### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY



### MEMORANDUM

Date: l 7-S E P- 2015 

### WASHINGTON

, D

. C. 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### SUBJECT: Diqu a t Dibromide

- Draft Hum a n Health Ri sk Assess ment for Registration
R ev i ew

PC Co de: 03220 I
Deci s i o n No.: 482019

Pet iti on No.: NA
Ri s k As s ess m en t T y pe: Single Chemical/Aggrega t e TXR No.: NA
MRIO No.: NA OP B a rc ode: 04 1 4 1 47

R eg i s tr a ti o n No.: N I A

Re g ul a tor y Action: R eg i s tr a ti o n Review Risk Asse ss m ent
Case No.: 0288
CAS No.: 85-00

- 7

, 2764-72-9 (cati on )
40 CFR: § 180 .2 26



### FROM: Moniqu e M. Perron

, Sc .D.

, Toxi co lo g i st
G e or ge F. Kr a mer , Ph.D

., Se ni or C h e mi s t
James S. Mill e r , E n vironme nt a l Sc i e nti st**..,_ ~~.....--.......­**  

### Ri s k Assess m e nt Branch I (RAB l )
H ea lth Eff e ct s Di vis i on ( HED ; 7509P )

THROUGH: Thur s t o n G

. Morton, A cting Branch C hi e f
RAB I ! H ED (7 509 P )

and

.

J effrey D awson 

# A

Christoph e r Sch lo sse r Risk Assess m e nt Review C'01

H E D (7 509P )

TO: Bonnie Ad l e r P est i c id e R e

- eva l uation D ivis i on ( PRO ; 7508P)

Th i s docu m ent provides the HED 's draft hum an health ri s k assess ment fo r Regi s tration Re v i ew of diquat d i bromide (6,7-d ih yd r o dip y rid o[ 1 ,2 -a: 2', 1 '-c]py r az i ned iiu m dibromid e ). The h azar d
characterization

, e n dpoint se l ection, a nd ri sk assessme nt were provided by Moniqu e P e rron ( RAB l ); the r es i due c hemistr y and dietar y exposure assess m e nt s we r e pro v id ed b y Geo r ge Kramer (RAB I ); a nd the occ upation a l and r es id e nti a l exposure assessment by Jame s Miller 

### ( RABI).

Page I of53

### Diquat Dibromide Human Health Ri sk Assessmen t 0414147



### Table of Co ntent s 1.0 Executive Su mm ary

........ ..... ... .... ... .. . .... . .. .. . ... ... .. ... .................................. .... .. . .......... . ... . . .. .. .. 4
2.0 HED R eco mm e nd at i o n s

.... . ..... . ... ... .... . ........ . .. ... .......... .. ... .. ... . . .. .. .. . ...... . . . .... . . . .. .. . ... . .. ........... 6
2. 1 Data Deficienci es

.... ... . ... ..... . . .. ... . ...... .. .. .. ... .. . ... . . . . .. ... ..... . ... .. ....................... . .... . ... . .. ..... . ..... 6
2.2 T o l e ran ce Con s id era tion s

. ...... .. .. .. ....... . ................ .. ....... .. ... . . .. .. .. . ...... .. . ............................. 7
2.2. 1 Enforcemen t Analy ti cal Method

...... . .... . ........... . ........................................ ... .. .. ..... .. .. .. .... . 7
2.2.2 To l e r ance Recommendations

.. .. ......... ... .. .................. .. .. .... ... .. .. ..... .. . . .. . . .. .. .. ............ .. .. .... .. . 7
2.3 Internat i o nal Harmonization

.. .. . .. . ... . ... . ........ .. ...... . ... . . ... . ..... ... . ...... . .. ..... . ... . ............. . ..... .. .. . 7
3.0 I ntroduction

.................... ......... .. .. ... . .. ... . . .. . ... .. ................... .. . ... .. .. .. .. . .... .. . .. ..... ... ........... .. .. . 8
3. 1 Chemica l Id e ntit y

.................. . ... .. ... . . ... . . .. . . ... .. .. . ... .. .. ............. .. .. . ......... .. ...................... .. .... 8
3.2 Phy s ical / C h e mi ca l Characte ri s tic s

... .. .. .. ........... .. .. ...... . .. ... ... ................. . ... .. . .. . .. ...... . ......... 8
3

. 3 P es ti c id e Use P a ttern

.. . .......... ... .. ..... . ......................................... .. .. .... .. .. ... . ..... .. ............ . ... . 8
3.4 An ti c i pated Exposu r e P athways

.. .. ... .. . .. .. .. ... .......... .. .. ......... .......... .... .. ....... .. .. .. . .. .. .. . ...... . .. 9
3.5 Co n s ideration of Environment a l Ju st i ce

.. ...... . ... ... ... . . .... .. ... . .. . .. .. .. .... ... . ....................... .. .... 9
4.0 H aza rd C h arac t er

i za ti o n and Do se -R es p o ns e Assessment..

...................... . ..... .. .. ... ... .. ..... 9
4 .1 Toxicology St udie s Ava il ab le for Analysis

.................................... . ...... . .. .. ..... . ................. 9
4.2 Absorpt i o n , Di s tributi o n , Metabo li s m , & 

### E limin at i on (A D ME )

.. .............. . .. .. ... . ..... .. .... l 0
4.2.1 De n na ! A b so rpt i o n

................................................... . ...... . . . .. ... . .. . .. ... . .. . .. . ... .. . .. . ............... 1 0
4. 3 S ummar y of Tox ic o lo g i ca l Effec t s

... ... . .. .. .. .. . . ....... . . . ... .. ..... . .... . ....................................... 1 0
4.4 Safety F ac tor fo r In f ant s and Ch il d ren (FQ P A Safety F acto r )

.................. .. .................... 11
4.4. l Co mpletene ss of the T ox icolo gy Database

............................... . ...... . ... . . .... .. .. .... ... . ......... . 11
4.4.2 Ev id ence of N'ebro toxi c it y

..... .... .... ... .. ... .. ... .... ... .. ... .. ..... . . . ........ .. . .. . ... . ... .................. . ... .. .. 11
4.4.3 Ev id e nc e of Sens itivit y / Suscept ibility in the Dev e l o ping or Young Animal

... .. .. ..... . ... .. 12
4.4.4 R es idual U n certai nt y in t h e Ex po su re Database

. ... .. ........................................................ 1 2
4.5 Toxicity E ndpoint a nd Po i nt of D eparture Se l ec ti ons

.......................... . ... .... .. .. ..... .. .. ... ... 1 2
4

. 5.1 Recommendation fo r Co m bin in g Route s of Ex p os ur es fo r Risk Assessment

. .. . . . . .. ..... . . 1 3
4.5.2 Cance r C l ass ifi ca tion and Ri sk Assessmen t Recommendation

. ...... . .. .. . ...... . ...... . .. .. ... . ... 1 3
4 .5.3 S ummary of P oi nt s of Departure a nd Toxici t y Endpo int s Used in Hu man Hea l th Risk
Assess m ent

..................................... .. .......... .. ...... .. .. .. .................................................................... 14
4.6 Endocrine Di sruptor Screening Pr og r am

.. .. .. ..... ... ........ .. .... ... ... . ..... .. .. ..... . .. . .. . .. . . ... .. .. . ..... 1 5
5.0 Dietary Expos ur e and Ri sk Assessment

... . ....... . ................. .... . ..... ......... ... . .. .... .. ..... . ..... . .. 1 6
5.1 Metabo lit e / D egradate Residu e Pr ofile

. .. .. ...... .. ... .. ... . .. .. .. .. .. . .. .. .. . .. .. .. . ...... . .. ..... .. .. ..... . .. . .. . 1 6
5 .1.1 Summary o f Plant and A nimal Met abo li s m Studies

.... . .................................................. 1 6
5. 1. 2 Summary of E n v ironm e nt al Degradation

....................................... . ..... .. ... ... ... . ..... .. ... .... . 1 7
5. 1 .3 Co mpari so n of Metabo lic P athways

... .... . ... .. ....... . ... . ..... ... .. .... ... .. .. . ...... .. ..... . .. .. ... .. . . .. ..... . 1 7
5. 1 .4 R esi due s of Conce rn Summary and R at i o n a l e

. ...... . ... .. ..... . .. . .. ..... .. ... . . . .. . .. .. . .. .. .. . .. . ... .. .... 1 7
5 .2 F ood Re s idu e Pr ofi l e

... .. ... .... ................................. . .. .. ...... .. .. ..... . ... . ...... . .......................... 17
5

. 3 Drin ki n g Wate r Re s idu e Profil e

. ... .. .. .. .. . . .. ... . ....... . . . . .. .. ...... . ..... .. .. .. ..... . ........ . .................. 18
5.4 Diet ary (Food + Water) Ri s k Assessme nt

. ........... . ...... . .. ... ..... . ... .... . .......... .. .... .. ... . ...... . ... 1 8
6.0 R es idential (Non -O cc upational) Exposure/Risk C h aracterizat i on

...................... .. ..... .. ... 18
6.1 Resid en ti a l H an dl e r Expos ur e .

.. .. . ... .. .. ... . ..... .. . .... . ... . .. . . .. .. .. . .. .. .. .... . .. .. .. . .. . . .. . ... .. .. .. ..... .. .. . 1 8

6 .2 Residential Po s t-Application Exposure

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

6

. 3 R es id e nt i a l Ri sk Es tim a te s for Use in Aggregate Assess m e nt..

..................... .. ..... .. .. ..... . 22
6.4 Residential B ystande r P ost-Applicatio n In hal at i o n Ex po s ur e

.. .... .. ..... .. .. .... .. ... ..... . .. ..... .. 23
6.5 Sp ra y Drift

. .. .. ......................................... .. .......... .. .......... .. .. .. ................ . . ............. .. . ...... . .. 23
7 .0 Aggregate Exposu r e /Risk C h aracter i za ti on

. .. ... . .. .. ... . ... . .. . ... . ...... . ... .... .. ... . . .. . ... . .. . .. ......... 24
8.0 C umul at i ve Exposure/Risk Charac t erization

..... . .............................. ... ........................... 25
9.0 Occupational Exposure/Risk C h aracter i zat ion

................. .. ...... . ......... .. ..... .. .. .. ..... .. .... .. .. . 25
9.1 S h ort

- / In te rm ediate- T e rm H and l e r Ri sk

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

P age 2 of 5 3Diquat Dibromide Human Health Risk Assessment D414147

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Page 3 of 53 

### 9.2 Occupational Post

- Application Exposure

................................ ................................ ........ 31
A.1 Toxicology Data Requirements

................................ ................................ ....................... 34
A.2 Toxicity Profiles

................................ ................................ ................................ .............. 35 Appendix D. Physical/Chemical Properties

................................ ................................ ................. 45 Appendix E. Summary of Registered Uses of Diquat

................................ ................................ . 46 Appendix F. International Residue Limits

................................ ................................ ................... 49 Appendix G. Review of Human Research

................................ ................................ ................... 53Diquat Dibromide Human Health Risk Assessment D414147

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Page 4 of 53 

### 1.0 Executive Summary

Background: Diquat dibromide (referred to as diquat for the remainder of this document) is a

non

- selective contact herbicide, algicide, desiccant , and defoliant. It is formulated as a soluble
concentrate and ready

- to

- use (RTU) liquid. As an algicide/herbicide, it is used to control aquatic
and terrestrial weeds through application via direct pouring, hand

- held or mechanical sprayer, and injection below the water surface. As a terrestrial herbicide and crop desiccant /defoliant, it is applied by hand

- held sprayer, aircraft, or ground equipment. Its largest use is as a desiccant on potatoes. Minor food use applications include use as a desiccant on crops grown for seed.
D iquat is also used on resistant dorma nt turf (Bermuda and Zoysia grass ) for weed control

. Additionally, use of irrigation water containi ng residues of diquat may result in residues in plants
and livestock.

Dietary exposure is an anticipated exposure pathway as residues of diquat may be found in/on crops, livestock commodities, and drinking water. There are residential and aquatic uses of diquat and potential for spray drift, so there is exposure in resident ial and non

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

- application exposure for workers re

- entering trea ted sites.

This draft risk assessment (D RA) provides information to support the Registration Review of diquat and addresses the exposures and risk estimates associated with all currently registered
uses. This document incorporates all available data an d reflects current HED policies. All data requirements identified during the scoping process have been satisfied ( B. Daiss; 0 2

- DEC

- 2009;
D365773 ).

Hazard Assessment : The eye was a target organ following subchronic and chronic oral exposures in rats, mic e, and dogs causing opacity, lesions, discharge, and cataracts. The physical properties of diquat indicate it is highly hydrophilic and such chemicals will often cause ocular effects due to the high water content of the eye. Clinical signs and body weigh t decrements were noted throughout the database following acute, subchronic, and chronic exposures to diquat. The majority of the clinical signs were associated with ocular toxicity (e.g., eye discharge, opaque eyes) or general systemic toxicity (e.g., di arrhea, urinary incontinence, lack of grooming). In several studies, including the acute neurotoxicity study, there was evidence of potential neurotoxicity based on increased incidence of piloerection, abnormal posture and gait, and subdued behavior; howe ver, these signs are most likely indicative of overt toxicity rather than direct neurotoxicity since they were only seen at the highest dose tested and are consistent with those observed at overtly toxic doses in other studies following diquat exposure.

T here was no evidence of increased pre

- or post

- natal susceptibility. The maternal/parental effects were consistent with those seen in the toxicological database, and observed at doses at or below those producing developmental (decreased fetal body weights and skeletal variations) or offspring (reduced number of live pups, kidney lesions, and body weight decrements) effects.

An acceptable route

- specific inhalation subchronic toxicity study in rats is available for diquat. Portal of entry effects occurred at doses much lower than those eliciting oral toxicity and consisted of microscopic lung lesions and increased lung weights in both sexes.

The diquat risk assessment team recommends that the 10X Food Quality Protection Act (FQPA)Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 5 of 53 

### Safety Factor (SF) be reduced to 1X for all exposure scenarios for the following reasons: (1) t he exposure databases are sufficient to determine the nature/magnitude of the residue in food and

water and exposure analyses are unlikely to underestimate risk of exposure from diq uat

, (2) there is no evidence of increased offspring sensitivity/susceptibility in the database

, ( 3 ) a lthough there is evidence of potential neurotoxicity in the database, the effects are well

- characterized with clearly established no

- observed adverse

- effe ct level (NOAEL)/ lowest

- observed adverse

- effect level (LOAEL) values

, and selected endpoints are protective for the observed effects.

Dietary Risk Estimates (Food + Drinking Water) : Acute and chronic dietary (food and drinking water) exposure and risk assessments were conducted using the Dietary Exposure
Evaluation Model

- Food Consumption Intake Database (DEEM

- FCID, ver. 3.16) which incorporates consumption data from the United States Department of Agriculture (USDA) National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA; 2003

- 2008). For drinking water, the assessments used the Office of Water’s Maximum Contaminant Level (MCL; 0.02 ppm), w hich is considered a worst

- case estimate. The acute dietary assessment assumed 100% crop treated (CT) and tolerance

- level residues of diquat for all foods with registered uses. Acute dietary risk estimates were below the
level of concern (LOC) ( i.e., <10 0% of the acute population

- adjusted dose; aPAD) for all population subgroups. The population subgroup with the greatest exposure and risk estimate was
children 1

- 2 years old, which utilized 1% of the aPAD. The chronic assessment was based on
tolerance

- le vel residues and 100% CT for crops with direct diquat uses (except alfalfa). For crops with tolerances to cover irrigation with diquat

- treated water, anticipated residue levels from irrigation trials were used in conjunction with estimates of percent of c rops irrigated. For alfalfa, fish

, crustaceans, and mollusks, average residues were assumed. Chronic dietary risk
estimates were below the LOC (i.e., <100% of the chronic population

- adjusted dose; cPAD ) for all population subgroups. The population subgr oup with the greatest exposure and risk estimate
was children 1

- 2 years old, which utilized 33 % of the cPAD.

Residential Risk: There is the potential for residential exposure from the registered uses for handlers (i.e., mixing, loading, and applying wi th manually pressurized handwands and backpack

sprayers and applying RTU products) and for individuals performing activities on treated turf, in treated gardens, and in aquatic are a s

. For most short

- term residential handler and all post

application exposu re scenarios, there are no risk estimates of concern associated with the use of diquat (i.e., margins of exposure (MOEs) ≥ 100 for dermal or incidental oral and MOEs ≥ 30 for inhalation) . However, there are inhalation risk estimate s of concern to handlers using backpack sprayers to apply to gardens, trees and turf (lawns), and aquatic areas, such as recreational/backyard ponds.

