CLETHODIM Human Health Risk Assessment DP No. D41 1899 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

DATE: January 30,2014 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Clethodim. Preliminary Risk Assessment for Registration Review. 

PC Code: 121011 

Decision No.: 478940 

Regulatory Action: Registration Review 

Risk Assessment Type: Single. Chemical/Aggregate 

TXRNo.: NA 

MRIDNo.: NA 

DP Barcode: D411899 

Registration No.: NA 

Petition No.: NA 

Case No.: 7226-1 

CAS No.: 99129-21-2 

40 CFR: §180.458 

..::::----::> ~ 

FROM: Nancy 

Meheret 

Tsaur, 

Neguss

Chemist 

ie, Chemistf ~ 'J::t:d, t:r:e::: _).!~"f:_. Whang Phang, Senior Toxicologist ~ r ~ 

Barry O'Keefe, Senior Biologist /3. () ~ 

Risk Assessment Branch 3 (RAB3) 

Health Effects Division (7509P) 

THROUGH: Christine Olinger, Branch Chief (j / tf/ 

Risk Assessment Branch 3 (RAB3) t 

Health Effects Division (7509P) 

TO: Neil Anderson, Chemical Review Manager 51 

Ricardo Jones, Chemical Review Manager 

Pesticide Reevaluation Division (7508P) 

Page 1 of 41 
CLETHODIM Human Health Risk Assessment DP No. D411899 

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

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

2.1 Data Deficiencies ............................................................................................... : ............ 6 

2.2 Tolerance Considerations .............................................................................................. 6 

2.2.1 Recommended Changes to Tolerances ............................. ............ ............................ 6 

2.2.2 International Harmonization ..................................................................................... 7 

3.0 Introduction ..................................................... ....................... ............... .. : .......................... 8 

3.1 Chemical Identity .......................................................................... ................................. 9 

3.2 PhysicaVChemical Characteristics ............................................................................... 9 

3.3 Pesticide Use Pattern ..... .... ....... .......................... ....................... ............................. ........ 9 

3.4 Anticipated Exposure Pathways ................... ........................................... ......... .......... 10 

3.5 Consideration of Environmental Justice ......................................................... ......... .. 10 

4.0 Hazard Characterization and Dose-Response Assessment .......................................... 11 

4.1 Summary of Toxicological Effects .... ................... ....................................................... 11 

4.2 Safety Factor for Infants and Children (FQP A Safety Factor) ....... .... .................. .. 12 

4.2.1 Completeness of the Toxicology Database .............................................................. 12 

4.2.2 Evidence of Neurotoxicity ........................................................................................ 12 

4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal.. ...... 13 

4.2.4 Residual Uncertainty in the Exposure Database ... ................................................ 13 

4.3 Toxicity Endpoint and Point of Departure Selections .............................................. 13 

4.3.1 Recommendation for Combining Routes of Exposure for Aggregate Risk 

Assessment .............................................. . · .............................................................................. .. 14 

4.3.2 Cancer Classification and Increased Tumor Incidence Risk Assessment 

Recommendation ...................... ........................................................................................ ....... 14 

4.3.3 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment ................................................................. ....................................... ....................... 14 

4.4 Endocrine Disruptor Screenin'g Program ............... .... ........ ....................................... 15 

5.0 Dietary Exposure and Risk Assessment ......................................................................... 16 

5.1 Residues of Concern Summary and Rationale .......................................................... 16 

5.2 Food Residue Profile .................................................................................................... 17 

5.3 Water Residue Profile ........................................................................................... ....... 1 7 

5.4 Dietary Risk Assessment .. ......................... ................................................................. .. 18 

5.4.1 Description of Residue Data Used in Dietary Assessment.. .................................. 18 

5.4.2 Acute Dietary Risk Assessment ......... .......................................................... ............ 18 

5.4.3 Chronic Dietary Risk Assessment ........................................................................... 18 

5.4.4 Cancer Dietary Risk Assessment.. ....................................... .................................... 19 

5.4.5 Summary Table .................... ................................................................. .................... 19 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ... .......................... 19 

6.1 Residential Handler Exposure ...... ............... ............................................................... 19 

6.2 Residential Post-Application Exposure ................... ................................................... 20 

6.3 Residential Risk Estimates for Use in Aggregate Assessment ............... ................... 20 

6.4 Residential Bystander Post-Application Inhalation Exposure .......................... ...... 20 

6.5 Spray Drift .................................................................................................................... 21 

7.0 Aggregate Exposure/Risk Characterization ............................................... ................... 21 

7.1 Acute Aggregate Risk ................................. .................................................................. 22 

7.2 Short-Term Aggregate Risk ........................................ ................................................ 22 

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CLETHODIM Human Health Risk Assessment DP No. D411899 

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7.3 Intermediate-Term Aggregate Risk ........................................................................... 22

7.4 Chronic Aggregate Risk .............................................................................................. 22

8.0 Cumulative Exposure/Risk Characterization ............................................................... 22

9.0 Occupational Exposure/Risk Characterization ............................................................ 23

9.1 Short- and Intermediate-Term Handler Risk ........................................................... 23

9.2 Post-Application Risk .................................................................................................. 23

9.2.1 Dermal Post-Application Risk ................................................................................. 23

9.2.2 Inhalation Post-Application Risk ............................................................................ 24

10.0 References ......................................................................................................................... 24

Appendix A. Registered Clethodim End-Use Products .......................................................... 26

Appendix B. Toxicology Profile and Executive Summaries................................................... 30

B.1 Toxicology Data Requirements ................................................................................... 30

B.2 Endpoint Selection ....................................................................................................... 31

B.3 Toxicity Profiles ............................................................................................................ 33

Appendix C. Physical/Chemical Properties ............................................................................. 38

Appendix D. International Residue Limit Status.................................................................... 39
CLETHODIM Human Health Risk Assessment DP No. D411899 

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1.0 Executive Summary 

Clethodim [2-[(1E)-1-[[[(2E)-3-chloro-2-propenyl]oxy]imino]propyl]-5-[2-(ethylthio)propyl]-3-

hydroxy-2-cyclohexen-1-one] is a systemic and selective post-emergence herbicidal active 

ingredient (ai) used to control existing annual and perennial grasses. In plants, clethodim inhibits 

acetyl-CoA carboxylase, which regulates fatty acid metabolism. The mode of action in the 

mammalian system is not known at this time. 

This preliminary risk assessment provides information to support the registration review of 

clethodim and addresses the exposures and risk estimates associated with all currently registered 

uses. Since the last risk assessment, new data have been submitted, and policies have changed. 

This document incorporates changes made to the selected endpoints, points of departure (PODs), 

residential risk estimates, drinking water exposure contributions, recommended tolerances, and 

potential for spray drift exposure (K. Rury, DP384944, 09/26/2011). All data requirements 

previously addressed during the scoping process have been satisfied (B. O’Keefe, DP349757, 

09/09/2008). 

Use Profile

Clethodim is currently registered for use on several agricultural crops and a variety of non-food 

uses, including residential landscaped areas. It is formulated into numerous suspension 

concentrate (SC) and emulsifiable concentrate (EC) products. These end-use products range 

from 12.4% ai to 36.7% ai. The registered labels permit application via aerial and ground 

equipment for all crops, as well as chemigation for some. All occupational labels require 

personal protective equipment (PPE) for all applicators and other handlers consisting of a longsleeved shirt, long pants, shoes plus socks, chemical-resistant gloves, and protective eyewear. 

Exposure Profile

Non-occupational exposures to clethodim are expected for short-, intermediate-, and long-term 

(chronic) durations. Routes of exposure include diet, drinking water, and residential exposure 

sources. The dermal route of exposure is not relevant because there is no systemic toxicity up to 

the limit dose via the dermal route of exposure. Occupational inhalation exposures are expected 

for short- and intermediate-term durations only. The existing residential uses only result in 

inhalation exposures for adults (handlers) and do not result in post-application incidental oral 

exposures for children (non-dietary ingestion exposure is not expected). 

Hazard Characterization

The risk assessment for clethodim is based on a well-characterized and complete toxicology 

database. Overall, the database shows relatively low toxicity. The liver is the target organ based 

on repeated dosing by either oral or dermal routes in rats, mice, and dogs. The observed liver 

effects are characterized by increased liver weights, clinical chemistry changes, and centrilobular 

hepatic hypertrophy. Most of the liver effects that occurred at or below 100 mg/kg were 

considered adaptive effects. Decreased body weight was also a common finding across studies 

and species. In the 1-year dog oral toxicity study, hematological changes such as increased 

platelet and leukocyte counts were also noted. 
CLETHODIM Human Health Risk Assessment DP No. D411899 

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Clethodim has a low order of acute toxicity via oral, dermal, and inhalation routes of exposure as 

demonstrated by the toxicity categories. It produces mild acute ocular irritation and mild acute 

skin irritation, but it is not a dermal sensitizer. Developmental effects were not present in 

rabbits, and the toxicity data did not show an increased susceptibility in the young; the rat 

developmental toxicity study showed reduced fetal body weights and an increase in the incidence 

of delayed ossification of the lower vertebrae at the same dose where maternal toxicity was 

found. Furthermore, neither reproductive nor offspring effects were seen in the 2-generation rat 

reproduction study. Therefore, the data support a reduction of the Food Quality Protection Act 

(FQPA) safety factor to 1X. The rat and mouse carcinogenicity studies did not show treatmentrelated increases in tumor incidence. Clethodim is not genotoxic and is classified as “not likely 

to be carcinogenic to humans.” The toxicity endpoints and POD for acute dietary exposure is 

based on the acute neurotoxicity rat study. For chronic dietary, they are based on the 

carcinogenicity mouse study. For short-/intermediate-term incidental oral and inhalation 

exposure, they are based on the 90-day oral toxicity dog study. 

Dietary Risk Estimates (Food + Drinking Water)

Unrefined acute and chronic dietary analyses were conducted assuming tolerance-level residues 

for all commodities and 100% crop treated (CT). Unless tolerances were established for 

processed commodities, DEEM version 7.81 default processing factors were assumed. 

Estimated drinking water concentrations (EDWCs) were incorporated directly into the dietary 

assessment: 1,430 μg/L for acute and 1,150 μg/L for chronic. 

All dietary risk assessments do not result in risk estimates of concern. The acute dietary (food 

and drinking water) exposure is estimated at 10% of the acute Population Adjusted Dose (aPAD) 

for the general U.S. population and 29% of the aPAD for all infants (<1 year old), the population 

subgroup with the highest estimated acute dietary exposure to clethodim. The chronic dietary 

(food and drinking water) exposure is estimated at 12% of the chronic Population Adjusted Dose 

(cPAD) for the general U.S. population and 30% of the cPAD for all infants (<1 year old), the 

population subgroup with the highest estimated chronic dietary exposure to clethodim. 

Residential Risk

The residential handler, post-application, and spray drift risk assessments do not result in risk 

estimates of concern. All risk estimates for residential handler do not exceed HED’s level of 

concern (LOC), i.e. an MOE of 100. Residential post-application exposures are not of concern 

because there is no systemic toxicity up to the limit dose via the dermal route of exposure. 

Furthermore, incidental oral exposures are not expected from direct residential applications. 

Aggregate Risk

There is potential for short-term aggregate exposure to clethodim via the dietary (background 

exposure) and residential (primary exposure) pathways. The adult short-term aggregate (dietary 

+ residential) risk estimate is not of concern. The adult assessment results in an MOE of 2,000 

which does not exceed HED’s LOC, i.e. an MOE of 100. Intermediate-term and chronic 

aggregate risk estimates are expected to be equivalent to chronic exposure via the dietary 

pathway. 
CLETHODIM Human Health Risk Assessment DP No. D411899 

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Occupational Risk

The occupational handler risk assessments for short- and intermediate-term do not result in risk 

estimates of concern at baseline (without any PPE). All risk estimates for occupational handlers 

(inhalation only) do not exceed HED’s LOC, i.e. an MOE of 100. Post-application assessments 

were not completed because there is no systemic toxicity up to the limit dose via the dermal 

route of exposure. The restricted entry interval (REI) of 24 hours on the registered labels is 

considered adequate. Based on the Agency's current practices, a quantitative occupational postapplication inhalation exposure assessment was not performed for clethodim at this time. If new 

policies or procedures are put into place, the Agency may revisit the need for a quantitative 

occupational post-application inhalation exposure assessment for clethodim. 

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).

