2,4-D; Order Denying NRDC's Petition To Revoke Tolerances, 23135-23158 [2012-9106]

Agencies

• ENVIRONMENTAL PROTECTION AGENCY

[Federal Register Volume 77, Number 75 (Wednesday, April 18, 2012)]
[Rules and Regulations]
[Pages 23135-23158]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2012-9106]


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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.

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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 https://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 https://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: (703) 308-0136; fax number: (703) 308-8005; 
email address: britton.cathryn@epa.gov.

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

[[Page 23136]]

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: https://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 (703) 305-5805.

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

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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

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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

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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.
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    \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.
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    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

[[Page 23140]]

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

[[Page 23141]]

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

[[Page 23142]]

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

[[Page 23143]]

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

[[Page 23144]]

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

[[Page 23145]]

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

[[Page 23146]]

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

[[Page 23147]]

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

[[Page 23148]]

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).

[[Page 23149]]

    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

[[Page 23150]]

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).


[[Page 23151]]


(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

[[Page 23152]]

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 
composition in maternal milk may provide an explanation for effects 
seen in the pups but do not constitute an adverse effect independent of 
effects in the pups.
---------------------------------------------------------------------------

    \2\ The study does not make clear whether it was reporting 
decrements in body weight gain (the amount of weight gained between 
designated time periods) or absolute body weight. Body weight is 
generally regarded as the more important measure because decrements 
in body weight gain, which is a calculated value and may be 
misleading, may occur even though the pup is otherwise within normal 
body weight levels.
---------------------------------------------------------------------------

    Thus, to the extent NRDC's petition argues that the Sturtz study 
showed the 2,4-D tolerances to be unsafe, that claim is denied.

B. Exposure

    1. Aggregate exposures and risk--residential use--a. NRDC claims. 
In its petition, NRDC restates its comments submitted in 2002 and 2004 
concerning the Agency's aggregate assessment (Ref. 1 at 11). In its 
comments submitted in 2002 and 2004, NRDC claims that EPA failed to 
conduct adequate aggregate risk assessment due to outstanding data gaps 
and missing information, and that EPA did not consider exposure through 
drift, migration of contaminated soil, or residential track-in 
exposures. (Refs. 23 and 24). In its comments, NRDC cites two studies 
(Nishioka (1996 and 2001)) in support of these comments that pertain to 
track-in exposures. (Refs. 81 and 82).
    b. Public comments. There were no public comments received on this 
issue.
    c. Agency response. In addition to the generalized claims regarding 
inadequate assessment of aggregate exposure in the RED risk assessment, 
NRDC does specifically allege that ``[t]he use of 2,4-D in and around 
the home could itself exceed appropriate risk levels if properly 
calculated.'' (Ref. 24 at 28). If the evidence adduced by NRDC 
substantiates this point--the Nishioka studies (1996 and 2001)--this 
claim would be sufficient grounds for revocation of 2,4-D tolerances.
    In response to NRDC's claims regarding the level of 2,4-D exposure 
from residential use, the Agency reviewed both Nishioka studies (1996 
and 2001) to ascertain if the risk assessment completed for 2,4-D was 
protective. (Ref. 83 at 13).
    Residential exposure to 2,4-D results from its use on turf in 
residential environments. In the RED risk assessment this use pattern 
was evaluated using a screening level methodology that considers direct 
contact by toddlers with treated turf. Toddlers are considered the most 
highly exposed group in the population to turf uses because their 
behavior patterns (e.g., playing on turf, mouthing of hands and other 
objects) lead to both increased dermal and non-dietary ingestion 
exposures. The screening methodology assumes that these behaviors co-
occur and also aggregates exposures from the pesticide in food and 
water. For 2,4-D, this screening methodology did not indicate a risk of 
concern even taking into account that the RED risk

[[Page 23153]]

assessment retained the full 10X FQPA safety factor due to missing data 
on pre- and post-natal toxicity.\3\
---------------------------------------------------------------------------

    \3\ In 2011, EPA removed the FQPA safety factor because the data 
gaps were filled by submission of the extended one-generation rat 
reproduction study.
---------------------------------------------------------------------------

