EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: Kathryn V. Montague PM-23, 703-305-1243

Dow AgroSciences LLC

2F8120

EPA has received a pesticide petition 2F8120 from Dow AgroSciences, 9330 

Zionsville Road, Indianapolis, IN 46268 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 180.610 by establishing a tolerance for combined residues of aminopyralid (XDE750: 4-amino-3,6-dichloropyridine-2-carboxylic acid) and its glucose conjugate, 

expressed as total parent in or on the raw agricultural commodity, Fish – shellfish, 

mollusc at 0.01 parts per million (ppm), Fish – shellfish, crustacean at 0.01 parts per 

million (ppm), Fish – freshwater finfish at 0.04 parts per million (ppm). EPA has 

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

in section 408 (d)(2) of 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 metabolism. The nature of the residue in plants (grass and wheat) and 

in animals is adequately understood for the purpose of this tolerance. Based on the 

findings from these metabolism studies, the residues of concern in corn are the 

combined residues of aminopyralid and its glucose conjugates, expressed as the total 

parent. In animal commodities, the residue of concern is only the parent, 

aminopyralid (free).

2. Analytical method. Adequate analytical methods for enforcement purposes 

are available to monitor residues of aminopyralid in fish and shellfish. The 

analytical method GRM 07.08 uses liquid chromatography and positive ion 

electrospray tandem spectrometry (LC/MS/MS) with limits of quantitation (LOQ) 
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of 0.01 ppm. The methods had been successfully validated independently by outside 

laboratories. Aminopyralid had also been tested through the Food and Drug 

Administration (FDA), Multi-residue Methodology, Protocols C, D, and E.

3. Magnitude of residues. Under OPPTS guideline 860.1400, fish (bottom 

feeder (catfish) and predator (bluegill sunfish)) and shellfish (crustacean (crayfish) 

and mollusk (freshwater clams)) were exposed to aminopyralid while present in 

small ponds at field sites in Indiana and Texas). Formulated aminopyralid 

(formulation code GF-871, commercial name Milestone VM Herbicide with 

aminopyralid formulated as a triisopropanolammonium salt) was applied to two 

treated ponds at each field site to attain a target aquatic concentration of 40 ug/L 

(ppb); each site also contained one untreated control pond. The target 

concentration of aminopyralid in water was calculated based on a maximum per 

area application rate of aminopyralid at 120 g ae (acid equivalent) per hectare (0.11 

lb ae/acre) and a water depth of 30 cm. The fish and shellfish were confined in cages 

moored near the edge of each pond and samples were periodically collected for 

residue analysis. Samples were frozen and shipped in a frozen state to the analytical 

facility where the samples were maintained frozen until prepared for analysis. The 

proposed tolerances in fish and shellfish are adequate to cover the highest residues 

from the maximum label use of aminopyralid in certain aquatic sites.

B. Toxicological Profile

1. Acute toxicity. Aminopyralid has low acute toxicity. The rat oral LD50 is 

>5000 mg/kg and the rat inhalation LC50 is >5.5 mg/L. In addition, aminopyralid is 

not a dermal sensitizer in guinea pigs, has no dermal irritation in rabbits, and shows 

ocular irritation in rabbits.

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 using rat 

lymphocytes, and an in vivo cytogenetic assay in the mouse bone marrow 

(micronucleus test) have been conducted with aminopyralid. Taken together, these 

studies show a lack of genotoxicity.

3. Reproductive and developmental toxicity. Developmental studies in rats and 

rabbits were conducted with aminopyralid. Studies with aminopyralid showed 

maternal NOAELs of 1000 mg/kg/day (rat) and 250 mg/kg/day (rabbit) and fetal 

NOAELs of 1000 mg/kg/day (rat) and 500 mg/kg/day (rabbit). These studies show 

that aminopyralid is not teratogenic nor will it interfere with in utero development. 

A multi-generation reproduction study conducted with aminopyralid in SpragueDawley rats showed a NOAEL for reproductive effects of 1000 mg/kg/day for males 
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and 1000 females (highest dose tested). The NOAEL for neonatal effects was also 

1000 mg/kg/day.

