Page 1 of 48 UNITED STATES ENVIRONMENTA L PROTECTION A GENCY

WASHINGTON, D.C. 20460 OFFICE OF PREVENTION, PESTICIDE

AND TOXIC SUBSTANCES

MEMORANDUM D ATE : 10 /22 /200 9 SUBJECT: Aminopy

ralid . Human Health Risk Assessment for the Prop osed Use on Field Corn (PP# 8F7 4 55 ) PC Code s : 0 0 51 0 0 (Aminopy ralid) and 005209 (Aminopy

ralid TIPA S alt) DP Barcode: D 359088 Decision No s . 401475 Registration No s . : 62719 - 519 Petition No s .: 8 F7 455 Regulatory Action: Section 3 Risk Assess Ty

pe: Single Chemical Aggregate Case No.: None T XR No.: None CAS No.: 150114 - 71 - 9 ( Aminopy ralid) 566191 - 89 - 7 ( Aminopy

ralid TIPA S alt) MRID No.: None 40 C FR: 180.371 FROM: Douglas Dotson, Ph.D., Chem ist

Karl yn Middleton , Toxicologist Zaida Figueroa , Industrial Hygien ist Risk Assessment Branch II Health Effects Division (7509P) THROUGH: Alan Lev y , Ph.D., Toxicologist

Michael Doherty , Ph.D. , Chemist Margarita Collant es , Biologist Richard Loranger, Ph.D., Senior Scientist Christina Swartz, Branch Chief Ris k A ssessment Branch II , Health Effects Division (7509P) TO: Kathry

n Montague/Joanne Miller, RM Team 23 Herbicide Branch Registration Division (7505P)Page 2 of 48 Ta ble of Contents 1.0 E xecuti ve Summary ................................ ................................ ................................ ............ 4 2.0 In gredient Profile ................................ ................................ ................................ ................ 8 2.1 Summary

of Registered/Proposed Uses ................................ ................................ ...... 9 2.2 Structure and Nomenclature ................................ ................................ ...................... 10 2.3 Phy sical and Chemical Properties ................................ ................................ ............. 11 3.0 Hazard Characterization/A ssessment ................................ ................................ ................ 11 3.1 Hazard and Dose - Response Characterization ................................ ........................... 11 3.1.1 Database Summary ................................ ................................ ............................... 11 3.1 . 1 .1 Sufficiency

of Studies/Data ................................ ................................ ...... 11 3.1 . 1 . 2 Mode of Action ................................ ................................ ......................... 1 2 3.1.2 Toxicological Effects ................................ ................................ ............................ 12 3.1.3 Dose Response ................................ ................................ ................................ ...... 13 3.1.4 FQPA ................................ ................................ ................................ .................... 13 3.2 Adsorption, Distribution, Metabolism, Excretion ................................ ..................... 13 3.3 FQPA Considerations ................................ ................................ ................................ 14 3. 3 .1 Adequacy

of the Toxicity

Database ................................ ................................ ...... 14 3. 3 .2 Evidence of Neurotoxicity ................................ ................................ .................... 14 3. 3.3 Developmental Toxicity Studies ................................ ................................ ........... 14 3.3.4 Reproductive Toxicity Study ................................ ................................ ................ 15 3. 3.5 Additional Information from L iterature Sources ................................ .................. 15 3.3.6 Pre - and/or Postnatal Toxicity ................................ ................................ .............. 15 3.3 .6.1 Determination of Susceptibility ................................ ................................ 15 3.3 .6. 2 Degree of Concern Analysis and Residual Uncertainties ......................... 15 3.3.7 Recommendation for Not Requiring a Developmental Neurotoxicity Study ....... 15 3. 4 FQPA Safet y Factor for Infants and Children ................................ ........................... 16 3 . 5 Hazard Identification and Toxicity Endpoint Selection ................................ ............ 16 3.5.1 Acute Reference Dose (aRfD) - General Population and Females 13 - 49 ............ 16 3.5. 2 Chronic Reference Dose ( cRfD) ................................ ................................ ........... 16 3.5.3 In cidental Oral Exposure ................................ ................................ ...................... 17 3.5.4 Dermal Absorption ................................ ................................ ................................ 17 3.5.5 Dermal Exposure ( Short - , Intermediate - , and Long - Term ) ................................ .. 17 3.5. 6 Residential and Occupational Dermal Exposure ................................ .................. 18 3.5.7 Residential and Occupational Inhalation Exposure ................................ .............. 18 3.5. 8 Level s of Concern for Occupational and Residential Exposure Assessments ...... 18 3.5.9 Recommendati on for Aggregate Exposure Risk Assessments ............................. 19 3.5.10 Classification of Carcinogenic Potential ................................ ............................... 19 3.5.11 Summary

of Toxological Doses and Endpoints ................................ .................... 20 3 .6 Endocrine disruption ................................ ................................ ................................ . 21 4 .0 Dietary

Exposure/Risk Charact erization ................................ ................................ ................ 22 4 .1 Pesticide Metabolism and Environmental Degradation ................................ ............ 22 4 .1.1 Metabolism in Primary Crops ................................ ................................ ............... 22 4 .1 .2 Metabolism in Rotational Crops ................................ ................................ ........... 22 4 .1.3 Metabolism in L ivestock ................................ ................................ ....................... 22Page 3 of 48

4 .1 .4 Analy

tical Methodology ................................ ................................ ....................... 22 4 .1.5 Environmental Degradation ................................ ................................ .................. 24 4 .1 .6 Comparative Metabolic Profile ................................ ................................ ............. 24 4 .1.7 Toxi city

Profile of Maj or Metabolites and Degradates ................................ ........ 24 4 .1.8 Pesticide Metabolites and Degradates of Concern ................................ ................ 25 4 .1 .9 Drinking Water Residue Profile ................................ ................................ ............ 25 4 .1 .10 Food Residue Profile ................................ ................................ ............................. 26 4 .1.11 International Residue Limits ................................ ................................ ................. 28 4 .2 Dietary

Exposure and Risk ................................ ................................ ........................ 28 4 . 2.1 Acute Dietary

Exposure/Risk ................................ ................................ ............... 2 8 4 .2.2 Chronic Dietary

Exposure/Risk ................................ ................................ ............ 28 4 .2.3 Cancer Dietary

Exposure/Risk ................................ ................................ .............. 29 4 .3 Anticipated Residue and Percent Crop Treated (%CT) Information ........................ 30 5 .0 Residential (Non - Occupational) Exposure/Risk Characterization ................................ ... 30 5 . 1 O ther (Spray

Drift, etc.) ................................ ................................ ............................ 30 6 .0 Aggregate Risk Assessments and Risk Characterization ................................ .................. 31 6 .1 Acute Aggregate Risk ................................ ................................ ............................... 31 6 .2 Short - Term Aggregate Risk ................................ ................................ ...................... 31 6 . 3 Intermediate - Term Aggregate Risk ................................ ................................ ........... 32 6 . 4 Long - Term Aggregate Risk ................................ ................................ ....................... 32 6 . 5 Cancer Aggregate Risk ................................ ................................ .............................. 32 7 .0 Cumulative Risk Characterization/Assessment ................................ ................................ 32 8 .0 Occupational Exposure/Risk Assessment Pathway ................................ .......................... 33 8.1 Han dler Exposure ................................ ................................ ................................ ...... 33 8 . 1.1 Data and Assumptions for Proposed Handler Exposure Scenarios ...................... 33 8.1. 2 Handler Risk and Exposure ................................ ................................ .................. 35 8 . 2 Postapplication Exposure ................................ ................................ .......................... 36 9 .0 Data Needs and Label Re commendations ................................ ................................ ........ 36 9 .1 Toxicology ................................ ................................ ................................ ................. 36 9 .2 Residue Chemistry ................................ ................................ ................................ .... 37 9 .3 Occupational Exposure ................................ ................................ .............................. 37 References: ................................ ................................ ................................ ................................ .... 38 Appendi x A: Aminopy

ralid Toxicology ................................ ................................ ...................... 39 Appendi x B: Tolerance Summary for Aminopy

ralid ................................ ................................ .. 48Page 4 of 48

EXECUTIVE SUMMARY HED has p erformed a human h ealth risk assessment for the herbicide aminopy ralid (4 - amino 3,6 - dichloro - 2 - py

ridinecarboxylic acid), and has determined that there is a reasonable certainty that no harm will result from aggregate exposure to aminopy ralid residue s , including all anticipated dietary

exposures and all other exposures for which there is reliable information. Dow AgroSciences is requesting a Section 3 registration to add uses on field corn to Milestone ® (EPA Reg. No. 62719 - 519), a liquid soluble concentrate (SL) formulation in which aminopy ralid is formulated as the triisopropanol - ammonium (TIPA) salt. The product contains 40.6% aminopy ralid TIPA salt at an acid equivalent (ae) of 21.1% or 2 lb ae/gal. The product is proposed for postemergence foliar broad cast or spot applications to field corn at a maximum seasonal rate of 0.027 lb ae/A. Preharvest intervals (PHI s) of 0 day s for grain and 8 day s for forage or silage are proposed. The most recent Section 3 risk assessment performed for aminopy ralid was co mpleted i n July , 200 7 (D 301689 , M. Doherty , 7 / 12 /200 7 ). Toxicology Acute toxicity

data indicate that aminopy ralid (XDE - 750 and GF - 871) has low toxicity via oral, dermal, and inhalation routes of exposure; however, the free acid form (XDE - 750) of the mole cule produces severe eye irritation. The stomach, ileum and cecum appear to be targets for this chemical. At mid - and high - level doses, ulcers and erosion of the mucosal lining were noted in the stomach. At high level doses, effects on the mucosal linin g of the ileum and cecum were observed. Developmental and reproduction studies show that there is no evidence of increased qualitative or quantitative susceptibility of the fetuses or offspring to aminopy ralid. Consequently , the FQPA Safety Factor was re duced to 1x because of the lack of residual uncertainty for pre - and postnatal toxicity . Dermal studies indicate that aminopy ralid does not have an y significant toxicity via the dermal route of exposure. Aminopy ralid has been classified as “ not likely

to be carcinogenic to humans , ” and there is no evidence that aminopy ralid is mutagenic or an endocrine disruptor. Based on the available data, HED has determined that an acute dietary

assessment is not needed for the general population , and there is no appropriate endpoint to support an acute exposure assessment for pregnant females (13 - 49). The toxicological data support an assessment for chronic dietary exposure based on effects observed in the cecum (enlargement, hy perplasia) and body weight changes in a combined chronic/carcinogenicity s tudy in rats. Additionally , short - , and intermediate - term durations for incidental oral and inhalation exposures were assessed based on the results of the developmental toxicity study in rabbits (body

weight changes, inc oordinated gait , and inanition (i.e., exhaustion resulting from lack of food) ) . Dermal exposure was not assessed because of the low toxicity observed in a 28 - day

dermal toxicity

study . As a result of the new EPA P art 158 Guidelines, an immunotoxicity

stu dy in rats and/or mice is now required for aminopy ralid. HED concludes that a database uncertainty

factor is not needed for the lack of this study because the overall weight of evidence suggests that aminopy ralid does not directly

target the immune sy stem .Page 5 of 48

Metabolic Profile Adequate studies are available depicting the metabolism of aminopy ralid in rats, primary

crops (grass and wheat), rotational crops (turnips, lettuce, sorghum), and livestock (lactating goats, laying hens). Metabolism in primary and rotational crops is comparable. Parent compound was the primary residue in rats, goats, and hens. Parent compound was also found in plants and drinking water. In addition, conjugates of the parent compound were found in plants and bound residues of the parent were found in drinking water. These residues of concern have been accounted for in the rat toxicity studies. Sufficient metabolism data have been submitted for the purposes of the current tolerance petitions. As the parent compound and either co njugates of the parent or bound residues of the parent were found in all metabolism studies, the submitted toxicity database is adequate to account for the toxicity of all residues to which humans are expected to be exposed. HED has determined that the re sidues of concern for purposes of human health risk assessment and for expression of tolerances are equivalent. For plant commodities, th e residues of concern are combined free and conjugated aminopy ralid, calculated as parent aminopy ralid. For livestock commodities, th e residue of concern is parent aminopy ralid. The residue of concern in drinking water is also parent aminopy ralid. Residue Chemistry

and Dietary

Risk Estimates HED evaluated the residue chemistry database for aminopy

ralid . In general , the residue chemistry data are sufficient to evaluate the nature and magnitude of residues in the proposed commodities. An analy

tical method is available for enforcement of the proposed tolerances. Adequate high performance liquid chromatography (LC) methods with tandem mass spectroscop y detection (MS/MS) have been submitted for tolerance enforcement for crop and livestock commodities . The validated limit of quantitation (L OQ) is 0.01 ppm in each matrix. Samples from the submitted field corn crop fie ld trial and processing studies were anal yz ed using the crop commodity

tolerance enforcement method. Samples of grass and wheat commodities from the submitted storage stability study were analyzed using a previous version of the crop commodity

