide at levels, or
in a manner, not permitted on the label.
3. The safety determination - risk assessment. Once a tolerance
value is chosen, EPA then evaluates the safety of the pesticide
tolerance using the process of risk assessment. To assess risk of a
pesticide, EPA combines information on pesticide toxicity with
information regarding the route, magnitude, and duration of exposure to
the pesticide.
In evaluating a pesticide's potential hazards (e.g., liver effects,
carcinogenicity), EPA examines both short-term (e.g., ``acute'') and
longer-term (e.g., ``chronic'') adverse effects from pesticide
exposure. (Ref. 2 at 8-10). EPA also considers whether the ``effect''
has a threshold - a level below which exposure has no appreciable
chance of causing the adverse effect. For non-threshold effects, EPA
assumes that any exposure to the substance increases the risk that the
adverse effect may occur. At present, EPA only considers one adverse
effect, the chronic effect of cancer, to potentially be a non-threshold
effect. (Ref. 2 at 8-9). Not all carcinogens, however, pose a risk at
any exposure level (i.e., ``a non-threshold effect or risk''). Advances
in the understanding of carcinogenesis have increasingly led EPA to
conclude that some pesticides that cause carcinogenic effects only
cause such effects above a certain threshold of exposure. EPA has
traditionally considered adverse effects on the endocrine system to be
a threshold effect; that determination is being reexamined in
conjunction with the endocrine disruptor screening program.
Once EPA identifies a hazard for a durational scenario, EPA must
determine the toxicological level of concern and then compare estimated
human exposure to this level of concern. This comparison is done
through either calculating a safe dose in humans (incorporating all
appropriate safety factors) and expressing exposure as a percentage of
this safe dose (the reference dose (``RfD'') approach) or dividing
estimated human exposure into an appropriately protective dose from the
relevant studies (the margin of exposure (``MOE'') approach). How EPA
determines the level of concern and assesses risk under these two
approaches is explained in more detail below. EPA's general approach to
estimating exposure is also briefly discussed.
a. Levels of concern and risk assessment--i. Threshold effects. In
assessing the risk from a pesticide's threshold effects, EPA evaluates
an array of toxicological studies on the pesticide. In each of these
studies, EPA attempts to identify the lowest observed adverse effect
level (``LOAEL'') and the next lower dose at which there are no
observed adverse affect levels (``NOAEL''). Generally, EPA will use the
lowest NOAEL from the available studies, taking into account the route
and duration of exposure, as a starting point in estimating the level
of concern for humans for a given exposure scenario (e.g., acute oral
exposure). This selected NOAEL is usually referred to as the Point of
Departure. In estimating and describing the level of concern, however,
the Point of Departure is at times manipulated differently depending on
whether the risk assessment addresses dietary or non-dietary exposures.
(Refs. 2 at 3-8; 5 at 8, 52-52; and 6).
For dietary risks, EPA uses the Point of Departure to calculate a
safe dose or RfD. The RfD is calculated by dividing the Point of
Departure by applicable safety or uncertainty factors. Typically, a
combination of safety or uncertainty factors providing a hundredfold
(100X) margin of safety is used: 10X to account for uncertainties
inherent in the extrapolation from laboratory animal data to humans and
10X for variations in sensitivity among members of the human population
as well as other unknowns. Further, to account for deficiencies in the
database or the results seen in the database, EPA has traditionally
applied additional safety factors on a case-by-case basis. The FQPA
amendments to FFDCA section 408 require an additional safety factor of
10X to protect infants and children (to address data completeness and
pre- and post-natal toxicity concerns), unless reliable data support
selection of a different factor.
In implementing FFDCA section 408, EPA's Office of Pesticide
Programs, also calculates a variant of the RfD referred to as a
Population Adjusted Dose (``PAD''). A PAD is the RfD divided by any
portion of the FQPA children's safety factor that does not correspond
to one of the traditional additional safety factors used in general
Agency risk assessment. (Ref. 5 at 13-16). The reason for calculating
PADs is so that other parts of the Agency, which are not governed by
FFDCA section 408, can, when evaluating the same or similar substances,
easily identify which aspects of a pesticide risk assessment are a
function of the particular statutory commands in FFDCA section 408.
Today, RfDs and PADs are generally calculated for both acute and
chronic dietary risks although traditionally a RfD or PAD was only
calculated for chronic dietary risks. Throughout this document general
references to EPA's calculated safe dose are denoted as a RfD/PAD.
To quantitatively describe risk using the RfD/PAD approach,
estimated exposure is expressed as a percentage of the RfD/PAD. Dietary
exposures lower than 100 percent of the RfD/PAD are generally not of
concern.