2.0 HED Recommendations 

HED has examined the toxicology and residue chemistry databases for clethodim. As detailed 

below in Sections 2.2.2 and 2.2.3, HED recommends revising several tolerances to accommodate 

crop group revisions, and harmonization of U.S. tolerances with Codex maximum residue limits 

(MRLs). 

2.1 Data Deficiencies 

There are no data deficiencies for clethodim at this time. 

2.2 Tolerance Considerations 

2.2.1 Recommended Changes to Tolerances 

Permanent tolerances have been established in 40 CFR §180.458 for the combined residues of 

clethodim and its metabolites containing the 5-(2-ethylthiopropyl)cyclohexene-3-one and 5-(2-

ethylthiopropyl)-5-hydroxycyclohexene-3-one moieties, and their sulphoxides and sulphones, 

expressed as clethodim in/on various raw agricultural commodities ranging from 0.2 ppm to 20 

ppm. 

The proposed tolerance changes are a result of crop group revisions and thus conversions from 

existing groups/subgroups or representative commodities. The recommended revisions are 

presented in Table 2.2.1. 

The existing U.S. tolerances for bean dry seed (2.5 ppm) and potato (0.5 ppm) need to be 

removed from 40 CFR §180.458(a) since these commodities are included in crop group 6 (3.5 

ppm) and 1C (1.0 ppm), respectively. 
CLETHODIM Human Health Risk Assessment DP No. D411899 

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Tolerances on rapeseed subgroup 20A (0.6 ppm), sunflower subgroup 20B (5.0 ppm), and 

cottonseed subgroup 20C (1.0 ppm) need to be established. In conjunction with establishment of 

these tolerances, the existing tolerances for canola, seed; cotton, undelinted seed; flax, seed; 

mustard, seed; safflower, seed; sesame, seed; and sunflower, seed need to be removed from 40 

CFR §180.458(a). 

The existing tolerances for onion, bulb (0.20 ppm) needs to be revised to onion, bulb, subgroup 

3-07A and onion, green (2.0 ppm) needs to be revised to onion, green, subgroup 3-07B. The 

existing tolerances for vegetable, fruiting group 8 (1.0 ppm) need to be revised to vegetable, 

fruiting, group 8-10. 

Table 2.2.1. Tolerance Recommendations for Clethodim

Commodity

Tolerance (ppm)

Comments Established Recommended

Bean, dry, seed 2.5 None

Remove

Covered by vegetable, legume, group 6, except 

soybean tolerance at 3.5 ppm

Onion, bulb 0.2 0.50

Establish as Onion, bulb, subgroup 3-07A at 0.5 ppm 

and increase tolerance to harmonize with Codex

Onion, green 2.0 2.0 Establish as Onion, green, subgroup 3-07B at 2.0 ppm

Potato 0.5 None

Remove

Covered by vegetable, tuberous and corm, subgroup 

1C tolerance at 1.0 ppm

Canola, seed 0.50

0.60 Establish as Rapeseed subgroup 20A at 0.6 ppm Flax, seed 0.6

Mustard, seed 0.50

Sesame, seed 0.35

Safflower, seed 5.0 5.0 Establish as Sunflower subgroup 20B at 5.0 ppm Sunflower, seed 5.0

Cotton, undelinted seed 1.0 1.0 Establish as Cottonseed subgroup 20C at 1.0 ppm

Peanut 3.0 5.0 Increase to Harmonize with Codex

Vegetable, fruiting group 8 1.0 1.0 Establish as Vegetable, fruiting, group 8-10

2.2.2 International Harmonization 

The U.S. residue definition is harmonized with Codex, but not Canada. Canada’s tolerance 

expression includes clethodim and its metabolites containing the 2-cyclohex-1-enone moiety, but 

does not include the sulphoxides and sulphones. 

For numerous commodities, there are no Codex/Canada MRLs and thus no need to evaluate 

harmonization. Table 2.2.2 provides detailed explanations of whether or not the U.S. can 

achieve harmonization with Codex and/or Canada. For a complete summary of U.S. tolerances, 

international tolerances, and MRLs for plant and animal commodities, refer to Appendix D. 
CLETHODIM Human Health Risk Assessment DP No. D411899 

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Table 2.2.2. Tolerance Recommendations for Clethodim

Commodity(ies) Tolerance Harmonization Comments

alfalfa hay (fodder), soybean, 

milk, meat, and meat byproducts 

(of cattle, goats, hogs, horses, 

poultry, and sheep)

U.S. and Codex are harmonized.

bean fodder, fodder beet, garlic

Codex has established MRLs.

U.S. does not establish tolerances on bean fodder and fodder beet

U.S. did not establish a tolerance on garlic because it is covered by the onion 

dry bulb tolerance.

coriander seed, fenugreek seed MRLs are established in Canada.

U.S. did not establish tolerances on these commodities (subgroup 19B).

peanut, onion bulb

U.S. tolerances on peanut (3 ppm) and onion bulb (0.20) are increased to 5 

ppm and 0.50 ppm, respectively to harmonize with the Codex MRL.

Harmonization with Codex creates a discrepancy for onion bulb with Canada.

sugar beet (roots), eggs

U.S. tolerances cannot be harmonized because the Codex MRLs are lower. 

Thus, setting the U.S. tolerance to be consistent with the Codex MRLs might 

lead to residues in excess of the tolerance despite legal use of the pesticide in 

accordance with the registered label.

subgroups 1C, 20A, 20B, 20C; 

crop groups 6, 8

U.S. tolerances are not harmonized with Codex MRLs due to different Codex 

crop grouping classifications, lower Codex MRLs, and use of different data 

sets to establish MRLs. The tolerance value for crop group 8 is the same as 

the MRL for tomato which is one of the representatives for crop group 8.

subgroup 13-07B, soybeans U.S. tolerances are in agreement with Canadian MRLs.

subgroups 1C, 4A, 20A, 20B; 

crop group 6

U.S. tolerances are not harmonized with Canadian MRLs.

Canadian MRLs are not established as crop groups.

Canadian MRLs are established on spinach; beans dry, chickpeas, dry lentils, 

dry peas; potatoes; rapeseed (canola), flaxseed, mustard seeds; and sunflower 

seeds respectively. 

Canadian MRLs on mentioned crop groups/subgroups (except 4A) are lower 

than the U.S. tolerances. The tolerance value for subgroup 4A is the same as 

the MRL for spinach which is one of the representatives for subgroup 4A.

livestock commodities There are no Canadian MRLs on livestock commodities.

Canada does not establish tolerances on livestock feedstuffs.

3.0 Introduction

Clethodim is a selective post-emergence cyclohexanedione herbicide used to control annual and 

perennial grasses around a wide variety of broad leaf crops. It is rapidly absorbed and readily 

translocated from treated foliage to the roots as well as other growing plant parts. In plants, 

clethodim inhibits acetyl-CoA carboxylase, which regulates fatty acid metabolism. However, the 

mode of action in the mammalian system is not known at this time. 

This preliminary risk assessment provides information to support the registration review of 

clethodim and addresses the exposures and risk estimates associated with all currently registered 

uses. Since the last risk assessment, new data have been submitted, and policies have changed. 

This document incorporates changes made to the selected endpoints, PODs, residential risk 

estimates, drinking water exposure contributions, recommended tolerances, and potential for 
CLETHODIM Human Health Risk Assessment DP No. D411899 

Page 9 of 41 

spray drift exposure. All data requirements previously addressed during the scoping process 

have been satisfied (B. O’Keefe, DP349757, 09/09/2008). 

3.1 Chemical Identity

The chemical structure and nomenclature of clethodim are presented in Table 3.1. 

Table 3.1. Test Compound Nomenclature

Chemical Structure

Empirical Formula C17H26ClNO3S

Common Name Clethodim

Company experimental name RE45601

IUPAC name (5RS)-2-{(E)-1-[(2E)-3-chloroallyloxyimino]propyl}-5-[(2RS)-2-

(ethylthio)propyl]-3-hydroxycyclohex-2-en-1-one

CAS Name 2-[(1E)-1-[[[(2E)-3-chloro-2-propenyl]oxy]imino]propyl]-5-[2-

(ethylthio)propyl]-3-hydroxy-2-cyclohexen-1-one

CAS Registry Number 99129-21-2

Chemical Class cyclohexenone

Known Impurities of Concern None

3.2 Physical/Chemical Characteristics

The physiochemical properties of clethodim are summarized in Appendix C. Clethodim has a 

low vapor pressure (<1x10-7 mm Hg). Thus, clethodim is unlikely to volatilize significantly. 

Clethodim has a relatively high octanol/water partition coefficient log (Kow) of 4.51 (at 20°C)

which indicates moderate fat solubility and, however, studies show minimal potential for 

bioaccumulation. At 20°C, the Henry’s Law constant was calculated to be <2×10-9 atm·m3/mol 

based on vapor pressure and water solubility. Clethodim is hydrolytically stable under acid and 

neutral conditions, and has some water solubility. 

3.3 Pesticide Use Pattern

Clethodim is currently registered on the following agricultural crops: alfalfa, artichoke, 

asparagus, beans (dry and succulent), beets (garden), Brassica vegetables (head and stem), 

bushberries, caneberries, canola, carrot, clover, corn (field), cotton, cranberry, cucurbits, flax, 

fruiting vegetables, garlic, herbs, hops, leafy petioles, leafy Brassica greens, leaf lettuce, leafy 

greens, legume vegetables, mint, mustard seed, onion (bulb and green), pea (shelled and 

succulent), peach, peanut, potato, radish, root vegetables (except radish), rhubarb, safflower, 

sesame, shallot (bulb and green), soybean, spinach, strawberry, sugar beet, sunflower, sweet 

O

OH

N

CH3

O Cl

S

CH3

3CH
CLETHODIM Human Health Risk Assessment DP No. D411899 

Page 10 of 41 

potato (including yam and other tuberous and corm vegetables, except potato), tomato, and 

turnip greens. 

Clethodim is also registered for a variety of non-food uses including the following: non-bearing 

fruit and nut trees, ornamentals, conifer trees, Christmas trees, fallow land, wildlife food plots, 

and sod farms. Furthermore, there is one clethodim product (EPA Reg. No. 59639-175) labeled 

specifically for residential homeowner use on landscaped areas, ornamental plant beds, and in 

and around trees and mulched areas. Additionally, there are various 24(C) products registered 

for use on sod farms only. 

Clethodim is currently formulated into numerous soluble concentrate (SC) and emulsifiable 

concentrate (EC) formulation products. The end use formulation products contain between 

12.4% to 36.7% ai. A complete list of these currently registered end use products, along with 

uses and application rates, is presented in Appendix A. 

3.4 Anticipated Exposure Pathways 

The Pesticide Reevaluation Division (PRD) has requested an assessment of human health risk to 

support the registration review of all existing registered uses of clethodim. Humans may be 

exposed to clethodim via drinking water since application may result in clethodim reaching 

surface and ground water sources of drinking water, and via dietary exposure from applications 

to agricultural commodities. There are residential uses of clethodim and potential for spray drift, 

so there is exposure in residential and non-occupational settings. In an occupational setting, 

applicators may be exposed while handling the pesticide prior to application, as well as during 

application. There is also potential for post-application exposure for workers re-entering treated 

sites. This risk assessment considers all of the aforementioned exposure pathways based on the 

existing uses of clethodim. 

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 U.S. Department of 

Agriculture’s 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 and ethnic group. 

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 
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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

The risk assessment for clethodim is based on a well-characterized and complete toxicology 

database. The available toxicology studies include (1) subchronic oral toxicity studies in rats, 

mice, and dogs; (2) two 21/28 day dermal toxicity studies in rats; (3) developmental toxicity 

studies in rats and rabbits; (4) a 2-generation reproduction study in rats; (5) chronic toxicity 

studies in rats and dogs; (6) carcinogenicity studies in mice and rats; (7) a battery of genotoxicity 

studies; (8) a metabolism study in rats; (9) a dermal penetration study in rats; (10) a neurotoxicity 

battery in rats; and (11) an immunotoxicity study in mice. In addition, studies are also available 

on metabolites: imine sulfone (5-week oral toxicity, prenatal developmental, gene mutation, and 

CHO assay); and 5-hydroxy sulfone (prenatal developmental and gene mutation). The 

requirement for a subchronic inhalation toxicity study has been waived (HASPOC, TXR 

0056491, 2/20/2013). 

Since the last risk assessment, acute and subchronic neurotoxicity studies were submitted and 

reviewed. Furthermore, some toxicity studies were reevaluated according to the current 

guidelines, and the NOAELs and LOAELs of some studies were changed. The changes were 

taken into consideration during the process of toxicity endpoint and POD selections. 

