1

Final Registration of Enlist Duo TM Herbicide

Regulatory Rationale

The Agency has granted a registration for Enlist Duo TM , a herbicide containing the active ingredients 2,4

- d ichlorophenoxyacetic acid (2,4

- D ) choline salt and glyphosate dimethylammonium salt (glyphosate) to Dow AgroSciences (DAS)

. On November 1, 2011, DAS submitted an application for registration to the Environmental Protection Agency (EPA or the Agency ) for Enlist Duo TM , which is used on corn and soybean crops that are genetically engineered (GE) to be resistan t to 2,4

- D and glyphosate (GE crops)

. Under the Plant Protection Act, the United States Department of Agriculture (USDA) reviewed a separate request from DAS to deregulate its Enlist TM GE herbicide tolerant corn and soybean crops and granted the request on September 18, 2014

.

2

, 4

- D is an active ingredient that is currently registered in a variety of salt , amine, and ester formulations and is registered for a variety of food and feed uses, i ncluding corn and soybeans. This new use w ill expand the current t iming of applications of 2,4

- D on corn and soybeans, thereby enhancing the flexibility in weed control . 2,4

- D was previously registered for over

- the

top applications to corn up to 8 inches tall and only pre

- plant applications to soybeans. Th is registrati on allow s over

- the

- top applications of 2,4

- D choline sal t formulation to GE corn up to 48 inches tall and over

- the

- top applications to GE soybeans.

Although the use on GE crops is a new use pattern for the 2,4 D component of this product, it is
not a new use for glyphosate containing products. All uses for this product are already registered on other glyphosate products and are currently in use on GE corn and soybeans for the same use pattern. Since no new use pattern and no new exposures for glyphosate were being considered with this registration action, no new assessment s were performed for glyphosate. However, as described above, the expanded timing of applications is a change in the use pattern for the choline salt of 2,4

- D. Therefore, this documen t is intended to discuss the results of the Agency’s findings specifically to the assessment of the choline salt of 2,4

- D on GE corn and soybeans.

I. Chemical Information

Chemical Name: Ethanaminium, 2

- hydroxy

- N,N,N

- trimethyl

- , 2

- (2,4

- dichlorophenoxy)ac etic acid hydroxide (1:1:1)

EPA PC Code: 051505

Chemical Abstracts Service (CAS) Num ber: 1048373

- 72

- 3

Mode of Action: 2,4

- D is an herbicide in the phenoxyacetic acid family that is used postemergence for selective control of broadleaf wee d s. 2,4

- D, a s ynthetic auxin herbicide, causes disruption of plant hormone responses.

Registrant: Dow AgroSciences

, LLC2

Product : GF

- 2726 ( Enlist Duo TM )

– EPA Registration Number 62719

- 649 , an end

- use product containing 24.4% 2,4

- D choline salt and 22.1% g lyphosate, us ed on EnlistTM AAD

- 1 Corn (Trait Code: DAS

- 40278

- 9) and EnlistTM AAD

- 12 Soybean (Trait Code: DAS

- 68416

- 4)

.

II. Human Health Risk

A summary of the human health effects and risk of 2,4

- D choline salt as assessed in the EPA document en titled, 2,4

- D. Human Hea lth Risk Assessment for a Proposed Use of 2,4

- D Choline on Herbicide

- Tolerant Corn and Soybean , is provided below.

A. Summary of Toxicological Effects

The toxicology database on 2,4

- D is complete and sufficient for assessing the toxicity and characterizing the hazard of all formulations of 2,4

- D , including the choline salt

. Data on other forms of 2,4

- D were also used to assess the choline formulation.

2,4

- D has been classified as having low acute toxicity via the oral, dermal, and inhalation routes of expos ure (Toxicity Category III). It is not a dermal irritant (Toxicity Category IV) or dermal sensitizer but it is a severe eye irritant (Toxicity Category I).

The toxicity profile of the active ingredient 2,4

- D shows that the principal toxic effects are cha nges in the kidney, thyroid, liver, adrenal, eye, and ovaries/testes in the rat following exposure to 2,4

- D via the oral route only at dose levels above the threshold of saturation of renal clearance. No systemic toxicity was observed in rabbits following repeated exposure via the dermal route at dose levels up to the limit dose. Neurotoxicity was observed in the acute neurotoxicity study in rats at the high dose. In an extended one

- generation reproductive toxicity study in rats, reproductive toxicity, dev e lopmental neurotoxicity, and im munotoxicity were not observed

. T he thyroid effects observed at dose levels approaching renal saturation were considered treatment

- related (i.e., resulted from dosing with 2,4

- D) , although not adverse (i.e., the effects are n ot harmful to the organism) . Maternal and developmental toxicity were observed at high dose levels exceeding the threshold of saturation of renal clearance. There are no residual uncertainties for pre

- and/or postnatal toxicity.

2,4

- D is classified as “n ot classifiable as to human carcinogenicity

, ” based upon bioassays in rats and mice that showed no statistically significant tumor response in either species. The Agency determined, based on several reviews of epidemiological studies, in addition to the

an imal studies, that the existing data did not support a conclusion that links human cancer to 2,4

- D exposure.

B. Toxicological End Points and Doses Used in the Human Health Risk Assessment

Once a pesticide’s toxicological profile is determined, EPA identifie s toxicological P oints of D eparture (POD) and L evels of C oncern (LOC) to use in evaluating the risk posed by human exposure to the pesticide. For hazards that have a threshold below which there is no appreciable risk, the toxicological POD is used as the basis for derivation of reference values for risk assessment. PODs are developed based on a careful analysis of the doses in each3

toxicological study to determine the dose at which no adverse effects are observed (the NOAEL ; No Observed Adverse Effect Lev el ) and the lowest dose at which adverse effects of concern are identified (the LOAEL ; Lowest Observed Adverse Effect Level ). Uncertainty/safety factors are used in conjunction with the POD to calculate a safe exposure level

- generally referred to as a P o pulation

- adjusted D ose (PAD) or a R eference D ose (RfD)

- and a safe M argin of E xposure (MOE). For non

- threshold risks ( e.g. , cancer)

, EPA assumes that any amount of exposure will lead to some degr ee of risk. Thus, EPA estimates risk in terms of the proba bility of an occurrence of the adverse effect expected in a lifetime. For more information on the general principles EPA uses in risk characterization and a complete description of the risk assessment process, see http://www.epa.gov/pesticides/factsheets/riskassess.htm

.

1. Acute Dietary

a. General P opulation (Including Infants and C hildren )

An acute dietary endpoint for the general population, including infants and children, was selected fro m the acute neurotoxicity study in rats with a NOAEL of 67 mg/kg. At the study LOAEL of 225 mg/kg, an increased incidence of incoordination and slight gait abnormalities (forepaw flexing or knuckling) and decreased motor activity were observed. A 100X unce rtainty factor was applied to account for inter

- and intra

- species variability . As discussed in section C below, t he Food Quality and Protection Act ( FQPA ) safety factor was reduced to 1X resulting in an acute Population Adjusted Dose (aPAD) of 0.67 mg/kg/ day.

b. Females of Child

- Bearing Age ( 13

- 49 years old )

An acute dietary endpoint for females 13+ was selected from the developmental toxicity study in rats with a NOAEL of 25 mg/kg/day. At the study LOAEL of 75 mg/kg/day, fetal skeletal malformations (14 th rudimentary ribs) were observed. A 100X uncertainty factor was applied to account for inter

- and intra

- species variability and the FQPA safety factor was reduced to 1X resulting in an acute Population Adjusted Dose aPAD of 0.25 mg/kg/day.

2. Chronic Dietary

The chronic dietary endpoint was selected from the extended one

- generation reproduction toxicity study in rats with a NOAEL of 21 mg/kg/day. At the study LOAEL of 55.6 mg/kg/day for males and 46.7 mg/kg/day for females, kidney toxicity, manifested as incr eased kidney weights and increased incidence of degeneration of the proximal convoluted tubules, was observed and decreased body weight in pups was observed throughout lactation. A 100X uncertainty factor was applied to account for inter

- and intra

species variability and the FQPA safety factor was reduced to 1X resulting in a chronic Population Adjusted Dose (cPAD) of 0.21 mg/kg/day.

