Document ID: EPA-HQ-OPP-2014-0195-2414
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2014-10-15T04:00Z

MEMORANDUM

Date:		October 14, 2014

Subject:	Response to Public Comments Received Regarding New Uses of
Enlist DuoTM on Corn and Soybeans

	  	Product Name: Enlist DuoTM

               	EPA Registration Number: 62719-649

	   	Application Date: November 1, 2011

Response to Comments

The Agency received 417,301 comments in response to the public
participation process (Docket ID: EPA-HQ-OPP-2014-0195) regarding the
Environmental Protection Agency’s (EPA’s) proposed decision for the
application to register the use of 2,4-D choline salt on (Genetically
Engineered) GE 2,4-D and glyphosate tolerant corn and soybeans. 
Comments received were both in favor of and opposed to the decision to
register Enlist DuoTM, which will provide growers with additional tools
to control a broad spectrum of weeds.  The EPA welcomes input from the
public during the decision process when registering pesticides, and is
committed to thoroughly evaluating and mitigating any potential risks
from registered pesticides, consistent with applicable statutory
standards.  Also, EPA strives to document and explain the basis of its
regulatory decisions through these and other public documents. 

I. Human health

A common concern expressed in the submitted comments regarded the human
health effects of the potential increased use, and therefore exposure
of, 2,4-D.  Because similar human health issues were raised by many
commenters, the comments are grouped into major topic areas and each
topic area is addressed below.  These topic areas fall under 4 major
headings:  toxicity, risk, exposure, and epidemiology/incidents.

A. Toxicity

Commenters questioned EPA’s assessment of toxic effects including
developmental, mutagenic, thyroid, endocrine, cancer, reproductive,
immunotoxic, and kidney effects.  Commenter’s questions focused on how
a safety finding could be made when these effects were observed in some
toxicity studies, and they expressed concerns about the completeness and
adequacy of the toxicity database.  In order to address these comments,
EPA first presents two important overarching considerations; second, we
discuss the Agency’s consideration of the toxic effects regarding each
organ system.  Following this discussion, EPA identifies and responds to
other specific comments regarding toxicity.

1. Overarching Considerations

First, the toxicity database for 2,4-D is complete and robust.  This
includes a recently completed and reviewed Extended One-Generation
Reproductive Toxicity Study (EOGRTS), a study which measures numerous
toxic effects in multiple organ systems (endocrine, thyroid,
reproductive, developmental, immuno-, and nervous), and across the
lifetime of an organism from conception to adulthood.  EPA also
completed a thorough literature search considering all pertinent
toxicity research and found no information which would change the
conclusions drawn in the Agency’s risk assessment.  

A second overarching consideration in responding to commenters’
questions is the pharmacokinetic behavior of 2,4-D.  2,4-D is readily
absorbed into the blood stream, is removed from the blood by the kidneys
unchanged (it is not metabolized), and is rapidly excreted via the
urine. At high dose levels, renal saturation occurs, which means that
the ability of the kidney (renal) to excrete 2,4-D is overwhelmed.  As a
consequence, 2,4-D builds up in the body.  When this occurs, toxic
effects are observed.  Studies referenced by some commenters utilized
dose levels above those causing renal saturation.  However, at doses
below those causing renal saturation, toxic effects are not observed. 
This is an essential consideration in EPA’s 2,4-D assessment: the
Agency’s assessment establishes a maximum allowable dose which is at
least 100-fold below this level, assuring protection of public health,
and the levels at which people might be exposed are far below even this
level since estimated risks are well below the maximum allowable
exposure threshold.  Therefore, the Agency’s assessment is protective
for any effects seen in these studies.

2. Agency Consideration of Toxic Effects regarding Each Organ System

a. Developmental Effects

2,4-D has been thoroughly studied with respect to potential effects on
the developing animal. There are two (rat and rabbit) guideline
developmental toxicity studies on 2,4-D, which are designed to provide
information concerning the effects of exposure of the pregnant test
animal on the developing organism (fetal effects including death,
structural abnormalities, or altered growth) and an assessment of
maternal effects. Functional deficiencies and other postnatal effects
have been assessed in the guideline 2-generation reproduction study on
2,4-D and in the 2,4-D extended 1-generation reproduction study, which
included a developmental neurotoxicity and immunotoxicity assessment.
Developmental toxicity was identified/observed in the rat and rabbit
developmental toxicity studies at a maternally toxic dose that exceeded
the maternal animal’s ability to excrete 2,4-D (i.e., above levels of
renal saturation; see 2,4-D.   Human Health Risk Assessment for a
Proposed Use of 2,4-D Choline on Herbicide-Tolerant Corn and Soybean,
LaMay, August 8, 2013). There are clear no-observed-adverse-effect
levels (NOAELs; defined as doses at which no adverse toxic effects are
seen in toxicology studies, and upon which the Agency’s estimates are
typically quantified) in both studies for the developmental effects
observed, and an acute dietary risk assessment point of departure (POD;
defined as the NOAEL or other dose level to which safety factors are
typically applied when quantifying risks) is based on the rat
developmental toxicity study [where fetal skeletal abnormalities (14th
rudimentary ribs were observed at a dose level that exceeded the
maternal animal’s ability to excrete 2,4-D)].  Therefore, the Agency
has considered and addressed concerns for developmental toxicity in its
risk assessment.  

b. Mutagenicity

While the concern for mutagenicity was raised by commenters, no
supporting evidence was provided.  Similar claims were submitted by the
Natural Resources Defense Council (NRDC) in a November 6, 2008 petition
requesting that EPA revoke all pesticide tolerances for 2,4-D under
section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), and
were thoroughly addressed by the Agency in an April 18, 2012 Order
denying that petition (see 77 FR 23135, 23149-23151 (Apr. 18, 2012)).
EPA’s current testing requirements focus on tests for mutagenic
effects, i.e., heritable changes in DNA that could potentially lead to
disease.  Based on a full battery of mutagenicity testing, 2,4-D is not
considered to be a mutagen.

c. Thyroid Toxicity

The Agency identified thyroid toxicity as a potential effect of concern
and required additional testing. Potential for thyroid toxicity was
assessed in the extended one-generation reproduction study (EOGRTS) on
2,4-D, which assessed numerous thyroid parameters. These included
thyroid weights, thyroid hormone levels (T3, T4, TSH), and
histopathology evaluation of the thyroid. These parameters were assessed
in the young animal on postnatal days 4, 22, and 70 and in pregnant
females on gestation day 17. At the highest dose tested, the predicted
pattern of thyroid hormone changes that could signify a thyroid effect
was observed in the adult females (i.e., ↓T3 and ↓T4 with ↑TSH
levels). These hormone findings are considered treatment-related but
adaptive and not adverse; i.e., the thyroid responded to the insult and
corrected itself. The thyroid findings in the other age groups were not
treatment-related because there was no dose-response in the changes,
and/or the predicted pattern of thyroid hormone changes was not evident.
In this study and in other studies where thyroid effects were observed,
clear NOAELs were identified, and the endpoints selected for risk
assessment are protective of potential thyroid effects. EPA has
quantified risk of 2,4-D to assure exposures are at least 100-fold lower
than levels where renal saturation occurs.  

d. Endocrine Effects

The Agency has comprehensively evaluated the endocrine effects of 2,4-D.
 As noted in the Order denying the NRDC petition seeking revocation of
2,4-D tolerances under the FFDCA (77 FR 23135 (Apr. 18, 2012)),
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 (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 in its review of the data submitted as part of this petition
that the rat two-generation reproduction study protocol described in the
1998 test guidelines 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 Federal Insecticide,
Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP),
and acceptance by member countries of the Organisation for Economic
Cooperation and Development (OECD). The results of this study were
consistent with other toxicity studies in the database showing that
toxic effects occur only at doses above levels of renal saturation.  

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
(EOGRTS) as an alternate EDSP (Endocrine Disruptor Screening Program)
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.

Both the rat two-generation reproduction study and the EOGRTS are
available for 2,4-D and have been evaluated by the Agency and
incorporated into the hazard assessment of 2,4-D. 

The EOGRT study on 2,4-D examined endocrine related parameters, which
included parental (male and female) reproductive function; offspring
survival, growth, and development; endocrine and systemic toxicity
parameters, including estrous cyclicity (adult and offspring); sperm
parameters; anogenital distance; nipple retention; sexual maturation
(vaginal opening and balano-preputial separation); organ weights
(adrenal, thyroid/parathyroid, pituitary, testes and ovaries/other
reproductive organs, liver, kidney); thyroid hormone effects; and
histopathology of the thyroid, adrenal, pituitary, liver, pancreas,
testes, and ovary/other reproductive organs. For all of the parameters
assessed, a clear NOAEL (= 21 mg/kg/day) was identified, which was used
as the point of departure for risk quantification, and as in other
toxicity studies in the database, adverse toxic effects were observed
only at levels that exceed the body’s ability to excrete 2,4-D.

Finally, in response to the 2009 Test Order, EPA determined not to
require the in vivo mammalian Tier 1 tests for 2,4-D (i.e, Uterotrophic,
Hershberger, the Male and Female Pubertal Assays) due to the
availability of the extended one generation reproduction study. EPA has
received all required final study reports and data for the five in vitro
assays from the Tier 1 battery for 2,4-D.  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 that
comprehensively examined the risks to human health from 2,4-D’s
interaction with endocrine system endpoints.  

e. Cancer

Studies in rats and mice showed no statistically significant tumor
response in either species; furthermore, 2,4-D is not mutagenic, a flag
for potential carcinogenicity. The Agency determined, based on several
reviews of epidemiological studies, in addition to the animal studies,
that the existing data did not support a conclusion that links human
cancer to 2,4-D exposure.  This is further discussed in the Agency’s
response to epidemiology comments. In accordance with the Agency’s
1986 “Guidelines for Carcinogen Risk Assessment, 2,4-D was classified
a “Group D Chemical: Not Classifiable as to Human Carcinogenicity.”
This classification was based on the lack of evidence of carcinogenicity
in two well-designed and well-conducted animal studies of adequate power
and dose in two species (mice and rats), and on the lack of
epidemiological data supporting an association between 2,4-D exposure
and cancer.  Although 2,4-D’s classification has not be been evaluated
according to the 2005 classification scheme, based on weight of evidence
consideration of the available data, 2,4-D would be classified as “Not
Likely to be Carcinogenic to Humans.”

f. Reproductive Effects

For 2,4-D, there are two studies that specifically assess reproductive
toxicity. These are the 2-generation reproduction toxicity study and the
extended one-generation reproductive toxicity (EOGRT) study. Evidence of
possible reproductive effects observed in the 2,4-D database at dose
levels that exceeded the rat’s ability to excrete 2,4-D led to the
requirement of further testing included in the EOGRTS.  In the EOGRT
study, the following reproductive parameters were assessed:  parental
male and female reproductive function; offspring growth and development;
estrous cyclicity (adult and offspring); sperm parameters; anogenital
distance; nipple retention; sexual maturation (vaginal opening and
balano-preputial separation); organ weights (testes and ovaries/other
reproductive organs); and histopathology (testes, ovary, and other
reproductive organs). For all of the parameters assessed, a
No-Observed-Adverse-Effect Level (NOAEL) was identified and selected as
the point of departure for risk assessment.  Since there were no adverse
effects observed at this dose, quantifying risks using this dose is
protective for any effects occurring at higher dose levels that exceed
the body’s ability to excrete 2,4-D. 

Commenters expressed specific concerns regarding certain reproductive
effects.  These include estrous cycle changes, increased uterine
weights, and effects on male reproductive organ weights.  Estrous cycle
changes observed were not an adverse effect; differences in the stage of
cycling are normal among females.  An adverse effect would be the lack
of cycling or persistent estrous, which did not occur.  Regarding
increased uterine weights, the pattern of effects must be considered
when determining whether the effects are adverse.  For 2,4-D there was
no consistent pattern of perturbations in the estrogen pathway as
evidenced by the lack of effects in a number of estrogen-dependent
parameters including but not limited to  pregnancy rate, number corpora
lutea, estrous cycling, and sexual maturation.  Given that none of these
were affected, an isolated finding of increase in uterine weights is not
considered adverse.  Finally, regarding male reproductive organ weight
effects, a pattern of effects is again important when considering
whether the effect is adverse.  In this case there was no consistent
pattern of androgenicity observed, fertility was not affected, mating
behavior was normal, sexual maturation was not affected, and sperm
motility, count and morphology were unaffected.  Therefore, the effect
was not considered adverse.

Also, see the response above for endocrine effects for additional
information.

g. Immunotoxicity

The standard suite of immunotoxicity effects were measured in the
EOGRTS.  One measure of the potential for immunotoxicity is thymus
effects, and decreased thymus weight was observed in the EOGRTS. 
However, changes in thymus weight alone are not an indication of
immunotoxicity. The decreases observed in thymus weight in the EOGRT
study showed no dose-response, and there were no histopathological
changes in the thymus. Moreover, no evidence of a functional deficit in
the immune system was observed in the SRBC AFC (Sheep Red Blood Cell
Antibody Forming Cell) response and the Natural Killer Cell Activity
assays at dose levels approaching or exceeding renal saturation.  In the
absence of these additional findings, the decreased thymus weight is not
considered an effect of concern.  

h. Kidney Effects

The kidney is the major target organ of 2,4-D.  2,4-D is readily
absorbed into the blood, removed from the blood by the kidneys
unchanged, and excreted via the urine. At dose levels in the rat greater
than 50 mg/kg/day, the ability of the kidney to excrete 2,4-D is
overwhelmed, and 2,4-D builds up in the body resulting in toxic effects.
For all of the kidney parameters assessed in the studies on 2,4-D, clear
No-Observed-Adverse-Effect Levels (NOAELs) were identified.  Points of
departure selected for quantifying risk assessment are below levels at
which kidney effects were observed and are therefore protective of any
potential kidney effects occurring at higher dose levels that exceed the
body’s ability to excrete 2,4-D.

3. Responses to Other Specific Comments Regarding Toxicity

Comment:  Synergistic effects of 2,4-D and glyphosate and/or formulation
inerts must be considered

Response:  The Agency routinely requires submission of acute toxicity
data for both individual pesticide active ingredients and formulated
pesticide products.  Acute oral, dermal, and inhalation data, skin and
eye irritation data, and skin sensitization data are available for the
2,4-D choline salt and glyphosate formulation for comparison with the
2,4-D parent compound and glyphosate parent compound data, and these
test results show similar profiles. The mixture does not show a greater
toxicity compared to either parent compound alone.  Although no longer
duration toxicity studies are available, toxic effects would not be
expected as the maximum allowed 2,4-D exposure is at least 100-fold
below levels where toxicity to individual chemicals might occur, and
exposure to people is far below even that level.  

Comment:  Toxicity of the 2,4-D metabolite, 2,4-dichlorophenol
(2,4-DCP), must be considered

Response:  There are adequate toxicity data available on 2,4-DCP, which
show that 2,4-DCP is less toxic than 2,4-D (i.e., higher dose levels are
tolerated; NOAELs/LOAELs are higher).  Both the rat National Toxicology
Program (NTP) carcinogenicity and mouse NTP carcinogenicity studies
(1989) on 2,4-DCP are negative for carcinogenicity.  In the 2-generation
reproduction study on 2,4-DCP, the NOAEL for effects on offspring is
2,000 ppm (134 mg/kg/day), based on a slight decrease in the number of
pups, delayed eye opening in both sexes and generations, and slight
(≤1 day) delays in sexual maturation at 543 mg/kg/day. The
reproductive toxicity NOAEL is 2,000 ppm (134 mg/kg/day, based on
decreased number of implantation sites (F1 parental/F2 offspring) at the
LOAEL of 543 mg/kg/day. Developmental toxicity was not observed in the
rat.  

Although 2,4-DCP is shown to be less toxic than 2,4-D, the Agency
assessment assumes 2,4-DCP is as toxic as 2,4-D – thus the risk
assessment over-estimates risk and could be refined by considering the
reduced toxicity of the metabolite.  However, this is not necessary
since the assessment assuming equivalent toxicity showed no risks of
concern.  

Comment:  EPA should use the 2,4-D dose of 100 ppm, not 300 ppm, as the
point of departure for human health risk assessment and apply an
additional 10-fold safety factor to protect children’s health,
pursuant to the Food Quality Protection Act.

Response:  The commenter indicated that toxic effects were observed in
the EOGRTS below 300 ppm, the dose selected by the Agency as the No
Observed Adverse Effect Level (NOAEL).  The effects included increased
uterine weight, decreased reproductive organ weight in males, thyroid
hormone level changes, decreased thymus weight, and kidney effects. 
Each of these was discussed earlier, but are repeated below to provide
in one place a concise response to specific concerns raised regarding
the EOGRTS.

Regarding the reproductive effects, the Agency’s conclusions were
based on the following.  Differences in the stage of estrous cycling are
normal among females; an adverse effect would be the lack of cycling or
persistent estrous, which did not occur in the study.  Increased uterine
weight was not considered adverse since there was no consistent pattern
of estrogenicity, pregnancy rate was not affected, the number corpora
lutea was unaffected, estrous cycling was normal, and sexual maturation
was not affected.  Regarding male reproductive organ weight effects,
there was no consistent pattern of androgenicity observed, fertility was
not affected, mating behavior was normal, and sexual maturation was not
affected.  

Regarding thyroid toxicity, at the highest dose tested, the predicted
pattern of thyroid hormone changes that could signify a thyroid effect
was observed in the adult females (i.e., ↓T3 and ↓T4 with ↑TSH
levels). These hormone findings are considered treatment-related but
adaptive and not adverse; i.e., the thyroid responded to the insult and
corrected itself. The thyroid findings in the other age groups were not
treatment-related because there was no dose-response in the changes,
and/or the predicted pattern of thyroid hormone changes was not evident.

The standard suite of immunotoxicity effects were measured in the
EOGRTS.  One measure of the potential for immunotoxicity is thymus
effects, and decreased thymus weight was observed in the EOGRTS. 
However, changes in thymus weight alone are not an indication of
immunotoxicity. The decreases observed in thymus weight in the EOGRT
study showed no dose-response, and there were no histopathological
changes in the thymus. In the absence of these additional findings, the
decreased thymus weight is not considered an effect of concern.  

For all of the kidney parameters assessed in the studies on 2,4-D, clear
No-Observed-Adverse-Effect Levels (NOAELs) were identified, and the
points of departure selected for risk assessment are protective of any
potential kidney effects occurring at dose levels that exceed the
body’s ability to excrete 2,4-D.

The conclusions drawn by the Agency regarding setting of NOAELs and
LOAELs for the EOGRTS are consistent with accepted standards for
evaluation of toxicology data and determination of whether a toxic
effect should or should not be considered adverse.  

Comments regarding EPA’s decision to reduce the FQPA safety factor to
1X are addressed below.  

Although the Agency believes its decision to establish the NOAEL from
the EOGRTS at 300 ppm and to reduce the FQPA safety factor to 1X is
scientifically sound and consistent with established science policy, in
order to more fully characterize risk potential, risks were also
assessed using the NOAEL = 100 ppm as the risk assessment point of
departure and retaining the FQPA safety factor of 10X.  Using these
inputs, risks were still acceptable for all age groups for all
components of the assessment:  dietary food and drinking water exposure,
volatility, spray drift, residential, and aggregate assessment.  

Comment:  The Agency’s assessment was largely based on forms of 2,4-D
other than the choline salt; the choline salt may exhibit differences in
toxicity and absorption relative to other forms of 2,4-D

Response:  The extensive database on 2,4-D was used in the risk
assessment on the choline salt of 2,4-D. This is consistent with the use
of the 2,4-D database for other 2,4-D salts. There are data that
demonstrate similar toxicities among the various salts of 2,4-D, and
there are data available to show that 2,4-D salts readily dissociate
into 2,4-D acid and the cation. The counter-ion in the Enlist DuoTM
formulation, choline, is an essential nutrient, and not of toxicological
concern.  

Commenters provided no data to substantiate or explain the concern for
differences in absorption. As noted above, choline is an essential
nutrient, and available toxicity data demonstrate a similar toxicology
profile across 2,4-D salts.  A similar toxicity profile suggests that
any differences in absorption are not of concern.  

B. Risk

Comment:  The Food Quality Protection Act (FQPA) “additional tenfold
margin of safety” to protect infants and children should be applied
because the Agency’s toxicity and exposure assessments do not
adequately protect childrens’ health

Response:  As a result of Section 405 of the Food Quality Protection Act
of 1996 (P.L. 104-170), in establishing a “tolerance” under section
408 of the Federal Food, Drug, and Cosmetic Act (FFDCA), section
408(b)(2)(C) of the FFDCA states, in part, that:

“… an additional tenfold margin of safety for the pesticide chemical
residue and other sources of exposure shall be applied for infants and
children to take into account potential pre- and post-natal toxicity and
completeness of the data with respect to exposure and toxicity to
infants and children.  Notwithstanding such requirement for an
additional margin of safety, the Administrator may use a different
margin of safety for the pesticide chemical residue only if, on the
basis of reliable data, such margin will be safe for infants and
children.”  

This is commonly referred to as the “FQPA safety factor” or the
“10X” safety factor.

Section 2(bb) of FIFRA, in turn, defines “unreasonable adverse effects
on the environment” to mean, in part:  “… a human dietary risk
from residues that result from a use of a pesticide in or on any food
inconsistent with the standard under section 408 of the [FFDCA].”  

Whether a margin of safety different from the tenfold margin of safety
under this provision should be applied was assessed in a manner
consistent with all pesticide assessments.  Major considerations include
the completeness of the 2,4-D database with respect to toxicity and
exposure, whether the assessment is protective for any observed
sensitivity in infants and children (including developing fetuses), and
whether the exposure data is protective for exposure to infants and
children (including fetuses).

As discussed in other comment responses, the Agency has a complete and
robust database for 2,4-D for both toxicity and exposure.  Please refer
to other specific comments for details.

Increased sensitivity was observed in fetuses in the rat developmental
study and the rat 2-generation reproduction study.  In order to assure
that the human health assessment adequately protected children and
fetuses for these sensitivities, doses were chosen for regulation which
were below the levels at which these effects were seen, i.e., the
starting points for determining maximum allowable human exposures
(before applying any safety factors) were well below levels at which
these more sensitive toxic effects were observed – this assures
protection of infants and children for these sensitivities.  Additional
safety factors of 10X for extrapolation across species and 10X for
variability within the human population (total = 100X) were then applied
to these doses to assure adequate human health protection.  

The Agency assessed all potential 2,4-D exposure pathways for children
for all uses of the chemical – dietary exposure through food and
drinking water, residential exposures, spray drift, volatilization, and
swimming – using protective assumptions which will not underestimate
childrens’ exposures.  These exposure assessments are discussed in
detail in the exposure section of this response (pp. 12-17).  

Based on these 3 considerations – a complete database for toxicity and
exposure, adequate protection for sensitivity in infants and children,
and an exposure assessment which will not underestimate childrens’
exposures – sufficient reliable information is available showing that
risks to infants and children will not be underestimated, and EPA
determined that the 10X FQPA safety factor could be reduced to 1X,
consistent with the requirements of the Food Quality Protection Act.  

Comment:  EPA failed to thoroughly examine all of the significant health
and environmental risks of 2,4-D including that of inhalation and
aggregate exposure

Response:  EPA thoroughly examined all of the significant environmental
and health risks of 2,4-D including inhalation and aggregate exposure. 
EPA’s inhalation assessment evaluated risks using the most sensitive
toxic effect – effects in the respiratory tract.  Exposure to both
residential pesticide users and professional applicators who would be
applying the new 2,4-D formulation to herbicide resistant corn and
soybeans were well below levels of risk concern.  

Regarding inclusion of inhalation exposure in the aggregate assessment,
aggregating exposures when toxic effects are different for the different
exposure routes (e.g., oral and inhalation) is not scientifically
appropriate.  Furthermore, EPA calculated the systemic dose
corresponding to the inhalation level at which the very sensitive portal
of entry inhalation effects occur.  These Human Equivalent Doses (HEDs)
are well below levels at which effects from oral exposure are regulated;
therefore, regulating based on the portal of entry effects will be
protective for any contribution from inhalation route to the aggregate
exposure.  

EPA’s aggregate exposure assessment included contributions from food,
drinking water, and non-occupational exposure, and was done for both
adults and children.  High-end, unrefined screening level inputs were
used which resulted in exposure estimates well below levels of risk
concern.  Adult aggregate exposure included contributions from food,
drinking water, and incidental oral exposure from swimming in a 2,4-D
treated water body; the aggregate MOE was 1,800.  Children’s aggregate
exposure included contributions from food, drinking water, and
incidental oral exposure hand to mouth from turf; the aggregate MOE was
340.  

Therefore, EPA’s risk assessment considered both inhalation and
aggregate exposures and concluded that there were no risks of concern.  

Comment:  2,4-D is a major source of dioxins presenting risk concerns
for use of the chemical; 2,4-D is a component of Agent Orange and
therefore of significant risk concern

Response:  As a result of changes in the manufacturing processes for
2,4-D over the past 15-20 years, dioxins are no longer found at
detectable levels in 2,4-D products sold and used in the United States. 
The Agency has required testing of all 2,4-D products for dioxins using
very sensitive methods.  Additionally, the Agency conducted an
assessment assuming that dioxins were present at the detection limit in
all 2,4-D products – an implausible situation, but a very protective
assumption.  Human health risks assessed with this assumption were
insignificant.  

Related to the dioxin comments, some commenters questioned 2,4-D’s
hazard potential referring to its presence in Agent Orange, a defoliant
used during the Vietnam War thought to cause a range of health effects. 
Although 2,4-D is known as one of the components of Agent Orange, it is
not the one responsible for the adverse health effects experienced by
those exposed to Agent Orange. Agent Orange was a mixture of two
different herbicides—2,4,5-T and 2,4-D—as well as kerosene and
diesel fuel. Agent Orange contained high levels of dioxin, a contaminant
found in 2,4,5-T that causes cancer and other health concerns in people.
EPA cancelled all use of 2,4,5-T in 1985 because of these risks.

Comment:  EPA must consider cumulative risk to 2,4-D and other
structurally related compounds

Response:  Chemicals from the same chemical class have been identified
and will be further investigated as a possible common mechanism group
during the Agency’s Registration Review process.  However, we note
that the compounds with the closest structural similarity to 2,4-D are
2,4-DB (4-(2,4-dichlorophenoxy)butyric acid) and 2,4-DP
(2-(2,4-dichlorophenoxy)propanoic acid).  The most recent assessments
indicate that the dietary risks for these compounds are insignificant. 
Furthermore, using a highly protective screening-level approach of
combining high-end children’s risks from the two chemicals results in
no risks of concern.  

Comment:  2,4-D is linked to Non-Hodgkin’s Lymphoma (NHL)

Response:  The FIFRA Scientific Advisory Panel, a Federal Advisory
Committee with whom EPA consults regarding novel or contentious
scientific issues, evaluated the cause and effect relationship between
exposure to 2,4-D and non-Hodgkin’s lymphoma in 1994.  They concluded
that “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,” and “[s]ome case-control studies have shown a risk of
non-Hodgkin’s lymphoma (NHL) in association with farming but many of
these studies did not control for other agents in addition to 2,4-D.” 
(US EPA, March, 1994. 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)

In both 1996 and 2004 further reviews were conducted of additional
epidemiological studies by Blondell (D311464, 12/8/04) both with similar
conclusions.  

In 2012, the Agency considered additional information provided by the
Natural Resources Defense Council regarding, among other things,
2,4-D’s linkage to non-Hodgkin’s lymphoma, again resulting in
similar conclusions.  

Most recently, an abstract was presented at the 23rd Conference on
Epidemiology in Occupational Health (EPICOH 2.0.13; Improving the
Impact, 18-21 June, 2013, the Netherlands, Freeman, et. al.) considering
a prospective cohort of licensed pesticide applicators within the
National Agricultural Health Study.  The results of this study showed no
association between 2,4-D and non-Hodgkins lymphoma.

While there has been much focus on epidemiology data suggesting a
linkage between NHL and farm work, there is insufficient scientific
evidence supporting a specific linkage with 2,4-D.  Furthermore, this
linkage is not supported by data on laboratory animals as discussed in
the cancer assessment portion of this response.  

Based on the available epidemiology data and controlled studies, the
Agency therefore concludes that there is not sufficient information to
show a cause and effect linkage between 2,4-D exposure and NHL.  This
conclusion was also reached by Health Canada’s Pesticide Management
Regulatory Agency.   

Comment:  2,4-D is linked to Parkinson’s disease (PD)

Response:  The Agency has reviewed key literature regarding the link
between 2,4-D exposure and Parkinson’s Disease, including the recent
epidemiology report sponsored by the European Food Safety Authority
(EFSA).  Overall, six key studies explicitly evaluated the putative
association of PD with 2,4-D exposure, with four studies documenting
elevated risks (Odds Ratios (OR) >1) and two studies finding no
increased risk.  Of the four studies associating elevated odds for PD
with 2,4-D exposure, only one study had statistically significant
results   ADDIN EN.CITE
<EndNote><Cite><Author>Tanner</Author><Year>2009</Year><IDText>Occupatio
n and risk of parkinsonism: a multicenter case-control
study</IDText><DisplayText>(Tanner et al.,
2009)</DisplayText><record><dates><pub-dates><date>Sep</date></pub-dates
><year>2009</year></dates><keywords></keywords><isbn>0003-9942</isbn><ti
tles><title>Occupation and risk of parkinsonism: a multicenter
case-control study</title><secondary-title>Arch
Neurol</secondary-title><alt-title>Archives of
neurology</alt-title></titles><pages>1106-13</pages><number>9</number><c
ontributors><authors><author>Tanner, C. M.</author><author>Ross, G.
W.</author><author>Jewell, S. A.</author><author>Hauser, R.
A.</author><author>Jankovic, J.</author><author>Factor, S.
A.</author><author>Bressman, S.</author><author>Deligtisch,
A.</author><author>Marras, C.</author><author>Lyons, K.
E.</author><author>Bhudhikanok, G. S.</author><author>Roucoux, D.
F.</author><author>Meng, C.</author><author>Abbott, R.
D.</author><author>Langston, J.
W.</author></authors></contributors><edition>2009/09/16</edition><langua
ge>eng</language><added-date
format="utc">1401224640</added-date><ref-type name="Journal
Article">17</ref-type><auth-address>Department of Clinical Research, The
Parkinson&apos;s Institute, Sunnyvale, California 94085, USA.
CTanner@thepi.org</auth-address><remote-database-provider>NLM</remote-da
tabase-provider><rec-number>6532</rec-number><last-updated-date
format="utc">1401224640</last-updated-date><accession-num>19752299</acce
ssion-num><electronic-resource-num>10.1001/archneurol.2009.195</electron
ic-resource-num><volume>66</volume></record></Cite></EndNote> (Tanner et
al., 2009) .  Although Tanner et al. (2009) did find a significant
association between 2,4-D exposure and PD with OR of 2.59 (95% CI= 1.03,
6.48; p-value= 0.04), they did not find a statistically significant
evaluated risk associated with 2,4-D in 2011 (OR of 1.2 for men and
women, with the CI, 0.57-2.4). Overall, the Agency concludes that the
available evidence is not sufficient to conclude that there is a causal
link between exposure to 2,4-D and PD.   

C. Exposure

Comment:  The dietary risk assessment does not adequately capture all
reasonable exposure risks (assumptions were not adequately articulated;
it was not clearly demonstrated that breast milk was considered in
dietary exposure assessment; high levels of 2,4-D metabolites were not
adequately considered; must incorporate increased use of 2,4-D into the
assessment)

Response:  Field trials were conducted in which 2,4-D tolerant corn and
soybean were treated with 2,4-D choline according to label directions,
and in the manner likely to lead to highest potential food residues. 
These field trials were used to determine the residue levels of 2,4-D
and 2,4-DCP (2,4-dichlorophenol) in tolerant corn and soybean, which
were used in the updated dietary risk assessment and for tolerance
setting purposes.  

For 2,4-D-tolerant field corn and soybean, the metabolite 2,4-DCP was
included as a residue of concern for dietary risk assessment purposes,
as there are greater amounts of 2,4-DCP found in resistant crop compared
to non-resistant crop.  Therefore, the dietary assessment considered the
combined residues of 2,4-D and 2,4-DCP in tolerant corn and soybean
based on use patterns expected to result in the highest food residues
(maximum use rates, maximum number of applications, minimum interval
between applications, minimum interval between last treatment and
harvest).  Furthermore, the Agency assumed tolerance level residues (or
higher) in all crops – the tolerance is a statistically-derived upper
bound on allowable residues in crops which will not be exceeded with
legal use of the pesticide.  

Additionally, the dietary risk assessment assumed that 100% of the U.S.
corn and soybean crops are treated to account for potential increased
use of 2,4-D.  

Livestock can also ingest 2,4-D and its metabolites in their diets as a
result of eating treated feeds such as corn grain.  The Agency’s
assessment of residues in meat, milk, poultry and eggs will not change
as a result of increased usage on any given feed item since the
percentage of crop treated is not factored into these assessments; the
entire feed crop is assumed to be treated, and livestock are assumed to
ingest the corresponding residues.  Therefore, the high-end residues and
dietary risk estimates assumed to potentially result in livestock
commodities will not increase if the usage of 2,4-D expands.  

In assessing 2,4-D exposure from breast milk consumption, the Agency
considered available data on the ruminant metabolism and magnitude of
the residue; a tolerance for residues of 2,4-D in cow’s milk is set at
0.05 ppm.  As stated above, the tolerance is a statistically-derived
upper bound on allowable residues which will not be exceeded with legal
use of the pesticide.  

The Agency also considered the chemical properties of 2,4-D,
specifically the octanol-water partition coefficient (KOW).  This is one
predictor of the potential for a pesticide or any chemical to
bioaccumulate because high values of KOW indicate a tendency for a
chemical to partition into lipids (fat, including milk fat) rather than
water.  Chemicals that partition into lipids can accumulate in the fatty
tissues and milk of an organism, while chemicals that partition into
water will be excreted rapidly.  2,4-D has a low log KOW (log KOW = 0.18
at neutral pH). This low value indicates that the chemical prefers to
partition into water and would not partition into and accumulate in
milk, fat and tissues.  The metabolism study in rats confirms this
showing that 2,4-D is well absorbed orally, undergoes limited
metabolism, and is eliminated quickly from the body primarily unchanged
in the urine by active saturable renal transport.  Based on this
information, EPA does not anticipate that residues in breast milk would
be greater than those found in cow’s milk. Since tolerance level
residues in milk were used in the dietary risk assessment, the human
health risk assessment is expected to be protective for breast milk
consumption.  No data have been submitted, or have been found by the
Agency in the literature, refuting this conclusion.  

Drinking water estimates used in the dietary assessment were derived
from modeling using modeling inputs designed not to underestimate
residues in drinking water.  Modeled residue estimates are far higher
than residues found in monitoring data.  These residue estimates will
not underestimate exposures to anyone in the U.S. population, and will
be far higher than those to which the vast majority of the population
will be exposed.  Drinking water model descriptions are available on the
EPA websites, and the models themselves are available for download. 
Specific inputs for the 2,4-D assessment are described in the Agency
review of this action.  

Finally, as discussed in the response to comments section on toxicity,
the toxicity endpoint used in the dietary assessment for both 2,4-D and
2,4-DCP was for 2,4-D parent toxicity; since 2,4-DCP is less toxic than
2,4-D, comparing 2,4-DCP residues to 2,4-D endpoints is very protective.
 

In summary, using the highly protective assumptions described above, the
acute and chronic dietary risk estimates for 2,4-D were not of concern
for adults, children, pregnant women, or any other population group. 
Since the Agency assumed that all crops/foods with registered uses for
2,4-D would be treated, and that everyone who ate these foods would
consume high-end residues of 2,4-D in all of these foods, any increased
usage of 2,4-D will not result in risk estimates higher than those
already calculated, which are not of concern.  

Comment:  The Agency did not properly account for volatility of 2,4-D
(did not consider available monitoring data; it’s unclear if
reasonable worst-case assumptions were used in the assessment;
surfactants and solvents can alter 2,4-D volatility; temperature and
field conditions can alter 2,4-D volatility; not enough information was
provided on the 2,4-D flux data)

Response: The Agency conducted a volatility assessment using
health-protective assumptions. 

2,4-D specific flux monitoring data were used for the volatility
assessment.   Trials were conducted at different sites (Indiana,
Arkansas, and Georgia) to reflect a range of temperature and field
conditions.  Trials were conducted with applications to bare soil,
soybean (30 cm crop height with 80% canopy closure), soybean (15 cm crop
height with 15% canopy cover), and cotton (50 cm crop height with 40%
canopy cover).  These flux studies used products with differing
formulations: 2,4-D choline-specific flux study was completed using the
experimental formulations (both 2,4-D choline alone and 2,4-D choline
plus glyphosate end use products).  

Results showed that 2,4-D choline salt has lower volatility than 2,4-D
esters and other salts.  The maximum application rate was used for the
assessment.

Volatilization modeling was completed by the Agency using Probabilistic
Exposure and Risk model for fumigants (PERFUM). Approaches EPA has used
previously to assess inhalation exposures to fumigant pesticides were
used for the assessment, consistent with the recommendations of the
December 2009 Federal Insecticide, Fungicide, and Rodenticide Act
Scientific Advisory Panel (SAP)  meeting on the scientific issues
associated with field volatilization of conversional (semi-volatile)
pesticides. The PERFUM modelling results are based on Bradenton, FL;
Yakima, WA; Flint, MI; and Ventura, CA weather datasets which have been
used in the past for other volatilization analyses and represent a range
of conditions including those which have consistently provided the
highest risk estimates.  

The portal-of-entry inhalation toxicity endpoint was used in the
volatilization assessment, the most sensitive inhalation toxicity
observed for 2,4-D.  By using this endpoint, the Agency assumed that
bystanders are exposed every day for 28 consecutive days at the maximum,
day-of-application volatilization exposure near the field – this is a
very health-protective assumption.  Combining this protective assumption
with the exposure assumptions discussed above which reflect the highest
exposure scenario results in a very health protective assessment.  

Estimated risks from volatility will not increase if there is increased
use of 2,4-D; the current assessment assumes that bystanders are exposed
to air concentrations at the edge of a field treated using the use
pattern likely to result in the highest residues possible.  

Based on these assumptions, airborne concentrations of 2,4-D at the edge
of the treated field are not of concern.  Although the Agency believes
its decision to reduce the FQPA safety factor to 1X is scientifically
sound and consistent with established science policy, in order to more
fully characterize risk potential, volatility risks were also assessed
retaining the FQPA 10X safety factor.  It should be noted that even with
application of an additional 10X FQPA safety factor, there are no risks
of concern at the field edge.  

Comment:  Invalid assumptions were used for spray drift (an increased
frequency of applications will cause increase in exposure; OPP should
evaluate the AgDRIFT and AgDISP models according to CREM
recommendations)

Response:  In assessing risks from spray drift, the Agency assumes that
spray drifts onto a lawn adjacent to an agricultural field being
treated, and children immediately play on that lawn.  This approach has
been vetted both through the FIFRA Scientific Advisory Panel and a
public comment process.  If the pesticide being assessed also has a lawn
use, and that lawn use has higher lawn turf residues than those
estimated from spray drift, then risks from spray drift will be less
than risks from lawn use - if the lawn use shows no risk concern, spray
drift will have no risk concern.  This is the case for 2,4-D.  

The use rate for direct application of 2,4-D to residential turf exceeds
the use rate on corn and soybean, thus the residential turf assessment
is protective of any potential drift onto nearby lawns.  The residential
turf uses were assessed using the 2012 Residential Standard Operating
Procedures as well as chemical-specific residue data.  By using a
toxicity value representing 30 days of exposure combined with maximum
day-of-treatment turf residues, people on treated lawns were assumed to
have the maximum day-of-application exposure every day for 30
consecutive days, a very health protective assumption.  There were no
risks of concern.

In addition to the lawn use assessment completed to support the
aggregate risk assessment for this new use, a quantitative spray drift
assessment specific to the new corn and soybean uses was also completed
to address several comments brought up during the public comment period.
 This assessment used the AgDRIFT model to assess spray drift.  AgDRIFT
has undergone extensive validation including evaluation by a FIFRA
Scientific Advisory Panel.   This model quantifies residues deposited on
a residential lawn that is adjacent to the field being treated.  These
residues were used in conjunction with the 2012 Residential SOP for turf
assessment to determine exposure to children via contact of residues
that have deposited on lawns via spray drift.  To address specific
comments submitted, the Agency conducted this assessment using a risk
assessment Point of Departure (PoD) 3-fold lower (more protective) than
used in the Agency assessment, and also applied the 10X FQPA safety
factor. As with the turf assessment, considering the Agency’s use of a
toxicity value representing 30 days of exposure combined with maximum
day-of-treatment spray drift residue, people on lawns exposed to spray
drift were assumed to have the maximum day-of-application exposure every
day for 30 consecutive days, a very health protective assumption.  There
were no risks of concern using even these extremely protective
assumptions.  

The Agency did not use AgDISP in its assessment, so comments related to
use of that model are not pertinent.  AgDRIFT was not used in the
Agency’s initial risk assessment, but was used as described above, to
more fully characterize risks from drift in response to comments
received on the petition.  While AgDRIFT has not gone through the formal
CREM (Council for Regulatory Environmental Modeling) evaluation process,
it has been evaluated by the Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) which uses
essentially the same criteria in its evaluation and found the model to
be scientifically supported and sound.  The AgDRIFT model is based on
well-established physics, and was developed jointly by the EPA, USDA,
and industry, undergoing many quality assurance steps in the process. 
The model is well supported by data from drift studies.  For these
reasons, we believe that the study has gone through sufficient review to
be used in this context.  

Some commenters indicated that residential exposure to 2,4-D would
increase as a result of the proposed use. Since there is no change in
the residential use patterns, the only potential for increased
residential exposure is to bystanders exposed through drift or
volatility, neither of which have risk concerns, as described above.  

Comment:  The Agency’s worker exposure must use maximum application
rate

Response:  The worker exposure assessment was completed using the
maximum application rate.

Comment:  Residential exposure will increase with this new use (2,4-D is
found in carpet dust even though they had not used the pesticide
recently; 2,4-D is blowing in or tracked into homes; farmer and farm
families’ exposures are underestimated)

Response:  EPA believes that the current method of hand-to-mouth
exposure assessment for pesticide residues from applications directly to
turf is protective of exposure to indoor house dust. The current
approach accounts for exposure to residues immediately after a direct
application is made at the maximum application rate, residues which will
be much higher than those found in house dust from track-in. 
Furthermore, residues immediately after a direct turf application were
used and compared to a toxicity endpoint representing 30 days of
exposure.  As discussed earlier, this results in very protective
estimates of risk. 

II. Environment

Another area of concern for many commenters was the risk of adverse
environmental impacts from the increased application of 2,4-D.  As with
comments regarding human health issues, many commenters expressed
similar concerns involving the environment, so the comments are grouped
into major topic areas and addressed below.

A. Spray Drift 

Comment:  Spray drift is a complete exposure pathway for the proposed
new uses of 2,4-D.  2,4-D is known to drift and there have been numerous
spray drift incidents (mainly crop damage) that have been associated
with the use of 2,4-D.  Drift will adversely affect sensitive crops in
neighboring fields as well as endangered/threatened species or other
non-target organisms.  In particular, the later timing of 2,4-D
applications will increase direct risk to non-target plants (indirect
risks to other species that rely on plants) because application events
will occur when more plants are more fully leafed out.  Spray drift
cannot be reasonably restricted to the field to which 2,4-D is being
applied and the proposed buffer of 30 ft is too small.

Response:  The Environment Fate and Effects Division (EFED) did identify
spray drift as a complete exposure pathway for non-target organisms in
the original risk assessment (USEPA 2013a, D400223+).  The assessment
also acknowledged a large number (~460) of plant incidents as well as
incidents to other non-target organisms (reported to the Agency as of
October 31, 2012).  Dicotyledonous terrestrial plants were identified as
the most sensitive non-target organisms and spray drift buffers of >
1000 ft were calculated to be protective.  The 2,4-D choline salt itself
has drift/volatility-reducing characteristics.  Consequently, the
assessment was refined using droplet spectrum data that were specific to
the GF2726 formulation (MRID 48844001).  As a result, spray drift buffer
distances for the most sensitive species (dicotyledonous terrestrial
plants) were reduced to 202 ft.  

In June 2013, EPA issued an addendum to the original risk assessment
(USEPA 2013b, D411614) that revised the terrestrial dicotyledon endpoint
that was used in the risk assessment.  Originally, an endpoint from a
2,4-D ester had been chosen because it was the most sensitive among all
the plant data.  EPA reconsidered that endpoint given that 2,4-D choline
is not an ester, and changed the endpoint to reflect the most sensitive
toxicity value for a 2,4-D salt or amine, consistent with the approach
taken in the Registration Eligibility Decision (RED) (USEPA 2005a). 
Based on the 2,4-D salt/amine endpoint, spray drift buffer distances
ranged from < 25 ft to 30 ft to protect the most sensitive plant
species.  EPA believes this new endpoint is the most appropriate and the
buffers are adequate to protect the most sensitive plant species from
spray drift.

After determining the appropriate buffer, EPA discussed mitigation
measures with Dow AgroSciences, LLC (DAS).  To confine spray drift to
the field, DAS agreed to implement a 30 ft in-field buffer when the wind
is blowing towards a sensitive area that could provide habitat for a
non-target species.  Non-sensitive areas are considered fields with
crops, buildings, or pavement; all other areas constitute potential
habitat for non-target species.  In cases where the wind is blowing
towards a sensitive area, a 30 ft in-field buffer must be implemented. 
The 30 ft buffer strip may be sprayed at a later time when the wind
direction has shifted and is no longer blowing towards the sensitive
area.  EPA determined that by using this approach, any spray drift from
2,4-D choline salt remains on the corn or soybean field that is being
treated.

The proposed use allows for one application pre-plant and up to two
applications post-plant.  The herbicide resistant traits in the
genetically engineered corn and soybean plants allow the timing of the
post-applications to be much later in the season (up to 48-in sized corn
and flowering soybeans) than conventional corn (up to 8-in sized corn)
and soybean (no post-plant applications).  Potential risk concerns to
non-target species were therefore considered in light of the later
timing of applications of 2,4-D choline salt.  For those groups of
organisms identified in the original screening-level risk assessment
(USEPA 2013a) as potentially at risk, the 2014 endangered species
assessment (USEPA 2014, D418022) considered how the later 2,4-D
application timing could affect non-target species.  Using a combination
of species-specific biology, diet, habits, migration, and geographic
proximity, the assessment (USEPA 2014) determined that no species
(terrestrial and aquatic plants, mammals, birds, reptiles, amphibians,
terrestrial invertebrates, aquatic invertebrates, or fish) within the
6-state action area (Illinois, Indiana, Iowa, Ohio, South Dakota,
Wisconsin) exceeded the level of concern for spray drift as established
by the Agency. 

B. Synergy of glyphosate and 2,4-D

Comment:  The Enlist formulation is a combination of two herbicides
(2,4-D choline salt and glyphosate) as well as adjuvants and inerts. 
The Agency did not address the potential synergistic effects between
2,4-D choline salt and glyphosate nor potential reactions with the other
chemical components of the formulation.

Response:  Although the Agency does not routinely include a separate
evaluation of mixtures of active ingredients, EPA believes it adequately
addressed the issue of synergism between 2,4-D and glyphosate by
evaluating data on the chemicals individually as well as with
formulation-specific information.  

In the case of a formulation with multiple active ingredients, each
active ingredient is subject to an individual risk assessment for a
regulatory decision regarding the active ingredient on a particular use
site.  If effects data are available for a formulated product containing
more than one active ingredient, they may be used qualitatively or
quantitatively in accordance with the Agency’s Overview Document and
the Services’ Evaluation Memorandum (USEPA 2004; USFWS/NMFS/NOAA
2004). 

Synergistic reactions among chemicals are possible, but considered rare.
 For 2,4-D and glyphosate specifically, the Agency compared the Enlist
DuoTM formulation-specific acute oral rat study (OPPTS 870.1100; MRID
48289803) LD50 of 623 mg ae/kg-bw (confidence interval of 389 to 4980)
with the 2,4-D-only LD50 used in the assessment (441 mg ae/kg-bw) (MRID
41413501).  The endpoints are similar and do not indicate a synergistic
effect of 2,4-D and glyphosate for mammals.

Furthermore, EPA considered an open literature peer-reviewed published
study by Abdelghani et al. (1997) that specifically looked at the
toxicity of glyphosate/2,4-D mixture on channel catfish, bluegill
sunfish, and crawfish.  The experiment first tested the toxicity of
2,4-D and glyphosate individually.  Then the two chemicals were mixed
together in a 1:4 ratio (glyphosate:2,4-D); it is recognized that the
ratio of glyphosate to 2,4-D choline salt in the Enlist DuoTM
formulation (1:1) is higher.  After accounting for the inherent
differences in toxicity between the individual chemicals, the study
concluded that no synergistic effects were observed.  EPA agrees with
the findings in this study that there is no synergistic interaction of
2,4-D and glyphosate for freshwater fish or freshwater invertebrates. 

Given that there is no indication of synergism between 2,4-D and
glyphosate for mammals, freshwater fish, and freshwater invertebrates,
EPA believes it is reasonable to assume that there are no synergistic
interactions for the taxonomic groups that were not tested, including
plants.

C. Volatility

Comment:  2,4-D has been known to volatize under certain environmental
conditions and cause damage to off-site plants.  EPA’s volatility
assessment relied on questionable laboratory plant data.  Furthermore,
the volatility study used to derive a vapor flux rate specific to 2,4-D
choline salt was not fully reviewed.  Overall, there are uncertainties
regarding EPA’s conclusions that the volatilization exposure pathway
does not present risk concerns for Enlist Duo.

Response:  EFED’s risk assessment considered potential effects from
the volatilization of 2,4-D choline salt (USEPA 2013a) using several
lines of evidence.  First, data from a laboratory plant vapor study
(MRID 48911801) indicated that grape was more sensitive to 2,4-D vapor
than cotton, tomato, or soybean (this study was only available for
qualitative use because of the methodology used to conduct the
experiment).  Second, data from several field studies related plant
damage in grape, cotton, and soybean to growth or yield endpoints
(Andersen et al., 2004; Everitt and Keeling, 2009; Kelley et al., 2005;
Marple et al., 2008; Ogg et al., 1991; Robinson et al., unpublished). 
Again, grape was the most sensitive with 20% damage resulting in
decreases in growth and yield (cotton ranged from 58 to 66% damage and
soybean from 35 to 52% damage before decreases in yield occurred). 
Third, a field study (MRID 48862902) placed potted grapes and cotton on
and off of a field (5 m and 15 m) that had recently been treated with
2,4-D choline salt.  At the end of the 3-day exposure period and 27 day
observation period, only plants placed directly on the field showed
outward signs of damage (cotton – 40%; grape – 0.6%).  From these
three lines of evidence, a conservative plant toxicity threshold of 20%
physical damage was chosen for the volatility analysis. 

2,4-D choline vapor flux data from a field volatility study (MRID
48862902) was used to address exposure from volatilized 2,4-D to plants
that were off the field.  At the time of the ecological risk assessment,
the study was under review, but preliminarily considered to be
scientifically sound and appropriate for use in the risk assessment. 
The review of the field volatility study was completed on November 18,
2013 (USEPA, 2013c) and found acceptable for quantitative use in risk
assessments.  The highest 2,4-D choline flux rate from the study was
used as the input parameter for two models:  AERSCREEN and PERFUM. 
AERSCREEN predicts 2,4-D exposure from wet and dry deposition off of the
field.  The model indicated negligible amounts of 2,4-D would be
deposited through this pathway, and thus there were no risk concerns for
plants.  The PERFUM model predicts the air concentration of 2,4-D that
is expected at the edge of the field and various distances beyond.  The
results showed that the air concentrations of 2,4-D were below the 20%
plant damage threshold at the edge of the field, thus indicating no risk
concerns to plants from vapor exposures.  

D. Data Gaps

Comment:  EPA’s ecological risk assessment contained a number of
ecological and fate data gaps that are usually required to be filled for
outdoor pesticide use patterns.   

Response:  The ecological risk assessment (USEPA 2013a) acknowledged a
number of ecotoxicological and environmental fate data gaps and
explained the assumptions that were made in absence of the data:

Acute oral toxicity test for passerines:  This is a generic data gap and
the study has been requested as part of the Registration Review data
call-in.  In the absence of passerine-specific data, EPA routinely
relies on data from bobwhite quail or mallard duck as surrogate species.
 Data for both species were available for 2,4-D and scaled to adjust for
the smaller passerine bird body size.

Estuarine/marine invertebrate chronic toxicity test:  This is a generic
data gap, but the Agency has not requested the data because 2,4-D is not
expected to remain in the aquatic environment long enough to result in
chronic exposures.  For screening-level risk assessment purposes, an
acute-to-chronic ratio (commonly used to estimate missing toxicity
information when toxicity information is available for similar
organisms), based on freshwater invertebrates, was used to estimate the
missing chronic toxicity value.  Given that chronic exposures are
unlikely, the Agency considers this a protective approach.

Terrestrial plant seedling emergence and vegetative vigor tests for
Enlist DuoTM:  This is a data gap that is specific to Enlist DuoTM. 
Terrestrial plant data for commonly-used formulations are usually
required by EPA.  In the absence of formulations-specific information,
EPA uses the most sensitive data from other formulations.  This is a
routine practice with 2,4-D and many other pesticides because data are
not available for all registered formulations of 2,4-D.  In this case,
data from 2,4-D salts/amines were used as surrogates for Enlist DuoTM. 
The surrogate approach assumes that although data are not available for
every formulation, that the available data capture a range of
toxicological responses.  For 2,4-D, the Agency has a robust set of
plant studies; consequently, we can be reasonably confident that by
choosing the most sensitive toxicity values from 2,4-D amine/salt
studies, that we are being protective.  Consequently, these data are not
necessary. 

Terrestrial field dissipation study with 2,4-D choline salt:  This is a
generic data gap for 2,4-D choline salt.  The bridging strategy
developed for other salt and amine forms of 2,4-D was assumed applicable
to 2,4-D choline salt because the salt form is similar to other 2,4-D
forms.

Comment:  In addition, data from volatility/spray drift and the Enlist
Duo formulation (2,4-D choline salt and glyphosate) were not considered
in the risk assessment.  

Response:  Risk assessments are usually conducted on a single active
ingredient basis.  Consequently, mixture data for products with multiple
active ingredients (i.e., 2,4-D choline salt and glyphosate) are not
usually required.  Furthermore 2,4-D choline salt/glyphosate data for
the acute oral rat study (MRID 48289803) did not show an increased
toxicological response compared with the most sensitive 2,4-D endpoint
that was used in the risk assessment (MRID 41413501) (see Synergism
comment and response for more discussion).  

EFED’s assessment incorporated data from several studies into the
assessment to account for spray drift and volatility.  2,4-D choline
salt-specific deposition  curve was developed for the AIXR 11004 nozzle
to determine a spray drift buffer distance. 2,4-D choline salt vapor
flux data were used in conjunction with terrestrial plant ecotoxicity
data to set conservative levels of concern for adverse effects and to
model whether off-field plant damage was expected to occur.  

Comment:  Effects from low dose exposures may not be captured in the
standard suite of ecotoxicity studies listed in Part 158 of the Code of
Federal Regulations.

Response:  While studies specifically measuring low-dose effects of a
chemical are usually not required by the Agency, the normal suite of
toxicity studies captures this same information in the form of
sub-lethal effects seen at dosing levels below the LD50/EC25 thresholds.
 Sub-lethal effects are incorporated into the risk characterization
section for every taxonomic group.

E. Honeybees

Comment:  Enlist Duo will contribute to the decline of honeybees and
other pollinators.  In particular, pesticides are a contributor to
colony collapse disorder in honeybees.  EPA did not follow its own
Pollinator Risk Assessment Framework when conducting the risk assessment
on Enlist Duo.

Response:  EPA recognizes the importance of pollinators and that colony
collapse disorder is a complex phenomenon to which pesticide exposure
may contribute.  The Agency strives to incorporate the most up-to-date
pollinator data and risk assessment practices into its analyses.  The
Pollinator Risk Assessment Framework was adopted in June of 2014, well
after the 2,4-D choline salt risk assessment was developed [the honeybee
analysis risk assessment (USEPA 2013a) applied the methodology in the
RED (2005)].

Honeybee Assessment Using Pollinator Risk Assessment Framework

Honeybee data for acute contact exposures (LD50 > 88 µg ae/bee) and
acute oral exposure (LD50 > 62.6 µg ae/bee) indicated that 2,4-D
choline salt is “practically non-toxic” to honeybees on an acute
contact basis.  No laboratory data are available for chronic effects to
adults or acute or chronic effects to larvae, which are considered
generic data gaps for 2,4-D under the Framework (USEPA 2013a).

The environmental exposure concentration (foliar spray) for honeybee via
contact exposure is 2.7 µg ae/bee.  When compared with the LD50 of > 88
µg ae/bee for 2,4-D choline salt or the most sensitive 2,4-D value
(from an ester form) of LD50 > 66 µg ae/bee, the estimated exposure
concentration is lower than the LD50 threshold.  

For the dietary pathway, the estimated exposure concentration for adult
honeybees is 32.12 µg ae/bee/day.  When compared with the LD50 of >
62.6 µg ae/bee, the estimated exposure concentration is about half of
the LD50, if taken at face value.  The LD50 could be much larger, but
this is an uncertainty given the “greater than” value derived from
the honeybee acute oral toxicity study.  

Considering the results of the acute contact and oral analyses conducted
in accordance with the Pollinator Risk Assessment Framework, acute risk
concerns to adult honeybees are not expected.  

F. Dioxins and Other Chemical Impurities

Comment:  Dioxins are known to be formed during the manufacturing
process of 2,4-D.  The increased use of 2,4-D associated with
herbicide-tolerant corn and soybean will lead to an increase in dioxins,
as well as other impurities formed during the manufacturing process, in
the environment.

Response:  The 2,4-D choline salt risk assessment (USEPA 2013a)
evaluated the risk from polychloro dibenzo-p-dioxin (PCDD) and
polychloro dibenzo-p-furans (PCDF) that may be formed during the
manufacture of 2,4-D.  The Agency reviewed product chemistry data for
2,4-D choline salt (USEPA 2012, D405897; Confidential memo) and found
that PCDD and PCDF concentrations were lower than those identified in an
earlier assessment with 2,4-D and 2,4-D ethylhexyl.  The earlier
assessment concluded that there were no risk concerns from these
concentrations of PCDD and PCDF; thus those same conclusions hold for
2,4-D choline salt given that dioxin concentrations were even lower
(USEPA 2005b, D317729).  

G. Glyphosate Specific Comments

Comment:  The population of monarch butterflies is declining.  Monarchs
rely on milkweed for egg-laying and larval development.  The widespread
use of glyphosate has drastically decreased the milkweed populations as
they are often found within or along the edges of agricultural fields. 
Enlist, which contains glyphosate as well as 2,4-D choline salt, is
anticipated to further the decline of milkweed, and indirectly, the
monarch butterfly.  EPA’s risk assessment for 2,4-D choline salt nor
existing risk assessments for glyphosate did not take into account the
adverse effects of Enlist on the monarch.

Response:  Glyphosate is currently undergoing Registration Review, and a
draft risk assessment is scheduled for completion by December 2014.  In
this assessment, EPA is considering glyphosate’s direct and indirect
effects on monarch butterflies (including its obligate plant, milkweed)
and other non-target species.  

Comment:  No endangered species risk assessment has been performed for
glyphosate.  EPA has not examined the direct or indirect effects of the
glyphosate component of Enlist for the proposed uses on
herbicide-tolerant corn and soybean.

Response: EPA did not conduct an endangered species risk assessment for
the glyphosate component of the Enlist DuoTM formulation because the
uses on this new formulation were not new to glyphosate.  Instead, an
endangered species risk assessment will be included in the final
registration review decision consistent with the National Academy of
Sciences (NAS) recommendations. See the response to the Endangered
Species comments below. Given that the agencies are continuing to
develop and work toward implementation of the NAS recommendations to
assess the potential risks of pesticides to listed species and their
designated critical habitat, the draft ecological risk assessment
supporting the proposed interim registration review decision for
glyphosate will not contain a complete ESA analysis. Once the agencies
have fully developed and implemented the scientific methods necessary to
complete risk assessments for endangered and threatened (listed) species
and their designated critical habitats, these methods will be applied to
subsequent analyses for glyphosate as part of completing the final
registration review decision.  

H. General Ecotoxicity Concerns

Comment:  EPA’s risk assessment states that 2,4-D is toxic to fish,
aquatic invertebrates, birds, and mammals.  Ecotoxicity data for plants
also showed them to be sensitive to 2,4-D.  In addition to mortality,
many of the ecotoxicological studies documented other signs of
toxicity/poisoning.

Response:  EPA requires a suite of toxicological data on mammals, birds,
honeybees, freshwater fish and invertebrates, estuarine/marine fish and
invertebrates, aquatic plants, and terrestrial plants.  The purpose of
the data is to determine the toxicity of the pesticide when direct
exposures occur.  This is known as “hazard” and is one of two
components that make up “risk.”

The second consideration is “exposure.”  Exposure constitutes how
much of the pesticide will come into contact with an organism. 
“Risk” is a combination of the hazard of the pesticide and the
anticipated exposure of the pesticide.  For example, a pesticide that is
highly toxic to mammals, but is incorporated in the ground may present
low risk to mammals because most mammals would not be exposed to it.

The risk assessment for 2,4-D choline salt incorporates both the hazard
and exposure components into its conclusions; thus although it may be
toxic to some groups of organisms, the risk varies proportionately with
exposure.  In particular, the mitigation requirements (in-field buffer,
wind direction, rainfastness) and drift reducing properties of the 2,4-D
choline salt/glyphosate formulation made it possible to limit the
exposure from spray drift to sprayed corn and soybean fields.  After
toxicity information and Enlist DuoTM exposure were considered (USEPA
2014), EPA determined that there are no risk concerns from spray drift
for any threatened or endangered species in the 6 states (IN, IL, IA,
OH, SD, WI) that were assessed for this registration.  From this
information (USEPA 2014), EPA made a “no effect” determination under
the Endangered Species Act for threatened and endangered species within
these states.  Additional assessments will be performed if new states
are added to the registration.

See also Comment K. below. 

I. Registration Review

Comment:  2,4-D and glyphosate are currently undergoing Registration
Review.  EPA should delay its decision until the comprehensive
Registration Review risk assessments, including endangered species, have
been completed for both chemicals.

Response:  The Federal Insecticide, Fungicide, and Rodenticide Act
(FIFRA), as amended by the Food Quality Protection Act (FQPA) of 1996,
mandates the continuous review of existing pesticides.  The Registration
Review program is intended to make sure that, as the ability to assess
and reduce risk evolves and as policies and practices change, all
registered pesticides continue to meet the statutory standard of no
unreasonable adverse effects.  The Agency periodically reevaluates
pesticides to make sure that products in the marketplace can continue to
be used safely.  During this process, label revisions, mitigation
measures, and other registration changes are equitably applied to all
registrations and registrants.  

As noted in an earlier comment (above), EPA is currently reviewing
glyphosate within the framework of the Registration Review risk
assessment process. This analysis will consider the available data to
assess exposures that may cause direct and/or indirect effects to taxa,
including non-target organisms such as the monarch butterfly.  EPA
intends to issue a draft risk assessment by the end of December 2014.
Once the agencies have fully developed and implemented the scientific
methods necessary to complete risk assessments for endangered and
threatened (listed) species and their designated critical habitats,
these methods will be applied to subsequent analyses for glyphosate as
part of completing this registration review.  

2,4-D began the Registration Review process in 2012 and is currently
receiving and reviewing data submitted by registrants as a result of the
data call-in.  Given that Registration Review is a lengthy process that
may take many years to complete, the Agency’s policy is to continue to
make registration determinations for new actions during this process. 
Proposed new registrations are held to the most current data
requirements and up-to-date risk assessment practices and must meet the
FIFRA no unreasonable adverse effects standard to be registered.  

J. Water Quality

Comment:  2,4-D is likely to leach to aquatic environments because of
its low soil-adsorption coefficient.  Increased use of 2,4-D will lead
to elevated surface water pollution, which will affect the quality of
water near agriculture as well as non-target organisms.

Response:  The ecological risk assessment considered 2,4-D exposure to
aquatic non-target organisms.  The Pesticide Root Zone Model and
Exposure Analysis Modeling System (PRZM/EXAMS) was used to estimate
conservative environmental exposure concentrations (EECs) based on the
environmental fate properties, proposed crops, and application methods
and rates of 2,4-D choline salt.  These EECs are then compared with
ecotoxicity information for fish, aquatic invertebrates, aquatic plants,
and terrestrial plants to identify potential risk concerns.

The 2,4-D choline salt assessment also considered real-world monitoring
data.  Formulated 2,4-D rapidly dissociates into its acid form, so the
available monitoring data are not specific to any formulated products. 
However, 2,4-D acid concentrations in surface water from 2,4-D choline
is expected to be lower than other formulated products because of its
application restrictions (i.e., ground applications only; nozzle and
pressure restrictions). 

Monitoring data from the United States Geological Survey’s (USGS)
National Water Quality Assessment Program (NAWQA), indicate that 2,4-D
is present in groundwater (concentrations up to 1.4 µg ae/L) and
surface water (concentrations up to 8.7 µg ae/L).  These concentrations
are much lower than the 58 µg ae/L that was predicted as the exposure
value using PRZM/EXAMS and subsequently used in the risk assessment. 
The monitoring data showed that 2,4-D is being detected at
concentrations that are below the values that are being predicted by
EPA’s computer simulation models.  Consequently, EPA is being
protective by using the modeled number (58 µg ae/L) versus the
monitoring number (8.7 µg ae/L).  The Agency recognizes that the NAWQA
monitoring data may not capture the highest 2,4-D concentrations in the
environment, but they would need to be an order of magnitude higher to
approach the modeled concentration.  Using the 58 µg ae/L from
PRZM/EXAMS, no direct risk concerns were identified for aquatic taxa
(USEPA 2013a).

K. Risk Determinations and Endangered Species Assessment 

Comment:  EPA’s risk conclusions for listed and non-listed species are
flawed.  

Response:  The Agency will address each item under this comment
specifically.  The Agency has concluded that it conducted the risk
assessment consistent with its policies and guidance in place at the
time of the submission of the proposal for registration.  

Comment:  The assessment did not consider 2,4-D choline salt degradates,
of which 2,4-DCP may be more toxic to some organisms.

Response:  The initial ecological risk assessment considered 2,4-DCP, a
major degradate of 2,4-D choline salt, in its analysis.  Peer reviewed
literature and data presented on the European Footprint Database
indicate that 2,4-DCP may be more toxic to freshwater fish and
invertebrates than 2,4-D.  Table 30 in the assessment compares the
2,4-DCP toxicity endpoints with the predicted environmental
concentrations of 2,4-DCP, based on PRZM/EXAMS (USEPA 2013a).  The
toxicity values are several orders of magnitude higher than the
estimated environmental concentrations.  Consequently, risks to aquatic
organisms are not a concern from 2,4-DCP.

Comment:  Effects to migratory birds were not assessed, as required,
under the Migratory Bird Treaty Act. 

Response:  Migratory birds are assessed as part of EFED’s standard
screening-level risk assessment process.  Migratory birds are included
in the risk conclusions for non-listed birds (for those species that
have not been designated as threatened or endangered under the
Endangered Species Act), and listed birds (for those species that are
threatened or endangered).  Acute exposure risk concerns were identified
for both listed and non-listed birds in the screening level assessment. 
The refined endangered species spray drift risk assessment (USEPA 2014)
for the six states (IN, IL, IA, OH, SD, WI) made a “no effect”
determination for threatened and endangered birds.  A memorandum of
understanding (MOU) on the Migratory Bird Treaty Act between EPA and the
Department of Interior’s Fish and Wildlife Service is in development;
the public comment period ended March 7, 2014 ( HYPERLINK
"http://www.regulations.gov/" \l "!docketDetail;D=EPA-HQ-OPP-2013-0744"
EPA-HQ-OPP-2013-0744  at  HYPERLINK "http://www.regulations.gov/"
www.regulations.gov ).  The 2,4-D choline salt risk assessment is in
accord with the process outlined in the MOU. 

Comment:  Direct and indirect effect determinations were not made for
all species.

Response:  EPA’s ecological risk assessment considered both direct and
indirect effects to non-target organisms.  Indirect effects occur when a
species that is not directly affected by the pesticide use rely upon a
species that is directly affected.  For example, monarch butterfly
larvae rely on milkweed for food.  If an herbicide kills the milkweed
(direct effect on the milkweed), the monarch butterfly may be indirectly
affected because its food source has been affected.  In the case of the
2,4-D choline salt assessment (USEPA 2014), no indirect effects to
endangered or threatened (listed) species were identified based on
mitigation measures to limit spray drift exposure to only corn and
soybean fields based on species biology and species proximity.  Indirect
effects to non-listed species would be limited to those species that
rely on other non-listed species for food, habitat, or other resources. 
By requiring pesticide application restrictions that limit off-site
exposure to levels below effects thresholds of the most sensitive
taxonomic group, the action area (the geographic extent to where effects
can reasonably be expected to occur), is limited to the directly treated
footprint of the soy or corn field.  Consequently, no direct or indirect
effects are expected for threatened and endangered species (USEPA 2014)
(Addendum to 2,4-D Choline Salt Section 3 Risk Assessment: Refined
Terrestrial Plant Exposure Estimates and Effects Determination). 

Comment:  EPA did not adequately address risk concerns from runoff. 

Response:  EPA acknowledges that these public comments on the risk
assessment and effects determination pointed out that the Agency did not
explicitly include a consideration of the risk findings for non-target
plants as a result of off-field runoff.  The Agency considered the spray
drift exposure to be the principal risk issue associated with the
proposed labeled use of 2,4-D choline, owing to a variety of lines of
evidence, including past experience with other 2,4-D formulations and
associated spray drift incident reporting.  However, in light of these
public comments, the Agency reconsidered the runoff risks and the
effects of the proposed mitigation to limit off-site runoff in listed
species effects determinations. 

For this registration action, spray drift and runoff were considered as
exposure pathways for 2,4-D choline to terrestrial plants and aquatic
organisms.  For aquatic organisms, the consideration of both spray
drift and runoff loadings to surface waters did not trigger concerns. 
Risk concerns from spray drift to terrestrial plants were mitigated with
an in-field 30-foot buffer that takes into account wind direction during
application, and this mitigation yielded no spray drift concerns off
field, when incorporated into spray drift modeling. 

 

The in-field spray drift buffer does not mitigate concerns from runoff
because 2,4-D choline can be applied up to the edge of the field when
the wind is not blowing in that direction; there is no “buffer
strip” between the edge of the field and sensitive habitat.  The
Agency does not currently have a tool to evaluate the effectiveness of
buffers in reducing pesticide exposure via runoff.  The Agency has
implemented vegetative buffer or filter strips in a few instances to
lessen herbicide loading in runoff waters, however in this case there
are no risk concerns for aquatic organisms.  To assess exposure to
terrestrial plants the Agency looked at several lines of evidence to
determine potential effects as described below.

 

2,4-D is absorbed by both shoots and roots and is active at the growing
points of the shoot and root.  Translocation to the site of action is
primarily via the symplastic pathway (with photosynthates in the phloem)
and accumulates principally at the growing point of the shoot and
root.  2,4-D is not translocated as well in the apoplast (carried with
the water and nutrients in the xylem), which would occur with root
uptake.  Therefore, growth inhibition tends to be more pronounced with
foliar uptake than with root uptake (Shaner 2002).  Consequently, 2,4-D
in runoff waters would not be readily available for mature plant
uptake.  The Agency is including a statement on the label based on the
rainfast period for 2,4-D that prohibits the application of Enlist Duo
if rain or irrigation is expected within 24 hours.  A rainfast period
is the time required for the herbicide to be absorbed into the plant
after application and before a rain/irrigation event so as to provide
reasonable weed control.  The provision of a labeled rainfast period
would increase the time available for on-field herbicide adsorption,
thereby reducing the amount available for runoff.  This, in combination
with 2,4-D’s limited uptake by roots of terrestrial plants, is
anticipated to reduce the amount of 2,4-D choline salt that could
adversely affect plants via runoff.

 

Further, EPA has evaluated the assumptions regarding runoff of 2,4-D
from treated fields to adjacent terrestrial habitat.  The model
TerrPlant assumes, for a chemical with the solubility of 2,4-D in the
most mobile acid form, that runoff would amount to 5% of the field
applied mass of the herbicide.  This modeling approach does not account
for pesticide degradation and for pesticide partitioning.  These
processes that account for loss are important in the mechanistic
pesticide runoff models used by EPA (Pesticide Root Zone Model
(PRZM)) and in the field.  The Agency has compared the TerrPlant
assumption of 5% runoff to the runoff predictions for PRZM runs used to
characterize pesticide runoff for aquatic exposure.  This comparison
revealed that runoff predicted by TerrPlant for 2,4-D is grossly
overestimated.  The total annual runoff is less than a fifth of the
amount predicted by TerrPlant for a single runoff event. 

 

In light of these additional lines of evidence, combined with proposed
mitigations such as a mandatory rainfast period, the Agency has
determined that risks to terrestrial plants from runoff as predicted by
TerrPlant modeling are grossly overestimated in the case of 2,4-D
choline and a finding of no effects to listed or non-listed species off
the treated field is appropriate.

 

 Comment:  The risk assessment analyses did not follow the National
Academy of Sciences (NAS) recommendations.  The assessment dismissed
risks, even when risk quotients were above the level of concern and
failed to come to a “may affect” conclusion, when any risk concerns
were identified.  

Response:   EPA acknowledges that it did not follow the NAS
recommendations when evaluating whether the 2,4-D choline salt
formulation would affect listed species.  However, EPA’s determination
of “no effect” (USEPA 2014) (Addendum to 2,4-D Choline Salt Section
3 Risk Assessment: Refined Terrestrial Plant Exposure Estimates and
Effects Determination)was based on a scientifically valid methodology
consisting of an ecological risk assessment conducted in accordance with
Agency guidance at the time of drafting the risk assessment and
consistent with the methods described in the “Overview of the
Ecological Risk Assessment Process in the Office of Pesticide Programs,
U.S. Environmental Protection Agency:  Endangered and Threatened Species
Effects Determinations,” Office of Pesticide Programs 2004 Overview
Document.  This assessment included a problem formulation describing the
nature of the Federal action, an assessment of potential pesticide
exposure, an assessment of the toxicological hazards associated with the
pesticide, and a risk characterization that integrated all available
lines of evidence to support the effects characterization for each
taxonomic group and species.  Moreover, in situations where there was a
potential taxonomic concern, the Agency used available U.S. Fish and
Wildlife Service information (i.e., Species Recovery Plans, Species
5-Year Reviews) to conduct focused assessments for individual species.  

The National Academy of Sciences’ (NAS) report was issued in 2013,
after the screening level ecological assessment for 2,4-D choline salt
was finalized.  EPA and the U.S. Fish and Wildlife Service and the
National Marine Fisheries Service have adopted a “day forward”
approach for endangered species risk assessments that will begin once
consensus is reached on the risk assessment methodology and process. 
Thus, the analyses used in the 2,4-D choline salt assessments  (USEPA
2014) (Addendum to 2,4-D Choline Salt Section 3 Risk Assessment: Refined
Terrestrial Plant Exposure Estimates and Effects Determination), use a
combination of “old” methods alongside some tools that are being
considered for the revised endangered species risk assessment approach. 

The assessment process employed in the effects determination is composed
of three parts:  (1) the original screening-level assessment conducted
under the provisions of the Overview Document , (2) a plant
endpoint/spray drift addendum that further characterized plant endpoints
taking into account all available toxicological information, and (3) an
endangered species risk assessment addendum that used the results of the
screening risk assessment, drift effects addendum and information on the
biology (e.g. food requirements and habitat needs) for each species
within the proposed action area to determine if pesticide exposure would
have a direct or indirect effect on each species.  

The screening level assessment (USEPA 2013a) considered risks to all
non-target taxonomic groups of organisms in a manner consistent with the
pre-NAS risk assessment process used to support effects determinations. 
That process uses available environmental fate and effects information
to make preliminary determinations of whether conservative estimates of
pesticide exposure would raise concerns for one or more taxonomic
groups.  The screening assessment results suggested that, should actual
exposures occur, direct effects may be possible only for mammals, birds,
reptiles, land-phase amphibians and terrestrial plants (risk quotients
were above the level of concern).  However, additional information
related to specific species within these taxonomic groups was needed to
ascertain if species biology, geography and timing would lead to a
determination that exposures would reasonably occur for these organisms.
 Additional information included:  species specific biology, geographic
location, and the ability of spray drift mitigation measures to reduce
the geographic extent of exposures of concern to a limit of the
boundaries of the treatment site.  When these types of information were
considered, the endangered species assessment addendum (USEPA 2014)
(Addendum to 2,4-D Choline Salt Section 3 Risk Assessment: Refined
Terrestrial Plant Exposure Estimates and Effects Determination)
concluded that there were no direct risk concerns for mammals, birds,
reptiles, land-phase amphibians, and terrestrial plants.

Comment:  Disagreement with the process used to reach a “no effects”
determination for threatened and endangered species.

Response:  In conducting the effects determinations, the Agency used the
most sensitive taxonomic group effects thresholds to establish the
extent to which effects were possible (USEPA 2014).  This approach is
consistent with both the Overview Document approach and the NAS approach
for defining the action areas of the proposed Federal action, when spray
drift mitigation measures were taken.  Mitigation steps were
incorporated into modifications of the proposed Federal action and were
incorporated into the risk screening risk assessment that was used as a
quantitative input to the effects determinations.  Environmental
exposures, through the action of proposed mitigation (USEPA 2014), were
concluded to be below effects thresholds – the no effect threshold for
the most sensitive taxa for areas off the field.  This effectively
limited this action area of the Federal action to within the bounds of
the specific target crop application sites for the pesticide product. 
Using the process outlined in the Overview Document for the remaining
species within the action area, the Agency conducted additional exposure
and effects assessment and biological evaluation (USEPA 2014), specific
to those species, to determine if effects would occur for those species
and to assess whether habitat utilization of the cropped areas was such
that herbicide application would result a species relevant effects. See
also the comment response on runoff.

Comment:  The number of uncertainties in the risk assessment reduces the
confidence in its conclusions.

Response:  The agency believes that despite uncertainties, the
conservative nature of the exposure and hazard evaluations as well as
the careful consideration of species biology and habitat uses are
sufficient to reason that the assessment is reasonable.

III. Other Concerns

A. Labeling

Comment:  The label language regarding the required spray drift buffer
was unclear.  More specifically, label language concerning the buffer in
relation to wind direction needed clarification.

Response: EPA has worked with the registrant to clarify the intent of
this restriction, and to eliminate any confusion that may arise from the
buffer label language.  The intent of the label is to require a 30 foot
in-field buffer at the downwind edge of the field.  For example, if the
wind is blowing in a southern direction, the buffer would be the 30 foot
section of the corn or soybean field to be treated at the southern edge
of the field.  Therefore the label contains the modified language to
read as follows: 

You must maintain a 30 foot downwind buffer (in the direction in which
the wind is blowing) from any area except:

Roads, paved or gravel surfaces. 

Planted agricultural fields. (Except those crops listed in the
“Susceptible Plants” section)

Agricultural fields that that have been prepared for planting.

Areas covered by the footprint of a building, shade house, green house,
silo, feed crib, or other man made structure with walls and or roof.

To maintain the required downwind buffer zone:

Measure wind direction prior to the start of any swath that is within 30
feet of a sensitive area. 

No application swath can be initiated in, or into an area that is within
30 feet of a sensitive area if the wind direction is towards the
sensitive area.

EPA also suggested that Dow AgroSciences develop a diagram to clarify
this issue which they have added to the label.  Please see the buffer
diagram on the final approved label in the docket.

Comment:  The restriction of application of Enlist Duo to only one
nozzle type and pressure combination does not allow the grower adequate
flexibility to other low drift nozzle technologies.

Response: The registrant has submitted additional data to demonstrate
the drift potential of the Enlist DuoTM technology applied with a
variety of different nozzles.  After careful review of the data, EPA has
determined that additional nozzles provide the same or better drift
protection as the specific nozzle originally proposed with the
registration.  As a result, 22 additional nozzles have now been added to
the label, providing additional flexibility for the grower.  More
nozzles can be added to the label, as appropriate, as additional data is
submitted that demonstrates at least the same drift reduction
properties.  See the final approved label for exact nozzle
specifications.

Comment:  This product should not be restricted to use in only 6 states
when the need for weed resistance management is not limited to these six
states alone.

Response:  EPA is currently conducting additional evaluations to assess
the use of Enlist DuoTM in the remaining corn and soybean growing
states.

B. Registration

Comment:  EPA should not delay the expected timing of this action
provided by the Pesticide Registration Improvement Act (PRIA) by the
development of endangered species assessments and weed resistance
stewardship plans.

Response:  EPA has noted the potential for higher acreage that may
result from the amended use of 2,4-D that could lead to increased
exposure to non-target species.  The increase in acres where this
pesticide could be applied could also select for weeds that develop
resistance to the herbicide, therefore EPA determined that management of
weed resistance in order to prolong the effective use of existing
herbicides and allow growers the tools necessary to manage America’s
food supply must be addressed in this registration decision.  Although
PRIA does stipulate timeframes deemed necessary to conduct assessments
and make regulatory decisions for routine applications of various
pesticide actions, it does not supersede the Agency’s responsibility
to ensure that regulatory decisions meet the standards for registration.
 There are occasions when an action is more complex than expected by the
PRIA timeframes. In these instances, the Agency will typically
renegotiate the timeframe with the registrant to describe the additional
time that is needed for a complete evaluation and to allow the
additional work to be completed.  The Agency will only issue a
regulatory decision once all assessments deemed necessary are carefully
and thoroughly completed, providing a full understanding of the
potential risks and benefits of a pesticide use.

Comment:  An increase in glyphosate use could occur with the
registration of Enlist Duo.  Therefore, glyphosate should be assessed
when considering the registration of Enlist Duo.

Response:  The registration of Enlist DuoTM does not represent any new
exposures or increase in exposures for glyphosate.  Glyphosate is
already used on the majority of corn and soybean production acres in the
United States today.  Glyphosate is presently being applied in the same
fields where Enlist DuoTM applications would be expected, using the same
application methods as registered for Enlist DuoTM.  Since the use of
Enlist DuoTM would represent an alternative to other registered
glyphosate products that already apply glyphosate in the same manner, it
would be considered to be a substitute for another equivalent glyphosate
application and not an additional one.

Comment:  The use of products containing non-choline 2,4-D on Enlist
crops could occur and resulting damage to other crops from drift may
occur.

Response:  Enlist DuoTM provides benefit to the grower by allowing the
application of the choline salt of 2,4-D at a later growth stage for
corn and soybeans, providing control of problem weeds that are present
during this application timing.  No other 2,4-D product is registered
for use on corn and soybeans during this specified time period.  EPA
notes that it is a violation of Federal Law to use a pesticide not in
accordance with its label.  EPA prosecutes illegal use of pesticides to
strongly dissuade and correct for any illegal activity.

In addition, although not required by EPA, the Agency is aware of
contractual agreements that Dow AgroSciences has developed in a
technology use agreement that is legally binding between the grower and
the registrant.  This contract prohibits the use of 2,4-D products
without the choline salt technology on any Enlist seed.  If violations
to this contract are detected, it is EPA’s understanding that DAS
reserves the right to discontinue the sale of the seed to any grower who
does not comply with this requirement.

Comment:  Enlist Duo may contribute to the weed resistance problem that
has been caused by older products labeled for use on GE crops in
general, especially those that are known to have aided in widespread
weed resistance historically.

Response:  EPA and other stakeholders have studied the resistance
problems associated with glyphosate and other pesticides, and EPA has
worked with Dow AgroSciences to develop a robust resistance management
stewardship plan designed to address this concern.  In addition, because
the issue of weed resistance is an extremely important issue to keep
under control and can be very fast moving, this registration will expire
in either 5 years (if there is use of the product on 100,000 or more
acres in the first year) or 6 years (if there is use of the product on
less than 100,000 acres in the first year) unless this term is removed
or modified by EPA.  This will ensure that EPA retains the ability to
easily modify the registration or allow the registration to terminate if
necessary.

C. Benefits of Registration of Enlist DuoTM

Comment: The BEAD benefits memo (April 30, 2014) stated that
registration of Enlist Duo would save costs for farmers in controlling
glyphosate-resistant weeds. However, if these resistant weeds are in
fields, then application of the dual active ingredient product
essentially has only one effective herbicide active ingredient.  BEAD
stated that this scenario would likely require additional herbicide
mode(s) of action.  This situation would negate the benefit of a dual
active ingredient product and would result in more cost to the user.

Response:  The Agency's assessment outlined the general benefits of the
Enlist DuoTM technology and identified benefits beyond Enlist DuoTM's
ability to manage weeds already resistant to glyphosate. The benefits
included increased flexibility to corn and soybean growers, a new tool
for broadleaf weed control in herbicide-tolerant soybean, improved
ability to manage broadleaf weeds already resistant to glyphosate or
other herbicides, and in some cases, extending the viability of
glyphosate.

The Agency acknowledges that in cases where resistance to 2,4-D or
glyphosate exists, measures must be taken by the herbicide's users to
avoid selection for resistance (e.g. add an additional effective
mechanism of action).  The benefits document states:

“While there are benefits to the proposed use of Enlist DuoTM in the
EnlistTM system, it will be important that the system be supported by an
active stewardship program as well as a robust program of early
intervention and remediation when a lack of herbicide efficacy may be an
early sign of resistance developing.”

Therefore, the Agency is requiring that DAS have an Herbicide Resistance
Management (HRM) Plan in place, which includes education and outreach
programs. The HRM Plan, which is detailed in the final decision, will
involve DAS working with growers to help identify early signs of weed
resistance and to resolve the problem before it spreads.  The HRM Plan
also requires education and reporting to the Agency.

Comment:  Although the development of resistance to one or more of the
active ingredients in Enlist Duo is possible, the potential for
resistance development does not eliminate the utility of the product if
it is used according to an appropriate management plan.  

Response:  The Agency agrees with the comments.  As described in its
benefits analysis of April 30, 2014, the Agency believes that the
registration of Enlist DuoTM would provide weed control benefits to some
soybean and corn growers.  Also, the registration requires an Herbicide
Resistance Management (HRM) Plan that is designed to provide early
warning of likely resistance.  Moreover, this HRM Plan includes the
registrant being proactive in addressing local reports of likely
resistance, including investigation, remediation assistance, and
reporting.  Also, education of users of Enlist DuoTM in resistance
management is required.  

D. Resistance Management – Enlist DuoTM Use Practices in the Field

Comment: Certain parts of the use directions described in the proposed
decision were overly prescriptive and would not allow growers the
flexibility needed to use the herbicide product effectively (e.g., the
requirement for growers to scout fields 7-21 days following
application).   Growers' privacy rights could be at risk due to the
requirement for the registrant to investigate reports of lack of
herbicide efficacy, or that the Agency could strictly enforce some of
the detailed practices described on proposed labels.  

Response:  The Agency considered these concerns and determines that
these types of labeling requirements are not necessary to ensure that
the use of the product not result in resistance to certain weeds.
Instead, EPA is placing the burden on the registrant through its
stewardship plan and other regulatory measures in the registration. 
Although the scouting labeling requirement has been removed, the Agency
firmly believes that it is a good best management practice to scout
fields before and after herbicide application, which is consistent with
integrated pest management (IPM) and is essential to early
identification of lack of herbicide efficacy that could be an early sign
of weed resistance. The critical importance of scouting is widely
recognized by research and extension specialists in pest control and
should be practiced when using Enlist DuoTM or other pesticides. 
However, the Agency also recognizes that on-field weed resistance is
best managed by the grower who understands his or her specific
situation. Therefore, the requirement to scout fields 7-21 days after
application will not be imposed, but the labels will contain
recommendations for field scouting.  This scouting will be specific to
Enlist DuoTM and will be designed to ensure proper use of the herbicide
and to detect lack of efficacy quickly so that potential resistance can
be managed effectively.  The Agency is confident that field scouting
programs designed by the registrant will be flexible and will respect
the privacy rights of individual growers.

Comment:  The term “eradicate” in the proposed decision, i.e.,
“DAS [the Enlist Duo registrant] must take immediate action to
eradicate likely resistant weeds in the infested area” (emphasis
added) is not practical.  Also, in many cases, a lack of weed control
following an herbicide application is a result of other factors, not a
lack of herbicide efficacy.

Response:  The Agency agrees that the term "eradicate" is not
appropriate in this context.  Moreover, it does not adequately convey
the Agency's intent.  The Agency believes that areas where there is a
lack of herbicide efficacy (not due to other mechanical or environmental
causes) must be managed aggressively to minimize the potential for
resistance to develop and spread.  In areas where the most likely cause
of poor weed control is a lack of herbicide efficacy, steps must be
taken to destroy likely resistant weeds.  Moreover, when weed
populations that may be developing resistance are observed, the
registrant will become actively involved with growers to ensure that
these populations were managed properly.  There will also be a
requirement for the registrant to report to the Agency and to
stakeholders when incidents of unresolved likely resistance are
identified.

The Agency recognizes that many incidents of lack of weed control are
not related to possible resistance.  Rather, lack of weed control may be
due to factors such as unexpected rain, a clogged nozzle, a missed spot
on the field, or other equipment-related problem.  In these cases, the
Agency recognizes that on-site investigation and follow up by the
registrant are not necessary.

E. Stewardship: Education and Training

Comment: Stewardship efforts, including education and training programs,
are needed to ensure proper use of Enlist Duo, as growers may rely too
heavily on Enlist Duo in weed control programs.  In these cases, the
potential to select for resistant weeds will be greater.  Stewardship
programs should be flexible and facilitate local management of
resistance.  Also, the approach to education and training should be
generally consistent for pesticides.  Responsibility for oversight for
education and training requirements was not clear in the proposed
decision.

Response: The Agency agrees that the registration of Enlist DuoTM for
use on Enlist seed presents the potential for growers to over-rely on a
single product that contains two herbicidal active ingredients.  If it
happens, the over-dependence can increase the selection pressure on
weeds and lead to resistance.  Because herbicide use on
herbicide-resistant crops presents this increased risk, the Agency is
addressing resistance potential in this registration in an unprecedented
manner.  

The terms of registration for Enlist DuoTM place the responsibility on
the registrant for reducing the potential for resistance or to
significantly delay the onset of resistance.   The Agency is also
requiring the registrant to develop education and training programs that
will provide growers with the best available information on herbicide
resistance management.  Although requiring the registrant to provide
education and training, the Agency has not imposed label or use
restrictions on the grower, enabling him or her to exercise flexibility
in weed control practices based on local conditions.   

F. Reporting

Comment: The reporting requirements outlined in the proposed decision
were overly strict and could actually deter growers from reporting
likely resistance to the registrant. The registrant should report
confirmed resistance to the Agency through adverse effects reporting
required in section 6(a)(2) of the Federal Insecticide, Fungicide and
Rodenticide Act (FIFRA).

Response: The Agency believes that timely and accurate reporting is
needed to fully understand the nature and extent of possible resistance
that may develop as a result of Enlist DuoTM use.  The Agency believes
that growers will be the first ones to recognize the early signs of
herbicide resistance.  Therefore, the Agency has specified in the terms
of registration that it must be easy for growers to report the early
signs of resistance to the registrant.  The Agency has not mandated
specific reporting requirements for growers.  Further, the Agency
believes it is common practice for growers to readily report the early
signs of resistance to the chemical dealer or the registrant.

 

Instead of placing the burden on the growers, the Agency has determined
that the registrant must report to the Agency on a regular basis
concerning likely resistance.  These reports are needed by the Agency to
facilitate its understanding of whether resistance may be developing
and, if it is, its severity and geographic distribution.  Also, the
registrant will be required to report likely resistance to growers who
could be affected so they can take appropriate measures to minimize the
impact of resistance on their crop production.

The Agency agrees that confirmed resistance must be reported under FIFRA
section 6(a)(2).  However, it may take several years before resistance
is confirmed even though its early signs appeared much sooner. The
Agency therefore is requiring the specific reporting described in the
final decision.  This early warning can help growers understand the
potential for resistance to develop and also serve as an early warning
system if resistance is found nearby.

G. Other Comments

Comment: The Agency should consider the Agricultural Biotechnology
Stewardship Technical Committee (ABSTC) model for resistance management
for Enlist Duo.  This model has been adopted for plant-incorporated
protectants (PIPs) such as Bt crops.  ABSTC is an industry-led structure
which is preferable to the proposed registration decision for Enlist Duo
which appeared to place more responsibility on the grower and makes him
or her liable for a lack of compliance.  

Response:  The Agency agrees that the ABSTC model, if modified for an
herbicide registered for use on an herbicide-tolerant crop, is relevant
for Enlist DuoTM.  The ABSTC model was consulted when determining the
appropriate terms of the registration for the Enlist DuoTM product.  In
addition, the Agency is requiring registrants to implement practices
intended to facilitate early identification of possible resistance, to
remediate lack of herbicide efficacy that could be the start of
resistance, follow-up, and reporting.  Further, the Agency has not
mandated specific practices on labels, thereby allowing maximum
flexibility for users of Enlist DuoTM.  

Comment:  New resistance management requirements for Enlist Duo should
also apply for other products and for future registrations as well. 
Also, the many registrations for 2,4-D and glyphosate make it difficult
to address related resistance issues when this proposal applies only to
Enlist Duo.

Response: With the registration of Enlist DuoTM, the Agency is
establishing a new approach for resistance management for herbicides
registered for use on herbicide-tolerant crops.  Future registration
actions for herbicides used on herbicide-tolerant crops will be
patterned after the Enlist DuoTM decision.  The Agency will use the
registration review process to address resistance managment for the
existing registrations of 2,4-D, glyphosate and other herbicides where
resistance is an important issue.  

Comment:  From 1993 to 2008-2009 there has been approximately a 10-fold
increase in the amount and acreage of glyphosate use.  In some cases
where Enlist Duo may be used, glyphosate-resistant weeds are already
present, and resistance to 2,4-D may develop. 

Response:  The Agency agrees that glyphosate use has substantially
increased since the early 1990s.  However, the Agency does not believe
there will be an increase in glyphosate use resulting from this action
because glyphosate is already used extensively on corn and soybean.  

The Agency agrees that Enlist DuoTM may be used on fields where
glyphosate resistance is already present.  In some of these cases,
judicious use of Enlist DuoTM may help manage the glyphosate resistance.
 However, care must be taken by the herbicide user to carefully manage
the potential for these glyphosate-resistant weeds to become resistant
to the 2,4-D component of Enlist DuoTM.  In such cases, the DAS
stewardship program will educate the user on the importance of using
diverse methods of weed control to reduce the likelihood of 2,4-D
resistance developing.  

Comment:  Although EPA has recognized that glyphosate-resistance is an
important issue, it is not approaching the problem appropriately. 
Rather than “taking a step back” and reevaluating the GE strategy,
the Agency is “rushing” to approve a technology that will continue
the “pesticide treadmill” with increased resistance now to 2,4-D.

Response:  The Agency recognizes that the development and spread of
herbicide resistant weeds is an important issue for all herbicides, not
just for glyphosate and 2,4-D. The presence of herbicide resistant weeds
results in increased costs of production to the grower, increases the
difficulty of managing crop production, and can require control measures
that may have negative effects on the environment (e.g., requiring
cultivation that could increase soil erosion).

After extensive analysis and review, the Agency has determined that
Enlist DuoTM meets the statutory criteria for registration.  Further,
the Agency has required as part of the terms and conditions of the
Enlist DuoTM registration that the registrant proactively manage the
potential development of resistance.  

Comment:  While registrants for new auxin-based herbicides claim
resistance is unlikely, they leave out that 1) a similar argument was
made prior to glyphosate release, 2) it is not the case that “very
few” weed species are resistant to 2,4-D—worldwide there are 16
species resistant to 2,4-D, and 3) while the theory that weeds are
statistically less likely to develop resistant to two herbicide active
ingredients—the fact that the glyphosate-resistant population in some
fields is so great that there is a high likelihood that exposure to
2,4-D will result in populations resistant to 2,4-D as well as
glyphosate.  In addition, these fields are most likely to be planted
with stacked tolerant GM crops.

Response:   The Agency agrees with the commenter’s concern over the
potential for weed resistance development, especially to multiple
mechanisms of action.  The terms of registration and stewardship
requirements are intended to provide early warning and allow for timely
intervention when likely resistance is detected.  The Agency recognizes
that where glyphosate resistance is already present, the 2,4-D component
of Enlist DuoTM will only be effective against the broadleaf weeds.  In
those cases, the Agency will require that the registrant’s stewardship
plan alert growers to the special problem of glyphosate resistance and
provide the grower with education and training to use best management
practices that will reduce the probability of resistance to 2,4-D. 

Comment:  Traditionally, 2,4-D was registered for use as a single
preplant herbicide on cereal fields.  The new GM crop will allow higher
rates, more applications, in successive crops, over a wider area than
currently.  Therefore, the potential is high for greater development of
resistance to 2,4-D (and other auxin-based herbicides). 

Response:  The Agency agrees that there is the potential for resistance
to develop as a result of over-use of Enlist DuoTM, or using it without
best management practices.  Therefore, the Agency is requiring the
registrant to develop an extensive stewardship program to educate users
of this problem.  Moreover, through the terms of registration for Enlist
DuoTM, the Agency is requiring the registrant to undertake several steps
that are intended to provide early detection and remediation in cases
where a lack of herbicide efficacy may be an early sign of resistance
developing.

Comment:  StarlinkTM was also regulated but the release failed.  What is
different about Enlist Duo’s possible release? 

Response:  The StarLinkTM issue related to the release of
genetically-modified corn that was not approved for human consumption. 
That situation, and the circumstances surrounding it, is not comparable
to the Agency’s action on Enlist DuoTM.  The USDA Biotechnology
Regulatory Services has jurisdiction over the deregulation of the Enlist
corn seed.  The Agency’s action is limited to the registration of
Enlist DuoTM, the herbicide product that is intended for use on corn and
soybean crops grown from Enlist seed.

 

Comment:   2,4-D usage was estimated to increase 3 to 7 times by 2020
in the USDA 2014 Environmental Impact Statement.  As a result of this
increased usage the evolution of 2,4-D resistance will be facilitated
and will result in changes of conservation tillage practices.

Response:  The Agency agrees that there will be increased usage of
2,4-D because of the longer period of time that applications can be made
in corn and that for the first time, up to two applications can be made
over-the-top in soybeans.  Increased usage of 2,4-D was fully accounted
for in the risk assessments that the Agency has conducted for Enlist
DuoTM.  Further, because of the likelihood of the development of
resistant weeds and their associated impacts, the Agency has established
and implemented its new herbicide resistance management approach as
described in the Final Registration of Enlist DuoTM Herbicide, dated
October 14, 2014.

IV. References

Abedlghani, A.A., P.B. Tchounwou, A.C. Anderson, H. Sujono, L.R. Heyer,
and A. Monkiedje.  1997.  Toxicity evaluation of single and chemical
mixtures of Roundup, Garlon-3A, 2,4-D, and Syndets surfactant to channel
catfish (Ictalurus punctatus), bluegill sunfish (Lepomis macrochirus),
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Andersen, S.M., S.A. Clay, L.J. Wrage, and D. Matthees.  2004.  Soybean
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Everitt, J.D. and J.W. Keeling.  2009.  Cotton growth and yield response
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Kelley, K.B., L.M. Wax, A.G. Hager, and D.E. Riechers.  2005.  Soybean
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Marple, M.E., K. Al-Khatib, and D.E. Peterson.  2008.  Cotton injury and
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MRID 41413501.  Berdasco, N.; Schuetz, D.; Jersey, G. et al. (1989)
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MRID 48289803.  Durando, J.  2010.  GF-2726.  Acute oral toxicity study
up and down procedure in rats.  Unpublished study performed by
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MRID 48844001 . Havens, P.L., Hillger, D.E., Hewitt, A.J. and Kruger,
G.R. 2012. Field spray drift determinations with GF-2726 and
2,4-D/Glyphosate tank mixes. Unpublished study performed by Dow
AgroSciences LLC, Indianapolis, Indiana; Lincoln Ventures Limited,
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Safety Labs, Dayton, New Jersey; sponsored and submitted by Dow
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as “supplemental” USEPA 2013, (D402860+).

MRID 48862902. Havens, P.L., Hillger, D.E. and Cryer, S.A. 2012. Updated
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MRID 48911801.  Ouse, D.G., J.M. Gifford, A.A. Ahmed, and C.J. Jennings.
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Ogg, A.G. Jr., M.A. Ahmedullah, and G.M. Wright.  1991.  Influence of
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Robinson, A.P., V.M. Davis, D.M. Simpson, and W.G. Johnson.  In review. 
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USEPA 2005b.  Revised screening level ecological risk assessment of
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(PCDFs) contaminants from technical products of
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USEPA 2012. Product name:  GF 2654 TC.  Registration Division, Office of
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USEPA.  2013a. EFED environmental risk assessment of proposed label for
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tolerant) and Enlist (2,4-D + glyphosate tolerant) corn and field corn. 
Environmental Fate and Effects Division, Office of Pesticide Programs,
United States Environmental Protection Agency (D400223+).

USEPA.  2013b. Addendum to EFED environmental risk assessment of
proposed label for Enlist (2,4-D choline salt) new uses on soybean with
DAS 68416-4 (2,4-D tolerant) and Enlist (2,4-D + glyphosate tolerant)
corn and field corn.  Environmental Fate and Effects Division, Office of
Pesticide Programs, United States Environmental Protection Agency
(D411614).

USEPA.  2013c. Reviews of Environmental fate studies of 2,4-D Choline.
Environmental Fate and Effects Division, Office of Pesticide Programs,
United States Environmental Protection Agency (D402860+).

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 to 2,4-D choline salt Section 3 risk assessment:  refined endangered
species assessment for proposed new uses on herbicide-tolerant corn and
soybean.  Environmental Fate and Effects Division, Office of Pesticide
Programs, United States Environmental Protection Agency (D418022).

USEPA, PMRA, and CDPR.  2014.  Guidance for assessing pesticide risk to
bees.  Office of Pesticide Program, United States Environmental
Protection Agency; Health Canada Pest Management Regulatory Agency; and
California Department of Pesticide Regulation.

USFWS/NMFS/NOAA.  2004.  50 CFR Part 402.  Joint Counterpart Endangered
Species Act Section 7 Consultation Regulations; Final Rule. Federal
Register Volume 69.  Number 20.Pages 47731-47762. August 5, 2004.

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                          UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

                                                             WASHINGTON,
DC  20460

	

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OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION