Fluroxypyr Human Health Risk Assessment DP No. 396339

Page 3 of 35 6.2 Postapplication Exposure

................................ ................................ ............................ 21

6.3 Combined Exposure

................................ ................................ ................................ ..... 22

6.4 Residential Bystander Postapplication Inhalation Exposure

................................ ... 23

6.5 Spray Drift

................................ ................................ ................................ .................... 23

7.0 Aggregate Exposure/Risk Characterization

................................ ................................ .. 24

7.1 Acute Aggregate Risk

................................ ................................ ................................ ... 24

7.2 Shor t

- Term Aggregate Risk

................................ ................................ ........................ 24

7.3 Chronic Aggregate Risk

................................ ................................ .............................. 25

8.0 Cumulative Exposure/Risk Characterization

................................ ............................... 25

9.0 Occupational Exposure/Risk Characterization

................................ ............................ 25

9.1 Short

- /Intermediate

- Term Handler Risk

................................ ................................ ... 26

9.2 Short and Intermediate

- Term Postapplication Risk

................................ ............... 27

9.2.1 Dermal Postapplication Risk

................................ ................................ ................... 27

9.2.2 Inhalation Postapplication Risk

................................ ................................ .............. 27 Appendix A. Toxicology Profile and Executive Summaries

................................ .................. 29 A.1 Toxicology Data Available for Fluroxypyr

................................ ................................ ........ 29

A.2 Toxicity Profiles

................................ ................................ ................................ ............ 30 Appendix B. Review of Human Research

................................ ................................ ............... 35Fluroxypyr Human Health Risk Assessment DP No. 396339

Page 4 of 35 1.0 Executive Summary

HED has conducted a human health risk assessment for the herbicide, fluroxypyr for the purpose

of establishing tolerance s for a proposed new use on ri c e as requested by Dow Agrosciences

LLC.

The proposed use directions specify that fluroxypyr is to be applied by broadcast ground and

aerial application to the ri c e field at a maximum single applicatio n rate of 0. 2 4 lb ae/A ( 0. 34 lbs

ai/A ) . Two applications per season are permitted with a 60

- day preharvest interval (PHI).

The kidney is the target organ for flu ro xypyr (and fluroxypyr MHE) following oral exposure to rats, mice, and dogs. There was no evidence of increased susceptibility following in utero exposure to the acid and the ester in rats and rabbits, or following pre and/or postnatal exposure

to the acid form in rats

. Neither developmental toxicity nor reproductive toxicity was observed in

ra ts. In rabbits, developmental toxicity was not observed following exposure to fluroxypyr , but abortions were observed in rabbits following exposure to fluroxypyr MHE at the limit dose. There was no evidence of neurotoxicity or neuropathology in any stud y

. T here were no

treatment

- related effects in an i mmunotoxicity study in rats

. Fluroxypyr is classified “not likely to be carcinogenic to humans ” and there i s no concern for its mutagenicity potential.

Endpoints for risk assessment wer e based on kidney effects. Doses selected for risk assessment purposes are summarized below. The FQPA safety factor was reduced to 1X since the toxicity database was considered complete, there were no residual uncertainties for pre

- and/or post natal

toxi city, no evidence of neurotoxicity or neuropathology was found, and the estimated exposures were not likely to underestimate risk.

An acute dietary risk assessment was not required as there were no effects seen in the database which could be attributable to exposure to a single dose of fluroxypyr. Chronic dietary exposure and risk assessments were conducted assuming 100% crop treated and tolerance level residues for all existing and new uses of fluroxypyr. Modeled drinking water estimated environmental concentrations (EECs) were incorporated into the chronic dietary risk assessment. No chronic dietary risks of concern were identifie d for the U.S. population or any subgroup. The most highly exposed subpopulation was infants (< 1 year) with an estimated risk equivalent to 3.5 % of the chronic population adjusted dose (cPAD). A quantitative dietary cancer risk assessment was not requir ed.

There were no new residential uses requested in this petition. The existing residential uses have been assessed using the new residential SOP ( 01 / 01 /2012) and all calculated residential MOEs were greater than the target of 100, and therefore, were no t of concern to HED.

Human health aggregate risk assessments were conducted for the chronic aggregate exposure (food + drinking water) scenario, as well as the short

- /intermediate

- term aggregate exposure
scenario. Short

- , intermediate

- and chronic aggr egate risks were not of concern.Fluroxypyr Human Health Risk Assessment DP No. 396339

Page 5 of 35 Occupational handler and post application exposures and risks were evaluated for the proposed

new use on ri c e. MOEs for all scenarios exceeded the target MOE of 100 and were not of

concern.

This risk assessment does not rely on any toxicity data from studies in which human subjects were intentionally exposed to a pesticide or other chemical. The ORE assessment used generic exposure data from exposure studies that have been subject to OPP ethics review and have been

appr oved for use in human health risk assessment s

.

2.0 HED Recommendations

HED has no objection to establishment of the proposed tolerances shown below or to registration

of the new use of flurox y py r on ri c e

.

2.1 Data Deficiencies/Conditions of Registration

There are no data gaps with respect to toxicology, residue chemistry, or occupational exposure for fluroxypyr.

2.2 Tolerance Considerations

Tolerances are established for the residues of the herbicide fluroxypyr , including its metabolites and degradates, under 40 CFR 180.535. Compliance with the established tolerance levels is determined by meas uring only the sum of fluroxypyr 1

- methylheptyl ester [1

- methylheptyl ((4

- amino

- 3, 5

- dichloro

- 6

- fluoro

- 2

- pyridinyl)oxy) acetate] and its metabolite fluroxypyr [((4

- amino

3,5

- dichloro

- 6

- fluoro

- 2

- pyridinyl)oxy)acetic acid] calculated as the stoichiometric equivalent of fluroxypyr. The established tolerances for plant commodities range from 0.02 ppm (field corn grain, sweet c orn K+CWHR, and sorghum grain) to 160 ppm (grass hay) [40 CFR 180.535(a)]. The established tolerances for livestock commodities range from 0.1 ppm (fat, meat, and meat byproducts) to 1.5 ppm (kidney). Time

- limited tolerances for combined residues of flur oxypyr 1

- MHE and its metabolite fluroxypyr in/on field corn, sweet corn, onion, and sorghum commodities have been established in connection with use of fluroxypyr 1

- MHE under Section 18 emergency exemptions [40 CFR 180.535(b)]; time

- limited tolerances have past due expiration dates (12/31/05 and 12/31/06), except for onion with an expiration date of 0 6/30/07.

2.2.1 Enforcement Analytical Method

Adequate GC/ECD (gas chromatography/electron capture detection) analytical methods are available to enforce the proposed plant tolerances. The available methods for plant commodities

involve extraction of fluroxypyr residues with acetone, partitioning with hexane, purification using a Florisil column, and analysis of residues by GC/ECD

.

2.2.2 International Harmonization

There are no Maximum Residue Limits (MRLs) established by Codex, Canada, or Mexico for any of the proposed commodities in the current registration action (Section 3).Fluroxypyr Human Health Risk Assessment DP No. 396339

Page 6 of 35 2.2.3 Recommended Tolerances

Pe rmanent t olerances are e stablished under 40 CFR §180. 535 (a) for the combined residues of fluroxypyr 1

- MHE and its metabolite fluroxypyr on a number of plant and livestock

commodities

. Tolerances are already set on most of the representative crops listed fo r the cereal grains crop group 15 (sweet corn, field corn, sorghum & wheat), and the forage, fodder, and straw of cereal grains crop group 16 (corn & wheat) except for rice. To support this registration, Dow has submitted field trial data and a processing study for rice. For this pe tition request

, Dow is proposing that permanent tolerances be established for the residues of fluroxypyr in/on the following rice commodities:

Rice

................................ ................................ .......... 1.5 ppm Rice, bran

................................ ................................ . 3.0 ppm

2.3 Label Recommendations

No label revisions are needed and no recommendations are being made by HED.

2.3. 1 Recommendations from Occupational Assessment

N o label revisions are needed based on the occupational exposure risk assessments.

2.3. 2 Recommendations f rom Residential Assessment

No recommendations are needed based on HED’s residential exposure and risk assessment.

3.0 In troduction

Fluroxypyr is a member of the pyridinoxy acid class of herbicides. Other chemicals in this class include triclopyr, picloram, and clopyralid. Fluroxypy r induces auxin

- type responses in susceptible annual and perennial broadleaf weeds. The pesticide active ingredient is flu r oxypyr methylheptyl ester (fluroxypyr MHE)

. The end

- use products are emulsifiable concentrate formulations of fluroxypyr 1

- methylheptyl ester ( fluroxypyr 1

- MHE), with a maximum single application rate of 0.24 lb acid equivalents (a.e.) or 0.34 lb ai/ per acre

.Fluroxypyr Human Health Risk Assessment DP No. 396339

Page 7 of 35 3.1 Chemical Identity

Table 3.1. Fluroxypyr 1

- MHE Nomenclature.
Compound

Common name Fluroxypyr 1

- methylheptyl ester Company experimental name XRM

- 5316

IUPAC name 1

- methylheptyl

- 4

- amino

- 3,5

- dichloro

- 6

- fluoro

- 2

- pyridyloxyacetate

CAS name [(4

- amino

- 3,5

- dichloro

- 6

- fluoro

- 2

- pyridinyl)oxy]acetic acid, 1

- methylheptyl ester

CAS # 81406

- 37

- 3

End

- use product/EP 1.5 lb ae/gal EC formulation (Starane TM Herbicide; EPA Reg. No. 62719

- 286)
Fluroxypyr, free acid

Common Name Fluroxypyr

CAS name [(4

- amino

- 3,5

- dichloro

- 6

- fluoro

- 2

- pyridinyl)oxy]acetic acid

CAS # 69377

- 81

- 7

3.2 Physical/Chemical Characteristics

Table 3.2. Physicochemical Properties of the Fluroxypyr 1

- MHE.