Spray Drift: T he existing turf post

- application assessment is considered protective of spray

- drift exposure based on the maximum application rate on crops and the existing turf application rates; therefore, a separate quantitative spray drift assessment was not conducted. Dermal and incidental oral post

- application MOEs for turf were not of concern (MOEs ≥ 100).

Aggreg ate Risk: In accordance with the FQPA, the HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential

exposures. For diquat, acute and chronic aggregate estimates are equivalent to the acute and chronic dietary estimates, respectively, and are not of concern. For short

- and intermediate

- term exposures, several scenarios were of concern based on residential handler risk alone ; therefore, those scenarios cannot be used in aggregate a ssessment (i.e., these scenarios will also be ofDiquat Dibromide Human Health Risk Assessment D414147

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Page 6 of 53 

### concern for aggregate) . Using the worst

- case residential scenarios that were not of concern,
short

- and intermediate

- term aggregate MOEs were not of concern (i.e., MOEs ≥100).

Occupational Risk: There is the potential for occupational exposure from the registered uses of diquat. There are no dermal short

- or intermediate

- term occupational risk estimates of concern at baseline (i.e., no gloves) associated with the existing uses of diquat (i.e., MO Es ≥ 100). Some occupational scenarios reached acceptable inhalation MOEs at baseline (i.e., no respirator); however, several exposure scenarios presented risk estimates of concern (MOE <30) at baseline and reached acceptable MOEs with the addition of a r espirator or engineering controls . Current label personal

- protective equipment (PPE) does not require occupational handlers to wear respirator s

. Mixing/loading/applying diquat for mechanically pressurized handgun s application in greenhouses did not reach acceptable MOE s even with maximum PPE.

An occupational dermal post

- application assessment was conducted for workers performing golf
course maintenance activities on treated turf . There were no risk s of concern (i.e., MOEs ≥ 100).
A n occupational post

- application risk assess ment was not conducted for pre

- and post

- harvest desiccant/defoliant burn

- down uses , turf applications to industrial areas

, or aquatic uses since workers are not expected to be in these areas post

- treatment or conducting activit ies that would lead to exposure

.

Environmental Justice: Potential areas of environmental justice concerns, to the extent possible, were conside red in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to A ddress Environmental Justice in Minority Populations and Low

- Income Populations," http://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf.

Review of Human Research: This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. Please refer to Appendix G for a discussion of the human study data used in this risk assessment.

2.0 HED Recommendations

No additional residue chemistry or toxicological data are required for R egistration R eview. No label changes are required based on residue chemistry. Current tolerances need updated as
discussed below (Section 2.2.2)

.

HED calculat ed inhalation risk estimates that are of concern for residential and occupational
handlers

. For several occupational scenarios, acceptable MOEs were reached with the addition of a respirato r or engineering controls. Additionally, aquatic use labels need clarification as to whether aerial applications are allowed as part of the surface spray application directions for use.

2.1 Data Deficiencies

There are no data deficiencies for the Registration Review of diquat.Diquat Dibromide Human Health Risk Assessment D414147

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Page 7 of 53 

### 2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

The Pesticide Analytical Manual (PAM) Vol. II. lists a spectrophotometric method, designated as Method A (also referenced as Chevron Chemical Company RM

- 8

- 7) as available for the enforcement of tolerances for residues of diqu at per se in/on plant and in livestock commodities. In this method, residues are extracted with sulfuric acid to free diquat from the bound state, absorbed on cation exchange resin, and eluted with saturated ammonium chloride. The diquat in
the eluate is reduced with the addition of sodium dithionate, forming an intense green color and is measured spectrophotometrically at 337 μm. The limit of quantitation (LOQ) is 0.01 ppm.

The HED has determined that analytical method number RAM 272/02 (“The Determination of Residues of Paraquat and Diquat in crops and Soil

– A High Performance Liquid Chromatographic Method”) is scientifically acceptable as an enforcement method for the
determinati on of residues of diquat in crops, including oil seed crops ( B. Daiss , 12

- MAY

- 2010; D375811 ). RAM 272/02 has a LOQ in the range of 0.01

- 0.05 ppm depending on the crop type and mass of sample analyzed. With this method, samples are extracted by refluxing in dilute sulfuric acid. The filtered digest is diluted and percolated through a column of cation

- exchange
resin that retains diquat. The column is washed with hydrochloric acid, ammonium chloride solution to remove endogenous materials. Diquat residues are eluted with saturated ammonium chloride solution. A portion of the column eluent is passed through a preconditioned C18 solid

phase extraction cartridge to remove further co

- extractives. Final determination of diquat residues is made using ion

- pair high

- performance liquid chromatography/ultraviolet (HPLC/UV).

The data requirements for multiresidue methods (MRMs) are fulfilled. The FDA's PESTDATA dated 11/6/90 (Pam Vol. I, Appendix) indicates that recovery of diquat using Multiresidue
Protocols is unlikely. The updated PESTDATA dated 08/93 does not have an entry for diquat.

2.2. 2 Tolerance Recommendations

Permanent tolerances have been established in 40 CFR §180.226 for residues of the plant growth regulator and herbicide diquat, (6,7

- dihydrodip yrido (1,2

- a:2′1′

- c)pyrazinediium) derived from application of the dibromide salt and calculated as the cation in/on various raw agricultural commodities, ranging from 0.02 ppm to 20.0 ppm.

Appendix C is a summary of the established and HED

- recommended to lerances for residues of diquat per se

.

2.3 International Harmonization

The U.S. residue definitions are harmonized with Canada and Codex. The U.S. tolerances and
Canadian and Codex maximum residue limits (MRLs) are harmonized for several commodities ( bulb vegetables, potato, pome fruit, and stone fruit). For several commodities, the U.S.
tolerances are harmonized with either the Canadian or the Codex MRL (livestock commoditie s, berry and small fruit group, cereal grain group, tree nuts, cucurbit vegetables, root and tuber vegetables, and beans (dry)). For bananas and coffee, HED is recommending that the U.S. tolerances (0.05 ppm) be harmonized with the Codex MRLs (0.02 ppm) a s there are no U.S.Diquat Dibromide Human Health Risk Assessment D414147

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Page 8 of 53 

### registrations for these crops. For the following crops, the U.S. tolerance values are either significantly higher or lower than the Canadian and/or the Codex MRLs, precluding harmonization: canola, milk, citrus fruit, Brassica leafy v egetables, foliage of legume vegetables, fruiting vegetables, oilseeds, and legume vegetables (except dry beans). For a summary of U.S. tolerances and international MRLs, refer to Appendix F

.

2.4 Label Recommendations

A summary of risk estimates has bee n provided, and shows that there are residential and occupational risk estimates of concern for registered uses of diquat based on the use information,
label

- required PPE, and restricted

- entry intervals ( REIs )

.

Additionally, a quatic use labels need clarification as to whether aerial applications are allowed as part of the surface spray application directions for use (see Section 6.5)

.

3.0 In troduction

3.1 Chemical Identity

The chemical structure and nomenclature of diquat is presented in Table 3.1.1.

Table 3.1.1. Nomenclature for Diquat.
Chemical Structure

Common name Diquat dibromide Company experimental name NA
IUPAC name 9,10

- dihydro

- 8a,10a

- diazoniaphenanthrene dibromide
CAS name 6,7

- dihydrodipyrido[1,2

- a :2′,1′

- c ]pyrazinediium dibromide
CAS # 85

- 00

- 7, 2764

- 72

- 9 (cation)



### 3.2 Physical/Chemical Characteristics

Pure diquat dibromide is an odorless, colorless to yellow crystal. It is hydrophilic with a log

octan ol

- water partition coefficient ( K ow 

### ) of

- 4.60 and very soluble in water, slightly soluble in alcohol and hydroxylic solvents, and insoluble in non

- polar organic solvents. It is susceptible to ultraviolet decomposition. It has a low vapor pressure of <1×1 0

- 8 

### mm Hg at 25°C. A detailed description of the physicochemical properties of diquat is provided in Appendix D

.

3.3 Pesticide Use Pattern

D iquat is used as an herbicide/algaecide, and is formulated as a soluble concentrate (SC) and a
RTU intended for use on aquatic, terrestrial, and non

- terrestrial weeds, and as a pre

- harvest desiccant and post

- harvest defoliant on various crops. T olerances derived from application of diquat in/on food commodities include alfalfa, bananas, canola, coffee, clover, potatoes

, and livestock commodities. Based on aquatic application of diquat and use of irrigation waterDiquat Dibromide Human Health Risk Assessment D414147

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Page 9 of 53 

### containing residues of diquat, tolerances have been established for residues in/o n additional commodities/crop groups (see Appendix C)

.

Diquat is appl ied by direct pouring, handheld or mechanical sprayer, injection below the water surface, aircraft, and ground equipment. Maximum application rates vary according to use descript ion. Maximum application rates for occupational use sites range from 0.25 lb / A to 0.5 lb ai/acre for terrestrial, non

- crop terr estrial, and farmland uses

, and 4 lb ai/acre /4 ft to 0.04 lb ai/gal for applications to aquatic areas such as lakes and ponds. Maximum application rates for residential use sites range from 0.5 lb ai/acre to 0.01 lb ai/gal for gardens, trees, and turf (resistant dormant Bermuda and Zoysia) and up to 0 .000092 lb ai/ft 2 

### for aquatic uses such as backyard ponds. Appendix E provides a summary of the registered uses of diquat.

3.4 Anticipated Exposure Pathways

Based on the registered diquat application scenarios, dietary exposure is an anticipated exposur e pathway as residues of diquat may be found in/on crops, livestock commodities, and drinking water. There are residential and aquatic uses of diquat and potential for spray drift, so there is exposure in residential and non

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

- application exposure for workers re

- entering treated sites. This
risk assessment considers all of the aforementioned exposure pathways based on the existing uses of diquat.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf) . As a part of every pesticide risk assessment, the Office of Pesticide Programs ( 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 pa tterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA’s NHANES/WWEIA and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessme nts are performed when conditions or circumstances warrant. Whenever appropriate, non

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

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider lifestyle and traditional dietary patterns among spe cific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

4.1 Toxicology Studies Available for Analysis

The toxicological database for diquat is complete and adequate for hazard characterization, toxicity endpoint selection, and FQPA SF evaluation. Since the last risk assessment (B. Daiss;Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 10 of 53 

### 12

- MAY

- 2010; D372014), an acceptable immunotoxicity study ha s been submitted and
reviewed.

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

Diquat was poorly absorbed from the intestinal tract when administered orally as 14 

### C

- diquat
dibromide with approximately 90% of the radioactivity eliminated via the feces following oral dosing. After a subcutaneous injection to circumvent the intestine, nearly a ll of the labeled material was recovered in the urine after 2 days . This is consistent with the physical/chemical properties of diquat indicating it is a highly hydrophilic compound (log K ow 

### =

- 4.6) . Diquat did

not significantly accumulate in tissues by either route of administration. Some retention was noted in the kidney after repeated oral dosing . I ntravenous injection results indicated diquat concentrated in cartilaginous tissues, liver, and urinary bladder, as well as the brain and spinal
cord.

Rats excreted 6.3% and 89.3% of the radioactivity in the urine and feces, respectively, within 4 days following oral exposure, with most being excreted within the first 48 hours

. In the urine, most of the excreted radioactivity (5.3%) was the unchanged pa rent compound

, whereas the remaining 1% was associated with diquat monopyridone (0.2%) , diquat dipyridone (0.1%) , and
unidentified metabolites ( 0.3% )

. In the feces, 65.5% of excreted radioactivity was detected in
the sulfuric acid

- extractable fraction and 15.7% in the ammonium sulfate

- unextractable fraction. In the sulfuric acid fraction, the radioactivity was distribute d as unchanged diquat ( 57.1% )

, diquat monopyridone ( 4.3% ) , and unidentified material (4.1%)

. The ammonium sulfate fraction

wa s not analy zed for metabolites. Following subcutaneous injection, most the radioactivity (87.1%) was excreted as unchanged parent in the urine after 4 days.

4.2.1 Dermal Absorption

In a rat dermal

- penetration study (MRID 41238701 ) 

### , absorption of diquat was found t o be relatively low following application of 0.05, 0.5, and 5 mg diquat cation/rat to a 10

- cm 2 

### area for
2

- , 10

- , and 24

- hour exposures. After 10 hours of exposure, absorption (sum of dose measured on/in skin, blood, urine, feces, carcass, and cage wash) was 5.5%, 5.5%, and 2.5% at 0.05, 0.5, and 5 mg/rat, respectively.

A human dermal absorption study from the literature (MRID 43736616) 1 

### was cited by the registrant in comments to the Tolerance Reassessment Eligibility Document (TRED) (B. Daiss;
25

- MAR

- 2002; D281890). The study has been subj ected to ethics review and was used to update dermal exposure values originally reported in the TRED (B. Daiss; 13

- MAR

- 2002 ; D28163 ). Using the data from this human study, a dermal absorption factor (DAF) of 0.3% will be applied to convert oral doses to dermal equivalent doses s ince an oral toxicity study was
selected to assess risks from der mal exposur es (see Section 4.5)

.

4.3 Summary of Toxicological Effects

T he eye was a target organ following subchronic and chronic oral exposures in rats, mice, and dogs causing opacity, lesions, discharge, and cataracts. The physical properties of diquat indicate it is highly hydrophilic and such chemicals will often cause ocular effects due to the

1 Feldman, RJ and Maibach, HI. 1974. Percutaneous penetration of some pesticides and herbicides in man. Tox. Appl. Pharm. 28: 126

- 132.Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 11 of 53 

### high water content of the eye

. Clinical signs and body weight decrements were noted throughout the database following acute, subchronic, and chronic exposures to diquat. The majority of the clinical signs in rats, mice, and dogs were associated with ocular toxicity ( e.g., eye discharge, opaque eyes) or general systemic toxicity ( e.g., diarrhea, urinary incontinence, lack of

gro oming). Clinical signs associated with general systemic toxicity were also seen in rabbits; however, there were no ocular effects observed in this species. In several studies, including the acute neurotoxicity study, there was evidence of potential neuro toxicity based on increased incidence of piloerection, abnormal posture and gait, and subdued behavior; however, these signs are most likely indicative of overt toxicity rather than direct neurotoxicity since they were only seen at the highest dose tested and are consistent with those observed at overtly toxic doses in other studies following diquat exposure.

There was no evidence of increased pre

- or post

- natal susceptibility. The maternal/parental
effects were consistent with those seen in the toxicolo gical database

, and observed at doses at or below those producing developmental (decreased fetal body weights and skeletal variations) or offspring (reduced number of live pups , kidney lesions, and body weight decrements) effects.

An acceptable r oute

- spec ific inhalation subchronic toxicity study in rats is available for diquat.
P ortal of entry effects occurred at doses much lower than those eliciting oral toxicity and
consisted of microscopic lung lesions and increased lung weights in both sexes.

4.4 S afety F actor for Infants and Children (FQPA Safety Factor)

The diquat risk assessment team recommends that the 10X FQPA SF be reduced to 1X for all exposure scenarios. The exposure databases are sufficient to determine the nature/magnitude of
the residue in food

, and dietary exposure analyses are unlikely to underestimate risk of exposure
from diquat . Additionally, t here is no evidence of increased offspring sensitivity/susceptibility in
the database. Although there is evidence of potential neurotoxicit y in the database, the effects
are well

- characterized with clearly established NOAEL/LOAEL values

, and selected endpoints are protective for the observed effects.

4.4 .1 Completeness of the Toxicology Database

The existing toxicological database is comple te and adequate for characterizing diquat toxicity and quantifying hazard for dietary , residential

, and occupational exposures. The developmental toxicity studies in rats, rabbits, and mice

, as well as the two

- generation reproduction toxicity study in rat s , are available to assess potential fetal/offspring sensitivity. The acute and chronic neurotoxicity studies are available to assess potential neurotoxicity.

4.4.2 Evidence of Neurotoxicity

Although there was evidence of potential neurotoxicity (increa sed incidence of piloerection, abnormal posture and gait, and subdued behavior) in several studies in the diquat database

, concern is low since 1) the effects are well

- characterized with clear NOAEL/LOAEL values, 2) there was no additional evidence of pote ntial neurotoxicity in the rest of the database, including the subchronic neurotoxicity study, and 3) selected endpoints are protective of the observed
effects.Diquat Dibromide Human Health Risk Assessment D414147

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Page 12 of 53 

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

There was no e vidence of increased offspring sensitivity/susceptibility following diquat

exposure.

