E. I. DuPont de Nemours and Company Aminocyclopyrachlor

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ENVIRONMENTAL PROTECTION AGENCY 

Notice of Filing of a Pesticide Petition for the Establishment of Tolerances for 

Residues of Aminocyclopyrachlor in or on Food Commodities 

AGENCY: Environmental Protection Agency (EPA). 

ACTION: Notice. 

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SUMMARY: This notice announces the initial filing of a pesticide petition 

proposing the establishment of tolerances for residues of aminocyclopyrachlor in 

or on food commodities under the Federal Food, Drug, and Cosmetic Act 

(FFDCA), as amended by the Food Quality Protection Act of 1996 (FQPA). 

FOR FURTHER INFORMATION CONTACT: By mail: Kable Bo Davis, 

Product Manager (PM 25), Registration Division, (7505P), Office of Pesticide 

Programs, Environmental Protection Agency, Ariel Rios Building 1200 

Pennsylvania Avenue, N. W., Washington, DC 20460. Office location and 

telephone number: Arlington, VA., (703) 306-0415. Email: davis.kable@epa.gov 

SUPPLEMENTARY INFORMATION: EPA has received a pesticide petition as 

follows proposing the establishment and/or amendment of regulations for residues 

of certain pesticide chemicals in or on various raw agricultural commodities under 

section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 

346a (d). EPA has determined that this petition contains data or information 

regarding the elements set forth in section 408(d)(2); however, EPA has not fully 

evaluated the sufficiency of the submitted data at this time or whether the data 

supports granting of the petition. Additional data may be needed before EPA rules 

on the petition. 

 

List of Subjects 

Environmental Protection, Agricultural Commodities, Food Additives, Feed 

Additives, Pesticides and Pests, Reporting and Recordkeeping Requirements. 

Summary of Petition 

A summary of the pesticide petition is given below. The petitioner prepared the summary 

of the petition. 

EPA Registration Division contact: Kable Bo Davis, Product Manager 25, (703) 306-

0415. 

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 E. I. DuPont de Nemours and Company Aminocyclopyrachlor

E. I. DuPont de Nemours and Company, DuPont Crop Protection 

0F7817 

EPA has received a pesticide petition (0F7817) from E. I. DuPont de Nemours and 

Company, DuPont Crop Protection, Wilmington, Delaware, proposing, pursuant to section 

408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 

40 CFR Part 180 to establish tolerances for residues of aminocyclopyrachlor [6-amino-5-

chloro-2-cyclopropyl-4-pyrimidinecarboxylic acid] and aminocyclopyrachlor methyl ester 

[methyl 6-amino-5-chloro-2-cyclopropyl-4-pyrimidinecarboxylate], expressed as 

aminocyclopyrachlor in or on grass forage at 65 parts per million (ppm), grass hay at 125 

ppm, fat (of cattle, goat, horse and sheep) at 0.07 ppm, meat (of cattle, goat, horse and 

sheep) at 0.02 ppm, meat byproducts - excluding liver (of cattle, goat, horse and sheep) at 0.4 

ppm, liver (of cattle, goat, horse and sheep) at 0.06 ppm and milk at 0.035 ppm. EPA has 

determined that the petition contains data or information regarding the elements set forth in 

section 408(d)(2) of the FFDCA; however, EPA has not fully evaluated the sufficiency of the 

submitted data at this time or whether the data supports granting of the petition. Additional 

data may be needed before EPA rules on the petition.

A. Residue Chemistry 

1. Plant and animal metabolism. 

i. Plant metabolism. The nature of the residue in plants (grass) is adequately understood 

for the purpose of these tolerances. Based on the findings from this metabolism study, the 

residues of concern in grass are the combined residues of aminocyclopyrachlor and 

aminocyclopyrachlor methyl, expressed as aminocyclopyrachlor. 

ii. Animal metabolism. 

The nature of residue of aminocyclopyrachlor in ruminants is adequately understood for 

the purpose of this tolerance. In animal commodities, the residues of concern are the 

combined residues of aminocyclopyrachlor and aminocyclopyrachlor methyl, expressed 

as aminocyclopyrachlor. 

2. Analytical method. Adequate analytical methods for enforcement purposes are 

available to monitor residues of aminocyclopyrachlor in grass commodities, milk, meat 

and meat by-products. The analytical methods for both grass commodities and ruminant 

commodities use an LC/MS/MS system operating with an electrospray interface (ESI) in 

positive ion mode) with limits of quantitation (LOQ) of 0.01 ppm. 

Both methods have been successfully independtly validated by outside laboratories. 

Aminocyclopyrachlor had also been tested through the Food and Drug Administration 

(FDA), Multi-residue Methodology. EPA offers enforcement methodology to anyone 

interested in pesticide enforcement when requested by mail from: Public Response and 

Program Resources Branch, Field Operations Division (7506C), Office of Pesticide 

Programs, Environmental Protection Agency, 401 M St., SW., Washington, DC 20460. 

Office location CM#2, 1801 South Bell Street, Arlington, VA 22202. 

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 E. I. DuPont de Nemours and Company Aminocyclopyrachlor

3. Magnitude of residues 

i. Plant residues. 

Grass crop group 17 - Geographically representative field trials were conducted on grass 

pastures according to use patterns which support the proposed tolerances in or on grass 

forage and grass hay. The proposed tolerances in grass commodities, and subsequently in 

milk, meat and meat by-products are adequate to cover the highest residues from the 

maximum label use of aminocyclopyrachlor in grass pastures. 

ii. Animal residues. Of the commodities for which tolerances are being proposed, grass 

hay and grass forage are possible animal feed items. Therefore, a cattle feeding study was 

conducted to establish tolerances on meat, meat by-products and milk. The proposed 

tolerances in milk, meat and meat by-products are adequate to cover the highest residues 

from the maximum label use of aminocyclopyrachlor in grass pasture. 

B. Toxicological Profile 

1. Acute toxicity. Aminocyclopyrachlor has low acute toxicity. Aminocyclopyrachlor is 

considered toxicology category IV for acute oral toxicity (LD50 > 5000 mg/kg), acute 

dermal toxicity (LD50 > 5000 mg/kg), acute inhalation toxicity (LD50 > 5.4 mg/L), and 

skin irritation. Aminocyclopyrachlor is not a dermal sensitizer. Aminocyclopyrachlor is 

considered category III for eye irritation. 

2. Genotoxicty. Short-term assays for genotoxicity consisting of a bacterial reverse 

mutation assay (Ames test), an in vitro assay for cytogenetic damage using the Chinese 

hamster ovary cells, an in vitro chromosomal aberration assay in human lymphocytes, and 

an in vivo cytogenetic assay in the mouse erythrocytes (micronucleus test) have been 

conducted with aminocyclopyrachlor. The weight of evidence from these studies indicates 

that aminocyclopyrachlor is non-genotoxic. 

3. Reproductive and developmental toxicity. 

i. Rat developmental study. A developmental study was conducted in rats administered 

technical aminocyclopyrachlor by oral gavage at dose levels of 0, 30, 100, 300, or 1000 

mg/kg/day on gestation days 6 through 20. No treatment-related effects were noted on 

maternal or developmental toxicity up to and including the highest dose tested of 1000 

mg/kg. The LOAEL for maternal and developmental toxicity could not be determined and 

the NOAEL is 1000 mg/kg/day for both maternal and developmental toxicity. 

ii. Rabbit developmental study. A developmental study was conducted in rabbits 

administered technical aminocyclopyrachlor by oral gavage at dose levels of 0, 30, 100, 300, 

or 1000 mg/kg/day on gestation days 7 through 28. The NOAEL for maternal toxicity is 500 

mg/kg/day) and the LOAEL is 1000 mg/kg/day based on decreased food consumption and 

body weights and increased incidences of mortality and abortion. The LOAEL for 

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 E. I. DuPont de Nemours and Company Aminocyclopyrachlor

developmental toxicity could not be established. The NOAEL for developmental toxicity is 

1000 mg/kg/day (highest dose tested.) 

iii. Two-generation rat reproduction study. A two-generation reproduction toxicity study 

was conducted in rats with aminocyclopyrachlor at dietary concentrations of 0, 500, 

1500, 5000 and 17000 ppm. The LOAEL for parental toxicity was 17,000 ppm (1285 / 

1454 mg/kg/day for males/females) and the NOAEL was 5000 ppm (363 / 416 

mg/kg/day for males/females). The parental LOAEL was based on reduced food 

efficiency and body weights. Reduced offspring bodyweights were also observed. The 

LOAEL for offspring toxicity was 17,000 ppm and the NOAEL was 5000 ppm. No 

LOAEL was observed for reproductive toxicity and the NOAEL was 17,000 ppm. 

4. Subchronic toxicity. 

i. 90-Day rat feeding study. A 90 day study in rats was conducted at dose levels of 0, 600, 

2000, 6000, and 18000 ppm (equivalent to 0/0, 35/45, 114/146, 349/448 and 1045/1425 

mg/kg/day for males / females, respectively). Reduced food consumption, food 

efficiency and body weights/weight gains were observed at the highest dose tested. A 

LOAEL for subchronic toxicity of this test material is 18000 ppm (1045/1425 mg/kg/day 

for males / females) and a NOAEL is 6000 ppm (349/448 mg/kg/day for males / 

females). 

ii. 90-Day mouse study. A 90 day study in mice was conducted at dose levels of 0, 300, 

1000, 3000, and 7000 ppm (equivalent to 0/0, 47/61, 154/230/ 459/649 and 1088/1623 

mg/kg/day for males / females, respectively). No LOAEL was established, and the 

NOAEL is 7000 ppm (1088/1623 mg/kg/day for males / females). 

 

iii. 90-Day dog study. A 90 day study in dogs was conducted at dose levels of 0, 250, 

1250, 5000, and 15000 ppm (equivalent to 0/0, 6.5/7, 33/38, 126/124, and 426/388 

mg/kg/day for males / females, respectively). No LOAEL was established, and the 

NOAEL is 15000 ppm (426/388 mg/kg/day for males / females). 

iv. 28-day dermal study. A 28 day dermal study was conducted in rats at dose levels of 0, 

150, 400, and 1000 mg/kg/day. No LOAEL was established, and the NOAEL is 1000 

mg/kg/day for male and female rats. 

5. Chronic toxicity and oncogenicity 

i. 18-Month mouse oncogenicity study. An 18-month carcinogenicity study was 

conducted dose levels of 0, 300, 1000, 3000 and 7000 ppm (equivalent to 0/0, 39/50, 

133/171, 393/527, and 876/1190 mg/kg/day in males / females, respectively). 

Aminocyclopyrachlor is not an oncogen in mice. Under the conditions of this study, the 

NOAEL for aminocyclopyrachlor was 7000 ppm (876/1190 mg/kg/day in males / 

females). 

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 E. I. DuPont de Nemours and Company Aminocyclopyrachlor

ii. 1-Year chronic dog study. A 1-year feeding study was conducted with dogs fed dosages 

of 0, 1250, 5000, 15000 and 30000 ppm (equivalent to 0, 38/47, 178/175, 465/542 and 

1077/1073 mg/kg/day in males /females, respectively). Under the conditions of this study, 

the (NOAEL) for aminocyclopyrachlor was considered to be 30000 ppm, (1077 and 1073 

mg/kg/day in males and females, respectively. 

iii. Two-year combined rat chronic toxicity/oncogenicity study. A combined chronic 

toxicity/oncogenicity 2-year feeding study was conducted in rats fed dosages of 0, 600, 

2000, 6000, or 18000 ppm (equivalent to 0/0, 27/29, 97/100, 279/309, and 892/957 

mg/kg/day for males / females, respectively). Aminocyclopyrachlor is not an oncogen in 

rats. Under the conditions of this study, the NOAEL for aminocyclopyrachlor was 6000 

ppm, equivalent to 279 /309 mg/kg/day in males/females, respectively. Under the 

conditions of this study, The NOAEL is based on adverse test article related effects on 

body weights in rats fed 18000 ppm (892/957 mg/kg/day for males / females). 

6. Acute and subchronic neurotoxicity 

i. Acute neurotoxicity - An acute neurotoxicity study was conducted in rats administered 

a single oral (gavage) dose of 0, 200, 1000 or 2000 mg/kg aminocyclopyrachlor. Under 

the conditions of this assay, aminocyclopyrachlor was not neurotoxic. The NOAEL was 

2000 mg/kg. There was no LOAEL for acute neurotoxicity established. 

ii. Subchronic neurotoxicity – A combined 90 day systemic toxicity and neurotoxicity 

study in rats was conducted at dose levels of 0, 600, 2000, 6000, 18000 ppm (equivalent 

to 0/0, 35/45, 114/146, 349/448 and 1045/1425 mg/kg/day for males / females, 

respectively). A NOAEL for neurotoxicity is 18000 ppm (1045/1425 mg/kg/day for 

males / females). There was no LOAEL for subchronic neurotoxicity established. 

7. Immunotoxicity 

i. 28-Day immunotoxicity study in rats. A 28-day immunotoxicity study was conducted 

in male rats fed diets that contained 0, 600, 6000 or 18000 ppm aminocyclopyrachlor. 

This was equivalent to 0, 42, 407, and 1277 mg/kg/day. There was no LOAEL 

established for immunotoxicity or systemic toxicity. The NOAEL was 18000 ppm (1277 

mg/kg/day). 

ii. 28-Day immunotoxicity study in mice. 28-Day immunotoxicity study in mice. A 28-

day immunotoxicity study was conducted in male mice fed diets that contained 0, 300, 

3000 or 7000 ppm aminocyclopyrachlor. This was equivalent to 0, 45, 425 and 1056 

mg/kg/day. There was no LOAEL established for immunotoxicity or systemic toxicity. 

The NOAEL was 7000 ppm (1056 mg/kg/day). 

8. Rat metabolism

The metabolism of aminocyclopyrachlor has been evaluated in rats. The results 

demonstrated rapid absorption and clearance, with an average of 82 to 93% excreted in 

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 E. I. DuPont de Nemours and Company Aminocyclopyrachlor

urine and feces during the first 24 hours following administration. By 72 hours postadministration 95 to 98% of the administered dose was eliminated in urine and feces, 

with a mean percent dose in urine ranging from 40 to 56.5% and that in the feces ranging 

from 40 to 54.8%. By 72 hours following single or multiple-dose administration the 

body burden was very low ranging from 0.03 to 0.22%. There were no sex differences or 

impact of single or multiple exposures evident for the excretion rates. Based on analyses 

of data from single and multiple exposures and tissue:plasma concentration ratio data, 

there was no evidence for accumulation of aminocyclopyrachlor in tissues. Chemical 

analyses of urine, feces and bile demonstrated that aminocyclopyrachlor was not 

metabolized in the rat. 

9. Metabolite toxicology 

There is no evidence that the metabolites of aminocyclopyrachlor identified in either the 

grass residue study or feeding study are of toxicological significance.

 

10. Endocrine disruption

In the available toxicity studies on aminocyclopyrachlor, there was no estrogen, androgen, 

and/or thyroid mediated toxicity.

C. Aggregate Exposure

 

1. Dietary exposure – 

i. Food and Water. 

Chronic dietary exposure assessment. Chronic dietary exposure resulting from the 

currently approved uses and proposed uses of aminocyclopyrachlor is well within 

acceptable limits for all sectors of the population. The chronic module of the Dietary 

Exposure Evaluation Model with Food Commodity Intake Database (DEEM-FCIDTM, 

version 2.16, Exponent, Inc.) was used to conduct the assessment with the chronic 

reference dose (cRfD) of 2.80 mg/kg/ day. This model incorporates nationwide food 

consumption data as reported by respondents in the U.S. Department of Agriculture 

(USDA) 1994-1996, 1998 Continuing Surveys of Food Intake by Individuals (CSFII). 

The analysis used tolerance values in place of residue values for meat and milk. The 

chronic dietary exposure of the US population to aminocyclopyrachlor utilizes <1% of 

the cRfD for the overall U.S. population. No population subgroup had an exposure that 

utilized more than 1% of the cRfD. There are large margins of safety for each population 

subgroup and very low probability of effects resulting from chronic exposure to 

aminocyclopyrachlor. 

Acute Dietary Exposure. Acute dietary risk assessments are performed for a food-use 

pesticide if a toxicological study indicates the possibility of an effect of concern as a 

result of a one day or a single exposure. No acute dietary endpoint attributable to a single 

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 E. I. DuPont de Nemours and Company Aminocyclopyrachlor

dose was identified for aminocyclopyrachlor. Therefore the quantification of acute 

dietary risk is not considered necessary. There is reasonable certainty that no acute effects 

would result from dietary exposure to aminocyclopyrachlor.

ii. Drinking water. Based on the FIRST Tier 1 surface water and SCI GROW Tier 1 

groundwater models under worst-case conditions the chronic estimated environmental 

concentrations (EECs) of aminocyclopyrachlor are 16.965 ug/L for surface water and 

40.2 ug/L for ground water. 

When the higher surface water concentration was included in the chronic dietary risk 

assessment, the predicted exposure for the general population was <1% of the cRfD. No 

population subgroup had an exposure that utilized more than 1% of the cRfD. Thus, the 

chronic dietary exposure of aminocyclopyrachlor including the contribution of drinking 

water clearly meets the standard of reasonable certainty of no harm. 

 

2. Non-dietary exposure. Assessment of hypothetical post-application consumer exposure 

from use on turf results in margins of exposure greater than 100 for inhalation, hand to 

mouth oral, and soil ingestion exposures. Thus these are not of concern. Quantification 

of dermal exposures is not required because no toxicity was observed in a dermal study 

conducted at limit dose. 

D. Cumulative Effects

EPA has not made a common mechanism of toxicity finding as to aminocyclopyrachlor 

and any other substances and has not assumed that aminocyclopyrachlor has a common 

mechanism of toxicity with other substances. 

E. Safety Determination 

1. U.S. population. Based on the completeness and reliability of the toxicity data and the 

conservative exposure assessments, there is a reasonable certainty that no harm will result 

from the establishment of the proposed tolerances as evidenced by the assessment of the 

aggregate exposure of residues of aminocyclopyrachlor including all anticipated dietary 

exposure and all other non-occupational exposures. 

2. Based on the completeness and reliability of the toxicity data, the lack of toxicological 

endpoints of special concern, the lack of any indication that children are more sensitive 

than adults to aminocyclopyrachlor, and the conservative exposure assessment, there is a 

reasonable certainty that no harm will result to infants and children from the aggregate 

exposure of residues of aminocyclopyrachlor, including all anticipated dietary exposure 

and all other non-occupational exposures. Accordingly, there is no need to apply an 

additional safety factor for infants and children. 

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 E. I. DuPont de Nemours and Company Aminocyclopyrachlor

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F. International Tolerances 

There is neither a Codex proposal, nor an established Canadian or Mexican tolerance for 

grass and/or ruminant commodities.