For non-dietary, and often for combined dietary and non-dietary,
risk assessments of threshold effects, the toxicological level of
concern is not expressed as a safe dose or RfD/PAD but rather as the
margin of exposure (MOE) that is necessary to be sure that exposure to
a pesticide is safe. To calculate the MOE for a pesticide for a given
exposure scenario, the expected human exposure to the pesticide is
divided into the dose identified as the Point of Departure. A safe MOE
is generally considered to be a margin at least as high as the product
of all applicable safety factors for a pesticide. For example, if a
pesticide needs a 10X factor to account for interspecies differences, a
10X factor for intraspecies differences, and a 10X FQPA children's
safety factor, the safe or target MOE would be a value of at least
1,000. In contrast to the RfD/PAD approach, the higher the MOE, the
safer the pesticide. Accordingly, if the target MOE is 1,000, MOEs
exceeding 1,000 would generally not be of concern. Like RfD/PADs,
specific MOEs are calculated for exposures of different durations. For
non-dietary exposures, EPA typically examines short-term, intermediate-
term, and long-term exposures. Additionally, non-dietary exposure often
involves exposures by various routes including dermal, inhalation, and
oral.
The RfD/PAD and MOE approaches are fundamentally equivalent. For a
given risk and given exposure of a pesticide, if the pesticide were
found to be safe under a RfD/PAD analysis it would also pass under the
MOE approach, and vice-versa.
ii. Non-threshold effects. For risk assessments for non-threshold
effects, EPA does not use the RfD/PAD or MOE approach. Rather, EPA
calculates the slope of the dose-response curve for the non-threshold
effects from relevant studies using a model that assumes that any
amount of exposure will lead to some degree of risk. The slope of the
dose-response curve can then be used to estimate the probability of
occurrence of additional adverse effects as a result of exposure to the
pesticide. For non-threshold cancer risks, EPA generally is concerned
if the probability of increased cancer cases exceed the range of 1 in 1
million. Because NRDC's petition concerns the children's safety factor
and
[[Page 52112]]
the children's safety factor is only applicable to threshold risks, no
further discussion of non-threshold risk assessment is included here.
b. Estimating human exposure. Equally important to the risk
assessment process as identifying hazards and determining the
toxicological level of concern is estimating human exposure. Under
FFDCA section 408, EPA is concerned not only with exposure to pesticide
residues in food but also exposure resulting from pesticide
contamination of drinking water supplies and from use of pesticides in
the home or other non-occupational settings. (See 21 U.S.C.
346a(b)(2)(D)(vi)). There are two critical variables in estimating
exposure in food: (1) The types and amount of food that is consumed;
and (2) the residue levels in those foods. Consumption is estimated by
EPA based on scientific surveys of individuals' food consumption in the
United States conducted by the U.S. Department of Agriculture. (Ref. 2
at 12). Information on residue levels comes from a range of sources
including crop field trials, data on pesticide reduction due to
processing and other practices, information on the extent of usage of
the pesticide, and monitoring of the food supply. (Id. at 17).
In assessing exposure from pesticide residues in food, EPA, for
efficiency's sake, follows a tiered approach in which it, in the first
instance, conducts an initial, screening-level exposure assessment
using the worst case assumptions that 100 percent of the crop in
question is treated with the pesticide and 100 percent of the food from
that crop contains pesticide residues at the tolerance level. (Id. at
11). When such an assessment shows no risks of concern, EPA's resources
are conserved because a more complex risk assessment is avoided and
regulated parties are spared the cost of any additional studies that
may be needed. If, however, a first tier assessment suggests there
could be a risk of concern, EPA then attempts to refine its exposure
assumptions to yield a more realistic picture of residue values through
use of data on the percent of the crop actually treated with the
pesticide and data on the level of residues that may be present on the
treated crop. These latter data are used to estimate what has been
traditionally referred to by EPA as ``anticipated residues.'' Use of
percent crop treated data and anticipated residue information is
appropriate because EPA's worst case assumptions of 100 percent
treatment and residues at tolerance value significantly overstate
residue values. (71 FR 43906, 43909-43910 (August 2, 2006)).
In estimating pesticide exposure levels in drinking water, EPA most
frequently uses mathematical water exposure models rather than
pesticide-specific monitoring data. (69 FR 30042, 30058 (May 26, 2004).
EPA's models are based on extensive monitoring data and detailed
information on soil properties, crop characteristics, and weather
patterns. These models calculate estimated environmental concentrations
of pesticides using laboratory data that describe how quickly the
pesticide breaks down to other chemicals and how it moves in the
environment (i.e., does it bind to the soil or is it highly water
soluble). Although computer modeling provides an indirect estimate of
pesticide concentrations, these concentrations can be estimated
continuously over long periods of time, and for places that are of most
interest for any particular pesticide. Modeling is a useful tool for
characterizing vulnerable sites, and can be used to estimate peak
concentrations from infrequent, large storms. Whether EPA assesses
pesticide exposure in drinking water through monitoring data or
modeling, EPA uses the higher of the two values from surface and ground
water in assessing overall exposure to the pesticide. In most cases,
pesticide residues in surface water are significantly higher than in
ground water.
Generally, in assessing residential exposure to pesticides, EPA
relies on its Residential Standard Operating Procedures (``SOPs'')(Ref.
7). The SOPs establish models for estimating application and post-
application exposures in a residential setting where pesticide-specific
monitoring data is not available. SOPs have been developed for many
common exposure scenarios including pesticide treatment of lawns,
garden plants, trees, swimming pools, pets, and indoor surfaces
including crack and crevice treatments. The SOPs are based on existing
monitoring and survey data including information on activity patterns,
particularly for children. Where available, EPA relies on pesticide-
specific data in estimating residential exposures.
C. Children's Safety Factor Policy
As part of implementation of the major changes to FFDCA section 408
included in the FQPA, EPA has issued a number of policy guidance
documents addressing critical science issues. On January 31, 2002, EPA
released its science policy guidance on the children's safety factor.
(Ref. 5) [This policy is hereinafter referred to as the ``Children's
Safety Factor Policy'']. The Children's Safety Factor Policy emphasizes
throughout that EPA interprets the children's safety factor provision
as establishing a presumption in favor of application of an additional
10X safety factor for the protection of infants and children. (Id. at
4, 11, 47, A-6). Further, the policy notes that the children's safety
factor provision permits a different safety factor to be substituted
for this default 10X factor only if reliable data are available to show
that the different factor will protect the safety of infants and
children. (Id.). Given the wealth of data available on pesticides,
however, the policy indicates a preference for making an individualized
determination of a protective safety factor if possible. (Id. at 11).
The policy states that use of the default factor could under- or over-
protect infants and children due to the wide variety of issues
addressed by the children's safety factor. (Id.). Further, the policy
notes that ``[i]ndividual assessments may result in the use of
additional factors greater or less than, or equal to 10X, or no
additional factor at all.'' (Id.).
In making pesticide-specific assessments regarding the magnitude of
the children's safety factor, the policy stresses the importance of
focusing on the statutory language that ties the children's safety
factor to concerns regarding potential pre- and post-natal toxicity and
the completeness of the toxicity and exposure databases. (Id. at 11-
12). As to the completeness of the toxicity database, the policy
recommends use of a weight-of-the-evidence approach which considers not
only the presence or absence of data generally required under EPA
regulations and guidelines but also the availability of ``any other
data needed to evaluate potential risks to children.'' (Id. at 20). The
policy indicates that the principal inquiry concerning missing data
should center on whether the missing data would significantly affect
calculation of a safe exposure level. (Id. at 22; accord 67 FR 60950,
60955 (September 27, 2002) (finding no additional safety factor
necessary for triticonazole despite lack of developmental neurotoxicity
(``DNT'') study because the ``DNT [study] is unlikely to affect the
manner in which triticonazole is regulated.'')). When the missing data
are data above and beyond general regulatory requirements, the policy
states that the weight of evidence would generally only support the
need for an additional safety factor where the data ``is being required
for `cause,' that is, if a significant concern is raised
[[Page 52113]]
based upon a review of existing information, not simply because a data
requirement has been levied to expand OPP's general knowledge.'' (Ref.
5 at 23).
As to potential pre- and post-natal toxicity, the Children's Safety
Factor Policy lists a variety of factors that should be considered in
evaluating the degree of concern regarding any identified pre- or post-
natal toxicity. (Id. at 27-31). As with the completeness of the
toxicity database, the policy emphasizes that the analysis should focus
on whether any identified pre- or post-natal toxicity raises
uncertainty as to whether the RfD/PAD is protective of infants and
children. (Id. at 31). Once again, the presence of pre- or post-natal
toxicity, by itself, is not regarded as determinative as to the
children's safety factor. Rather, the policy stresses the importance of
evaluating all of the data under a weight of evidence approach focusing
on the safety of infants and children. (Id.).
In evaluating the completeness of the exposure database, the policy
explains that a weight-of-the-evidence approach should be used to
determine the confidence level EPA has as to whether the exposure
assessment ``is either highly accurate or based upon sufficiently
conservative input that it does not underestimate those exposures that
are critical for assessing the risks to infants and children.'' (Id. at
32). EPA describes why its methods for calculating exposure through
various routes and aggregating exposure over those routes generally
produce conservative exposure estimates - i.e. health-protective
estimates due to overestimation of exposure. (Id. at 40-43).
Nonetheless, EPA emphasizes the importance of verifying that the
tendency for its methods to overestimate exposure in fact were
adequately protective in each individual assessment. (Id. at 44).
IV. The Challenged Tolerance Decision
On April 5, 2006, EPA promulgated a final rule establishing
tolerances for the fungicide pyraclostrobin on shelled succulent beans;
foliage in the legume crop group; mangoes; and papayas. (71 FR 17014
(April 5, 2006)). Pyraclostrobin is a synthetic analog of a natural
antifungal substance which inhibits spore germination, mycelial growth,
and sporulation of the fungus on the leaf surface. (Ref. 8 at 4). The
tolerances were requested in petitions from the pyraclostrobin
registrant, BASF Corporation, and the Interregional Research Project
Number 4 (``IR-4''). The IR-4 is a program sponsored by the U.S.
Department of Agriculture and land grant universities and directed
toward obtaining regulatory approval for pesticide uses on minor and
speciality food crops that are not likely to be supported by private
sector companies. EPA evaluated the petitions in a joint effort with
the Pest Management Regulatory Agency of Canada.