4.4.4 Residual Uncertainty in the Exposure Database

The exposure databases are sufficient to determine the nature/magnitude of the residue in food and drinking water

. The dietary exposure analyses are unlikely to underestimate exposure as they incorporated tolerance

- level residues

, 100% CT , and MCL

- level residues in water

. The residential post

- application exposure assessments are based upon the 2012 R esidential S tandar d
O perating P rocedures (SOPs). These assessments of exposure are not likely to underestimate the resulting estimates of risk from exposure to diquat

.

4.5 Toxicity Endpoint and Point of Departure Selections

Since the last risk assessment for diquat, the classification of the mouse developmental study has been changed to unacceptable due to poor dosing/intubation errors. Additionally,
NOAEL/LOAEL values and statements have been updated for the developmental rat, developmental rabbit , and chronic dog s tudies to reflect current policies. The changes in these decisions did not impact the studies selected for endpoint selection; however, the value for the point of departure (POD) was revised for incidental oral and dermal exposures to reflect the updated NOAEL/LOAEL value s in the developmental rabbit study. Additional studies in the database were not updated to reflect current policies since these changes would not affect current PODs and the selected endpoints are protective of all effects seen in the di quat database.

Acute Dietary (all populations): The acute reference dose (aRfD) for all populations was established using the NOAEL of 75 mg/kg/day from the acute neurotoxicity study. The LOAEL of 150 mg/kg/day is based on increased incidence of clinica l signs, such as piloerection, diarrhea, urinary incontinence, upward curvature of the spine, and subdued behavior. Similar clinical signs were seen in the developmental studies in rats and rabbits at lower doses, but only after repeated dosing. This stu dy is appropriate for the duration and route of exposure. There were no other effects in the database considered to be attributable to a single dose. The aPAD of 0.75 mg/kg/day is derived from the NOAEL of 75 mg/kg/day and a 100

- fold uncertainty factor ( UF) (10X for interspecies extrapolation, 10X for intraspecies variation, and 1X for FQPA SF).

Chronic Dietary (all populations): The chronic reference dose (cRfD) for all populations was established using the NOAEL of 0.5 mg/kg/day from the chronic oral toxicity study in dogs. The
LOAEL of 2

. 5 mg/kg/day is based on cataracts in females. Similar NOAEL/LOAEL values were obtained in the rat reproduction toxicity and rat chronic/carcinogenicity studies. T he chronic oral toxicity study in dogs is appropriat e for the d uration and route of exposure. The study is protective of effects seen following chronic exposure in all species

. The c PAD of 0.00 5 mg/kg/day is derived from the NOAEL of 0 .5 mg/kg/day and a 100

- fold UF (10X for interspecies extrapolation, 10X for intraspecies variation, and 1X for FQPA SF).

Short

- and In termediate

- Term Incidental Oral : The developmental toxicity study in rabbits was selected to evaluate incidental oral exposures ( maternal NOAEL = 3 mg/kg/day). The maternal LOAEL of 10 mg/ kg/day is based on an increased incidence of clinical signs (diarrhea, subdued

app earance, and thin appearance). The endpoint is appropriate for the duration and route ofDiquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 13 of 53 

### exposure. Although the effects were seen in adult animals, similar NOAEL/LOAEL valu es were seen for offspring in the reproduction toxicity study; therefore

, it is still considered appropriate for the population of concern. The LOC for incidental oral exposure s is for MOEs less than 100 (10X for interspecies extrapolation, 10X for intraspecies variation, and 1X for FQPA SF).

Short

- and Intermediate

- Term Dermal: The developmental toxicity study in rabbits was selected to evaluate incidental oral exposures (maternal NOAEL = 3 mg/kg/day). The maternal LOAEL of 10 mg/kg/day is based on an increased incidence of clinical signs (diarrhea, subdued appearance, and thin appearance). The endpoint is appropriate for the duration of exposure. Although subchronic dermal toxicity studies are available for diquat in the rat and rabbit, the se

s tudies were not selected due to concerns that the skin was compr om ised. As a result, an oral study was selecte d to evaluate dermal exposure. The LOC for dermal exposures is for MOEs
less than 100 (10X for interspecies extrapolation, 10X for intraspecies variation, and 1X for FQPA SF when applicable ). Since an oral study was selected, a DAF of 0.3 % should be applied for all dermal exposure scenarios.

Short

- and Intermediate

- Term Inhalation: The route

- specific subchronic inhalation study in rats
was sele cted to evaluate inhalation exposures with a NOAEL of 0.1 μg/L. The LOAEL of 0.49 μg/L is based on increased mean lung weights and microscopic lesions

. Human

- equivalent concentrations (HECs) for residential and occupational scenarios were derived using the NOAEL and the regional deposited

- dose ratio (RDDR ). The RDDR accounts for the particulate diameter [mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD)] and estimates the different dose fractions deposited along the respiratory tract

. The RDDR also accounts for interspecies differences in ventilation and respiratory tract surface areas

. For the subchronic inhalation toxicity study with diquat, a RDDR was estimated at 0.591 based on the pulmonary effects s een at the LOAEL of 0.49 μg /L, with a MMAD of 1.9 μm and GSD of 1.9

.

Human

- equivalent doses were subsequently calculated from the HECs for residential and occupational handler scenarios

. For occupational handlers, human

- equivalent doses of 0.0025,
0.00 51, and 0.0088 mg/kg/day correspond to breathing rates of 8.3 L/min, 16.7 L/min, and 29
L/min

. For residential handlers and swimmers , the human

- equivalent dose of 0.0017 mg/kg/day is only calculated for the 16.7 L/min breathing rate

. HEC and human

- equiva lent dose
calculations are summarized in Appendix B

. The standard interspecies extrapolation UF can be reduced from 10X to 3X due to the calculation of HECs accounting for pharmacokinetic (not pharmacodynamic) interspecies differences

. Therefore, the LOC for inhalation exposures is for
MOEs less than 30 (3X for interspecies extrapolation, 10X for intraspecies variation, and 1X for FQPA SF when applicable ).

4.5.1 Recommendation for Combining Routes of Exposures for Risk Assessment

Based upon common effects and the use the rabbit developmental toxicity study for incidental
oral and dermal route s, these exposu res can be combined. Common effects were not seen in the

route

- specific inhalation study in rats ; therefore, inhalation exposu res may not be combined with
these routes.

4.5. 2 Cancer Classification and Risk Assessment Recommendation

Diquat is classified as a Category E (evidence of non

- carcinogenicity to humans) chemical based on no evidence of carcinogenicity in rats and mice. The weight of evidence was predominantlyDiquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 14 of 53 

### negative for mutagenicity.

4. 5

. 3 Summary of Points of Departure and Toxicity Endpoints Used in Human Health Risk Assessment

Table 4.5. 3 .1. Summary of Toxicological Doses and Endpoints for Diquat for Use in Dietary and Non

Occupational Human Health Risk Assessments.

Exposure/ Scenario POD Uncertainty/ FQPA SF RfD, PAD, LOC

for Risk
Assessment Study and Toxicological Effects

Acute Dietary (All populations) NOAEL =

7 5 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X aRfD =

0.7 5 mg/kg/day

aPAD =
0.7 5 mg/kg/day Acute Neurotoxicity Study in Rats

LOAEL = 150 mg/kg/day bas e d on clinical signs

.

Chronic Dietary (All Populations) NOAEL =

0. 5 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X cRfD =

0.0 0 5 mg/kg/day

cPAD =
0.0 0 5 mg/kg/day Chronic Toxicity in Dogs

LOAEL = 2.5 mg/kg/day based on
cataracts in females

.

Incidental Oral
Short

- Term (1

- 30 days) and
Intermediate

Term (1

- 6 months) NOAEL =

3 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X Residential LOC

for MOE = 100 Developmental Toxicity Study in

Rabbits

LOAEL = 10 mg/kg/day based on clinical signs

.

Dermal Short

Term (1

- 30 days) and
Intermediate

Term (1

- 6 months) NOAEL =

3 mg/kg/day

DAF = 0.3 % UF A = 10X

UF H = 10X FQPA SF = 1X Residential LOC

for MOE = 100 Developmental Toxicity Study in

Rabbits

LOAEL = 10 mg/kg/day based on clinical signs

.

Inhalation
Short

- Term (1

- 30 days) and
Intermediate

term (1

- 6 months) NOAEL =

0.1 μg/L UF A = 3 X

UF H = 10X FQPA SF = 1X Residential LOC

for MOE = 3 0 Subchronic Inhalation Toxicity

Study in Rats

LOAEL = 0.49 μg/L based on increased mean lung weights and microscopic lesions in the lung

. Cancer (oral, dermal, inhalation) Classified as “Category E

– evidence of non

- carcinogenicity to humans

. ”

Point of departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL =

no

- obs erved adverse

- effect level. LOAEL = lowest

- observed adverse

- effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population

- adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern.Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 15 of 53 Table 4.5. 3 .2. Summary of Toxicological Doses and Endpoints for Diquat for Use in Occupational Human Health Risk Assessments. Exposure/
Scenario POD UFs LOC for Risk
Assessment Study and Toxicological Effects

Dermal
Short

- Term (1

- 30 days)
and
Intermediate

Term (1

- 6 months) NOAEL =

3 mg/kg/day

DAF = 0.3 % UF A = 10X

UF H = 10X FQPA SF = 1X Occupational LOC

for MOE = 100 Developmental Toxicity Study in

Rabbits

LOAEL = 10 mg/kg/day based on clinical signs

.

Inhalation
Short

- Term (1

- 30 days)
and
Intermediate

term (1

- 6 months) NOAEL =

0.1 μg/L UF A = 3X

UF H = 10X FQPA SF = 1X Occupational LOC

for MOE = 30 Subchronic Inhalation Toxicity

Study in Rats

LOAEL = 0.49 μg/L based on increased mean lung weights and microscopic lesions in the lung

. Cancer (oral, dermal, inhalation) Classified as “Category E

– evidence of non

- carcinogenicity to humans

. ”

Point of departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL =

no

- ob served adverse

- effect level. LOAEL = lowest

- observed adverse

- effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern.



### 4.6 Endocrine Disruptor Screening Program

As required by Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA ) and 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, reproductive, and general or systemic toxici ty. These studies include endpoints that 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 rati os 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 re registration dec i sion for diquat , EPA reviewed th ese 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), diquat is subject to the endocrine screening part of the Endocrine Disruptor Screeni ng Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other su ch 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 i nteract with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and
establish a dose

- response relationship between the dose and the E, A, or T effect.Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 16 of 53 

### 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 i ngredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 2 

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

. Neither of these lists
should be con strued 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 an d the Tier 1 screening battery, please visit our
website. 3



### 5.0 Dietary Exposure and Risk Assessment G. Kramer, 17

- SEP

- 2015 , D417172



### 5.1 Metabolite/Degradate Residue Profile

5

. 1.1 Summary of Plant and Animal Metabolism Studies

The qualitative nature of the residue in plants (primary and rotational) is adequately understood based on an acceptable potato metabolism study and a rat bioavailability study. The HED Metabolism Assessment Review Committee (MARC) has concluded that the terminal residue of concern in plants is the diquat cation (T. Morton, 08

- NOV

- 2001; D277765). The established tolerance expression for residues of diquat in/on plant (primary and rotational) commodities is appropriate and no changes are required.

The potato metabolism study indicated that no metabolism of diquat occurred in p otato tubers following preharvest application of [ 14 

### C]

- diquat as a desiccant to potato stalks and stems. Previously submitted soybean and wheat metabolism studies were deemed marginal because of inadequate characterization and identification of 14 

### C

- residu es in the commodities of concern. In lieu of additional crop metabolism studies, HED recommended several alternatives for this requirement. The registrant opted to conduct a bioavailability study. The results of the bioavailability study showed that diq uat plant residues are largely not bioavailable; < 5% of the

14 

### C is absorbed as a result of feeding diquat field residues in/on wheat chaff to rats. In addition, there was minimal uptake of residues in the confined rotational crop study.

The qualitative n ature of the residue in livestock and fish /shellfish is adequately understood based on acceptable poultry, ruminant, and fish metabolism studies. The metabolism studies on
ruminants , fish, and poultry showed that parent compound is the only significant re sidue in muscle, fat

, and milk. In liver, kidney

, and eggs

, however, the presence of the predominant
metabolites 1

- oxo

- 1,2,3,4

- tetrahydropyrido[1,2

- a]pyrazin

- 5

- ium (TOPPS), diquat monopyridone, and diquat dipyridone indicated extensive degradation of the parent compound. The HED
MARC has concluded the residue of concern for livestock and fish /shellfish is the diquat cation (T. Morton, 08

- NOV

- 2001; D277765). The established tolerance expression for residues of diquat in livestock commodities is appropriate and no changes are required.

2 See http://www.regulations.go v/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of
chemicals.

3 See http://www.epa.gov/endo/

.Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 17 of 53 

### 5.1.2 Summary of Environmental Degradation

Diquat is persistent but essentially immobile in the environment, indicating that it will most likely be associated with the soil and sediment instead of water. The prim ary route of environmental dissipation of diquat used in terrestrial settings is strong adsorption to soil. When used as an aquatic herbicide, diquat is removed from the water column by adsorption to sediment, aquatic vegetation

, and organic matter. Base d on acceptable guideline studies, diquat does not hydrolyze or photodegrade

, and is resistant to microbial degradation under aerobic and anaerobic conditions. There were no major degradates isolated from any of the environmental fate studies.
Environmen tal fate data indicate that diquat is miscible in water (7 x 10 5 

### ppm), is stable to hydrolysis

, photolysis, and metabolism, but is essentially immobile in soil and sediment. The extent of adsorption appears to be related to soil pH, with is consistent wit h cation exchange in soil.

5.1.3 Comparison of Metabolic Pathways

The general metabolic pathways in rodents and livestock were found to be comparable, involving successive oxidations followed by cleavage of the parent molecule. No metabolites were identified in the plant and fish metabolism studies.

5. 1.4 Residues of Concern Summary and Rationale

The residues of concern in primary crops, rotational crops, livestock, and drinking water, as identified by the MARC, are shown in Table 5.1.4 below.

Table 5.1.4. Residues of Concern in Crops, Livestock, and Drinking Water.

Matrix Residues of Concern for Tolerance Expression Residues of Concern for Risk Assessment Primary Crops Diquat Diquat Rotational Crops Diquat Diquat
Livestock and fish /shellfish Diquat Diquat

Water N ot applicable Diquat



### 5.2 Food Residue Profile

Tolerances are currently established under 40 CFR §180.226(a)(1) for residues of the plant growth regulator and herbicide diquat, derived from application of the dibromide salt and calculated as the cation, resulting from direct uses of diquat. Tolerance levels range f rom 0.02 to 6.0 ppm. In addition, permanent tolerances are established under 40 CFR §180.226(a)(1) for residues of the herbicide diquat (calculated as the cation) derived from the aquatic application of the dibromide salt in/on numerous food commodities; these established tolerances range from 0.02 ppm (various plant commodities) to 20 ppm (shellfish). Tolerances of diquat have also been established under 40 CFR §180.226(a)(3) and 40 CFR §180.226(a)(4) for imported coffee and bananas and the processed com modities of soybean and potato , respectively

.

The submitted field trial residue data for all registered crops are adequate. The field trial data
reflect the registered use patterns; an adequate number of trials were conducted in the appropriate geographic regions; and samples were analyzed for the residue of concern using validated data

collection methods. The storage intervals were also validated. The data requiremen ts for magnitude of the residue in livestock and fish/shellfish are also fulfilled. There are no outstanding residue chemistry data gaps. HED is recommending that tolerances be established under 40 CFR §180.226(a)(1) for residues of diquat derived from t he aquatic application of the dibromide saltDiquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 18 of 53 

### in/on crop groups 2, 3, 18, 19, and 20 in order to support irrigation of all food/feed crops.

5.3 Drinking Water Residue Profile

As per the 2002 Tier 1 drinking water assessment 4 

### , the Office of Water’s MCL (0. 02 ppm), which is considered a worst

- case estimate, was assumed for both the acute and chronic

assessments.

5.4 Dietary (Food + Water) Risk Assessment

Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments

were conducted using DEEM

- FCID (ver. 3.16) which incorporates consumption data from the USDA NHANES/WWEIA; 2003

- 2008. For drinking water, the assessments used the MCL of 0.02 ppm, which is considered a worst

- case estimate. The acute dietary assessment assumed 100% CT and tolerance

- level residues of diquat for all foods with registered uses. Acute dietary
risk estimates were below the LOC (i.e., <100% of the aPAD) for all population subgroups. The population subgroup with the greatest exposure and risk estima te was children 1

- 2 years old, which utilized 1% of the aPAD. The chronic assessment was based on tolerance

- level residues and 100% CT for crops with direct diquat uses (except alfalfa). For crops with tolerances to cover irrigation with diquat

- treated w ater, anticipated residue levels from irrigation trials were used in conjunction with estimates of percent of crops irrigated. For alfalfa, fish

, crustaceans, and mollusks, average residues were assumed. Chronic dietary risk estimates were below the
LOC (i.e., <100% of the cPAD) for all population subgroups. The population subgroup with the greatest exposure and risk estimate was children 1

- 2 years old, which utilized 33 % of the cPAD.

Table 5.4.1. Summary of Dietary (Food + Drinking Water) Exposure and Risk for Diquat

.

Population Subgroup Acute Dietary (95 th Percentile) Chronic Dietary

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

General U.S. Population 0.007855 1 0.000808 16 All Infants (<1 year old) 0.005755 1 0.001518 30
Children 1

- 2 years old 0.009535 1 0.001673 33
Children 3

- 5 years old 0.008057 1 0.001387 28
Children 6

- 12 years old 0.006941 1 0.000942 19
Youth 13

- 19 years old 0.004296 1 0.000626 12
Adults 20

- 49 years old 0.008672 1 0.000745 15
Adults 50

- 99 years old 0.008203 1 0.000723 14
Females 13

- 49 years old 0.006255 1 0.000702 14 The highest exposure/risk estimate for each duration is bolded.



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization J. Miller, 17

- SEP

- 2015 , D427297



### 6.1 Residential Handler Exposure

The HED uses the term “handlers” to describe those individuals who are involved in the pesticide application process. The HED believes that there are distinct tasks related to

4 Tier I Drinking Water and Aquatic Ecological Exposure Assessments for Diquat Dibromide. J Bre ithaupt ( 0 5

- MAR

- 20 02, D281199)Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 19 of 53 

### applications and that exposures can vary depending on the specifics of each task. Residential handlers are addressed somewhat differently by the HED as homeowners are assumed to complete all elements of a n application (mixing, loading, and application) without use of any protective equipment.

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, short

- term residential handler dermal an d inhalation exposures are expected from the existing uses of diquat . The quantitative exposure/risk assessment developed for residential handlers is based on the following scenarios:

 Mixing/loading/applying with m anually p ressurized h andwand: gardens/trees/t urf (around the home and garden), residential lawns, ornamentals, and greenhouses

. Aquatic herbicide/algaecide uses include recreational /backyard ponds.

 Mixing/loading/applying with b ackpack s prayer: g ardens/ t rees/ t urf (around the home

an d garden). Aquatic herbicide/algaecide uses include recreational /backyard ponds.

 Applying with RTU t rigger

- s pray b ottle: gardens/trees/t urf (around the home and garden).

A series of assumptions and exposure factors served as the basis for completing the residential handler risk assessments. Assumptions and factors, as well as algorithms used to estimate non

cancer exposure and dose for residential handlers

, are detailed in the most recent occupational and residential exposure ( ORE ) assessment memo (J. M iller; 17

- SEP

- 2015; D427297 ).

Table 6.1.1 is a summary of residential handler risk estimates. For most short

- term residential
handler scenarios , there are no risk estimates of concern associated with the use of diquat (i.e., MOEs ≥ 100 for dermal a nd MOEs ≥ 30 for inhalation); h owever, the following inhalation exposure scenarios presented risk estimate s of concern for residential handlers :

 Backpack sprayer applications to gardens, trees and turf (lawns)

 A quatic uses for recreational/backyard ponds.

Table 6 .1.1. Residential Handler Non

- Cancer Exposure and Risk Estimates for Diquat.

Exposure Scenario Dermal Unit

Exposure (mg/lb ai) Inhalation

Unit Exposure (mg/lb ai) Max.

App.
Rate 1 Area Treated

or Amount Handled Daily 2 Dermal Inhalation

Dose (mg/kg/day) 3 MOE 4

(LOC = 100 ) Dose

(mg/kg/day) 5 MOE 6

(LOC = 30 )

Mixer/Loader/Applicator (Soluble Concentrate) Manually
Pressurized Handwand/ Handgun to Turf/Gardens
/Trees 63 0.018 0.01 lb ai/gal

5 gal 0.00012 25,000 0.00001 150

Backpack Sprayer

to Turf

130 0.14 0.01 lb ai/gal 0.00024 12,000 0.00008 20 Backpack Sprayer to Gardens and
Trees

Trigger

- Spray Bottle
to Gardens and 85.1 0.061 0.0025 lb ai/
bottle 7 2 bottles 0.000016 190,000 0.0000038 450Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 20 of 53 Table 6 .1.1. Residential Handler Non

- Cancer Exposure and Risk Estimates for Diquat.

Exposure Scenario Dermal Unit

Exposure (mg/lb ai) Inhalation

Unit Exposure (mg/lb ai) Max.

App.
Rate 1 Area Treated

or Amount
Handled Daily 2 Dermal Inhalation

Dose (mg/kg/day) 3 MOE 4

(LOC = 100 ) Dose

(mg/kg/day) 5 MOE 6

(LOC = 30 )

Trees

Trigger

- Spray Bottle to Gardens and
Trees 1 bottle 0.000008 380,000 0.0000019 890

Aquatic Areas

Manually
Pressurized
Handwand 63 0.018 0.000092 lb ai/ft 2 500 ft 2 0.00011 28,000 0.00001 160

Backpack Sprayer 130 0.14 0.000092 lb ai/ft 2 500 ft 2 0.00022 13,000 0.000081 21

Bolded values are below the LOC (100 for dermal and 30 for inhalation) and represent risks of concern

. 1. Application rates primarily based on use information provided by r egistrant ( supplied by email from PRD 9/5 /2014) . The use information provided was noted to be b ased primarily on representative Section 3 and 24C labels from Syngenta Crop Protection. In addition, information provided in the TRED (D281890) for diquat was used for the residential use information.
2. Based on the HED ’s SOPs for Residential Pesticide Exposure Assessment; Lawns/Turf (Feb. 2012) and Aquatic SOP. 3. Dose (mg/kg/day) = daily unit exposure (mg/lb ai) x application rate (lb ai/area treated or amount handled) x Area treate d or amount handled * absorption factor (inhalation = 0.3 %) / body we ight (80 kg). 4. Dermal MOE = NOAEL (3 mg/kg/day) / daily dose (mg/kg/day )

. LOC= 100

. 5. Inhalation Dose = daily unit exposure (mg/lb ai) x application rate (lb ai/area treated or amount handled) x Area treated or amount handled / body weight (80 kg). 6. Inhalation MOE = Human

- equivalent dose (0.0017 mg/kg/day) / daily dose (mg/kg/day). LOC = 30

.



### 6.2 Residential Post

- Application Exposure

There is the potential for post

- application exposure for individuals exposed as a result of being in
an environme nt that has been previously treated with diquat. The quantitative exposure/risk assessment for residential post

- application exposures is based on the following scenarios:

Lawns and Turf:

 High

- contact activities, mowing

, and golfing [ used on resistant dormant turf ( Bermuda grass and Zoysia grass) for weed control ].

 Incidental oral: h and

- to

- mouth (HtM), o bject

- to

- m outh (OtM), and soil i ngestion (SI)

Gardens and Trees:

 Garden activities

Aquatic Activities:

 Swimming

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

- application risk assessments. Assumptions and factors, as well as algorithms used to
estimate non

- cancer exposure and dose for residential post

- application are detailed in the most recent ORE assessment memo (J. Miller; 17

- SEP

- 2015; D427297).Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 21 of 53 

### The incidental oral scenarios (i.e., HtM and OtM ) should be considered inter

- related and it is likely that they occur interspersed amongst each other across time. Combining these scenarios with the dermal exposure scenario would be overly

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

- application exposure scenario with the highest exposure (HtM) was c ombined with dermal exposures for children 1 < 2 years old. The residential post

- application exposures are summarized in Table 6.2.1. All combined dermal and incidental oral MOEs are ≥ 100.

Table 6.2.1. Residential Post

- application Non

- cancer Exposur e and Risk Estimates for Diquat.

Lifestage Post

- application Exposure Scenario Application
Rate 1 Dose

(mg/kg/day) 2 MOEs 3 Combined Routes (X indicates
included in Combined MOE) Combined

MOEs 4 Use Site Route of Exposure /

Activity

Adult

Lawns and

Turf Dermal / High

- Contact

Activities

0.5 lb

ai/Acre 0.00060 5,300 N/A

N/A Dermal / Mowing 0.000012 260,000 N/A

Dermal / Golfing 0.000044 68,000 N/A

Child
1 to < 2 years old Dermal / High

- Contact
Activities 0.0011 2,700
X 350 Incidental Oral / Hand

to

- Mouth 0.0076 390

Incidental Oral / Object

to

- Mouth 0.00023 13,000 N/A
N/A Incidental oral / Soil Ingestion 1.7E

- 05 180,000 N/A

Child
11 to < 16 years old

Lawns and

Turf Dermal / Mowing

0.5 lb
ai/Acre 0.000013 230,000 N/A

N/A Child
11 to < 16
Years old Dermal / Golfing 0.00052 58,000 N/A

Child
6 to < 11
Years old 0.000060 50,000 N/A

N/A Adult Gardens General Activities 0.00096 31,000

N/A Child
6 < 11

years Gardens General Activities 0.00070 4,600

Adult

Aquatic (swimming) Inhalation

0.000092 lb
ai/ft 2 2.42E

- 12 7.00E+08 N/A 7.00E+08

Dermal 2.23E

- 09 1.30E+09
X 4.20E+05 Ingestion 7.20E

- 06 4.20E+05

Child
3 to < 6 years old Inhalation 2.67E

- 12 6.40E+08 N/A 6.40E+8

Dermal 1.47E

- 09 2.00E+09
X 2.50E+05 Ingestion 1.2E

- 05 2.50E+05

1 Application rates primarily based on use information provided by the r egistrant (supplied by email from PRD 9/5 /2014) . The use information provided was noted to be based primarily on representative Section 3 and 24C labels from Syngenta Crop Protection. In addition, information provided in the TRED (D281890) for diquat was used for the residential use information

. 2 Dose (mg/kg/day) equations provided in Appendix A of the most recent ORE memo (J. Miller; 17

- SEP

- 2015 ; D427297).Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 22 of 53 3 MOE = POD (mg/kg/day) ÷ Dose (mg/kg/day).
4 Combined MOE = POD (3 mg/kg/day) / (dermal dose + incidental oral dose).



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

There were certain residential handler scenarios with risks of concern for inhalation using backpack sprayer applications (LOC < 30). Since these scenarios represent risks of concern alone, they are not used in aggregate assessment (i.e., these scenarios will also be of concern for aggregate). O nly the residential exposure scenarios that were not of concern (MOE ≥ 100 for
dermal and incidental oral and 30 for inhalation) are included in the aggregate assessment.

Table 6. 3 .1 reflect s the residential risk estimates that are recommended for use in the agg regate assessment for diquat :

 The recommended residential exposure for use in the adult aggregate assessment reflects dermal and inhalation exposure from mixing/loading/applying a (SC) liquid with a manually pressurized handwand to turf, gardens

, and tree s.

 The recommended residential exposure for use in the children 1 to 2 years old aggregate
assessment reflects high

- contact activity exposures from post

- application exposure to outdoor treated turf. This lifestage is the most highly exposed population for this exposure scenario; therefore, it is considered protective of the other lifestages.

 The recommended residential exposure for use in the children 3 to 6 years old aggregate
assessment reflects post

- application exposure from swimming in treated areas. This lifestage is the most highly exposed population for this exposure scenario; therefore, it is considered protective of the other lifestages.

Table 6. 3 .1

. Recommendations for the Residenti al Exposures for the D iquat Aggregate Assessment.

Lifestage Exposure

Scenario Dose (mg/kg/day) 1 MOE 2

Dermal Inhalation Oral Total 3 (dermal + oral) Dermal

(LOC =100) Inhalation

(LOC = 30) Oral Total 3 ,4

(dermal + oral)

Adult Handler:

Manually
Pressurized
Handwand Sprayer Treating
Turf/Gardens/
Trees 0.00012 0.000011 N/A N/A 25,000 150 N/A N/A

Child 1 to 2 years
old High

- contact

Activities
from Treated
Turf 0.0011 N/A 0.0076 0.0 087 2,700 N/A 390 350

Child
3 to < 6 years old Aquatic

(swimming) 1.47E

- 09 2.67E

- 12 1.2E

- 05 1.20E

- 5 2.00E+09 6.40E+08 2.50E+05 2.50E+05

1. Dose = the highes t dose for each applicable life stage of all residential scenarios assessed (that was not of concern)

. 2. MOE = POD (mg/kg/day) ÷ Dose (mg/kg/day).
3 . Inhalation endpoint is based on a different study with different effects thus not combined with the other routes. Therefore, total = dermal + incidental oral (where applicable).
4 . Total MOE = [3.0 mg/kg/day / ( Combined dermal + oral dose )], where applicable.Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 23 of 53 

### 6.4 Residential Bystander Post

- Application Inhalation Exposure

Volatilization of pesticides may be a source of post

- application inhalation exposure to
individuals nearb y pesticide applications. The A gency sought expert advice and input on issues
related to volatilizati on of pesticides from its FIFRA Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 5 

### . The Agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis 6



### . D uring Registration Re view, 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 diquat.

6.5 Spray Drift

Off

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

target and can lead to exposures to those it may directly con tact. They can also deposit on surfaces where contact with residues can eventually lead to indirect 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 onto 50

- feet wide lawns coupled with methods employed for residential risk assessments for turf products.

The approach to be used for quantitatively incorporating spray drift into risk assessment is based on a premise of co mpliant applications which, by definition, should not result in direct exposures to individuals because of existing label language and other regulatory requirements intended to prevent them. 7 

### 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 impacted areas, such as residential lawns, when compliant applications are conducted. Given this premise, exposures for children (1 to 2 ye ars old) and adults who have contact with turf where residues are assumed to have deposited via spray drift thus resulting in an indirect exposure are the focus of this analysis analogous to how exposures to turf products are
considered in risk assessment.

Several diquat products have existing labels for use on turf, thus it was considered whether the
risk assessment for that use may be considered protective of any type of exposure that would be associated with spray drift. It should be noted that the r egistered residential uses on turf result in exposure greater than potential exposure from spray drift; therefore, no new residential assessment needs to be completed. If the maximum application rate on crops adjusted by the amount of drift expected is le ss than or equal to existing turf application rates, the existing turf assessment is considered protective of spray drift exposure. The currently registered maximum single application rate of diquat for crops is (0.5 lb ai/A) . The highest degree of spray drift noted for any application method immediately adjacent to a treated field (Tier 1 output from the aerial application using fine to med ium spray quality) results in a deposition fraction of 0.26 of the application rate. A quantitative spray drift ass essment for diquat is not required because the maximum application rate to a crop/target site multiplied by the adjustment factor for drift of 0.26 is less than the maximum direct spray residential turf application rate (0.5 lb ai/A) 8 

### for any

5 http://www.epa.gov/scipoly/SAP/meet ings/2009/120109meeting.html

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

- HQ

- OPP

- 2014

- 0219

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

8 0.5 lb ai/A x 0.26 ≤ 0.5 lb ai/ADiquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 24 of 53 

### diquat products. The turf post

- application MOEs have been previously assessed and are based on the revised SOPs for Residential Exposure Assessment (see Section 6.2).

For aquatic uses, subsurface, bottom placement, and surface applications (by aerial or handhel d equipment) may be made. Of the three applications, t he only application with the potential for spray drift is surface a pplication as a spray. Although the label does not prohibit the use of aerial applications for aquatic areas, it is unlikely aerial a pplications would be made given the types of water bodies the product is being applied to and the alternative application options (handheld application equipment). Clarification should be added to aquatic use labels regarding whether aerial applications a re allowed.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, the HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assess ment, 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, both the route and
durat ion of exposure are considered

.

