Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: March 11, 2015 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Sethoxydim: Human Health Risk Assessment for Registration Review to 

Support the Section 3 Registration of Proposed Uses on High Bush Blueberry and 

Fine Fescue Grasses, as well as Requested Crop Group Conversions. D418280; 

0424578. 

PC Code: 121001 

Decision No.: 487076 

Petition No.: 4£8239 

DP Barcode: 418280; 424578 

Registration No.: 7969-56 & 7969-58 

Regulatory Action: Section 3; Registration 

Review 

Risk Assessment Type: Single Chemical 

Aggregate 

CaseNo.: NA 

TXRNo.: NA CAS No.: 74051-80-2 

MRIDNo.: NA 40 CFR: §180.412 

FROM: 0 • ~ -· ·-- . Ronnie 

Seyed Tadayon, 

Bever, PhD, 

Chemist;A'4~~ 

DABT; ~ ~ 

Peter Savoia, Chemist 

Katelynn King, Biologist ~ 

Risk Assessment Branches V and VII (RAB V NII) 

Health Effects Division (HED; 7509P) 

THROUGH: Ideliz Negr6n-Encarnaci6n, Chemist !J.~C 1. <ft Michael S. Metzger, Chief, RAB VNII • 

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 

Page 1 of73 
Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

Table of Contents

1.0 Executive Summary............................................................................................................. 4

2.0 HED Recommendations....................................................................................................... 6

2.1 Data Deficiencies/Conditions of Registration and Re-Registration................................. 6

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.................................................................... 9

2.2.4 International Harmonization ................................................................................... 10

2.3 Label Recommendations................................................................................................ 10

2.3.1 Recommendations from Residue Reviews ............................................................. 10

2.3.2 Recommendations from Occupational Assessment................................................ 10

3.0 Introduction........................................................................................................................ 10

3.1 Chemical Identity ........................................................................................................... 10

3.2 Physical/Chemical Characteristics................................................................................. 11

3.3 Pesticide Use Pattern...................................................................................................... 11

3.4 Anticipated Exposure Pathways..................................................................................... 15

3.5 Consideration of Environmental Justice ........................................................................ 15

4.0 Hazard Characterization and Dose-Response Assessment................................................ 16

4.1 Toxicology Studies Available for Analysis ................................................................... 16

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)................................... 16

4.2.1 Dermal Absorption.................................................................................................. 16

4.3 Toxicological Effects ..................................................................................................... 17

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)....................................... 18

4.4.1 Completeness of the Toxicology Database............................................................. 18

4.4.2 Evidence of Neurotoxicity ...................................................................................... 19

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ......... 19

4.4.4 Residual Uncertainty in the Exposure Database..................................................... 19

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........ 21

4.5.3 Cancer Classification and Risk Assessment Recommendation.............................. 21

4.5.4 Summary of Points of Departure and Toxicity Endpoints...................................... 22

4.6 Endocrine Disruption ..................................................................................................... 23

5.0 Dietary Exposure and Risk Assessment ............................................................................ 24

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

5.1.3 Comparison of Metabolic Pathways....................................................................... 25

5.1.4 Residues of Concern Summary and Rationale........................................................ 26

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Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

5.2 Food Residue Profile...................................................................................................... 26

5.3 Water Residue Profile .................................................................................................... 27

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.............................................................................. 28

5.4.4 Chronic Dietary Risk Assessment .......................................................................... 29

5.4.5 Cancer Dietary Risk Assessment............................................................................ 29

5.4.6 Summary Table....................................................................................................... 29

6.0 Residential (Non-Occupational) Exposure/Risk Characterization .................................... 29

6.1 Residential Handler Exposure........................................................................................ 30

6.2 Post-Application Exposure............................................................................................. 31

6.3 Residential Risk Estimates for Use in Aggregate Assessment ...................................... 31

6.4 Residential Bystander Post-Application Inhalation Exposure ....................................... 32

6.5 Spray Drift...................................................................................................................... 32

7.0 Aggregate Exposure/Risk Characterization....................................................................... 33

7.1 Acute Aggregate Risk .................................................................................................... 33

