### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON

, D

. C

. 20460

MEMORAN D UM

Date: J une 3, 20 15 OFFICE OF C H E M ICAL S A FETY

A N D POLLUTION PREVE N TION



### SUBJECT: H exaz inon e: Dr aft Human H eal th Ri sk Assessment for R egistration Rev i ew.



### PC Code: 10720 I



### D e ci s ion No.: 498287



### Petition No. : NA

Ri s k Assess m e nt Type: Single

C hemical / Aggregate

TXRNo. : NA



### MR ID No.: NJ\ 

### DP Barcod e: D4 2 4526



### Re g i s tration No. : NA

R eg ul a to ry Act i o n : Regi s tration Revi ew 

### Case N o. : 0266



### CAS No. : 5 1 235

- 04-2

40 

### C FR: 

### § 180.396



### F R OM: Sheila Piper

, Risk

# Assessor**M-(t~** Shal

. u Shelat

, Indu str ial

## ygenist/Oi;**~ Asses** **so~** Yang Yun g, Ph.D.

, Toxicolo g i s t 

## 7 

# 6

.**~** 

# · Ri s k Assessment Branch 

### VI

THRO UG H : D o nna D avis, Acting Br anch Chief

# /LJ~-z__,, Ri s k Assessment Branch 

### VI 

## li..).)

H ea lth Effects Di v ision

TO : D ana Friedman. Chemica l Revi ew Manager

Jo se Gay oso, Chemical R ev iew Mana ge r
Tom Myers. T eam Leader

K ev in Costello

, Branch Chief

Ri s k Management and Implem en tation Branch I

Pe s ticide R e -e va lu ation Division ( 7508P)

The Health Effect s Divi s i o n ( H ED) of the Offi ce of P es ticid e Programs (OPP) is cha rg ed wi th

estimat in g the ri sk to human health from exposure t o pest i cides

. As part of R egistratio n R eview,

the P est i cide Re- eva luation Divi s ion ( PRD) of OPP ha s requ es ted that HED evaluate the hazard

and ex p os ure data and conduct dietary. oc cupational

, r es idential

, and aggregate exposure

as sess m ents

, as n eeded, to est imat e the r i sk to human health that wi ll re s ult from the regi s tered

u ses of he xaz in o n e

.

Pa ge I of 64

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 2 of 64 HED has evaluated the toxicity and exposure databases for the active ingredient, hexazinone

, and

has conducted a human heal th risk assessment in support of Registration Review

.

A summary of the findings and an assessment of human health risk resulting fro m the currently registered uses of hexazinone are provided in this document. The HED team members contributing to this risk assessment include Sheila Piper (risk assessment , chemistry

, and dietary

assessment ), Shalu Shelat (occupational and residential as sessment), and Yang Yung (hazard assessment). Jos é Mel é ndez of the Environmental Fate and Effects Division (EFED) performed the drinking water assessment.

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 3 of 64 1.0 Executive Summary

................................ ................................ ................................ ........... 5

2.0 HED Recommendations

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

2.1 Data Deficiencies

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

2.2 Tolerance Considerations

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

2.2.1 Enforcement Analytical Method

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

2.2.2 Recommended Tolerances

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

2.2.3 Revisions to Petitioned

- For Tolerances

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

2.2.4 International Harmonization

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

3.0 Introduction

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

3.1 Chemical Identity

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

3.2 Physical/Chemical Characteristics

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

3.3 Pesticide Use Pattern

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

3.4 Anticipated Exposure Pathways

................................ ................................ ................. 1 3

3.5 Consideration of Environmental Justice

................................ ................................ .... 1 3

4.0 Hazard Characterization and Dose

- Response Assessment

................................ .......... 14

4.1 Toxicology Studies Available for Analysis

................................ ................................ . 1 4

4.2 Absorption, Distribution, Metabolism and Elimination

................................ .......... 1 5

4.2.1 Dermal Absorption

................................ ................................ ................................ ....... 1 5

4.3 Toxicological E ffects

................................ ................................ ................................ .... 1 5

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

............................... 1 6

4.4.1 Completeness of the Toxicology Database

................................ ................................ . 16

4.4.2 Evidence of Neurotoxicity

................................ ................................ ............................ 1 6

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

........... 1 7

4.4.4 Residual Uncertainty in the Exposure Database

................................ ...................... 17

4.5 Toxicity Endpoint and Point of Departure Selections

................................ ............... 17

4.5.1 Dose

- Response Assessment

................................ ................................ .......................... 17

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment

.......... 18

4.5.3 Cancer Classification and Risk Assessment Recommendations

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

4 .5.4 Summary of P oints of Departure and Toxicity Endpoints

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

4. 6 Endocrine Disruption

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

5.0 Dietary Exposure and Risk Assessment

................................ ................................ ......... 2 2

5.1 Residue of Concern Summary

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

5. 2 Food Residue Profile

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

5. 3 Summary of Environmental Degradation

................................ ................................ .. 2 3

5. 4 Water Residue Profile

................................ ................................ ................................ .. 2 3

5.4. Dietary Risk Assessment

................................ ................................ ............................. 2 4

5.5 .1 Description of Residue Data Used in Dietary Assessment

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

5.5 .2 Percent Crop Treated Used in Dietary Assessment

................................ .............. 2 5

5.5 .3 Acute Dietary Risk Assessment

................................ ................................ ............... 2 5

5.4.4 Chronic Dietary Risk Assessment

................................ ................................ ........... 2 6

5.5 .5 Cancer Dietary Risk Assessment

................................ ................................ ............. 2 6

5.5 .6 Dietary Sum mary Table

................................ ................................ ........................... 2 6

6.0 Residential Exposure/Risk Estimates

................................ ................................ ............. 2 9

6. 1 Spray Drift

................................ ................................ ................................ .................... 2 9

6. 2 R isk Estimates from Lawn Deposition Adjacent to Agricultural Application

.......... 30

6.3 Residential Bystander Post

- Application Inhalation Exposure

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

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 4 of 64 7.0 Aggregate Exposure/Risk Characterization

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

8.0 Cumulative Exposure/Risk Characterization

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

9.0 Occupational Exposure and Risk Estimates

................................ ................................ .. 3 3

9.1 Occupational Handler Exposure/Risk Estimates

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

9.2 Occupational Post

- Application Exposure/Risk Estimate

................................ ......... 45

9.2.1 Occupational Post

- Application Inhalation Exposure/Risk Estimates

................. 4 5

9.2.2 Occupational Post

- Application Dermal Exposure/Risk Estimates

...................... 4 5

10.0 Human Study Review

................................ ................................ ................................ ...... 46

11.0 Review of Incident Report

................................ ................................ ............................... 46

12.0 References

................................ ................................ ................................ ......................... 46 Appendix A. Toxicology Assessment

................................ ................................ ........................ 4 7

A.1 Toxicology Data Requirements

................................ ................................ ................... 4 8

A.2 Toxicity Profiles

................................ ................................ ................................ ............ 49

A ppendix B. Chemical Structures of Hexazinone and its Regulated Metabolites

............. 5 2

A ppendix C

. International Residue Limits

................................ ................................ ............ 5 5

A ppendix D Food/Feed Use Patterns Subject to Registration for Hexazinone...

............ 5 8 Appendix E. Risk Estimates Related to Spray Drift Exposure to Hexazinone from the Registered Agricultural Uses.............................................................................61

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 5 of 64 1.0 Executive Summary

Hexazinone is a tri azine

- dione herbicide registered for use on alfalfa, blueberries, pasture and range grasses, pineapple, and sugarcane. It is also registered for use on ornamental plants, forest trees, and non

- crop areas. There are no residential uses of the chemical. H exazinone is used to control a variety of weed species and works through inhibition of photosynthesis. Hexazinone may be applied for pre

- or post

- emergence weed control by layby, directed spray, broadcast spray, or basal soil treatments and can be applied using either ground or aerial equipment.

The toxi cology database for hexazinone is complete , no additional data are required

. Body weight decrement and liver toxicity were the most frequent effects shown in studies with hexazinone. Liver toxicity was s een in the chronic dog and mouse studies. Body weight decrement was seen in the chronic and reproductive toxicity studies in rats. In a reproduction study in rats, pup weight decrement occurred at the same dose as parental body weight decrement. No reprodu ctive effects were seen in the study other than pup weight decrement. In the rat developmental toxicity study, developmental effects (kidneys with no papillae and misaligned sternebrae) were seen at a higher dose than the dose causing maternal toxicity. In the rabbit study, fetal weight decrements were seen at the same dose that caused maternal weight

decreases.

The 21

- day dermal study in the rabbit showed mild dermal irritation but no systemic toxicity was

observed at the limit dose. A 28

- day inhalation study in rats showed effects in the portal

- of

- entry

as squamous and mucous cell metaplasia at the ventral base of the epiglottis and in the nose, nasal septum and nasopharynx

. In an acute neurotoxicity study, reduced motor activity was

observed in rats of both sexes, and decreased body temperature and increased incidences in posture and palpebral closure parameters were observed in females at the highest dose tested ( 500 mg/ kg)

. In a subchronic neurotoxicity study, no neuro toxicity was observed up to the

hi ghest dose tested

. There was no evidence of immunotoxicity in a rat immunotoxicity study.

Hexazinone is classified as " Group D chemical, not classifiable as to human carcinogenicity "

based on weight

- of

- evidence (WOE) considerations in carcinogenicity studies in rats and mi ce and no evidence of mutagenicity.

Hexazinone has low acute toxicity by the oral ( Toxicity Category III), dermal ( Toxicity Category IV)

, and inhalation ( Toxicity Category III) routes. Primary eye irritation is severe, causing corneal opacity and moderate irritation in unwashed eyes ( Toxicity Category I). Hexazinone causes mild skin irritation ( Toxicity Category IV) but it is not a skin sensitizer.

There is no evidence of increased quantitative or qualitative s usceptibility of the young following

in utero and pre

- and post

- natal exposure to hexazinone based on the results from developmental studies conducted with rats and rabbits, as well as a two

- generation reproduct ion study

conducted with rats. The refore, the risk assessment team concluded that the 10

- fold Food Quality Protection Act ( FQPA ) Safety Factor may be reduced to 1 x

. Also, a target margin of exposure (MOE) of 100 is considered adequate for all exposure scenarios (10x) for interspecies extrapolation and 10x for intraspecies variability. The uncertainty factor of 30 x was applied for

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 6 of 64 inhalation risk assessment (3 x for interspecies extrapolation, 10x for intraspecies variation

, and a

1 x FQPA SF) resulting in a level of concern (LOC) of 30

.

The residue chemistry database for hexazinone is complete. Acceptable data were submitted depicting residues in target crops. These data are supported by storage stability data and were generated using adequately validated analytical methods. There is an analytical method to enforce the proposed tolerance. The nature of the residue in plants and livestock is adequately

understood. The field tr ial data for hexazinone and its metabolites in/on warm

- season pasture grass forage and hay was used to recalculate the maxim um reasonably balanced dietary burden ( MRBDB )

. The feeding study data indicate that the establis hed tolerances for residues of hexazinone in/on ruminant meat, meat byproducts, and fat for cattle, goats, horses and sheep

livestock commodities should be reta ined. Based on the dietary burden calculation and the residue profile in the feeding study, the Agency concludes that there are not likely to be quantifiable residues of hexazinone and its metabolites in eggs, poultry

, and hog commodities, and a Categor y 3 of 40 CFR§180.6 (a)(3) should remain

.

EFED has determined that a new drinking water assessment should be cond ucted which considers the potential for hexazinone formation during water treatment. EFED shared with HED preliminary estimated drinking water concentrations (EDWCs) for various application scenarios

and additional refinements were conducted

.

The acute aggregate (food and drinking water) dietary exposure estimates for various scenarios are below HED’s level of concern (<100 % of the acute popul ation adjusted dose ( aPAD ) ) for the U.S. population and all population subgroups. The worst case scenario was the N orth

Carolina c oastal rights

- of

- ways PRZM

- GW that resulted in the combined acute dietary exposure and risk estimates from food and drinking w ater which utilized 23 % of the aPAD for the U.S. population and 73 % of the aPAD for children 1

- 2 years old at the 95 th 

### percentile , the most highly exposed population subgroup. For chronic

, the dietary exposure is estimated to be 29 % of the

cPAD for the U.S. population, and 7 1% of the cPAD for children 1

- 2 years old, the population with the highest estimated chronic dietary exposure to hexazinone from the pasture/rangeland (2 lbs ai application rate for WI sand) PRZM

- GW scenario

.

There are no re gistered residential uses of hexazinone ; therefore

, a residential handle r and post

application assessment was not conducted.

In the absence of systemic dermal toxicity, dermal handler and post

- application exposure assessments were not conducted, and there is no risk associated with dermal exposure to workers. An occupational handler inhalation exposure and risk assessment was c onducted. There are some occupational handler inhalation risk estimates of concern for the registered uses of hexazinone at baseline (i.e., no respirator). Occ upational inhalation MOEs ranged from 0.8 to 9,600 (LOC = 30) at baseline attire with labeled pe rso nal protective equipment (PPE; i.e., gloves and no respirator). The inhalation scenarios have been assessed for additional PPE which include PF5 respirators, PF10 respirators, and engineering controls. Some scenarios have risks

of concern even with th e consideration of engineering controls. The re

- entry interval (REI) is based on the acute toxicity of hexazinone and a 48 hour REI is adequate for the registered uses.

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 7 of 64 Based on the Agency's current practices, a quantitative non

- cancer occupational pos t

- application inhalation exposure assessment was not performed for hexazinone 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 f or hexazinone

.

A quantitative non

- occupational spray drift assessment was conducted for hexazinone

. Children’s (1 to < 2 year s old) incidental oral risk estimates from indirect exposure to hexazinone related to spray drift did not exceed HED’s level of c oncern at the edge of the treated

field (MOEs ≥ 100).

2.0 HED Recommendations

2.1 Data Deficiencies

There are no data deficiencies relating t o toxicology, residue chemistry

, or occupational exposure associated with this regis tration review for hexazinone

.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate methods are available for purposes of enforcement of tolerances and data collection for residues of hexazinone and metabolites A, B, C, D, and E in/on plant commod ities. For

tolerance enforcement , the Pesticide Analytical Manual (PAM) Volume II lists Method I as available for the determination of hexazinone residues of concern in/on plant commodities. The combined limit of quantitation (LOQ) for hexazinone residue s (parent and metabolites) by Method I in PAM Volume II, is 0.55 p p m. A liquid chromotography/mass spectroscopy (LC/MS) method (AMR 3783

- 96) is available as an enforcement method for livestock commodities. The reported LOQs were 0.02 ppm for hexazinone and metabolite B and 0.05 ppm for metabolites C,

C

- 2, and F.

2.2.2 Recommended Tolerances

Permanent tolerances are currently established for residues of the herbicide hexazinone, including its metabolite and degradates, in or on the commodities in the 40 CFR § 180. 396. The tolerance expression listed in the 40 CFR § 180. 396 complies with the HED interim tolerance expression policy (S. Knizner, 5/27/99). Previously, HED recommends that a tolerance for

inadvertent hexazinone residues in/on corn stover, sorghum stover, and wheat straw at 0.50 ppm

be established.

Table 2.2.2 . Tolerance Summary for Hexazinone , §180. 396(3)(d) Commodity Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments

( correct commodity definition )

Corn stover

-- 0.50 Sorghum stover

-- 0.50

Wheat straw

-- 0.50

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 8 of 64 * NA

– Not applicable.



### Note to PRD: Previously, HED recommended that residues in/on hog commodities are not expected. Therefore, t he established to lerances for hog commodities that are listed in the 40 CFR§180.396 for hexazinone should be removed.

2.2.3 Revisions to Petitioned Tolerances

None

2.2.4 International Harmonization

There are no established Codex maximum residue limits (MRLs) on hexazinone . Canadian MRLs are established on livestock commodities only. The Canadian tolerance expression for ruminant tissues include hexazinone and metabolite B and the tolerance is 0.04 ppm for livestock

commodities

. The Canadian tolerance expression for milk include hexazinone and metabolites B and C and the tolerance is 0.09 ppm for milk. T h e tolerance/MRL definition in the US and Canada are different; therefore, tolerance and MRLs cannot be harmonized at this time.

3 .0 In troduction

Hexazinone [3

- cyclohexyl

- 6

- (dimethylamino)

- 1

- methyl

- 1, 3,5

- triazine

- 2,4

- (1H,3H)

- dione] is used to control a variety of weed species including geratum, alder, and alexander grass and works through inhibition of photosynthesis. Hexazinone is a proprietary chemical of E.I. du

Pont d e Nemours Inc. which is the sole producer and primary registrant of this broad spectrum

herbicide

. It was first registered on November 1975 for general weed control in non

- cropland

areas

. The most recent human health risk assessment for hexazinone was conducted 2002 (D275621, C. Christensen, 8/22/02 ).

3 .1 Chemical Identity

Table 3.1. Hexazinone Nomenclature

Chemical Structure

Empirical Formula 

### C 12 

### H 20 

### N 4 

### O 2


### Common Name 

### Hexazinone

IUPAC name 

### 3

- cyclohexyl

- 6

- dimethylamino

- 1

- methyl

- 1,3,5

- triazine

- 2,4(1 H ,3 H )

- dione

CAS Name 

### 3

- cyclohexyl

- 6

- (dimethylamino)

- 1

- methyl

- 1,3,5

- triazine

- 2,4(1 H ,3 H )

- dione

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 9 of 64 Table 3.1. Hexazinone Nomenclature CAS Registry

Number 

### 51235

- 04

- 2

Chemical Class 

### Triazinone herbicide

3 .2 Physical/Chemical Characteristics

Hexazinone is high ly soluble in water (29,800 ppm), it has a relatively low vapor pressure (1.9 x

10

- 7 

### mmHg), and a very low Henry’s Law Constant (2 x 10

- 12 

### atm

- m 3 

### /mol). Based on these properties, it appears hexazinone is mobile in the environment, partitions into water more than to

soil and has a very low potential to bioaccumulate

.

Table 3.2

. Hexazinone Physical and Chemical Properties

Parameter Value 

### Molecular Weight 252.3 g Water solubility (20°C) 2.98 g/100 @25 o 

### C

Vapor pressure (20°C) 1.9 x 10

- 7 

### mmHg@25 o 

### C

Henry’s Law Constant (25°C) 2 x 10

- 12 

### atm

- m 3 

### /mol; @ 25 o 

### C Octanol/water partition coefficient (25°C) log Kow = 1 .9 5

3 .3 Pesticide Use Pattern

Hexazinone is currently formulated as pellets/tablets, dry flowable, and water dispersible granules, liquids, and granules. Products are applied using aerial or ground equipment

, by hand, or using a hand

- held, backp ack

, or pressurized sprayer. Hexazinone is registered for pre

emergent, post

- emergence, layby, dir ected spray

, and basal soil applications. The maximum single application rates for each crop or use site range from 1. 12 5 to 8 lb s ai/A. For the pellet application, the maximum single application rate is 7000 pellets/A (7. 5 lbs ai/A) and for tree injecti on or basal soil single stem injection, the maximum rate is 4 mL per each inch stem

diameter. There are no registered residential uses. The uses and application rates are

summarized in Table 3.3

.

Table 3.3 . Summary of Directions for Use of Hexazinone.

Applic. Timing, Type, and Equip. Formulation 1

[EPA Reg. No.] Maximum

Applic.

Rate (lb ai/A) Max. No.

Applic. per

Season Max. Seasonal

Applic. Rate (lb ai/A) PHI (days) Use Directions and

Limitations

Alfalfa

Ground

Aerial Chemigation Dry Bulk Fertilizer 1 EC [352

- 392;

5905

- 579;

84229

- 35]

WDG /DF [352

- 581; 352

- 634; 1.5 1 1.5 30 Do not apply within 30 days of harvest (cutting for hay), or feeding of forage or grazing. Do not exceed 1.5 pounds active ingredient

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 10 of 64 Table 3.3 . Summary of Directions for Use of Hexazinone.

Applic. Timing, Type, and Equip. Formulation 1

[EPA Reg. No.] Maximum

Applic.

Rate (lb ai/A) Max. No.

Applic. per

Season Max. Seasonal

Applic. Rate (lb ai/A) PHI (days) Use Directions and

Limitations

352

- 665; 352

- 666; 84229

- 32] hexazinone per acre per

year.

Do not apply within 30 days of harvest (cutting for hay), o r feeding of forage or grazing.
High Bush Blueberry

Spring before leave

emergence Ground Dry Bulk Fertilizer 1 EC [352

- 392;

5905

- 579;

84229

- 35]

WDG/ DF [352

- 581; 84229

- 32] 2 N/S N/S 90 Do not apply through any type of irrigation system. Do not apply to

flooded field with standing water. Application to blueberry foliage will result in crop injury.
Low Bush Blueberry

Spring before leave

emergence Ground Dry Bulk Fertilizer 1 EC [352

- 392;

5905

- 579;

84229

- 35]

WDG/ DF [ 352

- 581 ; 84229

- 32] 3 N/S N/S 450 Do not apply through any type of irrigation

system.

Sugarcane

Pre

- and post

emergent, and layby

Ground

Aerial EC [352

- 392;

84229

- 35]

WDG /DF [352

- 618; 352

- 633 ; 352

- 581 ; 84229

- 32 ] 3.6 (HI)

0.9 (LA) 0.5 (PR) 1.75 (TX) N/S 3.6 (HI) 1.5 (LA) 1 (PR) 1.75 (TX) 180 (HI)

234 (LA) 288 (PR) 234 (TX) Do not feed sugarcane

forage to livestock. Do not apply postemergence over the

top to sugarcane beyond a height of 18

inc hes.
Pineapple

Ground

Aerial

Handheld EC [352

- 392;

5905

- 579;

84229

- 35]

WDG/DF [84229

- 32 ; 352

- 581 ] 3.6 (field

edges and

roadside )

0.036 lbs ai/gallon N/S 3.6 181 Do not exceed 3.6 lbs ai per acre per crop. Intercrop period, post

mulch pre

- plant, post

plant, post

- emergence (3

- 10 months after planting) 1.75

0.0175 lbs ai/gallon
Bermudagrass/Bahiagrass (Industrial Turf Grass)

Ground EC [84229

- 35 ;

5905

- 579 ] WDG/DF [ 352

- 581; 84229

- 32] 1.125 N/S N/S 60 Do not use on lawns, driveways, tennis courts, or other

residential or

recreational areas or golf courses
Pastures; Rangeland

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 11 of 64 Table 3.3 . Summary of Directions for Use of Hexazinone.

Applic. Timing, Type, and Equip. Formulation 1

[EPA Reg. No.] Maximum

Applic.

Rate (lb ai/A) Max. No.

Applic. per

Season Max. Seasonal

Applic. Rate (lb ai/A) PHI (days) Use Directions and

Limitations

Ground EC [352

- 392;

5905

- 579;

84229

- 35] WDG/DF [352

- 581; 84229

- 32] 2 1 2 60 Do not cut treated vegetation for feed, or

graze livestock on

treated areas for 60 days following application at broadcast rates exceeding 4.5 pints per acre. Late winter to early

summer

Hand dispersal

Handheld equipment Pellets 2 [33560

-

41] 4

pellets/plant

600 pellets/acre N/S N/S Apply by hand to the soil around specific plants or in a grid pattern for area control

Non

- Crop Sites: Agricultural Rights of Way/Fence Rows/Hedge Rows; Airport/Landing Fields; Industrial Areas (outdoors); Sewage Disposal Areas; Non

- Crop Sites; Intermittently Flooded Areas/Water; Drainage Systems

Ground

Aerial

Airblast EC [352

- 392;

84229

- 35 ; 5905

- 579 ] 8

(0.32 lb ai/gallon) N/S N/S Do not use on lawns, driveways, tennis courts, or other

residential or recreational areas;

Ground Aerial (helicopter only) or (military installations only) WDG/DF [352

-

626; 84229

- 32;

352

- 581] 2.7

- 8 N/S N/S 60 Not labeled for use on

recreation areas or for direct application to paved areas (surfaces). Do not apply this product through any type of irrigation system. Do not use in nurseries, seed beds or ornamental plantings

Residential areas: Do not apply on areas such as lawns, walks, driveways, or tennis

courts.

Ground

Handheld

Aerial (military installations only) G [352

- 450 ; 81927

- 31 ] 4

- 8

(0.000134 lbs ai/sq ft) N/S N/S 60 For rates above 8 1b per acre, do not cut for forage or hay nor graze

domestic animals for 1

year. Residential areas: Do not apply on areas such as lawns, walks, driveways, or tennis

courts. Hand dispersal

Handheld equipment Pellets 2 [33560

-

41] 7000

pellets/A N/S N/S N/A None

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 12 of 64 Table 3.3 . Summary of Directions for Use of Hexazinone.

Applic. Timing, Type, and Equip. Formulation 1

[EPA Reg. No.] Maximum

Applic.

Rate (lb ai/A) Max. No.

Applic. per

Season Max. Seasonal

Applic. Rate (lb ai/A) PHI (days) Use Directions and

Limitations

2 pellets per

inch of stem

diameter

Christmas Tree Plantations

Pre

- and early post

emergence Ground

Aerial (helicopter only) Chemigation

Handheld EC [352

- 392;

5905

- 579;

84229

- 35] WDG/DF [352

- 626; 84229

- 32;

352

- 581] 2

(0.2 lb ai/gallon) 1 1 N/A Do not apply with air

blast spray equipment.

Do not use in

Christmas tree seed beds or transplant nurseries. Apply only

when trees are dormant

for broadcast applications.

D o not use in nurseries, seed beds, or

ornamental plantings.
Forestry (various) and Forestry and Herbaceous Weed Release

Pre and early post

emergence Ground

Aerial (helicopter only)

Handheld Single Stem

Treatment Tree Injection Dry Bulk Fertilizer 1 EC [352

- 392;

5905

- 579;

84229

- 35]

WDG /DF [352

- 626 ; 352

- 581;

84229

- 32] 4

- 5

2 lbs ai/gallon N/S 5 N/A Single Stem Treatment: Apply at the rate of 2

- 4

rnl for each inch of

stem diameter at breast height. Direct the

treatment to the soil

within 3 feet of the root collar of woody plants

to be controlled.

Tree Injection: Inject 1 ml of undiluted product through the bark of

undesirable trees. Make injections at 4 inch

intervals around the

circumference of the tree. When using tubular injection equipment, inject near the ground level.

Spring or early Fall

Ground

Aerial

Handheld equipment G [352

- 603 ;

81927

- 31; 350

- 450 ] 4.7 (Eastern)

4 (Western) N/S N/S N/A Do not apply this product through any type of irrigation system. Do not use in nurseries, seed beds or ornamental plantings. Do not apply to trees grown for Christmas

trees or ornamentals Late winter to early

summer

Hand dispersal Pellets 2 [33560

- 41] Forestry:

5800 pellets/A

Release: N/S N/S N/A Apply at a rate of 1,700 to 5,800 pellets per acre

for

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 13 of 64 Table 3.3 . Summary of Directions for Use of Hexazinone.

Applic. Timing, Type, and Equip. Formulation 1

[EPA Reg. No.] Maximum

Applic.

Rate (lb ai/A) Max. No.

Applic. per

Season Max. Seasonal

Applic. Rate (lb ai/A) PHI (days) Use Directions and

Limitations

Handheld equipment 3,800 pellets/A preharvest, site preparation, and wildlife openings, and

900 to 3,800 pellets per

acre for release.
1. Bulk fertilizer application rate calculated for the maximum rate on the various labels: 40 pts of liquid product (12 lbs a i hexazinone) per ton of fertilizer OR 16 lbs o f dry flowable product (12 lbs ai) per ton of fertilizer. 2. 700 pellets per pound of Pronone Power Pellet Herbicide with 75% Hexazinone = 0.001071 lbs ai/pellet



### Conclusion The proposed labels for hexazinone are adequate to allow evaluation of the residue data relative to the proposed uses.

3.4 Anticipated Exposure Pathways

Humans may be exposed to hexazinone in food because hexazinone may be applied directly to growing crops. In addition, runoff, soil erosion and/or off

- target spray drift can result in hexazinone reaching surface water and ground water

, both of which can serve as sources of drinking water. Residential handler and post

- application exposure is not expected since hexazinone is currently not registered for non

- occupational use

. In an occupational setting, handlers may be exposed while handling the pesticide prior to application, as well as during application. There is also a potential for post

- application exposure for workers re

- entering

treated sites.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions

to Address Environmental Justice in Min ority Populations and Low

- Income Populations,” ( http://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf ) . As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to

well

- established procedures . In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential

set ting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture (USDA) under the National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). These food consumption patterns are used in pe sticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups, and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for children, youths, and adults entering or playing on treated areas post

- application are evaluated. Exposure risk estimates were not of concern. Further considerations are currently in development, as OPP has

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 14 of 64 committed resources and expertise to the development of specialized software and models that

consi der exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

Hexazinone hazard was previously reviewed by HED’s Hazard Identification Assessment Review Committee in 2002 (TXR# 0051033). New data have been submitted since that review including acute and subchronic neurotoxicity, 28

- day inhalation

, and immunotoxicity studies. The risk assessment team has incorporated these data into this risk assessment and reevaluated the points of departure and toxicity endpoints for the acute and chronic dietary and the occupational and residential scenarios using current policies on select ing endpoints and uncertainty factors.

4.1 Toxicology Studies Available for Analysis

T he toxicology database for hexazinone is complete; no additional data is required. The scientific quality of the database for hexazinone is relatively high and the toxi city profile can be characterized for a wide range of effects, including developmental, reproductive, neurotoxic, carcinogenic, mutagenic, and immunotoxic effects. The toxicity data requirements and toxicity profile are listed in Appendix A. The data from the following studies were used to evaluate the hazard potential of hexazinone :

 Acute lethality studies (oral, dermal, inhalation, primary eye and dermal irritation, and dermal sensitization)

 Acute and subchronic neurotoxicity studies (rats)

 Subchronic or al toxicity studies (rats and dogs)

 28

- day inhalation study (rats)

 21

- day dermal toxicity study (rabbits)

 Developmental (rats and rabbits) and reproductive toxicity (rats) studies

 Chronic oral toxicity studies (rats and dogs)

 Carcinogenicity studies (rats and mice)

 Metabolism studies (rats)

 Mutagenicity battery

 Immunotoxicity study (rats)

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 15 of 64 4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

A metabolism study (MRID 00109237

, 0014016) was conducted to evaluate the absorption, distribution, metabolism, and excretion of hexazinone in CD rats by gavage to groups of one male and one female rat at concentrations of 14 mg/kg or 1000 mg/kg. A third group of two
male and two female rats received unlabeled hexazinone (5 mg/kg/day) in the diet for three

weeks before being given a single 14 mg/kg radiolabe l ed gavage dose.

Mass balance was excellent and ranged from 95

- 102% recovery for all treatment groups. Based on the amount of radiolabel recovered in the urine and cage wash, absorption of the test
material was at least 83% with no dose

- or sex

- dependent differences noted. By 72 hours

after treatment, essentially none of the radiolabeled test material was present in the tissues.

Urine was the primary route of elimination accounting for

~ 83% of the administered dose. Urinary elimination was rapid and ~96% complete within 48 hours of treatment. No
apparent sex or dose

- related differences were found. Fecal excretion was a minor route of elimination, accounting for ~16% of the dose and was rapid with ~95% occurring within 72

hours of treatment. Once again, no apparent sex or dose

- related differences were found. Essentially none of the parent compound was found in the urine or feces of male and female

rats following multiple low

- dose or a single high

- dose treatment with hexazinone.

Three metabolites were identified in the urine of males and females (metabolite A and C,

~ 57% and

~ 28% of identified metabolites, respectively). Two of the metabolites were identical to those found in the feces. The third metabolite (3

- ( cyclohexyl )

- 6

- ( methylamin o )

- 1

- methyl

- 1 , 3,5

- triazine

- 2,4(1H,3H)

- dione) (metabolite B,

~ 9% of urinary metabolites)

resulted from demethylation of the 6

- dimethyl amine group to form a secondary amine

without hydroxylation of the 4

- position on the cyclohexyl ring. Approximately 3% of the

urine metabolites were unidentifie d as polar compounds and 5% were isolated from the hydrolyzed urine, suggesting they ha d undergone glucuronide or sulfate conjugation. No

differences between the sexes or dose groups in the metabolic conversion of hexazinone were found.

4.2.1 Dermal Absorption

No dermal absorption study is available; however, since no dermal hazard has been identified for hexazinone, dermal endpoint s w ere not selected for use in this risk assessment

.

4.3 Toxicological Effects

Body weight decrement and liver toxicity were the most frequent effects shown in studies with hexazinone. Liver toxicity was seen in the chronic dog and mouse studies. Body weight decrement was seen in the chronic and reproductive toxicity studies in rats.

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 16 of 64 In a reproduction study in rats, pup weight decrement occurred at the same dose as parental body weight decrement. No reproductive effects were seen in the study other than pup weight decrement. In the rat developmental toxicity study, developmental effe cts (kidneys with no papillae and misaligned sternebrae) were seen at a higher dose than the dose causing maternal toxicity. In the rabbit study, fetal weight decrements were seen at the same dose that caused maternal weight decreases. Thus, no offspring s usceptibility is seen in rat or rabbit prenatal studies or the rat reproduction study.

The 21

- day dermal study in the rabbit showed mild dermal irritation but no systemic toxicity was

observed at the limit dose. A 28

- day inhalation study in rats showed e ffects in the portal

- of

- entry

as squamous and mucous cell metaplasia at the ventral base of the epiglottis and in the nose, nasal septum and nasopharynx

. In an acute neurotoxicity study, reduced motor activity was

observed in rats of both sexes, and decrea sed body temperature and increased incidences in posture and palpebral closure parameters were observed in females only at the highest dose tested ( 500 mg/

kg)

. In a subchronic neurotoxicity study, no neurotoxicity was observed up to the highest dose tested

. There was no evidence of immunotoxicity in a rat immunotoxicity study.

Hexazinone is classified as " Group D chemical, not classifiable as to human carcinogenicity "

based on WOE considerations in carcinogenicity studies in rats and mi ce and no evidence of mutagenicity

.

Hexazinone has low acute toxicity by the oral ( Toxicity Category III), dermal ( Toxicity Category IV) and inhalation ( Toxicity Category III) routes. Primary eye irritation is severe, causing corneal opacity and moderate i rritation in unwashed eyes ( Toxicity Category I). Hexazinone causes mild skin irritation ( Toxicity Category IV) but it is not a skin sensitizer.

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

There is no evidence of increased quantitati ve or qualitative susceptibility of the young following

in utero and pre

- and post

- natal exposure to hexazinone based on the results from developmental studies conducted with rats and rabbits, as well as a two

- generation reproduct ion study

conducted with ra ts. The risk assessment team concluded that the 10

- fold FQPA Safety Factor may be reduced to 1 x

.

4.4.1 Completeness o f the Toxicology Database

The toxic ology database for hexazinone is complete and adequate to support risk assessments.

4.4.2 Evidence of N eurotoxicity

Hexazinone is not considered a neurotoxic chemical. In an acute neurotoxicity study, reduced motor activity in both sexes and some FOB findings (decreased body temperature and increased incidences in posture and palpebral closure paramete rs) in females were observed at 500 mg/kg on Day 0 only. These findings were considered treatment

- related with an impairment of the overall condition of the animals following a gavage treatment, rather than direct neuro toxic

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 17 of 64 effects of the hexazinone exposure based on the absence of any neurohistopathological changes

in the treated animals and the transient nature of the observed FOB and neurobehavioral assessments. In a subchronic neurotoxicity study, no neurotoxicity was observed in rats fe d dietary concentrations of hexazinone up to the highest dose tested at 273/350 

### mg/kg/day ( males/females, respectively) for 90 days

. In addition, the toxicology database does not reveal any evidence of neurotoxic clinical signs, changes in brain weight, or histopat hology of the nervous system in any study with hexazinone.

4.4.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

The toxicology data on hexazinone provides no indication of enhanced sensitivity of infants and children based on the results from developmental studies conducted with rats and rabbits as well

as a two

- generation reproduction study conducted with rats. No quantitative or qualitative

evide nce of increased susceptibility was seen following in utero or pre

- /post

- natal exposure to rats or rabbits. In the rat developmental toxicity study, developmental effects (kidneys with no papillae and misaligned sternebrae) were seen at a higher dose than the dose causing maternal toxicity. In the rabbit study, fetal weight decrements were seen at the same dose that caused maternal weight decreases. In the two

- generation reproduction study, offspring toxicity (decreased pup weights) was seen at the same dos e that caused parental toxicity.

4.4.4 Residual Uncertainty in the Exposure Datab ase

The exposure database is complete and t here are no residual uncertainties in the expos ure database that would result in an underestimation of risk.

4.5 Toxicity Endpoin t and Point of D eparture Selections

4.5.1 Dose

- Response Assessment

Acute Dietary Endpoint for the General Population (Including Females 13

- 49 Years of Age) : An acute neurotoxicity study in rats (MRID 48931901) was selected with a NOAEL of 125 mg/kg

and a LOAEL of 500 mg/kg based on reduced motor activity in both sexes and reduced body temperature and FOB findings in females. The route and the single exposure of this study are appropriate for acute dietary risk assessment. Previously, a developmental toxic ity study in rats (MRID 40397501) was selected for female 13

- 49 years of ages with a NOAEL of 400 mg/kg/day and a LOAEL of 900 mg/kg/day based on increased incidence of kidneys with no papillae and misaligned sternebrae. The newly established point of depa rture (PoD) of 125 mg/kg from the acute neurotoxicity study is considered protective of this developmental effect which was seen at 900 mg/kg/day (almost 10 folds higher than the PoD). The UF is 100x (10x for interspecies extrapolation, 10x for intraspeci es variation and 1x for FQPA Factor). The aPAD for the general population is 1.25 mg/kg.

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 18 of 64 Chronic Dietary Endpoint for the General Population : An one

- year oral toxicity study in dogs (MRID 42162301) was selected with a NOAEL of 5.0 mg/kg/day and a LOAEL of 41.2/37.6 (M/F) mg/kg/day based on body weight decrements, elevated clinical chemistry values (serum alkaline phosphatase, serum aspartate aminotransferase), and histopathologic lesions of the liver

. An UF of 100x (10x for interspecies extrapolation and 10x for intraspecies variation and 1x for FQPA Factor ) is applied to the NOAEL of 5.0 mg/kg/day to obtain a cRfD of 0.05 mg/kg/day. The population adjusted dose (cPAD) is 0.05 mg/kg/day.

Incidental Oral E xposure (Short

- Term) : A two

- generation reproductio n study in rats (MRID 42066501) was selected with a NOAEL of 12 mg/kg/day and a LOAEL of 117/143 (M/F) mg/kg/day based on offspring toxicity seen as decreased pup weights at birth and during lactation. This study is appropriate for this exposure scenario s ince the sub

- populations of interest (infants, toddlers, and young children) are considered for this endpoint selection. The UF is 100x (10x for interspecies extrapolation, 10x for intraspecies variation and 1x for FQPA Factor).

Dermal Exposure ( Short

- , I ntermediate

- Term) : A 21

- day dermal toxicity study in rabbits (MRID 41309005) is available with a NOAEL of 1000 mg/kg/day (the limit dose) and no systemic toxicity was seen. Since no dermal toxicity was observed at the limit dose and there are no developmen tal toxicity concerns, risk assessment for short

- and intermediate

- term occupational dermal exposure is not necessary.

Dermal Exposure (Long

- Term) : The current use pattern does not indicate a concern for long

term exposure/risk, and no long

- term uses are proposed. Therefore, risk assessment for long

- term dermal exposure is not needed.

Inhalation Exposure ( short and Intermediated

- Term) : A 28

- day inhalation study in rats (MRID 49221101) was selected with a NOAEL of 0.031 mg/L and a LOAEL of 0.11 mg/L based on effects seen in the portal

- of

- entry as squamous and mucous cell metaplasia at the ventral base of the epiglottis and in the nose, nasal septum and nasopharynx. T he NOAEL (0.031 mg/L) is then

converted to a Human Equivalent Concentration (HEC) and Human Equivalent Dose ( HED) based on the portal of entry effects, a ccording to the Agency’s Reference Concentration (RfC)

1994 Methodology for occupational and residential assessments and the latest HED inhalation guidance policy (2014). The uncertainty fa ctor of 30 x was applied (3 x for interspecies extrapolation, 10x for intraspecies variation and a 1 x FQPA SF). The interspecies uncertainty factor was reduced to 3x because of adjustment for species differences that affect pharmacokinetics.

In halation Expo sure (Long

- Term) : The current use pattern does not indicate a concern for long

term exposure/risk, and no long

- term uses are proposed. Therefore, risk assessment for long

- term inhalation exposure is not needed.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 19 of 64 Hexazinone does not pose a dermal risk; therefore

, quantification of dermal r isk is not required. Dietary (food + water) exposure is the only component of an aggregate exposure analysis and

risk assessment. The inhalation exposure was based on port of entry (not systemic effects) and

should not be combined for risk assessment.

4.5.3 Cancer Classification and Risk Assessment Recommendation

HED’s Carcinogenicity Peer Review Committee (CPRC) classified hexazinone as " Group D chemical, not classifiable as to human carcinogenicity” based on the following weight of evidence considerations. In rats, females showed no evidence for carcinogenicity; males showed a significant trend only for thyroid adenomas. In mice, the evid ence of carcinogenicity was equivocal: a positive trend test for liver tumors was observed in female mice, but no significant difference was seen by pair

- wise comparison

. There is n o evidence of mutagenicity for

hexazinone (CPRC Report, July 27, 1994). No quantitative cancer risk assessment is required.

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 20 of 64 4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk

Assessment

Table TABLE 4 .5. 4. 1 Summary of Toxicological Doses and Endp oints for Use in Hexazinone Human

Health Risk As sessments. Exposure
Scenario Point of Departure

,

Uncertainty/FQPA Safety Factors RfD, PAD, LOC for

Risk Assessment Study and Toxicological Effects

Acute Dietary ( All Populations including F emales 13

- 49 Years of Age ) N OAEL = 125 mg/kg/day

UF A = 10x

UF H = 10x FQPA SF = 1x aRfD= 1.25 mg/kg aPAD= 1.25 mg/kg Acute neurotoxicity study in rats

(MRID 48931901) LOAEL= 500 mg/kg based on reduced motor activity in both sexes, decreased body temperature and other FOB findings in females Chronic Dietary ( All P opulations) NOAEL = 5.0 mg/kg/day

UF A = 10x

UF H = 10x FQPA SF = 1x cRfD= 0.05 mg/kg/d cPAD= 0.05 mg/kg/d One

- year oral toxicity study in dogs

(MRID 42162301)

LOAEL = 38 mg/kg/day

, based on decreased body weight and hepatotoxicity as evidence by changes in clinical chemistry parameters and microscopic lesions

. Incidental Oral

- (Short

- Term) NOAEL= 12 mg/kg/day

UF A = 10x

UF H = 10x FQPA SF = 1x LOC for

MOE= 100 Two

- gen reproduction study in rats

(MRID 42066501) Offspring LOAEL= 117 mg/kg/day

based on reduced pup weights at birth and during lactation.

Dermal (Short

- and

Intermediated

- Term) Quantification of dermal risk is not required due to lack of dermal, systemic, or

developmental toxicity concerns. In a 21

- day dermal toxicity study in rabbits, n o systemic toxicity was observed

, NOAEL=1000 mg/kg/day.

Dermal (Long

- Term) No long

- term dermal exposure anticipated from currently use pattern.

Inhalation (Short

- and

Intermediate

- Term) NOAEL= 0.031 mg/ L

HEC=(see below) HED=(see below)

UF A = 3 x UF H = 10x FQPA SF = 1x LOC for

MOE = 3 0 28

- day inhalation study in rats

(MRID 49221101)

LOAEL= 0.11 mg/L/day, based on squamous and mucous cell metaplasia at the ventral base of the epiglottis and in the nose, nasal septum and nasopharynx (portal

- of

entry)

. Occupational handler HEC=0.00391 mg/L Occupational scenarios assigned a breathing rate of 8.3 L/min: HED=0.222 mg/kg/d ay Occupational scenarios assigned a breathing rate of 16.7 L/min: HED=0.447 mg/kg/d ay Occupational scenarios assigned a breathing rate of 29 L/min: HED=0.777 mg/kg/d ay Inhalation (Long

- Term) No long

- term inhalation exposure anticipated from currently use pattern.

Cancer ( O ral, D ermal,

I nhalation) Classification : Group D chemical, not classifiable as to human carcinogenicity

. No quantitative cancer risk assessment is required.

Point of Departure (POD) = data point or estimated point, derived from observed dose

- response data, and used to mark the beginning of extrapolation to determine risk associated with lower environmentally r elevant 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 o f the human population (intraspecies). FQPA SF = FQPA Safety Factor. RfD= reference dose. PAD = population adjusted dose (a = acute, c = chronic). MOE = margin of exposure. LOC = level of concern. HEC = Human equivalent concentration. HED = Human equiv alent dose.

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 21 of 64 4.6 Endocrine Disruption

As required by the Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA ) and the Federal Food, Drug, and Cosmetic Act ( FFDCA ) , EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductiv e, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates

, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its most recent reg ist ration decision for hexazinone

, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p),

hexazinone is subject to the endocrin e screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect prod uced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal

systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems w ill proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and

estab lish a dose

- response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 1 

### and includes some pesticides scheduled for registration review and chemicals foun d in water

. Neither of these lists should be construed as a list of known or likely endocrine disruptors.

For further information on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tie r 1 screening battery, please visit our

website. 2

1 See http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of

chemicals.

2 http://w ww.epa.gov/endo/

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 22 of 64 5 .0 Dietary Exposure and Risk Assessment

5

. 1 Residue of Concern Summary

The qu alitative nature of the residues of hexazinone in plants and animals has been adequately

identified/characterized and is understood. The HED Metabolism Assessment Review Committee (MARC) has reviewed the hexazinone toxicology and metabolism data (meeting dates 01/29/02 and 03/12/02) and recommends th at the tolerance expression and risk assessment for plants should include hexazinone (parent) and metabolites A, B, C, D, and E. The tolerance expression for milk should include hexazinone (parent) and metabolites B, C, C

- 2, and F, and the tolerance expres sion for ruminant tissue should include hexazinone (parent) and metabolites B

and F. The MARC also recommended that for the purposes of risk assessment estimates of dietary exposure and risk should be based on residue estimates of hexazinone and metabolite s B, C, C

- 1, C

- 2, and F for ruminant commodities

. The Agency has determined that tolerances for hexazinone residues in eggs

, poultry and hog tissue s are not required based on the results of the respective poultry metabolism and feeding studies (CFR §180.6 (a)(3)). S ee Appendix B for

names and structures of the metabolites

.

Table 5.1 . Summary of Metabolites and Degradates of Hexazinone

. Matrix Residues included in Risk

Assessment Residues included in Tolerance Expression

Plants Primary

Crop Hexazinone, metabolites A, B,

C, D, and E Hexazinone, metabolites A, B, C, D, and E Rotational Crop Poultry Not Required Not Required

Ruminant Hexazinone, metabolites B, C,

C

- 1, C

- 2 and F Milk

- Hexazinone, B, C, C

- 2 and

F

Tissues

- Hexazinone, B and F Drinking Water Hexazinone and metabolites G3170, A, A

- 1, B, C, D, I (JS472) and 2 (JT677) Not Applicable

5.2 Food Residue Profile

The plant metabolism studies indicate that root uptake is the principal mechanism for the absorption of hexazinone by plants from soils. Hexazinone is translocated through the xylem to the foliage when it blocks the photosynthetic process. The submitted field trial studies demonstrated that, among registered crops, quantifiable residues are only expected in forage,

s tover, hay

, and/ or straw. Also, hexazinone residue of concern may transfer to milk and edible tissues of livestock as a result of ingestion of feed items such as alfalfa forage, hay, and meal ; grass forage and hay; and sugarcane molasses. The data from the limited field trials indicate that quantifiable residues occur in field corn stover and wheat straw.

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 23 of 64 HED reviewed previously submitted field trial data for hexazinone and its metabolites in/on

warm

- season pasture grass forage and hay and the study was deemed adequate. Residue values in the study have a potential impact on the livestock dietary burden; therefore, t he potential dietary exposure to livestock from consuming hexazinone

- treated feedstuffs was re

- calculated using Agency guidance on calcul atin g dietary exposure from the maximum theoretical dietary burden (S. Piper, D427006, June 2, 2015). The dairy cattle feeding study data indicate that the

establis hed tolerances for residues of hexazinone in/on ruminant meat, meat byproducts, and fat

for catt le, goats, horses and sheep livestock commodities should be retained. Based on the dietary burden calculation and the residue profile in the feeding study, the Agency concludes that there are not likely to be quantifiable residues of hexazinone and its met abolites in/on eggs, poultry, and hog commodities , and a Category 3 of 40 CFR§180.6 (a)(3) should remain.

Previously the Agency indicated that extended field rotational crop trials and tolerances for inadvertent hexazinone residues in corn stover, sorghum stover, and wheat straw were required to support a 12

- month rotational interval because the limited field trials indicated that quantifiable residues occur in field corn stover and wheat straw (S. Piper, D380507, August 16, 2010). The Agency has determin ed that the available limited rotational field trial data can be used to established inadvertent tolerances for residues of hexazinone in corn stover, sorghum stover, and wheat straw at 0.50 ppm (Table 2.2.2); therefore, extended field rotational crop tria ls for corn stover, sorghum stover, and wheat straw are no longer required.

5.3 Summary of Environmental Degradation

Based on the available information, hexazinone residues ( parent and degradates ) appear to be persistent and mobile in soil and aquatic environments

. Leaching and runoffs are expected to be primary dissipation routes. Hexazinone is stable to hydrolysis and photolysis and degrades at moderately slow rates under aerobic soil metabolism conditions . Aerobic and anaerobic aquatic

metabolism a nd anaerobic soil metabolism studies show slow degradation for hexazinone

. Consistent with this persistence, f ield dissipation half

- lives were 123 to 154 days for the parent compound in bare ground silt loam, silty clay loam

, and sandy loam soils. Labora tory adsorption data show low water/soil partitioning for hexazinone (K OC 

### = 38

- 77 mL/g ). These data indicate that hexazinone is mobile, thus, combined with its persistence, having stro ng potential to leach to ground water systems, especially in soil syste ms such as loam y and sand y soils that are poor in organic matter.

5 .4 Water Residue Profile

EDWCs for hexazinone were generated using the Surface Water Concentration Calculator (SWCC) computer model, the Pesticide Root Zone Model for Groundwater (PRZM

- GW)

, and

the Screening Concentration in Ground Water (SCI

- GROW) model. Both point estimates and distributions of water residues were provided. EFED shared with HED preliminary EDWCs for the acute and chronic dietary exposures and provided additional refinements

. EFED provided

d aily time series outputs that simulate 29 years of residues of hexazinone in drinking water for

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 24 of 64 various application scenarios (See Tables 5. 5.6 a

- c ). These scenarios encompass both surface water and groundwater for agricultura l and non

- agricultural uses of hexazinone

.

For the hexazinone total toxic residues ( TTRs ; i.e. , hexazinone plus its transformation products), the results of these drinking water a ssessment s show that for surface water, the maximum acute

EDWC is associated with the use on LA sugarcane

. The maximum groundwater screening EDWC for acute exposure is associated with the use on NC coastal rights

- of

- way (Table 5.4a). Additionally, EFED calculated upperbound estimates of the EDWCs associated with hexa zinone TTRs, including the unextracted residues (UERs) observed in the aerobic soil metabolism study (Table 5.4b ). It was noted that when the UERs were included, the peak EDWCs were the same

as for the TTRs without the UERs.

EFED calculated refined groun dwater EDWCs associated with hexazinone TTRs applied on pastures/rangeland rangeland ( 2 lb s ai application rate for WI sand ) . The results presented in

Table 5.4c represent applications on sandy loam or sandy soils), for which the labeled application rate is smaller than for other types of soils.

For the acute assessment, the entire 30

- year distribution of estimated daily concentrations from various scenarios incorporated into the Pesticide Root Zone Model and Exposure Analysis Modeling System (PRZM/EXAM s) were used in the probabilistic analyses. For the chronic assessment, the average residue from each scenario shown in Tables 5 .4 a

- c were used.

Table 5.4 a. Maximum Estimated Drinking Water Concentrations for the Use of

Hexazinone Total Toxic Residues (TTRs, excluding the unextracted residues)

DRINKING

WATER SOURCE (MODEL USED) SCENARIO (USE) (rate modeled per year ) MAXIMUM ESTIMATED DRINKING WATER
CONCENTRATION (EDWC) ( ppb )

Groundwater ( PRZM

- GW ) NC coastal 1 (rights

- of

- way) (8 lb s a.i.) Acute 3090

WI sand 1 (rights

- of

- way) (8 lb s a.i.) Chronic 2260

Surface water (SWCC ) LA sugarcane with HI meteorological file

(sugarcane in HI) (3.6 lb s a.i.) Acute 502

Chronic 206

Cancer 77.3

1 Scenario was used as a surrogate and run with the maximum application rate for rights

- of

- ways

.



### Table 5.4 b. Maximum Estimated Drinking Water Concentrations for the Use of

Hexazinone Total Toxic Residues (TTRs), including the Unextracted R esidues (UERs) (these EDWCs provide an upperbound estimate of the TTRs)

DRINKING

WATER SOURCE (MODEL USED) SCENARIO (USE) (rate modeled per year ) MAXIMUM ESTIMATED DRINKING WATER
CONCENTRATION (EDWC) ( ppb )

Groundwater ( PRZM

- GW ) NC coastal 1 (rights

- of

- way) (8 lb s a.i.) Acute 3,710

Chronic 2,600

Surface water (SWCC ) LA sugarcane with HI meteorological file

(sugarcane in HI) (3.6 lb s a.i.) Acute 502

Chronic 207

Cancer 77.6

1 Scenario was used as a surrogate and run with the maximum application rate for rights

- of

- ways

.



### Table 5.4 c. Refined Estimated Groundwater Drinking Water Concentrations for the Use of Hexazinone, for the TTRs

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 25 of 64 DRINKING

WATER SOURCE (MODEL USED) SCENARIO (USE) (rate modeled per year) MAXIMUM ESTIMATED DRINKING WATER
CONCENTRATION (EDWC) ( ppb )

Groundwater (PRZM

- GW) NC coast al 1 (pastures/rangeland) (2 lb s a.i.) Acute 773

WI sand 1 (pastures/rangeland) (2 lb s a.i.) Chronic 564

1 Scenario was used as a surrogate and run with the prescribed application rate for sandy loam and loamy sand soils on pasture/rangeland.



### 5

. 5 Dietary Risk Assessment

5. 5 .1. Description of Residue Data Used in Dietary Assessment

U pdated acute and chronic dietary ( food and drinking water ) exposure and ris k assessments were conducting 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 USDA’s NHANES/WWEIA. The drinking water estimates provided by EFED are modeled estimates, and were generated using the most conservative model availabl e for the existing uses. The partially refined assessments assumed anticipated residues, DEEM default processing factors, and 100% crop treated ( P CT) for the acute assessment and average PCT data

for the chronic assessment . The acute and chronic approach to dietary risk exposure analysis will not underestimate risk to the general U.S. population or any population subgroup.

5. 5 .2 Percent Crop Treat ed Used in Dietary Assessment

The Biological and Economic Analysis Division (BEAD) has provided an updated Screening Level Usage Analysis (SLUA) for hexazinone ( J. Alsadek, 01/22/2015 ) which includes both an average and maximum P CT for the established us es.

For the acute dietary exposure assessment, maximum percent crop treated values were provided for the following commodities: alfalfa ( 5%); blueberries (15%); and sugarcane (10%); however, 100% CT was assumed. For the chronic dietary exposure assessment, the average percent crop treated values were used for the following commodities: alfalfa (5%), blueberries (10%) and sugarcane (5%). Also, 5% CT (from alfalfa/sugarcane) was assumed for livestock commodities.

5. 5 .3 Acute Dietary Risk Assessment

The food only dietary exposure estimates contribute 83% of the aPAD at the 95 th 

### percentile for

children 1

- 2 years, the most highly exposed population subgroup. The acute aggregate (food and drinking water) die tary exposure estimates for the va rious scenarios are below HED’s level of concern (<100 % aPAD) for the U.S. population and all population subgroups. T he worst

- case scenario (NC coastal rights

- of

- ways using the PRZM

- GW distribution) resulted in combined dietary exposure and risk estimates from food and drinking water at the 95 th 

### percentile that

utilized 23 % of the aPAD for the U.S. population and 73 % of the aPAD for children 1

- 2 years old, the most highly exposed population subgroup. The summary results for the general population and all population subgroups are shown below in Table 5. 5 .6

.

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 26 of 64 5. 5 .4 Chronic Dietary Risk Assessment

The food only dietary exposure estimates contribute 37% of the chronic population adjusted dose (c PAD ) for children 1

- 2 years, the most highly exposed population subgroup. Combined chronic dietary exposure estimates for food and drinking water using the surface water LA sugarcane scenario are below HED’s level of concern. Using the DEEM

- FCID software, d ietary exposure

is estimated to be 1 4 % of the cPAD for the U.S. population, and 50 % of the cPAD for children

1

- 2 years old, the population with highest estimated chronic dietary exposure to hexazinone for

the LA sugarcane water scenario

.

For the chronic P RZM

- GW rights

- of

- ways scenarios, some of the scenarios exceeded the levels of concern when using higher rates (8 lb s ai /A)

. Further examination of the labels indicated that

for m ajority of uses the maximum labeled application rate is lower for coarse text ured soil s, like

the soils in all PRZM

- GW scenarios. W hen u sing t he refined EDWC s at a 2 lb s ai /A application

rate

, which is the maximum labeled rate for pasture s /rangeland for coarse textured soils, for WI

sand PRZM

- GW scenario, the dietary exposure is estimated to be 29 % of the cPAD fo r the U.S. population, and 7 1% of the cPAD for children 1

- 2 years old, the population with the highest estimated chronic dietary exposure to hexazinone. The summary res ults for the general population and all population subgroups are shown below in Table 5. 5 .6 c

.

5. 5 .5 Cancer Dietary Risk Assessment

Hexazinone is classified as “ Likely at high doses, but unlikely to be carcinogenic to humans at

low doses .” Therefore, a ca ncer dietary exposure analysis is not required.

5. 5 .6 Dietary Summary Table

The acute and chronic dietary exposure and risks for hexazinone are summarized below. Only the population with the highest risk was shown (See dietary memo for detailed summary of all population subgroups).

Table 5. 5 .6a. Summary of Acute Dietary (Food and Drinking Wa ter) Exposures and Risks

for Hexazinone using Surface Water

Drinking Water

Scenario App.

Method App.

Rate (lb
a.i./A) Surface Waters EDWCs (ppb) Acute Food and Water Exposure and Risk Estimates at

95 th Percentile Acute (1

- in

10

- year) Chronic (1

- in

- 10

- year) Cancer

30

- year Daily Average National

PCA 1
(fraction) Population

Subgroup 2 Exposure

(mkd) %

PAD

Tier II Estimated Drinking Water Concentrations (EDWCs) for Surface Water Based on Application of Hexazinone Products Modeled in the SWCC, for the TTRs (Excluding the UERs)

NC

alfalfa /Alfalfa Aerial 1.5 35.5 11.2 5.81 1.00 2 Children

1

- 2 0.855439 68

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 27 of 64 Drinking Water

Scenario App.

Method App.

Rate (lb a.i./A) Surface Waters EDWCs (ppb) Acute Food and Water Exposure and Risk Estimates at

95 th Percentile Acute (1

- in

10

- year) Chronic (1

- in

- 10

- year) Cancer

30

- year Daily Average National

PCA 1
(fraction) Population

Subgroup 2 Exposure

(mkd) %

PAD

LA sugarcane (HI met file)/Sugarcane in

HI Aerial 3.6 502 206 77.3 1.00 2 Children

1

- 2 0.856927 69

CA wine grape /

Blueberries Ground 2 20.9 12.7 8.58 1.00 2 Children

1

- 2 0.856279 69

CA rights

- of

way/CA impervious /Non

crop sites (weed

and brush
control) Aerial

helicopt

er 6 204 88.0 45.2 1.00 3 Children

1

- 2 0.856093 68

CA rights

- of

way/CA impervious /Non

crop sites (weed

and brush
control) Ground 8 260 112 52.5 1.00 3 Children

1

- 2 0.856155 68

CA forestry (MI met file)/Conifer

release in Eastern

and Lakes states Aerial

helicopt

er 4 103 84.9 64.6 1.00 3 Children

1

- 2 0.856599 69

OR Christmas

trees / Christmas

trees Aerial 2 28.9 21.8 18.8 1.00 3 Children

1

- 2 0.857025 69

CA rangeland hay (NY met file)/Pastures/ Rangeland in

Eastern US Aerial

helicopt

er 4 159 71.9 36.5 1.00 3 Children

1

- 2 0.856597 69

PA

turf /Bermudagra ss/ Bahiagrass;

Industrial turfgrass Ground 1.125 10.4 8.24 6.05 1.00 2 Children

1

- 2 0.856134 69

Tier II Estimated Drinking Water Concentrations (EDWCs) for Surface Water Based on Application of

Hexazinone Products Modeled in the SWCC, for TTRs + UER
LA sugarcane (HI met file)/Sugarcane in

HI Aerial 3.6 10

- 01 502 207 77.6 Children

1

- 2 0.856600 69

PA turf / Bermudagrass/ Bahiagrass;

Industrial turfgrass Ground 1.125 01

- 03 10.4 8.25 6.06 Children

1

- 2 0.856595 69

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 28 of 64 Drinking Water

Scenario App.

Method App.

Rate (lb a.i./A) Surface Waters EDWCs (ppb) Acute Food and Water Exposure and Risk Estimates at

95 th Percentile Acute (1

- in

10

- year) Chronic (1

- in

- 10

- year) Cancer

30

- year Daily Average National

PCA 1
(fraction) Population

Subgroup 2 Exposure

(mkd) %

PAD

Bolded values represent the highest EDWCs in surface waters.

1 Guidance on Development and Use of Community Water System Drinking Water Intake Percent Cropped Area Adjustment Factors for use in Drinking Water Exposure Assessments: 2014 Update, dated 09/09/2014 and approved 09/12/2014.

2 PCA for Turf

- All Agriculture.

3 No PCAs have been issued for these non

- agricultural uses.



### Table 5. 5 .6b. Summary of Acute Dietary (Food and Drinking Wa ter) Exposures and Risks

for Hexazinone using Ground Water

Drinking Water Scenario Highest Daily

Value (ppb) Post

Breakthrough Average (ppb) Cancer 30

-

year Daily Average (ppb) Acute Food and Water

Exposure and Risk Estimates

at 95 th Percentile
Population Subgroup Exposure

(mkd) %

PAD


### Hexazinone Ground Water Estimated Drinking Water Concentrations (EDWCs) Resulting from the Use of the Chemical on Rights

- of

- Ways, for the TTRs+UERs
Rights

- of

- way/Tier I

Delmarva 2760 2110 1752 Children 1

- 2 0.856595 69

Rights

- of

- way/Tier I FL

Citrus 2390 1990 1294 Children 1

- 2 0.862892 69

Rights

- of

- way/Tier I FL

Potato 1530 1250 1800 Children 1

- 2 0.870681 70

Rights

- of

- way/Tier I GA

Coast 1060 852 2166 Children 1

- 2 0.862892 69

Rights

- of

- way/Tier I NC

Coast al 3710 2600 2485 Children 1

- 2 0.909053 73

Rights

- of

- way/Tier I WI

Sand 2680 2390 3141 Children 1

- 2 0.899158 72

Bolded values represent the highest EDWCs in surface waters.

1 Guidance on Development and Use of Community Water System Drinking Water Intake Percent Cropped Area Adjustment Factors for use in Drinking Water Exposure Assessments: 2014 Update, dated 09/09/2014 and approved 09/12/2014.

2 PCA for Turf

- All Agriculture.

3 No PCAs have been issued for these non

- agricultural uses.



### T able 5. 5 .6c. Summary of Chronic Dietary (Food and Drinking Wa ter) Exposures and

Risks for Hexazinone

Drinking Water Scenario Post Breakthrough Average (ppb) Chronic Food and Water Exposure and Risk Estimates
Population Subgroup Exposure

(mkd) % PAD



### Maximum EDWCs for the use of Hexazinone Total Toxic Residues for the TTR

PRZM

- GW NC Coastal (rights

- of

- way) (8 lb s ai) 2 260 All Infants 0.12 6765 25 4

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 29 of 64 Drinking Water Scenario Post Breakthrough Average (ppb) Chronic Food and Water Exposure and Risk Estimates
Population Subgroup Exposure

(mkd) % PAD



### SWCC LA Sugarcane with HI meterological file
(3.6 lb s ai) 206 Children 1

- 2 0.02 4752 5 0

Groundwater EDWCs Resulting from the use of the Chemical on Rights

- of

- Ways for the TTR Rights

- of

- way Tier1 FL Potatoes 951 All Infants 0.05 6090 1 12 Rights

- of

- way Tier1 GA Coast 765 All Infants 0.04 0637 9 2 Groundwater EDWCs Resulting from the use of the Chemical on Rights

- of

- Ways for the TTR +

UERs Rights

- of

- way Tier1 GA Coast 852 All Infants 0.051936 104 Rights

- of

- way Tier1 FL Potatoes 1250 All Infants 0.07223 4 14 5

PRZM

- GW NC Coastal (rights

- of

- way) (8 lb s ai) 2600 All Infants 0.14512 2 29 0 Refined Estimated Groundwater Drinking Water Concentrations for the Use of Hexazinone for

the TTRs WI Sand (pastures/rangeland) (2 lb s ai) 564 Children 1

- 2 0.0 35565 7 1



### 6.0 Residential Exposure and Risk Estimates

There are no proposed or registered residential uses of hexazinone at this time , therefore no quantitative residential exposure assessment was performed. T he re are existing occupational

uses that could result in drift onto residential areas and result in potential residential post

application exposure. A residential spray drift assessment was performed for the highest application rate scenario s

.

6. 1 Spray Drift

Off

- target movement of pesticides can occur via many types of pathways and it is governed b y a variety of factors. Sprays that are released and do not deposit in the application area end up off

target and can lead to exposures to those it may directly contact. They can also deposit on surfaces where contact with residues can eventually lead to exposures (e.g., children playing on lawns where residues have deposited next to treated fields). The potential risk estimates from these residues can be calculated using drift modeling coupled with methods employed for

residential risk assessments for t urf products.

The approach to be used for quantitatively incorporating spray drift into risk assessment is based on a premise of compliant applications which, by definition, should not result in direct exposures to individuals because of existing label la nguage and other regulatory requirements intended to

prevent them. 3 

### Direct exposures would include inhalation of the spray plume or being sprayed directly. Rather, the exposures addressed here are thought to occur indirectly through contact with impact ed areas, such as residential lawns, when compliant applications are conducted.

3 This approach is consistent with the requirements of the EPA’s Worker Protection Standard.

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 30 of 64 Given this premise, exposures for children (1 to < 2 years old) and adults who have contact with turf where residues are assumed to have deposited via spray drift thus resulti ng in an indirect exposure are the focus of this analysis analogous to how exposures to turf products are

considered in risk assessment.

In order to evaluate the drift potential and associated risks, an approach based on drift modeling coupled with techniques used to evaluate residential uses of pesticides was utilized. Essentially, a residential turf assessment based on exposure to deposi ted residues has been completed to address drift from the agricultural applications of hexazinone

. In the spray drift scenario, the deposited residue value was determined based on the amount of spray drift that may occur at varying distances from the edge of the treated field using the AgDrift (v2.1.1) model and the Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift Policy . Once the deposited residue values were determined, the remainder of the spray drift assessment was based on the algorithms and input values specified in the recently revised (2012) Standard Operating Procedures f or Residential Risk Assessment (SOPs)

.

A screening approach was developed based on the use of the AgDrift model in situations where specific label guidance that defines application parameters is not available. 4 

### AgDrift is appropriate for use only when applications are made by aircraft, airblas t orchard sprayers, and groundboom sprayers. When AgDrift was developed, a series of screening values (i.e., the Tier 1 option) were incorporated into the model and represent each equipment type and use under varied conditions. The screening options spec ifically recommended in this methodology were selected because they are plausible and represent a reasonable upper bound level of drift for common application methods in agriculture. These screening options are consistent with how spray drift is considere d in a number of ecological risk assessments and in the process used to develop drinking water concentrations used for risk assessment. In all cases, each scenario is to be evaluated unless it is not plausible based on the anticipated use pattern (e.g., h erbicides are not typically applied to tree canopies) or specific label prohibitions (e.g., aerial applications are not allowed).

In many cases, risks are of concern when the screening level estimates for spray drift are used as the basis for the analys is. In order to account for this issue and to provide additional risk management options additional spray drift deposition fractions were also considered. These drift estimates represent plausible options for pesticide labels

6. 2 Risk Estimates f

rom La wn Deposition Adjacent to Agricultural Applications

Hexazinone is used on numerous agricultural crops and can be applied via aerial and groundboom equipment. The pesticide is also registered on non

- agricultural crop sites such as

forestry areas and rig hts of ways. For the non

- crop sites, hexazinone can be applied via aerial, groundboom, and airblast equipment. For the purposes of the spray drift assessment, the most protective agricultural use rates as well as the non

- agricultural crop sites (e.g., fo restry and non

crop sites) are assessed. The spray drift risk estimates are based on an estimated deposited

4 http://www.agdrift.com/

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 31 of 64 residue concentration as a result of the screening level agricultural application scenarios. The recommended drift scenario screening level option s are listed below:

 Groundboom applications are based on the AgDrift option for high boom height and using very fine to fine spray type using the 90 th 

### percentile results.

 

### Aerial applications are based on the use of AgDrift Tier 1 aerial option for a fi ne to medium spray type and a series of other parameters which will be described in more detail below (e.g., wind vector assumed to be 10 mph in a downwind direction for entire application/drift event). 5



###  Orchard airblast applications are based on the AgDrift option for Sparse (Young/Dormant) tree canopies.

Only the incidental oral risk estimates for children 1<2 years old were calculated for hexazinone because no adverse systemic effect was identified in the dermal toxicity study. Children’s (1<2

yea r s old) incidental oral risk estimates from indirect exposure to hexazinone related to spray drift result in buffers of 0 feet for groundboom and aerial applications, and were not of concern. The highest exposure resulted from drift following hexazinone a pplications using aerial equipment for children 1 to <2 years ol d where the MOE is 380 , with a LOC =100

. See Table

5.1.2 for detailed results.

5 AgDrift allows for consideration of even finer spray patterns characterized as very fine to fine. However, this

sp ray pattern was not selected as the common screening basis since it is used less commonly for most agriculture. If assessors identify this use pattern it should be used as the screening criteria and deposition values associated with it are provided in Tab le 1 below. Justification for including this spray quality should be included in any assessment based on specific label directions for its use.

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 32 of 64 Table 5.1.2. Children Incidental Oral Risk Estimates (MOEs) Related to Spray Drift Exposure to Hexazinone from the Registered Agricultural Uses. 1,2

Crop/Rate Group Spray Type/ Nozzle Configuration Application Rate (lbs ai/A) Estimated or

Adjusted TTR t (ug/cm2) At Edge

HtM MOE

Non

- Crop Sites

Aerial Fine to Medium

8 0.8892 380

Groundboom High Boom Very fine to Fine 530

Airblast Sparse 690

Forestry 3

Aerial Fine to Medium 5 0.55575 610

Groundboom High Boom Very fine to Fine 840

Sugarcane

Aerial Fine to Medium 3.6 0.40014 850

Groundboom High Boom Very fine to Fine 1,200

1. The highest application rate for an agricultural crop application is for aerial and ground applications to sugarcane use sites with an application rate of 3.6 lbs ai per acre. This use site and application equipment is representative of the other currently registered crop use sites.

2. The full spray drift risk estimate table, including various levels of nozzle type and release height can be found in Appendix E.

3. There is some uncertainty associated with the drift predictio ns associated with forestry uses because in some situations pesticides like hexazinone are applied in rugged terrain using rotary aircraft and smaller droplets. A more appropriate modeling approach is currently under development for such situations. Even

s o, this would not alter the risk conclusions for the current human health risk assessment spray drift scenario because, in the case of hexazinone, if the 100% of application rate assumption is used rather than the screening level assumptions, there would b e no risks of concern for the incidental oral risk estimates for

children.



### 6.3 Residential Bystander Post

- Application Inhalation Exposure



### Volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The A gency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fu ngicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/ 2009/120109meeting.html). The

A gency has evaluated the SAP report and has develope d a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis 6 

### . During Registration Review , the A gency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is required for hexazinone.

6 Available at: http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219

.

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 33 of 64 7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, H ED considers both the route and duration of exposure.

For hexazinone , there are currently no registered residential uses, nor are any proposed. Therefore, at this time, dietary (food + water) exposure is the only component of an aggregate

exposure analysis and risk assessment. As shown in Sections 5. 5 .3 and 5. 5 .4, there are no aggregate dietary (food plus water) risks of concern for hexazinone when further refined

.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as

to hexazinone and any other substances. For the purposes of this assessment, therefore, EPA has

not assumed tha t hexazinone has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy stateme nts released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on

EPA’s website at http://www.epa.gov/pesticides/cumulative/

.

9 .0 Occupational Exposure and Risk Estimates

9 .1 Occupational Handler Exposure/Risk Estimates

HED uses the term handlers to describe those 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 t ask. 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 and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the registered u ses.

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 34 of 64 The quantitative exposure and risk assessment developed for o ccupational handlers is based on

the scenarios listed in Table 9 .1.1.

Occupational Handler Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the occupational

handler risk assessments. Each ass umption and factor is detailed below on an individual basis.

Application Rate : The maximum single application rates are listed in Appendix D

.

Unit Exposures: It is the policy of HED to use the best available data to assess handler exposure.

Sources o f 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 subjec t 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 R eference Table 7 

### ”, 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 8



### .

For the dry bulk fertilizer scenarios, HED assumed a closed mixing/loadi ng scenario for commercial impregnation of dry bulk fertilizer, and an open mixing/loading scenario for grower

owned equipment impregnation of dry bulk fertilizer. For all applications of dry bulk fertilizer, HED assumed the use of an open

- cab spreader.

A rea Treated or Amount Handled: The area treated or amount handled is based on HED ExpoSAC Policy 9.1. HED does not have data regarding the mixing/loading or the application

of hexazinone

- impregnated dry bulk fertilizer. The mixing/loading processing ra te for commercial impregnation of dry bulk fertilizer has been estimated to be 960 tons of fertilizer processed per 8 hour day based on information supplied by a registrant concerning the chemical alachlor (as referenced in its reregistration eligibility d ocument (RED ) document). Mixing/loading for on

- farm impregnation of dry bulk fertilizer was then assessed using an estimate of 160 acres/day. Application of dry bulk fertilizer was assessed assuming application to up to 320 acres/day for commercial equip ment and 160 acres/day for grower

owned equipment.

The amount/area treated for each scenario is listed in the Occupational Handler Table ( Table

9.1 .1).

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

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

- exposure

- table.pdf

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

- exposure

- data.html

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 35 of 64 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 la rge 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 hexazinone , based on the registered use pattern , short

- and intermediate

- ter m exposures are expected. However, since the short

- and intermediate

- term inhalation POD is the same for both durations, the assessment is protective of both durations.

Mitigation/Personal Protective Equipment: Estimated inhalation exposure were calculated for

various levels of PPE. According to the currently registered hexazinone labels, o ccupational

handlers must wear baseline attire and chemical

- resistant gloves. Results are presented for

“baseline”, defined as a s ingle layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator, as well as baseline with various levels

of inhalation PPE as nec essary (e.g., PF5 respirator and PF10 respirator) as well as engineering

controls.

Summary of Occupational Handler Non

- Cancer Exposure and Risk Estimates

There are some occupational handler risk estimates of concern for the registered uses of hexazinone at baseline, PPE, and engineering control mitigation. The L OC for occupational handler inhalation risk estimates is a MOE of 30. At baseline, occupational inhalation MOEs ranged from 0.8 to 9,600. A summary of risk estimates is provided in Table 9.1.1.

The tree injection use directions do not indicate that the formulation for tree injection is in a ready to use packaging therefore its anticipated that a handler may mix and load the formulation for the tree injection application. This mixing and loading exposure scenario has been assessed for ground application to forestry use sites and should be considered a surrogate for the tree injection application.

In general, the mixing and loading handler activities with the dry flowable and water dispersible granular formulations result in MOEs of concern at baseline attire with no respirator. Below is a summary of the scenarios grouped by formulation and PPE:

The following mixing/loading dry flowable scenarios are not of concern with the use of a PF5 respirator :

 A erial application for bermudagrass/ bahiagrass;

 A irblast for non

- crop areas;

 C hemigation application for pineapple and alfalfa; and

 A ll groundboom applications

.

The following mixing/loading dry flowable scenarios are not of concern with the use of a PF10 respirator :

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 36 of 64  A erial application for pasture/ran geland, blueberry (low and high bush ), pineapple, and christmas tree;

 C hemigation application for sugarcane and christmas tree ; and,

 Groundboom application for sugarcane.

The following mixing/loading dry flowable scenarios are not of concern with the use of Engineering Controls:

 A erial application for non

- crop areas, forestry, alfalfa, and sugarcane.

 Impregnation of dry bulk fertilizer for on

- farm treatment.

The following mixing/loading dry flowable scenarios are of concern with the use of E ngineering

Controls:

 Impregnation of dry bulk fertilizer for commercial treatment.

The following mixing/loading granule scenarios are not of concern with the use of a PF5 respirator :

 Aerial application for non

- crop and forestry use sites.

The following m ixing/loading liquid scenarios are not of concern with the use of a PF5 respirator:

 Aerial application for forestry use sites.

The following mixing/loading liquid scenarios are of concern with the use of Engineering

Controls:

 Impregnation of dry bulk fertilizer for commercial treatment.

In general, the applicator handler activities do not result in MOEs of concern at baseline attire with no respirator, with the exception of the following:

The following applicator liquid scenarios are not of concern with the use of a PF5 respirator :

 Airblast application for non

- crop use sites.

The following applicator granule scenarios are of concern with the use of Engineering Controls:

 Aerial application for non

- crop and forestry use sites.

The following applicat or pellet formulation are not of concern with the use of a PF5 respirator :

 Hand dispersal application for non

- crop and forestry use sites.

In general, the mixer/loader/applicator activities do not result in MOEs of concern at baseline attire with no respi rator, with the exception of the following:

The following mixer/loader/applicator scenarios are not of concern with the use of a PF5 respirator :

 Dry flowable and liquid formulation with mechanically

- pressurized handgun for forestry

use sites.

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 37 of 64 

Table 9 .1.1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Hexazinone.

Exposure

Scenario Crop or Target Inhalation Unit Exposure (μg/lb ai) 1

Maximum
Application

Rate 2 Area

Treated or

Amount

Handled Daily 3 Inhalation Risk Estimates 4 (LOC = 30)

Baseline PF5 PF10 Engineering

Controls Baseline

MOE PF5

MOE PF10

MOE Engineering

Control

MOE

Mixer/Loader

Mixer/Loader Dry

Flowable/Water Dispersible

Granules for Aerial Application Bermudagrass/

Bahiagrass

8.96 1.792 0.896 0.24 1.125

350 10 51 100 660

Pastures/ rangeland 2 5.7 29 57 370

Non

- Crop 8 1.4 7.1 14 93

Low bush blueberry 2 5.7 29 57 370

High bush blueberry 3 3.8 19 38 250

Pineapple 1.75 6.5 32 65 420

Christmas Tree 2 5.7 29 57 370

Forestry 5

1200 0.66 3.3 6.6 43

Alfalfa 1.5 2.2 11 22 140

Sugarcane 3.6 0.92 4.6 9.2 60

Mixer/Loader Dry

Flowable/Water Dispersible

Granules for

Airblast Application Non

- crop 8.96 1.792 0.896 0.24 8 40 12 62 120 810

Mixer/Loader Dry

Flowable/Water Dispersible

Granules for Chemigation Application Pineapple

8.96 1.792 0.896 0.24 1.75

350 6.5 32 65 420

Christmas Tree 2 5.7 29 57 370

Alfalfa 1.5 7.6 38 76 490

Sugarcane 3.6 3.2 16 32 210

Mixer/Loader Dry

Flowable/Water Dispersible

Granules for

Groundboom Application Bermudagrass/

Bahiagrass

8.96 1.792 0.896 0.24 1.125

80 44 220 440 2900

Pastures/ rangeland 2 25 120 250 1600

Non

- Crop 8 6.2 31 62 400

Low bush blueberry 3 17 83 170 1100

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 38 of 64 Table 9 .1.1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Hexazinone.

Exposure

Scenario Crop or Target Inhalation Unit Exposure (μg/lb ai) 1

Maximum
Application

Rate 2 Area

Treated or

Amount

Handled Daily 3 Inhalation Risk Estimates 4 (LOC = 30)

Baseline PF5 PF10 Engineering

Controls Baseline

MOE PF5

MOE PF10

MOE Engineering

Control

MOE

High bush blueberry 2 25 120 250 1600

Pineapple 1.75 29 140 290 1900

Christmas Tree 2 25 120 250 1600

Forestry 5 10 50 100 650

Alfalfa 1.5 200 13 66 130 860

Sugarcane 3.6 5.5 28 55 360

Mixer/Loader

Granules for Aerial Application Non

- crop 1.7 0.34 0.17 0.083 8 350 13 65 130 270

Forestry 4.7 1200 6.5 32 65 130

Mixer/Loader

Granules for

Ground Application Non

- crop

1.7 0.34 0.17 0.083 8 80 57 280 570 1200

Forestry 4.7 80 97 490 970 2000

Mixer/Loader Liquids for Aerial Application Bermudagrass/bahiag

rass

0.219 0.0438 0.0219 0.083 1.125

350 410 2100 4100 1900

Pastures/ rangeland 2 230 1200 2300 1100

Low bush blueberry 3 160 780 1600 710

High bush blueberry 2 230 1200 2300 1100

Pineapple 1.75 270 1300 2700 1200

Non

- crop 8 58 290 580 270

Christmas Tree 2 230 1200 2300 1100

Forestry 5

1200 27 140 270 120

Alfalfa 1.5 91 450 910 420

Sugarcane 3.6 38 190 380 170

Mixer/Loader Liquids for

Airblast Application Non

- crop

0.219 0.0438 0.0219 0.083 8 40 510 2600 5100 2300

Mixer/Loader Pineapple 0.219 0.0438 0.0219 0.083 1.75 350 270 1300 2700 1200

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 39 of 64 Table 9 .1.1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Hexazinone.

Exposure

Scenario Crop or Target Inhalation Unit Exposure (μg/lb ai) 1

Maximum
Application

Rate 2 Area

Treated or

Amount

Handled Daily 3 Inhalation Risk Estimates 4 (LOC = 30)

Baseline PF5 PF10 Engineering

Controls Baseline

MOE PF5

MOE PF10

MOE Engineering

Control

MOE

Liquids for Chemigation Application Christmas Tree 2 230 1200 2300 1100

Alfalfa 1.5 310 1600 3100 1400

Sugarcane 3.6 130 650 1300 590

Mixer/Loader Liquids for

Groundboom Application Bermudagrass/

bahiagrass

0.219 0.0438 0.0219 0.083 1.125

80 1800 9100 18000 8300

Pastures/ rangeland 2 1000 5100 10000 4700

Low bush blueberry 3 680 3400 6800 3100

High bush blueberry 2 1000 5100 10000 4700

Pineapple 1.75 1200 5800 12000 5400

Non

- crop 8 260 1300 2600 1200

Christmas Tree 2 1000 5100 10000 4700

Forestry 5 410 2000 4100 1900

Alfalfa 1.5 200 540 2700 5400 2500

Sugarcane 3.6 230 1100 2300 1000

Mixer/Loader Dry

Flowable/Water Dispersible

Granules for Impregnation for

Bulk Fertilizer Application Alfalfa

No Data No Data No Data 0.24 12 lbs ai/ton

960 tons
(Commercial Treatment) No Data No Data No Data 6.4

Low bush blueberry 24 lbs ai/ton No Data No Data No Data 3.2

High bush blueberry 16 lbs ai/ton No Data No Data No Data 4.8

Forestry 32 lbs ai/ton No Data No Data No Data 2.4

Alfalfa

8.96 1.792 0.896 0.24 12 lbs ai/ton

160 tons

(On Farm Treatment) 2.1 10 21 130

Low bush blueberry 24 lbs ai/ton 1 5.2 10 68

High bush blueberry 16 lbs ai/ton 1.6 7.8 16 100

Forestry 32 lbs ai/ton 0.78 3.9 7.8 50

Mixer/Loader Liquids for Impregnation for

Bulk Fertilizer Application Alfalfa

No Data No Data No Data 0.083 12 lbs ai/ton

960 tons

(Commercial Treatment) No Data No Data No Data 19

Low bush blueberry 24 lbs ai/ton No Data No Data No Data 9.3

High bush blueberry 16 lbs ai/ton No Data No Data No Data 14

Forestry 32 lbs ai/ton No Data No Data No Data 7

Alfalfa 0.219 0.0438 0.0219 0.083 12 lbs ai/ton 160 tons 85 430 850 390

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 40 of 64 Table 9 .1.1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Hexazinone.

Exposure

Scenario Crop or Target Inhalation Unit Exposure (μg/lb ai) 1

Maximum
Application

Rate 2 Area

Treated or

Amount

Handled Daily 3 Inhalation Risk Estimates 4 (LOC = 30)

Baseline PF5 PF10 Engineering

Controls Baseline

MOE PF5

MOE PF10

MOE Engineering

Control

MOE

Low bush blueberry 24 lbs ai/ton (On Farm Treatment) 43 210 430 190

High bush blueberry 16 lbs ai/ton 64 320 640 290

Forestry 32 lbs ai/ton 32 160 320 150

Applicator

Applicator for Sprays via Aerial Application Bermudagrass/

bahiagrass

No Data No Data No Data 0.0049 1.125

350 No Data No Data No Data 9200

Pastures/ rangeland 2 No Data No Data No Data 5200

Low bush blueberry 3 No Data No Data No Data 3400

High bush blueberry 2 No Data No Data No Data 5200

Pineapple 1.75 No Data No Data No Data 5900

Non

- crop 8 No Data No Data No Data 1300

Christmas Tree 2 No Data No Data No Data 5200

Forestry 5

1200 No Data No Data No Data 600

Alfalfa 1.5 No Data No Data No Data 2000

Sugarcane 3.6 No Data No Data No Data 840

Applicator for Sprays via Airblast Application Non

- crop 4.71 0.942 0.471 0.068 8 40 12 59 120 810

Applicator for Sprays via

Groundboom Application Bermudagrass/

bahiagrass

0.34 0.068 0.034 0.043 1.125

80 580 2900 5800 16000

Pastures/ rangeland 2 330 1600 3300 9000

Low bush blueberry 3 220 1100 2200 6000

High bush blueberry 2 330 1600 3300 9000

Pineapple 1.75 370 1900 3700 10000

Non

- crop 8 81 410 810 2300

Christmas Tree 2 330 1600 3300 9000

Forestry 5 130 650 1300 3600

Alfalfa 1.5 200 170 870 1700 4800

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 41 of 64 Table 9 .1.1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Hexazinone.

Exposure

Scenario Crop or Target Inhalation Unit Exposure (μg/lb ai) 1

Maximum
Application

Rate 2 Area

Treated or

Amount

Handled Daily 3 Inhalation Risk Estimates 4 (LOC = 30)

Baseline PF5 PF10 Engineering

Controls Baseline

MOE PF5

MOE PF10

MOE Engineering

Control

MOE

Sugarcane 3.6 73 360 730 2000

Applicator for

Granules via Aerial Application Non

- crop No Data No Data No Data 1.3 8 350 No Data No Data No Data 17

Forestry 4.7 1200 No Data No Data No Data 8

Applicator for

Granules via

Tractor

- drawn Spreader Application Non

- crop

1.2 0.24 0.12 0.22 8 80 81 400 810 440

Forestry

4.7 140 690 1400 750

Applicator for Sprays via Mechanically

pressurized Handgun Application Pineapple (edging

rates) 3.9 0.78 0.39 No Data 0.036 1000 gallons 440 2200 4400 No Data

Applicator for Granules (pellets ) via Hand Dispersal Non

- Crop

470 94 47 No Data 7.5 1 18 88 180 No Data

Pasture/ rangeland 0.64 1 210 1000 2100 No Data

Forestry 6.2 1 21 110 210 No Data

Forestry Release 4.1 1 33 160 330 No Data

Applicator for Dry

Bulk Fertilizer via

Tractor Drawn Spreader Low bush blueberry

1.2 0.24 0.12 0.22 3

320

(Commercial Treatment) 54 270 540 290

High bush blueberry 2 81 400 810 440

Forestry 5 32 160 320 180

Alfalfa 1.5 110 540 1100 580

Low bush blueberry 3

160

(On Farm Treatment) 110 540 1100 580

High bush blueberry 2 160 810 1600 880

Forestry 5 65 320 650 350

Alfalfa 1.5 220 1100 2200 1200

Flagger

Liquid Applications Bermudagrass/

bahiagrass 0.35 0.07 0.035 No Data 1.125 350 450 2300 4500 No Data

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 42 of 64 Table 9 .1.1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Hexazinone.

Exposure

Scenario Crop or Target Inhalation Unit Exposure (μg/lb ai) 1

Maximum
Application

Rate 2 Area

Treated or

Amount

Handled Daily 3 Inhalation Risk Estimates 4 (LOC = 30)

Baseline PF5 PF10 Engineering

Controls Baseline

MOE PF5

MOE PF10

MOE Engineering

Control

MOE

Pastures/ rangeland 2 250 1300 2500 No Data

Low bush blueberry 3 170 850 1700 No Data

High bush blueberry 2 250 1300 2500 No Data

Pineapple 1.75 290 1400 2900 No Data

Non

- crop 8 63 320 630 No Data

Christmas Tree 2 250 1300 2500 No Data

Forestry 5 100 500 1000 No Data

Alfalfa 1.5 340 1700 3400 No Data

Sugarcane 3.6 140 710 1400 No Data

Granular Applications Forestry Pellets

0.15 0.03 0.015 No Data 6.2142

350 190 950 1900 No Data

Forestry 4.7 250 1300 2500 No Data

Non

- crop 8 150 740 1500 No Data

Mixer/Loader/Applicator

Dry

Flowable/Water Dispersible

Granules for Backpack Applications Non

- Crop

2.58 0.516 0.258 No Data 0.32
lbs ai/gallon

40

gallons 1100 5400 11000 No Data

Christmas Tree farm 0.2
lbs ai/gallon 1700 8700 17000 No Data

Forestry 2
lbs ai/gallon 170 870 1700 No Data

Pineapple (edging rate) 0.036
lbs ai/gallon 9600 48000 96000 No Data

Dry

Flowable/Water Dispersible

Granules for Mechanically

Pressurized Handgun Non

- Crop

3.9 0.78 0.39 No Data 0.32
lbs ai/gallon

1000

gallons 50 250 500 No Data

Christmas Tree farm 0.2
lbs ai/gallon 80 400 800 No Data

Forestry 2
lbs ai/gallon 8 40 80 No Data

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 43 of 64 Table 9 .1.1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Hexazinone.

Exposure

Scenario Crop or Target Inhalation Unit Exposure (μg/lb ai) 1

Maximum
Application

Rate 2 Area

Treated or

Amount

Handled Daily 3 Inhalation Risk Estimates 4 (LOC = 30)

Baseline PF5 PF10 Engineering

Controls Baseline

MOE PF5

MOE PF10

MOE Engineering

Control

MOE

Pineapple edging 0.036
lbs ai/gallon 440 2200 4400 No Data

Liquid for Backpack Applications Non

- Crop

2.58 0.516 0.258 No Data 0.32
lbs ai/gallon

40

gallons 1100 5400 11000 No Data

Christmas Tree farm 0.2
lbs ai/gallon 1700 8700 17000 No Data

Forestry 2
lbs ai/gallon 170 870 1700 No Data

Pineapple edging 0.036
lbs ai/gallon 9600 48000 96000 No Data

Liquids for Mechanically

Pressurized Handgun Non

- Crop

3.9 0.78 0.39 No Data 0.32
lbs ai/gallon

1000

gallons 50 250 500 No Data

Christmas Tree farm 0.2
lbs ai/gallon 80 400 800 No Data

Forestry 2
lbs ai/gallon 8 40 80 No Data

Pineapple edging 0.036
lbs ai/gallon 440 2200 4400 No Data

Granules (Pellets) for Backpack Applications Non

- Crop

23.8 4.76 2.38 No Data 7.5 1 200 1000 2000 No Data

Pasture/ rangeland 0.64 1 2300 12000 23000 No Data

Forestry (pellets) 6.2 1 240 1200 2400 No Data

Forestry Release 4.1 1 370 1800 3700 No Data

Granules for Backpack Applications Non

- Crop 8 1 190 940 1900 No Data

Forestry and Forestry

Release 4.7 1 320 1600 3200 No Data

Granules (Pellets) for Belly Grinder Applications Non

- Crop

62 12.4 6.2 No Data 7.5 1 130 670 1300 No Data

Pasture/ rangeland 0.64 1 1600 7800 16000 No Data

Forestry (pellets) 6.2 1 160 810 1600 No Data

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 44 of 64 Table 9 .1.1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Hexazinone.

Exposure

Scenario Crop or Target Inhalation Unit Exposure (μg/lb ai) 1

Maximum
Application

Rate 2 Area

Treated or

Amount

Handled Daily 3 Inhalation Risk Estimates 4 (LOC = 30)

Baseline PF5 PF10 Engineering

Controls Baseline

MOE PF5

MOE PF10

MOE Engineering

Control

MOE

Forestry Release 4.1 1 250 1200 2500 No Data

Granules for Belly

Grinder Applications Non

- Crop 8 1 130 630 1300 No Data

Forestry and Forestry

Release 4.7 1 210 1100 2100 No Data

Granules (Pellets) for Rotary Spreader Applications Non

- Crop

10 2 1 No Data 7.5

5 95 480 950 No Data

Pasture/ rangeland 0.643 1100 5600 11000 No Data

Forestry (pellets) 6.21 110 580 1100 No Data

Forestry Release 4.07 180 880 1800 No Data

Granules for Rotary Spreader Applications Non

- Crop 8 89 450 890 No Data

Forestry and Forestry

Release 4.7 150 760 1500 No Data

 1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( Feb 2015 ); Level of mitigation: Baseline, PPE, Eng. Controls.

 2 Based on registered labels (See Table 4.1).

 3 Exposure Science Advisory Council Policy #9.1 and assumptions in the Occupational Exposure Handler Spreadsheet (February 2015 ).

 4 Inhalation MOE = Inhalation HEC (mg /kg/day) ÷ Inhalation Dose (mg/kg/day).

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 45 of 64 9.2 Occupational Post

- application Exposure/Risk Estimates

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. Post

- 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 prope rties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post

- application exposure.

9 .2.1 Occupational Post

- application Inhalation Exposure/Risk Estimates

There are multiple potential sources of post

- application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain

pes ticides. The A gency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on Marc h 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The A gency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

OPP

- 2014

- 0219 ). During Registration Review , the A gency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxi cological studies) or further analysis is required for hexazinone

.

In addition, the Agency is continuing to evaluate the available post

- application inhalation exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post

- applicatio n inhalation exposure into the A gency's risk assessments.

9.2.2 Occupational Post

- application Dermal Exposure/Risk Estimates

Occupational Post

- application Dermal Exposure Data and Assumptions

No dermal hazard was identified for hexazinone, therefore a dermal post

- application risk assessment was not completed.

Restricted Entry Interval The REI specified on the registered labels is 48 hou rs. Hexazinone is classified as Toxicity Category IV via the dermal route, dermal irritation, and is not a skin sensitizer. Hexazinone is Toxicity Category III for oral and inhalation potential, however, it is a Category I for eye

irritation. Based on t he acute toxicity of hexazinone a 48 hour REI is adequate.

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 46 of 64 10.0 Human Study Review

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from PHED 1.1; and the AHETF database are (1) subject to ethics review pu rsuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board.

D escriptions of data sources, as well as gui dance on their use, can be found at the Agency

website 9



### .

11.0 Review of Incident Report

The Incident Data System (IDS) analysis from January 1, 2010 through March 12, 2015, shows two incidents reported involving hexazinone in Main IDS and 21 incidents r eported to Aggregate IDS. Further, a query of SENSOR

- Pesticides 1998

- 2011 identifies a total of 13 cases involving hexazinone. Four of these cases involved the single active ingredient hexazinone. These incidents were classified as low severity. Based on the low frequency and low severity of incident cases reported for hexazinone in both IDS and National Institute of Occupational Safety and Health Sentinel Event Notification System for Occupational Risks (NIOSH SENSOR

Pesticides), there does not appear to be a concern at this time that would warrant further investigation. The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be conducted.

The Agricultural Health Study (AHS) is also a potential source of information associated with human health effects associated with certain pesticides. Hexazinone is not included in the AHS, and therefore this study does not provide information for this report

.

12 .0 References

Christensen, C. (2002). Revised. HED Chapter for the Hexazinone Tolerance Reassessment Eligibility Decision. DP Number: D275621, dated August 22, 2002.

Piper, S. (2015). Hexazinone: Updated Dietary Burden for Beef and Dairy Cattle. DP Number: D427006, d ated June 2 , 2015.

Piper, S. (2015). Hexazinone. Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments to Support Registration Review. DP Number: D427004, dated

June 2 , 2015.

Melendez, J. (2015). Estimated Drinking Water Concentrations for the Registration Review of Hexazinone, DP Number: D424532, dated April 23, 2015.

9 http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 47 of 64 Recore, S. (2015) Hexazinone : Tier I Update Revi ew of Human Incidents/Epidemiology for

Draft Risk Assessment. DP Number: D427025, dated April 29, 2015.
Shelat. S. (2015) Hexazinone. Occupational and Residential Exposure Assessment for Registration Review, DP Number: D426399, dated June3 , 2015.

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 48 of 64 APPENDIX A: TOXICOLOGY ASSESSMEN T

A.1 Toxicology Data Requirements

The requirements (40CFR §158.3 40) for food use of hexazinone are in Table A.1, below. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 49 of 64 TABLE A.1 Toxicology Data Requirements for Hexazinone

.

Test Technical

Required Conducted

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 (non

- rodent)

870.3200 21/28

- Day Dermal

870.3250 90

- Day Dermal

870.3465 90

- Day Inhalation yes

yes

yes

no

yes yes

yes

yes

no

yes

870.3700a Developmental Toxicity (rodent) 870.3700b Developmental Toxicity (non

- rodent) 870.3800 Reproduction yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent) 870.4100b Chronic Toxicity (non

- rodent) 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 870.5395 Mutagenicity

— Other Genotoxic Effects 870.5500 Mutagenicity

— Other Genotoxic Effects yes

yes

yes

yes

yes yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)

870.6100b 90

- Day Neurotoxicity (hen) 870.6200a Acute Neurotoxicity Screening Battery (rat)

870.6200b 90

- Day Neurotoxicity Screening Battery (rat) 870.6300 Developmental Neurotoxicity no

no

yes

yes

no no

no

yes

yes

no

870.7485 General Metabolism

870.7600 Dermal Penetration 870.7800 Immunotoxicity yes

no

yes yes

yes

yes



### A.2 Toxicity Profiles

TABLE A.2.1 Acute To xicity Profile for Hexazinone

Guideline

Number Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [Rat] 41235004 LD 50 = 1200 mg/kg (M,F) III

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 50 of 64 870.1200 Acute dermal [Ra bbi t] 00104974 LD 50 ≥ 5278 mg/kg IV

870.1300 Acute inhalation [Rat] 41756701 LC 50 ≥ 3.94 mg/L (4 hours) III

870.2400 Acute eye irritation [Rabbit] 00106003 Irreversible corneal opacity I

870.2500 Acute dermal irritation [Rabbit] 00106004 Mild skin irritation IV

870.2600 Skin sensitization [Guinea pig] 41235005 Not a sensitizer (Buehler test) NA

TABLE A.2.2 Subchronic, Chronic and Other Toxicity Profile for Hexazinone

Guideline Number/ Study Type MRID(s) [year]/

Classification/Doses Results

870.3100

90

- Day oral toxicity [rat] 0010977 [1973]

Acceptable/guideline 0, 200, 1000, 5000 ppm M: 0, 16, 81, 440 mg/kg/day F: 0, 16.4, 87.3, 451 mg/kg/day NOAEL = 81/87.3 mg/kg/day (M/F) LOAEL = 440/451 mg/kg/day (M/F) based on decreases in body weight and food efficiency.

870.3150

90

- Day oral toxicity [dog] 00114484 [1973]

Acceptable/guideline 0, 200, 1000, 5000 ppm M: 0, 5.1, 25.9, 122.5 mg/kg/day F: 0, 7, 31.6, 137.3 mg/kg/day NOAEL= 25.9/31.6 [M/F] mg/kg/day LOAEL= 122.5/137.3 [M/F] mg/kg/day based on decreased body weight gains, increased liver weights, and increased alkaline phosphatase levels in both sexes.

870.3200

21

- day dermal toxicity [rabbit] 41309005 [1989]

Acceptable/guideline 0,50,400,1000 mg/kg/day 6 hr/day, 21 consecutive days NOAEL=1000 mg/kg/day [M/F]

No effects seen at the limit dose

870.3465

28

- day inhalation [rat] 49221101 [2013]

Acceptable/guideline 0, 0.031, 0.11, 0.31, 1.05 mg/L 6 hr/day, 5 day/wk NOAEL= 0.031 mg/L LOAEL= 0.11 mg/L based on squamous and mucous cell metaplasia at the ventral base of the epiglottis and in the nose, nasal septum and nasopharynx (portal of
entry effects).

870.3700a

Prenatal developmental [rat] 40397501 [1987]

Acceptable/guideline 0, 40, 100, 400, 900 mg/kg/day (GD 7

- 16, gavage) Maternal NOAEL = 100 mg/kg/day LOAEL = 400 mg/kg/day based on decreased food consumption and body weight gains on days 7

- 17. Developmental NOAEL= 400 mg/kg/day. LOAEL= 900 mg/kg/day based on decreased female fetal weight, increased incidence of kidneys with no papilla (malformation), and an increased incidence of misaligned sternebrae (variation).

870.3700a

Prenatal

dev elopmental [rat] 00114486 [1974]

Unacceptable/upgradeable 0, 18.9, 94.5, 482 mg/kg/day (GD 6

- 15, in diet) Maternal NOAEL= 94.5 mg/kg/day LOAEL= 482 mg/kg/day based on decreased body weight, body weight gain and food efficiency. Developmental NOAEL= 482 mg/kg/day (HDT).

870.3700b

Prenatal developmental [rabbit] 45677801 [2002]

Acceptable/guideline 0, 20, 50, 125, 175 mg/kg/day (GD 7

- 28, gavage) Maternal NOAEL = 50 mg/kg/day LOAEL = 125 mg/kg/day based on a decreased body weight gains and food consumption , increased abortions, death and clinical signs. Developmental NOAEL = 50 mg/kg/day. LOAEL= 125 mg/kg/day based on decreased fetal weights in both sexes.

870.3700

Prenatal developmental [rabbit] 00028863 [1980]

Unacceptable/upgradeable 0, 20, 50, 125 mg/kg/day (GD 6

- 19, gavage) Materna l NOAEL = 50 mg/kg/day LOAEL = 125 mg/kg/day based on decreased body weight gain and food consumption. Developmenta l NOAEL= 50 mg/kg/day LOAEL = 125 mg/kg/day based on possible skeletal

a bnormalities and total abnormali e s. No historical

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 51 of 64 TABLE A.2.2 Subchronic, Chronic and Other Toxicity Profile for Hexazinone

Guideline Number/ Study Type MRID(s) [year]/

Classification/Doses Results

co ntrol, and no individual litter data available. New study was being conducted.

870.3800 Reproduction and fertility effects [rat] 42066501 [1991]

Acceptable/guideline 0, 200, 2000, 5000 ppm M: 0, 11.8, 117, 294 mg/kg/day F: 0, 14.3, 143, 383 mg/kg/day Parental/Systemic NOAEL = 11.8/14.3 [M/F] mg/kg/day

LOAEL = 117/143 [M/F] mg/kg/day based on decreased body weights and body weight gains in F1

males and F0 and F1 females

. Offspring NOAEL = 11.8/14.3 [M/F] mg/kg/day

LOAEL = 117/143 [M/F ] mg/kg/day based on

decreased pup body weights at birth and during

lactation

. Reproductive NOAEL= 294/383 [M/F] mg/kg/day. No reproductive effects seen.

870.4100b

One

- year toxicity [dog] 42162301 [1991]

Acceptable/guideline 0, 200, 1500, 6000 ppm M: 0, 5.0, 41.2, 161 mg/kg/day F: 0, 4.9, 37.6, 167 mg/kg/day NOAEL = 5.0/4.9 [M/F] mg/kg/day LOAEL = 41.2/37.6 [M/F] mg/kg/day based on decreased body weight and hepatotoxicity as evidence by changes in clinical chemistry parameters and microscopic lesions.

87 0.4300
Combined Chronic/ Carcinogenicity [rat] 00108638 [1977]

Acceptable/guideline 0, 200, 1000, 2500 ppm M: 0, 10.2, 53.4, 138.3 mg/kg/day F: 0, 12.5, 67.5, 178.6 mg/kg/day NOAEL = 10.2/12.5 [M/F] mg/kg/day LOAEL = 53.3/67.5 [M/F] mg/kg/day based on

dec reased body weight and food efficiency. No evidence of carcinogenicity.

870.4300 Carcinogenicity [mouse] 00079203 [1981],

41359301[1989], 42509301 [1992], 43202901[1994] Acceptable/ guideline 0, 200, 2500, 10000 ppm M: 0, 28, 366, 1635 mg/kg/day F: 0, 34, 450, 1915 mg/kg/day NOAEL= 28 mg/kg/day [M]/ 450 mg/kg/day [F] M: LOAEL= 366 mg/kg/day based on gross liver and centrilobular hepatocyte hypertrophy; F: LOAEL=1915 mg/kg/day based on decreased body weights, increased relative liver weight/gall bladder

we ights, hyperplastic nodules and centrilobular hepatocyte hypertrophy. Evidence of carcinogenic potential was equivocal.

870.5100

Gene Mutation

Reverse mutation in

Salmonella 40826201 [1977]

Unacceptable/guideline 200, 400, 600, 800, 1000 μg/plate (

- S9) 400, 800, 1200, 1600, 2000 μg/mL (+S9) No mutagenic potential was seen, but doses insufficient to cause cell toxicity

870.5300

Gene Mutation

Hamster CHO cells/HPRT assay 00076956 [1980]

Acceptable/guideline Trial 1: 2.0, 11.1, 13.1, 13.9, 14.3 mM (

- S9); 2 .0, 7.9, 8.9, 9.3, 9.9 mM (+S9) Trial 2: 2.0, 5.9, 11.1, 13.1, 13.9 mM (

- S9); 2.0, 7.9, 8.9, 9.3, 9.9 mM (+S9) No evidence of mutagenic effect either in the presence

or the absence of S9 activation.

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 52 of 64 TABLE A.2.2 Subchronic, Chronic and Other Toxicity Profile for Hexazinone

Guideline Number/ Study Type MRID(s) [year]/

Classification/Doses Results

870.5375
In vitro mammalian

chromosome

aberration test 00130709 [1982]

Acceptable/guideline Trial 1: 1.58, 3.94, 15.85, 19.82 mM (

- S9); 0.32, 3.17, 7.93, 15.85 mM (+S9) Trial 2: 1.58, 3.94, 7.93, 15.85 mM (

- S9); 0.32, 3.17, 7.93, 15.85 mM (+S9) Positive for chromosome aberrations with or without

S9.

870.5385 In vivo cytogenetics assay in rat bone

morrow cells 00131355 [1982]

Unacceptable/guideline 100, 300, 1000 mg/kg by gavage No evidence of clastogenic potential but insufficient

animals and cell were tested.

870.5395

Mammalian erythrocyte

micronucleus test 45124401 [2000]

Acceptable/guideline 1000, 2000, 3000 mg/kg No evidence of clastogenic or aneugenic effect in bone

morrow at toxic doses.

870.5500
UDS in rat hepatocytes 00130708 [1983]

Acceptable/guideline

Trial 1: 1x10

- 5 , 1x10

- 4 , 1x10

- 3

, 1x10

- 2 , 0.1, 1 .0, 10.0, 30 mM

Trial 2: 1x10

- 5 , 1x10

- 4 , 1x10

- 3

, 1x10

- 2 , 0.1, 1.0, 5.0, 10.0, 30 mM No evidence of genotoxic potential at precipitating

concentrations.

870.6200 Acute neurotoxicity [rat] 48931901 [2012]

Acceptable/guideline 0, 32.25, 125, 500 mg/kg

gavage NOAEL= 125 mg/kg LOAEL= 500 mg/kg based on reduced motor activity in both sexes, decreased body temperature and increased incidences in posture and palpebral closure in females.

870.6200
Subchronic neurotoxicity [rat] 48379701 [2011]

Acceptable/guideli ne 0, 100, 300, 1250, 5000 ppm M: 0, 6, 17, 68, 273 mg/kg/day F: 0, 7, 20, 81, 350 mg/kg/day Systemic NOAEL= 68/81 mg/kg/day [M/F] LOAEL= 273/350 mg/kg/day based on reduced body weights and gains and reduced food consumption. No neurotoxicity was seen.

870.7800 Immunotoxicity [female rat] 48963501 [2012]

Acceptable/guideline 0, 100, 300, 1250, 5000 ppm 0, 7, 2 3, 89, 376 mg/kg/day NOAEL = 376 mg/kg/day (HDT) No evidence of immunotoxicity.

870.7485

Metabolism and pharmacokinetics [rat] 00140162, 00109237 [1980,

1982] Acceptable Hexazinone was rapidly absorbed and excreted, no difference in males and females at high or low dose levels. No parent was recovered in urine or feces. Two major metabolites were recovered from feces and urine,

in addition to lesser amount of a third metabolite and small amounts conjugated products from urine.



### Appendix B. Chemical Structures of Hexazinone and its Regulated Metabolites (Metabolites A through F)

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 53 of 64 Common Name/Code

Chemical name Structure

Hexazinone

3

- cyclohexyl

- 6

- (dimethylamino)

- 1

- methyl

- 1,3,5

- triazine

- 2,4

- (1 H ,3 H )

- dione

Metabolite A

3

- (4

- hydroxycyclohexyl)

- 6

- (dimethylamino)

- 1

- methyl

- 1,3,5

- triazine

- 2,4

- (1 H ,3 H

)

- dione

Metabolite A

- 1 is hydroxylated at the

2

- position of the cyclohexyl ring;

Metabolite A

- 2 is hydroxylated at the

3

- position of the cyclohexyl ring.

Metabolite B

3

- cyclohexyl

- 6

- (methylamino)

- 1

- methyl

- 1,3,5

- triazine

- 2,4

- (1 H ,3 H )

- dione

Metabolite C

3

- (4

- hydroxycyclohexyl)

- 6

- (methylamino)

- 1

- methyl

- 1,3,5

- triazine

- 2,4

- (1 H ,3 H )

- dione

Metabolite C

- 1 is hydroxylated at the

2

- position of the cyclohexyl ring;

Metabolite C

- 2 is hydroxylated at the

3

- position of the cyclohexyl ring.

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 54 of 64 Common Name/Code

Chemical name Structure

Metabolite D

3

- cyclohexyl

- 1

- methyl

- 1,3,5

- triazine

2,4,6

- (1 H ,3 H ,5 H

)

- trione

Metabolite E

3

- (4

- hydroxycyclohexyl)

- 1

- methyl

1,3,5

- triazine

- 2,4,6

- (1 H ,3 H ,5 H )

- trione

Metabolite F

3

- cyclohexyl

- 6

- amino

- 1

- methyl

1,3,5

- triazine

- 2,4

- (1 H ,3 H )

- dione

Appendix C: International Residue Limits

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 55 of 64 

## Hexazinone (107201; Date of Request: 3/18/2015)

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 

### Codex



### 40 CFR 180 .396 (a) General (1)

Plant: Compliance with the tolerance levels specified in this paragraph is to be determined by measuring only the sum of hexazinone, 3

- cyclohexyl

- 6

- (dimethylamino)

- 1

- methyl

- 1,3,5

- triazine

- 2,4

- (1 H , 3 H

)

- dione, and its plant metabolites: metabolite A, 3

- (4

- hy droxycyclohexyl)

- 6

- (dimethylamino)

- 1

- methyl

- 1,3,5

- triazine

- 2,4

- (1 H , 3 H )

- dione, metabolite B, 3

- cyclohexyl

- 6

- (methylamino)

- 1

- methyl

- 1,3,5

- triazine

- 2,4

- (1 H , 3 H )

- dione, metabolite C, 3

- (4

- hydroxycyclohexyl)

- 6

- (methylamino)

- 1

- methyl

- 1,3,5

- triazine

- 2,4

- (1 H

, 3 H )

- dione, metabolite D, 3

- cyclohexyl

- 1

- methyl

- 1,3,5

- triazine

- 2,4,6

- (1 H , 3 H , 5 H )

- trione, and metabolite E, 3

- (4

- hydroxycyclohexyl)

- 1

- methyl

- 1,3,5

- triazine

- 2,4,6

- (1 H , 3 H , 5 H )

- trione,

calculated as the stoichiom etric equivalent of

hexazinone None None

Commodity

US Canada Mexico 1 

### Codex 

### Alfalfa, forage 2.0 Alfalfa, hay 4.0
Alfalfa, seed 2.0 Blueberry 0.6 Grass, forage 250 Grass, hay 230 Pineapple 0.6 Sugarcane, cane 0.6 Sugarcane, molasses 4.0

40 CFR 180 .396 (2) Canada Mexico 1 

### Codex

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 56 of 64 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 

### Codex 

### Livestock: Compliance with the tolerance levels specified in this paragraph is to be determined by measuring only the sum of hexazinone,

3

- cyclohexyl

- 6

- (dimethylamino)

- 1

- methyl

- 1,3,5

- triazine

- 2,4

- (1 H , 3 H )

- dione, and its animal tissue metabolites: metabolite B, 3

- cyclohexyl

- 6

- (methylamino)

- 1

- methyl

1,3,5

- triazine

- 2,4

- (1 H , 3 H )

- dione, and metabolite F, 3

- cyclohexyl

- 6

- amino

- 1

- methyl

- 1,3,5

- triazine

- 2,4

- (1 H , 3 H )

- dione, calculated as the stoichiometric equivalent of hexazinone All livestock commodity except poultry: 3

- cyclohexyl

- 6

- (dimethylamino)

- 1

- methyl

- 1,3,5

- triazine

2,4

- (1H,3H)

- dione, including the metabolite

3

- cyclohexyl

- 1

- methyl

6

- (methylamino)

- 1,3,5

- triazine

- 2,4

- (1H,3H)

- dione, expressed as hexazinone equivalents None



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

US Canada Mexico 1 

### Codex 

### Cattle, fat 0.1 0.04
Cattle, meat 0.5 0.04 Cattle, meat byproducts 4.0 0.04 meat byproducts of

cattle
Goat, fat 0.1 0.04
Goat, meat 0.5 0.04 Goat, meat byproducts 4.0 0.04 meat byproducts of

goats Sheep, fat 0.1 0.04 Sheep, meat 0.5 0.04 Sheep, meat byproducts 4.0 0.04 meat byproducts of sheep
Horse, fat 0.1 0.04
Horse, meat 0.5 0.04 Horse, meat byproducts 4.0 0.04 meat byproducts of

horses Hog, fat Revoke 0.04 Hog, meat Revoke 0.04 Hog, meat byproducts Revoke 0.04 meat byproducts of hogs

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 57 of 64 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 

### Codex 

### 40 CFR 180.396 (3) Compliance with the tolerance level specified in this paragraph is to be determined by measuring only the sum of hexazinone,

3

- cyclohexyl

- 6

- (dimethylamino)

- 1

- methyl

- 1,3,5

- triazine

- 2,4

- (1 H , 3 H )

- dione, and its metabolites: metabolite B, 3

- cyclohexyl

- 6

- (methylamino)

- 1

- methyl

- 1,3,5

- triazine

- 2,4

- (1 H , 3 H )

- dione, metabolite C, 3

- (4

- hydroxycyclohexyl)

- 6

- (methylamino)

- 1

- methyl

- 1,3,5

- tria zine

- 2,4

- (1 H , 3 H )

- dione, metabolite C

- 2, 3

- (3

- hydroxycyclohexyl)

- 6

- (methylamino)

- 1

- methyl

- 1,3,5

- triazine

- 2,4

- (1 H , 3 H )

- dione, and metabolite F, 3

- cyclohexyl

6

- amino

- 1

- methyl

- 1,3,5

- triazine

- 2,4

- (1 H , 3 H )

- dione, calculated as the stoichiometric equivalent of

h exazinone. 3

- cyclohexyl

- 6

- (dimethylamino)

- 1

- methyl

- 1,3,5

- triazine

2,4

- (1H,3H)

- dione, including the metabolites

3

- cyclohexyl

- 1

- methyl

6

- (methylamino)

- 1,3,5

- triazine

- 2,4

- (1H,3H)

- dione and 3

- (3

- hydroxycyclohexyl)

- 1

- methyl

- 6

- (methylamino)

- 1,3,5

- triazine

- 2,4

- (1 H,3H)

- dione, expressed as hexazinone equivalents None

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

US Canada Mexico 1 

### Codex

Milk 11 0.09

Completed: M. Negussie; 03/30/15

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

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 58 of 64 Appendix D: Food/Feed Use Patterns Subject To Reregistration for Hexazinone (PC Code 107201).

Site Application Type Application Timing Application Equipment Formulation [EPA Reg.
No.] Max. Single

Application

Rate (lb ai/A) Max. #

Apps./

Season Maximum

Seasonal

Rate (lb ai/A) Preharvest

or Pregrazing

Interval (Days) Use Directions and Limitations 1

Alfalfa (grown for hay)

Broadcast application
Dormant, non

- dormant, and

semi

- dormant

Ground or aerial 90% SC [352

- 378] 1.35

0.675 (for alfalfa less than one year old) 1 1.35/year 30 Use prohibited in ND and SD.

Broadcast application
Dormant, non

- dormant, and

semi

- dormant

Ground or aerial 2 lb/gal EC [352

- 392]

75% DF [352

- 581] 1.5

For the EC

formulation only: 0.75 (for alfalfa <1 year old) 1 1.5/year 30 (75% DF only)

Alfalfa (grown for seed)

Broadcast application
Dormant, non

- dormant, and

semi

- dormant

Ground or aerial 90% SC [352

- 378]

2 lb/gal EC [352

- 392]

75% DF [352

- 581] 0.5 1 0.5 Not specified (NS) Use limited to CA. A maximum rate of 0.5

lb ai/A is specified for fields with sandy loam or loamy sand soils having 1

- 2% OM

and on seed alfalfa that has been established for only one growing season.

Alfalfa (grown for forage)

Broadcast application

Dormant

Ground 2 lb/gal EC [MT940001] [WY920001] 1.0 1 1.0 30 (75% DF) Use limited to MT, ND, SD, and WY for

established stands of forage alfalfa. Application to soils with <1.5% OM is prohibited for the EC formulation.

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 59 of 64 Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Max. Single

Application

Rate (lb ai/A) Max. #

Apps./

Season Maximum

Seasonal

Rate (lb ai/A) Preharvest

or Pregrazing

Interval (Days) Use Directions and Limitations 1

75% DF [ND970002] [SD970001]

Blueberry 2

Broadcast application Spring of fruiting year (prior to budbreak)

Ground 2 lb/gal EC [ME980002]

75% DF [ME980003] 2.0 NS 2.0 450 Use limited to ME for established lowbush

blueberries. Do not exceed 2.0 or 1.8 lb ai/A if soil has been respectively treated

with the EC or DF formulations of hexazinone within the past 8 years.

Broadcast application Dormant (prior to budbreak)

Ground 2 lb/gal EC [NC830012] 2.0 NS NS 50 Use limited to NC. Application may be made in sufficient water to provide thorough and uniform coverage, usually 20 gal/A.

Pineapple

Broadcast or directed spray application

Ground or aerial 90% SC [352

- 378]

2 lb/gal EC [352

- 392]

75% DF [352

- 581] 1.8 NS 3.6/crop cycle 181 Broadcast applications may be made between successive pineapple crops, preplant after rows have been mulched, and postplant prior to active growth. Three to ten months after planting, directed spray applications may be made to the soil between crop rows. Broadcast applications may be made in 100

- 400 gallons of water/A using ground equipment, or in at least 10 gal/A using aer ial equipment. Directed sprays may be applied at 50

- 200 gal/A using ground equipment. Directed spot treatments are also permitted at 0.9

- 1.8 lb ai/100 gal prior to floral induction.

Pasture

Broadcast application

Ground 90% SC [352

- 378]

2 lb/gal EC 1.125 1 1.125 (implied) 60 Use limited to Bermuda grass/Bahia grass pastures. Applications may be made in a

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 60 of 64 Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Max. Single

Application

Rate (lb ai/A) Max. #

Apps./

Season Maximum

Seasonal

Rate (lb ai/A) Preharvest

or Pregrazing

Interval (Days) Use Directions and Limitations 1

[352

- 392]

75% DF [352

- 581] minimum of 25 gal/A using ground equipment.

Basal soil application (undiluted)

Ground 2 lb/gal EC [352

- 392] 2

- 4 mL of

product for each

inch of stem

diameter NS 0.67/year NS Use limited to brush control in pastures and rangelands. No restrictions on grazing by domestic animals nor on cutting surrounding vegetation for forage and hay when product is applied a s a basal soil treatment. Basal soil application

Ground 75% DF [352

- 581] 2 lb/1 gal

[2

- 4 mL of suspension for

each inch of stem diameter] NS 0.67/year NS

Rangeland

Basal soil application (undiluted)

Ground 2 lb/gal EC [352

- 392] 2

- 4 mL of

product for each

inch of stem

diameter NS 0.67/year NS Use limited to brush control in pastures and rangelands. No restrictions on grazing by domestic animals nor on cutting surrounding vegetation for forage and hay when product is applied as a basal soil treatment. Basal soil application

Ground 75% DF [352

- 581] 2 lb/1 gal

[2

- 4 mL of suspension for

each inch of stem diameter] NS 0.67/year NS

Sugarcane

Broadcast application Preemergence and

postemergence
Ground or aerial 90% SC [352

- 378]

2 lb/gal EC [352

- 392]

75% DF [352

- 581] 3.6 1 3.6/crop cycle (18

- 24 months) 180 Use limited to HI. Application may be

made with a nonionic surfactant at 0.25%

v/v.

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 61 of 64 Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Max. Single

Application

Rate (lb ai/A) Max. #

Apps./

Season Maximum

Seasonal

Rate (lb ai/A) Preharvest

or Pregrazing

Interval (Days) Use Directions and Limitations 1

Sugarcane ( continued )

Broadcast application Preemergence (in fall) and postemergence (in spring before active cane tillering begins)

Ground or aerial 90% SC [352

- 378]

2 lb/gal EC [352

- 392]

75% DF [352

- 581] 0.9 NS 0.45/year for

the 90% SC

1.5/year for the 2 lb/gal

EC and 75%

DF 234 Use limited to LA.

Broadcast application Preemergence and

postemergence
Ground or aerial 90% SC [352

- 378]

2 lb/gal EC [352

- 392]

75% DF [352

- 581] 0.45

- 0.5 NS 0.9/crop cycle 288 Use limited to PR.

Preemergence, early postemergence, and/or directed layby

Ground or aerial 90% SC [352

- 378]

2 lb/gal EC [352

- 392]

75% DF [352

- 581] 0.9 NS 1.8/crop cycle 234 Use limited to TX. Two treatments are allowed (one early treatment plus one directed treatment at layby), provided 60 days have elapsed and at least 3" of rainfall

have occurred.

Sugarcane ( continued )

Preemergence, early postemergence, or directed layby

Ground or aerial 90% SC [TX940008] 0.45 1 0.45 NS Tank mix use with diuron (Karmex DF Herbicide) limited to TX. Application may be made in a minimum of 5 gal/A by air or in a minimum of 25 gal/A using ground equipment. The feeding of sugarcane forage to livestock is prohibited. Use on gravelly

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 62 of 64 Site Application Type Application Timing Application Equipment Formulation [EPA Reg. No.] Max. Single

Application

Rate (lb ai/A) Max. #

Apps./

Season Maximum

Seasonal

Rate (lb ai/A) Preharvest

or Pregrazing

Interval (Days) Use Directions and Limitations 1

or rocky soils, thinly

- covered subsoils,

coarse

- textured soils with <2% OM, or on any soil with <1% OM is prohibited. The planting of any crop other than sugarcane within 18 months of the last application is prohibited.

1 The restricted entry interval (REI) for the 90% SC (EPA Reg. No. 352

- 378), 2 lb/gal EC (EPA Reg. No. 352

- 378), and 75% DF (EPA Reg. No. 352

- 581)

formulations is 24 hours.

2 A REFS search, conducted 7/26/01, listed blueberries as a use site for the Federal labels of the 2 lb/gal EC (EPA Reg. No. 352

- 392) and the 90% SC (EPA Reg. No. 352

- 378). However, upon label examination of these products, it was determined that there are no Section 3 registrations of hexa zinone on

blueberries ; only Section 24(c) registr ations exist.

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 63 of 64 Appendix E. Risk Estimates Related to Spray Drift Exposure to Hexazinone from the Registered Agricultural Uses.

Table A.1. Children Incidental Oral Risk Estimates (MOEs) Related to Spray Drift Exposure to Hexazinone from the Registered Agricultural Uses. 1

Crop/Rate Group Spray Type/ Nozzle Configuration Application Rate (lbs ai/A) Estimated

TTR t (ug/cm2) At Edg e

HtM MOE

Sugarcane

Aerial Fine to Medium

3.6 0.40014 850

Medium to Coarse 1,000 Coarse to Very Coarse 1,200 Very Fine to Fine 590 AT401, M, 10 mph, 37% SD 940 WASP, M, 10 mph, 37% SD 1,000 AT401, C, 10 mph, 25% SD 1,100 WASP, C, 10 mph, 25% SD 1,300 AT401, VC, 10 mph, 20% SD 1,300 WASP, VC, 10 mph, 20% SD 1,600

Groundboom High Boom Very fine to Fine 1,200

Low Boom Very fine to Fine 2,600 High Boom Fine to Medium/Coarse 4,500

Low Boom Fine to Medium/Coarse 6,600 Forestry 2

Aerial Fine to Medium

5 0.55575 610

Medium to Coarse 750 Coarse to Very Coarse 860 Very Fine to Fine 420 AT401, M, 10 mph, 37% SD 670
WASP, M, 10 mph, 37% SD 720 AT401, C, 10 mph, 25% SD 800 WASP, C, 10 mph, 25% SD 920 AT401, VC, 10 mph, 20% SD 900 WASP, VC, 10 mph, 20% SD 1,100

Groundboom High Boom Very fine to Fine 840

Low Boom Very fine to Fine 1,900 High Boom Fine to Medium/Coarse 3,200

Low Boom Fine to Medium/Coarse 4,800

Non

- Crop Sites

Aerial Fine to Medium

8 0.8892 380

Medium to Coarse 470 Coarse to Very Coarse 540 Very Fine to Fine 260 AT401, M, 10 mph, 37% SD 420 WASP, M, 10 mph, 37% SD 450 AT401, C, 10 mph, 25% SD 500
WASP, C, 10 mph, 25% SD 580 AT401, VC, 10 mph, 20% SD 560 WASP, VC, 10 mph, 20% SD 710

Groundboom High Boom Very fine to Fine 530

Low Boom Very fine to Fine 1,200

### Hexazinone Human Health Risk Assessment DPNo. 424526

Page 64 of 64 Table A.1. Children Incidental Oral Risk Estimates (MOEs) Related to Spray Drift Exposure to Hexazinone from the Registered Agricultural Uses. 1

Crop/Rate Group Spray Type/ Nozzle Configuration Application Rate (lbs ai/A) Estimated

TTR t (ug/cm2) At Edg e

HtM MOE

High Boom Fine to Medium/Coarse 2,000

Low Boom Fine to Medium/Coarse 3,000

Airblast Sparse 690

Normal 33,000

Dense 2,300 Vineyard 12,000

1. The highest application rate for an agricultural crop application is for aerial and ground applications to sugarcane use sites with an application rate of 3.6 lbs ai per acre. This use site and application equipment is representative of the other currently registered crop use sites.

2. There is some uncertainty associated with the drift predictions associated with forestry uses because in some situations pesticides like hexazinone are applied in rugged terrain using rotary aircraft and smaller droplets. A mor e appropriate modeling approach is currently under development for such situations. Even so, this would not alter the risk conclusions for the current human health risk assessment spray drift scenario because, in the case of hexazinone, if the 100% of appl ication rate assumption is used rather than the screening level assumptions, there would be no risks of concern for the incidental o ral risk estimates for