Proposed Aminocyclopyrachlor Import Meat and Milk Tolerances

United States Environmental Protection Agency 

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Table of Contents

Overview.......................................................................................................................................................3

What is EPA proposing?..................................................................................................................3

What is the requested action? ..........................................................................................................3

What does EPA consider in its registration decision? .....................................................................3

What did EPA consider for this action?...........................................................................................3

What are the next steps? ..................................................................................................................4

1. Pesticide Chemical and Use Description ..................................................................................................4

1.1. What is aminocyclopyrachlor? .................................................................................................4

1.2. How is aminocyclopyrachlor used in the United States?..........................................................4

2. Human Health Considerations ..................................................................................................................5

2.1. What is the risk to human health from this action?...................................................................5

2.2. Aminocyclopyrachlor toxicity profile.......................................................................................5

2.3. Cyclopropane carboxylic acid toxicity profile..........................................................................5

2.4. Toxicological endpoints............................................................................................................5

2.5. Dietary risk ...............................................................................................................................6

2.5.1. Food and drinking water exposures ..........................................................................6

2.5.2. Dietary risk estimates................................................................................................7

2.6. Other (non-dietary) risks...........................................................................................................7

3. Environmental Considerations..................................................................................................................7

4. Regulatory Considerations........................................................................................................................8

4.1. Data requirements .....................................................................................................................8

4.2. Risk mitigation..........................................................................................................................8

4.3. International tolerances.............................................................................................................8

5. Proposed Regulatory Decision..................................................................................................................8

6. References.................................................................................................................................................9
Proposed Aminocyclopyrachlor Import Meat and Milk Tolerances

United States Environmental Protection Agency 

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Overview

What is EPA proposing?

EPA is proposing to establish tolerances (maximum allowable pesticide residue levels) in Title 40 of the 

United States Code of Federal Regulations (40 CFR) § 180 for the herbicide aminocyclopyrachlor in 

imported milk and meat commodities under § 408(d) of the Federal Food, Drug, and Cosmetics Act.

After evaluating available scientific information, EPA determined that this proposed action will not cause 

unreasonable risks to human health. There is no environmental risk since there will be no environmental 

load in the U.S. as this proposed action only impacts consumption of imported meat and milk.

This document summarizes the human health risk assessment and its findings. For detailed information, 

refer to the documents listed in the References section which are posted in the public docket at

www.regulations.gov under docket number EPA-HQ-OPP-2011-0144.

What is the requested action?

In 2010, the registrant, E.I. du Pont de Nemours and Company (DuPont), requested to amend the 

registration for aminocyclopyrachlor under the Federal Insecticide, Fungicide, and Rodenticide Act 

(FIFRA) by adding the first feed/food uses on rangeland, pastures, and Conservation Reserve Program 

(CRP) acres. DuPont also petitioned for tolerances in/on grasses, milk, and livestock commodities to 

support the proposed new uses.

In 2015, DuPont withdrew the new use request and amended the tolerance petition to support import 

instead of domestic use. EPA is soliciting comments for this proposed action under the public 

participation process since this is the first time tolerances will be established for aminocyclopyrachlor.

What does EPA consider in its review?

Section 408(b)(2)(A)(i) of FFDCA allows EPA to establish a tolerance (the legal limit for a pesticide 

chemical residue in/on a food/feed commodity) if it is determined that the tolerance level is “safe”,

meaning that there is a reasonable certainty that no harm will result from aggregate exposure to the 

pesticide chemical residue, including all anticipated dietary exposure and all other exposure for which 

there is reliable information. Additional consideration is given to protect infants and children from

aggregate exposure to the pesticide residue. For more information on how EPA regulates pesticides and 

conducts risk assessments, go to www.epa.gov/pesticides.

What did EPA consider for this proposed action?

