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 reque sted 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 aminoc yclopyra chlor? .............................................................................................. ...4 1.2. How is aminocyclopyrachlor us ed 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 ac id 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 C onsiderations................................................................................................... .....................8 4.1. Data requirements ......................................................................................................... ............8 4.2. Risk m itigatio n........................................................................................................... ...............8 4.3. Internationa l tolera nces.................................................................................................. ...........8 5. Proposed Regulatory Decision................................................................................................ ..................8 6. Refere nces.................................................................................................................. ...............................9Proposed 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 Fede ral 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 chemicalregistration 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 m ode of action is dysregulation of gene expression which interferes with normal shoot and root devel opment 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 herbicid es 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 ofaminocyclopyrachlor 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 en vironmental 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 th ere 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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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 UF A = 10x UF H = 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 UF A = 10x UF H = 10x FQPA SF (UF DB , UF L ) = 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 UF A = 10x UF H = 10x FQPA SF (UF DB , UF L , UF S ) = 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/kilogr am/day. NOAEL = no-observed-adverse-effect-level. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. UF = u ncertainty factor. UF A = extrapolation from animal to human (interspecies). UF DB = to account for the absence of data or other data deficiency. UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = 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 e xposure to aminocyclopyrachlor and drinking water exposure to CPCA were also low and did not exc eed 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-c yclopropyl-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 to lerances/maximum residue limits

Commodity Proposed U.S. Tolerance 1 (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 millionProposed 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 C ancer 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.