4.1 Summary of Toxicological Effects 

In general, the clethodim toxicity database shows relatively low toxicity. With repeated dosing 

by the oral or dermal routes, the liver is the target organ of clethodim toxicity. Liver effects 

(characterized by increased liver weights, clinical chemistry changes, and centrilobular hepatic 

hypertrophy) were seen in rats, mice, and dogs. Clinical chemistry changes include the 

following: slight alkaline phosphatase increase, slight elevation of cholesterol values, and slight 

elevation of glucose levels (in dogs only). However, most of the liver effects produced by 

clethodim at 100 mg/kg/day or below were shown to be adaptive effects. Decreased body weight 

was also a common finding across studies and species. In the 1-year oral toxicity study in dogs, 

hematological changes (increased platelet and leukocyte counts) were also seen. 

No developmental effects were present in the rabbits. In the rat developmental toxicity study, 

reduced fetal body weights and an increase in the incidence of delayed ossification of the lower 

vertebrae were seen at the dose where maternal toxicity was also found. No reproductive or 

offspring effects were seen in the 2-generation rat reproduction study. Therefore, the toxicity 

data showed no increased susceptibility in the young. Treatment related increase in tumor 

incidence was not observed in rat and mouse carcinogenicity studies. Clethodim is not genotoxic 

and was classified as “not likely to be carcinogenic to humans.” 

Clethodim has low acute toxicity via oral, dermal and inhalation routes of exposure as 

demonstrated by the toxicity categories (III & IV). Clethodim produces mild ocular irritation 

(Category III) and mild skin irritation (Category IV). It is not a dermal sensitizer. 
CLETHODIM Human Health Risk Assessment DP No. D411899 

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Oral administration of clethodim to rats resulted in rapid absorption with greater than 89% of the 

administered dose absorbed. The absorbed clethodim was distributed to blood, kidneys, liver, 

adrenal, and other tissues. There was no difference in the concentration of radiocarbon in the 

tissues between the repeated dose group and single dose group. The adrenal glands showed the 

highest concentration of clethodim equivalents. The absorbed clethodim was extensively 

metabolized by (1) oxidation to clethodim sulfoxide and further to clethodim sulfone, (2) 

converted to S-methyl via sulfonium cation intermediate, (3) converted to imine, or (4) 

hydroxylated at the 5 position. The predominant metabolite was clethodim sulphoxide (48-

68%). Elimination was rapid; most of the recovered dose in all treatment groups was eliminated 

after 48 hours with <1% eliminated as parent clethodim. Clethodim was shown to be eliminated 

mostly via the urine (87-92%), and a relatively minor percentage was eliminated via feces (9.3-

17%). Excretory metabolites which accounted for more than 5% each of the administered dose 

were: clethodim sulfoxide (48-63%), S-methyl sulfoxide (6-12%), and imine sulfoxide (7-10%). 

There was no gender difference in the rate of elimination, and the urinary metabolite profile was 

very similar for males and females. Bioaccumulation was not demonstrated. The total dermal 

absorption for clethodim should be 42.0% of the applied dose with 10 hours of exposure. 

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

The toxicology and the exposure databases support the recommendation that the FQPA SF be 

reduced to 1X as there is a complete toxicology database, no neurotoxicity concern, and no 

evidence of susceptibility in the developing organisms. Furthermore, there are no uncertainties 

in the exposure database.

4.2.1 Completeness of the Toxicology Database 

The toxicity database for clethodim is complete and sufficient for selecting toxicity endpoints 

and PODs for risk assessment. The required subchronic inhalation study was waived (HASPOC, 

TXR 0056491, 2/20/2013). The selected toxicity endpoints and PODs for risk assessment are 

based on the most sensitive and relevant data. 

4.2.2 Evidence of Neurotoxicity 

In two acute neurotoxicity studies in rats, clinical signs such as decreased spontaneous activity, 

ruffled fur, hunched posture, and abnormal gaits were seen at 1000 mg/kg during the first three 

days after dosing. Subsequently, treatment-related clinical signs were not present, and 

histopathology of the brain and peripheral nervous system were not found. Furthermore, 

evidence of neurotoxicity was not found in the subchronic neurotoxicity study in the rats. 

Therefore, the transient clinical signs may indicate general malaise of the treated animals which 

received a limit dose of clethodim (1000 mg/kg/day), and a developmental neurotoxicity study is 

not required.
CLETHODIM Human Health Risk Assessment DP No. D411899 

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

There is no evidence of susceptibility following in utero and/or postnatal exposure in the 

developmental toxicity studies in rats or rabbits, and in the 2-generation rat reproduction study.

4.2.4 Residual Uncertainty in the Exposure Database 

The exposure databases are complete or are estimated based on data that reasonably account for 

potential exposures. The acute and chronic dietary food exposure assessments were 

conservatively based on 100% crop treated (CT) assumptions and conservative ground water 

drinking water modeling estimates. New 2012 Residential Standard Operating Procedures 

(SOPs) were used to assess residential handler exposure, assuming that maximum application 

rates are applied. All of the exposure estimates are based on conservative assumptions and are 

not likely to result in underestimated risk. 

4.3 Toxicity Endpoint and Point of Departure Selections 

The toxicity endpoints and PODs are presented in Section 4.3.3, and the details for selecting 

toxicity endpoints and PODs for various exposure scenarios are presented in Appendix B.

For clethodim, HED has selected the most sensitive and protective endpoints from the database 

to establish PODs for the risk assessment. Developmental effects attributable to a single dose 

were not seen following in utero exposures to rats and rabbits; therefore, a dose and endpoint 

were not selected for acute oral exposure for the female 13 plus subpopulation. For the general 

population, the clinical observations found at 1000 mg/kg (LOAEL) in the two acute 

neurotoxicity studies were used to establish the toxicity endpoint, and the NOAEL of 100 mg/kg 

was used as the POD for risk assessment. HED acknowledges that there is a large spread 

between the LOAEL and NOAEL (10X difference), and the true NOAEL may lie between 1000 

and 100 mg/kg. Therefore, the POD for the acute dietary exposure for the general population is 

considered to be conservative. 

For chronic oral exposure, the chronic toxicity studies in rats, mice, and dogs demonstrated that 

most of the adverse effects occurred at dose levels of approximately 100 mg/kg/day or above. 

The NOAELs/LOAELs established for the rat chronic/carcinogenicity study (21/113 mg/kg/day) 

and the mouse carcinogenicity study (30/150 mg/kg/day) were relatively similar. However, the 

adverse effects seen at the LOAEL (150 mg/kg/day) in the mouse study were more robust 

(reduced survival; red cell mass; and increased incidences of bile duct hyperplasia, pigmentation 

of the liver, and foci of amphophilic macrophages in the lung) than those seen in the rat 

chronic/carcinogenicity study (decreases in body weights and food consumption, increases in 

liver weights and the incidence of liver hypertrophy with no reported changes in clinical 

chemistry parameters). The differences in NOAELs/LOAELs in these two studies could be 

influenced by the dose selection. Therefore, it is appropriate to select the NOAEL (30 

mg/kg/day) from the mouse carcinogenicity study as the POD for assessing the risk for the 

chronic dietary exposure, and it is also protective of the effects seen at the LOAEL (113 

mg/kg/day) of the rat chronic/carcinogenicity study and the 1-year toxicity in dogs (LOAEL, 300 

mg/kg/day). 
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For dermal exposure, a 28-day dermal toxicity study was conducted up to the limit dose (1000 

mg/kg/day) and the results did not show any adverse effects. Therefore, neither a dermal toxicity 

endpoint nor a POD for risk assessment was identified. 

For short- and intermediate-term inhalation exposure, the 90-day oral toxicity study in dogs was 

selected to establish the POD (75 mg/kg/day) risk assessment. The toxicity endpoints were 

based on the effects (increased absolute and relative liver weights, cytoplasmic vesiculation, and 

vacuolation of the central lobular hepatocytes) seen at the LOAEL (125 mg/kg/day). Since 

inhalation absorption data are not available, toxicity by the inhalation route is considered to be 

equivalent to the estimated toxicity by the oral route of exposure (i.e. an inhalation absorption 

factor is not needed).

4.3.1 Recommendation for Combining Routes of Exposure for Aggregate Risk 

Assessment 

For short-term aggregate risk assessments, oral and inhalation routes can be combined due to the 

selection of a common toxicological endpoint of concern. Intermediate- and long-term aggregate 

exposure is not expected for the currently registered uses of clethodim. 

4.3.2 Cancer Classification and Increased Tumor Incidence Risk Assessment 

Recommendation 

Increased tumor incidence was not seen in acceptable carcinogenicity studies in rats and mice, 

and clethodim is classified as “Not likely to be Carcinogenic to Humans.” Cancer risk 

assessments do not need to be conducted. 

4.3.3 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment 

Table 4.3. Summary of Toxicological Doses and Endpoints for Clethodim for Use in Dietary, NonOccupational, and Occupational Human Health Risk Assessmentsa

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary

(All 

Populations)

NOAEL = 

100 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF= 1X

RfD = 1 

mg/kg/day

aPAD = 1 

mg/kg/day

Acute neurotoxicity studies- rats

LOAEL =1000 mg/kg based on clinical 

observation from two acute neurotoxicity 

studies (one study was conducted in 2006 and 

another was completed in 2012). The clinical 

observation included decreased spontaneous 

activity, ruffled fur, head tilt, and hunched 

posture
CLETHODIM Human Health Risk Assessment DP No. D411899 

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Table 4.3. Summary of Toxicological Doses and Endpoints for Clethodim for Use in Dietary, NonOccupational, and Occupational Human Health Risk Assessmentsa

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Chronic 

Dietary

(All 

Populations)

NOAEL = 

30 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF= 1X

RfD = 0.3

mg/kg/day

cPAD = 0.3 

mg/kg/day

Carcinogenicity study-mice

LOAEL=150 mg/kg/day based on reduced 

survival; decreased red cell mass; and 

increased incidences of bile duct hyperplasia, 

of pigmentation of the liver, and of foci of 

amphophilic macrophages in the lung.

Incidental Oral 

Short-Term

(1-30 days)

NOAEL =

75

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF=1X

LOC for 

MOE = 100

90-day oral toxicity-dogs 

LOAEL = 125 mg/kg/day based on increased 

absolute and relative liver weights, and 

histological changes characterized by 

cytoplasmic vesiculation and vacuolation of 

the central lobular hepatocytes in both sexes.

Dermal

Short-Term

(1 to 30 days)

and 

IntermediateTerm

(1-6 months)

A dermal assessment is not required. The NOAEL for the 28-day dermal toxicity study is the 

limit dose of 1000 mg/kg/day.

Inhalation

Short-Term

(1 to 30 days) 

and 

IntermediateTerm

(1-6 months)

NOAEL = 

75 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

LOC for 

MOE = 100

90-day oral toxicity-dogs 

LOAEL = 125 mg/kg/day based on increased 

absolute and relative liver weights, and 

histological changes characterized by 

cytoplasmic vesiculation and vacuolation of 

the central lobular hepatocytes in both sexes.

Cancer (oral, 

dermal, 

inhalation)

Clethodim is classified as "Not Likely" to be carcinogenic based no treatment-related increase 

in tumor incidence in rat and mouse carcinogenicity studies.

a 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. 

4.4 Endocrine Disruptor Screening Program 

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 
CLETHODIM Human Health Risk Assessment DP No. D411899 

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chronic studies that assess growth, developmental and reproductive effects in different 

taxonomic groups. As part of its most recent registration decision for clethodim, EPA reviewed 

these data and selected the most sensitive endpoints for relevant risk assessment scenarios from 

the existing hazard database. As required by FFDCA section 408(p), clethodim 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. 

Clethodim is on List 2. List 2 represents the next set of chemicals for which EPA intends to 

issue test orders/data call-ins in the near future. For further information on the status of the 

EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the 

Tier 1 screening battery, please visit our website.2

5.0 Dietary Exposure and Risk Assessment 

For this preliminary risk assessment, a new dietary exposure/risk assessment was conducted to 

incorporate updates in recommended international harmonization tolerances, and drinking water 

exposure contributions (G. Orrick, DP412704, 06/24/2013). 

5.1 Residues of Concern Summary and Rationale 

New residue studies were not submitted. Furthermore, changes have not been made since the 

prior decisions on residues of concern. The residues of concern for dietary risk assessment and 

the tolerance expression are summarized in Table 5.1. A detailed discussion can be found in a 

previous risk assessment conducted in 2010 (N. Dodd, DP364473, 02/24/2010). The residues of 

concern in plants, livestock, and drinking water are clethodim and its metabolites containing the 

 

1

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

chemicals. 

