Document ID: EPA-HQ-OPP-2009-0141-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-04-07T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460      

	OFFICE OF PREVENTION, PESTICIDE

	AND TOXIC SUBSTANCES

	

  SEQ CHAPTER \h \r 1 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)  SEQ CHAPTER \h \r 1 		

		

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)

Table of Contents

  TOC \o "1-6" \f  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

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

 

EXECUTIVE SUMMARY

HED has performed a human health risk assessment for the herbicide
aminopyralid (4-amino-3,6-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.

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.  DEEM™ 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 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 short-term aggregate risk MOEs range from 25,000 to
33,000 and are not of concern to HED.

Dietary (food + water) consumption is the only source of exposure to
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.  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.

  SEQ CHAPTER \h \r 1 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.

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  TC \l1 "2.0	Ingredient Profile 

  SEQ CHAPTER \h \r 1 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 PP#8F7455, Dow AgroSciences
is proposing aminopyralid for use on field corn.    SEQ CHAPTER \h \r 1
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  TC \l2 "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 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

  TC \l2 "2.2	Structure and Nomenclature 

Table 2.2.	Aminopyralid Nomenclature.

Chemical structure	

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	

Common name	  SEQ CHAPTER \h \r 1 Aminopyralid, triisopropanolammonium
(TIPA) salt

PC Code	  SEQ CHAPTER \h \r 1 005209

Company experimental name	  SEQ CHAPTER \h \r 1 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)

2.3	Physical and Chemical Properties  TC \l2 "2.3	Physical and Chemical
Properties 

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

Parameter	Value	Reference

Melting point/range	  SEQ CHAPTER \h \r 1 163.5ºC	  SEQ CHAPTER \h \r 1
MRID 46235703

pH	  SEQ CHAPTER \h \r 1 2.31 at 23.4ºC (1% solution in water)	MRID
46235703

Density	  SEQ CHAPTER \h \r 1 1.72 at 20ºC	MRID 46235703

Water solubility	  SEQ CHAPTER \h \r 1 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	  SEQ CHAPTER \h \r 1 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	  SEQ CHAPTER \h \r 1 2.59 x 10-8 Pa at 25ºC; 9.52 x
10-9 Pa at 20ºC	MRID 46235703

Dissociation constant, pKa	  SEQ CHAPTER \h \r 1 2.56	MRID 46235703

Octanol/water partition coefficient, Log(KOW)	  SEQ CHAPTER \h \r 1
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	  SEQ CHAPTER \h \r 1 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 tc "3.1  Hazard and
Dose-Response Characterization" \f C \l 0000000002 

3.1.1  Database Summary tc "3.1.1  Database Summary" \f C \l 0000000003 

Sufficiency of Studies/Data tc "3.1.1.1  Sufficiency of studies/data" \f
C \l 0000000004 

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.  

3.1.1.2  Mode of Action tc "3.1.1.2  Mode of action, metabolism,
toxicokinetic data" \f C \l 0000000004 

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.

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.  

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 (GF-871) 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. tc "3.1.3  Dose-response" \f C \l 0000000003 

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 tc "3.2 
Absorption, Distribution, Metabolism, Excretion (ADME)" \f C \l
0000000002 

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%.  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 amino-dichloro-picolinate portion of the molecule.

3.3  FQPA Considerations tc "3.3  FQPA Considerations" \f C \l
0000000002 

3.3.1  Adequacy of the Toxicity Database tc "3.3.1  Adequacy of the
Toxicity Database" \f C \l 0000000003 

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 tc "3.3.2  Evidence of Neurotoxicity"
\f C \l 0000000003 

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 tc "3.3.3  Developmental Toxicity
Studies" \f C \l 0000000003 

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.

     

3.3.4  Reproductive Toxicity Study tc "3.3.4  Reproductive Toxicity
Study" \f C \l 0000000003 

No adverse effects were observed in a reproduction study in rats with
XDE-750.

3.3.5  Additional Information from Literature Sources tc "3.3.5 
Additional Information from Literature Sources" \f C \l 0000000003 

A literature search did not reveal information that would impact the
risk assessment. 

3.3.6  Pre-and/or Postnatal Toxicity tc "3.3.6  Pre-and/or Postnatal
Toxicity" \f C \l 0000000003 

3.3.6.1  Determination of Susceptibility tc "3.3.6.1  Determination of
Susceptibility" \f C \l 0000000004 

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 tc "3.3.6.2  Degree of Concern Analysis
and Residual Uncertainties for Pre- and/or Postnatal Susceptibility" \f
C \l 0000000004 

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 tc "3.3.7  Recommendation for not requiring a Developmental
Neurotoxicity Study" \f C \l 0000000003 

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. 

3.4  FQPA Safety Factor for Infants and Children tc "3.4  FQPA Safety
Factor for Infants and Children" \f C \l 0000000002 

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 tc "3.5 
Hazard Identification and Toxicity Endpoint Selection" \f C \l
0000000002 

3.5.1  Acute Reference Dose (aRfD) – General Population and Females
13-49  tc "3.5.1  Acute Reference Dose (aRfD) – General Population" \f
C \l 0000000003 

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) tc "3.5.3  Chronic Reference Dose
(cRfD)" \f C \l 0000000003  

Study Selected:  Combined Chronic Toxicity/Carcinogenicity Study in Rats

MRID No: 46235615

Dose and Endpoint for Risk Assessment:  NOAEL= 50 mg/kg/day 

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

  = 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 tc "3.5.4  Incidental Oral Exposure" \f
C \l 0000000003 

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  TC \l3 "4.4.5	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)  TC \l3
"4.4.6	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.

3.5.6  Residential and Occupational Dermal Exposure tc "3.5.6 
Residential and Occupational Dermal Exposure" \f C \l 0000000003 

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  TC \l3 "4.4.8	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	

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  TC \l3
"4.4.9	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  TC \l3 "4.4.10
Classification of Carcinogenic Potential 

There was no evidence of carcinogenicity in cancer studies with mice and
rats.  Therefore,   SEQ CHAPTER \h \r 1 in accordance with EPA’s Final
Guidelines for Carcinogen Risk Assessment (March, 2005), aminopyralid is
classified as “not likely to be carcinogenic to humans.”



Summary of Toxicological Doses and Endpoints for Use in Human Risk
Assessments

Table 3.5.11a Summary of Toxicological Doses and Endpoints for
Aminopyralid for Use in Dietary and Non-Occupational 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)

Intermediate-Term (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 Short-Term (1-30 days)

Intermediate-Term (1-6 months)	N/A	

N/A

	N/A	28-day dermal toxicity study in rats. 

No systemic toxicity seen at the limit dose (1,000 mg/kg/day) (XDE-750) 

Dermal risks are not of concern.  

Inhalation Short- Term (1-30 days)

Intermediate-Term (1-6 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

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 Short-Term (1-30 days)

Intermediate-Term (1-6 months)	N/A	

N/A

	N/A	

28-day dermal toxicity study in rats. 

No systemic toxicity seen at the limit dose (1,000 mg/kg/day) (XDE-750) 

Dermal risks are not of concern.  

Inhalation Short- Term (1-30 days)

Intermediate-Term (1-6 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

   

Endocrine disruption

 tc "3.6  Endocrine disruption" \f C \l 0000000002 

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.

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  TC \l3 "3.2.3	Description of
Rotational Crop Metabolism  

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  TC \l3 "3.2.2	Description of Livestock
Metabolism 

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 Method GRM 02.31 uses a
different internal standard (13C215N-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 (13C215N-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.

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  TC \l2 "3.1 	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   TC \l2 "3.5
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 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  TC \l2 "3.6
Summary of Residues for Tolerance Expression and Risk Assessment 

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

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.

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  TC \l3 "6.1.1	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.

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 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.

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-FCID™, 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.  DEEM™ 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 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.

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  TC
\l2 "6.3	Residential (Non-Occupational) Exposure/Risk Pathway 

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.)  TC \l3 "6.3.3	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 off-target drift risks associated with pesticide
application.



	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  TC \l2 "7.2	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.



Table 6.2.  Short-Term Aggregate Exposure and Risk Calculations for
Aminopyralid

Population

Subgroup	

NOAEL

mg/kg/day

	Exposure, mg/kg/day	

Aggregate MOE*

(Food and Residential)

Dietary

	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  TC \l2 "7.5	Cancer 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  TC \l1 "8.0	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 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   HYPERLINK
http://www.epa.gov/pesticides/cumulative/.
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

  SEQ CHAPTER \h \r 1 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 intermediate-term 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 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   SEQ CHAPTER \h \r 1 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.

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

  SEQ CHAPTER \h \r 1 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)

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  TC \l1 "10.0	Data Needs and
Label Requirements 

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.

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.

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.

	

REFERENCES  TC \l1 "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

Appendix A:  Aminopyralid Toxicology

Appendix A.1.   Toxicology Data Requirements TC \l2 "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.

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



Table A.2.b.  Subchronic, Chronic and Other Toxicity Profile.

GDLN 	Study Type 	Dose Levels	MRID	Results

870.3100	2001-13 WEEK FEEDING-RAT (XDE-750) with 4 week recovery period

	•  mg/kg/day =

0, 10, 100, 500, 1000

Acceptable/Guideline	46235621	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 (GF-871)‡	XDE-750 TIPA*

• mg/kg/day=

0, 192, 500, 1000

¶ ACID EQUIVALENT (ae)

   mg ae/kg/day=

   0, 100, 260, 520 

Acceptable/Guideline	46235622	NOAEL (mg/kg/day): 

520

LOAEL (mg/kg/day): not determined

870.3100	2001-13 WEEK FEEDING-MOUSE

(XDE-750)

	•  mg/kg/day =

0, 10, 100, 500, 1000

Acceptable/Guideline	46235618	NOAEL (mg/kg/day): 1000

LOAEL (mg/kg/day): not determined

870.3150	2002-13 WEEK FEEDING-DOG (XDE-750)

 

	%=0, 0.15, 0.75, 3.0

§ ppm= 0, 1500, 7500, 

  30000

mg/kg/day =

M: 0, 55, 282, 1070

F: 0, 53, 232, 929

Acceptable/Guideline	46235623	NOAEL (mg/kg/day): 

M=282, F= 232

LOAEL  (mg/kg/day): M=1070, F=929

based on stomach histopathology (slight diffuse hyperplasia and
hypertrophy of the mucosal epithelium).

870.3200	2002-28 DAY DERMAL-RAT (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

870.3700	2004-DEVELOPMENTAL TOX-RABBIT (GF-871)‡	XDE-750 TIPA*

mg/kg/day=

0, 200, 500, 1000

¶ ACID EQUIVALENT (ae)

mg ae/kg/day=

0, 104, 260, 520  

Acceptable/Guideline	46235632	Maternal: NOAEL (mg/kg/day): 104

LOAEL (mg/kg/day): 260

based on severe inanition and body weight loss, decreased fecal output,
and mild incoordinated gait.  

Developmental: NOAEL (mg/kg/day): 260

LOAEL (mg/kg/day): 520 

based on decreased fetal body weights.

870.3800	2003-2-GENERATION REPRODUCTION-RAT (XDE-750)

	•  mg/kg/day =

0, 50, 250, 1000

Acceptable/Guideline

 

	46235635	Parental: 

NOAEL (mg/kg/day):

1000   

LOAEL (mg/kg/day): not determined

Reproductive:

NOAEL (mg/kg/day):

1000

LOAEL (mg/kg/day): not determined

Offspring:  

NOAEL (mg/kg/day):

1000

LOAEL (mg/kg/day): not determined

870.4100	2003-1 YEAR FEEDING-DOGS

(XDE-750)	% =0, 0.03, 0.30, 3.0

§ ppm= 0, 300, 3000,  

  30000

mg/kg/day =

M: 0, 10, 99, 967

F: 0, 9, 93, 1038

Acceptable/Guideline	46235627	NOAEL (mg/kg/day): 

M=99, F= 93

LOAEL (mg/kg/day): M=967, F=1038 

based on thickening of stomach mucosa (females), and 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).

870.4200	2003-18 MONTH

CARCINOGENICITY-MICE (XDE-750)	• mg/kg/day =

0, 50, 250, 1000

Acceptable/Guideline	46235628	NOAEL (mg/kg/day):

M=1000

LOAEL (mg/kg/day):

not determined.

870.4300	2004-2 YEAR TOXICITY/

CARCINOGENICITY-RAT

(XDE-750)	•  mg/kg/day =

0, 50, 500, 1000

Acceptable/Guideline	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)

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).

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

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).

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

870.7485	2004-METABOLISM AND PHARMACOKINETICS-RAT (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 wash-3%), 95% in high dose

(urine-41%, feces-43%, tissues-1%, cage wash-10%), and 95% in the
repeated low dose (urine-59%, feces-33%, tissues-0.1%, cage wash-3%). 
XDE -750 represented >96% of administered dose (AD) in urine and 100% AD
in feces.  Three unknown components (> 4%) found in urine were also
found in dose formulations.

Non-

Guideline	XDE-750, Triisopropanolamine salt

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§ ppm calculated by reviewer

• dose levels were not given in ppm

¶ acid equivalents calculated by reviewer

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.

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.” 

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