    Dusts are thought by some to possibly contribute more than 
negligible levels to potential exposures in indoor environments but a 
methodology has not been developed which definitively establishes a 
link between levels in dust with a clearly defined exposure pathway. 
This construct was discussed extensively at a 2009 meeting of the FIFRA 
SAP related to the revisions of the EPA's Standard Operating Procedures 
for Residential Exposure Assessment. (Ref. 84). The conclusions of that 
panel were that insufficient information is currently available to 
definitively link residues in dusts to specific exposure pathways. 
Nonetheless, to examine whether 2,4-D contamination of indoor dust 
might significantly alter the RED risk assessment, EPA considered how 
the indoor residue values in the Nishioka studies would affect the risk 
assessment. EPA assumed for screening purposes that toddlers consume 
100 mg/day of dust containing the highest 2,4-D concentration found in 
Nishioka studies (67 micrograms/gram ([mu]g/g)). The 2,4-D levels in 
dust in the Nishioka studies were generally much lower than 67 [mu]g/g 
(e.g., 1996 maximum is 4.85 [mu]g/g, and 2001 median is 10 [mu]g/g). 
The value of 100 mg/day for dust consumption is drawn from the EPA's 
Child Specific Exposure Factors Handbook (Ref. 85), and is the same 
value assumed for soil consumption. This value was also used in the 
Nishioka studies. Additional conservatisms in this screening assessment 
are the assumptions that (1) exposures from dust residues are assumed 
despite the uncertainties noted in the 2009 FIFRA SAP Report; and (2) 
2,4-D residues do not decline over time even though 2,4-D is known to 
dissipate quickly. (Ref. 84 at 26 and Ref. 86). Based on these 
assumptions, margins of exposure range from approximately 32,000 to 
150,000 depending upon whether the duration of exposure considered is 
acute-, short- or intermediate-term. (Ref. 30 at 66). As such, use of 
this highest dust concentration value would not impact the findings of 
the current risk assessment. If it is further assumed that dusts 
persist in impacted residences in such a way that ingestion of the 
highest concentration would occur in a chronic exposure pattern and 
that the highest noted concentration in dust would never dissipate, 
which is counter-intuitive given how 2,4-D is used and its known rapid 
dissipation characteristics, risks are still not of concern. In such 
situations, dust would be the predominant source for chronic exposures 
but margins of exposure still would exceed 11,000 based on the chronic 
dietary POD (5 mg/kg/day). (Ref. 30 at 66). It should also be noted 
that Nishioka (1996) indicated that such exposures could be chronic in 
nature after a single application of 2,4-D, but this is viewed by EPA 
as unlikely due to a lack of empirical information to support such a 
supposition. Nishioka (1996) projected that 2,4-D would be found in 
residential carpet dust up to 1 year later based on short-term track-in 
sampling. However, the value estimated by Nishioka (0.5 [mu]g/g) is two 
orders of magnitude less than the value used in the extremely 
conservative assessments described above. Given that these unrealistic 
and high-end assumptions yield MOEs greater than 10,000, EPA concludes 
that the cited data do not support NRDC's allegation that ``[t]he use 
of 2,4-D in and around the home could itself exceed appropriate risk 
levels if properly calculated.'' To the contrary, even assessing 
exposure using unrealistic, high-end values for 2,4-D, levels in dust 
indicates that residential dust exposures to 2,4-D are a relatively 
minor exposure. NRDC's claim regarding track-in exposures is denied.
    Finally, it should be noted that the Agency is currently in the 
process of evaluating the state of the science related to the exposure 
pathways from indoor dust as illustrated by the SAP review of 
residential methods and an additional review related to exposures from 
volatilization. Additionally, EPA is developing more definitive methods 
focused on addressing and characterizing potential exposures from 
chemical trespass. These efforts were recently described in a 2011 
meeting of the Pesticide Program Dialogue Committee. (Ref. 87). Once 
final, any potential modifications to methods impacting residential 
risk assessment will be accounted for in the upcoming registration 
review process for 2,4-D.
    2. Exposure through maternal milk-- a. NRDC claims. NRDC asserts 
that EPA failed to include any lactational exposure in its aggregate 
risk assessment, although it was aware of research demonstrating the 
potential exposure to 2,4-D from maternal milk. (Ref. 1 at 11). NRDC 
cites several studies involving lactational exposure to show potential 
effects of 2,4-D on the brain of neonatal rats exposed lactationally. 
(Id.). The cited studies provide an assessment of the levels of 2,4-D 
attained in the milk of the dams and in the plasma and brain of the 
pups. NRDC also cites studies that it claims ``confirm the lactational 
exposure and identify adverse effects in the offspring.'' (Id.)
    b. Public comments. In its comments, the Industry Task Force 
disputes NRDC's allegation that EPA failed to address 2,4-D exposure 
from maternal milk. (Ref. 26 at 24-27). The Task Force comments that 
EPA was aware, when conducting the aggregate risk assessment, that 2,4-
D may be present in maternal milk because of the results of animal 
feeding studies using exaggerated doses of 2,4-D. Further, the Task 
Force argues that NRDC's claim that EPA failed to include any 
lactational exposure in its aggregate risk assessment is not correct. 
According to the Task Force, the Agency used half the limit of 
detection (LOD) for milk value in its 2005 risk assessment because no 
detectable residues were found in milk samples over several years of 
Pesticide Data Program (PDP) monitoring. Thus, the Task Force asserts 
that EPA assumed that 2,4-D would be present in milk at 0.004 ppm for 
both acute and chronic exposure (despite it being non-detectable in PDP 
sampling). (Id. at 26).
    The Task Force states that large doses of 2,4-D administered in the 
Sturtz et al (2000) study cited by NRDC render the study uninformative 
for human health risk assessment. (Id. at 24). The Task Force cites 
biomonitoring data from farm families to support its contention that 
EPA's exposure estimates are reasonable. (Id. at 25).
    c. EPA's response. Initially, EPA would note that the studies NRDC 
cited to support its claim that 2,4-D exposure through maternal milk 
causes adverse effects were considered together with other studies 
cited by NRDC pertaining to toxicity issues. See Unit VII.A. above.
    With regard to human exposure to 2,4-D through maternal milk, NRDC 
alleges that such exposure occurs and was ignored by EPA despite the 
fact that it could result in ``potentially significant exposures.'' As 
discussed in Unit VII.A.1.c., this ground for objection is denied 
because (1) the standard for revocation is that the tolerance is unsafe 
not that there are ``potentially significant exposures'' that should be 
included in an aggregate assessment; and (2) NRDC presents no evidence 
to support its assertion that potentially significant exposures were 
excluded from EPA's risk assessment. Accordingly, NRDC's claim that the 
2,4-D tolerance should be revoked due to exposure to 2,4-D in human 
breast milk is denied due to a failure to allege facts sufficient to 
meet the statutory standard for revocation and a failure to support the 
allegations that are made.

