
                 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

5.1.1.1	 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).


5.1.1.2	 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
LOAEL = 143 mg/kg/day based on decreased body weights in females, increased serum total bilirubin in both sexes, increased incidences of eosinophilic foci in livers in males, centrilobular hypertrophy in both sexes, centrilobular fatty infiltration in males, interstitial fibrosis in the lungs in females, and heart failure cells in lungs in both sexes
No evidence of carcinogenicity
870.4300b

Combined Chronic/ Carcinogenicity (mouse)
00100527 (1981)
Acceptable, guideline
♂♀: 0, 40, 120, 360, or 1080 ppm 
♂: 0, 5, 14, 41, 134 mg/kg/day
♀: 0, 5, 15, 44, 143 mg/kg/day
NOAEL = 14 mg/kg/day
LOAEL = 41 mg/kg/day based on hepatocellular hypertrophy and liver fatty degeneration in males
At 134/143 mg/kg/day (♂/♀): in males - ↓BW, ↑ liver weight, ↑ALT, ↑AST, hepatocellular hypertrophy, focal granulomatous inflammation, fatty degeneration in liver; in females - ↑ liver weight, fatty degeneration in liver
No evidence of carcinogenicity
870.5100 

Genotoxicity
Bacterial gene mutation assay
00153604
Acceptable, guideline

Negative
870.5100 

Genotoxicity
Bacterial gene mutation assay
41885904
Acceptable, guideline
Concentrations of 313-5000 ug/mL
Negative
870.5100 

Genotoxicity
Bacterial gene mutation assay
41915901
Acceptable, guideline
Concentrations of 312-5000 ug/mL
Negative
870.5300 

Genotoxicity
In vitro mammalian cell gene mutation 
00155130 
Unacceptable, guideline
Highest dose tested: 5000 ug/mL
Negative
This report was lacking a description of the procedures actually used in performing this study.
870.5300 

Genotoxicity
In vitro mammalian cell gene mutation 
41421301
Acceptable, guideline
Concentrations of 500-5000 ug/mL
Negative
870.5300 

Genotoxicity
In vitro mammalian cell gene mutation 
00130710 
Acceptable, guideline
Highest dose tested: 10,000 mg/kg
Negative
870.5300 

Genotoxicity
In vitro mammalian cell gene mutation 
00138950
Acceptable, guideline

Negative
870.5550 

Genotoxicity
Unscheduled DNA synthesis (rat hepatocyte cells) 
41885905
Acceptable, guideline
Concentrations of 10-507 ug/mL
Negative
870.5915 

Genotoxicity
In vivo sister chromatid exchange (Chinese hamster bone marrow)
41475206
Acceptable, guideline
0, 0.5, 1.67, 5 g/kg
Negative
870.6200a

Acute neurotoxicity screening battery
Not submitted and not required.
-
870.6200b

Subchronic neurotoxicity screening battery
46845301 (2006)
Acceptable, non-guideline
♂♀: 0, 300, 980, 3200 ppm
♂: 0, 18.4, 59.3, 206.9 mg/kg/day
♀: 0, 22.2, 72.0, 234.3 mg/kg/day
NOAEL = 206.9 mg/kg/day
LOAEL was not determined
870.6300

Developmental neurotoxicity
Not submitted and not required
-
870.7485

Metabolism and pharmacokinetics (rat)
00045868 (1980)
00153605 (1985)
Acceptable, guideline

Excretion is extremely rapid and tissue accumulation is negligible, assuming DMSO vehicle does not affect excretion or storage of sethoxydim, 78% excreted into urine and 20% in feces. Administration of radioactively labeled sethoxydim yielded 0.8% radioactivity in urine identified as three hydroxymetabolites.
870.7600
Dermal penetration (species)
Not submitted and not required.
-
870.7800
Immunotoxicity
Not submitted and not required.
-


A.3	Hazard Identification and Endpoint Selection

A.3.1	Acute Reference Dose (aRfD)  -  All Populations

Study selected: Prenatal developmental study in rats 
MRID No.:  43092902
Executive Summary:  See Appendix A.4, Guideline OPPTS 870.3700a
Dose and Endpoint for Risk Assessment:  Maternal NOAEL = 180 mg/kg/day; LOAEL = 650 mg/kg/day based on irregular gait that was observed in 12/34 dams on the first day of dosing
Developmental NOAEL = 180 mg/kg/day; LOAEL = 650 mg/kg/day based on decreased fetal body weight, tail abnormalities, and delayed ossification
Comments about Study/Endpoint/Uncertainty Factors:  The selected endpoints are the lowest values for this exposure scenario and are the most protective.  The fetal anomalies are presumed to occur following a single dose in utero and, thus, this endpoint would be applicable to females 13-50 years of age.  A 100-fold uncertainty factor (10X interspecies and 10X intraspecies) was applied.  Thus, an aRfD of 1.8 mg/kg/day was calculated for all populations.  The FQPA SF is 1X; therefore, the aPAD is also 1.8 mg/kg/day. 


A.3.2	Chronic Reference Dose (cRfD)

Study selected: Carcinogenicity study in mice 
MRID No.:  00100527
Executive Summary:  See Appendix A.4, Guideline OPPTS 870.4200b
Dose and Endpoint for Risk Assessment:  NOAEL = 14 mg/kg/day; LOAEL = 41 mg/kg/day based on liver hypertrophy and fatty degeneration 
Comments about Study/Endpoint/Uncertainty Factors:  The selected endpoints are the lowest values for this exposure scenario and are the most protective.  A 100-fold uncertainty factor (10X interspecies and 10X intraspecies) was applied.  Thus, a cRfD of 0.14 mg/kg/day was calculated.  The FQPA SF is 1X; therefore, the cPAD is also 0.14 mg/kg/day. 

A.3.3	Incidental Oral Exposure (Short-Term)

Short-Term (1-30 days)

Study selected: Prenatal developmental study in rats 
MRID No.:  43092902
Executive Summary:  See Appendix A.4, Guideline OPPTS 870.3700a
Dose and Endpoint for Risk Assessment:  Maternal LOAEL = 650 mg/kg/day based on irregular gait that was observed in 12/34 dams on the first day of dosing
Developmental LOAEL = 650 mg/kg/day based on decreased fetal body weight, tail abnormalities, and delayed ossification
Comments about Study/Endpoint/Uncertainty Factors:  The selected endpoints are the lowest values for this exposure scenario and are the most protective.  The fetal anomalies are presumed to occur following a single dose in utero and, thus, this endpoint would be applicable to females 13-50 years of age.  A 100-fold uncertainty factor (10X interspecies and 10X intraspecies) was applied.  The FQPA SF is 1X.  The residential level of concern for MOE = 100; an occupational LOC is not appropriate for this exposure scenario.

Intermediate-Term (1-6 Months)

Study Selected: No study was selected, because intermediate-term exposure is not anticipated.