For diquat , aggregate exposure and risk assessments were assesse d for the following scenarios:

acute aggregate exposure , s hort

- and intermediate

- term aggregate exposure, and chronic aggregate exposure. Diquat is classified as “Category E

– evidence of non

- carcinogenicity to humans” ; therefore

, a cancer aggregate ri sk assessment was not performed.

7.1 Acute Aggregate Risk

The acute aggregate risk is equivalent to the acute dietary risk estimates. The acute di etary exposure estimates are not of concern (<100% aPAD) for the general U.S. population and all populat ion subgroups (see Section 5.4 ).

7.2 Short

- and Intermediate

- Term Aggregate Risk

Short

- term (1 to 30 day) and intermediate

- term (1 to 6 months) aggreg ate risk assessments are necessary since there is potential for post

- application exposure from the uses of diquat in residential settings . Since the short

- term assessment as sumed no dissipation (i.e., day

- zero residues) for the entire exposure duration (u p to 30 days), and the short

- and intermediate

- term PODs are the same, the short

- term assessment is expected to be protective of intermediate

- term exposure durations.

Several scenarios were of concern based on residential handler risk from inhalation ex posure alone (see Section 6.1); t herefore, these scenarios cannot be used in the aggregate assessment.

Table 7.2.1 presents short

- and intermediate

- term aggregate risk calculations using worst

- case residential scenarios that were not of concern. Aggregate MOEs were not of concern for these scenarios (i.e., MOEs ≥ 100 ).Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 25 of 53 Table 7.2.1

. Short

- and Intermediate

- Term Aggregate Risk Calculations

.

Population Short

- or Intermediate

- Term Scenario

NOAEL mg/kg/day LOC 1 Max

Allowable Exposure 2 mg/kg/day Average

Food and
Water Exposure mg/kg/day 3 Residential

Exposure mg/kg/day 4 Total

Exposure mg/kg/day 5 Aggregate

MOE (food, water, and residential) 6

Adult 3 3 100 0.03 0.000 745 0. 00012 8.65E

- 4 34 0 0

Child
1 to 2 years old 3 100 0.03 0.001673 0.0 087 0. 01037 290

Child 3 to < 6 years old 3 100 0.03 0.001387 1.2E

- 5 0.001 40 21 0 0

1 LOC = 100 (10X intraspecies UF , 10X interspecies UF , and 1X FQPA SF)

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

. 3 Values taken from Table 5.4.1 for the appropriate population subgroup . For adults, the most highly exposed adult population subgroup was adults 20

- 49 years old.

4 Residential Exposure = [Oral exposure + Dermal exposure]. Inhalation endpoint is based on a diff erent study with different effects thus not combined. See Table 6.3.1 for recommended values for aggregate assessment.

5 Total Exposure = Avg

. Food & Water Exposure + Residential Exposure

. 6 Agg regate MOE = [NOAEL / (Avg

. Food & Water Exposure + Residenti al Exposure)]

.



### 7. 3 Chronic Aggregate Risk

There are no chronic residential exposure scenarios; therefore, the chronic aggregate risk is equival ent to the chronic dietary risk estimate . The chronic dietary exposure estimates are not of concern (<100% cPAD) for the general U.S. population and all population subgroups (see Section 5.4 ).

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 diquat and any other substances and diquat does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not
assumed that di quat has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements
rel eased by EPA’s OPP concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

9.1 Short

- /Intermediate

- Term Handler Risk

The HED uses the term handlers to describe those individuals who are involved in the pesticide application process. T here are distinct job functions or tasks related to applications and

exposures can vary depending on the specifics of each task. Job requirements ( the 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 mann er specific to each application event.Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 26 of 53 

### Based on the anticipated use patterns and current labeling, occupational handler exposure is expected from the registered uses of diquat . The quantitative exposure/risk assessment developed for occupational handle rs is based on the following scenarios:

 Mixing/loading for aerial application on typical and high

- acreage crops and aquatic areas;

 Mixing/loading for groundboom application on typical and high

- acreage crops, turf (golf courses)

, orchard/vineyard crops , a nd aquatic areas;

 Applying via aerial equipment on typical and high

- acreage crop s , and aquatic areas;

 Applying via groundboom on turf (golf course), field grown ornamentals, orchards, greenhouses, typical and high

- acreage field crops, and aquatic areas;

 Applying via mechanically pressurized handgun on rights of way/industrial areas ;

 Applying via trigger

- spray bottle on foundations/perimeters, landscaping and turf (lawns, athletic fields, parks, etc.);

 Mixing/loading/applying via a backpack sprayer for orc hard/vineyards, greenhouse use, rights

- of ways, landscaping, turf, structural areas (bridges, shipyards) ; industrial/commercial areas, foundations/perimeter, and aquatic areas (lakes/ponds);

 Mixing/loading/applying for a manually pressurized handwand for u se in greenhouses, turf (lawns, athletic fields, parks, etc.), rights of way/industrial areas, foundations/perimeters, and aquatic areas (lakes, ponds, etc.);

 Mixing/loading/applying via mechanically pressurized handgun for orchards (in and around trees), greenhouses, turf (golf courses), landscaping and turf (lawns, athletic fields, parks, etc.), industrial/commercial areas, typical field crops and aquatic areas (lakes/ponds); and

 Flagger for typical and high

- acreage field crops.

A series of assumptions a nd exposure factors served as the basis for completing the occupational handler risk assessments. Assumptions and factors, as well as algorithms used to estimate non

cancer exposure and dose for occupational handlers

, are detailed in the most recent ORE

a ssessment memo (J. Miller; 17

- SEP

- 2015; D427297). B ased on the registered uses, short

- , and
intermediate

- term exposures are expected for the following reasons: (1) type of application method (aquatic, ground directed defoliant/desiccant), and (2) max imum number of applications per year (2).

Estimates of dermal and inhalation exposure were calculated for various levels of PPE. The diquat product labels direct mixers, loaders, applicators and other handlers to wear long

- sleeved shirt and long pants, cover alls, shoes plus socks, chemical

- resistant gloves

, and protective eyewear such as goggles or face shield, chemical

- resistant headgear for overhead exposure,
chemical

- resistant apron when cleaning equipment

, and no respirator.

T he occupational handler non

- cancer exposure and risk estimates for diquat are summarized in
Table 9 .1.1. There are no dermal short

- or intermediate

- term occupational risk estimates of

concern when handlers use label

- specific PPE for the existing uses of diquat (i.e., MOEs ≥ 100). Some occupational scenarios reached acceptable inhalation MOEs (MOEs ≥ 30) at baseline /label

- specific PPE (i.e., no respirator); however, several exposure scenarios presented risk estimates of concern (MOE <30) at baseline / label

- specifi c PPE . R isk estimates were calculated for these scenarios using additional PPE or engineering controls

.

The following scenarios reached acceptable MOEs with the addition of a PF5 respirator:

 Mixing/loading for aerial applications to typical

- acreage crops and aquatic areas;Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 27 of 53 

###  Mixing/loading for groundboom applications to high

- acreage crops and aquatic areas;

 Applying with groundboom on turf (golf course), field

- grown ornamentals, orchards, aquat ic areas, and typical

- acreage field crops;

 Applying with mechanically pressurized handgun on rights of way/industrial areas;

 Mixing/loading/applying for a mechanically pressurized handgun application for use in orchards (in and around trees), industrial/co mmercial areas, and typical field crops; and

 Flagger for typical

- and high

- acreage field crops.

The following scenarios reached acceptable MOEs with the addition of a PF10 respirator:

 Mixing/loading for aerial applications to high

- acreage crops and aquatic areas;

 Applying with groundboom to high

- acreage field crops and aquatic areas; and

 Mixing/loading/applying for a mechanically pressurized handgun application in lakes/ponds.

The following scenarios reached acceptable MOEs with the addition of engi neering controls (enclosed cab) :

 Applying with groundboom to aquatic areas.

The following scenarios do not reach acceptable MOEs even with maximum PPE (engineering
controls cannot be utilized for hand

- held equipment) :

 Mixing/loading/applying for a mechanically pressurized handgun application in greenhouses.

Table 9 .1.1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Diquat.

Exposure Scenario Crop

or Target Mitigation

Level Mitigation

Level Max.

App.
Rate 2 Area
Treated

or Amount Handled Daily 3 Dermal Inhalation

Dermal Unit Exposure (μg/lb ai) 1 Inhalation

Unit Exposure (μg/lb ai) 1 Dose (mg/kg/day) 4 MOE 5

LOC = 100 Dose

(mg/kg/day) 6 MOE 7

LOC = 30

Mixer/Loader (SC)

Aerial Field Crop/ 8

Typical

Label 10

29.1 Label

0.219

0.5 lb

ai/acre 350 0.00019 16,000 Label
0.000479 11

Mitigation 9
PF 5
0.0438 Mitigation PF
5 0.0000959 53

Field Crop, High

acreage (Canola/
Potato

- Pre

- harvest) Label
0.219

1200 0.00066 4,600 Label
0.00164 3.1

Mitigation 9
PF 5
0.0438 Mitigation 9
PF 5
0.0438 16

Mitigation
PF 10 0.0219 Mitigation PF
10
0.000164 31

Aquatic Areas (lakes, ponds, etc.) Label
0.219 Mitigation
PF 10 0.0219 4 lb

ai/a cre

feet 120 acre

feet 0.00053 5,700 Label
0.00131

--------------- Mitigation
PF 10
0.000131 3.9

------------

39 Groundboom Aquatic Areas

(lakes, ponds, etc.) Label

29.1Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 28 of 53 Table 9 .1.1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Diquat.

Exposure Scenario Crop

or Target Mitigation

Level Mitigation

Level Max.

App.
Rate 2 Area Treated

or Amount Handled Daily 3 Dermal Inhalation

Dermal
Unit Exposure (μg/lb ai) 1 Inhalation

Unit Exposure (μg/lb ai) 1 Dose (mg/kg/day) 4 MOE 5

LOC = 100 Dose

(mg/kg/day) 6 MOE 7

LOC = 30

Golf Course (fairways, tees, greens)

Label
0.219

0.5 lb

ai/acre 40 0.000022 140,000 Label
0.0000548 93 Field

- grown Ornamental Crops

Orchard/ Vineyard

Field Crop/ Typical 80 0.000044 69,000 Label
0.000479 46

Field Crop, High

- acreage Label
0.219

200 0.00011 28,000 Label
0.0219 19

Mitigation
PF 5
0.0438 Mitigation
PF 5
0.00438 93

Applicator

Aerial Field crop/

Typical EC

2.08 EC

0.0049 0.5 lb

ai/acre 350 EC

0.000014 EC

220,000 0.000011 230

Field Crop, High

- acreage 1200 EC
0.000047 EC

64,000 0.000037 68

Aquatic Areas (lakes, ponds, etc.) EC

2.08 4 lb

ai/acre

feet 120 acre

feet EC
0.000037 EC

80,000 EC

0.000029 85

Groundboom Golf Course

(fairways, tees, greens)

Field

- grown Ornamental Crops

Orchard/ Vineyard

Label

12.6 Label

0.34

0.5 lb

ai/acre 40 0.0000095 320,000 Label
0.000085 29

Mitigation
PF 5
0.068 Mitigation
PF 5
0.000017 150

Field Crop, Typical Label
0.34

80 0.000019 160,000 Label
0.000085 15

Mitigation
PF 5
0.068 Mitigation
PF 5
0.000034 74

Field Crop, High

- acreage Label
0.34

200 0.000047 63,000 Label
0.0004 3 5.9

Mitigation
PF 5
0.068 Mitigation
PF 5
0.000085 29Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 29 of 53 Table 9 .1.1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Diquat.

Exposure Scenario Crop

or Target Mitigation

Level Mitigation

Level Max.

App.
Rate 2 Area Treated

or Amount Handled Daily 3 Dermal Inhalation

Dermal
Unit Exposure (μg/lb ai) 1 Inhalation

Unit Exposure (μg/lb ai) 1 Dose (mg/kg/day) 4 MOE 5

LOC = 100 Dose

(mg/kg/day) 6 MOE 7

LOC = 30

Mitigation
PF 10
0.034 Mitigation
PF 10
0.00004 3 59

Aquatic Areas (lakes, ponds, etc.) Label
0.34
4 lb

ai/acre

feet 120 acre

feet 0.000092 33,000 Label
0.0020 1.2

Mitigation
PF 10
0.034 Mitigation
PF 10
0.00020 12

EC
0.043 EC
0.00026 34

Mechanically
Pressurized Handgun Rights

- of

- way (e.g., utilities, Railroad, Roadways Label

290 Label

3.9 0.01 lb

ai/gal 1,000

gal 0.00011 28,000 Label
0.000488 18

Mitigation
PF 5
0.078 Mitigation
PF 5 0.00009 8 90

Trigger

- Spray bottle (R

- T

- U) Foundations/

Perimeter
Label

11100 Label

61.2 0.0045

lb ai/bottle 2

bottles 0.00000021 14,000,000 0.00000 3 8 1,300 Landscaping, T urf (lawns, athletic fields, parks, etc.)

Flagger (SC)

Aerial Field Crop /

Typical
and High

- acreage Label

10.6 Label

0.35 0.5 350 0.000070 43,000 Label
0.000766 11

Mitigation
PF 5
0.000154 57

Mixer/Loader/Applicator (SC)

Backpack Sprayer Orchard/

Vineyard (Ground/soil

directed)

Label

4120 Label

2.58 0.01 lb ai/gal 40 gal 0.000062 48,000 0.0000129 400 Rights

- of

- way (e.g., utilities, railroad, roadways)
Landscaping, Turf (lawns, athletic fields, parks, etc.) Spot Treatment

Foundations/
Perimeter

Aquatic Areas (lakes, ponds, etc.) 0.04 lb ai/gal 0.00025 6,100 0.0000516 99Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 30 of 53 Table 9 .1.1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Diquat.

Exposure Scenario Crop

or Target Mitigation

Level Mitigation

Level Max.

App.
Rate 2 Area Treated

or Amount Handled Daily 3 Dermal Inhalation

Dermal
Unit Exposure (μg/lb ai) 1 Inhalation

Unit Exposure (μg/lb ai) 1 Dose (mg/kg/day) 4 MOE 5

LOC = 100 Dose

(mg/kg/day) 6 MOE 7

LOC = 30

Structural (e.g., bridges, shipyards, home decks, foundations) Label

1600 Label

30 0.01 lb ai/gal 0.000024 130,000 0.00015 59 Industrial/
C ommercial (tires, rail yards, junk yards, etc.)

Manually

pressurized
Handwand Greenhouse

(ornamentals, roses, cut flowers, container stock, vegetables)

Label

365 Label

30 0.01 lb

ai/gal

40 gal 0.0000055 550,000 0.00015 59 Landscaping, Turf (lawns, athletic fields, parks, etc.)

Industrial/ Commercial

Foundations/
Perimeter

Structural (e.g., bridges, shipyards, home decks, foundations)

Aquatic Areas (lakes, ponds, etc.) Label

365 Label

30 0.04 lb

ai/gal 0.000022 140,000 Label
0.0006 15

Mitigation
PF5
6 Mitigation
PF 5
0.00012 73

Mechanically

pressurized Handgun Orchard/

Vineyard
Drench/Soil

- /Ground

- directed Industrial/ Commercial / Field crop, Typical Label

290 Label

3.9

0.01 lb

ai/gal 1000 gal 0.00011 28,000 Label
0.000488 18

Mitigation
PF 5
0.078 Mitigation
PF 5 0.00009 8 90

Greenhouse (ornamentals, roses, cut flowers, container stock, vegetables)
Drench/Soil

- /Ground

- directed Label

1,600 Label

120

0.00060 5,000 Label
0.015 0.59

Mitigation
PF 5
24 Mitigation
PF 5
0.003 2.9

Mitigation
PF 10
12 Mitigation
PF 10
0.0015 5.9

Golf Course (fairways, tees, greens) Label

450 Label

1.9 0.5 lb ai/Acre 5 acres 0.000042 71,000 0.0000594 86Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 31 of 53 Table 9 .1.1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Diquat.

Exposure Scenario Crop

or Target Mitigation

Level Mitigation

Level Max.

App.
Rate 2 Area Treated

or Amount Handled Daily 3 Dermal Inhalation

Dermal
Unit Exposure (μg/lb ai) 1 Inhalation

Unit Exposure (μg/lb ai) 1 Dose (mg/kg/day) 4 MOE 5

LOC = 100 Dose

(mg/kg/day) 6 MOE 7

LOC = 30

Landscaping, T urf (lawns, athletic fields, parks, etc.)

Aquatic Areas (lakes, ponds, etc.) Label

290 Label

3.9

0.04 lb

ai/gal 1000 gal 0.00044 6,900 Label
0.00195 4.5

Mitigation
PF 5
0.078 Mitigation
PF 5
0.00039 23

Mitigation
PF 10 0.39 Mitigation
PF 10 0.000195 45

Bolded values are below the LOC (100 for dermal and 30 for inhalation).
1

. Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( 201 3 ); Level of mitigation: Label specific and PPE

- (respirator).
2

. Based on Appendix E. 3

. Exposure Science Advisory Council Policy #9. 0

., draft Aquatic SOP September 2013.
4

. Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) × DAF ( 0.3 %) ÷ BW (80 kg).
5

. Dermal MOE = Dermal NOAEL (3 mg/kg/day) ÷ Dermal Dose (mg/kg/day).
6

. Inhalation Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW (80 kg).
7

. Inha lation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). NOAEL = 0.0025, 0.0051, 0.0088 mg/kg/day for breathing rates of 8.3, 16.7, and 29 L/min, respectively. 8. Field Crop/Typical : carrots, coriander, radishes, spinach, sugar beets, tab le beets, turnips, calendula, tomato vines, cantaloupe vines, cucumbers, squash, watermelon vines, acorn squash, peppers, eggplant, green pepper, tomato, green peppers, tomatoes. 9. Mitigation: Level of PPE above what is currently required on the labels needed to achieve a MOE = 30 for inhalation exposure.
10. The diquat product labels direct mixers, loaders, applicators and other handlers to wear long

- sleeved shirt and long pants, coveralls, shoes plus socks, chemical

- resistant gloves and protective eyew ear such as goggles or face shield, chemical

- resistant headgear for overhead

exposure, chemical

- resistant apron when cleaning equipment and no respirator.



### 9.2 Occupational Post

- Application Exposure

The 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 previous ly treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. In the case of post

- harvest treatment, post

- application activities include sorting and packing the treated crop. Post

- ap plication 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 application
method , and the chemical’s degradation properties.

9.2.1 Occupational Post

- application Inhalat ion 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 re

- suspension of dusts and/or particulates that contain pesticides. The A gency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009, and received the SAP’s final report on MarchDiquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 32 of 53 

### 2, 2010 9 

### . Th e A gency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis 10 

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

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

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

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

9.2.2 Occupational Post

- application Dermal Exposure/Risk Estima tes

D ue to the nature of the chemical ( desiccant /defoliant herbicide ) a nd the exposure scenarios (pre

and post

- harvest for the control of weeds and aquatic uses), a quantitative occupational post

application dermal exposure assessment was not warranted for most diquat use patterns

. However, a dermal post

- application assessment was completed for the registered golf course turf

uses to address exposure to workers performing maintenance activities on golf courses after the application of diquat since diqu at can be applied to dormant turf to control weeds and nuisance grasses in certain seasons.

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

- application risk assessment. Each assumption and factor i s detailed in the most recent ORE memo (J. Miller; 17

- SEP

- 2015 ; D427297 ). Chemical

- specific dislodgeable foliar residue "turf"
data ha ve been s ubmitted for diquat; h owever, the Agency

- preferred method (the m odified
California r oller method ) was not used for data gathering . This assessment uses HED’s default assumption that 1% of the application is available for transfer on day 0 following the application and the residues dissipate at a rate of 10% each following day. Post

- application derma l MOEs

w ere not of concern (i.e., MOEs ≥ 100).

Table 9.2.2.1. Occupational Post

- application Non

- Cancer Exposure and Risk Estimates for Diquat.

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

Short

- and Intermediate

- T erm

Turf: Golf Course Maintenance 3700

0.056 0.000062 48,000

Maintenance/greens only 2500 0.000042 71,000

1 TTR = Application Rate × F × (1

- D) t × 4.54E8 μg/lb × 2.47E

- 8 acre/cm 2 ; where F = 0.1 and D = 0.10 per day

. 2 Daily Dermal Dose = [DFR (μg/cm 2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption ( 0.3 %)]  BW (80 kg).

3 MOE = POD ( 3 mg/kg/day) / Daily Dermal Dose. Daily Dermal Dose = [DFR/TTR (μg/cm 2 ) × TC × 0.001 mg/μg × 8 hrs/day × DAF (0.3 %)]  BW (80 kg).



### Restricted

- Entry Interval (REI)

Diquat exhibits low acute toxicity via the oral (Toxicity Category II for technical, III for formulation) and inhalation (Toxicity Category III) routes of exposure but is moderately

- to

severely toxic via the dermal route of exposure (Toxicity Categories I for technical and II for formulation). Diquat is not an acute skin irritant (Toxicity Category IV) nor a dermal sensitizer,

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

10 http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 33 of 53 

### but it is considered a moderate

- to

- severe eye irritant (Toxicity Category II). Although s hort

- an d
intermediate

- term post

- application risk estimates were not of concern on day 0 (12 hours after application) for any post

- application activities , the appropriate REI is based on acute toxicity via the dermal route of exposure (Toxicity Categories I for te chnical and II for formulation)

. Accordingly

, HED recommend s a n REI of 48 hours per 40 CFR 156.208 (c) (2) (i )

. The current product labels require a 24

- hour REI.

cc: M. Perron, G. Kramer, J. Miller RDI: RAB1 ( 17

- SEP

- 2 01 5 )
M.M. Perron:S10955:PY

- S:(703)347

- 0395:7509P:RAB1Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 34 of 53 

### A ppendix A

. Toxicology Profile

A.1 Toxicology Data Requirements

Study requirements (40 CFR 158.340) for diquat are presented below. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Study Technical Required Satisfied 870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ .................. 870.1300 Acute Inhalation Toxicity

................................ .............. 870.2400 Acute Eye Irritation

................................ ....................... 870.2500 Acute Dermal Irritation

................................ ................. 870.2600 Skin Sensitization

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

yes
yes
yes
yes
yes 870.3100 90

- Day Oral Toxicity (rodent)

................................ ...... 870.3150 90

- Day Oral Toxicity (nonrodent)

................................ 870.3200 21/28

- Day Dermal Toxicity

................................ .......... 870.3250 90

- Day Dermal Toxicity

................................ ............... 870.3465 90

- Day Inhalation Toxicity

................................ ........... no 1

no 2

yes

no
yes --

-- yes

-- yes 870.3700a Prenatal Developmental Toxicity (rodent)

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

.............. 870.3800 Reproduction and Fertility Effects

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

yes
yes 870.4100a Chronic Toxicity (rodent)

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

................................ ........ 870.4200a Carcinogenicity (rat)

................................ ...................... 870.4200b Carcinogenicity (mouse)

................................ ............... 870.4300 Combined Chronic Toxicity/Carcinogenicity

............... yes
yes
yes
yes
yes y es 3

yes
yes 3

yes
yes 870.5100 Mutagenicity

— Bacterial Reverse Mutation Test

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

— Mammalian Cell Gene Mutation Test

.. 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations

.. 870.5xxx Mutagenicity

— Other Genotoxic Effects

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

yes
yes
yes 870.6200a Acute Neurotoxicity Screening Battery (rat)

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

- Day Neurotoxicity Screening Battery (rat)

.............. 870.6300 Developmental Neurotoxicity

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

no yes

yes

-- 870.7485 Metabolism and Pharmacokinetics

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

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

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

yes
yes

1 Subchronic exposure in the rat has been evaluated in the subchronic neurotoxicity study , prenatal developmental toxicity study, and as part of the combined chronic toxicity/carcinogenicity study. Therefore, a study is not required at this time.

2 A subchronic dog study is not needed given a chronic dog study was submitted.

3 The combined chronic toxicity/carcinogenicity study satisfies the requirement of the study.Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 35 of 53 

### A.2 Toxicity Profile s

Table A.2.1

. Acute Toxicity Profile

– Diquat

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

870.1100 Acute oral (rat) 00081506 LD 50 = 810 mg/kg
LD 50 = 600 mg/kg III

870.1200 Acute dermal (rabbit) 00100614 LD 50 = 262 mg/kg
LD 50 = 315 mg/kg
LD 50 = 288.5 mg/kg II

870.1300 Acute inhalation (rat) Accession No.
26385 LC 50 = 0.80 mg/L

LC 50 = 1.09 mg/L
LC 50 = 0.97 mg/L III

870.2400 Acute eye irritation (rabbit) 00081507 Slight to severe eye
irritant II

870.2500 Acute dermal irritation (rabbit) 00107903 Slight irritation IV

870.2600 Skin sensitization (guinea pig) 00107903 Not a dermal sensitizer N/A

With the exception of the dermal sensitization study, which was conducted with the technical diquat (Diquat Herbicide Concentrate), the above studies were conducted with the end

- use products [Diquat Water Weed Killer and Diquat 2 Spray (eye irritation study only)] and not in terms of the diquat ion. Because the only difference between the technical diquat and the end

use products is 2.15% water, studies with the end

- use products have been accepted to satisfy the generic data requirements for acute studies. The above LD and LC values are expressed in terms of the test material and no, as is commonly done with diqua t, in t erms of the diquat cation.

Table A.2.2

. Subchronic, Chronic, and Other Toxicity Profile

– Diquat

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

870.3200 21/ 28

- Day Dermal

Toxicity (rat)

Technical ( 20.64% diquat cation ) 40308101 ( 1987 )

Acceptable/guideline 0, 5, 20, 40, or 80 mg/kg/day Dermal Toxicity NOAEL <5 mg/kg/day

. Dermal Toxicity LOAEL = 5 mg/kg/day, based on dermal irritation at application site [erythema, edema, atonia, and desquamation] and tissue destruction [necrosis and eschar formation]. Systemic Toxicity NOAEL = 5 mg/kg/day

. Systemic Toxicity LOAEL = 20 mg/kg/day, based
on a dose

- related mortality and clinical signs [hypothermia, hypoactivity, dyspnea, cyanosis, pale extremities, general poor condition, and emaciate d appearance]. Based on the severity of the effects observed [death and clinical signs (hypothermia, hypoactivity, dyspnea, cyanosis, pale extremities, general poor condition, and emaciated appearance)] and the extent of skin toxicity [dermal irritation ( erythema, edema, and desquamation) and tissue destruction (necrosis and eschar formation); sores, severe erythema, fissures, acute necrotizing purulent dermatitis, and degeneration of the hair follicles and sebaceous glands] observed at the site of applica tion in one or both sexes, it was concluded that the study was not appropriate for use in risk assessment since the NOAEL is artificially low due to the fact that the skin is compromised.Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 36 of 53 Table A.2.2

. Subchronic, Chronic, and Other Toxicity Profile

– Diquat

. Guideline
No. Study Type MRID No. (year)/ Classification/Doses Results
870.3200 21/28

- Day Dermal

Toxicity (ra bbi t)

Technical 00140576 (1966)

Acceptable/non

- guideline 0, 20, 40, 80, or 160 diquat
cation mg/kg/day Dermal Toxicity NOAEL = <20 mg/kg/day

. Dermal Toxicity LOAEL = 20 mg/kg/day, based on erythema and scabbing.

Systemic Toxicity NOAEL = 20 mg/kg/day

. Systemic LOAEL = 40 mg/kg/day, based on weight loss, unsteadiness, muscular weakness and inability to stand, and pathological changes in the distal
convoluted renal tubules with cell necros is ( thought
to be associate d with an electrolyte imbalance)

.

Extensive areas of necros is of the epidermis were noted.
870.3465 Subchronic

Inhalation Study (rat)

– 21 days

Technical ( 21.6% and 23.5% diquat
cation ) 40301701, 40640801 (1987)

Acceptable/guideline (when
both studies considered together) 0, 0.49, 1.1, 3.8 μg/L; 0 and 0.1 μg/L NOAEL = 0.1 μg/L/day [males 0.024 mg/kg/day; females 0.026 mg/kg/day], based on increased lung weights and microscopic lesions [mottling and reddening of the lungs in females, multifocal, chronic, interstitial pneumonia

, and alveolar macrophages in both se xes] in the lungs at the LOAEL of 0.49 μg/L [males 0.117 mg/kg/day; females 0.128 mg/kg/day].
870.3700a Prenatal

Developmental in Rodent (rat)

Technical ( 26.2% diquat cation ) 41198902 (1989)

Acceptable/guideline 0, 4, 12, or 40 mg/kg/day Maternal NOAEL = 12 mg/kg/day

. Maternal LOAEL = 40 mg/kg/day based on death of one dam, increased incidence of subdued appearance and piloerection, and a slightly lower gravid uterine weight.

Developmental NOAEL = 12 mg/kg/day

. Developmental LOAEL = 40 mg/kg/day based on decreased fetal body weight (91% of control), decreased litter weight, an increased incidence of hemorrhagic kidney, and poor ossification as evidenced by higher incidences of minor skeletal alterations compared to controls.
870.3700 a Prenatal

Developmental in Rodent ( mouse )

Analytical standard 00061637 (1978)

Una cceptable/non

- guideline 0, 1, 2, or 4 mg/kg/day Poor dosing technique /intubation errors resulting in incidental exposure into lungs.

870.3700b Prenatal

Developmental in
Non

- Rodent (rabbit)

Technical ( 26.2% diquat cation ) 41198901 (1989)

Acceptable/guideline 0, 1, 3, or 10 mg/kg/day Maternal NOAEL = 3 mg/kg/day

. Maternal LOAEL = 10 mg/kg/day based on mortality and an increased incidence of clinical signs (diarrhea, subdued appearance, and thin appearance).

Developmental NOAEL = 3 mg/kg/day

. Developmental LOAEL = 10 mg/kg/day based on an increased incidence of friable and/or mottled livers and poorer ossification, as evidenced by
minor skeletal alterations.Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 37 of 53 Table A.2.2

. Subchronic, Chronic, and Other Toxicity Profile

– Diquat

. Guideline
No. Study Type MRID No. (year)/ Classification/Doses Results
870.3800 Reproduction and

Fertility Effects (rat)

Technical ( 20.09% diquat cation ) 41531301 (1990)

Acceptable/guideline 0, 0.8, 4, or 20/12 mg/kg/day Parental NOAEL = 0.8 mg/kg/day

. Paren tal LOAEL = 4 mg/kg/day based on clinical signs, ophthalmoscopic signs, ulceration of the tongue, and cataract s

. At HDT, additional findings
include clinical signs (piloerection, lack of grooming, opaque eyes, and ulcers on the palate), ophthalmoscopic signs (eye opacity, total cataracts, and iritis) , and body weight decrements

. Reproductive/Developmental NOAEL = 4 mg/kg/day

. Reproductive/D evelopmental LOAEL = 12 mg/kg/day , based on decreased number of live pups per litter o n days 1

- 22, decreased pup body weight gain during lactation, and increased incidence of kidney lesions.
870.4100a Chronic Toxicity

(rodent) See 870.4300 See 870.4300

870.4100b Chronic Toxicity

(dog)

Technical ( 26.7% diquat cation ) 41730301 (1990)

Acceptable/guideline 0, 0.5, 2.5, or 12.5 mg/kg/day NOAEL = 0.5 mg/kg/day

. LOAEL = 2.5 mg/kg/day based on u nilateral
cataracts in females. At the HDT, bilateral cataracts
and inflammatory lesions in the large inte stine

.