enforcement method. HED has identified residue chemistry data deficiencies in the submitted tolerance petition concern ing directions for use, proposed tolerances, and crop field trials. To evaluate c hronic dietary risks, HED used information in the residue chem istry database along with modeled estimates of aminopy ralid in drinking water to conduct dietary (food + water) exposure assessments. The unrefined chronic assessment is based on the assumption that aminopy ralid residues are present at tolerance levels in all commodities for which tolerances have been proposed or established, and that 100% of those crops are treated. DEEMTM Version 7.81 default processing factors were applied to all processed commodities for which they were available. Drinking water was i ncorporated directly into the dietary

assessment using thePage 6 of 48

estimated drinking water concentration (EDWC) for surface water generated by the Tier 1 FQPA Index Reservoir Screening Tool (FIRST) Model. The resulting chronic dietary exposure estimates for food and water combined are well below HED’s level of concern for the general U.S. population and all population subgroups. Using the DEEM - FCID software, dietary exposure is estimated at 0.000 703 mg/kg/day for the U.S. population (<1% of the chronic populatio n adjusted dose (cPAD)) and 0.00 2097 mg/kg/day (<1% of the cPAD) for children 1 to 2 years old, the population subgroup with the highest estimated chronic dietary exposure to aminopy ralid . Tolerance Harmonization Codex and Canadian MRLs have been estab lished for residues of aminopy ralid; however, no MRL s have been established for the requested crop commodities (field corn grain, forage, and stover) . No Mexican MRL s have been established for aminopy ralid. Residential Exposure Residential exposures a ssociated with the use of aminopy ralid to control weeds on residential and recreational sites were previousl y assessed in support of the 2005 risk assessment for the proposed use of aminopyarlid on wheat, grasses, non - cropland areas, and natural areas (Mem o, D305672, M. Collantes, 5 /2 4/200 5) . The results of the residential exposure assessment indicate that there are no risks of concern for postapplication exposure . A residential handler assessment was not needed because aminopy ralid is not applied by

home owners. T he registrant has not proposed an y new residential and/or non - occupational uses for aminop yr alid at this time; therefore, a new residential/non - occupational exposure assessment is not required. Aggregate Exposure No toxic effects attributable to a single dose were identified for aminop yr alid. As a result, an acute aggregate risk assessment is not needed for this chemical. There are residential uses for aminop yralid on recreational sites . The exposures resulting from this residential use mu st be aggregated with the dietary (food and drinking water) exposures. At this time, there are no non - dietary scenarios for aminopy

ralid that are appropriate for assessing adults, therefore, the aggregate exposure estimates for adults are equivalent to th e chronic dietary (food + water) estimates, which are not of concern to HED. The non - dietary scenario s included in the aggregate assessment are short - term in duration and apply to children only . They consist of incidental oral exposures (e. g. , hand - to - mo uth , object - to - mouth , and ingestion of soil ) . In estimating short - term aggregate risk, HED has combined the chronic dietary (food + drinking water) exposure estimate and the total non - dietary exposure estimate for children. The short term aggregate risk MOEs range from 25,000 to 33,000 and are not of concern to HED. Dietary (food + water) consumption is the only source of exposure to aminopy ralid that is expected to result in chronic exposure. Therefore, the long - term aggregate exposure and riskPage 7 of 48

estimat es are equivalent to the chronic dietary exposure and risk estimates. The most highl y exposed population subgroup is Children 1 - 2 . The general U.S. population and all population subgroups utilize <1% of the cPAD. The risk estimates are all below HED’s l evel of concern (100% of the cPAD). Aminopy ralid has been classified as “not likel y to be carcinogenic to humans ; ” therefore, cancer risk is not a concern . Occupational Exposure T he registrant did not submit any chemical - specific exposure data for asse ssing the occupational risks involved while handling the proposed product, Milestone® . In the absence of these data , the Agency

used surrogate exposure data from the Pesticide Handlers Exposure Database (PHED) and the Outdoor Residential Exposure Task Force (ORETF) default values established by HED’s Science Advisory Council for Exposure (ExpoSAC) for calculating the exposure of mixers, loaders , and applicators. Margins of Exposure (MOEs) of 100 or greater are required for handlers of agricultural crops i n order for risks not to be of concern to HED. All handler short - and intermediate - term MOEs are greater than 100 and, therefore, are not of concern . T here are potential dermal exposures to workers entering treated sites after pesticide application is co mplete. These workers perform activities such as scouting, detasselling weeding, and harvesting. N o dermal point of departure ( P o D ) was selected for aminopyralid ; therefore , risks from such exposures are not of concern. Restricted Entry

Interval Milestone ® Herbicide contains the triisopropanolammonium salt of aminopyralid . However, after application of the product, a gricultural workers could be exposed to residues in both the acid and salt form . Therefore, the restricted entry interval (REI) for agricultural occupational exposure resulting from treated corn is based on the acute toxicity of the acid form (i.e., aminopy ralid itself) because of its higher irritation potential . Aminopy ralid is classified as Category IV for acute der

mal and dermal irritation and Category Ifor eye irritation. Chemicals identified as toxicity

Category Irequire a 48 - hour REI . Furthermore, chemicals classified as toxicity Category Ifor eye irritation require the use of protective eyewear. The supple mental label does not include an REI . Therefore, the Registration Division should ensure that the proper REI of 48 hours appears on the registered label. Environmental Justice Considerations Potential areas of environmental justice concerns, to the exte nt possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, “ Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations, ” http://www.eh.doe.gov/oepa/guidance/jus tice/eo12898.pdf .Page 8 of 48

As a part of every

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well - established procedures. In line with OPP policy , HED estimates risks to population subgroups from pesticide exposures th at are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake s by

Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized by

subgroups based on age, season of the year, ethnic group, and region of the country . Additionally , OPP is able to assess dietary exposure to smaller, specialized subgroups , and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, nondietary

exposures based on home - use of pesticide produc ts and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currentl y in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to b ys tanders and farm workers as well as lifestyl e and traditional dietary patterns among specific subgroups. Review of Human Research This risk assessment relies in part on data from studies in which adult human subjects were intentionally

exposed to a pesticide or other chemical. These studies, which comprise the Pesticide Handlers Exposure Database (PHED) and the Outdoor Residential Exposure Task Force (ORETF) , have been determined to require a review of their ethical conduct, have received that review , and have been determined to be ethical . Conclusion s HED concludes that the registrant has submitted adequate data for the Agency to make the safety finding with respect to the use of aminopy ralid on the registered and proposed use s . With the exception of the deficiencies listed in Section 9 , Data Needs and Label Recommendations, the toxicology , residue chemistry , and occupational databases are adequate for the purposes of the curre nt tolerance petition for field corn . Provided that the label changes and revised tolerances detailed in Section 9 are submitted, HED recommends in favor of a conditional registration on field corn and establishment of the tolerances listed in the toleran ce summary table of Appendix B using the tolerance expression specified in that appendix. HED recommends that submission of an immunotoxicity

study be a condition of registration . 2.0 INGREDIENT PROFILE Aminopy ralid is a sy stemic postemergence herbicide that belongs to the py ridine carboxylic acid class of compound s. It is currentl y registered for use on rangeland, permanent grass pastures, and wheat. In addition, it is registered for use on wildl ife habitat and industrial vegetation management areas, including right - of - way for roads, railroads, and utility lines. UnderPage 9 of 48

PP# 8F7455 , Dow AgroSciences is proposing aminopy ralid for use on field corn. The end - use product (EP) prop osed for use on field corn is a SL formulation, Milestone Specialty Herbicide (EPA Reg. No. 62719 - 519), in which aminopy ralid is formulated as the TIPA salt . T he product contain s 40.6% aminop yralid TIPA salt at an acid equivalent (ae) of 21.1% or 2 lb ae/ gal. 2.1 Summary of Registered/Proposed Uses Tolerances for aminopy

ra lid are currentl y established under 40CFR §180.610. Tolerances for residues in/on crop commodities are established under 180.610(a)( 1) and are expressed in terms of free and conjugated residues of aminopy ralid , calculated as aminopy ralid. T olerances have been established for aspirated grain fractions, grass forage and hay , and wheat bran, forage, grain, hay , and straw. Tolerances for residues in livestock commodities are established under 180.610(a)(2) and are expressed in terms of aminopy ralid . T olerances have been established for milk and the fat, kidney , meat, and meat b yproducts of cattle, goat, horse, and sheep. The petitioner submitted a proposed supplemental label (pin punched with date 10/1 5 /08) for the 2 lb ae/gal SLproduct ( Milestone ® , EPA Reg. No. 62719 - 519) for use on field corn. The proposed use directions are presented in Table 2.1 . Table 2.1 . Summary of Directions for Use of Aminopyralid. Applic. Timing, Ty pe, and Equip. Form

ulation [EPA Reg. No.] Applic.

Rate (lb ae/A) Max. No.

Applic. per Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations Field Corn and Field Corn Grown for E nsilage Postemergence, Broadcast, Ground 2 lb ae/gal

SL [62719 - 519] 0.0089 -

0.027 Not

specified 0.027 0 (grain); 8 (forage or silage) Application is to be

made to actively growing corn before it reaches 20 inches in height or V6 growth stage. Spot treatments are to be made at rates equivalent to broadcast application, in a minimum spray volume of 0. 5 gal/1,000 ft2

. Postemergence, Spot treatment, Ground 0.0002 1 - 0.0006 3 lb ae/1,000 ft2 The supplemental label states that use is subject to all use pre cautions and limitations imposed by the label on the parent product. The label specifies that aerial applications are not to be made unless permitted by

EPA - approved supplemental labeling. Under the mixing instructions, the master label specifies that a non - ionic surfactant at 0.25 - 0.5% v/v (1 - 2 quarts per 100 gallons spray) is recommended to enhance herbicide activity under adverse environmental conditions. The following rotational crop restrictions are specified: 0 - month plantback interval for wheat; 4 - month plantback interval for grasses and field corn ; 12 - month plantback interval for barley , canola (rapeseed), flax, grain sorghum, mustard, oats, sweet corn, and popcorn; and a 24 - month plantback interval for crops not listed. The label also specifies that a field bioassay should bePage 10 of 48

conducted within 18 months of application prior to planting an y broadleaf crops not listed . HED received a second, undated supplemental label for Milestone ® which has different plantback intervals. The appropriate plantba ck intervals appear on the label pin punched 10/15/08. 2.2 Structure and Nomenclature Table 2.2. Am inopyralid Nomenclature . Chemical structure

N Cl N H

2 Cl

O O H Common name Aminopyralid Com pany experimental name XDE - 750 IUP AC name 4 - amino - 3,6 - dichloropyridine - 2 - carboxylic acid CAS name 4 - amino - 3,6 - dichloro - 2 - py ridinecarboxylic acid CAS registry number 150114 - 71 - 9 Chemical structure

N Cl N H 2 Cl

O O H N C H 3 O H C H 3 O H C H 3 O H 

## .

Common name Aminopyralid, triisopropanolammonium (TIPA) salt PC Code 005209 Com pany experimental name XDE - 750 TIPA salt IUPAC name 4 - amino - 3,6 - dichloropyridine - 2 - carboxylic acid - (2RS,2 ′RS,2′′RS) - 1,1 ′,1′′ - nitrilotripropan - 2 - ol (1:1) CAS name 4 - amino - 3,6 - dichloropyridine - 2 - c arboxylic acid compound with 1,1 ′,1′′ - nitrilotris[2 - propanol] (1:1) CAS registry number 566191 - 89 - 7 End - use product (EP) Milestone ® (2 lb ae/gal SL; EPA Reg. No. 62719 - 519)Page 11 of 48

2.3 Physical and Chemical Properties TABLE 2. 3 . Physicochemical Pro perties of the Technical Grade of Aminopyralid . Parameter Value Reference Melting point/range 163.5 o C MRID 46235703 pH 2.31 at 23.4 o C (1% solution in water) MRID 46235703 Density 1.72 at 20 o C MRID 46235703 Water solubility 2.48 g/L unbuffered water at 18 o C 212 g/L pH 5 buffer at 20 o C 205 g/L pH 7 buffer at 20 o C 203 g/L pH 9 b uffer at 20 o C MRID 46235703 Solv ent solubility at 20°C methanol 52.2 g/L acetone 29.2 g/L n - octanol 3.9 g/L ethyl acetate 3.9 g/L 1,2 - dichloroethane 0.2 g/L xylene 0.04 g/L heptane <10 μ g/mL MRID 46235703

Vapor pressure 2.59 x 10 - 8 Pa at 25 o C; 9.52 x 10 - 9 Pa at 20 o C MRID 46235703 Dissociation constant, pKa 2.56 MRID 46235703 Octanol/water partition coefficient, Log(KOW) 0.201 unbuffered water at 19 o C

- 1.76 at pH 5

- 2.87 at pH 7

- 2.96 at pH 9 MRID 46 235703 UV/visible absorption spectrum Solution Wavelength λ max, nm Extinction

coefficient L/(mol*cm) Neutral 217 29100 Basic (pH 12.6) 220 26100 Basic (pH 12.6) 245 10150 Acidic (pH 1.4) 217 22800 Acidic (pH 1.4) 270 9140 MRI D 46235703

3.0 H AZARD C HARACTERIZATION/A SSESSMENT 3.1 Hazard and Dose - Response Characterization 3.1.1 Database Summary 3.1.1.1 Suffici ency of S tudies/Data The toxicology

database for aminopy

ralid is not complete. In accordance with the new 40CFR P art 158 Guidelines, an immunotoxicity study in rats and/or mice is now required . Acceptable studies available for endpoint selection include: 1) subchronic oral toxicity studies in rats, mice, and dogs; 2) a chronic oral toxicity study in dogs and chronic/ carcinogenicity studies in rats and mice; 3) developmental and reproduction st udies in rats and a developmental study in rabbits; 4) acute and chronic (1 year) neurotoxicity studies in rats; and 5 ) a subchronic dermal toxicity study in rats. There is also a complete mutagenicity battery , as well as a metabolism study in the rat. A developmental neurotoxicity study is not required at this tim e.Page 12 of 48

3.1.1.2 Mode of A ction Aminopy ralid is a py

ridine carbox yl ic acid herbicide possessing auxin - like qualitie s. It moves sy stemicall y throughout the plant and deregulates plant growth metabolic pathway s affecting the growth process of the plant. This disruption of plant growth processes, b y binding of aminopy ralid at receptor sites normally used by the plant’s natural growth hormones, results in control and death of susceptible plant species. 3.1.2 Toxicological Effects The toxicology

database for aminopy

ralid includes toxicity

studies with the acid (XDE - 750) as well as the TI PA salt (GF - 871) . The acute toxicity data indicate that XDE - 750 has low toxicity (Category IV) via oral, dermal, and inhalation routes of exposure. It is not irritating to the skin ; however, it is severel y irritating to the eye (Category I). Aminop yralid is not a skin sensitizer. GF - 871 also has low toxicity via oral, dermal, and inhalation routes of exposure (Category IV). It is not irritating to the eye or skin , and it is not a skin sensitizer. The toxicology

database for aminopy

ralid indicates that the stomach, ileum , and cecum are targe ts for this chemical. In a subchronic feeding study in rats (XDE - 750), hy

perplasia of the mucosal epithelium of the ileum and cecum was observed at the highest dose tested (HDT) of 1000 mg/kg/day . Chronic exposure in rats (XDE - 750) also resulted in h yp er plasia of the mucosal epithelium, along with cecal enlargement and decreased body weights at a lower dose of 500 m g/kg/day . Hy

pertrophy and h yp erplasia of the mucosal epithelium were seen after subchronic exposure in dogs (XDE - 750) at the HDT of 929 mg/kg/day . Thickening of the stomach mucosa (females), hy perplasia and hy

pertrophy of the mucosal epithelium, slight ly mphoid hy

perplasia of the gastric mucosa , and very slight/slight chronic mucosal inflammation were observed in dogs after chronic exposure at the HDT of 967 mg/kg/day. No adverse effects were observed in subchronic or chronic feeding studies in mice. Stomach effects were also observed in a developmental toxicity study in rabbits (XDE - 750). U lcers and erosions were seen in the glandular mucosa of the stomach at 500 mg/kg/day in maternal animals . Other effects noted were decreased body weights and incoordinated gait. No developmental effects were seen in fetuses at 500 mg/kg/day . The high dose group was removed from the study beca

use of the severity of the clinical signs that were observed ( incoordinated gait, significant body weight losses, and decreased food intake) . In another developmental rabbit study (GF - 871), severe inanition (exhaustion from lack of food), body weight loss , decreased fecal output, and incoordinated gait were observed at 260 mg/kg/day . At 520 mg/kg/day , decreased fetal body weights were observed. No effects were noted in developmental toxicity studies in rats with XDE - 750 or GF - 871 or a reproduction study in rats with XDE - 750. No sy stemic toxic effects were observed in a 28 - day dermal toxicity

study in rats with XDE - 750 ; h owever, dermal toxicity was indicated b y slight epidermal hyperplasia in males at 1000 mg/kg/day .Page 13 of 48

In an acute neurotoxicity

study in rats (XDE - 750), fecal soiling in males and urine soiling in females were observed at 2000 mg/kg/day . No adverse effects were observed in a chronic neurotoxicity

study in rats up to 1000 mg/kg/day . Aminopy ralid is classified as “not likely to be carcinogenic to humans.” No increase in any tumors were found in carcinogenicity studies in rats and mice. Aminopy ralid was negative in all mutagenicity

studies, except for an in vitro chromosome aberration assay in Sprague Dawley rats. In this assay , XDE - 750 induced chromosome aberrations, but only at cy totoxic concentrations. The clastogenic response was induced secondary to toxicity . 3.1.3 Dose - response HED has determined that there is no appropriate endpoint to support an acute exposure assess ment for the general population or for pregnant females (13 - 49). For chronic dietary exposure, a combined chronic/carcinogenicity study in rats was used to select the dose and endpoint for establishing the chronic reference dose (cRfD) of 0.5 mg/kg/day. The NOAEL is 50 mg/kg/day , based on effects observed in the cecum (enlargement, h yperplasia) and body weight changes at the LOAELof 500 mg/kg/day . For short - and intermediate - term incidental oral exposure , as well as inhalation exposure, the developmental toxicity study in rabbits (GF 871) was used for endpoint selection, based on inanition, body weight changes, and incoordinated gait seen at the L OAEL of 260 mg ae/kg/day (NOAEL = 104 mg ae/kg/day). Dermal exposure was not assessed because of the low tox icity observed in a 28 - day

dermal toxicity study . 3.1.4 FQPA After evaluation of the toxicological and exposure data for aminopy ralid, HED recommends that the FQPA S afety F actor be reduced to 1x (see Section 3.4). 3.2 Absorption, Distribution, Metabolism, Excretion In a metabolism study

in rats, aminopy

ralid (XDE - 750) is rapidl y absorbed, distributed and excreted followin g oral administration. Total 24 - hour recoveries of the radioactivity were high for all groups (~41 - 59% and 33 - 43% of the administered dose in urine and feces, respectivel y). The absorption and excretion patterns of the 14 C moiety were similar among all groups. Study results indicated that XDE - 750 was not metabolized to volatile compounds, including CO 2 . The average α - phase elimination half - lives (T 1/2 α) of 14 C - XDE - 750 equivalents were 2.85, 3.27 , and 3.78 hours for the single low, repeated low , and si ngle high dose groups, respectively . The average β - phase urinary

elimination half

- lives (T 1/2 β) of 14 C - XDE - 750 equivalents were 10.23, 12.25 , and 10.88 hours for the single low, repeated low , and single high dose groups, respectivel y. Tissue distributi on and bioaccumulation of XDE - 750 were minimal , with <0.73% of the administered dose being recovered in tissues 7 day s after oral administration for all dosing groups. Highest levels of radioactivity were found in the skin and carcass. XDE - 750 was excret ed unchanged indicating an absence of metabolism. Of the total radioactivity in urine, parent accounted for  96% , and of the total radioactivity in feces, parent accounted for 100%.Page 14 of 48

Three unknown components (  4%) found in urine were also detected in simi lar quantities in the anal ys is of the dose formulation, suggesting that they were trace impuritie s in the radiolabeled material . When administered orally to rats, 14 C - XDE - 750 and 14 C - XDE - 750 - TIPA are bioequivalent in terms of absorption, distribution, met abolism, and excretion of the amino dichloro - picolinate portion of the molecule. 3.3 FQPA Considerations 3.3.1 Adequacy of the Toxicity Database Acceptable/guideline studies for developmental toxicity in rats and rabbits, a 2 - generation reproduction study in rats, and neurotoxicity studies are available for FQPA assessment. However, an immunotoxicity study is required as a part of the ne w data requirements in 40 CFR Part 158 for conventional pesticide registration. The toxicology database for aminopy

ralid does not show any

evidence of treatment - related effects on the immune sy stem. The overall weight of evidence suggests that this chemi cal does not directly target the immune system , and the Agency does not believe that conducting a functional immunotoxicity study will result in a lower P o D than that currently

use d for overall risk assessment. Therefore, a database uncertainty factor (UF DB ) is not needed to account for lack of this study . 3.3.2 Evidence of Neurotoxicity N o evidence of neurotoxicity was observed in acute or chronic neurotoxicity studies. In coordinated gait alon g with a lack of ambulatory movement was observed in developmental toxicity studies (XDE - 750 and GF - 871) in rabbits at 500 mg/kg/day . The inco ordination was characterized b y a reluctance to move unless manually stimulated b y the observer. Significant sti ffening or dragging of the limbs was evident when movement was attempted , and on various occasions several rabbits tipped onto their sides. In most cases, the incoordination was transient, with complete resolution within two hours postdosing, and did not appear to worsen progressivel y on subsequent days. The effects observed seem to be more an indication of overt toxicity and not a result of frank neurotoxicity . No signs of neurotoxicity were observed in other toxicity studies . 3.3.3 Developmental Tox icity Studies In a developmental toxicity study in rabbits, ulcers and erosions were observed in the glandular mucosa of the stomach . D ecreased body weights and incoordinated gait were observ ed at ≥ 500 mg/kg/day

in maternal animals. Developmental toxicity could not be determined in the study a s the high - dose group was removed because of the severity of clinical signs observed ( incoordinated gait, significant body weight losses, and decreased food intake) . In another developmental rabbit s tudy (GF - 871), severe inanition , body weight loss, decreased fecal output, and incoordinated gait were observed at 260 mg ae/kg/day . At 520 mg ae/kg/day , decreased fetal body weights were observed. No effe cts were noted in developmental toxicity studies in rats with XDE - 750 or GF - 871.Page 15 of 48

3.3.4 Reproductive Toxicity Study No adverse effects were observed in a reproduction study in rats with XDE - 750. 3.3.5 Additional Information from Literature Sources A literature search did not reveal information that would impact the risk assessment. 3.3.6 Pre - and/or Postnatal Toxicity 3.3.6.1 Determination of Susceptibility No quantitative or qualitative evidence of increased susceptibility , as compared to adults, of rat fetuses to in utero or postnatal exposure to aminopy ralid was observed in developmental toxicity studies in rats or rabbits or a reproduction study in rats. 3.3.6.2 Degree of Concern Analysis and Residual Uncertainties for Pre - and/or Postnatal Susceptibility The purposes of the Degree of Concern anal ys is are: (1) to determine the level of concern fo r the effects observed when considered in the context of all available toxicity data; and (2) to identify any residual uncertainties after establishing toxicity endpoints and traditional uncertainty factors to be used in the risk assessment. I f residual uncertainties are identified, then HED determines whether these residual uncertainties can be addressed by the FQPA S afety F actor and, if so, the size of the factor needed. No evidence of quantitative or qualitative susceptibility was observed in developme ntal toxicity studies in rats or rabbits or a reproduction study in rats. As a result, there are no residual uncertainties or concerns for pre - and/or post - natal toxicity . Therefore, HED recommends that the FQPA S afety F actor be reduced to 1x. 3.3.7 R ecommendation for N ot R equiring a Developmental Neurotoxicity Study N o evidence of neurotoxicity was observed in acute or chronic neurotoxicity studies. In coordinated gait , along with a lack of ambulatory movement , was observed in developmental toxicity studies (XDE - 750 and GF - 871) in rabbits at 500 mg/kg/day . However, the incoordination was transient ( complete resolut ion within two hours postdosing) and considered to be a result of frank toxicity , rather than a neurotoxic event . Additionally , n o signs of neurotoxicity

were observed in other toxicity studies , and no evidence of quantitative or qualitative susceptibility

was observed in developmental toxi city studies in rats or rabbits or a reproduction study in rats. Therefore, a developmental neurotoxicity study is not warranted at this time.Page 16 of 48

3.4 FQPA Safety Factor for Infants and Children A fter having evaluat ed the toxicological and exposure data for aminop yr alid, HED recommends that the FQPA SF be reduced to 1x . This recommendation is based on the following:

 In accordance with the new 40 CFR P art 158 data requirements , an immunotoxicity study in rats and/or mice is now required. Although the toxicological database is not complete, i t does not show any

evidence of treatment - related effects on the immune system. The overall weight of evidence suggests that this chemical does not directly target the immune sy stem , and the Agency does not believe that conducting a functional immunotoxicity

study will result in a lower P o D than that currently use d for overall risk assessment. Therefore, a database uncertainty factor (UF DB ) i s not needed to account for the lack of this study .  No evidence of quantitative or qualitative susceptibility was observed in developmental toxicity studies in rats or rabbits or a reproduction study in rats.

 There is no concern for neurotoxicity

 The dietary

food exposure assessment is based on the assumptions of tolerance - level residues and 100% crop treated for all commodities . These assumptions result in very high - end estimates of dietary exposure. Actual exposures and risks from aminopy ralid will likely

be lower.