3. Incidental Oral, Short and Intermediate T erm4

Short

- term and intermediate

- term incidental oral endpoints for risk assessmen t were selected from the extended one

- generation reproduction toxicity study in rats with a NOAEL of 21 mg/kg/day. At the study LOAEL of 55.6 mg/kg/day for males and 46.7 mg/kg/day for females , kidney toxicity, manifested as increased kidney weights and in creased incidence of degeneration of the proximal convoluted tubules, was observed and decreased body weight in pups was observed throughout lactation. A 100X uncertainty factor was applied to account for inter

- and intra

- species variability and the FQPA s afety factor was reduced to 1X resulting in a target MOE of 100 for non

- dietary risk assessment

.

4. Inhalation , Short and Intermediate T erm

Short

- term and intermediate

- term inhalation endpoints for risk assessment were selected from the route

- specific 28

- da y inhalation toxicity study in rats with a LOAEL of 0.05 mg/L/day. A NOAEL for portal

- of

- entry effects was not determined. At the study LOAEL of 0.05 mg/L/day, squamous metaplasia and epithelial hyperplasia with increased mixed inflammatory cells within th e larynx, which was not totally resolved following a 4

- week recovery period, were observed. Human Equivalent Concentrations (HEC)/Human Equivalent Doses (HED) for residential and occupational scenarios were calculated. A 3X uncertainty factor was applied to account for inter

- species variability (to account for the pharmacodynamic differences), a 10X uncertainty factor was applied to account for intra

species variability, and a 10X uncertainty factor was applied to account for the lack of a NOAEL. The lack of an assessment of the thyroid and other systemic effects in the inhalation study is considered inconsequential because the portal of entry endpoint is protective of potential systemic effects expected to occur at higher concentrations; i.e., at doses tha t exceed the level of renal clearance. Portal

- of

- entry effects were observed at all dose levels, and an additional 10X uncertainty factor is applied to the LOAEL to obtain an extrapolated NOAEL used for the inhalation risk assessments. The use pattern indi cates that dose levels required to exceed the renal clearance mechanism will not be attained following human inhalation exposure.

5. Dermal (All Durations)

No quantification of dermal risk is required. Although the dermal toxicity study did not evaluate dev elopmental endpoints, the following were noted:

a. T here was no dermal or systemic toxicity observed following repeated dermal applications to rabbits at the Limit Dose (1000 mg/kg/day)

.

b. T here was no qua l itative susceptibility observed in the developmental or reproductive toxicity studies

.

c. T he use of a 10% human dermal absorption factor (DAF) with the oral developmental LOAEL of 90 mg/kg/day established in the rabbit developmental toxicity study yields a dermal equivalent dose (DED) of 900 mg/kg/day, which is5

numerically similar to the high

- end dermal NOAEL (1000 mg/kg/day) in the dermal rabbit study

.

d. No quantitative susceptibility/sensitivity was observed in the developmental and/or reproductive toxicity studies between adults and young animals (maternal and developmental/offspring NOAELs/LOAELs are the same). Therefore, any dose that would be protective of effects in adults will also be protective of effects in the developing organism.

e. T he use pattern indicates that dose levels required to exceed the re nal clearance mechanism will not be attained following human dermal exposure.

6. Cancer

The Cancer Peer Review Committee (CPRC; TXR No. 0050017, dated January 29, 1997) classified 2,4

- D as “not classifiable as to human carcinogenicity

, ” based upon bioassays in rats and mice that showed no statistically significant tumor response in either species. EPA determined, based on several reviews of epidemiological studies, in addition to the animal studies, that the existing data did not support a conclusion that li nks human cancer to 2,4

- D
exposure.

C. FQPA Safety Factor

EPA determined that the 10X FQPA Safety Factor (for the protection of infants and children mentioned above ) could be reduced to 1X for all oral endpoints for the following reasons:

The toxicity data base is complete and adequate to assess safety for infants and children. T here is evidence of increased qualitative susceptibility ( i.e., severity of effects) in the rat developmental toxicity study and in the rat two

- generation reproduction study

. Howeve r, there is no quantitative susceptibility since the maternal and developmental/offspring NOAELs/LOAELs identified in these studies are the same. Moreover, the points of departure used in the risk assessment are below where these findings occur and are pr otective. There are acute and subchronic neurotoxicity studies, a developmental neurotoxicity cohort in the extended one

- generation reproductive toxicity study in rats, a detailed evaluation of thyroid function across life stages, and a developmental immun otoxicity cohort in the extended one

generation reproductive toxicity study in rats. Therefore, the Agency has a complete database addressing potential hazard to infants and children. The exposure assessment will not underestimate children’s exposure to 2 ,4

- D. Further details may be found in the following sections:

1. Completeness of the Toxicology Database

The toxicology database for 2,4

- D is complete. Acceptable rat and rabbit developmental toxicity studies, a rat two

- generation reproduction study, an ext ended one

- generation rat reproduction toxicity study (F1 offspring evaluated for potential effects on the nervous system, immune system, reproductive and endocrine systems, thyroid function, and other6

systemic toxicity parameters), and acute, subchronic, a nd developmental neurotoxicity studies in rats are available.

2. Evidence of Neurotoxicity

Evidence of neurotoxicity was observed in the acute neurotoxicity study in rats, as evidenced by an increase in the incidence of incoordination and sli ght gait abnorm alities (forepaw flexing or knuckling) during the Functional Observation Battery ( FOB ) assessment at the high dose in both sexes. In the subchronic neurotoxicity study, relative forelimb grip strength was significantly increased in rats of both sexes at th e high

- dose level, although there was no treatment

- related change in absolute grip strength. Clinical signs of neurotoxicity (decreased motor activity, ataxia, loss of righting reflex, extremities cold to the touch) were observed in maternal rabbits in the developmental toxicity study. Developmental neurotoxicity was not observed in the developmental neurotoxicity cohort in the extended one

- generation reproductive toxicity study in rats. Neuropathological effects were not observed in any study. While neuro toxic effects were observed in some studies, these effects all occurred at doses exceeding renal saturation; endpoints were selected to assure that the risk assessment is protective for these effects.

3. Evidence of Sensitivity/Susceptibility in the Develop ing or Young Animal

There is evidence of increased qualitative susceptibility ( i.e., severity of effects) following in utero exposure to 2,4

- D in the rat developmental toxicity study and following in utero and/or pre

- /post

- natal exposure in the rat two

- ge neration reproduction study. However, there is no quantitative difference between young and adult animals ( i.e., the NOAELs are the same in adult and young animals). There is no evidence of increased susceptibility following in utero exposure to 2,4

- D in the rabbit developmental toxicity study or following in utero and/or pre

- /post

- natal exposure in the rat extended one

- generation reproduction toxicity study.

2,4

- D has been evaluated for potential developmental effects in the rat and rabbit. Maternal toxi city included decreased body weight gains in the rat study at the same dose level where developmental effects (occurrence of skeletal malformations) were observed. Maternal toxicity in the rabbit included decreased body weight gain, clinical signs of toxic ity (decreased motor activity, ataxia, loss of righting reflex, extremities cold to the touch), and abortions, the latter being indicative of potential developmental toxicity. Decreased maternal body weight gains were observed in the rat two

- generation rep roduction study at a dose that exceeded renal saturation and resulted in reduced viability of the F1 pups. There are clearly established NOAELs and LOAELs for the population of concern, there are no data gaps in the toxicology database, and the POD s are pr otective of susceptibility.

4. Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database. The dietary exposure estimates are unrefined and reflect primarily tolerance

- level residue in food, 100% crop7

treated

, and upper

- bound drinking water estimates based on modeling . Additionally, non

occupational exposure estimates were determined using the Residential Standard Operating Procedures which utilize a combination of central tendency and high end inputs designed to result in protective exposure estimates which will not underestimate residential
exposures

.

D. Cumulative Effects

2,4

- D is a n herbicide in the phenoxyacetic acid family of pesticides. This class also includes MCPA, 2,4

- DB, and 2,4

- DP. A cumulative risk a ssessment has not been performed as part of this human health risk assessment because EPA has not made a determination as to which of these compounds , if any, to which humans may be exposed, have a common mechanism of toxicity. Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to 2,4

- D and any other substances. For the purposes of this action, therefore, EPA has not assumed that 2, 4

- D has a common mechanism of toxicity with other substances.

For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements rele ased by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://w ww.epa.gov/pesticides/cumulative/

.

E. Dietary (Food + Drinking Water) Risk

2,4

- D is a phenoxyacetic acid herbicide used to control a variety of broadleaf weeds. It is a longstanding active ingredient (ai) registered for a variety of food/feed uses. Permane nt tolerances for 2,4

- D are established under 40 CFR 180.142 for a wide variety of crops and livestock commodities.

