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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 

OFFICE OF PREVENTION, PESTICIDE

AND TOXIC SUBSTANCES

MEMORANDUM

DATE: 10/22/2009

SUBJECT: Aminopyralid. Human Health Risk Assessment for the Proposed Use on Field 

Corn (PP#8F7455) 

PC Codes: 005100 (Aminopyralid) and 

 005209 (Aminopyralid TIPA Salt)

DP Barcode: D359088

Decision Nos. 401475 Registration Nos.: 62719-519

Petition Nos.: 8F7455 Regulatory Action: Section 3 

Risk Assess Type: Single Chemical Aggregate Case No.: None 

TXR No.: None CAS No.: 150114-71-9 (Aminopyralid)

 566191-89-7 (Aminopyralid TIPA Salt)

MRID No.: None 40 CFR: 180.371

 

 

FROM: Douglas Dotson, Ph.D., Chemist

Karlyn Middleton, Toxicologist

Zaida Figueroa, Industrial Hygienist

Risk Assessment Branch II

Health Effects Division (7509P)

THROUGH: Alan Levy, Ph.D., Toxicologist

Michael Doherty, Ph.D., Chemist

Margarita Collantes, Biologist

Richard Loranger, Ph.D., Senior Scientist

Christina Swartz, Branch Chief

Risk Assessment Branch II, Health Effects Division (7509P)

TO: Kathryn Montague/Joanne Miller, RM Team 23

Herbicide Branch

Registration Division (7505P)
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Table of Contents

1.0 Executive Summary............................................................................................................ 4

2.0 Ingredient Profile ................................................................................................................ 8

2.1 Summary of Registered/Proposed Uses...................................................................... 9

2.2 Structure and Nomenclature...................................................................................... 10

2.3 Physical and Chemical Properties............................................................................. 11

3.0 Hazard Characterization/Assessment................................................................................ 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......................................................................................... 12

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 Literature 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 Safety 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 Incidental 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 Levels of Concern for Occupational and Residential Exposure Assessments...... 18

3.5.9 Recommendation 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 Characterization................................................................................ 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 Livestock....................................................................................... 22
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4.1.4 Analytical Methodology ....................................................................................... 22

4.1.5 Environmental Degradation.................................................................................. 24

4.1.6 Comparative Metabolic Profile............................................................................. 24

4.1.7 Toxicity Profile of Major 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 ............................................................................... 28

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 Other (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 Handler 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 Recommendations ........................................................................ 36

9.1 Toxicology................................................................................................................. 36

9.2 Residue Chemistry .................................................................................................... 37

9.3 Occupational Exposure.............................................................................................. 37

References:.................................................................................................................................... 38

Appendix A: Aminopyralid Toxicology...................................................................................... 39

Appendix B: Tolerance Summary for Aminopyralid .................................................................. 48
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EXECUTIVE SUMMARY

HED has performed a human health risk assessment for the herbicide aminopyralid (4-amino3,6-dichloro-2-pyridinecarboxylic acid), and has determined that there is a reasonable certainty

that no harm will result from aggregate exposure to aminopyralid residues, 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 aminopyralid 

is formulated as the triisopropanol-ammonium (TIPA) salt. The product contains 40.6% 

aminopyralid TIPA salt at an acid equivalent (ae) of 21.1% or 2 lb ae/gal. The product is 

proposed for postemergence foliar broadcast or spot applications to field corn at a maximum 

seasonal rate of 0.027 lb ae/A. Preharvest intervals (PHIs) of 0 days for grain and 8 days for 

forage or silage are proposed. The most recent Section 3 risk assessment performed for 

aminopyralid was completed in July, 2007 (D301689, M. Doherty, 7/12/2007).

Toxicology

Acute toxicity data indicate that aminopyralid (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 

molecule 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 lining 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 aminopyralid. 

Consequently, the FQPA Safety Factor was reduced to 1x because of the lack of residual 

uncertainty for pre- and postnatal toxicity. Dermal studies indicate that aminopyralid does not 

have any significant toxicity via the dermal route of exposure. Aminopyralid has been classified 

as “not likely to be carcinogenic to humans,” and there is no evidence that aminopyralid 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, hyperplasia) and body weight changes in a combined 

chronic/carcinogenicity study 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, incoordinated 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 Part 158 Guidelines, an 

immunotoxicity study in rats and/or mice is now required for aminopyralid. HED concludes that 

a database uncertainty factor is not needed for the lack of this study because the overall weight of 

evidence suggests that aminopyralid does not directly target the immune system.
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Metabolic Profile

Adequate studies are available depicting the metabolism of aminopyralid 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 conjugates 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 residues of concern for purposes of human health risk assessment 

and for expression of tolerances are equivalent. For plant commodities, the residues of concern 

are combined free and conjugated aminopyralid, calculated as parent aminopyralid. For 

livestock commodities, the residue of concern is parent aminopyralid. The residue of concern in 

drinking water is also parent aminopyralid. 

Residue Chemistry and Dietary Risk Estimates

HED evaluated the residue chemistry database for aminopyralid. In general, the residue 

chemistry data are sufficient to evaluate the nature and magnitude of residues in the proposed 

commodities. An analytical method is available for enforcement of the proposed tolerances. 

Adequate high performance liquid chromatography (LC) methods with tandem mass 

spectroscopy detection (MS/MS) have been submitted for tolerance enforcement for crop and 

livestock commodities. The validated limit of quantitation (LOQ) is 0.01 ppm in each matrix. 

Samples from the submitted field corn crop field trial and processing studies were analyzed 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

concerning directions for use, proposed tolerances, and crop field trials.

 

To evaluate chronic dietary risks, HED used information in the residue chemistry database along 

with modeled estimates of aminopyralid in drinking water to conduct dietary (food + water) 

exposure assessments. 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 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 incorporated directly into the dietary assessment using the 
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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 0.000703 mg/kg/day for the U.S. 

population (<1% of the chronic population adjusted dose (cPAD)) and 0.002097 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 aminopyralid. 

Tolerance Harmonization

Codex and Canadian MRLs have been established for residues of aminopyralid; however, no 

MRLs have been established for the requested crop commodities (field corn grain, forage, and 

stover). No Mexican MRLs have been established for aminopyralid. 

Residential Exposure

Residential exposures associated with the use of aminopyralid to control weeds on residential 

and recreational sites were previously assessed in support of the 2005 risk assessment for the 

proposed use of aminopyarlid on wheat, grasses, non-cropland areas, and natural areas (Memo, 

D305672, M. Collantes, 5/24/2005). 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 aminopyralid is not applied by homeowners. The registrant has not 

proposed any new residential and/or non-occupational uses for aminopyralid 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 aminopyralid. As a result, an 

acute aggregate risk assessment is not needed for this chemical. 

There are residential uses for aminopyralid on recreational sites. The exposures resulting from 

this residential use must be aggregated with the dietary (food and drinking water) exposures. At 

this time, there are no non-dietary scenarios for aminopyralid that are appropriate for assessing 

adults, therefore, the aggregate exposure estimates for adults are equivalent to the chronic dietary

(food + water) estimates, which are not of concern to HED. The non-dietary scenarios 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-mouth, 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 shortterm 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 aminopyralid that is 

expected to result in chronic exposure. Therefore, the long-term aggregate exposure and risk 
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estimates are equivalent to the chronic dietary exposure and risk estimates. The most highly 

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 level of concern 

(100% of the cPAD).

Aminopyralid has been classified as “not likely to be carcinogenic to humans;” therefore, cancer 

risk is not a concern.

Occupational Exposure

The registrant did not submit any chemical-specific exposure data for assessing 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 in 

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.

There are potential dermal exposures to workers entering treated sites after pesticide application 

is complete. These workers perform activities such as scouting, detasselling weeding, and 

harvesting. No dermal point of departure (PoD) 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, agricultural 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., 

aminopyralid itself) because of its higher irritation potential. Aminopyralid is classified as 

Category IV for acute dermal and dermal irritation and Category I for eye irritation. Chemicals 

identified as toxicity Category I require a 48-hour REI. Furthermore, chemicals classified as 

toxicity Category I for eye irritation require the use of protective eyewear. The supplemental 

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 extent 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 Low-Income Populations,”

http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.
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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 that 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 Intakes by Individuals (CSFII) and are used 

in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed 

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 products and associated risks 

for adult applicators and for toddlers, youths, and adults entering or playing on treated areas 

postapplication are evaluated. Further considerations are currently in development as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers as well as lifestyle 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.

Conclusions

HED concludes that the registrant has submitted adequate data for the Agency to make the safety 

finding with respect to the use of aminopyralid on the registered and proposed uses. 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 

current 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 tolerance 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

Aminopyralid is a systemic postemergence herbicide that belongs to the pyridine carboxylic acid 

class of compounds. It is currently registered for use on rangeland, permanent grass pastures, 

and wheat. In addition, it is registered for use on wildlife habitat and industrial vegetation 

management areas, including right-of-way for roads, railroads, and utility lines. Under 
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PP#8F7455, Dow AgroSciences is proposing aminopyralid for use on field corn. The end-use 

product (EP) proposed for use on field corn is a SL formulation, Milestone Specialty Herbicide 

(EPA Reg. No. 62719-519), in which aminopyralid is formulated as the TIPA salt. The product 

contains 40.6% aminopyralid TIPA salt at an acid equivalent (ae) of 21.1% or 2 lb ae/gal. 

2.1 Summary of Registered/Proposed Uses

Tolerances for aminopyralid are currently 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 aminopyralid, calculated as aminopyralid. Tolerances 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 aminopyralid. Tolerances have been established for 

milk and the fat, kidney, meat, and meat byproducts of cattle, goat, horse, and sheep.

The petitioner submitted a proposed supplemental label (pin punched with date 10/15/08) for the 

2 lb ae/gal SL product (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, 

Type, and 

Equip.

Formulation

[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 Ensilage

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

0.00021-

0.00063 lb 

ae/1,000 ft2

The supplemental label states that use is subject to all use precautions 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 be 
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conducted within 18 months of application prior to planting any broadleaf crops not listed. HED 

received a second, undated supplemental label for Milestone® which has different plantback 

intervals. The appropriate plantback intervals appear on the label pin punched 10/15/08.

2.2 Structure and Nomenclature

Table 2.2. Aminopyralid Nomenclature.

Chemical structure

Cl N

NH2

Cl

O

OH

Common name Aminopyralid

Company experimental name XDE-750

IUPAC name 4-amino-3,6-dichloropyridine-2-carboxylic acid

CAS name 4-amino-3,6-dichloro-2-pyridinecarboxylic acid 

CAS registry number 150114-71-9

Chemical structure

Cl N

NH2

Cl

O

OH

N

HO CH3

H3C

OH

CH3

OH

.

Common name Aminopyralid, triisopropanolammonium (TIPA) salt

PC Code 005209

Company 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-carboxylic 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)
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2.3 Physical and Chemical Properties

TABLE 2.3. Physicochemical Properties of the Technical Grade of Aminopyralid.

Parameter Value Reference

Melting point/range 163.5oC MRID 46235703

pH 2.31 at 23.4oC (1% solution in water) MRID 46235703

Density 1.72 at 20oC MRID 46235703

Water solubility 2.48 g/L unbuffered water at 18oC

212 g/L pH 5 buffer at 20oC

205 g/L pH 7 buffer at 20oC

203 g/L pH 9 buffer at 20oC

MRID 46235703

Solvent 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 μg/mL

MRID 46235703

Vapor pressure 2.59 x 10-8Pa at 25oC; 9.52 x 10-9Pa at 20oC MRID 46235703

Dissociation constant, pKa 2.56 MRID 46235703

Octanol/water partition coefficient, Log(KOW) 0.201 unbuffered water at 19oC

-1.76 at pH 5

-2.87 at pH 7

-2.96 at pH 9

MRID 46235703

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

MRID 46235703

3.0 HAZARD CHARACTERIZATION/ASSESSMENT

3.1 Hazard and Dose-Response Characterization

3.1.1 Database Summary

3.1.1.1 Sufficiency of Studies/Data

The toxicology database for aminopyralid is not complete. In accordance with the new 40CFR

Part 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 studies 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 time. 
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3.1.1.2 Mode of Action

Aminopyralid is a pyridine carboxylic acid herbicide possessing auxin-like qualities. It moves 

systemically throughout the plant and deregulates plant growth metabolic pathways affecting the 

growth process of the plant. This disruption of plant growth processes, by binding of 

aminopyralid 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 aminopyralid includes toxicity studies with the acid (XDE-750) as 

well as the TIPA 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 severely irritating to the eye (Category I). Aminopyralid 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 aminopyralid indicates that the stomach, ileum, and cecum are 

targets for this chemical. In a subchronic feeding study in rats (XDE-750), hyperplasia 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 hyperplasia of the 

mucosal epithelium, along with cecal enlargement and decreased body weights at a lower dose of 

500 mg/kg/day. Hypertrophy and hyperplasia 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), hyperplasia and hypertrophy of the mucosal epithelium, slight 

lymphoid hyperplasia 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). 

Ulcers 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 because 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 systemic toxic effects were observed in a 28-day dermal toxicity study in rats with XDE-750; 

however, dermal toxicity was indicated by 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. 

Aminopyralid is classified as “not likely to be carcinogenic to humans.” No increase in any

tumors were found in carcinogenicity studies in rats and mice. Aminopyralid 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 cytotoxic 

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 

assessment 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, hyperplasia) and body 

weight changes at the LOAEL of 500 mg/kg/day. For short- and intermediate-term incidental 

oral exposure, as well as inhalation exposure, the developmental toxicity study in rabbits (GF871) was used for endpoint selection, based on inanition, body weight changes, and 

incoordinated gait seen at the LOAEL of 260 mg ae/kg/day (NOAEL = 104 mg ae/kg/day). 

Dermal exposure was not assessed because of the low toxicity observed in a 28-day dermal 

toxicity study.

3.1.4 FQPA

After evaluation of the toxicological and exposure data for aminopyralid, HED recommends that 

the FQPA Safety Factor be reduced to 1x (see Section 3.4).

3.2 Absorption, Distribution, Metabolism, Excretion

In a metabolism study in rats, aminopyralid (XDE-750) is rapidly absorbed, distributed and 

excreted following 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, respectively).

The absorption and excretion patterns of the 14C moiety were similar among all groups. Study

results indicated that XDE-750 was not metabolized to volatile compounds, including CO2. The 

average α-phase elimination half-lives (T1/2 α) of 14C-XDE-750 equivalents were 2.85, 3.27, and 

3.78 hours for the single low, repeated low, and single high dose groups, respectively. The 

average β-phase urinary elimination half-lives (T1/2 β) of 14C-XDE-750 equivalents were 10.23, 

12.25, and 10.88 hours for the single low, repeated low, and single high dose groups, 

respectively. Tissue distribution and bioaccumulation of XDE-750 were minimal, with <0.73% 

of the administered dose being recovered in tissues 7 days after oral administration for all dosing 

groups. Highest levels of radioactivity were found in the skin and carcass. XDE-750 was 

excreted 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 similar quantities in the 

analysis of the dose formulation, suggesting that they were trace impurities in the radiolabeled 

material. When administered orally to rats, 14C-XDE-750 and 14C-XDE-750-TIPA are 

bioequivalent in terms of absorption, distribution, metabolism, and excretion of the aminodichloro-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 new data requirements in 40 CFR 

Part 158 for conventional pesticide registration. The toxicology database for aminopyralid 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 system, and the Agency

does not believe that conducting a functional immunotoxicity study will result in a lower PoD 

than that currently used for overall risk assessment. Therefore, a database uncertainty factor 

(UFDB) is not needed to account for lack of this study.

3.3.2 Evidence of Neurotoxicity

No evidence of neurotoxicity was observed in acute or chronic neurotoxicity studies. 

Incoordinated 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. The incoordination was 

characterized by a reluctance to move unless manually stimulated by the observer. Significant 

stiffening 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 

progressively 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 Toxicity Studies

In a developmental toxicity study in rabbits, ulcers and erosions were observed in the glandular 

mucosa of the stomach. Decreased body weights and incoordinated gait were observed at ≥ 500 

mg/kg/day in maternal animals. Developmental toxicity could not be determined in the study as 

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 study (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 effects 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 aminopyralid 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 analysis are: (1) to determine the level of concern for 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. If residual uncertainties are identified, then HED determines 

whether these residual uncertainties can be addressed by the FQPA Safety Factor and, if so, the 

size of the factor needed.

No evidence of quantitative or qualitative susceptibility was observed in developmental 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 Safety Factor be reduced to 1x. 

3.3.7 Recommendation for Not Requiring a Developmental Neurotoxicity Study

No evidence of neurotoxicity was observed in acute or chronic neurotoxicity studies. 

Incoordinated 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 resolution within two hours postdosing) and considered 

to be a result of frank toxicity, rather than a neurotoxic event. Additionally, no signs of 

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

qualitative susceptibility was observed in developmental toxicity 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

After having evaluated the toxicological and exposure data for aminopyralid, HED recommends 

that the FQPA SF be reduced to 1x. This recommendation is based on the following: 

 In accordance with the new 40 CFR Part 158 data requirements, an immunotoxicity study

in rats and/or mice is now required. Although the toxicological database is not complete, 

it 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 system, and the Agency does not believe that conducting a functional 

immunotoxicity study will result in a lower PoD than that currently used for overall risk 

assessment. Therefore, a database uncertainty factor (UFDB) is 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 aminopyralid 

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 Identification 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 soiling 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 establishing 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/day
Page 17 of 48

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

Chronic RfD = 

100 ( )

50 / /

UF

mg kg day = 0.5 mg/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 and the 

LOAEL of 500 mg/kg/day are based on cecal enlargement, slight mucosal hyperplasia 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 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 route of exposure and duration of 

this study are appropriate for assessing such exposures. The maternal NOAEL of 104 mg 

ae/kg/day and the maternal LOAEL 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 for aminopyralid. However, a 28-day dermal toxicity

study in rats was submitted. No systemic toxicity occurred at the limit dose (1000 mg/kg/day),

and the primary toxic effects of concern were adequately assessed in the study. Therefore, it is 

concluded that aminopyralid 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 systemic 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 

hyperplasia in males only. Dermal toxicity (inflammation and slight hyperplasia) 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 systemic 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 concern were adequately 

addressed; therefore, dermal risks from systemic 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 LOAEL of 260 mg ae/kg/day are based on severe inanition and body

weight loss, decreased 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 Exposure 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 required N/A

Inhalation 100 100 N/A

N/A = Not applicable
Page 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 

conventional uncertainty 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 indicate 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 routes: oral, dermal and inhalation. HED 

considers the potential for concurrent exposure via different routes that produce the same 

toxicological effects. In the event that the same toxicological effect is produced upon exposure 

through different routes, HED aggregates those exposures. Based on the available toxicological 

information for aminopyralid, dermal exposures do not result in any adverse systemic 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 implicitly 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), 

aminopyralid 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 NonOccupational Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute 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 

was not seen in the toxicity database; 

therefore, an acute endpoint has not been 

identified. 

Chronic 

Dietary (All 

Populations)

NOAEL= 50 

mg/kg/day

UFA= 10x

UFH=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)

IntermediateTerm (1-6 

months) 

NOAEL=104 

mg ae/kg/day

UFA= 10x

UFH=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 ShortTerm (1-30 

days)

IntermediateTerm (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)

IntermediateTerm (1-6 

months)

NOAEL=104 

mg ae/kg/day

UFA= 10x

UFH=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 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = 

population adjusted dose (a = acute, c = chronic). RfD = reference dose. N/A = not applicable. ae=acid equivalent
Page 21 of 48

Table 3.5.11b Summary of Toxicological Doses and Endpoints for Aminopyralid for Use in Occupational 

Human 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 ShortTerm (1-30 

days)

IntermediateTerm (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)

IntermediateTerm (1-6 

months)

NOAEL=104 

mg ae/kg/day

UFA= 10x

UFH=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 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 

exposures. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from 

animal to human (interspecies). UFH = 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 by a naturally occurring estrogen, 

or other such endocrine effects as the Administrator 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 thyroid hormone systems, in addition to the estrogen hormone system. 

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, aminopyralid might 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: Aminopyralid and Aminopyralid Triisopropanolammonium (TIPA) Salt. Request to 

Add Uses on Field Corn to Milestone® (EPA Reg. No. 62719-519). Summary of Analytical 

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 adequately 

understood based on acceptable grass and wheat metabolism studies. HED concluded that the 

residues of concern in grass and cereal grain commodities are free and conjugated aminopyralid.

4.1.2. Metabolism in Rotational Crops

A confined rotational crop study was submitted previously. Lettuce, sorghum, and turnips were 

planted as rotational crops at plantback intervals (PBIs) of 90 and 120 days. Residue profiles 

were similar between the matrices. Aminopyralid 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 aminopyralid. 

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 too 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 aminopyralid 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 aminopyralid. This finding is supported by the residues of concern for the related 

compounds picloram and clopyralid 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 currently 

available for the enforcement of tolerances for aminopyralid 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 aminopyralid in a variety of crop 

commodities (wet, dry, acidic, and oily crops). The method description indicates that Method 

GRM 07.07 supersedes Method 02.31. The major differences between the two methods are that 
Page 23 of 48

Method GRM 02.31 uses a different internal standard (13C2

15N-aminopyralid) and only includes 

instructions for the determination of residues in barley, sorghum, wheat, and grass commodities. 

Method GRM 07.07 was adequately 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 oily 

crops (palm oil and sunflower seed) fortified with aminopyralid 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 types of crops tested. The method includes instructions for 

monitoring up to three ion transitions for aminopyralid; therefore, confirmatory analysis 

procedures are not needed. 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 Method 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 currently 

available for the enforcement of tolerances for aminopyralid residues in ruminant milk and 

tissues. The method was adequately 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 AgroSciences 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 (13C2

15N-aminopyralid) and only includes instructions for the 

determination of residues in bovine commodities (muscle, fat, liver, kidney, and milk). Method 

GRM 07.08 was adequately validated using samples of untreated cattle milk, kidney, and fat and 

poultry egg, liver, and muscle fortified with aminopyralid at 0.01 and 2 ppm. Recoveries were 

within acceptable ranges for milk and tissues. The method includes instructions for monitoring 

up to three ion transitions for aminopyralid; 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 testing data have been submitted previously for aminopyralid. 

The results of the study indicate that the FDA multiresidue methods in PAM Vol. I are not 

suitable for the determination of aminopyralid.
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 Aminopyralid on Field Corn and Field Corn Grown for Ensilage, 

D361926, R. Barris, 7/24/2009

The registrant previously submitted environmental fate studies for aminopyralid. The aqueous

photolysis study (MRID 46235727) is the only study in which degradates of aminopyralid were 

observed. They were identified 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 CO2 and bound 

residues were observed in the remaining fate studies.

4.1.6 Comparative Metabolic Profile

Adequate studies are available depicting the metabolism of aminopyralid 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. In wheat and grasses 

as target crops, the major residues, totaling approximately 90% of the TRR in each matrix, were 

parent aminopyralid and glucose conjugates of aminopyralid. In lettuce, sorghum, and turnips 

planted as rotated crops, aminopyralid 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 aminopyralid and, 

with the exception of goat kidney, radioactivity in animal tissues was too low for compound 

identification. In goat kidney, 80% of the TRR was parent aminopyralid. In all of the 

environmental fate studies except aqueous photolysis, residues were identified as aminopyralid, 

CO2, or bound residues. In the aqueous photolysis study, residues of oxamic acid and 

malonamic acid were identified.

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.

4.1.7 Toxicity Profile of Major Metabolites and Degradates 

The submitted toxicity database is adequate to account for the toxicity of all residues to which 

humans are expected to be exposed. HED bases this 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 metabolized 
Page 25 of 48

and/or rapidly 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; therefore, 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 aminopyralid is not 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 aminopyralid by acid and/or base 

hydrolysis. The plant analytical method includes both base and acid hydrolysis 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 of 

tolerances are equivalent (Table 4.1.8). For plant commodities, the residues of concern are

combined free and conjugated aminopyralid, calculated as parent aminopyralid. For livestock 

commodities, the residue of concern is parent aminopyralid. The residue of concern in drinking 

water is also parent aminopyralid. 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 included as residues of concern in drinking water.

Table 4.1.8. Residues of Concern for Human Health Risk Assesment and Residue Tolerance Expressions

Matrix Risk Assessment Residue Tolerance Expression

Plants Primary Crop Aminopyralid, free and conjugated 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 Aminopyralid 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 Aminopyralid on Field Corn and Field Corn Grown for Ensilage, 

D361926, R. Barris, 7/24/2009

EFED used the screening model FIRST (FQPA Index Reservoir Screening Tool, version 1.1, 

01/01/07) to calculate the surface water EDWCs. The acute value represents a 1-in-10 year peak 

value and the chronic value 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 aminopyralid 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

 Rangeland Grasses (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

4.1.10 Food Residue Profile

Reference:

Aminopyralid and Aminopyralid Triisopropanolammonium (TIPA) Salt. Request to Add Uses 

on Field Corn to Milestone®(EPA Reg. No. 62719-519). Summary of Analytical 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. Overall 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 analyzed using 

Method GRM 02.31; overall concurrent method recoveries ranged from 71 to 106%. The 

submitted crop analytical 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 analysis were not provided for the subject field trial and processing studies. For 

future submissions, the petitioner should note that dates of extraction and analysis 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

Residues 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 beef and dairy cattle are predominantly driven by residue contributions 

from grass forage and hay. The tolerances for grass forage and hay are considerably higher than 

the recommended tolerances for field corn commodities. HED is in agreement with the 

registrant 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. Although 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 number 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 specified 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 days for grain and 8 days for forage or silage are not supported 

by the submitted data. The proposed label should be modified to specify that spray or spot 

applications 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.

 

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 for 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 field 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 

aminopyralid residues might concentrate in field corn grits and meal. Based on the HAFT 
Page 28 of 48

residues for aminopyralid in/on field corn grain (0.155 ppm), and the processing factors, 

expected residues of aminopyralid in corn grits and meal following treatment at 1x would be 

0.17 and 0.20 ppm, respectively. 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 aminopyralid. 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 adequate. 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 aminopyralid; however, no 

MRLs have been established for the requested crop commodities. No Mexican MRLs have been 

established for aminopyralid.

4.2 Dietary Exposure and Risk

Reference: Aminopyralid Chronic Aggregate Dietary (Food and Drinking Water) Exposure and 

Risk Assessment for the Section 3 Registration on Field Corn, D369212, 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, which 

uses food consumption data from the U.S. Department of Agriculture’s Continuing Surveys of 

Food Intakes by Individuals (CSFII). The surveys were taken from 1994-1996 and included a 

supplemental children’s survey taken in 1998.

4.2.1 Acute Dietary Exposure/Risk

A toxic effect attributable to a single dose was not identified for aminopyralid. 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 applied to all processed commodities for which they were available. Drinking water 
Page 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 0.000703 mg/kg/day for the U.S. 

population (<1% of the chronic population adjusted dose (cPAD)) and 0.002097 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 aminopyralid. The dietary exposure and 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 Chronic (Non-Cancer) Dietary Exposure and Risk for Aminopyralid

 (Food and Drinking Water)

Population Subgroup

Acute Dietary Chronic Dietary

Dietary Exposure 

(mg/kg/day) % aPAD Dietary Exposure(mg/kg/day) % cPAD

General U.S. Population

N/A N/A

0.000703 <1

All Infants (< 1 year old) 0.001081 <1

Children 1-2 years old 0.002097 <1

Children 3-5 years 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 Exposure/Risk

As aminopyralid was classified as “not likely to be carcinogenic to humans,” a quantitative 

cancer dietary exposure assessment was not performed. Cancer risk is not a concern for 

aminopyralid.
Page 30 of 48

4.3 Anticipated Residue and Percent Crop Treated (%CT) Information

These chronic dietary exposure and risk estimates are highly conservative. They are based on 

the assumption that 100% of crops with existing or proposed tolerances are treated with 

aminopyralid, 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-Occupational) EXPOSURE/RISK CHARACTERIZATION

Reference:

Occupational and Residential Exposure Risk Assessment for Proposed Uses of Aminopyralid, 

D305672, M. Collantes, 5/24/2005

No new residential and/or non-occupational uses for aminopyralid are being proposed at this 

time. Residential exposures associated with the use of aminopyralid to control weeds on 

residential and recreational sites were previously assessed (Memo, D305672, M. Collantes,

5/24/2005). The results of the residential exposure assessment indicated that risks are not of 

concern (the MOEs were all greater 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 

resulted in a MOE of 19,000,000.

5.1 Other (Spray Drift, etc.)

Spray drift is always 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 aminopyralid could also be a 

potential source of exposure. The Agency has been working with the Spray Drift Task Force (a 

membership of U.S. pesticide 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

appropriately 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 might impose further refinements in spray drift management practices to reduce offtarget drift risks associated with pesticide application.
Page 31 of 48

6.0 AGGREGATE RISK ASSESSMENTS and RISK CHARACTERIZATION

References:

1) Occupational and Residential Exposure Risk Assessment for Proposed Uses of Aminopyralid, 

D305672, M. Collantes, 5/24/2005

2) Aminopyralid: Aggregate Human Health Risk Assessment for the Proposed Uses on Wheat, 

Grasses, Non-cropland, and Natural Areas, D301689, M. Doherty, et al., 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 exposures associated with aminopyralid 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 aminopyralid. As a result, an 

acute aggregate risk assessment is not a concern. 

6.2 Short-Term Aggregate Risk

There are residential uses for aminopyralid 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 aminopyralid 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 exposure from food and drinking water. 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-Term Aggregate Exposure and Risk Calculations for Aminopyralid

Population

Subgroup

NOAEL

mg/kg/day

Exposure, mg/kg/day

Aggregate MOE*

Dietary (Food and Residential)

Total

Non-Dietary

Total

Aggregate

All Infants <1 year 104 0.00108 0.0021 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 aggregate MOEs for aminopyralid are not of concern to HED. The aggregate 

MOEs range from 25,000 to 33,000. These values are above the LOC of 1,000.

6.3 Intermediate-Term Aggregate Risk

Based on the registered and proposed uses, there are no residential scenarios that are likely to 

result in intermediate-term exposure (30-180 days, continuous). Therefore, HED has not 

conducted an intermediate-term aggregate risk assessment for aminopyralid.

6.4 Long-Term Aggregate Risk

Dietary (food + water) consumption is the only source of exposure to aminopyralid 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 highly 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 level of concern (100% of the cPAD).

6.5 Cancer Aggregate Risk

As aminopyralid has been classified as “not likely to be carcinogenic to humans,” cancer risk is 

not a concern for this chemical.

7.0 CUMULATIVE 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 aminopyralid and any other substances, and aminopyralid does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 

EPA has not assumed that aminopyralid has a common mechanism of toxicity with other 

substances. For information regarding EPA’s efforts to determine which chemicals have a 
Page 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 OCCUPATIONAL EXPOSURE/RISK ASSESSMENT PATHWAY

References:

1) Aminopyralid: Occupational Exposure Assessment for the Registration of Milestone®

Herbicide for Use on Corn, D370497, Z Figueroa, 10/22/2009

2) Occupational and Residential Exposure Risk Assessment for Proposed Uses of Aminopyralid, 

D305672, M. Collantes, 5/24/2005

Based on the proposed uses specified on 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 aminopyralid end-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 on corn as a single broadcast application 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 year (0.027 lb a.e./A). For spot treatments, the maximum single application 

rate is 1.2 mL per 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 aminopyralid during mixing, loading, and application activities 

associated with agricultural crops. Based on the proposed use patterns short- and intermediateterm dermal and inhalation exposure are expected to occur. However, as no dermal point of 

departure was selected, this risk assessment will only assess inhalation exposure risks.

 The following exposure scenarios will be assessed for aminopyralid:

• Mixing/loading liquid sprays for groundboom

• Applying liquid sprays for groundboom

• Mixing/loading/applying liquid sprays for handgun spray

The registrant did not submit a chemical-specific exposure study for assessing the occupational 

exposure of 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 calculating the extent of exposures to handlers from the proposed use on corn. For 
Page 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) = 0.027 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) = 0.027 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/Loader 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/Loader/Applicator Unit Exposure (Handgun) 

Inhalation = 1.8 μg/lb ae or 0.0018 mg/lb ae

Area Treated

Based on HED’s Exposure Science Advisory Committee Policy Number 9.1, the following areas

treated per day were assumed:

• 200 acres/day for mixing/loading and applying liquids for groundboom for field corn;

• 25 acre/day for mixing/loading and applying liquids for handgun for field corn (spot 

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 as 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 intermediate term risks to 

mixers/loaders and applicators were calculated (Table 8.1). For aminopyralid, 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 are greater than the target MOE of 100 and,

therefore, risks do not exceed HED’s level of concern.

Based on the proposed use pattern, long-term exposure is not anticipated for occupational 

handlers. Aminopyralid exhibits no evidence of carcinogenicity; therefore, cancer risk is not of 

concern.

Table 8.1. Short- and Intermediate-Term Handler Exposure and Risk for Aminopyralid

Exposure 

Scenario 

(Scenario #)

Mitigation 

Level

Inhalation Unit 

Exposure

(mg/lb ai)

Crop Application Rate

(lb ae/A)

Amount 

Treated

Inhalation Dose 

(mg/kg/day)

Total MOE

Mixer/Loader 

Mixing/Loading 

liquid sprays for 

groundboom

(PHED data)

Baseline 0.0012 Corn 0.027 200 acres/day

(broadcast)

0.0000926 1,100,000

Applicator

Applying liquid 

sprays for 

groundboom

(PHED data)

Baseline 0.00074 Corn 0.027 200 acres/day

(broadcast)

0.000057 1,800,000

Mixer/Loader/Applicator

Mixing/Loading 

Applying sprays 

for handgun

(ORETF data)

Baseline 0.0018 Corn 0.027 25 acres/day

(spot 

treatment)

0.0000174 6,000,000

Note:

Short- and Intermediate-term Inhalation 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 determined that there are potential exposures to persons entering treated sites (e.g. 

scouting, detasselling, weeding, harvesting) after application of pesticide is complete. However, 

as no dermal PoD was selected, a postapplication risk assessment for agricultural uses was not 

possible. 

Aminopyralid 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 aminopyralid, postapplication 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® Herbicide contains the triisopropanolammonium salt of aminopyralid. However, 

after application of the product, agricultural 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., aminopyralid itself) because of 

its higher irritation potential. Aminopyralid is classified as Category IV for acute dermal and 

dermal irritation and Category I for eye irritation. Chemicals identified as toxicity Category I

require a 48-hour REI. Furthermore, chemicals classified as toxicity Category I for eye irritation 

require the use of protective eyewear. The supplemental label does not include an REI.

Therefore, the Registration 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 LOC. All MOEs exceed the LOC of 100. 

9.0 DATA NEEDS AND LABEL RECOMMENDATIONS

9.1 Toxicology

As part of the new Part 158 data requirements, an immunotoxicity study in the rat and/or mouse 

is required (See Appendix A.3). HED recommends that RD make the submission of this study a 

condition of registration.

Dermal toxicity (inflammation and slight hyperplasia) should be reflected on the chemical label 

as a potential concern.
Page 37 of 48

9.2 Residue 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 registration for the requested uses of aminopyralid, 

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 aminopyralid 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 applications 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 as specified in Appendix B.

9.3 Occupational Exposure

 The following amendment on the proposed label of Milestone® Herbicide is 

recommended. A 48-hour REI is required based on the acute toxicity category of the 

active ingredient in the formulation for eye irritation (Category I).

 The 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 coveralls, not just long pants and shirt.

 The proposed supplemental label states “Do not aerially apply Milestone unless 

permitted by EPA approved supplemental labeling.” The Registration Division should 

ensure that no aerial applications are allowed on the Milestone® Herbicide supplemental 

label for use on field corn.
Page 38 of 48

REFERENCES

D301689, Aminopyralid: Aggregate Human Health Risk Assessment for the Proposed Uses on 

Wheat, Grasses, Non-cropland Areas, and Natural Areas, M. Doherty, 7/12/2005

D360100, Aminopyralid and Aminopyralid Triisopropanolammonium (TIPA) Salt. Request to 

Add Uses on Field Corn to Milestone®(EPA Reg. No. 62719-519). Summary of Analytical 

Chemistry and Residue Data, D. Dotson, 10/22/2009

D369212, Aminopyralid 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 Aminopyralid on Field Corn and Field Corn Grown for Ensilage, R. 

Baris, 7/24/2009

D370497, Aminopyralid: Occupational Exposure Assessment for the Registration of Milestone®

Herbicide for Use on Corn, Z. Figueroa, 10/22/2009
Page 39 of 48

Appendix A: Aminopyralid Toxicology

Appendix A.1. Toxicology Data Requirements

The requirements (40 CFR 158.340) for food use for aminopyralid 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 Acute Oral Toxicity........................................................

870.1200 Acute Dermal Toxicity...................................................

870.1300 Acute Inhalation Toxicity...............................................

870.2400 Primary Eye Irritation.....................................................

870.2500 Primary 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 Inhalation...........................................................

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 (nonrodent).........................................

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 Mutagenicity—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 Acute Delayed Neurotoxicity. (hen)...............................

870.6100b 90-Day Neurotoxicity (hen) ...........................................

870.6200a Acute Neurotoxicity Screening Battery (rat)..................

870.6200b 90 Day Neurotoxicity Screening Battery (rat)................

870.6300 Develop. Neurotoxicity ..................................................

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 Acute oral-rat 46235603 LD50 = >5000 mg/kg/bw

(both sexes)

IV

870.1200 Acute dermal-rabbit 46235605 LD50 = >5000 mg/kg/bw

(both sexes)

IV

870.1300 Acute inhalation-rat 46235607 LC50 = >5.5 mg/L 

(both sexes)

IV

870.2400 Acute eye irritation-rabbit 46235609 Corneal opacity in 1/3 

unresolved through day 35

I

870.2500 Acute 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 Acute oral-rat 46235604 LD50 = >5000 mg/kg/bw

(both sexes)

IV

870.1200 Acute dermal-rabbit 46235606 LD50 = >5000 mg/kg/bw

(both sexes)

IV

870.1300 Acute inhalation-rat 46235608 LC50 = >5.79 mg/L (both 

sexes)

IV

870.2400 Acute eye irritation-rabbit 46235610 No positive signs of corneal 

opacity, iritis or conjunctivitis 

observed

IV

870.2500 Acute 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/A
Page 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 (XDE750) with 4 week recovery 

period

• mg/kg/day =

0, 10, 100, 500, 1000

Acceptable/Guideline

46235621 NOAEL (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 (GF871)‡

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 (XDE750)

%=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 DERMALRAT (XDE-750)mg/kg/day =

0, 100, 500, 1000

Acceptable/Guideline

46235626 Systemic: 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 (mg/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 in 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 

determined
Page 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 FEEDINGDOGS

(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 stomach 

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

CARCINOGENICITYMICE (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/

CARCINOGENICITYRAT

(XDE-750)

• mg/kg/day =

0, 50, 500, 1000

Acceptable/Guideline

46235615 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

(1st assay); 250, 500, 

1000, 2000, 4000 g/mL 

(2nd 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 Negative
Page 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 (1st assay); 0, 

125, 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 (2nd assay); 

400, 600, 800, 1000, 

1200, 1400, 1600, 1700, 

1800, 2070 μg/mL 

without metabolic 

activation (3rd assay).

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

Acceptable/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

Acceptable/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 

determined
Page 46 of 48

870.7485 2004-METABOLISM 

AND 

PHARMACOKINETICSRAT (XDE-750)

mg/kg/day =

Low dose: 50

High dose: 1000

Repeated low dose: 

50 (unlabelled)

for 14 days, 50 (labelled) 

on day 15 

Acceptable/Guideline

46235807 Recovery after 168 hrs: 

96% in low dose

(urine-50%, feces-43%, 

tissues-0.1%, cage wash3%), 95% in high dose

(urine-41%, feces-43%, 

tissues-1%, cage wash10%), and 95% in the 

repeated low dose (urine59%, feces-33%, tissues0.1%, 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.

NonGuidelineXDE-750, 

Triisopropanolamine salt

DISSOCIATION AND 

METABOLISM IN 

MALE FISCHER 344 

RATS

mg/kg/day=

50 or 96

46235833 14C-XDE-750 and 14CXDE-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 

molecule(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 reviewer
Page 47 of 48

Appendix A.3. Rationale for Toxicology Data Requirements

Table A. 3 Guideline Number: 870.7800

Study Title: Immunotoxicity

Rationale for Requiring the Data

The 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 highly 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 subchronic 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 scientific 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 considered 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 decision-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 these 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 Aminopyralid

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, stover 0.20 0.20 Corn, field, stover

HED recommends that 40CFR §180.610(a)(1) be amended by replacing the tolerance expression 

with the following: “Tolerances are established for residues of aminopyalid (4-amino-3,6-

dichloro-2-pyridinecarboxylic acid), including its metabolites and degradates, in or on the 

commodities in the table below. Compliance with the tolerance levels specified below is to be 

determined by measuring only free and conjugated aminopyralid.” HED further recommends 

that 40CFR §180.610(a)(2) be amended by replacing the tolerance expression with the 

following: “Tolerances are established for residues of aminopyralid, including its metabolites 

and degradates, in or on the commodities in the table below. Compliance with the tolerance 

levels specified below is to be determined by measuring only aminopyralid.”