 The dietary

drinking water assessment is based on values generated by a model whose associated modeling parameters are designed to provide conservative, health protective, high - end estimates of water concentrations. 3.5 Hazard Identif

ication and Toxicity Endpoint Selection 3.5.1 Acute Reference Dose (aRfD) – General Population and Females 13 - 49 An acute reference dose for the general population has not been established. In an acute neurotoxicity

study in rats, a NOAEL was set at 1000 mg/kg/day based on toxic effects seen at 2000 mg/kg/day . These effects are urine soili ng in females and fecal soiling in males. As these effects occurred at such a high dose, there is no concern for acute dietary risk. Therefore, an acute RfD for the general population is not required. Additionally , there is no appropriate endpoint for e stablishing an acute RfD for women of child - bearing age. 3.5.2 Chronic Reference Dose (cRfD ) Study Selected: Combined Chronic Toxicity /Carcinogenicity Study in Rats MRID No: 46235615 Dose and Endpoint for Risk Assessment : NOAEL= 50 mg/kg/dayPage 17 of 48

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability)

Chronic RfD = ) ( 100 / / 50 UF day kg mg = 0.5 m g/kg/day Comments about Study/Endpoint/Uncertainty Factors: The rat combined chronic toxicity /carcinogenicity study (XDE - 750) was used to select the dose and endpoint for establishing the cRfD of 0.5 mg/kg/day . The NOAEL of 50 mg/kg/day an d the LOAEL of 500 mg/kg/day are based on cecal enlargement, slight mucosal hy p erplasia of the cecum in males , and slightly decreased body weights. The route of exposure and duration of this study are appropriate for assessing risks from chronic dietary exposure. 3.5.3 Incidental Oral Exposure Short - Term (1 -30 days) and Intermediate- Term (1 - 6 Months) Study Selected: Developmental toxicity study - Rabbit MRID No: 46235632 Dose and Endpoint for Risk Assessment: NOAEL = 104 mg ae/kg/day Uncertainty Factor: 100x (10x inte rspecies extrapolation, 10x intraspecies variability) Comments about Study/Endpoint/Uncertainty Factors: A developmental rabbit study (GF - 871) was used to select a dose and endpoint for evaluating short - and intermediate - term incidental oral exposures. The route of exposure and duration of this study are appropriate for assessing such exposures. The maternal NOAELof 104 mg ae/kg/day and the maternal L OAEL of 260 mg ae/kg/day are based on severe inanition and body weight loss, decreased fecal output, and mild incoordinated gait. 3.5.4 Dermal Absorption No dermal absorption study is available f

or aminopy

ralid. However, a 28 - day dermal toxicity study in rats was submitted. N o s ys temic toxicity occurred at the limi t dose (1000 mg/kg/day) , and the primary

toxic effects of concern were adequately assessed in the study . Therefore, it is concluded that aminop yr alid is not absorbed , or is poorly absorbed , through the skin. 3.5.5 Dermal Exposure (Short, Intermediate , and Long Term) In a 28 - day

dermal toxicity study

in rats, no sy stemic toxicity was observed up to the limit dose tested of 1 , 000 mg/kg/day . At 500 mg/kg/day , there was inflammation and slight epidermal hy perplasia in males only . Dermal toxicity (inflammation and slight hy perplasia) should be reflected on the chemical label as a potential concern.Page 18 of 48

3.5.6 Residential and Occupational Dermal Exposure Short - and Intermediate- Term Dermal Exposure No sy stemic toxicity

was observed in a 28 - day dermal toxicity

study in rats up to the limit dose of 1 , 000 mg/kg/day . In the study , the primary toxic effects of co ncer

n were adequatel y addressed; therefore, dermal risk s from sy stemic toxicity are not of concern . 3.5.7 Residential and Occupational Inhalation Exposure Short - Term (1 -30 days) and Intermediate- Term Study Selected: Developmental toxicity study - Rabbit MRID No: 46235632 Dose and Endpoint for Risk Assessment: NOAEL= 104 mg ae/kg/day Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability) Comments about Study/Endpoint/Uncertainty Factors: A developmental rabbit study (GF - 871) was used to select a dose and endpoint for evaluating short - and intermediate - term incidental oral exposures. The maternal NOAEL of 104 mg ae/kg/day and the maternal L OAEL of 260 mg ae/kg/day are based on severe inanition and body weight loss, de creased fecal output, and mild incoordinated gait. The route of exposure for this study does not reflect inhalation exposure. The inhalation absorption factor should be assumed to be 100%. 3.5.8 Levels of Concern for Occupational and Residential Expos ure Assessments Table 3.5.8 . Summary of the Levels of Concern (LOC) for Occupational and Residential Exposure Risk Assessments for Aminopyralid. Route/Duration Short - Term (1 - 30 days) Intermediate - Term (1 - 6 months) Long - Term (> 6 months) Occupational (Worker) Exposure Dermal Not required Not required N/A Inhalation 100 100 N/A Residential (Non - Dietary Exposure) Oral 100 100 N/A Dermal Not required Not requi red N/A Inhalation 100 100 N/A N/A = Not applicablePage 19 of 48

For occupational and residential exposure, short - and intermediate - term oral and inhalation risk assessments, a LOC of 100 is supported by the available data. The LOC is based on the convent ional un certainty

factor of 100x (10x for intraspecies variation and 10x for interspecies extrapolation). Generally, HED does not have a concern for occupational or residential exposures when the calculated MOEs are greater than the LOC (i.e., higher MOEs indicat e lower risk). 3.5.9 Recommendation for Aggregate Exposure Risk Assessments As per FQPA, 1996, when there are potential residential exposures to a pesticide, aggregate risk assessment must consider exposures from three major route s: oral, dermal and inhalation. HED consider s the potential for concurrent exposure via different routes that produce the same toxicological effects. In the event that the same toxicological effect is produc ed upon exposure through different routes, HED aggregates those exposures. Based on the available toxicological information for aminop yr alid , dermal exposures do not result in any adverse sy stemic effect; therefore, dermal exposures do not need to be included in the estimation of aggregate risk. Short - and intermediate - term oral and inhalation exposures are being regulated based on effects seen in the developmental rabbit toxicity study . The use of a single study to evaluate multiple routes of exposure i mplicitly assumes that different routes of exposures will result in the same toxicological effects and should, therefore, be aggregated. 3.5.10 Classification of Carcinogenic Potential There was no evidence of carcinogenicity in cancer studies with mice and rats. Therefore, in accordance with EPA’s Final Guidelines for Carcinogen Risk Assessment (March, 2005), aminopy ralid is classified as “ not likely to be carcinogenic to humans. ”Page 20 of 48

3.5.11 Summary of Toxicological Doses and Endpoints for Use in Human Risk Assessments Table 3.5.11a Summary of Toxicological Doses and Endpoints for Aminopyralid for Use in Dietary and Non Occupational Hum an Health Risk Assessments Exposure/ Scenario Point of

Departure Uncertainty/

FQPA Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects Ac ute Dietary (General Population, including Infants and Children and females 13 - 49) N/A N/A N/A A toxic effect attributable to a single dose wa s not seen in the toxicity database; therefore, an acute endpoint has not been identified.

Chronic Dietary (All Populations) NOAEL= 50

mg/kg/day UF A= 10x

UF H =10x FQPA SF=1x Chronic RfD

=0.5 mg/kg/day cPAD = 0.5 mg/kg/day Chronic toxicity/carcinogenicity study in

rats (XDE - 750) LOAEL=500 mg/kg/day based on cecal enlargement, slight mucosal hyperplasia in males and slightly decreased body weights Incidental Oral Short - Term

(1 - 30 days) Intermediate Term (1 - 6 mo nths) NOAEL =104

mg ae/kg/day UF A= 10x

UF H =10x FQPA SF=1x Residential

LOC for MOE = 100 Developmental rabbit study (GF - 871)

LOAEL=260 mg/kg/day based on severe inanition (exhaustion resulting from lack of food) and body weight loss, decreased fecal output, and mild incoordinated gait. Dermal Short Term (1 - 30 days) Intermediate Term (1 - 6 mo nths) N/A N/A N/A 28 - day dermal toxicity study in rats. No systemic toxicity seen at the limit dose (1 , 000 mg/kg/day) (XDE - 750) Dermal risks are not of concern . Inhalatio n Short - Term (1 - 30 days) Intermediate Term (1 - 6 mo nths) NOAEL=104

mg ae/kg/day UF A= 10x

UF H =10x FQPA SF=1x Residential

LOC for MOE = 100 Developmental rabbit study (GF - 871)

LOAEL=260 mg/kg/day based on severe inanition (exhaustion resulting from lack of food) and body weight loss, decreased fecal output, and mild incoordinated gait. Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the absence of significant

tumor increases in two adequate rodent carcinogenicity studies. Point of Departure = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposur es. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human populatio n (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. N/A = not applicable. ae=acid equivalentPage 21 of 48

Table 3.5.11 b Summ ary of Toxicological Doses and Endpoints for Aminopyralid for Us e in Occupational Hum an Health Risk Assessments Exposure/ Scenario Point of

Departure Uncertainty/

FQPA Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects

Dermal Short Term (1 - 30 days) Intermediate Term (1 - 6 months) N/A N/A N/A 28 - day dermal toxicity study in rats. No systemic toxicity seen at the limit dose (1 , 000 mg/kg/day) (XDE - 750) Dermal risks are not of concern. Inhalation Short - Term (1 - 30 days) Intermediate Term (1 - 6 mo nths) NOAEL=104

mg ae/k g/day UF A= 10x

UF H =10x Occupational

LOC for MOE = 100 Developmental rabbit study (GF - 871)

LOAEL=260 mg/kg/day based on severe inanition (exhaustion resulting from lack of food) and body weight loss, decreased fecal output, and mild incoordinated gait. Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the absence of significant

tumor increases in two adequate rodent carcinogenicity studies. Point of Departure = A data point or an estimated point tha t is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. ). FQPA SF = FQPA Safety Factor . MOE = margin of exposure. LOC = level of concern. N/A = not applicable. ae=acid equivalent 3.6 Endocrine disruption EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances (including all pesticide active and other ingredients) “may have an effect in humans that is similar to an effect produced b y a naturall y occurring estrogen, or other such endocrine effects as the Administrat or may designate.” Following the recommendations of its Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC), EPA determined that there were scientific bases for including, as part of the program, androgen and thy roid hormone s ys tems, in addition to the estrogen hormone sy stem. EPA also adopted EDSTAC’s recommendation that the Program include evaluations of potential effects in wildlife. When the appropriate screening and/or testing protocols being considered under the Agency ’s Endocrine Disrupter Screening Program (EDSP) have been developed and vetted, aminopy

ralid m ight be subjected to additional screening and/or testing to characterize more fully

the effects related to endocrine disruption.Page 22 of 48

4 .0 DIETARY EXPOSURE/RISK CHARACTERIZATION 4 .1 Pesticide Metabolism and Environmental Degradation Reference: Aminopy

ralid and Aminopy

ralid Triisopropanolammonium (TIPA) Salt. Request to Add Uses on Field Corn to Milestone® (EPA Reg. No. 62719 - 519) . Summary of Anal yt ical Chemistry

and Residue Data , D360100, D. Dotson, 10/22 /2009 4. 1.1 Metabolism in Primary Crops No plant metabolism studies were submitted with the petition for the new use, field corn . For the purposes of this tolerance petition, the qualitative nature of the residue in plants is adequatel y understood based on a cceptable grass and wheat metabolism studies. HED concluded that the residues of concern in grass and cereal grain commodities are free and conjugated aminopy ralid. 4 .1.2. Metabolism in Rotational Crops A confined rotational crop study was submitted previously . L ettuce, sorghum, and turnips were planted a s rotational crops at plantback intervals (PBIs) of 90 and 120 day s. R esidue profiles were similar between the matrices. Aminopy ralid and its glucose conjugates accounted for 88 to 97% of the TRR. HED concluded that the residues of concern in rotational crop commodities are the same as for primary crop commodities, free and conjugated aminopy ralid . 4 .1.3. Metabolism in Livestock The nature of the residue in livestock is adequately understood based on previously submitted studies with goat and hen. Although the residues in the goat and hen studies were t oo low to allow adequate characterization/identification of residues, HED concluded that new studies would not be needed. The available metabolism data from the goat, hen, and rat indicate that the majority of the administered aminopy ralid is excreted as unchanged parent in all three species, and the small amount which is absorbed remains unchanged. Therefore, the residue of concern in livestock is aminopy

ralid. This finding is supported by the residues of concern for the related compounds picloram and c lopy ralid which, in each case, show parent compound to be the major residue. 4.1.4 Analytical Methodology Plant commodities Enforcement method: An acceptable LC/MS/MS method, Method GRM 02.31, is currentl y available for the enforcement of tolerances fo r aminopy ralid residues in grass and wheat commodities. With PP# 8F7455, Dow AgroSciences has proposed a similar LC /MS/MS method, Method GRM 07.07, for the determination of residues of aminop yralid in a variety of crop commodities (wet, dry , acidic, and oi ly crops). The method description indicates that Method GRM 07.07 supersedes Method 02.31. The major differences between the two methods are thatPage 23 of 48