7.2 Short-Term Aggregate Risk ........................................................................................... 33

7.3 Intermediate- and Long-Term Aggregate Risk .............................................................. 34

7.4 Cancer Aggregate Risk................................................................................................... 34

8.0 Cumulative Exposure/Risk Characterization..................................................................... 34

9.0 Occupational Exposure/Risk Characterization .................................................................. 34

9.1 Short-/Intermediate-Term Handler Risk ........................................................................ 34

9.2 Short-/Intermediate-Term Post-Application Risk .......................................................... 37

9.2.1 Dermal Post-Application Risk ................................................................................ 37

9.2.2 Inhalation Post-Application Risk............................................................................ 37

9.2.3 Restricted Entry Interval......................................................................................... 38

10.0 Incident Report............................................................................................................... 38

11.0 References.......................................................................................................................... 40

Appendix A. Toxicology Profile and Executive Summaries....................................................... 42

A.1 Toxicology Data Requirements...................................................................................... 42

A.2 Toxicity Profiles............................................................................................................. 43

A.3 Hazard Identification and Endpoint Selection ............................................................... 47

A.4 Executive Summaries..................................................................................................... 49

A.5 Calculation of the HED and HEC for Sethoxydim ........................................................ 63

Appendix C. Metabolites/Degradates.......................................................................................... 68

Appendix D. Physical/Chemical Properties................................................................................. 72

Appendix E. Review of Human Research ................................................................................... 73

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Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

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.

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Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

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 postapplication 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 

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Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

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 nonchemical 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 postapplication 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

HED recommends for a registration amended use of sethoxydim on high bush blueberry. No 

additional data are needed, as outlined in section 2.1 below. The specific tolerance 

recommendations are discussed in 2.2, and label modifications are discussed in section 2.3.

2.1 Data Deficiencies/Conditions of Registration and Re-Registration

The toxicity, exposure, and residue chemistry databases 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. 

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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 Sethoxydim1

Commodity Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity 

Definition

Calendula, meal - 20

Castor oil plant, meal - 20

Chinese tallowtree, meal - 20

Cuphea, meal - 40

Echium, meal - 40

Euphorbia, meal - 20

Evening primrose, meal - 20

Flax, meal - 40

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, subgroup 

13-07H 2.5 2.5 Berry, low growing, subgroup 13-07H, except strawberry

Hare’s ear mustard, meal - 40

Jojoba, meal - 20

Lesquerella, meal - 40

Lunaria, meal - 40

Meadowfoam, meal - 40

Milkweed, meal - 40

Mustard, meal - 40

Niger seed, meal - 20

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Table 2.2.2. Tolerance Summary for Sethoxydim1

Commodity Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity 

Definition

Oil radish, meal - 40

Poppy seed, meal - 40

Rapeseed, subgroup 20A 35.0 35

Rose hip, meal - 20

Sesame, meal - 40

Stokes aster, meal - 20

Sunflower, except safflower, 

subgroup 20B 7.0 7.0 Sunflower subgroup 20B, except safflower

Sweet rocket cultivars, meal - 40

Cottonseed, subgroup 20C 5.0 5.0

Tallowwood, meal - 20

Tea oil plant, meal - 20

Vegetable, bulb, group 3-07 1.0 1.0

Vegetable, fruiting, group 8-10 4.0 4.0

Veronia, meal - 20

Fescue, forage 6.0 72

Fescue, hay 4.0 42

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, 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 expressions specified for sethoxydim have been reviewed and should be updated 

as follows based on HED’s Interim Guidance on Tolerance Expressions (S. Knizner, 

05/27/2009).

(a) General. 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 the herbicide 2-[1-(ethoxyimino)butyl]-5-[2-(ethylthio)propyl]-3-hydroxy-2-

cyclohexen-1-one (CAS Reg. No. 74051-80-2) and its metabolites containing the 2-

cyclohexen-1-one moiety, calculated as the stoichiometric equivalent of sethoxydim, in 

or on the commodity. 

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(c) Tolerances with regional registration. Tolerances with regional registration are 

established, as defined in §180.1(l), 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 the herbicide 2-[1-(ethoxyimino)butyl]-5-[2-(ethylthio)propyl]-3-hydroxy-2-

cyclohexen-1-one (CAS Reg. No. 74051-80-2) and its metabolites containing the 2-

cyclohexen-1-one moiety, calculated as the stoichiometric equivalent of sethoxydim, in 

or on the commodity. 

2.2.3 Revisions to Petitioned-For Tolerances

For the requested rapeseed subgroup 20A and sunflower subgroup 20B crop group conversions, 

each raw agricultural commodity (RAC) could be potentially processed into meal. Following the 

established meal tolerance of the representative crop, canola meal at 40 ppm for subgroup 20A 

and sunflower meal at 20 ppm for subgroup 20B, tolerances for the residues of sethoxydim are 

also required for translation to the applicable commodities. 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.

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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

No revisions to the labels are required.

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.

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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® 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

OH

CH3

O

N

O CH3

S

CH3

H3C

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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

Lowbush Blueberry When Needed EC 18%, 

POAST®

0.47(0.047)

based on 10 

gals/A 

dilution

PPE*/12hrs, 1 day PHI

Fine Fescue Grasses When fescue is semidormant (Nov 1st to 

March 15th) 

EC

18%, 

POAST®

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

Page 12 of 73
Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

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

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

Page 13 of 73
Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

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

Nonagricultural Rights-OfWay/Fencerows/HedgerowsWhen 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

Page 14 of 73
Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

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

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 

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Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

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 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

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Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

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 6th 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 

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Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

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 preand/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. 

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Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

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 6th

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 

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Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

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 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 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 childbearing 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 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 

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Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

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 depositeddose 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 21-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.

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Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

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 NonOccupational 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

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

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.

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Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

Table 4.5.4. Summary of Toxicological Doses and Endpoints for Sethoxydim for Use in Dietary and NonOccupational 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

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 (occ

upational 

handler)

HED = 26.7 

mg/kg/day (resi

dential 

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 

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Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

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, 20131 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 website2.

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

1 See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of chemicals.

2 http://www.epa.gov/endo/

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Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

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-oxo2-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; 14C-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). 

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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 

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Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

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 PRZMGW 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

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Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

The following maximum percent crop treated estimates were used in the acute dietary risk 

assessment for the following crops that are currently registered for sethoxydim: alfalfa 2.5%; 

almonds 5%; apples 2.5%; apricots 10%; artichokes 2.5%; asparagus 10%; beans, green 15%; 

blueberries 10%; broccoli 5%; cabbage 10%; caneberries 10%; canola 2.5%; cantaloupes 25%; 

carrots 5%; cauliflower 10%; celery 2.5%; cherries 2.5%; corn 2.5%; cotton 2.5%; cucumbers 

10%; dry beans/peas 35%; eggplant 10%; fallow 2.5%; garlic 5%; grapefruit 2.5%; grapes 5%; 

hazelnuts 2.5%; lettuce 10%; oats 2.5%; onions 15%; oranges 5%; peaches 2.5%; peanuts 10%; 

pears 2.5%; peas, green 15%; pecans 2.5%; peppers 15%; pistachios 2.5%; plums/prunes 2.5%; 

potatoes 5%; pumpkins 10%; soybeans 2.5%; spinach 2.5%; squash 10%; strawberries 10%; 

sugar beets 5%; sunflowers 10%; sweet corn 5%; tobacco 10%; tomatoes 5%; walnuts 5%; 

watermelons 20%; wheat 2.5%. 

The following average percent crop treated estimates were used in the chronic dietary risk 

assessment for the following crops that are currently registered for sethoxydim: alfalfa 1%; 

almonds 2.5%; apples 1%; apricots 2.5%; artichokes 2.5%; asparagus 5%; beans, green 10%; 

blueberries 5%; broccoli 2.5%; cabbage 5%; caneberries 5%; canola 2.5%; cantaloupes 5%; 

carrots 2.5%; cauliflower 5%; celery 2.5%; cherries 2.5%; corn 1%; cotton 1%; cucumbers 5%; 

dry beans/peas 30%; eggplant 5%; fallow 1%; garlic 2.5%; grapefruit 2.5%; grapes 2.5%; 

hazelnuts 2.5%; lettuce 2.5%; oats 1%; onions 5%; oranges 2.5%; peaches 1%; peanuts 5%; 

pears 2.5%; peas, green 5%; pecans 2.5%; peppers 5%; pistachios 1%; plums/prunes 1%; 

potatoes 2.5%; pumpkins 5%; soybeans 1%; spinach 2.5%; squash 5%; strawberries 2.5%; sugar 

beets 2.5%; sunflowers 5%; sweet corn 2.5%; tobacco 5%; tomatoes 2.5%; walnuts 2.5%; 

watermelons 10%; wheat 1%. 

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 99.9th 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.). 

Page 28 of 73
Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

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 (99.9th 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 

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Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

Operating Procedures (SOPs)3. 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 

Rate1

Area

Treated or 

Amount 

Handled 

Daily2

Inhalation

Dose

(mg/kg/day)3 MOE4

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/ ft2 1000 ft2 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 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html

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Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

3 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × 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) × 1.2 × 11.8 L/hr/kg BW × 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. Postapplication inhalation exposures while performing activities in previously treated turf or 

ornamentals are not expected, primarily due to the very low vapor pressure (1.6 × 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 Dose1 MOEs2

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/cm2

) × (fraction hand surface area mouthed/event (0.127/event) × typical surface area of one 

hand (150 cm2

)) × (exposure time (1.5 hrs/day) × number of replenishment intervals/hr (4 intervals/hr) × (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) × dermal exposure (mg))/typical surface area of one hand (150 cm2

). 

 Object-to-Mouth = ((Object Residue (μg/cm2

) × CF1 (1.0E-3 mg/μg) x Object Surface Area Mouthed/Event (10 cm2/event)) × (Exposure 

Time (1.5 hrs/day) × #Replenishment Intervals/hr (4)) × (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 μg/g) × Ingestion Rate (50 mg/kg/day) × 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 nonoccupational residential uses. The appropriate residential scenarios for the sethoxydim aggregate 

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Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

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

PostApplication: 

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 × 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 postapplication 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

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Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

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.

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Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

Table 7.2.1 Short-Term Aggregate Risk Calculations

Population

(representative residential 

scenario)

Short- Term Scenario

LOC for 

Aggregate 

Risk1

Dietary

MOE2

MOE Oral 

Residential 

Exposure3

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 

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Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

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 chemicalspecific 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 Targeta

Baseline 

Inhalation 

Unit 

Exposureb

Maximum

Application 

Ratec

Area 

Treated 

or 

Amount 

Handled 

Dailyd

Baseline Inhalation

Dosee MOEf

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 Crops1

0.219

0.47 350 0.00045 180,000

Typical Field Crops2 0.28 0.000269 300,000

High-Acreage Field Crops3 0.47

1200

0.00155 52,000

High-Acreage Field Crops4 0.28 0.00092 87,000

Mixing/Loading 

Liquids for

Chemigation

Typical Field Crops1 0.47

350

0.00045 180,000

Typical Field Crops2 0.28 0.000269 300,000

High-Acreage Field Crops3 0.47 0.00045 180,000

High-Acreage Field Crops4 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 Crops1 0.47 80 0.000103 780.000

Typical Field Crops2 0.28 0.0000614 1,300,000

High-Acreage Field Crops3 0.47 200 0.000258 310,000

High-Acreage Field Crops4 0.28 0.000154 520,000

Applicator

Applying Sprays for 

Aerial Application

Typical Field Crops1

0.0049

0.47 350 0.0000101 14,000,000

Typical Field Crops2 0.28 0.000006 23,000,000

High-Acreage Field Crops3 0.47

1200

0.0000345 4,000,000

High-Acreage Field Crops4 0.28 0.0000206 6,700,000

Golf Courses (tees and greens only) 0.34 0.47 5 0.0000099 4,000,000

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Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

Table 9.1. Short- and Intermediate-Term Occupational Risk assessment for Sethoxydim

Exposure 

Scenario Crop or Targeta

Baseline 

Inhalation 

Unit 

Exposureb

Maximum

Application 

Ratec

Area 

Treated 

or 

Amount 

Handled 

Dailyd

Baseline Inhalation

Dosee MOEf

μg/lb ai

lb ai/A or

lb ai/gal

Acres or 

gals mg/kg/day LOC = 100

Applying Sprays for 

Groundboom 

Application

Golf Courses (fairways, tees, and greens) 0.47 40 0.0000799 500,000

Typical Field Crops1 0.47 80 0.00016 250,000

Typical Field Crops2 0.28 0.0000953 420,000

High-Acreage Field Crops3 0.47

200

0.0004 99,000

High-Acreage Field Crops4 0.28 0.00238 170,000

Orchard (Ground/Soil)5 0.47 40 0.0000799 500,000

Flagger

Flagging for Aerial 

Applications

Typical Field Crops1&3

0.35 0.47 350 0.00072 190,000

Typical Field Crops2&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 

MechanicallyPressurized Handgun 

Sprayers

Structural (e.g., bridges, shipyards, home 

decks, foundations), Typical Field Crops1&2, 

Orchard Crops5

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

1Typical 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. 

2Typical 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).

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Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

d Exposure Science Advisory Council Policy #9.1.

e Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × 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 × 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 postapplication 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, 20104. The Agency is in the process of 

evaluating the SAP report. In addition, the Agency is continuing to evaluate the available postapplication 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.

4 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html

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Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

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 intermediateterm 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 Incident Report 

One component of the Agency’s registration review program is consideration of human 

observational information including incident data, medical case reports, general medical 

information, and epidemiology studies. In conjunction with a human health risk assessment 

based on other data sources, such human incident and other human data can assist the Agency in 

better defining and characterizing the risk of pesticides/pesticide products. 

Based on the low frequency and severity of incident cases reported for sethoxydim in both IDS 

and CDC/NIOSH SENSOR-Pesticides, there does not appear to be a concern at this time with 

respect to incident cases that would warrant further investigation. Sethoxydim is no included in 

the Agricultural Health Study (AHS). The Agency will continue to monitor the incident 

information and will re-evaluate these conclusions as needed.

HED has prepared a sethoxydim incident report review (Evans and Recore, 2014, D422759). The 

review considers a variety of types and sources of human observational information including 

human incident data, medical data/case report information, and epidemiological information in 

an effort to inform the re-evaluation of sethoxydim in this phase of registration review. The 

human incident databases that were reviewed are: the OPP Incident Data System (IDS) and 

CDC/NIOSH’s Sentinel Event Notification System for Occupational Risks (SENSOR).

OPP’s IDS includes reports of alleged human health incidents from various sources, including 

mandatory Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Section 6(a)(2) reports 

from registrants, other federal and state health and environmental agencies, and individual 

consumers. Overall, there are few incidents involving sethoxydim reported to IDS. Incidents in 

the IDS system include:

• For the Main IDS, from January 1, 2009 to August 12, 2014, there were no incidents 

reported involving sethoxydim. 

• In Aggregate IDS, from January 1, 2009 to August 12, 2014, there were 10 reported 

incidents involving sethoxydim. These incidents were classified as minor severity. 

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The SENSOR-Pesticides database covers 11 states from 1998-2010, although reporting varies 

from state to state. Cases of pesticide-related illnesses are ascertained from a variety of sources, 

including: reports from local Poison Control Centers, state Department of Labor workers’ 

compensation claims when reported by physicians, reports from State Departments of 

Agriculture, and physician reports to state Departments of Health. A query of SENSORPesticides 1998-2010 identifies seven cases involving sethoxydim (PC Code 121001), five of 

which involved a single active ingredient. These five cases were analyzed for this memo. Four 

cases were low in severity and one case was moderate in severity. The moderate severity case 

was an intentional ingestion for self-harm and will not be further considered. Of the remaining 

four low severity cases, one man was accidentally sprayed in the face with the product. Another 

case was exposed when the product exploded. Two cases that occurred in California in 2002 do 

not include case descriptions. Symptoms experienced by the four cases are summarized in Table 

2.

Table 2. SENSOR-Pesticides 1998-2009: Reported 

Health Effects for Sethoxydim Cases (N=4)

Health Effect # of Times Reported

Dermal 1

Ocular 1

Respiratory 0

Gastrointestinal 2

Renal 0

Nervous System 2

Cardiovascular 0

Miscellaneous 0

* Cases may report multiple health effects

In addition to the incident/poisoning data and medical case reports, epidemiological research can 

be an important source for human observational data and can potentially assist in identifying, 

characterizing, and (ideally) quantifying linkages between human exposures and resulting health 

effects. For sethoxydim, epidemiological data is not available from the AHS.

In summary, based on the low frequency and low severity of cases involving sethoxydim 

reported in both IDS and SENSOR-Pesticides, there does not appear to be a concern at this time 

that would warrant further investigation. The Agency will continue to monitor the incident 

information and if a concern is triggered, additional analysis will be included in the risk 

assessment.

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11.0 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.

Evans, E. and Recore, S. 10/23/2014. D422759. Sethoxydim: Tier 1 Review of Human 

Incidents. 

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.

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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.

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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).

Page 42 of 73
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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.

Page 43 of 73
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Sethoxydim

Guideline 

No. Study Type

MRID No. (year)/ 

Classification /Doses Results

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

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Sethoxydim

Guideline 

No. Study Type

MRID No. (year)/ 

Classification /Doses Results

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

Page 45 of 73
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Sethoxydim

Guideline 

No. Study Type

MRID No. (year)/ 

Classification /Doses Results

870.5100 Genotoxicity

Bacterial gene

mutation assay

41885904

Acceptable, guideline

Concentrations of 313-

5000 μg/mL

Negative

870.5100 Genotoxicity

Bacterial gene 

mutation assay

41915901

Acceptable, guideline

Concentrations of 312-

5000 μg/mL

Negative

870.5300 Genotoxicity

In vitro 

mammalian cell 

gene mutation 

00155130 

Unacceptable, guideline

Highest dose tested: 5000 

μg/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 μg/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 

μg/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.

-

Page 46 of 73
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Sethoxydim

Guideline 

No. Study Type

MRID No. (year)/ 

Classification /Doses Results

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) – Females Age 13-49

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: 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 Acute Reference Dose (aRfD) – General Population

Page 47 of 73
Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

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

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, 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.3.3 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.3.4 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 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

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. 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.3.5 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 6th sternebrae was 

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Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

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.3.6 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.

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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,

Page 50 of 73
Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

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® 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 

Page 51 of 73
Sethoxydim Human Health Risk Assessment DP Nos. D418280; D424578

slit limp, using a mydriatic. Surviving dogs were sacrificed after 26 weeks by exsanguination 

while under the effect of Surital® 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.

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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.

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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 μm, 1.4 ± 1.8 μm, and 1.5 ± 2.4 μm, 

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 

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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® 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.

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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 6th

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 6th 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.

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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.

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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.

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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.

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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-

14C) - 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 l4C-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 

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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 14C-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 14C 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

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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 [σg] 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 

× 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 rth 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 

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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 durationadjusted 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:

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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 

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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 Mexico2 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

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 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

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Table B1. Summary of US and International Tolerances and Maximum Residue Limits for 

Sethoxydim (121001)

Residue Definition:

US Canada Mexico2 Codex

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.

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Appendix C. Metabolites/Degradates

Sethoxydim = MS; 2-[1-(ethoxyimino)butyl]-5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen1-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-hydroxy2-cyclohexen-1-one

MSO2 = sethoxydim sulfone; 2-[1-(ethoxyimino)butyl]-5-[2-(ethylsulfonyl)propyl]-3-hydroxy2-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

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Appendix D. Physical/Chemical Properties

Table 2. Physicochemical Properties of Sethoxydim

Parameter Value Reference

Boiling point/range >130 °C at 6 × 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/cm3 at 20 °C (specific gravity)

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

Solvent solubility Freely soluble (>103 g/100 mL) in organic

solvents (methanol, n-octanol, ethyl acetate, 

n-hexane, toluene, and xylene) at 20 °C

Vapor pressure 1.6 × 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 × 103 at pH 5; 45.1 at pH 7; and 

0.93 at pH 9

UV/visible absorption 

spectrum

Not available

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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. 

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