Parameter Value
Melting point/range 57.5°C
pH 6.81 in solution containing 90.1 μg/L Density 1.30 g/mL at 21°C Water solubility ( 20 °C) 90.1 μg/L in purified water 294 μg/L in pH 5 buffer 136 μg/L in pH 7 buffer 57.2 g/L in pH 9 buffer Solvent solubility (20 °C) 6.23 g/100 mL in n

- heptane >200 g/100 mL in xylene 377 g/100 mL in methanol 22.0 g/100 mL in n

- octanol >300 g/100 mL in acetone
Vapor pressure 2.0 x 10 - 5 kPa at 25 ° C

1.0 x 10 - 5 kPa at 20 ° C

Dissociation constant Not applicable Octanol/water partition coefficient Log(K OW ) 4.57 at pH 5 5.04 at pH 7 5.31 at pH 9 UV/visible absorption spectrum Not availableFluroxypyr Human Health Risk Assessment DP No. 396339

Page 8 of 35 3.3 Pesticide Use Pattern

The herbicide fluroxypyr

- 1

- methylheptyl ester is currently registered for use in or on field corn, sweet corn, sorghum, range and pasture grasses, turf

, dry bulb onions, garlic

, p ome fruits and

shallots

. Current petition is to establish tolerances for flu r oxypyr on rice and rice bran. The most recent risk assessment was performed for the proposed uses of flu r oxypyr on pome fruits and shallots ( Donna S. Davis

, 200 7 ; D 344540 ). Flu r oxyp yr is registered for use on residential turfgrass and recreational sites, such as golf courses, parks, and sports fields. The summary of purposed use pattern is presented in Table 3.3.

Table 3.3 Summary of Purposed Use Patterns/Formulation Informatio n Crop Trade Name Number of Application per Season Max Appli cation

lb ai/A . per Season Max. Single

Application lb ai/A PHI

Rice Starane Ultra TM Herbicide 2 0.57 0.34 60

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed new use of the herbicide fluroxpypyr on rice. Fluroxpypyr is currently registered for use on field corn, and there are tolerances for residues in crop group 15 (cereal grains) and crop group 16 (forage, fodder and straw of cereal grains) and livestock commodities

. Therefore, humans may be exposed to fluroxpypyr in food and drinking water, since the chemical may be applied directly to growing crops and may rea ch surface and ground water sources of drinking water. While the product s containing fluroxpypyr do not appear to be intended for homeowner use, there is the potential for homeowners to purchase and apply the product to their own lawns, and the potential f

or this exposure has been considered in the risk assessment. In an occupational setting, applicators may be exposed while handling the pesticide prior to application (i.e., mixing/loading), as well as during application. There is the potential for

postap plication exposure to workers re

- entering treated fields , but since there is no dermal endpoint (toxicity) associated with f luroxypyr

, there are no human health concerns for risk by this route of exposure

.

Risk assessments have been previously prepared fo r the existing use of flurox y py r on residential

turf (K. O’Rourke, D328799, 07/06/2006) . This risk assessment considers all exposure pathways based on the existing and proposed new use of fluroxypyr

.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income P opulations," ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to wel l

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.Fluroxypyr Human Health Risk Assessment DP No. 396339

Page 9 of 35 Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. T hese data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed wh en conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplicatio n are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditio nal dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

The toxicology database is complete . The Fluroxypyr Risk Assessment Team has reviewed the toxicity database and concluded that the doses and endpoint s previously selected for risk

assessment purposes are consistent with current HED policy and are appropriate for the routes and durations of exposure anticipated from the existing and newly proposed uses of fluroxypyr.

4.1 Toxicology Studies Available for Analysis

The toxicology database on fluroxypyr , which includes studies on both fluroxypyr and fluroxypyr methylheptyl ester) is sufficient for assessing the toxicity and characterizing the hazard of fluroxypyr

. The toxicology studies for fluroxypyr an d fluroxypyr methylheptyl ester are summarized in Table A.1 in Appendix A. The database includes the following studies.

Acute/lethality studies (oral, dermal, inhalation, primary eye and dermal irritation, and dermal sensitization)

– fluroxypyr and flur oxypyr MHE Subchronic oral toxicity studies (rat, mouse, and dog)

- fluroxypyr Developmental (rat and rabbit) and reproductive (rat) toxicity (oral) studies

– fluroxypyr

and fluroxypyr MHE Dermal (21

- day) toxicity (rabbit) study

- fluroxypyr MHE

Chronic oral toxicity studies (rat and dog)

- fluroxypyr Carcinogenicity (oral) studies [rat (chronic combined) and mouse]

- fluroxypyr Metabolism study (rat)

- fluroxypyr MHE Mutagenicity battery

- fluroxypyr MHE Immunotoxicity study (rat)

- fluroxypyr

The stu dies available for consideration of fluroxypyr toxicity provide a comprehensive database, with routes of administration which are consistent with potential exposure scenarios.Fluroxypyr Human Health Risk Assessment DP No. 396339

Page 10 of 35 4. 2 Absorption, Distribution, Metabolism, and Elimination (ADME)

Radiola beled fluroxypyr methylheptyl ester (MHE) was readily absorbed and rapidly eliminated following a single oral dose to male Fischer 344 rats. Approximately 90% of the administered dose was absorbed. Once absorbed, it was extensively metabolized (≈20 metabol ites) and rapidly expired as 14 CO 2 or eliminated in the urine , primarily as metabolites . Peak plasma concentrations were attained by 7 hours, and the half

- live for the elimination phase was ≈18 hours. Approximately 7% of the administered dose was found in the carcass and ≈0.14% was found in

the blood.

4.2.1 Dermal Absorption

No dermal absorption studies are available. A dermal absorption factor is not required since quantification of dermal risk is not required based on lack of toxicity observed in the dermal toxicity study, and the lack of pertinent effects in other toxicity studies not measured in the dermal toxicity study

.

4.3 Toxicological Effects

The kidney is the target organ for flu ro xypyr following oral exposure to rats, mice, and dogs. In the rat, increased kidney weight , nephrotoxicity, and death were observed in both sexes in the

90

- day feeding study, and increased kidney weight and chronic progressive glomerulonephropathy were observed in both sexes in the chronic study . In creased kidney weight was observed in maternal rat s in the developmental toxicity study with fluroxypyr , and kidney effects (deaths due to renal failure; increased kidney weight, and microscopic kidney

lesion s) were observed in both sexes in the 2

- generation reproduction study in rats . Although kidney toxicity (early signs of acute tubular nephrosis) was observed in dogs in the 28

- day feeding study, no kidney effects or other treatment related toxicity w ere s een in the chronic feeding study in dogs at the same doses used in the 28

- day study

. K idney lesions (increased incidences of renal papillary necrosis and regenerative nephrosis in females) were observed in mice following long

- term exposure.

There was no evidence of increased susceptibility (quantitative/qualitative) following in utero exposure to the acid and the ester in rats and rabbits, or following pre and/or postnatal exposure

to the acid form in rats

. Neither developmental toxicity nor reproductive toxicity was observed in rats. In rabbits, developmental toxicity was not observed following exposure to fluroxypyr at dose levels that resulted in maternal death. Abortions were observed in rabbits following

exposure to fluroxypyr MHE at the limit dose. There was no evidence of neurotoxicity or neuropathology in any of the studies. An immunotoxicity study in rats found no indication of immunotoxicity. Fluroxypyr is classified “not likely to be carcinogenic to humans ”

, and there i s no concern for its mutagenicity potential.

Fluroxypyr has low acute toxicity by the oral and dermal routes of exposure and moderate acute

tox icity by the inhalation route of exposure, based on lethality studies. F luroxypyr (MHE) ester
is l ess acutely toxic than the acid by the oral route of exposure . Neither chemical is irritating to the skin. Fluroxypyr M HE is not a dermal sensitizer; however, it is a mild eye irritant. TheFluroxypyr Human Health Risk Assessment DP No. 396339

Page 11 of 35 acute toxicity profiles for fluroxypyr and fluroxypyr MHE techn ical are contained in Attachment

1 of this risk assessment.

The toxicity profile of fluroxypyr and fluroxypyr 1

- MHE technical is shown in Attachment 2 of

this risk assessment.

4.4 Safety F actor for Infants and Children (FQPA Safety Factor)

HED reco mmends that the 10X FQPA Safety Factor (for the protection of infants and children) be reduced to 1X. An FQPA Safety Factor of 1X is appropriate for the following reasons:

The toxicity database is complete and adequate to assess safety for infants and children. There is no evidence of increased qualitative or quantitative susceptibility in the developmental rat and

rabbit studies or in the rat 2

- generation reproduction study. These studies have clearly defined

NOAEL/LOAELs. Both the neurotoxicity screening battery and the developmental neurotoxicity study have been waived

. The exposure assessment will not underestimate children’s exposure to fluroxypyr . Further details may be found in the following sections.

4.4 .1 Completeness o f the Toxicology Database

The toxicology database for fluroxypyr is complete

. . Acceptable developmental toxicity studies

in rats and rabbits are available for fluroxypyr and fluroxypyr MHE , in addition to an acceptable reproduction st udy for fluroxypyr in rats. The HED’s Hazard and Science Policy Council (HASPOC) determined that the acute and subchronic neurotoxicity studies may be waived

.

4.4.2 Evidence of N eurotoxicity

There is no evidence of neurotoxicity or neuropathology in the available studies. The salivation and ataxia seen in animals prior to death were considered to be agonal; the salivation in the rat studies occurred following gavage dosing and was attributed t o localized irritation; the decreased brain weight in the 90

- day rat study was not substantiated in other studies. There is not a concern for developmental neurotoxicity.

4.4.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

There is no evidence of increased qualitative or quantitative susceptibility following in utero exposure to the acid and the ester in rats and rabbits or following pre and/or postnatal exposure

to the acid in rats.

Flu r oxypyr is neither a developmental n or a reproductive toxicant in rats. Fluroxypyr has been evaluated for potential developmental effects in the rat and rabbit (gavage administration). Maternal toxicity included death in rats and rabbits. There were no developmental effects in the

rat, and w hile abortions were observed in the rabbit , they occurred only at the limit dose.

The Fluroxypyr Risk Assessment Team reviewed the toxicity database and HIARC recommendations for consistency with current policy and reaffirmed the previous assessmentFluroxypyr Human Health Risk Assessment DP No. 396339

Page 12 of 35 that the FQPA SF could be reduced to 1X based on the following considerations:

The toxicological database is considered complete

. There are no concerns or residual uncertainties for pre

- and/or post

- natal toxicity. There was no evidence of neurotoxicity or neu ropathology in the available studies and the neurotoxicity battery (acute and subchronic) and developmental neurotoxicity study requirements have been waived

. The chronic dietary food exposure assessment utilizes tolerance level residue estimates

and assum es 100 % CT for all commodities. This assessment will not underestimate exposure/risk. The dietary drinking water assessment utilizes water concentration values generated by model and associated modeling parameters which are designed to provide conservati ve, health protective, high

- end estimates of water concentrations which will not be exceeded. The previous residential exposure assessment was conducted using standard assumptions and is not likely to underestimate exposure.

4.4.4 Residual Uncertainty in the Exposure Datab ase

There are no residual uncertaint ies in the f luroxypyr database in re gard to dietary (food and drinking water), occupational

, and residential exposures. The residue data used for dietary exposure assessment are described in Section 5. 4.1 of this document. Further, occupational and residential exposure estimates are based on conservative, health

- protective assumptions that also ensure exposures are not underestimated.

4.5 Toxicity Endpoint and Point of D eparture Selections

The available hazard database is adequate to characterize any potential for prenatal or postnatal

risk for infants and children.

4. 5.1 Dose

- Response Assessment

The studies used for selecting toxicity endpo ints and points of departure (Po Ds) for various exposure scenarios are presented in Appendix A

. A2

. The exposure profile includes all routes and durations of exposure, but b ased on the proposed use pattern s for f luroxypyr , the expected exposure profile will be for chronic dietary, inhalation and incid ental oral exposures.

While the description of the toxicity studies used for selecting toxicity endpoints and points of departure for various exposure scenarios is presented in Appendix A, the following outlines the

dose

- response assessment and a general description of the endpoint selection. A summary of the endpoint and point of departure selections for fluroxypyr is shown in Tables 4.5.4.1 and 4.5.4.2.

Acute Dietary Endpoint : An acute endpoint was not identified. No adverse effects were

identified following a single oral dose

, and there are no developmental or neurotoxicity concerns noted in the database.Fluroxypyr Human Health Risk Assessment DP No. 396339

Page 13 of 35 Chronic Dietary Endpoint : The chronic endpoint was selected from the chronic/carcinogenicity study in rats (NOAEL= 100 mg/kg/day; LOAEL= 500 mg/k g/day), based on kidney effects that include increased kidney weights, alterations in clinical chemistry parameters indicative of impaired renal function, and an increase in the severity of chronic progressive glomerulonephropathy in both sexes. The NOAEL /LOAEL are supported by the kidney effects

observed in male rats in the 2

- generation reproduction study (increased kidney weights with corresponding gross and microscopic kidney findings, including papillary atrophy, edema, necrosis, hyperplasia of the pel vic epithelium, degeneration/regeneration of the tubular epithelium, tubule

- interstitial nephritis, and dilatations of the tubules). Although a lower NOAEL (50 mg/kg/day) was observed in a 28

- day oral toxicity study in dogs (acute tubular necrosis), the f

inding was not replicated in the chronic dog study at the same dose levels that

were tested in the 28

- day study, and no other toxicity was observed in the chronic dog study.

Short

- and Intermediate

- Term Incidental Oral Endpoints:

The incidental oral endpoint was selected from the chronic/carcinogenicity study in rats (NOAEL= 100 mg/kg/day; LOAEL= 500 mg/kg/day), based on kidney effects that include increased kidney weights, alterations in clinical chemistry parameters indicative of impaired

renal func tion, and an increase in the severity of chronic progressive glomerulonephropathy in

both sexes. This dose/endpoint would address the nephrotoxicity concern for these exposure periods since signs of nephrotoxicity were observed in both sexes of rat s after 90 days of exposure. Although a lower NOAEL was observed in the 90

- day rat study (80 mg/kg/day), the apparent difference in NOAELs is attributed to dose

- spacing (LOAEL 750 mg/kg/day). The 28

- day dog study also was not selected due to the low confidence in this study (2 dogs/sex were tested; the results were not replicated in the 1

- year dog study; and no other toxicity was observed in the chronic study).

Short

- and Intermediate

- Term Dermal Endpoints: No dermal endpoint was selected because no dermal or systemic toxicity at the limit dose was observed in the dermal toxicity study in rabbits, and there was no concern for developmental toxicity in rats or ra bbits. The developmental toxicity observed in the rabbit occurred at the limit dose. Also, there was no evidence of progression of nephrotoxicity in the rat since the NOAELs/LOAELs were comparable between the subchronic and chronic toxicity studies.

Short

- and Intermediate

- Term Inhalation Endpoint : The most appropriate endpoint for non

occupational and occupational inhalation exposure was determined to be from the chronic oral toxicity study in rats (NOAEL=100 mg/kg/day; LOAEL=500 mg/kg/day), based o n kidney effects that include increased kidney weights, alterations in clinical chemistry parameters

i ndicative of impaired renal function, and an increase in the severity of chronic progressive glomerulonephropathy in both sexes. Although a point of depar ture obtained from a study

conducted via the most relevant route of exposure is preferred for risk assessment, there is no repeat exposure inhalation toxicity study on fluroxypyr

. HED waived the requirement for the 28

- day inhalation toxicity study, b ased o n a weight of evidence (WOE) approach (TXR No. 0056397) that considered the entire available hazard and exposure information for fluroxypyr.Fluroxypyr Human Health Risk Assessment DP No. 396339

Page 14 of 35 The level of concern for the relevant non

- occupational and occupational exposure scenarios is an

MOE of less than 100, based on the standard uncertainty factors for intraspecies variation (10X) and interspecies extrapolation (10X).

Long

- Term Dermal and Inhalation Endpoints: No long

- term exposure scenarios exist for fluroxypyr

.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

Dermal exposure was not quantitatively assessed due to a lack of toxicity via the dermal route. Since adults were assessed for potential inhalation exposure while applying f luroxypyr to lawns, this exposure should be combined with background levels in food and water to determine

aggregate exposure. For children’s residential exposure, only oral postapplication exposure was assessed, and this exposure should be combined with exposure from food and drinking water to determine aggregate exposure. For occupational workers, only inhalation exposure and risk were

assessed.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Under the revised 2005 Agency cancer assessment guidelines, f luroxypyr is classified as “not likely to be a human carcinogen.” There were no treatment

- related increases in the incidence of tumors in either the rat or mouse carcinogenicity studies, both of which were tested at adequate

doses.

4. 5

. 4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk

Assessment Tables 4.5.4.1 and 4.5.4.2 summarize the points of departure and toxicity endpoints used in the dietary/non

- occupational and occupational human health risk assessments, respectively.Fluroxypyr Human Health Risk Assessment DP No. 396339

Page 15 of 35 Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Flu r oxypyr for Use in Non

- Occupational

Human Health Risk Assessments Exposure/

Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors RfD/PAD,

Level of

Concern for

Risk

Assessment Stu dy and Toxicological Effects

Acute Dietary (All populations) No adverse effects were identified following a single oral dose and there are no developmental

concerns noted in the database. Chronic Dietary (All populat i ons) NOAEL= 100

mg/kg/day UF A 10x

UF H 10x

FQPA SF = 1x chronic RfD =

1 mg/kg/day

chronic PAD= 1 mg/kg/day Chronic/ Carcinogenicity

- Rat

LOAEL = 500 mg/kg/day

, based on kidney

effects ( increased kidney weights, alterations in clinical chemistry parameters indicative of impaired renal functions, and increase in severity of chronic progressive glomerulonephropathy in both sexes).

Incidental Oral (Short

- and

I ntermediate

Term ) NOAEL= 100

mg/kg/day UF A 10x

UF H 10x

FQPA SF = 1x Residential

LOC is for

MOE below

1 00 Chronic/ Carcinogenicity

- Rat

LOAEL = 500 mg/kg/day

, based on kidney

effects ( increased kidney weights, alterations in clinical chemistry parameters indicative of impaired renal functions, and increase in severity of chronic progressive glomerulonephropathy in both sexes).

Dermal (Short

- and

Intermediate

term) Quantification not required since 21

- Day dermal rabbit NOAEL = 1000 mg/kg/day

, and there are

no developmental toxicity concerns.

Dermal (Long

- term) Long

- term dermal exposure is not expected based on the current use pattern.

Inhalation (All durations) Oral study

NOAEL= 100 mg/kg/day

(inhalation and oral toxicity

assumed to be equivalent ) UF A 10x

UF H 10x

FQPA SF = 1x Residential

LOC is for

MOE below

1 00 Chronic/ Carcinogenicity

- Rat

LOAEL = 500 mg/kg/day

, based on kidney

effects ( increased kidney weights, alterations in clinical chemistry parameters indicative of impaired renal functions, and increase in severity of chronic progressive glomerulonephropathy in both sexes).

Cancer (oral) Classified as a “Not Likely” human carcinoge n. UF = uncertainty factor, FQPA SF = Food Quality Protection Act safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic), RfD = reference dose, MOE = margin of exposure, LOC = level of concern, NA = Not ApplicableFluroxypyr Human Health Risk Assessment DP No. 396339

Page 16 of 35 Table 4.5.4.2. Summary of Toxicological Doses and Endpoints for Flu r oxypyr for Use in Occupational Human

Health Risk Assessments Exposure/

Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors RfD/PAD,

Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Inhalation (All durations) Oral study

NOAEL= 100 mg/kg/day

(inhalation and oral toxicity

assumed to be equivalent ) UF A 10x

UF H 10x

FQPA SF = 1x Occupational

LOC is for

MOE below

1 00 Chronic/ Carcinogenicity

- Rat

LOAEL = 500 mg/kg/day

, based on kidney

effects ( increased kidney weights, alterations in clinical chemistry parameters indicative of impaired renal functions, and increase in severity of chronic progressive glomerulonephropathy in both sexes).

Cancer (oral) Classified as a “Not Likely” human carcinoge n. UF = uncertainty factor, FQPA SF = Food Quality Protection Act safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic), RfD = reference dose, MOE = margin of exposure, LOC = level of concern, NA = Not Applicable

5.0 Dietary Exposure and Risk Assessment

A chronic dietary exposure analysis was performed for the purposes of this human health risk assessment (Fluroxypyr Chronic Dietary (Food and Drinking Water) ), (S

. Tadayon , D 40 5555

, 09 / 11 / 12 ).

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

There have been no new data submitted with respect to metabolism in plants and livestock. HED previously concluded that the nature of the residue is adequately understood based on studies in corn, in rotational crops and in livestock. The residue of concern includes the parent f luroxypyr

1

- MHE and its acid metabolite, f luroxypyr

.

5.1.2 Summary of Environmental Degradation

Degradation of f

luroxypyr

– MHE and f

luroxypyr in environmental fate laboratory studies occurs through base

- catalyzed hydrolysis and microbial

- medicated metabolism under aerobic

conditio ns. In sterilized buffered water, f luroxypyr

– MHE hydrolyzed to the f luroxypyr acid

with half li ves of 3 and 454 days at PH 9 and 7, respectively. Hydrolysis of f luroxypyr

- MHE was not observed in the acidic test system at PH 5. In the aerobic soil metabolism study, microbial degradation of f luroxypyr

- MHE appears to follow a biphasic degradation pattern with

an initial first order half life of 1

- 3 weeks in four soils. The rate of metabolism decreased significantly after 2 months. F luroxypyr and f luroxypyr

– MHE degrade rapidly in the aerobic aquatic environment (half life 14 days). F luroxypyr and f luroxypyr

- MHE do not degrade by photolysis in aqu eous environments or in soil . Volatility is not a significant rout of dissipation.Fluroxypyr Human Health Risk Assessment DP No. 396339

Page 17 of 35 5.1.3 Comparison of Metabolic Pathways

T he metabolism of fluroxypyr 1

- MHE in plants is similar in wheat, onions, and broad

- leaved weeds. Metabolism involves cleavage of the ester to the acid, fol lowed by conjugation of the acid. Cleavage of the ether linkage to yield the pyridinol metabolite was insignificant. T he primary route of uptake is through the plant cuticle, and other forms of uptake (i.e., via the roots) are less significant. The peti tioner presented the metabolic summary for fluroxypyr MHE shown below and taken directly without alteration from MRID 47017103.

In addition to weed metabolites, rice roots may also be exposed to soil degradates of fluroxypyr

. An aerobic soil metabolism study demonstrated that fluroxypyr 1

- MHE is rapidly hydrolyzed to the acid, though not completely as some of the ester remained more than 5 months after application. Mineralization to CO 2 was a significant route of degradatio n in the soil. Two soil metabolites were formed: pyridinol and methoxypyridine. The confined rotational crop studies (30

- day PBI (plant back interval) with wheat, lettuce and turnips) demonstrated that the two soil metabolites were present at ≤0.01 ppm fluroxypyr acid equivalents in lettuce and turnip tops, and not present in wheat grain. Free or conjugated fluroxypyr acid was the most commonly observed residue and fluroxypyr 1

- MHE was not detected at levels >0.01 ppm fluroxypyr acid equivalents.

5.1.4 Residues of Concern Summary and Rationale

The residues of concern for tolerance setting and risk assessment purposes in plants and livestock commodities are fluroxypyr 1

- MHE and its metabolite fluroxypyr, free and conjugated, all expressed as fluroxypyr as shown in Table 5.1.4. The rationale for inclusion of these compoundsFluroxypyr Human Health Risk Assessment DP No. 396339

Page 18 of 35 in the residue of concern is as follows. Fluroxypyr is the major residues in plants. In livestock, very low levels of residue transfer to tissues were seen, and fluroxypyr was the s ole residue identified in livestock tissues. Further, the analytical enforcement method includes a hydrolysis step and detects the combined residues of parent and acid, expressed as fluroxypyr equivalents. Lastly, the parent and acid are considered to be of equal toxicity ( DP # : D402134, Peter Savoia, 09/11/2012).

Table 5.1.4. Summary of Metabolites and Degradates to be included in the Risk Assessment

and Tolerance Expression.

Matrix Residues Included In Risk

Assessment Residues Included In Tolerance Expression

Plants Primary Crops Fluroxypyr 1

- MHE and Fluroxypyr , free and conjugates Fluroxypyr 1

- MHE and Fluroxypyr , free and conjugates Rotational Crops

Livestoc

k Ruminant Fluroxypyr 1

- MHE and Fluroxypyr , free and conjugates Fluroxypyr 1

- MHE and Fluroxypyr , free and conjugates Poultry & Eggs Drinking Water Fluroxypyr 1

- MHE, Fluroxypyr Not Applicable

5.2 Food Residue Profile

Currently the use of fluroxypyr is limited to application to cereal grains and a new use on rice is proposed in this action. Fluroxypyr is applied post

- emergent and consequently, significant residues are seen in forages of grains and rice. The plant metabolism data indicate translocat ion of residues throughout the plant and field trial data support this, as low, but quantifiable residues are seen in cereal grains and rice. Transfer of residues to livestock through consumption of treated feed items may occur. Low levels are expected in meat, meat by products, and fat. The highest residues are expected in kidney.

5.3 Water Residue Profile

The proposed new use label for application to rice permits a single maximum application of 0.34 lb ai per acre per year and allows for two applica tions with a maximum total of 0.568 lb ai per acre per year with a minimum retreatment interval (RTI) of ten days. The label also requires a

pre

- harvest interval (PHI) of 60 days of harvest. This assessment reflects a high

- exposure scenario by assuming the maximum application amount of 0.568 lb ai/A (0.64 kg/ha) is used per

year.

Tier 1 Rice Model (v1)

, When using the Tier 1 rice model, EFED assumes pesticide application to a static rice paddy with no inflow from rainfall or outflow from seepage, overflow or evaporation. The only process simulated by the model is partitioning of the applied chemical

between the 10

- centimeter deep water column and the 1

- centimeter deep sediment layer of the paddy. The partitioning is based on the pesticide’s K d . Degradation in the paddy is not calculated by the model so the pesticide is assumed to remain at the initial concentration in the waterFluroxypyr Human Health Risk Assessment DP No. 396339

Page 19 of 35 indefinitely. Results of the tier 1 rice modeling are presented in Table 5.3 . Acute and chronic values are equal because the model d oes not simulate degradation of the pesticide in the paddy.

Table5.3. Summary of Tier 1 Rice Model EDWC for Use on Rice

Assessment Type Acute EDWC Chronic EDWC Tier 1 Rice Model (conc in paddy) 540 μg/L (ppb) 540 μg/L (ppb)

5.4 Dietary Risk Assessment

Memo, S.Tadayon

, 09 / 11 / 2012

, D 40 5555

5.4.1 Description of Residue Data Used in Dietary Assessment

For this analysis existing and recommended tolerance levels were used, as well as 100% crop treated ( CT ) assumptions for all commodities. DEEM (Version 7.81) default processing factors were used for most processed commodities that do not have individual tolerances. The existing

tolerances for livestock commodities were considered adequate ( DP # : D 40 5555 , S. Tadayon

, 09 / 11 / 2012

.

Drinking water was incorporated directly into the dietary assessment using the maximum chronic concentration for surface water generated by the Rice Model (v1) at 540 ppb.

5.4.2 Percent Crop Treated Used in Dietary Assessment

The chronic dietary exposure assessments based on food and drinking water includes the assumption of 100% crop treated (PCT) for all existing and proposed uses.

5.4.3 Acute Dietary Risk Assessment

There was no appropriate endpoint identified for assess ing acute dietary exposure; therefore, no acute dietary risk assessment was performed.Fluroxypyr Human Health Risk Assessment DP No. 396339

Page 20 of 35 5.4.4 Chronic Dietary Risk Assessment

An unrefined chronic dietary analysis for fluroxypyr was conducted using tolerance level residues and 100% crop

- treated (CT) fo r all existing and proposed crop uses. Fluroxypyr chronic dietary (food + drinking water) exposure estimates using the DEEM

- FCIDTM software

are below HED ’s level of concern for the U.S. population and each of the population subgroups

. Chronic dietary expo sure was 1.5 % of the cPAD for the general U.S. population. T he chronic dietary exposure for the highest reported exposed population subg roup, all infants (< 1 year old)

,

was 3.5 % of the cPAD

. The results of the analysis indicate that chronic risk from the dietary (food + drinking water) exposure to fluroxypyr will not exceed HED’s level of concern for the general U.S. population, nor any other population subgroups.

The results of the chronic dietary exposure analys i s are reporte d in the Summary Table 5.4. 5

.

Table 5.4. 5 . Summary of Dietary (Food and Drinking Water) Exposure and Risk for Fluroxypyr

.

Population Subgroup Acute Dietary ( 95th Percentile) Chronic Dietary Cancer

Dietary Exposure (mg/kg/day) % aPAD* Dietary Exposure (mg/kg/day) % cPAD* Dietary Exposure (mg/kg/day) Risk

General U.S. Population

N/A N/A 0.01476 1.5

N/A N/A All Infants (< 1 year old) 0.03514 3.5

Children 1

- 2 years old 0.03286 3.3

Children 3

- 5 years old 0.02411 2.4

Children 6

- 12 years old 0.01597 1.6

Youth 13

- 19 years old 0.01124 1.1

Adults 20

- 49 years old 0.01367 1.4

Adults 50+ years old 0.01312 1.3

Females 13

- 49 years old 0.01349 1.3

*Population subgroups with the highest exposure are shown in bold.

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

Memo, M

. Lloyd

, 0 9 / 11 / 2012 , D 402132

There are no proposed residential uses in this petition ; however, there are existing residential turf uses that have been reassessed in this document to reflect updates to HED’s 2012 Residential SOPs along with policy changes for body weight assumptions.Fluroxypyr Human Health Risk Assessment DP No. 396339

Page 21 of 35 A product containing fluroxypyr (i.e., Vista TM ) is re gistered for application to residential turfgrass and recreational sites such as golf courses, parks, and sports fields. It may be applied to turf at rates ranging from 0.125 to 0.47 lbs ai/A, but may not exceed 0.47 lbs ai/A/yr. The label does not prohi bit homeowners from mixing/loading/applying Vista TM

.

6.1 Residential Handler Exposure

The residential handler assessment only quantitated the inhalation exposure route because there were no toxicity findings for the dermal route of exposure up to the l imit dose , and there are no developmental effects of concern

.

The maximum application rate is used for assessing risk estimates for all exposure scenario s (Table 6.1). All risk estimates have MOEs significantly greater than 100 (ranging from 3,800 to 1,500, 000 ) and are not of concern.

Table 6.1. Short

- Term Residential Handler Exposure and Risk Estimates for Application of Fluroxypyr on Residential Turf.

Exposure Scenario Application

Rate a Area Treated

Daily b Baseline Inhalation

Unit Exposure b Baseline Dose d Baseline

Inhalation MOE e

lb a i /A Acres/gallons mg/lb ai mg/kg/day

Manually

- pressurized Handwand 0.47 5 0.018 0.0034 30,000

Hose

- end Sprayer 0.47 0.5 0.022 0.000065 1,500,000

Backpack 0.47 5 0.14 0.026 3,800

a Application Rates based on maximum application rates of registered residential turf uses for fluroxypyr : Starane Ultra (EPA Reg. No. 6217

- 577 )

. b Based on HED’s SOPs: Lawns/Turf ( January 2012).

c Baseline Inhalation: no respirator.

d Dose (mg/kg/day) = daily unit exposure (mg/ lb ai) x application rate ( lb a i /gal) x area treated (Acres/day) x absorption factor (%) / body weight (80 kg). No inhalation absorption factor.

e MOE = NOAEL ( ST Inhalation NOAEL = 100 mg/kg/day ) / daily dose (mg/ kg/ day). Level of concern = 100.

6.2 Post a pplication Exposure

Post

- application exposure can result from a number of activities following pesticide applications

on turf. E xposure may occur for people of all ages, adults, children 11 < 16 years old, children 6 < 11 years old, and children 1 < 2 years old . These populations are considered the index lifestages for lawns and turf depending on the exposure scenario. Young children 1 to <2 years old may receive incidental oral post

- application exposu re to fluroxypyr from treated turf. The postapplication exposures for children playing on treated turf resulting in incidental oral exposure as a result of mouthing behaviors were assessed using the new residential lawn/turf SOP (1/1/2012)

.

Although a d ults and children performing physical activities on treated turf (e.g. golfing, mowing) may also receive dermal exposure to flu roxypyr residues , a quantitative risk assessment for the dermal route of exposure was not conducted for reasons previously d escri bed

. In addition, a quantitative postapplication inhalation exposure assessment was not conducted because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure ( 9.27 x 10 - 7 mm Hg) and the relatively low p roposed use rate (0. 47 lb ai/A)

. T he low application rate and

vapor pressure ; the inhalation assessment for handlers is protective of potential postapplication exposure and risk.Fluroxypyr Human Health Risk Assessment DP No. 396339

Page 22 of 35 The MOEs for incidental oral scenarios are summarized in Tables 6.2

. The MOEs ranged from 14,000 to 6,500,000 for incidental oral ingestion. All assessed residential exposures and risk

estimates resulted in MOEs of > 100 ; and therefore, are not of concern to HED.

Table 6.2. Children’s Short

- term Non

- Dietary Ingestion Fluroxypyr Exposure and Risk E stimate

Lifestage Post

- Application Exposure Scenario Dose MOEs mg/kg/day

Emulisiable Concentrate ( E C) Liquid Formulation

GF

- 2764 (EPA Reg. No. 62719

- 577) 3 lb ae/gallon max single application rate: 0.4 7 lb ae/A

Child 1 to < 2 year old Hand to Mouth 0.0070 14,000 Object to Mouth 0.00022 460,000 Incidental Soil Ingestion 0.000015 6,500,000

Hand

- to

- Mouth Dose = hand residue loading (mg/cm 2 ) x fraction of hand mouthed (0.127) x surface area of 1 hand (150 cm 2 ) x exposure time (1.5 hrs/day) x # of replenishment intervals/hr (4 int/hr) x (1

- ((1

- saliva extraction factor (0.5))^(Number of hand

to

- mouth events per hour (13.9 events/hr)/# of replenishment intervals/hr)) / body weight (11 kg). Object

- to

- Mouth Dose = object residue loading (μg/cm 2 ) * unit conversion factor (0.001 mg/μg) * object surface area mouthed / event (10 cm 2 /event) * exposure time (1.5 hrs/day) * # replenishment intervals/hr (4 int/hr) * (1

- ((1

- saliva extraction factor (0.50))^(# Object

- to

- Mout h Events/hr (8.8 events/hr) / # replenishment intervals/hr)) / body weight (11 kg). Soil Ingestion = soil residue (μg/g) * ingestion rate (50 mg/day) * conversion factor (0.000001 g/μg) / body weight (11 kg).

6.3 Combined Exposure

HED combines risk value s resulting from separate exposure scenarios when it is likely they can occur simultaneously based on the use pattern and the behavior associated with the exposed population. In evaluating combined residential uses of fluroxypyr , HED reviewed all resident ial sources of exposure which consisted of : 1) adult inhalation handler (lawns only) exposure, and 2) child postapplication oral exposure.

Since a dermal endpoint was not selected for fluroxypyr , the only route of exposure for which risks were quantified for adults is through the inhalation route, and therefore, a combined residential exposure assessment is not applicable

.

For children, because of the high

- end assumptions used in each incidental oral scenario (hand to mouth, object to mouth, and soil ingestion), the exposures from these scenarios are not combined; rather, the highest (typically hand to mouth exposure) is used to assess aggregate risk, as described below. Since dermal and inhalation risks were not quant ified, no post

- application

children’s risks were combined.

Table 6.3 identifies the residential scenarios and MOEs for adults and children for use in performing an aggregate exposure assessment as part of the f luroxypyr human health risk

assessment. The re are no risks of concern.Fluroxypyr Human Health Risk Assessment DP No. 396339

Page 23 of 35 Table 6.3. Summary of Residential Exposure and Risk Estimates.

Scenario Daily Dose 1 MOE 2 mg/kg/day

Adults
Residential Handler Inhalation Exposure (Backpack) 0.026 3,800

Children

Post

- Application Incidental Oral Exposure: Hand

- to

- Mouth (After Liquid Application to Turf) 0.0070 14,000

1 Daily Dose = See Table 6.1 for adult handler scenarios and Table 6.2 for post

- application incidental oral

scenarios.

2 MOE = NOAEL/Daily Dose (mg/kg/day). ST Inhalation = 100; ST Incidental Oral = 100 mg/kg/day. LOC = 100.

6.4 Residential Bystander Postapplication Inhalation Exposure

Based on the Agency's current practices, a quantitative postapplication inhalation exposure assessment was not performed for fluroxypyr at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure ( 9.27 x 10 - 7 mm Hg) and the relatively low p roposed use rate (0. 47 lb ai/A) . However, volatilization of pesticides may be a potential source of postapplication inhalation exposure to individuals nearby to pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Adviso ry Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the

pro cess of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

- application inhalation exposure into the Agency's risk assessments. If new policies or proce dures are developed, the Agency may revisit the need for a quantitative pos t application inhalation exposure assessment

for fluroxypyr

. Although a quantitative residential postapplication inhalation exposure assessment was not performed, an inhalation expo sure assessment was performed for residential handlers. This exposure scenario is representative of a worse case inhalation exposure and should be considered protective of other postapplication inhalation exposure scenarios.

6. 5 Spray Drift

Spray drift is always a potential source of exposure to residents near spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for fl uroxypyr . The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for m ore information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has com pleted its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pest icides applied by air, orchard airblast and ground hydraulic methods.Fluroxypyr Human Health Risk Assessment DP No. 396339

Page 24 of 35 After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off

- target drift with specific products with significant risks

asso ciated with drift.

Although a quantitative residential post

- application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flagg ers. This exposure scenario , for which no risks of concern were identified, is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post

- application inhalation

exposure sce narios

.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate

assessment, exp osures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. In the case of fluroxypyr , acute and chronic aggregate risks result from exposure through food and water only. For short

- term risks, residential handlers’ inhalation exposure and children’s incidental oral exposures were combined w ith background exposure

from food and water.

7.1 Acute Aggregate Risk

Acute aggregate risk is equivalent to acute dietary exposure and risk, which is not of concern.

Refer to Section 5.4.3.

7.2 Short

- Term Aggregate Risk

The residential handler exposure from applying fluroxypyr using a Backpack sprayer and children’s postapplication oral exposure (Table 6. 3 ) were combined with the chronic dietary exposure from the mostly highly exposed adult (General US population) and chi ldren’s (all infants <1 year old) subpopulations (Table 5.4. 5 )

, respectively, to determine aggregate exposure

and risk as shown in Table 7.2. Despite the numerous conservative assumptions in developing these estimates, the MOEs are above the LOC of 100, a nd are not of concern.

Table 7.2

. Short

- Term Aggregate Risk Calculations for Flurox y pyr

Population NOAEL

mg/kg/day LOC 1 Max

Allowable Exposure 2
mg/kg/day Average

Food and

Water Exposure mg/kg/day Residential

Exposure mg/kg/day 3 Total

Exposure mg/kg/day 4 Aggregate

MOE (food, water, and residential) 5

Adult (Handler) 100 100 1 0.014 73 0.026 0.040 73 2500

Child (Postapplication) 100 100 1 0.035 1 4 0.0070 0.0421 0 2400Fluroxypyr Human Health Risk Assessment DP No. 396339

Page 25 of 35 1 T he LOC is based on the standard inter

- and intra

- species uncertainty factors totaling 100 . The FQPA Safety Factor has been

reduced to 1X.

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Residential Exposure (Adult Handler) = I nhalation Exposure (Table 6.1)

. Residential Exposure (Child Postapplication) = Hand

to

- Mouth Expo su re (Tabl e 6.2).

4 Total Exposure = ( Avg

. Food & Water Exposure + Residential Exposure)

5 Aggregate MOE = [ 100 / Total Exposure ]

7. 3 Chronic Aggregate Risk

Chronic aggregate risk is equivalent to chronic dietary exposure and risk, which is not of

concern. Refer to Section 5.4.4.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as

to fluroxypyr an d any other substances and fluroxypyr does not appear to produce a toxic metabolite produced by other substances. For the purposes of this action, therefore, EPA has not

assumed that fluroxypyr has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mecha nism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

Fluroxypyr may be applied to rice as a f oliar spray via groundboom and aerial application. The proposed use pattern is summarized in Table 9.1

. Handler exposure is expected to be short

- or intermediate

- term based on information provided on the proposed label. The personal protective equipment (PPE) label requirements include: long

- sleeved shirt, long pants, and shoes plus

socks.

The quantitative exposure/risk assessment developed for occupational handlers is based on the following exposure scenarios:

Mixer/Loaders

1. Mixing/loading liquids to support groundboom applications,

2. Mixing/loading liquids to support aerial applications

, Flaggers

3. Flagging to support aerial application, Applicators

4. Applying sprays with groundboom equipment , and

5. Applying sprays with aerial equipment

.Fluroxypyr Human Health Risk Assessment DP No. 396339

Page 26 of 35 9.1 Short

- /Int ermediate

- Term Handler Risk

No chemical

- specific handler exposure data were submitted in support of th e proposed use , and therefore HED relied on the best available surrogate data to complete the occupational handler

assessment

. Sources of generic handle r data, used as surrogate data in the absence of chemical

specific data, include the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the Agricultural Handler Exposure Task Force (AHETF) database, and the Outdoor Residential Exposure Task Force (ORETF) database. Some of these data are proprietary (e.g., AHETF data, MRID No. 44339801), and subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting handler exposure that are used in this assessment, known as “unit exposures

, ” are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( http://www.epa.gov/opp00001/science/handler

- exposure

- table .pdf ), which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at http://www.epa.gov/pestici des/science/handler

- exposure

- data.html

.

The proposed product label involved in this assessment directs applicators and other handlers to wear long sleeved shirt and long pants, shoes plus socks, and chemical

- resistant gloves. HED typically assesses handler exposure using “baseline” clothing assumptions, and if risks of concern are identified, the use of personal protective equipment (PPE) may be incorporated into the exposure assessment. In the case of fluro xypyr
, there is no toxicity via the dermal route, and only inhalation exposures were assessed . No additional PPE (i.e., respirators) were needed to

achieve MOEs above the LOC of 100.

Standard assumptions were used with respect to body weight for adult ha ndlers ( 8 0 kg), the exposure duration (i.e., short

- and intermediate

- term), and the area treated for various types of application equipment and application sites. In conjunction with these standard values, HED used the maximum application rates from the p roposed label directions. Each of the risks is presented as a n MOE, or the ratio of the NOAEL to the calculated daily dose.

Table 9.1 shows the results of HED’s exposure and risk assessment for occupational handlers.

The MOEs shown in the table are all significantly higher than HED’s LOC of an MOE of 100,

with the lowest MOE of 90,000 identified for handlers conducting mixing/loading activities for aerial application . Risk associated with this and all other scenarios is not of concern.

Table 9.1. Baseline Short

- and Intermediate

- Term Occupational Exposures and Risk Estimates for Fluroxypyr Use on Rice.

Exposure Scenario Application

Rate a Area

Treated Daily b ST/IT

Baseline

Inhalation

UEs c ST/IT

Baseline

Inhalation

Dose d ST/IT

Baseline

Inhalation

MOE e

lb ai/A acres μg/lb ai mg/kg/day

Mixer/Loader

Mixing/Loading Liquids for Groundboom Application 0.34 200 0.219 0.00019 540,000

Mixing/Loading Liquid s for Aerial Application 0.34 1200 0.219 0.0011 90,000
Flagger Flagging for Aerial Application 0.34 350 0.35 0.000520 190,000Fluroxypyr Human Health Risk Assessment DP No. 396339

Page 27 of 35 Applicator
Applying Sprays via Groundboom Equipment 0.34 200 0.34 0.000289 350,000
Applying Sprays via Aerial Equipment 0. 34 1200 0.068 0.000346 290,000

a Application Rates based on proposed uses for fluroxypyr ( GF

- 2764 Herbicide , EPA Reg. No. 62719

- 577 ).

b Acres Treated Per Day is taken from Exposure Science Advisory Council (ExpoSAC) Policy No. 9.1.

c UEs = Unit Exposures based on PHED Version 1.1, ORETF, or AHETF data. Baseline = no gloves, no respirator.

d Dose (mg/kg/day) = daily unit exposure (μg/lb ai) × application rate (lb ai/acre) × amount handled/day (acres/day) x conversion factor (1 mg/1,000 μg) × absorption factor (%) ÷ body weight (80 kg). No inhalation absorption factor.

e MOE = NOAEL ÷ Dose (mg/kg/day). ST/IT Inhalation NOAEL = 100 mg/kg/day. ST/IT level of concern = 100.

9.2 Short and Intermediate

- Term Post a pplication Risk

9.2.1 Dermal Postapplication Risk

Agricultural workers performing typical post

- application activities (e.g. scouting, hand weeding) may receive exposure to fluroxypyr residues. As no dermal endpoint has been identified, no quantitative dermal postapplication assessment is necessary.

Ty pically, under WPS for Agricultural Pesticides, active ingredients classified as acute Toxicity Category III or IV for Acute Dermal, Eye Irritation, and Primary Skin Irritation are assigned a

12

- hour REI. Based on the quantitative post

- application assessm ent, the 12

- hour REI on the proposed label is acceptable for rice.

9.2.2 Inhalation Postapplication Risk

Based on the Agency's current practices, a quantitative postapplication inhalation exposure assessment was not performed for fluroxypyr at this time primarily because it has a low vapor pressure ( 9.7 x 10 - 7 mm Hg), it is applied at an application rate of 0. 34 lbs ai/A, and it is not projected to be applied via typically high inhalation exposure application equipment (e.g., airblast). However, volatili zation of pesticides may be a potential source of postapplication inhalation exposure to individuals nearby to pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide

, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate postapplication inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative postapplication inhalation expo sure assessment
for f luroxypyr

.

Although a quantitative occupational postapplication inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from a pplication of pesticides outdoors is likely to result in higher exposure than postapplication exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of occupational postapplication inhalation

exposure scen arios.Fluroxypyr Human Health Risk Assessment DP No. 396339

Page 28 of 35 10.0 References

Residue Chemistry

Fluroxypyr

, Section 3 Registration of Fluroxypyr on Rice

, Summary of Analytical Chemistry

and Residue Data.

Fluroxypyr : Chronic Dietary (Food and Drinking Water) Exposure and Risk

Assessment for the Section 3 Registration Action to Support New Use on Rice, and for all the Commodities of Crop Group 15 (Cereal Grains).

Occupational and Residential Exposure

Fluroxypyr : Occupational Exposure Assessment for a Proposed New Use on Rice with an Updated Residential Exposure Assessment of All Existing Residential Uses (Turf). Matthew Lloyd, D 402132

, 09 / 11 /2012.Fluroxypyr Human Health Risk Assessment DP No. 396339

Page 29 of 35 A ppendix A

. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Available for Fluroxypyr

The toxicological data requirements (40 CFR 158.340) for food uses for fluroxypyr are in Table A1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A.1 Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ ................... 870.1300 Acute Inhalation Toxicity

................................ .............. 870.2400 Primary Eye Irritation

................................ .................... 870.2500 Primary Dermal Irritation

................................ ............... 870.2600 Dermal Sensitization

................................ ...................... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rat and mouse)

................................ ... 870.3150 Oral Subchronic (dog)

................................ .................... 870.3200 21/28

- Day Dermal (rat)

................................ .................. 870.3250 90

- Day Dermal

................................ ............................... 870.3465 28

- Day Inhalation

................................ .......................... yes

yes

yes
CR

no A yes

yes

yes

no

no

870.3700a Developmental Toxicity (rat)

................................ ......... 870.3700b Developmental Toxicity (rabbit)

................................ .... 870.3800 Reproduction (rat)

................................ .......................... yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rat)

................................ .................... 870.4100b Chronic Toxicity (dog)

................................ ................... 870.4200a Carcinogenicity (rat)

................................ ...................... 870.4200b Carcinogenicity (mouse)

................................ ................ 870.4300 Chronic/Carcinogenicity (rat)

................................ ........ yes

yes

yes

yes

yes yes

yes

yes

yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

..................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

................ 870.5375 Mutagenicity

— Structural Chromosomal Aberrations

... 870.5395 Mutagenicity

— Mammalian Erythrocyte Micronucleus

. 870.5500 Mutagenicity

— Bacterial DNA Damage or Repair Test 870.5550 Mutagenicity

— Unscheduled DNA Synthesis

................. yes

yes

yes

yes

yes

yes yes

yes

yes

yes

no

no

870.6100a Acute Delayed Neurotoxicity. (hen)

.............................. 870.6100b 90

- Day Neurotoxicity (hen)

................................ ........... 870.6200a Acute Neurotoxicity Screening Battery (rat)

.................. 870.6200b 90 Day Neurotoxicity Screening Battery (rat)

............... 870.6300 Developmental Neurotoxicity (rat)

................................ no

no

yes A

yes A

CR ---

--- NA

NA

NA

870.7485 General Metabolism (rat)

................................ ............... 870.7600 Dermal Penetration (8

- hour)

, in vivo (male rat)

............. yes
CR yes

yes

870.7800 Immunotoxicity (rat)........................... Yes Y es

A waived ( HASPOC TXR No. 0056397 )Fluroxypyr Human Health Risk Assessment DP No. 396339

Page 30 of 35 A.2 Toxicity Profile s

Table A.2.1. Acute Toxicity of Fluroxypyr Acid and Fluroxypyr 1

- Methylheptyl Ester (MHE) Technical

Guideline No. Study Type MRIDs # Results Toxicity Category

870.1100 Acute Oral

- rat Acid 40354010 LD 50 = 2405 mg/kg III

MHE 40354005 LD 50 > 5000 mg/kg IV

870.1200 Acute Dermal

– rabbit

- rat Acid 40354010 LD 50 > 5000 mg/kg III

MHE 40354006 LD 50 > 2000 mg/kg III

870.1300 Acute Inhalation Acid 40354011 LD 50 > 296 mg/m 3 II

MHE 40354004 LD 50 > 1.0 gm/m 3 III

870.2400 Primary Eye Irritation

- rabbit A cid 49354010 not applicable not applicable

MHE 40354007 mildly irritating III

870.2500 Primary Skin Irritation

rabbit Acid 40354010 non

- irritating IV

MHE 40354008 non

- irritating IV

870.2600 Dermal Sensitization

- guinea pig Acid

- none not applicable not applicable

MHE 42137335 &

42540900 not a sensitizer not applicable

Attachment 2. Toxicity Profile for Fluroxypy r

Table A 2. Toxicity Profile of Fluroxypyr Technical (Fluroxypyr acid and Fluroxypyr MHE)

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3150

28

- day oral toxicity Dog MRID 42137340 (1983)/ acceptable/ fluroxypyr acid 98% a.i.

0, 20, 50, 150 mg/kg/day in diet NOAEL = 50 mg/kg/day LOAEL= 150 mg/kg/day, based on kidney lesions (early signs of acute tubular nephrosis), increased adrenal wts ( both

sexes ), decreased testes wts ( males )

870.3100

90

- Day oral toxicity rodents (rats)

- Fischer 344 MRID 44080316(1991)/ acceptable/ fluroxypyr acid 98.9% a.i.

0, 320, 700, 1000 mg/kg/day NOAEL = 700 mg/kg/day LOAEL = 1000 mg/kg/day, based on decreased body weight gain & testis weight ( males ), decreased brain weight ( females ) , and increased kidney weight (both sexes ). There

were no treatment

- related microscopic lesions.

870.3100

90

- Day oral toxicity rodents (rats)

-- Wistar MRID 42164502 (1987)/ acceptable/ fluroxypyr acid 98.3

- 98.5% a.i.

0, 80, 750, 1000, 1500 mg/kg/day Mean intake: M 79, 721, 924, 1215; F 81, 755, 969, 1392 mkd Males

NOAEL = 80 mg/kg/day

LOAEL = 750 m g /kg/day, based on nephrotoxicity and death

Females

NOAEL = 750 mg/kg/day

LOAEL = 100 0 m g /kg/day, based on nephrotoxicity and

deathFluroxypyr Human Health Risk Assessment DP No. 396339

Page 31 of 35 Table A 2. Toxicity Profile of Fluroxypyr Technical (Fluroxypyr acid and Fluroxypyr MHE)

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3100

90

- Day oral toxicity rodents (mice)

– SPF ICR MRID 42137337(1988)/ acceptable/ fluroxypyr acid 99.3% a.i.

0, 200, 500, 2500, 10000 ppm Male: 0, 27, 67, 336, 1342 mg/kg/day Female: 0, 35, 87, 437, 1748 mg/kg/day NOAEL = 1342 mg/kg/day (males)/ 1748 mg/kg/day ( f emales)

LOAEL not established.

870.3150

90

- Day oral toxicity (nonrodents) NA NA

870.3200

21

- Day dermal toxicity (rabbits) MRID 42137338(1991)/ acceptable/ fluroxypyr MHE 98.5% a.i.

0, 100, 300, 1000 mg/kg/day NOAEL = 1000 mg/kg/day (HDT)

LOAEL not established.

870.3250

90

- Day dermal toxicity NA NA

870.3465

4

- Week inhalation toxicity (rat) NA NA

870.3700a Prenatal developmental toxicity (rats)

- CD MRID 40244509 (1983) acceptable/ fluroxypyr acid 99% a.i.

GD 6

- 19 0, 125, 250, 500 mg/kg/day Maternal NOAEL = 250 mg/kg/day LOAEL = 500 mg/kg/day, based on increased kidney weights (one death)

. Developmental NOAEL = 500 mg/kg/day (HDT)

LOAEL not established.

870.3700a Prenatal developmental toxicity (rats)

– Sprague

Dawley MRID 44094901 (1994) acceptable/ fluroxypyr MHE 95.8% a.i.

GD 6

- 15 0, 100, 300, 600 mg/kg/day Maternal NOAEL = 300 mg/kg/day LOAEL = 600 mg/kg/day, based on increased maternal

deaths (days 4, 6, 7, 7, 8, 8, 10, 10) and decreased body weight gains and food consumption. Developmental NOAEL = 600 mg/kg/day (HDT)

LOAEL = not established.

870.3700b Prenatal developmental toxicity (rabbits) MRID 40354013 (1984) acceptable/ fluroxypyr acid 95.8% a.i.

0, 25, 100, 250, 400 mg/kg/day

GD 6

- 19 Maternal NOAEL = 250 mg/kg/day

LOAEL = 400 mg/kg/day, based on increased maternal

deaths. Due to a large number of maternal deaths in th is group, a dose level of 250 mg/kg/day was added to the study, and the 400 mg/kg/day dose level was discontinued early (terminated on day 9)

.

Developmental NOAEL = 250 mg/kg/day (HDT)

LOAEL not established.Fluroxypyr Human Health Risk Assessment DP No. 396339

Page 32 of 35 Table A 2. Toxicity Profile of Fluroxypyr Technical (Fluroxypyr acid and Fluroxypyr MHE)

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3700b Prenatal developmental toxicity (rabbits) MRID 44080319 (1996) acceptable/ fluroxypyr MHE 95.8% a.i.

0, 100, 500, 1000 mg/kg/day

GD 7

- 19 (acid equivalent doses: 69, 346,

or 693 mg/kg/day) Maternal NOAEL = 500 mg/kg/day

LOAEL = 1000 mg/kg/day, based on increased abortions (one doe on GD 25)

. At 1000 mg/kg/day, 3 does aborted (GD 22, GD 25, GD 25) and 1 death GD 20

. Developmental NOAEL = 500 mg/kg/day

LOAEL = 1000 mg/kg/day, based on increased abortions (one doe on GD 25)

. At 1000 mg/kg/day, 3 does aborted (GD 22, GD 25, GD 25) and 1 death GD 20.

870.3800 Reproduction and fertility effects (rats)

– Sprague

Dawley MRID 44080321 (1996) acceptable/ fluroxypyr acid 99% a.i.

0, 100, 500, 750 mg/kg/day (M) 0, 100, 500, 1000 mg/kg/day (F) Parental/Systemic NOAEL = 100 mg/kg/day (males) / 500 mg/kg/day ( f

emales) LOAEL = 500 mg/kg/day ( m ales)/ 1000 mg/kg/day ( f emales), based on kidney effects ( both sexes; increas ed kidney weight with micro scopic findings ) and increased deaths ( females ) due to renal failure. Reproductive NOAEL = 750 mg/kg/day (Males)/ 1000 mg/kg/day (f

emales) (HDT)

LOAEL not established. Offspring NOAEL = 500 mg/kg/day

LOAEL = 1000 mg/kg/day, based on decreased pup weight

and body weight gain and slightly lower survival.

870.4100a Chronic toxicity (rodents) NA; see 870.4300 NA

870.4100b Chronic toxicity (dogs) MRID 40244507(1988) acceptable/ fluroxypyr acid 98%a.i.

0, 20, 50, 150 mg/kg/day NOAEL = 150 mg/kg/day (HDT)

LOAEL not established.

870.4200a Carcinogenicity (rats) NA; see 870.4300 NA

870.4200b Carcinogenicity (mice)

- CD

- 1 MRID 44080317 (1991) acceptable/ guideline fluroxypyr acid 98.9% a.i.

0, 100, 300, 1000 mg/kg/day NOAEL = 300 mg/kg/day

LOAEL = 1000 mg/kg/day, based on decreased body weight and body weight gain ( males ) and increased kidney lesions ( increased incidences of renal papillary necrosis and regenerative nephrosis ) in females

. No evidence of carcinogenicity.

870.4300

Combined Chronic/carcinogenicity (r ats)

— Fischer 344 MRID 44080322 (1994) acceptable/ guideline fluroxypyr acid 99% a.i.

0, 100, 500, 1000 mg/kg/day NOAEL =100 mg/kg/day LOAEL = 500 mg/kg/day, based on increased kidney weights

and chronic progressive kidney glomerulonephropathy ( both

sexes ). No evidence of carcinogenicity. At 1000 mg/kg/day, 5 male rats died within first 90 days on

test.Fluroxypyr Human Health Risk Assessment DP No. 396339

Page 33 of 35 Table A 2. Toxicity Profile of Fluroxypyr Technical (Fluroxypyr acid and Fluroxypyr MHE)

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.5100

Bacterial reverse mutation MRID 44080323 (1995) acceptable/ fluroxypyr MHE 95.8% a.i.

100

- 5000 ug/plate Negative.

870.5300

In vitro mammalian cell gene mutation MRID 44080324 (1996) unacceptable/ fluroxypyr MHE 95.8% a.i.

1.25

- 50 ug/mL Negative, but did not test a soluble dose.

870.5375

In vitro mammalian

chromosome aberration (HL) MRID 44080325 (1996) acceptable/ fluroxypyr MHE 95.8% a.i.

0.42

– 1250 ug/mL Negative.

870.5395

Mammalian micronucleus (mouse) MRID 44080326 (1996) acceptable/ fluroxypyr MHE 95.8% a.i. oral gavage of 225, 450 or 900 mg/kg Negative.

870.6200a Acute neurotoxicity screening battery (rats) NA NA

870.6200b Subchronic neurotoxicity screening battery (rats) NA NA

870.6300 Developmental neurotoxicity (rats) NA NAFluroxypyr Human Health Risk Assessment DP No. 396339

Page 34 of 35 870.7485

Metabolism ( Fischer 344 rats) MRID 44080327 (1996) acceptable/ fluroxypyr MHE 99% a.i.

Males: 50 mg/kg (labeled) as single oral dose Total recovery of the administered dose was 105%, with the principal route of excretion being expired 14 CO 2 , which contained approximately 61% of the radioactivity for the fluroxypyr MHE. The urine contained approximately 30%

and the feces c ontained 5% of the administered dose. At 48 hours post dose, approximately 7% of the administered dose was recovered in the blood, carcass, and skin. Approximately 52% of the administered dose was absorbed and expired as

14 CO 2 within 12 hours post dose, and an additional 18% of

the administered dose was excreted in the urine within 12 hours post dose. Based on the percentage of dose in the expired 14 CO 2 , urine, and tissues, approximately 90% of the dose was absorbed. Once absorbed, it was extensively

me tabolized and rapidly expired as 14 CO 2 and eliminated in

the urine with a half

- life of 6 hours. Peak plasma

concentrations of 14 C

- radioactivity were attained by 7 hours post dose.

870.7600 Dermal penetration NA NA

870.7800 Immunotoxicity ( Crl:WI (Han) rats) MRID 48581311 (2011) Acceptable/guideline fluroxypyr 99.9% Males: 0, 80, 250, 750 mg/kg/day for 29 days NOAEL = 750 mg/kg/day (highest dose tested; actual dose was 816 mg/kg/day); no treatment

- related decrease i n primary immune response to SRBCs in male rats; spleen or thymus weights comparable to control.Fluroxypyr Human Health Risk Assessment DP No. 396339

Page 35 of 35 Appendix B

. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database; and the Outdoor Residential Exposure Task Force (ORETF) database; are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requiremen ts. For certain studies that review may have included review by the Human Studies Review Board. Descriptions of data sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler

exposure

- data.html and http://www. epa.gov/pesticides/science/post

- app

- exposure

- data.html

.