Acute and chronic aggregate (food + dietary drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluat ion Model software with the Food Commodity Intake Database (DEEM

- FCID) Version 3.16. This software uses 2003

- 2008 food consumption data from the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey, What We Eat in Amer ica, (NHANES/WWEIA).

1. Acute Dietary Risk

For acute exposure assessments, individual one

- day food consumption data are used on an individual

- by

- individual basis. The reported consumption amounts of each food item can be multiplied by a residue point estima te and summed to obtain a total daily pesticide exposure for a deterministic exposure assessment, or “matched” in multiple random pairings with residue values and then summed in a probabilistic assessment. The resulting distribution of exposures is express ed as a percentage of the aPAD on both a user (i.e., only those who reported eating relevant commodities/food forms) and a per

- capita (i.e.,8

those who reported eating the relevant commodities as well as those who did not) basis. In accordance with EPA poli cy, per capita exposure and risk are reported for analyses.

The resulting acute food plus drinking water risk estimates are not of concern to EPA (≤100% aPAD) at the 95 th percentile of the exposure distribution for the general population and all population subgroups. The resulting acute risk estimate for children 1 to 2 years old, the subgroup with the greatest exposure, was 14% of the aPAD at the 95 th percentile of the exposure. The acute dietary assessment is unrefined; to further refine the 2,4

- D dietary exposure and risk estimates, percent crop treated (%CT) , anticipated residues, or monitoring data, if available, c ould be used.

2. Chronic Dietary Risk

For chronic dietary exposure assessment, an estimate of the residue level in each food or food

- form on the food commodity residue list is multiplied by the average daily consumption estimate for that food/food form to produce a residue intake estima te. The resulting residue intake estimate for each food/food form is summed with the residue intake estimates for all other food/food forms on the commodity residue list to arrive at the total average estimated exposure. Exposure is expressed in mg/kg body weight/day and as a percent of the cPAD. This procedure is performed for each population subgroup.

The resulting chronic food plus drinking water risk estimates are not of concern to EPA for the general population and all population subgroups. The most h ighly exposed population was children 1 to 2 years old utilizing 15% of the cPAD. The chronic dietary assessment is unrefined; to further refine the 2,4

- D dietary exposure and risk estimates, percent crop treated , anticipated residues, or available monitor ing data could be used.

F. Residential (Non

- Occupational) Exposure/Risk Characterization

There are registered uses of 2,4

- D on turf including golf courses and parks as well as aquatic uses; therefore, residential handler exposure and post

- application exposu re to treated turf and aquatic sites is possible. There is no hazard via the dermal route for 2,4

- D, therefore the handler assessment included quantification of risks for only the inhalation route of exposure and the post

- application assessment included on ly the inhalation and incidental oral route of exposure. The residential handler and post

- application risk estimates are not of concern for 2,4

- D for all scenarios and all routes of exposure.

For non

- dietary exposures, EPA uses the term Margin of Exposure ( MOE ) to refer to the risk associated with the exposure estimate. The MOE is defined as the ratio of the selected toxicological POD, usually the NOAEL, to the estimat ed human exposure. A target MOE of 300 means that the estimated maximum safe level of h uman exposure is 300 times lower than the highest dose that produced no adverse effects in the relevant toxicology study ; the target MOE is calculated by multiplying together the safety / uncertainty factors appropriate for each
assessment

. Risk estimates that are not of concern are indicated by a n actual MOE of 300 or greater for residential handler exposure and 100 or greater for post

- application exposure.9

1. Residential Handler Exposure

Residential handlers may receive short

- term dermal and inhalation ex posure to 2,4

- D when mixing, loading, and applying the pesticide to ornamental turf as well as aquatic uses. Only inhalation risk estimates were quantitatively assessed because there is no hazard via the dermal route for 2,4

- D. The handler inhalation exp osure scenarios considered were mixing, loading and applying :

 Liquid/

Wettable Powder ( WP ) / Dry Flowable ( DF ) to Lawns/Turf with Hose

- End Sprayer

 Liquid/WP in Water Soluble Packets ( WSP ) to Lawns/Turf/Aquatic Sites with m anually

pressurized handwand

 Ready

- t o

- Use/WP in WSP to Lawns/Turf with Hose

- End Sprayer

 Liquid to Lawns/Turf/Aquatic Sites with Backpack

 Liquid/WP/DF to Lawns/Turf with Manually

- pressurized handwand or backpack

 Granule to Lawns/Turf with Push

- type spreader, Belly Grinder, Spoon, Shaker Can, Cup or Hand dispersal

The MOEs for the six exposure scenarios range from 460 to 3,400,000. Since the re is potential risk concern only when MOEs are less than 300, residential handler exposures are
not a concern.

2. Post

- Application Exposure

There is the p otential for post

- application exposure for individuals exposed as a result of being in an environment that has been previously treated with 2,4

- D. The quantitative exposure/risk assessment for residential post

- application exposures is based on the followin g scenarios:

 Incidental ingestion (i.e., hand

- to

- mouth, object

- to

- mouth, soil ingestion exposure) from contact with treated turf (children 1 to < 2 years old only)

 Episodic granular ingestion on treated turf (children 1 to < 2 years old only)

 Incidental i ngestion of water during recreational swimming (both adults and children).

Assessment of post

- application exposure to turf treated with liquid formulations is protective of exposure to solid formulations since exposures to liquid formulations are generall y higher than exposures to solid formulations. The lifestages selected for
assessment are health protective for the exposures and risk estimates for any other potentially exposed lifestages.

a. Residential Post

- application Exposure for Turf Use

Incidental oral risk estimates were quantitatively assessed for residential post

application exposure for turf use. The incidental oral scenarios (i.e., hand

- to

- mouth and object

- to

- mouth) have been considered inter

- related as it is likely that they occur intersperse d amongst each other over time. Episodic granular ingestion on treated turf10

was not combined as this exposure would not occur as a result of routine behavior and is considered an episodic even t related to poisoning.

The residential post

- application ris k estimates for turf use have MOEs that range from 490 to 430,000 for all incidental oral scenarios so are not of concern for 2,4

- D.

b. Residential Post

- application Exposure for Aquatic Use

2,4

- D is used for aquatic weed control of surface and submerged wee ds. Many treatments are applied to aquatic areas where recreational swimming is not likely to occur but some subsurface treatments are made at recreational lakes . Since this can result in individuals being exposed to 2,4

- D residues in water by entering t hese areas if they have been previously treated, there is a 24

- hour swimming restriction

. The extent of exposure during recreational swimming is assumed to be short

- term in duration. Risk estimates were calculated for post

- application incidental oral inges tion while swimming in treated lakes or ponds. Inhalation exposure is expected to be negligible for swimmers; therefore, a post

- application inhalation assessment was not conducted. Furthermore, the inhalation assessment for residential handlers is expected to be protective of potential post

- application exposure and risk.

The residential post

- application risk estimates for aquatic use have MOEs that range from 690 to 5,300 for incidental oral ingestion so are not of concern for 2,4

- D.

3. Residential Bystander Post

- application Inhalation Exposure (Volatilization)

The potential exposure to bystanders from the vapor phase of the 2,4

- D choline salt formulation residues emitted from treated fields was evaluated using data submitted to the Agency that used the chol ine salt formulation in its study for this use on GE corn and soybean. The two main factors that bystander exposure depends on are the rate at which these chemicals come off of a treated field which is described as the off

- gassing, emission or flux, and h ow those vapors are dispersed in the air over and around the treated field. Volatilization can occur during the application process or thereafter. It can result from aerosols evaporating during application, while deposited sprays are still drying or after as dried deposited residues volatilize. The volatilization assessment used an analysis after sprays dried.

Flux data was submitted measuring flux rates of 2,4

- D ethylhexyl ester (EHE), 2,4

- D dimethylamine salt (DMA salt) and 2,4

- D choline salt. 2,4

- D ch oline salt was found to have a reduced potential for volatility. For this assessment, the data from the 2,4

- D choline salt applications only were used as this action speci fically sought registration for 2,4

- D choline salt product use in conjunction with GE soybean and corn with resistance traits.

