Aminocyclopyrachlor Human Health Risk Assessment DP No. D387448

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1.0 Executive Summary

This document describes the human health risk assessment conducted to support the Section 3 

registration decision for the first food use of aminocyclopyrachlor. Aminocyclopyrachlor is 

proposed for use on rangeland, pastures, and Conservation Reserve Program (CRP) acres. The 

associated tolerances for residues on grass and livestock commodities are also described. 

Aminocyclopyrachlor has previously been registered for non-food, herbicidal use. 

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. Three 

formulations of aminocyclopyrachlor are being registered in this action: the parent acid (PC 

Code 288008, Reg. Nos. 352-782, 352-787); the potassium salt (PC Code 288010, Reg. No. 

352-786); and the methyl ester (aminocyclopyrachlor-methyl, PC Code 288009, Reg. Nos. 

352-783, 352-784, 352-785). Two formulations are the parent acid co-formulated with 

chlorsulfuron (352-ILR) or metsulfuron (352-ILN). The parent acid (aminocyclopyrachlor) is 

considered the active ingredient.

Hazard and Dose-Response Considerations 

Aminocyclopyrachlor and aminocyclopyrachlor-methyl

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

proposed use patterns. There are no target organs of toxicity for aminocyclopyrachlor. Mild 

systemic toxicity is observed via the oral route with repeated exposures at very high (limit) 

doses. This systemic toxicity is limited to decreased body weight and body weight gain. There 

are no appreciable increases in the severity of these effects with time. The most sensitive species 

is the rat. 

Aminocyclopyrachlor has been classified as ―Not Likely to be Carcinogenic to Humans‖ because 

it is not tumorgenic in rodents and was negative in a full panel of in vitro and in vivo 

genotoxicity assays. Therefore, carcinogenicity was not quantified. 

Repeated-dose toxicity studies via the dermal route showed no systemic toxicity of 

aminocyclopyrachlor at the limit dose. No repeated-exposure studies were available via the 

inhalation route. Therefore, extrapolation from the oral route of exposure was used to assess 

inhalation risks. 

The toxicity database for aminocyclopyrachlor-methyl is being bridged with 

aminocyclopyrachlor. Support for bridging is provided by evidence that aminocyclopyrachlormethyl is rapidly metabolized in rats to aminocyclopyrachlor. Furthermore, oral toxicity studies 

at select endpoints show that aminocyclopyrachlor-methyl causes effects similar to 

aminocyclopyrachlor at the same dose levels. 
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Cyclopropane carboxylic acid 

Cyclopropane carboxylic acid is an environmental photodegradate of aminocyclopyrachlor 

present only in surface water. This photodegradate has a different mode of toxic action than 

aminocyclopyrachlor and aminocyclopyrachlor-methyl. The target organ is the liver and the 

mechanism of toxic action is impairment of mitochondrial function by inhibiting the beta 

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

in cells) that 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 repeated (up to 14 days) exposures. 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 (Food and Water)

Dietary exposures to aminocyclopyrachlor and aminocyclopyrachlor-methyl may occur in food 

(meat and milk) and drinking water. Dietary exposure to the environmental photodegradate, 

cyclopropane carboxylic acid, will occur in drinking water only. For aminocyclopyrachlor, no 

acute dietary endpoint was identified, and so acute dietary risks were not assessed. Assessment 

of chronic dietary risks in all population subgroups that included an estimated drinking water 

concentration of 42.2 ppb resulted in no risks of concern. Cancer risks for aminocyclopyrachlor 

were not assessed because no cancer endpoint was identified. 

Risks from dietary exposures to cyclopropane carboxylic acid in drinking water were assessed 

using an annual peak estimated drinking water concentration (EDWC) of 2.12 ppb for acute 

dietary exposure and an annual average EDWC of 1.52 ppb for chronic dietary exposure. No

risks of concern were identified in any population subgroup. Risks from drinking water 

exposure were not aggregated with aminocyclopyrachlor/aminocyclopyrachlor-methyl due to the 

different mechanism of toxic action of cyclopropane carboxylic acid. Cancer risks for dietary 

exposure to cyclopropane carboxylic acid in drinking water were not quantitatively assessed

because structure-activity relationship (SAR) analysis and the open scientific literature indicated 

no carcinogenicity hazard, and because dietary exposures are very low (< 1 μg/kg/day). 

Residential Exposure 

Aminocyclopyrachlor is currently registered for use on turf. No new residential uses for 

aminocyclopyrachlor are proposed in this action. The Agency has previously assessed exposures 

and risks for residential uses of aminocyclopyrachlor for non-food uses on turf (D369057, March 

17, 2010). No risks of concern were identified for application to lawn/turf from 

short/intermediate-term inhalation exposures during open mixing/loading and applying. Postapplication hand-to-mouth, object-to-mouth, and soil ingestion exposures and risks were also 

assessed for children and no risks of concern were identified. Dermal risks were not assessed 

because no dermal endpoint was identified. 
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Aggregate exposures to aminocyclopyrachlor were considered for residential short- and 

intermediate-term scenarios and dietary exposures for children and adults. No risks of concern 

were identified.

Occupational Exposure 

Aminocyclopyrachlor will be applied to rangeland, pastures, or Conservation Reserve Program 

(CRP) acres aerially or by groundboom. Occupational handler exposures may occur via the 

dermal and inhalation routes. These exposures are short-term or intermediate-term in duration. 

Dermal risks were not assessed because no dermal endpoint was identified from the toxicity 

database. Cancer risks for occupational handlers were not assessed because no cancer hazards 

were identified. 

Inhalation risk for applicators in the absence of respiratory protection was assessed by analysis of 

short/intermediate-term exposures using the product with the highest application rate. No risks 

of concern were identified. 

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 better characterize the hazard of chronic exposure to the environmental 

photodegradate, cyclopropane carboxylic acid. The Registrant is currently conducting a study to 

address this duration of exposure. The aminocyclopyrachlor database is not sufficient to support 

rotation to crops other than grasses at this time, as limited rotational crop field trials remain 

outstanding. 

HED recommends conditional registration for use on grasses and further recommends that labels 

be amended to prohibit rotation to crops other than grasses until these outstanding data needs are 

addressed. HED is also providing recommendations for proposed tolerances. 

Use of Human Studies

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. Some of these studies are also 

subject to review by the Human Studies Review Board. All of the studies used have received the 

appropriate review.
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2.0 HED 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, 

repeated-dose toxicity data are needed to identify a NOAEL for microvesicular hepatic steatosis 

in a sensitive species for the environmental photodegradate cyclopropane carboxylic acid. The 

Registrant is currently conducting a study to address this. The database is not sufficient to 

support rotation to crops other than grasses at this time, as limited rotational crop field trials 

remain outstanding. HED also recommends that an analytical reference standard for 

aminocyclopyrachlor-methyl be supplied and that supplies be replenished as requested by the 

Repository. 

HED recommends conditional registration for use on grasses. The revised label should include 

a rotational crop restriction (i.e., 1 year plantback interval (PBI)) in order for rotation not to be a 

condition of registration.) If a shorter PBI is requested, rotational data should be submitted. 

HED is also providing recommendations for proposed tolerances. 

2.1 Data Deficiencies/Conditions of Registration

HED recommends conditional registration for use on grasses pending receipt of a repeated-dose 

toxicity data for cyclopropane carboxylic acid to identify a NOAEL for microvesicular hepatic 

steatosis in a sensitive species. This study was a condition of registration for the previous risk 

assessment and the Registrant is currently conducting the study. 

HED further recommends that labels be amended to prohibit rotation to crops other than grasses 

until a guideline (860.1900) Field Accumulation in Rotational Crops study is received. 

HED also recommends that an analytical reference standard for aminocyclopyrachlor-methyl be 

supplied and that supplies be replenished as requested by the Repository, as discussed in 

Memorandum D387442 (T. Morton, April 18, 2012). 
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2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

The recommended tolerance expression and tolerance proposals for aminocyclopyrachlor are 

found in Section 2.2.3.

The petitioner has proposed high performance liquid chromatography methods with tandem mass 

spectrometry detection (LC/MS/MS) for enforcement of tolerances for aminocyclopyrachlor on 

grass commodities, DuPont-22582 SU1 RV2, and livestock commodities, DuPont-27162, 

Revision No. 1. The methods adequately determine residues of aminocyclopyrachlor and 

aminocyclopyrachlor-methyl as well as the metabolites IN-LXT69 and INQFH57 and INQGC48 (grass commodities only), in/on grass forage and hay and milk, eggs, and bovine tissues. 

The validated limit of quantitation (LOQ) is 0.01 ppm for each analyte. HED has concluded that 

the livestock and grass methods are adequate for enforcement purposes. HED has determined 

that tolerance method validation (TMV) by EPA’s Analytical Chemistry Branch is not needed 

for the proposed enforcement methods for plant and livestock commodities. The proposed 

enforcement methods or earlier versions of the methods were used for data collection in the 

submitted storage stability, cattle feeding, and grass crop field trial studies. 

Acceptable multiresidue methods test data have been submitted for aminocyclopyrachlor and 

aminocyclopyrachlor-methyl. The data indicate that multiresidue methods may be appropriate 

for determination of aminocyclopyrachlor-methyl but are not suitable for determination of 

aminocyclopyrachlor or for determination of the two analytes together. The submitted data will 

be forwarded to the U.S. Food and Drug Administration (FDA) for further evaluation.

2.2.2 International Harmonization

There are no established or proposed Codex or Canadian maximum residue limits (MRLs) for 

aminocyclopyrachlor in or on any food or feed crops. Therefore, there are no harmonization 

issues. 

2.2.3 Recommended Tolerances

It is recommended that tolerances be established for residues of the herbicide 

aminocyclopyrachlor, including its metabolites and degradates, in or on the commodities

specified in Table 2.1. 

Compliance with the specified tolerance levels is to be determined by measuring only the sum of 

aminocyclopyrachlor [6-amino-5-chloro-2-cyclopropyl-4-pyrimidinecarboxylic acid], and 

aminocyclopyrachlor-methyl [methyl 6-amino-5-chloro-2-cyclopropyl-4-pyrimidinecarboxylate] 

calculated as the stoichiometric equivalent of aminocyclopyrachlor, in or on the commodity.
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Table 2.1 Tolerance Summary for Aminocyclopyrachlor

Commodity Established/Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments

Cattle, fat 0.07 0.05

Cattle, liver 0.06 Not required Based on current Agency policy a separate lower tolerance for liver is not 

appropriate

Cattle, meat 0.02 0.02

Cattle, meat byproducts, except liver 0.4 Not required

Cattle, meat byproducts -- 0.30 Based on current Agency policy, the meat byproducts tolerance should be based 

on the highest residue between liver, kidney, and fat.

Goat, fat 0.07 0.05

Goat, liver 0.06 Not required See comment for cattle, liver

Goat, meat 0.02 0.02

Goat, meat byproducts, except liver 0.4 Not required

Goat, meat byproducts -- 0.30 See comment for cattle, meat byproducts, except kidney

Grass, forage 65 80*

Grass, hay 125 200*

Horse, fat 0.07 0.05

Horse, liver 0.06 Not required See comment for cattle, liver

Horse, meat 0.02 0.02

Horse, meat byproducts, except liver 0.4 Not required

Horse, meat byproducts -- 0.30 See comment for cattle, meat byproducts

Milk 0.035 0.02

Sheep, fat 0.07 0.05

Sheep, liver 0.06 Not required See comment for cattle, liver

Sheep, meat 0.02 0.02

Sheep, meat byproducts, except liver 0.4 Not required

Sheep, meat byproducts -- 0.30 See comment for cattle, meat byproducts

*Based on OECD MRL Calculator
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2.2.4 Revisions to Petitioned-For Tolerances

The Agency used the OECD MRL Calculator (March 2011 version) to determine the appropriate 

tolerance levels in grass forage and hay, whereas the petitioner used a NAFTA calculator. In 

instances in which these calculators yielded different results, the Agency used the OECD 

calculator to establish tolerances. The OECD calculator indicated that proposed tolerances of 65

ppm and 125 ppm for grass forage and hay were too low and should be established at 80 ppm 

and 200 ppm, respectively. The cattle feeding study data indicate that tolerances are needed for 

milk, and the tissues of cattle, goat, horse, and sheep. The proposed tolerance in milk is too high, 

and the proposed tolerances for liver and meat byproducts, except liver are not consistent with 

Agency policy. For livestock commodities, individual tolerances in cow, goat, horse, and sheep 

should be established for meat byproducts at 0.30 ppm, fat at 0.05 ppm, and meat at 0.02 ppm. 

The tolerance for milk should be established at 0.02 ppm. The tolerances for liver and meat 

byproducts, except liver are not needed. 

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

Pending submission of the required limited field rotational crop trials, HED recommends that 

labels be revised to prohibit rotation to any crop other than grasses following application of 

aminocyclopyrachlor or aminocyclopyrachlor-methyl.

2.3.2 Recommendations from Occupational Assessment

There are no label recommendations from the occupational assessment. 

2.3.3 Recommendations from Residential Assessment

There are no label recommendations from the residential assessment. 
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3.0 Introduction

3.1 Chemical Identity

Table 3.1 Test Compound Nomenclature-Aminocyclopyrachlor (parent acid)

Chemical Structure

N

N

NH2

Cl

O

OH

Empirical Formula C8H8ClN3O2

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

End-use product/EP 352-782, 352-787, 352-ILR (with chlorsulfuron), 352-ILN (with 

metsulfuron)

Chemical Class Pyrimidine carboxylic acid 

Known Impurities of Concern None
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Table 3.2 Test Compound Nomenclature—Aminocyclopyrachlor (potassium salt)

Chemical Structure

N

N

NH2

Cl

O

O

– K+

Empirical Formula C8H7ClKN3O2

Common Name Aminocyclopyrachlor, potassium salt

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

End-use product/EP 352-786

Chemical Class Pyrimidine carboxylic acid 

Known Impurities of Concern None
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Table 3.3 Test Compound Nomenclature— Aminocyclopyrachlor-methyl (methyl ester)

Chemical Structure

N

N

NH2

Cl

O

O

CH3

Empirical Formula C9H10ClN3O2

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

End-use product/EP 352-783, 352-784, 352-785

Chemical Class Pyrimidine carboxylic acid 

Known Impurities of Concern None

3.2 Physical/Chemical Characteristics

Aminocyclopyrachlor has a log octanol/water partition coefficient of -2.48 at pH 7, a molecular 

weight of 213.6 g/mole (Memorandum D357886, 8/16/2009), and contains functional groups 

(e.g. carboxylic acid and a primary amine) that will be ionized at physiological pH. For these 

reasons, the potential for aminocyclopyrachlor to cross biological barriers (such as the skin) and 

biological membranes is considered low. Aminocyclopyrachlor-methyl has a log octanol/water 

partition coefficient of 1.87, a molecular weight of 227.6 g/mole (Memorandum D357975, 

8/25/2009) and one functional group that will be ionized at physiological pH (a primary amine). 

The presence of fewer charged groups and a log octanol-water partition coefficient in the range 

of -1 to 3.5 indicates an increased potential for aminocyclopyrachlor-methyl to cross biological 

barriers (such as the skin) compared to aminocyclopyrachlor. 

The potential for aminocyclopyrachlor and aminocyclopyrachlor-methyl to be inhaled as a 

volatile is considered low. Aminocyclopyrachlor has a vapor pressure of 6.92 x10-6Pa (6.92 

x10-9kPa) at 20 C and 4.91 x10-9kPa at 25 C (Memorandum D357886, August 16, 2009).

Aminocyclopyrachlor-methyl has a vapor pressure of 4.192 x 10-4Pa (4.192 x 10-7 kPa) at 20 C 

and 4.451 x 10-4Pa (4.451 x 10-7kPa) at 25 C. It was considered to have negligible tendency to 

evaporate from aqueous solutions based on Henry’s Law (Memorandum D357975, August 25, 

2009). 
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3.3 Pesticide Use Pattern

DuPont has submitted draft amended labels for the 50% WG formulation (EPA Reg. No. 352-

787), the 2 lb/gal SL formulation (EPA Reg. No. 352-786) of the potassium salt, and the 80% 

WG formulation (EPA Reg. No. 352-786) of aminocyclopyrachlor-methyl. A summary of the 

proposed use pattern is presented in Table 3.4 on page 13. 

The labels state that a nonionic surfactant (NIS) is the preferred adjuvant, to be included at 0.06-

0.50% v/v; crop oil concentrates (COCs), including petroleum or modified seed oil (MSO) may 

be used at up to 0.5% v/v for MSOs or at 1-2% v/v for all others. 

The products may be tank mixed with other herbicides, insecticides, and fungicides that are 

registered for the same use sites, methods of application, and timings. When tank mixing, the 

most restrictive label limitations of the products being used are to be followed; use of a spray 

adjuvant is specified for post emergence applications.

The label specifies a restricted entry interval (REI) of 12 hours. Coveralls and shoes plus socks 

are specified as PPE for contact with anything that has been treated with early entry into treated 

areas as permitted by the Worker Protection Standard. The Agency considers this REI and PPE 

adequate for the proposed use patterns. 

The following rotational crop restrictions are specified: a 4-month Plant Back Interval (PBI) is 

specified for grasses (over-seeding or renovation); and a 1-year PBI is specified for all other 

crops. Forage legumes may be seeded after a soil bioassay has been conducted verifying that the 

level of aminocyclopyrachlor in the soil will not adversely affect the new crop. 
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Table 3.4 Summary of Directions for Use of Aminocyclopyrachlor.

Applic. Timing, 

Type, and 

Equip.1

Formulation

[EPA Reg. No.]

Applic. 

Rate2

(lb ai/A)

Max. No. 

Applic. per 

Season 2

Max. 

Seasonal 

Applic. 

Rate

(lb ai/A)

PHI

(days)

Use Directions and 

Limitations

Pasture (including grass grown for hay) and Rangeland Grasses

Foliar,

Broadcast,

Ground (min. 10 

gal/A) or aerial 

(min. 2 gal/A)

50% WG [352-787]

2 lb/gal SL of the K 

salt 3

[352-786]

80% WG of 

aminocyclopyrachlormethyl 4

[352-785]

0.038-

0.172 2 0.281

0

(forage 

and hay)

Apply to new plantings 

when the majority of grasses 

are in the 3- to 4-leaf stage 

or to perennial native grasses 

and pasture grasses 

established for at least one 

growing season. A 30-day 

treatment interval is 

specified. Use of a spray 

adjuvant (nonionic surfactant 

or crop oil concentrate) is 

specified. Minimum spray 

volume of 10 gal/A for 

ground applications and 2 

gal/A for aerial applications.

1

 Do not apply through any type of irrigation system; a 12-hour reentry interval is specified.

2

 Rates expressed in terms of the aminocyclopyrachlor ai. Based on calculations, individual maximum application 

rates are 0.166 lb ai/A for the 50% WG, 0.172 lb ai/A for the 2 lb/gal K SL, and 0.164 lb ai/A for the 80% WG 

formulation. 

3

 Equivalent to 2 lb ae/gal aminocyclopyrachlor.

4

 Equivalent to 75% ae/gal aminocyclopyrachlor.

3.4 Anticipated Exposure Pathways

Humans may be exposed to aminocyclopyrachlor in meat and milk, since aminocyclopyrachlor

may be applied directly to pasture and rangelands on which cattle graze. Humans may also be 

exposed to aminocyclopyrachlor in surface and ground sources of drinking water after 

application. Non-dietary exposures to aminocyclopyrachlor can occur in residential settings 

during and after application to turf. In an occupational setting, applicators may be exposed while 

handling the pesticide prior to application, as well as during application. There is a potential for 

post-application exposure for workers re-entering treated fields. 

This risk assessment considers dietary and occupational exposures for the proposed new (first 

food) uses of aminocyclopyrachlor. It also considers the existing non-food uses that result in 

additional dietary exposures in drinking water. Risks from residential exposures were discussed 

in a previous assessment (Memorandum D369057, March 17, 2010). 
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3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf). As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the USDA under the Continuing 

Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all 

registered food uses of a pesticide. These data are analyzed and categorized by subgroups based 

on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to 

assess dietary exposure to smaller, specialized subgroups and exposure assessments are 

performed when conditions or circumstances warrant. Whenever appropriate, non-dietary 

exposures based on home use of pesticide products and associated risks for adult applicators and 

for children 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.
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4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

Aminocyclopyrachlor and aminocyclopyrachlor-methyl 

The toxicity database is sufficient for characterizing the hazards of aminocyclopyrachlor for 

exposures that are anticipated to occur via the dermal and oral routes. Dermal exposures are 

anticipated to be acute to subchronic, and a subchronic dermal toxicity study is available. 

Inhalation exposures are also anticipated to occur and are expected to be short-term to 

intermediate-term in duration. Oral exposures to aminocyclopyrachlor are expected to range in 

duration from acute to chronic, and there are several oral toxicity studies available from which to

assess these effects: 

An EPA guideline acute neurotoxicity study;

Subchronic EPA guideline toxicity studies in rats, mice, and dogs; prenatal development 

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

neurotoxicity study; and immunotoxicity studies in rats and mice;

A chronic toxicity study in dogs, a chronic toxicity and carcinogenicity study in rats, and 

a carcinogenicity study in mice.

There is also a complete genotoxicity battery of in vitro and in vivo studies, metabolism studies 

in rats that characterize the absorption, distribution, metabolism, and excretion (ADME) of 

aminocyclopyrachlor, and acute toxicity studies (oral, dermal, and inhalation studies in rats, eye 

irritation and dermal irritation studies in rabbits, and a skin sensitization study in guinea pigs). 

The toxicity database for aminocyclopyrachlor-methyl is being bridged by aminocyclopyrachlor 

and is also considered sufficient. The toxicity data supplied for aminocyclopyrachlor-methyl 

provide comparative endpoints with effects similar to aminocyclopyrachlor that support the 

bridging strategy. These studies are: 

An EPA guideline subchronic oral toxicity study in rats;

An OECD guideline one-generation reproduction study in rats that includes a modified 

functional observational battery;

Metabolism studies in rats that characterize the ADME of aminocyclopyrachlor-methyl 

and show that it is rapidly converted to aminocyclopyrachlor in rats; 

An in vitro genotoxicity (gene mutation) study.

No inhalation studies are available for aminocyclopyrachlor or aminocyclopyrachlor-methyl. An 

inhalation study is not required for the proposed uses because the risk estimates for occupational 

handlers are sufficiently protective (vapor pressure ≤ 4.5 x 10-7kPa, see Section 3.0; MOEs ≥ 

49,000, see Section 9.0). Since the MOEs were determined using the maximum seasonal 

application rate (as opposed to the lower single application rate) the MOEs are considered to be 

conservative. Future use requests may require that this decision be re-evaluated. 

No data in the open scientific literature are currently available for characterizing the hazard of 

aminocyclopyrachlor or aminocyclopyrachlor-methyl. 
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Cyclopropane carboxylic acid 

The toxicity database for the environmental photodegradate, cyclopropane carboxylic acid, is not 

considered complete. Literature studies are available that describe the mechanism of toxic action 

for cyclopropane carboxylic acid after limited repeated-dose exposure and the most sensitive 

species for this effect is also known, but the NOAEL for this effect has not been identified. 

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

The ADME data for aminocyclopyrachlor and aminocyclopyrachlor-methyl in rats indicate rapid 

absorption, low tissue bioavailability, and rapid clearance. The data further indicate that there is 

near-complete conversion of aminocyclopyrachlor-methyl to aminocyclopyrachlor and no 

metabolism of aminocyclopyrachlor. 

Pharmacokinetic studies in rats show that both aminocyclopyrachlor and aminocyclopyrachlormethyl 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. 

Aminocyclopyrachlor was distributed primarily to the GI contents (47-67%) and GI tract (10-

13%) after administration of a single dose of 25 or 500 mg/kg, with lower amounts present in 

the carcass (up to 5%), muscle (up to 2%), skin (up to 1.4%) and blood (up to 1%). The apparent 

lack of dose-related increase in the tissue content of radiolabel suggested saturation of uptake. 

However, levels in all of these tissues declined to very low levels (<0.5%) by 72 hours. Tissue 

distribution after repeated dosing at 25 mg/kg bw/day for 14 days was also examined. On Day 

13 at 6 hours following dose administration, levels were again highest in the GI tract (0.16-

0.22%) and GI contents in males/females (7.11-1.14%), but were reduced in magnitude 

compared to 6 hours following single-dose administration of 25 mg/kg in the GI tract (1.36-

1.42%) and GI contents (41.7% and 46.77%) in both sexes. Tissue distribution was similar with 

carcass > skin > blood, with all levels less than 0.5% within 6 hours of dosing and less than 

0.05% by 72 hours. 

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 aminocyclopyrachlor-methyl, the majority was recovered in the urine (78.80-

78.82%), with a smaller amount eliminated in the feces (1.72-4.57%). Bile duct cannulation 

experiments indicated a limited role for secretion of aminocyclopyrachlor or

aminocyclopyrachlor-methyl into the bile. 

Metabolite identification studies in urine, feces, and bile after administration of aminocyclopyrachlor confirmed that aminocyclopyrachlor is not metabolized. Aminocyclopyrachlormethyl was completely metabolized to aminocyclopyrachlor in urine and feces. In bile, <1%
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of aminocyclopyrachlor-methyl was not metabolized, with the majority (>99%) metabolized to 

aminocyclopyrachlor. 

Neither aminocyclopyrachlor nor aminocyclopyrachlor-methyl was eliminated as expired air. No 

sex differences in absorption, distribution, metabolism, or excretion were observed for either 

aminocyclopyrachlor or aminocyclopyrachlor-methyl. 

Evidence that aminocyclopyrachlor can be excreted into milk was not available in rat 

metabolism studies. However, a metabolism study with aminocyclopyrachlor-methyl in goats 

identified aminocyclopyrachlor residues in milk. 

4.3 Toxicological Effects

Aminocyclopyrachlor 

There are no target organs of toxicity for aminocyclopyrachlor. Mild systemic toxicity is 

observed via the oral route with repeated exposures at very high (limit) doses. This systemic 

toxicity is limited to decreased body weight and body weight gain. There is no appreciable 

increase in the severity of these effects with time. The most sensitive species is the rat. 

Toxic effects of aminocyclopyrachlor via the oral route of exposure (in the diet) in subchronic 

dietary studies in rats were limited to decreases in body weights (≤10%), body weight gains, 

food consumption, and food efficiency in both sexes when these compounds were at the limit 

dose (1000 mg/kg/day). Chronic dietary studies resulted in similar effects at the limit dose, with 

no appreciable increase in severity over time. No treatment-related tumors were observed in 

carcinogenicity studies. 

Subchronic dietary exposure of dogs to aminocyclopyrachlor resulted in no adverse effects at 

doses up to the highest dose, which was almost half the limit dose (426/388 mg/kg/day in 

males/females) in both sexes. A subsequent dietary study in dogs in which the dose was 

increased to the limit dose and the duration of exposure was extended to one year showed no 

evidence of toxicity at the limit dose. Similarly, subchronic and chronic dietary exposure studies 

in mice showed no adverse effects at the limit dose. No treatment-related tumors were observed 

in mice in carcinogenicity studies. 

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). 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%. These maternal weight losses occurred over a period of approximately 

5-7 days. No developmental effects were observed in rabbit kits. There were no effects of 
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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. A 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 

route in rats at the limit dose for 28 days. No repeated-exposure inhalation studies are available 

for aminocyclopyrachlor. 

Aminocyclopyrachlor has low acute toxicity by all routes of exposure (oral, dermal, inhalation) 

in rats and does not cause skin irritation in rats or skin sensitization in guinea pigs. However, 

aminocyclopyrachlor does cause mild eye irritation in rats. A full genotoxicity panel of in vitro

mutation assays in bacteria and mammalian cells as well as in vitro and in vivo studies for 

chromosomal aberrations showed that aminocyclopyrachlor is not genotoxic in the presence or 

absence of metabolic activation. 

Aminocyclopyrachlor-methyl 

The toxicity database for aminocyclopyrachlor-methyl is being bridged with 

aminocyclopyrachlor. Support for bridging via the oral route is provided by metabolism studies 

and by a full acute toxicity database and comparative toxicity studies with common endpoints for 

repeated exposures. Metabolism studies via the oral route show that that aminocyclopyrachlormethyl is rapidly converted to aminocyclopyrachlor. Acute toxicity studies resulted in the same 

toxicity category classifications for aminocyclopyrachlor-methyl as aminocyclopyrachlor for all 

studies. A subchronic dietary exposure study conducted in rats with aminocyclopyrachlormethyl showed effects of decreased body weight and body weight gain at the limit dose that were 

similar those observed with aminocyclopyrachlor. Similarly, an oral one-generation 

reproduction study in rats that includes a modified functional observational battery and a 

subchronic dietary study in rats showed no evidence of reproductive, developmental, or 

neurotoxicity at the limit dose. The results of these studies, together with decreased body weight 

and body weight gain at the limit dose, were similar to aminocyclopyrachlor. 

Aminocyclopyrachlor-methyl was also negative in a genotoxicity test (bacterial mutation) at 

doses similar to those tested for aminocyclopyrachlor. 

Cyclopropane carboxylic acid 

The toxicity of the environmental photodegradate of aminocyclopyrachlor, cyclopropane 

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

identified by structural activity relationships (SAR) in an Agency Memorandum (D370638, 

10/15/2009). There is a substantial amount of information on the toxicity of cyclopropane 

carboxylic acid in the open scientific literature that identifies the target organ of toxicity, the 

mechanism of toxicity, and the most sensitive species. As described in another Agency

Memorandum (D371431, 12/13/2009), the mechanism of toxicity of cyclopropane carboxylic 

acid has been identified by extensive pre-clinical study of the anxiolytic drug candidate 

panadiplon, which is metabolized to cyclopropane carboxylic acid after oral administration. This 

mechanism is severe impairment of mitochondrial function by inhibition of beta oxidation of 

fatty acids in the mitochondria. This results in decreased energy production in diverse organs, 

with the liver being highly sensitive. The toxic endpoint of concern to the Agency for 
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cyclopropane carboxylic acid was identified as microvesicular steatosis and necrosis in the liver. 

Hepatic microvesicular steatosis/necrosis can occur within 1-3 days and has also been observed 

after 2 weeks. The most sensitive species in which to observe hepatic microvesicular 

steatosis/necrosis resulting from cyclopropane carboxylic acid exposure is the rabbit. 

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

Aminocyclopyrachlor and aminocyclopyrachlor-methyl

The FQPA Safety Factor for aminocyclopyrachlor and aminocyclopyrachlor-methyl is reduced 

to 1X. 

Cyclopropane carboxylic acid 

The FQPA Safety Factor for cyclopropane carboxylic acid is retained at 10X for acute dietary 

exposures. This safety factor subsumes extrapolation from a LOAEL to a NOAEL for hepatic 

steatosis/necrosis in rabbits as well as a (low) potential for cyclopropane carboxylic acid to cause 

developmental toxicity that cannot be ruled out based on the available data. A 10X FQPA 

Safety Factor is considered protective because hepatic steatosis/necrosis and any developmental 

toxicity would be caused by the same cellular mechanism. Therefore, protecting for hepatic 

steatosis/necrosis would protect for any potential developmental toxicity resulting from very low 

dietary exposures to cyclopropane carboxylic acid. For chronic dietary exposures, the FQPA 

Safety Factor is increased from 10X to 30X due to an increase in duration of exposure while still 

using the same study utilized for the acute endpoint (hepatic steatosis/necrosis in rabbits). This

3-fold increase in the magnitude of the FQPA Safety Factor for extrapolation from acute to 

chronic duration is considered protective because the duration of this study was 14 days with the 

dose administered as a bolus (via gavage). Because the exposures in this study were repeated 

and a bolus dose was used that would over-estimate dietary exposure, the severity of the effects 

of hepatic steatosis/necrosis are not expected to vary substantially with time. 

4.4.1 Completeness of the Toxicology Database

Aminocyclopyrachlor and aminocyclopyrachlor-methyl

The toxicity database is considered adequate for assessing the sensitivity of infants and children 

under FQPA and selecting endpoints for dietary exposure to aminocyclopyrachlor and 

aminocyclopyrachlor-methyl. Therefore, no additional database uncertainty factors are needed. 

Cyclopropane carboxylic acid 

The toxicity database for cyclopropane carboxylic acid is adequate. There is a substantial 

amount of toxicological information for cyclopropane carboxylic acid available in the open 

scientific literature that identifies the target organ of toxicity, the mechanism of toxicity, and the 

most sensitive species. The FQPA Safety Factor for acute and chronic exposures accounts for 

residual uncertainties in the toxicity database. 
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4.4.2 Evidence of Neurotoxicity

Aminocyclopyrachlor and aminocyclopyrachlor-methyl

A developmental neurotoxicity study (DNT) is not required because no evidence of 

developmental toxicity and because no evidence of neurotoxicity was observed in the toxicity 

database. No evidence of peripheral or central nervous system toxicity 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 a one-generation 

reproduction study in rats with aminocyclopyrachlor-methyl that included a modified functional 

observational battery. 

Cyclopropane carboxylic acid 

Based on the mechanism of toxicity for cyclopropane carboxylic acid that has been identified in 

the open scientific literature, the Agency does not expect the nervous system to be more sensitive 

than the liver. Although there are no studies available that directly investigate the effects of 

cyclopropane carboxylic acid on the nervous system, there is indirect evidence that the endpoint 

on which the Agency is regulating cyclopropane carboxylic acid (hepatic steatosis/necrosis) is 

protective of the nervous system. First, the molecular mechanism underlying hepatic steatosis 

has been identified as inhibition of the metabolic pathway of beta oxidation of fatty acids in the 

mitochondria. This is a major, energy producing pathway in liver but not in brain. Since the 

ketone bodies generated by this process in the liver are metabolized by the brain for energy, any 

brain effects from inhibition of this pathway would be secondary to liver effects. Second, 

cyclopropane carboxylic acid is a metabolite of panadiplon, a drug that was developed to target 

the nervous system as an anxiolytic. Panadiplon failed in preclinical development, not as a 

result of neurotoxicity, but as a result of liver toxicity that was caused by cyclopropane 

carboxylic acid. The result that it was the adverse effects of cyclopropane carboxylic acid on the 

liver but not the nervous system that limited development of this drug provides further support 

that the liver is more sensitive than the brain. The Agency’s risk assessment is protective for 

hepatic steatosis/necrosis, and is therefore protective for any primary or secondary neurotoxicity 

that may result from cyclopropane carboxylic acid. 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

Aminocyclopyrachlor and aminocyclopyrachlor-methyl

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 these abortions were considered secondary to severe decreases in 

maternal body weight. There was also no evidence of increased susceptibility of offspring to 
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aminocyclopyrachlor or aminocyclopyrachlor-methyl 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. 

Cyclopropane carboxylic acid 

There is no information available that directly investigates the effects of this photodegradate 

during development or on young animals. However, there is indirect evidence from the open 

scientific literature that the young may potentially be more sensitive to the metabolic effects of 

cyclopropane carboxylic acid, and this evidence does not allow this potential sensitivity to be 

ruled out. This evidence is provided by inherited conditions, specifically inborn errors of 

metabolism, that result in an effect (compromised metabolism of fatty acids) that is qualitatively 

similar to that of cyclopropane carboxylic acid (inhibition of beta oxidation of fatty acids). 

These inborn errors of metabolism result in energy deficiencies during periods of fasting, and it

is known that developing/young children are more sensitive to these effects than pregnant 

women or adults. The magnitude of this effect would be much more severe in the inherited case 

than for cyclopropane carboxylic acid. This is because fatty acid oxidation is almost completely 

compromised in the inherited case and other cellular processes are also impacted, whereas only 

beta oxidation of fatty acids would be impacted for cyclopropane carboxylic acid, and the 

magnitude of this impact is anticipated to be negligible for the estimated (low-level) dietary 

exposures. 

4.4.4 Residual Uncertainty in the Exposure Database

Aminocyclopyrachlor and aminocyclopyrachlor-methyl

The dietary exposure assessment is based on conservative, health-protective assumptions that 

ensure that exposures to aminocyclopyrachlor and aminocyclopyrachlor-methyl are not 

underestimated. These assumptions include tolerance-level residues and 100% crop treated 

estimates for all commodities. Furthermore, conservative, upper-bound assumptions were used 

to determine exposure through drinking water and residential sources, such that these exposures 

have not been underestimated.

Cyclopropane carboxylic acid 

The dietary exposure assessment is based on conservative, health-protective assumptions that 

ensure that exposures to cyclopropane carboxylic acid are not underestimated. These 

assumptions include tolerance-level residues and 100% crop treated estimates for all 

commodities. Furthermore, conservative, upper-bound assumptions were used to determine 

exposure through drinking water and residential sources, such that these exposures have not been 

underestimated.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment
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Aminocyclopyrachlor

The only endpoint identified in the toxicity database for aminocyclopyrachlor was decreased

body weight. The only species in which this effect was observed was the rat. The dose-response 

for this effect is very shallow, with adverse effects on body weight occurring only at the limit 

dose with subchronic or chronic administration. There is no acute endpoint because body weight 

decreases occurring from aminocyclopyrachlor are a repeated-dose effect. The dose-levels at 

which no adverse effects were identified were similar between subchronic and chronic studies, at 

about 380 mg/kg bw/day and 280 mg/kg bw/day, respectively. This difference may be only 

apparent as a consequence of dose spacing in these studies, or may be due to an increase in the 

severity of this effect with time. Selection of endpoints based on decreased body weight for a rat 

study of an appropriate duration relevant to the exposure scenario of interest is therefore 

protective of all adverse effects. 

Cyclopropane carboxylic acid 

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 conducted in rabbits that was published in the open

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. 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

The same toxicity endpoint has been identified for oral, dermal, and inhalation exposures to 

aminocyclopyrachlor. This endpoint is decreased body weight, and was the only endpoint 

identified in the hazard database for this chemical. Moreover, this same endpoint is used for 

exposures by all relevant routes to aminocyclopyrachlor-methyl due to evidence that 

aminocyclopyrachlor-methyl is rapidly converted to aminocyclopyrachlor in the body. No 

dermal hazard was identified at the limit dose. However, oral and inhalation routes of exposure 

should be combined based on use of the same endpoint for aminocyclopyrachlor/

aminocyclopyrachlor-methyl for any scenarios in which simultaneous exposures via these routes 

is anticipated. 

The only anticipated route of exposure to the environmental photodegradate cyclopropane

carboxylic acid is oral (in drinking water). Since the toxicity of cyclopropane carboxylic acid is 

biologically and quantitatively different than aminocyclopyrachlor/ aminocyclopyrachlormethyl, coincident oral exposures to these chemicals should not be combined. 

4.5.3 Cancer Classification and Risk Assessment Recommendation
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Aminocyclopyrachlor 

The carcinogenic potential of aminocyclopyrachlor was examined in chronic dietary studies in 

rats and mice, a full battery of in vitro and in vivo genotoxicity assays, and by structure-activity 

relationships (SAR). Chronic administration of aminocyclopyrachlor in rats and mice did not 

cause treatment-related tumors at doses up to the limit dose. Genotoxicity assays were negative. 

SAR analysis in conjunction with experimental data indicated no basis for concern. In 

accordance with the EPA's Final Guidelines for Carcinogen Risk Assessment1, the 

aminocyclopyrachlor was classified as ―Not Likely to be Carcinogenic to Humans‖ (CARC 

Memo, J. Kidwell, November 9, 2011). Therefore, there is no cancer risk associated with 

aminocyclopyrachlor. 

Cyclopropane carboxylic acid

No chronic dietary studies have been performed to assess the carcinogenic potential of 

cyclopropane carboxylic acid. No structural alerts for genotoxicity or carcinogenicity were 

observed in SAR analysis, and there are no reports of tumorgenic responses to cyclopropane 

carboxylic acid or panadiplon (which is metabolized to cyclopropane carboxylic acid) in the 

open scientific literature. 

 

1 Guidelines for Carcinogen Risk Assessment. Risk Assessment Forum, US EPA, Washington, DC. EPA/630/P03/001F. March 2005. 
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4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

Aminocyclopyrachlor 

Table 4.1 Summary of Toxicological Doses and Endpoints for Aminocyclopyrachlor for Use 

in Dietary and Non-Occupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary 

(General 

Population, 

including 

Females 13-49 

years of age)

NA

(No hazard 

was 

identified).

NA NA

Acute Neurotoxicity-rat (870.6200a) 

NOAEL = 2000 mg/kg/day. No acute 

neurotoxicity. 

Chronic Dietary 

(All 

Populations)

NOAEL= 

279

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Chronic RfD 

= 2.79 

mg/kg/day

cPAD = 2.79

mg/kg/day

Combined chronic toxicity/

carcinogenicity-rat

LOAEL = 892/957 mg/kg/day based on 

mild decreases in body weight/body 

weight gain.

Incidental Oral 

Short-/Intermediate Term

(1-30 days/1-6 

months)

NOAEL= 

350 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Residential 

LOC for 

MOE = 100

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 

Short-/Intermediate Term

(1-30 days/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-/Intermediate Term

(1-30 days/1-6 

months)

NOAEL= 

350 

mg/kg/day

UFA= 10x

UFH=10x

Residential 

LOC for 

MOE = 100

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)

―Not likely‖ to be carcinogenic in humans 

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 FQPA SF = FQPA Safety Factor. PAD = 

population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not 

applicable.
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Table 4.2 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 

Short-/Intermediate Term

(1-30 days/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-/Intermediate Term

(1-30 days/1-6 

months)

NOAEL= 

350 

mg/kg/day

UFA= 10x

UFH=10x

LOC for MOE = 

100

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)

―Not likely‖ to be carcinogenic in humans 

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. N/A = not applicable.
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Cyclopropane carboxylic acid 

Table 4.3 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

FQPA SF1=10x

RfD=

0.026 

mg/kg/day

aPAD=0.0026

mg/kg/day

Rabbit study 

MRID 47916803 (1998)

Non-guideline, oral (gavage) for 14 days

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

0, 2.55, 5 mg/kg/day (cyclopropane carboxylic 

acid) 

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

FQPA SF2=30x

RfD=

0.0087

mg/kg/day

cPAD=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. UFDB = to account for the absence of key 

data (i.e., lack of a critical study). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

1The FQPA SF of 10X is a composite of UFL and UFDB.

2The FQPA SF of 30X is a composite of UFL,UFDB, and UFS.

5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The nature of the residue in grass and livestock is adequately understood for the purposes of this 

petition. Metabolism studies in grasses, rotational crops, and livestock were performed using 

[2-pyrimidinyl14C] aminocyclopyrachlor-methyl, which is considered sufficient to evaluate the 

metabolism of aminocyclopyrachlor and the aminocyclopyrachlor potassium salt. Because 

grass is not a significant feed stuff for poultry, a hen metabolism study is not required at this 

time; however, a hen metabolism study may be needed to support future uses on additional 

crops. 
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Primary crops (grasses)

Aminocyclopyrachlor-methyl was identified in grass from all harvest intervals; residues declined 

from 24.7% TRR (3.86 ppm) at 0 days after application (DAA) to 8.6% total radioactive residues

(TRR) (0.211 ppm) at 60 DAA. Aminocyclopyrachlor was the major identified residue in grass 

samples at all harvest intervals, accounting for 32.9-67.7% TRR (0.805-10.5 ppm). Several 

minor metabolites were identified, including IN-LXT69, IN-QFH57, IN-QGC48, IN-Q3007, and 

IN-V0977. IN-LXT69 was identified at all sampling intervals, accounting for 4.2-6.1% TRR 

(0.138- 0.769 ppm); the remaining metabolites were each present at ≤ 4.1% TRR.

Rotational crops

Aminocyclopyrachlor accounted for 83.1% and 80.1% TRR (0.014 and 0.021 ppm) in 30- and 

60-days after treatment (DAT) immature cabbage and for 60.0% and 60.6% TRR (0.014 and 

0.008 ppm) in 30- and 60-DAT mature cabbage following application at 0.067 lb ai/A, and for 

54.3% TRR (0.006 ppm) and 83.0% TRR (0.010 ppm) in 300-DAT immature and mature 

cabbage following application at 0.329 lb ai/A. In turnips, aminocyclopyrachlor accounted for 

96.0% TRR (0.010 ppm) in 30-DAT immature roots, for 57.3-83.1% TRR (0.010-0.017 ppm) in 

30-, 60-, 120-, and 300-DAT immature tops following application at 0.067 lb ai/A, and for 40.5-

59.3% TRR (0.004-0.007 ppm) in 60- and 120-DAT mature turnip tops; residues of 

aminocyclopyrachlor were 85.6% TRR (0.072 ppm) in 300-DAT immature turnip tops following 

application at 0.329 lb ai/A.

In corn, aminocyclopyrachlor accounted for 62.7-71.4% TRR (0.007-0.176 ppm) in 15-, 120-, 

and 300-DAT forage following application at 0.067 and/or 0.329 lb ai/A. In stover, 

aminocyclopyrachlor accounted for 71.9% TRR (0.106 ppm) declining to 45.9% TRR (0.026 

ppm) in 15-, 120-, and 300-DAT samples following application at 0.067 lb ai/A, and for 58.0% 

TRR (0.151 ppm) in 300-DAT samples following application at 0.329 lb ai/A. Residues of 

aminocyclopyrachlor in cobs accounted for 58.9% and 43.8% TRR (0.014 and 0.005 ppm) in 15-

DAT and 300-DAT samples harvested following application at 0.067 and 0.329 lb ai/A, 

respectively. Residues in grain were 70.9-76.0% TRR (0.009-0.064 ppm) in 15-, 120-, and 300-

DAT samples following application at 0.067 and/or 0.329 lb ai/A. 

Aminocyclopyrachlor-methyl was identified in immature and mature 30-DAT cabbage, mature 

60-DAT cabbage, and immature 300-DAT cabbage following application at 0.329 lb ai/A, and 

immature turnip roots at 3.3-4.6% TRR. In turnip tops, residues accounted for 15.9-17.8% TRR 

(0.002-0.003 ppm) in 30- and 60-DAT immature and mature tops, and for 5.6% TRR (0.001 

ppm) in 120-DAT immature tops. In 15-DAT corn forage and stover, aminocyclopyrachlormethyl accounted for 9.1-10.0% TRR (0.009-0.013 ppm); residues were identified at ≤5.4% 

TRR in 15-DAT grain and cobs, and 300-DAT forage and/or stover and grain following 

application at 0.067 and/or 0.329 lb ai/A. Remaining residues were characterized as minor 

unknowns, including an apolar unknown and multicomponent minor unknowns, which 

accounted for 5.0-6.9% TRR (0.012-0.018 ppm) and 16.3-25.3% TRR (0.038-0.064 ppm), 

respectively, in 300-DAT corn forage and stover following application at 0.329 ppm, and 

together accounted for ≤0.014 ppm in all remaining matrices. 
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Livestock 

Aminocyclopyrachlor-methyl was not detected in excreta, milk, or any tissue. The parent acid, 

aminocyclopyrachlor, was the only compound identified and was found in all matrices. It was 

the single radiolabeled component detected in liver (65.7% TRR; 0.197 ppm), kidney (55.3% 

TRR; 0.925 ppm), omental fat (47.5% TRR; 0.005 ppm), renal fat (83.8% TRR; 0.013 ppm), and 

subcutaneous fat (80.7% TRR; 0.021 ppm). Aminocyclopyrachlor was detected in muscle at 

43.3% TRR (0.018 ppm) along with two minor unknowns (14.4-18.3% TRR; 0.006- 0.008 ppm), 

and in milk at 15.9% TRR (0.004 ppm) along with three minor unknowns (7.4-29.5% TRR; 

0.002-0.007 ppm). TLC analysis of liver and kidney extracts prior to SPE clean-up (86.7% TRR 

and 98.3% TRR, respectively) confirmed that aminocyclopyrachlor was the only compound 

present in these samples.

5.1.2 Summary of Environmental Degradation

The following information on environmental stability and degradation products of 

aminocyclopyrachlor is summarized from EFED’s ―Drinking Water Degradates Identification 

Memorandum for Aminocyclopyrachlor‖ Memorandum (D368339, August 25, 2009). 

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. 
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5.1.3 Comparison of Metabolic Pathways

The metabolism of aminocyclopyrachlor and aminocyclopyrachlor-methyl in grass, rotational 

crops, livestock, and rats has been well characterized. In crops, livestock, and rats 

aminocyclopyrachlor-methyl is converted to aminocyclopyrachlor. For mammals (livestock and 

rats), there is no further metabolism. However, in plants aminocyclopyrachlor is subsequently 

decarboxylated to form the metabolite IN-LXT69. Photo-induced simultaneous elimination of 

hydrogen chloride and pyrimidine ring contraction (occurring as a minor pathway) yields the 

imidazole-nitrile metabolite, IN-QGC48, which undergoes demethylation to form IN-QFH57; 

IN-QFH57 may also be formed through photolysis of aminocyclopyrachlor. An additional minor 

pathway involves pyrimidine ring opening proceeding through the postulated intermediate INYY905, with subsequent oxidations to form the amide and carboxylic acid compounds, INQ3007 and IN-V0977, respectively. 

5.1.4 Residues of Concern Summary and Rationale

Plants and livestock

For grass and rotational crops and livestock commodities, the Residues of Concern 

Knowledgebase Subcommittee (ROCKS) recommended that aminocyclopyrachlor and 

aminocyclopyrachlor-methyl be the residues of concern for both the tolerance expression and the 

risk assessment (Memorandum D393619, September 22, 2011). Although additional metabolites 

were measured in grass crop field trials, they were all present at low levels, ranging from less 

than the Level of Quantification (LOQ) to 0.11 ppm. Results from metabolism and feeding 

studies show that aminocyclopyrachlor is the major residue in ruminant commodities. Although 

quantifiable residues of aminocyclopyrachlor-methyl are not expected in edible livestock 

commodities, its inclusion as a residue of concern is recommended for the convenience to have 

the same tolerance expression for all relevant agricultural commodities. The analytical method 

determines both the ester and acid in the same analysis. Based on these considerations, the 

ROCKS recommended that aminocyclopyrachlor and aminocyclopyrachlor-methyl are included 

for risk assessment and tolerance enforcement purposes. 

Drinking water

For drinking water, the ROCKS recommended that residues of concern are aminocyclopyrachlor 

and cyclopropane carboxylic acid (IN-V0977) in surface water and aminocyclopyrachlor in 

ground water (Memorandum D370638, October 15, 2009). Four of the degradates (IN-LXT69, 

IN-QFH57, 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 mechanism of toxic action is impairment of mitochondrial function by 

inhibiting the beta oxidation of fatty acids in the liver, resulting in microvesicular steatosis 

(accumulation of small fat droplets in cells) in the liver that is often accompanied by liver 

necrosis and inflammation, decreased hepatic glycogen, and decreased blood glucose levels. The 

time of onset, dose-response, and species sensitivity for this effect also differ from 

aminocyclopyrachlor (Memorandum D371431, December 31, 2009). 
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Table 5.1 Summary of Metabolites and Degradates to be included in the Risk 

Assessment and Tolerance Expression

Matrix Residues included in Risk Assessment Residues included in Tolerance 

Expression

Plants Primary Crop

(Grass Only)

Aminocyclopyrachlor and 

Aminocyclopyrachlor-methyl1

Aminocyclopyrachlor and 

Aminocyclopyrachlor-methyl

Rotational Crop Aminocyclopyrachlor and 

Aminocyclopyrachlor-methyl

Aminocyclopyrachlor and 

Aminocyclopyrachlor-methyl

Livestock Ruminant Aminocyclopyrachlor and 

Aminocyclopyrachlor-methyl

Aminocyclopyrachlor and 

Aminocyclopyrachlor-methyl

Poultry Not Applicable Not Applicable

Drinking water Aminocyclopyrachlor

Cyclopropane carboxylic acid 

(IN-V0977)

Not Applicable

1 Aminocyclopyrachlor is 6-amino-5-chloro-2-cyclopropyl-4-pyrimidinecarboxylic acid; Aminocyclopyrachlormethyl is methyl 6-amino-5-chloro-2-cyclopropyl-4-pyrimidinecarboxylate.

5.2 Food Residue Profile

Adequate residue data are available to support dietary risk assessment and proposed tolerances 

on grasses and livestock commodities. However, rotational crop studies indicate that rotational 

crop tolerances may be needed. Adequate data are not available to support a dietary assessment 

or proposed tolerances on rotational crop commodities. In the absence of the required limited 

field rotational crop trials, the labels must be revised to prohibit rotation to any crop other than 

grasses following application of aminocyclopyrachlor or aminocyclopyrachlor-methyl. The 

revised label should include a rotational crop restriction (i.e. 1 year plantback interval (PBI)) in 

order for rotation not to be a condition of registration. If a shorter PBI is requested, rotational 

data should be submitted. 

A detailed description of crop field trials is provided in Memorandum D387442 (April 18, 2012). 

Crop field trials (grass forage and hay) were conducted in North America. Residues were 

quantifiable and combined residues of aminocyclopyrachlor-methyl and aminocyclopyrachlor 

declined with increasing PHI in grass forage and hay. Storage stability studies on grass forage 

and hay showed that residues of aminocyclopyrachlor and aminocyclopyrachlor-methyl are 

stable in/on grass forage and hay stored frozen (-20 °C) for up to 499-502 days (~16.5 months). 

Cattle feeding studies showed that residues of aminocyclopyrachlor were quantifiable in milk 

and cream but did not concentrate in cream. Residues were highest in kidney, followed by fat, 

liver, and muscle. Storage stability studies showed that aminocyclopyrachlor and 

aminocyclopyrachlor-methyl are stable when stored frozen (-20 °C) for up to 146 days (4.8 

months) in milk, skim milk and cream; up to 138 days (4.5 months) in muscle; and up to 147 

days (4.8 months) in fat. Residues of aminocyclopyrachlor-methyl were unstable in kidney and 

liver and underwent biotransformation to aminocyclopyrachlor during frozen storage (-20 °C). 

However, residues of aminocyclopyrachlor were stable in liver up to 147 days (2.9 months) and 
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in kidney up to 88 days (2.9 months). 

Residue studies in rotational crops indicate that residues of aminocyclopyrachlor may exceed the 

0.01-ppm trigger value in turnip tops and corn forage, stover, and grain at a 300-day PHI 

following application of aminocyclopyrachlor at ~1x the maximum proposed seasonal 

application rate to grass. Based on the study results limited rotational crop field trials are 

required for aminocyclopyrachlor to establish PBIs and/or tolerances for rotational crops. 

Pending submission of the required limited field rotational crop trials, the labels must be revised 

to prohibit rotation to any crop other than grasses following application of aminocyclopyrachlor 

or aminocyclopyrachlor-methyl. 

HED does not require residue data for any processed commodities associated with grass. 

Therefore, data requirements for processed food and feed are not relevant to this tolerance 

petition.

5.3 Water Residue Profile

The previous drinking water assessment for aminocyclopyrachlor (D368238, October 15, 2009) 

was updated for the proposed new use on rangeland (D394887, November 3, 2011). It was also 

updated to reflect no application of percent cropped area for non-agricultural crops (e.g. 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 of aminocyclopyrachlor and cyclopropane carboxylic acid (IN-V0977), 

which were identified as residues of concern. For ground water, the SCI-GROW model 

(Screening Concentration in Ground Water Program Version 2.3 was used to predict the 

maximum acute and acute concentrations of aminocyclopyrachlor present in shallow ground 

water. Cyclopropane carboxylic acid (IN-V0977) is not anticipated to be present in ground 

water due to the absence of sunlight (IN-V0977 is a photodegradate of aminocyclopyrachlor). 
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Table 5.2 Summary of Estimated Surface Water and Groundwater Concentrations for 

Aminocyclopyrachlor

Drinking 

Water 

Source 

(Model)

Compound Use Method

Application 

Rate

(interval 

between 

applications)

Adjustment 

Factor 1

Peak Day 

(acute) 

Concentration 

(μg/L)

Annual 

Average

(chronic) 

Concentration 

(μg/L)

Surface Water 

(FIRST)

Aminocyclopyrachlor 

Rangeland Aerial

2 app @ 

0.17 lb a.e./A 

(30 days)

1.0

34.28 21.32

Turf Granular

3 app @ 0.108 

lb a.e./A

(30 days)

31.36 19.50

Cyclopropanecarboxylic 

Acid (IN-V0977)

Rangeland

Granular 2

2 app @ 

0.01 lb a.e./A

(30 days)

2.12 1.52

Turf

3 app @ 

0.006 lb a.e./A

(30 days)

2.00 1.43

Ground Water 

(SCI-GROW) Aminocyclopyrachlor 

Rangeland ---

2 app @

0.17 lb a.e./A

(30 days)

--- 42.2 <42.2

Turf 3 ---

3 app @ 0.108 

a.e./acre

(30 days)

--- 40.2 <40.2

Bold values denote maximum Estimated Drinking Water Concentrations (EDWCs)

1 Adjustment Factors: PCA = Percent Crop Area

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

All applications are liquid unless otherwise noted. 

3 Model estimates obtained from D386238
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5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Aminocyclopyrachlor was registered only for non-food uses. The current proposed use on 

grass and pastureland was described in a memorandum (D387446, 04/18/2012) that updates the 

previous assessment (D372779, 1/19/10) by adding this proposed new use and incorporating 

revised Estimated Drinking Water Concentrations (EDWCs). A chronic dietary exposure 

analysis (food and drinking water) was performed in order to support a Section 3 request for the 

new use of aminocyclopyrachlor on livestock commodities after grazing on treated grass and 

pastureland The analysis was performed using the Dietary Exposure Evaluation Model DEEMFCIDTM, Version 2.03. This model uses food consumption data from the U.S. Department of 

Agriculture’s (USDA’s) Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-

1996 along with a supplemental children’s survey from 1998. The analysis included tolerance 

residue levels and a 100% crop treated assumption. For the chronic exposure to 

aminocyclopyrachlor the ground water EDWC of 42.2 ppb was used. 

Dietary assessments for the drinking water degradate, cyclopropane carboxylic acid, were also 

performed using the revised EDWCs. An annual peak of 2.12 ppb was used for the acute 

dietary assessment and an annual average of 1.52 ppb was used for the chronic dietary 

assessment. 

5.4.2 Percent Crop Treated Used in Dietary Assessment

Percent crop treated values were not estimated. A default of 100% was used. 

5.4.3 Acute Dietary Risk Assessment

There is no acute dietary risk for aminocyclopyrachlor because no hazard was identified. For 

cyclopropane carboxylic acid, the most highly exposed population subgroup is All Infants (<1 

year old), with risk estimates of 16% of the acute population adjusted dose (aPAD)(See Table 

5.4). This is below HED’s level of concern for all population subgroups (<100% (aPAD) acute 

Population Adjusted Dose). 

5.4.4 Chronic Dietary Risk Assessment

A chronic dietary analysis was conducted for both aminocyclopyrachlor and cyclopropane 

carboxylic acid. For aminocyclopyrachlor, the most highly exposed population subgroup is All 

Infants (<1 year old), with risk estimates of <1 % of the acute population adjusted dose (cPAD)

(see Table 5.3). For the cyclopropane carboxylic acid, the most highly exposed population 

subgroup is All Infants (<1 year old), with risk estimates of 12% of the chronic population

adjusted dose (cPAD) (see Table 5.4). These risk estimates for aminocyclopyrachlor and 

cyclopropane carboxylic acid are below HED’s level of concern for all population subgroups 

(<100% (cPAD) acute Population Adjusted Dose). 
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The most conservative (e.g. largest magnitude) estimates of chronic dietary exposure to 

aminocyclopyrachlor for children and adults were used to determine aggregate risk from 

exposure to aminocyclopyrachlor from residential and dietary scenarios in Section 7.0. These 

estimates for adults were 0.001054 mg/kg bw/day determined for the General U.S. Population 

and 0.003184 mg/kg bw/day determined for All Infants (< 1 year old) in Table 5.4.1. 
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5.4.5 Cancer Dietary Risk Assessment

No cancer dietary risk assessment was performed because aminocyclopyrachlor was classified as 

―Not Likely to be Carcinogenic to Humans‖ (CARC Memo, J. Kidwell, November 9, 2011). 

5.4.6 Summary Tables

Table 5.3 Summary of Dietary Exposure and Risk for Aminocyclopyrachlor and 

Aminocyclopyrachlor-methyl (Food and Drinking Water)

Population Subgroup*

Acute Dietary Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day) % aPAD

Dietary 

Exposure

(mg/kg/day) % cPAD

Dietary 

Exposure

(mg/kg/day) Risk

General U.S. Population

Not applicable: No acute 

dietary endpoint was 

identified

0.0010541 <1

Not Applicable at this 

time. 

All Infants (< 1 year old) 0.0031842 <1

Children 1-2 years old 0.002122 <1

Children 3-5 years old 0.001771 <1

Children 6-12 years old 0.001171 <1

Youth 13-19 years old 0.000786 <1

Adults 20-49 years old 0.000922 <1

Adults 50+ years old 0.000959 <1

Females 13-49 years old 0.000919 <1

* The values for the highest exposed population for each type of risk assessment are bolded.

1Used for Adult Male and Adult Female in Dietary MOE calculations for aggregate risk in Table 7.2. 

2Used for Child Dietary MOE calculations for aggregate risk in Table 7.2. 
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Table 5.4 Summary of Dietary Exposure and Risk for Aminocyclopyrachlor Metabolite

Cyclopropane Carboxylic Acid (IN-V0977) (Drinking Water Only)

Population Subgroup*

Acute Dietary

95th percentile Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day) % aPAD

Dietary 

Exposure

(mg/kg/day) % cPAD

Dietary 

Exposure

(mg/kg/day) Risk

General U.S. Population 0.000111 4.3 0.000032 3.7

Not applicable at this 

time. 

All Infants (< 1 year old) 0.000418 16 0.000105 12

Children 1-2 years old 0.000174 6.7 0.000048 5.5

Children 3-5 years old 0.000159 6.1 0.000045 5.1

Children 6-12 years old 0.000111 4.3 0.000031 3.5

Youth 13-19 years old 0.000090 3.5 0.000023 2.7

Adults 20-49 years old 0.000103 4.0 0.000030 3.4

Adults 50+ years old 0.000093 3.6 0.000031 3.6

Females 13-49 years old 0.000103 4.0 0.000030 3.4

* The values for the highest exposed population for each type of risk assessment are bolded.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

No new residential uses for aminocyclopyrachlor are proposed in this action. The Agency has 

previously assessed exposures and risks for residential uses of aminocyclopyrachlor for non-food 

uses on turf (Memorandum D369057, March 17, 2010). No risks of concern were identified for 

application to lawn/turf from short-term and intermediate-term inhalation exposures during open 

mixing/loading and applying when using a LOC of 100. Although a point of departure from an 

oral study was used to assess residential handler inhalation risks for aminocyclopyrachlor, HED 

does not believe this assessment is under-protective of adult handlers. MOEs calculated for 

residential handlers were all ≥ 7,300,000 and thus provided an ample margin of safety to account 

for any uncertainties in route-to-route extrapolation. Post-application hand-to-mouth, object-tomouth, and soil ingestion exposures and risks were also assessed for children and no risks of 
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concern were identified when using a LOC of 100. Dermal risks were not assessed because no 

dermal endpoint was identified. The data tables containing these risk estimates are reproduced 

below, and the most conservative estimates are labeled with an asterisk (*). 

Table 6.1 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

( g/lb ai)

Inhalation

Daily Dose

(mg/kg/day)

Inhalation

Short/IntermediateTerm MOE

Open Mixing, Loading, 

and Applying

Low Pressure 

Handwand

(Soluble Liquid)

0.07

0.5

30

0.000015 23,000,000

Open Mixing, Loading, 

and Applying

Hose-end Sprayer

(Dry Flowable)

17 0.0000085 41,200,000

Open Mixing, Loading, 

and Applying

Belly Grinder

(Granular)

0.10 62 0.000048 7,300,000**

*Designated as Table 6.1.1 in D369057, March 17, 2010.

**Most conservative estimate for use in aggregate risk calculations (MOE Inhalation Residential Exposure, Adult 

Male, Adult Female in Table 7.2). 

ae=acid equivalent; A=acre; ai=active ingredient
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Table 6.2 Residential Risk Estimates for Post-Application Exposure to 

Aminocyclopyrachlor (Acid and Potassium Salt) and Aminocyclopyrachlor-Methyl for 

Children 3-6 Years of Age* 

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

N/A Oral 0.1

234,000** 493,000

Object to Mouth 322,000

Activity on Turf

938,000

Soil Ingestion 70,000,000

*Designated as Table 6.2.1: Toddler Residential Risk Estimates for Post-Application Exposure to 

Aminocyclopyrachlor (Acid and Potassium Salt) and Aminocyclopyrachlor-Methyl in Memorandum D369057, 

March 17, 2010. Note that ―Toddler‖ has been changed to Children 3-6 years of age. 

**Most conservative estimate for use in aggregate risk calculations (MOE Oral Residential Exposure, Child in Table 

7.2). 

Aminocyclopyrachlor is persistent in soil and has the potential to accumulate with repeated 

applications. In a recent assessment (Memorandum D38477, 04/18/2012), the Agency assessed 

intermediate-term risk from soil ingestion by using a yearly application rate of 0.56 lb ai/A for

aminocyclopyrachlor, which is double the maximum single rate of 0.28 lb ai/A. This is a 

conservative approach that would address incidental oral risk due to the potential build up of 

aminocyclopyrachlor in the soil and would also be protective for long-term soil ingestion. The 

same oral endpoint and LOC for MOE of 100 were utilized. No risks of concern were identified 

(MOE = 1.25 x 107). 

Importantly, this risk estimate for intermediate-/long-term soil ingestion is 50-fold less 

conservative than the short-term Hand-to-Mouth Activity on Turf estimate of 234,000 in Table 

6.2. It is this latter (more conservative) estimate that is used to determine aggregate risk. 

6.1 Combined Exposure

The potential for combined exposure to aminocyclopyrachlor by both children and adults was 

considered in this assessment. No endpoint has been identified for dermal toxicity due to lack of 

toxicity at the limit dose. The same toxicity endpoint was identified for inhalation and incidental 

oral exposures. However, HED anticipates that adults would have only inhalation exposures that 

would be limited to application and that children would have only oral exposures that would be 

limited to post-application. Therefore, HED considers it unlikely that simultaneous exposure to 

aminocyclopyrachlor would occur for non-food routes and so routes of exposure were not 
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combined for non-food risk assessments. However, HED is aggregating inhalation and 

incidental oral exposures with dietary exposures, as described in Section 7.0. Humans will be 

exposed to cyclopropane carboxylic acid, an environmental degradate of aminocyclopyrachlor, 

only in drinking water. The toxicity endpoint for this degradate is qualitatively and 

quantitatively different from aminocyclopyrachlor. 

6.2 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 (see the Agency’s Spray Drift website for more 

information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). 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.

Although a quantitative residential post application inhalation exposure assessment was not 

performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation 

exposure assessment was performed for flaggers. This exposure scenario is representative of a 

worse case inhalation (drift) exposure and may be considered protective of most outdoor 

agricultural and commercial post application inhalation exposure scenarios.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

risks from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure. Although there is potential for aggregate exposures to 

aminocyclopyrachlor from residential uses and dietary exposure, there is no potential for 

aggregate exposures to cyclopropane carboxylic acid because exposure can only occur in 

drinking water. 
Aminocyclopyrachlor Human Health Risk Assessment DP No. D387448

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7.1 Acute Aggregate Risk

No acute dietary endpoint for aminocyclopyrachlor was identified. Therefore, acute aggregate

risks from combined exposures to aminocyclopyrachlor were not assessed. 

7.2 Short-/Intermediate-Term Aggregate 

In aggregating short-term risk, HED considers background chronic dietary exposure (food + 

water) and short-term, residential exposures. Aggregate risk for adults was determined by 

combining short/intermediate-term inhalation risks during application of aminocyclopyrachlor 

with risks from chronic dietary exposure. Aggregate risk for children was determined by 

combining risks from short-term, post-application incidental oral exposures with chronic dietary 

exposure. These risk estimates are summarized in Table 7.2. The LOC for all residential 

scenarios and dietary exposures was 100. No aggregate risks of concern were identified. 

Table 7.2 Short-/Intermediate Term Aggregate Risk Calculations for 

Aminocyclopyrachlor and Aminocyclopyrachlor-methyl

Population

Short- or Intermediate-Term Scenario

LOC for 

Aggregate 

Risk1

Dietary

MOE2

MOE Oral 

Residential 

Exposure3

MOE

Dermal 

Residential 

Exposure4

MOE

Inhalation 

Residential 

Exposure5

Aggregate 

MOE (food, 

water, and 

residential)6

Adult Male 100 265,000 NA NA 7, 300,000 260,000

Adult Female 100 265,000 NA NA 7, 300,000 260,000

Child 100 88,000 234,000 NA NA 64,000

1

10X (interspecies), 10X (intraspecies)

2 MOE dietary = Chronic dietary POD [Table 4.5.4.1] / dietary exposure [Table 5.4.1]. 

MOE dietary (Adult Male, Adult Female) = [(279 mg/kg bw/day) / (0.0010504 mg/kg bw/day)]= 265,000. 

MOE dietary (Child) = [(279 mg/kg bw/day )/(0.003184 mg/kg bw/day)] = 88,000. 

3 Most conservative estimate in Table 6.2 (Short-Term Hand-to-Mouth Activity on Turf). 

4 No dermal endpoint was identified. 

5 Most conservative estimate in Table 6.1 (Belly Grinder). 

6 MOE Aggregate = 1 / [(1/MOE dietary) + (1/MOE oral) + (1/MOE dermal) + (1/MOE inhalation)]

7.3 Chronic Aggregate Risk

There are no long-term residential exposure scenarios for aminocyclopyrachlor, and so chronic 

aggregate risks were not assessed. Chronic dietary risks for exposure to aminocyclopyrachlor 

were assessed in Section 5. 

7.4 Cancer Aggregate Risk
Aminocyclopyrachlor Human Health Risk Assessment DP No. D387448

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Cancer aggregate risk was not assessed because aminocyclopyrachlor was classified as ―Not 

Likely to be Carcinogenic to Humans‖ (CARC Memo, J. Kidwell, November 9, 2011). 

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to aminocyclopyrachlor and any other substances and aminocyclopyrachlor does not appear to 

produce a toxic metabolite produced by other substances. For the purposes of this tolerance 

action, therefore, EPA has not assumed that aminocyclopyrachlor has a common mechanism of 

toxicity with other substances. For information regarding EPA’s efforts to determine which 

chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such 

chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning 

common mechanism determinations and procedures for cumulating effects from substances 

found to have a common mechanism on EPA’s website at 

http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

Occupational exposures and risks were assessed for aminocyclopyrachlor and 

aminocyclopyrachlor-methyl. Exposure to the environmental degradate, cyclopropane 

carboxylic acid, is not expected because residue chemistry studies (MRID 4833617) indicate that 

cyclopropane carboxylic acid is not found on the surface of crops. 

9.1 Short-/Intermediate-Term Handler Risk

Aminocyclopyrachlor will be applied to rangeland, pastures, or CRP acres aerially or by 

groundboom. Occupational handler exposures to aminocyclopyrachlor and 

aminocyclopyrachlor-methyl via these application methods during application or following 

application (post-application) may occur dermally and by inhalation. These exposures are shortterm or intermediate-term in duration based on the potential for multiple applications per season. 

Cancer risks for occupational handlers were not assessed because no cancer hazards were 

identified. 

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 for applicators was not 

done. Inhalation risk for applicators in the absence of respiratory protection was assessed by 

analysis of short-term and intermediate-term exposures using the product (EPA Reg. No. 352-

786) with the highest application rate (0.28 lbs of acid equivalent/acre). Inhalation unit

exposures were quantified using the PHED Surrogate Exposure Guide (August 1998). Hazards 

were quantified from subchronic oral toxicity studies. A target margin of exposure (MOE) of 
Aminocyclopyrachlor Human Health Risk Assessment DP No. D387448

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100 was utilized. Risk estimates for the proposed new use on rangeland/pastures/CRP acres are 

summarized in Table 9.1.

No risks of concern for applicators were identified in occupational exposure scenarios, as the 

calculated MOEs were 81-fold to 13,000-fold higher than the target MOE of 100. 
Aminocyclopyrachlor Human Health Risk Assessment DP No. D387448

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Table 9.1. Short-/Intermediate-Term Occupational Exposure and Risk Estimates for

Aminocyclopyrachlor and Aminocyclopyrahclor-methyl . All estimates are without mitigation (e.g. 

without PPE)

Exposure 

Scenario Crops

Application.

Rate

(lb ae/A)1

Area Treated

(A/day)2

Inhalation

Unit Exposure

( g/lb ai)7

Inhalation

Daily Dose

(mg/kg/day)3

Inhalation

Short/Intermediate-term 

MOE4

Mixer/Loader (dry flowable) 5

Groundboom

Pasture/ Rangeland 

grasses6 0.28

200

8.96

0.007168 49,000

Aerial 1200 0.043008 8,100

Applying (dry flowable)

Groundboom

(Open Cab) Pasture/ Rangeland 

grasses

0.28

200 0.34 0.000272 1,300,000

Aerial

(enclosed Cockpit) 1200 0.068 0.000327 1,100,000

Flagging (dry flowable)

Aerial

Flagging

Pasture/ Rangeland 

grasses

0.28 1200 0.35 0.00168 210,000

1. Application rates are based on maximum values found in proposed labels (ae = acid equivalent) 

2. Daily area treated is based on the area or gallons that can be reasonably applied in a single day or ―one time application-(non-crop)‖ for each exposure scenario of concern based on the 

application method and formulation/packaging type. (standard EPA/OPP/HED values).

3. Daily Dose (mg/kg/day) was calculated by Unit Exposure * 100% * Appl. rate * Area treated} / 70 kg. Short and Intermediate-term endpoints are the same, thus one column. 

4. Short-/Intermediate-Term MOE = Inhalation NOAEL (350 mg/kg/day). The LOC for the target MOE = 100.

5. Note: Open mixing and loading formulation was calculated using a ―dry-flowable‖ exposure scenario. See PHED version 1.1 for details.

6. Rangeland Grasses: Weeds /non-agricultural item. Max. "Yearly" application label rate for pasture/rangeland only: 9 oz./Acre/application.: (9oz./Acre x 1lb/16 oz) x 50% = .28 lbs ae/ 

Acre) "One time Application/year" Reference label [352-786].

7. HED policies on use of surrogate data, including their sources, are presented in the ―Occupational Pesticide Handler Unit Exposure Surrogate Reference Table‖ 

(http://www.epa.gov/pesticides/science/handler-exposure-table.pdf) and (http://www.epa.gov/pesticides/science/handler-exposure-data.html)
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9.2 Short-/Intermediate-Term Post-Application Risk

9.2.1 Dermal Post application Risk

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

hazard was identified at the limit dose in a subchronic dermal toxicity study. 

9.2.2 Inhalation Post application Risk

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for aminocyclopyrachlor at this time primarily because of the low 

acute inhalation toxicity (Toxicity Category III and IV), low vapor pressure (less than 1x10-5

kPa), and the low proposed use rate. However, there are multiple potential sources of postapplication inhalation exposure to individuals performing post-application activities in 

previously treated fields. These potential sources include volatilization of pesticides and 

resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert 

advice and input on issues related to volatilization of pesticides from its Federal Insecticide, 

Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and 

received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate occupational 

post-application inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for aminocyclopyrachlor.

Although a quantitative occupational postapplication inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

higher exposure than postapplication exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of most occupational postapplication 

inhalation exposure scenarios.
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10.0 References (in Data Package Number Order)

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

August 25, 2009, D357975. 

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

August 16, 20009, D357886. 

Drinking water assessment for aminocyclopyrachlor acid and its degradate cyclopropane

carboxylic acid (IN-V0977) for non-crop and turf use, C. Khoper, January 8, 2010, D368238. 

Aminocyclopyrachlor. Report of the Residues of Concern Knowledgebase Subcommittee 

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

Aminocyclopyrachlor: Human Health Risk Assessment for Proposed Uses as an Herbicide, J. 

Ryman, J, Miller, T. Morton, March 17, 2010, D369057. 

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

D371413, TXR 0055290.

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. 

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

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

Aminocyclopyrachlor. Petition for Tolerances in Support of New Uses on Grasses (PP#0F7817). 

Summary of Analytical Chemistry and Residue Data, T. Morton, April 18, 2012, D387442. 

Aminocyclopyrachlor: Acute and Chronic Dietary Exposure Analysis for the Section 3 

Registration Action, T. Morton, April 18, 2012, D387446. 

Aminocyclopyrachlor, Aminocyclopyrachlor Methyl Ester, and Aminocyclopyrachlor Potassium 

Salt: Worker Risk Analysis for Amended Use on Rangeland Grasses, J. Miller, April 18, 2012, 

D387447. 

Aminocyclopyrachlor. Report of the Residues of Concern Knowledgebase Subcommittee 

(ROCKS), I. Negron-Encarnacion, September 22, 2011, D393619. 

Updated Drinking Water Exposure Assessment for Aminocyclopyrachlor Acid and its Degradate 

Cyclopropanecarboxylic Acid (IN-V0977) for Turf, and the Proposed New Use on Rangeland

(Tolerance # 0F7817), R. Baris and M. Corbin, November 3, 2011, D394887. 
Aminocyclopyrachlor Human Health Risk Assessment DP No. D387448

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AMINOCYCLOPYRACHLOR: Report of the Cancer Assessment Review Committee, J. 

Kidwell, November 9, 2011, TXR 0056120. 

Aminocyclopyrachlor-ToxSAC Meeting on September 15, 2011, J. Kidwell, October 11, 2011. 

Lowrie, C. (2009) The Metabolism of [14C]DPX-KJM44 (Methyl Ester of DPX-MAT28) in 

Grass. Project ID Number: 807943. Sponsor Study Number: DuPont-22393. Unpublished 

study prepared by E. I. du Pont de Nemours and Company. 102 p. MRID 48333617. 
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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for FOOD use for AMINOCYLOPYRACHLOR are in Table 1. (Use of the 

new guideline numbers does not imply that the new (1998) guideline protocols were used).

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

yes

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

yes

yes

yes

yes

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

1Rationale described in a Memorandum entitled ―Recommended waivers of conditionally required toxicology studies for non-food uses of 

aminocyclopyrachlor‖ (J. Ryman, February 4, 2010, D373897). 

2Rationale 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).
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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

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.
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0/0, 34.8/44.8, 

114.3/145.7, 

349.4/448.0, 

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.

870.4100b

Chronic Toxicitynonrodent 

48333608 (2010)

Acceptable/guideline

0, 1250, 5000, 15,000,

NOAEL = 30,000 ppm (1077/1073 mg/kg/day M/F) 

LOAEL = Not observed. 
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or 30, 000 ppm

0/0, 38/47, 178/175, 

465/542, 1077/1073 

mg/kg/day M/F

870.4200a 

Carcinogenicity-mouse

48333606 (2010)

Acceptable/guideline

0, 300, 1000, 3000, 

7000 ppm 

0/0, 39/50, 133/171, 

393/527, 876/1190 

mg/kg/day M/F

Chronic toxicity NOAEL = 7000 ppm (876/1190 mg/kg 

bw/day) 

Chronic toxicity LOAEL = Not observed. 

Not carcinogenic.

870.4300

Combined chronic 

toxicity/carcinogenicityrat 

48333607 (2010)

Acceptable/guideline

0, 600, 2000, 6000, 

18,000 ppm 

0/0, 27/29, 97/100, 

279/309, 892/957

mg/kg/day M/F

Chronic toxicity NOAEL = 6000 ppm (279/309 mg/kg 

bw/day) 

Chronic toxicity LOAEL = 18,000 ppm (892/957 mg/kg 

bw/day) based on mild decreases in body weight/body 

weight gain

Not carcinogenic. 

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 Waiver recommended
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Delayed Neurotox-hen No study available 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, 

1044.6/1424.9 

mg/kg/day (M/F)

NOAEL = 18,000 ppm (limit dose) (1044.6/1424.9 

mg/kg/day M/F) 

No subchronic neurotoxicity.

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.

870.7485

Metabolism and 

Pharmacokinetics-rat

48333610 (2010)

Acceptable/guideline

Confirms 47560023 and extends observations to bile-duct 

cannulated animals, tissue distribution, and metabolism for 

single and repeated-dose administration. There was 

evidence for a limited role of enterohepatic circulation. 

Distribution highest in GI tract/GI contents followed by 

carcass, skin, and blood. Elimination near-complete (<1%) 

72 hours after administration. Evidence of saturation of 

uptake, as percentage of radiolabel in tissues decreases with 

repeated-dose administration. DPX-MAT28 identified as 

sole radiolabelled substance in excreta, indicating no 

metabolism. 

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
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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 –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 

Mutation

47560033 (2005)

Acceptable/Nonguideline

0, 100, 333, 1000, 

3333, or 5000 

μg/plate (+/-S9)

There was no evidence of induced mutant colonies over 

background in the presence or absence of S9-activation.

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. 

870.7485

Metabolism and 

Pharmacokinetics-rat

48333609 (2010)

Acceptable/guideline

Confirms 47560024 and extends observations to bile-duct 

cannulated animals, tissue distribution, and metabolism. 

There was no evidence of elimination in bile. Tissue 

distribution was less than 1%. The majority was eliminated 

in the urine as DPX-MAT28 with less than 1% of DPXKJM44 remaining. In the bile, no unmetablolized DPXKJM44 was identified, as all had been metabolized to DPXMAT28.
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Table A.2.5 Toxicity Profile for Cyclopropane Carboxylic Acid (IN-V0977, 

Environmental Degradate) 

Guideline No

Study Type 

MRID 

Classification

Doses 

Results 

Non-guideline 14-day 

oral toxicity study

47916803 (1995)

Acceptable/nonguideline

0, 10, 20 mkd oral 

(gavage) 

administration of 

panadiplon* to 

rabbits (10/dose) for 

14 days 

*metabolized to 

cyclopropane 

carboxylic acid 

NOAEL = Not observed 

LOAEL = 10 mkd panadiplon (2.5 mkd cyclopropane 

carboxylic acid) based on gross liver lesions and microscopic 

effects of microvesicular hepatic steatosis and necrosis. 

A.3.1 Acute Reference Dose (aRfD) - Females age 13-49

Aminocyclopyrachlor 

Study Selected: Acute neurotoxicity-rat 

MRID No.: 47560015

Executive Summary: See Appendix A, Guideline 870.6300

Dose and Endpoint for Risk Assessment: NOAEL = 2000 mg/kg/day. No LOAEL was 

identified. 

Comments about Study/Endpoint/Uncertainty Factors: This study was selected because it 

of the most relevant exposure duration and there is no evidence of any effects in the toxicity 

database for longer duration studies that may be attributable to a single exposure. Maternal 

deaths and abortions were observed in the prenatal developmental study in rats at 1000 mg/kg 

bw/day. This study was considered as an acute endpoint. However, it was not selected because 

these maternal deaths/abortions were considered secondary to large weight losses that occurred 

over a period of 5-7 days, and so were not considered a single dose effect. A 10X interspecies 

and a 10X intraspecies uncertainty factors are required. Reduction of the FQPA Safety Factor to 

1X is justified. 

Cyclopropane carboxylic acid 

Study Selected: 14 day oral toxicity study

MRID No.: 47916803

Executive Summary: See Appendix A

Dose and Endpoint for Risk Assessment: NOAEL = Not observed. LOAEL=10 mg/kg/day 

panadiplon* (2.5 mg/kg/day cyclopropane carboxylic acid). (*Panadiplon is metabolized to 

cyclopropane carboxylic acid). 

Comments about Study/Endpoint/Uncertainty Factors: This study was selected because it 

measures the most sensitive effect (hepatic microvesicular steatosis) in the most sensitive species 

(rabbit) via a relevant route of exposure (oral). This is a non-guideline, literature study and the 
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only duration of exposure examined was 14 days. This study was considered as an acute 

endpoint. For acute exposures, the standard 10X FQPA safety factor is retained due to lack of a 

NOAEL and lack of data examining the toxicity of this degradate during development. The 

standard 10X interspecies and a 10X intraspecies uncertainty factors will also be utilized. 

A.3.2 Acute Reference Dose (aRfD) - General Population

Aminocyclopyrachlor 

Same as Acute Reference Dose (aRfD)-Females age 13-49. 

Cyclopropane carboxylic acid

Same as Acute Reference Dose (aRfD)-Females age 13-49. 

A.3.3 Chronic Reference Dose (cRfD) `

Aminocyclopyrachlor

Study Selected: Combined chronic toxicity/carcinogenicity-rat 

MRID No.: 48333607

Executive Summary: See Appendix A, Guideline 870.4300

Dose and Endpoint for Risk Assessment: NOAEL = 279/309 mg/kg/day in males/females (use

279 mg/kg bw/day). The LOAEL is 892/957 mg/kg bw/day in males/females based on mild 

decreases in body weight/gain with no treatment-related tumors. 

Comments about Study/Endpoint/Uncertainty Factors: This study was selected because this 

is the lowest NOAEL at which body weight decreases (the only adverse effect observed in the 

toxicity database for rats) were observed. When compared to the 90-day rat oral study, this 

NOAEL is lower than the 349/448 mg/kg bw/day. It is unclear if this difference is due to an 

increase in the sensitivity of the rats over time to the test substance, or if it is an artifact of dose 

spacing. Regardless, using the NOAEL in the chronic/carcinogenicity study as the POD is 

protective. A 10X interspecies and a 10X intraspecies uncertainty factor are required. Reduction 

of the FQPA Safety Factor to 1X is justified. 

Cyclopropane carboxylic acid 

Study Selected: 14 day oral toxicity study

MRID No.: 47916803

Executive Summary: See Appendix A

Dose and Endpoint for Risk Assessment: NOAEL = Not observed. LOAEL=10 mg/kg/day 

panadiplon* (2.5 mg/kg/day cyclopropane carboxylic acid). (*Panadiplon is metabolized to 

cyclopropane carboxylic acid). 

Comments about Study/Endpoint/Uncertainty Factors: This study was selected because it 

measures the most sensitive effect (hepatic microvesicular steatosis) in the most sensitive species 

(rabbit) via a relevant route of exposure (oral). This is a non-guideline, literature study and the 

only duration of exposure examined was 14 days. The standard 10X FQPA safety factor is 

retained due to lack of a NOAEL and lack of data examining the toxicity of this degradate during 

development. The standard 10X interspecies and a 10X intraspecies uncertainty factors will also 

be utilized. An additional 3X uncertainty factor is also applied for extrapolation from an acute 

to a chronic endpoint.
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A.3.4 Incidental Oral Exposure (Short- and Intermediate-Term)

Study Selected: 90 day oral-rat

MRID No.: 475373403/47560007

Executive Summary: See Appendix A, Guideline 870.3100

Dose and Endpoint for Risk Assessment: NOAEL = 349/448 mg/kg/day (use 350 mg/kg 

bw/day). The LOAEL is 1045/1425 mg/kg bw/day base on decreased body weight/gain, food 

consumption/efficiency in both sexes. 

Comments about Study/Endpoint/Uncertainty Factors: This study was selected because it is 

of the most relevant exposure duration (a 28 day oral toxicity study was not available), the 

endpoints of concern for this chemical are included, and the rat is the most sensitive species at 

this endpoint. Therefore, use of this study for the endpoint is both conservative and protective. 

A 10X interspecies and a 10X intraspecies uncertainty factors are required. Reduction of the 

FQPA Safety Factor to 1X is justified. 

A.3.5 Dermal Exposure (Short-, Intermediate- and Long-Term)

Study Selected: 28-day dermal toxicity-rat 

MRID No.: 47725701

Executive Summary: See Appendix A, Guideline 870.3200

Dose and Endpoint for Risk Assessment: NOAEL = 1000 mg/kg/day. No LOAEL was 

identified. 

Comments about Study/Endpoint/Uncertainty Factors: This study was selected because it is 

a route-specific study in the most sensitive species that measured the endpoint of concern 

(decreased body weight/gain) for this chemical. A 10X interspecies and a 10X intraspecies 

uncertainty factors are required. Reduction of the FQPA Safety Factor to 1X is justified. 

A.3.6 Inhalation Exposure (Short-, Intermediate-Term) 

Study Selected: 90 day oral-rat

MRID No.: 475373403/47560007

Executive Summary: See Appendix A, Guideline 870.3100

Dose and Endpoint for Risk Assessment: NOAEL = 349/448 mg/kg/day (use 350 mg/kg 

bw/day). The LOAEL is 1045/1425 mg/kg bw/day based on decreased body weight/gain, food 

consumption/efficiency in both sexes. 

Comments about Study/Endpoint/Uncertainty Factors: This study was selected because no 

route-specific study was available. Therefore, extrapolation from the oral route at 100% is being 

performed. This study is of an appropriate duration to cover intermediate-term exposure. It is 

also protective for short-term exposures (a 28-study is not available). The endpoints of concern 

for this chemical are included and the rat is the most sensitive species. A 10X interspecies and a 

10X intraspecies uncertainty factors are required. Reduction of the FQPA Safety Factor to 1X is 

justified. 

A.4 Executive Summaries
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A.4.1 Subchronic Toxicity

Non-guideline 14-Day Oral Toxicity-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 

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. 
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This 90-day oral toxicity study in female Dutch-belted rabbit is acceptable/non-guideline. 

870.3100 90-Day Oral Toxicity - Rat

EXECUTIVE SUMMARY: In a subchronic oral and neurotoxicity study (MRID 47573403), 

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. 

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 
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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-MAT29 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. 

.

870.3100 90-Day Oral Toxicity - Mouse

EXECUTIVE SUMMARY: In a subchronic oral toxicity study (MRIDs 47560010 and 

47560011), Aminocyclopyrachlor (92.2% a.i.; Batch# DPX-MAT28-009) was administered to 

15 CD-1 mice/sex/dose group in the diet at dose levels of 0, 300, 1000, 3000, or 7000 ppm 

(equivalent to 0/0, 47/61, 154/230, 459/649, and 1088/1623 mg/kg/day, in males/females) for 

approximately 90 days (95/96 days in males/females). At Day 60, blood was collected from the 

orbital sinus or tail vein of each mouse from the satellite groups (5/sex/concentration) for the 

determination of plasma concentration of the test substance (DPX-MAT28) and metabolite (INLXT69).

There were no treatment-related deaths during the study. Small but statistically significant 

decreases in body weights were seen for males starting at Day 49 and continuing through the end 

of treatment at doses of 1000, 3000, and 7000 ppm (↓4-8%). Significant decreases in body 

weights (↓8-11%) were observed for females at 1000, 3000, and 7000 ppm. Body weight gains 

from Day 0-91 were significantly decreased in males ( 12-27%) at 1000 and 7000 ppm. 

Decreases in body weight gains were not statistically significant for females. There were no 

effects on food consumption for either sex. Overall food efficiency (Days 0-91) was significantly 

decreased (↓24%) in the 7000 ppm males and in females at 1000 ppm and 7000 ppm ( 28-36%), 

but not at 3000 ppm. 

The number of reticulocytes in the 7000 ppm females was significantly decreased (p<0.05) by 

15% compared to controls, but this was not considered adverse. 
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Absolute and relative (to brain weight) changes in organ weights were observed, 

but these were not considered adverse due to a lack of corroborating macroscopic or microscopic 

effects. These changes were: decreased absolute and relative heart weights (↓17-19%) at 

7000 ppm compared to controls, increased relative (to body weight) brain weights in the 1000 

ppm males, decreased relative (to brain) heart weights in the 1000 ppm females, and increased 

relative (to body weight) kidney weights in the 1000 ppm females.

The LOAEL was not observed. The NOAEL is 7000 ppm (equivalent to 1088/1623 

mg/kg/day in males/females).

The plasma concentration of the parent DPX-MAT28 and the metabolite IN-LXT69 were 

measured on Day 60. Plasma concentrations of DPX-MAT28 were increased in all treated 

groups and was slightly higher in males than females at all dose levels. The IN-IXT69 

metabolite was not detected in any samples. 

This study is classified as Acceptable/Guideline and satisfies the guideline requirements 

(OPPTS 870.3100a; OECD 408) for a subchronic oral toxicity study in mice.

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 
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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.

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. 

870.3465 90-Day Inhalation – Rat

None available. 

A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study - Rat
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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.

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 
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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 anogenital 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 

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.
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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.

A.4.3 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. 

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. 
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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. 

A.4.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity – Rat

EXECUTIVE SUMMARY: Five groups of Main male and female Crl:CD(SD) rats 

(70/sex/group) were administered DPX-MAT28 in the diet at concentrations of 0, 600, 2000, 

6000, or 18000 ppm (0/0, 27/29, 279/309, 892/957 mg/kg bw/day in males/females) for 2 years. 

Satellite animals (10/sex/dose) were administered DPX-MAT28 at these same dietary 

concentrations. For both Main and Satellite animals, body weights and food consumption were 

evaluated prior to dietary exposure, weekly for the first 13 weeks, and then biweekly thereafter. 

Body weights were also recorded on the day of necropsy. Detailed clinical observations were 

performed prior to dietary exposure, on the day of first dietary exposure, and weekly thereafter. 

Ophthalmological assessments were performed prior to the start of dietary exposure and near the 

end of the exposure period. For Satellite animals, hematology, clinical chemistry, and urinalysis 

were performed at 6 months and 1 year and coagulation measurements were performed at 1 year. 

For Main Study animals, blood smears and white blood differential counts were performed at 1 
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year and 2 years and for animals sacrificed in extremis. Satellite and Main Study animals were 

sacrificed, organ weights were recorded, and gross and histopathology performed at 1 year and 2 

years, respectively. 

Mild effects on body weight and body weight gain were observed in both sexes at the highest 

dose. These effects were considered transient, since they resolved by study completion. 

Quantification of body weight decreases at Days 189, 385, and 539 revealed that the magnitudes 

of the decreases in body weight were less than 10% in males and were above 10% in females (at 

12%) only at Day 539. Quantification of decreases in body weight gain over Weeks 1, 1-13, 1-

52, and 1-104 revealed that decreased body weight gain never exceeded 10% in males and 

exceeded 10% (at 11%) in females only at Weeks 1-52. Together, these data indicate that the 

effects of the test substance on body weight gain and body weight were mildly adverse. No test 

article effects on food consumption or food efficiency were observed. 

No effects of the test article were observed on clinical signs, ophthalmology, clinical chemistry 

parameters (including coagulation), hematology, urinalysis, organ weights, and gross pathology. 

There were also no effects of the test article on mortality. 

No microscopic effects of the test article were observed in Satellite animals. 

The LOAEL for chronic toxicity is 18,000 ppm (892/957 mg/kg bw/day in males/females) 

based on mild decreases in body weight and body weight gain. The NOAEL is 6,000 ppm 

(279/309 mg/kg bw/day). 

No treatment-related tumors were observed. 

This study in the rat is Acceptable/Guideline and satisfies the guideline requirements for a 

Combined Chronic Toxicity/Carcinogenicity Study (OPPTS 870.4300) in rats. 

870.4100b Chronic Toxicity - Dog

EXECUTIVE SUMMARY: In a chronic oral toxicity study (MRID 48333608), DPX-MAT28-

23 technical (88.3% a.i.; Batch No. 8571-1 ) was administered to four beagle dogs/sex/dose 

group in the diet at doses of 0, 1,250, 5,000, 15,000 or 30,000 ppm (equivalent to 0, 37.9, 178.0, 

465.1 and 1076.7 mg/kg/day in males and equivalent to 0, 46.9, 174.6, 542.1 and 1072.5 

mg/kg/day in females) for 12 months. 

There were no treatment related deaths in the study. No adverse treatment-related effects were 

observed in the following parameters e.g. body weight and body weight gain, food consumption 

and food efficiency, clinical signs (including neurological parameters), ophthalmology 

evaluation, hematology (including coagulation), clinical chemistry, urinalysis, gross findings, 

organ weights and histopathology. 

The NOAEL is 30,000 ppm (1076.6/1072.5 mg/kg bw/day in males/females). The LOAEL was 

not observed. 
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This study is classified as Acceptable/Guideline and satisfies the guideline requirements 

(OPPTS 870.4100b; OECD 452) for a chronic oral toxicity study in dogs.

A.4.5 Carcinogenicity

870.4200a Carcinogenicity Study - rat

EXECUTIVE SUMMARY: Five groups of Main male and female Crl:CD(SD) rats 

(70/sex/group) were administered DPX-MAT28 in the diet at concentrations of 0, 600, 2000, 

6000, or 18000 ppm (0/0, 27/29, 279/309, 892/957 mg/kg bw/day in males/females) for 2 years. 

Satellite animals (10/sex/dose) were administered DPX-MAT28 at these same dietary 

concentrations. For both Main and Satellite animals, body weights and food consumption were 

evaluated prior to dietary exposure, weekly for the first 13 weeks, and then biweekly thereafter. 

Body weights were also recorded on the day of necropsy. Detailed clinical observations were 

performed prior to dietary exposure, on the day of first dietary exposure, and weekly thereafter. 

Ophthalmological assessments were performed prior to the start of dietary exposure and near the 

end of the exposure period. For Satellite animals, hematology, clinical chemistry, and urinalysis 

were performed at 6 months and 1 year and coagulation measurements were performed at 1 year. 

For Main Study animals, blood smears and white blood differential counts were performed at 1 

year and 2 years and for animals sacrificed in extremis. Satellite and Main Study animals were 

sacrificed, organ weights were recorded, and gross and histopathology performed at 1 year and 2 

years, respectively. 

Mild effects on body weight and body weight gain were observed in both sexes at the highest 

dose. These effects were considered transient, since they resolved by study completion. 

Quantification of body weight decreases at Days 189, 385, and 539 revealed that the magnitudes 

of the decreases in body weight were less than 10% in males and were above 10% in females (at 

12%) only at Day 539. Quantification of decreases in body weight gain over Weeks 1, 1-13, 1-

52, and 1-104 revealed that decreased body weight gain never exceeded 10% in males and 

exceeded 10% (at 11%) in females only at Weeks 1-52. Together, these data indicate that the 

effects of the test substance on body weight gain and body weight were mildly adverse. No test 

article effects on food consumption or food efficiency were observed. 

No effects of the test article were observed on clinical signs, ophthalmology, clinical chemistry 

parameters (including coagulation), hematology, urinalysis, organ weights, and gross pathology. 

There were also no effects of the test article on mortality. 

No microscopic effects of the test article were observed in Satellite animals. 

The LOAEL for chronic toxicity is 18,000 ppm (892/957 mg/kg bw/day in males/females) 

based on mild decreases in body weight and body weight gain. The NOAEL is 6,000 ppm 

(279/309 mg/kg bw/day). 

No treatment-related tumors were observed. 
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This study in the rat is Acceptable/Guideline and satisfies the guideline requirements for a 

Combined Chronic Toxicity/Carcinogenicity Study (OPPTS 870.4300) in rats. 

870.4200b Carcinogenicity (feeding) - Mouse

EXECUTIVE SUMMARY: 

The objective of this study (MRID 48333606) was to assess the carcinogenic potential of DPXMAT28 Technical (DPX-MAT28) in mice. Five groups of young adult male and female 

Crlj:CDl(ICR) mice (60/sex/group) were administered diets that contained 0, 300, 1000, 3000, or 

7000 ppm (corresponding to 0/0, 39/50, 133/171, 393/527, 876/1190 mg/kg bw/day) DPXMAT28 for approximately 18 months. 

Body weights and food consumption were evaluated weekly for the first 13 weeks, then every 

other week thereafter. Detailed clinical observations were evaluated weekly. Ophthalmological 

assessments were performed prior to the start of dietary exposure and near the end of the 

exposure period. White blood cell differential counts (via blood smear) were evaluated in 

surviving mice at the end of the exposure period and in mice that were sacrificed in extremis. 

After approximately 18 months of dietary exposure, mice were sacrificed and given a gross and 

microscopic pathological examination.

No test article-related changes were observed in the following observations in male and female 

mice fed up to 7000 ppm DPX-MAT28: clinical observation, body weight parameters, food 

intake parameters, ophthalmology, white blood cell differential counts, cause of death, organ 

weights and gross pathological parameters, and neoplastic or non-neoplastic changes.

DPX-MAT28 is not an oncogen in mice. 

The NOAEL for chronic toxicity is 7000 ppm (876/1190 mg/kg bw/day in males and females). 

The LOAEL was not observed. 

This study is classified as Acceptable/Guideline and satisfies the guideline requirements for a 

carcinogenicity study (OPPTS 870.4200b) in mice. 

A.4.6 Mutagenicity

Gene Mutation

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 

47560020 (2007)

Acceptable/guideline

0, 750, 1000, 1500, 

1750, or 2150 μg/mL 

There was no evidence of induced mutant colonies over 

background in the presence or absence of S9-activation.
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(Chinese Hamster 

Ovary Cells) 

(+/-S9)

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.

Cytogenetics

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.

Other Genotoxicity

No other genotoxicity studies are available. 

A.4.7 Neurotoxicity

870.6100 Delayed Neurotoxicity Study - Hen
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Not available and not required. 

870.6200 Acute Neurotoxicity Screening Battery

EXECUTIVE SUMMARY: 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.

870.6200 Subchronic Neurotoxicity Screening Battery

EXECUTIVE SUMMARY: In a subchronic oral and neurotoxicity study (MRID 47573403), 

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. 
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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. 

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-MAT29 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. 

.
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870.6300 Developmental Neurotoxicity Study

Not available and not required at this time. 

A.4.8 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 g*h/g at 25 mg/kg and 150.8-168.4 

g*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.
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EXECUTIVE SUMMARY: A previous study (MRID 47560023) characterized the plasma 

pharmacokinetics of DPX-MAT28 in male and female rats after administration of a single

low or high dose and provided a pilot material mass balance. 

In metabolism studies (MRID 48333610), [pyrimidine-2-

14C]-aminocyclopyrachlor (14C -DPXMAT28) (99.5% radiochemical purity) was administered in 0.5% methylcellulose by oral gavage 

to male and female Sprague-Dawley Crl:CD(SD) rats (4/sex/dose). Control animals (1/sex/dose) 

were administered 0.5% methylcellulose. Different study designs were employed to investigate 

metabolism and disposition. 

In the first study, 14C -DPX-MAT28 was administered at a single dose of 25 or 500 mg/kg bw. 

Total recovery and recovery in urine, feces, and as exhaled CO2 were monitored for 72 hours. 

Total recovery was excellent at ≥97.4%. Negligible amounts were exhaled as CO2. Recoveries 

in urine and feces were similar for both sexes and doses (with feces being slightly higher) and 

was near-complete by 72 hours. Recoveries in urine peaked at 6 hours, whereas recoveries in 

feces peaked at 12-24 hours. At 72 hours, percent recoveries in urine were 47.74 ± 3.75 and 

40.04 ± 5.14 for males at 25 and 500 mg/kg bw. For females, these values were 56.51 ± 14.55 

and 44.08 ± 4.78, respectively. Percent recoveries in feces at 72 hours were 47.97 ± 3.32 and 

54.76 ± 5.14 for males at 25 and 500 mg/kg bw. For females, these values were 39.48 ± 13.42 

and 51.08 ± 3.33and 56.51 ± 14.55, respectively. 

In the second study, biliary elimination was examined by administration of a single dose of 25 or 

500 mg/kg bw in bile duct-cannulated rats for 48 hours. Total recovery and recovery in urine, 

feces, and bile were monitored for 48 hours. Total recovery was excellent at ≥95.1%. Maximum 

recoveries and times of peak recoveries in urine and feces were similar to uncannulated rats. 

However, a larger fraction of radioactivity was increased in the feces than the urine. At 48 

hours, percent recoveries in feces were 62.06 ± 3.41 and 57.86 ± 7.77 for males at 25 and 500 

mg/kg bw and 68.47 ± 6.59 and 60.68 ± 4.87, respectively, for females. In urine at 48 hours, 

percent recoveries were 34.52 ± 3.57 and 30.06 ± 7.89 at 25 and 500 mg/kg bw for males and 

22.18 ± 2.13 and 32.24 ± 5.60, respectively for females. Maximum excretion in the bile for both 

sexes occurred by 6 hours. However, total excretion in the bile within 48 hours was low at less 

than 0.3% for both sexes at both doses. Together, this data indicate a minor role for 

enterohepatic circulation in the metabolism of 14C -DPX-MAT28. 

The tissue distribution of radiolabel was observed at TMAX (1 hour), TMAX + 5 hours, and 72 

hours following a single oral (gavage) dose of 25 or 500 mg/kg bw in males/females. The 

majority of the dose was found in the GI contents (46.7-67.0%) and GI tract (9.54-13.08%) in 

both sexes at both doses by TMAX + 5 hours without an apparent dose-related increase. 

Radioactivity was largely absent in the GI contents/GI tract by 72 hours (<<1%). The highest 

levels or radiolabel for both sexes and doses were found in the carcass (up to about 5%), 

followed by the muscle (up to 2%), skin (up to 1.4%), and blood (up to 1%). Again, there was 

no apparent dose-related increase in tissue levels. However, levels in all of these tissues declined 

to very low levels (<0.5%) by 72 hours. The apparent lack of dose-related increase in the tissue 

content of radiolabel suggested saturation of uptake. 
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Tissue distribution after repeated dosing the 25 mg/kg bw/day for 14 days was also examined. 

On Day 13 at 6 hours following dose administration, Levels were again highest in the GI tract 

(0.16-0.22%) and GI contents in males/females (7.11-1.14%), but were reduced in magnitude 

compared to 6 hours following single-dose administration of 25 mg/kg in the GI tract (1.36-

1.42%) and GI contents (41.7% and 46.77%) in both sexes. Tissue distribution was similar with 

carcass > skin > blood, with all levels less than 0.5% within 6 hours of dosing and less than 

0.05% by 72 hours. 

The analysis of urine, feces and bile for potential metabolites clearly showed that 14C-DPXMAT28 was the sole 14C component in excreta. No metabolism was evident.

This metabolism study in the rat is classified acceptable/guideline and satisfies the guideline 

requirement for a metabolism study [OPPTS 870.7485 (§85-1)] in rats. 

870.7600 Dermal Absorption - Rat

Not available and not required at this time. 

A.4.9 Immunotoxicity

870.7800 Immunotoxicity

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.
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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.
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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.

Appendix B. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide to determine their dermal and inhalation exposure. Many 

such studies, involving exposure to many different pesticides, comprise generic pesticide 

exposure databases such as PHED and the Outdoor Residential Exposure Task Force (ORETF). 

EPA has reviewed all the studies supporting these multi-pesticide generic exposure databases, 

and has found no clear and convincing evidence that the conduct of any of them was either 

fundamentally unethical or significantly deficient relative to the ethical standards prevailing at 

the time the research was conducted. All applicable requirements of EPA’s Rule for the 

Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there is no 

regulatory barrier to continued reliance on these studies.
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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

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

N N

H2N

Cl
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Degradate 3: IN-Q3007

IUPAC Name: 

Cyclopropanecarboxamide

CAS Name: 

Cyclopropanecarboxamide

CAS. No.: 6228-73-5

Degradate 4: IN-V0977

IUPAC Name: 

Cyclopropanecarboxylic acid

CAS Name: 

Cyclopropanecarboxylic acid

CAS. No.: 1759-53-1

HN N

OH

N O

O

N

H

H
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Degradate 5: IN-YY905

IUPAC Name: 

Cyclopropanecarboximidamide

CAS Name: 

Cyclopropanecarbamidine

CAS. No.: Not reported

O

HO

NH

H2N