For this proposed action, only human health dietary risk was assessed, since the establishment of import 

tolerances does not increase non-dietary exposure/risks to the U.S. population. Similarly, environmental 

risk was also not assessed for this proposed action since it will not increase environmental load. Previous 

non-dietary human health and environmental risk conclusions from the 2010 new pesticide chemical 

registration action remain unchanged. The 2010 assessments are located under docket number EPA-HQOPP-2009-0789 at www.regulations.gov.
Proposed Aminocyclopyrachlor Import Meat and Milk Tolerances

United States Environmental Protection Agency 

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What are the next steps?

Under EPA’s public participation process, the general public has 30 days to review and comment on the 

proposed decision and its supporting documents. After the comment period closes, EPA will review and 

respond to comments and make any necessary changes before issuing a final decision. Since this is a 

tolerance petition action, a final rule will also be published in the Federal Register with a 60-day objection 

period when the final decision is issued.

1. Pesticide Chemical and Use Description

1.1. What is aminocyclopyrachlor?

Aminocyclopyrachlor (6-amino-5-chloro-2-cyclopropyl-4-pyrimidinecarboxylic acid) is a selective, 

systemic herbicide in the pyrimidine carboxylic acid chemical class of synthetic auxins (WSSA Group 4 / 

HRAC Group O) for controlling broadleaf weeds, grasses, vines, and woody plants. It is biologically 

active in soil and is rapidly absorbed by plant leaves, stems, and roots, which is then translocated through

xylem and phloem to the meristematic regions. Its mode of action is dysregulation of gene expression

which interferes with normal shoot and root development resulting in undifferentiated cell division and 

elongation. Symptoms include bending and twisting of leaves and stems, stem thickening, growth 

stunting, leaf crinkling and cupping, calloused stems and leaf veins, enlarged roots, and severe necrosis. 

Symptoms may occur within a few hours up to days after application, and plant death may take weeks to 

several months.

1.2. How is aminocyclopyrachlor used in the United States?

Currently, aminocyclopyrachlor is registered for pre- and post-emergent control of broadleaf weeds, 

grasses, vines, and woody species in non-crop areas including uncultivated non-agricultural areas 

(airports, highways, rights-of-ways, sewage disposal areas, etc.); uncultivated agricultural areas 

(farmyards, fuel storage areas, fencerows, non-irrigation ditch banks, barrier strips, etc.); industrial sites 

(lumberyards, pipeline and tank farms, etc.); and natural areas (wildlife management areas, wildlife 

openings, wildlife habitats). It is formulated as soluble concentrate and water dispersible granules. There 

are end-use products co-formulated with the herbicides imazapyr, triclopyr, chlorsulfuron, metsulfuron, 

and sulfometuron. Aminocyclopyrachlor is available as aminocyclopyrachlor acid, aminocyclopyrachlor 

methyl, aminocyclopyrachlor potassium salt, and aminocyclopyrachlor triethylamine salt.

Aminocyclopyrachlor was registered as a new pesticide active ingredient in 2010 for use in the non-crop 

areas listed above, and additionally in recreational areas and on turf including golf courses, sod farms, and 

residential lawns. In 2011, EPA issued a Stop Sale, Use, or Removal Order for the commercial lawn and 

turf product DuPont Imprelis Herbicide, after receiving numerous incidents of non-target tree damage. 

Subsequently, all uses in lawn, turf, and recreational areas were voluntarily-canceled from all end-use 

products by 2014.
Proposed Aminocyclopyrachlor Import Meat and Milk Tolerances

United States Environmental Protection Agency 

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2. Human Health Considerations

2.1. What is the risk to human health from this action?

There is low risk to human health from consuming imported meat and milk commodities containing 

residues of aminocyclopyrachlor. There is also low risk from drinking water containing residues of 

aminocyclopyrachlor and its degradate cyclopropane carboxylic acid through exposure from existing nonfood uses. There are no additional non-dietary related risks from occupational/residential application, 

post-application, or bystander exposure from those identified in the 2010 risk assessment since this 

proposed action is for imported food commodities only. 