Method GRM 02.31 uses a different internal standard ( 13 C 2 15 N - aminopy ralid) and onl y includes instructions fo r the determination of residues in barley , sorghum, wheat, and grass commodities. Method GRM 07.07 was adequatel y validated using samples of untreated wet crops (broccoli and tomato), dry

crops (wheat forage, grain, and straw, corn forage and grain, and grass forage and straw), acidic crops (lemon whole fruit and orange peel, pulp, and whole fruit), and oil y crops (palm oil and sunflower seed) fortified with aminopy ralid at 0.01 and 2 ppm for all crops other than grass forage and straw, and at 0.01 and 50 ppm for grass forage and straw. Recoveries were within acceptable ranges for all ty pes of crops tested . The method includes instructions for monitoring up to three ion transitions for aminopyralid; therefore, confirmatory anal ys is procedures are not need ed. The method is very similar to the current enforcement method, LC/MS/MS Method GRM 02.31, for which adequate radiovalidation and independent laboratory validation data have been submitted. As Method GRM 07.07 is considered to be an improvement to Meth od GRM 02.31, no independent laboratory validation or validation by ACB is needed. Livestock commodities Enforcement method: An acceptable LC/MS/MS method, Method GRM 02.31, is currentl y available for the enforcement of tolerances for aminopy ralid res idues in ruminant milk and tissues. The method was adequatel y validated in bovine whole milk, cream, skimmed milk, fat, kidney , liver, and muscle , and adequate ILV data were submitted for the method using bovine milk and kidney . With PP# 8F7455, Dow AgroS ciences proposed LC/MS/MS Method GRM 07.08 for the determination of residues of aminopyralid in cattle and poultry tissues, milk, and eggs. The method description indicates that Method GRM 07.08 supersedes Method GRM 03.18. The major differences between the two methods are that Method GRM 03.18 uses a different internal standard ( 13 C 2 15 N - aminopy ralid) and only

includes instructions for the determination of residues in bovine commodities (muscle, fat, liver, kidney , and milk). M ethod GRM 07.08 was ad equat ely validated using samples of untreated cattle milk, kidney , and fat and poultry egg, liver, and muscle fortified with aminopy ralid at 0.01 and 2 ppm. Recoveries were within acceptable ranges for milk and tissues . The method includes instructions for mo nitoring up to three ion transitions for aminop yralid; therefore, confirmatory analysis procedures are not needed. The method is very similar to the current enforcement method, LC/MS/MS Method GRM 03.18. Because Method GRM 07.08 is considered to be an improvement to Method GRM 03.18, no independent laboratory validation or validation by ACB is needed. Method GRM 07.08 satisfies all requirements for an enforcement method for livestock commodities. Multiresidue Methods Adequate multiresidue method testin g data have been submitted previously for aminop yralid. The results of the study i ndicate that the FDA multiresidue methods in PAM Vol. Iare not suitable for the determination of aminopy ralid.Page 24 of 48

4.1.5 Environmental Degradation Reference: Tier I Drinking Water Exposure Assessment for the Section 3 New Use of Triisopropanolamine Salt of Aminopy ralid on Field Corn and Field Corn Grown for Ensilage, D361926, R. Barris, 7/24/2009 The registrant previously submitted environmental fate studies for aminopyralid. T he aqueous photoly sis study (MRID 46235727) is the only study in which degradates of aminopy ralid were observed . They

were id entified as oxamic acid and malonamic acid . Unidentified degradates were also found. These degradates were 2 - 3 - carbons long and contained oxygen and/or nitrogen atoms , as well as other substituents. No environmental degradates other than CO 2 and bound residues were observed in the remaining fate studies. 4 .1.6 Comparative Metabolic Profile Adequate studies are available depicting the metabolism of aminopy ralid in rats, primary

crops ( grass and wheat), rotational crops (turnips , lettuce , sorghum ), and livestock (lactating goats, laying hens). Metabolism in primary and rotational crop s i s comparable. In wheat and grasses as target crops, the major residues, totaling approximately 90% of the TRR in each matrix, were parent aminop yr alid and glucose conjugates of aminopy ralid. In lettuce, sorghum, and turnips planted as rotated crops, aminopy ralid and its glucose conjugates accounted for 88 to 97% of the TRR. In goats, hens, and rats, the majority of the dose was excreted as parent aminopy ralid and, with the exception of goat kidney , radioactivity in animal tissues was too low for compo und identification. In goat kidney , 80% of the TRR was parent aminopy ralid. In all of the environmental fate studies except aqueous photolysis, residues were identified as amin o py ralid, CO 2 , or bound residues . In the aqueous photol ys is study , residues o f oxamic acid and malonamic acid were identified. P arent compound was the primary residue in rats, goats, and hens. Parent compound was also found in plants and drinking water. In addition, con jugates of the parent compound were found in plants , and bound residues of the parent were found in drinking water. T he se residues of concern have been accounted for in the rat toxicity studies. Sufficient metabolism data have been submitted for the purposes of the current tolerance petitions. 4 .1.7 Toxicity Pro file of Major Metabolites and Degradates T he submitted toxicity

database is adequate to account for the toxicity of all residues to which hum ans are expected to be exposed. HED bases th is conclusion on the fact that the parent compound and either conjugates of the parent or bound residues of the parent were found in all metabolism studies. HED has very

low concern regarding the hazard associated with the environmental metabolites oxamic acid and malonamic acid. Searches of various hazard databases (e.g., TOXNET, MEDLINE, and others) did not reveal any cause for concern for either chemical. Both chemicals are small amino acid analogs. Following uptake, they are expected to be readily m etabolizedPage 25 of 48

and/or rapidl y excreted without any significant biological effects. Based on the available information, HED does not believe that it is appropriate to include residues of either oxamic acid or malonamic acid in dietary risk assessments; therefo re, these compounds are not included as residues of concern in drinking water. 4 .1.8 Pesticide Metabolites and Degradates of Concern Overall, it appears that aminopy ralid is n ot extensively

metabolized in plants or animals. Grasses and wheat are able to conjugate significant amounts of the aminopyralid with glucose. These conjugates are readily convertible back to free aminop yr alid by acid and/or base hydrol ys is. The plant analy tical method includes both base and acid hydroly sis as an integral step in the extraction process. Based on the available metabolic data, HED has determined that the residues of concern for purposes of human health risk assessment and for expression o f tolerances are equivalent (Table 4.1.8 ). For plant commodities, th e residues of concern are combined free and conjugated aminop yralid, calculated as parent aminop yralid. For livestock commodities, th e residue of concern is parent aminopy ralid. The res idue of concern in drinking water is also parent aminopy ralid. As stated above, HED does not believe that it is appropriate to include residues of either oxamic acid or malonamic acid in dietary risk assessments; therefore, these compounds are not include d as residues of concern in drinking water. Table 4.1.8 . Residues of Concern for Hum an Health Risk Assesment and Residue Tolerance Expressions

Matrix Risk Assessment Residue Tolerance Expression Plants Primary Crop Aminopyralid, free and conju gated Aminopyralid, free and conjugated; expressed as aminopyralid Rotational Crop Aminopyralid, free and conjugated Aminopyralid, free and conjugated; expressed as aminopyralid Livestock Ruminant Aminopyralid Aminopyralid

Poultry Aminopyr alid Aminopyralid Drinking Water Aminopyralid Not Applicable 4.1.9 Drinking Water Residue Profile Reference: Tier I Drinking Water Exposure Assessment for the Section 3 New Use of Triisopropanolamine Salt of Aminopy ralid on Field Corn and Field Corn Grown for Ensilage, D361926, R. Barris, 7/24/2009 EFED used the screening model FIRST (FQPA In dex Reservoir Screening Tool, version 1. 1 , 0 1 /01/0 7 ) to calculate the surface water EDWCs. The acute value represents a 1 - in - 10 year peak value and the chronic va lue represents the 1 - in - 10 year annual mean. Estimated groundwater EDWCs were calculated using the screening model SCI - GROW (Screening Concentrations in Ground Water, version 2.3, 07/29/ 03). The groundwater EDWC applies to both acute and chronic exposure . The maximum EDWCs result from aminopy ralid application to rangeland grasses. These maximum values are given in Table 4.1.9, below.Page 26 of 48

Table 4.1.9 . Tier I EDWCs for drinking water risk assessment based on aminopyralid use on

R angel and G rasses (application rate of 0.11 lbs a.e./A/yr) Drinking Water Source Crop Acute (ppb) Chronic (ppb) Cancer (ppb) Surface water Rangeland Grasses 10.024 1.937 N/A Groundwater Rangeland Grasses 0.630 0.630 N/A 4 .1.1 0 Food Residue Profile Reference: Aminopy ralid and Aminopy

ralid Triisopropanolammonium (TIPA) Salt. Request to Add Uses on Field Corn to Milestone ® (EPA Reg. No. 62719 - 519) . Summary of Analy t ical Chemistry

and Residue Data, D360100, D. Dotson, 10/22 /2009 Data Collection Methods Method GRM 07.07 was used for data collection in samples of corn forage, grain, stover, aspirated grain fractions, and processed commodities from the crop field trial and processing studies submitted with this petition. Ove rall concurrent method recoveries ranged 69 - 90% from forage, 75 - 97% from grain, 72 - 94% from stover , and 75 - 98% from corn processed commodities. Samples of grass and wheat commodities from the storage stability study were anal yz ed using Method GRM 02.31 ; o verall concurrent method recoveries ranged from 71 to 106% . The submitted crop anal yt ical method data are adequate to satisfy data requirements. Storage Stability The submitted storage stability study is adequate to fulfill data requirements for samples of field corn forage, grain, stover , and processed commodities from the submitted field trial and processing studies. The data indicate that no correction for residue decline during storage will be needed for these commodities. The dates of anal ys is wer e not provided for the subject field trial and processing studies. For future submissions, the petitioner should note that dates of extraction and analy sis should be provided for all samples. Submission of the final report of the grass and wheat storage stability study satisfies the data requirements for storage stability identified in PP#4F6827 (Memo, D305665, M. Doherty, 7/12/05 ) . No correction for residue decline is needed for any of the grass or wheat commodity samples submitted under PP#4F6827.Page 27 of 48

Res idues in Meat, Milk, Poultry , and Eggs The proposed uses include the following livestock feedstuffs : field corn grain, forage, and stover. The registrant did not propose changes in the current livestock commodity tolerances. The dietary

burdens for bee f and dairy cattle are predominantly

driven b y residue contributions from grass forage and hay. The tolerances for grass forage and hay are considerabl y higher than the recommended tolerances for field corn commodities. HED is in agreement with the regis trant that no revisions are needed to the tolerances for beef and dairy cattle commodities. With respect to poultry

and swine commodities, no tolerances are currently in effect and none are needed as a result of this tolerance petition for field corn. Al though field corn grain is a significant feed item for poultry and swine, there is no reasonable expectation of finite residues in poultry and swine commodities, and a 40 CFR §180.6(a)(3) situation exists. Magnitude of the Residue in Field Corn The numb er and locations of the corn field trials are in accordance with those specified in OPPTS Guideline 860.1500 for use on field corn. Field trials were conducted at ~1x the proposed maximum seasonal rate , and application was made at the growth stage specifi ed on the proposed label. The submitted field corn field trial data are adequate to fulfill data requirements provided the proposed use is amended as follows. The submitted crop field trial data represent application at the proposed maximum seasonal rate (with a nonionic surfactant) and at the proposed growth stage. The proposed PHIs of 0 day s for grain and 8 day s for forage or silage are not supported by the submitted data. The proposed label should be modified to specify that spray

or spot application s may

not be made after the V6 growth stage (BBCH 16) and that forage may not be harvested prior to the dent stage of growth. If the petitioner wishes to support a shorter PHI for field corn forage (or harvest of forage at an earlier growth stage), then a dequate crop field trial data reflecting the shorter PHI and/or earlier forage harvest must be submitted. Provided the label is modified as specified above, the available data support the proposed tolerances of 0.30 ppm for field corn forage, 0.20 ppm f or field corn grain, and 0.20 ppm for field corn stover . Processing Studies The submitted processing data are adequate to satisfy data requirements for field corn processed commodities. The processing data indicate that no tolerances are needed for fie ld corn flour, starch, or refined oil, and that no change in the existing tolerance for aspirated grain fractions, at 0.20 ppm, is needed as a result of the proposed use on field corn. The processing data indicate that aminopy ralid residues m ight concentrate in field corn grits and meal. Based on the HAFTPage 28 of 48

residues for aminopy

ralid in/on field corn grain (0.155 ppm), and the processing factors, expected residues of aminopy ralid in corn grits and meal following treatment at 1x would be 0.17 and 0.20 ppm, re spectively . Because these values are not greater than the recommended tolerance of 0.20 ppm for field corn grain, no tolerances are needed for grits and meal. Field Rotational Crops No field rotational crop data have been submitted for aminopy ralid. As the only

rotational crops likely to have residues are also primary crops with tolerances , a limited field rotational crop study does not need to be submitted. HED considers the rotation intervals listed on the supplemental label for field corn to be adeq uate. The supplemental label specifies that wheat may be planted at any

time after harvest. Grasses and field corn may be planted at a 4 - month plantback interval. Barley , canola (rapeseed), flax, grain sorghum, mustard, oats, sweet corn, and popcorn may be planted at a 12 - month plantback interval. The crop rotational interval for all other crops not listed on the label is 24 months. 4 .1.11 International Residue Limits Codex and Canadian MRLs have been established for residues of aminopy ralid; howev er, no MRL s have been established for the requested crop commodities. No Mexican MRL s have been established for aminop yr alid. 4.2 Dietary Exposure and Risk Reference: Aminopy

ralid Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assess ment for the Section 3 Registration on Field Corn , D36 9212 , D . Dotson , 10 /22 /2009 . A chronic aggregate dietary (food and drinking water) exposure and risk assessment was conducted using the Dietary Exposure Evaluation Model, DEEM - FCIDTM, Version 2.03, whic h uses food consumption data from the U.S. Department of Agriculture’s Continuing Survey s of Food Intakes by

Individuals (CSFII). The survey s were taken from 1994 - 1996 and included a supplemental ch ildren’s survey taken in 1998. 4 .2.1 Acute Dietary Expos ure/Risk A toxic effect attributable to a single dose was not identified for aminop yr alid . As a result, there is no acute endpoint and acute dietary exposure is not of concern . 4 .2.2 Chronic Dietary Exposure/Risk The unrefined chronic assessment is based on the assumption that aminopyralid residues are present at tolerance levels in all commodities for which tolerances have been established or proposed , and that 100% of those crops are treated. DEEMTM Version 7.81 default processing factors were app lied to all processed commodities for which they were available. Drinking waterPage 29 of 48

was incorporated directly into the dietary assessment using the estimated drinking water concentration (EDWC) for surface water generated by the FIRST Model. The resulting chronic dietary exposure estimates for food and water combined are well below HED’s level of concern for the general U.S. population and all population subgroups. Using the DEEM - FCID software, dietary exposure is estimated at 0.000 703 mg/kg/day for the U. S. population (<1% of the chronic population adjusted dose (cPAD)) and 0.00 2097 mg/kg/day (<1% of the cPAD) for children 1 to 2 years old, the population subgroup with the highest estimated chronic dietary exposure to aminopy ralid . The dietary

exposure an d risk estimates for the general U.S. population and all population subgroups are given in Table 4.2.2 . Table 4.2.2 . Summary of C hronic (Non - Cancer) Dietary Exposure and Risk for Am inopyralid

(Food and Drinking Water) Population S ubgroup Ac ute Dietary Chronic Dietary Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD General U.S. Population

N/A N/A 0.000 703 <1 All Infants (< 1 year old) 0.00 1081 <1 Children 1 - 2 years old 0.00 2097 <1 Children 3 - 5 year s old 0.001827 <1 Children 6 - 12 years old 0.001266 <1 Youth 13 - 19 years old 0 .000822 <1 Adults 20 - 49 years old 0.000515 <1 Adults 50+ years old 0.000359 <1 Females 13 - 49 years old 0.000516 <1 N/A: Not applicable 4 .2.3 Cancer Dietary Ex posure/Risk As aminopy

ralid was classified as “not likely to be carcinogen ic to human s ,” a quantitative cancer dietary

exposure assessment was not performed. Cancer risk is not a concern for aminopy ralid.Page 30 of 48

4 .3 Anticipated Residue and Percent Crop Treate d (%CT) Information These chronic dietary

exposure and risk estimates are highl y conservative. They are based on the assumption that 100% of crops with existing or proposed tolerances are treated with aminopy ralid, and that residues in foods “as eaten” are present at tolerance levels. As a result, no anticipated residues or %CT estimates were used. 5 . 0 RESIDENTIAL (Non - O ccupational) E XPOSURE /RISK C HARACTERIZATION Reference: Occupationa l and Residential Exposure Risk Assessment for Proposed Uses of Aminopy ralid, D305672, M. Collantes , 5 /2 4/200 5 No new residential and/or non - occupational uses for aminopy ralid are being proposed at this time . Residential exposures associated with the use of aminopy ralid to control weeds on residential and recreational sites were previously assessed ( Memo, D305672 , M. Collantes , 5/2 4 /2005). The results of the residential exposure assessment indicate d that risks are not of concern ( the MOE s were all greate r than 100). Postapplication risk for hand - to - mouth transfer resulted in a MOE of 61,000, postapplication risk for ingestion of pesticide - treated turfgrass resulted in a MOE of 250,000, and postapplication risk for ingestion of pesticide - treated soil resu lted in a MOE of 19,000,000 . 5 . 1 Other (Spray Drift, etc.) Spray drift is alway s a potential source of exposure to residents living in close proximity to spraying operations. This situation is particularly the case with aerial application. However, to a lesser extent, spray

drift resulting from the ground application of aminopy ralid could also be a potential source of exposure. The Agency has been working with the Spray Drift Task Force (a membership of U.S. p esticide registrants), EPA Regional Offices, State Lead Agencies for pesticide regulation, and other parties to develop the best spray drift management practices. The Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by

the Spray

Drift Task Force, and is developing a policy on how to apply appropriatel y the data and the AgDRIFT computer model to its risk assessments for pesticides applied by

air, orchard airblast, and ground hydraulic methods. After the policy is in place, the Agency m ight impose further refinements in spray drift management practices to reduce offtarget drift risks associated with pesticide appl ication.Page 31 of 48

6.0 AGGREGATE RISK A SSESSMENTS and RISK C HARACTERIZATION References: 1) Occupational and Residential Exposure Risk Assessment for Proposed Uses of Aminopy ralid, D305672, M. Collantes, 5 /2 4/200 5 2 ) Aminopy

ralid: Aggregate Human Health Risk Asse ssment for the Proposed Uses on Wheat, Grasses, Non - cropland, and Natural Areas , D301689, M. Doherty, et a l., 7/12/2005 In accordance with the FQPA, HED must consider and 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 exposures and risks from various sources, HED considers both the route and duration of exposure. There are residential exposure s associated with aminopy ralid that must be aggregated with the dietary (food and drinking water) exposures . 6 .1 Acute Aggregate Risk No toxic effects attributable to a single dose were identified for aminopy ralid. As a result, an acute aggregate risk assessment is not a concern . 6 .2 Short - Term Aggregate Risk There are residential uses for amino py ralid on recreational sites (e.g., campgrounds ) . The exposures resulting from this use must be aggregated with the dietary (food and drinking water) exposures . The non - dietary scenarios included in the aggregate assessment consist of incidental oral exposures (e.g., hand - to - mouth transfer of residues , object - to - mouth, and ingestion of soil). These scenarios are short - term in duration and are applicable to children only. At this time, there are no non - dietary

scenarios for aminopy

ralid that are appropriate for assessing adults, therefore, the aggregate exposure estimates for adults are equivalent to the chronic dietary (food + water) estimates presented in Section 4.2.2, above. In estimating short - term aggregate risk, HED has combined the chronic dietary (food + drinking water) exposure estimate and the total non - dietary exposure estimate for children. Chronic dietary exposure values were used for the aggregate calculations in order to provide an estimate of background exposur e from food and drinking w ater. The chronic dietary exposure therefore, serves as an estimate of dietary exposure that co - occurs with potential short - term non - dietary exposure. The short - term aggregate risk assessment data and results are given in Table 6. 2 , below.Page 32 of 48

Table 6 . 2 . Short - TermAggregate Exposure and Risk Calculations for Aminopyralid Population Subgroup NOAEL

mg/kg/day Exposure, mg/kg/day Aggregate MOE * ( F ood and Residential) Dietary Total

Non - Dietary Total

Aggregate All Infants <1 year 104 0.00108 0.0 021 0.00318 33,000 Children 1 - 2 years 104 0.00210 0.0021 0.00420 25,000 Children 3 - 5 years 104 0.00183 0.0021 0.00393 26,000 Children 6 - 12 years 104 0.00127 0.0021 0.00337 31,000 *Aggregate MOE = NOAEL ÷ Total Aggregate Exposure The short - term aggregat e MOEs for aminopy ralid are not of concern to HED. The aggregate MOEs range from 25 , 0 00 to 33 ,0 00. These values are above the LOC of 1,0 00 . 6.3 Intermediate - Term Aggregate Risk Based on the registered and proposed uses, there are no residential scenari os that are likel y to result in intermediate - term exposure (30 - 180 day s, continuous). Therefore, HED has not conducted an intermediate - term aggregate risk assessment for aminopy ralid. 6 .4 Long - Term Aggregate Risk Dietary (food + water) consumption is th e only source of exposure to aminopy ralid that is expected to result in chronic exposure. Therefore, the long - term aggregate exposure and risk estimates are equivalent to the chronic dietary exposure and risk estimates discussed in Section 4 .2.2 , above . The most highl y exposed population subgroup is Children 1 - 2 . The general U.S. population and all population subgroups utilize <1 % of the cPAD. T he risk estimates are all below HED’s level of concern (100% of the cPAD). 6 . 5 Cancer Aggregate Risk As aminopy

ralid has been classified as “not likel y to be carcinogenic to humans,” cancer risk is not a concern for this chemical . 7.0 C UMULATIVE RISK CHARACTERIZATION/ASSESSMENT 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 aminopy

ralid and any

other substances , and aminopy ralid does not appear to produce a toxic metabolite produced b y other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that aminopy ralid has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to d etermine which chemicals have aPage 33 of 48

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released 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://www.epa.gov/pesticides/cumulative/. 8.0 O CCUPATIONAL EXPOSURE/RISK ASSESSMENT PATHWAY References: 1) Aminopy

ralid: Occupational Exposure Assessment for the Registration of Milestone ® Herbicide for Use on Corn, D3 70497 , Z Figueroa, 10 /22 /2009 2) Occupational and Residential Exposure Risk Assessment for Proposed Uses of Aminopy ralid, D305672, M. Collantes, 5 /2 4/200 5 Based on the proposed uses specified o n the label, occupational exposure is expected to be short - and intermediate - term in duration. No long - term (chronic) exposure is expected. 8. 1 Handler Exposure The aminopy

ralid e nd - use product (Milestone ® ) will be formulated as a soluble liquid containing 2 pounds acid equivalent per gallon and will be applied by ground and handgun equipment (spot treatment) . The maximum amount of Milestone ® used o n corn as a single broadcast ap plication is 1.7 fl oz per acre (0.027 lb a.e./A). The total amount of Milestone ® applied broadcast cannot exceed 1.7 fl oz per acre per ye ar (0.027 lb a.e./A). For spot treatments, the maximum single application rate is 1.2 mLper 1,000 ft2 (0.027 lb a. e./A). 8.1.1 Data and Assumptions for Proposed Handler Exposure Scenarios Workers may

be exposed to aminopy

ralid during mixing, loading , and appl ication activities assoc iated with agricultural crops. Based on the proposed use patterns short - and interm ediate term dermal and inhalation exposure are expected to occur. However, a s no dermal point of departure was selected, this risk assessment will only assess inhalation exposure risks. The following exposure scenarios will be assessed for aminop yral id:

• Mixing/loading liquid spray s for groundboom • Applying liquid spray s for groundboom • Mixing/loading/appl yi ng liquid spray s for handgun spray The registrant did not submit a chemical - specific exposure study for assessing the occupational exposure o f handlers. Therefore, the Agency used surrogate exposure data from the Pesticide Handlers Exposure Database ( PHED ) version 1.1 and default values established by the HED's ExpoSAC for c alculating the extent of exposures to handlers from the proposed use o n corn. ForPage 34 of 48

assessing the occupational exposure and risk to handlers (mixers/loaders and applicators) when using Milestone ® Herbicide on corn, the following assumptions and parameters were considered: Application Rates Maximum Single Broadcast Application Rate (1.7 fl oz/A) (1 gal/128 oz) (2 lbs a.e./gal) = 0.02 7 lb a.e./A Maximum Single Spot Application Rate (1.2 mL/1,000 ft2 ) (1oz/29.57 mL) (1 gal/128 oz) (2 lbs a.e./gal) (43,560 ft2 /A) = 0.02 7 lb a.e./A Unit Exposures The default unit exposure values from PHED are surrogate values for the baseline PPE for an emulsifiable concentrate formulation applied using ground equipment. Mixer/L oader Unit Exposure (Baseline Liquid Formulation: Open Mixing) Inhalation = 1.2 μg/lb ae or 0.0012 mg/lb ae Applicator Unit Exposure (Groundboom Open Cab) Inhalation = 0.74 μg/lb ae or 0.00074 mg/lb ae Mixer/L oader/Applicator Unit Exposure (Handgun) Inhalation = 1.8 μg/lb ae or 0.0018 mg/lb ae Area Treated Based on HED’s Exposure Science Advi sory Committee Policy

Number 9.1, the following areas treated per day

w ere assumed:

• 200 acres/day

for mixing/loading and applying liquids for groundboom for field corn; • 25 acre/ day

for mixing/loading and appl yi ng liquids for handgun for field corn (sp ot treatment). Personal Protective Equipment The personal level of protection for baseline unit exposure is long pants, long sleeve shirt, no respirator, no gloves, and shoes plus socks. Body Weight The average adult body

weight of 70 kg was used for non - cancer assessments a s the endpoint was based on effects that were not sex - specific.Page 35 of 48

Handler Equations and Calculations PDD = (UE × AR × A)/(BW) PDD = Potential Daily Dose (mg/kg/day) UE = Unit Exposure (mg/lb ai) AR = Maximum Application Rate (lb ai/A) A = Maximum Area Treated (A/day) BW = Body Weight (kg) Inhalation MOE (All Durations) = Inhalation NOAEL (104 mg/kg/day)/Dose (mg/kg/day) 8 .1.2 Handler Risk and Exposure Applying these assumptions and risk parameters, the short - and interme diate term risks to mixers/loaders and applicators were calculated (Table 8. 1 ). For aminop yralid, MOEs of 100 are required for handlers of agricultural crops in order for risks not to be of concern to HED. All handler short - and intermediate - term MOEs ar e greater than the target MOE of 100 and , therefore , risks d o not exceed HED’s level of concern. Based on the proposed use pattern, l ong - term exposure is not anticipated for occupational handlers. Aminopy

ralid exhibits no evidence of carcinogenicity; the refore, cancer risk is not of concern. Table 8.1 . Short - and Intermediate - TermHandler Exposure and Risk for Aminopyralid Exposure Scenario (Scenario #) Mitigation

Level Inhalation Unit

Exposure (m g/lb ai) Crop Application Rate (lb ae/A) Am ount

Treated I nhalation Dose

(m g/k g/day) Total MOE Mixer/Loader Mixing/Loading liquid sprays for groundboom (PHED data) Baseline 0.0012 Corn 0.027 200 acres/day (broadcast) 0.00009 26 1,100,000 Applicator Applying liquid sprays for groundboom (PHED data) Baseline 0. 00074 Corn 0.027 200 acres/day (broadcast) 0.00005 7 1 , 8 00,000 Mixer/Loader/Applicator Mixing/Loading Applying sprays for handgun (ORETF data) Baseline 0.0018 Corn 0.027 25 acres/day (spot treatment) 0.000017 4 6 , 0 00,000

Note: Short - and I

ntermediate - term I

nhalation Dose (mg/kg/day) = [Rate (lb ai/A) x UE (mg /lb ai ) x IAF (1.0) x Amount Treated (acres or gal/ day)] / BW (70 kg) Total MOE = NOAEL (104 mg/kg/day) / Total Dose (mg/kg/day)Page 36 of 48

8.2 Postapplication Exposure HED has determ ined that there are potential exposures to persons entering treated sites (e.g. scouting, detasselling, weeding, harvesting) after application of pesticide is complete. However, a s no dermal P o D was selected, a postapplication risk assessment for agricultural uses was not possible. Aminopy ralid has a relatively

low vapor pressure (7.14 x 10 - 11 mm Hg at 20oC) and is intended to be used during early season post emergence broadleaf control. Because of outdoor air dilution and the low vapor pressure of amin opy ralid , po stapplication inhalation exposures are expected to be negligible and less than handler’s inhalation exposures. Therefore, a quantitative postapplication inhalation exposure assessment was not performed. Restricted Entry

Interval Milestone ® H erbicide contains the triisopropanolammonium salt of aminopyralid . However, after application of the product, a gricultural workers could be exposed to residues in both the acid and salt form. Therefore, the REI for agricultural occupational exposure resulting from treated corn is based on the acute toxicity of the acid form (i.e., aminopy ralid itself) because of its higher irritation potential . Aminopy ralid is classified as Category IV for acute dermal and dermal irritation and Category Ifor eye irritat ion. Chemicals identified as toxicity Category I require a 48 - hour REI. Furthermore, chemicals classified as toxicity Category Ifor eye irritation require the use of protective eyewear. The supplemental label does not include an REI. Therefore, the Re gistration Division should ensure that the proper REI of 48 hours appears on the registered master label and all supplemental labels . Mixer, loader, and applicator short - and intermediate - term exposures from the application of Milestone ® Herbicide on corn do not exceed HED ’ s L OC. All MOEs exceed the L OC of 100. 9 . 0 D ATA NEEDS AND LABE L RE COMMENDATIONS 9 .1 Toxicology A s part of the new Part 158 data requirement s, an immunotoxicity study in the rat and/ or mouse is required (See Appendix A. 3 ). HED recommends that RD make the submission of th i s study a condition of registration. Dermal toxicity

(inflammation and slight hy perplasia) should be reflected on the chemical label as a potential concern.Page 37 of 48

9 . 2 R esidue Chemistry Pending submission of a revised Section B (see requirements under Directions for Use) and a revised Section F (see requirements under Proposed Tolerances), there are no residue chemistry issues that would preclude granting Section 3 regis tration for the requested uses of amin o py ralid, or establishment of the recommended tolerances . With the review of the interference study and the final report of the grass and wheat storage stability study in this document, all the data requirements that were identified as conditions of registration in the previous aminopy ralid petition (PP#4F6827; D305665, M. Doherty, 7/12/05) have now been satisfied. 860.1200 Directions for Use

 The proposed label should be modified to specify that spray

or spot applic ations may not be made after the V6 growth stage (BBCH 16) and that forage may not be harvested prior to the dent stage of growth. If the petitioner wishes to support a shorter PHI for field corn forage (or harvest of forage at an earlier growth stage), then adequate crop field trial data reflecting the shorter PHI and/or earlier forage harvest must be submitted. 860.1550 Proposed Tolerances

 The proposed tolerances should be revised to reflect the tolerance expression and correct commodity

definitions a s specified in Appendix B . 9.3 Occupational Exposure

 The following amendment on the proposed label of Milestone ® Herbicide is recommended. A 48 - hour REIis required based on the acute toxicity category of the active ingredient in the formulation for eye irritation (Category I ).

 T he Registration Division should ensure that the proper PPE appears on the registered master label and all the supplemental labels. The personal protective equipment (PPE) on the label is incorrect . Early entry PPE should be cov eralls, not just long pants and shirt.

 The proposed supplemental label states “ Do not aerially apply Milestone unless permitted by EPA approved supplemental labeling .” T he Registration Division should ensure that no aerial applications are allowed o n the Milestone ® Herbicide supplemental label for use on field corn.Page 38 of 48

REFERENCES D301689, Aminopy

ralid: Aggregate Human Health Risk Assessment for the Proposed Uses on Wheat, Grasses, Non - cropland Areas, and Natural Areas, M. Doherty, 7/12/2005 D360100, Aminopy

ralid and Aminopy

ralid Triisopropanolammonium (TIPA) Salt. Request to Add Uses on Field Corn to Milestone ® (EPA Reg. No. 62719 - 519) . Summary of Analy tical Chemistry

and Residue Data , D. Dotson, 10 /22 /2009 D369212, Aminopy

rali d Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section 3 Registration on Field Corn , D. Dotson, 10 /22 /2009 D361926, Tier I Drinking Water Exposure Assessment for the Section 3 New Use of Triisopropanolamine Salt of Aminopy ralid on Field Corn and Field Corn Grown for Ensilage , R. Baris, 7/24/2009 D3 70497 , Aminopy

ralid: Occupational Exposure Assessment for the Registration of Milestone ® Herbicide for Use on Corn, Z. Figueroa, 10/22 /2009Page 39 of 48 Appendix A : Aminopyralid Toxicology Appendix A .1 . Toxicology Data Requirements The requirements (40 CFR 158.340) for food use for aminopy ralid are in Table A. 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used. Table A.1 Test Technical Required Satisfied 870.1100 Ac ute Oral Toxicity ................................ ........................ 870.1200 Ac ute Dermal Toxicity ................................ ................... 870.1300 Ac ute Inhalation Toxicity ................................ ............... 870.2400 Primary Eye Irritation ................................ ..................... 870.2500 Pri mary Dermal Irritation ................................ ............... 870.2600 Dermal Sensitization ................................ ...................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 Oral Subchronic (rodent) ................................ ................ 870.3150 Oral Subchronic (nonrodent) ................................ .......... 870.3200 21/28 - Day Dermal ................................ .......................... 870.3250 90 - Day

Dermal ................................ ............................... 870.3465 90 - Day

Inhalatio n ................................ ........................... yes yes yes no no yes

yes yes

---

--- 870.3700a Developmental Toxicity (rodent) ................................ ... 870.3700b Developmental Toxicity (nonrodent) ............................. 870.3800 Reproduction ................................ ................................ .. yes yes yes yes

yes yes 870.4100a Chronic Toxicity (rodent) ................................ ............... 870.4100b Chronic Toxicity (nonro dent) ................................ ......... 870.4200a Oncogenicity (rat) ................................ ........................... 870.4200b Oncogenicity (mouse) ................................ .................... 870.4300 Chronic/Oncogenicity ................................ .................... yes yes yes yes yes yes

yes yes yes yes 870.5100 Mutagenicity

—Gene Mutation - bacterial ...................... 870.5300 Mutagenicity

—Gene Mutation - mammalian ................. 870.5375 Mutag enicity

— Structural Chromosomal Aberrations .... 870.5395 Mutagenicity

—Mammalian Erythrocyte Micronucleus . 870.5550 Mutagenicity

— Unscheduled DNA Synthesis ................ 870.5915 Mutagenicity

— In Vivo Sister Chromatid Exchange yes yes yes no no no yes

yes yes yes yes yes 870.6100a Ac ute Delayed Neurotox icity . (hen) ............................... 870.6100b 90 - Day

Neurotoxicity (hen) ................................ ........... 870.6200a Ac ute Neurotoxicity Screening Battery (rat) .................. 870.6200b 90 Day Neurotoxicity Screening Battery (rat) ................ 870.6300 Develop. Neuro toxicity ................................ .................. no no yes yes no ---

--- yes yes *

--- 870.7485 General Metabolism ................................ ....................... 870.7600 Dermal Penetration ................................ ......................... no no yes

yes 870.7800 Immunotoxicity................................................ yes no * Requirement fulfilled by chronic neurotoxicity study .Page 40 of 48

Appendix A .2 Toxicity Profiles Table A.2a Acute Toxicity Profile - Aminopyralid Technical (XDE - 750) Guideline No. Study Type MRID(s) Results Toxicity Category 870.1100 Ac ute oral - rat 46235603 LD 50 = >5000 mg/kg/bw (both sexes) IV 870.1200 Ac ute dermal - rabbit 46235605 LD 50 = >5000 mg/kg/b w (both sexes) IV 870.1300 Ac ute inhalation - rat 46235607 LC 50 = >5.5 mg/L (both sexes) IV 870.2400 Ac ute eye irritation - rabbit 46235609 Corneal opacity in 1/3 unresolved through day 35 I 870.2500 Ac ute dermal irritation - rabbit 46235611 non - irritant IV 870.2600 Skin sensitization - guinea pig 46235613 Not a sensitizer N/A

Acute Toxicity Profile - Aminopyralid Triisopropanolamine Salt (GF - 871) Guideline No. Study Type MRID(s) Results Toxicity Category 870.1100 Ac ute oral - rat 46235604 LD 50 = >5000 mg/kg/bw (both sexes) IV 870.1200 Ac ute dermal - rabbit 46235606 LD 50 = >5000 mg/kg/bw (both sexes) IV 870.1300 Ac ute inhalation - rat 46235608 LC 50 = >5.79 mg/L (both sexes) IV 870.2400 Ac ute eye irritation - rabbit 46235610 No positive signs of c orneal opacity, iritis or conjunctivitis observed IV 870.2500 Ac ute dermal irritation - rabbit 46235612 Slight erythema observed at 24 hours and 72 hours, resolving by study day 7 IV 870.2600 Skin sensitization - guinea pig 46235614 Not a sensitizer N/APage 41 of 48

Table A.2.b. Subchronic, Chronic and Other Toxicity Profile. GDLN Study Type Dose Levels MRID Results 870.3100 2001 - 13 WEEK

FEEDING - RAT (XDE 750) with 4 week recovery period • mg/kg/day = 0, 10, 100, 500, 1000 Acceptable/Guideline 46235621 NO AEL (mg/kg/day): M=500, F= 1000 LOAEL (mg/kg/day): M=1000 based on hyperplasia of the mucosal epithelium of the ileum and cecum. F=not determined 870.3100 2004 - 13 WEEK

FEEDING - RAT (GF 871) ‡ XDE - 750 TIPA * • mg/kg/day= 0, 192, 500, 1000 ¶ ACID EQUIVALENT (ae) mg ae/kg/day= 0, 100, 260, 520 Acceptable/Guideline 46235622 NOAEL (mg/kg/day): 520 LOAEL (mg/kg/day): not determined

870.3100 2001 - 13 WEEK

FEEDING - MOUSE (XDE - 750) • mg/kg/day = 0, 10, 100, 500, 1000 Acceptable/Guideline 46235618 NOAEL (mg/kg/day): 1000 LOAEL (mg/kg/day): not determined 870.3150 2002 - 13 WEEK

FEEDING - DOG (XDE 750) %=0, 0.15, 0.75, 3.0 § ppm= 0, 1500, 7500, 30000 mg/kg/day = M: 0, 55, 282, 1070 F: 0, 53, 232, 929 Acceptable/Guideline 46235623 NOAEL (mg/kg/day): M=282, F= 232 LOAEL (mg/kg/day): M=1070, F=929 based on stomach histopathology (slight diffuse hyperplasia and hypertrophy of the mucosal epithelium).Page 42 of 48

870.3200 2002 - 28 DAY DERMAL RAT (XDE - 750) mg/kg/day = 0, 100, 500, 1000 Acceptable/Guideline 4623562 6 Sy stemic: NOAEL (mg/kg/day): 1000 LOAEL: (mg/kg/day) not determined Dermal: NOAEL (mg/kg/day): M=100, F=1000 LOAEL (mg/kg/day): M=500, based on histopathological changes (slight epidermal hyperplasia). F=not determined 870.3700 2001 -

DEVELOPMENTAL TOX - RAT (XDE - 750) mg/kg/day = 0, 100, 300, 1000 Acceptable/Guideline 46235629 Maternal : NOAEL (mg/kg/day): 1000 LOAEL (mg/kg/day): not determined Developmental : NOAEL (mg/kg/day): 1000 LOAEL (mg/kg/day): not determined 870.3700 2004 -

DEVELOPMENTAL TOX - RAT (GF - 871) ‡ XDE - 750 TIPA * mg/kg/day= 0, 200, 500, 1000 ¶ ACID EQUIVALENT (ae) mg ae/kg/day= 0, 104, 260, 520 Acceptable/Guideline 46235631 Maternal : NOAEL (mg/kg/day): 520 LOAEL (mg/kg/day): not determined Developmental : NOAEL (mg/kg/day): 520 LOAEL (m g/kg/day): not determined 870.3700 2002 -

DEVELOPMENTAL TOX - RABBIT (XDE - 750) mg/kg/day = 0, 25, 100, 250 (phase 1) mg/kg/day = 0, 500, 750 (phase 2) Acceptable/Guideline 46235630 Maternal : NOAEL (mg/kg/day): 250 LOAEL (mg/kg/day): 500 based on decrease i n body weight (GD 7 - 10), decreased food consumption, incoordinated gait (23/26), and ulcers and erosions of the stomach. Developmental : NOAEL (mg/kg/day): 500 LOAEL (mg/kg/day): not determinedPage 43 of 48

870.3700 2004 -

DEVELOPMENTAL TOX - RABBIT (GF - 871) ‡ XDE - 750 TIPA * mg/kg/day= 0, 200, 500, 1000 ¶ ACID EQUIVALENT (ae) mg ae/kg/day= 0, 104, 260, 520 Acceptable/Guideline 46235632 Maternal : NOAEL (mg/kg/day): 104 LOAEL (mg/kg/day): 260 based on severe inanition and body weight loss, decreased fecal output, and mild incoordinated gait. Developmental : NOAEL (mg/kg/day): 260 LOAEL (mg/kg/day): 520 based on decreased fetal body weights. 870.3800 2003 - 2 - GENERATION

REPRODUCTION - RAT (XDE - 750) • mg/kg/day = 0, 50, 250, 1000 Acceptable/Guideline 46235635 Parental : NOAEL (mg/kg/day): 1000 LOAEL (mg/kg/day): not determined Reproductive : NOAEL (mg/kg/day): 1000 LOAEL (mg/kg/day): not determined Offspring : NOAEL (mg/kg/day): 1000 LOAEL (mg/kg/day): not determined 870.4100 2003 - 1 YEAR FEEDING DOGS (XDE - 750) % =0, 0.03, 0.30, 3.0 § ppm= 0, 300, 3000, 30000 mg/kg/day = M: 0, 10, 99, 967 F: 0, 9, 93, 1038 Acceptable/Guideline 46235627 NOAEL (mg/kg/day): M=99, F= 93 LOAEL (mg/kg/day): M=967, F=1038 based on thickening of stomach mucosa (females), and st om ach histopathology in all animals (slight diffuse hyperplasia and hypertrophy of the mucosal epithelium, slight lymphoid hyperplasia of the gastric mucosa and very slight/slight chronic mucosal inflammation).Page 44 of 48

870.4200 2003 - 18 MONTH

CARCINOGENICITY MICE (XDE - 750) • mg/kg/day = 0, 50, 250, 1000 Acceptable/Guideline 46235628 NOAEL (mg/kg/day): M=1000 LOAEL (mg/kg/day): not determined. 870.4300 2004 - 2 YEAR

TOXICITY/ CARCINOGENICITY RAT (XDE - 750) • mg/kg/day = 0, 50, 500, 1000 Acceptable/Guideline 462356 15 NOAEL (mg/kg/day):50 LOAEL (mg/kg/day): 500 based on cecal enlargement, slight mucosal hyperplasia (males) and slightly decreased body weights. 870.5100 2004 - BACTERIAL

REVERSE MUTATION ASSAY (XDE - 750) 0, 100, 333, 1000, 3300 or 5000 g/plate ( Salmonella -Escherichia coli) in the presence and absence of metabolic activation ( + S9). Acceptable/Guideline 46235636 Negative

870.5100 2004 - BACTERIAL

REVERSE MUTATION ASSAY (GF - 871) XDE TIPA * 33, 100, 333, 1000, 3330, 5000 g/plate ( Salmonella -Escherichia coli) in the presence and absence of metabolic activation ( + S9). Acceptable/Guideline 46235637 Negative

870.5300 2004 -IN VITRO

MAMMALIAN CELL GENE MUTATION TEST 0, 31, 63, 125, 250, 500, 1000, 1500, 2070 μg/mL (1 st assay); 250, 500, 1000, 2000, 4000  g/mL (2 nd assay), both in the presence and absence of metabolic activation ( + S9). Acceptable/Guideline 46235801 Negative

870.5300 2004 -IN VITRO

MAMMALIAN CELL GENE MUTATION TEST (GF - 871) XDE TIPA * 250, 500, 1000, 2000, 4000 g/mL in the presence and absence of metabolic activation ( + S9). Acceptable/Guideline 46235804 NegativePage 45 of 48

870.5375 2002 -IN VITRO

MAMMALIAN CELL CHROMOSOME ABERRATION TEST (XDE - 750) 0, 32, 65, 129, 259, 518, 1035, 2070 μg/mL with and without metabolic activation (1 st assay); 0, 12 5, 250, 500, 750, 1000, 1400, 1700, 2070 μg/mL without metabolic activation and 0, 62.5, 125, 500, 1000 or 2070 μg/mL with metabolic activation (2 nd assay); 400, 600, 800, 1000, 1200, 1400, 1600, 1700, 1800, 2070 μg/mL without metabolic activation (3 rd a ssay). Acceptable/Guideline 46235802 XDE induced chromosome aberrations, but only at cytotoxic concentrations; the clastogenic response was induced secondary to toxicity.

870.5375 2004 -IN VITRO

MAMMALIAN CELL CHROMOSOME ABERRATION TEST (GF - 871) XDE TIPA * 1000, 2000, 4000  g/mL with and without metabolic activation ( + S9); 0, 500, 1000, 2000  g/mL without metabolic activation. Acceptable/Guideline 46235803 Negative

870.5395 2002 - MAMMALIAN

ERYTHROCYTE MICRONUCLEUS TEST (XDE - 750) mg/kg/day = 0, 500, 1000 or 2000 Acceptabl e/Guideline 46235805 Negative

870.5395 2004 - MAMMALIAN

ERYTHROCYTE MICRONUCLEUS TEST (GF - 871) mg/kg/day = 0, 500, 1000, or 2000 Acceptable/Guideline 46235806 Negative

870.6200 ACUTE

NEUROTOXICITY - RAT (XDE - 750) • mg/kg/day = 0, 500, 1000, 2000 Acceptabl e/Guideline 46235616 NOAEL (mg/kg/day): 1000 LOAEL (mg/kg/day): 2000 based on fecal soiling in males and urine soiling in females. 870.6200 CHRONIC

NEUROTOXICITY - RAT (XDE - 750) • mg/kg/day = 0, 5, 50, 500, 1000 Acceptable/Guideline 46235617 NOAEL (mg/kg/day): 1000 LOAEL (mg/kg/day): not determinedPage 46 of 48

870.7485 2004 - METABOLISM

AND PHARMACOKINETICS RAT (XDE - 750) mg/kg/day = Lo w dose: 50 High dose: 1000 Repeated low

dose: 50 (unlabelled) for 14 days, 50 (labelled) on day 15 Acceptable/Guideline 4623 5807 Recovery after 168 hrs: 96% in low

dose (urine - 50%, feces - 43%, tissues - 0.1%, cage wash 3%), 95% in high dose (urine - 41%, feces - 43%, tissues - 1%, cage wash 10%), and 95% in the repeated low

dose (urine 59%, feces - 33%, tissues 0.1%, cage wash - 3%). XDE - 750 represented > 96% of administered dose (AD) in urine and 100% AD in feces. Three unknown components ( > 4%) found in urine were also found in dose formulations. Non Guideline XDE - 750,

Triisopropanolamine salt DISSOCIATION AND METABOLISM IN MALE FISCHE R 344 RATS mg/kg/day= 50 or 96 46235833 14 C - XDE - 750 and 14 C XDE - 750 - TIPA, when administered orally to rats, were bioequivalent in terms of absorption, distribution, metabolism, and excretion of the amino - dichloro - picolinate portion of the mo lecule(s). * XDE - 750 TIPA (aminopyralid triisopropanolammonium salt) ‡ GF - 871 (41.3% TIPA) § ppm calculated by reviewer • dose levels were not given in ppm ¶ acid equivalents calculated by reviewerPage 47 of 48

Appendix A.3 . Rationale for Toxicology Data Require ments Table A. 3 Guideline Number : 870.7800 Study Titl e: Immunotoxicity Rationale for Requiring the Data Th e immunotoxicity study is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide (food and non - food uses). The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity testing and is designed to evaluate the potential of a repeated chemical exposure to produce adverse effects (i.e., suppression) on the immune system. Immunosuppression is a deficit in the ability of the immune system to respond to a challenge of bacterial or viral infections such as tuberculosis (TB), Severe Acquired Respiratory Syndrome (SARS), or neoplasia. Because the immune system is h ighly complex, studies not specifically conducted to assess immunotoxic endpoints are inadequate to characterize a pesticide’s potential immunotoxicity. While data from hematology, lymphoid organ weights, and histopathology in routine chronic or subchroni c toxicity studies may offer useful information on potential immunotoxic effects, these endpoints alone are insufficient to predict immunotoxicity. Practical Utility of the Data How will the data be used? Immunotoxicity studies provide critical scienti fic information needed to characterize potential hazard to the human population on the immune system from pesticide exposure. Since epidemiologic data on the effects of chemical exposures on immune parameters are limited and are inadequate to characterize a pesticide’s potential immunotoxicity in humans, animal studies are used as the most sensitive endpoint for risk assessment. These animal studies can be used to select endpoints and doses for use in risk assessment of all exposure scenarios and are consi dered a primary data source for reliable reference dose calculation. For example, animal studies have demonstrated that immunotoxicity in rodents is one of the more sensitive manifestations of TCDD (2,3,7,8 - tetrachlorodibenzo -p - dioxin) among developmental, reproductive, and endocrinologic toxicities. Additionally, the EPA has established an oral reference dose (RfD) for tributyltin oxide (TBTO) based on observed immunotoxicity in animal studies (IRIS, 1997). How could the data impact the Agency's future d ecision - making? If the immunotoxicity study shows that the test material poses either a greater or a diminished risk than that given in the interim decision’s conclusion, the risk assessments for the test material may need to be revised to reflect the magnitude of potential risk derived from the new data. If the Agency does not have th e s e data, a 10x database uncertainty factor may be applied for conducting a risk assessment from the available studies.Page 48 of 48 Appendix B : Tolerance Summary for Am inopy ralid Table B - 1 . Tolerance Summary for Aminopyralid. Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity

Definition Corn, forage 0.30 0.30 Corn, field, forage Corn, grain 0.20 0.20 Corn, field, grain Corn, stov er 0.20 0.20 Corn, field, stover HED recommends that 40CFR §180.610(a)(1) be amended b y replacing the tolerance expression with the following: “Tolerances are established for residues of aminopyalid (4 - amino - 3,6 - dichloro - 2 - py

ridinecarboxylic acid), inc luding its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined b y measuring only free and conjugated aminopyralid.” HED further recommends that 40CFR §180.610(a)(2) be amended b y replacing the tolerance expression with the following: “Tolerances are established for residues of aminopy ralid, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance level s specified below is to be determined b y measuring onl y aminop yralid.”