### CLETHODIM Human Health Risk Assessment DP No. D41 1 899



### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON

, D.C

. 20460

MEMORANDUM

DATE: January 30,2014 OFFIC E OF

CHEMICA L SAFETY AND
POLLUTIO N PREVENTION



### SUBJECT: Clethodim. Preliminary Risk Assessment for Registration Review.

PC Code: 121011

Decision No.: 478940 Regulator y Action: Registration Review

Risk Assessment Type: Single

. Chemical/Aggregate

TXRNo.: NA

MRIDNo.: NA DP Barcode: D411899 Regi strat ion No.: NA

Petition No.: NA

Case No.: 7226-1

CAS No.: 99129-21-2

40 CFR: §180.458


## ..::::----::>**~** 

### Nancy Tsaur, Chemist f

# ~ FROM:

Meheret Neguss ie

, Chemist

# 'J::t:d, 

# t:r:e:::**_).!~"f:_.** Whang Phang

, Senior Toxicologi st**~** 

## r**~** 

### Barry O'Keefe, Senior Biologist 

# /3. ()**~** 

### Risk Assessment Branch 3 (RAB3)

Health Effects Division (7509 P )

THROUGH: Chri s tine Olinger, Branch Chief 

# (j / 

# tf/

Risk Assessment Branch 3 (RAB3) 

# t

Health Effects Division (750 9P)

TO: Neil Anderson

, Chemical Review Manager 51

Ricardo Jones

, Chemical Review Manager

Pesticide Reevaluation Division (750 8P)

Page 1 of 41

### CLETHODIM Human Health Risk Assessment DP No. D4 1 1899



### 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 Harmonizati on

..................................................................................... 7

3.0 Introduction

. . .. . ... . ... . .. . ... . .. . ... . .. . ... . ... . .. . ... . ... . .. .. .. . ... . .. . . .. .. .. . ... .. .. . ... . .... . ... . . :

.... .. ... . ................ 8

3. 1 Chemical Identity

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

3.2 Physi caVChemica l 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 Toxicologica l Effects

.. .. .. .. .. . ... . ... . .. .. .. . ... . ................................................ 11



### 4

. 2 Safety Fact or for Infants and Children (FQP A Safety Factor)

. . ... .. .. .. .. .. .. .. .. ... .. ... .. 12



### 4.2.1 Completeness of the Toxi cology 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 Endp oin t 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 Asse ssment

.. . ...................... .. ... . .. . ... . ... . ...... .. .. . ............................ . ... . ... ... . . 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 Char acterization

. .. .. .. .. ... . ... . ............ 19



### 6.1 Residential Handler Exposure

. . .. .. .. .. .. . .. .. .. .. ... . .. .. .................................. . ... . ... . ... .. ... . ... 19



### 6.2 Residential Post-Application Exposure

................. .. . .. ... . ... . ................ . . .................. . ... 20

6.3 R esidential 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 Exp osure/Risk Characterization

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



### 7

. 1 Acute Aggregate Risk

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

7.2 Short-Term Aggregate Risk

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

Page 2 of 41

### CLETHODIM Human Health Risk Assessment DP No. D411899

Page 3 of 41 7.3 Intermediate-Term Aggregate Risk ........................................................................... 22

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

8.0 Cu mulative 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 App endix A. Registered Clethodim End-Use Products

................................ .......................... 26 App endix 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

Page 4 of 41 1.0 Executive Summary

Clethodim [2-[(1 E

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

- (ethylthio)propyl]-3-

h ydroxy-2-cyclohexen-1 -one] is a systemic and selective post-emergence herbicid al 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),

re sidential risk estimates, drinking water exposure contributions, recommended tolerances, and potential for spray drift exposure (K. Rury, DP384944, 09/26/2011). All data requirements

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

09/09/ 2008).

Use Profile

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

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

c oncentrate (SC) and emulsifiable concentrate (EC) products. The se 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 requirepersonal protective equipment (PPE) for all applicators and other handlers consisting of a longsleeved shirt, long pants, shoes plus socks, chemical-resistant gloves, and protective eyewe ar

.

Exposure Profile Non-occupational exposures to clethodim are expected for short-, intermediate-, and long-term (c hronic) durations. Routes of exposure include diet, drinking water, and residential exposure

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

the lim it 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

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

e xposures 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

he patic 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 plate let and leukocyte counts were also noted.

### CLETHODIM Human Health Risk Assessment DP No. D411899

Page 5 of 41 Clethodim has a low order of acute toxicity via oral, dermal, and inhalation routes of exposure a s 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

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

de velopmental 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

re production 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 treatmentre lated 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

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

pr ocessed commodities, DEEM version 7.81 default processing factors were assumed

. Esti mated 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 assessment s do not result in risk estimates of concern. The acute dietary (food

a nd 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 (c PAD) for the general U.S. population and 30% of the cPAD for all infants (<1 year old), the population subg roup 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

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

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

be cause there is no systemic toxicity up to the limit dose via the dermal route of exposure. Furthermore, incidental oral exposures are not expected fr om di rect residential applications.

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

e xposure) 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

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

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

pa thway.

### CLETHODIM Human Health Risk Assessment DP No. D411899

Page 6 of 41 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

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

po licies 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

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

c rop 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

- et hylthiopropyl)cyclohexene-3-one and 5- (2

-

e thylthiopropyl)-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 re visions 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

re moved 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

Page 7 of 41 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) need s 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,

fr uiting, 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 0.5 0 Establish as O nion, bulb, subgroup 3

- 07A at 0.5 ppm

and increase tolerance to harmonize with Codex Onion, green 2.0 2.0 Establish as O nion, 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

0.6 0 Establish as Rapeseed s ubgroup 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 S unflower s ubgroup 20B at 5.0 ppm Su nflower, seed 5.0 Cotton, undelinted seed 1.0 1.0 Establish as Cottonseed s ubgroup 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 V egetable, 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

doe s not include the sulphoxides and sulphones.

F or 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

a chieve 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

Page 8 of 41 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 (s ubgroup 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 can not be harmonized because the Codex MRLs are lower. Thus, s etting the U.S. tolerance to be consistent with the Codex MRLs might

le ad 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 group s 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 ar e 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 Canadia n MRLs on livestock commodities.

Canada does not establish tolerances on livestock feedstuffs.



### 3.0 In troduction

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,

c lethodim 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

e stimates, 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

ha ve 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 C 17 H 26 ClNO 3 S

Common Name Clethodim

Company experimental name RE45601

IUPAC name ( 5RS )

- 2

- { (E)

- 1

- [( 2 E )

- 3

- chloroallyloxyimino]propyl }

- 5

- [ ( 2 RS )

- 2

- (ethylthio)propyl]

- 3

- hydroxycyclohex

- 2

- en

- 1

- one

CAS Name 2

- [(1 E )

- 1

- [[[(2 E )

- 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 va por pressure (<1x10 -7 

### mm Hg). Thus, clethodim is unlikely to volatilize significantly. Clethodim has a relatively high octanol/water partition coefficient log (K

ow 

### ) of 4.51 (at 20° C) which indicates moderate fat solubility and, however, studies show minimal potential for

bioac cumulation. At 20°C, the Henry’s Law constant was calculated to be <2 ×10 -9 

### atm·m 3 

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

ne utral conditions, and has some water solubility.

3.3 Pesticide Use Pattern

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

a sparagus, 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

### 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.

C lethodim 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.

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

c oncentrate (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

e xposed to clethodim via drinking water since application may result in clethodim reaching

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

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

so t here 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

sit es. 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.

Additi onally, 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

### CLETHODIM Human Health Risk Assessment DP No. D411899

Page 11 of 41 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

re quirement 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

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

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

No de velopmental 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

da ta 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.”

C lethodim 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

Page 12 of 41 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,

a drenal, 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 hig hest concentration of clethodim equivalents. The absorbed clethodim was extensively

meta bolized 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%).

The re 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

a bsorption 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 t he 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

ba sed 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

h istopathology 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

Page 13 of 41 4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

The re 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

dr inking water modeling estimates. New 2012 Residential Standard Operating Procedures (S OPs) we re used to assess residential handler exposure, assuming that maximum application

ra tes 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

tox icity 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

we re 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

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

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

c onsidered 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

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

liv er 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

c hronic 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).

### CLETHODIM Human Health Risk Assessment DP No. D411899

Page 14 of 41 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

e ndpoint 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

ba sed 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

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

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

fa ctor is not needed ).

4.3.1 Recommendation for Combining Routes of Exposure for Aggregate Risk

Asse ssment

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

e xposure 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 Toxicol o gical Doses and Endpoints for Clethodim for Use in Dietary

, Non

Occupational , and Occupational Human Health Risk Assessments a

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 UF A = 10X

UF H = 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 stud y 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

Page 15 of 41 Table 4. 3 . Summary of Toxicol o gical Doses and Endpoints for Clethodim for Use in Dietary

, Non

Occupational , and Occupational Human Health Risk Assessments a

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 UF A = 10X

UF H = 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 UF A = 10X

UF H = 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

Intermediate

Term (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

Intermediate

Term (1

- 6 months) NOAEL =

75 mg/kg/day UF A = 10X

UF H = 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. UF A = extrapolation from animal to human (interspecies). UF H = 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

c hronic 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

Page 16 of 41 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

e ndocrine 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 effec t 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

c hemical 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

int eract with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine-related effects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 1 

### 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

e xposure 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

pr ior 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

c oncern 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

Page 17 of 41 5

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

- ethylthiopropyl)-5-hydroxycyclohexene-3-one

moi eties 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 sul f

oxides and sul f

ones, 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 sul f

oxides and sul f

ones, expressed as clethod im

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 sul f

oxides and sul f

ones, 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 sul f

oxides and sul f

ones, 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,

0 6/24/2013). 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

de gradates rather than parent clethodim based on greater persistence an d m obility of these degradates.

### CLETHODIM Human Health Risk Assessment DP No. D411899

Page 18 of 41 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 an nual 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

S creening 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 mode ling 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 R esidues of C oncern EDWCs for Clethodim Uses a

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 a i/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).

DEE M 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. F or 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. F or 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

re ported exposed population subgroup, all infants (<1 year old), utilized 30% of the cPAD.

### CLETHODIM Human Health Risk Assessment DP No. D411899

Page 19 of 41 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 Clethodim a

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

c ase” high-end exposure. The assessment reflect ed updates to HED’s 2012 Residential SOPs 3


### 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 E stimates for Clethodim

Exposure Scenario Inhalation Unit Exposure
(mg/lb ai) Maximum

Application

Rate a
(lb ai/ft 2 ) Area Treated

Daily b

(ft 2 /day) Inhalation

Dose (mg/kg/day) c MOE d

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

Page 20 of 41 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/ft 2 ) × Area Treated (ft 2 /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

a ssessment 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 tr eated 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 re commended 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 be ds, trees, and ground covers via backpack sprayer.

Table 6.3

. Recommendations for the Residential Exposures for the Clethodim Aggregate Assessment a

Lifestage (Scenario) Dose (mg/kg/day) b MOE c

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

Page 21 of 41 and received the SAP’s final report on March 2, 2010 4 

### . 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,

a pplicators). 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

Of f-target movement of pesticides can occur via many types of pathways and it is governed by avariety 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

surf aces 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 wher e 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.

S ince 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

Page 22 of 41 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

a ggregate 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

a ssessment 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

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

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

Table 7.2

. Short

- Term A ggregate Risk Calculations

Population LOC for

Aggregate Risk a Dietary

Exposure b MOE Inhalation Residential

Exposure c Aggregate MOE (food, water, and residential) d

Adult s 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

int ermediate-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

subst ances. 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

e xceed 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

irr itation are assigned a 12-hour REI. Therefore, the [156 subpart K] Worker ProtectionStatement 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), lo w 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, 2010 5



### . 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

ha ndlers. 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, 1 1/13 /2013, DP412296, “Clethodim: Acute and Chronic Aggregate Dietary (Food

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

B. O’Keefe, 09/09/2008, DP349757, DP356151, “ R evised Clethodim Human Health Assessment Scoping Document in Support of Registration Review.”

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

Asse ssment for Registration Review.”

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

R egistration 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

tox icity-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

Page 26 of 41 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

Page 27 of 41 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 Curran t, 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 r ights

- 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

Page 28 of 41 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 L ettuce 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, Radi cchio (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

Page 29 of 41 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 pere n nial 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 Chay ote (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/ft 2 4 NS NA 14 to

21

### CLETHODIM Human Health Risk Assessment DP No. D411899

Page 30 of 41 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 CR a (no)

CR a (yes) yes

yes

yes

no waived b

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 CR a (no) -

-

yes

yes

no

870.7485 General Metabolism

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

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

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

no

yes yes

yes

yes c

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

Page 31 of 41 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.

Unc ertainty 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

surviva l; reduced red cell mass; and increased incidences of bile duct hyperplasia, of pig mentation of the liver, and of foci of amphophilic macrophages in the lung. The chronic

tox icity 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

Page 32 of 41 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 NOA EL 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

P OD (75 mg/kg/day) is protective for the short- (1

- 30 day) and intermediate-term (1-6 months)

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

studi es 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

Page 33 of 41 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

P OD (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

studi es 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) LD 50 =

males 1.63 g/kg

f emales 1.36 g/kg III

870.1200 Acute dermal [rabbit] 40974510 (1986) LD 50 > 5.0 g/kg I V

870.1300 Acute inhalation [rat] 40974512 (1986) LC 50 > 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 I II

870.2600 Skin sensitization [ g uinea pig] 40974518 (1986) n ot 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 weig hts, 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 (198 7)

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)

Deve l opmental 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

o n 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 S tudies

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 treatment

related effects on survival, decreased red cell mass ( decreased erythrocyte counts, hemoglobin, and hematocrit values) , increased liver weight s, and increased foci of amphophilic alveolar ma crophages 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 B attery

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 treatment

related 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 in solubility 0.3 and 1.0 μl/ml Negative. There was no evidence of a dose

related 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

(ra t ) 41030125 (1987)

Acceptable up toxic dose 1,500 mg/kg/day (gavage) Negati ve. There is no evidence that c lethodim

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 P enetration

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 u nchanged 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 B attery

870.6200 a Acute neurotoxicity

rats

HanRcc:WIST (SPF) rats 48141801 (2006)

Unacceptable/non

guideline (Upgradable) 0, 10, 100, 1000 mg/kg (gavage) NOAEL = 100 mg/kg LOAEL = 1000 mg/kg based on clinical signs (decreased spontaneous activity, ruffled f ur, head tilt, hunched posture)

.

Acute neurotoxicity

rats 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 po sture).

### CLETHODIM Human Health Risk Assessment DP No. D411899

Page 37 of 41 870.6200 b 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) Range

finding study Under review The preliminary evaluation showed that clethodim did not produce immunotoxicity. NOAEL = 1312 mg/kg/day (HDT)

C lethodim M etabolites 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

De velopmental 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 stern al ossification, and an

increased incidence of a cervical rib.

### CLETHODIM Human Health Risk Assessment DP No. D411899

Page 38 of 41 870.5100

5

- Hydroxy

clethodim

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

Imine

sulfone 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

Imine

sulfone CHO Assay 41030130 (1988) Acceptable Negative. There w as no evidence of a dose

related 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 w eight 359.91 g/mol MRID 46124103

pH 4.1 1,2 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 K OW (25°C) 4.51 (21°C) MRID 48881405

Aerobic soil h alf

- 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 Mexico 1 Codex 2

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

- cy clohex

1

- 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 Mexico 1 Codex 2

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,

sa lal 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 Mexico 1 Codex 2

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 Mexico 1 Codex 2

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