A.3.4	Dermal Exposure (Short-, Intermediate-, and Long-Term)

The HIARC concluded that for all durations of dermal exposure, quantification of non-cancer risk is not required.  No dermal or systemic toxicity was seen following repeated dermal applications at the limit dose (1000 mg/kg/day) in rabbits.  Developmental toxicity occurred at the same dose as maternal toxicity in the rat.  Incomplete ossification of the 6[th] sternebrae was noted in rabbit fetuses at 400 mg/kg/day (the highest dose tested), while no adverse effect was noted in the dams at that dose level. 

Dermal Absorption Factor:  A dermal absorption factor was not determined, because a dermal assessment is not required for sethoxydim, and there is no evidence of carcinogenicity or genotoxicity.

A.3.5	Inhalation Exposure (Short- and Intermediate-Term)

Study selected: 28-Day inhalation study in rats 
MRID No.:  44021202
Executive Summary:  See Appendix A.4, Guideline OPPTS 870.3465
Dose and Endpoint for Risk Assessment:  NOAEL = 0.3 mg/L; LOAEL = 2.4 mg/L based on increased liver weight, increased total serum bilirubin, and increased incidence of slight centrilobular hepatocyte swelling
Comments about Study/Endpoint/Uncertainty Factors:  The dose/endpoint is derived from a study conducted via the appropriate route of concern.  This study was the only inhalation study available, and the HED gives a more protective value than the oral studies.  


A.4	Executive Summaries

Executive Summaries are provided below for the studies used in the sethoxydim risk assessment, as well as some other sethoxydim toxicity studies.  Executive Summaries may be available for some of the other guidelines, but not reported here.  However, many of the studies are old and in some cases the Executive Summaries could not be located and in other cases existed in a very truncated form (Tox One-Liners) or in an atypical format.

A.4.1	Subchronic Toxicity

	870.3100	90-Day Oral Toxicity - Rat

MRID 00045859: Protocol: Six groups of six week old Wistar-SLC rats, each group consisting of 20 males and 20 females were fed a diet containing technical NP-55 dissolved in acetone to make the following doses administered for 14 weeks: 2700 ppm, 900 ppm, 300 ppm, 100 ppm, 33 ppm and 0 ppm. Mean NP-55 intakes over the study period in mg/kg/day were as follows for males and females respectively: 196.34 and 200.45 (2700 ppm group), 60.43 and 66.8 (900 ppm group), 20.12 and 21.43 (300 ppm group), 6.75 and 7.08 (100 ppm group), 2.25 and 2.42 (33 ppm group). The 0 ppm group was the vehicle control group (acetone added to diet), Animals were observed daily for mortalities, pharmacotoxic symptoms, physiological changes and central nervous system effects. Body weights were measured weekly. Food consumption was estimated weekly for 4 weeks and biweekly thereafter. Water consumption estimates, urinalysis, hematology tests were done at 4 and 14 weeks. For urinalysis, 10 males and 10 females from each group were tested. For hematology 8 males and 8 females from each group were tested. Blood chemistry, gross necropsies, organ weights and histopathologies were performed on all surviving animals at 14 weeks.

Resu1ts: No mortalities occurred in any groups and no pharmacotoxic signs were observed over the 14 week test period. Total weight gains for the 2700 ppm group were significantly retarded (p < 0.001} but other dosage groups were similar to controls. Food consumption in the 2700 ppm group was depressed but of other groups was similar to controls. Control and experimental groups water consumption were similar. On hematological examination, mean corpuscular hemoglobin decreased for 100 ppm males and increased for females of 100 ppm and 2700 ppm groups. Platelet increases occurred for 100 ppm females, 900 ppm ma1es and females, and 2700 ppm males. Total leucocytes increased in 2700 ppm males and females. Urinalysis showed no significant differences between controls and experimentals. The following differences in blood chemistries between experimentals and controls were noted: protein increased in 33 ppm females, 300 ppm males and females and 2700 ppm males. Albumin increased in 33 ppm and 300 ppm males, but decreased in 300 ppm, 900 ppm and 2700 ppm females. Glutamic pyruvic transaminase decreased in the 2700 ppm group. Alkaline phosphatase decreased in 900 ppm and 2700 ppm females. Glucose decreased in 2700 ppm females. Bilirubin increased in 900 and 2700 ppm groups. Total cholesterol increased in 100 ppm females, 900 ppm males and all of 2700 ppm group. Total calcium increased in 33 ppm males and decreased in 300, 900, and 2700 ppm females.

At gross necropsy, random changes seen in organs of experimentals and controls included thymus petichia, lung, stomach, small intestine and testes changes. Organ weights of liver were increased at high doses, but to a significant level in 900 ppm males and 2700 ppm females. In
2700 ppm males, heart, lung, spleen, kidney and adrenals were significantly decreased in weight. In 2700 ppm females, lung, spleen and adrenals were significantly decreased in weights. Organ/body weight ratios differed from controls as follows: livers of 900 ppm groups and
2700 ppm groups were larger. Brain was larger in the 2700 ppm group, but spleen was smaller. Thymus of females in the 2700 ppm group was smaller. On histopathological examinations, pathological changes were observed in heart, lungs, kidneys, testes and thymus, but were not NP-55 related. However, swollen liver cells at incidences of 100% and 25% in 2700 ppm males and females respectively and at 60% incidence in 900 ppm males were attributable to NP-55 treatment. Such hepatic abnormalities were considered responsible for growth retardation, decreased food efficiency and increased serum cholesterol and bilirubin. The target organ of NP-55 is considered the liver with a no effect leve1 of NP-55 at 300 ppm.

Adverse Effects: The liver at greater than 300 ppm is the target organ for NP-55 in the rat. Associated effects are increases 1n cholesterol and bilirubin and increase in size and organ/body weight ratio of the liver, with swollen cells as histopathological findings.

NOEL = 300 ppm
Core Study - Guidelines.


	870.3100	90-Day Oral Toxicity - Mouse

MRID 00045858: In a 14-week (98-day) oral toxicity study (MRID 00045858) NP-55 (95.9%
a.i., lot #PN-1-1) was administered to 20 ICR mice/sex/dose in the diet at levels of 0, 100, 300,
900, or 2700 ppm (equivalent to 0, 15.4, 45.6, 137.1, or 373.6 mg/kg bw/day for males and 0,
17.2, 52.7, 164.4, or 486.3 mg/kg bw/day for females).

There were no compound-related effects on mortality, clinical signs, body weight, food consumption, hematology, clinical chemistry, or gross pathology. Absolute liver weights of males in the 900 and 2700 ppm groups and of females in the 2700 ppm group were increased by 13 and 33% (both, p<0.01l) and 32% (non-significant), respectively. Hepatocellular hypertrophy was observed microscopically in the livers of these dose groups. Liver weights relative to body weights were also significantly increased in both males and females in the 900 and 2700 ppm dietary groups. The increased liver weights accompanied by histopathological evidence hepatocellular changes are considered treatment-related effects.

The NOAEL for NP-55 in mice is 300 ppm in the diet (males, 45.6 mg/kg/day; females, 52.7 mg/kg/day). The LOAEL is 900 ppm (males, 137.1 mg/kg/day; females, 164.4 mg/kg/day) based on increase liver weight and histopathological evidence of hepatocellular hypertrophy.

This 98-day oral toxicity study in the mouse is Acceptable/Guideline and satisfies the guideline requirement for a 90-day oral toxicity study (OPPTS 870.3100; OECD 408) in the rodent. Although many guideline requirements/recommendations were not fulfilled, these were generally minor deviations that did not impact the results of the study.

	870.3150	90-Day Oral Toxicity - Dog

MRID 00045860: Protocol: Four groups of male beagle dogs (Hazelton Research Animals Inc., Cumberland, Va.) aged 30-34 weeks, weighing between 6.7-13.7 kg, each group consisting of 6 animals, were fed Wayne(R) dog meal containing the following amounts of technical NP-55 for a period of 26 weeks: 0 ppm (control): 120 ppm (3.0 mg/kg/day); 600 ppm (15.0 mg/kg/day) and 3000 ppm (75.0 mg/kg/day). Four similar groups of female dogs weighing between 5.4-11.6 kg were similarly fed for 26 weeks. Appropriate diet was fed once weekly for the first six weeks and twice weekly thereafter, and was available ad libitum. All dogs were observed daily for mortality and signs of pharmacotoxic effects for the first 2 weeks and weekly thereafter. If clinical signs were seen, observations were made daily thereafter. Body weights and food consumption were recorded weekly to week 6 and twice weekly thereafter. Clinical chemistry, hematology and urinalysis were performed on all dogs prior to treatment and at weeks 4. 8, 13 and 26. Blood was collected by jugular puncture. Urine was collected from cage floor runoff except for phenolsulphonthalene determination for which urine was collected by catheterization. Hematology studies included hematocrit, hemoglobin, erythrocyte and platelet counts, total and differential leucocyte counts, mean corpuscular volume, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration. Clinical chemistry tests included total protein, albumin, alkaline phosphatase, total and direct bilirubin, blood urea nitrogen, calcium, lactic acid dehydrogenase, bromosulphalen dye retention. phenolsulfonphthalen dye excretion, fasting glucose, serum glutamic pyruvic transaminase, serum glutamate- oxaloacetic transaminase, total globulin, albumin/globulin ratio, potassium and total cholesterol. Urinalysis included appearance, pH, specific gravity, glucose, ketones, total protein, bilirubin, urobilinogen, reducing substances and microscopic examination of sediment. Opthalmoscopic examinations were performed initially and terminally on all dogs with an indirect opthalmoscope and a hand held slit limp, using a mydriatic. Surviving dogs were sacrificed after 26 weeks by exsanguination while under the effect of Surital(R) anesthesia. Complete necropsies were done on all dogs and included total body weight measurement and organ/body weight ratio of brain, pituitary, thyroid, heart, liver, lung, kidney, adrenal, testes with epididymis (males) and ovaries (females). Preserved tissues from all dogs which died or were sacrificed were sectioned, stained with hematoxylin and eosin and examined microscopically. These included brain, pituitary, thoracic and lumbar spinal cord, eyes, salivary glands, thyroid with parathyroid, thymus, trachea, esophagus, lungs with bronchi, heart, aorta, liver, gallbladder, spleen, intestine (duodenum, jejunum and ileum), large intestine, mesenteric lymph node, urinary bladder, prostate (males), testes with epididymis (males), ovaries and uterus {females), mammary skin, costachondral junction, bone marrow (femur) and sciatic nerve with adjacent muscle. Statistical comparisons were made on the following: body weight changes (weeks 0-4, 0-8, 0-13, 0-26); food consumption (weeks 4, 8, 13, 26); hematology and clinical chemistry and absolute and relative organ weight data. Data of control groups were compared to treated groups of the same sex by Bartlett's test first and the 1-way classification of variance (ANOVA). If Bartlett's and
ANOVA yielded significant results, a multiple pairwise comparison procedure (Games and Howell) was used to compare group mean values. If only ANOVA gave significant results, Scheffe's multiple pairwise comparison procedure was used to compare group mean values. All analyses were evaluated at the 5% probability level.

Results: Non-treatment related effects included non-specific dermatitis, injected scleras, lacrimation, soft stools or diarrhea, and sores on body. One high-dose male (75 mg/kg/day) was sacrificed moribund as a result of complications due to urinary calculi-obstructed urethra. No other mortalities occurred. No treatment-related behavioral symptoms were noted. The most significant treatment related clinical symptoms included cystitis and/or urinary calculi among low, mid and high dose males observed during catheterization and in the high dose moribund male. One low dose, 2 mid dose and 2 high dose males had such symptoms. Occasional instances of bloody urine were found among low, mid and high dose males. No significant changes in body weights attributable to NP-55 were observed over the 26 week test period. Treatment related changes were found in clinical chemistry, hematology, urinalysis, gross necropsy and histopathology; however, as these results were suspect due to the study design, only a summary of the adverse effects followed by a commentary on the study deficiencies are detailed below.

Adverse Effects:  Random effects on RBC, MCH, SGOT, BIT, and lung weight were seen in 120 ppm (7.5 mg/kg/day) animals. Effects of NP-55 showing a dose-response relationship were seen in 600 ppm and 3000 ppm animals in LDH, A/G, PSP excretion, urinary calculi present, liver and thyroid weight, and pathology in renal pelvis and urinary bladder. A/G ratio of 120 ppm animals showed a dose-response relationship, but this observation was not considered significant. Cystitis was observed in 2/6 males and 3/6 females at the lowest dose, l/6 males and 2/6 females at the mid dose and 2/6 males and 3/6 females at the highest dose. The above effects were not observed in control animals.

NOEL = 120 ppm

Core Study - Minimum data.

Commentary:

   1. NP-55 is reported as slightly unstable at room temperature, but stable at -22°C (Report Cl-C13). In the present study, NP-55 was stored at room temperature from November 30, 1978 to January 4, 1979; then refrigerated from January 4 to March 6, 1979 (study week 6) and frozen from March 6 to termination of the experiment. (In reports C1-Cl3, it was noted that careful procedures were used (i.e. freezing to prevent NP-55 treatment materials from deterioration.)
   2. Dosage of NP-55 were prepared according to the 96.1% purity stated by the sponsor, but no testing was done to confirm purity or to determine if deterioration had occurred during storage. 
   3. No report has been received to date concerning homogeneity or accuracy of NP-55 feeding mixture (although sponsor, as per telephone conversation of November, 1980, said this information would be sent).
   4. At the start of the feeding experiment, NP-55 food mixture was offered once weekly for 6 weeks to the young dogs and was available ad libitum, suggesting the possibility that non-uniformity of dosage could easily occur. 
   5. The results of this study are at variance with those obtained and reported by Nisso Institute (Reports C12 and Cl3). This is discussed in the accompanying commentary (Report Cl4 Comment):
      
            Statement for Toxicological Study No. 001. Reason to Make Additional Test of Six Month Dog Feeding Study of NP-55. Nisso Institute for life Science Tab. Report C14 Comment. December 27, 1979; Scientific Comment on Six Month Dog Feeding Study of NP -55.
            
            This commentary deals with the findings reported by Hazelton Laboratories America Inc., in their six month feeding study, employing a diet of 120 ppm; 600 ppm and 3000 ppm in beagle dogs. In all treated animals a significant decrease in PSP excretion was noted and acute cystitis of urinary bladder and pyelitis of the renal pelvis were observed microscopically. Because Nisso Institute had previously performed two subacute toxicity studies (rat and mouse, see reports Cl2 and C13), Nisso Soda Co. and found the target organ for compound UP-55 was the liver, another subchronic dog feeding study of NP-55 was begun in order to confirm the differences in target between dogs and rodents. The second report is in progress and the final report is expected in January 1981.

Addendum to Twenty-Six Week Toxicity Study in Dogs of NP-55. Report Cl4 Hazelton Laboratories America, Inc. Tab. C14, pp. 1-147. Accession No. 099536. Analysis of Diet, Accession No. 099802, December 8, 1980, pp. 1-3 and Tables 1-5.

Protocol: Two-gram samples of dietary feed in duplicate, were analyzed to determine the concentration of NP-55 in canine food for Project No. 886-103. Three-hour extracts were made with methylene chloride, the extract evaporated and analysis made of aliquots for the 120, 600 and 3000 ppm dietary levels using high pressure liquid chromatography.

Results: The analytical method was successful in demonstrating near quantitative recovery techniques, but revealed that a homogeneity problem was present in bulk preparation of the animal diet. The homogeneity problem was overcome by switching from the Hobart blender to pre-mixing diet in a Waring blender, thereby achieving target concentration of NP-55 in the feed mix. However, analysis of the diet mixes used throughout the canine feeding studies revealed failure to achieve target doses. (The Hobart mixer was evidently used to prepare the diet for the feeding studies.) (See Tab1e 2 of this report.) Average percent of target dose for the 120 ppm diet varied from 16.0 to 76.5~ of target; for the 600 ppm dose diet, average percent ranged from 77.32 to 87.8% of target and for the 3000 ppm dose diet, the average percent of target dose ranged from 82.7 to 110/2%.

Comments: The non-uniformity of diet dosage, inadequate storage procedures for the administered chemical as well as the method of diet administration (for the latter two see detailed toxicological review - Protocol and comment) have a deleterious effect on the quality of the feeding test protocol and probably affect the results.

	870.3200	21/28-Day Dermal Toxicity  -  Rat

MRID 41987203: In a 21-day dermal toxicity study (MRID 41987203), groups of 5 male and 5 female New Zealand White rabbits were dermally dosed with sethoxydim 6 hours per day over 21 consecutive days at 0 (vehicle control), 40, 200, and 1000 mg/kg/day. The only dose-related dosing site lesion was slight epidermal hyperplasia, which was found in nearly all high-dose males and females, and was probably an adaptive response. There was no evidence of compound-related toxicity on clinical signs, body weights, food consumption, food efficiency, eye health, clinical pathology, organ weights, or gross pathology. The NOAEL is > 1000 mg/kg/day (limit dose) and the systemic LOAEL is not identified.

This study is Acceptable-Guideline, and thus satisfies data requirement 82-2 for a 21-Day
Dermal Toxicity Study. This study received Quality Assurance review.

	870.3465	28-Day Inhalation  -  Rat

MRID 44021202: In a 28-day toxicity study (MRID 44021202), sethoxydim (96.8%; batch no. NS-9212) was administered by inhalation (nose only) to 5 Wistar rats/sex/dose at aerosol analytical concentrations of 0.04, 0.3, and 2.4 mg/L. The control group received filtered air only and the sethoxydim was administered as received from the sponsor. Exposures were 6 hours/day, 5 days/week, for a total of 21 exposures. The mass median aerodynamic diameter (+- geometric standard deviation) for Groups 1, 2, and 3 were 0.8 +- 3.7 um, 1.4 +- 1.8 um, and 1.5 +- 2.4 um, respectively.

No animals died prior to terminal sacrifice. Clinical signs included nasal irritation (bloody crust formation on the nose) in all mid and high-dose rats, salivation during and after exposure in high-dose rats, and fur stained with the test substance at the high dose throughout most or all of the study. Body weights and body weight gains were similar to controls (food consumption was not reported). Clinical chemistry analysis revealed a significant increase in total serum bilirubin high dose males (164% of controls; p<=0.05) and females (239% of controls; p<=0.02), although these levels are not considered to be toxicologically significant. There were no treatment-related findings at necropsy, but microscopic examination showed an increased incidence of slight (grade 2) centrilobular hepatocyte swelling in high-dose males (5/5 vs. 1/5 for controls; p<0.05). The absolute and relative (to terminal body weight) liver weights were increased 14-16% for both sexes (p<=0.05 or 0.01 for females and for relative weight in males). The liver weight increases in both sexes and the microscopic changes in males are general adaptive responses of the liver to a xenobiotic and are not considered adverse effects. A slight increase was also seen in kidney weights of high-dose males (6-8%, NS) and females (12-13%, p<0.05 for absolute weight), but it was unclear if this effect was treatment-related due to a lack of histopathological correlates.

Under the conditions of this one-month study, the LOAEL was 2.4 (651 mg/kg/day) based on increased liver weight, clinical chemistry (increased total serum bilirubin), and liver histopathology. The NOAEL was 0.3 mg/L (81 mg/kg/day), for both male and female rats. 

This 28-day study was conducted appropriately and is Acceptable/Non-Guideline.


A.4.2	Prenatal Developmental Toxicity

	870.3700a Prenatal Developmental Toxicity Study - Rat

MRID 43092902: Pregnant CD(R) rats received doses of 0 (vehicle control), 50, 180, 650, and 1000 mg/kg/day by gavage between gestation days 6 and 15. Satellite dams were included in all but the 180 mg/kg/day dose, and the 1000 mg/kg/day group consisted entirely of satellites.  Fetuses carried by satellite dams were not examined. The dams were sacrificed on gestation day 20, and their uteri and ovaries were examined. The fetuses were examined for external, visceral, and skeletal anomalies.

There were no deaths in any group. Clinical signs, seen mostly in the 650 and 1000 mg/kg/day dams, included irregular gait and decreased activity which reversed after several days; and excessive salivation and anogenital staining which did not reverse. Biologically significant decreases in maternal body weights (12-15%, compared to controls) were seen only in the 1000 mg/kg/day satellite group. No compound-related gross lesions were found. The LOAEL for maternal toxicity is 650 mg/kg/day based on irregular gait, decreased activity, excessive salivation, and anogenital staining. The NOAEL for maternal toxicity is 180 mg/kg/day.

There were no resorptions, abortions, premature births, or dead fetuses. The number of corpora lutea, implantation sites, resorptions, and viable fetuses, as well as mean litter sizes and sex ratios were similar for all groups. External and skeletal anomalies, including filamentous tail and lack of tail due to the absence of sacral and/or caudal vertebrae, were dose-related, but visceral anomalies were not. The LOAEL for developmental toxicity is 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. The NOAEL for developmental toxicity is 180 mg/kg/day.

This study is Acceptable-Guideline, and satisfies the requirement 83-3a for a Developmental Toxicity study in rats. Satellite dams were added at the 650 and 1000 mg/kg/day level "...to clarify maternal effects seen in pilot studies." There was no mention of what these effects were, or what was learned from the satellite animals.

	870.3700b Prenatal Developmental Toxicity Study  -  Rabbit

MRID 43092901: Sethoxydim (96.8% a.i., Lot #NS-9203) was administered in 1% aqueous carboxymethylcellulose to groups of 15 pregnant New Zealand White rabbits by gavage at dose levels of 0, 80, 160, 320 or 400 mg/kg/day from gestation day 6 through 18 (gestation day 0 was the day of mating). Animals were sacrificed on gestation day 30 and uteri were examined for live fetuses and intra-uterine deaths. Fetuses were weighed and examined for external, visceral and skeletal alterations.

Body weight gains were reduced during the dosing period in comparison to control values by 37% for the 400 mg/kg/day dose group without significant differences in group mean body weights. Food consumption values were similarly decrease in the highest dose group (by 10- 25%) during dosing, but were not considered adverse as terminal body weights were not impacted. The LOAEL for maternal toxicity was not observed. The NOAEL for maternal toxicity is 400 mg/kg/day.

There was an apparently dose-related increase in the incidence of incompletely ossified 6[th] sternebrae (1/13, 4/12, 3/15, 6/13 and 9/13 litters in the 0, 80, 160, 320 and 400 mg/kg/day groups, respectively), and the incidence of this variation at the highest dose level was outside the reported historical range (average incidence is 35.1% of litters ranging from 0-57.1%). However, the incidence of all other skeletal ossifications variations was not increased in a dose-related manner. The LOAEL for developmental toxicity is 400 mg/kg/day based on an increase in the incidence of incompletely ossified 6[th] sternebrae. The NOAEL for developmental toxicity is 320 mg/kg/day.

This study is acceptable, guideline and satisfies the requirement for a guideline series §83-3b developmental toxicity study in rabbits.



A.4.3	Reproductive Toxicity

	870.3800 Reproduction and Fertility Effects - Rat

MRID 41510606: In a 2-generation reproduction study (MRID 41510606), NP-55 (sethoxydim technical, 96.86 % a.i., Lot # KK-1240) was administered to 13 male and 26 female/group/dose F0 Charles River CD rats at dose levels of 0, 7.5, 30 or 150 mg/kg/day. The F0 animals produced 2 litters (F1a and F1b). The F1b animals produced 2 litters (F2a and F2b). Clinical signs, body weights, reproductive parameters, necropsy and histopathology data were obtained from parental animals and/or offspring.

There were no indications of systemic toxicity in the F0 parental animals. In the F1 dams in the 150 mg/kg/day group, maternal body weights were slightly decreased during the F2a and F2b gestation and lactation periods (8-10%), with no concomitant effect on food consumption. The 150 mg/kg/day F2b pups had a decrease in body weight of up to -13% by lactation day 21. Malformations were only observed in one F1b (1/240 total pups in litter) and two F2b pups (2/344 total pups in litter). In the F1b litter, cleft palate was observed in one high dose pup. In the F2b litter, one high-dose pup had a thread-like tail, no anal opening, malformed hindlimb, malpositioned kidneys and another high-dose pup had cleft lip, cleft palate and microphthalmia. There were no dose-related gross or microscopic lesions, or developmental variations (cannibalism complicated the evaluation).

Parental Systemic Toxicity NOAEL > 150 mg/kg/day
Parental Systemic Toxicity LOAEL > 150 mg/kg/day

Offspring/Developmental Toxicity NOAEL = 30 mg/kg/day
Offspring/Developmental Toxicity LOAEL =150 mg/kg/day based on decreased pup body weight in F1a, F1b, and F2b during lactation.

Reproductive Toxicity NOAEL > 150 mg/kg/day
Reproductive Toxicity LOAEL > 150 mg/kg/day

The study is Acceptable-Guideline and satisfies the requirement for a guideline series 83-4 Reproduction study in rats. The study is not upgradable. The doses tested were too low to elicit toxicity, and did not approach the limit dose.

The HIARC determined that the Parental Systemic Toxicity NOAEL is > 150 mg/kg/day (HDT) and that the LOAEL could not be established, based on the endpoints of 8-10% decreased in body weight seen at 150 mg/kg/day is not considered adverse (LOEL but not LOAEL is established). The Reproductive Toxicity NOAEL/LOAEL > 150 mg/kg/day (HDT). The Offspring Toxicity NOAEL is 30 mg/kg/day, the LOAEL is 150 mg/kg/day, based on decreased pup body weight of 11-13% in F1a, F1b, and F2b during lactation.

A.4.4	Chronic Toxicity/Carcinogenicity

	870.4300a Chronic Toxicity/Carcinogenicity Study  -  Rat

MRID 43939101: In a chronic toxicity/carcinogenicity study (MRID 43939101), Sethoxydim (96.8% a.i.) was administered to groups of 50 male and 50 female Wistar rats at dietary concentrations of 0, 264, 1000, or 3000 ppm (equivalent to 0, 12, 48, and 143 mg/kg/day for males and 0, 17, 66, and 204 mg/kg/day for females) for up to 24 months (main study groups). Additional groups of 10 rats per sex/per group were fed the same concentrations for up to 24 months for terminal evaluation (satellite groups).

No adverse, treatment-related effects were observed on mortality, clinical signs, hematology, or clinical chemistry.

Body weights were decreased in the 3000 ppm females (main study) during most of the study, becoming most severe between Days 476-644, ranging up to approximately 15% less than controls.  A similar effect was noted in the males, but less severe (not considered adverse).  

The liver was the primary target for sethoxydim. Serum total bilirubin levels were increased in the 1000 and 3000 ppm groups by approximately 1.5  -  3.8-fold; however, only the effects at 3000 ppm were considered adverse because of the magnitude of the effect, the consistency across time, and the other adverse effects noted in the liver at this dose.  Eosinophilic foci were noted in the livers in 33/60 (p<0.01) males at 3000 ppm compared with 14/60 controls.  Centrilobular hepatocellular hypertrophy was observed in 38/60 (p<0.01) males at 3000 ppm, 10/60 (p<0.01) males at 1000 ppm, and 33/60 (p<0.01) females at 3000 ppm compared with 0/60 controls of either sex. The hypertrophy at 1000 ppm was not considered adverse in the absence of corroborating evidence of hepatoxicity.  In addition, centrilobular fatty infiltration in the liver was increased in male rats (20/60 vs 7/60 controls, p<0.01) at 3000 ppm. 

Treatment-related effects in the lungs included increased incidences of interstitial fibrosis in the 3000 ppm female rats (9/60 vs 2/60 for controls, p<0.05) and heart failure cells in the lungs of 3000 ppm male (16/60 vs 4/60 for controls, p<0.01) and female rats (10/60 vs 3/60, p<0.05). 

The LOAEL is 3000 ppm (equivalent to 143 mg/kg/day in males and 204 mg/kg/day in females) based on decreased body weights in females, increased serum total bilirubin in both sexes, increased incidences of eosinophilic foci in livers in males, centrilobular hypertrophy in both sexes, centrilobular fatty infiltration in males, interstitial fibrosis in the lungs in females, and heart failure cells in lungs in both sexes.  The NOAEL was 1000 ppm (equivalent to 48 mg/kg/day in males and 66 mg/kg/day in females). 

At the doses tested, there was not a treatment-related increase in tumor incidence when compared to controls.  Dosing was considered adequate based on decreased body weights in females, increased serum total bilirubin in both sexes, and histological lesions in the liver and lung in both sexes. 

This study is classified as acceptable, guideline and satisfies the guideline requirements (OPPTS 870.4300; OECD 453) for a combined chronic toxicity/carcinogenicity study in rats. 



	870.4300b Chronic Toxicity/Carcinogenicity Study  -  Mouse

MRID 00100527: In a combined chronic toxicity/carcinogenicity study (MRID 00100527) NP-55 (sethoxydim technical, 95.4% a.i., lot # PN-1-2) was administered to 60 BDF1 mice/sex/dose in the diet at concentrations of 40, 120, 360, or 1080 ppm (equivalent to 4.48, 13.77, 41.16, or 134.46 mg/kg bw/day for males and 4.85, 14.86, 44.33, or 142.85 mg/kg bw/day for females) for 24 months. A group of 90 males and 90 females administered the vehicle- (acetone) treated food served as the control. Additional groups of 10/mice/sex/dose were sacrificed at 12 months.

There were no compound-related effects on clinical signs or mortality. The final body weight and body weight gain of male mice in the 1080-ppm group were reduced by 10% and 21%, respectively, compared with the control group. Mean body weights and body weight gains of females were unaffected by treatment. Both absolute and relative liver weights were significantly increased (by 115-138%) at the 24 month sacrifice in males and females in the 1080 ppm group. Increases were also observed in males and females (relative weight only) in this group at the 12-month interim sacrifice. At the 24-month terminal sacrifice, increases in liver weight correlated with clinical chemistry parameters of elevated alanine aminotransferase and aspartate aminotransferase activities and the microscopically-observed lesions including hepatocellular hypertrophy in males in the 1080 ppm group (all p<0.01). Focal granulomatous inflammation, fatty degeneration, and hemosiderin deposition were also observed in the livers of males in the 1080 ppm group (all p<0.01). Fatty degeneration of the liver was present in 87% of males in the 1080 ppm group and 1% of males in the control group. The incidences of fatty degeneration (p<0.05) and hemosiderin deposition (non-significant) in the liver were also elevated in males in the 360 ppm group, although the increased incidences (7-8%) were small compared with incidences (0-1%) in the control group. Only the incidence of fatty degeneration of the liver was significantly elevated in female mice in the 1080 ppm group at 24 months (control, 7%; 1080, 20%; p<0.01).

The LOAEL for NP-55 for systemic toxicity is 360 ppm in the diet (41.2 mg/kg/day) based on early onset of liver effects including hepatocellular hypertrophy and fatty degeneration in male mice. The NOAEL is 120 ppm in the diet (13.8 mg/kg/day).

This chronic/carcinogenicity study in the mouse is Acceptable/Guideline and satisfies the guideline requirement for a chronic/carcinogenicity study OPPTS 870.4300); OECD 453] in mice. Although data on the homogeneity, concentration, and stability of the test material in the diet were not included with the present report, acceptable data are available from related studies.


A.4.5	Neurotoxicity

	870.6200 Subchronic Neurotoxicity Screening Battery

MRID 46846301:  In a subchronic neurotoxicity study (MRID 46845301), Sethoxydim (95.4% a.i., Lot # TM3145] was administered daily to 10 Crl:CD(SD) rats/sex/group in the diet at dose levels of 0, 300, 980, or 3200 ppm (equivalent to 0, 18.4, 59.3, or 206.9 mg/kg bw/day in males, respectively, and 0, 22.2, 72.0, or 234.3 mg/kg bw/day in females, respectively) for 13 weeks.  Neurobehavioral assessment (functional observational battery and motor activity testing) was performed on 10 animals/sex/group during pre-exposure and during Weeks 2, 4, 8, and 13.  Cholinesterase activity was not measured.  At study termination, five animals/sex/group were euthanized and perfused in situ for neuropathological examination.  Of the perfused animals, rats from the control and high-dose groups were subjected to histopathological evaluation of brain and peripheral nervous system tissues.

Effects of treatment were limited to reductions in body weight gain and food consumption at the high dose of 3200 ppm.  In males, body weight gain was transiently reduced over Days 1-8 and 8-15 (76% of controls for both), but was comparable to controls at all other intervals including the overall study interval of Days 1-91 (91% of controls).  In females, body weight gain was reduced over Days 1-8 and 8-15 (61% and 77% of controls, respectively) and for the entire interval of Day 1-91 (79% of controls).  No significant differences in mean absolute body weights were observed in high dose males or females.  Correlating with the reductions in body weight gain were reductions in food consumption in high dose males and females the first two weeks of the study (mean absolute food consumption in males was 92% of controls over Days 8-15 and in females was 85% and 89% of controls over Days 1-8 and 8-15, respectively; mean relative food consumption in females was 87% and 92% of controls, respectively), with high dose females also exhibiting statistically reduced relative food consumption over Days 1-29 (93% of controls).  Mean relative food consumption was statistically increased in high dose males over Days 57-91 (111% of controls), indicating recovery.  No treatment-related adverse effects on body weight or food consumption were noted in males or female rats fed the low- or mid-dose.

No adverse effects of treatment were observed in clinical signs, mortality, ophthalmoscopic findings, FOB parameters, motor activity, brain weights, or during gross or microscopic examination.

The LOAEL for Sprague-Dawley rats was 3200 ppm (equivalent to 206.9 mg/kg bw/day in males and 234.3 mg/kg bw/day in females) based on reduced body weight gain and food consumption, with a NOAEL of 980 ppm (equivalent to 59.3 mg/kg bw/day in males and 72.0 mg/kg bw/day in females). 

The study is classified as Acceptable/ Guideline and satisfies the guideline requirement for a subchronic neurotoxicity study in rats (OCSPP 870.6200b; OECD 424).  


A.4.6	Metabolism

	870.7485	Metabolism  -  Rat

MRID 00045868: Protocol: Four groups of male and female rats (Fischer strain, Charles River, Japan) aged 9 weeks (groups A, B and D) or 8 weeks (group C) were treated as outlined in Table I to determine the metabolic fate of radioactively labeled technical NP-55. The radioactive sample of NP-55 [(*4-[14]C) - NP-55] was synthesized (Japan Atomic Energy Research Institute) with a specific activity of 10.3 mCi/mM and a radiochemical purity of 98%. Five males and five females from each group selected as representative of the group by uniformity of plasma levels of [l4]C-NP-55 were then individually housed and tested until 95% of the administered radioactive dose was eliminated (48 hours), and then sacrificed. During the 48 hours period, blood, urine and feces were collected for analysis of metabolites and measurement of radioactivity. Blood samples were collected as 0.25, 0.5, 1.0, 2, 3, 4, 6, 12, 24 and 48 hours following treatment. Urine and feces were separately collected on day 1 and 2 from cage apparatus arranged to receive them and during sampling procedures for blood. At 48 hours sacrifice, rats were exsanguinated from the carotid artery, with the plasma separated from blood by centrifugation. Residual bladder urine was pooled with the previously collected 2 day urine sample. Tissues and structures removed weighed and analyzed for metabolites and radioactivity included fat, gonads (testes plus epididymides of males or ovaries of females), spleen, kidney, liver, heart, lung, urinary bladder, femoral muscle and femoral bone. Remaining structures reserved as the carcass were weighed. Radioactivity in samples was measured by liquid scintillation spectrophotometry with external standard, using appropriate methodology for liquid or solid samples. Statistical methods were used to determine means and standard errors for all analytical procedures with the Student's t-test applied to determine differences between 2 groups and a 5% level of significance was adopted.

Results: During the 48 hour test period, all groups showed an average percent of 78.5% administered radioactivity excreted into urine and 20.1% in feces. Less than 2% of the administered radioactive dose was tissue-associated. In the tissues, residual levels of [14]C-NP-55 were highest in liver, with values of 0.6 ppm in groups A, B and C and 13 ppm in group D (the high dose group). The extent of absorption was almost 100% in groups B, C and D, based on radioactivity excreted in urine by group A (intravenous administration considered highest absorption rate). Of remaining tissue-bound [14]C residues, one half remained bound in groups A, B and C and one third in group D (high dose group).

Conclusion: Excretion of NP-55 1n rats in extremely rapid and tissue accumulation is negligible, assuming the DMSO vehicle does not affect excretion or storage of the chemical.

Core Study Category  -  Guidelines






A.5	Calculation of the HED and HEC for Sethoxydim 

The methods and dosimetry equations described in EPA's RfC guidance (1994) are suited for calculating HECs based on the inhalation toxicity NOAEL for use in MOE calculations.  The procedure provided in the Office of Pesticide Programs Inhalation Risk Assessment Guidance on the Applications of the RfC Methodology (2014) were followed.

The regional deposited-dose ratio (RDDR), which accounts for the particulate diameter (mass median aerodynamic diameter [MMAD] and geometric standard deviation [g] of aerosols), can be used to estimate the different dose fractions deposited along the respiratory tract.  The RDDR is also based on interspecies differences in ventilation and respiratory-tract surface areas.  Thus, the RDDR can be used to adjust an observed inhalation particulate exposure of an animal to the predicted inhalation exposure for a human. 

The RfC methodology applies a dosimetric adjustment that takes into consideration not only the differences in ventilation rate (MV) but also the physicochemical properties of the inhaled compound, the type of toxicity observed (e.g., systemic vs. portal-of-entry) and the pharmacokinetic (PK) (but not pharmacodynamic) differences between animals and humans.  Based on the EPA's RfC guidance (1994), the methodology for RfCs derivation is an estimate of the quantitative dose-response assessment of chronic non-cancer toxicity for individual inhaled chemicals and includes dosimetric adjustment to account for the species-specific relationships of exposure concentration to deposited/delivered dose.  This adjustment is influenced by the physicochemical properties of the inhaled compound as well as the type of toxicity observed (e.g., systemic vs. portal-of-entry), and takes into consideration the PK differences between animals and humans.  Though the RfC methodology was developed to estimate toxicity of inhaled chemicals over a lifetime, it can be used for other inhalation exposures (e.g., acute and short-term exposures) since the dosimetric adjustment incorporates mechanistic determinants of disposition that can be applied to shorter duration of exposures provided the assumptions underlying the methodology are still valid.  

Sethoxydim is not volatile in ambient conditions.  The vapor pressure of sethoxydim is only 1.6 x 10[-7] mm Hg at 25 °C.  Sethoxydim would be inhaled as an aerosol.  Calculations used to estimate the inhalation risk to humans from aerosols are dependent on the regional deposited dose ratio (RDDR).  Inhalation studies using aerosols characterize particulate exposure by defining the particulate diameter (mass median aerodynamic diameter [MMAD]) and the geometric standard deviation (σg), which is then used to determine the RDDR.  The RDDR is a multiplicative factor used to adjust an observed inhalation particulate exposure concentration of an animal (A) to the predicted inhalation particulate exposure concentration for a human (H) that would be associated with the same dose delivered to the r[th] region or target tissue.

	RDDRr = (RDDr/Normalizing Factor)A / (RDDr/Normalizing Factor)H  

As with calculations for gases, the r regions and potential target tissues are the three respiratory regions (ET, TB, PU).  The RDDR is easily calculated by using a software program designed specifically for computing the RDDR from the MMAD and σg defined from an aerosol inhalation study.  The values for the species-specific parameters used to calculate the RDDR are provided in the EPA document "Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry." 

The most sensitive endpoint of toxicity for sethoxydim is hepatotoxicity at 2.4 mg/L, an extrarespiratory effect.  Portal of entry effects were noted as nasal irritation (bloody crust formation on the nose) in all 0.3 and 2.4 mg/L rats (not considered adverse at 0.3 mg/L). The MMAD and GSD reported for the 0.3 mg/L group, as measured by a cascade impactor (from page 27 of the study report), are MMAD = 1.40 and GSD = 1.80.  The resulting RDDR for males and females is 3.105 for extrarespiratory effect.  The body weight value for the RDDR calculation was based on an average of male and female body weights.  


Regional Deposited Dose Ratio (RDDR) for Sethoxydim 

                       Regional deposited dose ratios

MMAD    =  1.40
Sigma g =  1.80

           Body               Extrathoracic    Tracheobronchial      Pulmonary
SPECIES  weight(g)  VE(ml)    SA(cm^2)   dep   SA(cm^2)   dep    SA(m^2)    dep
--------------------------------------------------------------------------------
    rat      252     181.0    15.000   0.348    22.500   0.073     0.340   0.076
  human    70000   13800.0   200.000   0.245  3200.000   0.062    54.000   0.277
--------------------------------------------------------------------------------
 RATIO     0.004     0.013     0.075   1.422     0.007   1.182     0.006   0.275

 RDDR                              0.249             2.204            0.573

                              Thoracic         Total RT        Extrarespiratory
                              SA(m^2)    dep   SA(m^2)    dep     BW(g)     dep
--------------------------------------------------------------------------------
    rat                        0.342   0.149     0.344   0.497       252   0.497
  human                       54.320   0.125    54.340   0.583     70000   0.583
--------------------------------------------------------------------------------
 RATIO                         0.006   1.190     0.006   0.852     0.004   0.852

 RDDR                              0.917             1.767            3.105
         
To calculate the HEC and HED, a point of departure (PoD) value of 0.3 mg/L and RDDR of 3.105 were entered into the May 2014 version of the RDDR Excel spreadsheet program.  This program implements the Office of Pesticide Programs Inhalation Risk Assessment Guidance on the Application of the RfC Methodology (February 11, 2014).  Briefly, the following steps are performed: (i) PoD is adjusted for exposure duration using Haber's Law; (ii) the dosimetry adjustment factor (DAF) is derived which compares the minute ventilation rate, deposition fraction for aerosols, and surface area of the affected respiratory tract in the test animal to humans; (iii) the human equivalent concentration (HEC) is estimated as the product of duration-adjusted PoD and the DAF, and (iv) the HEC is converted to the human equivalent dose (HED), with the consideration of volume respired per unit time.  Formulas and a more detailed explanation are provided in the cited document.  The following results were calculated:


Occupational Handler (HEC = 0.699 mg/L)
                                HED (mg/kg/day)
Occupational scenarios assigned a breathing rate of 8.3 L/min
                                    39.762
Occupational scenarios assigned a breathing rate of 16.7 L/min
                                    80.003
Occupational scenarios assigned a breathing rate of 29 L/min
                                    138.927


Residential Handler HEC = 0.932 mg/L and HED = 26.6 mg/kg/day  


Appendix B.  International Residue Limits Table

Table B1.  Summary of US and International Tolerances and Maximum Residue Limits for Sethoxydim (121001)
Residue Definition:
US
Canada
Mexico[2]
Codex
40 CFR 180.412:
Plant: sethoxydim: 2-[1-ethoxyimino)butyl]-5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen-1-one
(+-)-2-[1-(ethoxyimino)butyl]-5-[2-(ethylthio)propyl]-
3-hydroxy-2-cyclohexen-1-one, including metabolites
containing the cyclohexen-2-one moiety, expressed
as sethoxydim

None
Commodity[1]
Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US
Canada
Mexico[2]
Codex
Fruit, citrus, group 10-10
0.5



Fruit, pome, group 11-10
0.2



Fruit, caneberry, subgroup 13-07A 
5.0
5 raspberries 


Fruit, bushberry, subgroup 13-07B
4.0
4 aronia berries, buffalo currants, Chilean guavas,  currants, elderberries, European barberries, gooseberries, highbush  (blueberries, cranberries), honeysuckle, huckleberries, jostaberries,  Juneberries (Saskatoon berries), lingonberries, lowbush blueberries, native currants, salal berries, sea buckthorn


Fruit, small vine climbing, except fuzzy kiwifruit, subgroup 13-07F
1.0
0.2 amur river grapes, , grapes, hardy kiwifruit, maypop, schisandra berries

4 gooseberries

0.6 raisins


Fruit, low growing berry, except cranberry, subgroup 13-07G
10.0
2 cranberries
4 lowbush blueberries, lingonberries
10 strawberry


Fruit, low growing berry, except strawberry, subgroup 13-07H
2.5  
2 cranberries
4 lowbush blueberries, lingonberries


Rapeseed, subgroup 20A
35.0
2.5 borage seeds
0.2 flax seeds
25 rapeseeds (canola) 


Sunflower, except safflower, subgroup 20B
7.0
7 sunflower seeds


Cottonseed, subgroup 20C
5.0



Vegetable, bulb, group 3-07
1.0
0.2 onions


Vegetable, fruiting, group 8-10
4.0
2 eggplants
0.5 peppers
4 tomatoes
15 tomato paste


Grass, forage, fodder and hay, group 17, forage
6.0



Grass, forage, fodder and hay, group 17, hay
4.0








Completed: M. Negussie; 11/13/14 
[1] Includes only commodities of interest for this action.  Tolerance values should be the HED recommendations and not those proposed by the applicant.
2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.


Appendix C.  Metabolites/Degradates

Sethoxydim = MS; 2-[1-(ethoxyimino)butyl]-5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen-
1-one

DME = 3-[2-(ethylsulfonyl)propyl]-pentanedioic acid dimethyl ester

DME-OH = 3-[2-(ethylsulfonyl)propyl]-3-hydroxypentanedioic acid dimethyl ester

MSO = sethoxydim sulfoxide; 2-[1-(ethoxyimino)butyl]-5-[2-(ethylsulfinyl)propyl]-3-hydroxy-
2-cyclohexen-1-one

MSO2 = sethoxydim sulfone; 2-[1-(ethoxyimino)butyl]-5-[2-(ethylsulfonyl)propyl]-3-hydroxy-
2-cyclohexen-1-one

M1SO = 2-[1-(imino)butyl]-5-[2-(ethylsulfinyl)propyl]-3-hydroxy-2-cyclohexen-1-one

M2SO = 6-[2-(ethylsulfinyl)propyl]-6,7-dihydro-2-propyl-4(5H)-benzoxazolone

M2SO2 = 6-[2-(ethylsulfonyl)propyl]-6,7-dihydro-2-propyl-4(5H)-benzoxazolone

5-OH-MSO2 = 5-hydroxy sethoxydim sulfone; 2-[1-(ethoxyimino)butyl]-5-[2-
(ethylsulfonyl)propyl]-3,5-dihydroxy-2-cyclohexen-1-one










Appendix D.  Physical/Chemical Properties

Table 2.	Physicochemical Properties of Sethoxydim
Parameter
Value
Reference
Boiling point/range
>130 °C at 6 x 10[-1] mm Hg
HED Chemistry Chapter of the Sethoxydim RED, 6/22/05, W. Donovan
pH
3.95 at 20 °C

Density
1.058 g/cm[3] at 20 °C (specific gravity)

Water solubility
257 ppm at pH 5, 4390 ppm at pH 7 (25 °C)

Solvent solubility
Freely soluble (>10[3] g/100 mL) in organic solvents (methanol, n-octanol, ethyl acetate, n-hexane, toluene, and xylene) at 20 °C

Vapor pressure
1.6 x 10[-7] mm Hg at 25 °C

Dissociation constant, pKa
4.6 at pH 4.5 and 25 °C

Octanol/water partition coefficient, Log(KOW)
KOW = 3.26 x 10[3] at pH 5; 45.1 at pH 7; and 0.93 at pH 9

UV/visible absorption spectrum
Not available





Appendix E.  Review of Human Research

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