Volatilization modeling for a single day was completed using Probabilistic Exposure and Risk model for fum igants (PERFUM). There are a variety of factors that potentially affect the emission rates of 2,4

- D cholin e salt and subsequent offsite transport and to the extent possible, these factors were considered. They include field condition ( e.g ., bare soil,11

growing, or mature crop canopy), field parameters ( e.g. , soil type, moisture, etc.), formulation type, meteor ological conditions, and application scenario ( e.g ., rate, method). Flux estimates from all monitored trials, a number of field sizes, and various meteorological data were used with PERFUM to estimate risk based on the 2,4

- D choline salt field volatility s tudy data.

The field volatility study suggests that volatilization of 2,4

- D choline salt from treated crops does occur and could result in bystander exposure to vapor phase 2,4

- D choline salt

. However, r esults of PERFUM modeling indicate that airborne con centrations, even at the edge of the treated fields, are not above our levels of concern.

4. Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. Off

- target movement of pesticides can occur via many t ypes of pathways and it is governed by a variety of factors. Sprays that are released and do not deposit in the application area end up off

- target and can lead to exposures to those it may directly contact. They can also deposit on surfaces where contact w ith residues can eventually lead to indirect exposures ( e.g. , children playing on lawns where residues have deposited next to treated fields). The potential risk estimates from these residues can be calculated using drift modeling coupled with methods empl oyed for residential risk assessments for turf products.

The approach to be used for quantitatively incorporating spray drift into risk assessment is based on a premise of compliant applications which, by definition, should not result in direct exposures to individuals because of existing label language and other regulatory requirements intended to prevent them. Direct exposures would include inhalation of the spray plume or being sprayed directly. Rather, the exposures addressed here are thought to

occur indirectly through contact with impacted areas, such as residential lawns, when compliant applications are conducted. Given this premise, exposures for children (1 to 2 years old) and adults who have contact with turf where residues are assumed to have dep osited via spray drift thus resulting in an indirect exposure are the focus of this analysis analogous to how exposures to turf products are considered in risk assessment.

Several currently

- registered 2,4

- D products have labels that allow for use on turf, thus it was considered whether the risk assessment for that use may be considered protective of any type of exposure that would be associated with spray drift. If the maximum application rate on crops adjusted by the amount of drift expected is less than or equal to existing turf application rates, the existing turf assessment is considered protective of sp ray drift exposure. The maximum single application rate of 2,4

- D choline salt on GE corn and soybean is 1 lb ae/acre. This is less than the previously r egistered application rate on t urf of 1.5 lb ae/acre, which was previously assessed and was updated based on the revised Standard Operating Procedures ( SOPs ) for Residential Exposure Assessment. Thus, even if 100% of the application rate of the choline sal t formulation on GE corn and soybean is deposited on an adjacent lawn, calculated risk estimates from drift are not be of concern.12

Again, this is because all existing registered uses on lawns had been previously assessed and no risks of concern were identi fied.

5. Aggregate Risk Assessment

In accordance with the FQPA, EPA must aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating expo s ures and risks from various sources, EPA considers both the route and duration of exposure.

a. Acute Aggreg ate Risk

The acute aggregate risk assessment includes only food and water exposure. The acute food plus drinking water risk estimates are not of con cern to EPA (≤100% aPAD) at the 95 th percentile of the exposure distribution for the general population and all population subgroups.

b. Short

- Term Aggregate Ris k

The short

- term aggregate risk assessment includes food, water, and residential exposure. The resulting short

- term aggregate risks are not of concern to EPA (MOEs > LOC of 100) for adults and childre n.

c. Intermediate

- Term Aggregate Risk

Intermediate

- term residential exposures are not likely because of the intermittent application of 2,4

- D by homeowners; therefore, the intermediate

- term aggregate risk assessment includes only food and drinking water exposure, and are less than or equivalent to the chronic food plus drinking water exposure. The chronic food plus drinking water risk estimates are not of concern to EPA for the general population and all population subgroups.

d. Long

- Term Aggregate Risk

The chronic (long

- term) aggregate risk assessment includes only food and water exposure. The chronic food plus drinking water risk estimates are not of concern to EPA for the general population and all population subgroups.

6. Occupational Risk Assessment

a. Short

- and Intermediate

- Term Handler Risk

EPA uses the term occupational handler to describe people who mix, load and / or apply pesticides professionally (e.g., farmers, professional pesticide applicators). Based on13

the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used (mixing/loading liquid grou n dboom application, applying spray by groundboom equipment) , occupational handler exposure is expected from the new

uses.
Occupational handler ris k estimates are not of concern (i.e., MOEs > LOC of 300) for all scenarios for use of 2,4

- D choline salt on GE corn and soybean. At baseline personal protective equipment ( PPE ) (i.e., no respirator), the occupational handler inhalation MOE is 4,900 for mix er/loaders and 3,200 for applicators using groundboom equipment.

b. Short

- and Intermediate

- Term Post

- Application Risk

EPA uses the term post

- application to describe exposures that occur when individuals

are present in an environment that has been previo usly treated with a pesticide (also referred to as reentry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Post

- application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical’s degradation properties. In addition, the timing of p esticide applications, relative to harvest activities, can greatly reduce the potential for post

- application exposure.

i. Dermal Post

- application Risk

There is no potential hazard via the dermal route for 2,4

- D choline salt ; therefore, a quantitative occ upational post

- application dermal risk assessment was not completed.

ii. Inhalation Post

- application Risk

Based on the EPA’ s current practices, a quantitative occupational post

- application inhalation exposure assessment was not performed for 2,4

- D cholin e salt at this time primarily because of the low acute inhalation toxicity (Toxicity Category III) and vapor pressure (1.4 x 10

- 7 mm Hg at 25°C for 2,4

- D acid).

Although a quantitative occupational post

- application inhalation exposure assessment was not p erformed, an inhalation exposure assessment was performed for occupational/commercial handlers and showed no risks of concern . Handler exposure resulting from application of pesticides outdoors is anticipated to result in higher exposure than post

- applicat ion exposure. Therefore, it is expected that these handler inhalation e xposure estimates will be protective of most occupational post

application inhalation exposure scenarios. Furthermore, a quantitative volatilization inhalation exposure assessment was a ssessed for bystanders and indicates no risk of concern for bystanders.14

III. Environmental Risk

A summary of the environmental fate and ecological effects and risks of 2,4

- D choline salt as

assesse d in the Agency document titled

, Ecological Risk Assessme nt for the Section 3 New Use Registration of 2,4

- D Choline Salt on Soybean with DAS 68416

- 4 (2,4

- D Tolerant) and 2,4

- D + Glyphosa te Tolerant Corn and Field Corn, and its addendums entitled, Addendum to 2,4

- D Choline Salt Section 3 Risk Assessment: Refined Endangered Species Assessment for Proposed New Uses on Herbicide

- Tolerant Corn and Soybean and Addendum to 2,4

- D Choline Salt Section 3 Risk Assessment: Refined Terrestrial Plant Exposure Estimates and Effects Determination are provided below.

A. Environment al Fate

1. Degradation

The degradation of 2,4

- D occurs via oxidative microbially

- mediated mineralization in terrestrial environments, and photodegradation in water. Degradation under aerobic soil conditions is rapid to moderately rapid with half

- lives rang ing from 1.4 to 12.4 days

. In terrestrial field dissipation studies, 2,4

- D acid half

- lives range from 1.1 days to 42.5 days. There are three major degradates (2,4

- D ichlorophenol (2,4

- DCP), 1,2,4

- bezenetriol, and chlorohydroquinone (CHQ)) and three minor degradates (4

- chlorophenol, 4

- CPA and 2,4

- DCA) of 2,4

- D. Formation of these degradates varies by environmental component (e.g., soil vs. water), and availability of oxygen. Under natural conditions certain degradates may be less likely to occur.

2. Mobili ty

Under most environmental conditions 2,4

- D is an anionic acid, hence it is expected to be mobile to moderately mobile. Risk of bioaccumulation is low for 2,4

- D given the low value of the log octanol/water partition coefficient (log Kow = 0.18 at neutra l pH). The vapor pressure (1.4 × 10

- 7 mm Hg) and Henry's Law Constant (8.56 x 10

- 6 atm

- m3/mol) indicate that 2,4

- D acid has a low volatility. R esults from a field volatility study performed with 2,4

- D choline salt, 2,4

- D ethylhexyl ester (EHE), and 2,4

- D dimethylamine salt (DMA salt) indicate that the estimated volatility flux rate of 2,4

- D choline salt is lower than the EHE and DMA salt formulations.