4. Subchronic toxicity. Aminopyralid showed a NOAEL of 100 mg/kg/day in a 

28-day rat dermal study. Ninety day feeding studies with aminopyralid showed 

NOAELs of 500 mg/kg/day in Fischer 344 rats, 232 mg/kg/day for females and 282 

mg/kg/day for male Beagle dogs, and 1000 mg/kg/day in CD-1 mice.

5. Chronic toxicity. Based on chronic testing with aminopyralid in the mouse, 

dog, and rat (two studies), a reference dose (RfD) of 0.5 mg/kg/day is established. 

The RfD has incorporated a 100-fold safety factor to the NOAEL found in the rat 

chronic test. NOAELs found in the chronic dietary studies are as follows: 96 

mg/kg/day (male and female dogs), 250 mg/kg/day in female mice and 1000 

mg/kg/day in male mice, and 50 mg/kg/day in male Fischer 344 rats and 500 

mg/kg/day in female Fischer 344 rats.

6. Animal metabolism. Aminopyralid have been evaluated in a rat metabolism 

study. In summary, this study shows that aminopyralid is efficiently cleared through 

the urine and feces with an average of 74 - 93% of the administered radioactivity 

excreted during the first 24-hours post-dose administration. Aminopyralid is 

rapidly absorbed and urinary and fecal elimination totaled 41-59 and 33-43% of the 

administered dose, respectively. Analysis of excreted material indicate no evidence 

of metabolism. Repeated administration of aminopyralid was not associated with 

accumulation in tissues.

7. Metabolite toxicology. No mammalian metabolites of aminopyralid have 

been identified in the rat metabolism study. Nature of residue studies in wheat and 

grass (3 species) revealed the presence of unchanged parent aminopyralid and 

glucose conjugates of aminopyralid.

8. Endocrine disruption. There is no evidence to suggest that aminopyralid has 

an effect on any endocrine system.

C. Aggregate Exposure

1. Dietary exposure. The 2009 EPA Human-Health Risk Assessment (D359088) 

remains applicable: chronic dietary exposure (general U.S. population and all population 

subgroups) assessments were conducted using the Dietary Exposure Evaluation Model -

Food Commodity Intake DatabaseTM (DEEM-FCIDTM; ver. 2.14) program which 

incorporates consumption data from USDA’s Continuing Surveys of Food Intakes by 

Individuals (CSFII), 1994-1996 and 1998. DEEM contains food consumption data as 

reported by respondents in the USDA Continuing Surveys of Food Intake by Individuals 

(CSFII) conducted in 1994-1996 and 1998 and food translation to RACs, as indicated by 

EPA/USDA FCID recipe sets.
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i. Food. In conducting the potential dietary exposure and risk assessments, 

Dow AgroSciences used the Dietary Exposure Evaluation Model (DEEMTM, Version 

2.14, Exponent) software that evaluated the individual food consumption as 

reported by respondents in the USDA 1994-1996, 1998 nationwide Continuing 

Surveys of Food Intake by Individuals (CSFII). The dietary exposure assessment 

was performed using a conservative approach (Tier I) wherein the estimated 

theoretical maximum residue contribution (TMRC) was based on the assumptions 

that 100% of the crops were treated with aminopyralid and the residues were 

present at the proposed tolerance levels.

The chronic population adjusted dose (cPAD) used was 0.50 mg/kg/day based on a 

NOAEL of 50 mg/kg/day from a 2-year combined chronic feeding/carcinogenicity 

rat study and an uncertainty factor of 100 (10 for intraspecies variation X 10 for 

interspecies variation). No additional FQPA safety factor is required. For the U.S. 

general population, the TMRC was estimated to be 0.000710 mg/kg/day that utilized 

less than 1% of the cPAD. The population sub-group with the highest potential 

exposure is children (1-2 years old) with a TMRC of 0.002107 mg/kg/day that 

represents only 0.4% of the cPAD. The percent of the cPAD is significantly below 

the acceptable 100%, therefore, demonstrates no chronic dietary concern.

No appropriate toxicological endpoint attributable to a single exposure was 

identified in the available toxicological studies on aminopyralid. Thus, the risk from 

acute exposure is considered negligible and no acute risk assessment was performed.

ii. Drinking water. No monitoring exposure data is available to complete 

comprehensive dietary exposure analysis and risk assessment for aminopyralid in 

drinking water. Guidance from EPA has indicated that drinking water models, such 

as PRZM-EXAMS and SCI-GROW, maybe used to estimate upper-bound pesticide 

residues in surface water and ground water when assessing potential exposure 

through drinking water. Based on these models, the estimated environmental 

concentration (EECs) of aminopyralid for chronic exposures are estimated to be 

1.937 ppb for surface water and 0.630 ppb for ground water. To assess total 

aggregate exposure to aminopyralid, the most conservative value of 1.937 ppb is 

used as an input to DEEM-FCIDTM, Version 2.14 as water EEC from direct and 

indirect exposure so as to be included in the dietary exposure and risk assessment. 

Potential exposure to aminopyralid in drinking water would not result in 

unacceptable levels of aggregate human health risk.

2. Non-dietary exposure. Aminopyralid is not currently registered for use on 

any sites that would result in residential exposure other than residential uses for 

aminopyralid on recreational sites (e.g., campgrounds). Therefore, considerations of 

short-term aggregate exposure to aminopyralid that consist of incidental oral 
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exposures (e.g., hand-to-mouth transfer of residues, object-to-mouth, and ingestion 

of soil) is considered. These scenarios are short-term in duration and are applicable 

to children only. The short-term aggregate MOEs for aminopyralid are not of 

concern.

D. Cumulative Effects

At this time, no data is available to determine whether aminopyralid has a 

common mechanism of toxicity with other substances. Unlike other pesticides for 

which EPA has followed a cumulative risk approach based on a common 

mechanism of toxicity, aminopyralid does not appear to produce a common toxic 

metabolite generated by other substances. For purposes of this tolerance action, 

therefore, it is assumed that aminopyralid does not have a mechanism of toxicity 

common with other substances.

E. Safety Determination

1. U.S. population. Using the above conservative exposure assumptions, 

aggregate exposure to aminopyralid from the proposed tolerances in corn 

commodities will utilize less than 1% of the cPAD for the general U. S. population. 

The population subgroup with the highest exposure of 0.4% of the cPAD is children 

(1-2 yrs old). Generally, EPA has no concern for exposures below 100% of the cPAD 

because the cPAD represents the level at or below which daily aggregate dietary 

exposures over a lifetime will not pose appreciable risks to human health. No 

endpoint of concern was identified to quantitate acute-dietary risk to the general 

population, therefore, acute risk exposure is considered to be negligible. 

Additionally, the potential contribution of aminopyralid residues in drinking water 

to aggregate exposure is expected to be minimal. Therefore, based on these risk 

assessments, Dow AgroSciences concludes that there is reasonable certainty that no 

harm will result to the U. S. population from aggregate exposure to aminopyralid 

residues.

2. Infants and children. FFDCA Section 408 provides that EPA may apply an 

additional safety factor for infants and children in the case of threshold effects to 

account for pre- and post-natal toxicity and the completeness of the database. Based 

on the current toxicological data requirements, the database for aminopyralid 

relative to pre- and post-natal effects for children is complete. Overall, 

aminopyralid had no effect on reproduction or embryo-fetal development at any 

dosage tested. No quantitative or qualitative susceptibility was seen following preand post-natal exposures. In a 2-generation reproductive toxicity study in rats, no 

effects on reproductive performance or neonatal development were observed. Dow
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AgroSciences concluded that there is no indication of increased sensitivity of infants 

and children relative to adults and that no additional FQPA safety factor is 

required.

Using the above conservative assumptions, aggregate exposure to aminopyralid will 

utilize only 0.2 % of the cPAD for all infants (<1 yr old), 0.4% of the cPAD for 

children 1-2 yrs old and 0.3% of the cPAD for children 6-12 yrs old. Even when 

considering the potential exposure to drinking water, the aggregate exposure is not 

expected to exceed 100% of the cPAD. Therefore, based on the completeness and 

reliability of the toxicity data and the conservative exposure assessment, Dow 

AgroSciences concludes with reasonable certainty that no harm will result to infants 

and children from the aggregate exposure to aminopyralid residues.

F. International Tolerances

There are no Codex, or Canadian MRLs for aminopyralid on commodities 

included in this tolerance petition (fish, shellfish). There are international MRLs 

established for other animal commodities (mammals, poultry) and several 

agricultural crops not included within this petition.