EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE

PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: Kathryn Montague/PM

- 23 703

- 305

- 1243

TEMPLATE:

Dow AgroSciences LLC

1F7928

EPA has received a pesticide petition (1F792 8 ) from Dow AgroSciences LLC, 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 .535 by establishing a tolerance for residues

of fluroxypyr MHE and its metabolite fluroxypyr (expressed as combined residues of total fluroxypyr) in or on the raw agricultural commodit ies of Crop Group 15

- C ereal grains [ barley, buckwheat, millet, oats,
rye, te osinte, triticale, wheat at 0.5 parts per million (ppm); corn, popcorn, and sorghum grain at 0.0 2 ppm; rice and wild rice at 1. 5 ppm ] ; in or on rice, bran at 3.0 ppm ; and in or on Crop Group 16

– f orage, fodder and straw of cereal grains at 12 ppm; ha y of cereal grains at 20 ppm; and stover of cereal grains at 4 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 metabolism The nature of the residue in plants and animals is adequately understood for the purpose of this tolerance. Based on the findings from these studies, the residues of concern in plants and animal commodities are the parent, fluroxypyr 1

- methylheptly ester (MHE ) and its metabolite fluroxypyr, free and conjugated. Therefore, the tolerance expression is the combined residues of total fluroxypyr.

2. Analytical method Adequate enforcement method for the combined residues of total fluroxypyr is

available to enfo rce the tolerance expression in or on food. The analytical method uses High Performance Liquid Chromatography with Tandem Mass Spectrometry with limits of quantitation (LOQ) of 0.01 ppm. Fluroxypyr has also been tested through the Food and Drug Administration (FDA), Multi

- residue Methodology, Protocols C, D, and E. The results have been published in the FDA Pesticide Analytical Manual, Volume 1.

3. Magnitude of residues

. Geographically representative field trials on rice using an emulsifiabl e concentrate formulation of fluroxypyr were conducted according to proposed use patterns using parameters that would likely result in the highest residues. Additional tolerances are based on existing tolerances for cereal grains. For rice t he proposed t olerance of 1.5 ppm was based on the maximum field trial residue and therefore, would be adequate to cover the highest residues resulting from thesefluroxypyr uses. Tolerances for the remaining cereal grains and crop groups 15 and 16 are proposed

based o n existing cereal data and were developed based on similarity in both agronomic practices and crop development.

B. Toxicological Profile

1. Acute toxicity. Fluroxypyr MHE has low acute toxicity. The rat oral LD50 is > 5000 mg/kg, the rabbit dermal LD50 is >2000 mg/kg, and the rat inhalation LC50 is >1.0 mg/l (1000 mg/cubic meter). In addition, fluroxypyr MHE is not a skin sensitizer in guinea pigs, has no dermal irritation in rabbits,

and shows mild ocular irritation in rabbits. The end use formulation of fluroxypyr MHE has a similar low acute toxicity profile. No appropriate endpoint has been identified to quantify a single exposure.

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 fluroxypyr MHE. These studies show a lack of genotoxicity. In addition, short term assays for genotoxicity consisting of an Ames metabolic activation test, possible i nduction of point mutations at the HGPRT

- Locus of Chinese hamster ovary cells, in vivo and in vitro chromosomal aberrations in the Chinese hamster ovary cells, unscheduled DNA synthesis in human embryonic cells, and an assay in mouse lymphoma cells have be en conducted with fluroxypyr. These studies also show a lack of genotoxicity.

3. Reproductive and developmental toxicity. Developmental studies in rats and rabbits were conducted with both fluroxypyr MHE and fluroxypyr. Studies with fluroxypyr MHE sho wed

maternal and fetal NOELs of 300 and 600 mg/kg/day (rat) and 500 and 500 mg/kg/day (rabbit). Studies with fluroxypyr showed NOAELs in the rat of 250 mg/kg/day for maternal effects and 500 mg/kg/day for fetal effects and a NOEL in the rabbit of 250 mg/k g/day for both maternal and fetal

effects. These studies show that fluroxypyr and fluroxypyr MHE are not teratogenic nor will they

interfere with in utero development. Two multi

- generation reproduction studies were conducted with fluroxypyr in rats. The first in Wistar rats showed no effect on fertility or reproductive performance and had a NOAEL of 500 mg/kg/day (highest dose tested). The second study in Sprague

- Dawle y rats showed a parental NOEL for systemic effects of 100 mg/kg/day in male rats and 500 mg/kg/day in

female rats. The NOEL for reproductive effects was 750 mg/kg/day for males and 1000 mg/kg/day for females (highest dose tested). The NOEL for neonatal e ffects was 500 mg/kg/day.

4. Subchronic toxicity. Fluroxypyr MHE showed a NOEL of 1000 mg/kg/day in a 90

- day rat dietary study and a 21

- day rabbit dermal study. Ninety day feeding studies with fluroxypyr showed NOELs of 80 mg/kg/day (Wistar rats), 700 mg/kg/day (Fischer 344 rats), 1342 mg/kg/day (male mice), and 1748 mg/kg/day (female mice). In a 4

- week dietary, range finding study with fluroxypyr in dogs th e NOEL found was 50 mg/kg/day.

