UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

PREVENTlON. PESTICIDES

AND TOXIC SUBSTANCES

Date: March 17,2010

MEMORANDUM

SUBJECT:

Herbicide.

Aminocyclopyrachlor: Human Health Risk Assessment for Proposed Uses as an

.sk Assessment Review Committee

1?.~ 3/(7/=0

~~ S/I7/4nD

Health Effects 01 15100 (7509

Ray Kent, Branch Chief

Susan Hummel, Senior Sci~csJ.1

Richard Loranger and Jack Arth

Health Effects Division (7509P)

Jim Tompkins and Mindy Ondish, PM 25

Herbicide Branch

Registration Division (7505P)

THROUGH:

TO:

PC Codes: 288008,288009,288010, DP Barcode: D369057

611472, 688008

Decision No.: 400967 Registration Nos.: 00352-lNG,00352-lNN,

00352-lNT, 00352-lNU, 00352-IRE, 00352-

IRG,00352-IRL,00352-IRR,00352-IRU,

00352-TIA,00352-TIL, 00352-TIT, 00352-

TIU, 00352-TOA, 00352-TOE, 00352-TOG,

00352-TOI, 00352-TOL, 00352-TOO,

00352-TOT,00352-TOU

Petition No.: N/A Re2Ulatorv Action: Section 3

Risk Assessment Type: Single Chemical Case No.: N/A

TXR No.: N/A CAS No,: 858956-08-8,1:58956-35-1,858954-

83-3,124423-84-3,1759-53-1

MRID Nos.: N/A 40 CFR: NA

FROM:

James

Jessica

S

Ryman,

Miller,

Ph.D.,

Environrnenta:..?.2;icx::::::.:...

D.A.B.T., Toxicolo}..ist

. dRi~~~)~ Thurston Morton,

'v'

Chemist

. Qrf(

./;)

IT-' . lJtt/~

Page I of76
Table of Contents

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

2.0 Ingredient Profile.............................................................................................................. 9 

2.1 Summary of Proposed Uses.................................................................................... 9 

2.2 Structure and Nomenclature ................................................................................. 11 

2.3 Physical and Chemical Properties......................................................................... 13 

3.0 Hazard Characterization and Dose-Response Assessment......................................... 15 

3.1 Hazard Characterization........................................................................................ 15 

3.1.1 Database Summary ................................................................................... 15 

3.1.1.1 Studies available and considered (animal, human, general 

literature)................................................................................................... 15 

3.1.1.2 Mode of action, metabolism, toxicokinetic data........................ 15 

3.1.1.3 Sufficiency of studies/data......................................................... 16 

3.1.2 Toxicological Effects................................................................................ 16 

3.2 Consideration of Toxicity to Children .................................................................. 17 

3.2.1 Adequacy of the Toxicity Database.......................................................... 18 

3.2.2 Evidence of Neurotoxicity ........................................................................ 18 

3.2.3 Evidence of Developmental Toxicity ...................................................... 18 

3.2.4 Evidence of Reproductive Toxicity .......................................................... 18 

3.2.5 Determination of Susceptibility ................................................................ 18 

3.2.6 Recommendation for a Developmenal Neurotoxicity Study.................... 19 

3.3 Dose-Response Assessment.................................................................................. 19 

3.3.1 Acute Reference Dose (aRfD) - All Populations...................................... 19 

 (Includes Females 13-49) 

3.3.2 Chronic Reference Dose (cRfD)............................................................... 19 

3.3.3 Incidental Oral Exposure (Short- and Intermediate-Term)....................... 19 

3.3.4 Dermal Absorption.................................................................................... 20 

3.3.5 Dermal Exposure (Short-, Intermediate- and Long-Term)....................... 20 

3.3.6 Inhalation Exposure (Short-, Intermediate- and Long-Term)................... 20 

3.3.7 Level of Concern for Margin of Exposure................................................ 21 

3.3.8 Recommendation for Aggregate Exposure Risk Assessments ................. 21 

3.3.9 Consideration of Carcinogenic Potential ................................................ 21 

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

Assessments .......................................................................................................... 22 

4.0 Public Health and Pesticide Epidemiology Data.......................................................... 24 

5.0 Dietary Exposure/Risk Characterization ..................................................................... 25 

5.1 Environmental Degradation.................................................................................. 25 

5.1.1 Stability, mobility, and degradates............................................................ 25 

5.1.2 Toxicity profile of major degradates......................................................... 25 

5.1.3 Degradates of concern............................................................................... 26 

5.1.4 Drinking Water Residue Profile................................................................ 27 

5.2 Dietary Exposure and Risk ................................................................................... 29 

5.2.1 Acute Dietary Exposure/Risk ................................................................... 30 

5.2.2 Chronic Dietary Exposure/Risk ................................................................ 30 

5.2.3 Cancer Dietary Risk.................................................................................. 32 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................ 32 

Page 2 of 76 
6.1 Residential Handler Exposure............................................................................... 33 

6.1.1 Data and Assumptions for Residential Handler Exposure Scenarios ....... 33 

6.1.1.1 Unit Expsoures........................................................................... 33 

6.1.1.2 Area Treated............................................................................... 33 

6.1.1.3 Application Rate ........................................................................ 33 

6.1.1.4 Results and Conclusions ............................................................ 34 

6.2 Residential Postapplication Exposure................................................................... 34 

6.2.1 Data and Assumptions for Residential Postapplication Scenarios ........... 35 

6.2.2 Results and Conclusions ........................................................................... 35 

6.3 Spray Drift ........................................................................................................... 35 

7.0 Aggregate Risk Assessments and Risk Characterization............................................ 36 

8.0 Occupational Exposure/Risk Pathway.......................................................................... 36 

8.1 Short-Term and Intermediate-Term Handler Risk................................................ 36 

8.1.1 Data and Asuumptions for Occupational Handler Exposure Scenarios ............... 37 

8.1.1.1 Unit Expsoures........................................................................... 37 

8.1.1.2 Area Treated............................................................................... 38 

8.1.1.3 Application Rate ........................................................................ 38 

8.1.1.4 Results and Conclusions ............................................................ 39 

8.2 Short-Term and Intermediate-Term Postapplication Risk.................................... 41 

9.0 Data Needs and Label Recommendations .................................................................... 41 

9.1 Toxicology ............................................................................................................ 41 

9.2 Occupational and Residential Expsoure ............................................................... 41 

10.0 References (Memoranda)............................................................................................... 42 

Appendix A: Toxicology Assessment ........................................................................... 43 

A.1 Toxicology Data Requirements ............................................................................ 43 

A.2 Toxicity Profiles.................................................................................................... 44 

A.3 Executive Summaries............................................................................................ 48 

A.3.1 Subchronic Toxicity................................................................................. 48 

A.3.2 Prenatal Developmental Toxicity............................................................. 53 

A.3.3 Reproductive Toxicity.............................................................................. 55 

A.3.4 Chronic Toxicity ...................................................................................... 56 

A.3.5 Carcinogenicity ........................................................................................ 57 

A.3.6 Mutagenicity ............................................................................................ 57 

A.3.7 Neurotoxicity ........................................................................................... 60 

A.3.8 Metabolism............................................................................................... 63 

A.3.9 Special/Other Studies............................................................................... 66 

A.4 References (In MRID Order) ............................................................................... 69 

Appendix B: Review of Human Research................................................................... 75 

Appendix C: Chemical Structures of Degradates ...................................................... 75 

Page 3 of 76 
1.0 Executive Summary

This document describes the human health risk assessment conducted to support the 

Section 3 registration decision of a new herbicide active ingredient, aminocyclopyrachlor. 

Aminocyclopyrachlor is a member of the pyrimidine carboxylic acid chemical class. The 

pesticidal mode of action is dysregulation of gene products involved in auxin receptor activity, 

which interferes with normal shoot and root development to stop the growth of weeds. 

Aminocyclopyrachlor is being registered for uses of general weed and brush control on private, 

public and military lands including sod farms, un-cultivated non-agricultural areas such as 

airports, highways, railroads, golf courses, lumber yards, wild life habitats, multi family 

residential complexes, recreation areas, utility rights of way, with residential use specified for 

lawn/turf. 

Three forms of aminocyclopyrachlor are being registered: the parent acid (PC Code 288008), 

the potassium salt (PC Code 288010), and the methyl ester (aminocyclopyrachlor-methyl, PC 

Code 288009). All three forms are components of both manufacturing and end-use products. 

The parent acid (aminocyclopyrachlor) is considered the active ingredient. 

Hazard and Dose-Response Considerations 

The toxicology database for aminocyclopyrachlor is adequate for risk assessment for the 

proposed use patterns. Acute toxicity studies investigated both aminocyclopyrachlor and 

aminocyclopyrachlor-methyl, since both will be marketed in end-use products. Both exhibit low 

acute toxicity by oral, dermal, or inhalation routes of exposure, and neither cause skin 

sensitization or irritation. However, both caused mild eye irritation. 

Pharmacokinetic studies via the oral route showed that both aminocyclopyrachlor and 

aminocyclopyrachlor-methyl are rapidly absorbed, with rapid metabolic conversion of 

aminocyclopyrachlor-methyl to aminocyclopyrachlor. Elimination is almost complete within 24 

hours. Subchronic dietary, reproductive toxicity, and gene mutation studies were performed with 

both aminocyclopyrachlor and aminocyclopyrachlor-methyl at similar doses. These studies all 

yielded similar results. These results, together with similar acute toxicity profiles and evidence 

from metabolism studies showing that aminocyclopyrachlor-methyl is rapidly converted to 

aminocyclopyrachlor, form a scientific justification for considering aminocyclopyrachlor and 

aminocyclopyrachlor methyl toxicologically equivalent, thus allowing bridging the toxicity 

database for aminocyclopyrachlor-methyl with studies using aminocyclopyrachlor. 

Aminocyclopyrachlor and aminocyclopyrachlor-methyl have low subchronic toxicity via the oral 

route. The most sensitive species is the rat, with decreased body weight at the limit dose in 

subchronic dietary studies as the most sensitive endpoint of toxicity. The major effect observed 

across species for aminocyclopyrachlor was decreased body weight at the limit dose. No toxicity 

was observed in subchronic dietary studies in dogs at the highest dose of aminocyclopyrachlor 

tested, which was half the limit dose. No target organ of toxicity was identified. No sex 

differences in toxicity were observed for either aminocyclopyrachlor or aminocyclopyrachlormethyl. 

Page 4 of 76 
Aminocyclopyrachlor was not neurotoxic when administered acutely or subchronically via the 

oral route. Aminocyclopyrachlor-methyl showed no evidence of neurotoxicity or reproductive 

toxicity in an extended one generation reproductive toxicity study in rats. Aminocyclopyrachlor 

did not cause developmental toxicity in rats and rabbits. Therefore, there is low concern for 

reproductive, developmental, or neurotoxicity for aminocyclopyrachlor and 

aminocyclopyrachlor-methyl. 

Aminocyclopyrachlor and aminocyclopyrachlor-methyl are considered to have low potential to 

cause chronic toxicity or carcinogenicity. No evidence of genotoxic effects were observed in 

mutagenicity studies in vitro for aminocyclopyrachlor and aminocyclopyrachlor-methyl or in 

vivo for aminocyclopyrachlor. No evidence of target organ toxicity was observed in oral 

subchronic studies for aminocyclopyrachlor and aminocyclopyrachlor-methyl at doses exceeding 

the limit dose. 

Immunotoxicity was investigated via the oral route in two species (rats and mice) for 

aminocyclopyrachlor. There was no evidence of immunotoxicity. 

Exposures to aminocyclopyrachlor and aminocyclopyrachlor-methyl will occur primarily by the 

dermal route and by inhalation during occupational and residential use. Acute toxicity via the 

dermal route for aminocyclopyrachlor or aminocyclopyrachlor-methyl was low (Category IV). 

No dermal toxicity endpoint was identified for aminocyclopyrachlor because no toxicity was 

observed at the limit dose in a 28 day dermal toxicity study. The dermal toxicity of 

aminocyclopyrachlor-methyl is expected to be similar to aminocyclopyrachlor, based on similar 

acute dermal, acute oral, and subchronic oral toxicity profiles. Acute studies also indicated low 

toxicity of aminocyclopyrachlor and aminocyclopyrachlor-methyl via inhalation, since acute 

inhalation toxicity with aminocyclopyrachlor was low (Category IV). No subchronic inhalation 

studies were available for aminocyclopyrachlor or aminocyclopyrachlor-methyl. However, 

subchronic toxicity is of low concern due to low acute toxicity and high margins of exposure. 

An environmental photodegradate of aminocyclopyrachlor present only in surface water is of 

concern for drinking water exposures. This photodegradate, IN-V0977 (cyclopropane carboxylic 

acid), has a different mode of toxic action than aminocyclopyrachlor. Oral administration of 

cyclopropane carboxylic acid causes severe impairment of mitochondrial function by inhibiting 

the beta oxidation of fatty acids, resulting in microvesicular steatosis (accumulation of small fat 

droplets in cells). The liver is the most sensitive organ, and hepatocellular microvesicular 

steatosis is often accompanied by liver necrosis and inflammation, decreased hepatic glycogen, 

and decreased blood glucose levels. These effects have been observed with acute (one to three 

days) and longer (up to 14 days) exposure. The most sensitive species is the rabbit. Hepatic 

microvesicular steatosis in the rabbit follows a different dose-response than body weight 

decreases observed with aminocyclopyrachlor and aminocyclopyrachlor-methyl in rats, with a 

LOAEL that is 100-fold lower. 

Dietary Exposure Considerations 

There are no proposed food uses for aminocyclopyrachlor, however, dietary exposure to 

aminocyclopyrachlor and its environmental degradates from drinking water were considered. . 

Page 5 of 76 
Page 6 of 76 

Since aminocyclopyrachlor-methyl rapidly hydrolyses to aminocyclopyrachlor in the 

environment, there are no risks of concern for drinking water exposures to aminocyclopyrachlormethyl. Aminocyclopyrachlor is persistent in both aerobic and anaerobic aquatic environments. 

Consideration of acute and chronic dietary endpoints is relevant for the proposed use patterns. 

No endpoint for acute toxicity was identified for aminocyclopyrachlor, and so no acute dietary 

risk assessment was performed. Risks for chronic dietary exposures to aminocyclopyrachlor 

from drinking water were considered, and the risk estimates for the general U.S. population and 

all other regulated population subgroups are below the level of concern. Cancer risks for dietary 

exposure to aminocyclopyrachlor in drinking water were not assessed. 

The major route of environmental degradation of aminocyclopyrachlor is aqueous photolysis, 

which produces five degradates. Of these, one environmental degradate, IN-V0977 

(cyclopropane carboxylic acid), was of concern. Dietary assessments of acute and chronic 

dietary exposures of cyclopropane carboxylic acid from drinking water were performed, and 

were below the level of concern. Cancer risks for dietary exposure to cyclopropane carboxylic 

acid in drinking water were not assessed. 

Residential Exposure Considerations 

Residential handler exposures to aminocyclopyrachlor and aminocyclopyrachlor-methyl may 

occur dermally and by inhalation. The durations of exposures relevant to the proposed use 

patterns are short-term and intermediate term. No dermal hazard for aminocyclopyrachlor and 

aminocyclopyrachlor-methyl was identified because no toxicity was observed at the limit dose in 

a subchronic dermal exposure study with aminocyclopyrachlor. Therefore, a quantitative dermal 

risk assessment was not done. Inhalation risk was assessed by analysis of short-term and 

intermediate-term exposures using the product with the highest application rate and hazards 

identified in subchronic oral toxicity studies. No risks of concern for residential handlers were 

identified in residential exposure scenarios. 

Residential exposures to aminocyclopyrachlor and aminocyclopyrachlor-methyl can also occur 

after application (post-application exposures) by different exposure routes for a variety of 

populations. Young children are a population of particular concern, and post-application 

exposures via the oral route (hand-to-mouth, object-to-mouth, and ingestion of soil) were also 

considered for the product with the highest application rate. No single or combined risks of 

concern for post-application exposures of concern were identified in any population, including 

children. 

Aggregate Exposure Considerations 

The potential for significant aggregate risks from exposures to aminocyclopyrachlor was 

considered. There are no food uses for aminocyclopyrachlor, and dietary exposure to 

aminocyclopyrachlor from drinking water is expected to be low. The margins of exposure from 

residential uses are very high. Thus, there is low potential for significant aggregate exposures 

and resulting risks from aminocyclopyrachlor from drinking water and from residential 

applications. 
Occupational Exposure Considerations 

Occupational handler exposures to aminocyclopyrachlor and aminocyclopyrachlor-methyl may 

occur dermally and by inhalation and are short-term or intermediate-term for the proposed use 

pattern. No dermal hazard for aminocyclopyrachlor and aminocyclopyrachlor-methyl was 

identified because no toxicity was observed at the limit dose in a subchronic dermal exposure 

study with aminocyclopyrachlor. Therefore, a quantitative dermal risk assessment was not done. 

Inhalation risk was assessed by analysis of short-term and intermediate-term exposures using the 

product with the highest application rate and hazards identified in subchronic oral toxicity 

studies. No risks of concern for occupational handlers were identified in occupational exposure 

scenarios. 

Occupational post-application exposures via the dermal route were not assessed because no 

toxicity was observed at the limit dose in a subchronic dermal toxicity study with 

aminocyclopyrachlor. Occupational post-application exposures to aminocyclopyrachlor and 

aminocyclopyrachlor-methyl via the inhalation route were not assessed because no risks of 

concern were identified in application scenarios, which would have higher exposures than postapplication due to low vapor pressure and dilution in outdoor air. 

Environmental Justice Considerations 

Environmental justice concerns, to the extent possible, were considered in this human heath risk 

assessment in accordance with U.D. Executive Order 12989, “Federal Actions to Address 

Environmental Justice in Minority Populations and Low-Income Populations” 

(http://www.epa/gov/compliance/resources/policies/ej/exec_order_12898.pdf). 

As 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. Whenever appropriate, non-dietary 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 post-application 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. 

Use of Humans in 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 (listed in Appendix B) have 

been determined to require a review of their ethical conduct, and have received that review, and 

were determined to be appropriate (ethically conducted) for purposes of risk assessment. 

Page 7 of 76 
Additional Data Needs and Recommendations 

No additional data are required to assess the human health risks of aminocyclopyrachlor or 

aminocyclopyrachlor-methyl for the use patterns described in this risk assessment. Additional 

data are needed to address the hazard of chronic exposure to the environmental degradate 

cyclopropane carboxylic acid. HED recommends that registration of the aminocyclopyrachlor 

and aminocyclopyrachlor-methyl products described in this risk assessment be conditional until 

the hazards of chronic exposure to cyclopropane carboxylic acid are identified in a repeated dose 

study in a sensitive species. 

Label directions call for a restricted entry interval (REI) of 4 hours, however due to a category III 

in acute eye irritation HED maintains that a REI of 12 hours is appropriate and that all label 

directions reflect this change. Also, labels for 352-TOA, 352-TIU, and 352-TOL do not state 

application rates and so should be revised. 

Page 8 of 76 
2.0 Ingredient Profile

2.1 Summary of Proposed Uses

Aminocyclopyrachlor (acid and potassium salt) and aminocyclopyrachlor-methyl are being 

registered for uses of general weed and brush control on private, public and military lands 

including sod farms, un-cultivated non-agricultural areas such as airports, highways, railroads, 

golf courses, lumber yards, wild life habitats, multi family residential complexes, recreation 

areas, utility rights of way, with residential use specified for lawn/turf. Products will be applied 

in three different formulations: granular, water dispersible granular (i.e. dry flowable), and as a 

soluble liquid. Occupational application scenarios include: aerial (fixed wing or helicopter), 

ground boom, right of way sprayer, push type spreader, push cyclone spreader, tractor drawn 

broadcast spreader, and LOC handgun equipment (which are typically used by a lawn care 

operator or landscape maintenance personnel). Broadcast applications may be performed by 

using either a single ground boom, a tractor type broadcast, or as a banded application for preplant, pre-emergence, or early post-emergence. Pre-plant applications can be made as either a 

single or split application that is either surface applied or incorporated. Residential application 

scenarios include low pressure handwand, hose-end sprayer, and hand held spreader (i.e. belly 

grinder). 

A summary of the proposed use profile is presented in Table 2.1.1. For products containing 

aminocyclopyrachlor-methyl, maximum application units are in pounds of acid equivalent per 

acre. 

Table 2.1.1. Summary of Directions for Use of Aminocyclopyrachlor (Parent Acid and 

Potassium Salt) and Aminocyclopyrachlor-Methyl 

Application 

Equipment1 Sites EPA Reg. # Max Application2 Formulation 

Non-Crop 

352-TIA 

352-TIT 

352-TIL 

0.28 

Turf/Sod Farm 352-TOE 

352-TOU 

352-TOE 

352-TOU 

Water 

Dispersible 

Granular 

Turf/Lawn Golf 

Course 

352-TOG 

Groundboom 

(Open Cab) 

Turf/Sod Farm. 352-TOG 

0.07 

Soluble Liquid 

1

No chemical-specific handler exposure data were submitted in support of this registration; therefore data from the 

Pesticide Handlers Exposure Database (PHED) Version 1.1 were used. 

2

The maximum application rate (lb ae/Acre) = pounds of acid equivalent per acre.

Page 9 of 76 
Table 2.1.1. Summary of Directions for Use of Aminocyclopyrachlor (Parent Acid and 

Potassium Salt) and Aminocyclopyrachlor-Methyl (Continued)

Application 

Equipment1 Sites EPA Reg. # Max Application2 Formulation 

Non-Crop 

352-TIA 

352-TIT 

352-TIL 

0.28 

Water 

Dispersible 

Granular 

LCO Handgun 

Turf/Lawn/Sod 

Farm/Golf Course 

352-TOG 

352-TOE 

352-TOU 

0.07 Soluble Liquid 

Aerial 

(Fixed Wing) 

Enclosed 

Cockpit 

Non-Crop 

352-TIA 

352-TIT 

352-TIL 

0.28 

Water 

Dispersible 

Granular 

Push Cyclone 

Spreader 

Push Type 

Spreader 

Tractor Drawn 

Broadcast 

Spreader 

Sod Farm Golf 

Course 

352-IRU 

352-IRE 

352-IRG 

352-TOT 

0.108 Granular 

Non-Crop 

352-TIA 

352-TIT 

352-TIL 

0.28 

Water 

Dispersible 

Granular 

Right of Way 

Sprayer 

Turf/Lawn 

Sod Farm 

Golf Course 

352-TOG 

352-TOE 

352-TOU 

0.07 Soluble Liquid 

1

No chemical-specific handler exposure data were submitted in support of this registration; therefore data from the 

Pesticide Handlers Exposure Database (PHED) Version 1.1 were used. 

2

The maximum application rate (lb ae/Acre) = pounds of acid equivalent per acre.

Page 10 of 76 
Table 2.1.1. Summary of Directions for Use of Aminocyclopyrachlor (Parent Acid and 

Potassium Salt) and Aminocyclopyrachlor-Methyl (Continued)

Application 

Equipment Sites EPA Reg. # Max Application1 Formulation 

Low Pressure 

Handwand Soluble Liquid 

Hose-End Sprayer 

("Mix Your Own" 

0.07 

Water 

dispersible 

granular 

Belly Grinder 

Turf 

(Lawns) 

352-TOG 

352-TOE 

352-TOU 

352-TOT 

352-IRG 

352-TOI 

352-IRU 

352-TOO 

352-IRL 

352-INN 

352-ING 

352-INU 

352-INT 

352-IRR 

0.108 Granular (dry 

bulk fertilizer) 

1

No chemical-specific handler exposure data were submitted in support of this registration; therefore data from the 

Pesticide Handlers Exposure Database (PHED) Version 1.1 were used. 

