### UN ITED STATES ENVIR O NMENTAL PROTECTION AG ENCY

WA SHINGTO N

, D.C

. 20460

MEMORANDUM

Date : Se p tem ber 3

, 2014 OFFICE OF C HEM ICAL SA FETY AND POLLUTION PRE VEN TIO N



### SUBJEC T : D im ethenamid!Dimethenamid-P

. H um an Hea lth Risk Assessmen t for Proposed New Use on Cottonseed Subgroup 20C

.

PC Code: 120051, 129051 Decision No

. : 482296

P etition N o .: 3F8 1 97 Risk A ssessment Type: Single Chemical Aggregate T XRNo .: NA MRIDNo.: NA DP Barcode: D 418 118 Registration N o

. : 7969

- 156

Regulatory Ac ti o n: Sec tio n 3 Case No. : 7223 CAS No.: 8 7 674-68

- 8

, 1635 15 -14- 8 40 CFR: §180.464



### FROM: I van

# eves, ORE, Ri s k Assessor 

# -PO.

. · f'

. ·. Bonrue Cropp-Kohlhgtan

,

## Envu~~~**/,-- .** **~** Marquea King, Ph.D.

,

## Toxicolo**~/~~** Ri s k Assessmen t Branch 4 {/ Health Effects Di v i sion (7509P)**~**



### THROUGH : Elissa Rea v es, Ph.D., Bran ch Chief

# ~j,~~**-­** Susan V. Humme l

, Branch Senior

## Scienti**.** Risk Assess men t B ranc h 4

, H ED (7509P )

T O: Kable Davis /E rik Kraft (RM25) Herbicide Branch Regis t ration Division (7505P)

Page I of 51

### Table of Contents


## 1 Exe cut · ive Summary

.. .... ... ..... ..... . ... ...... .. .............. .. ............................. .... . . ........ . .. .. .. ... ..... ....... 4

2 HE D Recommendations

.... .. ... ... .... . .. .. . . ................................................................................... 

### 6 2.1 Data D eficie n cies

......... . ... . ......... .. ............... . ................................................................... 7 2.2 Tol erance Conside r ations

...................... . ............... . ........... ...... ... . .. ... . ... . .. ....... ... . .. ....... .... 7 2.2 .1 Enf orc e m e nt Analytica l Method

........ .......... .... ...... .......... .. .......... ........ ........ .... ........... 7 2.2.2 Recommended T o l e ran ces

................................ .. ...... . ... .. .......... .. ... .. .......... ... .......... .. .. 7 2.2.3 Revisions to Petitioned-For To l erances

.. .. .......... .. .......... .. .......................................... 8 2.2 .4 Internati ona l Harmonization

.... . .................................................................................. 8 2.3 L abe l Re commendations

... . ......... .. ........... . ........................................ . ............................. 8 2.3.1 Recommendations from R esi du e Reviews

................................... . ............................. 8 2.3 .2 Recommendations from Occupational and Residentia l Assessments

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



### 3 Intr oduct io n

.. .. . . ......... .. .. . .......... . ...... . ... . ..................................................... . ........... . .............. .. . 8 3 .1 Chem ical Identity

.. .. ......... .. .. .. .......... . .. .. ...... ...... ........... ..... ........... . ..... .. ........................... 8 3.2 Physical/Chemical Cha ract eris tic s

............ . ........................... .. .......... ... ......................... 10 3.3 Pest i cide Use Pa ttern

................ .. .............. .. .......... .. .. .. ...... .. .. .. ........................ .. .......... ... 1 0 3.4 Ant i cipated Exposure Pathways

.............. .. ................................................................... 11 3.5 Consi derati on of Environmental Justice

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



### 4 Hazard Cha ract e rization and Dose

- Response Assessment

. ..... ... ......... .. ... . . . . .. .. . ... ... .. . ... . .. 12 4.1 Toxicology S tudie s Avai l able for Ana l ys i s

.................................................................. 1 2 4.2 Absorpt i on , Distribution, Metabolism

, Excretio n (ADME)

......................................... 1 3 4.2.1 Dermal Absorp t ion

.................................................................................................... 13 4.3 Tox icolo g i c al Effe cts

... .. .................. .. .............. .. ................ .. ......................................... 1 3 4 .4 Safety Factor f or Infants and Chi ldr en (F QP A Safety Factor)

..................................... 1 4 4.4.1 Co mpl eteness of the Toxico l ogy Database

........ .. .......... .. ........................................ . 1 4 4.4.2 Ev iden ce of Neuroto x icity

........................................................................................ 15 4.4.3 Evidence of Sensitivity/Susceptibility in th e D eve l o pin g or Young Animal

.......... . 1 5 4.4.4 Residual Unc e rtainty in the Exposure Datab ase

....................................................... 15 4 .5 Toxicity E ndpoint and Point of Departure Selections

........ .... ........ .... .......... .... ........ .... 15 4. 5

. 1 Dose- Response Assessme n t

.. . .......... .. .. . ........... . ........................................................ 15 4 .5.2 Recommendation for Combining Ro ute s of Exposures fo r Risk Assessment..

.... .. .. 17 4.5 .3 C lassifi ca tion of Car cinogenic Pot e ntia l.

.................................................................. 17 4.5.4 Summary of Toxico lo gical Doses and Endpoints for Dimethenamid-P for Use in Human Health Risk Assessm ent s

.......... .. ...... ...... .......... .. .......... .... ........ ....... ...... ........ .......... 18



### 5 Diet ary Exposure and Risk A ssessme nt

... ... .... .... ..... . ..... ....... ... ................. .. ...... . .... ....... ...... 19 5. 1 Residues of Co n cern S umm ary and Rat i ona l e

.................................. .. .......................... 1 9 5.2 Food Re sidue Profil e

............................. . ... . .. ..... .... .. ........... . .......................................... 20 5.3 W ater Re s idu e Pr ofi l e

................................................................................................... 23 5.4 Dietary Risk Assessme nt

...................................................... . ........... . ................ . ........ .. 24 5 .4. 1 Description of Residue Data Use d in Dietary Assessment..

...................... ...... ........ . 24 5 .4 .2 Percent Cro p Tr ea t e d U se d in Di etary Assess ment

.................................................. 24 5.4.3 Acute Dietary Risk Assess m ent..

........ .. .................................................................... 24 5.4.4 C hronic Die tary Risk Assessment

... ........ .......... .. ..................................................... 25 5 .4.5 Cancer Dietary Risk A ssess m ent..

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

Page 2 of 5 1Page 3 of 51



### 5.4.6 Summary Table

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

6 Residential (Non

- Occupational) Exposure/Risk Characterization

................................ .. 26 6.1 Residential Handler Exposure

................................ ................................ ....................... 26 6.2 Post

- Application Exposure

................................ ................................ ........................... 28 6.3 Residential Risk Estimates for Use in Aggregate Assessment

................................ ..... 30 6.4 Residential Bystander Post

- application Inhalation Exposure

................................ ....... 31 6.5 Spray Drift

................................ ................................ ................................ .................... 32

7 Aggregate Exposure/Risk Characterization

................................ ................................ ....... 32 7.1 Acute Aggregate Risk

................................ ................................ ................................ ... 32 7.2 Short

- and Intermediate

- Term Aggregate Risk

................................ .............................. 32 7.3 Chronic Aggregate Risk

................................ ................................ ................................ 33 7.4 Cancer Aggregate Risk

................................ ................................ ................................ . 33

8 Cumulative Exposure/Risk Characterization

................................ ................................ .... 33

9 Occupational Exposure/Risk Characterization

................................ ................................ . 33 9.1 Short

- /Intermediate

- Term Handler Risk

................................ ................................ ....... 33 9.2 Short

- /Intermedia te

- Post

- Application Risk

................................ ................................ .. 37 9.2.1 Dermal Post

- application Risk

................................ ................................ ................... 37 9.2.2 Inhalation Post

- application Risk

................................ ................................ ............... 39

10 References

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

................................ .................. 41 Appendix B. Physical/Chemical Properties

................................ ................................ ............. 48 Appendix C. Review of Human Research

................................ ................................ ............... 51Page 4 of 51



### 1 Executive Summary

This assessment provides information to support a proposed Section 3 use of dimethenamid

- P on cottonseed subgroup 20C. This document addresses the exposures and risks associated with exposures resulting from the new proposed use and currently registered residential uses of dimethenamid and dimethemamid

- P on turf and gardens. Tolerances of 0.01 ppm on cottonseed subgroup 20C

, 1 .5 ppm on cotton gin byproducts, and 0.02 ppm in cotton, seed, refined oil are proposed in connection with this action. Tolerances will be established in 40 CFR §180. 464.

Dimethenamid and dimethenamid

- P are selective chloroacetamide

- type herbicides registered for the control of annual broadleaf and grass weeds in a variety of field and vegetable crops. Dimethenamid is an equal part mixture of the S

- and R

- isomers (50:50, S:R); whereas, dimethenamid

- P is enriched in the biologically active S

- isomer (90:10, S:R). While there are minor inconsistencies between the two sets of toxicity data, [RS]

- dimethenamid and [S]

- dimethenamid

- P show similar toxicity (see Appendix A). For this risk assessment the toxic ology data from the 5050 S : R dimethenamid isomer is considered appropriate to use in characterizing the hazard for the dimethenamid

- P (90:10, S:R isomer). BASF is requesting an amendment to the Section 3 registration for Outlook® Herbicide (EPA Registrati on Number 7969

- 156), a 6.0 lb/gal emulsifiable concentrate (EC) formulation of dimethenamid

- P, to add preplant, preemergence and early postemergence broadcast applications to members of cottonseed subgroup 20C.

Preplant surface or preemergence applicati ons may be made at up to 0.47 lb ai/A and an early postemergence application may be made at up to 0.98 lb ai/A. Sequential applications of a preplant or preemergence application followed by an early postemergence application at least 14

- days after the ini tial application may be made at up to 1.45 lb ai/A/season. No pre

- harvest interval (PHI) is specified but the last application may be made two weeks after the R1 initial bloom stage. The restricted entry interval for the proposed use is 12 hours. The pr oposed label requires baseline clothing plus chemical

- resistant gloves, and protective eyewear as personal protective equipment (PPE). Applications for the proposed are expected to be made with an aircraft, groundboom truck, chemigation, and/or handheld e quipment.

Based on the application rate and label information, occupational exposure is expected to occur for short

- and intermediate

- term durations. Chronic exposure is not expected for the proposed use pattern. Potential routes of exposure include bot h dermal and inhalation. Non

- occupational (residential) exposures are not anticipated from the proposed new use, although residential exposure is expected for currently registered products. The existing residential uses have been reassessed to reflect upd ates to HED’s 2012 Residential SOPs 1 

### along with policy changes for body weight assumptions.

Hazard Characterization The primary target organ for dimethenamid (enriched (P) and racemic (RS) mixtures) is the liver and is displayed throughout the database and in all species tested. The toxicity in 90

- day feeding studies in rats with [S]

- dimethenamid

- P and [RS]

- dimethenamid were very similar with decreased body decreased body weights, increased cholesterol and changes in liver weights along with histopatho logy showing microscopic effects (centrilobular hypertrophy, periportal

1 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.htmlPage 5 of 51



### eosinophilic inclusions and necrosis) in the liver. Chronic studies performed with [RS]

- dimethenamid in the rat, mouse and dog showed decreases in body weight and food efficiency as

ac companying effects over time. At higher dose levels, liver pathology (hepatic lesions, bile duct hyperplasia, and tumors), stomach hyperplasia, and some indications of kidney effects were noted. Two 21

- day dermal toxicity studies in rabbits were conducted on [RS]

- dimethenamid and in one of those studies minor skin irritation was observed at all doses tested and a d ecrease in body weight gain was also seen at the lowest effect level.

Points of Departure for Risk Assessment The acute and chronic dietary p oints of departure (PODs) were based on a series of effects (depressed respiration, unsteady gait, poor general condition) which included the use of both the acute neurotoxicity study (general population) and a rabbit developmental study (females 13

- 49
yea rs) which displayed abortions, increased resorptions and post

- implantation loss The short

and intermediate

- term POD for dermal exposure ( No observed adverse affect level (NOAEL = 300 mg/kg/day) was based on decreased body weight in a 21 day dermal study in rabbits. The inhalation and incidental oral toxicity endpoint (NOAEL = 10 mg/kg/day) was selected from a subchronic and chronic oral toxicity study in dogs based on decreased body weight in females, increased relative to body liver weight in both sexe s, increased periportal cytoplasmic vacuolation in liver in both sexes, and dilation of liver sinusoids in females. A subchronic inhalation toxicity study is not available, however, the Hazard and Science Policy Council (HASPOC), using a weight of the evi dence (WOE) approach, concluded that a subchronic inhalation study is not required for dimethenamid

- P at this time (TXR# 0056993). For acute and chronic dietary risk assessments, a 100X uncertainty factor was applied (interspecies factor of 10X and intras pecies factor of 10X, FQPA factor of 1X).

Summary of Acute and Chronic Dietary Exposure and Risk Estimates Both the acute and chronic assessments are conservative and incorporated tolerance level residues, assume 100% crop treated and use default processing factors. Estimated drinking water concentrations (EDWCs) used in the assessments were generated using Tier I modeling.

For the acute assessment, aggregate d ietary (food and drinking water) exposures are below HED’s level of concern (<100% aPAD) at the 9 5 th 

### percentile of exposure for all population subgroups. The acute dietary exposure at the 9 5 th 

### percentile of exposure is estimated at 0.0 08399 mg/kg/day for the overall U.S. population, equivalent to <1 % of the aPAD. The population subgroup with the highest estimated acute dietary exposure is All Infants <1 year of age , with an estimated exposure at the 9 5 th 

### percentile of 0.0 26253 mg/kg/day, equivalent to 1.3 % of the aPAD.

For the chronic assessment, aggregate dietary (food and drinking water) exposures are below HED’s level of concern ( <100% c PAD) for all population subgroups. The chronic dietary exposure is estimated at 0.00 3241 mg/kg/day for the general U.S. population , equivalent to 6.5 % of the cPAD . The population subgroup with the highest estimated chronic dietary expos ure is All Infants <1 year of age, with an estimated exposure of 0.00 8326 mg/kg/day , equivalent to 17 % of the cPAD.Page 6 of 51



### Summary of Re sidential Exposure and Risk Estimates All existing residential exposures have been reassessed to reflect updates to HED’s 2012 Residential SOPs along with policy changes for body weight assumptions. No registered products resulted in residential handler o r post

- application risk estimates of concern. All risk estimates are greater than HED’s Level of Concern (LOC) of 100 and therefore not of concern. Dermal Margins of Exposure (MOEs) ranged from 250 to 5,300,000; Inhalation MOEs range from 7,700 to 1,500,0 00; and post

- application MOEs range from 310 to 200,000.

Aggregating Exposures/Risk Estimates The aggregate assessments of acute and chronic dietary exposure were based on food and water only. Short

- /intermediate

- term dietary exposure was aggregated with residential inhalation exposure because the PODs were based on the same study which showed toxicity effects in the liver. Dermal exposure was not included because the effect (body weight gain) was considered to be non

- specific. Aggregate risk estimates (food, water and residential) were not of concern for HED (LOC=100); MOEs were 2,200 for adults and 1,100 for children (1<2 years of age).

Summary of Occupational Exposure and Risk Estimates Occupational handler dermal and inha lation exposure and risk assessment are not of concern (i.e. all MOEs ≥ 100) at baseline mitigation (no PPE), with one exception. The dermal exposure scenario of mixing and loading a liquid formulation of dimethenamid

- P for aerial applications resulted in an MOE of 92. However, with the use of additional PPE (i.e., gloves) the risk estimate was mitigated to an MOE of 540. Dermal MOEs ranged from 92 to 9,100. Inhalation MOEs ranged from 3,100 to 140,000. Note that only engineering control (enclosed cockp it) data are available to assess risks to handlers operating aircrafts. Short

- and intermediate

- term post

application risk estimates were not a concern on day 0 (12 hours following application) for all post

- application activities (MOEs ranged from 5,100 to 15,000).

Restricted Entry Interval (REI) Under 40 CFR 156.208 (c) (2) (iii), active ingredients classified as Toxicity Category III or IV for acute dermal, eye irritation and primary skin irritation are assigned a 12

- hour REI. Therefore, the label req uired REI of 12 hours is adequate to protect agricultural workers from post

- application exposures to dimethenamid

- P

. Based on the Agency's current practices, a quantitative non

- cancer occupational post

- application inhalation exposure assessment was no t performed for dimethenamid

- P at this time. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post

- application inhalation exposure assessment for dimethenamid

- P

.

2 HED Recommendations

Deficiencies are outlined in Section 2.1 below. The specific tolerance recommendations are discussed in Section 2.2, and label modifications are discussed in Section 2.3.Page 7 of 51



### 2.1 Data Deficiencies

HED has examined the residue chemistry database for dimethena mid, and pending submission of a revised Section F of the petition (see requirements under Proposed Tolerances), there are no residue chemistry issues that would preclude granting an amended registration for Outlook® Herbicide (EPA Registration Number 7969

- 156) to permit the proposed use on members of cottonseed subgroup 20C.

A subchronic inhalation study is required but being waived at this time due to a weight of the evidence approach which considered all of the available hazard and exposure information for dimethenamid.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate enforcement method is available for determining residues of both dimethenamid and dimethenamid

- P residues in plant commodities. The GC/NPD method (AM

- 0884

- 0193

- 1) has been validated by the Agency and submitted for publication in FDA’s Pesticide Analytical Manual (PAM), Volume II. The method does not separate the S

- and R

- isomers of dimethenamid. The limit of quantitation (LOQ; determined as the l owest level of method validation, LLMV) is 0.01 ppm. As tolerances are not required for livestock commodities, no analytical methods for livestock commodities are required.

2.2.2 Recommended Tolerances

Tolerances for plant commodities are established under §1 80.464, and are expressed in terms of dimethenamid per se . The tolerance definition proposed by BASF is in terms of dimethenamid
per se . The tolerances proposed by BASF are listed in Table 2.2.2 along with the tolerance levels recommended by HED and corr ected commodity definitions.

Adequate residue data are available to support the proposed tolerances. The submitted data are adequate to support tolerances of 0.01 ppm and 1.5 ppm for residues of dimethenamid

- P in/on cottonseed subgroup 20C and cotton gin byproducts, respectively. The recommended cottonseed subgroup 20C tolerance was set at the LOQ of the enforcement method and the recommended cotton gin byproduct tolerance was calculated using the Organization for Economic Cooperation and Development (OECD) tolerance calculation procedures. The submitted cotton processing study conducted at an exaggerated rate (3x) is adequate to support the proposed use and demonstrates that separate tolerances for residues o f dimethenamid

- P are not need for processed commodities of cotton.Page 8 of 51

T able 2.2.2. Tolerance Summary for Dimethenamid

- P Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Correct Commodity Definition

Comments 40 CFR §180.464(a) Cottonseed subgroup 20C 0.01 0.01 Cottonseed subgroup 20C Cotton, gin byproducts 1.5 1.5 Cotton, gin byproducts

Cotton, seed, refined oil 0.02

-- While data suggest a very slight potential for concentration of dimethenamid in refined oil, a separate tolerance in refined oil will not be needed since the exaggerated rate processing study demonstrates that the petitioned

- for/recommended tolerance in/on cotton seed (0.01 ppm) will be adequate to cover potential residues of dimethenamid in refined oil.



### 2.2.3 Revisions to Petitioned

- For Tolerances

A separate tolerance in refined oil will not be needed since the exaggerated rate processing study demonstrates that the petitioned

- for/recommended tolerance in/on cotton seed (0.01 ppm) will be adequate to cover potential residues of dimethenamid

- P in refined oil.

2.2.4 International Harmonization

There are no established Codex, Canadian or Mexican maximum residue l imits (MRLs) for dimethenamid/ dimethenamid

- P in/on cotton commodities (email from M. Negussie to B. Cropp

Kohlligian dated 2/28/14). Therefore, there is no question about harmonization of the proposed tolerances.

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

No changes are required to the proposed label.

2.3.2 Recommendations from Occupational and Residential Assessment s

None.

3 In troduction

3.1 Chemical Identity

Structure and nomencla ture are reported in Table 3.1

.Page 9 of 51

Table 3.1

. Dimethenamid

- P Nomenclature. Compound

Common name Dimethenamid

- P (or S

- Dimethenamid); 90:10, S:R isomer ratio Company experimental name BAS 656H; SAN 1289
IUPAC name ( S )

- 2

- chloro

- N

- (2,4

- dimethyl

- 3

- thienyl)

- N

- (2

- methoxy

- 1

- methylethyl) acetamide
CAS name 2

- chloro

- N

- (2,4

- dimethyl

- 3

- thienyl)

- N

- [(1 S )

- 2

- methoxy

- 1

- methylethyl] acetamide CAS registry number 163515

- 14

- 8
End

- use product (EP) Not applicable Compound

Common name M23
Chemical name N

- (2,4

- dimethyl

- thiophen

- 3

- yl)

- N

- (2

- methoxy

- 1

- methy

- ethyl)

- oxalamic acid Compound

Common name M26
Chemical name 3

- {[(2,4

- dimethyl

- thiophen

- 3

- yl)

- (2

- methoxy

- 1

- methyethyl)carbamoyl]methylsulfanyl}

- 2

- hydroxy

- propionic acid Compound

Common name M27
Chemical name [(2,4

- dimethyl

- thiophen

- 3

- yl)

- (2

- methoxy

- 1

- methylethyl)carbamoyl]

- methanesulfonate [standard depicted]Page 10 of 51

Table 3.1

. Dimethenamid

- P Nomenclature. Compound

Common name M30
Chemical name 3

- [(2

- {(2,4

- dimethyl

- 3

- thienyl)[(1S)

- 2

- methoxy

- 1

- methylethyl]amino}

- 2

- oxoethyl)sulfinyl]

- 2

- hydroxypropanoic acid



### 3.2 Physical/Chemical Characteristics

The physicochemical properties of dimethenamid

- P are reported in Appendix B.

3.3 Pesticide Use Pattern

BASF has submitted a Section B of the petition proposing an amendment to the Section 3 registration for Outlook® Herbicide (EPA Registration Number 7969

- 156), a 6.0 lb/gal emulsifiable concentrate (EC) formulation of dimethenamid

- P, to add preplant, preemergenc e and early postemergence applications to members of cottonseed subgroup 20C. Preplant surface or preemergence applications may be made at up to 0.47 lb ai/A and an early postemergence application may be made at up to 0.98 lb ai/A. Sequential application s of a preplant or preemergence application followed by an early postemergence application at least 14

- days after the initial application may be made at up to 1.45 lb ai/A/season. No preharvest interval (PHI) is specified but the last application may be m ade two weeks after the R1 initial bloom stage. Section B of the petition is draft supplemental labeling to the current Outlook® Herbicide label (EPA Registration Number 7969

- 156). The use directions of the draft supplemental labeling to the subject end

- use product under consideration provided in Section B are summarized Table 3.3.Page 11 of 51

Table 3.3. Summary of Direc tions for Proposed Use of Dimethenamid

- P.

Appl. Timing, Type, and Equip. Formulation

[EPA Reg. No.] Max. Appl.

Rate (lb ai/A) Max.

No. Appl.
per Season Max.

Seasonal Appl. Rate (lb ai/A) PHI

(days) Use Directions and Limitations

Co ttonseed subgroup 20C: Cotton Preplant surface,
preemergence and/or postemergence foliar broadcast. Ground, aerial or chemigation 6.0 lb/gal EC [7969

- 156] 0.47

preplant surface

or preemergence 1 1.45 Not Specified May be applied as single application

or in sequential applications (preplant or preemergence followed by postemergence). Sequential applications must be separated by at least 14 days. No PHI is specified; however, postemergence applications may be made from first true leaf stage to the mid

- bloom stage (i.e., two weeks after R1 initial bloom stage). 0.98 postemergence 1

PHI = preharvest interval.



### The current label for Outlook® Herbicide (EPA Registration Number 7969

- 156; Accepted 3/20/14) specifies the following spray volume and rotational crop restrictions not provided in Section B of the petition:

 Ground Application: Apply in a minimum of 5 gallons of water per acre.

 Aerial Application: Apply in a minimum of 2 gallons of water per acre.

 Rotational Crop Restrictions: If any labeled crop treated with Outlook® Herbicide is lost to adverse weather or for other reasons, the area treated may be replanted to any of the labeled crops immediately, unless specified otherwise in the crop specific information section of this label. Fall seeded cereal crops may be planted 4 months or more following treatment. There are no rotational crop restrictions for the spring following the previous year’s application of Outlook® Herbicide.

The restricted ent ry interval for the proposed use is 12 hours. The proposed label requires baseline clothing plus chemical

- resistant gloves, and protective eyewear as personal protective equipment (PPE).

3.4 Anticipated Exposure Pathways

The Registration Division has reques ted an assessment of human health risk to support the proposed new use of dimethenamid

- P on cottonseed subgroup 20C: cotton. Humans may be exposed to dimethenamid

- P in food and drinking water, since this chemical may be applied directly to growing crops and application may result in dimethenamid

- P reaching surface and ground water sources of drinking water. In an occupational setting, applicators may be exposed whil e handling the pesticide prior to application, as well as during application. There is a potential for post

- application exposure for workers re

- entering treated fields. There are no proposed residential uses at this time; however, there are existing resi dential uses that have been reassessed to reflect updates to HED’s 2012 Residential SOPs 2 

### along with policy changes for body weight assumptions. The revision of residential exposures will impact the human health

2 Available: http://w ww.epa.gov/pesticides/science/residential

- exposure

- sop.htmlPage 12 of 51



### aggregate risk assessment for dimethenamid

- P.

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 Environ mental 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 consider s 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

ac tivities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the National Health and Nutrition Survey/What We Eat in America (NHANES/WWEIA) and are used in p esticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure a ssessments 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 tr eated areas post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4 Hazard Characterization and Dose

- Response Assessment

4.1 Toxicology Studies Available for Analysis

The toxicology database for dimethenamid

- P is considered complete. Dimethenamid ([RS]

- dimethenamid) and dimethenamid

- P ([S]

- dimethenamid

- P) are selective herbicides. Dimethenamid is a racemic 50:50 S:R isomer. Dimethenamid

- P is enriched in the biologically active S

- isomer (90:10, S:R). BASF stopped producing, marketing and selling the 50:50 S:R isomer for use in the US in 2002

- 2003 and has replaced it with dimethenamid

- P (90:10, S:R). While there are minor inconsistencies between the two sets of toxicity data, [RS]

- dimethenamid and [S]

- dimethenamid

- P show similar toxicity (see Appe ndix A). A subchronic inhalation toxicity study is not available. However, the Hazard and Science Policy Council (HASPOC), using a weight of the evidence (WOE) approach, concluded that a subchronic inhalation study is not required for dimethenamid

- P at t his time (TXR# 0056993). The toxicological studies for [S]

- dimethenamid

- P database are limited but include: 1) subchronic oral toxicity study in rats, 2) neurotoxicity battery in rats, 3) immunotoxicity in mice, 4) a mutagenicity battery, and 5) acute 6

- p ack of studies. The toxicological studies currently in the [RS]

- dimethenamid database which are used for bridging include: 1) subchronic oral toxicity study in rats, 2) chronic/carcinogenicity studies in rats and mice, 3) subchronic and chronic oral toxic ity study in dogs, 4) developmental studies in rats and rabbits, 5) reproduction study in rats, 6) metabolism studies in rats, 7) a mutagenicity battery, and 8) acute 6

- pack of studies. Therefore, the toxicity database for thePage 13 of 51



### [RS] mixture is complete and the bridging studies to the [S]

- dimethenamid

- P toxicity data are complete (TXR# 0051920). New toxicity data have been received since the last risk assessment (B.Daiss, D348401, 8/27/08). These new data include reviews of acute and subchronic neurotoxici ty and immunotoxicity studies.

4.2 Absorption, Distribution, Metabolism, Excretion (ADME)

Oral rat m etabolism studies with [RS]

- dimethenamid showed ext ensive metabolism (>30 metaboli tes). In the rat dimethenamid

- P parent was extensively metabolized, being essentially complete within 3 days . O ver 90% was excreted in the urine, feces, and bile within 7 days. Plasma data for the dimethenamid

- P indicate that the Cmax was about 72 hours post administration both for a dose of 10 mg/kg bw and a dose of 1000 mg/kg/bw. The blood levels did not decrease significantly between 72 and 168 hours post dosing. Metabolism studies with [RS]

- dimethenamid showed extensive metabolism (>30 metabolites). In the rat dimethenamid

- P parent was extensively metabolized, being essentially complete within 3 days over 90% excreted in the urine, feces, and bile within 7 days.

4.2.1 Dermal Ab sorption

Dermal absorption and dermal penetration studies are not available for either isomer.

4.3 Toxicological Effects

The primary target organ for dimethenamid (enriched (P) and racemic (RS) mixtures) is the liver and is displayed throughout the dat abase and in all species tested. The toxicity in 90

- day feeding studies in rats with [S]

- dimethenamid

- P and [RS]

- dimethenamid were very similar with decreased body decreased body weights, increased cholesterol and changes in liver weights along with histo pathology showing microscopic effects (centrilobular hypertrophy, periportal eosinophilic inclusions and necrosis) in the liver. Chronic studies performed with [RS]

- dimethenamid in the rat, mouse and dog showed decreases in body weight and food efficiency as accompanying effects over time. At higher dose levels, liver pathology (hepatic lesions, bile duct hyperplasia, and tumors), stomach hyperplasia, and some indications of kidney effects were noted. Two 21

- day dermal toxicity studies in rabbits were cond ucted on [RS]

- dimethenamid and in one of those studies minor skin irritation was observed at all doses tested and a d ecrease in body weight gain was also seen at the lowest effect level.

The concern for neurotoxicity is low based on the results of the n ewly submitted acute and subchronic neurotoxicity studies. The acute neurotoxicity study resulted in e ffects such as partially closed eyelids, lacrimation and slight salivation at the highest dose tested of (600 mg/kg/bw). There were no treatment

- related or toxicologically significant findings during the gross examination of rats or in the microscopic examination of neurological tissues. In the subchronic neurotoxicity study, there were no clinical signs seen and no adverse effects seen up to 3 23/390 mg/kg/bw day

. Systemic e ffects seen were renal pelvic dilation in males (considered incidental ) and a trend of higher liver weights in females was found at the lowest dose tested and

were not considered adverse nor were they corroborated with any other guidel ine studiesPage 14 of 51



### submitted within the database . There were no liver histopathology or clinical chemistry
measurements in the subchronic neurotoxicity study , however, the adversity of this finding is supported by the observation of multiple liver effects (incre ased cholesterol, increased total serum protein, increased liver weights, and enlarged centrilobular hepatocytes) in the 90

- day rat study at doses of 98/119 (M/F) mg/kg/day and above

. There was no neurotoxicity observed at higher doses nor in other guidel ine studies in the dimethenamid

- P database.

There is no concern for increased qualitative and/or quantitative susceptibility after exposure to either dimethenamid isomer in developmental toxicity studies in rats and rabbits, or a rat reproduction study. Developmental toxicity studies show increased post

- im plantation loss and minor skele tal variations in the rat, and late resorptions and minor skeletal variations in the rabbit at the highest dose tested (LOAEL, 425 mg/kg/day

- [RS]

- dimethenamid). In the rabbit, the developmental effects occurred at the same dose as maternal toxicity (LOAEL, 150 mg/kg/day), whereas in the rat, the developmental toxicity occurred at much higher doses than in the dams (LOAEL, 215 mg/kg/day). The chosen NOAEL of 75 mg/kg/day ([S]

- dimethenamid) is considered protective for effects seen in both studies. The reproduction study resulted in decreases in body weight in both pups and parental animals at the same dose levels. The only other effects noted at the LOAEL of 150 mg/kg/d ay were increases in liver weights in both male and female parental animals.

A review of the recently submitted immunotoxicity resulted in no immunotoxicity effects at the limit dose of 1167 mg/kg (MRID 49184307). There were, however, at this dose incre ased absolute and relative liver weights.

A battery of mutagenicity studies with [S]

- dimethenamid

- P is negative for genetic mutations, including unscheduled DNA synthesis. However, mutagenicity studies with [RS]

- dimethenamid showed positive results for u nscheduled DNA synthesis and there were equivocal results in two dominant lethal studies. [RS]

- dimethenamid has been classified as group “C” possible human carcinogen, based on an increasing trend for liver tumors (males) seen in the chronic toxicity/carcinogenicity rat study. There were no dose

- related tumors seen in the mouse carcinogenici ty study. For the purpose of risk characterization, the RfD approach should be used. The chronic RfD will be protective of both non

- cancer and cancer effects.

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

R egarding FQPA, the toxicity data base is complete and is considered adequate to evaluate risks to infants and children. All studies required as part of the 40 CFR Part 158 data requirements have been satisfied. There is no concern for increased qualitative and/or quantitative susceptibil ity following in utero and pre

- or post

- natal exposure. All guideline studies submitted have clearly defined NOAELs and LOAELs. Therefore, HED recommends that the 10x FQPA SF be reduced to 1x.

4.4.1 Completeness of the Toxicology Database

The toxicology da tabase for dimethenamid

- P is complete. Based on a WOE approach considering all the available hazard and exposure information for dimethenamid

- P, the HEDPage 15 of 51



### HASPOC concluded that a subchronic inhalation toxicity study is not required at this time (TXR# 0056993 ). Acceptable studies are available and are adequate to evaluate the potential risks for infants and children . Those studies include: d evelopmental, reproduction, chronic, subchronic, acute and subchronic neurotoxicity, and immunotoxicity.

4.4.2 Evidence o f Neurotoxicity

Acute and subchronic neurotoxicity studies are available for dimethenamid

- P. However, the concern for neurotoxicity is low since clinical signs were not observed until a high dose after a single dose and were likely agonal and not necess arily attributed to neurotoxicity. The subchronic neurotoxicity study did not result in neurotoxic effect but resulted in systemic effects at higher doses.

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

There is no concern for increased qualitative and/or quantitative susceptibility following in utero (rats and rabbits) and pre

- and post

- natal exposure (rats) to the [RS] or the [S] dimethenamid. NOAEL and LOAEL values for the fetal/pup effects observed in the developmental study and effects seen in the reproduction studies occurred at the same doses or higher than those which caused maternal toxicity. The rabbit developmental study was used as an acute dietary endpoint for females 13

- 49 years of age. The points of departure selected for risk assessment are protective of effects seen in these guideline studies. Therefore the acute and chronic dietary risk assessments are protective of potential fetal/offspring effects.

4.4.4 Residual Uncertainty in the Exposu re Database

There are no residual uncertainties in the exposure database. The dietary risk assessment is conservative and will not underestimate dietary and/or non

- dietary occupational exposure to dimethenamid

- P. The acute and chronic dietary assessments conducted with DEEM

- FCID were refined analyses. The assessments utilized anticipated residues, default processing factors, and available percent crop treated data. The DEEM analysis also used Tier 1 drinking water estimates. For these reasons it can be concluded that the DEEM

- FCID analysis does not underestimate risk from acute or chronic exposure to thiabendazole. Similarly, HED does not believe that the non

- dietary occupational exposures are underestimated because they are also based on conservative as sumptions, including maximum application rates, and standard values for unit exposures and acreage treated/amount handled.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose

- Response Assessment

Acute Dietary (general population) The acute rat neu rotoxicity study (49184304) NOAEL is 200 mg/kg with a LOAEL of 600 mg/kg, based on a number of clinical effects (slightly depressed respiration, semi

- closed eyelids, piloerection, slightly unsteady gait, smeared fur in anogenital region, slight twitching, and poorPage 16 of 51



### general condition) in females and some males. This endpoint is appropriate for the population of concern and is a result of a single dose.

Acute Dietary (females 13

- 49 y ea rs of age ) The rabbit developmental toxicity study (41706809) NOAEL is 75 mg/kg/day with a maternal LOAEL of 150 mg/kg/day, based on abortions. The developmental NOAEL is 75 mg/kg/day. The developmental LOAEL is 150 mg/kg/day based on increased resorptions and post

implantation loss. The resorptions and post implantation los s are presumed to be the result from a single dose. The developmental endpoint is female specific and therefore appropriate for females 13

- 49 years of age. The acute endpoint is supported by a range

- finding developmental study in rats with [S]

- dimethenam id

- P, which showed increased resorptions at 400 mg/kg/day.

Chronic Dietary The chronic toxicity/carcinogenicity rat study (MRIDs 41706808/42030102) was selected based on liver effects (decreases in body weight, weight gain, and increased microscopic hepatic lesions in both sexes) observed at the LOAEL of 36 mg/kg/day (NOAEL of 5 mg/kg/day). The duration of this study and the route of exposure are appropriate for assessing chronic dietary exposure. This endpoint and POD are protective of adverse effects observed at higher doses in other studies.

Incidental oral and Inhalation (short and intermediate) Co

- critical studies based on the dog subchronic oral toxicity study (MRID 41615902) and the dog chronic oral study (MRID 41615903) were selected. The NOAEL of 10.1 mg/kg/day is based on the chronic dog study. The LOAEL of 33.6 m g/kg/day from the subchronic dog study is based on decreased body weight in females, increased relative to body liver weight in both sexes, increased periportal cytoplasmic vacuolation in liver in both sexes, and dilation of liver sinusoids in females. The Level of Concern of 100 is required for the short

- and intermediate

term scenarios for inhalation exposure is based on the conventional uncertainty factor of 100. This includes 10x for interspecies extrapolation and 10x for intraspecies variation).

Der mal (short and intermediate) There are two 21

- day dermal toxicity studies in New Zealand White Rabbits used for points of departure for the dermal endpoint. In the first study (MRID 41662414), s igns of toxicity were limited to decreased body weight gain i n male rabbits at the 500 mg/kg/day dose level which was determined to be the LOAEL. No NOAEL was identified.

In a second study (MRID 41951301), [RS] dimethenamid (78.8%) at 1000 mg/kg/day for 21 days exceeded the maximum tolerated dose producing severe local irritation and death (5/5 males and 4/5 females). Dermal irritation was noted at 30 mg/kg/day but no systemic effects were observed. The systemic LOAEL was therefore established at 1000 mg/kg/day. The systemic NOAEL is 300 mg/kg/day. Therefore, w hen the studies are used in combination, the NOAEL of 300 mg/kg from the second dermal rabbit study may be used with the systemic effects noted in the first dermal rabbit study with a LOAEL of 500 mg/kg/day, based on decreased body weight gain.Page 17 of 51



### The route specific studies are appropriate for both the population and duration of exposure. The two 21

- day dermal toxicity studies together provide data that can be used determine the LOAELs and NOAELs for dermal toxicity. An MOE 100 is required for the short

- and intermediate

- term scenarios for dermal exposure is based on the conventional uncertainty factor of 100. This includes 10x for interspecies extrapolation and 10x for intraspecies variation.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assess ment

When there are potential occupational and residential exposures to a pesticide, the risk assessment must address exposures from three major sources: incidental oral, dermal and inhalation. It must be determined whether or not the individual exposur es have the same toxicological effects. If they do, then they can be combined. For dimethenamid

- P, the endpoints for inhalation and incidental oral were based on the same study, and therefore can be combined. However, the dermal assessment is based on n on

- specific effects (body weight gain only) and should not be combined.

4.5.3 Classification of Carcinogenic Potential

Dimethenamid

- P is classified as group “C” possible human carcinogen, based on weak evidence for carcinogenicity. The weak evidence is based only on an increasing trend for liver tumors in male rats at the highest dose. The liver tumors were not statistica lly significant for a pairwise test with controls. There is no evidence of cancer in male or female mice. The evidence for mutagenicity is equivocal. For [RS]

- dimethenamid, only one study showed positive DNA synthesis in vitro while there was no evidence o f mutagenicity in vivo . With the [S]

- dimethenamid, there is no evidence for gene mutation in the unscheduled DNS synthesis assay. There is lack of biological concern for the dominant lethal studies since the effects are not characteristic of a typical domi nant lethal response but rather was a result of resorptions noted in the assay. Therefore, based on the weight of the evidence the agency is confident the chronic endpoint and point of departure is protective of the liver tumors observed in the male rats.Page 18 of 51



### 4.5.4 Summary of Toxicological Doses and Endpoints for Dimethenamid

- P for Use in Human Health Risk Assessments

Table 4.5.4. Summary of Toxicological Doses and Endpoints for Dimethenamid

- P for Use in Human Health Risk Assessments
Exposure/ Scenario Point of Departure (mg/kg/day) Safety Factors POD for Risk Assessment (mg/kg/day) Study and Toxicological Effects

Acute Dietary (General Population, including Infants and Children) NOAEL = 200 UF A = 10x

UF H =10x FQPA SF= 1x aRfD = 2.0

aPAD = 2.0 Acute Neurotoxicity (MRID 49184305)

LOAEL= 600 mg/kg based on lacrimation, salivation, irregular and accelerated respiration, slight tremors, reduced exploration, unsteady gait, significantly reduced rearing \

Acute Dietary (Females 13

- 49 years of age) NOAEL = 75 UF A = 10x UF H =10x FQPA SF= 1x aRfD = 0.75

aPAD = 0.75 Developmental Rabbit Study (MRID

41706809) Maternal; LOAEL = 150 mg/kg/day based on abortions (not considered acute effect). Developmental; LOAEL = 150 mg/kg/day based on post

- implantation loss

Chronic Dietary (All Populations) NOAEL= 5 UF A = 10x UF H =10x FQPA SF= 1x cRfD = 0.05

cPAD = 0.05 Chronic/carcinogenicity rat study (MRIDs

41706808/42030102) LOAEL = M/F; 36/49 mg/kg/day based on decreased body weight and body weight gain in both sexes, increased food conversion ratios in females, and increased microscopic hepatic lesions in both sexes.

Incidental Oral Short

Term (1

- 30 days) and Intermediate

- Term (1

- 6 months) NOAEL= 10 UF A = 10 x UF H = 10 x Occupational

LOC for MOE = 100 Subchronic/chr onic oral dog studies (MRIDs

41615902 & 41615903) Chronic dog NOAEL = 10 mg/kg/day Chronic dog LOAEL = 48.7 mg/kg/day Subchronic NOAEL = 4.72 mg/kg day Subchronic LOAEL = 33.6 mg/kg/day based on decreased body weight in females, increased relative to body liver weight in both sexes, increased periportal cytoplasmic vacuolation in liver in both sexes, and dilation of liver sinusoids in females. Dermal Short

- Term (1

- 30 days) and Intermediate

- Term (1

- 6 months) NOAEL= 300 UF A = 10x

UF H =10x Occupational

L OC for MOE = 100 21 Day dermal rabbit study (MRIDs

41662414/419513010) LOAEL = 500 mg/kg/day based on decreased body weight gain only (non

- specific)

Inhalation Short

- Term (1

- 30 days) NOAEL= 10 UF A = 10 x UF H = 10 x Occupational

LOC for MOE = 100 Subchronic/chronic oral dog studies (MRIDs

41615902 & 41615903) Chronic dog NOAEL = 10 mg/kg/day Chronic dog LOAEL = 48.7 mg/kg/day Subchronic NOAEL = 4.72 mg/kg day Subchronic LOAEL = 33.6 mg/kg/day based on decreased body weight in females, increased re lative to body liver weight in both sexes, increased periportal cytoplasmic vacuolation in liver in both sexes, and dilation of liver sinusoids in females Cancer (oral, dermal, inhalation) “C” Possible human carcinogen. The cRfD is considered protective of the cancer effects.Page 19 of 51

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 po pulation (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short

- term study for long

- term risk assessment. UF DB = to account for the absence of key data (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = po pulation adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.



### 5 Dietary Exposure and Risk Assessment

5.1 Residues of Concern Summary and Rationale

The dimethenamid risk asse ssment team has determined the residues of concern for dietary risk assessment and the tolerance expression and these are summarized in Table 5.1.

Table 5.1. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expr ession

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression

Plants Primary

Crop Parent Parent

Rotational Crop Parent Parent

Livestock Ruminant N/A N/A

Poultry N/A N/A

Drinking Water Parent plus its degradates, dimethenamid ethanesulfonic acid and dimethenamid oxanilic acid. Not Applicable



### Plants For existing and currently proposed uses, the nature of dimethenamid residues in plants is adequately understood based on available soybean, corn and suga r beet metabolism studies. The residue of concern for purposes of the tolerance expression and risk assessment is parent only

. However, for future uses, new evidence including the new cotton gin byproducts field trial data suggest that additional residue s of concern could rise to the level of significance from mid

- to late

- season foliar uses of dimethenamid on food crops. Hence, additional metabolism data may be required and residues of concern may need to be re

- examined if mid

- to late

- season foliar use s of dimethenamid are proposed in the future. Also, sufficient magnitude of the residue data for known metabolites of dimethenamid may be needed for future uses.

Livestock The nature of dimethenamid residues in livestock is adequately understood based on available goat and poultry metabolism studies. For existing and currently proposed uses, there is no reasonable expectation of finite residues of concern in livestock commodities (40 CFR §180.6(a)(3)). This decision is based on the available livestock m etabolism data alone since feeding study data are not currently available. Hence, future new uses and/or significant increases in existing uses may precipitate the need for feeding study data.Page 20 of 51



### Drinking Water In previous assessments, the residue of concern in drinking water was considered parent only; however, the current risk assessment team has determined that the residues of concern in drinking water are parent plus its degradates, dimethenamid e thanesulfoni c acid and dimethenamid oxanilic acid. Although the degradates appear to be less toxic than parent (email from R. Kent to B. Cropp

- Kohlligian dated 5/22/14), they are included as residues of concern since they were identified as potentially significant degradates in the available fate data and found in greater abundance than the parent in some of the available water monitoring data.

5.2 Food Residue Profile

Crop Field Trials BASF has submitted field trial data for dimethenamid

- P on cotton . Eleven field tr ials were conducted in the United States during the 2012 growing season in the North American Free Trade Agreement (NAFTA) Growing Zones 2 (GA; 1 trial), 4 (AR and MO; 3 trials), 6 (TX; 1 trial), 8 (KS, OK, and TX; 4 trials), and 10 (CA; 2 trials). The pe titioner reported that a twelfth site in CA was terminated due to crop failure and has been reinitiated for the 2013 growing

season.

The submi tted cotton field trial data was found adequate to support the proposed use. Data were collected with an adequat e data

- collection method and are supported by adequate storage stability data. Although 1 trial is missing from region 10, the number of trials (11) and geographical representation is deemed adequate since residues of dimethenamid

- P were below the LOQ (<0 .01 ppm) in/on all samples of undelinted cottonseed. Residues of dimethenamid

- P were <0.01

- 0.814 ppm (per trial averages) in/on samples of cotton gin byproducts. The submitted data are adequate to support tolerances of 0.01 ppm and 1.5 ppm for residues o f dimethenamid

- P in/on cottonseed subgroup 20C and cotton gin byproducts, respectively. The recommended cottonseed subgroup 20C tolerance was set at the LOQ of the enforcement method and the recommended cotton gin byproduct tolerance was calculated using the Organization for Economic Cooperation and Development (OECD) tolerance calculation procedures.

Although not required, data were also generated for metabolites M26 and M30. Like dimethenamid

- P , r esidues of metabolites M26 and M30 were each below the L OQ in/on undelinted cottonseed. Residues (as per trial averages) of metabolites M26 and M30 were <0.01

- 0.045 ppm and <0.01

- 0.483 ppm, respectively, in/on cotton gin byproducts. These data demonstrate the potential for significant levels of metabolites of dimethenamid

- P resulting in/on plant commodities from mid

- to late

- season applications of dimethenamid

- P . However, since cotton gin byproducts is only a minor dairy cattle feed item, this is not a concern for the current petition. It is of note that the combined residues of dimethenamid

- P and its metabolites M26 and M30 in/on cotton gin byproduct (combined HAFT = 1.34 ppm) are less than the recommended tolerance (1.5 ppm).Page 21 of 51

TABLE 5.2.1. Summary of Residue Data from Crop Field Trials with Dimethenamid

- P

Commodity Total

Applic. Rate lb ai/A (g ai/ha) PHI

(days) Residue Levels (ppm) 1

n Min. Max. LAFT 2 HAFT 2 Median Mean Std. Dev.

Dimethenamid

- P Cotton, undelinted seed 1.437

-

1.490 (1611.2

- 1670.2) 54

- 103 11 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

Cotton gin byproducts <0.01 0.816 <0.01 0.814 0.031 0.114 0.236

M26 Cotton, undelinted seed 1.437

-

1.490 (1611.2

- 1670.2) 54

- 103 11 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A
Cotton gin byproducts <0.01 0.052 <0.01 0.045 0.010 0.017 0.014

M30 Cotton, undelinted seed 1.437

-

1.490 (1611.2

- 1670.2) 54

- 103 11 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A
Cotton gin byproducts <0.01 0.672 <0.01 0.483 0.050 0.097 0.141

1 Except for sample min/max, values reflect per trial averages; n = no. of field trials. For calculation of median, mean, and standard deviation, the LOQ (0.01 ppm for each analyte) was used for any results reported as <LOQ in Table C.3. N/A = Not Applic able.

2 LAFT = lowest average field trial; HAFT = highest average field trial.



### Processed Food and Feed BASF has submitted a processing study with dimethenamid

- P on cotton. The submitted cotton processing study conducted at an exaggerated rate (3x) was considered adequate to support the proposed use. Data were collected with an adequate data

- collection method and are supported by adequate storage stability data. The study d emonstrates that separate tolerances for residues of dimethenamid

- P are not needed for processed commodities of cotton. Residues of dimethenamid

- P did not concentrate in cotton meal, hulls and crude oil. While data suggest a very slight potential for con centration of dimethenamid

- P in refined oil, a separate tolerance in refined oil will not be needed since the exaggerated rate processing study demonstrates that the petitioned

- for/recommended tolerance in/on cotton seed (0.01 ppm) will be adequate to cove r potential residues of dimethenamid

- P in refined oil.

Although not required, data were also generated for metabolites M26 and M30. Like dimethenamid

- P , residues of its metabolites M26 and M30 do not concentrate in cotton meal and hulls. Data indicate a very slight potential for concentration of residues of M30 in oil but not M26.

Submittal of Analytical Reference Standards Analytical standards are currently available for dimethenamid (expiration 11/1/23; email from Theresa Cole, ACB, 2/28/14) and dim ethenamid

- P (expiration 7/1/16; email from Theresa Cole, ACB, 4/9/14).) in the EPA National Pesticide Standards RepositoryPage 22 of 51



### Confined and Field Accumulation in Rotational Crops Based on the current and proposed uses of dimethenamid /dimethenamid

- P

, requirements for confined/field accumulation in rotational crops are satisfied based on the acceptable confined rotational crop study. The submitted study includes data on winter wheat planted 141 DAT, lettuce planted 322 DAT, and carrots p lanted 332 DAT. The maximum concentration of any metabolite/degradate in harvested wheat was 0.01 ppm for the sulfoxide of thiolactic acid conjugate. Based on these data, HED determined that a 4

- month rotational interval is adequate for fall

- seeded cerea l grains, and other crops may be planted the following spring. These recommendations are consistent with the rotational crop restrictions on the current label for Outlook® Herbicide (EPA Registration Number 7969

- 156; Accepted 3/20/14). See Directions for Use section above for details.

Proposed Tolerances Tolerances for plant commodities are established under §180.464, and are expressed in terms of dimethenamid per se . The tolerance definition proposed by BASF is in terms of dimethenamid
per se . The tol erances propos ed by BASF are listed in Table 5.2.2 along with the tolerance levels recommended by HED and corrected commodity definitions.

Adequate residue data are available to support the proposed tolerances. The submitted data are adequate to support tolerances of 0.01 ppm and 1.5 ppm for residues of dimethenamid

- P in/on cottonseed subgroup 20C and cotton gin byproducts, respectively. The recommended cottonseed subgroup 20C tolerance was set at the LOQ of the enforcement method and the recommended cotton gin byproduct tolerance was calculated using the Organization for Economic Cooperation and Development (OECD) tolerance calculation procedures. The submitted cotton processing study conducted at an exaggerated rate (3x) is adequate to support the proposed use and demonstrates that separate tolerances for residues o f dimethenamid

- P are not need for processed commodities of cotton.

There are no established Codex, Canadian or Mexican maximum residue limits (MRLs) for dimethenamid

- P in/on cotton commodities (email from M. Negussie to B. Cropp

- Kohlligian dated 2/28/14 ). Therefore, there is no question about harmonization of the proposed tolerances.Page 23 of 51

TABLE 5.2.2. Tolerance Summary for Dimethenamid

- P Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Correct Commodity Definition /

Comments 40 CFR §180.464(a) Cottonseed subgroup 20C 0.01 0.01 Cottonseed subgroup 20C Cotton, gin byproducts 1.5 1.5 Cotton, gin byproducts

Cotton, seed, refined oil 0.02

-- While data suggest a very slight potential for concentration of dimethenamid

- P in refined oil, a separate tolerance in refined oil will not be needed since the exaggerated rate processing study demonstrates that the petitioned

- for/recommended tolerance in/on cotton seed (0.01 ppm) will be adequate to cover potential residues of dime thenamid

- P in refined oil.



### 5.3 Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by the Environmental Fate and Effects Division (EFED) in a drinking water assessment (DWA; D4 22167 , M. Biscoe, 8 / 14 /14) entitled: “Dimethenamid

- P: ADDENDUM Drinking Water Exposure Assessment for Existing Ornamental and Green Onion Uses and the Proposed Cotton Use.” Estimated Drinking Water Concentrations (EDWCs) f or dimethenamid

- P were calculated for the parent comp ound plus the dimethenamid ethanesulfonic acid and dimethenamid oxanilic acid degradates. These estimated drinking water concentrations (EDWCs) were incorporated directly into this dietary assessment in the DEEM

- FCID into the food categories “water, direc t, all sources” and “water, indirect, all sources.”

EFED generated the surface water EDWCs using the Surface Water Concentration Calculator (SWCC) and groundwater EDWCs were generated using Pesticide Root Zone Model for Ground Water (PRZM

- GW). EDWCs w ere derived based on the maximum registered use rate (ornamentals 3 lb ai/A/season), the maximum use rate on green onion (i.e., the scenario that resulted in the highest EDWCs in prior DWA) and the proposed use on cotton (1.4 5 lb ai/A).

The maximum EDWC s calculated in this assessment are shown in Table 5.3 . In surface water, the highest estimated peak (acute) concentration is 73 μg/L, the highest estimated 1

- in

- 10 year annual average concentration is 27 μg/L, and the highest estimated 30

- year annual ave rage concentration is 1 6 μg/L. In groundwater, the estimated peak (acute) concentration is 15 3 μg/L, and the estimated post

- breakthrough average (chronic) concentration is 1 40 μg/L. Because the maximum acute (groundwater 15 3 μg/L) and chronic (groundwate r 1 40 μg/L) EDWCs were so close, 15 3 μg/L was used in both the acute and chronic dietary assessments to estimate residues in drinking water.Page 24 of 51

Table 5.3 . Maximum estimated drinking water concentrations (EDWCs) in parts per billion (μg/L) for dimethenamid plus its degradates, dimethenamid ethanesulfonic acid and dimethenamid oxanilic acid, for use in the dietary risk assessments

. Drinking Water Source (model) [Tier] Model Scenario & Application Method Acute Chronic Cancer μg/L

Surface Water ( SWCC ) [Tier 2] New Jersey Nursery (Ornamentals) Ground Application Peak 1

- in

- 10 Year Chronic

1

- in

- 10 Year 30

- year Annual

Average

73 27 1 6

Groundwater (PRZM

- GW 30

- year simulation) [Tier 1] Wisconsin Corn (Ornamentals) Peak Post

- Breakthrough Average

15 3 1 40



### The drinking water models and their descriptions are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/

.

5.4 Dietary Risk Assessment

Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID) Version 3.16. This software uses 2003

- 2008 food consumption data from the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). The analyses were conducted in support of a human health risk assessment for the proposed Se ction 3 use of dimethenamid

- P on cottonseed subgroup 20C.

5.4.1 Description of Residue Data Used in Dietary Assessment

Both the acute and chronic assessments are conservative and incorporated tolerance level residues, assume 100% crop treated and use default processing factors. Estimated drinking water concentrations (EDWCs) used in the assessments were generated using Tier I modeling.

5.4.2 Percent Cro p Treated Used in Dietary Assessment

The acute and chronic assessments are based on the assumption that 100% of all commodities with tolerances will be treated.

5.4.3 Acute Dietary Risk Assessment

For the acute assessment, aggregate dietary (food and drinking water) exposures are below HED’s level of concern (<100% aPAD) at the 9 5 th 

### percentile of exposure for all population subgroups. The acute dietary exposure at the 9 5 th 

### percentile of exposure is estimated at 0.0 08399 mg/kg/day for the overall U.S. populati on, equivalent to <1 % of the aPAD. The population subgroup with the highest estimated acute dietary exposure is All Infants <1 year of age , with anPage 25 of 51



### estimated exposure at the 9 5 th 

### percentile of 0.0 26253 mg/kg/day, equivalent to 1.3 % of the aPAD.

5.4.4 Chronic Dietary Risk Assessment

For the chronic assessment, aggregate dietary (food and drinking water) exposures are below HED’s level of concern ( <100% c PAD) for all population subgroups. The chronic dietary exposure is estimated at 0.00 3241 mg/kg/day for the general U.S. population , equivalent to 6.5 % of the cPAD . The population subgroup with the highest estimated chronic dietary expos ure is All Infants <1 year of age, with an estimated exposure of 0.00 8326 mg/kg/day , equivalent to 17 % of the cPAD.

5.4.5 Cancer Dietary Risk Assessment

Dimethenamid /dimethenami

- P is classified as a Group C chemical (possible human carcinogen). C ancer dietary risk concerns due to long

- term consumption of dimethenamid /dimethenamid

- P residues are adequately addressed by the chronic dietary exposure analysis using the reference dose; therefore, a separate cancer dietary exposure analysis was not performed.

5.4.6 Summary Table

A dietary assessment was conducted for the proposed and registered uses of dimethenamid/ dimethenamid

- P . The diet ary risk estimates are below HED’s level of concern; see Table 5.4.6.1.

Table 5.4.6.1 . Summary of Dietary (Food and Drinking Water) Exposure and Risk for Dimethenamid/Dimethenamid

- P.

Population Subgroup Acute Dietary (95th Percentile) Chronic Dietary Cancer
Dietary Exposure (mg/kg/day) % aPAD* Dietary Exposure (mg/kg/day) % cPAD* Dietary Exposure (mg/kg/day) Risk

General U.S. Population 0.008 399 <1 0.003 241 6. 5

N/A All Infants (<1 year old) 0.02 6253 1.3 0.008 326 1 7
Children 1

- 2 years old 0.01 3042 <1 0.004 710 9. 4
Children 3

- 5 years old 0.010 635 <1 0.0039 80 8.0
Children 6

- 12 years old 0.00 8023 <1 0.0028 69 5.7
Youth 13

- 19 years old 0.006 982 <1 0.0023 7 3 4.7
Adults 20

- 49 years old 0.008 253 <1 0.003 228 6. 5
Adults 50

- 99 years old 0.007 364 <1 0.0031 86 6. 4
Females 13

- 49 years old 0.008 361 1.1 0.003 214 6. 4Page 26 of 51



### 6 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no proposed residential uses at this time; however, there are existing residential uses that have been reassessed in this document to reflect updates to HED’s 2012 Residential SOPs 3 

### along with policy changes for body weight assumptions. The revision of residential exposures will impact the human health aggregate risk assessment for dimethenamid

- P.

dimethenamid

- P is registered for residential use on turfgrass, ornamentals, and tree plantations, and is formulated as an emulsifiable concentrate (EC) and granule (G). The currently registered end

- use products (EPs) available for residential use include: 1. Tower Herbicide E C (EPA Reg. No. 7969

- 239; 63.9% dimethenamid

- P ), , 2. Freehand 1.75G Herbicide (EPA Reg. No. 7969

- 273; 0.75% dimethenamid

- P ), and 3. Freehand CA 1.75G Herbicide (EPA Reg. No. 7969

- 358; 0.75% dimethenamid

- P ).

BASF Corporation is the registrant of all three products.

6.1 Residential Handler Exposure

HED uses the term “handlers” to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct tasks related to applications and that exposures can vary depending on the specifics of each task. Residential handlers are addressed somewhat differently by HED as homeowners are assumed to complete all elements of an application without use of any protective equipme nt.

The quantitative exposure/risk assessment developed for residential handlers is based on various exposure scenarios that involve mixing/loading/applying various formulations with manually pressurized handguns, hose

- end sprayers, backpack sprayers, pus h

- type rotary spreaders and belly grinders.

Residential Handler Non

- Cancer Exposure and Risk Estimate Equations The algorithms used to estimate exposure and dose for residential handlers can be found in the 2012 Residential SOPs 4



### .

Com bining Exposures/Ris k Estimates Dermal and inhalation exposures to handlers were not aggregated because the toxicity endpoints for these exposure routes are not based on common toxicity effects in/of the liver. Dermal effects (body weight gain) were considered to be non

- spec ific.

Summary of Residential Handler Non

- Cancer Exposure and Risk Estimates Summaries of the short

- term dermal and inhalation risk estimates for residential handlers are included in Table 6.1 . The maximum application rate for each exposure scenario is presented as the worst case scenario. All risk estimates are greater than the LOC of 100 and therefore not of concern (Dermal MOEs range from 250 to 5,300,000; Inhalation MOEs range from 7,700 to 1,500,000).

3 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html

4 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html

### Page 27 of 51 Table 6.1 . Residential Handler Non

- cancer Exposure and Risk Estimates for Dimethenamid

- P.

Exposure Scenario Application

Equipment/
Method Dermal

Unit Exposure (mg/lb ai) Inhalation

Unit Exposure (mg/lb ai) Maximum

Application Rate 1 Area

Treated or Amount Handled Daily 2 Dermal Inhalation

Dose (mg/kg/day) 3 MOE 4

(LOC=100) Dose

(mg/kg/day) 5 MOE 6

(LOC=100)

Liquid Formulation

Lawns/Turf Hose

- end

Sprayer 13.4 0.022 1.5 lb ai/acre 0.5 acres 0.13 2,400 0.00021 49,000
Manually

pressurized handwand 63 0.018 0.15 lb ai/gal 5 gallons 0.59 510 0.00017 60,000

Backpack 130 0.14 1.2 250 0.0013 7,700

Gardens/Trees Sprinkler can 58 0.0014 0.15 lb ai/gal 5 gallons 0.54 550 0.000013 770,000

Hose

- end Sprayer 11 gallons 0.13 2,400 0.00021 49,000

Granular Formulation

Lawns/Turf Push

- type

rotary spreader 0.81 0.0026 1.5 lb ai/acre 0.5 acres 0.0076 40,000 0.000024 410,000

Belly grinder 360 0.039 3.4x10

- 5 lb ai/ ft 2 1,200 ft 2 0.19 1,600 0.000020 500,000

Gardens/Trees Hand

Dispersal 160 0.38 3.4x10

- 5 lb ai/ ft 2 1,200 ft 2 0.083 3,600 0.00020 52,000

Shaker can /Cup 0.0045 0.00054 0.000057 5,300,000 0.0000067 1,500,000
Spoon 6.2 0.087 0.0032 94,000 0.000045 220,00

1 Based on registered residential uses for dimethenamid

- P (Refer to section 6.0)

. 2 Based on HED’s 2012 Residential SOPs ( http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html ): Lawns/Turf; and Gardens/Trees

3 Dermal Dose = Dermal Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal or ft 2 ) × Area Treated or Amount Handled (A/day or gallons/day or ft 2 / day) × Dermal Absorption Factor (100 %) ÷ Body Weight (80 kg).

4 Dermal MOE = Dermal NOAEL ( 300 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

5 Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal or ft 2 ) × Area Treated or Amount Handled (A/day or gallons/day or ft 2 /day) ÷ Body Weight (80 kg).

6 Inhalation MOE = Inhalation NOAEL ( 10 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

### Page 28 of 51

6.2 Post

- Application Exposure

There is the potential for post

- application exposure for individuals exposed as a result of being in an environment that has been previously treated with dimethenamid

- P. The quantitative exposure/risk assessment for residential post

- application exposures is based on the following scenarios:

The scenarios, routes of exposure and lifestages of potential exposure include:

1. Physical activities on turf: adults (dermal) and children 1 to < 2 years old (dermal and incidental oral); 2. Mowing: adults (dermal) and children 11 to < 16 years old (dermal); 3. Golfing: adults (dermal), children 11 to < 16 years old (dermal), and children 6 to < 11 years old (dermal); and 4. Contact with Treated Gardens and Trees: adults (dermal) and children 6 to <11 years old (dermal).

The lifesta ges selected for each post

- application scenario are based on an analysis provided as an Appendix in the 2012 Residential SOPs 5 

### . While not the only lifestage potentially exposed for these post

- application scenarios, the lifestage that is included in the qu antitative assessment is health protective for the exposures and risk estimates for any other potentially exposed lifestage.

Residential Post

- application Exposure Data and Assumptions A series of assumptions and exposure factors served as the basis for co mpleting the residential post

- application risk assessment. Each assumption and factor is detailed in the 2012 Residential SOPs 5 : Lawns/Turf, and Gardens and Trees.

Furthermore, a chemical specific Transferable Turf Residue (TTR) Study was submitted by the registrant (MRID# 47901302), reviewed by HED (D376733, I. Nieves, 3/16/11) and found to be acceptable for use in exposure and risk assessmen ts. This study was designed to determine the transferable turf residue (TTR) of dimethenamid

- P dislodged from turf treated with an emulsifiable concentrate formulation containing 63.9% dimethenamid

- P as the active ingredient ( Tower® Herbicide ) and a sprea dable granule formulation containing 0.75% dimethenamid

- P ( FreeHand® 1.75 G Herbicide ) at three locations in the United States (Florida, New Jersey, and California). Transferable residues were sampled using the Modified California Roller technique.

The TTR values used to quantify potential exposure risk by performing residential post

application activities on lawns/turf were taken from the aforementioned study. For liquid formulations , the highest predicted dimethenamid

- P TTR level detected was 0.03 12 μg/cm 2 

### (California site). For granular formulations, since dimethenamid

- P TTR values were not detected above the LOQ at any sampling interval after application a TTR value of 0.00090 μg/cm2, equivalent to 1⁄2 the LOQ value (0.00179 μg/cm 2 

### ) is being used for human health exposure assessments.

5 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html

### Page 29 of 51

For post

- application dermal exposure resulting from contact with previously treated gardens and trees, the default Dislodgeable Foliar Residue (DFR) calculation was done in the absence of chemical

- specific data.

Res idential Post

- application Non

- Cancer Exposure and Risk Equations The algorithms used to estimate residential post

- application exposure and dose can be found in the 2012 Residential SOPs 5

. Combining Exposure and Risk Estimates HED combines risk estimates resulting from separate post

- application exposure scenarios when it is likely they can occur simultaneously based on the use pattern and the behavi or associated with the exposed population and when the toxicological effects are similar. However, the incidental oral scenarios (i.e., hand

- to

- mouth, object

- to

- mouth, soil ingestion, and granule ingestion) should be considered inter

- related and it is lik ely that they occur interspersed amongst each other

, across time. Combining all three of these scenarios would be overly

- conservative because of the conservative nature of each individual assessment. Therefore, the hand

- to

- mouth post

- application exposure scenario for children 1 to < 2 years old is conside red a protective estimate of children’s exposure to pesticides used on turf.

Summary of Residential Post

- application Non

- Cancer Exposure and Risk Estimates Table 6.2 presents the post

- application MOE values calculated for adults and children after turf applications of dimethenamid

- P . HED considers this liquid formulation risk estimates for post

application exposure to be protective of the granular product, because of its lower transferability properties compared to that observed for the liquid formulati on, Tower Herbicide (0.64% transferability for the liquid compared to 0.005% for the granular). This phenomena can be observed in the TTR study ( MRID# 47901302) submitted by the registrant, BASF, where TTR values were not detected above the LOQ at any sam pling interval for the granular formulation product. Post

- application non

- cancer risks do not exceed HED’s level of concern for any of the scenarios assessed (MOEs range from 310 to 200,000; LOC = 100).

### Page 30 of 51

Table 6.2. dimethenamid

- P Resi dential Risk Estimates for Post

- application Exposure.

Site Activity Route of Exposure TC

(cm 2 /hr) TTR (Study)

/DFR (Default) (μg/cm2 ) Exposure

Time (hrs/day) Short

- Term

Average Daily Dose (mg/kg/day) MOE

(LOC=100)

Adults Max single application rate: 1.5 lbs ai/A 1

Treated Lawns High Contact Activities

Dermal 180,000

TTR (Lawns/Turf): 0.0312 1.5 0.11 2,900 Mowing 5,500 1 0.0021 140,000
Golf Course Turf Golfing 5,300 4 0.0083 36,000

Gardens

High Contact Activities

(liquid and granular formulations) 8,400

DFR (Gardens/Trees): 4.2 2.2 0.96 310
Trees and Retail Plants 1,700 1 0.089 3,400

Indoor Plants 220 1 0.011 26,000

Children Max single application rate: 1.5 lbs ai/A 1

Treated Residential Areas High Contact Activities (1<2 years)

Dermal 49,000

0.0312 1.5 0.21 1,400

Mowing (11<16 years) 4,500 1 0.0025 120,000 Golfing (6<11 years) 2,900 4 0.011 27,000

Hand to Mouth Transfer of Pesticide Residue (1<2 years)

Oral N/A Hand Residue (mg/cm 2 ) 1.5 0.0043 2,300 0.00 04 2

Object to Mouth Transfer of Pesticide Residue (1<2 years) Object Residue (mg/cm 2 ) 1.5 0.00013 77,000 0. 031

Incidental Ingestion of Soil with Pesticide Residue (1<2 years) Soil Residue (mg/cm 2 ) N/A 0.000051 200,000 11.17

Incidental Granule Ingestion (1<2 years) Ingestion Rate (g/day; 0.8% ai) N/A 0.20 980 0.3
Gardens
High Contact Activities

(6<11 years) (liquid and granular formulations) Dermal 4,600

DFR (Gardens/Trees): 4.2 1.1 0.66 460 Trees and Retail Plants 930 0.5 0.061 5,000

Indoor Plants 120 0.5 0.0078 38,000

1 Based on regis tered labels (Refer to Section 6.0 ).



### 6.3 Residential Risk Estimates for Use in Aggregate Assessment

Table 6.3 reflects the residential exposure scenarios and associated risk estimates that are recommended for use in the aggregate assessment for dimethenamid

- P

.

 The recommended residential exposure for use in the adult aggregate assessment reflects hand ler inhalation exposure from liquid applications to turf via backpack sprayer.

### Page 31 of 51

 The recommended residential exposure for use in the children 1<2 years old aggregate assessment reflects incidental oral exposure from post

- application hand

- to

- mouth pesticide t ransfer from liquid application to residential turf.

Since it was determined that the effects noted for the dermal POD have no common toxicity effects with the incidental oral and/or inhalation PODs (same POD) the values recommended to be used for the agg regate assessment are based on the worst

- case residential exposure estimates via the inhalation (adult male) and oral (child 1<2 years old) routes. Only short

- term residential exposures are expected based on the Residential SOPs (2012). All residential h andler and post

application exposure estimate resulted in MOEs greater than 100, and are not of concern.

Table 6.3 . Recommendations for the Short

- and Intermediate

- Term Residential Exposures for the dimethenamid

- P Aggregate Assessment

Lifestage Handler Exposure

(mg/kg/day) 1 Residential

Handler Total Exposure (mg/kg/day) Residential

Handler Total MOE 2 Post

- application Exposure

(mg/kg/day) 3 Residential Post

application Total Exposure (mg/kg/day) Residential

Post

application MOE 4 Dermal Inhalation Dermal Inhalation Oral

Adult Male N/A 0.0013 0.0013 7,700 N/A N/A N/A N/A N/A

Child (1<2 years old) N/A N/A N/A N/A N/A N/A 0.0043 0.0043 2,300

1 Handler exposure represents high

- end handler exposure, where the exposure du ration is appropriate to assess (Table 6.1).

2 Residential Total MOE = Represents high

- end handler exposure MOE (Table 6.1) . Inhalation NOAEL = 10 mg/kg/day

. 3 Post

- application exposure represents high

- end incidental oral exposure for the relevant exposure duration (Table 6.2 )

. 4 Post

- application Total MOE = Represents high

- end post

- application exposure MOE (Table 6.2 )

. Incidental oral NOAEL = 10 mg/kg/day. Note: Only inhalation and oral exposure had common effects and therefore aggregated. Valu es for dermal exposure were not presented as they were not relevant for the aggregate assessment (i.e., no common effects).



### 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 dimethenamid

- P at this time primarily because of the low acute inhalation toxicity (Toxicity Category III). However, volatilization of pesticides may be a source of post

- application inh alation 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 Dece mber 2009, and received the SAP’s final report on March 2, 2010 6 

### . The Agency is in the process of evaluating t h e SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

- ap plication 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 dimethenamid

- P.

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

### Page 32 of 51

6.5 Spray Drift

Spray dr ift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for dimethenamid

- P

. The Agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call

- In issued by EPA), EPA Regional Offices and Sta te Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information). 7 

### The Agency is also taking means to qualitatively and qualitatively address spra y drift as a potential source of exposure in risk assessments for pesticides through existing programs such as Ag Drift and chemical specific properties of pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide durin g the Registration Review process which ensures that all uses for that pesticide will be considered concurrently.

7 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks from dietary (food and water) and residential (dermal, inhalation, and/or incidental oral) sources. When aggregating exposures and risks from these sources, HED considers the route and duration of exposure as well as the toxicological effects for each route. Aggregate risk assessments evaluate the combined risk from dietary exposure (food and water) and any non

- occupational (residential) uses. Non

- occupational (residential) exposures are not anticipated from the proposed new use, although residential exposure is expected for currently registered products. The existing residential uses have been reassessed in this document to reflect updates to HED’s 2012 Residential SOPs 8 

### along with policy changes for body weight assumptions. As a result, the dimethenamid

- P a ggregate risk assessment was updated accordingly.

Dimethenamid

- P is classified as group “C” possible human carcinogen, based on an increasing trend for liver tumors (males) seen in the chronic rat study. There were no dose

- related tumors seen in the mouse carcinogenicity study. Therefore, a cancer aggregate risk assessment is not
requ ired.

7.1 Acute Aggregate Risk

For the acute assessment, aggregate dietary (food and drinking water) exposures are below HED’s level of concern (<100% aPAD) at the 95 th 

### percentile of exposure for all population subgroups. Refer to section 5.4.3 for a more d etailed discussion of the acute dietary assessment.

7.2 Short

- and Intermediate

- Term Aggregate Risk

For the short

- /intermediate

- term aggregate assessment, exposures do not fall below HED’s level of concern (i.e., all MOEs are greater than 100). As summariz ed in Table 7.2, f or adults and

7 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm

8 Available: http://www.epa.gov/pesticides/scien ce/residential

- exposure

- sop.html

### Page 33 of 51

children

, only handler inhalation exposure and post

- application incidental oral exposure, respectively, were appropriate to aggregate with dietary exposure.

Table 7.2 Short

- Term and Intermediate Term Aggregate Risk Calc ulations

Population Short

- or Intermediate

- Term Scenario

NOAEL mg/kg/day LOC 1 Max

Allowable Exposure 2 mg/kg/day Average

Food and Water Exposure mg/kg/day Residential

Exposure mg/kg/day 3 Total

Exposure mg/kg/day 4 Aggregate

MOE (food, water, and residential) 5

Adult s 10 100 0.1 0.003 241 0.0013 0.0045 2200 Child 0.004 710 0.0043 0.0090 1100

1 LOC = 100 ( based on the standard 10

- fold inter

- and 10

- fold intra

- species uncertainty factors

, totaling 100)

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure]. Refer to Table 6.3; only inhalation exposure is relevant for adults and incidental oral exposure for children

. 4 Total Ex posure = Avg Food & Water Exposure + Residential Exposure

5 Aggregate MOE = [NOAEL: 10 mg/kg/day/(Avg Food & Water Exposure + Residential Exposure)]



### 7.3 Chronic Aggregate Risk

For the chronic assessment, aggregate dietary (food and drinking water) exposures are below HED’s level of concern (<100% cPAD) for all population subgroups. Refer to section 5.4.4 for a more detailed discussion of the chronic dietary assessment.

7.4 Cance r Aggregate Risk

Dimethenamid is classified as a Group C chemical (possible human carcinogen). C ancer dietary risk concerns due to long

- term consumption of dimethenamid residues are adequately addressed by the chronic dietary exposure analysis using the reference dose; therefore, a separate aggregate cancer dietary exposure analysis was not performed.

8 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 dimethenamid

- P and any other substances and dimethenamid

- P does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that dimethenamid

- P has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to d etermine 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 cu mulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9 Occupational Exposure/Risk Characterization

9.1 Short

- /Intermediate

- Term Handler Risk

### Page 34 of 51

HED uses the term handlers to describe tho se individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each task. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application event.

Based on the anticipated use patterns an d current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses. The quantitative exposure/risk assessment developed for occupational handlers is based on several scenari os which include mixing/loading/applying the liquid formulation of dimethenamid

- P. The use profile is summarized in Section 3.3 . Methods of application include aerial, chemigation, groundboom, and handheld equipment. Flagging for aerial use is also a
po tential source of work er exposure. Refer to Table 9 .1 for a detailed list of each scenario.

Occupational Handler Exposure Data and Assumptions A series of assumptions and exposure factors served as the basis for completing the occupational handler risk a ssessments. Each assumption and factor is detailed below on an individual basis.

Application Rate : Refer to table 9.1.

Unit Exposures: It is the policy of HED to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical

- specific data, include PHED 1.1, the AHETF database, or other registrant

- submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting handler exposure that are used in this assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table 9 

### ”, which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website 10



### .
Area Treated or Amount Handled: The area treated or amount handled is based on HED ExpoSAC Poli cy No. 9.1. R efer to Table 9 .1 for these assumptions for each scenario.

Exposure Duration: HED classifies exposures from 1 to 30 days as short

- term and exposures 30 days to six months as intermediate

- term. Exposure duration is determined by many things, including the exposed population, the use site, the pest pressure triggering the use of the pesticide, and the cultural practices surrounding that use site. For most agricultural uses, it is reasonable to believe that occupational handlers will not apply the same chemical every day for more than a one

- month time frame; however, there may be a large agribusiness and/or commercial applicators who may apply a product over a period of weeks (e.g., completing multiple applications for multiple clients within a region). For the proposed use on cotton subgroup 20C both short

- and intermediate

- term exposures are expected from occupational use.

9 Available: http://www.epa.gov/opp00001/science/handler

- exposure

- table.pdf

10 Available: http://www.epa.gov/pesticides/science/handler

- exposure

- data.html

### Page 35 of 51

Since the PODs for short

- and intermediate

- term exposure are the same, the short

- term assumptions and risk calculations are protective of both durations.

Mitigation/Personal Protective Equipment: Results are presented for “baseline,” defined as a single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respira tor, as well as baseline with various levels of PPE as necessary (e.g., gloves, respirator, etc). The dimethenamid

- P product labels direct mixers, loaders, applicators and other handlers to wear long

- sleeved shirts, long pants, shoes plus socks, protectiv e eyewear and chemical

- resistant gloves.

Combining Exposures/Risk Estimates: Dermal and inhalation exposures to workers were not aggregated because the toxicity endpoints for these exposure routes are not based on common toxicity effects in/of the liver. Dermal effects (body weight gain) were considered to be non

- specific.

Summary of Occupational Handler Non

- Cancer Exposure and Risk Estimates The results of the occupational handler exposure and risk assessment indicate that short

- and intermediate

- term d ermal and inhalation risk estimates are not of concern (i.e. all MOEs ≥ 100) at baseline mitigation (no PPE), except for the dermal exposure scenario of mixing and loading a liquid formulation of dimethenamid

- P for aerial applications which resulted in an MOE of 92. With the use of additional PPE (i.e., gloves) the risk estimate MOE is mitigated to 540. Inhalation MOEs ranged from 3,100 to 140,000 at baseline. Note that only engineering control (enclosed cockpit) data are available to assess risks to hand lers operating aircrafts.

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 be st 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 are for exposure to pilots in enclosed cockpits. Therefo re, 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 requ ired to wear protective gloves for the duration of the application. With this level of protection, there are no risk estimates of concern for applicators.

### Page 36 of 51

Table 9.1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for dimethenamid

- P

.

Exposure Scenario Crop or Target Level of

Concern Dermal Unit

Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application Rate 2 Area

Treated or Amount Handled Daily 3 Dermal Inhalation

Mitigation Level Mitigation Level Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7

Mixer/Loader

Mixing/Loading Liquids for Aerial Applications Cotton Subgroup 20C 100 220

(baseline)

37.6 (baseline + gloves) 0.219

(baseline: no respirator) 1.0 lb ai/A 1,200 3.25 (baseline)

0.555 (baseline + gloves) 92

(baseline)

540 (baseline +gloves) 0.0032

(baseline) 3,100

(baseline)

Mixing/Loading Liquids for Chemigation Applications 350 0.948 (baseline) 320

(baseline) 0.00094

(baseline) 11,000

(baseline) Mixing/Loading Liquids for Groundboom Applications 200 0.541 (baseline) 550

(baseline) 0.00054

(baseline) 19,000

(baseline) Applicator

Applying Liquids with Aerial Equipment Cotton

Subgroup 20C 100 2.08

(Eng. Controls) 0.0049

(Eng. Controls)
1.0 lb ai/A 1,200 0.0308 (Eng. Controls) 9,700

(Eng. Controls) 0.0000724

(Eng. Controls) 140,000

(Eng. Controls) Applying Liquids with Groundboom Equipment 78.6 (baseline) 0.34

(baseline) 200 0.194 (baseline) 1,500

(baseline) 0.00084

(baseline) 12,000

(baseline) Flagger

Flagging Liquids for Aerial Applicaitons Cotton

Subgroup 20C 100 11

(baseline) 0.35

(baseline) 1.0 lb ai/A 350 0.047 (baseline) 6,300

(baseline) 0.0015

(baseline) 6,700

(baseline)

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2013); Level of mitigation: Base line, PPE (i.e., gloves), Eng. Controls. 2 Based on proposed label use (EPA Reg No. 7969

- 156). 3 Exposure Science Advisory Council Policy #9.1. 4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) × DAF ( 100 %) ÷ BW ( 80 kg). 5 Dermal MOE = Dermal NOAEL ( 300 mg/kg/day) ÷ Dermal Dose (mg/kg/day). 6 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal ) × Area Treated or Amount Handled (A or gal/day) ÷ BW ( 80 kg). 7 Inhalation MOE = Inha lation NOAEL ( 10 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

### Page 37 of 51

9.2 Short

- /Intermediate

- Post

- Application Risk

HED uses the term post

- application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re

entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. P ost

- application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical’s degradation properties. In addition, the timing of p esticide applications, relative to harvest activities, can greatly reduce the potential for post

- application exposure.

9.2.1 Dermal Post

- application Risk

Exposure Duration: HED classifies exposures from 1 to 30 days as short

- term and exposures 30 days to six m onths as intermediate

- term. For dimethenamid

- P , since toxicological endpoints are the same for both durations (short

- , and intermediate), short

- term risk estimate quantification is presented in this memo and considered protective of longer exposure durati ons.

Transfer Coefficients: It is the policy of HED to use the best available data to assess post

application exposure. Sources of generic post

- application data, used as surrogate data in the absence of chemical

- specific data, are derived from ARTF exp osure monitoring studies, and, as proprietary data, are subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting post

- application exposure that are used in this assessment, known as “transfer coefficients”, are presented in the ExpoSAC Policy 3 11 

### ” which, along with additional information about the ARTF data, can be found at the Agency website 12 

### . Table 6.2.2.1 provides a summary of the anticipated post

- application activities and associated transfer coefficien ts for the proposed crops/use sites.

Table 6.2.2.1. Anticipated Post

- Application Activities and Dermal Transfer Coefficients.

Proposed Crops Policy Crop Group Category Crop

Height Foliage

Density Transfer

Coefficients (cm 2 /hr ) Activities

Cotton Subgroup 20C Field / row crop, low / medium Low Full/Min 210 Scouting

Full/Min 70 Weeding, Hand



### Application Rate: Maximum rate of 1.0 lb dimethenamid

- P /A was used. Refer to the proposed use pattern table in section 3.3 for more details.

Exposure Time: The average occupational workday is assumed to be 8 hours.

Dislodgeable Foliar Residues: Chemical

- specific dislodgeable foliar residue data have not been submitted for dimethenamid

- P . Therefore, this assessment uses HED’s default assumption that

11 Available: http://www.epa.gov/pesticides/science/exposac_policy3.pdf

12 Available: http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

### Page 38 of 51

25% of the application is available for transfer on day 0 following the application and the residues dissipate at a rate of 10% each following day.

Dislodgeable Foliar Residue (DFR): In accordance with 40CFR158, DFR data are required for all occupationa l (e.g., crop, nursery, greenhouse use sites) or residential (e.g., ornamental and vegetable gardens, pick your own farms, retail tree farms) uses that could result in post

application exposure to foliage. In the absence of chemical

- specific DFR data, EPA uses default values. The 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment includes an analysis of a number of DFR studies, which resulted in the selection of a revised default values for the fraction of the application rat e available for transfer after a foliar application (F AR 

### ). These values are based on an analysis of 19 DFR studies. Since that time, the Agricultural Re

- entry Task Force has submitted information (MRID 49299201) that corrects an application rate error made in the original submission of “ARF039

– Determination of Dermal and Inhalation Exposure to Reentry Workers During Chrysanthemum Pinching in a Greenhouse” (EPA MRID 45344501). As a result, the range of F AR 

### values was revised from 2%

- 89% to 2%

- 47%. In the data, a large range of transferability is observed and this variability can potentially be attributable to many factors such as active ingredient; formulation; field conditions in the studies; weather conditions (e.g., humidity); or many other dif ficult to quantify factors. Although witnessed across multiple chemicals, this range in F AR 

### values is not expected when considering DFR data for a single chemical. At this time, the ARTF submission did not alter the selection of 25% as the reasonable, hi gh

- end default value. Because DFR data are not available for dimethenamid

- P , EPA is using the default value of 25%. Although there may be a small degree of uncertainty in the use of the default DFR value for dimethenamid

- P (i.e., there is a small chance that the F AR 

### value may exceed the applicable default value ), it is likely that the health

- protective aspects of EPA’s occupational post

- application assessment methodology will more than compensate for this potential uncertainty. For example, when assessi ng residential and occupational post

- application exposure to gardens and ornamentals, EPA assumes the following: exposures occur to zero

- day (i.e., day of application ) residues every day of the assessed exposure duration (i.e., EPA assumes that no dissi pation or degradation occurs, it doesn’t rain, etc); individuals perform the same post

- application activities performed in the transfer coefficient study day after day (e.g., weeding, harvesting, pruning, etc.); and individuals engage in these post

- applica tion activities for a high

- end amount of time every day (represented by data reflecting time spent gardening based on survey data).

Given the conservatisms discussed above and the potential compounding nature of these conservatisms, EPA is able to rely up on the calculated exposure estimates with confidence that exposure is not being underestimated.

Since the highest estimated occupational post

- application exposure using default DFR values for dimethenamid

- P is minimal in comparison to the level of concern (i.e., the calculated MOE is greater than 2 times higher than the level of concern, ( MOE = 5,100 compared to the LOC of 100); EPA is waiving the 40CFR DFR data requirement. In this instance, it is unlikely that chemical

- specific DFR data would be needed to further refine exposure assessments or would add appreciably to our overall understanding of the availability of dislodgeable foliar pesticide residues for dimethenamid

- P

.

### Page 39 of 51

Occupational Post

- application Non

- Cancer Dermal Risk Estimates

Table 6.2.2.2. Occupational Post

- application Non

- Cancer Exposure and Risk Estimates for dimethenamid

P

.
Crop/Site Activities Transfer Coefficient (cm 2 /hr) DFR 1 Dermal Dose At Day 0 (mg/kg/day) 2 MOE 3

At Day 0 LOC=100

Short

- and Intermediate

- term

Cotton Subgroup 20C Scouting 210 2.8 0.059 5,100
Weeding, Hand 70 0.020 15,000

1 DFR = Application Rate × F × (1

- D) t × 4.54E8 μg/lb × 2.47E

- 8 acre/cm 2 ; where F = 0.25 and D = 0.10 per day 2 Daily Dermal Dose = [DFR (μg/cm 2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption ( 100 %)]  BW ( 80 kg). 3 MOE = POD ( 300 mg/kg/day) / Daily Dermal Dose


### Restricted Entry Interval The REI specified on the proposed label is based on the acute toxicity of dimethenamid

- P. Dimethenamid

- P is classified as Toxicity Category III via the dermal route, Toxicity Category III for eye irritation potential and Toxicity Category IV for skin irritation potential. It is a mild skin sensitizer. Short

- and intermediate

- term post

- application risk estimates were not a concern on day 0 (12 hours following application) for all post

- application activities. Under 40 CFR 156.208 (c) (2) (iii), ai’s classified as Acute III or IV for acute dermal, eye irritation and primary skin irritation are assigned a 12

- hour REI. Therefore, the [156 subpart K] Worker Protection Statement interim REI of 12 hours is adequate to protect agricultural workers from post

application exposures to dimethenamid

- P

.

9.2.2 Inhalation Post

- application Risk

Ba sed on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for dimethenamid

- P at this time primarily because of the low acute inhalation toxicity (Toxicity Category III), and the low proposed use rate (1.0 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 an d 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) i n December 2009, and received the SAP’s final report on March 2, 2010 13 

### . 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 dimethenamid

- P

. Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for oc cupational/commercial

13 Available: http://www.epa.gov/sci poly/SAP/meetings/2009/120109meeting.html

### Page 40 of 51

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post

- application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post

- application inhalation exposure scenarios.

10 References

- B. Daiss, 8/27/08, D348401, Dimethenamid

- P Human Health Risk Assessment for Proposed Use of Dimethenamid

- P on Turfgrass on Golf Courses.

- I. Nieves, 7/1/14, D418117, Dimethenamid

- P ( dimethenamid

- P ). Occupational and Residential Exposure Assessment for a Proposed Use on Cotton Subgroup 20C.

- B. Cropp

- Kohlligian, 6/14/14, D418115, Dimethenamid

- P. New Use and Tolerance in/on Cottonseed Subgrou p 20C. Summary of Analytical Chemistry and Residue Data.

- B. Cropp

- Kohlligian, 8/28 /14, D418116, Dimethenamid/Dimethenamid

- P. Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for Proposed New Use on Cottonseed Su bgroup 20C.

- M. Biscoe, 8/14 /14, D4 22167 , Dimethenamid

- P: ADDENDUM Drinking Water Exposure Assessment for Existing Ornamental and Green Onion Uses and the Proposed Cotton Use.

- M. King, B. Cropp

- Kohlligian, I. Nieves, D414651 (TXR# 0056993) , Dimethenamid

- P ( DMTA

- P) : Summary of Hazard and Science Policy Council (HASPOC) Meeting of June 19, 2014: Recommendations on the Need for a 28

- day Inhalation Study.

### Page 41 of 51

A ppendix A

. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements The requirements (40 CFR 158.340) for dimethenamid//dimethenamid

- P are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table 1. Guideline Data Requirements

Test 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

no yes yes

yes yes

- waived

870.3700a Developmental Toxicity (rodent)

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

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

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

yes yes 870.4100a Chronic Toxicity (rodent)

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

................................ ........ 870.4200a Oncogenicity (rat)

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

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

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

yes yes yes
yes 870.5100 Mutagenicity

— Gene Mutation

- bacterial

..................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

............... 870.5375 Mutagenicity

— Structural Chromosomal Aberrations

... 870.5900 Mutagenicity

— Other Genotoxic Effects

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

yes yes
yes 870.6100a Acute Delayed Neurotox. (hen)

................................ ..... 870.6100b 90

- Day Neurotoxicity (hen)

................................ .......... 870.6200a Acute Neurotox. Screening Battery (rat)

....................... 870.6200b 90

- Day Neuro. Screening Battery (rat)

......................... 870.6300 Develop. Neuro

................................ ............................. no

no yes yes

no -

- yes yes

-
870.7485 General Metabolism

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

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

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

- yes yes

- yes

### Page 42 of 51

A.2 Toxicity Profile s

Table A.2.1

. Acute Toxicity Profile

- [RS]

- dimethenamid [PC 129051]

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral/rats

[Sprague Dawley] TXR# 008285 41662409 (1989) 44097602 (1992) LD 50 = 2140

mg/kg (males) LD 50 = 1297 mg/kg (females) LD 50 = 1570 mg/kg mean both

sexes LD 50 = 500 III

II

- III

870.1200 Acute dermal/rabbits

[NZW] 41662410 (1988) LD 50 = >2000

mg/kg III

870.1300 Acute inhalation/rats

[Wistar] TXR# 008285 41662411 (1986) LC 50 = 4.99 mg/L III

870.2400 Acute eye irritation/rabbits 41662412 (1988) Minimally

irritating III

870.2500 Acute dermal irritation/ rabbits 41662413 (1988) Minimally

irritating IV

870.2600 Skin sensitization [Guinea Pigs] 41662407 (1987) Mild skin

sensitizer Sensitizer

Table A.2.2. Acute Toxicity Profile

- [S] dimethenamid

- P [PC 120051]
Guideline No. Study Type MRID(s) Results Toxicity Category*
870.1100 Acute oral/rats

[Sprague Dawley] 44097603 (1996) LD 50 = 429 mg/kg males

LD50 = 531 mg/kg females LD50 =480 mg/kg both sexes. II

870.1200 Acute

dermal/rabbits [NZW] 44332234 (1996) LD 50 = >2000 mg/kg III

870.1300 Acute inhalation

[Sprague Dawley] 44332235 (1996) LC 50 = 2.2 mg/L III

870.2400 Acute eye irritation

[NZW] 44332238 (1996) Minimally irritating III

870.2500 Acute dermal

irritation [NZW] 44332239 (1996) Minimally irritating IV

870.2600 Skin sensitization

[Guinea Pigs] 44097604 Mild skin sensitizer Sensitizer

### Page 43 of 51

Table A.2.3. Subchronic, Chronic and Other Toxicity Profile for [RS]

- dimethenamid
Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3100 90

- Day Feeding/Sprague Dawley rat 41615901 (1986)

Doses: 0, 50, 150, 500, 1500, 3000 ppm [M/F: 0/0/, 3.5/3.9, 10.0/11.8, 33.5/40.1, 98/119, 204/238 mg/kg/day] Acceptable in TXR# 008285 NOAEL=33.5/40.1 mg/kg/day [500 ppm] LOAEL=98/119 mg/kg/day [1500 ppm] based on decreased body weight and body weight gain, increased total protein in males; in females, increased cholesterol, increased adj liver weight and centrilobular hep atocytic enlargement.

870.3150 90

- Day oral toxicity (dog) 41615902 (1986 [Doses:

0, 100, 750, 2000 ppm][M/F: 0/0, 4.72/4.98, 33.6/39.7, 89.6/87.4 mg/kg/day] [From std tables(dry): 0, 2.5, 18.75, 50 mg/kg/day] [From std tables(wet): 0, 7.5, 56.25, 150 mg/kg/day] Acceptable TXR# 008285 NOAEL = 4.72/4.98 mg/kg/day [100 ppm ] LOAEL =33.6/39.7 mg/kg/day [750 ppm] based on decreased body weight and body weight gain in females, increased rel. liver wt in both sexes, increased periportal vacuolation in both se xes and dilation of liver sinusoids in females.

870.3200 21/28

- Day dermal toxicity (NZW rabbit) 41662414 (1989)

Doses: 0, 50, 150, 500 mg/kg/day Acceptable in TXR# 010012 LOAEL = 500 mg/kg/day based on decreased body weight gain.

870.3200 21/28

- Day dermal toxicity (NZW rabbit) 419513010 (1991)

Doses: 0, 30, 300, 1000 mg/kg/day LOAEL = 1000 mg/kg/day based on severe systemic toxicity and mortality. The NOAEL is 300 mg/kg/day.

870.3700a Prenatal developmental in (Sprague Dawley rats) 41615904 (1987) [Doses:

0, 50, 215, 425 mg/kg/day] Vehicle is 0.5% CMC, 10 ml/kg Acceptable in TXR# 008285 Maternal NOAEL = 50 mg/kg/day LOAEL =215 mg/kg/day based on body weight decrement on GD 12 (but not a single dose effect) and body weight and food consumption decre ase, both GD 6

- 9 & 6

- 16 Developmental NOAEL = 215 mg/kg/day LOAEL=425 mg/kg/day based on increased post implantation loss.

Prenatal Developmental (NZW/Rabbit) 41706809 (1988) Doses:

0, 37.5, 75, 150 mg/kg/day

Acceptable TXR# 008469 N/L change from previous Maternal NOAEL=75 mg/kg/day LOAEL=150 mg/kg/day based on slight body weight decrement (80g, GD 12

- 15), body weight loss (75g GD 15

- 19) and 2 abortions and in a 20 litter/group range

- finding study, death (13/20) and abortions (7/20) at 250 mg/kg/da y Developmental NOAEL=75 mg/kg/day LOAEL=150 mg/kg/day based on SS fetal incidence of irregular parietals and hyoid angulated. Litter incidence was nominally elevated by 50% and 100%, respectively, and nominally increased post implantation loss (double co ntrol).
870.3800 Reproduction and fertility effects (Wistar rats) 41615905 (1990) Doses:

0, 100, 500, 2000 ppm [M/F; 0/0, 7/8, 36/40, 150/160 mg/kg/day] Parental/Systemic NOAEL = 36/40 mg/kg/day [500 ppm] LOAEL =150/160 mg/kg/day [2000 ppm] based on decrease body weight, body weight gain, food consumption and abs & relative liver weight increase.

### Page 44 of 51

Table A.2.3. Subchronic, Chronic and Other Toxicity Profile for [RS]

- dimethenamid
Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

Acceptable TXR# 008285 Reproductive NOAEL = 150/160 mg/kg/day [2000 ppm] LOAEL = None Offspring NOAEL = 40 mg/kg/day [500 ppm] LOAEL = 160mg/kg/day [2000 ppm] based on f1 pup weight decrement at LD 21 and f2 pup weight decrease at LD day 7and 21.
870.4100b Chronic toxicity (dog) 41615903 (1990)

0, 25, 250, 1250 ppm [M/F 0/0, 1.95/2.1, 10.1/9.1, 48.7/49.3 mg/kg/day] [From std tables( dry): 0, 0.625, 6.25, 31.25 mg/kg/day] [From std tables(wet): 0, 2.5, 18.75, 50 mg/kg/day] Acceptable TXR# 008285 NOAEL = 10.1/9.1 mg/kg/day [250ppm] LOAEL =48.7/49.3 mg/kg/day [1250ppm] based on decreased body wt & body wt gains [43% to 60%,0

- 26wk] both sexes 100% in males wk 26

- 52] alkaline phosphatase increased in females 109

- 2185 throughout study and 80% in males. Portal vacuolation in males; vacuoles not lipid or glycogen

870.4200 b Carcinogenicity (mouse) 41662415 (1990)

0,30, 300, 1500, 3000 ppm [M/F: 0/0, 3.8/4.1, 40.8/40.1, 205/200, 431/411 mg/kg/day Acceptable TXR# 008315 NOAEL = 300 ppm (M/F: 40.8/40.1 mg/kg/day) LOAEL = 1500 ppm (M/F: 205/200 mg/kg/day) based on decreased body weight gain in both sexe s.

No treatment related tumors were seen at adequate doses.

870.4300 Chronic/ carcinogenicity (Sprague Dawley rat) 41706808 & 42030102

(1990) 0, 100, 700,1500 ppm [M/F: 0/0, 5.1/6.8, 36/49, 80/109 mg/kg/day] Acceptable TXR# 008315 & 008975 NOAEL = 100 ppm [M/F: 5.1/6.8 mg/kg/day] LOAEL = 7000 ppm [M/F: 36/49 mg/kg/day] based on decreased body weight and body weight gain in both sexes and microscopic hepatic lesions in both sexes. A dose related increased incidence of liver tumors in males (benign and malignant combined) were seen at 1500 ppm, both exceeding historical controls. Cancer Peer Rev (TXR# 012143 & 012831) characterized [RS]

- dimethenamid as a Group C

- possible human carcinogen, and recommended that for the purpose of risk assessment the R eference dose approach should be used for human risk assessment) Gene Mutation 870.5100 Bacterial Reverse mutation 41596542 (1989)

Reverse mutation in S. typhimurium strains TA 98, TA100, TA1535, TA1537, TA1538 Acceptable TXR# 008285 Strains tested at 1000

- 10000 μg/plate,

- S9 and 1000

- 6500 μg/plate, +S9. Cytotoxicity and precipitation were noted at higher doses.

Test was negative, +/

- S9.

Cytogenetics 870.5395 Mouse erythrocyte micronucleus test 43648401 (1993)

In vivo Bone marrow erythrocyte micronucleus
test Acceptable inn TXR# 011053 CD

- 1 mice dosed at 710 mg/kg in two daily doses. LD50 = 1417 mg/kg. Bone marrow erythrocytes harvested 24 and 48 hours later.

Test negative.

### Page 45 of 51

Table A.2.3. Subchronic, Chronic and Other Toxicity Profile for [RS]

- dimethenamid
Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

Cytogenetics 870.5395 Mouse erythrocyte micr onucleus test 41822703 (1986)

In vivo Bone marrow erythrocyte micronucleus test. Unacceptable in TXR# 008469 Mice dosed 0

- 1000 mg/kg in single doses. Mice showed no toxicity; only one mouse died.

Test negative.

Chromosomal aberration test 870.5375 41596543 (1985)

In vitro chromosomal aberration test in Chinese hamster ovaries (CHO) Unacceptable in TXR# 008285 & acceptable in TXR# 009070 Cells in 125

- 150 μg/mL,

- S9 and 400 to 500 μg/mL, +S9; all doses were cytotoxic. Study needs repeating at no cyto toxic doses.

Test considered equivocally positive.

UDS in rat hepatocytes 870.5550 41822702 (1986)

In vitro unscheduled DNA synthesis in rat hepatocytes Unacceptable in TXR# 008469 Cell in 1.0

- 100 nl/mL. No cytotoxicity was seen.

Test was negative.

UDS in rat hepatocytes 870.5550 43648402 (1993)

In vivo unscheduled DNA Synthesis in rat hepatocytes Acceptable to EEC requirements TXR# 011053 Fisher 344 rat administered SAN 582H doses of 158 or 500 mg/kg. Sampled 2

- 4 and 12

- 14 hour s after dosing. Only 0.2

- 3.6% cells in repair, but negative control was less than zero.

Test was negative for UDS at 158 and 500 mg/kg.

UDS in rat hepatocytes 870.5550 41596544 (1989)

In vitro unscheduled DNA synthesis in rat hepatocytes Acceptable in TXR# 008285 SAN 582H administered at 0.01 to 50 μg/mL. Unscheduled DNA synthesis was seen well below cytotoxic doses. Unequivocally positive for UDS.

Test positive.

UDS in rat hepatocytes 870.5550 41662416 (1990)

In vitro unschedule d DNA synthesis in rat hepatocytes. Acceptable in TXR# 008469 SAN 582H administered at 0.0128 to 1000 μg/mL to rat primary cultures of hepatocytes. Doses at 1000 μg/mL were cytotoxic. No UDS was noted.

Test negative for UDS.

Dominant Lethal 870.5450 43209201 (1994)

(Hazleton) Dominant lethal in CR
rats Acceptable in TXR# 011053 Male Charles River rats (40

- 55) administered SAN 582H in single oral doses of 275, 550 or 1100 mg/kg were mated starting at 10 weeks to 40

- 55 female undosed CR rats. Increased dead implants at week 1 and week 2 may suggest a dominant lethal effect. These were mostly late implant deaths, which some consultants claim are not characteristic of a dominant lethal effect. .
Dominant Lethal 870.5450 43814401 (1995)

(Microb iological Assoc.) Dominant lethal in Sprague Dawley rats Male Sprague Dawley rats (40

- 60) administered SAN 582H in single oral doses of 275, 550 or 1100 mg/kg were mated starting the day after dosing in Trial 1 and 2 days after dosing in Trial 2 to 80

- 120 female undosed Sprague Dawley rats . Each male was mat ed to 2 females over a five day

### Page 46 of 51

Table A.2.3. Subchronic, Chronic and Other Toxicity Profile for [RS]

- dimethenamid
Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

sequence. Results equivocal, but not considered to negate results from MRID# 43209201. Note: Both the high dose rabbit and rat developmental studies showed increased late and early resorptions.
BALB/3T3 cell transformat ion NG 41822701 (1986)

per

- 1996 in vitro cell transformation

Unacceptable in TXR# 008469 BALB/3T3 cells administered SAN 582H at 15.0 to 100 μg/mL. No transformed cells were noted, but several inadequacies were noted in the test report. Number of cell s transformed. Cell transformation yields variable results and is not an acceptable methodology.

Test negative
870.7485 Metabolism and pharmacokinetics (Wistar rats) 41596545 (1989) &

42289501 (1992) Single low and high doses
of [ 14 C] SAN 582H and af ter repeat doses of SAN 582H were administered

Unacceptable in TXR# 008285 Acceptable in TXR# 009867. Extensively metabolized, being essentially complete within 3 days and over 90% being excreted in the urine, feces and bile within 7 days. Total excretion products with the highest concentrations (in % of administered dose) in the male and female, respectively, were parent 1.4% and 1.2%, *M1

- 3.3 & 7.2%, *M2

- 3.6% & 9.8%, M3

- 0.6% & 0.4%, M14

- 2.8% & 3.3%, *M16

- 5.1% & 3.3%, M17

- 0.6% & 3.3%, M19

- 1 .1% & 1.4%. Parent was initially conjugated with glutathione and most metabolism taking place with the glutathione conjugate. No significant differences in metabolism were seen between males and females. Up to 45 putative metabolites were reported in the urine and up to 50 were reported in the feces. Of these metabolites, 31 were identified. Of the unidentified metabolites none exceeded 3.0% and most being less than 1% of the administered dose.

Chemical name of excretion products exceeding 5% in the mu ltidose 10 mg/kg study in males or females. M1 is N

- (2,4

- dimethyl

- 3

- thienyl)

- N

- (2

- hydroxy

- 1

- methylethyl)

- 2

- (methyl

- thio)

- acetamide

M2 is N

- (2,4

- dimethyl

- 3

- thienyl)

- MN

- (2

- hydroxy

- 1

- methylethyl)

- 2

- (methyl

- sulfinyl)

- acetamide M16 is N

- (2

- hydroxymethyl

- 4

- meth yl

- 3

- thienyl)

- N

- (2

- methoxy

- 1

- metylethyl)

- 2

-

(methylsulfinyl)

- acetamide

Table A.2.4. Subchronic, Chronic and Other Toxicity Profile for [S]

- dimethenamid

- P (PC 120051)
Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3100 90

- Day Feeding/Sprague Dawley Rat 44332242 (1996)

Doses: 0, 500, 1500, 3000 ppm [M/F: 0/0/, 37/40, 110/125, 222/256 mg/kg/day] Acceptable in TXR# 0050183 NOAEL=37/40 mg/kg/day [500 ppm] LOAEL=110/125 mg/kg/day [1500 ppm] based on decreased body weight a nd body weight gain in males and females, increased gamma

- glutamyl transferase in both sexes, increased cholesterol in males, increased abs. and rel. liver weight and periportal hepatocytic hypertrophy and periportal eosinophilic inclusions in males, centr ilobular hypertrophy in females and liver necrosis in females.

### Page 47 of 51

Table A.2.4. Subchronic, Chronic and Other Toxicity Profile for [S]

- dimethenamid

- P (PC 120051)
Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3700a Prenatal developmental in (Sprague Dawley rats) 44332243 (1996) [Doses:

0, 25, 150, 300 mg/kg/day] Vehicle is 0.5% CMC, 10 ml/kg

Acceptable in TXR# 0050183 Maternal LOAEL = 150 m g/kg/day based on a decrease in body weight/gain and feed consumption (clinical signs at 300 mg/kg/day). Maternal NOAEL is 25 mg/kg/day. Developmental LOAEL is 150 mg/kg/day based on an increased incidence of incomplete ossification of the second
sterna l central and/or pelvic pubis. The developmental NOEL is 25 mg/kg/day.

Gene Mutation 870.5100 Bacterial Reverse mutation Reverse mutation

44332244 (1997) S. typhimurium TA1535; E. coli WP2uvrA

Acceptable in TRX# 0052635 S. typhimurium exposed to 500

- 4000 μg/plate +/

- S9. E. coli exposed to 20

- 5000 μg/plate +/

- S9 using the Std plate incorp method or 4

- 2500 μg/plate +/

- S9 using the preincubation modification to the std test. Highest doses were cytotoxic.

All assays were negative.

Gene Mutation 870.5100 Bacterial Reverse mutation Reverse mutation

44332245 (1997) S. typhimurin TA1535, TA1537, TA 98, TA100; E. coli WP2uvrA

Acceptable in TRX# 0052635 Exposed to 20

- 5000 μg/plate in a plate incorporation assay. Marginal cytotoxicity at limit do se of 5000 μg/plate +/

- S9.

Assays were negative with both bacteria +/

- S9.

Gene Mutation 870.5100 Bacterial Reverse mutation Reverse mutation

44332246 (1997) S. typhimurin TA100.

Acceptable in TRX# 0052635 Repeat of MRID# 44123502. S. typhimurium TA100 was exposed to 100

- 5000 μg/plate

- S9.

Assay was negative.

Gene Mutation 870.5100 Bacterial Reverse mutation Reverse mutation

44123502 (1996) & resubmitted 44332250 (1996) S. typhimurin TA1535, TA1537, TA 98, TA100; E. coli WP2uvrA

Acceptable in TRX# 0052636 Exposed to 100

- 5000 μg/plate, +/

- S9, in a plate incorporation assay. Insolubility seen at 333 & 5000 μg/plate, but no toxicity at any dose. +/

- S9.

Assays were negative with both bacteria + S9, however,

- S9 induced 1 .5 fold increases at 333 μg/plate and 4.1 fold increases in reverents in TA100 strain at 5000 μg/plate. This mutagenic response was reproducible at 100 to 5000 μg/plate.

Mammalian cell mutation 870.5300 In vitro CHO/HGPRT

mutation assay 44123501 (1996) & resubmission as 44332248 Acceptable TXR# 12312 Chinese hamster ovary (CHO) cells were exposed to 100

- 400 μg/mL,

- S9, and 100

- 450 μg/mL, +S9. Slight cytotoxicity was seen at the highest dose and severe toxicity

was seen at  500 μg/mL.

Test was n egative for mutagenic effects, +/

- S9. Cytogenetics in Chinese Hamster Ovary (CHO) cells 870.5375 Chromosomal aberrations

in vitro 44332247 (1996) CHO cells were exposed to 2

- 120 μg/mL

- S9; cytotoxic at
 120 μg/mL. CHO cells were exposed to 15

- 120 μg/mL +S9; cytotoxic at  500 μg/mL. Assay was negative +/

- S9.

### Page 48 of 51

Table A.2.4. Subchronic, Chronic and Other Toxicity Profile for [S]

- dimethenamid

- P (PC 120051)
Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

Acceptable TXR# 0052635 Cytogenetics; mouse erythrocyte micronucleus test 870.5395 ICR mice in vivo test

44332249 (1996)

Acceptable TRX# 0052635 Mice (5/sex) were e xposed to i.p. injections of 103, 205, 410 mg/kg.

Assay was negative, indicating no clastogenic or aneugenic
response.

Other Effects 870.5550 UDS in mammalian cell culture Rat hepatocyte cell in

vitro test 44332251 (1996)

Acceptable TRX# 0052635 Cells tested at 7.8

- 125 μg/mL. Cytotoxicity and insolubility

were seen at  250 μg/mL.

Test was negative for UDS.

Acute Neurotoxicity 870.6200 0, 60, 200, & 600 mg/kg

Acceptable 49184304 (2013) NOAEL = 200 mg/kg LOAEL= 600 mg/kg based on lacrimati on, salivation, irregular and accelerated respiration, slight tremors, reduced exploration, unsteady gait, significantly reduced rearing Subchronic Neurotoxicity 870.6200 0, 19, 63 & 323mg/kg

– M

0, 23, 71, & 390 mg/kg

- F Acceptable 49184305 (2013) NOAEL for systemic toxicity 63 mg/kg based a trend of higher liver weights in females (pelvic dilation seen was considered incidental)

.
LOAEL 323 mg/ kg

Immunotoxicity 870.7800 0, 120, 385 & 1167

mg/kg Acceptable 49184307 (2013) The systemic LOAEL of female C57BL/6J Rj mice treated with BAS 656

- PH was 1500 ppm (385 mg/kg bw/day) based on increased absolute and relative liver weight. The NOAEL was 500 ppm (120 mg/kg bw/day).

The immunotoxicity NOAEL in female C57BL/6J Rj mice for BAS 656

- PH was 4000 p pm (1167 mg/kg bw/day) which was equivalent to the limit dose for the study. A LOAEL was not established.



### Appendix B

. Physical/Chemical Properties

### Page 49 of 51

Table B.1. Physicochemical Properties of Technical Grade Dimethenamid

- P.
Parameter Value Reference Melting point/range <

- 50oC MRID 47005001 pH 3.3 (in 1% aqueous emulsion) Density 1.195 g/ml Water solubility 1449 ±17 mg/L (pH 6.16) Solvent solubility 20.8g/100 ml in hexane; soluble in all proportions in tetrahydrofuran, isopropyl alcohol, acetone, CAN, DMSO, DCM, toluene and n

octanol. Vapor pressure 1.88 (±0.29) x 10

- 5 mm Hg Dissociation constant, pK a No dissociation Octanol/water partition coefficient 77.6 and 1.89 (P OW and log P OW ) UV/visible absorption spectrum ε = 7560; 33 nm

Table B.2. Tolerance Summary for Dimethenamid/Dimethenamid

- P excluding Livestock Feed Crops/Commodities.

Commodity Established Tolerance (ppm) Recommended

Tolerance(s) Under Current Petition (ppm) Comments

Bean, dry, seed 0.01

-- Beet, garden, roots 0.01

-- Beet, garden, tops 0.01

-- Beet, sugar, molasses 0.01

-- Beet, sugar, roots 0.01

-- Beet, sugar, tops 0.01

-- Corn, field, grain 0.01

-- Corn, pop, grain 0.01

-- Corn, sweet, kernel plus cob w/husks removed 0.01

--
Cottonseed subgroup 20C

-- 0.01 Crops in this subgroup include: cottonseed; cultivars, varieties, and/or hybrids of these. Garlic 0.01

-- Under §180.1(g) this tolerance also applies to great headed garlic and serpent garlic. Hops, dried cones 0.05

-- Horseradish 0.01

-- Leek 0.01

-- Onion, bulb 0.01

-- Under §180.1(g) this tolerance also applies to garlic; great headed garlic; serpent garlic; Chinese onion; pearl onion; potato onion; and shallot, bulb. Onion, green 0.01

-- Under §180.1(g) this tolerance also applies to lady's leek; leek; wild leek; Beltsville bunching onion;

### Page 50 of 51

Table B.2. Tolerance Summary for Dimethenamid/Dimethenamid

- P excluding Livestock Feed Crops/Commodities.

Commodity Established Tolerance (ppm) Recommended

Tolerance(s) Under Current Petition (ppm) Comments

fresh onion; tree onion, tops; Welsh onion; and shallot, fresh leaves. Onion, Welsh 0.01

-- Peanut 0.01

-- Pumpkin 0.01

-- Tolerance with regional restriction established under 40 CFR 180.464(c). Radish, roots 0.01

-- Radish, tops 0.01

-- Rutabaga, roots 0.01

-- Rutabaga, tops 0.1

-- Shallot, bulb 0.01

-- Shallot, fresh leaves 0.01

-- Squash, winter 0.01

-- Tolerance with regional restriction established under 40 CFR 180.464(c). Sorghum, grain, grain 0.01

-- Under §180.1(g) this tolerance also applies to Sorghum spp. [sorghum, grain, sudangrass (seed crop), and hybrids of these grown for its seed]. Soybean, seed 0.01

-- Turnip, greens 0.1

-- Under §180.1(g) this tolerance also applies to broccoli raab (raab, raab salad), hanover salad, turnip tops (turnip greens). Turnip, roots 0.01

-- Turnip, tops 0.1

-- Vegetable, tuberous and corm, subgroup 1C 0.01

-- Crops in this subgroup include: arracacha; arrowroot; artichoke, Chinese; artichoke, Jerusalem; canna, edible; cassava, bitter and sweet; chayote (root); chufa; dasheen; ginger; leren; potato; sweet potato; tanier; turmeric; yam bean; yam, true.

### Page 51 of 51

Appendix C

. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies were determined to require a review of their ethical conduct, have received that review and have been determined to be ethical.

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Task Force members Health Canada, U.S. Environmental Protection Agency, and the National Agricultural Chemica ls Association, released February, 1995.

The Agricultural Handler Exposure Task Force (AHETF), 2011. The Occupational Handler Unit Exposure Surrogate Reference Table. U.S. Environmental Protection Agency. Released June 21, 2011.