5. Chronic toxicity NOAELs found in the chronic dietary studies are as follows: 150 mg/kg/day (dog), 300 mg/kg/day (mouse), 100 mg/kg/day (male Fischer 344 rats), and 500 mg/kg/day (female Fischer 344 rats). Based on the chronic/carcinogenicity study on rat, EPA has establis h ed a chronic reference dose (cRf D) of 1 mg/kg/day. The NOAEL of 100 mg/kg/day was based on increased kidney weight in both sexes and an increase in the severity of chronic progressive glomerulo

- nephropathy in the kidney

in both sexes at the LOAEL of 500 mg/kg/day. No additional FQPA factor was required, therefore,the chronic population adjusted dose (cPAD) is equal to cRfD. Fluroxypyr is classified as "not likely

to be carcinogenic " and there was no concern for its mutagenicity potential.

6. Animal me tabolism Both fluroxypyr and fluroxypyr MHE have been evaluated in rat metabolism

studies. In summary, these studies show that fluroxypyr MHE is rapidly hydrolyzed and the fate of the hydrolysis products, fluroxypyr and 1

- methylheptanol, are independent of whether they were given as the ester or the acid. Fluroxypyr, per se , was extensively abs orbed and rapidly excreted principally unchanged in the urine; 1

- methylheptanol also was rapidly absorbed and rapidly eliminated. Repeated administration of fluroxypyr MHE was not associated with accumulation in tissues. Also, the metabolism and pharmaco kinetics of 1

- methylheptanol are comparable to that of the methylheptyl portion of fluroxypyr MHE.

7. Metabolite toxicology

. Administration of fluroxypyr, as the acid or methylheptyl ester, in a variety of toxicological studies has produced similar effec ts. The principal response to sufficiently high dosages, whether administered over the short

- term or, in some cases, over a lifetime, was nephrosis. Fluroxypyr is an organic acid that is actively excreted into the urine by the kidney. Thus, the target

o rgan and dose response relationship for fluroxypyr toxicity is entirely consistent with the data on the toxicokinetics of fluroxypyr. Metabolism studies have shown that fluroxypyr MHE is rapidly and completely hydrolyzed to fluroxypyr acid and methylhepta nol.

8. Endocrine disruption

. There is no evidence to suggest that fluroxypyr and fluroxypyr MHE have an effect on any endocrine system.

9. Immunotoxicity. Fluroxypyr was tested for immunotoxic potential using the sheep red blood cell assay after 28

- day dietary exposure to male Wistar rats, according to USEPA, OPPTS 870.7800 (1998). The study was GLP compliant. Under the test conditions, there were no treatm ent related symptoms of immunotoxicity in the tested animals and NOEL for immunotoxicity was the high dose of 750 mg/kg/day, the highest dose

- level tested.

10. Neurotoxicity. There is no indication that fluroxypyr is a neurotoxic chemical and there is no need for a developmental neurotoxicity study or additional UFs to account for neurotoxicity.

C. Aggregate Exposure

1. Dietary exposure

.

i. Food

. Tolerances have been established (40 CFR 180.535) for the combined residues of fluroxypyr in or on a variety of raw agricultural commodities, milk, meat and meat by

- products. In this petition, a dditional tolerances for Group/Crop 15. Cereal grains; Group/ C rop 16. Forage, fodder and straw of cereal grains; and Rice, bran are being proposed.

An acute dietary exposure is not required because no adverse effect attributable to a single exposure of fluroxypyr was observed in the available toxicity studies. Ther efore, EPA did not identify an acute dietary endpoint and no acute risk is expected.

In conducting the chronic dietary assessment, Dow AgroSciences used the Dietary ExposureEvaluation Model software with the Food Commodity Intake Database (DEEM

- FCID, Version

2. 14 ) which incorporates food consumption data as reported in the CSFII Survey 1994

- 1996 and 1998. A conservative analysis (Tier 1) was performed with the assumptions that 100% of crops with approved and proposed uses of fluroxypyr would be treated with the pesticide and that the residues would be present at the tolerance levels. Additionally, processing factors were used in

DEEM

- FCID for processed commodities. Based on these conservative assumptions and using a cPAD of 1 mg/kg/day, the exposure t o fluroxypyr from food will utilize <1% of the cPAD for the U. S. population, <1% of the cPAD for all infants, and 1. 5 % of the cPAD for children (1

- 2 years old), the population subgroup with the highest potential for exposure. Adverse effects are not

expec ted for exposures utilizing less than 100% of the RfD, therefore, chronic dietary exposure and risk for the general U.S. population and children are well within the acceptable levels.

ii. Drinking water

. Since the Agency lacks sufficient monitoring data to complete a comprehensive exposure and risk assessment for fluroxypyr in drinking water, drinking water concentration estimates are made on simulation taking into account data on the physical characteristics of fluroxypyr.

