UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                      OFFICE OF
                                                            CHEMICAL SAFETY AND
\* MERGEFORMAT
                                                           POLLUTION PREVENTION
MEMORANDUM

Date:	February 3, 2015

SUBJECT:	Sethoxydim:  Human Health Risk Assessment for Registration Review and to Support the Section 3 Registration of Proposed Uses on High Bush Blueberry and Fine Fescue Grasses

PC Code:   121001
DP Barcode: 418280; 424578
Decision No.:  487076
Registration No.:  7969-56 & 7969-58
Petition No.: 4E8239
Regulatory Action: Section 3; Registration Review
Risk Assessment Type: Single Chemical Aggregate
Case No.:  NA
TXR No.:  NA
CAS No.:  74051-80-2
MRID No.:  NA
40 CFR:  §180.412

FROM:	Ronnie Bever, Ph.D.; Risk Assessor
		Seyed Tadayon, Chemist
		Peter Savoia, Chemist
		Katelynn King, Biologist
		Risk Assessment Branch V (RAB V/VII)
		Health Effects Division (HED; 7509P)

THROUGH:	Ideliz Negrón-Encarnación, Chemist
	Michael S. Metzger, Chief, RAB V/VII
		HED (7509P)

TO:		Sydney Jackson/Barbara Madden, Risk Manager
      Minor Use and Emergency Response Branch
      Registration Division

      James Parker, Chemical Review Manager
      Risk Management and Implementation Branch I
      Pesticide Re-evaluation Division

Table of Contents
1.0	Executive Summary	4
2.0	HED Recommendations	6
2.1	Data Deficiencies/Conditions of Registration and Re-Registration	7
2.2	Tolerance Considerations	7
2.2.1	Enforcement Analytical Method	7
2.2.2	Recommended Tolerances	7
2.2.3	Revisions to Petitioned-For Tolerances	8
2.2.4	International Harmonization	9
2.3	Label Recommendations	9
2.3.1	Recommendations from Residue Reviews	9
2.3.2	Recommendations from Occupational Assessment	9
3.0	Introduction	10
3.1	Chemical Identity	10
3.2	Physical/Chemical Characteristics	10
3.3	Pesticide Use Pattern	10
3.4	Anticipated Exposure Pathways	14
3.5	Consideration of Environmental Justice	14
4.0	Hazard Characterization and Dose-Response Assessment	15
4.1	Toxicology Studies Available for Analysis	15
4.2	Absorption, Distribution, Metabolism, & Elimination (ADME)	16
4.2.1	Dermal Absorption	16
4.3	Toxicological Effects	16
4.4	Safety Factor for Infants and Children (FQPA Safety Factor)	17
4.4.1	Completeness of the Toxicology Database	18
4.4.2	Evidence of Neurotoxicity	18
4.4.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal	18
4.4.4	Residual Uncertainty in the Exposure Database	18
4.5	Toxicity Endpoint and Point of Departure Selections	19
4.5.1	Dose-Response Assessment	19
4.5.2	Recommendation for Combining Routes of Exposures for Risk Assessment	20
4.5.3	Cancer Classification and Risk Assessment Recommendation	21
4.5.4	Summary of Points of Departure and Toxicity Endpoints	21
4.6	Endocrine Disruption	22
5.0	Dietary Exposure and Risk Assessment	23
5.1	Metabolite/Degradate Residue Profile	24
5.1.1	Summary of Plant and Livestock Metabolism Studies	24
5.1.2	Summary of Environmental Degradation	24
5.1.3	Comparison of Metabolic Pathways	24
5.1.4	Residues of Concern Summary and Rationale	25
5.2	Food Residue Profile	25
5.3	Water Residue Profile	26
5.4	Dietary Risk Assessment	27
5.4.1	Description of Residue Data Used in Dietary Assessment	27
5.4.2	Percent Crop Treated Used in Dietary Assessment	27
5.4.3	Acute Dietary Risk Assessment	27
5.4.4	Chronic Dietary Risk Assessment	27
5.4.5	Cancer Dietary Risk Assessment	27
5.4.6	Summary Table	28
6.0	Residential (Non-Occupational) Exposure/Risk Characterization	28
6.1	Residential Handler Exposure	28
6.2	Post-Application Exposure	29
6.3 	Residential Risk Estimates for Use in Aggregate Assessment	30
6.4	Residential Bystander Post-Application Inhalation Exposure	31
6.5	Spray Drift	31
7.0	Aggregate Exposure/Risk Characterization	31
7.1	Acute Aggregate Risk	32
7.2	Short-Term Aggregate Risk	32
7.3	Intermediate- and Long-Term Aggregate Risk	33
7.4	Cancer Aggregate Risk	33
8.0	Cumulative Exposure/Risk Characterization	33
9.0	Occupational Exposure/Risk Characterization	33
9.1	Short-/Intermediate-Term Handler Risk	33
9.2	Short-/Intermediate-Term Post-Application Risk	36
9.2.1	Dermal Post-Application Risk	36
9.2.2	Inhalation Post-Application Risk	36
9.2.3	Restricted Entry Interval	37
10.0	References	37
Appendix A.  Toxicology Profile and Executive Summaries	39
A.1	Toxicology Data Requirements	39
A.2	Toxicity Profiles	40
A.3	Hazard Identification and Endpoint Selection	44
A.4	Executive Summaries	46
A.5	Calculation of the HED and HEC for Sethoxydim	60
Appendix C.  Metabolites/Degradates	65
Appendix D.  Physical/Chemical Properties	69
Appendix E.  Review of Human Research	70

1.0	Executive Summary

This assessment has been conducted to address two separate regulatory actions:  Section 3 registration for high bush blueberry and fescue grasses, and the Draft Risk Assessment (DRA) to support registration review.  As part of Registration Review, the Pesticide Re-evaluation Division (PRD) of OPP has requested that HED evaluate the hazard and exposure data and conduct occupational and residential exposure assessments, as needed, to estimate the risk to human health that will result from the currently registered uses of sethoxydim.  This memorandum serves both as HED's Registration Review risk assessment of the currently registered uses of sethoxydim, as well as addressing the Registration Division (RD) request that HED conduct an exposure and risk assessment for a proposed use of sethoxydim on high bush blueberry and fine fescue grasses.  This document also addresses and obviates the need for a separate scoping document.

Sethoxydim [2-[1-(ethoxyimino) butyl]-5-[2-(ethylthio) propyl] 3-hydroxy-2- cyclohexen-1-one] is a member of the cyclohexanedione or cyclohexenone class of herbicides.  Sethoxydim is registered for use on turf (e.g. golf courses, recreational parks, home lawns, and sod farms) and ornamentals (residential landscape areas), as well as numerous agricultural crops.  The mode of action for this herbicide is lipid biosynthesis inhibition (through the inhibition of the ACCase enzyme).  The mode of action for toxicity in animals is unknown.

The toxicology database is sufficient for characterizing toxicity and hazard. The toxicity profile of sethoxydim shows that the principal toxic effect is hepatotoxicity in the rat, mouse, and dog following exposure to sethoxydim via the oral route and in the rat via the inhalation route.  No systemic toxicity nor adverse local effects were observed in rabbits following repeated exposure via the dermal route at dose levels up to the limit dose.  There was no clear evidence of neurotoxicity in the database, including a subchronic neurotoxicity study.

In the developmental rat study, maternal toxicity was observed at the same dose as developmental toxicity.  Developmental toxicity was noted in rabbits at the highest dose tested, but maternal toxicity was not observed.  Developmental toxicity included decreased fetal weights and tail abnormalities in rats and delayed/incomplete ossification in rats and rabbits.  In the reproduction toxicity study, no adverse effect was noted on the parents or reproduction, but decreased pup body weight was noted during lactation.

There was no evidence of carcinogenicity in rats and mice, and no evidence of genotoxicity.  Sethoxydim is classified as "Not Likely to Be Carcinogenic to Humans."  Sethoxydim is not acutely (lethal) toxic via the oral, dermal, and inhalation routes (Toxicity Category III), is not an eye or dermal irritant, and is not a dermal sensitizer.

Based on the toxicity, duration of exposure, and uses of sethoxydim, the following toxicity endpoints were selected:
      Acute dietary (general population, including infants and children):  acute Population Adjusted Dose (aPAD) = 1.8 mg/kg/day derived from a NOAEL of 180 mg/kg/day in a rat developmental toxicity study in the rat. LOAEL = 650 mg/kg/day based on irregular gain that was observed in 12/34 dams on the first day of dosing.
      Acute dietary (females 13-49 years of age):  aPAD = 1.8 mg/kg/day derived from a NOAEL of 180 mg/kg/day in a rat developmental toxicity study in the rat. LOAEL = 650 mg/kg/day based on tail abnormalities.
      Chronic dietary:  chronic PAD (cPAD) = 0.14 mg/kg/day derived from a NOAEL of 14 mg/kg/day in a mouse carcinogenicity study. LOAEL = 41 mg/kg/day based on liver hypertrophy and fatty degeneration.
      Incidental oral exposures (short-term):  NOAEL = 100 mg/kg/day from data of the main and range-finding developmental toxicity studies in the rabbit. LOAEL = 125 mg/kg/day based on body weight loss.
      Dermal (short- and intermediate-term):  No point of departure was determined as a hazard was not identified.
      Inhalation (short- and intermediate-term):  NOAEL = 0.3 mg/L from a rat 28-day inhalation toxicity study. LOAEL = 2.4 mg/L based on increased liver weight, serum total bilirubin, and increased incidence of slight centrilobular hepatocyte swelling.  HEC = 0.932 mg/L/day (residential handler) and 0.699 mg/L/day (occupational handler).  HED = 26.7 mg/kg/day (residential handler) or 39.8  -  138.9 mg/kg/day (occupational handler).

For the occupational and residential risk assessments the level of concern (LOC) is for MOEs less than 100.  The FQPA safety factor has been reduced to 1X since the database is complete, points of departure are protective for all life stages, there is no clear evidence of neurotoxicity, and exposure estimates are not likely to underestimate risk.

The residue chemistry database for sethoxydim is complete.  The current tolerance expression should be updated to comply with HED's current policy on tolerance expressions, when the CFR is updated to incorporate the requested new uses.  There are no maximum residue limits (MRLs) established for the residues of sethoxydim by Codex or Mexico.  Canada has established MRLs on sethoxydim for a number of commodities, which are harmonized to the greatest extent possible with those tolerances set by the U.S.  As such, there are no international harmonization issues for sethoxydim associated with the requested new uses.  There are however, some issues with respect to established crop groupings.  The Canadian MRLs on rapeseed (canola), grapes, cranberry, and bulb vegetables are significantly less than those needed to cover the residues in the U.S.  Thus, tolerance harmonization for these crop groupings are not possible.  A revised dietary assessment was conducted in support of the current petition for establishing tolerances for sethoxydim in or on grass grown for seed and a request for an amended use on blueberry.  The acute and chronic dietary exposure and risk assessments were highly conservative, using tolerance levels and percent crop treated assumptions.  For these analyses, acute and chronic dietary (food and water) estimated risks were all well below HED's level of concern for the U.S. population and all population subgroups.

The registered uses may potentially result in non-occupational residential handler and post-application exposures (inhalation and dermal exposures for adults; and post-application dermal, and incidental oral exposures to children). Only inhalation and incidental oral exposures are assessed as a dermal hazard was not identified.  For residential handlers, inhalation MOEs are not of concern for all scenarios assessed.  Post-application inhalation exposures while performing activities in previously treated turf or ornamentals are not expected, primarily due to the very low vapor pressure of sethoxydim, and were not assessed.  These residential exposures are considered to be short-term in duration.  For residential handlers, inhalation MOEs are well above the LOC of 30 for all scenarios assessed and are not of concern. For the post-application assessment, incidental oral exposure is assessed for children playing on treated turf.  The turf use site assessed was residential lawn turf as exposures from that use are expected to be higher than any potential exposures from other turf uses (i.e., parks, golf courses).  Children incidental oral MOEs were well above the LOC of 100.

Occupational handler risks were assessed for the inhalation route of exposure only, as no dermal hazard was identified for sethoxydim. Since the same endpoint and point of departure were selected for short- and intermediate-term durations, short-term exposure and risk estimates are considered to be protective of intermediate-term exposure and risk. All occupational handler scenarios assessed for the proposed uses of sethoxydim, using baseline clothing and default non-chemical specific assumptions, resulted in estimated short- and intermediate-term inhalation MOEs well above the LOC of 30 for all scenarios assessed and, therefore, are not of concern (MOEs >=30).

Although a quantitative occupational post-application inhalation exposure assessment was not performed, the occupational handler inhalation exposure estimates would be protective of post-application inhalation exposure scenarios. The Worker Protection Standard interim REI of 12 hours is adequate to protect agricultural workers from post-application exposures to sethoxydim.

Potential areas of environmental justice concerns were considered in this human health risk assessment to the extent possible.  For more information, see Section 3.5.

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  Those studies are subject to ethics review, have received that review, and are compliant with applicable ethics requirements.

2.0	HED Recommendations

Pending submission of a revised Section F as detailed in Section 2.2.2 and a revised Section B as indicated in Section 2.3, there are no residue chemistry considerations that would preclude establishment of the recommended tolerances.   During the conduct of the sethoxydim PRA, HED did not identify any risks of concern or data deficiencies.  The supplemental label for fine fescue grown for turfgrass seed should indicate that the use is restricted to the Pacific Northwest region of the United States.

2.1	Data Deficiencies/Conditions of Registration and Re-Registration

The toxicity, exposure and residue chemistry data bases are considered complete for the purpose of registration review.  HED notes that the additional safflower field trial and storage stability data required by the 2005 Reregistration Eligibility Decision (RED) has been adequately fulfilled (D312563, April 12, 2012).

Further, no additional data are required to support the requested registration of sethoxydim on high bush blueberry and grasses.

2.2	Tolerance Considerations

2.2.1	Enforcement Analytical Method

An adequate gas chromatography/flame photometric detection GC/FPD method is available (Method I in PAM Vol. II) for determining the combined residues of sethoxydim and its metabolites containing the 3-alkyl substituted pentanedioic acid moiety in plant and livestock commodities (D312567, April 22, 2005).  This common moiety method proposed for tolerance enforcement involves solvent extraction followed by alkaline precipitation, acidification, and partitioning to convert sethoxydim and its metabolites into the 3-alkyl substituted pentanedioic acid moiety.  The acid moiety is methylated to dimethyl 3-[2-(ethylsulfonyl)propyl]pentanedioate (DME) and dimethyl 3-[2-(ethylsulfonyl)propyl]3-hydroxy pentanedioate (DME-OH).  These derivatives are then partitioned into methylene chloride and isolated by silica gel chromatography.  Analysis is performed by GC/FPD, which provides a 0.05 ppm limit of quantitation (LOQ).

2.2.2	Recommended Tolerances

Table 2.2.2 summarizes the sethoxydim tolerances resulting from the current petition requesting its new use on grass and a number of crop group conversions which are to be established under 40 CFR §180.412.

Table 2.2.2.  Tolerance Summary for Sethoxydim[1]
                                   Commodity
                           Proposed Tolerance (ppm)
                          Recommended Tolerance (ppm)
                    Comments; Correct Commodity Definition
Fruit, citrus, group 10-10
                                      0.5
                                      0.5

Fruit, pome, group 11-10
                                      0.2
                                      0.2

Fruit, caneberry, subgroup13-07A
                                      5.0
                                      5.0
Caneberry subgroup 13-07A
Fruit, bushberry, subgroup13-07B
                                      5.0
                                      4.0
Bushberry subgroup 13-07B
Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13-07F
                                      1.0
                                      1.0
Fruit, small, vine climbing, subgroup 13-07F, except fuzzy kiwifruit
Fruit, low growing berry, except cranberry, subgroup 13-07G
                                     10.0
                                      10
Berry, low growing, subgroup 13-07G, except cranberry
Fruit, low growing berry, subgroup 13-07H
                                      2.5
                                      2.5
Berry, low growing, subgroup 13-07H, except strawberry
Rapeseed, subgroup 20A
                                     35.0
                                      35

Sunflower, except safflower, subgroup 20B
                                      7.0
                                      7.0
Sunflower subgroup 20B, except safflower
Cottonseed, subgroup 20C
                                      5.0
                                      5.0

Vegetable, bulb, group 3-07
                                      1.0
                                      1.0

Vegetable, fruiting, group 8-10
                                      4.0
                                      4.0

Fescue, forage
                                      6.0
                                     7[2]

Fescue, hay
                                      4.0
                                     4[2]

[1] These tolerances should be established under 40 CFR §180.412(a).
[2] These tolerances should be established under 40 CFR §180.412(c).

Note to RD:  Upon establishment of the recommended tolerances listed above, tolerance listings for the following individual crops should be revoked, since they will be included in the new crop group and crop subgroups listings:  blueberry, borage meal, borage seed, canola seed, cotton undelinted seed, crambe seed, cupea seed, echium seed, flax seed, gold of pleasure seed, grape, hare's ear mustard seed, juneberry, lesquerella seed, lingonberry, lunaria seed, meadowfoam seed, milkweed seed, mustard seed, oil radish seed, poppy seed, rapeseed seed, salal, sesame seed, strawberry, sunflower seed, and sweet rocket seed.  The crop group and subgroup listings for caneberry subgroup 13A, citrus fruit group 10, pome fruit group 11, bulb vegetable group 3, and fruiting vegetable group 8 are also to be removed and replaced by the current crop group definitions.  In addition, the established tolerance for sugar beet tops should be revoked, since this commodity is no longer a significant livestock feed or a recognized human food item.  The tolerance with regional registration listed for rhubarb should also be revoked, since this commodity is included in crop group 4 which has an already established tolerance.

The tolerance expression for sethoxydim has been reviewed and should be updated as follows based on HED's Interim Guidance on Tolerance Expressions (S. Knizner, May 27, 2009).
      Tolerances are established for the herbicide sethoxydim, including its metabolites and degradates, in or on the commodities in the table below.  Compliance with the tolerance levels specified below is to be determined by measuring only the sum of DME (dimethyl 3-[2-(ethylsulfonyl)propyl]pentanedioate) and DME-OH (dimethyl 3-[2-(ethylsulfonyl)propyl]3-hydroxy pentanedioate), calculated as the stoichiometric equivalent of the parent compound, in or on the commodity.

2.2.3	Revisions to Petitioned-For Tolerances

The crop group conversion requested for the low growing berry subgroup 13-07G based on strawberry was not specified in Section F of the petition.  The tolerance for the bushberry subgroup 13-07B should be based on the residue data on blueberry, the representative crop at 4.0 ppm and not the previously established tolerances for juneberry, lingonberry, and salal at 5.0 ppm.  The juneberry, lingonberry, and salal tolerances are based on the translation of caneberry data, which is no longer relevant to these crops following updated crop grouping realignment.  In addition, the OECD MRL calculation procedures determine the recommended tolerance of 7.0 ppm for grass forage and not 6.0 ppm as proposed by the petitioner.  This difference stems from the conclusion that only 4 independent grass trials were conducted instead of 5 (as assumed by IR-4).  Therefore, the petitioner must submit a revised Section F in which the proposed tolerances are the same as those recommended by HED.

2.2.4	International Harmonization

There are no Codex or Mexican maximum residue limits (MRLs) established for the residues of sethoxydim in/on raw agricultural or processed commodities.  However, there are established MRLs for sethoxydim in Canada which have harmonized tolerance definitions with the U.S.  A summary of the U.S. and international tolerances and maximum residue limits for sethoxydim is presented in Appendix B.  All Canadian MRLs are harmonized with U.S. tolerances to the greatest extent possible.  In regard to the grass forage and hay tolerances requested in this petition, Canada does not establish MRLs on livestock feed items, so harmonization is not a consideration for these uses.  The data provided in support of the requested amended use on blueberry is consistent with the established 4.0 ppm U.S. tolerance on this commodity.  For the requested crop group conversions, these tolerances are supported by extension of the representative crop(s) already established for use.  As such, the establishment of subgroup 13-07B for bushberry will follow the representative crop of blueberry and the set tolerance of 4.0 ppm.  Although the bushberries of juneberry, lingonberry, and salal have established U.S. tolerances of 5.0 ppm, these limits were set on translation from caneberry data, which is no longer a crop in this subgroup.  Therefore, in following the blueberry representative crop, the bushberry subgroup will harmonize with the already established Canadian MRL of 4.0 ppm for this crop grouping.  For the other conversions, the Canadian MRLs on rapeseed (canola), grapes, cranberry, and bulb vegetables are significantly less than those needed to cover the residues in the U.S.  Thus, tolerance harmonization for these crop groupings are not possible.

2.3	Label Recommendations

The supplemental label for fine fescue grown for turfgrass seed should indicate that the use is restricted to the Pacific Northwest region of the United States.

2.3.1	Recommendations from Residue Reviews

The use directions are adequate to allow evaluation of the residue data relative to the proposed uses.  The proposed maximum application rates, re-treatment intervals, and pre-harvest intervals are supported by the submitted field trial data.  The fine fescue grass supplemental label should indicate that use is limited to the Pacific Northwest region of the United States.

2.3.2	Recommendations from Occupational Assessment

None.

3.0	Introduction

3.1	Chemical Identity

The structure and chemical identity for sethoxydim are shown in Table 3.1.  The structures for metabolites discussed in this risk assessment are shown in Appendix C.

Table 3. 1. Sethoxydim Nomenclature.
Chemical structure

Common name
sethoxydim
Company experimental name
BAS 9052 H or BAS 562 05H
IUPAC name
(5RS)-2-[(EZ)-1-(ethoxyimino)butyl]-5-[(2RS)-2-(ethylthio)propyl]-3-hydroxycyclohex-2-en-1-one
CAS name
2-[1-(ethoxyimino)butyl]-5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen-1-one
CAS registry number
74051-80-2
End-use product (EP)
1.5 lb ai/gal EC formulation (Poast(R) Herbicide; EPA Reg. No. 7969-58)

3.2	Physical/Chemical Characteristics

The physical and chemical properties are detailed in Appendix D.

Sethoxydim has a high solubility and mobility with a low octanol/water partition coefficient.
Sethoxydim is unlikely to contaminate ground or surface waters because it is not persistent under most conditions. Under aerobic conditions, half-lives were <1 day. However, the sethoxydim transformation products may be persistent and mobile enough to cause a potential threat to water resources. The transformation mechanisms of parent sethoxydim and residues include: photodegradation; aerobic metabolism in water and soil; and acid-catalyzed hydrolysis in water.

3.3	Pesticide Use Pattern

Sethoxydim products are intended to be used as an herbicide on a wide variety of crops, as well as turf grass and ornamentals.  Sethoxydim is generally applied 1-2 times with retreatment intervals ranging from 7- to 14-days, depending on crop, pest, and country/region.  The recommended application rates for agricultural crops range from 0.28 to 0.47 lb. ai per acre, and the pre-harvest intervals (PHIs) range from 1 to 75 days.  A summary of the use directions is provided below in Table 3.3.

The various end-use products may be applied through a variety of application methods, including aerial, chemigation and ground-boom sprayer.

Table 3.3.  Summary of Registered and Proposed Uses for Sethoxydim
                                 Crop/Use Site
                  Application Timing and Type of Application
                            Registered Formulations
                           Maximum Application Rate
                                    lb ai/A
                                or (lb ai/gal)
  Personal Protective Equipment (PPE) and Restricted Entry Interval (REI),PHI
                         Proposed Uses for Sethoxydim
                               Lowbush Blueberry
When Needed
                               EC 18%, POAST[(R)]
0.47(0.047)
 based on 10 gals/A dilution
                             PPE*/12hrs, 1 day PHI
                              Fine Fescue Grasses
When fescue is semi-dormant (Nov 1[st] to March 15[th])
                                      EC
                                18%, POAST[(R)]

                            PPE*/12hrs, 14 days PHI
                        Registered Uses for Sethoxydim
Agricultural Fallow/Idleland
When Needed
EC
(percent ai 13 to 25.5)
Labels REG#(228-619, 7969-58, 7969-88, 7969-194, 7969-317)

0.47

PPE[*]/12hrs
Airports/Landing Fields

Airports/Landing Fields

Alfalfa
Seedling Stage

PPE*/12hrs, 7 days PHI
Almond
Nonbearing

PPE*/12hrs, PHI[**]
Amaranth -  Chinese
When Needed, Foliar

0.28
PPE*/12hrs, 14 days PHI
Apple
Nonbearing, Foliar

0.47

PPE*/12hrs, 14 days PHI
Apricot

PPE*/12hrs, 25 days PHI
Arracacia (Persian Carrot)
When Needed, Foliar

PPE*/12hrs, 7 days PHI
Arrowroot

Artichoke

Artichoke -  Chinese

Artichoke -  Jerusalem

Asparagus

PPE*/12hrs, 7 days PHI
Avocado
Nonbearing,

PPE*/12hrs, PHI[**]
Beans -  Dried-Type
When Needed, Foliar

PPE*/12hrs, 15 days PHI
Beans -  Succulent (Snap)

PPE*/12hrs, 15 days PHI
Blackberry

PPE*/12hrs, 45 days PHI
Blueberry

PPE*/12hrs, 30 days PHI
Broccoli

0.28

PPE*/12hrs, 30 days PHI
Broccoli Raab

Broccoli -  Chinese

Brussels Sprouts

Cabbage

Canola\Rape
Foliar

0.47
PPE*/12hrs, 60 days PHI
Cardoon
When Needed, Foliar

0.28
PPE*/12hrs, 30 days PHI
Carrot (Including Tops)

0.47
PPE*/12hrs, 30 days PHI
Cauliflower

0.28

PPE*/12hrs, 30 days PHI
Celery

PPE*/12hrs, 30 days PHI
Celtuce

Chard -  Swiss

Cherry
Nonbearing

0.47
PPE*/12hrs, 25 days PHI
Chervil
When Needed, Foliar

0.28
PPE*/12hrs, 30 days PHI
Christmas Tree Plantations
Postemergence

0.47
PPE*/12hrs
Chrysanthemum -  Garland
When Needed, Foliar

0.28
PPE*/12hrs, 30 days PHI
Citrus

0.47

PPE*/12hrs, 15 days PHI
Clover
Foliar, Established Planting

PPE*/12hrs, 15 days PHI
Collards
When Needed, Foliar

0.28
PPE*/12hrs, 30 days PHI
Commercial/Institutional/Industrial premises/Equipment (Outdoor)
Postemergence

0.47

PPE*/12hrs, PHI[**]
Corn Salad
When Needed, Foliar

0.28

PPE*/12hrs, 30 days PHI
Corn -  Field

Corn -  Sweet

Cotton (Unspecified)

0.47

PPE*/12hrs, 40 days PHI
Crabapple

PPE*/12hrs, 14 days PHI
Crambe

PPE*/12hrs, 60 days PHI
Cranberry

PPE*/12hrs, 45 days PHI
Cress -  Garden

0.28

PPE*/12hrs, 30 days PHI
Cress -  Upland

PPE*/12hrs, 30 days PHI
Cucumber

PPE*/12hrs, 14 days PHI
Dandelion

PPE*/12hrs, 30 days PHI
Date
Nonbearing

0.47
PPE*/12hrs
Dock (Sorrel)
When Needed, Foliar

0.28

PPE*/12hrs, 30 days PHI
Eggplant

PPE*/12hrs, 20 days PHI
Endive (Escarole)

PPE*/12hrs, 15 days PHI
Fencerows/Hedgerows
When Needed

0.47
PPE*/12hrs
Fennel
When Needed, Foliar

0.28
PPE*/12hrs, 30 days PHI
Fig
Nonbearing

0.47
PPE*/12hrs, PHI[**]
Flax
When Needed, Foliar

0.28

PPE*/12hrs, 75 days PHI
Garlic

PPE*/12hrs, 30 days PHI
Gherkin

PPE*/12hrs, 14 days PHI
Ginger

0.47

PPE*/12hrs, 7 days PHI
Grapefruit
Nonbearing

PPE*/12hrs, PHI[**]
Grapes
When Needed, Foliar

PPE*/12hrs, 50 days PHI
Grasses Grown for Seed

PPE*/12hrs, 21 days PHI
Groundcherry (Strawberry Tomato/Tomatillo)

0.28
PPE*/12hrs, 20 days PHI
Horseradish

0.47
PPE*/12hrs, 60 days PHI
Industrial Areas (Outdoor)
When Needed

0.47
PPE*/12hrs
Kale
When Needed, Foliar

0.28

PPE*/12hrs, 30 days PHI
Kohlrabi

PPE*/12hrs, 30 days PHI
Leek

PPE*/12hrs, 30 days PHI
Lemon
Nonbearing

0.47

PPE*/12hrs, PHI[**]
Lentils
When Needed, Foliar

PPE*/12hrs, 50 days PHI
Leren

PPE*/12hrs, 7 days PHI
Lettuce -  Head

0.28

PPE*/12hrs, 30 days PHI
Lettuce - Leaf (Black Seeded Simpson - Salad Bowl - Etc.)

PPE*/12hrs, 15 days PHI
Lime
Nonbearing

0.47

PPE*/12hrs, PHI[**]
Loganberry
When Needed, Foliar

PPE*/12hrs, 45 days PHI
Macadamia Nut (Bushnut)
Nonbearing

PPE*/12hrs, PHI [**]
Manioc (Cassava)
When Needed, Foliar

PPE*/12hrs, 7 days PHI
Melons -  Cantaloupe

0.28

PPE*/12hrs, 14 days PHI
Melons -  Honeydew

PPE*/12hrs, 14 days PHI
Melons -  Musk

0.28

PPE*/12hrs, 14 days PHI
Melons -  Water

PPE*/12hrs, 14 days PHI
Mint/Peppermint/Spearmint

0.47
PPE*/12hrs, 7 days PHI
Mustard

0.28
PPE*/12hrs, 30 days PHI
Mustard Cabbage (Gai Choy -  Pak-Choi)

0.28
PPE*/12hrs, 30 days PHI
Nectarine
Nonbearing

0.47
PPE*/12hrs, PHI 25 days
Nonagricultural Rights-Of- Way/Fencerows/Hedgerows
When Needed, Foliar

0.28

PPE*/12hrs, 30 days PHI
Nonagricultural Uncultivated Areas/Soils
When Needed

0.47

PPE*/12hrs
Olive
Nonbearing

PPE*/12hrs
Onion
When Needed, Foliar

0.28

PPE*/12hrs, 30 days PHI
Onions (Green)

PPE*/12hrs, 30 days PHI
Orach (Mountain Spinach)

PPE*/12hrs, 30 days PHI
Orange
Nonbearing

0.47
PPE*/12hrs, PHI[**]
Ornamental And/or Shade Trees
When Needed

0.47/0.02lb ai/gal
20 gals/A dilutions
PPE*/12hrs
Ornamental Ground Cover

PPE*/12hrs
Ornamental Herbaceous Plants

PPE*/12hrs
Ornamental Lawns And Turf

PPE*/12hrs
Ornamental Nonflowering Plants

PPE*/12hrs
Ornamental Woody Shrubs And Vines

PPE*/12hrs
Parsley
When Needed, Foliar

0.28
PPE*/12hrs, 30 days PHI
Paved Areas (Private Roads/Sidewalks)
When Needed

0.47

PPE*/12hrs
Peach
 Nonbearing

PPE*/12hrs, PHI 25 days
Peanuts (Unspecified)
When Needed, Foliar

0.28
PPE*/12hrs, 40 days PHI
Pear
 Nonbearing

0.47

PPE*/12hrs, PHI 14 days
Peas -  Dried-Type
When Needed, Foliar

PPE*/12hrs, 30 days PHI
Peas -  Succulent

PPE*/12hrs, 30 days PHI
Pecan
 Nonbearing

PPE*/12hrs
Pepino (Melon Pear)
When Needed, Foliar

0.28

PPE*/12hrs, 20 days PHI
Pepper

PPE*/12hr, 20 days PHI
Pistachio
 Nonbearing

0.47

PPE*/12hrs
Plum

PPE*/12hrs
Pomegranate

PPE*/12hrs
Potato -  White/Irish
When Needed, Foliar

PPE*/12hrs, 30 days PHI
Potting Soil/Topsoil
When Needed

PPE*/12hrs
Prune
 Nonbearing

PPE*/12hrs
Pumpkin
When Needed, Foliar

0.28

PPE*/12hrs, 14 days PHI
Purslane -  Garden

PPE*/12hrs, 30 days PHI
Quince
 Nonbearing

0.47

PPE*/12hrs, PHI 14 days
Raspberry (Black -  Red)
When Needed, Foliar

PPE*/12hrs, 45 days PHI
Recreational Areas
When Needed

PPE*/12hrs
Rhubarb
When Needed, Foliar

0.28

PPE*/12hrs, 15 days PHI
Roquette (Arrugula)

PPE*/12hrs, 15 days PHI
Sainfoin

0.47

PPE*/12hrs, 7 days PHI
Sewage Disposal Areas
When Needed

PPE*/12hrs
Shallot
When Needed, Foliar

0.28
PPE*/12hrs, 30 days PHI
Soybeans (Unspecified)

0.47
PPE*/12hrs, 75 days PHI
Spinach

0.47
PPE*/12hrs, 15 days PHI
Spinach -  New Zealand

0.28

PPE*/12hrs, 30 days PHI
Squash (All Or Unspecified)

PPE*/12hrs, 14 days PHI
Strawberry

0.47

PPE*/12hrs, 7 days PHI
Sugar Beet

PPE*/12hrs, 60 days PHI
Sunflower

PPE*/12hrs, 70 days PHI
Sweet Potato

PPE*/12hrs, 30 days PHI
Tangelo
Nonbearing

PPE*/12hrs, PHI 30 days
Tangerines

PPE*/12hrs
Taro
Foliar

PPE*/12hrs
Tobacco
When Needed

0.19
PPE*/12hrs
Tomatillo

0.28

PPE*/12hrs, 20 days PHI
Tomato

PPE*/12hrs, 20 days PHI
Tree Nuts
 Nonbearing

0.47
PPE*/12hrs, PHI 15 days
Trefoil
When Needed, Foliar

0.28
PPE*/12hrs, 20 days PHI
Turmeric

0.47

PPE*/12hrs, 7 days PHI
Walnut (English/Black)
Nonbearing

PPE*/12hrs
Wide Area/General Outdoor Treatment (Public Health Use)
When Needed

PPE*/12hrs
Yam
When Needed, Foliar

PPE*/12hrs, 7 days PHI
Yam Bean

PPE*/12hrs, 7 days PHI
Youngberry

PPE*/12hrs, 7 days PHI
PPE[*]Label recommended PPE is coveralls, long sleeve shirt, chemical resistance gloves, shoes plus socks, protective eyewear and no respirator
PHI[**]Not available

3.4	Anticipated Exposure Pathways

Sethoxydim is proposed for use on numerous agricultural crops, as well as on turf (which could include lawns, golf courses, recreational parks, sod farms, etc.) and ornamentals.  Exposure to sethoxydim may occur from ingestion of residues on foods and in drinking water and via the dermal and inhalation routes for adults using sethoxydim products in occupational and residential settings.  In addition, both adults and children may be exposed dermally in post-application turf scenarios; children may also be exposed orally in post-application turf scenarios. There is a potential for post-application dermal exposure for workers re-entering treated fields.

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 Populations," (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 well-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.  Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and/or the CDC under the National Health and Nutrition Examination Survey/What We Eat in America (NHANES/WWEIA), and are used in pesticide risk assessments for all registered food uses of a pesticide.  These 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 when 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 post-application 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 traditional dietary patterns among specific subgroups.

4.0	Hazard Characterization and Dose-Response Assessment

4.1	Toxicology Studies Available for Analysis

The toxicology database for sethoxydim provides a robust characterization of the hazard potential of this pesticide. The toxicology studies for sethoxydim are summarized in Table A.1 in Appendix A.1.  There are studies available for toxicity endpoint selection, which include:

      Subchronic oral toxicity studies in rats and mice
      Chronic oral toxicity studies in rats, mice, and dogs
      Carcinogenicity studies in rats and mice
      Mutagenicity battery
      Developmental studies in rats and rabbits
      Reproduction study in rats
      Subchronic neurotoxicity study in rats
      Dermal toxicity study in rabbits
      Inhalation toxicity study in rats
      Metabolism study in rats

A waiver was granted by Hazard and Science Policy Council (HASPOC) for the acute neurotoxicity study and the immunotoxicity study (Leshin, 2015, TXR# 0057805).  Since the last risk assessment (Drew, 2005, D312569), a subchronic neurotoxicity study was received and reviewed.  The studies available for consideration of sethoxydim toxicity provide a comprehensive database, with routes of administration that are consistent with potential exposure scenarios.

4.2	Absorption, Distribution, Metabolism, & Elimination (ADME)

In the metabolism study, formulation were administered in dimethyl sulfoxide by intravenous injection or by oral gavage.  Absorption is extensive (possibly due to vehicle), and excretion is nearly complete within 48 hours of administration.  Tissue accumulation is negligible (<2% of administered dose [AD]).  Excretion occurs mainly in the urine (78.5% AD), but also in the feces (20.1% AD).  A negligible amount of parent was present in the excreta, and metabolites were principally identified as three sulphoxy compounds.

4.2.1	Dermal Absorption

In 2003, HIARC concluded that a dermal absorption factor and dermal risk assessment was unnecessary (Assaad and Bonner, 2003, TXR# 0051694).  No dermal absorption studies are available. However, a dermal absorption factor is not required, because quantification of dermal risk is not required based on lack of toxicity in the rabbit dermal toxicity study at the limit dose and a low concern for adverse findings in fetuses, offspring, and reproduction (detailed in section 4.5.1). Furthermore, this chemical is not likely a human carcinogen, so a dermal absorption factor is not needed for the estimation of carcinogenic risk either.

4.3	Toxicological Effects

Sethoxydim is an herbicide that works by inhibiting lipid biosynthesis in plants.  The hallmark toxicity of sethoxydim in animals (rats, mice, and dog) is liver toxicity, which may be characterized by increased liver weight; hypertrophy; fatty degeneration; hepatocyte swelling; increased serum bilirubin, alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase levels; focal granulomatous inflammation; and eosinophilic foci.  No dermal toxicity was noted, but liver toxicity was observed by exposure through both the oral and inhalation routes.

Findings other than liver toxicity were also observed.  In a subchronic rat study, decreased body weight, body weight gain, and food efficiency were noted at a lower dose than liver toxicity.  In a chronic dog toxicity study, increased hemosiderosis in the spleen and depressed myeloid erythropoiesis in the sternal bone marrow were observed.  Interstitial fibrosis and heart failure cells in lung in female rats were observed in the chronic toxicity/carcinogenicity study in rats.

In the developmental rat study, maternal toxicity was observed, as evidenced by an irregular gait, decreased activity, excessive salivation, and anogenital staining at a dose greater than half the limit dose and at the limit dose.  All clinical signs reported were transient, with the exception of the anogenital staining, which did not reverse.  Because the clinical signs occurred shortly after dosing, only occurred at very high treatment doses, and were transitory, they may be reflective of the general toxicity at high dose levels.  There is low concern for these findings since the selected points of departure are protective of these findings.  Developmental toxicity occurred at the same dose as maternal toxicity in rats and included decreased fetal weights, filamentous tail and lack of tail due to the absence of sacral and/or caudal vertebrae, and delayed ossification in the hyoids, vertebral centrum and/or transverse processes, sternebrae and/or metatarsals, and pubes.  No maternal toxicity was noted in rabbits at 400 mg/kg/day, and developmental toxicity was noted at 400 mg/kg/day (NOAEL = 320 mg/kg/day) as an increase in the incidence of incompletely ossified 6[th] sternebrae.  In the reproduction study, no parental or reproductive toxicity was observed at 150 mg/kg/day (highest dose tested), but offspring toxicity was noted at this dose as decreased pup weight in the F1a, F1b, and F2b generation during lactation (NOAEL = 30 mg/kg/day).  Again there is a low concern for these findings, since the selected points of departure are protective; there is low concern for pre- and/or postnatal toxicity resulting from exposure to sethoxydim (Assaad and Bonner, 2003, TXR# 0051694).

Dermal toxicity was not observed at the limit dose in a 21-day dermal study in rabbits.  No neurotoxicity or other toxicity was observed at the highest dose tested (207 mg/kg/day) in the subchronic neurotoxicity test in rats.  The only possible indications of neurotoxicity in the remainder of the database were seen at doses of 650 and 1000 mg/kg/day in the rat developmental study which may have been a result of general systemic toxicity.

There was no evidence of carcinogenicity in rats and mice, and no evidence of genotoxicity.  Sethoxydim is classified as "Not Likely to Be Carcinogenic to Humans."

The acute toxicity profile of sethoxydim is Toxicity Category III for oral, dermal, and inhalation in rats.  No eye or dermal irritation were noted in rabbits.  Based on the lack of sensitization of guinea pigs treated with the formulation (Poast), the requirement for a dermal sensitization study with the technical compound in guinea pigs was waived.

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

HIARC performed a Degree of Concern Analysis and concluded that there was low concern for pre- and/or post-natal toxicity resulting from exposure to sethoxydim (Assaad and Bonner, 2003, TXR# 0051694).  HED recommends 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 toxicological database for sethoxydim is complete under the new 40 CFR Part 158 data requirements for conventional pesticides.
   * There is evidence of increased susceptibility/sensitivity in rats and/or rabbits to pre- and/or post-natal exposure to sethoxydim. However, the concern is low based on clear no observed adverse effect (NOAEL) levels for the findings that are greater than the chosen points of departure.
   * There was no clear evidence of neurotoxicity or neuropathology in the available studies, which include a subchronic neurotoxicity study. The acute neurotoxicity study and developmental neurotoxicity study requirements have been waived.

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

4.4.1	Completeness of the Toxicology Database

The database of toxicology studies for sethoxydim is complete and considered adequate for risk assessment (see Appendix A.1).  Developmental toxicity studies in rats and rabbits and a reproductive toxicity study in rats are available.  A subchronic neurotoxicity is also available.  Waivers were granted by HED's HASPOC (Leshin, 2015, TXR# 0057805) for the acute neurotoxicity test and immunotoxicity test.

4.4.2	Evidence of Neurotoxicity

There is no evidence of neurotoxicity or neuropathology in the available studies. The irregular gait, decreased activity, and excessive salivation observed in the maternal rat in the developmental toxicity study were attributed to general toxicity, which occurred at a dose greater than half the limit dose and at the limit dose. In the subchronic neurotoxicity study in rats, there were no adverse effects on any functional operational battery (FOB) parameter monitored; motor activity was comparable among the groups; and there were no neuropathological effects observed in either sex. There is not a concern for developmental neurotoxicity, and HED RARC recommended waiving the requirement for a developmental neurotoxicity study (Drew, 2005, D312569).

4.4.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There is evidence of increased susceptibility following in utero exposure to sethoxydim in the rabbit developmental toxicity study and following in utero and/or pre-/post-natal exposure in the 2-generation reproduction study in rats.  However, there is low concern because the chosen points of departure for risk assessment for each exposure scenario are protective for these effects.

Sethoxydim has been evaluated for potential developmental effects in the rat and rabbit (gavage administration).  Maternal toxicity included transient clinical signs (irregular gait, decreased activity, excessive salivation, and anogenital staining) in rats at 650 mg/kg/day and at the limit dose.  Decreased fetal body weight, delayed ossification, and malformations (filamentous tail; lack of tail) were observed in the rat at 650 mg/kg/day and at the limit dose.  Maternal toxicity was not observed in rabbits, whereas an increased incidence of incompletely ossified 6[th] sternebrae was noted in fetuses at the high dose (400 mg/kg/day).  Decreased body weight was observed in F1a, F1b, and F2b pups during lactation in the 2-generation reproduction study at 150 mg/kg/day (highest dose tested), while parental toxicity was not observed.

4.4.4	Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database.  The dietary exposure estimates were refined by incorporation of percent of crop treated assumptions; however,  tolerance-level residue in food and upper-bound drinking water estimates based on modeling were used which are conservative assumptions, see Section 5.4.1.  HED is confident that the dietary risk is not underestimated.  Additionally, HED does not believe that non-occupational exposure and risk estimates are underestimated.  The assumptions are detailed in Section 6.0.

4.5	Toxicity Endpoint and Point of Departure Selections

4.5.1	Dose-Response Assessment

There have been no changes since the last risk assessment to the dose-response assessment, endpoint selection, or cancer classification, except for the addition of the human equivalent dose (HED) and human equivalent concentration (HEC) inhalation values.  The studies selected for risk assessment for each exposure scenario represent the lowest points of departure in the database and as such are protective for any other effects observed for the exposure scenario.  The detailed description of the toxicity studies used for selecting toxicity endpoints and points of departure for various exposure scenarios are presented in Appendix A.4.

Acute Dietary Endpoint (General Population, including Infants and Children):  Maternal effects observed in a rat developmental study were selected as the acute endpoint for the general US Population, including infants and children.  The acute Population Adjusted Dose (aPAD) of 1.8 mg/kg/day is based on a NOAEL of 180 mg/kg/day with a 100-fold uncertainty factor (10X interspecies and 10X intraspecies) applied and an FQPA SF of 1.  The maternal LOAEL of 650 mg/kg/day is based on irregular gait that was observed in 12/34 dams on the first day of dosing.

Acute Dietary Endpoint (Females 13-49 years of age):  Developmental effects from a rat developmental study were selected as the acute endpoint for the women of child-bearing age.  The aPAD of 1.8 mg/kg/day is based on a NOAEL of 180 mg/kg/day with a 100-fold uncertainty factor (10X interspecies and 10X intraspecies) applied and an FQPA SF of 1.  The developmental LOAEL was 650 mg/kg/day based on decreased fetal body weight, tail abnormalities, and delayed ossification.  The delayed tail abnormalities are considered to be possibly due to a single exposure; therefore, this finding is suitable for an acute endpoint.  The developmental toxicity provides a point of departure that specifically applies to women of child-bearing age.

Chronic Dietary Endpoint:  The chronic dietary endpoint was selected from a mouse carcinogenicity study.  The chronic PAD (cPAD) of 0.14 mg/kg/day is based on a NOAEL of 14 mg/kg/day with a 100-fold uncertainty factor (10X interspecies and 10X intraspecies) applied and an FQPA SF of 1.  At the study LOAEL of 41.2 mg/kg, hepatocellular hypertrophy and fatty degeneration were observed.

Short-Term Incidental Oral:  The dose and endpoint selected for short-term incidental oral exposure was from a rat developmental study.  The maternal NOAEL of 180 mg/kg/day and maternal LOAEL of 650 mg/kg/day were chosen based on based on irregular gait, decreased activity, excessive salivation, and anogenital staining.  The standard 100X UF was applied to account for interspecies extrapolation and intraspecies variation.  A margin of exposure (MOE) of 100 is considered adequate for incidental oral risk assessment level of concern.  Intermediate-term incidental oral exposure is not anticipated; therefore, no endpoint was selected.

Dermal Endpoints:  In 2003, HIARC concluded that a dermal absorption factor and dermal risk assessment was unnecessary (Assaad and Bonner, 2003, TXR# 0051694), and the current HED evaluation supports this conclusion.  In a 21-day dermal toxicity study in rabbits, no adverse local or systemic effects were observed at the limit dose.  Developmental effects occurred at the same dose as maternal effects in the rat, and developmental effects were noted in rabbits only at 400 mg/kg/day (highest dose tested; no maternal adverse effects observed).  No dermal penetration study was submitted.  However, a conservative scenario (likely an overestimation) would suggest a dermal absorption factor of 40% based on the toxicity observed in the fetuses at 400 mg/kg/day compared to the lack of toxicity observed in adults at 1000 mg/kg/day in the dermal rabbit toxicity study.  Applying this dermal absorption factor to the maternal exposure dose level eliciting adverse effect in fetuses would indicate that dermal exposure to the maternal animal would have to be >= limit dose to elicit the same effect.  Consequently, there is no concern for dermal toxicity.

Short- and Intermediate-Term Inhalation Endpoints:  The concentration and endpoint of 0.3 mg/L selected for short- and intermediate-term inhalation exposure was from a 28-day rat inhalation study.  At the study LOAEL of 2.4 mg/L effects observed included increased liver weight, increased total serum bilirubin, and increased incidence of slight centrilobular hepatocyte swelling.  The HED was calculated for various exposure scenarios using the regional deposited-dose ratio (RDDR) program and resulted in 39.8-138.9 mg/kg/day for occupational handlers (value chosen for each assessment depending on breathing rate assumed for a worker doing each task assessed, Appendix A.5.) and 26.7 mg/kg/day for residential handlers.  The HEC for residential handler is 0.932 mg/L/day, and for occupational handler is 0.699 mg/L/day.  For steady state inhalation exposures, a total uncertainty factor of 30X is appropriate (3X for interspecies extrapolation, 10X for intraspecies variation).  The interspecies factor was reduced from 10X to 3X, due to the HEC calculation accounting for pharmacokinetic interspecies differences.  For details regarding the calculation of the HECs and HEDs and values for specific exposure scenarios and ventilation rates, please consult Appendix A.5. Calculation of HED and HEC for Sethoxydim.

During Registration Review, the Agency will utilize this analysis to determine if data (i.e., flux studies or route-specific inhalation toxicological studies) or further analysis is required for sethoxydim.

Carcinogenicity: Sethoxydim is not a likely human carcinogen based on lack of evidence of carcinogenicity in rats and mice (Assaad and Bonner, 2003, TXR#0051694).

4.5.2	Recommendation for Combining Routes of Exposures for Risk Assessment

As indicated by 1996 FQPA, when there are potential residential exposures to the pesticide, aggregate risk assessment must consider exposures from three major routes: oral, dermal, and inhalation.  For short-term aggregate risk assessments, oral and inhalation exposures cannot be aggregated because of a lack of a common toxic endpoint across the exposure routes.  Intermediate-term and long-term aggregate exposures are limited to food and water.  No quantification of risk from dermal exposure is required for any time period because of lack of toxicity at the limit dose in a 28-day dermal toxicity study and a low concern for adverse findings in other toxicity studies which were not measured in the dermal toxicity study (detailed in section 4.5.1). A cancer aggregate risk assessment was not performed, because sethoxydim shows no evidence of carcinogenicity.  The endpoint selections for sethoxydim are listed in Table 4.5.4.

4.5.3	Cancer Classification and Risk Assessment Recommendation

Sethoxydim is characterized as "Not Likely to Be Carcinogenic to Humans" based on the lack of increased tumor incidence in the rat and mouse carcinogenicity studies and the absence of genotoxicity observed in the mutagenicity battery.

4.5.4	Summary of Points of Departure and Toxicity Endpoints

 Table 4.5.4.  Summary of Toxicological Doses and Endpoints for Sethoxydim for Use in Dietary and Non-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
Acute Dietary (General Population, including Infants and Children)
NOAEL = 180 mg/kg/day

UFA = 10x
UFH = 10x
FQPA SF = 1x

Acute RfD = aPAD = 1.8 mg/kg/day
43092902, Rat Developmental Toxicity
Maternal LOAEL = 650 mg/kg/day based on irregular gait that was observed in 12/34 dams on the first day of dosing
Acute Dietary
(Females 13-49 years of age)
NOAEL = 180 mg/kg/day

UFA = 10x
UFH = 10x
FQPA SF = 1x

Acute RfD = aPAD = 1.8 mg/kg/day
43092902, Rat Developmental Toxicity
Developmental LOAEL = 650 mg/kg/day based on decreased fetal body weight, tail abnormalities, and delayed ossification
Tail abnormalities were considered an acute effect.
Chronic Dietary
(All populations)
NOAEL= 14 mg/kg/day

UFA = 10x
UFH = 10x
FQPA SF = 1x

Chronic RfD = cPAD =
 0.14 mg/kg/day
00100527, Mouse Carcinogenicity Study
LOAEL = 41 mg/kg/day based on liver hypertrophy and fatty degeneration
Short-Term Incidental Oral
(1-30 days)
NOAEL = 180 mg/kg/day

UFA = 10x
UFH = 10x
FQPA SF = 1x
Residential LOC for MOE = 100

Occupational = N/A
43092902, Rat Developmental Toxicity
Maternal LOAEL = 650 mg/kg/day based on irregular gait, decreased activity, excessive salivation, and anogenital staining
Short- and Intermediate-Term Dermal
No dose/endpoint selected

Residential LOC for MOE = N/A

Occupational = N/A
41987203, Rabbit 21-Day Dermal Toxicity
Dermal risk assessments are not required because no dermal or systemic toxicity was seen following repeated dermal applications of sethoxydim at the limit-dose to rabbits.
Short-Term Inhalation [a]
(1 to 30 days)
Intermediate-Term Inhalation (1 to 6 months)

NOAEL = 0.3 mg/L

HEC = 0.932 mg/L/day (residential handler) and 0.699 mg/L/day (occupational handler)
HED = 26.7 mg/kg/day (residential handler) or 39.8  -  138.9 mg/kg/day (occupational handler)
UFA = 3x
UFH = 10x
FQPA SF = 1x

Residential LOC for MOE = 30

Occupational LOC for MOE = 30
44021202, Rat 28-day Inhalation Study
LOAEL = 2.4 mg/L based on increased liver weight, increased total serum bilirubin, and increased incidence of slight centrilobular hepatocyte swelling
Cancer
"Not Likely to Be Carcinogenic to Humans" based on the lack of evidence of carcinogenicity in rats and mice.
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  FQPA SF = FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c = chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level of concern.  N/A = not applicable.
[a] For details regarding the calculation of the HECs and HEDs and values for specific exposure scenarios and ventilation rates, please consult Appendix A.5. Calculation of HED and HEC for Sethoxydim.

4.6	Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its preliminary re-registration decision for sethoxydim, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), sethoxydim is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a "naturally occurring estrogen, or other such endocrine effects as the Administrator may designate." The EDSP employs a two-tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine-related effects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 and includes some pesticides scheduled for registration review and chemicals found in water. Neither of these lists should be construed as a list of known or likely endocrine disruptors. List 2 represents the next set of chemicals for which EPA intends to issue test orders/data call-ins in the near future. For further information on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website.

Sethoxydim is not a list 1 or list 2 chemical.  EDSP mandated testing has not yet been performed for sethoxydim.

5.0	Dietary Exposure and Risk Assessment

Sethoxydim. Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Proposed Uses on Highbush Blueberry and Fescue Grass as well as registration review for all registered crops and updating crop group and sub-groups for Sethoxydim, D422745, K. King, 12/16/2014.

5.1	Metabolite/Degradate Residue Profile

Refer to Appendix B for chemical names and structures.

5.1.1	Summary of Plant and Livestock Metabolism Studies

<IP_ADDRESS>	 Plant Metabolism Studies
      Residue Chemistry Memo, D422744, P. Savoia, 12/18/2014

The nature of the residue in plants is adequately understood for the crops that are the subject of this petition based on soybean, tomato, and sugar beet metabolism studies.  Sethoxydim is rapidly metabolized in plants to a multitude of cyclohexenone derivatives, including the corresponding parent sulfoxide, parent sulfone, their hydroxylated and desethoxylated analogs, and oxazole compounds; very little (<=0.5%) sethoxydim is not metabolized.  The residues of concern for tolerance expression and risk assessment in plants are the combined residues of sethoxydim and its metabolites containing the 2-cyclohexen-1-one moiety (calculated as sethoxydim).

<IP_ADDRESS>	 Livestock Metabolism Studies
      Residue Chemistry Memo, D422744, P. Savoia, 12/18/2014

The nature of the residue in livestock is understood based on acceptable metabolism studies in ruminants (goat) and poultry (hens).  The residues of concern for tolerance expression and risk assessment in livestock commodities are the combined residues of sethoxydim and its metabolites containing the 2-cyclohexen-1-one moiety (calculated as sethoxydim).

5.1.2	Summary of Environmental Degradation
      Drinking Water Memo, D418281, James Lin, 06/25/14

Sethoxydim hydrolyzes at moderately rapid rates at low pH's, but is more stable at high pH's.  The major observed hydrolysis transformation product is M2-S or 6-(2-(ethylthio)propyl)-4-oxo-2-propyl-4,5,6,7-tetrahydrobenzoxazole.

Sethoxydim and sethoxydim total residues degrade photolytically in both water and soil.  In pH 8.7 buffered water, the calculated photolysis half-life of sethoxydim is 5.23 days, and the major transformation product is M1-S or 2-(1-aminobutylidene)-5-(2-(ethylthio)-propyl)-cyclohex-1,3-dione.  Under anaerobic conditions, parent sethoxydim is more persistent than under aerobic conditions.

5.1.3	Comparison of Metabolic Pathways

The metabolism of sethoxydim in rotational crops is consistent with that of primary crops.  Sethoxydim is rapidly metabolized in plants to a multitude of cyclohexenone derivatives, including the corresponding parent sulfoxide, parent sulfone, their hydroxylated and desethoxylated analogs, and oxazole compounds.  Generally, very little (<=0.5%) sethoxydim is not metabolized.  In livestock, metabolism proceeds along a pathway similar to what occurs in plants.  It was concluded that the residues of concern for sethoxydim are the combined residues of sethoxydim and its metabolites containing the 2-cyclohexen-1-one moiety (calculated as sethoxydim).  In rats, excretion was extremely rapid and tissue accumulation was negligible. The major metabolites identified in the rat were similar to those found in plants and livestock; [14]C-Na-MSO, M2-SO2, M1-SO2, 6OH-M2-SO2, and Na-M2-SO2 (see Appendix B for the molecular structures of sethoxydim and some metabolites).

5.1.4	Residues of Concern Summary and Rationale
	Residue Chemistry Memo CBRS17851, L. Cheng, 04/04/1997 and MARC Memo D246356, R. Loranger, 	05/27/1998

The metabolism of sethoxydim in plants and livestock is adequately understood.  Residues of concern for both tolerance expression and risk assessment are the combined residues of sethoxydim and its metabolites containing the 2-cyclohexen-1-one moiety, calculated as sethoxydim (Phase V review of soybeans, tomatoes, goats, and poultry metabolism studies, CBRS17851, L. Cheng, 04/04/97).  The Metabolism Assessment Review Committee (MARC) has also met and discussed the residues of sethoxydim, which are found in water (D246356, R. Loranger, 05/27/1998).  The predominant degradates in soil are the sulfoxide and sulfone derivates of parent (MSO and MSO2),.  Those degradates are expected to be found in water along with M1S (loss of ethoxy group on imino nitrogen) and M2S (formation of oxazole ring).  In the absence of available toxicity data, the MARC considers the degradates of sethoxydim to have comparable toxicity to that of the parent compound.  Therefore, the MARC concluded that for risk assessment purposes the residues in water are the "total sethoxydim residues" in water (parent plus degradates).

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 and Rotational Crops)
Sethoxydim and all metabolites containing the  2-cyclohexen-1-one moiety
Sethoxydim and all metabolites containing the  2-cyclohexen-1-one moiety
Livestock
Sethoxydim and all metabolites containing the  2-cyclohexen-1-one moiety
Sethoxydim and all metabolites containing the  2-cyclohexen-1-one moiety
Drinking Water
Total sethoxydim residues (parent plus degradates)
Not Applicable

5.2	Food Residue Profile
      Residue Chemistry Memo, D422744, P. Savoia, 12/18/2014

Adequate residue chemistry data have been provided to support the registration of sethoxydim on grass grown for seed and its amended use on blueberry.  Field trials are of adequate number and geographic representation.  Data analyses employed validated analytical methods and are supported by adequate storage stability data.  No processing studies were submitted, because grass grown for seed and blueberries do not have processed commodities listed in the OCSPP Residue Chemistry Guidelines.  For the requested new use on grass grown for seed, the establishment of tolerances on grass forage and hay will not increase livestock dietary burden; therefore, no revisions to existing tolerances on livestock commodities are required.

The residue chemistry database of sethoxydim is considered complete.  Adequate metabolism studies and enforcement methods for plant and livestock are available.  Tolerances for plant commodities should be modified as described in section 2.2.2.  The tolerances established in the 40 CFR § 180.412 for livestock commodities are adequate.  No tolerances have been established for inadvertent or indirect residues of sethoxydim in or on rotational crops, and none are needed at this time.

5.3	Water Residue Profile
      Drinking Water Memo, D418281, J. Lin, 06/25/14

Revised estimated drinking water concentrations (EDWCs) were determined for dietary assessment to support the requested new uses proposed by IR-4.  These analyses were provided by EFED in the memorandum "Sethoxydim: Drinking Water Exposure Assessment for IR-4 Petition on Fescue, Oilseeds, Fruits, and Vegetables" (D418281, J. Lin, 06/25/2014).  This screening drinking water assessment utilizes the PRZM/EXAMS Surface Water Concentration Calculator (SWCC Version 1.106, released May 22, 2014) to assess residues in surface water.  Multiple application scenarios to calculate the estimated drinking water concentration (EDWC) in surface water were selected based upon the highest application rates, most vulnerable application methods, and the consideration of regional environmental characteristics resulting in the upper-bound exposure in surface water.

Multiple application scenarios for the surface water analysis are presented in this screening drinking water assessment to identify the upper-bound EDWC associated with all of the uses for sethoxydim.   Ground water concentrations are estimated using the Tier 1 mode of the PRZM-GW Model (Version 1.07, released January 23, 2014).  The maximum surface and ground water EDWCs for use in the human health risk assessment for sethoxydim are shown in Table 5.3.  The surface water values were selected for use in the dietary exposure assessment since they were higher than the ground water values.

Table 5.3. Maximum Screening Drinking Water Exposure Estimates for Proposed Sethoxydim Uses (Based on Sethoxydim Residues of Concern)*
Source (Model)
Use (Maximum Rate)
                             Peak Exposure (μg/L)
                         Annual Mean Exposure (μg/L)
Surface water (SWCC)
                            4 apps @ 0.47 lb ai/A
                             w/ a 14-day interval
                                     65.3
                                      6.6
Ground water (PRZM-GW)

                                     0.565
                                     0.511
Surface water (Provisional Cranberry Model)
                  2 apps @ 0.47 lb ai/A w/ a 14-day interval
                                     79.6
                                     13.9
*Maximum Values in Bold
5.4	Dietary Risk Assessment
      Dietary Exposure Memo, D422745, K. King, 12/16/14

5.4.1	Description of Residue Data Used in Dietary Assessment

The acute and chronic dietary exposure assessments for sethoxydim on food crops used tolerance level residues. The acute and chronic dietary assessments used DEEM-FCID default processing factors to account for processed commodities.

5.4.2	Percent Crop Treated Used in Dietary Assessment

Percent crop treated estimates of most agricultural uses were applied for both acute and chronic dietary assessments.

5.4.3	Acute Dietary Risk Assessment

A partially refined acute dietary risk assessment was conducted using percent crop treated data, but the overall dietary assessment represents high end exposure since high end or bounding residue estimates were used for food and drinking water.  This assessment used tolerance level residues for food, anticipated residues (based on maximum theoretical diets) for livestock commodities, assumed percent crop treated estimates (5/19/14) for most commodities, and screening level EDWCs.  Acute dietary (food and water) risk estimates for the registered and proposed uses of sethoxydim did not exceed HED's level of concern (LOC) for the general U.S. population or any population subgroup.  At the 99.9[th] percentile, the risk estimate was 5.4% of the aPAD for the general U.S. population. The risk estimate for the most highly exposed subgroup, children 1-2 year old, was 8.6% of the aPAD (see Table 5.4.6.).

5.4.4	Chronic Dietary Risk Assessment

A partially refined chronic dietary risk assessment was conducted, which used percent crop treated data (5/19/14), but the overall dietary assessment represents high end exposure because tolerance level residues were used for food and bounding modeled residues for drinking water.  Anticipated residues (based on maximum theoretical diets) were used for livestock commodities.  Chronic dietary (food and water) risk estimates for the proposed uses of sethoxydim did not exceed HED's LOC for the general U.S. population or any population subgroup.  The risk estimate was 7.3% of the cPAD for the general U.S. population. The risk estimate for the most highly exposed subgroup, children 1-2 year old, was 27% of the cPAD (see Table 5.4.6.).

5.4.5	Cancer Dietary Risk Assessment

Sethoxydim is classified as "Not Likely to Be Carcinogenic to Humans" based on lack of evidence of carcinogenicity in rats and mice; therefore, a dietary cancer exposure and risk analysis was not conducted.

5.4.6	Summary Table

Table 5.4.6.  Summary of Dietary Exposure and Risk for Sethoxydim Food and Drinking Water
                              Population Subgroup
                      Acute Dietary (99.9[th] Percentile)
                                Chronic Dietary

                         Dietary Exposure (mg/kg/day)
                                    % aPAD
                         Dietary Exposure (mg/kg/day)
                                    % cPAD
General U.S. Population
                                   0.096428
                                      5.4
                                   0.010161
                                      7.3
All Infants (< 1 year old)
                                   0.131546
                                      7.3
                                   0.024345
                                      17
Children 1-2 years old
                                   0.154424
                                      8.6
                                   0.037948
                                      27
Children 3-5 years old
                                   0.126045
                                      7.0
                                   0.025862
                                      19
Children 6-12 years old
                                   0.070304
                                      3.9
                                   0.014382
                                      10
Youth 13-19 years old
                                   0.055823
                                      3.1
                                   0.007565
                                      5.4
Adults 20-49 years old
                                   0.052940
                                      2.9
                                   0.007779
                                      5.6
Adults 50-99 years old
                                   0.052364
                                      2.9
                                   0.007590
                                      5.4
Females 13-49 years old
                                   0.055974
                                      3.1
                                   0.007405
                                      5.3

The acute and chronic assessments are refined by the use of percent of crop treated information; however, tolerance level residues and modeled drinking water residues are incorporated in the dietary assessment.  Therefore, this dietary assessment represents a high end estimate of potential dietary risks.  HED is confident that the dietary risk is not underestimated.

6.0	Residential (Non-Occupational) Exposure/Risk Characterization
      Occupational/Residential Exposure Memo, S. Tadayon, D422746, 10/30/14

Sethoxydim is registered for use on turf (e.g. golf courses, recreational parks, home lawns, and sod farms) and ornamentals (residential landscape areas). These uses may potentially result in non-occupational residential handler and post-application exposures (inhalation and dermal exposures for adults and post-application dermal, inhalation, and incidental oral exposures to children).  Therefore, non-occupational residential handler and residential post-application exposure assessments have been conducted according to HED's 2012 Residential Standard Operating Procedures (SOPs).  Note that dermal exposures resulting from residential uses are not quantitatively assessed as a dermal toxicity endpoint is not identified for sethoxydim. Only the inhalation and incidental oral exposures are assessed for the proposed residential uses.

6.1	Residential Handler Exposure

The registered uses of sethoxydim on turf and ornamentals in a residential setting by homeowners may result in residential handler (individuals who are involved in the pesticide application process) exposure.  Residential handler exposure is expected to be short-term in duration, as intermediate- or long-term exposures are not likely because of the intermittent nature of applications by homeowners.  Residential handlers are assumed to be wearing short-sleeved shirts, short pants, shoes and socks during application of sethoxydim (i.e., no protective equipment).  The assessments were conducted assuming the maximum application rates and used unit exposure values and estimates for area treated or amount handled, along with algorithms taken from HED's 2012 Residential SOPs.

The quantitative exposure/risk assessment developed for residential handlers is based on the following scenarios:
   * Mixing/Loading/Applying Liquid to Ornamentals and Turf with Hose-End Sprayer
   * Mixing/Loading/Applying Liquid to Ornamentals and Turf with Manually-Pressurized Handwand
   * Mixing/Loading/Applying Liquid to Ornamentals and Turf with Backpack
   * Mixing/Loading/Applying Liquid to Ornamentals an Turf with a Sprinkler Can

Since no dermal hazard was identified for sethoxydim in the toxicological database, only inhalation exposure assessments were conducted for residential handlers.  Inhalation margins of exposure (MOEs) are well above the level of concern (LOC) of 30 for all scenarios assessed and are not of concern (estimated ST inhalation MOEs are >= 150,000).  Short-term inhalation residential handler estimated exposure and risk estimates are shown in Table 6.1 below.

Table 6.1.  Short-Term Non-Occupational Residential Handler Exposure and Risk Estimates for Sethoxydim
                              Exposure Scenario
                               Level of Concern
                      Inhalation Unit Exposure (mg/lb ai)
                          Maximum Application Rate[1]
                    Area Treated or Amount Handled Daily[2]
                                  Inhalation

                              Dose (mg/kg/day)[3]
                                    MOE[4]
                         Emulsifiable Concentrate(EC)
             M/L/A with a Hose-end Sprayer to Turf and Ornamentals
                                      100
                                     0.022
                                 0.47 lb ai/A
                                   0.5 acres
                                   0.000065
                                    410,000
     M/L/A with a Manually Pressurized Handwand to Turf and Ornamentals

                                     0.018
                                0.02 lb ai/gal
                                     5 gal
                                   0.000023
                                   1,200,000
                          M/L/A with a Sprinkler Can

                                     0.022
                            0.011/1000 lb ai/ ft[2]
                                  1000 ft[2]
                                   0.000003
                                   8,800,000
            M/L/A with a backpack sprayer to Turf  and Ornamentals

                                     0.14
                                0.02 lb ai/gal
                                    5gals
                                    0.00018
                                    150,000
1 Based on purposed sethoxydim label.
2 Exposure Science Advisory Council Policy #9.1.
[3] Inhalation Dose = Inhalation Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gallons/day) / BW (80 kg).
[4] Short-Term Inhalation MOE = Short-Term Inhalation NOAEL (mg/kg/day) / Inhalation Dose (mg/kg/day) where NOAEL = HEC (0.932 mg/L) x 1.2 x 11.8 L/hr/kg BW x 2 hr = 26.7 mg/kg/day.

6.2	Post-Application Exposure

There is the potential for post-application exposure to individuals (adults and children), as a result of being in an environment that has been previously treated with sethoxydim.  However, since no dermal hazard was identified in the toxicity database for sethoxydim, a quantitative residential post-application dermal risk assessment is not required and was not completed.  Post-application inhalation exposures while performing activities in previously treated turf or ornamentals are not expected, primarily due to the very low vapor pressure (1.6 x 10[-][7] mm Hg at 25 ºC) and the expected dilution in outdoor air after an application has occurred.  Therefore, post-application inhalation exposures were not assessed.  The residential post-application assessment considers non-dietary incidental oral exposures only.  Residential post-application exposures are generally considered to be intermittent and short-term in duration.

For the residential turf use scenario, post-application incidental oral exposure is assessed for children (1 to < 2 years old as the sentinel population).  The turf use site assessed was residential lawn turf as exposures from that use are expected to be higher than any potential exposures from other turf uses (i.e., recreational parks, golf courses, or treated sod). The assessment was conducted assuming the maximum application rate (0.47 lbs ai/acre). Table 6.2 summarizes the short-term incidental oral exposures and risk estimates resulting from residential post-application exposures.  Children incidental oral MOEs ranged from 25,000 to 11,000,000 on the day of application, using default input values, and are not of concern.

Table 6.2.  Residential Post-Application Short-Term Oral Exposure and Risk Estimates for Sethoxydim
                                   Lifestage
                      Post-application Exposure Scenario
                               Application Rate
                                    Dose[1]
                                    MOEs[2]

                                   Use Site
                              Route of Exposures

                                     Child
                                 Turf - sprays
                                 Hand to Mouth
                                     0.47
                                   0.007157
                                    25,000

                                Object to Mouth

                                   0.0002173
                                    830,000

                           Incidental Soil Ingestion

                                  0.00001591
                                  11,000,000
   1  Hand-to-Mouth = [Hand residue loading (mg/cm[2]) x (fraction hand surface area mouthed/event (0.127/event) x typical surface area of one hand (150 cm[2])) x (exposure time (1.5 hrs/day) x number of replenishment intervals/hr (4 intervals/hr) x (1-(1-saliva extraction factor (0.5)^(number of hand-to-mouth contact events per hour (13.9 events/hr); Hand Residue Loading = (fraction of ai on hands compared to total surface residue from dermal TC study (0.06) x dermal exposure (mg))/typical surface area of one hand (150 cm[2]).
    Object-to-Mouth = ((Object Residue (ug/cm[2]) x CF1 (1.0E-3 mg/ug) x Object Surface Area Mouthed/Event (10 cm[2]/event)) x (Exposure Time (1.5 hrs/day) x #Replenishment Intervals/hr (4)) x (1-((1-Extraction by Saliva (0.48))^(#Object-to-Mouth Events/hr (8.8 events/hr)/# Replenishment intervals/hr))))/Body Weight (11kg).
Soil Ingestion = (Soil Residue (7.0746975 ug/g) x Ingestion Rate (50 mg/kg/day) x CF (0.000001))/Body Weight (11 kg).
 2 MOE = NOAEL/Daily Dose (mg ai/kg/day); Oral NOAEL = 180/kg/day.

6.3 	Residential Risk Estimates for Use in Aggregate Assessment

Table 6.3 reflects the residential risk estimates for use in the sethoxydim aggregate assessment. The scenarios and lifestages resulting in the highest residential exposures are selected for use in the aggregate assessment and are considered protective of other scenario exposures. An aggregate assessment that includes residential scenarios is only needed for short-term exposures as there are no intermediate- or long-term exposures expected from the proposed non-occupational residential uses. The appropriate residential scenarios for the sethoxydim aggregate assessments are: the short-term residential exposure for use in the child aggregate assessment reflects turf post-application hand-to-mouth exposure for children 1 to < 2 years.

Table 6.3.  Residential Exposures for the Sethoxydim Aggregate Assessment.
Lifestage
Exposure Scenario
                              Dose (mg/kg/day)[1]
                                      MOE

                                    Dermal
                                  Inhalation
                                     Oral
                                     Total
                                    Dermal
                                  Inhalation
                                     Oral
                                     Total
Child
Post-Application: Treated Turf
                                      NA
                                      NA
                                 HTM (0.0072)
                                    0.0072
                                      NA
                                      NA
                                    25,000
                                    25,000
1   Dose = the highest dose for each applicable lifestage of all residential scenarios assessed.  Total = dermal + inhalation + incidental oral

6.4	Residential Bystander Post-Application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for sethoxydim at this time primarily because of the very low vapor pressure (1.6 x 10[-][7] mm Hg at 25°C) and low to moderate acute inhalation toxicity (Toxicity Category III).  However, volatilization of pesticides may be a source of post-application inhalation exposure to individuals nearby 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, and received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).

6.5	Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications.  This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom) employed for sethoxydim.  The Agency has been working with the Spray Drift Task Force (a task force composed of various registrants, which was developed as a result of a Data Call-In issued by EPA), 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 more information (http://www.epa.gov/opp00001/factsheets/spraydrift.htm).  The agency has also developed a policy on how to appropriately consider spray drift as a potential source of exposure in risk assessments for pesticides.  The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process, which ensures that all uses for that pesticide will be considered concurrently.  The approach is outlined in the revised (2012) Standard Operating Procedures for Residential Risk Assessment (SOPs) - Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift.  This document outlines the quantification of indirect non-occupational exposure to drift.

Furthermore, residential turf uses were quantitatively assessed as part of this risk assessment; risk estimates addressed in the residential turf assessment provide a worst case estimate of potential exposure from spray drift.  It is noted that the 0.47 lb ai/acre application rate for turf was modeled to estimate post-application residential exposure for children.  As this rate is equal to the maximum agricultural application rate for sethoxydim, the turf scenario for same day contact with directly sprayed lawn turf is protective of any exposure of children via spray drift from agricultural sethoxydim applications.

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 (non-occupational) exposures.  In an aggregate assessment, exposures 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.

Based on the proposed uses of sethoxydim, exposures can occur both from dietary sources (food and water) and in residential settings.  Uses of sethoxydim that may result in residential exposures include turf (such as lawns and golf courses) and residential landscape ornamentals.

The aggregate risk assessments are intended to be representative of exposures that may co-occur.  The scenarios expected to result in the highest exposures are used as representative scenarios for the aggregate assessment and are considered protective of other scenarios. The lifestages selected for the aggregate assessments represent the population subgroups expected to be the most highly exposed for each scenario.  For more information on the residential exposure scenarios selected for aggregate assessment, see Section 6.3 above.

7.1	Acute Aggregate Risk

Typically, HED does not consider residential exposures when assessing acute aggregate risk, unless such exposures can be characterized as a series of single-day exposures, which is not the case for sethoxydim.  Therefore, acute aggregate risk estimates for sethoxydim are equivalent to the acute dietary (food and drinking water) risk estimates (Section 5.4) and are below HED's level of concern.

7.2	Short-Term Aggregate Risk

The short-term aggregate risk for sethoxydim includes background contribution from dietary (food and drinking water) exposure plus the highest short-term residential exposures for children (Table 7.2.1 below). There is no dermal toxicity endpoint; furthermore, the exposures from the oral and inhalation routes result in different toxic effects.  Therefore, only oral exposures are considered in the aggregate assessment.  The short-term aggregate assessment for children includes post-application oral exposure from treated turf and chronic dietary exposure.  The short-term aggregate risk estimate for children is below HED's level of concern.

Table 7.2.1   Short-Term Aggregate Risk Calculations
                                  Population
                     (representative residential scenario)
                             Short- Term Scenario

                           LOC for Aggregate Risk[1]
                                    Dietary
                                    MOE[2]
                       MOE Oral Residential Exposure[3]
                      MOE Inhalation Residential Exposure
                Aggregate MOE (food, water, and residential)[4]
                              Child , 1<2 yrs
                        (Post-application treated turf)
                                      100
                                     4750
                                    25,000
                                      NA
                                     4000
[1] LOC=100 (10x inter- and 10x intra- species uncertainty factors)
[2] MOE dietary = [(short-term oral NOAEL) / (Chronic dietary exposure value from Table 5.4.6)] = 180 / 0.037948 ~ 4750.
[3] MOE oral = [(short-term oral NOAEL) / (hand-to-mouth residential exposure from Table 6.3 (turf))] = 180 / 0.0072 = 25,000
[4] MOE Aggregate = 1 / [(1/MOE dietary) + (1/MOE oral)] = 1 / (0.00021 + 0.00004) = 1 / 0.00025 = 4000

7.3	Intermediate- and Long-Term Aggregate Risk

There are no intermediate- or long term-exposures expected from the proposed non-occupational residential uses of sethoxydim.  Current practice is to include only food and water in the chronic aggregate assessment.  See Section 5.4.4 for a detailed discussion of the chronic dietary assessment.

7.4	Cancer Aggregate Risk

Sethoxydim is classified as "Not Likely to Be Carcinogenic to Humans" based on lack of evidence of carcinogenicity in rats and mice; therefore, a separate cancer assessment was not performed.

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 sethoxydim and any 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 mechanism 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
      Occupational/Residential Exposure Memo, S. Tadayon, 10/30/14

9.1	Short-/Intermediate-Term Handler Risk

Occupational exposure is expected from the registered and proposed uses of sethoxydim on agricultural crops, turf, and ornamentals. The occupational exposure and risk assessment generally addresses risks to workers exposed in an occupational setting via the dermal and inhalation routes of exposure.  However, since no dermal hazard was identified in the toxicity database for sethoxydim, a quantitative dermal assessment is not required, and risks were quantitatively assessed for inhalation exposure only.  Based on registered and the proposed use pattern of sethoxydim, short- and intermediate-term exposures are anticipated for handlers for the following reasons:  (1) the product can be applied at least twice per season, (2) the product can be applied to multiple application sites, and (3) there may be large agribusinesses and/or commercial applicators who may apply a product over a period of a few months.  Long-term exposure is not expected for the proposed use patterns.  Since the same endpoint and point of departure were selected for short- and intermediate-term durations, short-term exposure and risk estimates are considered to be protective of intermediate-term exposure and risk.

Generic default data were used in this assessment as surrogate data in the absence of chemical-specific data, including the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1). Estimates of inhalation exposure were calculated for various levels of personal protective equipment (PPE).  Results are presented for "baseline" level of attire, defined as a single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator.  The sethoxydim product labels direct mixers, loaders, applicators, and other handlers to wear coveralls, long-sleeved shirts, long pants, protective eyewear, chemical-resistant gloves, and shoes plus socks.

All occupational handler scenarios assessed for the proposed uses of sethoxydim resulted in estimated short- and intermediate-term inhalation margins of exposure (MOEs) above the LOC of 30 for all scenarios assessed and, therefore, are not of concern (MOEs >=30). MOEs ranged from 7,000 to 23,000,000.  Occupational handler risk estimates are shown in Table 9.1.

Table 9.1.  Short- and Intermediate-Term Occupational Risk assessment for Sethoxydim
                               Exposure Scenario
                               Crop or Target[a]
                     Baseline Inhalation Unit Exposure[b]
                                    Maximum
                              Application Rate[c]
                    Area Treated or Amount Handled Daily[d]
                              Baseline Inhalation

                                    Dose[e]
                                    MOE[f]

                                   μg/lb ai
                                  lb ai/A or
                                   lb ai/gal
                                 Acres or gals
                                   mg/kg/day
LOC = 100
                     Mixer/Loader Emulsifiable Concentrate
                 Mixing/Loading Liquids for Aerial Application
                            Typical Field Crops[1]
                                     0.219

                                     0.47
                                      350
                                    0.00045
                                    180,000

                            Typical Field Crops[2]

                                     0.28

                                   0.000269
                                    300,000

                          High-Acreage Field Crops[3]

                                     0.47

                                     1200
                                    0.00155
                                    52,000

                          High-Acreage Field Crops[4]

                                     0.28

                                    0.00092
                                    87,000
                          Mixing/Loading Liquids for
                                  Chemigation
                            Typical Field Crops[1]

                                     0.47

                                      350
                                    0.00045
                                    180,000

                            Typical Field Crops[2]

                                     0.28

                                   0.000269
                                    300,000

                          High-Acreage Field Crops[3]

                                     0.47

                                    0.00045
                                    180,000

                          High-Acreage Field Crops[4]

                                     0.28

                                   0.000269
                                    300,000

                                Nursery Plants

                                     0.47
                                      60
                                   0.0000773
                                   1,000,000
               Mixing/Loading Liquids for Groundboom Application
                      Golf Courses (tees and greens only)

                                     0.47
                                       5
                                  0.00000644
                                   1,200,000

                   Golf Courses (fairways, tees, and greens)

                                     0.47
                                      40
                                   0.0000515
                                   1,600,000

                            Typical Field Crops[1]

                                     0.47
                                      80
                                   0.000103
                                    780.000

                            Typical Field Crops[2]

                                     0.28

                                   0.0000614
                                   1,300,000

                          High-Acreage Field Crops[3]

                                     0.47
                                      200
                                   0.000258
                                    310,000

                          High-Acreage Field Crops[4]

                                     0.28

                                   0.000154
                                    520,000
                                  Applicator
                    Applying Sprays for Aerial Application
                            Typical Field Crops[1]
                                    0.0049

                                     0.47
                                      350
                                   0.0000101
                                  14,000,000

                            Typical Field Crops[2]

                                     0.28

                                   0.000006
                                  23,000,000

                          High-Acreage Field Crops[3]

                                     0.47

                                     1200
                                   0.0000345
                                   4,000,000

                          High-Acreage Field Crops[4]

                                     0.28

                                   0.0000206
                                   6,700,000
                  Applying Sprays for Groundboom Application
                      Golf Courses (tees and greens only)
                                     0.34
                                     0.47
                                       5
                                   0.0000099
                                   4,000,000

                   Golf Courses (fairways, tees, and greens)

                                     0.47
                                      40
                                   0.0000799
                                    500,000

                            Typical Field Crops[1]

                                     0.47
                                      80
                                    0.00016
                                    250,000

                            Typical Field Crops[2]

                                     0.28

                                   0.0000953
                                    420,000

                          High-Acreage Field Crops[3]

                                     0.47

                                      200
                                    0.0004
                                    99,000

                          High-Acreage Field Crops[4]

                                     0.28

                                    0.00238
                                    170,000

                           Orchard (Ground/Soil)[5]

                                     0.47
                                      40
                                   0.0000799
                                    500,000
                                    Flagger
                       Flagging for Aerial Applications
                        Typical Field Crops[1][&3]
                                     0.35
                                     0.47
                                      350
                                    0.00072
                                    190,000

                        Typical Field Crops[2][&4]

                                     0.28

                                   0.000429
                                    320,000
                            Mixer/Loader/Applicator
                      M/L/A Liquids for Backpack Sprayers
Rights-of-way (e.g., utilities, railroad, roadways), Nursery (ornamentals, vegetables, trees, container stock), Landscaping, turf (lawns, athletic fields, parks, etc.)
                                     2.58
                                     0.02
                                  lb ai/gal)

                                      40
                                    gallons
                                   0.000026
                                   3,100,000
           M/L/A Liquids for Manually-Pressurized Handwand Sprayers
Structural (e.g., bridges, shipyards, home decks, foundations), Industrial/commercial (tires, rail yards, junk yards, etc.), Landscaping, turf (lawns, athletic fields, parks, etc.)

                                      30

                                    0.0003
                                    460,000
          M/L/A Liquids for Mechanically-Pressurized Handgun Sprayers
Structural (e.g., bridges, shipyards, home decks, foundations), Typical Field Crops[1&2], Orchard Crops[5]
                                      3.9

                                     1000
                                    gallons
                                   0.000975
                                    140,000

        Structural (e.g., bridges, shipyards, home decks, foundations)
                                      79

                                    0.0198
                                     7,000

Golf course (tees and greens only), Golf course (fairways, tees, greens), Landscaping, turf (lawns, athletic fields, parks, etc.)
                                      1.9
                                     0.47
                                       5
                                     acres
                                   0.0000559
                                   1,400,000
[1] Typical Field Crops at 0.47 lb ai/A or 0.02 lb ai/gal.
Arracacia Arrowroot, Artichoke, Asparagus, Blackberry, Blueberry, Canola, Crambe, Cranberry, Fine Fescue Grasses, Ginger, Grape
Horseradish, Lentils, Loganberry, Peppermint/Spearmint, Peas, Raspberry (Black - Red), Sainfoin, Sewage Disposal Areas, Strawberry, Sugar
Beet, Sunflower, Sweet Potato, Taro, Turmeric, Yam, Youngberry.

[2] Typical Field Crops at 0.28 lb ai/A.
Amaranth, Broccoli, Brussels Sprouts, Cabbage, Cardoon, Cauliflower, Celery, Celtuce, Chard -  Swiss, Collards, Corn Salad, Cress, Cucumber, Dandelion, Eggplant, Endive, Fennel, Flax, Garlic, Gherkin, Groundcherry, Kale, Kohlrabi, Leek, Lettuce -  Head, Lettuce -  Leaf, Manioc, Melons, Mustard, Onions (Green),  Ornamental Lawns And Turf, Parsley, Peanuts, Pepino, Pepper, Pumpkin, Rhubarb, Roquette, Shallot, Spinach, Squash, Tomatillo, Tomato

[3] High-Acreage Field Crop at 0.47 lb ai/A or 0.02 lb ai/gal
Alfalfa, Beans, Clover, Cotton, Mint, Potato , Soybeans

[4] High-Acreage Field Crop at 0.28 lb ai/A or 0.02 lb ai/gal
Field corn, sweet corn

[5] Orchard Crops
Almond, Apple, Apricot, Avocado, Cherry, Christmas Tree Plantations, Citrus, Crabapple, Date, Fig, Grapefruit, Grapes, Lemon, Lime, Macadamia nuts, Nectarine, Olive, Orange, Peach, Pear, Pecan, Pistachio, Plum, Pomegranate, Prune, Quince,  Tangelo, Tangerines Tree Nuts, Walnut.

a	Crop or Target
b	Based on the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (March 2012); Level of mitigation = Baseline.
c	Based on the maximum application rates on the proposed labels (Reg. Nos 228-619, 7969-56 (technical), 7969-58, 7969-58, 7969-88, 7969-194, 7969-294 (technical) and 7969-317.  See Table 4.1).
d	Exposure Science Advisory Council Policy #9.1.
e	Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated or Amount  Handled Daily (A or gal/day) / BW (80kg).
f	Short-term and intermediate-term Inhalation MOE =  Inhalation HED (Human Equivalent Dose (39.8,80,139 ) mg/kg/day / Inhalation Dose (mg/kg/day).

9.2	Short-/Intermediate-Term Post-Application Risk

9.2.1	Dermal Post-Application Risk

There is the potential for post-application exposure to workers as a result of proposed uses of sethoxydim.  However, since no dermal hazard was identified in the toxicity database for sethoxydim, a quantitative occupational post-application dermal risk assessment is not required and was not completed.

9.2.2	Inhalation Post-Application Risk

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for sethoxydim at this time primarily because of very low vapor pressure (1.6 x 10[-][7] mm Hg @ 25 ºC), the low to moderate acute inhalation toxicity (Toxicity Category III), and the low proposed use rate (<= 0.47 lb ai/A).  However, there are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated fields.  These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides.  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, and received the SAP's final report on March 2, 2010. The Agency is in the process of evaluating the SAP report. In addition, the Agency is continuing to evaluate the available post-application inhalation exposure data generated by the Agricultural Reentry Task Force.  Given these two efforts, the Agency will continue to identify the need for and, subsequently, the method to incorporate occupational post-application inhalation exposure into the agency's risk assessments.

In addition, the Agency is continuing to evaluate the available post-application inhalation exposure data generated by the Agricultural Reentry Task Force.  Given these two efforts, the Agency will continue to identify the need for and, subsequently, the method to incorporate occupational post-application inhalation exposure into the agency's risk assessments.

Although a quantitative occupational post-application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers.  Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post-application exposure.  Therefore, it is expected that these handler inhalation exposure estimates would be protective of occupational post-application inhalation exposure scenarios.  Since there are no risks of concern for occupational handlers, there are no risks of concern for post-application workers.

The Worker Protection Standard for Agricultural Pesticides contains requirements for protecting workers from inhalation exposures during and after greenhouse applications through the use of ventilation requirements.[40 CFR 170.110, (3) (Restrictions associated with pesticide applications)].

9.2.3	Restricted Entry Interval

 The REI specified on the proposed labels is based on the acute toxicity of sethoxydim.  Sethoxydim is classified as Toxicity Category III via the dermal route and Toxicity Category IV for skin irritation potential.  It is not a dermal sensitizer.  Occupational short- and intermediate-term post-application risk estimates were not evaluated for sethoxydim.  Under 40 CFR 156.208 (c) (2) (iii), ai's classified as Acute III for acute dermal, eye irritation and primary skin irrigation are assigned a 12-hour REI.  Therefore, the [156 subpart K] Worker Protection Statement interim REI of 12 hours is adequate to protect agricultural workers from post-application exposures to sethoxydim.

10.0	References

Assaad, A. and Bonner, M.  03/19/2003.  TXR# 0051694.  SETHOXYDIM - Second Report of the Hazard Identification Assessment Review Committee.

Cheng, L.  04/04/97.  Sethoxydim.  Case 2600.  Phase V Review of Soybeans, Tomatoes, Goats, and Poultry Metabolism Studies.  CBRS17851.  DP Barcode: None.

Donovan, W. H.  04/22/2005.  Sethoxydim.  HED Chemistry Chapter of the Reregistration Eligibility Decision (RED).  Summary of Analytical Chemistry and Residue Data.  Case No. 2600.

Drew, D.  3/30/05.  D312569.  Sethoxydim:  HED Chapter of the Reregistration Eligibility Decision (RED) Document.

King, K. 12/16/14. D422745. Sethoxydim. Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Proposed Uses on Highbush Blueberry and Fescue Grass as well as registration review for all registered crops and updating crop group and sub-groups for Sethoxydim.

Knizner, S.  05/27/09.  Interim Guidance on Tolerance Expressions.

Leshin, Jonathan.  12/xx/15.  TXR# 0057805.  Sethoxydim: Summary of Hazard and Science Policy Council (HASPOC) Meeting of October 23, 2014:  Recommendation on the Requirements for Acute Neurotoxicity and Immunotoxicity Studies.

Lin, J.  06/25/14. Sethoxydim: Drinking Water Exposure Assessment for IR-4 Petition on Fescue, Oilseeds, Fruits, and Vegetables.

Loranger, R.  05/27/98.  Sethoxydim.  Conclusions of the 5/14/98 Meeting of the Metabloism Assessment Review Committee.

Savoia, P.  12/18/2014.  Sethoxydim.  Section 3 Registration for Grass Grown for Seed; Request for an Amended Use on Blueberry; Crop Group Conversions; Group 3 to Group 3-07, Group 8 to Group 8-10, Group 10 to Group 10-10, Group 11 to Group 11-10; and Crop Subgroup Conversions: Caneberry to Subgroup 13-07A, Blueberry to Subgroup 13-07B, Grape to Subgroup 13-07F Except Fuzzy Kiwifruit, Strawberry to Subgroup 13-07G Except Cranberry, Cranberry to Subgroup 13-07H, Canola Seed to Subgroup 20A, Sunflower Seed to Subgroup 20B Except Safflower, and Cotton Undelinted Seed to Subgroup 20C.  Summary of Analytical Chemistry and Residue Data.

Soderberg, D.  04/12/12.  Sethoxydim: Submission of a Study of Residues on Safflower in Response to a RED Data Gap Requirement.

Tadayan, S.  10/30/14.  Sethoxydim:  Occupational and Residential Exposure and Risk Assessment for Registration Review and to Support the Registration of Proposed Uses on High Bush Blueberry and Fine Fescue Grasses.

Appendix A.  Toxicology Profile and Executive Summaries

A.1	Toxicology Data Requirements
The requirements (40 CFR 158.340) for food-use for sethoxydim are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

                                     Study
                                   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 (rodent)
870.3150    Oral Subchronic (nonrodent)
870.3200    28-Day Dermal
870.3250    90-Day Dermal
870.3465    28-Day Inhalation
                                      yes
                                      yes
                                      yes
                                      no
                                      yes
                                      yes
                                      yes
                                      yes
                                     yes a
                                      yes
870.3700a  Developmental Toxicity (rodent)
870.3700b  Developmental Toxicity (nonrodent)
870.3800    Reproduction
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.4100a  Chronic Toxicity (rodent)
870.4100b  Chronic Toxicity (nonrodent)
870.4200a  Oncogenicity (rat)
870.4200b  Oncogenicity (mouse)
870.4300    Chronic toxicity/carcinogenicity (rat)
                                      yes
                                      no
                                      yes
                                      yes
                                      yes
                                      yes
                                       -
                                      yes
                                      yes
                                      yes
870.5100    Mutagenicity -- Bacterial reverse mutation assay
870.5300    Mutagenicity -- In vitro mammalian cell gene mutation test
870.5550    Mutagenicity -- Unscheduled DNA synthesis in mammalian cells
870.5915    Mutagenicity -- In vivo sister chromatid exchange assay
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
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
                                      no
                                      no
                                      yes
                                      yes
                                      no
                                       -
                                       -
                                     yes b
                                      yes
                                       -
870.7485    General Metabolism
870.7600    Dermal Penetration
870.7800    Immunotoxicity
                                      yes
                                      no
                                      yes
                                      yes
                                       -
                                     yes b
[a] Test was not submitted nor required based on the results from the 28-day dermal toxicity test.
b A waiver for this study was obtained from HASPOC (Leshin, 2015, TXR# 0057805).

A.2	Toxicity Profiles

Table A.2.1	Acute Toxicity Profile - Sethoxydim
Guideline No.
Study Type
                                     MRID
                                    Results
                               Toxicity Category
870.1100
Acute oral (rats)
                                   00045847
LD50 = M: 3125 mg/kg
            F: 2676 mg/kg
                                      III
870.1200
Acute dermal (rats)
                                   00045848
LD50 = > 5000 mg/kg
                                      III
870.1300
Acute inhalation (rats)
                                   00045849
     LC50 = M: 6.03 mg/L
                 F: 6.28 mg/L
Aerosol composed of
NP-55  (25%), DMSO (75%)
                                      III
870.2400
Acute eye irritation (rabbits)
                                   00045850
No Irritation
                                      IV
870.2500
Acute dermal irritation (rabbits)
                                   00045851
No Irritation
                                      IV
870.2600
Skin sensitization (guinea pigs)
                                   00045852
Study waived based on lack of sensitization in guinea pigs treated with the formulation (Poast).

Table A.2.2	Subchronic, Chronic and Other Toxicity Profile - Sethoxydim
Guideline No.
Study Type
MRID No. (year)/ Classification /Doses
Results
870.3100

90-Day oral toxicity (rat)
00045859 (1978)
Acceptable, guideline
♂♀: 0, 33, 100, 300, 900, 2700 ppm
♂: 0, 2, 7, 20, 60,
196 mg/kg/day
♀: 0, 2, 7, 21, 66, 201 mg/kg/day
NOAEL = 60
LOAEL = 196 mg/kg/day based on decreases in body weight, body weight gain, and food efficiency
870.3100

90-Day oral toxicity (mouse)
00045858 (1978)
Acceptable, guideline
♂♀: 0, 100, 300, 900, 2700 ppm
♂: 0, 15, 46, 137, 374 mg/kg/day
♀: 0, 17, 53, 164, 486 mg/kg/day
NOAEL = 46 mg/kg/day
LOAEL = 137 mg/kg/day based on increased liver weight in both sexes and swollen liver cells in males

At 374/486 mg/kg/day, the findings became more severe and increased incidence of swollen liver cells were noted in both sexes.  Additional adverse findings were not observed.
870.3150

90-Day oral toxicity (dog; 26-week)
00045860 (1980)
Unacceptable, guideline
♂♀: 0, 120, 600, 3000  ppm
♂: 0, 4, 19, 89 mg/kg/day
♀: 0, 3, 17, 86 mg/kg/day
NOAEL was not determined
LOAEL = 3 mg/kg/day based on cystitis of the urinary bladder
The dogs were fed the formulated diet (concentrations deviated widely from nominal) once weekly for six weeks, then twice weekly for the remaining 26-week period.  Effects were not consistent with the acceptable chronic toxicity study in dogs.
870.3200

21-Day dermal toxicity (rabbit)
41987203 (1991)
Acceptable, guideline
♂♀: 0, 40, 200, 1000 mg/kg/day
NOAEL = 1000 mg/kg/day
LOAEL was not determined
870.3250

90-Day dermal toxicity (species)
Not submitted
-
870.3465

28-Day inhalation toxicity (rat)
44021202 (1993)
Acceptable, non-guideline
♂♀: 0, 0.04, 0.3, and 2.4 mg/L
NOAEL = 0.3 mg/L (81mg/kg/day)
LOAEL of 2.4 mg/L (651 mg/kg/day) based on increased liver weight, increased serum total bilirubin, and increased incidence of slight centrilobular hepatocyte swelling
870.3700a

Prenatal developmental (rat)
43092902 (1993)
Acceptable, guideline
♂♀: 0, 50, 180, 650, 1000 mg/kg/day
Maternal NOAEL = 180 mg/kg/day
LOAEL = 650 mg/kg/day based on irregular gait, decreased activity, excessive salivation, and anogenital staining
↓BW was noted at 1000 mg/kg/day.
Developmental NOAEL = 180 mg/kg/day
LOAEL = 650 mg/kg/day based on 21-22% decrease in fetal weights, filamentous tail and lack of tail due to the absence of sacral and/or  caudal vertebrae, and delayed ossification in the hyoids, vertebral centrum  and/or  transverse processes, sternebrae and/or  metatarsals, and pubes
870.3700b

Prenatal developmental (rabbit)
43092901 (1993)
Acceptable, non-guideline
♂♀: 0, 80, 160, 320, 400 mg/kg/day
Maternal NOAEL = 400 mg/kg/day
LOAEL was not determined
Developmental NOAEL = 320 mg/kg/day
LOAEL = 400 mg/kg/day based on an increase in the incidence of incompletely ossified 6th sternebrae
870.3800

Reproduction and fertility effects (rat)
41510606, 43366401 (1983)
Acceptable, non-guideline
♂♀: 0, 150, 600, 3000 ppm
♂♀: 0, 7.5, 30, 150 mg/kg/day

Parental/Systemic NOAEL = 150 mg/kg/day
LOAEL was not determined
Reproductive NOAEL = 150 mg/kg/day
LOAEL was not determined
Offspring NOAEL = 30 mg/kg/day
LOAEL = 150 mg/kg/day based on decreased pup weight in F1a, F1b, and F2b during lactation (↓11-13%)
870.4100a

Chronic toxicity (rat)
Not submitted. See 870.4300.
-
870.4100b

Chronic toxicity (dog)
00152669 (1984)
Acceptable, non-guideline
♂♀: 0, 300, 600, 3600 ppm
♂: 0, 9, 18, 110 mg/kg/day
♀: 0, 9, 20, 129 mg/kg/day
NOAEL = 18 mg/kg/day
LOAEL = 110 mg/kg/day based on increased hemosiderosis in the spleen and depressed myeloid erythropoiesis in the sternal bone marrow, increased absolute and relative liver weights, increased alkaline phosphatase and ALT levels
870.4200a

Carcinogenicity (rat)
Not submitted. See 870.4300.
-
870.4300a

Combined Chronic/ Carcinogenicity (rats)
43939101 (1995)
Acceptable, guideline
♂♀: 0, 264,1000, 3000  ppm
♂: 0, 12, 48, 143 mg/kg/day
♀: 0, 17, 66, 204 mg/kg/day
NOAEL = 48 mg/kg/day