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 e stablishing a tolerance for combined residues of aminopyralid (XDE

750: 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 F F DCA; 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 residue s of aminopyralid and its glucose conjugates, expressed as the total parent. In animal c ommodities, 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)2

of 0.01 ppm. The methods had been successfully validated independently by outside laboratories. Aminopyralid had also been tested thro ugh 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 triisop ropanolammonium 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 base d on a maximum per

are a 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

. S amples 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 LD 50 is >5000 mg/kg and the rat inhalation LC 50 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 condu cted 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 NO A ELs of 1000 mg/kg/day (rat) and 250 mg/kg/day (rabbit) and fetal NO A ELs 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 st udy conducted with aminopyralid in Sprague

Dawley rats showed a NO A EL for reproductive effects of 1000 mg/kg/day for males3

and 1000 females (highest dose tested). The NO A EL for neonatal effects was also 1000 mg/kg/day

. 4. Subchronic toxicity. Aminopyralid showed a NO A EL of 100 mg/kg/day in a 28

- day rat dermal study. Ninety day feeding studies with aminopyralid showed NO A ELs of 5 00 mg/kg/day in Fischer 344 rats, 2 32 mg/kg/day for females and 282 mg/kg/day for male Beagle dogs, and 1000 mg/kg/day in CD

- 1 mic e . 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 NO A EL found in the rat chronic test. NO A ELs 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 admi nistration 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. Th e 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. 2.1 4 ) 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

.4

i. Food. In conducting the potential dietary exposure and risk assessments, Dow AgroSciences used the Dietary Expos ure Evaluation Model (DEEMTM, Version 2.14 , Exponent) software that evaluated the individual food consumption as reported by respondents in the USDA 1994

- 199 6, 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 th at 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 NO A EL 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/d ay 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 0.00 210 7 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 consid ered 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 the se m odel s , 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 asses s 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 e xposure to aminopyralid in drinking water would not result in unacceptab le 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 oral5

exposures (e.g., hand

- to

- mouth transfer of residues, object

- to

- mouth, and ingestion of soil) is considered. These scenarios are short

- t erm 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 oth er 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 tole rance 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 h ealth. 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 a ggregate 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. In fants 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 t oxicological 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 qualita tive susceptibility was seen following pre

and post

- natal exposures. In a 2

- generation reproductive toxicity study in rats, no effects on reproductive performance or neonatal development were observed. Dow6

AgroSciences concluded that there is no indicatio n 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. Inter national 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 agricultu ral crops not included within this petition

.