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 (1F7928) 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 commodities of Crop Group 15 - Cereal grains [barley, buckwheat, millet, oats, 

rye, teosinte, triticale, wheat at 0.5 parts per million (ppm); corn, popcorn, and sorghum grain at 0.02 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 – forage, fodder 

and straw of cereal grains at 12 ppm; hay 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 enforce 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 emulsifiable 

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 the proposed tolerance of 1.5 ppm was based on the maximum 

field trial residue and therefore, would be adequate to cover the highest residues resulting from these 
fluroxypyr uses. Tolerances for the remaining cereal grains and crop groups 15 and 16 are proposed

based on 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 induction 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 been 

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 showed 

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/kg/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-Dawley 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 effects 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 the 

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 established a chronic reference 

dose (cRfD) 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 metabolism 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 absorbed 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 pharmacokinetics 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 effects. 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 

organ 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 methylheptanol.

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 treatment 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, additional tolerances for Group/Crop 15. Cereal grains; Group/Crop 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. Therefore, 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 Exposure 
Evaluation 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 to 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 

expected 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 indicated 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. 248 December 28, 2007, 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 model. The EECs for chronic 

exposures are estimated to be 0.439 ppm from the Tier I Rice Model. Estimated environmental 

concentration (EEC) from the Tier I Rice Model was 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 aggregate chronic exposure 

below 100% of the cPAD.

2. Non-dietary exposure. 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 children. 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 shortand intermediate-term oral exposure from incidental 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 Exposure Assessments and Recommended Revisions (HED Policy Number 11, 

February 22, 2001) along with the ORETF and turf transferable residue data were used as the basis 
for exposure calculations. 

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

MOEs of 4,600 for the U. S. population, 2,300 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/residential exposures is well 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 aggregate 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 residential exposures were combined into an aggregate MOE value, which was 

calculated to be 4,600 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 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 the U.S. 

population from chronic, short- and intermediate-term aggregate exposures to fluroxypyr residues 

from 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 fluroxypyr 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 were 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 Tolerances 

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.