2

 See http://www.epa.gov/endo/. 
CLETHODIM Human Health Risk Assessment DP No. D411899 

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5-(2-ethylthiopropyl)cyclohexene-3-one and 5-(2-ethylthiopropyl)-5-hydroxycyclohexene-3-one 

moieties and their sulfoxides and sulfones. 

Table 5.1. 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 Crop clethodim and its metabolites 

containing the 5-(2-

ethylthiopropyl)cyclohexene-3-one 

and 5-(2-ethylthiopropyl)-5-

hydroxycyclohexene-3-one moieties 

and their sulfoxides and sulfones, 

expressed as clethodim

clethodim and its metabolites 

containing the 5-(2-

ethylthiopropyl)cyclohexene-3-one 

and 5-(2-ethylthiopropyl)-5-

hydroxycyclohexene-3-one moieties 

and their sulfoxides and sulfones, 

expressed as clethodim

Rotational Crop Not applicable Not applicable

Livestock

Ruminant

clethodim and its metabolites 

containing the 5-(2-

ethylthiopropyl)cyclohexene-3-one 

and 5-(2-ethylthiopropyl)-5-

hydroxycyclohexene-3-one moieties 

and their sulfoxides and sulfones, 

expressed as clethodim

clethodim and its metabolites 

containing the 5-(2-

ethylthiopropyl)cyclohexene-3-one 

and 5-(2-ethylthiopropyl)-5-

hydroxycyclohexene-3-one moieties 

and their sulfoxides and sulfones, 

expressed as clethodim

Poultry

Drinking Water

clethodim and its degradates 

containing the 5-(2-

ethylthiopropyl)cyclohexene-3-one 

and 5-(2-ethylthiopropyl)-5-

hydroxycyclohexene-3-one moieties 

(including their sulfoxides and 

sulfones)

Not applicable

5.2 Food Residue Profile 

The residue profile of clethodim is supported by adequate data. Clethodim is rapidly absorbed 

and readily translocated from treated foliage to the roots as well as other growing plant parts. 

5.3 Water Residue Profile 

The Environmental Fate and Effects Division (EFED) provided the estimated drinking water 

concentrations (EDWCs) used in the chronic dietary risk assessment (G. Orrick, DP412704, 

06/24/2013). EDWCs were incorporated directly into the DEEM-FCID dietary assessment in the 

food categories “water, direct, all sources” and “water, indirect, all sources.” 

Based on the proposed application rates and the environmental fate properties of clethodim, 

surface and ground water contamination may occur from clethodim as well as its structurally 

similar degradates. Thus, the assessments were based on the total toxic residue rather than 

parent only. The risk of water contamination is primarily associated with the structurally similar 

degradates rather than parent clethodim based on greater persistence and mobility of these 

degradates. 
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The maximum screening-level acute and chronic EDWCs (1,430 and 1,150 μg/L, respectively) 

used in the dietary assessment are based on the maximum use pattern for clethodim, which 

includes non-cropped areas, fallow ground, alfalfa, and a maximum annual application rate of 

4.5 lb ai/A. The EDWCs are estimated with Pesticide Root Zone Model for Ground Water 

(PRZM-GW) to occur in an area of Wisconsin that is vulnerable to ground water contamination. 

These EDWCs are 43-53X greater than screening-level EDWCs for ground water from 

Screening Concentration In Ground Water (SCI-GROW) and 4-8X greater than screening-level 

EDWCs for surface water from FIRST (FQPA Index Reservoir Screening Tool) (Table 5.3). 

The variance with SCI-GROW may be due, in part, to two factors: 1) PRZM-GW is mechanistic 

and SCI-GROW is empirical, and 2) differences in modeling assumptions such as the duration of 

the modeling scenario. The models and their descriptions are available at the EPA internet site: 

http://www.epa.gov/oppefed1/models/water/. 

Table 5.3. Screening-Level Residues of Concern EDWCs for Clethodim Usesa

Source (Tier: Model) Use Site

(Max. Annual App. Rate)

Acute EDWC 

(μg/L)

Chronic 

EDWC (μg/L)

Surface water (Tier I: FIRST) Non-cropped (4.5 lbs ai/A) 330 137

Ground water (Tier I: PRZM-GW) Non-cropped (4.5 lbs ai/A) 1,430 1,150

Ground water (Tier I: SCI-GROW) Non-cropped (4.5 lbs ai/A) ≤27

a Maximum values in bold. 

5.4 Dietary Risk Assessment 

5.4.1 Description of Residue Data Used in Dietary Assessment 

Conservative, unrefined acute and chronic dietary analyses were conducted. The assumptions of 

the dietary assessment included tolerance levels for all commodities and 100% crop treated (CT). 

DEEM version 7.81 default processing factors were assumed except for where tolerances were 

established for processed commodities, or where processing studies indicated that concentration 

did not occur upon processing. EDWCs were incorporated directly into the dietary assessment 

from ground water estimates obtained using the PRZM-GW model. 

5.4.2 Acute Dietary Risk Assessment 

The acute dietary risk assessment shows that the acute dietary risk estimates do not exceed 

HED’s LOC, i.e. <100% of the aPAD. For the general U.S. population, the exposure for food 

and drinking water utilized 10% of the aPAD. The acute dietary risk estimate for the highest 

reported exposed population subgroup, all infants (<1 year old), utilized 29% of the aPAD. 

5.4.3 Chronic Dietary Risk Assessment 

The chronic dietary risk assessment shows that the chronic dietary risk estimates do not exceed 

HED’s LOC, i.e. <100% of the cPAD. For the general U.S. population, the exposure for food 

and drinking water utilized 12% of the cPAD. The chronic dietary risk estimate for the highest 

reported exposed population subgroup, all infants (<1 year old), utilized 30% of the cPAD. 
CLETHODIM Human Health Risk Assessment DP No. D411899 

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5.4.4 Cancer Dietary Risk Assessment 

Increased tumor incidence was not seen in carcinogenicity studies in rats and mice, and 

clethodim is classified as “Not Likely to be Carcinogenic to Humans.” Cancer risk assessments 

do not need to be conducted. 

5.4.5 Summary Table 

Table 5.4.5. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Clethodima

Population Subgroup

Acute Dietary Chronic Dietary

Dietary Exposure 

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

General U.S. Population 0.102035 10 0.037624 12

All Infants (< 1 year old) 0.285712 29 0.088802 30

Children 1-2 years old 0.176232 18 0.072515 24

Children 3-5 years old 0.156288 16 0.060925 20

Children 6-12 years old 0.105308 10 0.040709 14

Youth 13-19 years old 0.081638 8.2 0.028819 9.6

Adults 20-49 years old 0.094599 9.5 0.034952 12

Adults 50+ years old 0.085046 8.5 0.034444 12

Females 13-49 years old 0.095214 9.5 0.034659 12

a The values for the highest exposed population for each type of risk assessment are bolded. 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization 

A short-term residential handler inhalation exposure assessment for the end use product EPA 

Reg. No. 59639-175 was conducted to capture the exposure scenario that represents the “worst 

case” high-end exposure. The assessment reflected updates to HED’s 2012 Residential SOPs3

along with policy changes for body weight assumptions (B. O’Keefe, DP412295, 11/20/2013). 

6.1 Residential Handler Exposure 

All of the residential handler exposure risk estimates do not exceed HED’s level of concern 

(MOEs ≥100). The inhalation MOEs ranged from 6,300,000 to 630,000,000. See Table 6.1 for 

a summary of the residential handler risk estimates. 

Table 6.1. Residential Handler Exposure and Risk Estimates for Clethodim

Exposure Scenario 

Inhalation Unit 

Exposure 

(mg/lb ai)

Maximum 

Application 

Ratea

(lb ai/ft2)

Area Treated 

Dailyb

(ft2/day)

Inhalation

Dose 

(mg/kg/day)c MOEd

Mixer/Loader/Applicator

Manually Pressurized Handwand 0.018 0.000005647 1200 0.000001525 49,000,000

Hose-End Sprayer 0.0014 0.000005647 1200 0.0000001186 630,000,000

Backpack 0.14 0.000005647 1200 0.00001186 6,300,000

Sprinkler Can 0.0014 0.000005647 1200 0.0000001186 630,000,000

 

3

 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
CLETHODIM Human Health Risk Assessment DP No. D411899 

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a Based on registered label: EPA Reg. No. 59639-175. 

b Based on HED’s 2012 Residential SOPs (http://www.epa.gov/pesticides/science/residential-exposure-sop.html).

c Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/ft2) × Area Treated (ft2/day) ÷ 

BW (80 kg). 

d Inhalation MOE = Inhalation NOAEL (75 mg/kg/day) ÷ Inhalation Dose (mg/kg/day). 

6.2 Residential Post-Application Exposure 

There is the potential for residential post-application dermal exposure for individuals exposed as 

a result of being in an environment that has been previously treated with clethodim. However, 

no dermal toxicity endpoint and POD were identified. Therefore, a dermal post-application risk 

assessment was not conducted. Incidental oral post-application exposures are not expected from 

the use of clethodim in landscaped/ornamental residential areas (B. O’Keefe, DP412295, 

11/20/2013). Post-application non-dietary ingestion exposure is not assessed for young children. 

Unlike treated grass at home or in recreational areas, the potential for exposure via non-dietary 

ingestion for young children is greatly diminished since the extent to which young children 

engage in the types of activities associated with these areas or utilize them for prolonged periods 

of play is low. Therefore, non-dietary ingestion exposure is not expected. 

6.3 Residential Risk Estimates for Use in Aggregate Assessment 

Table 6.3 reflects the residential risk estimate that is recommended for use in the aggregate 

assessment for clethodim. The recommended residential exposure for use in the adult aggregate 

assessment reflects short-term inhalation exposure from applications in and around ornamental 

plant beds, trees, and ground covers via backpack sprayer. 

Table 6.3. Recommendations for the Residential Exposures for the Clethodim Aggregate Assessmenta

Lifestage

(Scenario)

Dose (mg/kg/day)b MOEc

Dermal Inhalation Oral Total Dermal Inhalation Oral Total

Residential Handler

Adult 

(Backpack 

Sprayer) 

NA 0.00001186 NA 0.00001186 NA 6,300,000 NA 6,300,000

a Bolded risk estimates should contribute to the residential exposure portion of the aggregate assessment. 

b Residential Handler Dose = the highest handler dose for all residential handler scenarios assessed. Total Dose = 

Inhalation Dose. 

c Residential Handler MOE = the MOEs associated with the highest residential handler doses. Total MOE = 

Inhalation MOE. 

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 clethodim at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV), low vapor pressure (<1x10-7 mm Hg), and the low 

proposed use rate (0.0455 to 0.25 lb ai/A). However, volatilization of pesticides may be a source 

of post-application inhalation exposure to individuals nearby pesticide applications. The Agency 

sought expert advice and input on issues related to volatilization of pesticides from its Federal 

Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, 
CLETHODIM Human Health Risk Assessment DP No. D411899 

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and received the SAP’s final report on March 2, 20104. The Agency is in the process of 

evaluating the SAP report and may, as appropriate, develop policies and procedures to identify 

the need for and, subsequently, the way to incorporate post-application inhalation exposure into 

the Agency's risk assessments. If new policies or procedures are developed, the Agency may 

revisit the need for a quantitative post-application inhalation exposure assessment for clethodim. 

Although a quantitative residential post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for handlers (i.e. mixers, loaders, 

applicators). This exposure scenario is representative of a worse case inhalation exposure and 

should be considered protective of most post-application inhalation exposure scenarios. 

6.5 Spray Drift 

Off-target movement of pesticides can occur via many types of pathways and it is governed by a 

variety of factors. Sprays that are released and do not deposit in the application area end up offtarget and can lead to exposures to those it may directly contact. They can also deposit on 

surfaces where contact with residues can eventually lead to exposures (e.g. children playing on 

lawns where residues have deposited next to treated fields). The potential risk estimates from 

these residues can be calculated using drift modeling coupled with methods employed for 

residential risk assessments for turf products. Essentially, a residential turf assessment based on 

exposure to deposited residues has been completed to address drift from the agricultural 

applications of clethodim. 

The approach used for quantitatively incorporating spray drift into risk assessment include 

assessing exposures for children (1 to 2 years old) and adults who have contact with turf where 

residues are assumed to have deposited via spray drift thus resulting in an exposure scenario. 