[[Page 23154]]

    Despite the inadequacy of petitioners' claim regarding 2,4-D 
exposure in human breast milk, 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.
    NRDC is incorrect in asserting that EPA assumed that humans are not 
exposed to 2,4-D through maternal milk. To the contrary, EPA assumed, 
in its RED risk assessment, that all milk--whether animal or human--
contained 2,4-D at levels that may be present in cow's milk. This is an 
extremely conservative assumption as it pertains to human breast milk.
    Residues in various food forms of cow's milk (e.g., milk fat, 
nonfat milk solids, etc.) have been accounted for in the dietary 
exposure assessment based on monitoring data from the USDA Pesticide 
Data Program (PDP). There were no detections of 2,4-D in any samples, 
so EPA assumed that all milk contains half the detection limit for 2,4-
D. (Ref. 19 at 47). This is a very conservative assumption as it 
pertains to human breast milk because 2,4-D levels in human breast milk 
are expected to be significantly lower than residues in cow's milk. 
Exposure of dairy cattle to pesticides are generally significantly 
higher than humans as residues in cows' key feed items, such as grass 
forage, are generally much higher than in human foods. As to 2,4-D, 
this is certainly the case given that the 2,4-D tolerances for grass 
(hay) and grass (forage) are 300 and 360 ppm, respectively, while 2,4-D 
tolerances for various human foods are all much lower--in the single 
digits or less than 1 ppm (40 CFR 180.142). Grass hay and forage can 
constitute 60 percent of the diets of beef and dairy cattle. (Ref. 88).
    Accordingly, EPA concludes that NRDC's claim regarding exposure to 
2,4-D through human breast milk 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. Dermal absorption--a. NRDC claims. NRDC asserts that in the 
final risk assessment, the dermal absorption factor used by EPA (10 
percent) was too low. Specifically, NRDC claims that the EPA failed to 
address the possibility of enhanced dermal absorption of 2,4-D due to 
the potentially interacting factors of alcohol consumption and 
application of sunscreen, and/or the insect repellent DEET. (Ref. 1 at 
12; Ref. 22 at 1). In its exposure comments on the RED, which NRDC 
incorporates in its petition, NRDC argued that EPA should increase its 
dermal absorption factor to at least 14 percent based on a human dermal 
absorption study by Moody (1992). (Ref. 24 at 16 and Ref. 89). NRDC 
claimed that such an adjustment of the dermal absorption factor would 
result in post-application exposures for toddlers exceeding the LOC. 
(Ref. 24 at 16). In addition, NRDC claims that the Agency did not 
sufficiently address that using rubber gloves when applying 2,4-D does 
not afford adequate dermal protection and the effect of 2,4-D soaking 
into clothing. (Ref. 1 at 13).
    b. Public comments. In its comments, the Task Force disagrees with 
NRDC's allegation regarding enhanced dermal absorption due to the 
interacting factors of alcohol consumption, sunscreen, and DEET. The 
Task Force argues that the study on which EPA relied to estimate dermal 
absorption, Feldmann and Maibach (1974), used ``extreme'' conditions. 
(Ref. 26 at 28 and Ref. 90). According to the Task Force, in this study 
2,4-D was applied with acetone which denatures skin and allows for 
increased absorption. Additionally, the Task Force noted that the skin 
was not protected and not washed for 24 hours to allow maximum 
absorption. That study showed absorption of 5.8 percent. The Task Force 
also cites a recent article, Ross (2005), which summarized numerous 
dermal absorption studies with 2,4-D. (Ref. 91). According to the Task 
Force, this study concluded that the available studies showed 
remarkable agreement and strongly supported the conclusion in the 
Fledmann and Maibach study.
    The Task Force also commented on other issues related to dermal 
exposure such as the use of rubber gloves by agricultural workers. 
Those comments are not relevant to the FFDCA portion of NRDC's petition 
and are thus addressed elsewhere.
    c. EPA's response. For the purposes of responding to the portion of 
NRDC's petition that requests EPA to revoke tolerances, EPA will 
respond to issues related to residential exposure here. Concerns about 
occupational exposures will be addressed elsewhere.
    Unlike most of NRDC's other claims, as to dermal absorption, NRDC 
alleges grounds that if substantiated would provide grounds for 
revoking the 2,4-D tolerances. As summarized above, NRDC alleges that 
EPA has understated dermal absorption and adjustment of dermal 
absorption factor to the degree supported by Moody (1992) would show a 
risk of concern (i.e., a lack of safety). (Ref. 24 at 16). In the 
petition, NRDC's focus shifts from the Moody study to a series of in 
vitro studies investigating the effect of the use of sunscreen and 
alcohol on 2,4-D dermal absorption. NRDC argues that these studies show 
that EPA has underestimated dermal absorption. The various combinations 
of in vitro results appear to indicate that dermal absorption was 
enhanced by up to a factor of about 2.5 while most tested scenarios 
indicate a factor of 2 or less. (Refs. 92,93,94 and 95). One study used 
human skin and the results suggest a factor of up to 3 depending upon 
sunscreen ingredient tested. (Ref. 92). NRDC also claims that use of 
the pesticide Deet increases dermal absorption of 2,4-D. Here, NRDC 
turns back to the Moody study but that study actually concluded that 
``Deet had no significant effect on total cumulative palmar 
permeability to this herbicide [2,4-D].'' (Ref. 89 at 245).
    EPA believes that its use of a 10 percent dermal absorption value 
for 2,4-D is protective. EPA's conclusion is supported by an extensive 
set of high quality human research results. Ross (2005) notes that 
``the degree of uncertainty and variability associated with human 
dermal absorption for 2,4-D is better defined than for virtually any 
other pesticide * * *.'' (Ref. 91 at 84). EPA principally relied on an 
in vivo human study which showed average human dermal absorption at 5.8 
percent. (Ref. 90). EPA also considered four other in vivo human 
studies. (Refs. 89, 96,97 and 98). These studies involved 8 separate 
trials using a total of 34 participants and had an average dermal 
absorption value of 5.7 percent. (Ref. 91 at 84, Table 2) To account 
for potential variability EPA chose a value of 10 percent.
    There are several factors that support reliance on these data and 
demonstrate the reasonableness of EPA's choice of a 10 percent dermal 
absorption factor. First, the data relied upon by EPA are from in vivo 
human studies. NRDC, with one exception, has cited only to in vitro 
data. EPA generally does not rely on in vitro dermal absorption data 
without corroboration from in vivo testing. The critical limitations 
with in vitro dermal absorption testing, such as the lack of an intact 
vasculature, make it an uncertain guide for risk assessment. The Moody 
study (1992) did involve in vivo human testing but the results of this 
study were similar to the higher values seen in the human in vivo 
studies considered by EPA. In fact, if the Moody study results from the 
trial combining 2,4-D and DEET are included in the overall average of 
dermal absorption from the human studies, the average absorption only 
increases from 5.7 percent to 6.4 percent. (Ref. 30). Second, the 
studies considered by EPA involved exposure

[[Page 23155]]

conditions that varied based on application site (forearms, hands), 
topical dose rates (1.7 to 1,100 [mu]g/cm\2\), form (acid or salt), 
application media (water, ethanol, acetone), and exposure time. As 
noted, the overall average dermal absorption value for all of these 
data combined (N=34), regardless of design, was 5.7 percent. 
Examination of these variables, particularly the use of different 
application vehicles and different anatomical sites, is likely to have 
captured much of the variability measured in the sunscreen and alcohol 
in vitro studies. On this latter point, it is worth noting that NRDC 
placed particular emphasis on the potential additive effect of 
sunscreen and alcohol. Yet, the relevant study on this point found that 
the effect from both sunscreen and alcohol to be no higher than a 
factor of 2.9 and that was only with an extremely high alcohol dose. 
(Ref. 92). At the lowest alcohol dose tested in the study, the 
researchers actually concluded that alcohol had an inhibitory effect on 
dermal absorption. This low dose, when converted to human consumption 
amounts, is the equivalent of 7 ounces of 100 proof liquor for women 
and just slightly less than 9 ounces for men. Third, the data 
considered by EPA was developed by different researchers at different 
laboratories. The reproducibility of results across these studies gives 
them enhanced reliability. As Ross (2005) notes: ``Multiple human 
studies conducted on the forearm and hand provide remarkably consistent 
results, especially considering the studies were performed years apart 
in time, at different laboratories by different personnel on totally 
different human subjects.'' (Ref. 91 at 84). On the other hand, the in 
vitro studies cited by NRDC all were conducted by the same group of 
researchers. Finally, the value chosen by EPA for dermal absorption was 
nearly twice the average value seen in human testing.
    Providing further support for the reasonableness of EPA's 
assumption on dermal absorption are exposure monitoring studies 
(including epidemiological analyses, environmental measurements, and 
methodological analyses) cited by NRDC and commenters. (Ref. 30 at 65-
69). In fact, many of these studies report exposure levels that are 
similar to or far below exposures estimated by EPA. For example, NRDC 
cited results from Lerda (1991), (Ref. 99), prior to the RED, which are 
similar to those predicted in the 2005 EPA risk assessment for 
applicators wearing normal work clothing. Current labels require the 
use of protective clothing and gloves. NRDC also cited median urinary 
values in children reported by Morgan (2008), (Ref. 100), which are 
lower than those used to establish risk estimates in the 2005 risk 
assessment. Other data cited in comments, such as Alexander (2007), 
(Ref. 101), cited by the 2,4-D Task Force, (Ref. 26 at 30), indicate 
values much lower than values that would reflect a risk concern for 
both applicators and their family members according to the 2005 
assessment. (Ref. 19 at 57-60).
    Accordingly, NRDC's claim regarding dermal absorption is denied.
    EPA is currently involved in processes to refine many of its 
exposure assessment inputs (https://www.epa.gov/pesticides/science/handler-exposure-data.html) and to establish better methods for the 
consideration of epidemiological research into the regulatory process. 
(See Ref. 102). The Agency is also re-evaluating pesticide risks on a 
cyclical basis under its registration review process. Given these two 
efforts, the Agency will further evaluate research related to 2,4-D 
during registration review. The Agency has also been actively 
participating in epidemiological research efforts such as the 
Agricultural Health Study and, as part of this process, will pursue 
additional information related to 2,4-D and the potential for health 
effects in potentially exposed populations.

C. Additional Issues Raised in Public Comments

    Some comments raised issues beyond the scope of NRDC's petition. 
For example, Beyond Pesticides, in its comments, claimed that EPA was 
not justified in removing the FQPA safety factor and had failed to 
address cumulative effects from 2,4-D and other chlorophenoxy 
pesticides. (Ref. 28 at 5-6). It is not appropriate for EPA to consider 
these comments in support of the petition because they have not been 
subject to the public comment process which is critical to the EPA's 
administrative review of the petition under section 408(d).

VIII. Statutory and Executive Order Reviews

    This action, denies a petition to revoke tolerances, is in the form 
of an order and not a rule. (21 U.S.C. 346a(f)(1)(C)). Under the 
Administrative Procedure Act (APA), orders are expressly excluded from 
the definition of a rule. (5 U.S.C. 551(4)). Accordingly, the 
regulatory assessment requirements imposed on a rulemaking do not apply 
to this action, as explained further in the following discussion.

A. Executive Order 12866 and Executive Order 13563

    Because this order is not a ``regulatory action'' as that term is 
defined in Executive Order 12866 entitled ``Regulatory Planning and 
Review'' (58 FR 51735, October 4, 1993), this action is not subject to 
review by the Office of Management and Budget (OMB) under Executive 
Orders 12866 and 13563 entitled ``Improving Regulation and Regulatory 
Review'' (76 FR 3821, January 21, 2011).

B. Paperwork Reduction Act

    This action does not contain any information collections subject to 
OMB approval under the Paperwork Reduction Act (PRA), 44 U.S.C. 3501 et 
seq.

C. Regulatory Flexibility Act

    Since this order is not a rule under the APA (5 U.S.C. 551(4)), and 
does not require the issuance of a proposed rule, the requirements of 
the Regulatory Flexibility Act (RFA) (5 U.S.C. 601 et seq.) do not 
apply.

D. Unfunded Mandates Reform Act; and Executive Orders 13132 and 13175

    This order denies a petition to revoke tolerances; it does not 
alter the relationships or distribution of power and responsibilities 
established by Congress in the preemption provisions of section 
408(n)(4) of FFDCA. As such, the Agency has determined that this action 
will not have a substantial direct effect on States or tribal 
governments, on the relationship between the national government and 
the States or tribal governments, or on the distribution of power and 
responsibilities among the various levels of government or between the 
Federal Government and Indian tribes. Thus, the Agency has determined 
that Executive Order 13132 entitled ``Federalism'' (64 FR 43255, August 
10, 1999) and Executive Order 13175 entitled ``Consultation and 
Coordination with Indian Tribal Governments'' (65 FR 67249, November 9, 
2000) do not apply to this order. In addition, this order does not 
impose any enforceable duty or contain any unfunded mandate as 
described under Title II of the Unfunded Mandates Reform Act (UMRA) (2 
U.S.C. 1531-1538).

E. Executive Orders 13045, 13211 and 12898

    As indicated previously, this action is not a ``regulatory action'' 
as defined by Executive Order 12866. As a result, this action is not 
subject to Executive Order 13045, entitled ``Protection of Children 
from Environmental Health Risks and

[[Page 23156]]

Safety Risks'', (62 FR 19885, April 23, 1997) and Executive Order 13211 
entitled ``Actions Concerning Regulations That Significantly Affect 
Energy Supply, Distribution, or Use'', (66 FR 28355, May 22, 2001). In 
addition, this order also does not require any special considerations 
under Executive Order 12898 entitled ``Federal Actions to Address 
Environmental Justice in Minority Populations and Low-Income 
Populations'' (59 FR 7629, February 16, 1994).

F. National Technology Transfer and Advancement Act

    This action does not involve any technical standards that would 
require Agency consideration of voluntary consensus standards pursuant 
to section 12(d) of the National Technology Transfer and Advancement 
Act (NTTAA), (15 U.S.C. 272 note).

IX. Congressional Review Act

    The Congressional Review Act, 5 U.S.C. 801 et seq. does not apply 
because this action is not a rule as that term is defined in 5 U.S.C. 
804(3).

X. References

1. Petition of Natural Resources Defense Council to Revoke All 
Tolerances and Cancel All Registrations for the Pesticide 2,4-D 
(November 6, 2008).
2. Office of Prevention, Pesticides and Toxic Substances, EPA, 
Memorandum from Elizabeth Resek to Jim Downing, ``Transmittal of 
Meeting Minutes of the FIFRA Scientific Advisory Panel Meeting Held 
on March 25-26, 2008 to review and consider the Endocrine Disrupter 
Screening Program (EDSP) Proposed Tier 1 Screening Battery.'' (June 
11, 2008).
3. Marino, T.; Coady, K.; Sosinski, L.; et al. (2010) 2,4-
Dichlorophenoxyacetic Acid: A Fish Short-Term Reproduction Assay 
Using the Fathead Minnow, Pimephales promelas. Project Number: 
101026. Unpublished study prepared by Dow Chemical, USA. 155 p. MRID 
48317001.
4. Coady, K.; Marino, T.; Thomas, J. (2010) 2,4-
Dichlorophenoxyacetic Acid: The Amphibian Metamorphosis Assay Using 
the South African Clawed Frog, Xenopus laevis. Project Number: 
101025. Unpublished study prepared by Dow Chemical, USA. 152 p. MRID 
48317002.
5. Schisler, M.; LeBaron, M.; Visconti, N. (2011) (Endocrine 
Disruptor Screening Program): Evaluation of 2,4-
dichlorophenoxyacetic Acid (2,4-D) in an in vitro Androgen Receptor 
Binding Assay. Project Number: 111111/OCR. Unpublished study 
prepared by Exponent, Inc. and The Dow Chemical Co. 91p. MRID 
48614301.
6. Coady, K.; Sosinski, L. (2011) (Endocrine Disruptor Screening 
Program): 2,4-Dichlorophenoxyacetic Acid: Evaluation of 2,4-
Dichlorophenoxy Acetic Acid in the Human Recombinant Aromatase 
Assay. Project Number: 111036/OCR 31868 P803. Unpublished study 
prepared by Exponent, Inc. and The Dow Chemical Co. 98p. MRID 
48614302.
7. LeBaron, M.; Schisler, M.; Visconti, N. (2011) (Endocrine 
Disruptor Screening Program): 2,4-Dichlorophenoxyacetic Acid: 
Evaluation of 2,4-dichlorophenoxyacetic Acid (2,4-D) in an in vitro 
Estrogen Receptor Binding Assay. Project Number: 111121/OCR. 
Unpublished study prepared by The Dow Chemical Co., and Exponent, 
Inc. 91p. MRID 48614303.
8. LeBaron, M.; Kan, H. (2011) (Endocrine Disruptor Screening 
Program): Evaluation of 2,4-Dichlorophenoxy Acetic Acid (2,4-D) in 
an in vitro Estrogen Receptor Transcriptional Activation Assay in 
Human Cell Line HELA-9903. Project Number: 111043/OCR. Unpublished 
study prepared by Exponent, Inc., and The Dow Chemical Co. 109p.MRID 
48614304.
9. LeBaron, M.; Kan, H.; Perala, A. (2011) (Endocrine Disruptor 
Screening Program): Evaluation of 2,4-Dichlorophenoxyacetic Acid 
(2,4-D) in the in vitro Steroidogenesis Assay. Project Number: 
111038/OCR. Unpublished study prepared by Exponent, Inc., and The 
Dow Chemical Co. 78p. MRID 48614305.
10. Office of Chemical Safety and Pollution Prevention, EPA, 
Memorandum from Greg Ackerman to Katie Weyrauch, ``2,4-
Dichlorophenoxyacetic Acid (2,4-D) - Report of the Endocrine 
Disruptor Review Team--Test Order : EDSP-031001-120'' 
(December 20, 2010).
11. EPA, A User's Guide to Available EPA Information on Assessing 
Exposure to Pesticides in Food (June 21, 2000).
12. Office of Pesticide Programs, EPA, Office of Pesticide Programs' 
Policy on the Determination of the Appropriate FQPA Safety Factor(s) 
for Use in the Tolerance Setting Process (February 28, 2002).
13. Office of Pesticides and Toxic Substances, EPA, Memorandum from 
Stephen L. Johnson to Douglas D. Campt, ``Transmittal of Final FIFRA 
Scientific Advisory Panel Reports on the June 25, 1987 meeting'' 
(July 8, 1987).
14. EPA, Scientific Advisory Panel Open Meeting (June 25, 1987).
15. EPA, An SAB Report: Assessment of Potential 2,4-D 
Carcinogenicity. Review of the Epidemiological and Other Data on 
Potential Carcinogenicity of 2,4-D by the SAB/SAP Joint Committee. 
(March 22, 1994).
16. EPA, Carcinogenicity Peer Review (4th) of 2,4-
Dichlorophenoxyacetic acid (2,4-D). (January 29, 1997).
17. EPA, Agency Review of Task Force II Study Submission: MRID 
44284501 and MRID 44284502. (March 16, 1999).
18. Office of Prevention, Pesticides and Toxic Substances, EPA, 
Reregistration Eligibility Decision for 2,4-D (June 2005).
19. Office of Prevention, Pesticides and Toxic Substances, EPA, 
Memorandum from Timothy C. Dole to Katie Hall, ``2,4-D. HED's 
Revised Human Health Risk Assessment for the Reregistration 
Eligibility Decision (RED) Revised to Reflect Public Comments. PC 
Code 030001; DP Barcode D316597'' (May 12, 2005).
20. Office of Chemical Safety and Pollution Prevention, EPA, 
Memorandum from Alexandra LaMay to Michael Walsh, ``Petition for the 
Establishment of a New Formulation of 2,4-D Choline on Herbicide 
Tolerant Field Corn Containing the Aryloxyalkanoate Dioxygenase-1 
(ADD-1) Gene. (October 27, 2011).
21. Office of Chemical Safety and Pollution Prevention, EPA, 
Memorandum from Alexandra LaMay to Michael Walsh, ``2,4-D: Amended 
Petition for the Establishment of a New Formulation of 2,4-D Choline 
on Herbicide Tolerant Field Corn Containing the Aryloxyalkanoate 
Dioxygenase-1 (ADD-1) Gene.'' (February 22, 2012).
22. NRDC, ``Supplement To The Natural Resources Defense Council 
Petition To Revoke All Tolerances And Cancel All Registrations For 
The Pesticide 2,4-D'' (February 23, 2009).
23. Boston Women's Health Book Collective, et al., Objections to the 
establishment of a tolerance for pesticide chemical residues of 2,4-
D. OPP 301219. (May 7, 2002).
24. Beyond Pesticides, NRDC, et. al. comments on RED 2004. At 
regulations.gov EPA-HQ-OPP-2004-0167-0072 (August 23, 2004).
25. Agricultural Retailers Association et al. Docket ID number EPA-
HQ-OPP-2008-0877. Available at regulations.gov EPA-HQ-OPP-2008-0877-
0104.
26. Industry Task Force II on 2,4-D Research Data, Comments on The 
Natural Resource Defense Council's Petition to Revoke All Tolerances 
and Cancel All Registrations for the Pesticide 2,4-D'' (February 23, 
2009).
27. National Council for Air and Stream Improvement, Inc., ``Re: 
Docket  EPA-HQ-OPP-2008-0877 (February 20, 2009).
28. Beyond Pesticides, ``Re: Petition to Revoke all Tolerances and 
Cancel all Registrations for the Pesticide 2,4-Dichlorophenoxyacetic 
Acid (2,4-D); Docket Number: EPA-OPP-2008-0877'' (February 23, 
2009).
29. New York State Department of Environmental Conservation, New 
York State Department of Health, ``RE: EPA-HQ-OPP-2008-0877'' 
(February 23, 2009).
30. Office of Chemical Safety and Pollution Prevention, EPA, 
Memorandum from Linda Taylor, Nancy McCarroll, and Khin Swe Oo to 
Joel Wolf, ``2,4-D: Evaluation of Data Identified in NRDC Petition 
and Associated Documents'' (March 27, 2012).
31. Risk Assessment Branch VII, Health Effects Division (7509P), 
EPA, 2,4-D: Review of Extended 1-Generation Reproduction Study and 
Dose-Range-Finding and Pharmacokinetic Titration Studies. D376556. 
MRID 47972101, 47417901, 47417902. (November 30, 2010).

[[Page 23157]]

32. Office of Chemical Safety and Pollution Prevention, EPA, 
Memorandum from Linda Taylor to Katie Weyrauch, ``2,4-D: Revised 
Executive Summary of the Data Evaluation record of the Extended 1-
Generation Reproduction Study'' (June 1, 2011).
33. Office of Prevention, Pesticides and Toxic Substances, EPA, 
Health Effects Test Guidelines, OPPTS 870.3800: Reproduction and 
Fertility Effects (August 1998).
34. Xie, L.; Thrippleton, K.; Irwin, M.A., et al. Evaluation of 
estrogenic activities of aquatic herbicides and surfactants using a 
rainbow trout vitellogenin assay. Toxicological Sciences 87(2):391-
398, 2005.
35. Rawlings, N.C.; Cook, S.J.; Waldbillig, D. Effects of the 
pesticides carbofuran, chlorpyrifos, dimethoate, lindande, 
triallate, trifluralin, 2,4-D, and pentachlorphenol on the metabolic 
endocrine and reproductive endocrine system in ewes. Journal of 
oxicology and Environmental Health 54:21-36, 1998.
36. Charles, J.M.; Cunny, H.C.; Wilson, R.D.; Bus, J.S. Comparative 
subchronic studies on 2,4-dichlorophenoxyacetic acid, amine, and 
ester in rats. Fundamental & Applied Toxicology 33:161-165, 1996.
37. Liu, R.C.; Hahn; Hurtt, M.E. The direct effect of hepatic 
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List of Subjects

    Environmental protection, Agricultural commodities, Pesticides and 
pests.

    Dated: April 7, 2012.
Steven Bradbury,
Director, Office of Pesticide Programs.
 [FR Doc. 2012-9106 Filed 4-17-12; 8:45 am]
BILLING CODE 6560-50-P