B. Ecological Risk

Ecological risk characterization for 2,4

- D choline salt integrates the results of the exposure and ecotoxicity data to evaluate the likelihood of adverse ecological effects. The means of integrating the results of exposure and ecotoxicity data is called the risk quotient method. For this method, risk quotients (RQs) are calculated by div iding exposure estimates by ecotoxicity values, both acute and chronic (RQ = Exposure / Toxicity). RQs are then compared to EPA’s levels of concern (LOCs). The LOCs are criteria used by the A gency to indicate potential risk
to non

- target organisms. The criteria indicate whether a pesticide, when used as directed, has the potential to cause adverse effects to non

- target organisms

.15

The risk quotient method was used to determine if 2,4

- D choline salt has the potential to cause adverse effects to non

- tar get organisms based on the new use patterns for 2,4

- D choline salt. Birds are considered a surrogate for terrestrial

- phase amphibians and reptiles, and freshwater fish are considered surrogates for aquatic

- phase amphibians, in the absence of taxa

- specific data. Submi tted ecotoxicity data for 2,4

- D choline salt (algae, freshwater fish, and honeybee) support bridging 2,4

- D choline salt to 2,4

- D acid ecotoxicity data. Only the most sensitive 2,4

- D toxicity value from the broader 2,4

- D dataset w ere used in r isk quotient calculations, as needed. The major degradates of 2,4

- D were considered, and all except 2,4

- DCP were eliminated as likely degradates of concern. 2,4

- DCP is a major degradate in certain aquatic environments; therefore, 2,4

- D and 2,4

- DCP were co nsidered stressors of concern in aquatic environments, and 2,4

- D alone was considered in terrestrial environments.

The results of this screening

- level risk assessment indicate that risks did not result in RQs that exceeded the Agency’s LOC for freshwater fish, aquatic

- phase amphibians, estuarine/marine fish, freshwater invertebrates, estuarine/marine invertebrates, terrestrial insects , or aquatic plants for either acute or chronic exposures. Risks for chronic exposures to birds, reptiles, and land

- phase amphibians do not result in RQs that exceed the Agency’s LOC.

The screening

- level analysis indicates that risks for acute exposures to birds, reptiles, and land

- phase amphibians do result in RQs that exceed the Agency’s LOC for acute exposures. Additiona lly, risks for mammals resulted in RQs that exceed the Agency’s LOC for both acute and chronic exposures. Risks for terrestrial plants resulted in RQs that exceed the Agency’s LOC for both terrestrial monocots and terrestrial dicots. The following section s discuss the results of the risk quotient analyses for these taxonomic groups with potential risk above the Agency’s LOC, characterization of those risks, and describe mitigation measures to reduce these potential risks of exposure to 2

, 4

- D choline salt

.

1. Risk to Birds:

The risk quotient analysis indicates that p otential risks from the new 2,4

- D choline salt uses result in RQs that exceed the Agency’s LOC for birds only on an acute basis.

Acute Risk : The acute oral toxicity study was conducted with the northern bobwhite quail and resulted in a classification of “moderately toxic” to birds on an acute oral basis. Toxic symptoms prior to death were lethargy, reduced reaction to external stimuli, depression, lower limb weakness, wing droop, prostrate p osture, loss of righting reflex, and a ruffled appearance. Sub

- lethal effects included a drop in body weight at two of the treatment levels (218.7 and 135 mg ae/kg

- bw). There was also a decrease in food consumption at the 218.7 mg ae/kg

- bw treatment level during the first 3 days after dosing, but this was compensated for by a 2

- 3 times higher food consumption rate from days 4 through 14.

Two acute dietary studies were available, classifying 2,4

- D choline salt as “practically non

toxic” on an acute dietary basis to birds. No mortalities occurred in either study. The northern bobwhite quail study exhibited a slight decrease in body weight gain at the 3035 and 1706 mg ae/kg

- diet treatment levels. The mallard duck study exhibited a decrease in16

body weight g ain and feed consumption, but only at the highest treatment level (3035 mg ae/kg

- diet).

In order to make the most conservative risk estimation, acute toxicity risk quotients were based on the oral toxicity study for the northerner bobwhite quail. The r is k quotients for birds of 0.01 to 4.18 were then compared to the Agency’s screening level of concern for

non

- listed species (RQ>0.5). The Agency risk screening assessment employed residue estimates based on reasonable upper bound assumptions and the maximu m labeled rate of the pesticide to determine the RQ values. At this high end exposure, residues for a variety of food items combined with a variety of body sizes triggered the screening concern threshold when compared to the most sensitive oral dose toxic ity estimate. While concern levels are triggered, further consideration of all lines of evidence does suggest that risks under more usually encountered circumstances may be lower. For example, high end residues compared to toxicity study endpoints using chemical s actually incorporated in the animal’s diet do not trigger non

- listed species concerns, suggesting that 2,4

- D choline consumed in the diet may possibly be less available than assumed using dose

- based
exposures. Further, more frequently expected r esidues levels, such as mean or median estimates of exposure would be lower by a factor of two or more, suggesting that residues are often not likely to trigger concerns for many food items. In addition, screening estimates of exposure and risk are maxima l at the actual point of application, right on the field. Available information in the Agency risk assessment indicates that the transport of pesticide off field by spray drift decreases with distance, suggesting that exposures to 2,4

- D choline salt and a ttendant risks can be substantially lower for organisms with territories established at distance from the field. With this last line of evidence in mind, a mitigation

measure has been incorporated into the pesticide label that require s a 30

- foot pesticide application setback from areas likely to be habitat for birds in order to further reduce off

site exposure for birds.

2. Risk to Mammals:

The screening level assessment indicates that potential ri sks from the new 2,4

- D choline salt uses result in RQs that e xceed the Agency’s LOC for mammals in both acute and chronic scenarios.

Risk quotients for mammals exceeded the Agency’s LOCs for mammals for acute dose

based exposure and chronic dose

- based and dietary

- based exposure. The chronic dose

based LOC (1.0) wa s exceeded for all size classes of mammals consuming all food items except for seeds. The chronic dietary

- based LOC (1.0) was exceeded for diets of short grass, tall grass, broadleaf plants, and arthropods for mammals.

Acute Risk: The acute toxicity of 2,4

- D choline salt to mammals was assessed using the oral gavage study conducted on laboratory rat. Based on the LD 50 , 2,4

- D choline salt is moderately toxic to mammals on an acute basis. The dose

- based acute mammalian risk quotients ranged from <0.01 to 0.57

.17

The acute LOC (0.5) was exceeded only for small mammals consuming short grass. All other scenarios resulted in RQs that did not exceed the Agency’s LOC. Because this assessment is conducted under screening level assumptions designed to be conserv ative (i.e., in the treated field, maximum use rates, eating only the single food source that is expected to result in the greatest exposure, high

- end environmental exposures), EPA expects that actual risks to these mammals is lower. Any deviation from th is worst case scenario would result in lower risk estimates and would be expected to result in RQs lower than the Agency’s LOC.

Chronic Risk: The two

- generation chronic study with the laboratory rat indicated endpoints in parental and offspring growth to be the most sensitive. Some reproductive effects were also identified. Chronic dose based risk quotients ranged from 0.32 to 50.2. The chronic LOC of 1.0 was exceeded for all size classes of mammals consuming all food items except for seeds. Chronic diet ary based risk quotients ranged from 0.36 to 5.78.

As in the case for birds

, risk quotients for mammals span an appreciable range of
outcomes. The principal focus is on the concern levels for reproduction effects, where RQ values range from <1 to 50, an d span the Agency’s screening level of concern for non

listed species (RQ > 1).

Again, the Agency risk screening assessment employed residue estimates based on reasonable upper bound assumptions and the maximum labeled rate of the pesticide to determine t he RQ values. Consideration of more realistic residue estimates and other lines of evidence such as food preferences and foraging ranges relative to distance from the site of application can lead to markedly reduced concerns for adverse effects in larger mammals with more varied diets, with larger home ranges with increased potential to be feeding well away from treatment areas.

Consideration of these lines of evidence also produces reduced risk estimates for small herbivorous mammals but do es not reduc e risk estimates for these organisms to the point that concern levels are not exceeded. As in the case for birds

, the provision of a 30

- foot buffer from areas potentially comprising habitat for such mammals is intended to reduce the areas where such risks may occur

.

