[Federal Register Volume 77, Number 75 (Wednesday, April 18, 2012)]
[Rules and Regulations]
[Pages 23135-23158]
[FR Doc No: 2012-9106]

-----------------------------------------------------------------------

ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 180

[EPA-HQ-OPP-2008-0877; FRL-9344-1]

2,4-D; Order Denying NRDC's Petition To Revoke Tolerances

AGENCY: Environmental Protection Agency (EPA).

ACTION: Order.

-----------------------------------------------------------------------

SUMMARY: In this Order, EPA denies a petition requesting that EPA
revoke all pesticide tolerances for 2,4-dichlorophenoxyacetic acid
(2,4-D) under section 408(d) of the Federal Food, Drug, and Cosmetic
Act (FFDCA). The petition was filed on November 6, 2008, by the Natural
Resources Defense Council.

DATES: This Order is effective April 18, 2012. Objections and requests
for hearings must be received on or before June 18, 2012, and must be
filed in accordance with the instructions provided in 40 CFR part 178
(see also Units I.B and I.C. of the SUPPLEMENTARY INFORMATION.)

ADDRESSES: EPA has established a docket for this action under docket
identification (ID) number EPA-HQ-OPP-2008-0877. All documents in the
docket are listed in the docket index available at http://www.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 either in the
electronic docket at http://www.regulations.gov, or, if only available
in hard copy, by appointment at One Potomac Yard (South Bldg.), 2777 S.
Crystal Dr., Arlington, VA, between 9 a.m. to 3 p.m., Monday through
Friday, excluding legal holidays. To schedule an appointment, call
(703) 305-5805.

FOR FURTHER INFORMATION CONTACT: Cathryn Britton, Pesticide Re-
evaluation Division, Office of Pesticide Programs, Environmental
Protection Agency, 1200 Pennsylvania Ave. NW., Washington, DC 20460-
0001; telephone number:<PHONE_NUMBER>; fax number:<PHONE_NUMBER>;
email address<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this action apply to me?

    In this document EPA denies a petition by the Natural Resources
Defense Council (NRDC) to revoke pesticide tolerances. This action may
also be of interest to agricultural producers, food manufacturers, or
pesticide manufacturers. Potentially affected entities may include, but
are not limited to:
     Crop production (North American Industrial Classification
System (NAICS) code 111), e.g., agricultural workers; greenhouse,
nursery, and floriculture workers; farmers.
     Animal production (NAICS code 112), e.g., cattle ranchers
and farmers, dairy cattle farmers, livestock farmers.
     Food manufacturing (NAICS code 311), e.g. agricultural
workers; farmers; greenhouse, nursery, and floriculture workers;
ranchers; pesticide applicators.
     Pesticide manufacturing (NAICS code 32532), e.g.
agricultural workers; commercial applicators; farmers, greenhouse,
nursery, and floriculture workers; residential users.
    This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in this unit could also be
affected. NAICS codes have been provided to assist you and others in
determining whether this action might apply to certain entities. If you
have any questions regarding the applicability of

this action to a particular entity, consult the person listed under FOR
FURTHER INFORMATION CONTACT.

B. Can I file an objection or hearing request?

    Under section 408(g) of FFDCA, any person may file an objection to
any aspect of this order and may also request a hearing on those
objections. You must file your objection or request a hearing on this
order in accordance with the instructions provided in 40 CFR part 178.
To ensure proper receipt by EPA, you must identify docket ID number
EPA-HQ-OPP-2008-0877 in the subject line on the first page of your
submission. All objections and requests for a hearing must be in
writing, and must be received by the Hearing Clerk on or before June
18, 2012. Addresses for mail and hand delivery of objections and
hearing requests are provided in 40 CFR 178.25(b).
    In addition to filing an objection or hearing request with the
Hearing Clerk as described in 40 CFR part 178, please submit a copy of
the filing that does not contain CBI for inclusion in the public docket
that is described in ADDRESSES. Information not marked confidential
pursuant to 40 CFR part 2 may be disclosed publicly by EPA without
prior notice. Submit this copy, identified by docket ID number EPA-HQ-
OPP-2008-0877, by one of the following methods:
     Federal eRulemaking Portal: http://www.regulations.gov.
Follow the on-line instructions for submitting comments.
      Mail: U.S. Environmental Protection Agency, Office of
Pesticide Programs (OPP) Public Regulatory Docket (7502P), 1200
Pennsylvania Ave. NW., Washington, DC 20460-0001.
     Delivery: OPP Regulatory Public Docket (7502P),
Environmental Protection Agency, Rm. S-4400, One Potomac Yard (South
Bldg.), 2777 S. Crystal Dr., Arlington, VA. Deliveries are only
accepted during the Docket Facility'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<PHONE_NUMBER>.

C. What should be included in objections?

    The objection stage is the second stage in the multi-stage petition
process under FFDCA section 408. This multi-stage process is initiated
by a petition requesting establishment, modification, or revocation of
a tolerance. In the petition, the petitioner has the opportunity to
make its best case for why its request should be granted. Notice and
comment on the petition gives interested parties the chance to express
views or provide information on the subject matter of the petition.
    Once EPA makes a decision on a petition, and publishes its decision
in the Federal Register, the second stage of the petition process is
triggered. At this point, parties who disagree with EPA's decision,
whether it is a decision to grant or deny the petition, may file
objections with EPA to the decision made. The objection stage gives
parties a chance to seek review of EPA's decision before the Agency.
This is an opportunity for parties to contest the conclusions EPA
reached and the determinations underlying those conclusions. As an
administrative review stage, it is not an opportunity to raise new
issues or arguments or present facts or information that was available
earlier. On the other hand, parties must do more than repeat the claims
in the petition. The objection stage is the opportunity to challenge
EPA's decision on the petition. An objection fails on its face if it
does not identify aspects of EPA's decision believed to be in error and
explain why EPA's decision is incorrect.
    This two-stage process ensures that issues are fully aired before
the Agency and a comprehensive record is compiled prior to judicial
review. The sequential nature of the petition and objection process is
essential for two reasons. The availability of administrative review
before EPA gives EPA, as well as other parties, an opportunity to
clearly define and articulate the complex science, policy, and legal
issues involved in tolerance decisions. The two-stage process also is
designed to make the administrative process as efficient as possible
while still providing parties an opportunity for an adjudicatory
hearing if needed. In the first stage, EPA is given the opportunity to
resolve the issues raised by petition through a process similar to
informal notice-and-comment rulemaking. Only material, factual issues
that remain disputed following this first stage may be raised in a
hearing request. Under this scheme, hearings, if needed, can focus on
the key areas of factual dispute. Of course, the first stage of the
petition process can only serve its winnowing function if parties are
restricted at the second (objection) stage from raising new issues.

II. Background

A. What action is the agency taking?

    On November 6, 2008, the Natural Resources Defense Council (NRDC)
filed with EPA a petition that, among other things, requested that EPA
revoke all tolerances for the pesticide 2,4-dichlorophenoxyacetic acid
(2,4-D) established under section 408 of the Federal Food, Drug, and
Cosmetic Act (FFDCA), 21 U.S.C. 346a (Ref. 1). NRDC claims that EPA's
conclusion outlined in the 2005 Reregistration Eligibility Decision
(RED) for 2,4-D, which allowed 2,4-D to be reregistered and its
tolerances retained, was based on a risk assessment that was deficient
in regard to the toxicity of 2,4-D and the amount of human exposure to
the chemical. Specific to 2,4-D tolerances, NRDC asserts that EPA
failed to incorporate information on the endocrine disrupting effects
of 2,4-D into its human health risk assessments; EPA disregarded data
on neurotoxicity related to 2,4-D; EPA disregarded information showing
that 2,4-D is mutagenic; EPA ignored data showing that dermal
absorption of 2,4-D is enhanced by alcohol consumption, sunscreen, and
DEET; and that EPA ignored the exposure of 2,4-D via breast milk to
infants. Numerous studies are cited in the petition that NRDC claims
supports its assertions. EPA has reviewed all of the studies cited by
NRDC.
    In this order, EPA is denying NRDC's petition to revoke 2,4-D's
tolerances in full. Many of NRDC's claims fail to state a sufficient
ground for revocation and instead merely critique the manner in which
the risk assessment underlying the 2,4-D RED was conducted. Those
claims that do allege relevant statutory grounds for revocation EPA
finds to be without merit. The other aspects of NRDC's petition not
concerning the 2,4-D tolerances are addressed in another EPA action.

B. What is the agency's authority for taking this action?

    Under section 408(d)(4) of the FFDCA, EPA is authorized to respond
to a section 408(d) petition to revoke tolerance either by issuing a
final rule revoking the tolerances, issuing a proposed rule, or issuing
an order denying the petition. (21 U.S.C. 346a(d)(4)).

III. Statutory and Executive Order Reviews

A. FFDCA/FIFRA and Applicable Regulations

    1. In general. EPA establishes maximum residue limits, or
``tolerances,'' for pesticide residues in food and feed commodities
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). Section 408 was substantially rewritten by the Food
Quality Protection Act of 1996 (FQPA), which added the provisions
discussed below establishing a detailed safety standard for pesticides,
additional protections for infants and children, and the estrogenic
substances screening program. (Pub. L. 104-170, 110 Stat. 1489 (1996)).
    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)).
    2. Safety standard for pesticide tolerances. A pesticide tolerance
may only be promulgated or left in effect by EPA if the tolerance is
``safe.'' (21 U.S.C. 346a(b)(2)(A)(i)). This standard applies when
responding both to petitions to establish and petitions to revoke
tolerances. ``Safe'' is defined by the statute to mean 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 includes
numerous provisions directing how EPA should quantitatively assess the
risks of pesticides in determining whether a tolerance meets the safety
standard. For example, section 408 either authorizes or requires EPA to
consider safety factors appropriate to use of animal experimentation
data, 21 U.S.C. 346a(b)(2)(D)(ix), aggregate and cumulative exposures
to the pesticide in question and other related substances, 21 U.S.C.
346a(b)(2)(D)(v) and (vi), anticipated or actual pesticide residue
levels as compared to the maximum levels permitted by tolerances, 21
U.S.C. 346a(b)(2)(E), and the percentage of crops that bear pesticide
residues, 21 U.S.C. 346a(b)(2)(F). See 21 U.S.C. 346a(b)(2)(B)(iv)
(limiting an exception to the safety standard to pesticides posing
risks that do not exceed ``10 times the yearly risk'' allowed under the
safety standard).
    Risks to infants and children are given special consideration.
Providing additional protection to infants and children was a
particular focus of the FQPA. Section 408(b)(2)(C) requires EPA to make
a specific determination regarding the safety of tolerances to infants
and children and to consider, among other things, information
``concerning the special susceptibility of infants and children to the
pesticide chemical residues * * *.'' (21 U.S.C. 346a(b)(2)(C)(i)(II)
and (ii)(II)). This provision also creates a presumptive additional
safety factor for the protection of infants and children. Specifically,
it directs that ``[i]n the case of threshold effects, * * * 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.). Due to Congress' focus on both pre- and
post-natal toxicity, EPA has interpreted this additional safety factor
as pertaining to risks to infants and children that arise due to pre-
natal exposure as well as to exposure during childhood years. For
convenience's sake, the legal requirements regarding the additional
safety margin for infants and children in section 408(b)(2)(C) are
referred to throughout this Order as the ``FQPA safety factor for the
protection of infants and children'' or simply the ``FQPA safety
factor.'' '
    3. Procedures for establishing, amending, or revoking tolerances.
Tolerances are established, amended, or revoked by rulemaking under the
unique procedural framework set forth in the FFDCA. Generally, a
tolerance rulemaking is initiated by the party seeking to establish,
amend, or revoke a 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 and requests public comment. (21 U.S.C.
346a(d)(3)). After reviewing the petition, and any comments received on
it, EPA may issue a final rule establishing, amending, or revoking the
tolerance, issue a proposed rule to do the same, or deny the petition.
(21 U.S.C. 346a(d)(4)).
    Once EPA takes final action on the petition by establishing,
amending, or revoking the tolerance or denying the petition, any party
may file objections with EPA to EPA's decision on the petition and seek
an evidentiary hearing on those objections. (21 U.S.C. 346a(g)(2)).
Objections and hearing requests must be filed within 60 days. (Id.).
The statute provides that EPA shall ``hold a public evidentiary hearing
if and to the extent the Administrator determines that such a public
hearing is necessary to receive factual evidence relevant to material
issues of fact raised by the objections.'' (21 U.S.C. 346a(g)(2)(B).
EPA regulations make clear that hearings will only be granted where it
is shown that there is ``a genuine and substantial issue of fact,'' the
requestor has identified evidence ``which, if established, resolve one
or more of such issues in favor of the requestor,'' and the issue is
``determinative'' with regard to the relief requested. (40 CFR
178.32(b)). Further, a party may not raise issues in objections unless
they were part of the petition and an objecting party must state
objections to the EPA decision and not just repeat the allegations in
its petition. Corn Growers v. EPA, 613 F.2d 266 (D.C. Cir. 2010), cert.
denied, 131 S. Ct. 2931 (2011). EPA's final order on the objections is
subject to judicial review. (21 U.S.C. 346a(h)(1)).
    4. Tolerance reassessment and FIFRA reregistration. The FQPA
required that EPA reassess the safety of all pesticide tolerances
existing at the time of its enactment. (21 U.S.C. 346a(q)). EPA was
given 10 years to reassess the approximately 10,000 tolerances in
existence in 1996. In this reassessment, EPA was required to review
existing pesticide tolerances under the new ``reasonable certainty that
no harm will result'' standard set forth in section 408(b)(2)(A)(ii).
(21 U.S.C. 346a(b)(2)(A)(ii)). This reassessment was substantially
completed by the August 3, 2006 deadline. Tolerance reassessment was
generally handled in conjunction with a similar program involving
reregistration of pesticides under FIFRA. (7 U.S.C. 136a-1).
Reassessment and reregistration decisions were generally combined in a
document labeled a Reregistration Eligibility Decision (RED).
    5. Estrogenic substances screening program. Section 408(p) of the
FFDCA creates the estrogenic substances screening program. This
provision directed EPA to ``develop a screening program 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 the Administrator may
designate.'' This screening program must use ``appropriate validated
test systems and scientifically relevant information.'' (21 U.S.C.
346a(p)(1)).
    Pursuant to the Administrator's discretionary authority, EPA
adopted a two-tiered screening and testing strategy and expanded the
EDSP to include the androgen and thyroid hormonal pathways and
ecological effects. (63 FR 71542, 71544, December 28, 1998). The first
tier involves screening ``to identify substances that have the
potential to interact with the endocrine system'' and the second tier
involves testing ``to determine whether the substance causes adverse
effects, identify the adverse effects caused by the substance, and
establish a quantitative relationship between the dose and the adverse
effect.'' (Id. at 71545). Tier 1 screening is limited to evaluating
whether a substance is ``capable of interacting with'' the endocrine
system, and is ``not sufficient to determine whether a chemical
substance may have an effect in humans that is similar to an effect
produced by naturally occurring hormones.'' (Id. at 71550). Based on
the results of Tier 1 screening, EPA will decide whether Tier 2 testing
is needed. Importantly, ``[t]he outcome of Tier 2 is designed to be
conclusive in relation to the outcome of Tier 1 and any other prior
information. Thus, a negative outcome in Tier 2 will supersede a
positive outcome in Tier 1.'' (Id. at 71554-71555).
    In 2008, after an extensive validation process, including peer
review of individual assays, EPA notified the public of the EDSP
proposed Tier 1 battery of screening assays in a Federal Register
Notice issued January 24, 2008 (73 FR 4216). EPA submitted the proposed
battery for peer review by FIFRA Scientific Advisory Panel (SAP). A
final report of the peer review is available. (Ref. 2). EPA announced
the issuance of orders for Tier 1 Screening on October 21, 2009 for 67
chemicals including 2,4-D. (74 FR 54422, 54425). With regard to
endocrine effects on humans, EPA has designated the 1998 rat two-
generation reproduction study (870-3800) as the applicable Tier 2 study
for the Endocrine Disruptor Screening Program. In this reproduction
study, potential hormonal effects can be detected through behavioral
changes, ability to become pregnant, duration of gestation, signs of
difficult or prolonged parturition, apparent sex ratio (as ascertained
by anogenital distances) of the offspring, feminization or
masculinization of offspring, number of pups, stillbirths, gross
pathology and histopathology of the vagina, uterus, ovaries, testis,
epididymis, seminal vesicles, prostate, and any other identified target
organs. EPA concluded that the rat two-generation reproduction study is
valid for the identification and characterization of reproductive and
developmental effects, including those due to endocrine disruption,
based on the long history of its use, the endorsement of the 1998 test
guideline by the FIFRA SAP, and acceptance by member countries of the
Organisation for Economic Cooperation and Development (OECD).
    In addition to the 1998 test guideline for the mammalian two-
generation reproductive toxicity study, EPA has proposed the new OECD
test guideline for the extended one-generation reproductive toxicity
study as an alternate EDSP Tier 2 test. The extended one-generation
reproductive toxicity study was not only designed to provide the
traditional spectrum of information from a reproductive study, but was
also enhanced to evaluate reproductive and developmental endpoints
associated with the endocrine, nervous, and immune systems in male and
female adult rodents and offspring at birth, weaning, and puberty,
which may not necessarily be covered in other 40 CFR part 158 test
guideline studies.
    EPA has received all required final study reports and data from the
Tier 1 battery of tests for 2,4-D. (Refs. 3,4,5,6,7,8, and 9). EPA
waived the in vivo mammalian Tier 1 tests for 2,4-D due to the
availability of a newly-submitted extended one generation reproduction
study with 2,4-D. (Ref. 10). The submitted EDSP Tier 1 assays will be
considered with regard to potential ecological effects and the need for
Tier 2 in vivo studies for effects in wildlife. Although the submitted
Tier 1 in vitro studies may inform EPA on mechanistic issues in
mammalian systems (e.g., whether 2,4-D can bind to the estrogen or
androgen receptor in mammals), the studies will not affect EPA's
conclusions on the quantitative endocrine risks posed by 2,4-D for
humans given the availability of the extended one-generation
reproduction study (an in vivo study in rats) that comprehensively
examined the risks to human health from 2,4-D's interaction with
endocrine system endpoints. (See discussion in Unit VII.A.1.c.).

B. EPA Risk Assessment for Tolerances--Policy and Practice

    1. The safety determination--risk assessment. To assess risk of a
pesticide tolerance, EPA combines information on pesticide toxicity
with information regarding the route, magnitude, and duration of
exposure to the pesticide. The risk assessment process involves four
distinct steps:
     Identification of the toxicological hazards posed by a
pesticide;
     Determination of the ``Level of Concern (LOC)'' with
respect to human exposure to the pesticide;
     Estimation of human exposure to the pesticide; and
     Characterization of risk posed to humans by the pesticide
based on comparison of human exposure to the LOC.
    a. Hazard identification. In evaluating toxicity or hazard, EPA
reviews toxicity data, typically from studies with laboratory animals,
to identify any adverse effects on the test subjects. Where available
and appropriate, EPA will also take into account studies involving
humans, including human epidemiological studies. For most pesticides,
the animal toxicity database usually consists of studies investigating
a broad range of endpoints including gross and microscopic effects on
organs and tissues, functional effects on bodily organs and systems,
effects on blood parameters (such as red blood cell count, hemoglobin
concentration, hematocrit, and a measure of clotting potential),
effects on the concentrations of normal blood chemicals (including
glucose, total cholesterol, urea nitrogen, creatinine, total protein,
total bilirubin, albumin, hormones, and enzymes such as alkaline
phosphatase, alanine aminotransferase and cholinesterases), and
behavioral or other gross effects identified through clinical
observation and measurement. EPA examines whether adverse effects are
caused by different durations of exposure ranging from short-term
(acute) to long-term (chronic) pesticide exposure and different routes
of exposure (oral, dermal, inhalation). Further, EPA evaluates
potential adverse effects in different age groups (adults as well as
fetuses and juveniles). (Ref. 11 at 8-10).
    EPA also considers whether the adverse effect has a threshold--a
level below which exposure has no appreciable chance of causing the
adverse effect. For effects that have no threshold, EPA assumes that
any exposure to the substance increases the risk that the adverse
effect may occur.
    b. LOC/dose-response analysis. Once a pesticide's potential hazards
are identified, EPA determines a toxicological LOC for evaluating the
risk posed by human exposure to the pesticide. In this step of the risk
assessment process, EPA essentially evaluates the levels of exposure to
the pesticide at which effects might occur in the toxicity studies. An
important

aspect of this determination is assessing the relationship between
exposure (dose) and response (often referred to as the dose-response
analysis). EPA follows differing approaches to identifying a LOC for
effects that only occur above a threshold (``threshold effects'') and
those for which a threshold dose cannot be determined (``non-threshold
effects''). Because EPA identified only threshold effect risks for 2,4-
D, only EPA's risk assessment procedures for threshold risks are
discussed in this Order.
    In examining the dose-response relationship for a pesticide's
threshold effects, EPA evaluates an array of toxicity studies on the
pesticide. Two critical parts of this evaluation involve identification
of a quantitative dose level(s) from these studies to be used in
assessing the pesticide's safety to humans (referred to as the Point of
Departure) and selection of appropriate safety factors for translating
the results of toxicity studies in relatively small groups of animals
or humans to the overall human population, including major identifiable
subgroups of consumers. The Point of Departure is used in conjunction
with identified safety factors to calculate a Level of Concern for a
pesticide.
    i. Point of Departure. A Point of Departure (POD) is the dose
serving as the `starting point' in extrapolating a risk to the human
population. In selecting the POD, EPA first evaluates all relevant
available toxicity data and conducts a weight of the evidence analysis,
considering consistency, reproducibility, temporal and dose
concordance, and biological plausibility of the effects reported. EPA
then selects a value from a dose-response curve that is at the low end
of the observable data (the no observed adverse effect level, or NOAEL,
the lowest-observed adverse effect level, or LOAEL, or an extrapolated
benchmark dose) as the POD. Doses in toxicology studies are generally
expressed in terms of milligrams of the test substance per kilogram of
body weight of the test subject per day (mg/kg/day). EPA will make
separate determinations as to the Points of Departure for both short
and long exposure periods as well as for the different routes of
exposure (oral, dermal, and inhalation).
    ii. Safety factors. It has long been a standard risk assessment
practice, to use numerical factors--variously referred to over time as
either uncertainty or safety factors \1\ in conjunction with
experimental toxicity data in assessing risk to humans. The two most
common safety/uncertainty factors are the factors used to address the
potential difference in sensitivity between humans and experimental
animals (i.e., inter-species sensitivity) and within the human
population (i.e., intra-species sensitivity). Generally a factor of
tenfold (10X) is used as a default for both the inter-species and
intra-(human) species safety factors. When EPA bases its POD on a dose
level from experimental animal data, it will generally use both factors
so that it accounts both for the fact that it is extrapolating a dose
level in animals to humans and that there may be a wide variation in
human response to the compound. This would result in a total safety
factor of 100X because each factor indicates that the potential
variations addressed constitute a multiple of 10X. When EPA bases its
POD on a dose level from human data, only the intra-species factor
would be needed because EPA is not extrapolating a dose used in an
animal study.
---------------------------------------------------------------------------

    \1\ Different terminology has been used to label factors used in
calculating safe doses of chemical substances. At first, they were
frequently referred to as ``safety'' factors. The terminology has
evolved over the decades, however, such that what was once generally
called a safety factor has come to be generally referred to as an
uncertainty factor. (Ref. 12 at A-3). The rationale for the change
was that although the use of such factors does promote safety, the
factors actually address uncertainty issues (e.g., uncertainty about
the differences in sensitivities of animals and humans, uncertainty
concerning variation inhuman sensitivities, uncertainty created by
missing data, etc.). The FQPA reintroduced the term ``safety''
factors with its reference to a ``margin of safety.'' Subsequent to
the passage of FQPA, the Office of Pesticide Programs has used the
terms safety factor and uncertainty factor interchangeably.
---------------------------------------------------------------------------

    In addition to the inter- and intra-species factors, risk assessors
also apply ``additional'' or ``modifying'' safety/uncertainty factors
based on specific circumstances related to the toxicity data,
particularly with regard to deficiencies in that data. Additional
factors are applied to address: (1) An absence of critical toxicity
data; (2) the failure of a study to identify a NOAEL; (3) the necessity
of using a sub-chronic data to choose a POD for estimating chronic
risk; and (4) results in a study that suggest the inter- or intra-
species factors may not be sufficient. Generally, a safety factor value
of 10X or 3X (which is considered to be one-half of 10X on the
logarithmic scale) is used to address these concerns.
    EPA's safety/uncertainty factor practice with regard to pesticides
was altered to a degree by the Food Quality Protection Act (FQPA).
(Ref. 12). That Act established a presumptive additional ``safety''
factor of 10X to protect infants and children. The additional factor
was designed to account for the completeness of the toxicity and
exposure databases and the potential for pre- and post-natal toxicity.
EPA has interpreted this legislation as both a ``codification and
expansion'' of prior EPA practice with regard to additional safety/
uncertainty factors. (Ref. 12 at A-4-A-5). It codified EPA's prior
practice by requiring the additional presumptive factor to address
toxicity data completeness issues (i.e., absence of a particular study,
a NOAEL in a completed study, or chronic data). These traditional
additional uncertainty factors became FQPA safety factors for the
protection of infants and children. EPA concluded that Congress had not
intended EPA to double-up on safety factors by, for example, applying
an ``additional'' uncertainty factor due to missing data, and apply a
FQPA safety factor as well to address the same missing data. (Ref. 12
at A-5). Congress expanded EPA's prior practice by providing that the
additional FQPA safety factor for the protection of infants and
children was designed to address not just toxicity data deficiencies
but exposure data deficiencies as well and by its emphasis on
protecting against potential pre- and post-natal toxicity. In theory,
EPA could have, prior to the enactment of the FQPA, used an
``additional'' or ``modifying'' factor to address health risks to
children not otherwise protected by the inter-species, intra-species,
or data deficiency safety factors, but use of such a factor was not
common. The FQPA also modified the status quo by making the additional
safety factor for infants and children presumptive in nature.
    The narrowly-focused and highly-prescriptive nature of the FQPA
safety factor provision has created some practical problems for EPA in
integrating the new statutory requirements with pesticide risk
assessment approaches and, more generally, with Agency risk assessment
practices. As noted above, the FQPA essentially codified EPA's prior
risk assessment practice as to ``additional'' uncertainty factors and
it expanded the use of additional uncertainty factors into new areas.
The FQPA, however, did not speak to use of traditional (non-additional)
uncertainty factors. Thus, the end result was that some uncertainty
factors for FFDCA pesticides remained unaffected by the new statutory
requirements (the inter- and intra-species factors), some uncertainty
factors became FQPA safety factors (additional uncertainty factors that
addressed toxicity data deficiencies), and some safety factors that
either had previously never existed or were at least extremely rare
were created as a

statutory phenomenon (a factor to address exposure data base
deficiencies and a factor to address potential pre- and post-natal
toxicity). This selective inter-weaving of statutory requirements with
Agency science policy made FFDCA risk assessments for pesticides unique
compared to general Agency risk assessment practice.
    Pesticide risk, however, is not regulated under a single statute.
Risks to workers or the environment from pesticide use are regulated by
EPA under FIFRA not the FFDCA. Further, EPA may address risks posed by
pesticide contamination of the environment under several other
statutes, including the Safe Drinking Water Act, 42 U.S.C. 300f et
seq., the Resource Conservation and Recovery Act, 42 U.S.C. 6901 et
seq., and the Comprehensive Environmental Response, Compensation, and
Liability Act, 42 U.S.C. 9601 et seq. Prior to enactment of the FQPA's
specific provisions on pesticide risk assessment, a pesticide risk
assessment performed by EPA's Office of Pesticide Programs under the
aegis of FFDCA section 408 could generally be easily translated for use
by the Office of Pesticide Programs under FIFRA, or by the other media
offices within EPA for use under other statutes. However, once
pesticide risk assessment under the FQPA became not simply a matter of
good scientific practice but was channeled by explicit statutory
requirements, it became incumbent upon the Office of Pesticide Programs
to prepare its FFDCA pesticide risk assessments in a manner that
clearly delineated what aspects of the assessment were driven solely by
science and what aspects primarily by FQPA statutory requirements.
Specifically, the Office of Pesticide Programs had to be transparent
with regard to whether it was relying on FQPA safety factors based on
unique FQPA requirements (exposure database deficiencies and potential
pre- and post-natal toxicity) or FQPA safety factors that are
essentially a codification of prior general EPA ``additional'' safety/
uncertainty factor practice.
    EPA addressed these ``transparency'' issues at length in its 2002
policy statement on the FQPA safety factor. To clarify how the FQPA
safety factor provision left a portion of prior safety/uncertainty
practice unchanged, codified another portion, and also expanded the use
of safety factors, EPA explained the overlap between the FQPA safety
factor and ``additional'' safety factors in depth and included the
following figure to graphically illustrate the issue:
[GRAPHIC] [TIFF OMITTED] TR18AP12.001

    With regard to providing transparency on the FQPA safety factor
decisions, EPA took two steps. First, it adopted a new term, the
``special'' FQPA safety factor, for children safety factors that were
based solely on the new FQPA requirements. Second, it adopted the
approach of calculating two different safe doses for a pesticide: One
that excluded any ``special'' FQPA safety factors and one that included
them. (See discussion of reference doses and population-adjusted doses
in Unit III.B.1.b.iii, below). Introducing the new terminology on FQPA
safety factors into

long-established safety factor practice has proved challenging. EPA
staff frequently drafted documents that (1) claimed no FQPA safety
factor was needed but applied an additional uncertainty factor to
address the completeness of the data base or reliance on a LOAEL; or
(2) treated the ``special'' FQPA safety factor as the only type of FQPA
safety factor. Such misstatements did not substantively change risk
assessment outcomes but they did raise the confusion level on an
already complex topic. Eventually, EPA determined that the term
``special'' FQPA safety factor caused more problems than it solved and
abandoned it. However, EPA has retained the approach of continuing to
calculate both a safe dose with, and without, what was once referred to
as ``special'' FQPA safety factors.
    (iii). Level of Concern. By Level of Concern (LOC), EPA means a
numerical value that separates exposures that would generally be
regarded as raising health concerns from those that do not. The POD
(see Unit III.B.1.b.i. above) is used in estimating and describing the
LOC; however, the LOC is expressed differently depending on whether the
risk assessment addresses dietary or non-dietary exposures. The use of
different approaches is due to the fact that non-dietary exposure
assessments often involve combining exposures from multiple pathways.
    For dietary risks, EPA uses the POD to calculate an acceptable LOC
that is referred to as a reference dose (RfD). The RfD is calculated by
dividing the POD by all applicable safety or uncertainty factors with
one exception (see below). (Ref. 12 at 4-11). Safety/uncertainty
factors are divided separately and sequentially into the POD. Thus, for
example, if the POD is 1 milligram/kilogram/day (mg/kg/day) and there
are two applicable 10X safety/uncertainty factors, then the reference
dose would be 0.01 mg/kg/day (i.e., 1 mg/kg/day divided twice by 10).
For convenience's sake, safety factors are often combined by
multiplying them by each other. This product when divided into the POD
would, of course, produce the same result as sequential division. For
reduction of a safety factor, a similar process is followed. For
example, if a safety factor is to be reduced by half, this is done by
taking the square root of the factor rather than dividing by two. See
73 FR 42683, 42696 (July 23, 2008).
    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 safety factor that does not correspond to one of the
traditional additional safety factors used in general Agency risk
assessments. (Ref. 12. at 13-16). As noted above, 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 RfDs and PADs
were only calculated for chronic risks. RfDs/PADs for acute and chronic
risks will generally have different Points of Departure (because they
are generally based on studies of different duration) and may be based
on different safety factors as well depending on the characteristics of
the studies relied on in choosing the POD. For example, if the study
used to pick the POD for acute risk identified a NOAEL but the study
used for chronic risk did not, any additional safety factor used to
address this lack of a NOAEL in calculating the RfD/PAD for chronic
risk would not be applicable to the acute RfD/PAD derivation.
    For non-dietary, and combined dietary and non-dietary, risk
assessments of threshold effects, the toxicological LOC is not
expressed as an RfD/PAD but rather in terms of an acceptable (or
target) Margin of Exposure (MOE) between human exposure and the POD.
The ``margin'' that is being referred to in the term MOE is the ratio
between human exposure and the POD which is calculated by dividing
human exposure into the POD. An acceptable 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 potential inter-species differences, 10X factor for
potential intra-species differences, and 10X factor for the FQPA
children's safety provision, the safe or target MOE would be a MOE of
at least 1,000. What that means is that for the pesticide in the
example to meet the safety standard, human exposure to the pesticide
would generally have to be at least 1,000 times smaller than the POD.
Like RfD/PADs, specific target MOEs are selected for exposures of
different durations and routes. For non-dietary exposures, EPA
typically examines short-term, intermediate-term, and long-term
exposures. Additionally, target MOEs may be selected based on both the
duration of exposure and the various routes of non-dietary exposure--
dermal, inhalation, and oral. Target MOEs for a given pesticide can
vary depending on the characteristics of the studies relied upon in
choosing the POD for the various duration and route scenarios.
    c. Estimating human exposure. Risk is a function of both hazard and
exposure. Thus, equally important to the risk assessment process as
determining the hazards posed by a pesticide and the toxicological LOC
for those hazards 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)).
Additionally, EPA must take into account non-occupational exposure from
``other related substances.'' (Id.).
    i. Exposure from food. There are two critical variables in
estimating exposure in food: (1) The types and amount of food that is
consumed; and (2) the residue level in that food.
    Consumption is estimated by EPA based on scientific surveys of
individuals' food consumption in the United States conducted by the
USDA. (Ref. 11 at 12). Information on residue values comes from a range
of sources including crop field trials; data on pesticide reduction (or
concentration) due to processing, cooking, 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, assesses exposure using the worst case assumptions that 100
percent of the crop or commodity in question is treated with, or
exposed to, the pesticide and 100 percent of the food from that crop or
commodity contains pesticide residues at the tolerance level. (Id. at
11). When such an assessment shows no risks of concern, a more complex
risk assessment is unnecessary. By avoiding a more complex risk
assessment, EPA's resources are conserved 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 or commodity actually treated with, or exposed to,
the pesticide and data on the level of residues that may be present on
the treated crop or

commodity. These latter data are used to estimate what has been
traditionally referred to by EPA as ``anticipated residues.'' More
information on refining estimates of pesticide exposure can be found at
Ref. 11; 70 FR 46706, 46732, August 10, 2005).
    ii. Exposure from water. EPA may use either or both field
monitoring data and mathematical water exposure models to generate
pesticide exposure estimates in drinking water. Monitoring and modeling
are both important tools for estimating pesticide concentrations in
water and can provide different types of information. Monitoring data
can provide estimates of pesticide concentrations in water that are
representative of specific agricultural or residential pesticide
practices and under environmental conditions associated with a sampling
design. Although monitoring data can provide a direct measure of the
concentration of a pesticide in water, it does not always provide a
reliable estimate of exposure because sampling may not occur in areas
with the highest pesticide use, and/or the sampling may not occur when
the pesticides are being used.
    In estimating pesticide exposure levels in drinking water, EPA most
frequently uses mathematical water exposure models. EPA's models are
based on extensive monitoring data and detailed information on soil
properties, crop characteristics, and weather patterns. (69 FR 30042,
30058-30065, May 26, 2004). These models calculate estimated
environmental concentrations of pesticides using laboratory data that
describe how fast the pesticide breaks down to other chemicals and how
it moves in the environment. 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.
    iii. Exposure from residential use of pesticides. Residential
assessments examine exposure to pesticides in non-occupational or
residential settings (e.g., homes, parks, schools, athletic fields or
any other areas frequented by the general public). Exposures to
pesticides may occur to persons who apply pesticides or to persons who
enter areas previously treated with pesticides. Such exposures may
occur through oral, inhalation, or dermal routes.
    Residential assessments are conducted through examination of
significant exposure scenarios (e.g., children playing on treated lawns
or homeowners spraying their gardens) using a combination of generic
and pesticide-specific data. To regularize this process, OPP has
prepared Standard Operating Procedures (SOPs) for conducting
residential assessments on a wide array of scenarios that are intended
to address all major possible means by which individuals could be
exposed to pesticides in a non-occupational environment (e.g. homes,
schools, parks, athletic fields, or other publicly accessible
locations). The SOPs identify relevant generic data and construct
algorithms for calculating exposure amounts using these generic data in
combination with pesticide-specific information. The generic data
generally involve survey data on behavior patterns (e.g., activities
conducted on turf and time spent on these activities) and transfer
coefficient data. Transfer coefficient data measure the amount of
pesticide that transfers from the environment to humans from a defined
activity (e.g., hand contact with a treated surface or plant). Specific
information on pesticides can include information on residue levels as
well as information on environmental fate such as degradation data.
    d. Risk characterization. The final step in the risk assessment is
risk characterization. In this step, EPA combines information from the
first three steps (hazard identification, LOC/dose-response analysis,
and human exposure assessment) to quantitatively estimate the risks
posed by a pesticide. Separate characterizations of risk are conducted
for different durations of exposure. Additionally, separate and, where
appropriate, aggregate characterizations of risk are conducted for the
different routes of exposure (dietary and non-dietary).
    For threshold risks, EPA estimates risk in one of two ways. Where
EPA has calculated a RfD/PAD, risk is estimated by expressing human
exposure as a percentage of the RfD/PAD. Exposures lower than 100
percent of the RfD/PAD are generally not of concern. Alternatively, EPA
may express risk by comparing the MOE between estimated human exposure
and the POD with the acceptable or target MOE. As described previously,
the acceptable or target MOE is the product of all applicable safety
factors. To calculate the actual MOE for a pesticide, estimated human
exposure to the pesticide is divided into the POD. In contrast to the
RfD/PAD approach, higher MOEs denote lower risk. Accordingly, if the
target MOE for a pesticide is 100, MOEs equal to or exceeding 100 would
generally not be of concern. As a conceptual matter, the RfD/PAD and
MOE approaches are fundamentally equivalent. For a given risk and given
exposure of a pesticide, if exposure to a pesticide were found to be
acceptable under an RfD/PAD analysis it would also pass under the MOE
approach, and vice-versa.
    2. EPA policy on the FQPA safety factor for the protection of
infants and children. As the previous brief summary of EPA's risk
assessment practice indicates, the use of safety factors plays a
critical role in the process. This is true for traditional 10X safety
factors to account for potential differences between animals and humans
when relying on studies in animals (inter-species safety factor) and
potential differences among humans (intra-species safety factor) as
well as the FQPA's additional 10X safety factor.
    In applying the FQPA safety factor provision, EPA has interpreted
it as imposing a presumption in favor of applying an additional 10X
safety factor. (Ref. 12 at 4, 11). Thus, EPA generally refers to the
additional 10X factor as a presumptive or default 10X factor. EPA has
also made clear, however, that this presumption or default in favor of
the additional 10X is only a presumption. The presumption can be
overcome if reliable data demonstrate that a different factor is safe
for children. (Id.). In determining whether a different factor is safe
for children, EPA focuses on the three factors listed in FFDCA section
408(b)(2)(C)--the completeness of the toxicity database, the
completeness of the exposure database, and potential pre- and post-
natal toxicity. In examining these factors, EPA strives to make sure
that its choice of a safety factor, based on a weight-of-the-evidence
evaluation, does not understate the risk to children. (Id. at 24-25,
35).

IV. 2,4-D Regulatory Background

    2,4-D is a phenoxy herbicide, plant growth regulator, and fungicide
that has been used in the United States since the mid 1940s. It comes
in multiple chemical forms and is currently found in approximately 600
end-use products registered for agricultural, residential, industrial,
and aquatic uses. It is formulated primarily as an amine salt in an
aqueous solution or as an ester in an emulsifiable concentrate. There
are 85 tolerances for 2,4-D listed in the Code of Federal Regulations.
    1. Special review based on human carcinogenicity. On September 22,
1986, the Agency issued a preliminary notification of Special Review of
2,4-D because of concerns for epidemiological links of 2,4-D to non-
Hodgkin's lymphoma from both occupational and residential exposure. In
1987, EPA requested that the FIFRA SAP examine

the evidence bearing on 2,4-D's carcinogenicity. The Panel concluded
that the present data for animals and humans were inadequate for
determining carcinogenicity and that 2,4-D should be classified under
Group D of EPA's cancer guidelines--Not Classifiable as to Human
Carcinogenicity. (Refs. 13 and 14). Based upon findings that existing
data did not support a link between 2,4-D and carcinogenicity, the
Agency published a proposed decision Not to Initiate Special Review on
March 23, 1988 (53 FR 9590) and deferred a final decision until
reregistration.
    To further address the potential link of non-Hodgkin's lymphoma to
2,4-D exposure, a joint Science Advisory Board (SAB)/SAP Special Joint
Committee was convened to review available epidemiological and other
data on 2,4-D. In 1994, the Committee concluded that ``the data are not
sufficient to conclude that there is a cause and effect relationship
between exposure to 2,4-D and non-Hodgkin's lymphoma.'' (Ref. 15). In
1997, EPA re-examined the weight of the evidence on cancer taking into
account two new cancer bioassays in mice and rats. (Ref. 16). These new
bioassays showed no statistically significant tumor response in either
species. Although EPA concurred with the Joint Committee's
recommendation to classify 2,4-D under Group D, EPA requested further
histopathological examinations of mouse and rat tissue from previously
conducted studies to further inform its decision. These exams showed no
evidence to alter the prior findings, and on March 16, 1999, the Agency
notified the 2,4-D Task Force that the EPA would continue to classify
2,4-D under Group D. (Ref. 17).
    Since the March 16, 1999 decision, the Agency has twice reviewed
epidemiological studies linking cancer to 2,4-D exposure during the
reregistration process of 2,4-D. In the first review, completed January
14, 2004, EPA concluded there was no additional evidence that would
implicate 2,4-D as a cause of cancer. (Ref. 14). The second review of
available epidemiological studies occurred in response to comments
received during development of the 2,4-D RED. EPA's report, dated
December 8, 2004, found that none of the more recent epidemiological
and animal studies supported a conclusion that 2,4-D was a likely human
carcinogen. (Ref. 15). Because the Agency determined that the existing
data did not support a conclusion that links human cancer to 2,4-D
exposure, it decided not to initiate a Special Review of 2,4-D in 2007.
(72 FR 44510, August 8, 2007).
    A part of this cancer assessment was the review of data bearing on
2,4-D's potential mutagenicity. EPA has consistently found that these
data do not support classification of 2,4-D as a carcinogen. This view
was concurred in by the Joint Committee of SAB/SAP.
    2. FFDCA tolerance reassessment and FIFRA pesticide reregistration.
As required by the Food Quality Protection Act of 1996, EPA reassessed
the safety of the 2,4-D tolerances under the safety standard
established in the FQPA. In the June 2005 RED for 2,4-D, EPA evaluated
the human health risks associated with all registered uses of 2,4-D and
determined that there is a reasonable certainty that no harm will
result from aggregate non-occupational exposure to the pesticide
chemical residue. (Refs.18 and 19). In making this determination, EPA
considered dietary exposure from food and drinking water and all other
non-occupational sources of pesticide exposure for which there is
reliable information. The Agency concluded that with the adoption of
the risk mitigation measures identified in the 2,4-D RED, all of the
tolerances for 2,4-D meet the safety standard as set forth in section
408(b)(2)(D) of the FFDCA. Therefore, the tolerances established for
residues of 2,4-D were considered reassessed as safe under section
408(q) of FFDCA.
    At the time of 2,4-D reregistration, there were no available
studies on 2,4-D that adequately assessed its endocrine disruption
potential, and the Agency determined that a repeat 2-generation
reproduction study should be conducted to evaluate comparative thyroid
effects in young and adult animals as well as the gonads and
reproductive/developmental endpoints more thoroughly. The 2,4-D RED
indicated that a new reproduction study using the revised 2-generation
reproduction study protocol and measurement of additional parameters
was needed to address these data gaps. EPA also required submission of
a developmental neurotoxicity study. Although these data were needed,
EPA concluded that the toxicology database was adequate for
identification of doses and endpoints of concern for risk assessments.
The values selected for risk assessments were protective of all
observed adverse effects. Additionally, EPA retained the additional
FQPA 10X safety factor for the protection of infants and children to
address the uncertainty raised by the missing data. Finally, 2,4-D
toxicity generally occurs at doses above renal saturation, i.e., doses
above which the excretory processes could readily eliminate the
chemical; the Agency's risk assessment regulated at doses below this
level. Consequently, the Agency had high confidence that the risk
assessment did not underestimate risks from exposure to 2,4-D.
    On February 28, 2006, EPA issued a data call-in for 2,4-D that,
among other things, required submission of the reproduction and
developmental neurotoxicity studies mentioned above. In February 2010,
in response to the data call-in, the Industry Task Force II on 2,4-D
Research Data submitted a state-of-the-science extended one-generation
reproduction toxicity study to fulfill these requirements. The 2,4-D
extended one-generation reproductive toxicity study included a detailed
assessment of endocrine endpoints (thyroid, estrus cyclicity, sexual
maturation (animals were observed for delays in vaginal opening and
preputial separation), andrology, and ovarian staging), in addition to
reproductive function, developmental neurotoxicity, and immunotoxicity
endpoints.
    3. More recent actions. EPA has conducted a number of rulemakings
with respect to 2,4-D tolerances since completion of tolerance
reassessment. In July, 2005, EPA established new 2,4-D tolerances on
hops, soybeans, and wild rice. (70 FR 43298, July 27, 2005). This
action was based on the safety determination in the 2,4-D tolerance
reassessment. No comments were received. In June 2007, EPA proposed
numerous changes to the 2,4-D tolerances to implement determinations
made in the 2,4-D tolerance reassessment (72 FR 31221). These proposed
changes included modification of the chemical terms used in the
tolerance expression, the amendment of various tolerance levels, and
removal of certain tolerances. No comments relevant to 2,4-D tolerances
were received and EPA finalized the tolerance actions on September 12,
2007 (72 FR 52013). 2,4-D tolerances have been modified three times
since 2007. In 2008, minor changes were made to correct errors in the
2007 rulemaking. (73 FR 53732, September 17, 2008). NRDC commented on
the proposal for these changes but did not raise any new information
that had not been addressed in response to their comments on the RED.
In 2009, EPA modified the 2,4-D tolerance for cranberries. No comments
were received. (74 FR 48408, September 23, 2009). In 2011, a tolerance
for teff was established, for which EPA received no significant
comments. (76 FR 55814, September 9, 2011).
    Additionally, in response to an application to amend the 2,4-D
FIFRA registration, EPA, in 2011, re-examined the risks of 2,4-D. That
re-examination

took into account the newly submitted extended one-generation
reproduction toxicity study evaluating 2,4-D's potential for causing
endocrine, neurotoxic, or imumunotoxic effects. As part of that risk
assessment, EPA re-evaluated the decision to retain the FQPA safety
factor. Because the FQPA safety factor had previously been retained due
to the absence of data on endocrine and neurotoxic effects and those
data requirements had been met, EPA determined that the 10X FQPA safety
factor should be removed. (Refs. 20 and 21).

V. The Petition To Revoke Tolerances

    NRDC filed a petition dated November 6, 2008 (petition),
requesting, among other things, that EPA revoke all 2,4-D tolerances.
(Ref. 1). In response to EPA's publication of the petition pursuant to
section 408(d) of the FFDCA, NRDC submitted a comment in support of its
petition. (Ref. 22). The petition asserts that EPA's conclusion
outlined in the 2005 2,4-D RED, allowing 2,4-D to be reregistered and
its tolerances retained, was based on incorrect information and
assumptions related to the toxicity of 2,4-D and the amount of human
exposure to the chemical. Specific to tolerances, the petition asserts
that EPA failed to incorporate information on the endocrine disrupting
effects of 2,4-D into its human health risk assessments; EPA
disregarded data on neurotoxicity related to 2,4-D; EPA disregarded
information showing that 2,4-D is mutagenic; EPA ignored data showing
that dermal absorption of 2,4-D is enhanced by alcohol consumption,
sunscreen, and DEET; and that EPA ignored the exposure of infants to
2,4-D via breast milk. Numerous studies are cited in the petition that
NRDC says supports their assertions. EPA has reviewed all of the
studies submitted by NRDC. NRDC also relies, in part, on portions of
its comments submitted on the 2,4-D RED in support of its petition.
(Ref. 1 at 11; Refs. 23 and 24).

VI. Public Comment

    EPA published notice of the petition for comment on December 24,
2008 (73 FR 79100). EPA received approximately 500 comments on the
petition. The vast majority of the comments were against the petition,
and many discussed the importance of 2,4-D to various industries,
including forestry, grains, landscaping, and minor use crops. (See
e.g., Ref. 25). These issues, however, are irrelevant to the safety
determination under FFDCA section 408. Two of the comments opposing the
petition, from the Industry Task Force on 2,4-D Research Data II (Task
Force), and National Council for Air and Stream Improvement (NCASI),
provided detailed comments on the petition and on the studies cited in
the petition. (Refs. 26 and 27). The Task Force and NCASI cited
additional studies during the comment period for EPA to consider in its
response to the petition.
    Twenty-three comments were in support of the petition and agreed
with NRDC that 2,4-D's tolerances should be revoked. Most of the
comments that were in support of the petition assert in a general way
that 2,4-D is ``unsafe,'' but provide little or no reasoning for this
conclusion. Two of the comments in support of the petition, one from
Beyond Pesticides and a combined comment from the New York State
Department of Health and New York State Department of Environmental
Conservation, identified additional studies for EPA consideration.
(Refs. 28 and 29). Additionally, the comment from Beyond Pesticides
asserts that EPA ignored evidence that EPA endangers children by
removing the FQPA 10X safety factor; and EPA has failed to perform a
cumulative assessment for 2,4-D and other phenoxy herbicides. Finally,
NRDC submitted as a comment additional material in support of its
petition. (Ref. 22).

VII. Ruling on Petition

    This Order addresses NRDC's petition to revoke 2,4-D tolerances.
EPA has divided NRDC's grounds for revocation into two main
categories--toxicology and exposure--and addressed separately each
claim under these categories. Each specific claim of NRDC is summarized
in Unit VII immediately prior to EPA's response to the claim.
    This Order also constitutes a response to the comments received
during the public comment period on the petition as they relate to
NRDC's arguments for revoking tolerances. Below are the Agency's
responses to NRDC's assertions and the related public comments.
Detailed reviews of the studies cited by NRDC and commenters can be
found in the docket. (Ref. 30).

A. Toxicology

    NRDC has raised four toxicological issues regarding the safety of
2,4-D: Endocrine disruption, neurotoxicity, mutagenicity, and impacts
on body weight. Each of these issues are addressed below.
    1. Endocrine Disruption--a. NRDC Claims. In support of their
petition, NRDC cites several studies that it says, ``* * * establish
the dangerous endocrine disrupting effects of 2,4-D and underscore the
need for EPA to consider these impacts in its assessment of the health
impacts of 2,4-D.'' (Ref. 1 at 2). NRDC asks EPA to incorporate
information on the endocrine disrupting effects of 2,4-D into its human
health risk assessments. (Id. at 2).
    Specifically, NRDC cites several studies, discussed below, that it
contends show that 2,4-D is an endocrine disruptor. (Id. at 4-5). NRDC
quotes a portion of the 2,4-D RED, which states: ``Based on currently
available toxicity data, there is evidence of the endocrine-disrupting
effects of 2,4-D on mammals. However, no specific measures of such
effect have been attempted'' and a statement that when the EDSP is
underway, 2,4-D may be subject to additional screening or testing. (Id.
at 5-6). NRDC argues that EPA has relied on the delay in conducting the
EDSP to neglect analyzing the endocrine effects of 2,4-D despite the
existence of ``an entire category of existing scientific studies
demonstrating adverse health effects.'' (Id. at 6). It uses atrazine as
an example of a case where EPA has considered endocrine disrupting
effects in the absence of the formal screening program. The atrazine
example, according to NRDC, shows that EPA cannot claim that the
existing studies on endocrine disrupting effects cannot be considered
in human health risk assessments. NRDC states that ``EPA should have
quantitatively incorporated these studies and these effects in its risk
assessment of 2,4-D.'' (Id.).
    b. Public comments. In its comments, Beyond Pesticides supports
NRDC's petition to cancel all 2,4-D product registrations due to the
alleged wealth of relevant scientific information available that
indicates that 2,4-D is a potential endocrine disruptor. (Ref. 28 at
3). Beyond Pesticides cites additional studies to those cited by NRDC.
(Id. at 3-4).
    The 2,4-D Task Force, in its comments, disputes NRDC's claim that
2,4-D is an endocrine disruptor. (Ref. 26 at 11-18). Specifically, the
Task Force argues that NRDC's assertions that 2,4-D has been shown to
be a potent endocrine disruptor are not supported by the weight of the
evidence surrounding 2,4-D's potential for endocrine disrupting
effects. The Task Force disagrees with NRDC's contention that EPA
ignored endocrine disrupting effects given that the Agency issued a
data call-in for a study that assesses thyroid, gonadal, reproductive
and other endocrine-sensitive endpoints and while awaiting the study
imposed an additional 10X uncertainty factor to account for the data
gap. (Id. at 11-12). The Task Force provided detailed

comments on each of the studies cited by NRDC disputing NRDC's
conclusions.
    Additionally, National Council for Air and Stream Improvement
(NCASI), in its comments, takes issue with NRDC's characterization of
various studies indicating that 2,4-D was an endocrine disruptor. (Ref.
27 at 2-3). NCASI indicates that studies cited by NRDC to support their
claim for endocrine disruption concerns are not consistent with other
studies of 2,4-D estrogenicity. (Id. at 3).
    c. EPA response. With regard to endocrine effects, NRDC argues that
EPA should revoke the 2,4-D tolerances because EPA failed to properly
assess 2,4-D's endocrine effects in the RED risk assessment. For
example, NRDC contends that ``[r]ecent studies [ ] establish the
dangerous endocrine disrupting effects of 2,4-D and underscore the need
for EPA to consider these impacts in its assessment of the health
impacts of 2,4-D.'' (Ref. 1 at 4). NRDC concludes this portion of its
petition by asserting that ``given the studies suggesting that 2,4-D
has the potential to cause endocrine disrupting effects, EPA should
have quantitatively incorporated these studies and these effects in its
risk assessment of 2,4-D.'' (Id. at 6).
    These claims by NRDC do not allege sufficient grounds for
revocation of the 2,4-D tolerances. The statutory standard for
revocation of a pesticide tolerance is that the tolerance is not
``safe.'' 21 U.S.C. 346a(b)(2)(A)(i). ``Safe'' is defined by the
statute to mean 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). As
explained in Unit II.B., EPA has implemented this safety standard,
consistent with the statute, by a quantitative risk assessment process
that (1) identifies the harms or toxic effects caused by the pesticide,
(2) ascertains the safe level of exposure as to those harms; and (3)
determines whether aggregate exposure to the pesticide exceeds that
safe level. Thus, safety is not simply a question of a pesticide's
potential to cause harm but an issue involving a combination of factors
including the pesticide's potential harms, the pesticide's potency
(i.e., at what exposure levels will it cause harm), and the level of
human exposure to the pesticide.
    The flaw in NRDC's petition with regard to its endocrine claim is
that it addresses only 2,4-D's potential harm and not 2,4-D's safety.
NRDC claims that 2,4-D has the ``potential to cause endocrine
disrupting effects * * * [and] EPA should have quantitatively
incorporated [this information on 2,4-D's harmful effects] in its risk
assessment of 2,4-D.'' While the reference to endocrine effects clearly
addresses the first element of the risk assessment process--
identification of a harm or toxic effect--NRDC's assertion that EPA
should quantitatively incorporate the endocrine studies cited by NRDC
in its risk assessment falls far short of addressing the other elements
of the risk assessment process. NRDC does not allege that quantitative
incorporation of the studies it cites would alter EPA's prior
conclusion regarding the safe exposure level for 2,4-D. Yet, unless
NRDC claims that the safe level of exposure should be lowered, it has
no basis to argue that the toxicity data on endocrine effects it cites
indicate a lack of safety. At best, NRDC is asking EPA to take a
revised look at the toxicity of 2,4-D. Yet, the ground for tolerance
revocation is a lack of safety. Accordingly, NRDC's claim that the 2,4-
D tolerance should be revoked due to 2,4-D's endocrine effects is
denied due to a failure to make a proper claim for revocation by, at
the very least, alleging facts that, if proven, would meet the
statutory standard for revocation.
    Despite the inadequacy of petitioners' endocrine claims, EPA has
examined the evidence cited by petitioners in light of the most current
toxicity data on 2,4-D for the purpose of evaluating whether the
evidence raises sufficient grounds for concern that EPA should consider
initiating action that might lead to revocation of the 2,4-D
tolerances.
    To the extent data were available, EPA examined 2,4-D's potential
for endocrine disruption in the 2005 RED. However, as noted there, EPA
was handicapped in this evaluation due to the fact that the otherwise
acceptable two-generation rat reproduction study conducted with 2,4-D
did not adequately address endocrine concerns. Although several
toxicity studies required under 40 CFR part 158 involve an examination
of organs or endpoints related to endocrine disruption, the rat
reproduction study is the most critical of these required studies. In
fact, the two-generation rat reproduction study, as described in the
1998 EPA guideline, has been designated as the study that will be used
in Tier 2 of the EDSP for evaluating mammalian endocrine effects. As
mentioned above, EPA issued a data call-in for a two-generation
reproduction study in rats to address this data gap. In response to the
data call-in, the Task Force submitted an extended one-generation
reproductive toxicity study to fulfill this requirement. The 2,4-D
extended one-generation study examined endocrine disruption as well as
developmental neurotoxicity and developmental immunotoxicity. This
extended one-generation reproductive toxicity study was conducted in
accordance with OECD guidelines and is considered a state-of-the-
science study with regard to examining these toxicological and
endocrine effects.
    As to endocrine effects, the extended one-generation reproduction
study examined: Potential effects on parental male and female
reproductive function, offspring survival and growth including
endocrine and systemic toxicity parameters such as estrous cyclicity
(female adult rats and offspring); sperm parameters; anogenital
distance; nipple retention; puberty onset (vaginal opening and balano-
preputial separation); adrenal weight, thyroid/parathyroid gland
weight, pituitary gland weight, testes and ovarian weight, thyroid
hormone effects; and histopathology of a wide range of tissues
including the thyroid, adrenal, pituitary, testes, and ovary. (Refs. 31
and 32). The endpoints examined in the extended one-generation
reproduction study meet or exceed the specifications in the latest
guideline (1998) for the two-generation reproduction study. (Ref. 33).
Specifically, this extended one-generation study included evaluation of
sperm parameters and thyroid assays across various age groups, which
are not part of the two-generation study. The main design difference
between an extended one-generation study and a two-generation study is
that the latter study is run for a full two generations no matter what
results are seen in the first generation. On the other hand, an
extended one-generation study is not continued into the second
generation if triggers on the key endpoints do not indicate there is a
potential concern. This design eliminates the needless destruction of
animals, but does not reduce the scientific value of the data.
    The extended one-generation study for 2,4-D showed no treatment-
related effects on potential estrogenic effects or androgen-sensitive
endpoints (no adverse effects on anogenital distance, nipple retention,
age at vaginal opening, estrous cycle length or pattern, mating,
fertility, time to mating, gestation length, pre-implantation loss,
number of corpora lutea, sperm parameters, ovarian follicle counts, and
reproductive organ weights and histopathology; no evidence of
hyposadias, ectopic tests, or treatment-related testicular prostate or
seminal vesicle histopathology). Anti-androgenic

effects in terms of decreased male reproductive organ weights were
observed in some animals but they were not statistically significant
and were associated with decreased body weight. No treatment-related
effects on reproductive organ histopathology were observed. Slight
effects were seen in the thyroid (increases or decreases in thyroid
weight and in T3, T4, and TSH hormones in some animals) but no dose
response relationship was shown. These effects were more significant at
the highest dose tested but still were considered adaptive and not
adverse (i.e., the thyroid responded to insult and corrected itself)
due to the fact that this dose exceeded the renal saturation level.
Accordingly, the highest dose was considered a No Observed Adverse
Effect Level (NOAEL) for thyroid effects.
    Overall, the effects observed at the lowest doses in the extended
one-generation reproductive study for both the parental rats and
offspring were not based on endocrine-related endpoints but on
nephrotoxicity manifested as increased kidney weights, and degenerative
lesions in the proximal convoluted tubules in the main study in the
first-generation adult rats (P1 generation; 45.3 mg/kg bw/
day); kidney toxicity manifested as increased kidney weights and
increased incidence of degeneration of the proximal convoluted tubules
in the adult offspring (F1 adults; 55.6/46.7 (M/F) mg/kg/
day); and decreased body weight observed in the male pup offspring
(F1, Set 1a males, PND 28-69; 76.6 mg/kg/day) (see
discussion in Unit VII.A.4.c.). The NOAEL for parents and offspring for
these effects is approximately 20 mg/kg/day, (Ref. 32), which is
greater than the NOAEL of 5 mg/kg/day from a rat chronic toxicity study
that was used as the POD in assessing chronic dietary, long-term
dermal, and long-term inhalation in the human health risk assessment
supporting the 2,4-D RED. (Ref. 18). In that chronic study, the effects
seen at the LOAEL of 75 mg/kg/day were decreased body-weight gain and
food consumption, alteration in hematology and clinical chemistry
parameters, decreased T4, glucose, cholesterol, and triglycerides. The
use of the NOAEL from the chronic rat study as the POD in the RED risk
assessment is protective of chronic effects identified in the extended
one-generation study.
    The NOAEL found in the extended one-generation reproductive study
is also similar to the NOAEL of 15 mg/kg/day seen in a rat subchronic
oral toxicity study and used to identify a POD for subchronic effects
in the RED. (Ref. 18 at 22). The effects seen at the LOAEL of 100 mg/
kg/day in the rat subchronic study were decreased body weight/body-
weight gain, alterations in some hematology [decreased platelets (both
sexes)] and clinical chemistry [decreased T3 (females) and T4 (both
sexes)] parameters, and cataract formation. This study was used for the
intermediate incidental oral and intermediate dermal and inhalation
assessments. Again, the NOAEL in the extended one-generation study is
greater than the NOAEL chosen as a POD for subchronic effects, and
therefore, the RED assessment is protective of any subchronic effects
identified in the extended one-generation study.
    As noted above, EPA concluded that this study showed no adverse
effects on endocrine endpoints. Accordingly, the extended one-
generation reproduction study's comprehensive examination of 2,4-D's
potential effect on the endocrine system provides no indication that
EPA should consider initiating action to revoke 2,4-D tolerances.
    Nothing in the data cited by NRDC or other commenters contradicts
this conclusion. For the most part, the data relied upon by NRDC
address whether 2,4-D is capable of interacting with the endocrine
system. The studies do not provide quantitative information appropriate
for use in risk assessment or the quantitative information they provide
shows that EPA's risk assessment is protective of endocrine effects.
Many of the studies cited by NRDC were studies conducted to investigate
2,4-D's mechanism of action and involved testing at a single high dose
designed to ensure effects were seen. In rats, although 2,4-D is
readily absorbed in the blood, it is not metabolized but removed from
the blood by the kidneys and rapidly excreted through the urine. Once
the dose of 2,4-D in rats exceeds about 50 mg/kg/day, however, the
kidney (renal) clearance mechanism is overwhelmed and 2,4-D builds up
in the body resulting in toxic effects. The toxic effects seen at doses
above the renal saturation level are generally not seen at lower doses.
EPA has assessed the risk of 2,4-D based on the dose levels below the
renal saturation level at which adverse effects occur.
    NRDC first cites a study in fish (Xie (2005)) that it contends
shows that 2,4-D has ``relatively potent estrogenic effects in fish.''
(Ref. 1 at 4 and Ref. 34). As an initial matter, a study in fish would
carry little weight regarding a safe tolerance level when compared to a
study in mammals such as the extended one-generation reproduction study
in rats. Additionally, EPA does not regard the Xie study as reliable
due to a failure to identify the sex of the fish used. The study
reported that 7-day exposure of rainbow trout juveniles to 1.64 mg/L
2,4-D (active or formulated product undetermined) produced a 93-fold
increase in plasma vitellogenin compared to untreated fish. This was a
significant difference from the untreated control. Six fish were used
per test concentration, and they were described as ``juvenile rainbow
trout (standard length: 11.5  2.2 cm) provided by the
California Department of Fish and Game Mojave River Hatchery
(Victorville, California)'' with no reference to their sex or specific
age information. However, the sex of the fish is significant with
regard to vitellogenin levels. Male fish generally maintain null or
very low levels of vitellogenin in their natural state. In the presence
of endocrine disruptors, male fish will have significant levels of
vitellogenin in their blood. Female fish will have naturally increasing
levels of vitellogenin as they approach maturity and maintain those
levels upon maturation. Given the sample size and a failure to identify
the sex of the fish, the results seen may be a result of unbalanced
numbers of male and female fish in the control and treated groups.
Several other difficulties with the Xie study, including the failure to
identify a biologically significant effect on vitellogenin, are noted
in the comments of the Task Force and NCASI.
    NRDC next relies on two studies (Rawlings (1998) and Charles
(1996)), which it alleges show that 2,4-D causes hormone suppression in
animals. (Refs. 35 and 36). In the Rawlings study, 2,4-D treatment
resulted in a significant (p <0.05) decrease in serum T4 concentrations
compared to control. No other significant effects were noted for serum
cortisol, insulin, estradiol, LH pulse frequency (mean and amplitude),
mean serum FSH, progesterone, or gross signs of toxicity or body weight
change. In the absence of a quantifiable relationship between serum T4
concentration and effects upon survival, growth, or reproduction, the
results of this study do not evidence an adverse effect that could be
incorporated directly into the Agency risk assessment process. The
Charles study reports on a subchronic study in rats and was submitted
to EPA and relied upon in the RED risk assessment. The study identified
a NOAEL of 15 mg/kg/day and a LOAEL of 100 mg/kg/day. The effects seen
at 100 mg/kg/day did include thyroid effects such as decreased
thyroxine, increased thyroid weight, and hypertrophy of follicular
cells. These effects were seen at a dose (100 mg/kg/day) that was well
above the

renal saturation level and the NOAEL from the study was used to set the
safe dose for subchronic exposures to 2,4-D and is protective of
effects occurring at higher dose levels. (Ref. 18 at 36).
    NRDC also cites several studies (Liu (1996), Kim (2005), Kim
(2002)) which it claims show that 2,4-D can result in effects on
testicular cells and the prostate. (Refs. 37, 38, and 39). Liu is an in
vitro study investigating possible mechanisms of action in relation to
Leydig cell adenomas and peroxisome proliferation. 2,4-D was one of the
peroxisome proliferators evaluated in the study. Kim (2005) also is an
in vitro study investigating potential androgenic mechanisms. EPA could
not evaluate the Kim (2002) study because it is written in Korean and
not available to EPA in English. The Task Force argues that the 2002
study is irrelevant because it involved doses above the renal
saturation level and thus the 2005 study, which was designed to
investigate the effects in the 2002 study, is of limited value given
the high dosing in the 2002 study. Liu also appears to have shown
statistically significant effects for 2,4-D on production of estradiol
only at very high doses. In any event, EPA has adequate data in living
animals regarding 2,4-D's potential to affect testicular cells or the
prostate. There is an adequate/guideline cancer study in rats that
dosed at levels of 5, 75, and 150 mg/kg/day (2-year study); there were
no effects observed in the prostate, including no tumors. In fact,
there was no increase in any tumor type in either the rat or mouse.
(Ref. 19 at 29). There are numerous studies in the rat of varying
duration, and no effects on the prostate have been observed. In the
studies available for the 2005 RED, effects on the testes and ovary
were identified, hence the request for the two-generation rat
reproduction study. The extended one-generation reproductive study is
now available and it assessed the prostate. There were no effects on
prostate weight and no histopathology findings in the prostate or other
male accessory sex organs.
    Finally, NRDC argues that studies have shown that 2,4-D causes
abnormalities in the estrus cycle (Duffard (1995)), lowers sperm counts
and causes other sperm abnormalities (Lerda (1991)), and results in
birth defects (Garry (1996)). (Refs. 40, 41, and 42). NRDC has only
cited an abstract of the Duffard study, which provides little
information. It is clear, however, that the Duffard study used a single
dose (70 mg/kg/day) that was at or above the renal clearance level.
Garry (1996) investigated the hypothesis that offspring of pesticide
applicators might have increased risks of birth anomalies. Although the
initial study found an apparent linkage between an area of high phenoxy
use and birth anomalies, a more detailed cross-sectional analysis of
this area showed no statistically significant correlations between
phenoxy use and excess adverse birth or neurodevelopmental effects.
(Ref. 43). Lerda (1991) reported an apparent link between exposures to
2,4-D in 32 male applicators and reproductive effects
(spermatogenesis). However, these results have little weight for
assessing 2,4-D risk because Lerda (1991) did not describe the nature
of applicators' exposures in sufficient detail to show that 2,4-D was
the causal agent and, if so, the level of that exposure. For example,
Lerda (1991) lacked information on the timing/duration of exposure
relative to sampling, the use of protective clothing/equipment, the
possible presence of manufacturing contaminants given timeframe of
study, and exposures to other pesticides. On the other hand, as noted
above, the extended one-generation reproduction study assessed 2,4-D's
potential impact on the estrous cycle and sperm counts/abnormalities,
and no adverse effects were found in these parameters.
    Beyond Pesticides, in commenting on the petition, cited Garry
(2001) and Malysheva (1997), in addition to studies referenced by NRDC,
as supporting NRDC's claim that 2,4-D is an endocrine disruptor. (Refs.
44 and 45). Garry (2001) indicated serum luteinizing hormone (LH)
values were correlated with urinary 2,4-D levels in humans, but
follicle-stimulating hormone and free and total testosterone were not.
Garry (2001) also found 2,4-D levels were not correlated with
chromosome aberration frequency in humans but that chromosome
aberration frequencies were correlated with the total volume of
herbicides applied, including products other than 2,4-D and the use of
adjuvants. This study is of limited value because of the small sample
size, as noted by the authors, and because it is not clear what other
pesticides the individuals were exposed to and how specific components
of adjuvant products in the pesticide may have impacted the findings.
    According to Beyond Pesticides, the Malysheva (1997) study found
that the thyroid glands of laboratory rats were sensitive to 2,4-D as
decreases in the thyroid gland transport and hormone production
functions, and impairment of hormone iodination in the thyroid were
observed after acute exposure. However, no information on the study was
presented and the cited article is in Russian and no translation was
available. Thyroid function was fully evaluated in the extended one-
generation reproduction study. As noted above, the extended one-
generation reproduction study examined 2,4-D's potential thyroid
effects and established a NOAEL for such effects demonstrating that
EPA's prior risk assessment was protective.
    In sum, the data cited by NRDC, Beyond Pesticides, and NYDOH do not
support changing the quantitative endpoints for assessing the risk
posed by 2,4-D for potential endocrine effects given the equivocal
results in the studies cited and/or the high doses involved in the
studies. Further, the recently-completed extended one-generation
reproduction study that was specifically designed to evaluate such
effects for the purpose of assessing human risks does not indicate that
existing Points of Departure for assessing 2,4-D risks are under
protective. Accordingly, EPA concludes that NRDC's petition does not
raise sufficient grounds for concern that EPA should consider
initiating action that might lead to revocation of the 2,4-D
tolerances.
    2. Neurotoxicity--a. NRDC Claims. NRDC asserts that ``the
neurotoxic and anti-thyroid effects of 2,4-D make it highly likely that
fetuses, infants, and children will be more susceptible to long-term
adverse health effects from exposure to this chemical.'' (Ref. 1 at 7).
It cites several studies that it claims provide evidence that postnatal
exposures to 2,4-D during the critical period for development of the
infant brain raise serious scientific concerns. The cited studies by
the same group of authors report alterations on the neurotransmitters
systems (catecholamine, indoleamine), marked depression in locomotor
activity, and moderate circling towards the right side following
exposure to 2,4-D via the diet, during gestation, and/or postnatally.
NRDC also cites a study reporting decreased serotonin levels were found
in various areas of the brain following direct injection of 2,4-D into
the brain. Impairment of normal deposition of myelin in the developing
brain was reported following exposure via the milk or direct
subcutaneous exposure. Several studies were cited to show potential
effects of 2,4-D on the brain of neonatal rats exposed lactationally.
(Id.).
    b. Public comments. The New York State Department of Health (NYS
DOH) submitted comments in support of the NRDC petition, stating that
various toxicological findings associated with 2,4-D in EPA's RED
document are weak. (Ref. 29 at 1). The RED, for example, identified
specific adverse health effects

of concern, including developmental neurotoxicity and endocrine
disruption, and required further studies from the registrants to
evaluate these effects. NYS DOH identifies additional studies for the
Agency to consider. (Id.).
    Beyond Pesticides, in its comments, argues that EPA has
underestimated 2,4-D's potential neurotoxic effects, and cites studies
which it says show changes to maternal behavior in rats, along with
increased catecholamine levels and a drastic decrease in indolamine
levels. (Ref. 28 at 3).
    The 2,4-D Task Force submitted comments arguing that the studies
cited by NRDC do not provide credible or substantive evidence that 2,4-
D causes developmental neurotoxicity at exposure levels or routes of
administration relevant to humans. (Ref. 26 at 18-21). It notes that in
response the reregistration data call-in issued for 2,4-D, the 2,4-D
Task Force agreed to conduct an extended one-generation reproduction
study in rats of 2,4-D in the diet. The Task Force points out that this
study would include assessment of developmental neurotoxicity
endpoints, and states that at the time it was preparing comments, there
were no dose-related statistically significant indications of
developmental neurotoxicity related to 2,4-D exposures, even at dose
levels demonstrated to be well above the renal clearance threshold in
rat dams and pups. (Id. at 4).
    c. Agency response. NRDC requests revocation of 2,4-D tolerances
because (1) ``[t]he neurotoxic and anti-thyroid effects of 2,4-D make
it highly likely that fetuses, infants, and children will be more
susceptible to long-term adverse health effects from exposure to this
chemical;'' and (2) data cited in the petition ``provide evidence that
postnatal exposures to 2,4-D during the critical period for development
of the infant brain raise serious scientific concerns.'' (Ref. 1 at 7).
However, such claims, as discussed in Unit VII.A.1.c., have the same
flaw as NRDC's endocrine arguments: The fact that the young are more
susceptible to adverse effects of a pesticide or that data on a
pesticide raise ``serious scientific concerns'' do not amount to a
showing that aggregate exposure to the pesticide is unsafe, the
standard for revoking tolerances. That the young may be more sensitive
to a pesticide than adults may be irrelevant to the safety
determination if both the young and adults have aggregate exposures
below the safe dose. Similarly, that exposure to a pesticide in high
dose testing may result in serious effects does not show that aggregate
actual exposure to the pesticide, as opposed to exposure levels in
laboratory testing, is unsafe. Again, NRDC has failed to address all
the steps in the risk assessment process necessary to a safety
determination. As with its endocrine claim, NRDC has done no more than
allege 2,4-D has the potential to cause harm. Accordingly, NRDC's claim
that the 2,4-D tolerance should be revoked due to 2,4-D's neurotoxic
effects is denied due to a failure to allege facts sufficient to meet
the statutory standard for revocation.
    Despite the inadequacy of petitioners' neurotoxicity claims, EPA
has examined the evidence cited by petitioners for the purpose of
evaluating whether the evidence raises sufficient grounds for concern
regarding 2,4-D that EPA should consider initiating action that might
lead to revocation of the 2,4-D tolerances.
    In the 2005 RED, EPA identified neurotoxic effects in the acute and
subchronic neurotoxicity studies as well as other studies. These
effects included clinical signs (e.g., ataxia, tremors, decreased motor
activity) as well as neuropathology (e.g., retinal degeneration);
however, these effects were only seen at doses above the level of
saturation of renal clearance. Given these neurotoxic effects, EPA
issued a data call-in for a developmental neurotoxicity study and
retained the FQPA safety factor for the protection of infants and
children in the absence of that data. To address this data gap, the
Task Force submitted an extended one-generation reproduction study with
a developmental neurotoxicity component.
    The extended one-generation reproductive toxicity study on 2,4-D
assessed developmental neurotoxicity at three dose levels up to the
saturation level for renal clearance. (Ref. 31). The potential for
neurotoxic effects was assessed using numerous parameters. First, the
study used a Functional Observation Battery (FOB) to evaluate whether
there were clinical signs of neuorotoxicity. This FOB included cage-
side, hand-held, and open-field observations of behavior, and
measurements of body weight, rectal temperature, grip performance, and
landing foot splay. Second, the study used an automated system for
measuring motor activity. Third, the study assessed the startle
response to auditory stimuli. Finally, a neuropathological exam was
conducted on the brain (including the cerebrum, thalamus/hypothalamus,
cerebellum and medulla), spinal cord, dorsal root ganglia, dorsal and
ventral roots, peripheral nerves, and skeletal muscle. The examination
of the brain included assessment of brain weight and gross
measurements, microscopic measurements (morphometrics), and brain
myelin. There were no treatment-related adverse effects on any of the
numerous parameters assessed across life stages, which included
multiple neurotoxicity-related endpoints similar to those in the
studies cited by NRDC (e.g., an assessment of motor activity,
myelination, and maternal behavior). Thus, the extended one-generation
reproduction study, in conjunction with all of the other data bearing
on neurotoxicity, supports EPA's risk assessment of 2,4-D and provides
no indication that EPA should consider initiating action to revoke 2,4-
D tolerances.
    The studies relied upon by NRDC in the portion of its petition
addressing neurotoxicity do not suggest that EPA has not protected
against potential neurotoxic effects of 2,4-D. Similar to its approach
to endocrine effects, NRDC appears to take the position that the mere
fact that 2,4-D could have a neurotoxic effect shows that it is unsafe.
Consistent with this approach, NRDC, for the most part, relies on
mechanism of action studies that involve a single, high dose as opposed
to risk assessment studies designed to investigate a chemical's dose
response relationship across a wide range of doses. NRDC relies on the
following 2,4-D studies: A study in fish showing adverse brain effects
(Ton (2006)); a study in rats showing delays in brain development and
abnormal behavior patterns (Evangelista (1995)); a study in rats
showing neurotoxic effects on the basal ganglia in the brain
(Bortolozzi (2001)); and three studies that appear to show impairment
of normal deposition of myelin in the developing brain (Rosso (2000);
Duffard (1996); Konjuh (2008)). (Refs. 46, 47, 48, 49, 50, and 51).
Each of these studies, however, either involve testing at levels above
the renal saturation dose or use routes of exposure or methodology
inappropriate to human risk assessment or both.
    Ton (2006) was a research study investigating the use of zebrafish
as a screening assay for identifying whether a chemical has the
potential for neurotoxic effects and requires further testing in
mammalian systems. For 2,4-D, appropriate testing in mammals is
available, including a developmental neurotoxicity study in rats.
Further, Ton only found potential neurotoxic effects at dose levels
exceeding the dose concentration that is lethal to 50 percent for
zebrafish (referred to as the LC50 (lethal concentration)).
Other limitations in this study are outlined in the Task Force's
comments. (Ref. 26 at 18-19).

    Evangelista (1995) used doses of 50 and 100 mg/kg/day of 2,4-D.
These doses meet or exceed the renal saturation level. Further
compromising interpretation of this study is the fact that the
identified neurotoxic effects were only detected when exposure to 2,4-D
was combined with doses of amphetamine. NRDC also inaccurately
describes this study as involving young rats when, in fact, adult
animals were tested.
    Bortolozzi (2001) investigated potential neurotoxic effects of 2,4-
D by directly injecting 2,4-D into different brain areas of rats. Such
a methodological approach is not useful for risk assessment because it
does not correspond to the routes of exposure for humans to 2,4-D and,
as noted, appropriate route of exposure studies are available for 2,4-
D. Further, the Task Force described the doses in the study as being
40- to 100-fold greater than the concentration in the brain after
systemic treatment.
    Rosso (2000), Duffard (1996), and Konjuh (2008) each involved
testing at 70 or 100 mg/kg/day. These doses exceed the renal saturation
level. Other limitations in these studies are detailed in the Task
Force's comments. (Ref. 26 at 20-21).
    Other studies cited by NRDC and Beyond Pesticides that address
neurotoxicity have similar weaknesses. Ferri (2007), Garcia (2004), and
Garcia (2008) used doses exceeding the renal saturation level. Sturtz
(2008) found effects on maternal care but these effects were not
duplicated in the extended one-generation reproduction study and the
effects were not associated with any adverse effects in the pups.
    Studies cited by the New York State Department of Health in
comments are similar to the NRDC studies in that they are studies
investigating mechanism of toxicity and were conducted at doses
exceeding the renal saturation level.
    In sum, EPA does not disagree with NRDC that 2,4-D, if administered
at high enough doses, may result in neurotoxic effects in animals.
However, the data regarding neurotoxicity relied upon by NRDC, or cited
by commenters, does not indicate that the existing Points of Departure
for evaluating 2,4-D risks are underprotective. Similarly, the extended
one-generation reproduction study confirms the protectiveness of the
existing Points of Departure as to neurotoxic effects. Accordingly, EPA
concludes that NRDC's petition does not raise sufficient grounds for
concern that EPA should consider initiating action that might lead to
revocation of the 2,4-D tolerances.
    3. Mutagenicity--a. NRDC claims. NRDC claims that in comments
submitted to EPA on the 2004 human health risk assessment for 2,4-D
risk assessment, it pointed out that EPA disregarded a number of
studies that highlight the mutagenicity and genotoxicity of 2,4-D.
(Ref. 1 at 7). NRDC states that at the time of the RED, EPA responded
that it was under no obligation to consider these studies because
``positive findings are always confined to samples of 2,4-D
formulations and not the pure substance.'' (Id. at 7). NRDC claims
EPA's response in 2005 was deficient first because nothing confines EPA
only to consider studies that examine the pure substance (that is, the
active ingredient). Second, recent studies involving just the active
ingredient do indeed confirm the mutagenicity and cytotoxicity findings
of the studies ignored by EPA. In light of these points, NRDC argues
that EPA should not allow the continued use of 2,4-D.
    NRDC also cited four studies it claims confirm the mutagenicity and
cytotoxicity of 2,4-D. (Id. at 8). Two of these were published since
the EPA RED was finalized and two were published shortly beforehand but
were not cited in the risk assessment. Three of these studies examined
just the active ingredient 2,4-D, while the third used a commercial
2,4-D product containing a mixture of 2,4-D and various inert
ingredients. NRDC states that these results must be considered in
determining whether users of these products are being exposed to
potential toxicity.
    NRDC also argues that apart from these new data, the discussion of
the carcinogenicity and mutagenicity of 2,4-D that was provided by EPA
in the 2004 risk assessment was inadequate because EPA failed to
acknowledge numerous additional positive genotoxicity studies in the
peer-reviewed scientific literature that together indicate that 2,4-D
formulations are likely to be cytotoxic and mutagenic. (Id. at 9).
According to NRDC, research in the open scientific literature have
reported oxidant effects of 2,4-D, indicating the potential for
cytotoxicity or genotoxicity. NRDC argues that another finding that may
provide a unifying explanation of some of the data on 2,4-D and
lymphoma is that the herbicide may increase lymphocyte replication.
(Id.)
    b. Public comments. The 2,4-D Task Force submitted comments stating
that 2,4-D is not mutagenic. (Ref. 26 at 4). The Task Force claims that
for reregistration, 2,4-D acid, plus eight different 2,4-D derivatives
have been tested in a battery of mutagenicity tests which are comprised
of a total of 28 studies. All of these studies were negative (non-
mutagenic). (Id. at 22). While the Task Force acknowledges that some
positive mutagenicity studies occur, it argues that the weight of the
evidence overwhelmingly supports a conclusion of minimal or no concern
for mammalian mutagenicity for 2,4-D. The Task Force notes that several
inherent characteristics of 2,4-D suggest that there is a very low
potential for it to cause mutagenic effects: The half-life of 2,4-D in
humans is less than 12 hours; 2,4-D does not metabolize or transform;
2,4-D is excreted unchanged; and it does not accumulate. (Id. at 23).
    Beyond Pesticides submitted comments to support the petition by
NRDC requesting the cancellation of all 2,4-D product registrations and
the revocation of all tolerances, stating that the Agency
underestimated 2,4-D's mutagenic effects. (Ref. 28 at 1). Beyond
Pesticides cites a study on plants which shows the induction and
frequency of certain point mutations by 2,4-D (and dicamba), suggesting
that these point mutations are important as they are frequently
associated with various types of cancer. Beyond Pesticides also cites a
study which they claim indicates 2,4-D is cytotoxic and induces
apoptosis via direct effect on mitochondrial membranes. (Id. at 2-3).
    NCASI, in its comments, asserts that the overwhelming weight of
evidence indicates that 2,4-D is neither mutagenic nor genotoxic. NCASI
states that tests of mutagenicity and genotoxicity are important in
this context as indicators of the potential for carcinogenicity. They
point out that the International Commission for Protection Against
Environmental Mutagens and Carcinogens, categorization of a chemical as
genotoxic is not an a priori indication of a health hazard. They note
that there is a large body of evidence and broad scientific consensus
that 2,4-D is not a carcinogen. (Ref. 27 at 4)
    c. Agency response. NRDC's petition argues that the 2,4-D
tolerances should be revoked on several grounds related to
mutagenicity. First, NRDC claims that EPA did not adequately address
NRDC's comments on the RED risk assessment regarding 2,4-D's
mutagenicity and that subsequent data confirm the accuracy of NRDC's
comments. NRDC argues that ``[i]n light of these points, EPA should not
allow the continued use of 2,4-D.'' (Ref. 1 at 7). Second, NRDC asserts
that ``the discussion of the carcinogenicity and mutagenicity of 2,4-D
that EPA does provide in the [RED] risk assessment is wholly
inadequate.'' (Id. at 8). NRDC argues that this inadequate discussion
led to EPA ``failing to assess fully the

risk of cancer in humans from [2,4-D] exposure and failing to protect
humans from this risk adequately.'' (Id. at 10)
    These assertions do not, however, provide a sufficient basis for
revoking the 2,4-D tolerances. The ground for seeking revocation of a
tolerance is a showing that the pesticide is not ``safe.'' Claiming
that EPA improperly conducted its reassessment of the 2,4-D tolerances
by failing to consider certain data bearing on its decision on
mutagenicity or carcinogenicity does not amount to a showing that the
tolerance is unsafe. Neither is the allegation that 2,4-D is a mutagen
or the derivative claim that EPA's failure to adequately consider
mutagenicity data results in its ``failing to assess fully the risk of
cancer'' sufficient to show that the 2,4-D tolerances are unsafe. As
explained in Unit VII.A.1.c., with regard to its endocrine and
neurotoxic claims, to properly assert grounds for revocation of a
tolerance, NRDC must allege facts showing that aggregate exposure to
2,4-D poses an unsafe mutagenic risk. That, it has not done. As to
mutagenicity, NRDC merely alleges that 2,4-D can cause mutagenic harm.
As to carcinogenicity, NRDC's claims are even more amorphous. It argues
that because EPA failed to consider 2,4-D's alleged mutagenic effects,
it thereby failed to ``assess fully,'' and adequately protect against,
2,4-D's cancer risks. As to neither mutagenicity nor cancer has NRDC
addressed what the safe level of exposure to 2,4-D is for humans or
alleged that the exposure levels of humans to 2,4-D exceed this safe
level. Accordingly, NRDC's claim that the 2,4-D tolerance should be
revoked due to 2,4-D's mutagenic effects or its failure to assess 2,4-
D's cancer risk in light of these mutagenic effects are denied due to a
failure to make a proper claim for revocation by, at the very least,
alleging facts that, if proven, would meet the statutory standard for
revocation.
    Despite the inadequacy of petitioners' mutagenicity claims, EPA has
examined the evidence cited by petitioners for the purpose of
evaluating whether the evidence raises sufficient grounds for concern
regarding 2,4-D that EPA should consider initiating action that might
lead to revocation of the 2,4-D tolerances.
    EPA requires the submission of mutagenicity data on pesticides to
assess a pesticide's potential to cause heritable mutations that may
contribute to cancer or other genetic diseases. (Refs. 52 and 53).
Mutagenicity analysis has been directed primarily at investigating the
mechanism of action with regard to toxic endpoints, particularly
cancer. (Refs. 54 and 55). It should be noted that EPA's data
requirements on mutagenicity have evolved over the years. Whereas
earlier data requirements identified a wide range of genotoxicity
tests, EPA's current testing requirements focus on tests for mutagenic
effects, i.e., heritable changes in DNA that could potentially lead to
disease. It is important to point out that genotoxicity assays include
any kind of study that evaluates cellular functions involving gene
damage, or interference with gene replication and repair. Mutagenic
effects are a subset of genotoxic ones. The difference between the
terms ``genotoxicity'' and ``mutagenicity'' is that ``genotoxicity
pertains to all types of DNA damage (including mutagenicity), whereas
mutagenicity pertains specifically to mutation induction at the gene
and chromosome levels.'' (Ref. 56). Importantly, ``[w]hile genotoxic
effects may be transient, mutagenic effects are persistent.'' (Id.). So
unlike mutagenic effects which are generally non-repairable, and
permanent, other genotoxic effects generally do not exhibit these same
traits. Consequently, non-heritable genotoxic effects do not
necessarily lead to adverse effects in a whole organism, and, for the
same reason, are also not a reliable predictor of such effects. While
genotoxicity data can help to inform an understanding of the adverse
outcome pathway for a chemical, by themselves, EPA does not accord much
weight in risk assessment to genotoxicity data that fail to show
heritable effects.
    EPA's current data regulations require, as to mutagenicity testing,
a bacterial reverse mutation assay, an in vitro mammalian cell assay,
and an in vivo cytogenetics test. 40 CFR 158.500(d). The recommended
study guidelines indicate a preference for tests directed at
identifying not merely genotoxicity but mutagenic effects in terms of
gene mutation or chromosomal aberrations. (40 CFR 158.500(d) (test
notes 31 and 32); (Refs. 57, 58, 59, 60, and 61). Omitted from the data
regulations is the former requirement pertaining to ``other genotoxic
effects * * * [such as] numerical chromosome aberrations, direct DNA
damage and repair, mammalian cells transformation, target organ/cell
analysis.'' 40 CFR 158.340(a) and (b)(22) (2007). The bacterial reverse
mutation assay (commonly known as the Ames test) is designed to detect
point mutations in genetic material. As the guideline indicates:
``Point mutations are the cause of many human genetic diseases and
there is substantial evidence that point mutations in oncogenes and
tumour suppressor genes of somatic cells are involved in tumour
formation in humans and experimental animals.'' (Ref. 57). For the in
vitro mammalian cell assay, the guidelines recommend either individual
assays directed at detecting gene mutations, (Ref. 58), or structural
chromosome aberrations, or both endpoints in a single assay. (Ref. 59).
For an in vivo cytogenetics test, the regulations recommend either an
assay for the detection of structural chromosome aberrations in bone
marrow cells of animals, usually rodents, (Ref. 60), or an assay for
the detection of cytogenetic damage which results in the formation of
micronuclei containing lagging chromosome fragments or whole
chromosomes. (Ref. 61). Between the in vitro and in vivo tests, the
latter carry the greater weight in assessing mutagenic potential
because in vitro tests do not capture how a living body responds to a
toxic insult, including its ability to detoxify putative mutagens and
genotoxicants. (Ref. 54 at 2-34; and Ref. 62).
    EPA has a large body of mutagenicity and genotoxicity data for 2,4-
D. Those data show little to no concern for heritable mutagenic effects
in mammals but some evidence supporting 2,4-D's potential to cause
genotoxic effects. More specifically, these data show: (1) That 2,4-D
is negative in bacterial mutation assays; (2) some positive results for
mutagenicity in assays in yeast, plants, and insects; (3) negative
results for mutagenicity in in vivo studies in animals; and (4) mixed
results for mutagenic and genotoxic results in in vitro tests in
mammalian cells. EPA summarized the results in the last formal cancer
assessment for 2,4-D in 1997 as follows:

    The mutagenic potential of 2,4-D has been extensively evaluated
in a range of in vivo and in vitro assays that have included tests
with human cells. Ames tests, with and without metabolic activation,
were consistently negative. Negative results were also seen in a
mouse bone marrow micronucleus and UDS assays in rat hepatocytes.
Conflicting results were obtained in Drosophila; positive effects
were seen in larvae, while negative results were seen in adults
after feeding or injection. Conflicting results were also seen in in
vitro mammalian cell cytogenetics assays; 2,4-D was negative for
structural chromosomal damage up to an insoluble level but positive
in the presence of metabolic activation at high doses. The positive
evidence, however, tends to be weak and generally not supported by
the data from in vivo cytogenetic assays. 2,4-D also was nonactive
in mammalian cell DNA repair assays. Overall, the pattern of
responses observed in both in vivo and in vitro tests indicated that
2,4-D was not mutagenic (although some cytogenetic effects were
seen).

(Ref. 16 at 17).

    Mutagenicity was considered as part of the weight of the evidence
determination on cancer. EPA concluded that 2,4-D should be classified
under Category D--Unclassifiable as to Human Carcinogenicity. This
determination was based primarily on the finding that in the two most
recent rodent studies there were no compound-related statistically
significant increases in tumors in either rats or mice and the
conclusion that epidemiology data failed to show a cause-and-effect
relationship between 2,4-D exposure and cancer. The weak evidence on
genotoxicity was not sufficient to outweigh the absence of positive
findings on tumor development in rodent carcinogenicity studies or
epidemiology studies. Similar conclusions on mutagenic (and
carcinogenic) potential of 2,4-D have been reached by independent
science review panels. In 1994, a joint committee of EPA's SAB and SAP
concluded that:

    The conflicting cytogenetic results do not provide evidence for
genotoxicity of 2,4-D. Studies with positive results have
significant experimental deficiencies as noted above, thus limiting
the value of these studies for assessing genotoxicity. Therefore,
although there are serious data deficiencies, the currently
available evidence suggests that 2,4-D is non-genotoxic. The lack of
genotoxicity may reduce the concern for potential carcinogenicity of
2,4-D, but it is recognized that not all carcinogens are necessarily
genotoxic.

(Ref. 15 at 19) (See Refs. 13 and 14 (earlier meeting of the FIFRA SAP
disagreeing with EPA's conclusion that there was limited evidence
supporting a carcinogenic designation for 2,4-D and instead concluding
that 2,4-D should be classified no higher than Category D because
evidence was only equivocal)).

    Since the 1997 EPA cancer assessment, the 2,4-D registrant has
submitted a series of mutagenicity tests with 2,4-D and its various
metabolites. The tests included bacteria mutation assays, and in vitro
mammalian assays investigating gene mutation and chromosomal
aberrations. These tests were uniformly negative. Further, in its
comments on the petition, the Task Force offers a plausible hypothesis
for the predominantly negative findings for 2,4-D in mutagenicity
testing. The Task Force notes that 2,4-D does not metabolize or
transform in the body and is rapidly excreted in an unchanged form.
This lack of reactivity supports a conclusion of low mutagenic
potential.
    NRDC in its petition has cited a number of positive mutagenicity
and genotoxicity studies. Taken together, these studies do not have a
significant effect on the balance of the weight of evidence on
mutagenicity and genotoxicity as summarized by EPA in its last cancer
assessment.
    Studies cited by NRDC and Beyond Pesticides do not significantly
add to the weight of evidence supporting a mutagenicity conclusion for
several reasons. First, NRDC only referenced one in vivo study
(Madrigal-Bujaidar (2001)) and that study only looked at a genotoxic,
as opposed to a mutagenic, endpoint (sister chromatid exchange). (Ref.
63). Further diminishing the weight of this study is the fact that the
authors described it as only showing ``weak positive results,'' and
concluded that given the ``moderate genotoxic effect produced by 2,4-D,
* * * the hazard for the general population appears to be small.''
(Id.). Second, many of the studies cited by NRDC looked only at DNA
damage (sister chromatid exchange), (Refs. 64 and 65), not mutagenic
effects, and at least two of these studies showed marginal positive
results at best (Arias (2003, 2007)). (Refs. 66 and 67). Although two
studies cited by NRDC did show a mutagenic (chromosomal aberration)
response in an in vitro mammalian cell assay, (Zeljezic (2004); Venkov
(2000)), two other in vitro studies were either negative (Figg (2000)
(authors conclude findings do not support a ``genotoxic pathway'') or
marginal (Holland (2002)). (Refs. 68, 69, 70, 71, and 72). As noted
above, conflicting results in in vitro testing for 2,4-D was previously
recognized by EPA. Other tests (Tuschl (2003); Bukowska (2003)) showed
cytotoxicity but studies on cytotoxicity alone do not provide evidence
of genotoxicity. (Refs. 73 and 74). Finally, NRDC and Beyond Pesticides
cited studies confirming EPA's earlier conclusion regarding positive
mutagenic effects in yeast and insects (Venkov (2000); Tripathy 1993).
(Refs. 75 and 76). Such studies are entitled to less weight compared to
mammalian studies, particularly in vivo mammalian studies. Finally,
NRDC's arguments regarding the reported oxidant effects of 2,4-D do not
change the weight of evidence as to 2,4-D's cancer classification
because the primary evidence on cancer--rodent carcinogenicity studies
and human epidemiology data--do not support a positive cancer finding.
    Accordingly, EPA concludes that NRDC's claim concerning
mutagenicity does not raise sufficient grounds for concern that EPA
should consider initiating action that might lead to revocation of the
2,4-D tolerances.
    4. Body weight. a. NRDC claim. In a section of its petition
addressing exposure to 2,4-D through maternal milk, NRDC argues that
EPA chose an incorrect POD for addressing short-term oral exposure and
should ``redo the short-term oral risk assessment * * *.'' (Ref. 1 at
11). NRDC cites a study conducted in rats by Sturtz (2006) which
identified 15 mg/kg/day as a LOAEL based on ``adverse effects on
breastmilk composition and on bodyweight in offspring * * *.'' (Id.;
Ref. 77) NRDC contrasts this value with the 25 mg/kg/day NOAEL that EPA
used as the POD in assessing short-term oral risk.
    b. Public comments. The Task Force responded that the results in
the Sturtz (2006) study were not replicated in a recent study performed
under Good Laboratory Practice conditions. (Ref. 26 at 27 and Ref. 78).
In this study, according to the Task Force, 2,4-D significantly
decreased pup body weights at dose levels above the renal saturation
level but not at lower levels.
    c. Agency response. NRDC's request on pup body weight is for EPA to
``redo'' the short-term oral risk assessment using a lower POD based on
a LOAEL rather than a NOAEL. Although this argument, like NRDC's other
claims as to 2,4-D toxicity, appears to state an insufficient basis, on
its face, for revoking the 2,4-D tolerances, EPA concludes that it is
qualitatively different than NRDC's claims regarding endocrine
disruption, neurotoxicity, and mutagenicity. Those claims did not
address the statutory standard for revocation. Although not clearly
articulated by NRDC, EPA can piece together a sufficient allegation
supporting revocation with regard to NRDC's body weight claim: Namely,
that, if EPA recalculated 2,4-D short-term risk using a revised POD of
a LOAEL of 15 mg/kg/day, it would find that short-term aggregate
exposure to 2,4-D exceeds the safe level.
    Nonetheless, while EPA has interpreted NRDC's allegation on body
weight as a legally sufficient ground for revocation, EPA denies NRDC's
claim on body weight because the cited evidence does not support NRDC's
allegation. EPA disagrees with NRDC's allegation that EPA has
misidentified the POD for adverse effects on pup body weight. The
recent extended one-generation rat reproduction study comprehensively
evaluated effects on pup body weights from pre- and post-natal
exposures to 2,4-D. (Refs. 31). In this study, intended doses were: 5
mg/kg/day for the low dose; 15 mg/kg/day for a mid dose; and 40 mg/kg/
day for males and 30 mg/kg/day for females for a high dose. Actual
calculated doses in post-natal pups following weaning (PND

21) were considerably higher with four of the five subsets within the
study (Sets 1a, 1b, 2a, and 2b) receiving almost double the intended
dose for the post-lactation period. Actual doses can differ from
intended doses when experimental animals consume different amounts of
food than projected. Body weights were tracked for all pups in the
study from PNDs 1-21. There were between 24 and 28 litters per dose
group with roughly 10 pups per litter which translates to roughly 250
pups per dose group. Looking across all pups in the study, no
statistically significant body weight decreases were seen for males or
females at any dose level for PND 1-21. A smaller subset of pups (Set
1a--20 pups per dose), was specifically examined as to general toxicity
effects including body weight effects. In that subset, statistically
significant effects were seen in the high dose group for males
generally between PNDs 28 and 69. No statistically significant body
weight effects were seen in males at the low or mid doses or at the
high dose prior to PND 28. No statistically significant body weight
effects were seen in females at any dose on any day. Other subsets
(Sets 1b, 2a, 2b, and 3) for which dosing continued past at least PND
55 showed no statistically significant decrease in body weight at the
conclusion of the study. Similar results were found in an earlier two-
generation study with 2,4-D. (Refs. 79 and 80). In that study, the
intended doses were: 5 mg/kg/day for the low dose; 20 mg/kg/day for a
mid dose; and 80 mg/kg/day for a high dose. Actual calculated doses in
post-natal pups after weaning were 7-14 mg/kg/day, 26-48 mg/kg/day, and
76-133 mg/kg/day. Body weight effects were seen at the mid-dose at PND
28 and at the high dose. No effects on body weight were observed prior
to weaning at the mid-dose. Additionally, in the range-finding study
for the extend one-generation reproduction study, similar effects
regarding pup body weight were seen--namely, statistically significant
body weight decrements were only observed at the high dose ((1,000 ppm)
123 mg/kg/day for males (calculated on PND 35) and (800 ppm) 121 mg/kg/
day for females (calculated on PND 35)). (Ref. 78).
    The Sturtz (2006) study reports decreases in body weight gain or
absolute body weight at doses as low as 15 mg/kg/day on PNDs 6 through
16.\2\ These results are not consistent with the prior two-generation
reproduction study and were not replicated by either the range-finding
study for the extended one-generation reproduction study or the one-
generation study itself. Moreover, there are several reasons to give
the Sturtz (2006) study less weight than the results of the other three
studies. First, the extended one-generation and two-generation study
were conducted under EPA's Good Laboratory Practice Standards
regulations, see 40 CFR part 160, and all underlying data for these
studies are available for review. Further, the extended one-generation
study is considered state-of-the-science because it considered the
toxicokinetic profile of 2,4-D as it makes its way from the mother to
the offspring, as well as a variety of other endpoints that are
considered more sensitive than body weight (e.g., hormones, hematology,
clinical chemistry, etc). The toxicokinetic aspect is particularly
important because, based on the toxicokinetic profile, the doses in the
extended one-generation reproduction study were adjusted during the
lactational period to prevent excessive dosing both to the maternal rat
and to the pups during early lactation and due to a ``double exposure''
when pups are both nursing and starting to consume diet (as in the case
on PND 16). Adjustments to the diet were also performed in the Sturtz
study, although the procedures used were different and may, to some
extent, explain the results in the Sturtz study compared to the
extended one-generation reproduction study. Second, the Sturtz (2006)
study does not show a clear dose response effect. Although there is a
greater effect on body weight comparing the lowest and highest doses,
the body weight effects are essentially the same in the lowest two
doses despite significant differences in the doses and that same
phenomena is seen with regard to the highest two doses. Third, the
extended one-generation reproduction study examined a much larger
sample of pups. Roughly four times as many pups were evaluated in the
extended one-generation reproduction study from PNDs 1-21 compared to
the Sturtz study, and the Sturtz study evaluated no pups after PND 16.
Finally, NRDC infers that the Sturtz study identified an ``adverse
effect'' on the composition of maternal milk. However, changes in the