870.4200a Carcinogenicity (rat) See 870.4300 See 870.4300

870.4200b Carcinogenicity

(mouse)

Technical ( 21.09% diquat cation ) 42219801, 42880701,

42905901, 42919501 (1991) Acceptable/guideline 0, 3.56/4.78, 11.96/16.03, or 37.83/48.27 mg/kg/day (M/F) NOAEL = 3

. 56/4.78 mg/kg/day (M/F)

. LOAE L = 11.96/16.03 mg/kg/day (M/F) based on clinical signs [eye discharge (males), subdued behavior (females)], and decreased body weight/body weight gain [males]. Diquat was not carcinogenic in male or female CD

- 1 mice.
870.4300 Combined Chronic

Toxicity/ Carcinogenicity (rat)

Technical ( 26.5% diquat cation ) 00145855, 00155474,

41085601 (1985) Acceptable/guideline 0, 0.19/0.24, 0.58/0.72, 2.91/3.64, or 14.88/19.44 mg/kg/day (M/F) NOAEL = 0.58/0.72 mg/kg/day (M/F)

. LOAEL = 2.91/3.64 mg/kg/day (M/F) based on eye lesions [total cataracts]. NOTE: The incidence of eye lesions increased with time on study, and effect
observed at lower dose level with time. Opacity first occurred in week 10 at 75 ppm and week 11 at 375 ppm. There was no treatment

- related increase
in tumor incidence in either sex.
870.5100

– 870.5915 Mutagenicity

Toxicity Tests 00061638, 00109564,

00131383, 00131720, 00144999, 00148843, 00148844, 00148845, 00148847, 00154265,
40323101

- 40323107 Negative for mutagenicity in a bacterial gene mutation (Ames) assay; however, positive for gene mutations in a mammalian cell line (mouse lymphoma) but at cytotoxic doses. In addition

, clastogenic in cultured human lymphocytes, but the

response was genera lly weak and observed at cytotoxic levels. In contrast, there was no evidence of clastogenicity in somatic cells (mouse bone marrow) or germinal cells (mouse spermatogonia) or unscheduled DNA synthesis (UDS) in rat hepatocytes in a series of in vivo studi es. Overall, the data suggest that there is no concern for mutagenicity.Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 38 of 53 Table A.2.2

. Subchronic, Chronic, and Other Toxicity Profile

– Diquat

. Guideline
No. Study Type MRID No. (year)/ Classification/Doses Results
870.6200a Acute Neurotoxicity

Screening Battery (rat)

Technical ( 20.1% diquat cation ) 42666801 (1992)

Acceptable/guideline 0, 25, 75, or 150 mg/ kg /day NOAEL = 75 mg/kg

. LOAEL = 150 mg/k g/day, based on clinical signs ( piloerection, diarrhea, staining around nose, urinary incontinence, upward curvature of the spine, tip toe gait, hunched posture, subdued behavior, and pinched side ) ] and decreased body weight gains.
870.6200b Subchronic

Neurotoxicity Screening Battery (rat)

Technical ( 20.8% diquat cation ) 42616101 (1992)

Acceptable/guideline 0, 1.6/1.9, 8.0/9.5, or 32.4/38.5 mg/kg/day (M/F) Sys temic Toxicity NOAEL = 8.0/9.5 mg/kg/day (M/F)

. Sys temic Toxicity LOAEL = 32.4/38.5 mg/kg/day (M/F) based on evidence of cataracts and decreased body weight gain and food utilization in both sexes.

870.7485 Metabolism and

Pharmacokinetics (rat) 00065592

Acceptable/guideline when considered with other two
studies Diquat did not accumulate in tissues and was slowly absorbed following either oral or iv exposure to single doses of [ 14 C] diquat dibromide to rats or
mice of both sexes. Following a single dose of 60 mg/kg, only 5.5% of the radiolabel was excreted in urine within 7 day s. Following an oral [feeding]
dose of unlabeled diquat dibromide [250 ppm] to rats of both sexes for 2, 4, or 8 weeks, no retention
of diquat was observed in the brain, liver, lung, stomach, small and large intestine, muscle, and blood, and little retent ion in the kidneys [0.18, 0.25, and 1.17 ppm during weeks 2, 4, and 8, respectively]. Ten minutes after iv injection, there
were indications that diquat concentrated in cartilaginous tissues, liver, and urinary bladder, as well as the brain and spinal cor d. After 24 hours, radiolabel was detected only in the urinary bladder
and intestines.
870.7485 Metabolism and

Pharmacokinetics (rat) 00065593

Acceptable/guideline when
considered with other two
studies Rats excreted 6.3% and 89.3% of [ 14 C] in the urine and feces, respectively, within 4 days following oral exposure, with most being excreted within the first 48 hours In urine, most of the excreted radioactivity was unchanged parent whereas the remaining 1% was associated with: diquat monopyridone [0.2%], diquat dipyridone [0.1%], and unidentified metabolites [0.3%]. In feces, 65.5% of excreted [ 14 C] was detected in sulfuric acid

- extractable fraction and 15.7% in the ammonium sulfat e

unextractable fraction. In the sulfuric acid fraction, [ 14 C] was distributed as follows: unchanged diquat [57.1%], diquat monopyridone [4.3%], and unidentified material [4.1%].
870.7485 Metabolism and

Pharmacokinetics (rat) 00055107

Acceptable/guideline when considered with other two
studies Following oral dosing,  90% of [ 14 C] was eliminated in the feces, indicating that diquat was poorly absorbed for the gastrointestinal tract. Following a subcutaneous injection of [ 14 C]

- diquat

to circumvent the intestine, nearly all [ 14 C] was recovered in the urine within 2 days.
870.7600 In vivo dermal

penetration (rat) 41238701 (1989)

Acceptable/guideline 0.05, 0.5, or 5 mg/rat After 10 hours of exposure, absorption (sum of dose
measured on/in skin, blood, urine, feces, carcass

, and cage wash) was 5.5%, 5.5%, and 2.5% at 0.05, 0.5, and 5 mg/rat, respectively.Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 39 of 53 Table A.2.2

. Subchronic, Chronic, and Other Toxicity Profile

– Diquat

. Guideline
No. Study Type MRID No. (year)/ Classification/Doses Results
870.7800 Immunotoxicity

(mouse) 48668101 (2011)

Acceptable/guideline 0, 23, 44, or 81 mg/kg/day Systemic NOAEL = 23 mg/kg/day

. Systemic LOAEL = 44 mg/kg/day based on lower body weights and body weight gains

.

Immunotoxicity NOAEL = 81 mg/kg/day

. Immunotoxicity LOAEL = not established

.Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 40 of 53 

### Appendix B. Calculation of Inhalation Human

- E quivalent Concentrations (HECs) and
Human

- E quivalent Doses

The calculation of HECs accounts for pharmacokinetic (not pharmacodynamic) interspecies
differences. HECs for residential and occupational scenarios were derived using the POD from
the route

- specific inhalation study and the regional deposited

- dose ratio (RDDR). The RDDR accounts for the particulate diameter [mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD)] and estimates the different dose fracti ons deposited along the respiratory tract. Table B.1 summarizes the inputs used to obtain the diquat RDDR for HEC
calculations.

Table B. 1

. Summary of RDDR Inputs for Diquat

.

Study
MRID Species

and
Strain Animal

Body Weight (g) 1 Duration of Exposure NOAEL ( mg /L) LOAEL

( m g/L) MMAD

at LOAEL ( μ m) GSD at
LOAEL Respiratory

Region for
Effect 2 RDDR h ours/day d ays/week

40301701,
40640801 Fischer

344
Rats 152 6 5 0. 000 1 0. 000 49 1.9 1.9 PU 0.591

NOAEL = no

- observed adverse

- effect level. LOAEL = lowest

- observed adverse

- effect level. MMAD = mass median aerodynamic diameter. GSD = geometric standard deviation. RDDR = regional deposited

- dose ratio.

1 Default Fischer 344 rat body weight for combined sexes.

2 ET = extrathoracic, TB = tracheobronchia l, PU = pulmonary, TH = thoracic, TR = total respiratory tract, ER = extrarespiratory (systemic).



### The POD from the route

- specific inhalation study was adjusted for expected human exposure
duration. Duration adjustment is performed based on Haber’s law

, which assumes that a toxicological effect is proportional to the product of exposure level and duration. Animal

- to

human ratios of daily (hours/day) and weekly (days/week) exposures are applied to the animal inhalation study P O D to result in a duration

- adjusted animal POD for HEC conversion. For example, expected human exposure for occupational exposures is 8 hours/day and 5 days/ week. Therefore, the adjusted NOAEL is 7.5x10

- 5 

### mg/L.

NOAEL adjusted 

### = 0

. 0001 mg

L × 6 h r / day

8 h r / day × 5 days / week

5 days / week = 7

. 5 x 10 − 5 

### mg

L

For residential handler and outdoor post

- application exposures, no duration adjustment was applied. For reside ntial indoor post

- application exposures, a duration adjustment to 7 days /week was applied with no daily exposure adjustment resulting in a duration

- adjusted POD of 7.5x10

- 5 

### mg/L. For residential bystander exposures, duration adjustments to 24 hours/day an d 7 days/week were applied resulting in a duration

- adjusted POD of 1.8x1 0

- 5 

### mg/L.

The RDDR was applied to the duration

- adjusted POD (except residential handler and outdoor post

- application exposures with no duration adjustment where the RDDR is applied directly to the POD) to calculate HECs. Human

- equivalent doses were sub sequently calculated from the
HECs for residential and occupational handler scenarios. The following equation describes the
conversion from HEC s to human

- equivalent doses :Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 41 of 53 

### The conversion to human

- equivalent doses is an approximation involving the application of a conversion factor (CF) that takes into account the typical human volume respired per unit time. As the default breathing rate in the HEC calculation is 13.8 L/min for a typical human (body weight of 70 kg) under light activity conditions, the corresponding CF is 11.8 L/hr

- kg. Absorption differences through the respiratory tract as compared to the oral route are expressed in the ratio “A.” In current practice

, HED customarily assumes “A” to be unity (i.e., the entire animal orally administered dose is assumed to be absorbed via the inhalation route). Because the inhaled dose depends on activity level which directly impacts breathing parameters (at least until blood steady state levels are reached), the activity factor (AF) is a relative ratio that attempts to account for differences in respiratory ra te due to activity level. Table B.2 lists the different exposure scenarios, the corresponding breathing rates associated with these activities, and the AF values that should be used for different occupational handler scenarios being assessed. Also
listed in Table B.2 is the AF value assigned to residential handlers

, which is assumed to be equal to occupational handlers in non

- agricultural settings. The daily exposure duration (D) is equivalent to the “hours/day” value used in POD duration adjustment calc ulations. A summary of duration adjustments, HECs, and human

- equivalent doses for all potential occupational and residential scenarios is presented in Table B.3.

1 AF = Exposure scenario

- specific human breathing rate (L/min) ÷ 13.8 L/min (the rate assumed in HEC calculation). Body weight is assumed to be 70 kg for all calculations. Table B.2. Assigned Activity Factor (AF) Values Based on Different Handler Exposure Scenar ios

.

Exposure Scenario Human Breathing Rate (L/min) HED Calculation Inputs

AF 1

Occupational Pilots, tractor drivers

(groundboom, airblast) 8.3 0.6

Mixer/loaders, lawn care operators (non

- agriculture) 16.7 1.2

Handheld spray applications (e.g., backpacks, handgun, etc.) 29 2.1

Residential Handlers 16.7 1.2 

### Human

- Equivalent Dose ≈ HEC (mg/L) × CF (L/hr

- kg BW) × A × AF × D (hr/day)

HED = Human

- Equivalent Dose (mg/kg BW /day)

. HEC = Human

- Equivalent Concentration (mg/L)

. CF = Human

- specific value that accounts for volume respired per unit time. CF equals 11.8 L/hr

- kg based on the
default

- breathing rate assumed for a typical human (bod y weight of 70 kg) in the HEC calculation

. A = Absorption ratio through the respiratory tract as compared to the oral route

– assumed to be unity

. AF = Relative ratio that accounts for relative changes in respiratory rate due to activity level. Differen t AF values should be used for different occupational and residential scenarios. D = Duration of daily exposure in hours : 8 hours assumed for occupational exposures ; 24 hours assumed for bystanders /residential exposure; and 2 hours is often assumed for res idential handler exposures.Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 42 of 53 Table B.3. Summary of Inhalation Calculations for Human

- E quivalent Concentrations and Doses for Diquat.

Population Scenario Toxicity Duration Adjustment Human

- E quivalent
Concentration Human

- E quivalent Dose

(mg/kg/day; breathing rate specific) hours/day days/week mg/L mg/m 3 8.3 L/min 16.7 L/min 29 L/min
Occupational Handler 8 5 4.43x10

- 5 0.044 0.0025 0.0051 0.0088

Residential Handler NA NA 5.91x10

- 5 0.059 NA 0.0017 NA

Outdoor post

application NA NA 5.91x10

- 5 0.059 NA NA NA

Indoor post

application NA 7 4.22x10

- 5 0.042 NA

Bystander 24 7 1.06x10

- 5 0.011 NA
NA = not applicable (the expected duration of the exposure scenario is less than the duration of available inhalation toxicit y studies; downward adjustments are not permitted)

.Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 43 of 53 

### Appendix C. Tolerance Summary for Diquat

Table C.1. Tolerance Summary for Diquat (40 CFR §180.226).

Commodity Established
Tolerance (ppm) HED

Recommended Tolerance (ppm) Comments ( correct commodity definition )

(a) General. (1) Tolerances are established for residues of the herbicide diquat, including its metabolites and degradates, derived from application of the dibromide salt in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only diquat (6,7

- dihydrodipyrido[1,2

- a :2′,1′

- c ]pyrazinediium).
Alfalfa, seed 3.0 3.0

Banana 1 0.05 0.02 Move from §180.226(a)(3), harmonize with Codex
Canola, meal 6.0 6.0 Canola, seed 2.0 2.0 Cattle, fat 0.05 0.05 Cattle, meat 0.05 0.05 Cattle, meat byproducts 0.05 0.05 Coffee, bean, green 1 0.05 0.02 Move from §180.226(a)(3), harmonize with Codex Coffee, green bean 1
Clover, seed

-- 2.0 Recommended in 2002 TRED Egg 0.05 0.05 Goat, fat 0.05 0.05
Goat, meat 0.05 0.05 Goat, meat byproducts 0.05 0.05 Hog, fat 0.05 0.05 Hog, meat 0.05 0.05 Hog, meat byproducts 0.05 0.05 Horse, fat 0.05 0.05
Horse, meat 0.05 0.05 Horse, meat byproducts 0.05 0.05

Milk 0.02 0.02

Potato 0.1 0.10 Correct number of significant figures to be consistent with HED policy Potato, granules/flakes 0.5 0.50 Move from §180.226(a)(4) and correct number of significant figures to be consistent with HED policy Potato, chips 0.5 0.50 Poultry, fat 0.05 0.05 Poultry, meat 0.05 0.05 Poultry, meat byproducts 0.05 0.05 Sheep, fat 0.05 0.05 Sheep, meat 0.05 0.05 Sheep, meat byproducts 0.05 0.05 (2)(i) Tolerances are established for residues of the herbicide diquat, including its metabolites and degradates, derived from application of the dibromide salt to ponds, lakes, reservoirs, marshes, drainage ditches, canals, streams, and rivers
which are slow

- moving or quiescent in programs of the Corp of Engineers or other Federal or State public agencies and to ponds, lakes and drainage ditches only where there is little or no outflow of water and which are totally under the control of the user, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only diquat (6,7

- dihydrodipyrido[1,2

- a :2′,1′

- c ]pyrazinediium). Animal feed, nongrass, group 18, forage - 0.20

Translated from irrigated grass data Animal feed, nongrass, group 18, hay - 0.20Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 44 of 53 Table C.1. Tolerance Summary for Diquat (40 CFR §180.226).

Commodity Established
Tolerance (ppm) HED

Recommended Tolerance (ppm) Comments ( correct commodity definition )

Avocado 0.2 0.20 Correct number of significant figures to be consistent with HED policy Berry group 13 0.05 0.05 Berry and small fruit, group 13

- 07 Cotton, undelinted seed 0.2 0.20 Oilseeds, group 20 Cranberry 0.05

- Member of berry and small fruit, group 13

- 07;
individual tolerance not needed.

Fish 2.0 2.0 Fruit, citrus, group 10 0.05 0.05 Fruit, citrus, group 10

- 10 Fruit, pome, group 11 0.02 0.02 Fruit, pome, group 11

- 10 Fruit, stone, group 12 0.02 0.02 Fruit, stone, group 12

- 12 Grain, cereal, forage, fodder and straw, group 16 0.02 0.02

Grain, cereal, group 15 0.02 0.02 Grape 0.05

- Member of berry and small fruit, group 13

- 07;
individual tolerance not needed. Grass, forage, fodder and hay, group 17 0.2 0.20 Correct number of significant figures to be consistent with HED policy Herb and spice, group 19

- 0.20 Translated from irrigated grass data Hop, dried cones 0.2 0.20 Correct number of significant figures to be consistent with HED policy Nut, tree, group 14 0.02 0.02 Nut, tree, group 14

- 12

Shellfish 20.0 20 Correct number of significant figures to be consistent with HED policy Strawberry 0.05

- Member of berry and small fruit, group 13

- 07;
individual tolerance not needed. Sugarcane, cane 0.2 0.20 Correct number of significant figures to be consistent with HED policy Vegetable, brassica, leafy, group
5 0.05 0.05 Vegetable, Brassica , leafy, group 5

Vegetable, bulb, group 3

- 0.02 Translated from irrigated carrot data Vegetable, cucurbit, group 9 0.02 0.02 Vegetable, foliage of legume, group 7 0.2 0.20 Correct number of significant figures to be consistent with HED policy Vegetable, fruiting, group 8 0.05 0.05 Vegetable, fruiting, group 8

- 10 Vegetable, leafy, except brassica, group 4 0.05 0.05 Vegetable, leafy, except Brassica , group 4

Vegetable, leaves of root and tuber, group 2 - 0.02 Translated from irrigated carrot data

Vegetable, root and tuber, group 1 0.02 0.02 Vegetable, root and tuber, group 1, except potato Vegetable, seed and pod 0.05 0.05 Vegetable, legume, group 6 (3) Tolerances are established for residues of the herbicide diquat, including its metabolites and degradates, derived from application of the dibromide salt in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring on ly diquat (6,7

- dihydrodipyrido[1,2

- a :2′,1′

- c ]pyrazinediium). Soybean, hulls 0.6

- Not required as use on soybeans cancelled

1 There are no U.S. registrations as of May 26, 2010.Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 45 of 53 

### Appendix D

. Physical/Chemical Properties

Table D .1 . Physicochemical Properties of Diquat.
Parameter Value Reference

Mol ecular Weight 344.1 (Cation

– 184) The Pesticide Manual 11 th
Edition Melting point/range 300 °C D277710 pH Not Provided NA Density (20°C) 1.22

- 1.27 g/cm 3 The Pesticide Manual 11 th
Edition
Water solubility (20°C) 700 g/L D277710 Solvent solubility slightly soluble in alcohol and hydroxylic solvents, and practically insoluble in nonpolar organic solvents D277710

Vapor pressure at 25°C <1×10

- 8 mm Hg Vencill, W.K. 2002. Herbicide Handbook, 8 th
Edition Dissociation constant (pK a ) Not Provided NA

K OW Octanol/water partition coefficient as Log P OW at 20°C - 4.60 The Pesticide Manual 11 th
Edition UV/visible absorption spectrum Neutral and acidic conditions

- one major peak at 309.5 nanometers.
Basic conditions

- two major peaks at 309.0 and 217.0 nanometers. D349998Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 46 of 53 

### Appendix E

. Summary of Registered Uses of Diquat

Table E .1. Summary of Directions for Use of Diquat. Applic. Timing, Type, and Equip. Crop Formln. [EPA Reg. No.] Applic.

Rate 1 Max. No.

Appl. Per
Season Max.

Seasonal Appl. Rate 2 PHI

(Days) Use Directions

and Limitations 8

Use Site 1 (Terrestrial Crop and Farmland)

Pre

- harvest/
desiccation

Ground and
Aerial Alfalfa, Clover,

(Seed crop) SC

(EPA Reg.#
100

- 1061)
0.5

lb ai/Acre 2 1.0 lb ai/Acre 3 Do not apply through irrigation systems. Do not graze or feed treated forage to
livestock

. Do not use seed
from treated plants for food, feed, or oil

purposes

.

24C:
FL

- 000009
SC

- 000005 Potato, Canola 7

Non

- bearing

crops: Ground
Directed Spray Crop Groups 3 :

4, 13

- 07, 14

- 12, 10

- 10, 99, 12

- 12, 11

- 10 SC

(EPA Reg.#
100

- 1061) 5 2.5 lb
ai/Acre 365

Post

- Harvest burn down:

Groundboom. Tomato Vines 0.38 lb
ai/Acre

2 0.75 lb
ai/Acre

N/A Cantaloupe Vines SC

(EPA Reg.# 100

- 1061) 0.25 lb

ai/Acre 0.5 lb ai/Acre Cucumber, Squash,
Watermelon 0.38 lb ai/Acre 0.75 lb ai/Acre

Acorn squash, Peppers 0.5 lb ai/Acre 1 lb ai/Acre

Weed
control: Middle Rows Ground

d irected Spray Eggplant, Green

Pepper, Tomato SC

(EPA Reg.#
100

- 1061)

0.5 lb ai/A 2 1 lb ai/Acre 30 Do not apply
when wind speed exceeds 5 mph

.

24C:
FL

- 000010
PR

- 030001

Pre

- Harvest desiccation

Ground and
Aerial Carrots, Coriander,

Radishes, Spinach, Sugar Beets, Table Beet, Turnips,
Calendulas SC

(EPA Reg.#
100

- 1061) 1 0.5 lb ai/Acre 3 Do not apply through irrigation systems. Use only on non

edible oilseed varieties of
calendula.

24C:
WA

- 040011
OR

- 080025
ID

- 100006
MN

- 090006

Non

- Crop or
Non

- Planted
Areas on
Farms

Ground

d irected Fence Lines,

Farmyards, Farm Buildings, Fuel Storage Areas, barrier Strips, and Equipment Areas around ponds, lakes and drainage
ditches on farms. SC

(EPA Reg.#
100

- 1061) 0.5 lb

ai/Acre 10 5 lb ai/Acre N/A For spot treatments, apply 2 qt product/100 gallon water (or
22 ml product/1 gallon water)

.

Use Site 2 (Non

- Crop Terrestrial)

Pre

- harvest
Desiccation Ground

directed Ornamental seed crops
SC (EPA Reg.#
100

- 1091,
100

- 1390) 0.5 lb

ai/Acre 3 1.5 lb ai/Acre N/A Do not apply

through any type of irrigation system. For seed crop only.
Not for food or Commercial Greenhouse (beneath benches), field grown
and container stock
and other similar areasDiquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 47 of 53 Table E .1. Summary of Directions for Use of Diquat. Applic. Timing, Type, and Equip. Crop Formln. [EPA Reg. No.] Applic.

Rate 1 Max. No.

Appl. Per
Season Max.

Seasonal Appl. Rate 2 PHI

(Days) Use Directions

and Limitations 8

Landscape, Industrial, Commercial areas 4 including golf courses fiber crops. Not allowed in
California.

Turf Renovation
2 1 lb ai/Acre Dormant Established Turf Grass

Pre

- plant,
Pre

emergence, Post

Emergence Directed Spray (Spot Treatment) Commercial

Greenhouse (beneath benches), field grown
and container stock
and other similar areas 0.01 lb ai/gal 5 2 lb ai/Acre Not for food or fiber crops. Avoid spray

contact with foliage of food

crops or ornamental plants or other
desirable vegetation

. Landscape, Industrial, Commercial,
Residential and Public
Areas

Use Site 3 (Aquatic

- Occupational and Residential)

Aquatic
Broadcast around lakes, ponds, drainage ditches, reservoirs, marshes,
canals and rivers Floating and Marginal

Weeds

SC

(EPA Reg.#
100

- 1091,
100

- 1390) 4 lb ai/.

Acre/4 feet

10 See table 4.1.A in appendix for extensive
directions and
limitations.

24C
FL

- 030006
FL

- 110009
ID

- 070012
AL

- 07001
GA

- 080004
NY

- 030001
NY

- 120007 Submersed Weeds
Standing and Flowing
Water

- Submerged
Weeds

Still Water

- Submerged Weeds

Still Water

- Floating
Weeds 1.5 lb ai/.
Acre

- ft

Still Water

- Duckweed, Cattails 2 lb ai/.
Acre

- ft

Aquatic 5 Spot
Treatment Floating and Marginal

Weeds SC

(EPA Reg.#
100

- 1091,
100

- 1390) 0.04 lb

ai/gal 40 lb/Sq.
Acre N/A See T able 4.1.A

in Appendix of
the most recent
ORE memo. 0.000092 lb
ai ft 2 N/A

Use Site 3 (Residential) 6

Manually
Pressurized Handwand

Gardens/Trees/Turf SC (EPA Reg.#
100

- 1091,
100

- 1390) 0.01 lb

ai/gal

N/A N/A N/A N/A 0.5 lb ai/Acre

Backpack Sprayer 0.01 lb ai/gal
Trigger

- spray Bottle 0.0025 lb ai/bottle 7

1, 2 Application rates primarily based on use information provided by r egistrant ( supplied by email from PRD 9/5/ 2014) . The use information provided was noted to be based primarily on representative Section 3 and 24C labels from Syngenta Crop Protection. In addition, information provided in the TRED (D281890) for diquat was used for the residential use information. 3. Crop groups (4, 13

- 07, 14

- 12, 10

- 10, 99, 12

- 12, 11

- 10): vegetable, l eafy, except Brassica ; fruit, berry and small fruit; nut, tree; fruit, citrus; fruit, stone; fruit, pome.
4. Areas of use ; around trees ornamental gardens, beneath commercial greenhouse benches

. Other non

- crop areas : buildings, parking lots, cart paths, p atios, dividers, pipelines, driveways, public utility lines, electric utilities, pumping stations, fence lines, railroad beds/yards, golf courses, rights of way, highways, roads, landscape beds, roadsides, lawns, transformer stati ons and substations, media ns, walkways, non

- flooded portions of ponds, lakes and ditches.
5. Label rate: 4 lb ai/Acre x Acre/43,560 sq ft = 0.000092 lb ai/ft sq. 6. Residential use information: See TRED (D281890) for specifics

.Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 48 of 53 7. TRED

- (D281890): Trigger Sprayer: high

- end = 0.0 1 lb ai.gal, so: 0.01 lbs ai/gal x gal/128 fl. oz. x 32 fl. oz/bottle = 0.0025 lb ai/bottle (32 fl. oz). 8. REI = 24 hr. (for occupational uses).Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 49 of 53 

### Appendix F

. International Residue Limits

Diquat ( 032201 ; 4/15/2015) Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 

### Codex §180.226 (a) General. (1) Tolerances are
established for residues of the herbicide diquat, including its metabolites and degradates, derived from application of
the dibromide salt in or on the
commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only diquat (6,7

- dihydrodipyrido[1,2

- a :2′,1′

-

c ]pyrazinediium). 6,7

- dihydrodipy rido[1,2

-

a :2',1'

- c ]pyrazinediium Diquat
The residue is not fat soluble.



### Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)
US Canada Mexico 1 

### Codex Alfalfa, seed 3.0
Banana 0.02 0.02 (*) Cattle, fat 0.05 Cattle, meat 0.05 0.05 meat 0.01 (*) meat
from mammals
other than marine mammals) (proposed) Cattle, meat byproducts 0.05 0.05 meat byproducts 0.01 (*) edible
offal (mammalian) (proposed) Canola, meal 6.0 Canola, seed 2.0 1 1.5 Coffee, green bean 0.02 0.02 (*) Egg 0.05 0.05 0.01 (*) (proposed) Goat, fat 0.05 Goat, meat 0.05 0.05 meat 0.01 (*) meat
from mammals
other than marine mammals) (proposed) Goat, meat byproducts 0.05 0.05 meat byproducts 0.01 (*) edible
offal (mammalian) (proposed) Hog, fat 0.05 Hog, meat 0.05 0.05 meat 0.01 (*) meat
from mammals
other than marine mammals) (proposed) Hog, meat byproducts 0.05 0.05 meat byproducts 0.01 (*) edible
offal (mammalian) (proposed)Diquat Dibromide Human Health Risk Assessment D414147

______________________________________________________________________________________ _______

Page 50 of 53 

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

### Codex Horse, fat 0.05 Horse, meat 0.05 0.05 meat 0.01 (*) meat from mammals
other than marine mammals) (proposed) Horse, meat byproducts 0.05 0.05 meat byproducts 0.01 (*) edible
offal (mammalian) (proposed)
Milk 0.02 0.05 0.001 (*) (proposed)
Potato 0.10 0.1 0.1 Potato, granules/flakes 0.50 Potato, chips 0.50 Poultry, fat 0.05 Poultry, meat 0.05 0.05 0.01 (*) (proposed) Poultry, meat byproducts 0.05 0.05 0.01 (*) poultry
edible offal of (proposed) Sheep, fat 0.05 Sheep, meat 0.05 0.05 meat 0.01 (*) meat from mammals
other than marine mammals) (proposed) Sheep, meat byproducts 0.05 0.05 meat byproducts 0.01 (*) edible
offal (mammalian) (proposed) 

### US Canada Codex (2)(i) Tolerances are established for residues of the herbicide diquat, including its metabolites and degradates, derived from application of the dibromide salt to ponds, lakes, reservoirs, marshes, drainage ditches, canals, streams, and rivers which are
slow

- moving or quiescent in programs of the Corp of Engineers or other Federal or State public agencies and to ponds, lakes and drainage ditches only
where there is little or no outflow of water and which are totally under the control of the user, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only diquat (6,7

- dihydrodipyrido[1,2

- a :2′,1′

-

c ]pyrazinediium). 6,7

- dihydrodipyrido[1,2

-

a :2',1'

- c ]pyrazinediium Diquat
The residue is not
fat soluble.



### Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)
US
Avocado 0.20Diquat Dibromide Human Health Risk Assessment D414147

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

### Codex Animal feed, nongrass, group 18, forage 0.20

Animal feed, nongrass, group 18, hay 0.20

Berry and small fruit, group 13

- 07 0.05 0.02 grapes 0.05 strawberry

Oilseeds, group 20 0.20 0.05 sunflower seed
0.5 f laxseeds
1 mustard seeds 0.5 Solin 0.9 sunflower
seed

Fish 2.0 Fruit, citrus, group 10

- 10 0.05 0.02 (*) Fruit, pome, group 11

- 10 0.02 0.02 apples, Asian pears, crabapples, loquats, mayhaws, pears, quinces, 0.02 (*)

Fruit, stone, group 12

- 12 0.02 0.02 apricots, fresh prune plums, nectarines, peaches, plumcots, plums, sweet cherries, tart cherries 0.02 (*)

Grain, cereal, forage, fodder and straw, group 16 0.02

Grain, cereal, group 15 0.02 0.02 barley, field corn, oats, rye, sweet corn kernels plus cob with husks removed, triticale, wheat 5 barley
2 3 oats, wheat, wheat bran, unprocessed,
wheat wholemeal (proposed)
0.5 3 wheat flour (proposed) Grass, forage, fodder and hay, group 17 0.20

Herb and spice, group 19 0.20 Hop, dried cones 0.20 Nut, tree, group 14

- 12 0.02 0.02 (*) cashew

nut Shellfish 20 Sugarcane, cane 0.20 Vegetable, Brassica , leafy, group 5 0.05 0.02 bok choy Chinese cabbages, broccoli, broccoli raab, Brussels sprouts, cabbages, cauliflower, Chinese broccoli, Chinese mustard cabbages, collards, kale, kohlrabi, mustard greens, mustard spinach, Napa Chinese cabbages, rape leaves Vegetable, bulb, group 3 0.02 0.02 dry bulb onions 0.02 green onions Vegetable, cucurbit, group
9 0.02 0.02 cucumbers

Vegetable, foliage of legume, group 7 0.20 50 pea hay or pea fodder (dry)Diquat Dibromide Human Health Risk Assessment D414147

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

### Codex Vegetable, fruiting, group
8

- 10 0.05 0.01 (*) fruiting vegetables other
than cucurbits (except sweet corn fungi and mushrooms) Vegetable, leafy, except
Brassica , group 4 0.05

Vegetable, leaves of root and tuber, group 2 0.02

Vegetable, root and tuber, group 1, except potato 0.02 0.02 carrot roots, garden
beet roots, turnip roots Vegetable, legume, group
6 0.05 0.2 Dry (adzuki beans, beans, black

- eyed peas, broad beans, catjang seeds, chickpeas, field peas, guar seeds, kidney beans, lablab beans, lentils, lima beans, moth beans, mung beans, navy beans, pigeon peas, pink beans, pinto beans, rice beans, southern peas, tepary beans, urd beans); grain lupi n 0.05 dry soybeans 0.05 beans (dry) (proposed)

0.2 3 lentil (dry) (proposed)

0.3 peas, soya bean (all dry)

MRLs with NO US Equivalent Cajou (pseudofruit) 0.02 (*) Cashew apple 0.02 (*) Completed: M. Negussie; 04/29/15

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

2 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat . (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.

3 = MRLs are under the 4 year rule awaiting data.Diquat Dibromide Human Health Risk Assessment D414147

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Page 53 of 53 

### Appendix G

. Review of Human Research

This risk assessment relies i n 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
the Pesticide Handlers Exposure Database ( PHED ) 1.1, the Agricultural Handler Exposure Task
Force ( AHETF ) database, the Outdoor Residential Exposure Task Force (ORETF) database
and the Agricultural Reentry Task Force ( ARTF ) database are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with a pplic able ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 11



### .

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

- exposure

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

- app

- exposure

- data.html