3. Risk to Plants:

For seedling emergence, onion was the most sensitive monocot and lettuce was the most sensitive dicot. Shoot length was the most sensitive parameter for both species, as well as for four of the other species that were tested (tomato, cucumber, soybean, turnip). Seedling emergence was the most sensitive parameter for one species (cabbage) and other toxicological observations included chlorosis and leaf curl. Onion and lettuce were also the most sensitive species for the veget ative vigor test. The most sensitive parameter for onion was fresh weight. Leaf distortion and necrosis were also observed. The most sensitive parameter for lettuce was dry weight. Chlorosis, necrosis, leaf curl, stem curl, wilt, and adventitious growt h were also reported as effects. Overall, the vegetative vigor18

and seedling emergence studies indicate that 2,4

- D choline salt is slightly more toxic to dicots than monocots.

As is expected with herbicides, terrestrial plants are sensitive to 2,4

- D resid ues. All terrestrial plant risk quotients exceeded the LOC (1.0). Risk quotients ranged from 1 to 90.62 for monocots and 12.35 to 1085.11 for dicots. In the initial assessments for the proposed decision ( Ecological Risk Assessment for the Section 3 New Use Registration of 2,4

- D Choline Salt on Soybean with DAS 68416

- 4 (2,4

- D Tolerant) and 2,4

- D + Glyphosa te Tolerant Corn and Field Corn, and its addendums entitled, Addendum to 2,4

- D Choline Salt Section 3 Risk Assessment: Refined Endangered Species Assess ment for Proposed New Uses on Herbicide

- Tolerant Corn and Soybean ), r isk was attributed to both spray drift and runoff from treated fields , which indicated that effects could be predicted from the new uses of 2,4

- D choline salt to terrestrial plants.

Alth ough the risk quotient analysis indicate d there may be risks to terrestrial plants from runoff and spray drift, data conducted on the Enlist Duo TM formulation demonstrates that the formulation has some properties that will reduce spray drift to non

- target areas. The registrant submitted additional studies for spray drift analysis, using the specific low drift nozzle s and the specific Enlist Duo TM formulation. The analysis indicates that this 2,4

- D choline salt formulation applied through specific low drif t nozzles is protect ive of non

listed dicots from exposures of 2,4

- D choline when an adequate buffer is incorporated between the application equipment and the downwind edge of the treated field

. Therefore, to mitigate against potential risks to plant s f rom spray drift , the product labeling require s the use of a 30

- foot buffer zone and specific nozzle specifications, thus reducing the potential spray drift exposure of non

- target plants to 2,4

- D choline salt residues. 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 asso ciated 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 the public comments, the Agency

rec onsidered the runoff risks and the effects of the proposed mitigation to limit off

- site runoff in listed species effects determinations.

Spray drift and runoff were considered as exposure pathways for 2,4

- D choline to terrestrial plants and aquatic organ isms. 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 u p to the edge of the field; 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 imple mented vegetative buffer or filter strips in a few instances to lessen19

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 o f 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 photosy nthates 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 in hibition 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 rainfa st 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 habi tat. 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 f

or 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 th e 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 pred icted by TerrPlant for a single runoff event.

4. Endangered Species for 2,4

- D Choline Salt

A summary of the endangered species assessment for 2,4

- D choline salt as assessed in the EPA document titled, Addendum to 2,4

- D Choline Salt Section 3 Risk Assessmen t: Refined Endangered Species Assessment for Proposed New Uses on Herbicide

- Tolerant Corn and Soybean, is provided below

. See also Addendum to 2,4

- D Choline Salt Section 3 Risk Assessment: Refined Terrestrial Plant Exposure Estimates and Effects Determinat ion

. In the environmental risk assessment performed for new uses of 2,4

- D choline salt on GE corn and soybean, EPA determined that direct concerns were unlikely for aquatic plants (vascular and non

- vascular), freshwater fish (acute and chronic), estuarine /marine fish (acute and chronic), freshwater invertebrates (acute and chronic), estuarine/marine invertebrates (acute and chronic), and terrestrial insects. While direct concerns were found to be unlikely for birds, reptiles and terrestrial phase amphibia ns for chronic risk, they20

could not be excluded for acute risk. In addition, potential direct risk concerns could not be excluded for mammals (acute and chronic) and terrestrial plants. Indirect effect risk concerns are possible for any species that has dependencies on species that are directly affected.

Registration of Enlist Duo TM is being registered for use in the states of Illinois, Indiana, Iowa, Ohio, South Dakota, and Wisconsin. Based on EPAs LOCATES database and data submitted by DAS , 53 listed species were identified as inside the “action area” (area of concern where use of pesticide may result in exposure to endangered species) associated with the new GE corn and soybean uses within these six states. Additional states may be added to the label ing once an assessment is completed and demonstrates that a no effects determination is appropriate for any such state

. The following criteria were used to asses s listed species in the spray drift action area :

 For listed individuals inside the action a rea but not part of an affected taxa nor relying on the affected taxa for services involving food, shelter, biological mediated resources necessary for survival and reproduction, use of a pesticide would be determined to have “no effect .”

 For listed indivi duals outside the action area, use of a pesticide would be determined to have “no effect .”

 Listed individuals inside the action area may either fall into the “no effect” or “may effect” categories depending upon their specific biological needs and circumst ances of exposure.

 Those that fall under the “may effect” category are found to be either “likely” or “not likely to adversely affect” the listed species.

 A “likely” or “not likely to adversely affect” determination is made using criteria that categori zes the effect as insignificant, highly uncertain, or wholly beneficial.

Spray drift mitigation language on the label is intended to limit off site transport of 2,4

- D choline salt in spray drift. Therefore, EPA expects that spray drift will remain conf ined to the 2,4

- D choline treated field . Consequently, EPA concluded that spray drift will have no effect on 49 of the 53 species originally identified as potentially at

- risk because they are not expected to occur on corn and soybean fields.

The 4 rema ining listed species that were not ruled out because their range contains areas that include treated fields were considered in more depth to refine the assessment : American burying beetle, Canada lynx, Indiana bat, and whooping crane . Species specific bio logical information and 2,4

- D choline salt use patterns were considered. After utilizing processes such as refined modeling incorporating species specific information and migration habits, EPA made a determination that exposure occurring on the field woul d have no effect on these species.

Additionally, as stated above, the Agency reconsidered the potential effects attributed to runoff. That analysis concluded that in light of the refined assessment, combined with proposed mitigations such as a mandatory r ainfast period, the Agency has determined that risks to terrestrial plants from runoff as predicted by TerrPlant modeling are grossly21

overestimated in the case of 2,4

- D choline and a finding of no effects to listed or non

- listed species off the treated fie ld is appropriate.

For more details on these findin gs, refer to the EPA document titled, Addendum to 2,4

- D Choline Salt Section 3 Risk Assessment: Refined Endangered Species Assessment for Proposed New Uses on Herbicide

- Tolerant Corn and Soybean.

As note d earlier in this decision, glyphosate is already registered for these uses and did not undergo a listed species review as part of the assessment for this pesticide product. However, glyphosate currently is in the registration review process and a listed s pecies analysis will be part of that process.

IV. Resistance Management

The emergence of herbicide resistant weeds is an increasing problem that has become a significant economic issue to growers. This has led to a concern that the use of 2,4

- D on GE crops may result in the development of more resistant weeds. In an effort to address this issue going forward, EPA is requir ing DAS to develop an Herbicide Resistance Management (HRM) plan that will promot e h erbicide resistance management efforts. T he pla n mandates that DAS must investigate any report s of lack of herbicide efficacy

. The initial mechanism users can use for communicating directly with DAS is a toll

- free number to get advice on how to resolve any uncontrolled weeds.

Academia, growers, USDA, and other leaders involved with pest management all acknowledge the importance of scouting in herbicide resistance management. Fields should be scouted before application of Enlist Duo TM to identify the weed species present as well as their stage of grow th. Fields should be scouted after each Enlist Duo TM application to identify poor performance or likely resistance . In the event that a user encounters a non

- performance issue, the toll

- free number is available to report the issue, which will initiate an intervention against that weed population.

W hen a lack of herbicide efficacy is identified, DAS or its representative will investigate and conduct a site visit if needed, to evaluate the lack of herbicide efficacy using decision criteria identified by le ading weed science experts (Norsworthy, et al. 2012 ), in order to determine if “likely herbicide resistance” ( poss i ble resistance) is present. This is distinct from the term “lack of herbicide efficacy

, ” as explained below. For purposes of this decision, a report of lack of herbicide efficacy to DAS will be the trigger to start this investigation

.

“ Lack of herbicide efficacy ” refers to inadequate weed control with various possible causes, including but not limited to: application rate, stage of gr owth, environmental conditions, herbicide resistance, plugged nozzle, boom shut off, tank dilution, post

- application weed flush, unexpected rainfall event, weed misidentification , etc . EPA recognizes that it can be challenging
to distinguish emerging weed resi stance from other causes at an early stage. Therefore, EPA has selected criteria that should be used to evaluate instances of “lack of herbicide efficacy” to determine if they do in fact constitute “likely herbicide resistance

. ” These “likely herbicide

r esistance” criteria are : (1) failure to control a weed species normally controlled by the herbicide22

at the dose applied, especially if control is achieved on adjacent weeds; (2) a spreading patch of uncontrolled plants of a particular weed species; and (3 ) surviving plants mixed with controlled individuals of the same species (Norsworthy

, et al., 2012). The identification of one or more of these criteria in the field indicates “likely herbicide resistance” is present.

When DAS or its representative appli es the Norsworthy, et al., criteria cited above and likely herbicide resistance is identified, then to the extent possible, DAS must proactively engage with the grower to control and contain likely resistant weeds in the infested area. This may be accompl ished by re

- treating with an herbicide or using mechanical control methods. After implementing these measures DAS must follow

- up with the growers , to the extent possible, to determine if the likely resistant weed(s) has /have been controlled

. DAS must als o annually report to EPA findings of likely herbicide resistance. In addition, prior to implementing control

measures , DAS will make best efforts to obtain s amples of the likely herbicide resistant weeds and/or seeds, and as soon as practicable, laborator y or greenhouse testing must be initiated in order to confirm whether resistance is the reason for the lack of herbicide efficacy.

Beginning January 15 th , 2016

, on or before January 15 th of each year, DAS will submit annual summary reports to EPA. These reports must include a summary of the number of instances of likely and confirmed resistance to Enlist Duo TM by weed species, crop, county and state. They will also summarize the status of laboratory or greenhouse testing for resistance. The annual
repor ts will also address the disposition of incidents of likely or confirmed resistance reported in previous years.

DAS must report annually any inability to control likely resistant weeds to relevant stakeholders. To accomplish this, EPA expects that DAS will establish a website to facilitate delivery of resistance information.

Several management practices that are designed to help users avoid initial occurrences of weed resistance appear on the product labeling under the Herbicide Resistance Management h eading of the label. These practices are discussed in Section VII.B.3 of this document.

Refer to Section VII.C below for EPA’s terms of registration to address the issue of weed resistance.

V. Response to Comments

The Agency received 417,301 comments i n response to the public participation process (Docket ID : EPA

- HQ

- OPP

- 201 4

- 0195) regarding EPA ’ s proposed decision to register the use of 2,4

- D choline salt on GE 2,4

- D and glyphosate tolerant corn and soybeans. Comments received were both in favor of and opposed to the de cision to register Enlist Duo TM

. 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, con sistent with applicable statutory standards. Also, EPA strives to document and explain the basis of its regulatory decisions through these and other public documents

. EPA reviewed and evaluated all comments received during the comment period before issuin g this final regulatory decision. Since many of the comments covered similar concerns, the comments were grouped into major23

topic areas. Please see Response to Public Comments Received Regarding New Uses of Enlist Duo TM on Corn and Soybeans

, dated Octobe r 1 4 , 2014

, for the Agency response to these
comments

.

VI. Benefits

The need for additional tools to manage resistant weeds has become important as resistance to glyphosate and other herbicides has become a significant economic and pest management issue to growers. The new uses of 2,4

- D choline salt will expand options for weed control in corn and soybean and enable control of additional broadleaf weeds, including s ome resistant biotypes. Previously registered uses of non

- choline 2,4

- D in corn allow ed f or over

- the

- top broadcast applications o nly up to 8 inches tall which are increased to up to 48 inches tall with GE 2,4

- D resista nt corn. Similarly, the previously registered use of non

- choline 2,4

- D in soybeans allowed
pre

- plant applications only, howeve r new uses of 2,4

- D choline salt expand uses to include over

the

- top broadcast applications to GE soybeans. T he addition of this new tool to the production of soybeans is expected to have a significant impact to broadleaf weed control.

The introduction o f a premix formulation combining 2,4

- D choline salt and glyphosate to be used on Enl istTM corn and soybeans will provide additional benefits. The use of a premix of 2,4

- D choline salt and glyphosate utilizes multiple mechanisms of action which delays the d evelopment of herbicide resistant weeds. The pairing of two well

- established herbicides into a systems approach with a GE crop will allow growers and applicators the opportunity to control many weeds in a way which fulfills the important principle of usin g multiple mechanisms of action, which the weed science community has been touting for many years.

The use of 2,4

- D choline salt and glyphosate on the Enlist TM corn and soybean seed technology will provide efficacious control of broadleaf weeds later in the growing season

, resulting in reduced spread and persistence of many broadleaf weeds

, thus maintaining yields. If widely adopted by growers, the herbicide combination in this wee d control systems approach will potentially prolong the use of the glyp hosate technology if the two herbicides are controlling weeds that are not resistant to either herbicide. In addition, this system will maintain the positive effect of reducing the need for tillage, thus preventing unnecessary erosion, in areas where 2,4

- D choline salt will control glyphosate resistant broadleaf weeds.

The use of the 2,4

- D choline salt offers environmental benefits over the use of traditional forms of 2,4

- D as well. Specifically, EPA has determined that the choline salt is less volatile than other forms of 2,4

- D

. T he 2,4

- D choline salt also demonstrates less potential for off

- site movement through spray drift than other forms of this herbicide . This will reduce the potential for damage
to non

- target plants, including vulnerable crops, w here 2,4

- D choline salt is to be used.

VII

. Registration Decision

Based on these considerations, consistent with the requirements of FIFRA Sec. 3(c)( 7 ) ( B )

, EPA concludes that (i) the Agency has satisfactory data pertaining to the expanded uses of Enlist D uo TM on corn and soybeans ; and (ii) approving this application as set forth below will not increase the risk of any unreasonable adverse effects on human health or the environment.24

Accordingly , the Agency has grant ed this registration with certain terms n ecessary to ensure that if weed resistance is likely, EPA can act quickly to address the problem

.

A. Data Requirements

There are no outstanding data requirements required to support the registration of this action. Although there are data that may be requi red in connection with registration review activities for 2, 4

- D and glyphosate , those requirements are generic to 2,4

- D and/or glyphosate use s and products in general and will be handled in accordance with the registration review process.

B. Labeling Require ments

In order to mitigate risks to non

- target plants and animals, label language is required that is intended to keep the pesticide on the treatment area, thereby reducing the potential for exposure of non

- target plants and animals. For example, spray d rift management language is required on the occupational/commercial labeling that advises users of applicator responsibilities and requires specific techniques to reduce the possibility of spray drift. In addition, surface and ground water advisories are required on all labeling, which may further reduce residues in drinking water and ex posure of non

- target organisms.

1. Worker Protection

Do not apply this product in a way that will contact workers or other persons, either directly or through drift. Only pro tected handlers may be in the area during application. For any requirements specific to your state or tribe, consult the agency responsible for pesticide regulation.

Do not enter or allow worker entry into treated areas during the restricted entry interv al (REI) of 48 hours.

PPE required for early entry to treated areas that is permitted under the Worker Protection Standard and that involves contact with anything that has been treated, such as plants, soil, or water, is:

 Long

- sleeved shirt and long pan ts

 Chemical resistant gloves as specified under category A

 Shoes plus socks

 Protective eyewear (goggles, faceshield, or safety glasses)

Some materials that are chemical

- resistant to this product are barrier laminate, butyl rubber >14 mils, nitrile rubbe r >14 mils, neoprene rubber >14 mils, natural rubber >14 mils, polyethylene, polyvinyl chloride (PVC) >14 mils, or viton >14 mils. If you want more options, follow the instructions for category A on an EPA chemical

- resistance category selection chart.

2. Envi ronmental Hazards25

This pesticide is toxic to fish and aquatic invertebrates. Do not apply directly to water, to areas where surface water is present, or to intertidal areas below the mean high water mark. Drift or runoff may adversely affect aquatic inv ertebrates and non

- target plants. Drift and runoff may be hazardous to aquatic organisms in water adjacent to treated areas. Do not contaminate water when disposing of equipment washwaters or rinsate.
This chemical has properties and characteristics ass ociated with chemicals detected in groundwater. The use of this chemical in areas where soils are permeable, particularly where the water table is shallow, may result in groundwater contamination. Application around a cistern or well may result in contam ination of drinking water or groundwater.