Guidance from EPA has indicat ed that Tier 1 screening level models, such as GENEEC and

SCI

- GROW, may be used to estimate upper

- bound pesticide residues in surface water and ground water when assessing potential exposure through drinking water. In a recent assessment (Federal Register Vol. 72 , No. 2 48 December 28 , 200 7

, pp 73631

- 73635 ), EPA used PRZM/EXAMS and

SCI

- GROW models to estimate the environmental concentrations (EECs) of fluroxypyr in surface water and ground water for applications to terrestrial crops

. This petition involves use of fluroxypyr in aquatic use (rice), and exposure from drinking water is aggregated to the dietary exposure, at the maximum residue level estimated by EPA’s Tier I Rice Model which is more conservative than EPA’s previous PRZM/EXAMS surface water mode l. The EECs for chronic exposures are estimated to be 0.439 pp m from the Tier I Rice Model

. Estimated environmental concentration (EEC) f

rom the Tier I Rice Model w as then inputted into DEEM model for estimation of dietary exposure from water both direct and indirect sources. The input of water residues along with food into the DEEM model provides a conservative estimate of the total exposure from food and water sources.

For the U.S. population, the exposures from food and water represent less than 1 .3 % of the cPAD. Additionally, for all infants (< 1 year old) , the population with the highest exposure, the exposures represent approximately 3.6% of the cPAD. EPA has no concern for a ggregate chronic exposure

below 100% of the cPAD

.

2. Non

- dietary expos ure

. Fluroxypyr is currently registered for use on residential turfgrass and recreational sites such as golf courses and sports fields. Short

- and intermediate

- term exposures to fluroxypyr may occur during post

- application activities for adults and child ren. The risk assessment was conducted using the following assumptions: Adults and children may be exposed from dermal contact with turf during post

- application activities. Toddlers may experience short

and intermediate

- term oral exposure from incident al non

- dietary ingestion during post

- application activities. Residential handlers may receive short

- term dermal and inhalation exposure during mixing, loading and applying the formulations. The HED's Draft Standard Operating Procedures

for Residential Ex posure Assessments and Recommended Revisions (HED Policy Number 11, February 22, 2001) along with the ORETF and turf transferable residue data were used as the basisfor exposure calculations.

Using the above assumptions, the aggregated food and residenti al exposures resulted in estimated

MOEs of 4

, 6 00 for the U. S. population

, 2

, 3 00 for all infants (<1 year old) and 2,700 for children

1

- 2 years old. These MOEs are substantially greater than 100, indicating that the risk from potential non

- dietary/residen tial exposures is w ell within an acceptable level.

D. Cumulative Effects

The potential for cumulative effects of fluroxypyr MHE and fluroxypyr and other substances that have a common mechanism of toxicity is also considered. There is no reliable information to indicate that toxic effects produced by fluroxypyr MHE and fluroxypyr would be cumulative with those of any other pesticide chemical. Thus, it is appropriate to consider only the potential risks of fluroxypyr MHE and fluroxypyr in an aggreg ate exposure assessment.

E. Safety Determination

1. U.S. population

. Chronic dietary exposure for the general U.S. population to residues of fluroxypyr from current and proposed uses were estimated to occupy 1 .3 % of the cPAD. Thus, the aggregated chronic exposure to fluroxypyr resulting from current and proposed uses is well within the acceptable levels of risk.

Use of fluroxypyr on turf results in potential short

- and intermediate

- term exposures. Potential food dietary and r esidential exposures were combined into an aggregate MOE value, which was

calculated to be 4

, 6 00 for the U.S. population. The aggregate MOE is well above 100, indicating risk is well within acceptable levels.

Thus, based on the completeness and reliabili ty of the toxicity data and the conservative exposure assessment, it is concluded that there is a reasonable certainty that no harm will result to the U.S. population from chronic, short

- and intermediate

- term aggregate exposures to fluroxypyr residues

fro m current and proposed uses.

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 fluroxypyr MHE relative to pre

- and post

- natal effects for children is complete. There were no indications of neurotoxicity and developmental toxicity was not

observed in the absence of maternal toxicity. It is concluded that there is no indication of increased sensitivity of infants and children relative to adults and that an additional FQPA safety factor is not required.

Chronic dietary exposure to residues of fluro xypyr from current and proposed uses was estimated to occupy only 1. 5 % of the chronic PAD for children 1

- 2 years old, the population subgroup predicted to be most highly exposed.Potential food dietary and residential exposures to children 1

- 2 years old w ere combined into an

aggregate MOE value. The aggregate MOE was estimated to be 2,700 and well above 100, indicating risk is well within acceptable levels.

Thus, based on the completeness and reliability of the toxicity data and the conservative exposure assessment, it is concluded that there is a reasonable certainty that no harm will result to infants and children from chronic, short

- and intermediate

- term aggregate exposures to fluroxypyr residues from current and proposed uses.

F. International Toler

ances

There are no Codex or Canadian maximum residue levels established for residues of fluroxypyr MHE and fluroxypyr for rice or cereals. There are international MRLs established for several crops within this petition for EU and Mexico

.