Given pyraclostrobin's exposure pattern and toxicological
characteristics, EPA determined that pyraclostrobin potentially
presented acute, chronic, short-term, and cancer risks and EPA
quantitatively assessed these risks in making its safety determination.
(71 FR at 17018-17019; 69 FR 63083, 93093-63095 (October 29, 2004);
Ref. 8 at 31-32). All of these risks were found to be below the
Agency's level of concern. (Id.). EPA concluded that there were
reliable data supporting its determination that the additional
children's safety factor was not needed to protect the safety of
children. In making this determination EPA considered the completeness
of the toxicity and exposure database and data bearing on pre- and
post-natal toxicity. (71 FR at 17018; 69 FR 63092-63093). EPA found
that there was adequate toxicity and exposure data. Although there was
some evidence of qualitative and quantitative increased sensitivity in
the young from the developmental study in rabbits and reproduction
study in rats, respectively, EPA concluded using a weight-of-the-
evidence test that residual concerns for increased sensitivity in the
young were low. (69 FR at 63093); (Ref. 9 at 8).
V. NRDC Objections
In its objections, NRDC cites various allegedly inadequate studies
and pre-natal toxic effects of pyraclostrobin as grounds for claiming
it was unlawful for EPA to remove the children's safety factor and
EPA's overall decision was arbitrary and capricious.
A. Children's Safety Factor
NRDC argues that EPA should have retained the children's safety
factor for two separate reasons: (1) pyraclostrobin demonstrated pre-
natal toxicity; and (2) there were inadequacies in the submitted
toxicity data on pyraclostrobin and additional toxicity and exposure
data are needed. NRDC claims that EPA's decision to remove the
children's safety factor violates the FFDCA; however, NRDC does not
allege that retention of the children's safety factor would result in
the pyraclostrobin tolerances exceeding the FFDCA section 408 safety
standard. NRDC expanded on its objections in comments it submitted on
its own objections. These comments principally argued that EPA had
wrongly interpreted the children's safety factor provision. (Ref. 10).
1. Legal requirements for imposing the children's safety factor and
the standard for choosing a different safety factor. NRDC describes the
children's safety factor provision as requiring that the additional
children's safety factor ``shall be applied'' to ``take into account''
(1) ``potential pre- and post-natal toxicity;'' (2) ``completeness'' of
toxicity data; and (3) ``completeness'' of the exposure data. With
regard to the reference to pre- and post-natal toxicity, NRDC argues
that this statutory language ``mandates application of the safety
factor to account for any potential for pre- or post-natal toxicity.''
(Ref. 10 at 2). As to completeness of the data, NRDC takes a similarly
rigid position: ``Where studies identified by EPA as necessary to
ensure safety have never been conducted or reviewed - or have been
determined to be inadequate - EPA by definition cannot find that there
is a `reasonable certainty' that `no harm will result' to children, as
required by law[,]'' and therefore, cannot modify the children's safety
factor. (Id.).
NRDC acknowledges that EPA may apply a factor different than
presumptive tenfold children's safety factor but stresses that a
different factor may be applied only if there is reliable data showing
the different factor is safe. EPA, NRDC claims, has applied a different
standard in the pyraclostrobin tolerance decision - requiring that
there be merely adequate data on pyraclostrobin toxicity and exposure
and that there be no substantial evidence of increased sensitivity of
infants and children to the pesticide. (Id.).
2. Pre-natal sensitivity. In discussing evidence on pre-natal
sensitivity, NRDC references both the developmental studies in rats and
in rabbits. NRDC asserts that the developmental rat study shows
qualitative increased sensitivity in the rat fetuses because the
effects in the rat fetuses (dilated renal pelvis and cervical ribs with
no cartilage) were more severe than the effects in adults (reduced body
weight, body weight gain, food intake, and food efficiency). (Ref. 1 at
7). Qualitative increased sensitivity is seen in the rabbit
developmental study, according to NRDC, again because the effects in
the fetuses were more severe than the effects in the adults (increased
resorption and post-implantation loss versus reduced body weight, body
weight gain, food intake, and food efficiency). (Id.). NRDC argues that
EPA erred by looking beyond the question of whether the animal studies
show fetuses to be qualitatively more sensitive than
[[Page 52114]]
maternal animals to examine whether it was safe to remove or reduce the
factor despite a finding of qualitative increased sensitivity.
According to NRDC, because the studies show qualitative increased
sensitivity in pre-natal animals as compared to adult animals, ``EPA
must retain the full tenfold safety factor . . . .'' (Id. at 5).
3. Inadequate and missing data--a. Immunotoxicity data. NRDC argues
that, because EPA has not required immunotoxicity data on
pyraclostrobin, EPA cannot explain the differential immunotoxic results
between males and females in the pyraclostrobin studies. Due to this
lack of understanding, NRDC claims that immunotoxicity ``should be
considered a serious potential risk of pyraclostrobin . . . [and] EPA
must retain the full tenfold safety factor as a result.'' (Id. at 6-7).
NRDC cites four studies in support of this argument. First, it
references a 90-day oral toxicity mouse study in which females
allegedly showed immunotoxic effects at a dose at which males only
showed more generalized toxicity (e.g., reduced body weight). Second,
NRDC points to a 90-day oral toxicity study in dogs in which NRDC
claims females suffered body weight loss, reduced food intake, and
reduced food efficiency in addition to the gastrointestinal effects
that occurred in both sexes. Third, NRDC cites two neurotoxicity
studies in which males were shown to be significantly more sensitive
than females. NRDC claims that these studies demonstrate that males and
females respond differently to pyraclostrobin and that EPA should be
particularly concerned about the immunotoxic effects in females because
there is ``substantial data demonstrating that females are more likely
than males to develop autoimmune diseases in response to environmental
stressors.'' (Id. at 6).
b. Two-generation reproduction study. NRDC asserts that the two-
generation rat reproduction study with pyraclostrobin relied upon by
EPA is ``invalid'' and that EPA cannot rehabilitate it by combining it
with a one-generation rat reproduction study because that study
produced results which contradict the two-generation study. (Id. at 7-
8). The two-generation study is invalid, according to NRDC, because it
showed no adverse effects at any of the doses tested. NRDC states that
such a study ``must be considered invalid because it is unknown whether
the study failed to find an effect because there really was no effect,
or if it was due to a lack of statistical power, poor study design, or
an endless number of potential fatal weaknesses (e.g., the test agent
could have degraded through poor storage conditions; the endpoint
measurements could have been reported in error; treated and control
animals could have been mis-categorized, etc.).'' (Id. at 8). NRDC
argues that the one-generation study contradicts the two-generation
study because the former identified adverse effects at a dose lower
than a dose in the two-generation study that showed no effects. NRDC
concludes that ``EPA must retain the full tenfold safety factor in
light of these invalid and deficient studies.'' (Id.)
c. Other data deficiencies. NRDC briefly mentions several other
alleged data gaps or deficiencies: (1) data on anticipated
pyraclostrobin residues which EPA has required to be submitted; (2) a
missing 28-day inhalation toxicity study; (3) a deficient chronic
toxicity study in rats due to failure to show adverse effects; (4) a
deficient mouse cancer study due to failure to show adverse effects;
and (5) an unacceptable dermal penetration study due to problems in
administration of the test dose. Categorizing these deficiencies as
``significant,'' NRDC argues EPA must retain the children's safety
factor to address them. (Id. at 8-10).
B. Arbitrary and Capricious
NRDC also argues that the tolerance decision was arbitrary and
capricious ``because EPA never received or reviewed information that
the agency considered necessary to review the pesticides' safety
(listed above), and because EPA failed to explain adequately its
departure from the required children's safety factor.'' (Id. at 10).
VI. Public Comment
A. In General
On July 19, 2006, EPA published a notice in the Federal Register
calling attention to and requesting comments on the NRDC Objections.
(71 FR 41015 (July 19, 2006)). The notice included a short summary of
the objections and referenced readers to EPA's electronic docket for a
full copy of the objections. EPA received three comments on the
objections. Other than NRDC's comments on its own objections, the only
significant comment EPA received was from BASF Corporation, the
registrant under FIFRA for pyraclostrobin.
B. BASF Corporation
BASF Corporation has registered pyraclostrobin for use as a
pesticide under FIFRA and petitioned for several of the tolerances that
are subject to the present objections. As to the potential for
pyraclostrobin to impact differently on males and females, BASF argues
in its comments that differential effects on the sexes are noted in
toxicology studies and taken into account in setting the RfD. (Ref.
11). Any uncertainty regarding the sensitivities of these two groups is
addressed, according to BASF, by the tenfold uncertainty factor used to
account for variable sensitivities in humans. Further, BASF argues that
the ``issue of differential sensitivity between sexes is not relevant
for evaluating the need to apply the FQPA safety factor'' because that
safety factor only addresses potential differences in sensitivities
between adults and children. (Id. at 1).
BASF challenges NRDC's assertion that qualitative sensitivity was
demonstrated in the rat and rabbit developmental studies. BASF claims
that the fetal effects seen in the rat study (dilated renal pelvis and
cervical ribs with no cartilage) were not due to treatment. This is
evidenced, according to BASF, by the fact that the incidence of these
effects was within the historical control range for the experimental
animal. As to the effects on rabbit fetuses (increased resorption and
post-implantation loss), BASF argues these effects are a result of the
severe effects that pyraclostrobin had on the maternal animals as
opposed to any direct toxic effect on the fetuses. According to BASF,
``maternal body weight gain during the treatment period was reduced by
a dramatic 77% at the high dose and 39% at the mid dose compared to
controls. This substantial effect to the maternal animals would be
expected to affect the dam's ability to deliver full-term fetuses and
does not reflect a direct action of the test material on the fetus.''
(Id. at 2).
With regard to the two-generation reproduction study in rats, BASF
contends that the results from this study are not inconsistent with the
one-generation reproduction study. BASF claims that body weight changes
were seen in the highest dose tested in the two-generation reproduction
study. Although the body weight changes in the two-generation study
were small, BASF argues that ``the effects at this dose fits along a
dose-response curve with the two doses in the range-finding [one-
generation] study.'' (Id. at 3).
BASF disputes NRDC's claims regarding data gaps and deficiencies.
First, BASF asserts that a 28-day inhalation study has been submitted
to EPA. Second, BASF contends that subsequent data submitted to EPA led
EPA to conclude that the rat and mouse carcinogenicity studies were
conducted at sufficiently high doses. Finally, BASF
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states that a repeat dermal penetration study was conducted. (Id. at
4).
C. NRDC
In its comments, NRDC expands on its legal argument that EPA must
retain the children's safety factor when data are absent. According to
NRDC, when data EPA has determined are ``necessary to evaluate safety''
are not available, EPA ``by definition'' may not remove the 10X
children's safety factor. (Ref. 10 at 2). NRDC also cites general
statements that children can be more vulnerable than adults to
pesticides and that children may have greater relative exposure to
pesticides than adults and argues that this means that the children's
safety factor must be retained for pyraclostrobin. (Id. at 3). Finally,
NRDC listed various documents that it claims support its objections.
(Id. at 4).
VII. Response to Objections
As summarized above, NRDC's objections pertain primarily to EPA's
decision on the children's safety factor - in brief, NRDC's argument is
that, due to evidence on pre-natal toxicity and immunotoxicity, and
data deficiencies, EPA erred in removing the children's safety factor.
NRDC also recasts these same allegations to claim that EPA acted
arbitrarily and capriciously in promulgating the pyraclostrobin
tolerances. These arguments are addressed separately below.
A. Children's Safety Factor
NRDC objects to the pyraclostrobin tolerances on the ground that it
was unlawful for EPA to remove the children's safety factor. Although
not stated, presumably NRDC believes that EPA should have denied the
petition seeking the pyraclostrobin tolerances for this reason. A
decision on the children's safety factor, however, is not outcome
determinative with regard to whether a petitioned-for tolerance meets
the safety standard for establishing tolerances. Retention of the
children's safety standard would generally result in a tenfold lowering
of the pesticide's RfD/PAD, thus decreasing by a factor of ten the
amount of aggregate exposure to the pesticide that would not exceed the
RfD/PAD; it would not, however, bar the establishment of the tolerance.
EPA has established many tolerances for which the children's safety
factor has been retained. (See, e.g., 71 FR 56369, 56372 (September 27,
2006); 70 FR 14535, 14541-14542 (March 23, 2005)). Similarly, EPA has
recently denied a petition to revoke tolerances which claimed that EPA
should have retained the children's safety factor where it was clear
that EPA could make the reasonable certainty of no harm finding with or
without retention of the additional safety factor. (72 FR 39318, 39323-
39324 (July 18, 2007)). For pyraclostrobin, EPA's exposure assessment,
which is partially refined, suggests that retention of the children's
safety factor may raise safety concerns for the pesticide. Because it
is unclear whether further refinement of the exposure assessment would
render the decision on the children's safety factor irrelevant to the
ultimate safety decision, EPA has chosen to address the merits of the
argument presented by NRDC.
NRDC makes two different types of arguments as to why the
children's safety factor should be retained. First, citing various
issues regarding pre-natal toxicity and data completeness, NRDC
essentially argues that the overall weight-of-evidence does not support
EPA's conclusion that there is reliable data showing it will be safe
for children to use a hundredfold margin of safety rather than a
thousand-fold margin. Second, NRDC argues that each of the individual
issues it raises ``compel'' EPA to retain the children's safety factor.
This second argument is more fully made in the legal contentions
presented in NRDC's comments on its objections.
In responding to NRDC's arguments, EPA first addresses the legal
contention that various findings ``compel'' the retention of the
children's safety factor. In this section, EPA explains why it
fundamentally disagrees with NRDC's approach to the safety factor
provision. Second, EPA examines the merits of the various factual
allegations made by NRDC concerning pre-natal toxicity and data
deficiencies. As EPA makes clear below, in most instances NRDC is
mistaken in its factual allegations. Finally, EPA addresses whether the
totality of the claims raised by NRDC alter EPA's conclusion regarding
removal of the children's safety factor.
1. Legal interpretation of the children's safety factor provision.
In its objections and its comments on its objections, NRDC claims that
(1) EPA is legally compelled to retain the children's safety factor
when there is a data gap; (2) EPA is legally compelled to retain the
children's safety factor when there is evidence showing that the young
are more sensitive to the effects of a pesticide or a pesticide causes
pre- or post-natal toxicity; and (3) EPA has applied an incorrect
standard in evaluating whether the presumptive tenfold children's
safety factor may be modified. Following a summary of the statutory
language on the children's safety provision, EPA explains why each of
these assertions are incorrect.
a. Children's safety factor provision. The statutory requirements
pertaining to the children's safety factor are contained in two
sentences in section 408(b)(2)(C). The first sentence commands that as
to ``threshold effects, for the purposes of [making the reasonable
certainty of no harm finding], an additional tenfold margin of safety
for the pesticide chemical residue and other sources of exposure shall
be applied for infants and children.'' (21 U.S.C. 346a(b)(2)(C)). This
sentence also explains that the purpose for this additional safety
factor is ``to take into account potential pre- and post-natal toxicity
and completeness of the data with respect to exposure and toxicity to
infants and children.'' (Id.). Switching course, the second sentence
then countermands the mandatory language in the first sentence (``shall
be applied'') and makes clear that EPA has the authority to deviate
from the requirement to apply an additional 10X safety factor. The
second sentence reads ``[n]othwithstanding such requirement for an
additional margin of safety, the Administrator may use a different
margin of safety for the pesticide chemical residue only if, on the
basis of reliable data, such a margin will be safe for children.''
(Id.).
b. Operation of the children's safety factor provision. EPA has
interpreted the children's safety factor provision as containing a
presumption in favor of retaining an additional tenfold safety factor
for the protection of infants and children. That presumption may be
overcome, however, when EPA has reliable data showing that use of a
different safety factor will protect the safety of infants and
children. Such a different safety factor may be lower or higher than
the default 10X value. In making decisions about whether it has
reliable data supporting a different safety factor, EPA has looked at
the totality of the evidence bearing on the safety of infants and
children and carefully weighed the strength of that evidence in
determining whether a different safety factor would be safe. That was
the approach followed with pyraclostrobin.
NRDC appears to interpret the children's safety factor provision
quite differently. Repeatedly in its objections, NRDC argues that EPA
``must'' retain the children's safety factor due to some data
deficiency or because of the identification of increased sensitivity in
the young. NRDC affirms this view in its comments stating that the
statute ``mandates application of the safety factor to account for any
potential for pre- or post-natal toxicity'' and, that
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where necessary studies are missing, ``EPA, by definition'' cannot make
the safety finding needed to choose a different safety factor. Under
NRDC's interpretation, the children's safety factor operates in a rigid
and automatic fashion: upon identification of a data gap or of
sensitivity in the young, EPA loses all discretion to choose a
different safety factor.
i. Data gaps. EPA has previously rejected NRDC's interpretation as
it applies to data gaps noting that the interpretation fails to take
into account the entire children's safety factor provision. In
responding to other tolerance objections filed by NRDC, EPA stated its
disagreement with the view ``that the mere absence of a required
[developmental neurotoxicity] study should, by itself, conclusively bar
EPA from applying a different additional safety factor than the 10X
default value.'' (70 FR at 46723). EPA pointed out that the statute
``expressly authorizes'' EPA to choose a different safety factor based
solely on whether EPA determined that a different factor was safe and
that EPA's policy of making children's safety factor decisions on a
case-by-case basis examination of all of the data on a pesticide is in
accord with this statutory provision. (Id.). EPA concluded that NRDC's
outcome-determinative approach to data gaps and the children's safety
factor simply did not address the statute's grant of discretion to EPA
to choose a different safety factor.
In its comments on its objections, NRDC now offers the following
argument as to why, when data on pesticide safety are lacking, EPA does
not have the authority to choose a different safety factor. NRDC claims
that, when needed safety data are missing, EPA, ``by definition,''
cannot make the reasonable certainty of no harm (i.e. safety) finding
necessary to choose a different safety factor. NRDC's logic seems to be
as follows: if EPA determines it needs additional data on safety, EPA
has necessarily concluded that such data are ``necessary to ensure
safety,'' and if data that are ``necessary to ensure safety'' are
lacking, EPA cannot make the safety finding required to apply a
different children's safety factor.
The main problem with this argument is that it ignores the plain
language of the statute. As noted above, section 408(b)(2)(C) contains
two sentences regarding application of an additional safety factor for
the protection of infants and children. The first sentence requires EPA
to apply an additional 10X safety factor to address, among other
things, data completeness issues. Importantly, the data completeness
issue mentioned by the statute is data bearing on toxicity and exposure
- i.e., data on safety. In the very next sentence, however, the statute
provides that ``notwithstanding such requirement'' to apply a safety
factor to address safety data completeness issues, EPA may choose a
different factor so long as that factor is safe for children. If there
is any definitional reading of this language, it is that EPA has the
authority to choose a different safety factor when safety data are
incomplete. NRDC's interpretation would read EPA's grant of authority
to choose a different factor when there are safety data completeness
issues out of the statute.
In addition to ignoring the plain language of the children's safety
provision, NRDC's argument also is inconsistent with the statutory
structure in at least two ways. First, NRDC's interpretation renders
the children's safety factor provision, itself, mere surplusage if data
completeness issues arise. If, as NRDC has argued, a request for data
means that the data are necessary to ensure safety, then EPA, in those
circumstances, not only cannot make the safety (reasonable certainty of
no harm) finding necessary to remove the children's safety factor but
EPA cannot make the safety (reasonable certainty of no harm) finding
necessary to grant the tolerance. In other words, under NRDC's
argument, the entire children's safety provision becomes irrelevant if
EPA has requested data, because that request, by itself, conclusively
bars EPA from establishing the tolerance. NRDC has not explained why it
is rational to assume that Congress drafted a provision addressing data
completeness issues but made the provision inoperative if data
completeness issues arise.
Second, NRDC's elevation of an EPA requirement for additional
safety data to a determination that a tolerance is unsafe (i.e. that a
safety determination cannot be made) is inconsistent with the structure
of section 408 that permits EPA to require additional safety data on
existing tolerances while at the same time commanding that tolerances
that do not meet the safety standard be revoked. Under section 408(f),
EPA is authorized to require the submission of data ``to support the
continuation of a tolerance . . . .'' (21 U.S.C. 346a(f)). The sole
criterion for the continuation of a tolerance is whether it continues
to meet the reasonable certainty of no harm standard. (21 U.S.C.
346a(b)(2)(A)(i)). Thus, Congress contemplated that EPA could require
safety data on existing tolerances. Yet, under NRDC's interpretation it
is difficult to see how EPA could ever require submission of safety
data on existing tolerances. NRDC has argued that if data bearing on
the reasonable certainty of no harm finding are needed (which is the
finding necessary to request data under section 408(f)), then the
reasonable certainty of no harm finding cannot be made. Thus, if EPA
were to determine that additional safety data are needed on an existing
tolerance, it would also be concluding that that tolerance is unsafe.
The statute, however, commands EPA to revoke unsafe tolerances, not
request more safety data concerning them. (21 U.S.C.
346a(b)(a)(2)(A)(ii)). In other words, under NRDC's approach, if EPA
determines that data were needed to support the continuation of a
tolerance, EPA would have to revoke the tolerance rendering moot any
decision to require submission of additional data to support the
tolerance. Presumably, Congress would not have enacted such a self-
defeating provision.
The underlying flaw in NRDC's argument is that it equates an EPA
decision to seek additional safety data with the proposition that EPA
has necessarily determined that a safety finding cannot be made in the
absence of such data. NRDC does not take into account that there are
many types of safety data and that the varying types of safety data
have varying degrees of importance to the ultimate reasonable certainty
of no harm finding. For example, the five core required toxicology
studies would generally be of greater importance to the children safety
factor determination than conditionally-required toxicology studies or
special studies, for instance, to determine mechanism of toxicity.
Similarly, as to pesticide exposure data, residue data on major crops
will be of more significance than data on minor crops, and even for
major crops the importance of the first 15 geographically-distributed
residue studies will be of more value than the next five such studies.
Further, not only are some studies more important or necessary to the
safety determination than others, but, in the absence of a study,
information from one study, or a group of studies, or the assumptions
made to compensate for the missing study, may significantly diminish
any uncertainty raised by the study's absence. For example, in the
absence of dermal absorption data, EPA generally assumes 100 percent of
a pesticide is dermally absorbed. Given all of these considerations and
the range of data that can be required, it is apparent that a request
for additional data is not synonymous with a determination that
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a safety finding cannot be me made. Thus, it is reasonable not to adopt
NRDC's absolutist approach but to evaluate on a case-by-case basis
whether the safety data that are available on a pesticide show that a
different safety factor is safe.
At bottom, the decision on the children's safety factor turns on
whether a safety finding can be made, not on whether any particular
study is available. If data are absent, EPA may still examine the
existing reliable data to determine if a factor different than 10X is
safe. NRDC is incorrect to the extent it argues that EPA is statutorily
barred from making this inquiry.
ii. Increased sensitivity in the young. In the current objections,
NRDC also argues that EPA ``must'' retain the children's safety factor
because ``[j]uveniles are qualitatively more sensitive than adults to
pyraclostrobin toxicity.'' (Ref. 1 at 7). NRDC criticizes EPA for
examining whether there is ``substantial evidence'' of sensitivity.
(Id. at 5). Presumably, NRDC's view is that any evidence of sensitivity
automatically requires EPA to retain the children's safety factor.
This rigid interpretation of the children's safety provision,
however, fails for the same reason NRDC's argument for automatic
retention of the children's safety factor for data deficiencies fails -
it is not in accord with the plain language of the statute. The statute
does direct EPA to consider ``susceptibility of infants and children''
to pesticides. (21 U.S.C. 346a(b)(2)(C)(i)(II)). It also states that an
additional safety factor to protect infants and children shall be
applied ``to take into account potential pre- and post-natal toxicity .
. . .'' (21 U.S.C. 346a(b)(2)(C)). Nonetheless, in clear and
unmistakable language, Congress decreed that, ``[n]otwithstanding such
requirement for an additional margin of safety'' to take into account
potential pre- and post-natal toxicity, EPA is authorized to choose a
different safety factor if EPA has reliable data showing a different
factor is safe. (Id.). Interpreting the statute as creating a rigid,
per se rule that the identification of sensitivity in the young removes
EPA's discretion to choose a different safety factor is inconsistent
with this language and the flexibility granted to the Agency. On the
other hand, EPA's policy, and the approach it followed with
pyraclostrobin, of examining the entire database to determine if,
despite a finding of sensitivity, there are reliable data showing a
different factor to be safe, is in full accord with the statutory
provision.
c. The standard for choosing a different safety factor.
Alternatively, NRDC argues that even if the statutory language does not
compel EPA to