3. Resistance Management

To aid in the prevention of developing weeds resistant to this product, the following steps should be followed:

 Scout fields before application to ensure herbicides and rates will be approp riate for the weed species and weed sizes present.

 Apply full rates of Enlist Duo for the most difficult to control weed in the field at the specified time (correct weed size) to minimize weed escapes.

 Scout fields after application to detect weed escapes or shifts in weed species.

 Report any incidence of non

- performance of this product against a particular weed species to your Dow AgroSciences retailer, representative or call 1

- 855

- ENLIST

- 1(1

- 855

- 365

- 4781)

 If resistance is suspected, treat weed escapes wit h an herbicide having a mode of action other than Group 4 or 9 and/or use non

- chemical methods to remove escapes, as practical, with the goal of preventing further seed production.

Additionally, users should follow as many of the following herbicide resis tance management practices practical:

 Use a broad spectrum soil

- applied herbicide with other modes of action as a foundation in a weed control program.

 Utilize sequential applications of herbicides with alternative modes of action.

 Rotate the use of this product with non

- Group 4 and non

- Group 9 herbicides.

 Incorp
orate non

- chemical weed control practices, such as mechanical cultivation, crop26

rotation, cover crops and weed

- free crop seeds, as part of an integrated weed control
program.

 Thorou ghly clean plant residues from equipment before leaving fields suspected to contain resistant weeds.

 Avoid using more than two applications of Enlist Duo and any other Group 4 or Group 9 herbicide within a single grow ing season unless in conjunction with another mode of action herbicide with overlapping spectrum.

 Manag e weeds in and around fields, during and after harvest to reduce weed seed production.

4. Spray Drift Management

a. Tank Mix Instructions:

TANK

- MIXING INSTRUCTIONS:

ENLIST Duo may only be tank

- mixed with produ cts that have been tested and found not to adversely affect the spray drift properties of Enlist Duo. A list of those products may be found at EnlistTankmix.com DO NOT TANK

- MIX ANY PRODUCT WITH Enlist Duo unless:

 You check the list of tested products fou nd not to adversely affect the spray drift properties of Enlist Duo at EnlistTankmix.com no more than 7 days before applying Enlist Duo; and

 The product you tank

- mix with Enlist Duo is identified on that list of tested products.

b. Droplet Size:

Use of Enl ist Duo requires the use of specific nozzle and spray pressure combinations. A chart is included in the product label that lists the specific nozzle and pressure combinations that are allowed.

c. Groundboom Application:

Use the minimum boom height based upon the nozzle manufacturer’s directions. Spray drift potential increases as boom height increases. Spray drift can be minimized if nozzle height is not greater than the maximum height specified by the nozzle manufacturer for the nozzle selected.

d. Wind Sp eed:

Do not apply at wind speeds greater than 15 mph.

e. Temperature and Humidity:27

When making applications in low relative humidi ty, set up equipment to produce larger droplets to compensate for evaporation. Droplet evaporation is most severe when conditi ons are both hot and dry.

f. Temperature Inversions:

Applications should not occur during a local, low level temperature inversion because drift potential is high. Temperature inversions restrict vertical air mixing, which causes small suspended droplets t o remain in a concentrated cloud. This cloud can move in unpredictable directions due to the light variable winds common during inversions. Temperature inversions are characterized by increasing temperatures with altitude and are common on nights with li mited cloud cover and light to no wind. They begin to form as the sun sets and often continue into the morning. Their presence can be indicated by ground fog; however, if fog is not present, inversions can also be identified by the movement of the smoke from a ground source generator. Smoke that layers and moves laterally in a concentrated cloud (under low wind conditions) indicates an inversion, while smoke that moves upward and rapidly dissipates indicates good vertical air mixing.

g. Application Restrict ions:

D o not aerially apply this product.
Do not irrigate treated fields for at least 24 hours after application of Enlist Duo

.
Do not make application of Enlist Duo if rain is expected in the next 24 hours.

5. Protection of Sensitive Areas:

a. Buffer

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 ( e xcept those crops listed in the “Susceptible Plants” section)

.

 Agricultural fields tha t 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.

b. Wind Direction

To maintain the required downwind buffer zone:

 Measure wind di rection prior to the start of any swath that is within 30 feet of a sensitive

area.28

 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.

6. Susceptible Plant s:
Do not apply under circumstances where spray drift may occur to food, forage, or other plantings that might be damaged or crops thereof rendered unfit for sale, use or consumption. Do not allow contact of herbicide with foliage, green stems, exposed

n on

- woody roots of crops, desirable plants; including cotton and trees, because severe injury or destruction may result. Small amounts of spray drift that may not be visible may injure susceptible broadleaf plants. Before making an application, please ref er to your state’s sensitive crop registry (if available) to identify any commercial specialty or certified organic crops that may be located nearby.

At the time of application, the wind cannot be blowing toward adjacent commercially grown tomatoes and ot her fruiting vegetables (EPA crop group 8), cucurbits (EPA crop group 9), grapes and cotton.

C. Registration Terms

EPA has determined that certain registration terms are needed to ensure that likely weed resistanc e as discussed in section IV will be adequate ly addressed. EPA believes that it is important to address likely weed resistance and not wait until confirmation that resistance has been found. EPA is basing the registration terms on a list of criteria, presented in the peer

reviewed publication, Nors worthy, et al., “Reducing the Risks of Herbicide Resistance: Best Management Practices and Recommendations,” Weed Science 2012 Special Issue: 31

– 62 (Norsworthy criteria).

1. Herbicide Resistance Management (HRM) Plan

EPA is issuing this registration with a term that requires DAS to have a n Herbicide Resistance Management (HRM) Plan for Enlist Duo TM . The HRM Plan will focus on educating growers on the appropriate use of EnlistTM technology. EPA is requiring that the HRM Plan must include the following meas ures that will reduce the potential for the development of weed resistance.

a. Investigation
EPA is requiring that DAS or its representative investigate reports of lack of herbicide efficacy as reported by users following “scouting.” When investigating any reports of lack of herbicide efficacy, DAS or its representative must make an effort to evaluate the field for “likely resistance” by applying the “Norsworthy criteria.”

b. Remediation
If “likely resistance” is found, EPA is requiring DAS to engage with the g rower to control and prevent the spread of likely resistant weeds in the affected area as well as requiring DAS to collect material , if possible, for further testing. DAS must provide the29

grower with specific information and recommendations to control and contain likely resistant weeds, including retreatment and/or other nonchemical controls, as appropriate, and if requested by the grower, DAS will assist the grower in implementing those additional weed control measures.

c. Annual Reporting of Herbicide Resis tance to EPA
EPA is requiring that DAS submit annual summary reports to EPA that include a summary of the number of instances of likely and confirmed weed resistance by weed species, crop, county and state. The annual reports must include summaries of the status of laboratory or greenhouse testing for resistance . The annual reports will also address the disposition of incidents of likely or confirmed resistance reported in
prev ious years. These reports will not replace or supplement adverse effects repor ting required under FIFRA 6(a)(2).

d. Reporting of Likely Resistance to other Interested Parties
EPA is requiring that DAS inform growers and other stakeholders of cases of likely resistance that are not resolved by the application of additional weed contro l measures.

e. Monitoring the use of Enlist Duo TM on EnlistTM Seed

EPA is requiring DAS to monitor whether Enlist Duo TM is being used on the EnlistTM seed purchased from DAS. EPA is requesting DAS provide EPA with a protocol to survey whether Enlist Duo TM is being used on EnlistTM seed purchased from DAS and not the non

- choline 2,4

- D products that are not registered for these application windows

.
f. Education

EPA is requiring DAS to develop an education program that will provide growers with the best available i nformation on herbicide resistance management.

2. EPA’s Continued Control over the Registration

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 unless this term is removed or modified by EPA. The date of expiration will be 5 years from the date of the Registration Notice if use in the first year is equal to or exceeds 100,000 acres. If use in the first year does not exceed 100,000 acres, the date of expirat ion will be 6 years from the date of Registration Notice. This will ensure that EPA retains the ability to easily modify the registration or allow the registration to terminate if necessary.

3. Geographic Limitation on Use of Enlist Duo TM

EPA is issuing this registration only to be sold and use d in Illinois, Indiana, Iowa, Ohio, South Dakota, and Wisconsin. Additional states may be added to the labeling in the future

.