2.2. Aminocyclopyrachlor toxicity profile

On a single-dose (acute) exposure basis, aminocyclopyrachlor causes mild eye irritation. It is not irritating 

or allergic to the skin, and is not toxic through oral, skin, or inhalation exposure. 

On a repeated-dose (chronic) basis, mild toxic effects of decreased body weight and decreased body 

weight gain were seen only at the highest (limit) dose tested. There is no indication that 

aminocyclopyrachlor targets any specific organ, and there are no adverse effects to the nervous system or 

the immune system. It does not affect reproduction or offspring development, and there is no indication 

that juveniles are more susceptible to its toxic effects than adults. Aminocyclopyrachlor is classified as 

“Not Likely to be Carcinogenic to Humans”.

2.3. Cyclopropane carboxylic acid toxicity profile

Cyclopropane carboxylic acid (IN-V0977) is an environmental degradate produced from photolysis of 

aminocyclopyrachlor in an aqueous environment. Runoff and spray drift from ground and aerial 

applications of aminocyclopyrachlor may reach surface water bodies which then reacts with sunlight to 

convert to cyclopropane carboxylic acid (CPCA) and other degradates. While aminocyclopyrachlor 

degrades into five major environmental degradates, CPCA is the only degradate of concern because it has 

a different mode of toxicity than aminocyclopyrachlor. Therefore, EPA is considering the risk from 

exposure to CPCA separately.

Results from extensive pre-clinical studies of the anti-anxiety drug panadiplon (which metabolizes to 

CPCA) indicate the liver as the target organ, causing liver damage from mitochondrial impairment

occurring from 1-14 days of exposure. Although there is a substantial amount of toxicological 

information in the open literature that adequately characterizes the toxicity profile of CPCA, additional 

safety/uncertainty factors are applied to risk estimates to account for any residual uncertainties in the 

toxicological database. 

2.4. Toxicological endpoints 

Based on the toxicological profiles of aminocyclopyrachlor and CPCA, EPA selected the following 

endpoints and safety/uncertainty factors (Tables 1 and 2) to use in evaluating human health risk from 

pesticide exposure. For this proposed action, only dietary exposure assessments were necessary. 
Proposed Aminocyclopyrachlor Import Meat and Milk Tolerances

United States Environmental Protection Agency 

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Table 1. Toxicological endpoints of aminocyclopyrachlor used in human health risk assessment.

Exposure/Scenario

Point of Departure and 

Uncertainty/Safety 

Factors

RfD and PAD for 

Risk Assessment Study and Toxicological Effects

Acute dietary 

(All populations) No endpoint selected due to no toxic effects attributable to a single exposure.

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 Study

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

decreases in body weight/body weight gain

Table 2. Toxicological endpoints of cyclopropane carboxylic acid used in human health risk assessment.

Exposure/Scenario

Point of Departure and 

Uncertainty/Safety 

Factors

RfD and PAD for 

Risk Assessment Study and Toxicological Effects

Acute dietary 

(All populations)

LOAEL= 2.55 mg/kg/day 

CPCA

UFA = 10x

UFH = 10x

FQPA SF (UFDB, UFL) = 

10x

Acute RfD = 0.026 

mg/kg/day

aPAD = 0.0026 

mg/kg/day

Panadiplon Subchronic Oral Rabbit 

Study LOAEL = 10 mg/kg/day panadiplon 

(calculated to 2.55 mg/kg/day CPCA) based on

hepatic steatosis

Chronic dietary 

(All populations)

LOAEL= 2.55 mg/kg/day 

CPCA 

UFA = 10x

UFH = 10x

FQPA SF (UFDB, UFL,

UFS) = 30x

Chronic RfD = 

0.0087 mg/kg/day

cPAD = 0.00087 

mg/kg/day

Panadiplon Subchronic Oral Rabbit 

Study LOAEL = 10 mg/kg/day panadiplon 

(calculated to 2.55 mg/kg/day CPCA) based on 

hepatic steatosis

FQPA SF = Food Quality Protection Act Safety Factor. LOAEL = lowest-observed-adverse-effect-level. mg/kg/day = milligram/kilogram/day. 

NOAEL = no-observed-adverse-effect-level. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. UF = uncertainty 

factor. UFA = extrapolation from animal to human (interspecies). UFDB = to account for the absence of data or other data deficiency. 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.

2.5. Dietary risk

There are no risks of concern from the consumption of imported milk and meat commodities containing 

residues of aminocyclopyrachlor and drinking water containing residues of aminocyclopyrachlor and 

cyclopropane carboxylic acid. 

2.5.1. Food and drinking water exposures

There are no existing food/feed uses for aminocyclopyrachlor. Therefore, food exposure is calculated 

from the consumption of milk and meat commodities only, at petitioned-for tolerances.

Although there are no food/feed uses for aminocyclopyrachlor, there is the potential for drinking water 

exposure from existing non-crop/non-food uses. However, this action will not increase drinking water 

exposure since it is for imported food only and will not increase pesticide use domestically. For 

aminocyclopyrachlor, ground water exposure estimates were used in calculating drinking water exposure,

which were higher than surface water estimates. For CPCA, surface water estimates were used since it is

only present in surface water from aqueous photolysis and is not expected in ground water.
Proposed Aminocyclopyrachlor Import Meat and Milk Tolerances

United States Environmental Protection Agency 

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2.5.2. Dietary risk estimates

Dietary risk is calculated as a function of a pesticide’s toxicity and exposure. For acute and chronic 

dietary assessments, risk is expressed as a percentage of the population-adjusted dose (PAD), or the 

maximum acceptable dose at which no unreasonable adverse health effects will occur. Toxicity is 

expressed as the PAD, which incorporates the point of departure, or the dose level used to quantify risk, 

with any uncertainty/safety factors. Dietary exposure is calculated based on residue estimates and 

consumption data. EPA’s level of risk concern is exceeded when the percentage of the PAD is greater 

than 100%. For example, if the cPAD is 5 mg/kg/day and the dietary exposure is 2.5 mg/kg/day, then the 

risk estimate equals 50% of the cPAD, which is below EPA’s level of concern. 

There is no risk from acute (1-day) dietary exposure of imported milk and meat commodities since 

aminocyclopyrachlor is not acutely toxic via oral route of exposure and no endpoint was identified. Acute 

risk to drinking water containing CPCA from registered uses is low and did not exceed EPA’s level of 

concern. Chronic (6-months to lifetime) dietary exposure to aminocyclopyrachlor and drinking water 

exposure to CPCA were also low and did not exceed EPA’s level of concern. Table 3 summarizes the 

acute and chronic dietary risk estimates based on the population group expected to receive the greatest 

exposure, and are therefore the most conservative and protective of all other populations.

Table 3. Dietary risk estimates for aminocyclopyrachlor and CPCA from imported milk and meat.

Exposure/Scenario Chemical Level of 

Concern Risk Estimate

Acute dietary 

(All populations) Aminocyclopyrachlor > 100% of aPAD No risk (food and drinking water)

Acute dietary 

(All infants less than 

one year old)

Cyclopropane carboxylic acid > 100% of aPAD 11% of aPAD (drinking water only)

Chronic dietary 

(All populations) Aminocyclopyrachlor > 100% of cPAD < 1% of cPAD (food and drinking water)

Chronic dietary 

(All infants less than 

one year old)

Cyclopropane carboxylic acid > 100% of cPAD 7.4% of cPAD (drinking water only)

PAD = population adjusted dose (a = acute, c = chronic). EPA’s level of concern = > 100% of PAD.

2.6. Other (non-dietary) risks

Non-dietary risk assessments are unnecessary since this proposed action will not cause any occupational 

or residential exposures to aminocyclopyrachlor. An aggregate (dietary plus residential) assessment is 

also unnecessary since there are no longer any turf/lawn/recreational uses where residential exposure may 

occur. No cumulative assessment is necessary since there is no indication that aminocyclopyrachlor or its 

metabolites share a common mechanism of toxicity with any other substances.

3. Environmental Considerations

An environmental risk assessment is unnecessary for this proposed action since there is no increased 

environmental exposure to aminocyclopyrachlor from U.S. consumption of imported milk and meat 

commodities. Environmental risk estimates and conclusions from existing uses remain unchanged. 
Proposed Aminocyclopyrachlor Import Meat and Milk Tolerances

United States Environmental Protection Agency 

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4. Regulatory Considerations

4.1. Data requirements

No additional data is required to support this proposed action.

4.2. Risk mitigation

No risk mitigation is necessary since this proposed action does not trigger any risks of concern. 

4.3. International tolerances

Presently, Canada is the only country that has established maximum residue limits (tolerances) for 

aminocyclopyrachlor (Table 4). To prevent potential trade irritant issues, EPA determined that the 

proposed tolerances for milk and meat (of cattle, goat, horse, and sheep) can be lowered to harmonize 

with Canadian limits. 

5. Proposed Decision

Based on the above considerations, EPA concludes that the proposed action will result in a reasonable 

certainty of no harm to the general population, including infants and children, from exposure to 

aminocyclopyrachlor and CPCA residues. 

Therefore, under section 408(d) of the Federal Food, Drug, and Cosmetics Act, EPA is proposing to 

establish tolerances in 40 CFR § 180 for residues of the herbicide aminocyclopyrachlor, including its 

metabolites and degradates (including CPCA) in/on the imported commodities listed in Table 4 below.

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

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

aminocyclopyrachlor methyl ester, methyl 6-amino-5-chloro-2-cyclopropyl-4-pyrimidinecarboxylate, 

calculated as the stoichiometric equivalent of aminocyclopyrachlor.

Table 4. Aminocyclopyrachlor tolerances/maximum residue limits

Commodity Proposed U.S. Tolerance1 (ppm) Established Canadian MRL (ppm)

Cattle, fat 0.05 0.05

Cattle, meat 0.01 0.01

Cattle, meat byproducts 0.30 0.30

Goat, fat 0.05 0.05

Goat, meat 0.01 0.01

Goat, meat byproducts 0.30 0.30

Horse, fat 0.05 0.05

Horse, meat 0.01 0.01

Horse, meat byproducts 0.30 0.30

Milk 0.01 0.01

Sheep, fat 0.05 0.05

Sheep, meat 0.01 0.01

Sheep, meat byproducts 0.30 0.30

1 Will be denoted in the 40 CFR for import tolerances only.

ppm = parts per million
Proposed Aminocyclopyrachlor Import Meat and Milk Tolerances

United States Environmental Protection Agency 

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6. References

USEPA. Aminocyclopyrachlor: Acute and Chronic Dietary Exposure Analysis for the Tolerance Petition 

in Milk and Livestock Commodities. Health Effects Division. DP432084. March 16, 2016.

USEPA. Aminocyclopyrachlor acid – Addendum to the Drinking Water Assessment for Non-Crop Uses. 

Environmental Fate and Effects Division. DP432215. March 15, 2016.

USEPA. Aminocyclopyrachlor: Human Health Risk Assessment for Section 3, Food Use on 

Rangeland/Pastures/CRP Acres. Health Effects Division. DP387448. April 18, 2012.

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

Summary of Analytical Chemistry and Residue Data. Health Effects Division. DP387442. April 18, 2012.

USEPA. Aminocyclopyrachlor: Report of the Cancer Assessment Review Committee. Health Effects 

Division. TXR0056120. November 9, 2011.

USEPA. 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). Environmental Fate and Effects Division. DP394887. November 3, 2011.

PMRA. Aminocyclopyrachlor. Registration Decision RD2014-30. Health Canada. November 18, 2014.

PMRA. Aminocyclopyrachlor. Proposed Registration Decision PRD2014-08. Health Canada. February 

28, 2014.