2

The maximum application rate (lb ae/Acre) = pounds of acid equivalent per acre. 

2.2 Structure and Nomenclature

Three forms of aminocyclopyrachlor are being registered: the parent acid (PC Code 288008), 

the potassium salt (PC Code 288010), and the methyl ester (aminocyclopyrachlor-methyl, PC 

Code 288009). All three forms are components of both manufacturing and end-use products. 

Page 11 of 76 
Table 2.2.1. Test Compound Nomenclature-Aminocyclopyrachlor (parent acid) 

Chemical Structure 

N

N

NH2

Cl

O

OH

Empirical Formula C8H8ClN3O2

Molecular Weight 213.6 g/mole 

Common Name Aminocyclopyrachlor 

Company Experimental 

Name DPX-MAT28 

IUPAC Name 6-amino-5-chloro-2-cyclopropyl-4-pyrimidinecarboxylic acid 

CAS Name 6-amino-5-chloro-2-cyclopropyl-4-pyrimidinecarboxylic acid 

CAS Registry Number 858956-08-8 

Chemical Class Pyrimidine carboxylic acid 

Impurities of Concern None 

Table 2.2.2. Test Compound Nomenclature-Aminocyclopyrachlor (potassium salt) 

Chemical Structure 

N

N

NH2

Cl

O

O– K+

Empirical Formula C8H7ClKN3O2

Common Name Aminocyclopyrachlor 

Company Experimental 

Name DPX-MAT28 

IUPAC Name potassium 6-amino-5-chloro-2-cyclopropylpyrimidine-4-

carboxylate 

CAS Name potassium 6-amino-5-chloro-2-cyclopropyl-4-

pyrimidinecarboxylate 

CAS Registry Number 858956-35-1 

Chemical Class Pyrimidine carboxylic acid 

Impurities of Concern None 

Page 12 of 76 
Table 2.2.3. Test Compound Nomenclature-Aminocyclopyrachlor-methyl (methyl ester) 

Chemical Structure 

N

N

NH2

Cl

O

O

CH3

Empirical Formula C9H10ClN3O2

Molecular Weight 227.6 g/mole 

Common Name Aminocyclopyrachlor-methyl 

Company experimental 

Name DPX-KJM44 

IUPAC Name methyl 6-amino-5-chloro-2-cyclopropylpyrimidine-4-

carboxylate 

CAS Name methyl 6-amino-5-chloro-2-cyclopropyl-4-

pyrimidinecarboxylate 

CAS Registry Number 858954-83-3 

Chemical Class Pyrimidine carboxylic acid 

Impurities of Concern None 

2.3 Physical and Chemical Properties

The physical and chemical property data for aminocyclopyrachlor technical (DPX-MAT 28 

Technical Herbicide 352-TIE) were summarized in a Memorandum from A. Abramovitch 

(D357886, August 16, 2009). These data are summarized in Table 2.3.1. 

The physical and chemical property data for aminocyclopyrachlor-methyl technical (DPXKJM44 Technical Herbicide 352-TIG) were also summarized in a Memorandum from A. 

Abramovitch (D357975, August 25, 2009). These data are summarized in Table 2.3.2.

Page 13 of 76 
Table 2.3.1. Physiochemical Properties of Aminocyclopyrachlor 

Parameter Value Reference 

Melting point 140.8oC 47559809 

pH (20.1°C) 3.34 47559812 

Density (20°C) 1.34 g/mL 47559809 

Water solubility (20°C) 

3.13 g/L (pH 4) 

4.20 g/L (pH 7) 

3.87 g/L (pH 9) 

47559816 

Vapor pressure 6.92 x10-6 Pa (20°C) 

4.91 x10-6 Pa (25°C) 47559818 

Dissociation constant (20°C) 4.65 47559814 

Octanol/water partition coefficient 

(log10) at 20°C 

-1.01 (pH 4) 

-2.48 (pH 7) 

1.07 (mili-Q water) 

47559815 

UV/visible absorption spectrum 

pH/nm 

1.8/220 

7.0/285, 240, 210 

10.5/280, 240, 210 

47573401 

Table 2.3.2. Physiochemical Properties of Aminocyclopyrachlor-methyl 

Parameter Value Reference 

Melting point 148.9oC 47559829 

pH (20.1°C) 6.16 47559832 

Density (20°C) 1.44 g/mL 47559828 

47559829 

Water solubility (20°C) 0.354 g/L 47559835 

Vapor pressure 

4.19 x10-4 Pa (20°C) 

4.45 x10-4 Pa (25°C) 47559902 

Dissociation constant (20°C) Not applicable Not applicable 

Octanol/water partition coefficient 

(log10) at 20°C 1.87 47559834 

UV/visible absorption spectrum 

pH/nm 

1.8/300, 220 

7.0/300, 235, 205 

10.5/285, 235 

47559833 

Page 14 of 76 
3.0 Hazard Characterization and Dose-Response Assessment 

3.1 Hazard Characterization 

3.1.1 Database Summary 

3.1.1.1 Studies available and considered (animal, human, general literature) 

The following studies were submitted to the Agency for endpoint selection: 

• Acute toxicity (OPPTS guideline) acute oral, dermal, inhalation, eye irritation, dermal 

irritation, and dermal sensitization studies for aminocyclopyrachlor and 

aminocyclopyrachlor-methyl and an acute neurotoxicity study for aminocyclopyrachlor. 

• Subchronic (OPPTS guideline) toxicity studies in rats, mice, and dogs; prenatal 

development studies in rats and rabbits; a reproduction and fertility effects study in rats; 

acute and subchronic neurotoxicity studies in rats; a complete mutagenicity battery; 

immunotoxicity studies in mice and rats; and a metabolism study in rats for 

aminocyclopyrachlor. There are also subchronic oral toxicity and metabolism studies in 

rats and an in vitro genotoxicity (gene mutation) study for aminocyclopyrachlor-methyl. 

• One (OECD guideline) extended one generation reproduction study in rats that includes a 

modified functional observational battery for aminocyclopyrachlor-methyl. 

3.1.1.2 Mode of action, metabolism, toxicokinetic data

Aminocyclopyrachlor is a pyrimidine carboxylic acid and an auxin-type herbicide. Like other 

auxin-type herbicides, the pesticidal mode of action in plants is disorganized plant growth. No 

toxic mode of action for aminocyclopyrachlor or aminocyclopyrachlor-methyl has been 

identified in mammals. 

Pharmacokinetic studies in rats show that both aminocyclopyrachlor and 

aminocyclopyrachlor-methyl are rapidly absorbed, with peak concentrations occurring in plasma 

and red blood cells (RBCs) at 0.3-1.0 hours for aminocyclopyrachlor and at 0.3-0.6 hours after 

dosing for aminocyclopyrachlor-methyl. Aminocyclopyrachlor-methyl was rapidly metabolized 

to aminocyclopyrachlor (within 30 minutes). No other metabolites were identified for either 

compound. The areas under the curve (AUCs) for both compounds scaled with dose, indicating 

that metabolic processes were not saturated. The (plasma) elimination half-life of 

aminocyclopyrachlor of 5.6-5.7 hours was shorter than that for aminocyclopyrachlor-methyl at 

8.7-13.3 hours. The majority of the administered dose of both compounds was excreted within 

24 h, although elimination differed slightly. For aminocyclopyrachlor, 35.8-53.71% was 

eliminated in the urine and 31.4-48.0% was eliminated in the feces. For aminocyclopyrachlormethyl, the majority was recovered in the urine 78.80-78.82%, with a smaller amount eliminated 

in the feces (1.72-4.57%). Neither aminocyclopyrachlor or aminocyclopyrachlor-methyl was 

eliminated as expired air. No sex differences in absorption, distribution, metabolism, or 

excretion were observed for either aminocyclopyrachlor or aminocyclopyrachlor-methyl. 

Page 15 of 76 
3.1.1.3 Sufficiency of Studies/Data 

No additional information was found when screening the general scientific literature for 

information relevant to the hazard assessment of aminocyclopyrachlor. However, these studies 

for aminocyclopyrachlor and aminocyclopyrachlor-methyl in the OPP toxicity 

database are adequate for risk assessment based on the proposed use pattern. 

3.1.2 Toxicological Effects

Acute toxicity studies investigated both aminocyclopyrachlor and aminocyclopyrachlor-methyl, 

since both will be marketed in end-use products. Both exhibit low acute toxicity by oral, dermal, 

or inhalation exposure, and neither cause skin sensitization or irritation. However, both cause 

mild eye irritation. Subchronic dietary, reproductive toxicity, and gene mutation studies were 

also performed with both aminocyclopyrachlor and aminocyclopyrachlor-methyl at similar 

doses. These studies all yielded similar results. These results, together with evidence from 

metabolism studies showing that aminocyclopyrachlor-methyl is rapidly converted to 

aminocyclopyrachlor, form a scientific justification for bridging the toxicity database for 

aminocyclopyrachlor-methyl with studies using aminocyclopyrachlor. 

. 

Toxic effects of aminocyclopyrachlor and aminocyclopyrachlor-methyl via the oral route of 

exposure (in the diet) in subchronic (90-Day) rodent studies were limited to decreases in body 

weights (≤10%), body weight gains, food consumption, and food efficiency in both sexes when 

these compounds were administered to rats at the limit dose (1000 mg/kg/day). These results 

were consistent with acute studies, which showed low toxicity via the oral route for 

aminocyclopyrachlor and aminocyclopyrachlor-methyl at the maximum dose (LD50 >5000 

mg/kg). Subchronic dietary exposure of dogs to aminocyclopyrachlor resulted in no adverse 

effects at doses up to almost half the limit dose (426/388 mg/kg/day in males/females) in both 

sexes (the limit dose was not tested). No evidence of neurotoxicity in rats was observed after 

acute (gavage) or subchronic (dietary) oral administration of aminocyclopyrachlor at the limit 

dose (2000 mg/kg for acute neurotoxicity, 1000 mg/kg for subchronic neurotoxicity). An 

extended one generation reproductive toxicity study in rats for aminocyclopyrachlor-methyl that 

included a functional observational battery also showed no evidence of neurotoxicity at the limit 

dose (1000 mg/kg/day). Aminocyclopyrachlor showed no evidence of immunotoxicity with 

dietary exposure at the limit dose (1000 mg/kg) in mice or rats. 

There were no adverse effects of aminocyclopyrachlor on prenatal development or maternal 

health in rats after oral (gavage) administration to dams at the limit dose (1000 mg/kg/day). 

Administration of aminocyclopyrachlor to rabbit dams via oral (gavage) at the limit dose resulted 

in one treatment-related death and two abortions that were considered secondary to maternal 

weight losses of 17-19%. No developmental effects were observed in rabbit kits. There were no 

effects of aminocyclopyrachlor on reproduction and fertility in rats at the limit dose. Toxicity in 

parental rats and offspring was limited to decreases in body weights at the limit dose. An 

extended one generation reproductive toxicity study in rats for aminocyclopyrachlor-methyl also 

showed no adverse effects on reproduction at the limit dose. 

There was no evidence of toxicity when aminocyclopyrachlor was administered via the dermal 

Page 16 of 76 
Page 17 of 76 

route in rats at the limit dose for 28 days. These results were consistent with acute studies, which 

showed no irritation or skin sensitization for aminocyclopyrachlor or aminocyclopyrachlormethyl. No subchronic dermal toxicity studies were available for aminocyclopyrachlor-methyl. 

However, subchronic dermal toxicity for aminocyclopyrachlor-methyl is expected to be similar 

to aminocyclopyrachlor, based on similar toxicity profiles in acute dermal, acute oral, and 

subchronic oral toxicity profiles. Subchronic inhalation studies for aminocyclopyrachlor and 

aminocyclopyrachlor-methyl were not available. However, the likelihood of subchronic toxicity 

by the inhalation route is expected to be low, based on acute inhalation studies showing that 

aminocyclopyrachlor and aminocyclopyrachlor-methyl had low toxicity at twice the limit 

concentration of 2 mg/L. 

Aminocyclopyrachlor and aminocyclopyrachlor-methyl are considered to have low potential to 

cause chronic toxicity or carcinogenicity. A battery of mutagenicity studies for 

aminocyclopyrachlor showed no mutagenicity in bacteria, or mammalian cells with or without 

metabolic activation. Aminocyclopyrachlor did not induce chromosomal aberrations in human 

peripheral blood lymphocytes in vitro in the presence of absence of metabolic activation. 

Aminocyclopyrachlor did not increase the frequency of micronucleated polychromactic 

erythrocytes in bone marrow. Together, these studies indicate that aminocyclopyrachlor is not 

genotoxic. Aminocyclopyrachlor-methyl also showed no evidence of mutagenicity in an in vitro

gene mutation study. No evidence of target organ toxicity was observed in oral subchronic 

studies for aminocyclopyrachlor and aminocyclopyrachlor-methyl at doses exceeding the limit 

dose. 

The toxicity of the environmental photodegradate of aminocyclopyrachlor, cyclopropane 

carboxylic acid, was also assessed because structural alerts for toxicity for this compound were 

identified by structural activity relationships (SAR). The most sensitive species, the most 

sensitive endpoint, and the mechanism of toxicity of cyclopropane carboxylic acid are known. 

Administration of cyclopropane carboxylic acid orally and by intraperitoneal injection (i.p.) 

acutely (one to three days) or longer (up to 14 days) results in hypoglycemia and liver toxicity in 

rabbits and rats characterized by microvesicular steatosis. The most sensitive species is the 

rabbit. Hepatic microvesicular steatosis is the most sensitive endpoint. The mechanism of 

toxicity is inhibition of beta oxidation of fatty acids in the mitochondria. 

3.2. Consideration of Toxicity to Children 

Food Quality Protection Act (FQPA) considerations do not apply to aminocyclopyrachlor for the 

(non-food) use patterns described in this risk assessment. However, the HED risk assessment 

team has reviewed the toxicity database for indications that young may be particularly sensitive 

to the effects of aminocyclopyrachlor, since some products may be used in residential settings. 
3.2.1 Adequacy of the Toxicity Database

Sufficient data in the form of acceptable OPPTS guideline and non-guideline studies are 

available to evaluate risks to children and are listed below: 

• One rat developmental toxicity study with aminocyclopyrachlor (guideline) 

• One rabbit developmental toxicity study with aminocyclopyrachlor (guideline) 

• One two-generation reproduction study in rats with aminocyclopyrachlor (guideline) 

• One extended one generation reproduction study in rats with aminocyclopyrachlormethyl (OECD 415) that includes a modified functional observational battery (nonguideline) 

3.2.2 Evidence of Neurotoxicity

Sufficient data in the form of acceptable OPPTS guideline and non-guideline studies are 

available to evaluate neurotoxicity. No evidence of neurotoxicity was observed in an acute or 

subchronic neurotoxicity studies in rodents at the limit dose after exposure to 

aminocyclopyrachlor. Also, no evidence of neurotoxicity was observed in an extended onegeneration reproduction study in rats with aminocyclopyrachlor-methyl that included a modified 

functional observational battery. 

3.2.3 Evidence of Developmental Toxicity

No evidence of developmental toxicity was observed when aminocyclopyrachlor was 

administered in the diet of rats or orally by gavage to rabbits at the limit dose. 

3.2.4 Evidence of Reproductive Toxicity 

No evidence of adverse effects of aminocyclopyrachlor or aminocyclopyrachlor-methyl on 

reproduction or fertility parameters were observed in dietary studies with rats. 

3.2.5 Determination of Susceptibility

There was no evidence of prenatal toxicity resulting from exposure to aminocyclopyrachlor. 

There is no evidence of increased susceptibility following in utero exposure to 

aminocyclopyrachlor in rats or rabbits in developmental toxicity studies, which showed no 

adverse effects in offspring at the limit dose. An increase in abortions in maternal rabbits was 

observed at the limit dose, but this was considered secondary to decreases in body weight. There 

was also no evidence of increased susceptibility of offspring to aminocyclopyrachlor in 

reproduction and fertility studies in rats, for which adverse effects were limited to decreased 

body weights in both maternal animals and offspring at the limit dose. Therefore, the young are 

not considered more susceptible than adults to adverse effects from aminocyclopyrachlor or 

aminocyclopyrachlor-methyl. 

Page 18 of 76 
3.2.6 Recommendation for a Developmental Neurotoxicity Study 

There was no evidence of acute or subchronic neurotoxicity in OPPTS guideline studies in adult 

animals and no evidence of increased susceptibility of offspring. Also, no evidence of 

neurotoxicity was found in mature offspring that were exposed to aminocyclopyrahclor-methyl 

in utero in an OECD 415 one generation reproduction study, which included a functional 

observational battery. Therefore, a Developmental Neurotoxicity Study is not required at this 

time for the use patterns described herein. 

3.3 Dose-Response Assessment 

3.3.1 Acute Reference Dose (aRfD) – All Populations 

No acute endpoint was identified because no toxicity was observed at the limit dose in acute oral 

studies. This is also applicable to Females 13-49. 

3.3.2 Chronic Reference Dose (cRfD)

 

Study selected: 90-day oral toxicity feeding study in rats (OPPTS 870.3100). 

MRID Nos.: 47573403 (2008) and 47560007 (2008) 

Executive Summary: See Appendix A 

Dose and Endpoint for Risk Assessment: The NOAEL is the point of departure at 349.4/448.0 

mg/kg/day M/F (350 mg/kg/day). The LOAEL is 1044.6/1424.9 mg/kg/day M/F (limit dose) 

based on decreased body weights, body weight gains, food consumption, and food efficiency in 

both sexes.

Uncertainty Factor(s): 1000X [10X interspecies x 10X intraspecies x 10 X subchronic to 

chronic] 

Comments about selected study: This study is suitable because it is route-specific, of relevant 

duration, addresses all endpoints of concern, and is performed in the most sensitive species at the 

most sensitive endpoints. Also, the results of this study with aminocyclopyrachlor are consistent 

with those of a similar 870.3100 Guideline study with aminocyclopyrachlor-methyl (MRIDs 

47560008 and 47560009, see Appendix A for the Executive Summary for this study), which also 

found decreased body weights, body weight gains, food consumption, and food efficiency in 

both sexes at the limit dose (1022/1219 mg/kg/day M/F). 

3.3.3 Incidental Oral Exposure (Short- and Intermediate-Term) 

Study selected: 90-day oral toxicity feeding study in rats (OPPTS 870.3100). 

MRID Nos.: 47573403 (2008) and 47560007 (2008) 

Executive Summary: See Appendix A 

Dose and Endpoint for Risk Assessment: The NOAEL is the point of departure at 349.4/448.0 

mg/kg/day M/F (350 mg/kg/day). The LOAEL is 1044.6/1424.9 mg/kg/day M/F (limit dose) 

Page 19 of 76 
Page 20 of 76 

based on decreased body weights, body weight gains, food consumption, and food efficiency in 

both sexes.

Uncertainty Factor(s): 100X [10X interspecies x 10X intraspecies] 

Comments about selected study: This study is suitable because it is route-specific, addresses all 

endpoints of concern, and is performed in the most sensitive species at the most sensitive 

endpoints. The duration of this study is relevant to intermediate-term exposure and is also 

protective of short-term exposures. Also, the results of this study with aminocyclopyrachlor are 

consistent with those of a similar 870.3100 Guideline study with aminocyclopyrachlor-methyl 

(MRIDs 47560008 and 47560009, see Appendix A for the Executive Summary for this study), 

which also found decreased body weights, body weight gains, food consumption, and food 

efficiency in both sexes at the limit dose (1022/1219 mg/kg/day M/F). Long-term incidental oral 

exposures are not anticipated based on the proposed use pattern. 

3.3.4 Dermal Absorption

There are no dermal absorption studies for aminocyclopyrachlor. Therefore, a conservative 

default dermal absorption factor of 100% was used. 

3.3.5 Dermal Exposure (Short and Intermediate-Term)

No dermal endpoint was identified because no toxicity was observed in a 28-day dermal toxicity 

study (OPPTS 870.3200) at the limit dose. A 90-day dermal toxicity study was not available. 

The requirement for a 90-day dermal toxicity study was waived because the 28-day dermal 

toxicity study is considered suitable for long-term exposures and all endpoints of concern were 

assessed (J. Ryman, May 13, 2009, D364576). 

3.3.6 Inhalation Exposure (Short and Intermediate-Term)

Study selected: 90-day oral toxicity feeding study in rats (OPPTS 870.3100). 

MRID Nos.: 47573403 (2008) and 47560007 (2008) 

Executive Summary: See Appendix A 

Dose and Endpoint for Risk Assessment: The NOAEL is the point of departure at 349.4/448.0 

mg/kg/day M/F (350 mg/kg/day). The LOAEL is 1044.6/1424.9 mg/kg/day M/F (limit dose) 

based on decreased body weights, body weight gains, food consumption, and food efficiency in 

both sexes.

Uncertainty Factor(s): 100X [10X interspecies x 10X intraspecies] 

Comments about selected study: A route-specific study of suitable duration was not available. 

Therefore, a subchronic oral toxicity study was used. This study was considered suitable 

because significant inhalation exposure is not anticipated for the proposed use patterns due to 

low volatility, outdoor uses, and application methods that are not anticipated to generate 

respirable aerosols. Long-term inhalation exposures are not anticipated based on the proposed 

use pattern. 
3.3.7 Level of Concern for Margin of Exposure

Route 

Short-Term 

(1 - 30 Days) 

Intermediate-Term 

(1 - 6 Months) 

Occupational (Worker) Exposure

Dermal NA NA 

Inhalation 100 100 

Residential Exposure

Dermal NA NA 

Inhalation 100 100 

Incidental Oral 100 100 

NA=Not applicable because no endpoint was identified 

3.3.8 Recommendation for Aggregate Exposure Risk Assessments 

Quantitative, aggregate exposure and risk assessments for aminocyclopyrachlor are not required 

for the proposed (non-food) use patterns because Food Quality Protection Act (FQPA) 

considerations do not apply. However, the potential for significant aggregate exposures and 

risks are estimated in this risk assessment. Since the oral and inhalation endpoints are based on 

the same effects (e.g., decreased body weights), it is appropriate to combine those exposures and 

risks. 

3.3.9 Consideration of Carcinogenic Potential

Aminocyclopyrachlor and aminocyclopyrachlor-methyl are considered to have low potential to 

cause chronic toxicity or carcinogenicity. No evidence of genotoxic effects were observed in 

mutagenicity studies in vitro for aminocyclopyrachlor and aminocyclopyrachlor-methyl or in 

vivo for aminocyclopyrachlor. No evidence of target organ toxicity was observed in oral 

subchronic studies for aminocyclopyrachlor and aminocyclopyrachlor-methyl at doses exceeding 

the limit dose. Therefore, cancer risk was not assessed. 

. 

Page 21 of 76 
3.3.10 Summary of Toxicological Doses and Endpoints for Use in Human Risk 

Assessments

Table 3.3.10.1 Summary of Toxicological Doses and Endpoints for Aminocyclopyrachlor 

for Use in Dietary and Non-Occupational (Residential) Human Health Risk Assessments 

Exposure/ 

Scenario 

Point of 

Departure 

Uncertainty 

Factors 

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment 

Study and Toxicological Effects 

Acute Dietary 

(General 

Population, 

including 

Females 13-49 

and Infants 

and Children) 

NA 

No hazard 

was 

identified. 

NA NA 

Acute Neurotoxicity-rat (870.6200a) 

NOAEL = 2000 mg/kg/day. No acute 

neurotoxicity. 

Chronic 

Dietary (>6 

months, 

General 

Population, 

including 

Females 13-49 

and Infants 

and Children )

NOAEL = 350 

mg/kg/day 

UFA = 10x 

UFH = 10x 

UFS= 10x 

RfD= 

0.35 mg/kg/day 

90-Day Oral Toxicity Feeding-rat 

(870.3100) 

LOAEL = 1045 mg/kg/day (limit dose) 

based on decreased body weights, body 

weight gains, food consumption, and food 

efficiency in both sexes

Incidental 

Oral ShortTerm (1-30 

days) 

NOAEL= 

350 

mg/kg/day 

UFA= 10 x 

UFH=10 x 

The LOC is 

3.5 

mg/kg/day 

90-Day Oral Toxicity Feeding-rat 

(870.3100) 

LOAEL = 1045 mg/kg/day (limit dose) 

based on decreased body weights, body 

weight gains, food consumption, and food 

efficiency in both sexes 

Incidental 

Oral 

IntermediateTerm (1-6 

months) 

NOAEL= 

350 

mg/kg/day 

UFA= 10 x 

UFH=10 x 

The LOC is 

3.5 

mg/kg/day 

90-Day Oral Toxicity Feeding-rat 

(870.3100) 

LOAEL = 1045 mg/kg/day (limit dose) 

based on decreased body weights, body 

weight gains, food consumption, and food 

efficiency in both sexes 

Dermal ShortTerm (1-30 

days) 

NA 

No hazard 

was 

identified. 

NA NA 

28-Day Dermal Toxicity- rat (870.3200) 

NOAEL = 1000 mg/kg/day. No dermal 

toxicity. 

Dermal 

IntermediateTerm (1-6 

months) 

NA 

No hazard 

was 

identified. 

NA NA 

28-Day Dermal Toxicity- rat (870.3200) 

NOAEL = 1000 mg/kg/day. No dermal 

toxicity. 

Page 22 of 76 
Page 23 of 76 

Table 3.3.10.1 Summary of Toxicological Doses and Endpoints for Aminocyclopyrachlor 

for Use in Dietary and Non-Occupational (Residential) Human Health Risk Assessments 

Exposure/ 

Scenario 

Point of 

Departure 

Uncertainty 

Factors 

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment 

Study and Toxicological Effects 

Inhalation 

Short- Term 

(1-30 days) 

NOAEL=350 

mg/kg/day 

(inhalation 

and oral are 

assumed to 

be 

equivalent) 

UFA= 10 x 

UFH=10 x 

Residential 

LOC for 

MOE = 100 is 

3.5 

mg/kg/day 

90-Day Oral Toxicity Feeding-rat 

(870.3100) 

LOAEL = 1045 mg/kg/day (limit dose) 

based on decreased body weights, body 

weight gains, food consumption, and food 

efficiency in both sexes

Inhalation 

IntermediateTerm (1-6 

months) 

NOAEL=350 

mg/kg/day 

(inhalation 

and oral are 

assumed to 

be 

equivalent) 

UFA= 10 x 

UFH=10 x 

Residential 

LOC for 

MOE = 100 is 

3.5 

mg/kg/day 

90-Day Oral Toxicity Feeding-rat 

(870.3100) 

LOAEL = 1045 mg/kg/day (limit dose) 

based on decreased body weights, body 

weight gains, food consumption, and food 

efficiency in both sexes

Cancer (oral, 

dermal, 

inhalation) 

NA 

Point of Departure (POD) = 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). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. RfD = reference dose. MOE = margin of 

exposure. LOC = level of concern. NA = not applicable. 
Table 3.3.10.2 Summary of Toxicological Doses and Endpoints for Aminocyclopyrachlor 

for Use in Occupational Human Health Risk Assessments 

Exposure/ 

Scenario 

Point of 

Departure 

Uncertainty 

Factors 

Level of Concern 

for Risk 

Assessment 

Study and Toxicological Effects 

Dermal ShortTerm (1-30 

days) 

NA 

No hazard 

was 

identified 

NA NA 

28-Day Dermal Toxicity- rat (870.3200) 

NOAEL = 1000 mg/kg/day. No dermal 

toxicity. 

Dermal 

IntermediateTerm (1-6 

months) 

NA 

No hazard 

was 

identified 

NA NA 

28-Day Dermal Toxicity- rat (870.3200) 

NOAEL = 1000 mg/kg/day. No dermal 

toxicity. 

Inhalation 

Short-Term 

(1-30 days) 

NOAEL=350 

mg/kg/day 

(inhalation 

and oral are 

assumed to 

be 

equivalent) 

UFA= 10 x 

UFH=10 x 

Occupational 

LOC for MOE = 

100 is 3.5 

mg/kg/day 

90-Day Oral Toxicity Feeding-rat 

(870.3100) 

LOAEL = 1045 mg/kg/day (limit dose) 

based on decreased body weights, body 

weight gains, food consumption, and food 

efficiency in both sexes 

Inhalation 

Intermediateterm (1-6 

months) 

NOAEL=350 

mg/kg/day 

(inhalation 

and oral are 

assumed to 

be 

equivalent) 

UFA= 10 x 

UFH=10 x 

Occupational 

LOC for MOE = 

100 is 3.5 

mg/kg/day 

90-Day Oral Toxicity Feeding-rat 

(870.3100) 

LOAEL = 1045 mg/kg/day (limit dose) 

based on decreased body weights, body 

weight gains, food consumption, and food 

efficiency in both sexes 

Cancer (oral, 

dermal, 

inhalation) 

NA 

Point of Departure (POD) = 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). MOE = margin of exposure. LOC = level of 

concern. NA = not applicable. 

4.0 Public Health and Pesticide Epidemiology Data

Aminocyclopyrachlor is a new active ingredient that has not been registered for use. There are no 

public health or epidemiological data. 

Page 24 of 76 
5.0 Dietary Exposure/Risk Characterization 

All of the proposed uses for aminocyclopyrachlor are non-food. Therefore, the only dietary 

exposures considered in this assessment are from drinking water exposures to 

aminocyclopyrachlor and environmental degradates. 

5.1. Environmental Degradation

5.1.1 Stability, mobility, and degradates 

The following information on environmental stability and degradation products of 

aminocyclopyrachlor are summarized from EFED’s “Drinking Water Degradates Identification 

Memorandum for Aminocyclopyrachlor” memorandum (C. Koper, August 25, 2009, D368339). 

Aminocyclopyrachlor is non-volatile and highly soluble in water, which indicates that dissipation 

of aminocyclopyrachlor in the environment is expected to occur predominantly via runoff and 

leaching. Terrestrial field dissipation studies conducted in the continental United States and 

Canada showed that dissipation occurred with half-lives ranging from 22 to 126 days. 

Aminocyclopyrachlor is characterized as being moderately mobile to slightly mobile in test soils 

based on the adsorption of aminocyclopyrachlor to test soils in batch equilibrium studies. 

Aminocyclopyrachlor was detected at soil depths of 70 – 90 cm at 365 days, indicating that 

leaching of residues into groundwater may occur. 

Aminocyclopyrachlor is environmentally persistent in diverse environments. It persists in 

aerobic aquatic environments with a dissipation time of greater than 100 days and in aerobic 

terrestrial environments with a half-life of 315 days. It is also stable in anaerobic aquatic 

environments with a half life of 1733 days and in anaerobic terrestrial environments with a halflife of 6932 days. 

The major route of degradation of aminocyclopyrachlor is abiotic via aqueous photolysis with a 

half-life of l.2 days in shallow, clear, and well-lit natural (pH 6.2) water bodies and 7.8 days in 

pH 4 buffer solution. However, it is slowly photolyzed on soil, with a half-life of 129 days. 

Aminocyclopyrachlor is stable to hydrolysis at pH 4 and 7. At pH 9, the half-life was calculated 

to be at least 34.7 days, however, the possibility that the compound does not degrade at this pH 

could not be ruled out due to mass balance issues. 

The major environmental degradates of aminocyclopyrachlor include IN-LXT69, IN-QFH57, 

IN-Q3007, IN-V0977, IN-YY905, CO2 and an unidentified aqueous photoproduct. The 

structures of these degradates are listed in Appendix C. 

5.1.2 Toxicity Profile of Major Degradates 

The following information was obtained from HED’s “Aminocyclopyrachlor. Report of the 

Residues of Concern Knowledgebase Subcommittee (ROCKS)” memorandum (from G. Kramer, 

October 15, 2009, D370638). The toxicity profiles of aminocyclopyrachlor and the five major 

Page 25 of 76 
environmental degradates [(IN-LXT69, 5-chloro-2-cyclopropyl-pyrimidin-4-ylamine); (INQFH57, 4-cyano-2-cyclopropyl-1H-imidazole-5-carboxylic acid); (IN-Q3007, 

cyclopropanecarboxamide); (IN-V0977, cyclopropane carboxylic acid); (IN-YY905, 

cyclopropanecarboximidamide)] were determined by structure-activity relationship (SAR) 

analysis using DEREK for Windows (Version 11.0.0). Four of the degradates (IN-LXT69, INQFH57, IN-V0977, IN-YY905) were excluded as residues of concern. However, structural 

alerts and studies in the general scientific literature indicated that the environmental degradate 

IN-V0977 (cyclopropane carboxylic acid) has a different mode of toxicity than the parent 

compound. 

The toxicity of IN-V0977 (cyclopropane carboxylic acid) was addressed by the registrant in a 

position paper (MRID 47898501) describing what is known about the toxicity of cyclopropane 

carboxylic acid from the scientific literature and other sources. This position paper was 

evaluated in a memorandum (from J. Ryman, December 31, 2009, D371431) entitled “Toxicity 

assessment of IN-V0977 (cyclopropane carboxylic acid)”. The mechanism of toxicity of 

cyclopropane carboxylic acid has been identified by extensive study of the drug panadiplon, 

which is metabolized to cyclopropane carboxylic acid after oral administration. The mechanism 

is severe impairment of mitochondrial function that causes decreased energy production in 

diverse organs, with the liver being highly sensitive. The toxic endpoint of concern to the 

Agency for cyclopropane carboxylic acid was identified as microvesicular steatosis, which can 

result in liver failure, pancreatitis, kidney failure, coma, and death. The health effects associated 

with microvesicular steatosis tend to be more adverse than those associated with macrovesicular 

steatosis (accumulation of large fat droplets in cells) in which mitochondrial function is not as 

compromised, although both can cause inflammation and scarring in the liver. The most 

sensitive species in which to observe hepatic microvesicular steatosis resulting from 

cyclopropane carboxylic acid exposure is the rabbit. 

5.1.3 Degradates of Concern 

One degradate of concern, cyclopropane carboxylic acid, has been identified. An acute RfD of 

0.0026 mg/kg/day and a chronic RfD of 0.00087 mg/kg/day were determined based on a 2-week 

oral (gavage) study published in the general scientific literature (MRID 47916803). This study 

investigated the toxicity of panadiplon, which is metabolized to cyclopropane carboxylic acid 

(the toxic entity) in the most sensitive species (the rabbit). The most sensitive 

endpoint was hepatic steatosis with a dose-related increase in the incidence and severity of liver 

damage. No NOAEL was identified, and so a LOAEL of 10 mg/kg/day was used as the point of 

departure (POD). This POD for panadiplon was converted to a POD of 2.55 mg/kg/day for 

cyclopropane carboxylic acid, based on molecular weights (337.35 g/mole for panadiplon and 

86.09 g/mole cyclopropane carboxylic acid) and a mole ratio of 1 mole of cyclopropane 

carboxylic acid/mole panadiplon, and assuming 100% conversion of panadiplon to cyclopropane 

carboxylic acid. Since there is evidence that hepatic steatosis can occur after acute exposure (1-3 

days), acute dietary exposure was assessed using this same study. Uncertainty factors used for 

acute dietary exposures were 10-fold for intraspecies differences, 10-fold for interspecies 

differences, and 10-fold for extrapolating from a LOAEL to NOAEL. For chronic dietary 

exposures, an additional 3X uncertainty factor was added for extrapolation from a 14 day study 

to chronic exposure (J. Ryman, December 31, 2009, D371431). No additional database 

Page 26 of 76 
uncertainty factors were added. The toxicological endpoints used for assessing dietary exposures 

to this degradate are summarized in Table 5.1.3. 

Table 5.1.3. Summary of Toxicological Doses and Endpoints for the Environmental 

Degradate, IN-V0977 (Cyclopropane Carboxylic Acid) for Use in Dietary Human Health 

Risk Assessments 

Exposure/ 

Scenario 

Point of 

Departure 

Uncertainty 

Factors 

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment 

Study and Toxicological Effects 

Acute Dietary 

(All 

Populations)

LOAEL = 

2.55 

mg/kg/day 

cyclopropane 

carboxylic 

acid 

UFA = 10x 

UFH = 10x 

UFL= 10x 

RfD= 

0.0026 

mg/kg/day 

Rabbit study 

MRID 47916803 (1998) 

Non-guideline, oral (gavage) for 14 days 

0, 10, 20 mg/kg/day (panadiplon) 

LOAEL = 10 mg/kg/day based on hepatic 

steatosis 

Chronic Dietary 

Long-term (>6 

months) 

LOAEL = 

2.55 

mg/kg/day 

cyclopropane 

carboxylic 

acid 

UFA = 10x 

UFH = 10x 

UFL= 10x 

UFS= 3x 

RfD= 

0.00087 

mg/kg/day 

Rabbit study 

MRID 47916803 1998) 

Non-guideline, oral (gavage) for 21 days 

0, 10, 20 mg/kg/day (panadiplon) 

LOAEL = 10 mg/kg/day based on hepatic 

steatosis 

Cancer (oral) NA 

Point of Departure (POD) = 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). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. RfD = reference dose. NA = not 

applicable. 

5.1.4 Drinking Water Residue Profile

The risk of ground and surface water contamination and the estimated drinking water 

concentrations of aminocyclopyrachlor and cyclopropane carboxylic acid in surface and ground 

water for non-crop and turf uses were described in a memorandum (from C. Koper, January 08, 

2010, D368238) entitled “Drinking water assessment for aminocyclopyrachlor acid and its 

degradate cyclopropane carboxylic acid (IN-V0977) for non-crop and turf use”. Based on the 

proposed application rates and the environmental fate properties of aminocyclopyrachlor acid, 

both surface water and ground water contamination may occur from aminocyclopyrachlor acid, 

but only surface water contamination is expected for the degradate cyclopropane carboxylic acid 

(IN-V0977). 

The risk of water contamination by the parent (aminocyclopyrachlor acid) is primarily associated 

with stability and mobility of the parent (aminocyclopyrachlor acid) and the toxicity and 

mobility of the degradate (cyclopropane carboxylic acid (IN-V0977)). The parent may move 

from the treated field to ground water through leaching. The primary route of formation of the 

degradate is through aqueous photolysis. Since the parent is not susceptible to soil photolysis (t 

Page 27 of 76 
1/2 = 129 days; MRID 47560213), the degradate is not an issue for ground water contamination 

and exposure to the degradate is most likely to occur from spray drift in aqueous environments. 

Due to the difference in toxicities, the parent and degradate were assessed separately. The 

Estimated Drinking Water Concentrations (EDWCs) for use in the human health risk assessment 

are based on the maximum proposed application rates specified in the product labels. For 

aminocyclopyrachlor acid for non-crop use, a single application of 0.284 lbs. a.i./acre can be 

applied for a yearly maximum application rate of 0.284 lbs. a.i./acre. For turf use, three 

applications of 0.108 lbs. a.i./acre can be applied with a 30-day application interval for a yearly 

maximum application rate of 0.324 lbs. a.i./acre. The application rate for the cyclopropane 

carboxylic acid (IN-V0977) degradate can be calculated by multiplying the application rate of 

the parent (e.g.: 0.284 lbs. a.i./acre) by the fraction of the maximum detected degradate from the 

submitted fate studies (0.146; MRID 47560211) then multiplying by the ratio of the molecular 

weights of the degradate to parent (86.09/213.62). Following this equation, the maximum single 

application rate was 0.017 lbs. degradate/acre for non-crop use and 0.006 lbs. degradate/acre for 

turf. 

Tier I screening models were employed for this assessment. For surface water, the FIRST 

(FQPA Index Reservoir Screening Tool, Version1.1.1) model was used to estimate drinking 

water concentrations. For ground water, the SCI-GROW model (Screening Concentration in 

Ground Water Program Version 2.3) was used to predict the maximum acute and chronic (annual 

average) concentrations present in shallow ground water. 

For drinking water derived from surface water for the parent aminocyclopyrachlor acid, the 

FIRST model estimated the acute and chronic (annual average) concentrations at 27.287 ug/L 

and 16.965 ug/L, respectively. For drinking water derived from surface water for the degradate 

cyclopropanecarboxylic acid (IN-V0977), the acute and chronic (annual average) concentrations 

are 1.742 ug/L and 1.246 ug/L, respectively. For drinking water derived from ground water for 

the parent aminocyclopyrachlor acid, the SCI-GROW model estimated the ground water 

concentration to be 40.2 ug/L. This concentration should be used for the acute and chronic 

values. In addition, since the parent is not susceptible to soil photolysis (t 1/2 = 129 days; MRID 

47560213), the degradate is not an issue for ground water contamination; therefore, no SCIGROW modeling was performed on the degradate. 

The estimated surface water concentrations of the parent aminocyclopyrachlor acid and its 

degradate cyclopropane carboxylic acid (IN-V0977) for the use on non-crop applications and 

turfgrasses are summarized in Table 5.1.4. The estimated ground water concentrations of 

aminocyclopyrachlor are also summarized in Table 5.1.4. Selected values from Table 5.1.4 

were used to calculate acute and/or chronic dietary exposures to aminocyclopyrachlor and its 

degradate from drinking water as described in Section 5.2. 

Page 28 of 76 
Table 5.1.4 Estimated Drinking Water Concentrations (EDWCs) resulting from 

applications of aminocyclopyrachlor acid and the degradate cyclopropane carboxylic acid 

(IN-V0977) for non-crop and turf use. 

Drinking 

Water 

Source 

(Model) 

Compound Use Method 

Application 

Rate 

(interval 

between 

applications) 

Adjustme

nt Factor 2

Peak Day 

(acute) 

Concentrati

on (μg/L) 

Annual 

Average 

(chronic) 

Concentrati

on (μg/L) 

Aerial 

1 app @ 0.284 

a.i./acre 

(NA) 

25.576 15.904

NonCrop 

Ground 

1 app @ 0.284 

a.i./acre 

(NA) 

25.641 15.943 Aminocyclopyrachl

or Acid 

Turf Granular

3 app @ 0.108 

a.i./acre 

(30 days) 

27.287 16.965

NonCrop 

1 app @ 0.017 

degradate/acre

(NA) 

1.515 1.084 

Surface 

Water 

(FIRST) 

Cyclopropane 

carboxylic Acid 

(IN-V0977) Turf 

Granular 1 3 app @ 0.006 

degradate/acre

(30 days) 

0.87 

1.742 1.246 

NonCrop --- 1 app @ 0.284 

a.i./acre 

(NA) 

--- Ground 35.2 35.2 

Water 

(SCIGROW) 

Aminocyclopyrachl

or Acid 

Turf --- 3 app @ 0.108 

a.i./acre 

(30 days) 

--- 40.2 40.2 

Bold values denote maximum Estimated Drinking Water Concentrations (EDWCs) 

1 Granular method of application was selected for the degradate (Drift = 0.0% and Application Efficiency = 100%). 

All applications are liquid unless otherwise noted. 

2 Adjustment Factors: PCA = Percent Crop Area 

NA = Not Applicable 

5.2 Dietary Exposure and Risk

An acute and chronic dietary exposure analysis was performed for drinking water only, since 

there are no food uses for this registration action. The analysis was performed using the Dietary 

Exposure Evaluation Model DEEM-FCIDTM, Version 2.03. This model uses food consumption 

data from the U.S. Department of Agriculture’s Continuing Surveys of Food Intakes by 

Individuals (CSFII) from 1994-1996 along with a supplemental children’s survey from 1998. 

Aminocyclopyrachlor is a new active ingredient (a.i.) and, as such, is not registered for any food 

or non-food uses. The proposed use is on turf and ornamentals. As there are no registered or 

proposed food uses for aminocyclopyrachlor, dietary exposure to the chemical will be through 

drinking water only. Dietary exposures to both aminocyclopyrachlor and the environmental 

degradate, IN-V0977 (cyclopropane carboxylic acid) from drinking water were considered in a 

memorandum (from T. Morton, January 19, 2010, D369058) entitled “Aminocyclopyrachlor: 

Revised Acute and Chronic Dietary (Drinking Water Only) Exposure Analysis for the Section 3 

Registration Action”. 

Page 29 of 76 
Page 30 of 76 

The Estimated Drinking Water Concentration (EDWC) used in the acute and chronic dietary risk 

assessment was provided by the corrected EFED (Memo, D368238, C. Koper, 01/08/2010). The 

annual average EDWC for chronic exposure assessment was incorporated directly into the 

dietary assessment in the food categories “water, direct, all sources” and “water, indirect, all 

sources.” The EDWCs for aminocyclopyrachlor were generated with the model FIRST for 

surface water and SCI-GROW for groundwater. Modeled surface and groundwater EDWCs are 

based on the label application rate to turf and non-crop. The FIRST annual average surface 

water estimate of 16.965 ppb is less than the SCI-GROW groundwater estimate of 40.2 ppb. As 

a result, the ground water estimate was used in the chronic dietary analysis for the parent. For 

the degradate, an annual peak EDWC of 1.742 ppb was used for the acute dietary analysis and an 

annual average EDWC of 1.246 ppb was used for the chronic dietary analysis. Additional 

information concerning the water models is available at the EPA internet site: 

http://www.epa.gov/oppefed/models/water/. 

Dietary risk assessment incorporates both exposure and toxicity of a given pesticide. For acute 

and chronic assessments, the risk is expressed as a percentage of a maximum acceptable dose 

(i.e., the dose that HED has concluded will result in no unreasonable adverse health effects). For 

chemicals that have only non-food uses, this dose is referred to as the reference dose (RfD). The 

RfD is equivalent to the point of departure (e.g., NOAEL, LOAEL) divided by the required 

uncertainty factors. 

For acute and non-cancer chronic exposures to non-food-use pesticides, HED is concerned when 

estimated dietary risk exceeds 100% of the RfD. HED is generally concerned when estimated 

cancer risk exceeds one in one million. References that discuss the acute and chronic risk 

assessments in more detail are available on the EPA/pesticides website: “Available Information 

on Assessing Exposure from Pesticides, A User’s Guide,” 6/21/2000, web link: 

http://www.epa.gov/fedrgstr/EPA-PEST/2000/July/Day-12/6061.pdf; or see SOP 99.6 

(8/20/1999). 

5.2.1 Acute Dietary Exposure/Risk

An acute dietary endpoint was not identified for the parent aminocyclopyrachlor (Table 5.2.1). 

An acute dietary endpoint was identified for the environmental degradate IN-V0977 (Table 

5.2.2). The most highly exposed population subgroup is All Infants (<1 year old) which utilizes 

13 % of the acute RfD (aRfD) for the environmental degradate IN-V0977. The risk estimates for 

the general U.S. population and all other regulated population subgroups are below HED’s level 

of concern (<100% of the cRfD) for the environmental degradate IN-V0977. 

5.2.2 Chronic Dietary Exposure/Risk

A chronic dietary endpoint was identified for aminocyclopyrachlor. The most highly exposed 

population subgroup is All Infants (<1 year old) which utilizes <1% of the chronic reference 

dose (cRfD). A chronic dietary endpoint was also identified for the environmental degradate INV0977. The most highly exposed population subgroup is All Infants (<1 year old) which uses 

9.9% of the cRfD. The risk estimates for the general U.S. population and all other regulated 

population subgroups are below HED’s level of concern (<100% of the cRfD) for both the parent 

aminocyclopyrachlor and the environmental degradate (IN-V0977). 
Table 5.2.1 Results of Acute and Chronic Drinking Water Exposure and Risk Estimates 

for Aminocyclopyrachlor 

Acute Dietary Chronic Dietary Cancer 

Population Subgroup* 

Dietary 

Exposure 

(mg/kg/day) % aPAD

Dietary 

Exposure 

(mg/kg/day) % cPAD

Dietary 

Exposure 

(mg/kg/day) Risk 

General U.S. Population 0.000847 <1 

All Infants (< 1 year old) 0.002778 <1

Children 1-2 years old 0.001258 <1

Children 3-5 years old 0.001178 <1

Children 6-12 years old 0.000812 <1

Youth 13-19 years old 0.000612 <1

Adults 20-49 years old 0.000791 <1

Adults 50+ years old 0.000832 <1

Females 13-49 years old 

Not Applicable: No 

Acute Dietary Endpoint 

Was Identified 

0.000788 <1

Not Applicable: No 

Cancer Dietary Endpoint 

Was Identified 

Table 5.2.2 Results of Acute and Chronic Drinking Water Exposure and Risk Estimates 

for Degradate (IN-V0977) 

Acute Dietary 

95th percentile Chronic Dietary Cancer 

Population Subgroup* 

Dietary 

Exposure 

(mg/kg/day) % aPAD

Dietary 

Exposure 

(mg/kg/day) % cPAD

Dietary 

Exposure 

(mg/kg/day) Risk 

General U.S. Population 0.000091 3.5 0.000026 3.0 

All Infants (< 1 year old) 0.000343 13 0.000086 9.9

Children 1-2 years old 0.000143 5.5 0.000039 4.5

Children 3-5 years old 0.000130 5.0 0.000037 4.2

Children 6-12 years old 0.000091 3.5 0.000025 2.9

0.000074 2.8 0.000019 

2.2

Not Applicable: No 

Acute Dietary Endpoint 

Was Identified 

Page 31 of 76 
Page 32 of 76 

Table 5.2.2 Results of Acute and Chronic Drinking Water Exposure and Risk Estimates 

for Degradate (IN-V0977) 

Acute Dietary 

95th percentile Chronic Dietary Cancer 

Population Subgroup* 

Dietary 

Exposure 

(mg/kg/day) % aPAD

Dietary 

Exposure 

(mg/kg/day) % cPAD

Dietary 

Exposure 

(mg/kg/day) Risk 

Youth 13-19 years old 

Adults 20-49 years old 0.000084 3.2 0.000025 2.8

Adults 50+ years old 0.000076 2.9 0.000026 3.0

Females 13-49 years old 0.000085 3.3 0.000024 2.8

5.2.3 Cancer Dietary Risk 

No cancer endpoint has been identified for aminocyclopyrachlor or cyclopropane carboxylic 

acid. Therefore, the cancer risk from dietary exposure were not assessed. 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization 

The residential risk assessment addresses exposures that individuals receive through their use of 

consumer products that contain aminocyclopyrachlor and through exposures they could receive 

from frequenting areas that have been previously treated. Residential uses in this registration 

action are control of broad leaf and woody species weeds including many terrestrial, riparian 

invasive, and noxious weeds on lawn/turf. Based on label specific information and information 

provided by the registrant, residential handler exposures are expected to be short- and 

intermediate-term in duration. The residential handler and postapplication exposure and risk, 

based on product labels, is summarized below and is also described in a Memorandum entitled 

“Occupational and Residential Risk Assessment to Support the Request for Registration of 

Aminocyclopyrachlor, its methyl ester and potassium salt on Turf and Non-crop areas” (J.S. 

Miller, January 30, 2010, D372493). 
6.1 Residential Handler Exposure

Based on label specific information and information provided by the registrant, residential 

handler exposures are expected to be short- and intermediate-term in duration. Long-term 

residential handler exposures are not expected. 

The Agency identified several residential exposure scenarios based on the types of equipment 

and techniques that potentially can be used for aminocyclopyrachlor applications. These 

scenarios include: 

• Mixing/Loading/Applying 

o Low Pressure Handwand: Dry flowable and soluble liquid formulations to 

lawn/turf 

o Hose-End Sprayer: Dry flowable and soluble liquid formulations to lawn/turf 

o Hand Held Spreader (Belly Grinder): Granular formulation to lawn/turf 

6.1.1. Data and Assumptions for Residential Handler Exposure Scenarios 

The following data and assumptions were used to calculate residential handler risks using a 

Margin of Exposure (MOE) of 100. Daily dose estimates were calculated using relevant 

application parameters (i.e., rate and area treated) along with unit exposures. Exposures were 

then adjusted for body weight (an average adult body weight of 70 kg was assumed). Routes of 

residential exposures are dermal and inhalation. Quantification of dermal exposures was not 

performed because no toxicity was observed in a subchronic dermal toxicity study at the limit 

dose (1000 mg/kg). Inhalation risks were assessed by using an absorption factor of 100% 

(assuming no respirator use) to calculate dose levels. 

6.1.1.1. Unit Exposures

Chemical-specific data for assessing exposure during pesticide handling activities were not 

submitted to the Agency in support of this Section 3 application. Therefore, unit exposure data 

from the PHED Surrogate Exposure Guide dated August 1998 were used. 

6.1.1.2. Area Treated

It is Agency policy to assume a lawn/turf treatment area of 0.5 acres per day for all residential 

handler scenarios. 

6.1.1.3. Application Rate 

Aminocyclopyrachlor (as parent acid and potassium salt) and aminocyclopyrachlor -methyl are 

applied in three different formulations: a water dispersible granular, a soluble liquid, and a 

granular. Labels were chosen that that were representative of these different formulations and all 

exposure scenarios, and while yielding the maximum application rate for exposure assessment 

(i.e. would be the most conservative). These application rates range from a minimum of 0.07 lbs 

acid equivalent/acre to a maximum of 0.10 lbs acid equivalent/acre (Table 2.1.1). 

 

Page 33 of 76 
6.1.1.4. Results and Conclusions 

Results of the residential handler risk assessment are summarized in Table 6.1.1. All exposure 

scenarios are for lawn/turf. For all residential exposure scenarios, MOEs were greater than 100 

(MOE >100), and therefore are not of concern. 

Table 6.1.1 Summary of Residential Short and Intermediate-Term Risk Assessment for 

Aminocyclopyrachlor (Acid and Potassium Salt) and Aminocyclopyrachlor-Methyl 

Exposure Scenario

Application 

Rate 

(lb ae/A) 

Area 

Treated 

(A/day)

Inhalation 

Unit 

Exposure 

(μg/lb ai) 

Inhalation 

Daily Dose 

(mg/kg/day) 

Inhalation 

Short/IntermediateTerm MOE

Open Mixing, Loading, 

and Applying 

Low Pressure 

Handwand 

(Soluble Liquid) 

30 0.000015 23,000,000 

Open Mixing, Loading, 

and Applying 

Hose-end Sprayer 

(Dry Flowable) 

0.07 

17 0.0000085 41,200,000 

Open Mixing, Loading, 

and Applying 

Belly Grinder 

(Granular) 

0.10 

0.5 

62 0.000048 7,300,000 

ae=acid equivalent; A=acre; ai=active ingredient 

6.2. Residential Postapplication Exposure

Individuals of varying ages and life stages can potentially be exposed to aminocyclopyrachlor 

when they do activities in areas that have been previously treated. Post-application exposure 

scenarios include scenarios that are relevant to toddlers, which were considered. These scenarios 

are non-dietary ingestion exposures resulting from transfer of pesticide resides on treated areas to 

hands that may put in the mouth (hand-to-mouth transfer), transfer of pesticide residues on 

treated areas to objects that may be put in the mouth (e.g. object-to-mouth), and ingestion of soil 

from pesticide treated areas. The postapplication exposure and risk, based on product labels, is 

summarized below and is also described in a Memorandum entitled “Occupational and 

Residential Risk Assessment to Support the Request for Registration of Aminocyclopyrachlor, 

its methyl ester and potassium salt on Turf and Non-crop areas” (J.S. Miller, January 30, 2010, 

D372493). 

Page 34 of 76 
Page 35 of 76 

6.2.1. Data and Assumptions for Residential Postapplication Scenarios 

The following data and assumptions were used to calculate residential postapplication risks using 

a Margin of Exposure (MOE) of 100. Routes of postapplication exposure were assumed to be 

dermal and oral. Quantification of dermal exposures was not performed because no toxicity was 

observed in a subchronic dermal toxicity study at the limit dose (1000 mg/kg). Oral exposures 

were determined by calculating daily dose estimates from hand-to-mouth, object-to-mouth, and 

soil ingestion exposures. Exposures were then adjusted for body weight (a child’s body weight 

of 15 kg was assumed). Oral exposures were then added to arrive at a combined MOE. 

6.2.2. Results and Conclusions

Results of the residential postapplication risk assessment are summarized in Table 6.2.1.

For all residential exposure scenarios, combined MOEs for Short-Term and Intermediate-Term 

exposure were greater than 100 (MOE >100) and therefore are not of concern. 

Table 6.2.1.: Toddler Residential Risk Estimates for Post-Application Exposure to 

Aminocyclopyrachlor (Acid and Potassium Salt) and Aminocyclopyrachlor-Methyl

Exposure Scenario TC 

cm2

/hr 

Route of 

Exposure Application Rate MOE at Day 0 

Combined MOE1 

Ingestion 

Outdoors S-Term Int-Term 

Hand to Mouth 

Activity on Turf 234,000 493,000 

Object to Mouth 

Activity on Turf 938,000 

Soil Ingestion 

N/A Oral 0.1 

70,000,000 

322,000 

1

Combined MOE value shown is for Intermediate-Term, but is inclusive of Short-Term. 

6.3 Spray Drift 

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

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for 

aminocyclopyrachlor. The Agency has been working with the Spray Drift Task Force, EPA 

Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop 

the best spray drift management practices. On a chemical by chemical basis, 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, a membership of U.S. pesticide registrants, and is developing a policy on 

how to appropriately apply 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 may impose further refinements in spray drift management practices to reduce 

off-target drift with specific products with significant risks associated with drift. 
7.0 Aggregate Risk Assessments and Risk Characterization

The potential for significant aggregate exposures to aminocyclopyrachlor from dietary and 

residential uses relative to non-aggregate exposures was considered. The highest estimated 

residential exposure (0.000048 mg/kg/day via inhalation during mixing, loading, and applying a 

granular formulation with a belly grinder, Table 6.1.1) combined with the highest estimated 

dietary exposure (0.002778 mg/kg/day for All Infants < 1 year, Table 5.2.1). This combined 

value of 0.003 was over 1000- fold lower than the point of departure of 3.5 mg/kg/day, based on 

the most conservative level of concern for margin of exposure (350 mg/kg/day with MOE=100). 

This estimate indicates that aggregate exposures to aminocyclopyrachlor will not result in 

significantly increased risk relative to non-aggregate exposure. 

8.0 Occupational Exposure/Risk Pathway

This section of the risk assessment addresses exposures to individuals who are exposed to 

aminocyclopyrachlor as part of their employment. These exposures can occur because people have 

contact with aminocyclopyrachlor while using commercial products containing aminocyclopyrachlor 

(i.e., handlers) or by being in areas that have been previously treated (post-application). 

Occupational uses in this registration action are general weed and brush control on private, 

public and military lands including un-cultivated non-agricultural areas such as airports, 

highways, railroads, golf courses, lumber yards, wild life habitats, multi family residential 

complexes, recreation areas, sod farms, utility rights of way, and residential lawns. Based on 

label specific information and information provided by the registrant, occupational handler 

exposures are expected to be short- and intermediate-term in duration. 

The occupational handler and post-application exposure and risk, based on product labels, is 

summarized below and is also described in a Memorandum entitled “Occupational and 

Residential Risk Assessment to Support the Request for Registration of Aminocyclopyrachlor, 

its methyl ester and potassium salt on Turf and Non-crop areas” (J.S. Miller, January 30, 2010, 

D372493). 

8.1 Short-Term and Intermediate-Term Handler Risk 

Based on label specific information and information provided by the registrant, occupational 

handler exposures are expected to be short- and intermediate-term in duration. Long-term 

occupational handler exposures are not expected. 

The Agency completes occupational handler risk assessments using scenarios as the basis for the 

calculations as described in the U.S. EPA Guidelines for Exposure Assessment. For commercial 

pesticide products, the Agency categorizes handler exposures based on the kinds of formulations 

(e.g., liquids), the kinds of equipment used to make applications (e.g., types of handheld 

equipment), the nature of the task (e.g., mixing/loading, applying, or both combined), and the 

level of personal protection used. Identifying the duration of exposure is also a critical element in 

the development of a risk assessment to ensure that the proper hazard component is used. 

Page 36 of 76 
The Agency identified several major occupational exposure scenarios based on the types of 

equipment and techniques that potentially can be used for aminocyclopyrachlor applications. 

These scenarios include: 

• Mixing/Loading 

o Groundboom: Dry flowable and soluble liquid formulations to non-crops, golf 

courses, sod farms, and lawn/turf 

o Aerial (fixed and non-fixed wing): Dry flowable formulation to non-crops 

o LCO handgun: Water dispersible granules and soluble liquid formulations to 

non-crops, golf courses, sod farms, and lawn/turf 

o Right of way sprayer: Water dispersible granules and soluble liquid formulations 

to non-crops, golf courses, sod farms, and lawn/turf 

o Push type spreader: Granular formulation to golf courses, sod farms, and 

lawn/turf 

o Tractor drawn broadcast spreader: Granular formulation to golf courses, sod 

farms, and lawn/turf 

o Push cyclone spreader: Granular formulations to golf courses, sod farms, and 

lawn/turf 

• Applying 

o Groundboom: Dry flowable and soluble liquid formulations to non-crops, golf 

courses, sod farms, and lawn/turf. 

o Aerial (fixed an non-fixed wing): Dry flowable formulation to non-crops 

o LCO handgun: Water dispersible granules and soluble liquid formulations to 

non-crops, golf courses, sod farms, and lawn/turf 

o Right of way sprayer: Water dispersible granules and soluble liquid formulations 

to non-crops, golf courses, sod farms, and lawn/turf 

o Tractor drawn broadcast spreader: Granular formulation to golf courses, sod 

farms, and lawn/turf 

• Flagging 

o Aerial (fixed and non-fixed wing): Dry flowable formulation to non-crops 

8.1.1. Data and Assumptions for Occupational Handler Exposure Scenarios 

The following data and assumptions were used to calculate occupational handler risks using a 

Margin of Exposure (MOE) of 100. Daily dose estimates were calculated using relevant 

application parameters (i.e., rate and area treated) along with unit exposures. Exposures were 

then adjusted for body weight (an average adult body weight of 70 kg was assumed). Routes of 

occupational exposures are dermal and inhalation. Quantification of dermal exposures was not 

performed because no toxicity was observed in a subchronic dermal toxicity study at the limit 

dose (1000 mg/kg). Inhalation risks were assessed by using an absorption factor for 100% 

(assuming no respirator use) to calculate dose levels. 

8.1.1.1. Unit Exposures

Chemical-specific data for assessing exposure during pesticide handling activities were not 

submitted to the Agency in support of this Section 3 application. It is HED policy to use data 

from the Pesticide Handlers Exposure Database (PHED) Version 1.1 to assess handler exposures 

Page 37 of 76 
Page 38 of 76 

for regulatory actions when chemical-specific data are not available (HED Science Advisory 

Council for Exposure, SOP Number .007, January 1999). 

8.1.1.2. Area Treated

Assumptions made regarding the number of acres of land treated per day for different mixing, 

loading, and application scenarios are described in a Standard Operating Procedure (SOP) of the 

HED Exposure Science Advisory Committee (Number 9.1). These assumptions relevant to 

occupational handler scenarios indicated by product labels are summarized below: 

• 40 acres per day for mixing/ loading, and applying for lawn/turf and golf courses when 

using groundboom equipment

• 80 acres per day for mixing/loading and applying for non-crops and sod farms with 

groundboom equipment 

• 350 acres per day for mixing/loading, applying and flagging for non-crops with aerial 

equipment 

• 5.0 acres per day for application for non-crop, lawn/turf, golf courses, and sod farms with 

LOC handgun equipment and right of way sprayers

• 100 acres per day for mixing and loading for non-crop and lawn/turf with LOC handgun 

equipment. (Based upon mixing and loading of 20 trucks that will apply 5 acres of 

formulation per day).

• 5.0 acres per day for loading and applying for sod farm and golf courses with a push type 

spreader

• 40 acres per day for application for sod farms and golf courses with a tractor drawn 

broadcast spreader or push cyclone spreader

8.1.1.3. Application Rate 

Aminocyclopyrachlor (parent acid and potassium salt) and aminocyclopyrachlor-methyl are 

applied in three different formulations: a water dispersible granular, a soluble liquid, and a 

granular. Labels were chosen that that were representative of these different formulations and all 

exposure scenarios, and while yielding the maximum application rate for exposure assessment 

(i.e. would be the most conservative). DuPont labels DPXKJM44 80XP Herbicide/EPA Reg. 

No. 352 – TOE, DPX-MAT28 240SL Turf Herbicide/EPA Reg No. 352-TOG, and DuPontTM 

DPX-MAT28 0.064G Lawn Herbicide + Fertilizer/EPA Reg No. 352-TOT satisfied this 

criterion. These application rates range from a minimum of 0.07 lbs acid equivalent/acre to a 

maximum of 0.28 lbs acid equivalent/acre. 
8.1.1.4. Results and Conclusions 

Results of the occupational handler risk assessment are summarized in Table 8.1.1. Inhalation 

Unit Exposure calculations were based on no respiratory protection. For all occupational 

exposure scenarios, MOEs were greater than 100 (MOE >100), and therefore are not of concern. 

Table 8.1.1. Summary of Occupational Short and Intermediate-Term Risk Assessment for 

Aminocyclopyrachlor (Acid and Potassium Salt) and Aminocyclopyrachlor-methyl 

Exposure Scenario Crops

Application

Rate

(lb ae/A)

Area 

Treated

(A/day)

Inhalation 

Unit 

Exposure

(μg/lb ai) 

Inhalation 

Daily Dose 

(mg/kg/day) 

Inhalation 

Short/ 

IntermediateTerm MOE

Open Mixing and 

Loading 

Groundboom 

(Dry Flowable) 

0.77 0.0002464 1,400,000 

Applying Sprays with 

Groundboom 

(Open Cab) 

(Dry Flowable) 

Non-Crop 0.28 

0.74 0.0002368 1,500,000 

Open Mixing and 

Loading 

Groundboom 

(Dry Flowable) 

0.77 0.0000616 5,700,000 

Applying Sprays with 

Groundboom 

(Open Cab) 

(Dry Flowable) 

Turf /Sod 

Farm 

80 

0.74 0.0000592 5,900,000 

Open Mixing and 

Loading 

Groundboom 

(Liquid) 

0.07 

1.2 0.000048 7,300,000 

Applying Sprays with 

Groundboom 

(Open Cab) 

(Liquid) 

Turf/Lawn 

Golf 

Course .

40 

0.74 0.0000296 12,000,000 

Open Mixing and 

Loading 

Groundboom 

(Liquid) 

1.2 0.000096 3,600,000 

Applying Sprays with 

Groundboom 

(Open Cab) 

(Liquid) 

Turf/Sod 

Farm 

0.07 

80 

0.74 0.0000592 5,900,000 

Page 39 of 76 
Table 8.1.1. Summary of Occupational Short and Intermediate-Term Risk Assessment for 

Aminocyclopyrachlor (Acid and Potassium Salt) and Aminocyclopyrachlor-methyl 

Application Inhalation Inhalation Area Inhalation 

Exposure Scenario Crops Rate

(lb ae/A) Treated

(A/day)

Unit Short/ Daily Dose Exposure Intermediate- (mg/kg/day) (μg/lb ai) Term MOE

Mixing/Loading 

LOC Handgun 

(Dry Flowable) 

Non-crop 0.28 1001 0.77 0.000308 1,100,000 

Applying 

LOC Handgun 

(Dry Flowable) 

Non-crop 0.28 5 1.4 0.000028 13,000,000 

Mixing/Loading 

LOC Handgun 

(Liquid) 

1001 1.2 0.00012 2,900,000 

Applying 

LOC Handgun 

(Liquid) 

Turf/Lawn 

Sod Farm 

Golf 

Course 

0.07 

5 1.4 0.000007 50,000,000 

Mixing/Loading 

Aerial 

(Dry Flowable) 

0.77 0.001078 320,000 

Applying Sprays 

Aerial 

(Enclosed Cockpit) 

(Dry Flowable) 

1.3 0.00182 190,000 

Aerial 

Flagging 

Non-Crop 0.28 350 

0.15 0.00021 1,700,000 

Mixing /Loading 

Push Type Spreader 

(Granular) 

1.7 0.00001 27,000,000 

Applying 

Push Type Spreader 

(Granular) 

5 

1.2 0.0000093 38,000,000 

Mixing/Loading/Applyi

ng 

Tractor Drawn 

Broadcast Spreader 

(Granular) 

Sod Farm 

Golf 

Course 

0.108 

40 7.3 0.000451 780,000 

Page 40 of 76 
Page 41 of 76 

Table 8.1.1. Summary of Occupational Short and Intermediate-Term Risk Assessment for 

Aminocyclopyrachlor (Acid and Potassium Salt) and Aminocyclopyrachlor-methyl 

Exposure Scenario Crops

Application

Rate

(lb ae/A)

Area 

Treated

(A/day)

Inhalation 

Unit 

Exposure

(μg/lb ai) 

Inhalation 

Daily Dose 

(mg/kg/day) 

Inhalation 

Short/ 

IntermediateTerm MOE

Applying 

Right of Way Sprayer 

(Dry Flowable) 

Non-Crop 0.28 5 3.9 0.000078 4,500,000 

Mixing/Loading 

Right of Way Sprayer 

(Dry Flowable) 

Non-Crop 0.28 0.77 0.0000154 23,000,000 

Applying 

Right of Way Sprayer 

(Soluble Liquid) 

Turf/Lawn 

Sod Farm 

Golf 

Course 

0.07 

5 

3.9 0.0000195 18,000,000 

ae=acid equivalent; A=acre; a.i.=active ingredient 1

100 acres represents an individual mixing and loading 20 trucks that will apply 5 acres 

8.2 Short-Term and Intermediate-Term Postapplication Risk

Postapplication exposures are expected to be short-term and intermediate term in duration. 

Long-term post-application exposures are not expected. Routes of occupational exposures are 

dermal and inhalation. Post-application inhalation exposures are expected to be negligible 

(based on the occupational handler inhalation MOE values of (190,000 – 50,000,000) and 

therefore were not assessed. Quantification of dermal exposures was not performed because no 

toxicity was observed in a subchronic dermal toxicity study at the limit dose (1000 mg/kg). 

9.0 Data Needs and Label Recommendations 

9.1 Toxicology

No additional toxicity data are required to assess the human health risks of aminocyclopyrachlor 

for the use patterns described in this risk assessment. A repeated dose study in a sensitive 

species is needed to address the hazard of chronic exposure to the environmental degradate 

cyclopropane carboxylic acid. 

9.2 Occupational and Residential Exposure

No additional data required. Label directions call for a restricted entry interval (REI) of 4 hours. 

However due to a category III in acute eye irritation, HED recommends a REI of 12 hours and 

that all label directions reflect this change. Labels for 352-TOA, 352-TIU, and 352-TOL do not 

state application rates, and so HED recommends that these labels be revised.
Page 42 of 76 

10.0 References (Memoranda) 

MRID references are listed in Appendix A (section A.4). The following Memoranda (listed in 

order of date) were cited within the main text of this risk assessment: 

Waiver request for a 90-day dermal toxicity study (870.3250) and status of the mutagenicity 

testing database for DPX-MAT28, J. Ryman, May 13, 2009, D364576, TXR 0055180. 

PRODUCT CHEMISTRY REVIEW OF: DPX MAT28 Technical Herbicide, A. Abramovitch, 

August 16, 20009, D357886. 

Drinking Water Degradates Identification Memorandum for Aminocyclopyrachlor, C. Koper , 

August 25, 2009, D368339. 

PRODUCT CHEMISTRY REVIEW OF: DPX KJM44 Technical Herbicide, A. Abramovitch , 

August 25, 2009, D357975. 

Aminocyclopyrachlor. Report of the Residues of Concern Knowledgebase Subcommittee 

(ROCKS), G. Kramer, October 15, 2009, D370638, 

Toxicity assessment of IN-V0977 (cyclopropane carboxylic acid).J. Ryman, December 31, 2009, 

D371413, TXR 0055290. 

Drinking water assessment for aminocyclopyrachlor acid and its degradate 

cyclopropanecarboxylic acid (IN-V0977) for non-crop and turf use, C. Koper, January 8, 2010, 

D368238. 

Aminocyclopyrachlor: Revised Acute and Chronic Dietary (Drinking Water Only) Exposure 

Analysis for the Section 3 Registration Action, T. Morton, January 19, 2010, D372779. 

Occupational and Residential Risk Assessment to Support the Request for Registration of 

Aminocyclopyrachlor, its methyl ester and potassium salt on Turf and Non-crop areas, J.S. 

Miller, January 30, 2010, D372493. 

Recommended waivers of conditionally required toxicology studies for non-food uses of 

aminocyclopyrachlor, J. Ryman, February 4, 2010, D373897. 
Page 43 of 76 

Appendix A: Toxicology Assessment

A.1 Toxicology Data Requirements

The requirements (40 CFR Part 158.510) for non-food pesticides are listed below: 

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-Day Dermal ..........................................................

870.3250 90-Day Dermal ..........................................................

870.3465 90-Day Inhalation......................................................

CR 

CR 

no 

yes 

CR 

yes 

Waiver recommended1

yes 

yes (waived)2

Waiver recommended1

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)................................................

CR 

CR 

CR 

CR 

Waiver recommended1 

Waiver recommended1 

Waiver recommended1 

Waiver recommended1

870.5100 Mutagenicity—Gene Mutation - bacterial.................

870.5300 Mutagenicity—Gene Mutation - mammalian............

870.5375 Mutagenicity—In Vitro Chromosomal Aberrations..

870.5385 Mutagenicity—In Vivo Bone Marrow 

Chromosomal ...............................................................................

870.5395 Mutagenicity—In Vivo Erythrocyte Micronucleus ...

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes (waived)2

yes 

870.6100a Acute Delayed Neurotox. (hen) .................................

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

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

870.6200b 90-Day Neuro. Screening Battery (rat)......................

870.6300 Develop. Neuro..........................................................

CR 

CR 

yes 

yes 

CR 

Waiver recommended1

Waiver recommended1

yes 

yes 

Waiver recommended1

870.7200 Companion animal safety ..........................................

870.7485 General Metabolism ..................................................

870.7600 Dermal penetration ....................................................

870.7800 Immunotoxicity .........................................................

CR 

CR 

CR 

yes 

Waiver recommended1

yes 

Waiver recommended1

yes` 

CR=conditionally required 

1

Rationale described in a Memorandum entitled “Recommended waivers of conditionally required toxicology 

studies for non-food uses of aminocyclopyrachlor” (J. Ryman, February 4, 2010, D373897). 

2

Rationale described in a Memorandum entitled “Waiver request for a 90-day dermal toxicity study (870.3250) and 

status of the mutagenicity testing database for DPX-MAT28” ( J. Ryman, May 13, 2009, D364576, TXR 0055180).
Page 44 of 76 

A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile for Aminocyclopyrachlor technical

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [rat] 47559934 LD50>5000 mg/kg IV 

870.1200 Acute dermal [rat] 47559935 LD50>5000 mg/kg IV 

870.1300 Acute inhalation [rat] 47560001 LD50>5.4 mg/L IV 

870.2400 Acute eye irritation [White New 

Zealand rabbit] 

47560002 Mild irritant III 

870.2500 Acute dermal irritation [rabbit] 47560003 Non-irritant IV 

870.2600 Skin sensitization [Guinea Pig] 47560004 Non-sensitizer IV 

Table A.2.2 Acute Toxicity Profile for Aminocyclopyrachlor-methyl technical

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [rat] 47560027 LD50>5000 mg/kg IV 

870.1200 Acute dermal [rat] 47560028 LD50>5000 mg/kg IV 

870.1300 Acute inhalation [rat] 47560029 LD50>5.4 mg/L IV 

870.2400 Acute eye irritation [White New 

Zealand rabbit] 

47560030 Mild irritant III 

870.2500 Acute dermal irritation [rabbit] 47560031 Non-irritant IV 

870.2600 Skin sensitization [Guinea Pig] 47560032 Non-sensitizer IV 

Table A.2.3 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for 

Aminocyclopyrachlor

Guideline No 

Study Type 

MRID 

Classification 

Doses 

Results 

870.3100 

90-Day Oral Toxicity 

Feeding-mouse 

47560010 (2008) 

47560011 (2008) 

Acceptable/guideline 

0, 300, 1000, 3000, 

7000 ppm 

0/0, 47/61, 154/230, 

459/649, and 

1088/1623 mg/kg/day 

(M/F) 

NOAEL= 7000 ppm (1088/1623 mg/kg/day M/F, limit dose) 

LOAEL = not established. 

 

870.3100 

90-Day Oral Toxicity 

Feeding-rat 

47573403 (2008) 

47560007 (2008) 

Acceptable/guideline 

0, 600, 2000, 6000, 

18000 ppm 

0/0, 34.8/44.8, 

114.3/145.7, 

349.4/448.0, 

NOAEL = 6000 ppm (349.4/448.0 mg/kg/day M/F) 

LOAEL = 18,000 ppm (1044.6/1424.9 mg/kg/day M/F), 

based on decreased body weights, body weight gains, food 

consumption, and food efficiency in both sexes. 
Page 45 of 76 

1044.6/1424.9 

mg/kg/day (M/F) 

870.3150 

90-Day Oral Toxicity 

Feeding-dog

47560012 (2008) 

47560013 (2008) 

Unacceptable/guideline 

0, 250, 1250, 5000, 

15000 ppm 

0/0, 6.5/7.0, 33/38, 

126/124, 426/388 

mg/kg /day M/F 

NOAEL = 15,000 ppm (426/388 mg/kg/day M/F) 

LOAEL = not established. 

870.3200 

28-Day Dermal 

Toxicity- rat 

47560014 (2008) 

Acceptable/guideline 

0, 150, 400, or 1000 

mg/kg/day 

NOAEL = 1000 mg/kg/day 

LOAEL = not established. 

870.3250 

90-Day Dermal 

Toxicity- rat 

47725701 (2009) Waived 

Memo D364756 (2009) 

870.3465 

90-Day Inhalation 

No study available. Waived 

Memo D373897 (2010) 

870.3700a 

Prenatal 

Developmental- rat 

47560016 (2008) 

Acceptable/guideline 

0, 30, 100, 300, or 

1000 mg/kg/day (GD 

6-20) 

Maternal NOAEL = 1000 mg/kg/day 

LOAEL = not established. 

Developmental NOAEL= 1000 mg/kg/day 

 LOAEL = not established. 

870.3700b 

Prenatal 

Developmentalrabbit 

47560015 (2008) 

Acceptable/guideline 

0, 100, 300, 500, or 

1000 mg/kg/day (GD 

7-28) 

Maternal NOAEL = 500 mg/kg/day 

LOAEL = 1000 mg/kg/day based on mortality and abortion 

and decreased body weight gains and food consumption. Developmental NOAEL = 1000 mg/kg/day 

LOAEL =not established. 

870.3800 

Reproduction and 

Fertility Effects-rat 

47575101 (2008) 

Acceptable/guideline 

0, 500, 1500, 5000, or 

17,000 ppm 

0/0, 36/41, 109/125, 

363/416, or 1285/1454 

mg/kg/day M/F 

Parental Systemic NOAEL = 5000 ppm (363/416 

mg/kg/day M/F) 

Parental Systemic LOAEL = 17000 ppm (1285/1454 

mg/kg/day) based on decreased body weights.

Reproduction NOAEL = 17000 ppm (1285/1454 

mg/kg/day M/F) 

Reproduction 

LOAEL was not established. 

Offspring NOAEL = 5000 ppm (363/416 mg/kg/day) 

Offspring LOAEL = 17,000 ppm (1285/1454 mg/kg/day 

M/F) based on decreased body weights in F1 and F2 pups. 

870.4100a 

Chronic Toxicityrodent 

No study available Waiver recommended 

Memo D373897 (2010) 

870.4100b 

Chronic Toxicitynonrodent 

No study available 

Waiver recommended 

Memo D373897 (2010) 

870.4200a Waiver recommended 
Page 46 of 76 

Oncogenicity-rat No study available Memo D373897 (2010) 

Waiver recommended 

Memo D373897 (2010)

870.4200a 

Oncogenicity-mouse No study available 

Waiver recommended 

Memo D373897 (2010) 

Gene Mutation 

870.5100 

In vitro Bacterial Gene 

Mutation 

47560019 (2007) 

Acceptable/guideline 

0, 50, 150, 500, 1500, 

or 5000 μg/plate (+/-

S9) 

There was no evidence of induced mutant colonies over 

background in the presence or absence of S9-activation. 

Gene Mutation 

870.5300 

In vitro Mammalian 

Cells Gene Mutation 

(Chinese Hamster 

Ovary Cells) 

47560020 (2007) 

Acceptable/guideline 

0, 750, 1000, 1500, 

1750, or 2150 μg/mL 

(+/-S9) 

There was no evidence of induced mutant colonies over 

background in the presence or absence of S9-activation. 

Cytogenetics 

870.5375 

In vitro Mammalian 

Cytogenetics 

Chromosomal 

Aberration Assayhuman peripheral blood 

lymphocytes 

47560021 (2007) 

Acceptable/guideline 

0, 267, 534, 1068, or 

2136 μg/mL (+/-S9) 

There was no evidence of chromosome aberrations induced 

over background in the presence or absence of S9-activation. 

Cytogenetics 

870.5385 

Mammalian Bone 

Marrow Chromosome 

Aberration Test 

No study available Waived 

Memo D364576 (2009) 

Cytogenetics-other 

870.5395 In Vivo

Mammalian 

Cytogenetics - 

Erythrocyte 

Micronucleus-mouse 

47560022 (2007) 

0, 500, 1000, or 2000 

mg/kg (limit dose) 

No significant increase in the frequency of micronucleated 

polychromatic erythrocytes in bone marrow after any 

treatment time. 

870.6100a Acute 

Delayed Neurotox-hen No study available 

Waiver recommended 

Memo D373897 (2010) 

870.6100b 90-Day 

Neurotox.-hen No study available 

Waiver recommended 

Memo D373897 (2010) 

870.6200a 

Acute Neurotoxicity-rat 

47725702 (2009) 

Acceptable/guideline 

0, 200, 1000, 2000 

mg/kg (limit dose) 

(0.5%carboxymethylcellulose 

vehicle) 

NOAEL = 2000 mg/kg (limit dose) 

No acute neurotoxicity. 

870.6200b 

Subchronic 

Neurotoxicity-rat 

47573403 (2008) 

47560007 (2008) 

Acceptable/guideline 

0, 600, 2000, 6000, 

18000 ppm 

0/0, 34.8/44.8, 

114.3/145.7, 

349.4/448.0, 

NOAEL = 18,000 ppm (limit dose) (1044.6/1424.9 

mg/kg/day M/F) 

No subchronic neurotoxicity. 
Page 47 of 76 

1044.6/1424.9 

mg/kg/day (M/F) 

870.7485 

Metabolism and 

Pharmacokinetics-rat 

47560023 (2007) 

Acceptable/guideline 

25 or 500 mg/kg bw 

(single oral dose) 

Peak plasma and RBC concentrations at 0.3-1.0 h. AUC 

scaled with dose. Whole blood radiolabel distribution: 

plasma (60%), RBCs (40%) in RBCs. Plasma elimination 

half-life was 5.6-5.7 h. Majority eliminated within 24 h as 

unmetabolized parent: 35.8-53.71% (urine) 31.4-48.0% 

(feces). No sex differences. 

870.7600 

Dermal penetration No study available 

Waiver recommended 

Memo D373897 (2010)

870.7800 

Immunotoxicity-rat 

47560025 (2008)\ 

Acceptable/guideline 

0, 600, 6000, 18000 

ppm (male rats) 

0, 42, 407, 1277 

mg/kg/day (male rats) 

Systemic NOAEL= 18,000 ppm (1277 mg/kg/day) 

Systemic LOAEL= not established 

Immunotoxicity NOAEL= 18,000 ppm (1277 mg/kg/day) 

Immunotoxicity LOAEL= not established 

870.7800 

Immunotoxicity-mouse 

47560026 (2008) 

Acceptable/guideline 

0, 300, 3000, 7000 

ppm (male mice) 

0, 45, 425, and 1056 

mg/kg/day (male mice 

Systemic NOAEL= 7,000 ppm (1056 mg/kg/day) 

Systemic LOAEL= not established 

Immunotoxicity NOAEL= 7,000 ppm (1056 mg/kg/day) 

Immunotoxicity LOAEL= not established 

Table A.2.4 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for 

Aminocyclopyrachlor-methyl

Guideline No 

Study Type 

MRID 

Classification 

Doses 

Results 

Non-guideline, OECD 

415 –Extended One Gen. 

Repro.-rat 

47560018 (2006) 

Acceptable/nonguideline 

0, 600, 5000, 17000 

ppm 

0/0, 49/53, 385/435, 

1378/1489 

mg/kg/day M/F (28 

d premating to PND 

60 of F1). 

Parental Systemic NOAEL = 5000 ppm (398/435 mg/kg/day 

M/F) 

Parental Systemic LOAEL = 17,000 ppm (1378/1489 

mg/kg/day) based on decreased food consumption and 

efficiency in the P generation and on decreased body weights 

and food consumption in the F1 generation. . 

No reproductive toxicity (NOAEL=17,000 ppm (1378/1489 

mg/kg/day). 

Offspring NOAEL = 5000 ppm (398/435 mg/kg/day M/F) 

Offspring LOAEL = 17,000 ppm (1378/1489 mg/kg/day 

M/F) based on dehydration, decreased pup body weight gains, 

and decreased body weights late in lactation. 

870.3100 

90-Day Oral Toxicity 

Feeding-rat 

47560008 (2008) 

47560009 (2008) 

Acceptable/guideline 

0, 600, 2000, 6000, 

18000 ppm 

0/0, 35/43, 117/133, 

347/405, 1022/1219 

mg/kg/day (M/F) 

NOAEL = 6000 ppm (347/405 mg/kg/day M/F) 

LOAEL = 18,000 ppm (1022/1219 mg/kg/day M/F) based on 

decreased body weights, body weight gains, food 

consumption, and food efficiency in both sexes. 

Gene Mutation 

870.5100 

In vitro Bacterial Gene 

47560033 (2005) 

Acceptable/Nonguideline 

There was no evidence of induced mutant colonies over 

background in the presence or absence of S9-activation. 
Page 48 of 76 

Mutation 0, 100, 333, 1000, 

3333, or 5000 

μg/plate (+/-S9) 

870.6300 

Developmental 

Neurotoxicity-rat 

No study available 

Waiver recommended 

Memo D373897 (2010) 

870.7200 

Companion animal 

safety 

No study available 

Waiver recommended 

Memo D373897 (2010) 

870.7485 

Metabolism and 

Pharmacokinetics-rat 

47560024 (2007) 

Acceptable/guideline 

25 or 500 mg/kg bw 

(single oral dose) 

Peak plasma and RBC concentrations at 0.3-0.6 h. AUC 

scaled with dose. Whole blood radiolabel distribution: 

plasma (60%), RBCs (40%) in RBCs. Plasma elimination 

half-life was 8.7-13.3 h. Majority eliminated within 24 h as 

DPX-MAT28: 78.80-78.82% (urine), minor in feces (1.72-

4.57%). No sex differences. 

A.3 Executive Summaries

A.3.1 Subchronic Toxicity

 870.3100 90-Day Oral Toxicity - Rat

EXECUTIVE SUMMARY: In a subchronic oral and neurotoxicity study (MRID 47573403 

and 47560007), aminocyclopyrachlor (DPX-MAT28; 92.2% a.i.; Batch No. DPX-MAT28-

009) was administered in the diet to Crl:CD(SD) rats (15/sex/dose) at doses (adjusted for 

purity) of 0, 600, 2000, 6000, or 18,000 ppm (equivalent to 34.8/44.8, 114.3/145.7, 

349.4/448.0, and 1044.6/1424.9 mg/kg/day) for 13 weeks (94-95 days in males and 96-97 

days in females). Neurobehavioral assessment (functional observational battery [FOB] and 

motor activity testing) was performed prior to treatment and during Weeks 4, 8, and 13 on 10 

rats/sex/group. On Day 56, plasma concentrations of DPX-MAT28 and the environmental 

degradateIN-LXT69 were measured in 5 rats/sex/dose. At study termination, gross and 

histopathology were performed on 10 rats/sex/group, while 5 rats/sex/group were 

anesthetized and perfused in situ for neuropathological examination. The tissues from the 

perfused animals in the control and 18,000 ppm groups were subjected to histopathological 

evaluation of brain, spinal cord, and peripheral nervous system tissues. 

All animals survived to the day of scheduled sacrifice. One control male and one 6000 ppm 

female were accidentally killed during blood collection just prior to necropsy. 

No treatment-related effects were observed in daily or weekly clinical observations and there 

were no test substance-related opthamological signs for either sex. There were no test 

substance-related or statistically significant effects on functional observational battery (FOB) 

parameters: forelimb and hindlimb grip strength, footsplay, body temperature, or behavioral 

parameters in either sex. Additionally, there were no test substance-related or statistically 

significant effects on duration of movement or number of movements measured in the motor 

activity analysis of males and females. 

At 18,000 ppm, decreases (p≤0.05; except as noted) in body weights were observed in the 

males from Days 28-91 (↓6-9%, NS at Days 56 and 70) and in the females on Days 56, 70, 

and 77 (↓8-10%). Overall (Days 0-91) body weight gain was decreased (p≤0.05) by 15-18% 
Page 49 of 76 

in both sexes. Significant decreases (p≤0.05) in food consumption were observed at 18,000 

ppm during Days 0-7, 21-28, and 42-49 in males (↓7-8%) and during Days 70-77 in females 

(↓11%). Decreased (p≤0.05) food efficiency was noted in males during Days 21-28, 70-77, 

and 77-84 (↓18-73%) and in females during Days 62-70 (↓112%). Overall (Days 0-91) food 

efficiency was decreased (p≤0.05) by 11% in males and 17% in females. 

There were no adverse effects of the test substance on organ weights, ophthalmology, 

hematology, coagulation, clinical chemistry, or urinalysis parameters in males and females. 

There were no effects of the test substance on brain weights or gross or microscopic 

neuropathology in either sex at any dose. 

The plasma concentrations of DPX-MAT28 and the metabolite IN-LXT69 were measured on 

Day 56 by high performance liquid chromatography with detection by tandem mass 

spectrometry (LC/MS/MS, MRID 47560007). DPX-MAT28 was the most abundant 

metabolite in male and female rats, with the highest concentrations at 10, 268 and 13, 428 

ng/mL for 18,000 ppm male and female rats, respectively. In contrast, plasma levels of INLXT68 were lower for this dose group at concentrations of 82 and 80 ng/mL for males and 

females, respectively. The average concentration of DPX-MAT28 in plasma was higher in 

females than in males at all dose levels. The IN-LXT69 plasma concentrations were below 

the limit of quantitation for the 600 ppm dietary concentration. The average IN-LXT69 

plasma concentrations appeared to be similar for males and females. There was no apparent 

plateau for the DPX-MAT28 of IN-LXT68 plasma concentrations when compared to dietary 

intake levels (e.g. plasma concentrations increased with increasing concentration in the diet). 

The LOAEL for systemic effects is 18,000 ppm (1044.6/1424.9 mg/kg/day), based on 

decreased body weights, body weight gains, food consumption, and food efficiency in 

both sexes. The NOAEL is 6000 ppm (349.4/448.0 mg/kg/day). 

The LOAEL for neurotoxicity was not observed. The NOAEL is 18,000 ppm 

(1044.6/1424.9 mg/kg/day) in both sexes. 

The study is classified as Acceptable/Guideline and satisfies the guideline requirements for 

a 90-day oral toxicity study (OPPTS 870.3100; OECD 408) and a subchronic neurotoxicity 

study (OPPTS 870.6200b; OECD 424) in rats. 

. 

COMPLIANCE: Signed and dated Data Confidentiality, GLP Compliance, Flagging, and 

Quality Assurance statements were provided. 

EXECUTIVE SUMMARY: In a subchronic oral toxicity study (MRIDs 47560008 and 

47560009), Aminocyclopyrachlor-methyl (95% a.i.; Lot #068) was administered to 10 

Sprague-Dawley rats/sex/dose group in the diet at dose levels of 0, 600, 2000, 6000, or 

18,000 ppm (equivalent to 0/0, 35/43, 117/133, 347/405, and 1022/1219 mg/kg/day in 

males/females) for approximately 90 days (94 or 95 days in males and 95 or 96 days in 

females). On Days 60 and 87, blood was collected from the orbital sinus or tail vein of 5 

rats/sex/dose group for the determination of plasma concentration of the test substance 

(methyl aminocyclopyrachlor) and the metabolites DPX-MAT28 (aminocyclopyrachlor) and 

IN-LXT69. 
Page 50 of 76 

All animals survived to scheduled sacrifice. There were no treatment-related clinical signs or 

effects on ophthalmology. Functional Observational Battery (FOB) parameters were 

measured in a different study (MIRD 47560018). At 18,000 ppm, body weight decreased 

with time and was decreased (↓8% ) in males and females by Day 91, although this decrease 

was not statistically significant. Statistically significant (p<0.05) decreases in body weight 

were observed in females at earlier time points (Day 42 and Day 84). Body weight gain also 

decreased with time, and was significantly decreased over the treatment period (Day 0-91) in 

males (↓14%) and females (↓24%). Food consumption also tended to decrease with time and 

was significantly decreased in males (↓9%) and females (↓11%) over the treatment period 

(Day 0-Day 91). Food efficiency was significantly decreased in females (↓31%) from Days 

0-7. Food efficiency over the treatment period (Days 0-91) was decreased in males (↓5%) 

and females (↓15%), but these decreases were not statistically significant. 

There were no adverse effects of treatment on hematology, clinical chemistry, or urinalysis 

parameters. 

There were decreases in organ weights that were not considered adverse due to lack of 

corroborating gross and histopathological changes. Absolute and relative (to brain weight) 

liver weights were decreased in the 18,000 ppm males (↓13%) and absolute, relative (to 

brain weight), and relative (to body weight) heart weights in the 6000 and 18,000 ppm 

females were decreased (↓8-16%). 

The parent compound DPX-KJM44 (aminocyclopyrachlor methyl) was not detected in any 

of the plasma samples. DPX-MAT28 was the predominant plasma metabolite. This 

metabolite was dose-dependently increased in all treated groups, with plasma concentrations 

of 254, 1489, 6444, and 20,660 ng/mL in the males and 376, 2202, 5316, and 29,784 ng/mL 

in the females fed the 600, 2000, 6000, and 18,000 ppm diets respectively. Plasma 

concentrations of the metabolite IN-LXT69 were considerably lower than DPX-MAT28, but 

were also dose-dependently increased in all treated groups, with plasma concentrations of 12, 

45, 136, and 439 ng/mL in the males and 15, 45, 125, and 415 ng/mL in the females fed the 

600, 2000, 6000, and 18,000 ppm diets respectively. All of the control plasma samples were 

below the limit of quantitation (LOQ) for DPX-KJM44 and IN-LXT69. Plasma 

concentrations for DPX-MAT28 were below the LOQ in all of the control samples for the 

males and in two of the samples from the females; however, 3 of the 5 female plasma 

samples had DPX-MAT28 at concentrations 2 to 4 times the LOQ. 

The LOAEL is 18,000 ppm (equivalent to 1022/1219 mg/kg/day in males/females) based 

on decreased body weights, body weight gains, food consumption, and food efficiency in 

both sexes. The NOAEL is 6000 ppm (equivalent to 347/405 mg/kg/day in 

males/females). 

This study is classified as Acceptable/Guideline and satisfies the guideline requirements 

(OPPTS 870.3100a; OECD 408) for a subchronic oral toxicity study in rats. 

COMPLIANCE: Signed and dated Data Confidentiality, GLP Compliance, Flagging, and 

Quality Assurance statements were provided.
Page 51 of 76 

870.3150 90-Day Oral Toxicity – Dog 

EXECUTIVE SUMMARY: In this subchronic oral toxicity study (MRID 47560012), 4 beagle 

dogs/sex/group were administered aminocyclopyrachlor (DPX-MAT28; 92.2% a.i.; Batch No. 

DPX-MAT28-009) daily via the diet (400 g offered daily for approximately 2 hours) at doses of 

0, 250, 1250, 5000, or 15,000 ppm (equivalent to 0/0, 6.5/7.0, 33/38, 126/124, and 426/388 

mg/kg/day in males/females) for 13 weeks. 

No treatment related effect was observed on mortality, clinical signs, neurological evaluations, 

body weight, body weight gains, food consumption, food efficiency, hematology, clinical 

chemistry, urinalysis, organ weights, or gross or microscopic pathology. 

A dose-related increase in the incidence of skin scaling on the feet was observed in males, with 

4/4 males affected at 15,000 ppm. Half of the females were affected at the high dose. In most 

cases, all 4 feet exhibited scaling. The time of onset of scaling in most cases was 41-56 days, 

continuing to study termination (Day 91). The clinical severity of this effect was not noted and 

the foot pads were not biopsied. This effect was not considered adverse, because no impairment 

in walking or weight bearing and no grooming (e.g. licking/biting) of the feet was observed. 

The plasma concentrations of parent increased with dietary intake ranging from 1968-63,000 

ng/mL in males and 3193-82,575 ng/mL in females at doses of 250-15,000 ppm. Plasma 

concentrations were always higher in the females than in the males. The metabolite IN-LXT69 

was below the limit of quantitation except at 15,000 ppm, where only minor amounts (11.6-11.7 

ng/mL) were noted (MRID 47560013). 

Total cytochrome P450 measured was unrelated to dose in both sexes and was 0.320-0.409 

nmol/mg in males and 0.378-0.421 nmol/mg in females. At 5000 and 15,000 ppm, induction of 

the isozymes 1A1 in males (↑402-420%) and 2B1/2 in males (↑91-125%) and females (↑34-

93%) was observed (p≤ 0.05 at 5000 ppm only). A decreased level of 2E1 was noted in the 

15,000 ppm males (↓37%). Although the effect on 2E1 seemed dose-dependent, the noted 

decrease was not statistically significant and a similar effect was not noted in females. It is 

unclear if there is an inhibitory effect on 2E1. 

The LOAEL was not observed. The NOAEL is 15,000 ppm (equivalent to 426/388 mg/kg/day 

in males/females). 

This study is classified Unacceptable/Guideline and does not satisfy the guideline requirements 

(OPPTS 870.3150; OECD 409) for a subchronic oral toxicity study in dogs. An adverse effect 

was not noted and the limit dose was not tested. This study is upgradable pending submission 

of a satisfactory dose-selection rationale. 

COMPLIANCE: Signed and dated Data Confidentiality, GLP Compliance, Flagging, and 

Quality Assurance statements were provided.
Page 52 of 76 

870.3200 21/28-Day Dermal Toxicity – Rat 

EXECUTIVE SUMMARY: In a 28-day dermal toxicity study (MRID 47560014), DPXMAT28 (Aminocyclopyrachlor; 90.9% a.i., Batch # DPX-MAT28-010) was applied to the 

shaved intact skin of 10 Sprague-Dawley rats/sex/dose at dose levels (adjusted for purity) of 0, 

150, 400, or 1000 mg/kg/day (limit dose) for 6 hours/day for 28 consecutive days. 

There were no unscheduled deaths. There were no effects of the test substance on 

ophthalmology parameters. The only clinical sign observed was limited and very slight (barely 

perceptible) erythema/edema (score of 1 on a scale of 4, 4 being severe) in three males. Animals 

affected were one male at 400 mg/kg/day on Day 28, one male at 1000 mg/kg/day on Day 3, and 

one male at 1000 mg/kg/day on Day 28. There were no adverse effects of the test substance on 

body weight, body weight gain, food consumption, food efficiency, clinical chemistry, 

hematology, gross pathology, or histopathology. 

There were statistically significant, dose-related changes in adrenal gland and ovary weights in 

1000 mg/kg/day females and a decrease in kidney weights in females at 150 mg/kg/day that were 

not considered adverse due to a lack of corroborating microscopic lesions. 

The LOAEL was not observed. The NOAEL is 1000 mg/kg/day (limit dose).

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a 

28-day dermal toxicity study (OPPTS 870.3200; OECD 410) in rats. 

COMPLIANCE: Signed and dated Data Confidentiality, GLP Compliance, and Quality 

Assurance statements were provided. 

 870.3250 90-Day Dermal Toxicity – Rat 

No study was submitted. This study was waived in a Memorandum entitled “Waiver request for 

a 90-day dermal toxicity study (870.3250) and status of the mutagenicity testing database for 

DPX-MAT28”, J. Ryman, May 13, 2009, D364576. 

 870.3465 90-Day Inhalation – Rat

No study was submitted. This study was recommended for a waiver in a Memorandum entitled 

“Recommended waivers of conditionally required toxicology studies for non-food uses of 

aminocyclopyrachlor” ( J. Ryman, February 4, 2010, D373897) because significant inhalation 

exposure is not anticipated for the proposed use patterns due to low volatility, outdoor uses, 

application methods that are not anticipated to generate respirable aerosols, and high margins of 

exposure.
Page 53 of 76 

A.3.2 Prenatal Developmental Toxicity

 870.3700a Prenatal Developmental Toxicity Study – Rat 

EXECUTIVE SUMMARY: In a developmental toxicity study (MRID 47560016), 

Aminocyclopyrachlor (92.2%; Batch #DPX-MAT28-9-009) in 0.5% methylcellulose was 

administered via daily oral gavage in a dose volume of 5 mL/kg to 25 time-mated presumed 

pregnant Sprague-Dawley rats/dose group at doses of 0, 30, 100, 300, or 1000 mg/kg/day from 

gestation days (GD) 6-20. On GD 21, all maternal rats were euthanized; each dam’s uterus was 

removed via cesarean section and its contents examined. The fetuses were examined for 

external, visceral, and skeletal malformations and variations. 

All maternal animals survived until scheduled termination. No clinical signs of toxicity were 

noted in any of the dams. Body weights, body weight gains, and food consumption in the treated 

groups were comparable to controls throughout the study. The only gross abnormality was liver 

discoloration in a single dam at 100 mg/kg/day, and this finding was considered incidental 

because it was minimal in incidence and not observed at the high dose. 

The maternal LOAEL was not observed. The maternal NOAEL is 1000 mg/kg/day (limit 

dose). 

There were no abortions, premature deliveries, late resorptions, complete litter resorptions, or 

dead fetuses. There were no effects of treatment on the numbers of litters, live fetuses, or early 

resorptions. Furthermore, sex ratio and post-implantation losses in the treated groups were 

comparable to controls. 

There was no evidence of altered growth or development. Fetal body weights in the treated 

groups were comparable to controls. 

There were no treatment-related external, visceral, or skeletal variations or malformations. 

Skeletal variations in the skull, vertebrae, ribs, and sternebrae were unrelated to dose. One 

skeletal malformation (fused cervical vertebrae) was found at 300 mg/kg/day. The only other 

malformations were: anophthalmia and eye bulge in one 300 mg/kg/day fetus and protruding 

tongue in another 300 mg/kg/day fetus. These findings were considered incidental because they 

only occurred in individual fetuses and were not observed at the high dose. 

The developmental LOAEL was not observed. The developmental NOAEL is 1000 

mg/kg/day (limit dose). 

This study is classified as Acceptable/Guideline and satisfies the guideline requirement (OPPTS 

870.3700a; OECD 414) for a developmental toxicity study in rats. 

COMPLIANCE: Signed and dated Data Confidentiality, GLP Compliance, Flagging, and 

Quality Assurance statements were provided.
Page 54 of 76 

 870.3700b Prenatal Developmental Toxicity Study - Rabbit

EXECUTIVE SUMMARY: In a developmental toxicity study (MRID 47560015), 

Aminocyclopyrachlor (92.2% a.i.; Lot #MAT28-009) in 0.5% methylcellulose was administered 

daily via oral gavage in a dose volume of 4 mL/kg to 22 time-mated presumed pregnant New 

Zealand White rabbits/dose group at doses of 0, 100, 300, 500, or 1000 mg/kg/day from 

gestation days (GD) 7-28. On GD 29, all maternal rabbits were euthanized; each dam’s uterus 

was removed via cesarean section and its contents examined. The fetuses were examined for 

external, visceral, and skeletal malformations and variations. 

There was one maternal death at 1000 mg/kg/day on GD 13 that was considered treatmentrelated. Increased respiration was observed 1 hour after dosing on GD 7 in this animal, and rales 

and decreased defecation were noted during GD 9-13. This female had a body weight loss of 

394 g from GD 7-13 and consumed ≤14 g food/day for 4-5 days prior to death. Also at 1000 

mg/kg/day, two animals aborted (one on GD 20 and the other on GD 26). Clinical findings 

noted for both females included decreased defecation several days prior to abortion and red 

material in the cage pan or angiogenital area on the day of abortion. These abortions may be 

secondary to body weight loss >10%. These females exhibited body weight losses of 636-643 g 

(17-19%) from GD 7 through the day of abortion. These maternal effects corresponded with 

reduced food consumption, generally ≤17 g/day from GD 13 or 17 through the day of abortion. 

There was one death at 1000 mg/kg/day unrelated to treatment that was attributed to a gavage 

error and another death at 100 mg/kg/day of unknown cause. One 300 mg/kg/day animal aborted 

on GD 28. Clinical findings noted for this female prior to abortion included 11 occurrences of 

decreased defecation and 3 occurrences of soft stool. This female consumed ≤18 g of food per 

day between GD 18-19 and 27-28, but had no notable effects on body weight gain. This abortion 

at 300 mg/kg/day was not considered an effect of treatment because it was not dose-related (no 

abortions at 500 mg/kg/day). Aside from the above-mentioned clinical signs associated with 

mortality and abortion, no treatment-related clinical signs were observed. The only treatmentrelated gross findings at necropsy were in animals that died or aborted. These findings included 

red skin matting around the urogenital or nasal areas, dark red contents in the vagina, and white 

precipitate in the abdominal soft tissue. 

Reductions in food consumption were statistically significant only in the 1000 mg/kg/day group. 

These reductions were consistently about 30% after GD 14-15 through the end of the study. 

Decreases in body weight gain were statistically significant only at GD 14-17, although the 

decreases throughout the remainder of the study are probably of biological significance. This 

consistent relationship between decreased food consumption and decreased body weight gain 

were not observed in the 500 mg/kg/day group. In this group, no significant differences in body 

weight gain were observed and there were no significant decreases in food consumption. 

The maternal LOAEL is 1000 mg/kg/day (limit dose) based on mortality, decreased body 

weight gains and food consumption, and abortion. The maternal NOAEL is 500 

mg/kg/day. 

At 1000 mg/kg/day, there were two animals that were not pregnant, two that died, and two that 

aborted, resulting in a lower number of litters at this dose (16) compared to controls (21). When 
Page 55 of 76 

examined on a per litter basis, there were no effects of treatment on the mean numbers live 

fetuses, early resorptions, or late resorptions. Furthermore, fetal body weights, sex ratio, and 

post-implantation losses in the treated groups were comparable to controls. 

There were no treatment-related external, visceral, or skeletal malformations or variations. 

The developmental LOAEL was not observed. The developmental NOAEL is 1000 

mg/kg/day (limit dose). 

This study is classified Acceptable/Guideline and satisfies the guideline requirement (OPPTS 

870.3700b; OECD 414) for a developmental toxicity study in rabbits.

COMPLIANCE: Signed and dated Data Confidentiality, GLP Compliance, Flagging, and 

Quality Assurance statements were provided. 

A.3.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects – Rat 

EXECUTIVE SUMMARY: In a two-generation reproduction toxicity study (MRID 

47575101), DPX-MAT28 (Aminocyclopyrachlor; 90.9-92.2% a.i.; Batch Nos. DPX-MAT28-

009 and DPX-MAT28-010) was administered in the diet to 28 Sprague Dawley (Crl:CD[SD]) 

rats/sex/dose group at dietary levels of 0, 500, 1500, 5000, or 17,000 ppm (equivalent to 0/0, 

36/41, 109/125, 363/416, and 1285/1454 mg/kg bw/day in males/females during pre-mating) for 

two successive generations with one litter per generation. The P (parental) generation animals 

were fed the test diets for at least ten weeks prior to mating to produce the F1 litters. The F1 

litters were culled on post-natal day (PND) 4 to eight pups/litter (four/sex where possible). On 

PND 21, one pup/sex/litter (where possible) was selected and fed the same test diet concentration 

as the dam. These animals were fed the test diets for at least ten weeks prior to mating (at 13 

weeks of age) to produce the F2 litters. 

No treatment-related effects were observed on mortality, clinical signs, or macroscopic or 

microscopic findings. 

Over the pre-mating period in P and F1 males, body weights were significantly (p≤0.05) 

decreased (↓6-15%) at 5000 ppm and above, as were body weight gains (↓7-17%). Food 

efficiency was decreased (↓8-15%) at 1500 ppm and above. For P and F1 females over this 

period, body weights were decreased (↓6-14%) at 17,000 ppm. Food efficiency and body weight 

gain were decreased for P females only at 17,000 ppm (↓12-16%). 

Over the period of gestation in P and F1 females, body weight and body weight gain was 

significantly decreased for P females only at 17,000 ppm (↓8-12%). Food consumption and food 

efficiency were also decreased for these animals (↓10% and ↓20%, respectively). There were no 

significant effects of the test substance on these parameters in F1 females. Over the lactation 

period, body weights were transiently but significantly decreased (↓7-9%) in P females at 17,000 

ppm on LD 0-7. Decreases in body weights of F1 females were not statistically significant. 
Page 56 of 76 

Terminal body weights were significantly (p≤0.05) decreased at 17,000 ppm for P males and 

females (↓6-7%) F1 males (↓16%). At 5,000 ppm, terminal body weight was decreased (↓9%) 

for F1 males only. There were significant decreases (↓4-5%) in absolute (but not relative) brain 

weights for P and F1 females at 17,000 ppm. At 5,000 ppm, decreases in absolute brain weights 

were observed for P females only (↓4%). There were no correlating microscopic findings. 

The LOAEL for parental toxicity is 17, 000 ppm (equivalent to 1285/1454 mg/kg in 

males/females), based on decreased body weights in parental males and females. The 

NOAEL is 5000 ppm (equivalent to 363/416 mg/kg in males/females).

No treatment-related effects on litter parameters were noted for the F1 or F2 generations. 

Specifically, there were no treatment-related effects on survival indices, clinical signs, sex ratio, 

attainment of developmental landmarks, or gross or microscopic pathology. 

At 17,000 ppm, body weights were significantly (p≤0.05) decreased at PND 21 in the F1 (↓15%) 

and F2 pups (↓8%). Body weights in the F1 pups were consistently decreased at PND 0, 4, 7, 

14, and 21 at this dose, whereas body weights were decreased in F2 pups only at PND 21. There 

were no statistically significant decreases in body weight gain. In weanlings, terminal body 

weights were significantly decreased in both generations for both sexes (F1 males, F1 females, 

F2 males, F2 females) at 17,000 ppm (↓9-14%). 

The LOAEL for offspring toxicity is 17,000 ppm (equivalent to 1285/1454 mg/kg in 

males/females), based on decreased body weights in the F1 and F2 pups. The NOAEL is 

5000 ppm (equivalent to 363/416 mg/kg in males/females). 

No treatment-related differences were observed in estrus cycle length or cyclicity, sperm 

parameters, numbers of primordial and pre-antral follicles, mating, fertility, pre-coital interval 

length, gestation length, number of implantation sites, or post-implantation loss, or reproductive 

failures. Thus reproductive performance of P and F1 animals was not affected by treatment. 

The LOAEL for reproductive toxicity was not observed. The NOAEL is 17,000 ppm 

(equivalent to 1285/1454 mg/kg in males/females).

This study is classified as Acceptable/Guideline and satisfies the guideline requirements 

(OPPTS 870.3800; OECD 416) for a two-generation reproduction study in the rat. 

COMPLIANCE: Signed and dated Data Confidentiality, GLP Compliance, Flagging, and 

Quality Assurance statements were provided. 

A.3.4 Chronic Toxicity

 870.4100a (870.4300) Chronic Toxicity – Rodent

No study was submitted. This study was recommended for a waiver in a Memorandum entitled 

“Waivers of conditionally required toxicology studies for non-food uses of 

aminocyclopyrachlor” ( J. Ryman, February 4, 2010, D373897). 
Page 57 of 76 

 870.4100b Chronic Toxicity -Nonrodent

No study was submitted. This study was recommended for a waiver in a Memorandum entitled 

“Waivers of conditionally required toxicology studies for non-food uses of 

aminocyclopyrachlor” ( J. Ryman, February 4, 2010, D373897). 

A.3.5 Carcinogenicity

 870.4200a Oncogenicity - rat

No study was submitted. This study was recommended for a waiver in a Memorandum entitled 

“Waivers of conditionally required toxicology studies for non-food uses of 

aminocyclopyrachlor” ( J. Ryman, February 4, 2010, D373897) because the proposed use 

patterns have low potential for chronic and significant exposure. Also, no evidence of genotoxic 

effects were observed in mutagenicity studies in vitro, and no pathological effects were observed 

in oral subchronic studies. 

 870.4200b Oncogenicity - Mouse

No study was submitted. This study was recommended for a waiver in a Memorandum entitled 

“Waivers of conditionally required toxicology studies for non-food uses of 

aminocyclopyrachlor” ( J. Ryman, February 4, 2010, D373897). 

A.3.6 Mutagenicity

870.5100 Bacterial Reverse Mutation 

EXECUTIVE SUMMARY: In two independent trials of a reverse gene mutation assay in 

bacteria (MRID 47560019), Salmonella typhimurium strains TA98, TA100, TA1535, and 

TA1537 and Escherichia coli strain WP2uvrA were exposed to DPX-MAT28 (Aminocyclopyrachlor, 92.2% a.i., Batch No.: DPX-MAT28-009) in DMSO at concentrations of 0, 1.5, 

5.0, 15, 50, 150, 500, 1500, or 5000 μg/plate (+/-S9, Trial 1) and 0, 50, 150, 500, 1500, or 5000 

μg/plate (+/-S9, Trial 2) using the standard plate incorporation method. The S9 fraction was 

derived from the livers of male Sprague-Dawley rats induced with Aroclor® 1254. Standard 

strain-specific mutagens served as positive controls. 

DPX-MAT28 was tested up to the limit dose (5000 μg/plate). No evidence of cytotoxicity was 

observed at any concentration in any strain in either trial in the presence or absence of S9-

activation. There were no marked increases in the mean number of revertants/plate in any strain. 

The positive controls induced the appropriate response in all strains in the presence and absence 

of S9-activation. There was no evidence of induced mutant colonies over background.

The study is classified as Acceptable/Guideline and satisfies the guideline requirements 

(OPPTS 870.5100; OECD 471) for in vitro mutagenicity (bacterial reverse gene mutation) data. 

COMPLIANCE: Signed and dated Data Confidentiality, GLP Compliance, and Quality 

Assurance statements were provided. 
Page 58 of 76 

EXECUTIVE SUMMARY: In a reverse gene mutation assay in bacteria (MRID 47560033), 

Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 and Escherichia coli strain 

WP2 uvrA were exposed to IN-KJM44 (aminocyclopyrachlor-methyl, 95.3% a.i., Batch No.: 

032) in DMSO at concentrations of 0, 100, 333, 1000, 3333, or 5000 μg/plate (+/-S9) using the 

standard plate incorporation method. The S9 fraction was derived from the livers of male 

Sprague-Dawley rats induced with Aroclor® 1254. Standard strain-specific mutagens served as 

positive controls. 

IN-KJM44 was tested up to the limit dose (5000 μg/plate). No evidence of cytotoxicity was 

observed at any concentration in any strain in either trial in the presence or absence of S9-

activation. There were no marked increases in the mean number of revertants/plate in any strain. 

The positive controls induced the appropriate response in all strains in the presence and absence 

of S9-activation. There was no evidence of induced mutant colonies over background.

The study is classified as Acceptable/Non-guideline and does not satisfy the guideline 

requirements (OPPTS 870.5100; OECD 471) for in vitro mutagenicity (bacterial reverse gene 

mutation) data. The study is upgradable to Acceptable, Guideline following receipt of GLP 

compliance and Quality Assurance statements. 

COMPLIANCE: A signed and dated Data Confidentiality statement was provided. The study 

was conducted in a GLP-compliant lab following SOPs but was not proven to be GLP compliant. 

A Quality Assurance statement was not provided. 

870.5300 In Vitro Mammalian Cell Mutation 

EXECUTIVE SUMMARY: In a mammalian cell gene mutation assay at the HGPRT locus 

(MRID 47560020), duplicate cultures of Chinese hamster ovary (CHO) cells cultured in vitro

were exposed to DPX-MAT28 (Aminocyclopyrachlor, 92.2% a.i., doses adjusted for purity, 

Batch No: DPX-MAT28-009) in DMSO at concentrations of 0, 750, 1000, 1500, 1750, or 2150 

μg/mL in the presence and absence of S9-activation for 5 hours. 

DPX-MAT28 was tested up to 2150 μg/mL, which was the solubility limit (4000 μg/mL +/-S9 

was precipitating). No precipitation of the test material or evidence of cytotoxicity were 

observed at any concentration in the presence or absence of S9. No marked increase in mutant 

frequency was observed at any concentration in the presence or absence of S9-activation. The 

positive controls induced the appropriate response in the presence and absence of S9. There was 

no evidence of induced mutant colonies over background in the presence or absence of S9-

activation.

This study is classified as Acceptable/Guideline and satisfies the guideline requirement (OPPTS 

870.5300, OECD 476) for in vitro mutagenicity (mammalian forward gene mutation) data. 

COMPLIANCE: Signed and dated Data Confidentiality, GLP Compliance, and Quality 

Assurance statements were provided. 

870.5375 In Vitro Mammalian Chromosomal Aberration 
Page 59 of 76 

EXECUTIVE SUMMARY: In a mammalian cell cytogenetics assay (chromosome aberration; 

MRID 47560021), lymphocyte cultures were prepared from human peripheral blood and exposed 

to DPX-MAT28 (92.2% a.i., doses adjusted for purity, Batch # DPX-MAT28-009) in DMSO at 

concentrations of 0, 267, 534, 1068, or 2136 μg/mL for either 4 hours followed by a 16 hour 

recovery period (+/-S9) or for 20 hours with no recovery period (-S9). The S9 fraction was 

derived from the livers of male rats induced with Aroclor 1254. Cyclophosphamide and 

mitomycin C served as the positive controls in the presence and absence of S9, respectively. 

DPX-MAT28 was tested up to the limit dose (2136 μg/mL, 10mM). No precipitation of the test 

material was observed at any concentration (+/-S9). No substantial decreases in mitotic index 

were observed at any concentration after 4 (+/-S9) or 20 hrs (-S9) of treatment; therefore, 

concentrations of 0, 534, 1068, and 2136 μg/mL were selected for evaluation of chromosomal 

aberrations in each assay. No significant increases in the mean percentage of cells with 

structural or numerical abortions or in aberrations per cell were observed after treatment for 4 hrs 

(+/-S9) or 20 hrs (-S9). The positive controls induced the appropriate response in the presence 

and absence of S9. There was no evidence of chromosome aberrations induced over 

background in the presence or absence of S9-activation.

This study is classified as Acceptable/Guideline and satisfies the Guideline requirement 

(OPPTS 870.5375, OECD 473) for in vitro mutagenicity (chromosome aberration) data. 

COMPLIANCE: Signed and dated Data Confidentiality, GLP Compliance, and Quality 

Assurance statements were provided.

870.5385 Mammalian In Vivo Bone Marrow Chromosomal 

No study was submitted. This study was waived in a Memorandum entitled “Waiver request for 

a 90-day dermal toxicity study (870.3250) and status of the mutagenicity testing database for 

DPX-MAT28”, J. Ryman, May 13, 2009, D364576. 

870.5395 Mammalian Erythrocyte Micronucleus 

EXECUTIVE SUMMARY: In a bone marrow micronucleus assay (MRID 47560022), 5 

young adult Crl:CD1(ICR) mice/sex/dose/sampling time were treated once via gavage (10 

mL/kg) with DPX-MAT28 (Aminocyclopyrachlor; 92.2% a.i., doses adjusted for purity; Batch 

No. DPX-MAT28-009) in sterile water at doses of 0, 500, 1000, or 2000 mg/kg (limit dose). 

Bone marrow cells were harvested at 24 and 48 hours post-dosing. Additionally, 5 mice/sex 

were treated with cyclophosphamide (50 mg/kg) and marrow cells were harvested at 24 hours 

post-dosing. 

DPX-MAT28 was tested at up to the limit dose (2000 mg/kg). No mortality or clinical signs of 

toxicity were observed at any dose at either time point. No significant decrease in polychromatic 

erythrocyte to normochromatic erythrocyte ratios (PCE:NCE) was observed, indicating that the 

test material was not toxic to the bone marrow. The positive control induced the appropriate 

response. There was no significant increase in the frequency of micronucleated 

polychromatic erythrocytes in bone marrow after any treatment time.
Page 60 of 76 

This study is classified as Acceptable/Guideline and satisfies the guideline requirement (OPPTS 

870.5395; OECD 474) for in vivo cytogenetic mutagenicity data. 

COMPLIANCE: Signed and dated Data Confidentiality, GLP Compliance, and Quality 

Assurance statements were provided.

A.3.7 Neurotoxicity

870.6100a Acute Delayed Neurotoxicity Study - Hen

No study was submitted. This study was recommended for a waiver in a Memorandum entitled 

“Waivers of conditionally required toxicology studies for non-food uses of 

aminocyclopyrachlor” ( J. Ryman, February 4, 2010, D373897) because aminocyclopyrachlor is 

not an organophosphate pesticide, nor was there evidence of acute or subchronic neurotoxicity. 

870.6100b 90-Day Neurotoxicity Study - Hen

No study was submitted. This study was recommended for a waiver in a Memorandum entitled 

“Waivers of conditionally required toxicology studies for non-food uses of 

aminocyclopyrachlor” ( J. Ryman, February 4, 2010, D373897) because aminocyclopyrachlor is 

not an organophosphate pesticide, nor was there evidence of acute or subchronic neurotoxicity. 

 870.6200a Acute Neurotoxicity Screening Battery

In an acute neurotoxicity study (MRID 47725702), DPX-MAT28 (92.2% a.i.; Lot # 009) in 0.5% 

aqueous methylcellulose was administered once via gavage (5 mL/kg) to 10 Sprague-Dawley 

rats/sex/group at dose levels of 0, 200, 1000, or 2000 mg/kg (limit dose). Neurobehavioral 

assessment (functional observational battery [FOB] and motor activity testing) was performed on 

all rats at pre-dosing and Days 1 (approximately 2 hours post-dosing; estimated time of peak 

effect), 8, and 15. At study termination, 5 rats/sex/group were anesthetized and perfused in situ

for neuropathological examination. The tissues from the perfused animals in the control and 

2000 mg/kg groups were subjected to histopathological evaluation of brain and peripheral 

nervous system tissues. Acceptable positive control data were provided. 

There were no treatment-related effects on mortality, clinical signs of toxicity, body weight, food 

consumption, brain weight, body weight gain, gross pathology, or neuropathology. FOB and 

motor activity testing revealed no treatment-related effects. 

There were no neurological effects observed at any dose in either sex.

The LOAEL was not observed. The NOAEL is 2000 mg/kg (limit dose). 

The study is classified as Acceptable/Guideline and satisfies the guideline requirement (OPPTS 

870.6200a) for an acute neurotoxicity study in rats.
 

COMPLIANCE: Signed and dated Data Confidentiality, GLP Compliance, Flagging, and 

Quality Assurance statements were provided. 

 870.6200b Subchronic Neurotoxicity Screening Battery 

EXECUTIVE SUMMARY: In a subchronic oral and neurotoxicity study (MRID 47573403 

and 47560007), aminocyclopyrachlor (DPX-MAT28; 92.2% a.i.; Batch No. DPX-MAT28-009) 

was administered in the diet to Crl:CD(SD) rats (15/sex/dose) at doses (adjusted for purity) of 0, 

600, 2000, 6000, or 18,000 ppm (equivalent to 34.8/44.8, 114.3/145.7, 349.4/448.0, and 

1044.6/1424.9 mg/kg/day) for 13 weeks (94-95 days in males and 96-97 days in females). 

Neurobehavioral assessment (functional observational battery [FOB] and motor activity testing) 

was performed prior to treatment and during Weeks 4, 8, and 13 on 10 rats/sex/group. On Day 

56, plasma concentrations of DPX-MAT28 and the metabolite IN-LXT69 were measured in 

5/sex/dose. At study termination, gross and histopathology were performed on 10 

rats/sex/group, while 5 rats/sex/group were anesthetized and perfused in situ for 

neuropathological examination. The tissues from the perfused animals in the control and 18,000 

ppm groups were subjected to histopathological evaluation of brain, spinal cord, and peripheral 

nervous system tissues. 

All animals survived to the day of scheduled sacrifice. One control male and one 6000 ppm 

female were accidentally killed during blood collection just prior to necropsy. 

No treatment-related effects were observed in daily or weekly clinical observations and there 

were no test substance-related opthamological signs for either sex. There were no test substancerelated or statistically significant effects on functional observational battery (FOB) parameters: 

forelimb and hindlimb grip strength, footsplay, body temperature, or behavioral parameters in 

either sex. Additionally, there were no test substance-related or statistically significant effects on 

duration of movement or number of movements measured in the motor activity analysis of males 

and females. 

At 18,000 ppm, decreases (p≤0.05; except as noted) in body weights were observed in the males 

from Days 28-91 (↓6-9%, NS at Days 56 and 70) and in the females on Days 56, 70, and 77 (↓8-

10%). Overall (Days 0-91) body weight gain was decreased (p≤0.05) by 15-18% in both sexes. 

Significant decreases (p≤0.05) in food consumption were observed at 18,000 ppm during Days 

0-7, 21-28, and 42-49 in males (↓7-8%) and during Days 70-77 in females (↓11%). Decreased 

(p≤0.05) food efficiency was noted in males during Days 21-28, 70-77, and 77-84 (↓18-73%) 

and in females during Days 62-70 (↓112%). Overall (Days 0-91) food efficiency was decreased 

(p≤0.05) by 11% in males and 17% in females. 

There were no adverse effects of the test substance on organ weights, ophthalmology, 

hematology, coagulation, clinical chemistry, or urinalysis parameters in males and females. 

There were no effects of the test substance on brain weights or gross or microscopic 

neuropathology in either sex at any dose. 

Page 61 of 76 
 

Page 62 of 76 

The plasma concentrations of DPX-MAT28 and the metabolite IN-LXT69 were measured on 

Day 56 by high performance liquid chromatography with detection by tandem mass spectrometry 

(LC/MS/MS, MRID 47560007). DPX-MAT28 was the most abundant metabolite in male and 

female rats, with the highest concentrations at 10, 268 and 13, 428 ng/mL for 18,000 ppm male 

and female rats, respectively. In contrast, plasma levels of IN-LXT68 were lower for this dose 

group at concentrations of 82 and 80 ng/mL for males and females, respectively. The average 

concentration of DPX-MAT28 in plasma was higher in females than in males at all dose levels. 

The IN-LXT69 plasma concentrations were below the limit of quantitation for the 600 ppm 

dietary concentration. The average IN-LXT69 plasma concentrations appeared to be similar for 

males and females. There was no apparent plateau for the DPX-MAT28 or IN-LXT68 plasma 

concentrations when compared to dietary intake levels (e.g. plasma concentrations increased 

with increasing concentration in the diet). 

The LOAEL for systemic effects is 18,000 ppm (1044.6/1424.9 mg/kg/day), based on 

decreased body weights, body weight gains, food consumption, and food efficiency in both 

sexes. The NOAEL is 6000 ppm (349.4/448.0 mg/kg/day). 

The LOAEL for neurotoxicity was not observed. The NOAEL is 18,000 ppm 

(1044.6/1424.9 mg/kg/day) in both sexes. 

The study is classified as Acceptable/Guideline and satisfies the guideline requirements for a 

90-day oral toxicity study (OPPTS 870.3100; OECD 408) and a subchronic neurotoxicity study 

(OPPTS 870.6200b; OECD 424) in rats. 

. 

COMPLIANCE: Signed and dated Data Confidentiality, GLP Compliance, Flagging, and 

Quality Assurance statements were provided. 

 870.6300 Developmental Neurotoxicity Study

No study was submitted. This study was recommended for a waiver in a Memorandum entitled 

“Waivers of conditionally required toxicology studies for non-food uses of 

aminocyclopyrachlor” ( J. Ryman, February 4, 2010, D373897) because there is no evidence of 

acute or subchronic neurotoxicity in adult animals and no evidence of increased susceptibility in 

young animals. 

 870.7200 Companion Animal Safety 

No study was submitted. This study was recommended for a waiver in a Memorandum entitled 

“Waivers of conditionally required toxicology studies for non-food uses of 

aminocyclopyrachlor” ( J. Ryman, February 4, 2010, D373897) because no uses on companion 

animals or companion animal exposures are expected. 
 

A.3.8 Metabolism

870.7485 Metabolism - Rat 

EXECUTIVE SUMMARY In this metabolism study (MRID 47560023), [pyramidine-2-14C]-

DPX-MAT28 (aminocyclopyrachlor; Lot No. 01; radiochemical purity 99.5%) in 0.5% 

methylcellulose (4 ml/kg) was administered by a single oral gavage to groups of Sprague Dawley 

rats for the following studies: (i) a pilot mass balance study conducted on one rat/sex dosed at 25 

mg/kg; (ii) a blood pharmacokinetic study conducted on four rats/sex given either a 25 or 500 

mg/kg dose; and (iii) a plasma metabolite study conducted on three rats/sex dosed at 500 mg/kg. 

Metabolite profiles were also determined for urine and feces collected in the pilot mass balance 

study. 

DPX-MAT28 was absorbed with peak concentrations occurring in plasma and RBCs at 0.3-1.0 h 

post-dosing. The AUC for DPX-MAT28 was 7.0-9.0 μg*h/g at 25 mg/kg and 150.8-168.4 

μg*h/g at 500 mg/kg, a difference of approximately 19 to 21-fold, which scaled with the 20-fold 

difference in dose. The majority of the whole blood radiolabel was found in the plasma (60%), 

with about 40% in RBCs, Total recoveries of the administered dose (AD) were 69.9% for the 

male (which is low) and 107.9% for the female. DPX-MAT28 was rapidly eliminated after a 

single oral gavage dose, with mean elimination half-life values of 5.6-5.7 h for plasma at 25 or 

500 mg/kg. The majority of radioactivity was recovered 0-24 h post-dosing, with 35.8-53.71% 

eliminated in the urine of males and females and 31.4-48.0% eliminated in the feces of males and 

females No radioactivity was detected in the expired air as exhaled volatiles or CO2 for DPXMAT28. Cage wash accounted for a small portion (0.36-1.21% AD) of radioactivity, and a 

minor amount of radioactivity was detected in the residual feed. At 168 h post-dosing, the 

residual carcass of the male accounted for 0.04% AD; radioactivity was below the limit of 

detection in the collected tissues from both sexes and in the female residual carcass. 

Plasma, urine, and feces were examined for metabolites at 30 minutes, 24 hours, and 24 hours, 

respectively. Only a single peak was observed in each matrix, and was identified as 

unmetabolized parent. In a concurrently reviewed subchronic oral toxicity study in rats (MRID 

47573403), a metabolite (IN-LTX69) was quantified in plasma; however, this metabolite was not 

detected in the present study following a single dose of the test compound. Control pooled 

plasma samples and pre-dose urine and fecal samples were fortified with radiolabeled DPXMAT28 dosing solution to determine stability at 3 (feces), 10 (urine), and 14 (plasma) days; no 

noticeable differences were observed, indicating that the test compound was stable in the plasma, 

urine, and feces, and in the prepared sample extracts. 

This metabolism study is classified Acceptable/Guideline and satisfies the guideline 

requirement for a Tier 1 metabolism study [OPPTS 870.7485, OECD 417] in rats. 

COMPLIANCE: Signed and dated Data Confidentiality, GLP Compliance, and Quality 

Assurance statements were provided. 

Page 63 of 76 
 

EXECUTIVE SUMMARY: In this metabolism study (MRID 47560024), [pyramidine-2-14C]-

DPX-KJM44 (Lot No. SEL/1539A; radiochemical purity 99.2%) in 4 ml/kg of 0.5% 

methylcellulose was administered by a single oral gavage to groups of Sprague Dawley rats for 

the following studies: (i) a pilot mass balance study conducted on one rat/sex dosed at 25 mg/kg; 

(ii) a blood pharmacokinetic study conducted on four rats/sex given either a 25 or 500 mg/kg 

dose; and (iii) a plasma metabolite study conducted on three rats/sex dosed at 500 mg/kg. 

Metabolite profiles were also determined for urine and feces collected in the pilot mass balance 

study. 

The test compound was rapidly absorbed with peak concentrations occurring in plasma and RBC 

at 0.3-0.6 h post-dosing. The AUC for DPX-KJM44 was 14.5-14.8 μg*h/g at 25 mg/kg and 

241.5-255.8 μg*h/g at 500 mg/kg, a difference of approximately 18-fold, which scaled with the 

20-fold difference in dose. The majority of the whole blood radiolabel was found in the plasma 

(60%), with about 40% in RBCs. No differences were observed between the sexes. 

Total recoveries of the administered dose (AD) were 89.2% for the male and 82.6% for the 

female. The plasma half-life for DPX-KJM44 was 8.7-13.3 h at 25 or 500 mg/kg . The 

majority of radioactivity was recovered in the urine by 24 h post-dosing. (78.80-78.82%) for 

both males and females. A small amount was eliminated in the feces (1.72-4.57%) within 24 

hours. No radioactivity was detected in the expired air as exhaled volatiles or CO2 during the 

first 48. Cage wash accounted for a small portion (0.08-1.92% AD) of radioactivity, and a minor 

amount of radioactivity was detected in the residual feed. At 168 h post-dosing, radioactivity 

was below the limit of detection in the collected tissues except for the male gastrointestinal tract 

and contents (0.01% AD). Minor amounts of radioactivity were also detected in the residual 

carcass (0.12-0.14% AD). 

Plasma, urine, and feces were examined for metabolites at 30 minutes, 24 hours, and 24 hours, 

respectively. Only a single metabolite, DPX-MAT28, (the free acid of DPXKJM44) was 

observed in each matrix. Identification was confirmed by comparison of mass spectrograph data 

from the experimental matrices with data obtained from fortified control plasma, and fortified 

pre-dose urine and feces. In a concurrently reviewed subchronic oral toxicity study in rats 

(MRID 47573403), a metabolite (IN-LTX69) was quantified in plasma; however, this metabolite 

was not detected in the present study following a single dose of the test compound. 

Control pooled plasma samples and pre-dose urine and fecal samples were fortified with 

radiolabeled DPX-KJM44 dosing solution to determine stability at 3 (feces), 10 (urine), and 14 

(plasma) days. No noticeable differences were observed in the urine and feces or in the prepared 

sample extracts. However, the majority of DPX-KJM44 in plasma was metabolized to DPXMAT28 when the sample was fortified and analyzed on the same day. Once the plasma was 

extracted, DPX-KJM44 appeared to be stable. 

This metabolism study is classified Acceptable/Guideline and satisfies the guideline 

requirement for a Tier 1 metabolism study [OPPTS 870.7485, OECD 417] in rats. 

COMPLIANCE: Signed and dated Data Confidentiality, GLP Compliance, and Quality 

Assurance statements were provided. 

Page 64 of 76 
 

Page 65 of 76 

870.7600 Dermal Absorption – Rat 

No study was submitted. This study was recommended for a waiver in a Memorandum entitled 

“Waivers of conditionally required toxicology studies for non-food uses of 

aminocyclopyrachlor” ( J. Ryman, February 4, 2010, D373897) because a dermal absorption 

factor of 100% was assumed and was appropriate for risk assessment of the proposed non-food 

uses. 

 870.7800 Immunotoxicity-Rat 

EXECUTIVE SUMMARY: In an immunotoxicity study (MRID 47560025) DPX-MAT28 

(Aminocyclopyrachlor; 92.2% a.i.; Batch No. DPX-MAT28-009) was administered to ten male 

Sprague Dawley (Crl:CD[SD]) rats/dose group in the diet at dose levels of 0, 600, 6,000 or 

18,000 ppm (equivalent to 0, 42, 407, and 1277 mg/kg bw/day) for 28 days. An additional group 

of five rats were dosed by intraperitoneal injection (10 mL/kg) with 25 mg/kg cyclophosphamide 

monohydrate to serve as positive controls. Systemic toxicity parameters were evaluated, and 

immunotoxicity was investigated by performing an enzyme-linked immunoabsorbant assay 

(ELISA) to measure serum IgM responses to sheep red blood cells (sRBC) following 

immunization with sRBC. 

Systemic toxicity was not observed. There were no effects of treatment on mortality, clinical 

signs, body weights, body weight gains, food consumption, food efficiency, organ weights, or 

gross pathology at any dose level. 

The LOAEL for systemic toxicity was not observed. The NOAEL for systemic toxicity is 

18,000 ppm (equivalent to 1277 mg/kg bw/day in males). 

There was no evidence of immunotoxicity. No effects of treatment were observed on the 

humoral immune response as measured by the primary serum IgM antibody response to the Tdependent antigen, sheep erythrocytes. Spleen and thymus weights were unaffected by 

treatment. 

Positive control rats demonstrated an 82% decrease in Log2 titer compared to concurrent 

controls, demonstrating the ability of this ELISA to detect suppression of the humoral immune 

response. 

The LOAEL for immunotoxicity was not observed. The NOAEL for immunotoxicity is 

18,000 ppm (equivalent to 1277 mg/kg bw/day in males). 

This immunotoxicity study is classified Acceptable/Guideline and satisfies the guideline 

requirements (OPPTS 870.7800) for an immunotoxicity study in rats. 

COMPLIANCE: Signed and dated Data Confidentiality, GLP Compliance, and Quality 

Assurance statements were provided.
 

 870.7800 Immunotoxicity-Mouse 

EXECUTIVE SUMMARY: In an immunotoxicity study (MRID 47560026) DPX-MAT28 

(Aminocyclopyrachlor; 92.2% a.i.; Batch Nos. DPX-MAT28-009) was administered to ten male 

CD-1 (Crl:CD[ICR]) mice/dose group in the diet at dose levels of 0, 300, 3,000 or 7,000 ppm 

(equivalent to 0, 45, 425, and 1056 mg/kg bw/day) for 28 days. An additional group of five mice 

were dosed by intraperitoneal injection (10 mL/kg) with 25 mg/kg cyclophosphamide 

monohydrate to serve as positive controls. Systemic toxicity parameters were evaluated, and 

immunotoxicity was investigated by performing an enzyme-linked immunoabsorbant assay 

(ELISA) to measure serum IgM responses to sheep red blood cells (sRBC) following 

immunization with sRBC. 

Systemic toxicity was not observed. There were no effects of treatment on mortality, clinical 

signs, body weights, body weight gains, food consumption, food efficiency, organ weights, or 

gross pathology at any dose level. 

The LOAEL for systemic toxicity was not observed. The NOAEL for systemic toxicity is 

7000 ppm (equivalent to 1056 mg/kg bw/day in males). 

There was no evidence of immunotoxicity. No effects of treatment were observed on the 

humoral immune response as measured by the primary serum IgM antibody response to the Tdependent antigen, sheep erythrocytes. Spleen and thymus weights were unaffected by 

treatment. 

Positive control mice demonstrated a 73% decrease in Log2 titer compared to concurrent 

controls, demonstrating the ability of this ELISA to detect suppression of the humoral immune 

response. 

The LOAEL for immunotoxicity was not observed. The NOAEL for immunotoxicity is 

7000 ppm (equivalent to 1056 mg/kg bw/day in males).

This immunotoxicity study is classified Acceptable/Guideline and satisfies the guideline 

requirements (OPPTS 870.7800) for an immunotoxicity study in mice. 

COMPLIANCE: Signed and dated Data Confidentiality, GLP Compliance, and Quality 

Assurance statements were provided.

A.3.9 Special/Other Studies

Non-Guideline 14-Day Oral Toxicity Study-Rabbit 

EXECUTIVE SUMMARY: Cyclopropane carboxylic acid has been identified as an 

environmental degradate of aminocyclopyrachlor that is of concern. There are no toxicity 

studies with cyclopropane carboxylic acid suitable for risk assessment. However, cyclopropane 

carboxylic acid is also a metabolite of a drug called panadiplon, the toxic effects of which are 

Page 66 of 76 
 

mediated by cyclopropane carboxylic acid. Therefore, the following study from the general 

scientific literature with panadiplon was used. 

In a 14-day oral toxicity study, micronized panadiplon (purity unknown, batch/lot unknown), 

which is metabolized to cyclopropane carboxylic acid, was administered to Dutch-belted 

rabbits/dose orally (via gavage) in 1.25% low viscosity, microcrystalline cellulose and sodium 

carboxymethylcellulose NF, 0.2% polysorbate NF food grade, and 0.1N sodium hydroxide in 

purified water USP without sorbic acid at dose levels of 0 mg/kg (9 rabbits), 10 mg/kg (10 

rabbits), or 20 mg/kg (10 rabbits) per day. 

In 20 mg/kg animals, there was treatment related mortality in 2/10 rabbits and clinical signs 

(lethargy and weakness) in 6/10 rabbits. Both treated groups had gross liver lesions (white 

streaks and masses on the liver from a few mm up to 2 cm) in 4/10 animals (10 mg/kg) and 10/10 

animals (20 mg/kg). Serum triglycerides were elevated on Day 14 only for 10 mg/kg animals, 

whereas 20 mg/kg animals had elevated serum triglycerides from Day 4 onward and elevated 

serum liver enzyme (aspartic acid transcarbamylase) from Day 8 onward. Microvesicular 

hepatic steatosis was observed in all treated animals. This was accompanied by single cell or 

multi-cell centrilobular necrosis in 7/10 animals at 10 mg/kg and centrilobular necrosis or focal 

coagulative necrosis in 10/10 animals at 20 mg/kg. Inflammatory cells and fibrosis were 

observed in larger necrotic foci that corresponded with gross lesions. 

The LOAEL for panadiplon is 10 mg/kg/day based on gross liver lesions and microscopic effects 

of microvesicular hepatic steatosis and necrosis. The NOAEL was not observed. 

The LOAEL for panadiplon (LOAELP) was converted to a LOAEL for CPCA (LOAELC) based 

on molecular weight and mole fraction, assuming a metabolic conversion of panadiplon to 

cyclopropane carboxylic acid of 100%. 100% was assumed because no experimental data were 

available regarding the percent conversion of panadiplon to cyclopropane carboxylic acid. 

LOAELP = 10 mg/kg/day x [(86.09 g CPCA/mole) / (337.35 g panadiplon/mole)] x [1 mole 

CPCA/mole panadiplon]= 2.55 mg/kg/day = LOAELC 

The LOAEL for cyclopropane carboxylic acid is 2.5 mg/kg/day, based on gross liver lesions 

and microscopic effects of microvesicular hepatic steatosis and necrosis. The NOAEL was 

not observed. 

This 90-day oral toxicity study in female Dutch-belted rabbit acceptable/non-guideline. 

COMPLIANCE: Signed and dated GLP, Quality Assurance, and Data Confidentiality 

statements were not provided. 

OECD 415 One Generation Reproduction-Rat 

EXECUTIVE SUMMARY: In a non-guideline one-generation reproduction toxicity study 

(MRID 47560018), IN-KJM44 (Aminocyclopyrachlor-methyl; 99.7% a.i.; Lot # 027) was 

administered in the diet to 10 Sprague Dawley rats/sex/dose group at dietary levels of 0, 600, 

5000, or 17,000 ppm (equivalent to an average of 0/0, 49/53, 398/435, and 1378/1489 mg/kg/day 

Page 67 of 76 
 

in P and F1 generation males/females during pre-mating). The P generation animals were fed the 

test diets for at least 28 days prior to mating to produce the F1 litters. Dams were allowed to 

deliver and rear their offspring until weaning on post-natal day (PND) 21. The F1 litters were 

culled to 4 pups/sex/litter (litter size permitting) on PND 4. In addition to the parameters 

typically evaluated in a reproductive toxicity study, hematology and clinical chemistry 

evaluations were performed on 5 rats/sex/dose from the P generation on Day 29 and at 

termination. Neurobehavioral evaluations (functional observational battery and motor activity 

measurements) were conducted on all P generation male (day 27) and female (day 28) animals 

during the pre-test period. At weaning, 10 F1 rats/sex/group were randomly selected to continue 

on study and were fed the same test diet concentration as their dam until termination at PND 60. 

One P male was found dead on Day 6; however, this mortality was not considered treatmentrelated because no clinical signs of toxicity were observed in this animal prior to death, and no 

gross lesions were noted at necropsy. All other P and F1 males and females survived to 

scheduled termination. No treatment-related effects were observed on clinical signs, FOB, motor 

activity, hematology, clinical chemistry, organ weights, gross pathology, or histopathology. 

At 17,000 ppm, during the pre-mating period, food efficiency was decreased by 27% (p<0.01) 

for Days 0-7 in the P males compared to controls. In the P females at this dose, food 

consumption was decreased (p<0.05) by 11-15% for Days 0-7 and 7-14 and for the overall (Days 

0-28) pre-mating period. However, body weights and body weight gains of the treated P females 

were unaffected by treatment. Body weights and body weight gains of the treated P males were 

comparable to controls throughout pre-mating, post-mating period (Days 28-60), and for the 

overall study (PND 0-60). In the P dams, body weights, body weight gains, food consumption, 

and food efficiency were unaffected by treatment throughout gestation and lactation. 

In the F1 adults at 17,000 ppm, body weights were decreased by 8-17% (p<0.05) in the males 

from Day 0 and continuing through Day 21 and by 11-15% in the females on Days 0 and 7. 

Food consumption was decreased (p<0.05) by 9-17% in the males for Days 0-7, 14-21, 21-28, 

and 0-39 and by 8% in the females for Days 0-39. 

The LOAEL for parental toxicity is 17,000 ppm (equivalent to 1378/1489 mg/kg/day in 

males/females), based on decreased food consumption and efficiency in the P generation 

and on decreased body weights and food consumption in the F1 generation. The NOAEL is 

5000 ppm (equivalent to 398/435 mg/kg/day in males/females).

There were no effects of treatment on sex ratio or on gestation, live birth, viability, lactation, or 

litter survival indices during the post-natal period. Sexual maturation, organ weights, and gross 

pathology were unaffected by treatment. 

At 17,000 ppm, eight pups from one litter were dehydrated compared to 0 controls. F1 pup body 

weights were decreased (p<0.05) by 9% on PND 14 and by 17% on PND 21 compared to 

controls. Pup body weight gains for the overall post-natal period (PND 0-21) were decreased 

(NS) by 20% compared to controls. 

Page 68 of 76 
 

The LOAEL for offspring toxicity is 17,000 ppm (equivalent to 1378/1489 mg/kg/day in 

males/females), based on dehydration, decreased pup body weight gains, and decreased 

pup body weights late in lactation. The NOAEL is 5000 ppm (equivalent to 398/435 

mg/kg/day in males/females).

There were no effects of treatment on mating or fertility indices, gestation duration, number of 

implantation sites, implantation efficiency, or post-implantation loss. Pre-coital duration was not 

reported, and sperm parameters were not measured. Estrus cycle stage for the pre-mating period 

was not reported. Microscopic examination of the vagina at study termination did not indicate 

any effects of treatment on the estrus cycle stage. 

The LOAEL for reproductive toxicity was not observed. The NOAEL is 17,000 ppm 

(equivalent to 1378/1489 mg/kg/day in males/females).

This study is classified as an Acceptable/Non-guideline one-generation reproduction study in 

rats. 

COMPLIANCE: Signed and dated Data Confidentiality, GLP Compliance, Flagging, and 

Quality Assurance statements were provided. 

A.4 References (In MRID Order) 

47559809 Anand, H. (2007) DPX-MAT28: Laboratory Study of Physicochemical Properties 

for Color, Odor, Physical State, Melting Point, Boiling/Decomposition, Relative Density and 

Bulk Density. Project Number: G4781, DUPONT/22551. Unpublished study prepared by 

Advinus Therapeutics Private Limited. 35 p. 

47559812 Moorthy, M. (2007) DPX-MAT28: Laboratory Study of pH. Project Number: 

G4785, DUPONT/22543. Unpublished study prepared by Advinus Therapeutics Private 

Limited. 19 p. 

47559814 Anand, H. (2007) DPX-MAT28: Laboratory Study of Dissociation Constants in 

Water. Project Number: G4789, DUPONT/22555. Unpublished study prepared by Advinus 

Therapeutics Private Limited. 28 p. 

47559815 Manjunatha, S. (2007) DPX-MAT28: Laboratory Study of n-Octanol/ Water 

Partition Coefficient. Project Number: G4782, DUPONT/22544. Unpublished study prepared 

by Advinus Therapeutics Private Limited. 63 p. 

47559816 Moorthy, M. (2007) DPX-MAT28: Laboratory Study of Water Solubility. Project 

Number: G4783, DUPONT/22541. Unpublished study prepared by Advinus Therapeutics 

Private Limited. 46 p. 

47559818 Moorthy, M. (2007) DPX-MAT28: Laboratory Study of Vapour Pressure. Project 

Number: DUPONT/22537, G4780. Unpublished study prepared by Advinus Therapeutics 

Private Limited. 57 p. 

Page 69 of 76 
 

47559820 Hirata, C. (2008) DPX-MAT28: Volatility, Calculation of Henry's Law Constant. 

Project Number: DUPONT/22545/EU. Unpublished study prepared by E. I. Du Pont De 

Nemours and Co., Inc. 8 p. 

47573401 Moorthy, M. (2007) DPX-MAT28: Laboratory Study of UV-VIS Absorption 

Spectrum and Molar Absorptivity. Project Number: G4784, DUPONT/22536. Unpublished 

study prepared by Advinus Therapeutics Private Limited. 35 p. 

47559828 Shalini, L. (2007) DPX-KJM44: Laboratory Study of Physicochemical Properties 

for Color, Odor, Physical State, Melting Point, Boiling Point/Decomposition and Relative 

Density. Project Number: G4792, DUPONT/23307. Unpublished study prepared by Advinus 

Therapeutics Private Limited. 32 p. 

47559829 Shalini, L. (2007) DPX-KJM44: Laboratory Study of Physicochemical Properties 

for Color, Odor, Physical State and Bulk Density. Project Number: G4890, DUPONT/22552. 

Unpublished study prepared by Advinus Therapeutics Private Limited. 22 p. 

47559832 Moorthy, S. (2007) DPX-KJM44: Laboratory Study of pH. Project Number: 

G4796, DUPONT/22532. Unpublished study prepared by Advinus Therapeutics Private 

Limited. 20 p. 

47559833 Moorthy, M. (2007) DPX-KJM44: Laboratory Study of UV-VIS Absorption 

Spectrum and Molar Absorptivity. Project Number: G4795, DUPONT/22546. Unpublished 

study prepared by Advinus Therapeutics Private Limited. 38 p. 

47559834 Manjunatha, S. (2007) DPX-KJM44: Laboratory Study of N-Octanol/Water 

Partition Coefficient. Project Number: DUPONT/22533, G4793. Unpublished study prepared 

by Advinus Therapeutics Private Limited. 34 p. 

47559835 Moorthy, M. (2007) DPX-KJM44: Laboratory Study of Water Solubility. Project 

Number: G4794, DUPONT/22530. Unpublished study prepared by Advinus Therapeutics 

Private Limited. 33 p. 

47559902 Moorthy, M. (2007) DPX-KJM44 (PAI): Laboratory Study of Vapour Pressure. 

Project Number: DUPONT/22547, G4791. Unpublished study prepared by Advinus 

Therapeutics Private Limited. 49 p. 

47559934 Carpenter, C. (2007) DPX-MAT28 Technical: Acute Oral Toxicity Study in RatsUp-and-Down Procedure. Project Number: DUPONT/22371, 17181, 834. Unpublished study 

prepared by E.I. du Pont de Nemours and Company. 27 p. 

47559935 Carpenter, C. (2007) DPX-MAT28 Technical: Acute Dermal Toxicity Study in Rats. 

Project Number: DUPONT/22370, 17181, 673. Unpublished study prepared by E.I. du Pont de 

Nemours and Company. 32 p. 

Page 70 of 76 
 

47560001 Anand, S. (2007) DPX-MAT28 Technical: Inhalation Median Lethal Concentration 

(LC50) Study in Rats. Project Number: 22373. Unpublished study prepared by E.I. du Pont de 

Nemours and Company. 42 p. 

47560002 Carpenter, C. (2007) DPX-MAT28 Technical: Acute Eye Irritation Study in Rabbits. 

Project Number: 22372. Unpublished study prepared by E.I. du Pont de Nemours and Company. 

21 p. 

47560003 Carpenter, C. (2007) DPX-MAT28 Technical: Acute Dermal Irritation Study in 

Rabbits. Project Number: 22369. Unpublished study prepared by E.I. du Pont de Nemours and 

Company. 22 p. 

47560004 Carpenter, C. (2007) DPX-MAT28 Technical: Local Lymph Node Assay (LLNA) in 

Mice. Project Number: 22374. Unpublished study prepared by E.I. du Pont de Nemours and 

Company. 36 p. 

47560007 Anand, S. (2008) DPX-MAT28 Technical: Subchronic Toxicity 90 Day Feeding 

Study in Rats. Project Number: 21490. Unpublished study prepared by E.I. du Pont de Nemours 

and Company. 30 p. 

47560008 Anand, S. (2008) DPX-KJM44 Technical: Subchronic Toxicity 90-Day Feeding 

Study in Rats. Project Number: 22570. Unpublished study prepared by E.I. du Pont de Nemours 

and Company, Critical Path Services, LLC, and Histo Techniques, Ltd. 438 p. 

47560009 Anand, S. (2007) DPX-KJM44 Technical: Subchronic Toxicity 90-Day Feeding 

Study in Rats. Project Number: 21491. Unpublished study prepared by E.I. du Pont de Nemours 

and Company. 30 p. 

47560010 Anand, S. (2008) DPX-MAT28 Technical: Subchronic Toxicity 90-Day Feeding 

Study in Mice. Project Number: 21491. Unpublished study prepared by E.I. du Pont de 

Nemours and Company. 403 p. 

47560011 Anand, S. (2008) DPX-MAT28 Technical: Subchronic Toxicity 90 Day Feeding 

Study in Mice. Project Number: 21491. Unpublished study prepared by E.I. du Pont de 

Nemours and Company. 26 p. 

47560012 Luckett, E. (2008) DPX-MAT28 Technical: Subchronic Toxicity 90-Day Feeding 

Study in Dogs: Revised Final Report. Project Number: DUPONT/21489, 125/068. Unpublished 

study prepared by MPI Research, Inc. 841 p. 

47560013 Luckett, E.; Mawn, M. (2008) DPX-MAT28 Technical: Subchronic Toxicity 90 Day 

Feeding Study in Dogs. Project Number: DUPONT/21489, 125/068. Unpublished study 

prepared by E.I. du Pont de Nemours and Company. 27 p. 

47560014 Merkel, D. (2008) DPX-MAT28 Technical: Dermal Toxicity Study (28 Day Repeat 

Dermal Application Study in Rats). Project Number: DUPONT/22796, 22352. Unpublished 

Page 71 of 76 
 

study prepared by Product Safety Laboratories, E.I. du Pont de Nemours and Company and 

Charles River Breeding Laboratories, Inc. 207 p. 

47560015 Fleeman, T. (2008) A Prenatal Development Toxicity Study of DPX-MAT28 in 

Rabbits: Revision 2 Final Report. Project Number: WIL/189193, DUPONT/22377. 

Unpublished study prepared by WIL Research Laboratories, Inc. 690 p. 

47560016 Lewis, J. (2008) DPX-MAT28 Technical: Developmental Toxicity Study in Rats. 

Project Number: DUPONT/22378, 07/CPS/032. Unpublished study prepared by E.I. du Pont de 

Nemours and Company and Critical Path Services, LLC. 372 p. 

47560018 Lewis, J. (2006) IN-KJM44: One-Generation Reproduction Study in Rats. Project 

Number: DUPONT/17315. Unpublished study prepared by E.I. du Pont de Nemours and 

Company. 741 p. 

47560019 Wagner, V.; VanDyke, M. (2008) DPX-MAT28 Technical: Bacterial Reverse 

Mutation Assay. Project Number: AC02HJ/503/BTL, 17293, H/27937. Unpublished study 

prepared by Bioreliance and Dupont Haskell Laboratory. 73 p. 

47560020 Clarke, J. (2007) DPX-MAT28 Technical: In vitro Mammalian Cell Gene Mutation 

Test (CHO/HGPRT Assay). Project Number: AC02HJ/782/BTL, 17293, 515. Unpublished 

study prepared by Bioreliance and Dupont Haskell Laboratory. 48 p. 

47560021 Gudi, R.; Rao, M. (2007) DPX-MAT28 Technical: In vitro Mammalian 

Chromosome Aberration Test in Human Peripheral Blood Lymphocytes. Project Number: 

AC02HJ/341/BTL, DUPONT/22709, 17293. Unpublished study prepared by Bioreliance. 58 p. 

47560022 Krsmanovic, L.; Huston, T. (2007) DPX-MAT28 Technical: Mouse Bone Marrow 

Erythrocyte Micronucleus Test: Final Report. Project Number: AC02HJ/123/BTL, 17293, 572. 

Unpublished study prepared by Dupont Haskell Laboratory and Bioreliance. 57 p. 

47560023 Himmelstein, M. (2008) [Carbon 14]-DPX-MAT28: Plasma Pharmacokinetics and 

Pilot Material Balance in Male and Female Rats. Project Number: DUPONT/22033, 17124, 

1017. Unpublished study prepared by E.I. du Pont de Nemours and Company. 91 p. 

47560024 Himmelstein, M. (2008) [carbon 14]-DPX-KJM44: Plasma Pharmaconkinetics and 

Pilot Material Balance in Male and Female Rats. Project Number: DUPONT/22375, 17271, 

1017. Unpublished study prepared by E.I. du Pont de Nemours and Company. 90 p. 

47560025 Hoban, D. (2008) DPX-MAT28 Technical: 28-Day Immunotoxicity Feeding Study 

in Male Rats . Project Number: DUPONT/22794, 17286, 1545. Unpublished study prepared by 

E.I. du Pont de Nemours and Company, Critical Path Services, LLC, and ImmunoTox, Inc. 93 p.

47560026 Hoban, D. (2008) DPX-MAT28 Technical: 28-Day Immunotoxicity Feeding Study 

in Male Mice. Project Number: DUPONT/22795, 17286, 1546. Unpublished study prepared by 

E.I. du Pont de Nemours and Company, Critical Path Services, LLC, and ImmunoTox, Inc. 99 p.

Page 72 of 76 
 

47560027 Carpenter, C. (2007) DPX-KJM44 Technical: Acute Oral Toxicity Study in RatsUp-and-Down Procedure. Project Number: DUPONT/22950, 17251, 834. Unpublished study 

prepared by E.I. du Pont de Nemours and Company. 28 p. 

47560028 Carpenter, C. (2007) DPX-KJM44 Technical: Acute Dermal Toxicity Study in Rats. 

Project Number: DUPONT/22951, 17251, 673. Unpublished study prepared by E.I. du Pont de 

Nemours and Company. 29 p. 

47560029 O'Neal, F. (2008) DPX-KJM44 Technical: Acute Inhalation Toxicology Test 

Waiver. Project Number: DUPONT/26475. Unpublished study prepared by DuPont Crop 

Protection. 11 p. 

47560030 Carpenter, C. (2007) DPX-KJM44 Technical: Acute Eye Irritation Study in Rabbits. 

Project Number: DUPONT/23435, 602, 17251. Unpublished study prepared by E.I. du Pont de 

Nemours and Company. 21 p. 

47560031 Carpenter, C. (2007) DPX-KJM44 Technical: Acute Dermal Irritation Study in 

Rabbits. Project Number: DUPONT/22952, 17251, 1008. Unpublished study prepared by E.I. 

du Pont de Nemours and Company. 22 p. 

47560032 Carpenter, C. (2008) DPX-KJM44 Technical: Local Lymph Node Assay (LLNA) in 

Mice. Project Number: DUPONT/23436, 17251, 1234. Unpublished study prepared by E.I. du 

Pont de Nemours and Company. 36 p. 

47560033 Ford, L. (2005) IN-KJM44: Bacterial Reverse Mutation Test. Project Number: 

DUPONT/17971, 15744, 502. Unpublished study prepared by E.I. du Pont de Nemours and 

Company. 33 p. 

47560211 Lowrie, C. (2008) Photodegradation of [Pyrimidine-2-(Carbon 14)]DPX-MAT28 in 

pH 4 Buffer and Natural Water by Simulated Sunlight: Final Report. Project Number: 212706, 

DUPONT/22117. Unpublished study prepared by Charles River Laboratories. 88 p. 

47560213 Wardrope, L. (2008) Photodegradation of [Pyrimidine-2-(Carbon 14)]-DPX-MAT28 

on Soil: Final Report. Project Number: DUPONT/22118, 807770. Unpublished study prepared 

by Charles River Laboratories. 76 p. 

47573403 Anand, S. (2008) DPX-MAT28 Technical: Subchronic Toxicity: 90-Day Feeding 

Study in Rats. Project Number: DUPONT/21490, 17053, 1026. Unpublished study prepared by 

E.I. du Pont de Nemours and Company. 583 p. 

47575101 Lewis, J. (2008) DPX-:MAT28 Technical: Multi-Generation Reproduction Study in 

Rats. Project Number: 17123, 904, DUPONT/22032. Unpublished study prepared by E.I. du 

Pont de Nemours and Company. 1642 p. 

47725701 O'Neal, F. (2009) Aminocyclopyrachlor (DPX-MAT28) Technical Registration: 

Waiver Request for the 90-Day Dermal Toxicity Study. Project Number: DUPONT/27949. 

Unpublished study prepared by DuPont Crop Protection. 10 p. 

Page 73 of 76 
 

Page 74 of 76 

47725702 Barnett, J. (2009) Oral (Gavage) Acute Neurotoxicity Study of DPX-MAT28-009 in 

Rats. Project Number: AUV00038, DUPONT/22792, WR/17270/SC/1261. Unpublished study 

prepared by Charles River Laboratories. 530 p. 

47898501 O'Neal F.; Snyder, N.; Hirata, C. (2009) IN-V0977: Exposure and Risk Assessments 

of Photolytic Decomposition Product of Aminocyclopyrachlor (DPX-MAT28). Project Number: 

DUPONT/29367. Unpublished study prepared by E.I. Du Pont de Nemours and Company. 41 p. 

47916803 Ulrich, R.; Bacon, J.; Branstetter, D.; et al. (1994) Induction of a Hepatic Toxic 

Syndrome in the Dutch-Belted Rabbit by a Quinoxalinone Anxiolytic. Toxicology 98: 187-198.
 

Appendix B: Review of Human Research 

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. 

Electronic Database. Task Force members Health Canada, U. S. Environmental Protection 

Agency, and the National Agricultural Chemicals Association, released February, 1995. 

Appendix C: Chemical Structures of Degradates 

The following chemical structures of the 5 environmental degradates of aminocyclopyrachlor 

were obtained from HED’s “Aminocyclopyrachlor. Report of the Residues of Concern 

Knowledgebase Subcommittee (ROCKS)” memorandum (from G. Kramer, October 15, 2009, 

D370638). 

Degradate 1: IN-LXT69 

IUPAC Name: 

5-Chloro-2-cyclopropyl-pyrimidin-4-ylamine 

CAS Name: 

Not reported 

CAS. No.: 

Not reported 

N N

2NH

Cl

Degradate 2: IN-QFH57 

IUPAC Name: 

4-Cyano-2-cyclopropyl-1H-imidazole-5-carboxylic acid 

CAS Name: 

4-Cyano-2-cyclopropyl-1H-imidazole-5- carboxylic acid 

CAS. No.: 

Not reported 

HN N

OH

N O

Page 75 of 76 
 

Page 76 of 76 

Degradate 3: IN-Q3007 

IUPAC Name: 

Cyclopropanecarboxamide 

CAS Name: 

Cyclopropanecarboxamide 

CAS. No.: 6228-73-5 

N O

H

H

Degradate 4: IN-V0977 

IUPAC Name: 

Cyclopropanecarboxylic acid 

CAS Name: 

Cyclopropanecarboxylic acid 

CAS. No.: 1759-53-1 

O OH

Degradate 5: IN-YY905 

IUPAC Name: 

Cyclopropanecarboximidamide 

CAS Name: 

Cyclopropanecarbamidine 

CAS. No.: Not reported 

NH 2NH