Aside from the predicted residues available for transfer, the routes of exposure and assessment 

methodology is analogous to how exposures to turf products are considered in risk assessment. 

The spray drift risk estimates are based on an estimated deposited residue concentration as a 

result of the screening level agricultural application scenarios. Clethodim is used on numerous 

agricultural crops and can be applied via groundboom, chemigation, and aerial equipment. 

Since neither a dermal toxicity endpoint nor a POD was identified for clethodim, only incidental 

oral risk estimates are presented. For children 1 to <2 years old, the highest incidental oral handto-mouth risk estimates from exposure to clethodim related to spray drift at the edge of the field 

are MOEs of 53,000 and 110,000 for aerial and groundboom scenarios, respectively. Therefore, 

residues of clethodim from spray drift do not exceed HED’s LOC, i.e. an MOE of 100 (B. 

O’Keefe, DP412295, 11/20/2013).

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

risks from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

 

4

 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
CLETHODIM Human Health Risk Assessment DP No. D411899 

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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. 

7.1 Acute Aggregate Risk 

Acute exposure is not expected for the residential exposure pathway. Therefore, the acute 

aggregate risk would be equivalent to the acute dietary exposure estimate. Refer to Section 

5.4.2.

7.2 Short-Term Aggregate Risk 

There is potential short-term exposure to clethodim via the dietary (which is considered 

background exposure) and residential (which is considered primary exposure) pathways. For 

adults, the oral and inhalation routes of exposure should be aggregated since the endpoints of 

concern are common. The recommended residential exposure for use in the adult aggregate 

assessment reflects inhalation exposure from applications in and around ornamental plant beds, 

trees, and ground covers via backpack sprayer. The short-term aggregate risk estimate (dietary 

and residential) is not of concern (as presented in Table 7.2). The MOE is 2,000 which does not 

exceed HED’s LOC, i.e. an MOE of 100. 

Table 7.2. Short-Term Aggregate Risk Calculations

Population LOC for 

Aggregate Riska

Dietary

Exposureb

MOE Inhalation Residential 

Exposurec

Aggregate MOE (food, 

water, and residential)d

Adults 100 0.037624 0.00001186 2000

a The LOC includes the standard inter- and intra- species uncertainty factors totaling 100X. 

b Chronic dietary exposure (see Table 5.4.5). 

c High end inhalation residential exposure (see Table 6.3). 

d Aggregate MOE = short-term NOAEL/(dietary exposure + high end inhalation residential exposure). NOAEL = 

75 mg/kg/day. 

7.3 Intermediate-Term Aggregate Risk 

Intermediate-term exposure is not expected for the residential exposure pathway. Therefore, the 

intermediate-term aggregate risk would be equivalent to the chronic dietary exposure estimate. 

Refer to Section 5.4.3.

7.4 Chronic Aggregate Risk 

There are no chronic residential exposure scenarios; therefore, the chronic aggregate risk would 

be equivalent to the chronic dietary (food and drinking water) risk estimate. Refer to Section 

5.4.3.

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 clethodim and any other substances and clethodim does not appear to produce a toxic 
CLETHODIM Human Health Risk Assessment DP No. D411899 

Page 23 of 41 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 

EPA has not assumed that clethodim has a common mechanism of toxicity with other 

substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

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

9.1 Short- and Intermediate-Term Handler Risk 

The occupational handler risk assessments for short- and intermediate-term do not result in risk 

estimates of concern at baseline levels of protection, without any mitigation of PPE (B. O’Keefe, 

DP412295, 11/20/2013). All risk estimates for occupational handlers (inhalation only) do not 

exceed HED’s LOC, i.e. an MOE of 100 (ranged from 21,000 to 82,000,000). 

The Agency matches quantitative occupational exposure assessment with appropriate 

characterization of exposure potential. While HED presents quantitative risk estimates for 

human flaggers where appropriate, agricultural aviation has changed dramatically over the past 

two decades. According the 2012 National Agricultural Aviation Association (NAAA) survey of 

their membership, the use of GPS for swath guidance in agricultural aviation has grown steadily 

from the mid 1990’s. Over the same time period, the use of human flaggers for aerial pesticide 

applications has decreased steadily from ~15% in the late 1990’s to only 1% in the most recent 

(2012) NAAA survey. The Agency will continue to monitor all available information sources to 

best assess and characterize the exposure potential for human flaggers in agricultural aerial 

applications. 

HED has no data to assess exposures to pilots using open cockpits. The only data available is for 

exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the 

engineering control (enclosed cockpits) and baseline attire (long-sleeve shirt, long pants, shoes, 

and socks); per the Agency’s Worker Protection Standard stipulations for engineering controls, 

pilots are not required to wear protective gloves for the duration of the application. With this 

level of protection, there are no risk estimates of concern for applicators. 

9.2 Post-Application Risk 

9.2.1 Dermal Post-Application Risk 

A dermal post-application risk assessment was not conducted because there is no systemic 

toxicity up to the limit dose via the dermal route of exposure. 

Restricted Entry Interval

The REI specified on the existing labels is based on the acute toxicity of clethodim. Clethodim 

is classified as Toxicity Category IV via the dermal route and Toxicity Category IV for skin 

irritation potential. It is not a skin sensitizer. Under 40 CFR 156.208 (c) (2) (iii), active 
CLETHODIM Human Health Risk Assessment DP No. D411899 

Page 24 of 41 

ingredients classified as Acute III or IV for acute dermal, eye irritation and primary skin 

irritation 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 postapplication exposures to clethodim. Registered labels list REIs of 24 hours, and are adequate. 

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 clethodim at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV), low vapor pressure (<1x10-7 mm Hg), and the low use 

rates (0.0455 to 0.25 lb ai/A). However, there are multiple potential sources of post-application 

inhalation exposure to individuals performing post-application activities in previously treated 

fields. These potential sources include volatilization of pesticides and resuspension of dusts 

and/or particulates that contain pesticides. The Agency sought expert advice and input on issues 

related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on 

March 2, 20105

. The Agency is in the process of evaluating the SAP report as well as available 

post-application inhalation exposure data generated by the ARTF and may, as appropriate, 

develop policies and procedures, to identify the need for and, subsequently, the way to 

incorporate occupational post-application inhalation exposure into the Agency's risk 

assessments. If new policies or procedures are put into place, the Agency may revisit the need 

for a quantitative occupational post-application inhalation exposure assessment for clethodim. 

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 most occupational post-application 

inhalation exposure scenarios.

10.0 References

N. Dodd, 02/24/2010, DP364473, “Clethodim: Human Health Risk Assessment for Proposed 

Uses on Caneberry Subgroup 13-07A, Bushberry Subgroup 13-07B, Peach, and Globe 

Artichoke.” 

M. Negussie, 11/13/2013, DP412296, “Clethodim: Acute and Chronic Aggregate Dietary (Food 

and Drinking Water) Exposure and Risk Assessments for Registration Review.” 

B. O’Keefe, 09/09/2008, DP349757, DP356151, “Revised Clethodim Human Health Assessment 

Scoping Document in Support of Registration Review.” 

B. O’Keefe, 11/20/2013, DP412295, “Clethodim. Occupational and Residential Exposure 

Assessment for Registration Review.” 

G. Orrick, 06/24/2013, DP412704, “Clethodim: Drinking Water Exposure Assessment for 

Registration Review.” 

 

5

 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
CLETHODIM Human Health Risk Assessment DP No. D411899 

Page 25 of 41 

W. Phang, 08/16/2013, DP411994, “Clethodim: New executive summaries for the re-evaluation 

of the one-year oral toxicity–dog, developmental toxicity study–rabbit, 28-day.dermal 

toxicity-rat, carcinogenicity study-mouse, and combined chronic/carcinogenicity study-rat.” 

K. Rury, 09/26/2011, DP384944, “Clethodim: Human Health Risk Assessment for Proposed 

Uses of Clethodim on Ornamental Plant Beds, Landscapes, Trees, Shrubs and Wildlife Food 

Plots.” 
CLETHODIM Human Health Risk Assessment DP No. D411899 

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Appendix A. Registered Clethodim End-Use Products 

Table A.1. Registered Clethodim End-Use Products

EPA Reg. No. Formulation 

Type Product Label Name Company

1381-204 EC Section 2EC Herbicide Winfield Solution, LLC

2749-546 EC Aceto Clethodim 2 EC Aceto Agricultural Chemicals Corp.

5905-578 EC Tapout Helena Chemical Co. 5905-586 EC Tapout WFP

9468-37 EC Cleo 26.4 Ritter Chemical, LLC

34704-864 EC Intensity Post-Emergence Grass 

Herbicide

Loveland Products, Inc. 34704-949 SC Intensity Max

34704-954 SC LPI Clethodim

34704-976 EC Intensity One Post-Emergence Grass 

Herbicide

42750-72 EC Clethodim 2E Albaugh, Inc.

59639-3 EC Select 2EC Herbicide

Valent USA Corp.

59639-78 EC Select Herbicide

59639-102 EC Select Super Herbicide

59639-132 EC V-10137 1 EC Herbicide

59639-133 EC V-10139 1.6 EC (Herbicide)

59639-174 SC Grass Killer For Wildlife Food Plots GL

59639-175 SC Select Grass Killer GL

66222-60 EC Mana Arrow 2EC Herbicide Makhteshim Agan

66330-328 EC Clethodim 2EC Herbicide

Arysta Life Science North America, 

LLC

66330-339 EC Clethodim 2EC AG Herbicide

66330-353 SC Clethodim 2EC Herbicide2

66330-395 EC ARY 0411-007 Herbicide

66330-412 EC ARY 0411-0485 Tank Mix Herbicide

66330-414 EC ARY 0411-004

72056-2 EC Clethodim 2EC Herbicide Nisso BASF Agro Co., Ltd

72159-15 EC Agrisel Grassout Max Herbicide Agrisel USA, Inc.

83222-30 EC Clethodim 2 EC Herbicide Direct Ag Source, LLC

83520-22 RTU Liquid Clethodim 2EC Tacoma Ag, LLC

83772-7 EC Agsaver Clethodim Ag Saver, LLC

83851-18 EC Clethodim 2EC Amtide, LLC

84229-21 EC Tide Clethodim 2EC Tide International, USA Inc.

84930-6 EC ARC-Clethodim #2 Arcana, LLC

85678-23 SC Clethodim 2E Red Eagle International, LLC

86363-12 EC KT Clethodim 2EC Kaizen Technologies, LLC

87290-11 EC Willowood Clethodim 2 EC Willowood, LLC

89168-11 EC Liberty Clethodim 2EC Liberty Crop Protection, LLC

89442-4 SC PS Clethodim Prime Source, LLC

AL980004000 EC Select Herbicide

Valent USA Corp.

FL00001200 EC Select Herbicide

GA98000600 EC Select Herbicide

NC0000200 EC Select Herbicide

SC98000200 EC Select Herbicide
CLETHODIM Human Health Risk Assessment DP No. D411899 

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Table A.2. Existing Use Pattern for Clethodim

Crop or Use Site

Single

Maximum

Application 

Rate

Maximum Seasonal 

PHI RTI

No. of 

Applications

Application 

Rate

lb ai/A lb ai/A days days

Alfalfa, including: Sainfoin, Holy Clover, Birdsfoot 

trefoil 0.25 NS 0.5 15 14

Alfalfa, Seedling 0.24 NS 0.5 15 14

Artichoke, Globe 0.12 NS 0.5 5 14

Asparagus 0.125 NS 0.5 1 14

Bean, Dry, including: Bean (Lupinus spp.; i.e. Grain, 

Sweet, White, White Sweet), Bean (Phaseolus spp.; 

i.e. Field, Kidney, Lima (dry), Navy, Pinto, Tepary), 

Bean (Vigna spp.; i.e. Adzuki Bean, Black-eyed Pea, 

Catjang, Cowpea, Crowder Pea, Moth Bean, Mung 

Bean, Rice Bean, Southern Pea, Urd Bean, Broad 

(dry), Chickpea (garbanzo), Guar, Lablab Bean, 

Lentil).

0.25 NS 0.5 30 14

Bean, Succulent Shelled, including: Bean (Phaseolus 

spp.; i.e. Broad Bean (succulent), Lima Bean (green)), 

Bean (Vigna spp.; Black-eyed Pea, Cowpea, Southern 

Pea).

0.125 1 0.125 21 NA

Beet, Garden 0.125 NS 0.5 30 14

Brassica Vegetables, Head & Stem, including: 

Broccoli, Chinese Broccoli, Cabbage, Chinese Napa 

Cabbage, Chinese Mustard, Cavalo Broccolo, 

Cauliflower, Brussel sprouts, Kohlrabi.

0.125 NS 0.5 30 14

Bushberry, including: Aronia Berry, Highbush 

Blueberry, Chilean Gauva, Highbush Cranberry, 

Black Currant, Buffalo Currant, Native Currant, Red 

Currant, Elderberry, European Barberry, Gooseberry, 

Edible Honeysuckle, Jostaberry, Juneberry, Saskatoon 

Berry, Salal, Sea Buckthorn.

0.121 NS 0.5 14 14

Caneberry, including: Blackberry, Loganberry, Black 

Raspberry, Red Raspberry, Wild Raspberry. 0.12 NS 0.5 7 14

Canola (not for use in CA) 0.095 NS 0.094 70 NS

Carrot 0.125 NS 0.5 30 14

Celery, including: Cardoon, Chinese Celery, Celtuce, 

Florence fennel, Swiss chard 0.125 NS 0.5 30 14

Clover 0.25 NS 0.25 15 14

Corn, Field 0.0455 1 0.0455 90 NA

Cotton 0.25 NS 0.5 60 14

Cranberry 0.125 NS 0.5 30 14

Cucurbits, including: Cantaloupes (all), Chayote, 

Chinese Wax Gourd, Citron melon, Cucumber, 

Gherkin, Honeydew Melon, Muskmelons (all), 

Pumpkin, Squash (all), Watermelon

0.125 NS 0.5 14 14

Fallow Land, Conifer Trees (including Christmas 

Tree Farms), Non-Crop or Non Planted Areas

(including rights-of-way, including railroads, 

highways, roads, dividers, medians, pipelines, public 

utility lines, pumping stations, transformer stations 

and substations; around airports; electric utilities; 

0.25 NS 1.0 NA 14
CLETHODIM Human Health Risk Assessment DP No. D411899 

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Table A.2. Existing Use Pattern for Clethodim

Crop or Use Site

Single

Maximum

Application 

Rate

Maximum Seasonal 

PHI RTI

No. of 

Applications

Application 

Rate

lb ai/A lb ai/A days days

commercial buildings; manufacturing plants; storage 

yards; rail yards; fence lines; parkways; post-harvest 

croplands; and beneath greenhouse benches and 

around golf courses).

Flax (not for use in CA) 0.125 NS 0.25 60 14

Fruiting Vegetables (except Tomato) including: 

Eggplant, Groundcherry, Pepino, Peppers (all), 

Tomatillo

0.125 NS 0.5 20 14

Herbs, including: Angelica, Balm, Basil, Borage, 

Burnet, Camomile, Catnip, Chervil (dried), Chive, 

Chinese Chive, Clary, Coriander (leaf), Costmary, 

Culantro (leaf), Curry (leaf), Dill (dillweed), 

Horehound, Hyssop, Lavender, Lovage (leaf), 

Marigold, Marjoram (Origanum spp.), Nasturtium, 

Parsley (dried), Pennyroyal, Rosemary, Rue, Sage, 

Summer Savory, Winter Savory, Sweet Bay, Tansy, 

Tarragon, Wintergreen, Woodruff, Wormwood.

0.125 NS 0.5 14 14

Hops 0.125 NS 0.5 21 14

Leafy Petioles, including: Cardoon, Celery, Celtuce, 

Chinese Celery, Florence Fennel (finochio), Rhubarb, 

Swiss Chard

0.125 NS 0.5 30 14

Leafy Brassica Greens, including: Broccoli raab, 

Chinese Cabbage (bok choy), Collards, Kale, Mizuna, 

Mustard greens, Mustard spinach, Rape greens, 

Turnip greens

0.125 NS 0.5 14 14

Leaf Lettuce 0.125 NS 0.5 14 14

Leafy Greens, including: Amaranth, Chinese 

Spinach, Leafy Amaranth, Tampala, Arugula 

(roquette), Chervil, Chrysanthemum, Edible-leaved 

Garland Chrysanthemum, Corn Salad, Garden Cress, 

Upland Cress (yellow rock and winter), Dandelion, 

Dock (sorrel), Endive (escarole), Head Lettuce, Leaf 

Lettuce, Orach, Parsley, Garden Purslane, Winter 

Purslane, Radicchio (red chicory), New Zealand 

Spinach, Vine Spinach (Indian and Malabar).

0.125 NS 0.5 14 14

Legume Vegetables, Edible Podded, including: 

Bean (Phaseolus spp.; i.e. Runner, Snap, Wax), Bean 

(Vigna spp.; i.e. Asparagus, Chinese Longbean, Moth, 

Yardlong, Jackbean), Edamame (immature soybean), 

Bean (Pisum spp.; i.e. Dwarf, Edible-pod, Snow, 

Sugar Snap, Pigeon, Sword Bean).

0.125 1 0.125 21 NA

Mint

0.25 NS

0.5 

(peppermint

)

1.0 

(spearmint)

21 14

Mustard Seed (not for use in CA on Select Herbicide 

& V-10137 1 EC) 0.095 NS 0.25 75 14
CLETHODIM Human Health Risk Assessment DP No. D411899 

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Table A.2. Existing Use Pattern for Clethodim

Crop or Use Site

Single

Maximum

Application 

Rate

Maximum Seasonal 

PHI RTI

No. of 

Applications

Application 

Rate

lb ai/A lb ai/A days days

Onion 0.25 NS 0.5 45 14

Garlic, Shallot 0.25 NS 0.5 45 14

Onion, Green, including: Leeks, Scallions, Spring 

Onions, Japanese Bunching Onions, 0.125 NS 0.25 14 14

Shallots, Green, including Green Eschalots 0.125 NS 0.5 14 14

Ornamentals 0.25 NS 1.0 NA 14

Non-Bearing Fruit & Nuts Trees, including: Sugar 

Maples 0.125 NS

0.5 or 1.0

(Select 

Herbicide)

NA 14

Pea, Shelled, including: Pea (Pisum spp.; i.e. Field, 

Pigeon) 0.125 1 0.125 30 NA

Pea, Succulent Shelled, including: Pea (Pisum spp.; 

i.e. English, Garden, Green, Pigeon) 0.125 1 0.125 21 NA

Peach 0.121 NS 0.5 14 14

Peanut, including perennial 0.25 NS 0.5 40 14

Potato 0.25 NS 0.5 30 14

Radish 0.125 NS 0.25 15 14

Root Vegetables (except Radish), including: 

Chicory, Ginseng, Horseradish, Turnip 0.125 NS 0.5 30 14

Rhubarb 0.125 NS 0.5 30 14

Safflower 0.125 NS 0.5 70 14

Sesame 0.125 NS 0.5 14 14

Soybean 0.25 NS 0.5 60 14

Spinach 0.125 NS 0.5 14 14

Strawberry 0.125 NS 0.5 4 14

Sugar Beet 0.25 NS 0.5 40 14

Sunflower 0.25 NS 0.5 70 14

Sweet potato, Yam and other Tuberous and Corm 

Vegetables (except Potato), including: Arracacha, 

Arrowroot, Chinese Artichoke, Jerusalem Artichoke, 

Edible Canna, Bitter Cassava, Sweet Cassava, Bitter 

and Sweet Chayote (root), Chufa, Dasheen (taro), 

Ginger, Leren, Tanier, Turmeric, Bean Yam.

0.25 NS 0.5 30 14

Tomato 0.25 NS 0.5 20 14

Turnip Greens 0.121 NS 0.5 14 14

Wildlife Food Plots 0.24 3 0.24 NA 14

Sod (five 24 (C) labels only)) 0.25 NS 0.5 NA 21-28

Residential/Homeowner Use

Outdoor Home Use, including: in and around 

ornamental plants, landscape areas, around trees, 

ground covers, around buildings, bare soil, mulched 

areas.

0.246 or

0.000005647 lb 

ai/ft2

4 NS NA 14 to 

21
CLETHODIM Human Health Risk Assessment DP No. D411899 

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Appendix B. Toxicology Profile and Executive Summaries 

B.1 Toxicology Data Requirements

The toxicology data requirements (40 CFR 158.340) for clethodim food use are presented in Table 1. Use of the new 

guideline numbers does not imply that the new (1998) guideline protocols were used. 

Table B.1. Toxicology Data Requirements for Technical Clethodim

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 21-Day Dermal ..............................................................

870.3250 90-Day Dermal ..............................................................

870.3465 90-Day Inhalation..........................................................

yes

yes

yes

CRa(no)

CRa(yes)

yes

yes

yes

no

waivedb

870.3700a Developmental Toxicity (rodent)...................................

870.3700b Developmental Toxicity (nonrodent).............................

870.3800 Reproduction .................................................................

yes

yes

yes

yes

yes

yes

870.4100b Chronic Toxicity (nonrodent)........................................

870.4200b Oncogenicity (mouse)....................................................

870.4300 Chronic/Oncogenicity....................................................

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial.....................

870.5300 Mutagenicity—Gene Mutation - mammalian................

870.5375 Mutagenicity—Structural Chromosomal Aberrations...

870.5395 Mutagenicity—Other Genotoxic Effects.......................

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 Develop. Neurotoxicity .................................................

no

no

yes

yes

CRa(no)

-

-

yes

yes

no

870.7485 General Metabolism ......................................................

870.7600 Dermal Penetration ........................................................

870.7800 Immunotoxicity .............................................................

yes

no

yes

yes

yes

yesc

a CR = conditionally required. 

b HASPOC, 02/25/2012. 

c This study is under review. The preliminary evaluation showed no immunotoxicity in mice at the highest dose 

tested (1312 mg/kg). 
CLETHODIM Human Health Risk Assessment DP No. D411899 

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B.2 Endpoint Selection 

Acute Reference Dose (aRfD) (all populations)

Study Selected: Acute Neurotoxicity Study (rat) 

MRID Nos: 48788502 (2012) and 48141801 (2006) 

Dose and Endpoint for Risk Assessment: NOAEL = 100 mg/kg/day based on clinical 

observations including decreased spontaneous activity, ruffled fur, head tilt, and hunched posture 

at the LOAEL of 1000 mg/kg/day. 

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA 

Safety Factor).

Comments: The results of two acute neurotoxicity studies in rats were used to select the dose and 

endpoints for establishing aRfD of 1 mg/kg for the general population. The effects produced in 

these studies are due to a single dose. The effects seen in at the LOAEL are decreased 

spontaneous activity, ruffled fur, head tilt and hunched posture. 

aRfD = aPAD = 100 mg/kg/day = 1 mg/kg/day 

100

Chronic Reference Dose (cRfD) 

Study Selected: Carcinogenicity Study (mouse) 

MRID No: 41030112 

Dose and Endpoint for Risk Assessment: NOAEL = 30 mg/kg/day based on reduced survival, 

decreased red cell mass and increased incidences of bile duct hyperplasia, of pigmentation of the 

liver and of foci of amphophilic macrophages in the lung at the LOAEL of 150 mg/kg/day. 

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA 

Safety Factor).

Comments: A carcinogenicity study in mice was used to select the dose and endpoint for 

establishing the cRfD of 0.3 mg/kg/day. The LOAEL of 150 mg/kg/day was based on reduced 

survival; reduced red cell mass; and increased incidences of bile duct hyperplasia, of 

pigmentation of the liver, and of foci of amphophilic macrophages in the lung. The chronic 

toxicity studies in rats, mice and dogs demonstrated that most of the adverse effects occurred at 

dose levels at approximately 100 mg/kg/day or above. The NOAEL/LOAELs established for the 

rat chronic/carcinogenicity study (21/113 mg/kg/day) and the mouse carcinogenicity study 

(30/150 mg/kg/day) were relatively similar. However, the adverse effects seen at the LOAEL 

(150 mg/kg/day) in the mouse study were more robust. The POD derived from the mouse 
CLETHODIM Human Health Risk Assessment DP No. D411899 

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carcinogenicity study (30 mg/kg/day) is protective of the effects seen at the LOAEL (113 

mg/kg/day).of the rat chronic/carcinogenicity study and 1-year toxicity in dogs (300 mg/kg/day). 

cRfD = cPAD = 30 mg/kg/day = 0.3 mg/kg/day 

100

Incidental Oral Exposure (short-term)

Study Selected: 90-day Oral Toxicity Study (dog) 

MRID No: 41030106 

Dose and Endpoint for Risk Assessment: NOAEL = 75 mg/kg/day based on increased absolute 

liver weights with histological correlates of cytoplasmic vesiculation and vacuolation of the 

central lobular hepatocytes at the LOAEL of 125 mg/kg/day. 

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA 

Safety Factor).

Comments: A subchronic toxicity study in dogs was used to select the dose and endpoint for 

assessing incidental oral exposure risks. The NOAEL was 75 mg/kg/day; the LOAEL was 125 

mg/kg/day based on increases in mean serum cholesterol and alkaline phosphatase levels 

(females), increases in absolute and relative liver weights (both sexes) and cytoplasmic 

vesiculation/ vacuolation of the central lobular hepatocytes in males and females. The selected 

POD (75 mg/kg/day) is protective for the short- (1-30 day) and intermediate-term (1-6 months) 

exposure scenarios. The POD is also protective of effects seen in other subchronic oral toxicity 

studies as well as any developmental or offspring effects. 

Dermal Exposure (short- and intermediate-term)

A dermal assessment is not required. The NOAEL for the 28-day dermal toxicity study is the 

limit dose of 1000 mg/kg/day. 

Inhalation Exposure (short- and intermediate-term)

Study Selected: 90-day Oral Toxicity Study (dog) 

MRID No: 41030106 

Dose and Endpoint for Risk Assessment: NOAEL = 75 mg/kg/day based on increased absolute 

liver weights with histological correlates of cytoplasmic vesiculation and vacuolation of the 

central lobular hepatocytes at the LOAEL of 125 mg/kg/day. 

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA 

Safety Factor).
CLETHODIM Human Health Risk Assessment DP No. D411899 

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Comments: The subchronic inhalation study has been waived (HASPOC, 2/20/2013, TXR 

0056491). A subchronic toxicity study in dogs was used to select the dose and endpoint for 

assessing incidental oral exposure risks. The NOEL was 75 mg/kg/day; the LOAEL was 125 

mg/kg/day based on increases in mean serum cholesterol and alkaline phosphatase levels 

(females), increases in absolute and relative liver weights (both sexes) and cytoplasmic 

vesiculation/ vacuolation of the central lobular hepatocytes in males and females. The selected 

POD (75 mg/kg/day) is protective for the short- (1-30day) and intermediate-term (1-6 months) 

exposure scenarios. The POD is also protective of effects seen in other subchronic oral toxicity 

studies as well as any developmental or offspring effects. 

B.3 Toxicity Profiles

Table B.3.1. Acute Toxicity Profile of Clethodim

Guideline No. Study Type MRID

(Date)

Results Toxicity Category

870.1100 Acute oral [rat] 40974507

(1986)

LD50 =

males 1.63 g/kg 

females 1.36 g/kg

III

870.1200 Acute dermal [rabbit] 40974510

(1986) LD50 > 5.0 g/kg IV

870.1300 Acute inhalation [rat] 40974512

(1986) LC50 > 3.9 mg/L IV

870.2400 Acute eye irritation [rabbit] 40974514

(1986)

mild ocular 

irritation III

870.2500 Acute dermal irritation [rabbit] 40974516

(1986)

moderate dermal 

irritation III

870.2600 Skin sensitization [guinea pig] 40974518

(1986)

not a dermal 

sensitizer N/A

Table B.3.2. Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

Subchronic Toxicity Studies

Note: The NOAEL and LOAEL of some subchronic studies were originally established based on the increased 

liver weights; those NOAEL and LOAEL were re-evaluated and raised in accordance to the current policy in 

evaluating the liver effects

870.3100 5-Week oral toxicity 

(rat)

41030110 (1986)

Acceptable/Nonguideline

0, 5, 200, 1000, 4000, 

8000 ppm

equivalent to 0, 0.256, 

12.5, 65.6, 261, 515 

mg/kg/day in males and 0, 

0.288, 13.9, 70.6, 291, 

554 mg/kg/day in females

NOAEL = 65.6/ 70.6 mg/kg/day (M/F)

LOAEL = 261/291 mg/kg/day (M/F) based on 

hematologic effects, increased liver weights 

with supportive pathology, reduced body 

weights, and decreased food intake.

870.3100 4-Week oral toxicity 

(mouse)

41030103 (1986)

Acceptable/Non-guideline

0, 100, 250, 625, 1500, 

4000 ppm

Calculated by standard 

conversion factor (1 ppm 

NOAEL = 600 mg/kg/day (HDT)
CLETHODIM Human Health Risk Assessment DP No. D411899 

Page 34 of 41 

Table B.3.2. Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

= 0.15 mg/kg/day): 0, 15, 

37.5, 93.8, 225.0, 600.0 

mg/kg/day

870.3100 90-Day oral toxicity 

(rat) with 6 week 

recovery groups

41030107 (1986)

Acceptable/Guideline

0, 50, 500, 2500, 5000 

ppm

0, 2.3/2.8, 25/30, 134/159, 

279/341 mg/kg/day (M/F)

NOAEL = 134/159 mg/kg/day (M/F)

LOAEL = 279/341 mg/kg/day (M/F) based on 

decreased body weights attributable to 

decreased food consumption, decreased body 

weight gains, and increased liver weights with a 

histological correlate of centrilobular hepatic 

hypertrophy.

870.3150 90-Day oral toxicity 

(dog)

41030106 (1987)

Acceptable/guideline

0, 1, 25, 75, 125 

mg/kg/day

NOAEL = 75 mg/kg/day

LOAEL = 125 mg/kg/day based on increased 

absolute liver weights with histological 

correlates of cytoplasmic vesiculation and 

vacuolation of the central lobular hepatocytes 

in male and female dogs.

870.3200

21/28-Day dermal 

toxicity (rat)

41030109 (1987)

Acceptable/non-guideline

0, 10, 100, 1000 

mg/kg/day

No adverse systemic toxicity was found; 

NOAEL = 1000 mg/kg/day (HDT; limit dose)

Dermal Toxicity NOAEL = not established.

Dermal Toxicity LOAEL = 10 mg/kg/day 

based on skin irritation.

870.3200

21/28-Day dermal 

toxicity (rat)

EC formulation 

(26.3% ai)

41030201 (1987)

Acceptable/Guideline 

0, 10, 50, 100/200 

mg/kg/day

(high dose reduced to 100 

after 4 applications due to 

severe irritation)

Systemic NOAEL = 200 mg/kg/day [HDT].

Dermal Toxicity NOAEL = not established

Dermal Toxicity LOAEL = 10 mg/kg/day 

based on observed dermal irritation.

870.3465 90-Day inhalation 

study 

Subchronic inhalation toxicity study waived (HASPOC; 2/20/2013; 

TXR 0056491)

Developmental and Reproductive Toxicity Studies

870.3700a Prenatal 

developmental in 

(rat)

41030114 (1986) pilot

41030116 (1987)

Acceptable/Guideline

0, 10, 100, 350, 700 

mg/kg/day

Maternal NOAEL = 100 mg/kg/day

Maternal LOAEL = 350 mg/kg/day based on 

reduced body weight gains clinical signs of 

toxicity (dose-related increased in the incidence 

of excessive salivation and lacrimation, red 

nasal discharge, and anagenital statining).

Developmental NOAEL = 100 mg/kg/day

Developmental LOAEL= 350 mg/kg/day based 

on reduced fetal body weights and delayed 

ossification of the lower vertebrae.

870.3700b Prenatal 

developmental in 

(rabbit)

41030113 (1986) pilot

41030115 (1987)

Acceptable/Guideline

0, 25, 100, 300 mg/kg/day

Maternal NOAEL = 100 mg/kg/day

Maternal LOAEL = 300 mg/kg/day based on 

clinical signs of toxicity (increased incidence of 

dried feces), reduced body weight gains, and 

reduced food consumption.
CLETHODIM Human Health Risk Assessment DP No. D411899 

Page 35 of 41 

Table B.3.2. Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

Developmental NOAEL > 300 mg/kg/day 

(HDT)

870.3800 Reproduction and 

fertility effects

(rat)

41030119 (1986) pilot

41030120 (1987)

Acceptable/Guideline

0, 5, 20, 500, 2500 ppm

0, 0-1/0-1, 1-2/1-3, 28-

60/36-61, 141-295/180-

282 mg/kg/day (M/F)

Parental NOAEL = 51 mg/kg/day.

Parental LOAEL = 263 mg/kg/day based on 

reduced body weight, particularly in males, and 

reduced food consumption during both 

generations. 

Reproductive: NOAEL = 263 mg/kg/day 

(HDT) 

Offspring NOAEL = 263 mg/kg/day. (HDT)

Chronic Toxicity Studies

870.4100b Chronic toxicity 

(dog)

41030111 (1988)

Acceptable/Guideline

0, 1, 75, 300 mg/kg/day in 

capsules

NOAEL = 75 mg/kg/day (M/F)

LOAEL = 300 mg/kg/day (M/F) based on 

increases in platelet count, leukocytes, and 

ALT & ALP activities; decreases in glucose, 

in RBC, I-IGB, and HCT levels.

870.4200 Carcinogenicity

(mouse)

78 weeks

41030112 (1988)

Acceptable/Guideline

0, 20, 200, 1000, 

2000/3000 ppm (high 

dose received 2000 ppm 

for first 15 weeks then 

increased to 3000 ppm)

Calculated by standard 

conversion factor (1 ppm 

= 0.15 mg/kg/day): 0, 3, 

30, 150, 450 mg/kg/day

NOAEL = 30 mg/kg/day

LOAEL = 150 mg/kg/day based on treatmentrelated effects on survival, decreased red cell 

mass (decreased erythrocyte counts, 

hemoglobin, and hematocrit values), increased 

liver weights, and increased foci of 

amphophilic alveolar macrophages in the lung, 

bile duct hyperplasia, and increased 

pigmentation in the liver.

No evidence of carcinogenicity.

870.4300

Combined Chronic 

Toxicity/

Carcinogenicity

(rat)

41030121 (1988)

Acceptable/Guideline

0, 5, 20, 500, 2500 ppm

(M: 0, 0.15, 0.57, 16, and 

86 mg/kg/day; F: 0, 0.2, 

0.72, 21, and 113 

mg/kg/day).

NOAEL = 21 mg/kg/day 

LOAEL = 113 mg/kg/day based on significant 

decreases in mean body weights in females

No evidence of carcinogenicity.

Genotoxicity Battery

870.5100 Gene Mutation 41030122 (1986)Acceptable

up to 10,000 μg/plate

Negative. There was no evidence of induced 

mutant colonies over background in strains 

TA98, TA100, TA1535 and TA1537 with and 

without S9 activation.

870.5100 Gene Mutation 41030123 (1986)Acceptable

up to 10,000 μg/plate

Negative. There was no evidence of treatmentrelated induced mutant colonies over 

background in strains TA98, TA100, TA1535, 

TA1537, or WP2 with or without S9 activation.

870.5375 CHO Assay

41030128 (1986)

Acceptable

1.0 and 1.2 μl/ml

Positive. There was evidence of a dose-related 

increase in structural chromosomal aberrations 

over background in the absence of metabolic 

activation at concentrations near the limits of 
CLETHODIM Human Health Risk Assessment DP No. D411899 

Page 36 of 41 

Table B.3.2. Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

solubility and cytotoxicity.

870.5375 CHO Assay

41030129 (1986)

Acceptable

up to levels of insolubility

0.3 and 1.0 μl/ml

Negative. There was no evidence of a doserelated increase in structural chromosomal 

aberrations over background in the presence or 

absence of metabolic activation at any 

concentration tested up to the limit of 

solubility.

870.5395 Micronucleus Assay

(rat)

41030125 (1987)

Acceptable

up toxic dose

1,500 mg/kg/day

(gavage)

Negative. There is no evidence that clethodim 

induced chromosomal aberrations in bone 

marrow cells of rats over background levels.

870.5550 Unscheduled DNA 

Synthesis

(mouse)

41030124 (1986)

Acceptable

up to lethal level

5,000 mg/kg/day

Negative. There was no evidence that 

unscheduled DNA synthesis, as determined by 

radioactive tracer procedures [nuclear silver 

grain counts] was induced.

Metabolism and Dermal Penetration 

870.7485 Metabolism and 

pharmacokinetics

(rat)

41030132 (1988)

Acceptable

Single oral dose 4.5 or 

450 mg

Repeated dose 4.5 or 450 

mg for 14 days

Clethodim is readily absorbed and eliminated 

(87-92%, urine; 9-17%, feces; <1% expired air) 

after 7 days. Gastrointestinal absorption 

estimated at 89-96%. No evidence of 

bioconcentration. Extensively metabolized 

with < 1% eliminated as unchanged parent 

compound. Predominant metabolite is 

clethodim sulphoxide (48-68%) after 48 hours.

870.7600

Select 2.0 

EC -

25.85% 

Clethodim

Dermal penetration

(rat)

41030202 (1987)

Acceptable

0.05, 0.5, 5.0 mg/rat

Based on the results of this study, the dermal 

absorption value for SELECT 2EC after 10-

hours of exposure, the typical worker exposure 

time, was 28.4%.

Neurotoxicity Battery

870.6200a

Acute neurotoxicityrats

HanRcc:WIST

(SPF) rats

48141801 (2006)

Unacceptable/nonguideline (Upgradable)

0, 10, 100, 1000 mg/kg 

(gavage) 

NOAEL = 100 mg/kg

LOAEL = 1000 mg/kg based on clinical signs 

(decreased spontaneous activity, ruffled fur, 

head tilt, hunched posture).

Acute neurotoxicityrats

Crl:CD(SD) rats

48788502 (2012)

Acceptable/non-guideline

0, 10, 100, 1000 mg/kg 

(gavage)

When the data from 2006 study (MRID 

48141801) considered together with this study,

NOAEL = 100 mg/kg

LOAEL =1000 mg/kg based on combined 

clinical observations (decreased spontaneous 

activity, ruffled fur, head tilt, hunched posture). 
CLETHODIM Human Health Risk Assessment DP No. D411899 

Page 37 of 41 

870.6200b

Subchronic 

neurotoxicity -rats

48788503 (2012)

Acceptable/non- guideline

0, 500, 1500, or 5000 ppm 

M: 0, 31, 94, and 331 

mg/kg/day,

F: 0, 38, 115, and 380 

mg/kg/day

48788501 (2012) dose 

range finding 

neurotoxicity study

NOAEL = 94/115 mg/kg/day, M/F 

LOAEL = 331/380 mg/kg/day, M/F based on 

decreases in body weight, body weight gain, 

and food consumption. 

Neurotoxicity was not observed in this study.

Immunotoxicity Studies

870.7800

Immunotoxicity 

study in B6C3F1 

mice

48788505 (2012)

0, 400, 2000, and 4000 

ppm

0, 136, 603, 1312,

and 0 mg/kg body 

weight/day

48788505 (2012) Rangefinding study

Under review

The preliminary evaluation showed that 

clethodim did not produce immunotoxicity. 

NOAEL = 1312 mg/kg/day (HDT)

Clethodim Metabolites Studies

870.3100

Imine 

Sulfone

5-Week oral 

toxicity (rat)

41030104 (1988)

Acceptable/non-guideline

0, 80.8, 871, 7820 ppm 

(nominal doses)

Equivalent to 0, 6.7/7.8, 

70.9/83.7, 604.0/723.0 

mg/kg/day (M/F)

Systemic Toxicity NOAEL = 70.9/83.7 

mg/kg/day (M/F)

Systemic Toxicity LOAEL = 604/723 

mg/kg/day (M/F) based on increased serum 

cholesterol and increased liver weights. 

870.3100

Clethodim

High Purity 

w/process 

neutrals

5-Week oral 

toxicity (rat)

41030108 (1987)

Acceptable/Nonguideline

0, 1200 (process neutrals), 

6800 (high purity 

clethodim) ppm

4.9/5.8, 148/175 

mg/kg/day (M/F)

This study was not to establish a NOAEL or 

LOAEL. 

The high purity clethodim produced lower body 

weight gain, mild anemia and mild liver 

hypertrophy at 148/175 mg/kg/day (M/F).

870.3700a

5-Hydroxy 

sulfone

Prenatal 

developmental in 

(rat)

41030118 (1988)

Acceptable/Nonguideline

0, 10, 100, 700 mg/kg/day

Maternal Systemic Toxicity NOAEL ≥ 700 

mg/kg/day

Maternal Systemic Toxicity LOAEL > 700 

mg/kg/day

Developmental Toxicity NOAEL ≥ 700 

mg/kg/day

Developmental Toxicity LOAEL > 700 

mg/kg/day

870.3700a

Imine 

Sulfone

Prenatal 

developmental in 

(rat)

41030117 (1988)

Acceptable/non-guideline

0, 10, 100, 700 mg/kg/day

Maternal Systemic Toxicity NOAEL = 10 

mg/kg/day

Maternal Systemic Toxicity LOAEL = 100 

mg/kg/day based on reduced body weight gains 

and food consumption.

Developmental Toxicity NOAEL = 100 

mg/kg/day

Developmental Toxicity LOAEL = 700 

mg/kg/day based on reduced fetal body 

weights, reduced sternal ossification, and an 

increased incidence of a cervical rib.
CLETHODIM Human Health Risk Assessment DP No. D411899 

Page 38 of 41 

870.5100 

5-Hydroxyclethodim 

sulfone

Gene Mutation 41030126 (1987)

Acceptable

Negative. There was no evidence of significant 

induced mutant colonies over background in 

strains TA98, TA100, TA1535 and TA1537 

and WP2 uvrA with and without S9 activation. 

870.5100 

Iminesulfone

Gene Mutation 41030127 (1988)

Acceptable

Negative. There was no evidence of significant 

induced mutant colonies over background in 

strains TA98, TA100, TA1535 and TA1537 

and WP2 uvrA with and without S9 activation. 

870.5375

IminesulfoneCHO Assay 41030130 (1988)

Acceptable

Negative. There was no evidence of a doserelated increase in structural chromosomal 

aberrations over background in the presence or 

absence of metabolic activation at any 

concentration tested up to the limit of 

solubility.

Appendix C. Physical/Chemical Properties

Table C. Physico-Chemical Properties

Parameter Value Reference

Molecular weight 359.91 g/mol MRID 46124103

pH 4.11,2 MRID 46124103

Water solubility (20°C) 0.54 g/100 mL (pH 7.0) MRID 48881405

Solvent solubility (20°C to 25°C) > 90 g/100 mL in most solvents MRID 46124103

Vapor pressure (25°C) <1 × 10-2 mPa at 20°C

1 × 10-7 mm Hg at 20°C MRID 48881405

Dissociation constant, pKa 4.62 MRID 48881405

Octanol/water partition coefficient, log KOW

(25°C) 4.51 (21°C) MRID 48881405

Aerobic soil half-life (20°C)

1.2 days MRID 41376801

2.5 days MRID 40974522

Photolysis half-life in soil (13-23C) 7 days MRID 41030135
CLETHODIM Human Health Risk Assessment DP No. D411899 

Page 39 of 41 

Appendix D. International Residue Limit Status 

Table D.1. Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex2

40 CFR 180.458:

Plants: (a) General. sum of clethodim, 

2-[(1E)-1-[[[(2E)-3-chloro-2-

propenyl]oxy]imino]propyl]-5-[2-

(ethylthio)propyl]-3-hydroxy-2-

cyclohexen-1-one, and its metabolites 

containing the 5-(2-

ethylthiopropyl)cyclohexene-3-one and 

5-(2-ethylthiopropyl)-5-

hydroxycyclohexene-3-one moieties 

and their sulphoxides and sulphones, 

calculated as the stoichiometric 

equivalent of clethodim

(E,E)-(±)-2-[1-[[(3-chloro-2-

propenyl)oxy]imino]

propyl]-5-[2-

(ethylthio)propyl]-3-

hydroxy-2-cyclohexen

-1-one, including metabolites 

containing the 2-cyclohex1-enone moiety

Sum of clethodim and its 

metabolites containing 5-

(2-

ethylthiopropyl)cyclohexe

ne-3-one and 5-(2-

ethylthiopropyl)-5-

hydroxycyclohexene-3-

one moieties

and their sulphoxides and 

sulphones, expressed as 

clethodim.

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

US Canada Mexico1 Codex2

Alfalfa, forage 6.0

Alfalfa, hay 10 10 alfalfa fodder

Artichoke, globe 1.2

Asparagus 1.7

Beet, sugar, molasses 1.0

Beet, sugar, roots 0.20 0.1 sugar beet

Beet, sugar, tops 1.0

Brassica, head and stem, 

subgroup 5A

3.0

Brassica, leafy greens, 

subgroup 5B

3.0

Bushberry subgroup 13-07B 0.20 0.2 aronia berries, buffalo 

currants, Chilean guavas, 

currants, elderberries, 

European barberries, 

gooseberries, highbush 

blueberries, highbush 

cranberries, honeysuckle, 

huckleberries, jostaberries, 

lingonberries, lowbush 

blueberries, native currants, 

salal berries, saskatoon 

berries (juneberries), sea 

buckthorn

Caneberry subgroup 13-07A 0.30

Canola, meal 1.0

Cattle, fat 0.2

Cattle, meat 0.2 0.2 (*) meat (from 

mammals other than 

marine mammals)

Cattle, meat byproducts 0.2 0.2 (*) Edible offal 

(mammalian)

Clover, forage 10.0

Clover, hay 20.0
CLETHODIM Human Health Risk Assessment DP No. D411899 

Page 40 of 41 

Table D.1. Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex2

Corn, field, forage 0.2

Corn, field, grain 0.2

Corn, field, stover 0.2

Cotton, meal 2.0

Cottonseed subgroup 20C 1.0 0.5 cotton seed

0.5 cotton seed oil (crude 

and edible) (*)

Cranberry 0.50

Egg 0.2 0.05 (*)

Flax, meal 1.0

Goat, fat 0.2

Goat, meat 0.2 0.2 (*) meat (from 

mammals other than 

marine mammals)

Goat, meat byproducts 0.2 0.2 (*) Edible offal 

(mammalian)

Herb subgroup 19A 12.0

Hog, fat 0.2

Hog, meat 0.2 0.2 (*) meat (from 

mammals other than 

marine mammals)

Hog, meat byproducts 0.2 0.2 (*) Edible offal 

(mammalian)

Hop, dried cones 0.5

Horse, fat 0.2

Horse, meat 0.2 0.2 (*) meat (from 

mammals other than 

marine mammals)

Horse, meat byproducts 0.2 0.2 (*) Edible offal 

(mammalian)

Leaf petioles subgroup 4B 0.60

Leafy greens subgroup 4A 2.0 2 spinach

Melon subgroup 9A 2.0

Milk 0.05 0.05 (*)

Onion, bulb, subgroup 3-07A 0.50 0.2 onions 0.5

0.5 garlic

Onion, bulb, subgroup 3-07B 2.0

Peach 0.20

Peanut 5.0 5

Peanut, hay 3.0

Peanut, meal 5.0

Peppermint, tops 5.0

Potato, granules/flakes 2.0

Poultry, fat 0.2

Poultry, meat 0.2 0.2 (*)

Poultry, meat byproducts 0.2 0.2 (*) poultry edible offal 

of

Radish, tops 0.70
CLETHODIM Human Health Risk Assessment DP No. D411899 

Page 41 of 41 

Table D.1. Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex2

Rapeseed subgroup 20A 0.6 0.05 rapeseeds (canola)

0.3 flaxseeds

0.4 mustard seeds 

(condiment type)

0.05 mustard seeds (oilseed 

type)

0.6 rape seed,

0.6 rape seed oil (crude 

and edible) (*)

Safflower, meal 10.0

Sheep, fat 0.2

Sheep, meat 0.2 0.2 (*) meat (from 

mammals other than 

marine mammals)

Sheep, meat byproducts 0.2 0.2 (*) Edible offal 

(mammalian)

Soybean 10.0

10 dry soybeans

10 soya bean (dry)

1 soya bean oil, crude

0.5 (*) soya bean oil, 

refined

Spearmint, tops 5.0

Squash/cucumber subgroup 

9B

0.50

Strawberry 3.0

Sunflower, meal 10.0

Sunflower subgroup 20B 5.0

0.2 sunflower seeds

0.5 sunflower seed

0.1 (*) sunflower seed oil, 

crude

Turnip, greens 3.0

Vegetable, fruiting group 8-

10

1.0 1 tomato

Vegetable, legume, group 6, 

except soybean

3.5 0.5 beans

0.5 dry (chickpeas, lentils, 

peas)

2 beans (dry)

0.5 (*) beans, except broad 

bean and soya bean

2 field pea (dry)

Vegetable, root, except sugar 

beet, subgroup 1B

1.0

Vegetable, tuberous and 

corm, subgroup 1C 1.0 0.5 potatoes 0.5 potato

MRLs with NO US equivalent

Coriander seeds 3

Fenugreek seeds 0.7

Bean fodder 10

Fodder beet 0.1 (*)

Completed: : M. Negussie; 08/22/2013

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes. 

2 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = 

processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the 

fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC