UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460
OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES

March 25, 2002 MEMORANDUM SUBJECT: Diquat Dibromide HED Risk Assessment for Tolerance Reassessment Eligibility

Docume nt (TRED.) PC Code No: 032201; DP Barcode: D281890; Submission Barcode: S611057 FROM: Becky

Daiss, Environmental Health Scientist Reregistration Branch 4 Health Effects Division (7509C) THROUGH: Susan V. Hummel, Branch Senior Scientist

Reregistration Branch 4 Health Effects Division (7509C) TO: Tyler Lane, Chemical Review Manager

Betty Shackleford, Branch Chief Registration Branch Special Review and Reregistration Division (7508C) Attached is the Health Effects Division (HED’s) revised risk assessme nt conducted to support a Tolerance Reassessment Eligibility Decision (TRED) for diquat dibromide. This document updates the March 6, 2001 version by incorporating revisions to the drinking water exposure assessment provided by the Environmental Fate and Effects Division (EFED). The disciplinary

science chapters and other supporting documents are included as appendices as follows:

Use Closure Memo. Ty ler Lane (10/31/01) Report of the Hazard Identification Assessment Review Committee. Linda Tay lor ( 12/1 4/01, HED DOC NO 014670) Report of the FQPA Safety Factor Committee. C. Christiansen (11/27/10, TXR NO. 0050293 ) Report of the Metabolism Assessment Review Committee. T. Morton (9/13/01, D277764) Product & Residue Chemistry Chapter. T. Morton (12/12/01, D277710) Residential Exposure Assessment. T. Brennan (12/14/01, D279507) Dietary Exposure and Risk Estimates for Tolerance Reassessment. B. Daiss (12/11/01, D277766) Incident Report. M. Spann and J. Blondell, Ph.D (10/15/01, D278482) Tier I Drinking W ater and Aquatic Ecological Exposure Assessments for Diquat Dibromide. J Breithaupt (3/5/02, D281199) Toxicology

Chapter, Linda Tay lor (12/14/01, D279696)

Table of Contents   2   44 pg. 1.0 EXECUTI VE SUMMARY
................................ ................................ ................................ .... 3 2. 0 PHYSI CAL/CHEMI CALPROPERTI ES CHARACTERI ZATION
................................ .... 8 3.0 HAZARD CHARACTERI ZATION
................................ ................................ ...................... 9 3.1 Hazard Profile
................................ ................................ ................................ ........................ 9 3.1.1 Acute Toxicity
................................ ................................ ................................ ............ 9 3.1.2 Toxicity

Profile
................................ ................................ ................................ ........ 10 3.1.3 Hazard Characterization
................................ ................................ ........................... 14 3.2 FQPA Considerations
................................ ................................ ................................ .......... 14 3.3 Dose Response Assessment
................................ ................................ ................................ . 15 3.3.1 Dietary

Endpoints
................................ ................................ ................................ ..... 15 3.3.2 Residential Exposure Endpoints
................................ ................................ .............. 16 3.4 Endocrine Disruptor Effects
................................ ................................ ................................ . 18 4.0 EXPOSURE ASSESSMENT
................................ ................................ .............................. 19 4.1 Summary

of Registered Uses
................................ ................................ ............................... 19 4.2 Dietary

Exposure/Risk Pathway
................................ ................................ ........................... 20 4.2.1 Residue Profile
................................ ................................ ................................ ......... 20 4.2.2 Dietary

Exposure/Risk Assessment
................................ ................................ ......... 24 4.3 Drinking Water Exposure/Risk Pathway
................................ ................................ ............. 26 4.3.1 Environmental Fate Assessment
................................ ................................ .............. 26 4.3.2 Estimated Environmental Concentrations
................................ ................................ 26 4.4 Residential Exposure/Risk Assessment
................................ ................................ ............... 29 4.4.1 Home Uses
................................ ................................ ................................ ............... 29 4.4.2 Recreational
................................ ................................ ................................ ............. 36 4.5 In cident Report Summ ary ................................ ................................ ................................ .... 38 4.5.1 Residential Handler Incidents
................................ ................................ .................. 39 4.5.2 Post
- Application and Recreational Incidents
................................ ........................... 39 5.0 AGGREGATE RI SK ASSESSMENT AND RI SK CHARACTERI ZATION
.................... 39 5.1 Acute Aggregate Risk Assessment
................................ ................................ ...................... 39 5.2 Short
- Term Aggregate Risk Assessment
................................ ................................ ............. 40 5.3 Chronic Agg regate Risk Assessment
................................ ................................ ................... 42 6.0 CUMUL ATI VE EXPOSURE AND RI SK
................................ ................................ .......... 43 7.0 DATA NEEDS
................................ ................................ ................................ ..................... 43   3   44

1.0 EXECUTIVE SUMMARY EPA issued a Reregistration Eligibility Decision (RED) for diquat dibromide in July , 1995. The RED recommended revisions to some of the existing t olerances for diquat dibromide. The purpose of this document is to reassess the findings and conclusions presented in the RED to determine whether infants and children exhibit enhanced sensitivity from dietary

and/or residential exposure to diquat dibromi de. This action is required under the Food Quality Protection Act (FQPA) of 1996. Occupational exposure/risk is not considered for this TRED. However, a separate but concurrent reassessment of occupational exposure/risk is also being conducted to addres s the registrant’s request to modify diquat dibromide label requirements (T. Brennan, D279612). Use Profile Diquat dibromide is a non
- selective contact herbicide, algicide, dessicant, and defoliant. As a herbicide/algicide, it is used to control aquati c and terrestrial weeds. I t is used as a preharvest dessicant/defoliant to facilitate the harvest of potatoes and various crops grown for seed. Its largest use is as a dessicant on potato crops. Other minor food use applications include use as a dessicant on crops grown for seed that is used for feed, i.e., alfalfa, sorghum, soy bean, and clover. Additionally , use of irrigation water containing residues of diquat may result in diquat residues in plants and livestock. Non
- food use applications include us e as a preharvest dessicant on carrot, radish and turnip grown for seed; as a post
- harvest dessicant on cantaloupe, cucumber, pepper, squash, tomato, and watermelon; and as a dessicant/defoliant for commercial greenhouses and nurseries, ornamental seed cr ops, and commercial and residential landscaping and grounds maintenance. Diquat dibromide is rapidly absorbed by

green plant tissue and interacts with the photosy nthesis process. I t works as an herbicide/dessicant by reacting with molecular oxygen to pro duce a superoxide anion in treated plants. The oxidative activity , which occurs subsequent to formation of the oxygen radicals, rapidly destroy s plant cell membranes. Herbicidal activity is usually quite rapid with effects visible in a few day s. Diquat dibromide is formulated as a soluble concentrate and ready
- to - use liquid. As an herbicide/algicide used to control algae and aquatic weeds, it is applied by direct pouring, hand
held or mechanical spray er, and injection below the water surface. As a ter restrial herbicide and crop dessicant/defoliant, it is applied by hand
- held spray er, aircraft, or ground equipment. Currently , 43 products containing the active ingredient diquat dibromide are registered and marketed under the trade name diquat dibromide . The largest markets for diquat, in terms of total pounds of active ingredient, include: aquatic uses (40%), potatoes (35%), home & garden (10%), and alfalfa for seed (5%). Most of the usage is in FL, ME, ND, NY, WA, and WI (T. L ane, Use Closure Memo, 10/31/01).   4   44

Regulatory History InJuly , 1995, EPA issued a RED for diquat dibromide. In the RED, the Agency recommended changes to published tolerances for several commodities, including fish (increase from 0.1 to 2.0 ppm) and fruiting vegetables (increa se from 0.02 to 0.05 ppm). The recommended changes to the tolerances have not y et been implemented. Based on the risk assessment conducted for the RED, EPA concluded that acute and chronic dietary risks from exposure to diquat are minimal, but found risk s of concern for some worker and residential exposure scenarios. To address these risks EPA required the following: closed mixing/loading of diquat dibromide for aerial applications; a longer interim restricted entry level (REI ) and more stringent persona l protective equipment (PPE) for uses within the scope of the Worker Protection Standard for Agricultural Pesticides; a four
- day reentry interval to reduce post
- application exposure for workers not covered by

the worker protection standard (e.g., golf cour se workers); and a ban on broadcast treatments to reduce the potential for post
- application residential exposure. Diquat labels have not ye t been revised in accordance with the requirements outlined in the RED. The RED also addressed the occurrence of ethylene dibromide (EDB) which is used as a starting material in the manufacture of diquat dibromide and may be present as a process impurity in final formulations. EDB is considered a carcinogen and all pesticide uses of EDB have been canceled. Previous E PA assessments indicate that the presence of EDB in diquat formulations does not pose a significant dietary risk. In addition, the registrant certified an upper limit of 10 ppm EDB in diquat dibromide, and demonstrated that EDB does not persist as an impu rity in diquat dibromide. InJanuary , 1998, HED conducted a human health risk assessment to evaluate the effect of a change in application and use patterns on potatoes and a new use on dried shelled peas and beans (W Cutchin, 1/23/98, D220714). Results from the 1998 assessment were consistent with the RED, as were the recommendations for additional restricted entry and PPE requirements. Only manufacturing use products (MPs) are subject to a reregistration eligibility decision. There are currently

only 2 diquat dibromide MPs; 41.1% and 37.3% a.i. formulation intermediates. Both of these MPs are currently registered to Sy

ngenta Crop Protection, Inc. The products were transferred from Zeneca to Sy ngenta and the product chemistry information for the Zenec a MPs was a repack of a registered product which is now canceled. From the confidential statements of formula provided by

Sy ngenta, it appears that the manufacturing process for the current MPs has changed. Therefore, the product chemistry data submitte d for the canceled products do not satisfy the requirements for the Sy ngenta products and a complete updated product chemistry data package on the currently

registered technicals must be submitted to support continued registration. Hazard Identification and Dose Response Assessment The toxicology

data base is adequate to characterize the toxicity of diquat dibromide, Diquat dibromide exhibits low acute toxicity via the oral (Toxicity Category I I for technical, I II for formulation) and inhalation (Toxici ty Category I II) routes of exposure but is moderately
- to severely toxic via the dermal route of exposure (Toxicity Categories I

for technical and I I for   5   44

formulation). Diquat dibromide is not an acute skin irritant (Toxicity Category I V) nor a dermal sensi tizer, but it is considered a moderate
- to - severe ey e irritant (Toxicity Category I I). Subchonic and chronic studies in several species indicate multiple target sites for diquat dibromide toxicity . In subchronic dermal exposure studies in rats, diquat di bromide showed evidence of severe sy stemic toxicity , i.e. high mortality and clinical signs. In subchronic inhalation study

in rats, the lung was determined to be the primary target site for inhalation toxicity . Chronic feeding studies in dogs, rats, mic e, and rabbits indicate that target sites include the ey es and kidney s in both males and females and the adrenals and epididy mides in males. Developmental toxicity

was observed in rat, rabbit, and mouse studies, and reproductive toxicity was observed in the rat in both generations. Rat and rabbit studies provided evidence of maternal toxicity . Acute and subchronic studies in mice and rats provided no evidence of neurotoxicity
. Available data provide no evidence of endocrine disruption following exposure to diquat dibromide. Carcinogenicity studies in rats and mice provided no evidence of an increased tumor incidence and diquat dibromide was classified as a Category E (evidence of non
- carcinogenicity to humans) by

the HED Cancer Peer Review Committee bas ed on the 1999 EPA Draft Proposed Guidelines for Carcinogen Risk Assessment . The weight of the evidence was predominantly negative for mutagenicity . The data provided no indication of increased sensitivity of rats, mice, or rabbits to in utero and/or earl y postnatal exposure to diquat dibromide. HED’s FQPA committee determined that the FQPA safety factor could be removed (1x) in assessing the risk posed by this chemical because the toxicological database is complete for FQPA assessment, there is no indic ation of quantitative or qualitative increased susceptibility of rats or rabbits to in utero and/or postnatal exposure, a developmental neurotoxicity study is not required, and the dietary (food and drinking water) and residential exposure assessments will not underestimate potential exposures for infants and children. There are no toxicological study data gaps at this time. Risk assessments were conducted for the exposure scenarios listed below. Route
- specific endpoints were selected for all but the d ermal scenario. The dermal exposure endpoint is based on oral toxicity

studies and therefore requires application of a dermal absorption factor (4.1%).

– acute dietary (general population): NOAEL= 75 mg/kg/day RfD=0.75 mg/kg/day

– chronic dietary : NOAEL= 0.5 RfD = 0.005 mg/kg/day

– short
- term oral: NOAEL= 1 mg/kg/day MOE=100

– short
- term dermal: NOAEL= 1 mg/kg/day MOE=100 Exposure Assessment Analy sis of dietary , drinking water, and residential exposure pathway s were included in the risk assessment for the diquat TRED. Sources of dietary exposure include potatoes and various crops grown for seed that is used for feed (e.g. alfalfa, sorghum) to which diquat has been applied as a dessicant. Residues in plants and livestock feeds may also occur through irrigation of crops with water containing diquat residues, resulting in dietary exposure through consumption of crops and secondary

residues in livestock tissues. Drinking water exposure may occur due to run
-   6   44

off from terrestrial use of diquat and use of diquat in lakes, ponds, streams, etc., to control aquatic weeds. Residential application and post
- application exposure may occur through the use of diquat on turf grass and weeds. Potential residential exposure routes include inhalation and dermal exposure to adult applicators/handlers, postapplication dermal exposure to adults and children, and incidental ingestion of residue by toddlers via hand
- to - mouth activity and ingestion of grass or soil from a treated area. Risk Assessment and Risk Characterization Risk assessments were conducted for dietary , drinking water, and residential exposure pathway s. An aggregate assessment of risk from the combined food, drinking water and residential pathway s was also conducted. A cumulative ri sk assessment considering risks from other pesticides or chemical compounds having a common mechanism of toxicity has not been conducted for this TRED because HED has not y et determined if there are any other chemical substances that have a mechanism of to xicity common with that of diquat dibromide. Food Pathway

Exposure and Risk HED conducted acute and chronic dietary exposure analy sis using the Dietary Exposure Evaluation Model (DEEM  ). The acute and chronic dietary exposure/risk analy ses were cond ucted using a conservative deterministic (Tier I ) methodology . The Tier Ianaly sis assumes that; 1) residues are present at published tolerances for registered uses and at recommended tolerances for proposed new uses, and 2) 100% crop treated (CT) for all commodities with existing and/or recommended tolerances. Tier I acute and chronic dietary analy ses were conducted for the general U.S. population and all population subgroups. The acute and chronic dietary risks are expressed as a percentage of the ac ute or chronic Population Adjusted Dose (aPAD or cPAD). A dietary risk of 100% of the PAD is the target level of exposure that should not be exceeded, (i.e., the estimated risk that is less than 100% of PAD is not of concern). The Population Adjusted Dose (PAD) is the Acute reference dose (RfD) or the Chronic RfD modified by the FQPA Safety

Factor. In the acute dietary assessment for diquat, acute exposure (mg/kg/day ) was compared to the aPAD which is based on the acute RfD and a FQPA safety

factor of 1x. . For the chronic dietary assessment, chronic exposure was compared to the cPAD which is based on the chronic RfD and an FQPA factor of 1x. Based on these analy ses, acute and chronic dietary

risk associated with exposure to diquat from existing and propo sed uses are below the Agency ’s level of concern for the general US population and population subgroups. The 95 th percentile acute exposure estimates were < 100% of the aPAD. The highest acute exposures ( 0.0054 mg/kg/day ) were in Children 1
- 6 y ears old (<1% aPAD). The chronic exposure estimates were <100% of the cPAD, with the highest chronic exposure (0.0031 mg/kg/day

) occurring in children 1
- 6 y ears old (62% cPAD).   7   44

Residential Pathway

Exposure and Risk Potential residential scenarios include expo sures to handlers (mixers, loaders, applicators, etc.) that occur during handling and application of diquat and/or to persons entering treated sites after its application. This TRED estimates exposure and risk for four residential handler scenarios four p ost - application scenarios, and two recreational scenarios. Residential handler scenarios include: 1) mixing, loading, and applying with a low pressure handwand (for lawns and backy ard ponds), 2) mixing, loading, applying with a backpack spray er(for lawns and backy ard ponds), 3) applying with an aerosol spray er (for lawns), and 4) applying with a trigger pump spray er. Postapplication scenarios include: 1) dermal exposure to treated turf grass (adults and children); 2) toddler ingestion of treated turf gras s via object
- to - mouth activities; 3) toddler ingestion of residue via hand
- to - mouth activity while on treated turf grass; and 4) toddler ingestion of soil from treated areas. Recreational exposures include: 1) golfer exposure from play ing on treated turf grass; and 2) exposure from swimming in treated lakes and ponds. A target Margin of Exposure (MOE) of 100 is considered adequate for all residential exposure routes. With one exception, the MOEs estimated for all of the residential exposure scenarios des cribed above showed no risks of concern (i.e. all MOEs were 100 or greater). An assessment of aggregate residential risks to children 1
- 6 ye ars from post
- application exposure to broadcast treated lawns resulted in an estimated MOE of 70, which exceeds the Agency ’s level of concern. The residential aggregate risk combines screening level risk estimates from individual exposure pathway s and should be viewed as a highly conservative estimate which is certain to over
- estimate risk. A refined analy sis would r esult in lower exposure estimates and higher MOEs. Drinking Water Pathway

Exposure and Risk The Environmental Fate and Effects Division (EFED) performed a Tier I drinking water assessment for diquat dibromide for both terrestrial and aquatic uses. EFED used both computer models and monitoring data to estimate environmental concentrations of diquat in surface and ground water. For terrestrial uses, EFED assessed preharvest application to potatoes, alfalfa, and clover with aerial and ground equipment and application to clover trees, vines, small fruits, and vegetables using directed spray from ground equipment. The FQPA Index Reservoir Screening Tool (FI RST) model was used to estimate environmental concentrations in drinking water from surface water cont aminated by terrestrial use of diquat. The surface water estimated environmental concentrations (EECs) generated by FIRST ranged from 6.3
- 13.2 ug/L (ppb) for peak exposure and 0.2
- 0.4 ug/L for average annual exposure. EFED relied on monitoring data to estimate concentrations in groundwater contaminated by terrestrial uses. Based on municipal monitoring data, EFED recommends use of EPA’s Office of Waters (OW) maximum contaminant level (MCL ) of 20 ppb for both peak and average annual EECs for groundw ater concentrations due to terrestrial use of diquat. EFED also used monitoring data to estimate surface water and ground water concentrations from aquatic uses of diquat. For surface water, EFED recommends use of the MCL of 20 ppb for both acute (peak) and chronic (annual average) EECs. For the aquatic use EFED relied on use information from the U.S. Corp of   8   44

Engineers and the states of Florida, Minnesota, and Michigan. The assessed aquatic uses include application to lakes and flowing streams. EFED al so recommends use of the MCL of 20 ppb for both acute and chronic EECs for groundwater. EFED recommends use of the same EECs for both surface and groundwater contaminated by aquatic uses of diquat because diquat is used near wells located next to lakes and ponds resulting in interaction between surface and ground water. Aggregate Exposures and Risks The aggregate risk assessment combines the exposure assessments conducted for dietary , drinking water, and residential exposure. Since there is potential for concurrent exposure via the food, water, and residential pathway s, the combined or aggregate exposures are estimated and expressed in terms of an aggregate MOE. The aggregate MOE is compared with the target MOE to determine whether there is an aggreg ate exposure of concern. All routes of diquat dibromide exposure were considered in the aggregate assessment for this TRED. Aggregate exposure pathway s for adults include dietary , drinking water, and dermal exposures from application and post - application activities. Aggregate exposure pathway s for children include dietary , drinking water, oral and dermal exposures from post
- application exposure. A target MOE of 100 is considered adequate for aggregate exposure/risk. Acute and chronic aggregate MOEs were not a risk concern, nor was the short term aggregate MOE for adults. The short
- term screening level aggregate MOE for the toddler (child 1
- 6) exposure scenario was 55. The short
- term aggregate risk combines screening level risk estimates from individual exposure pathway s and should be viewed as a highly

conservative estimate which is certain to over
- estimate risk. A refined analy sis would result in lower exposure estimates and higher MOEs. Data Gaps All product chemistry

data are required for the Sy n genta 41.1% and 37.3% Formulation In termediates (EPA Reg. Nos. 10
- 1062 and 100
- 1063). Magnitude of the residue in plants studies are required for sorghum aspirated grain fractions and soy bean aspirated grain fractions. 2.0 PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION Common Name: Diquat Dibromide Chemical Name: 6,7
- dihy drodipy rido(1,2
- a;2',1'
- c)py

razinediium dibromide Trade Names: Reglone, Weedkiller D, Aquacide, Dextrone, FB 2, Reglox, Reward Empirical Formula: C 12 H 12 Br2 N 2 CAS No.: 85
- 00
- 7 PC Co de: 032201 Structure:   9   44

Molecular Weight: 344 [Cation
- 184] Phy sical State: Cry stals Color: Colorless to Yellow Odor: Odorless Solubility in Water: 700 g/L at 20  C Vapor Pressure: < 0.03 mPa Melting Point: 300  C Density : 1 .22
- 1.27 at 20  C Pure diquat dibromide is an odorless, colorless to y ellow cry stal. I t is very soluble in water, slightly

soluble in alcohol and hydroxylic solvents, and insoluble in non
- polar organic solvents. I t is susceptible to ultraviolet decompo sition. Ethylene dibromide (EDB) may be present as a process impurity

in final formulations of diquat dibromide. However, the registrant has certified an upper limit of 10 ppm EDB in diquat dibromide and has demonstrated that EDB does not persist as an i mpurity in diquat dibromide and will slowly dissipate over time. 3.0 HAZARD CHARACTERIZATION 3.1 Hazard Profile The toxicity

data base for diquat dibromide is adequate for the selection of doses and endpoints for use in risk assessment. HED’s Hazard I dentification Assessment Review Committee (HI ARC) evaluated the acceptable studies available in the database and established acute and chronic reference doses (RfD), as well as doses and endpoints for short and intermediate
- term incidental oral exposure, and short
- term, intermediate
- term, and long
- term dermal and inhalation exposure scenarios. The Acute Reference Dose (Acute RfD) is an estimate (with uncertainty spanning an order of magnitude or greater) of a single day oral exposure level for the human p opulation, including the sensitive subpopulations, that is likely to be without an appreciable risk of deleterious effects. The Chronic Reference Dose (Chronic RfD) is an estimate (with uncertainty

spanning an order of magnitude or greater) of a daily or al exposure level for the human population, including sensitive subpopulations, that is likely to be without an appreciable risk of deleterious effects during a lifetime. The acute RfDs are calculated by dividing the NOAELby the Uncertainty

Factors (UF) . Uncertainty Factors are used to account for differences between humans (intraspecies variability ) and for differences between the test animals and humans (interspecies extrapolation). For residential exposures, uncertainty factors are used to determin e adequate margins of exposure (MOEs). The MOE is the ratio of the route appropriate NOAEL to estimated exposure. The HI ARC also evaluated available studies to determine if there is a special sensitivity

for infants and children. The toxicological data are summarized below.   10   44

3.1.1 Acute Toxicity Diquat dibromide exhibits low acute toxicity via the oral (Toxicity Category I I for technical, I II for formulation) and inhalation (Toxicity Category I II) routes of exposure but is moderately
- to - severely

toxi c via the dermal route of exposure (Toxicity Categories I

for technical and I I for formulation). Diquat dibromide is not an acute skin irritant (Toxicity Category I V) nor a dermal sensitizer, but it is considered a moderate
- to - severe ey e irritant (Toxicity Category I I). Acute toxicity

categories for diquat are shown in Table 1.

Table 1. Acute Toxicity Data on DIQUAT DIBROMIDE Guideline No. Study Type MRID #(S) Results Toxicity Category 870.1100 acute oral
- rat

Diquat Water Weed Killer 0008 1506 rat LD 50 = 810 mg/kg

 rat LD 50 = 600 mg/kg

 III 870.1200 acute dermal
- rat

Diquat Water Weed Killer 00100614 rabbits LD 50 = 262 mg/kg

 rabbits LD 50 = 315 mg/kg

 rabbits LD 50 = 288.5 mg/kg

 +

 II

870.1300 acute inhalation
- rat

Di quat Water Weed Killer 26385

 rat LC 50 = 0.80 mg/L

 rat LC 50 = 1.09 mg/L

 rat LC 50 = 0.97 mg/L

 +

 III

870.2400 primary eye irritation
-

Diquat Water Weed Killer 00081507 rabbit slight to severe eye irritant II 870.2500 primary skin irritatio n -

Diquat Water Weed Killer 00107903 slight irritation IV 870.2600 Dermal Sensitization 00107903 not a dermal sensitizer N/A

 Accession No.; With the exception of the dermal sensitization study, which was conducted with the technical diq uat [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 d iquat and the end
- use products is 2.15% of water, studies with the end
- use products have been accepted to satisfy the generic data requirements for acute studies. The above L D and L C values are ex pressed in terms of the test material and not, as is commonly done with diquat, in terms of the diquat cation. 3.1.2 Toxicity Profile Table 2 identifies and summarizes guideline studies conducted for diquat dibromide.

. Table 2. Toxicity Profile of DIQUAT DIBROMIDE GUIDELINE STUDY MRID RESULTS OPPTS 870. 3100 90
- day oral toxicity
- rat no study available OPPTS 870.3150 subchronic nonrodent oral toxicity
- 90
- day no study available OPPTS 870.3200 repeated dose dermal toxicity
- 21/28 days
- rat

20.64% diquat cation [doses: 0, 5, 20, 40, and 80 mg/kg/day] 40308101 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 dest ruction [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 [hy pothermia, hypoactivity, dyspnea, cyanosis, pale extremities, general poor condi tion, and emaciated appearance]. Based on the   11   44 Table 2. Toxicity Profile of DIQUAT DIBROMIDE GUIDELINE STUDY MRID RESULTS

Classification: Acceptable/Guideline 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 s kin toxicity [d erm al 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 application 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 d ue to the fact that the skin is compromised OPPTS 870.3200 repeated dose dermal toxicity
- 20 days
- rabbit

[doses: 20, 40, 80, 160 mg diquat cation/kg/day]

Classification: Acceptable/Non
- Guideline 00140576 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 necrosis [thought to be associated with an electrolyte im balance]. OPPTS 870.3250 subchronic dermal toxicity
- 90 days no study available OPPTS 870.3465 subchronic inhalation toxicity [21
- day]

21.6% and 23.5% diquat cation [doses: 0, 0.49, 1.1, 3.8 μg/L; 0, 0.1 μg/L] Classification: Acceptable/Guideli ne, when both studies are considered together. NOTE: Duration of study is 21 days, not 90 days. 40301701 40640801 NOAEL: 0.1 μg/L/day [m ales 0.024 mg/kg/day; females

0.026 mg/kg/day], based on increased lung weights and microscopic lesions [m ottling and reddening of the lungs in females, multifocal, chronic, interstitial pneumonia and alveolar macrophages in both sexes] in the lungs at the LOAEL of 0.49 μg/L [m ales 0.117 mg/kg/day; females 0.128 mg/kg/day]. OPPTS 870.3500 preliminary developmental toxi city screen no study OPPTS 870.3600 inhalation developmental toxicity study no study OPPTS 870.3700 prenatal developmental toxicity study
- rat

26.2% diquat cation [doses: 0, 4, 12, 40 mg/kg/day]

Classification: Acceptable/Guideline 41198902 Maternal NOAEL: 4 mg/kg/day Maternal LOAEL: 12 mg/kg/day, based on decreased body
weight gains and food consumption during dosing. At HDT, there was one death [G D 15], and clinical signs [piloerection and subdued activity] were observed [GD 13
- 22 ]. Developmental NOAEL: 12 mg/kg/day Developmental LOAEL: 40 mg/kg/day, based on decreased fetal, litter, and gravid uterine weights, an increased incidence of fetuses with hemorrhagic kidney, and delayed skeletal ossification [increased incidence of mino r skeletal variations, including unossified ventral tubercle, unossified cervical vertebral centra, and delayed ossification of the 2nd and 5th sternebrae]. OPPTS 870.3700 prenatal developmental toxicity study
- rabbit

26.2% diquat cation [doses: 0, 1, 3, 10 mg/kg/day] 41198901 Maternal NOAEL: 1 mg/kg/day Maternal LOAEL: 3 mg/kg/day, based on body
- weight loss [G D 7
- 10] and decreased food consumption [G D 7
- 10]. At HDT, there were deaths and clinical signs [diarrhea, subdued activity, thin appearance, mucus, blood, little or no feces in tray] Developmental NOAEL: 3 mg/kg/day Developmental LOAEL: 10 mg/kg/day, based on decreased fetal body weight, an increased incidence of friable/mottled livers, and an inc reased incidence of minor skeletal alterations [partially ossified ventral tubercle of cervical vertebrae, partially ossified 6th sternebrae, and unossified 6th sternebrae   12   44 Table 2. Toxicity Profile of DIQUAT DIBROMIDE GUIDELINE STUDY MRID RESULTS

Classification: Acceptable/Guideline and presacral vertebrae]. OPPTS 870.3700 prenatal developmental toxicity study
- mouse

analytical standard [doses: 0, 1, 2, 4 mg/kg/day]

Classification: Acceptable/Non
- Guideline 00061637 Maternal NOAEL: 1 mg/kg/day [as diquat cation] Maternal LOAEL: 2 mg/kg/day, based on mortality, clinical signs [piloerection, respiratory sounds], and decreased body
weight gain [during dosing period]. At HDT, additional clinical signs [abnormal posture (hunched or tail raised), lethargy, tremors, unsteadiness on feet, emaciation, ptosis] and a slight decrease in body weight [91% of control] at termination were observed also. NOTE: Poor dosing technique; incidental exposure into lungs. Developmental NOAEL: 2 mg/kg/day Developmental LOAEL: 4 mg/kg/day, based on decreased fetal body weight and an increased incidence of overall skeletal alterations. OPPTS 870.3800 reproduction and fertility effects

20.09% diquat cation [doses: 0, 16, 80, 400/240 ppm (0, 0.8, 4, 20/12 mg/kg/day)]

Classification: Acceptable/Guideline 41531301 Parental NOAEL: 16 ppm [0.8 mg/kg/day] Parental LOAEL: 80 ppm [4 mg/kg/day], based on clinical signs, ulceration of the tongue, and partial/total cataract. At HDT, increased incidence of clinical signs including ophthalmoscopic signs and lack of grooming, and gross and microscopic findings [ulceration of the ton gue and partial/total cataract]. Reproductive/Developmental NOAEL: 80 ppm [4 mg/kg/day] Reproductive/Developmental LOAEL: 400/240 ppm [12 mg/kg/day], based on decreased number of live pups per litter on days 1
- 22, decreased pup body
- weight gain during lact ation, and increased incidence of kidney lesions. OPPTS 870.4100 chronic toxicity [feeding] study
- beagle dog

26.7% diquat cation [doses: 0, 0.5, 2.5, 12.5 mg/kg/day for 52 weeks] Classification: Acceptable/Guideline 41730301 NOAEL: 0.5 mg/kg/day LOAEL: 2.5 mg/kg/day, based on unilateral cataracts in females, and decreased weights of epididymides and adrenals in males. At the HDT, bilateral lenticular opacity [cataracts], macroscopically and microscopically [in all dogs, both sexes]; inflammatory lesions in the large intestine [in all dogs, both sexes]; increased kidney weight [both sexes]. OPPTS 870.4200 carcinogenicity
- CD
- 1 mouse

21.09% diquat cation [doses: 0, 30, 100, 300 ppm (males 0, 3.56, 11.96, 37.83 mg/kg/day; females 0, 4.78, 16.03, 48.27 mg/kg/day)] for 104 weeks Classification: Acceptable/Guideline 42219801 42880701 42905901 42919501 NOAEL = 30 ppm [356/4.78 mg/kg/day]

LOAEL: 100 [11.96/16.03 mg/kg/day], based on clinical signs [eye discharge (males), subdued behavior (females)], and decreased body weight/body
- weight gain [m ales]. Diquat dibromide was not carcinogenic in male or female CD
- 1 mice.
OPPTS 870.4300 combined chronic toxicity/carcinogenicity
- rat

26.5% diquat cation [doses: 0, 5, 15, 75, and 375 ppm (0, 0.19, 0.58, 2.91, and 14.88 mg/kg/day for males and 0, 0.24, 0.72, 3.64, and 19.44 mg/kg/day for females)] for 104 weeks. Classification: Acceptable/Guideline 00145855 00155474 41085601 NOAEL: 15 ppm [0.58/0.72 mg/kg/day]

LOAEL: 75 ppm [2.91/3.64 mg/kg/day], 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 increa se in tumor incidence in either sex. OPPTS 870.5100
- 5915 genetic toxicity tests

Classification: Acceptable/Guideline negative for mutagenicity in a bacterial gene mutation [A mes] assay.; however, positive for gene mutations in a mammalian c ell line [m ouse lymphoma] but at cytotoxic doses. Also, clastogenic in cultured human lymphocytes, but the response was generally weak and observed at cytotoxic levels. In contrast, there was no evidence of clastogenicity in somatic cells [m ouse bone marro w] o r germinal cells [m ouse spermatogonia] or unscheduled DNA synthesis [UDS] in rat hepatocytes in a series of in vivo studies. Overall, the data suggest that there is no concern for mutagenicity.   13   44 Table 2. Toxicity Profile of DIQUAT DIBROMIDE GUIDELINE STUDY MRID RESULTS OPPTS 870.6100 delayed neurotoxicity of OPs following a cute/28
- day

exposures - no study OPPTS 870.6200 neurotoxicity screening battery
- acute [rat]

20.1% diquat cation [doses: 0, 25, 75, and 150 mg/kg]
Classification: Acceptable/Guideline 42666801 NOAEL = 75 mg/kg LOAEL = 150 mg/kg/day, based on cl inical signs [piloerection, diarrhea, staining around nose, urinary incontinence, upward curvature of the spine, tip toe gait, hunched posture, subdued behavior, and pinched sides] and decreased body
- weight gains. NOTE: Agency concluded that signs may not be due to direct neurotoxicity. OPPTS 870.6200 subchronic neurotoxicity
- Alpk:APfSD rats

20.8% diquat cation doses: 0, 20, 100, and 400 ppm [m ales 0, 1.6, 8.0, 32.4 mg/kg/day/females 0, 1.9, 9.5, and 38.5 mg/kg/day] Classification: Acceptable/Guideli ne 42616101 Systemic Toxicity NOAEL = 100 ppm [8.0/9.5 mg/kg/day Systemic Toxicity LOAEL = 400 ppm [32.4/38.5 mg/kg/day, based on evidence of cataracts and decreased body
- weight gain and food utilization in both sexes. There wa s no evidence of neurotoxic ity at any dose level.
OPPTS 870.6300 developmental neurotoxicity study
- no study OPPTS 870.7485 metabolism and pharmacokinetics [disposition and

metabolism]

Classification: Acceptable/Guideline when considered with other two studies 00065592 Diquat dibromide did not accumulate in tissues and was slowly absorbed following e ither 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 radiolabe l was excreted in urine within 7 days. 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, m

uscle, and blood, and little retention 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, a s well as the brain and spinal cord. After 24 hours, radiolabel was detected only in the urinary bladder and intestines.
Metabolism
- excretion

Classification: Acceptable/Guideline when considered with other two studies 00065593 Rats excre ted 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 [5.3%] of the [ 14 C] was unchanged Diquat, 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 sulfate
unextractable fraction. In the sulfuric ac id fraction, [ 14 C] was distributed as follows: unchanged diquat [57.1%], diquat monopyridone [4.3%], and unidentified material [4.1%]. Metabolism Classification: Acceptable/Guideline when considered with other two studies 00055107 Following oral d osing,  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 with in 2 days. OPPTS 870.7600 dermal penetration

Classification: Acceptable/Guideline 41238701 dermal absorption of Diquat dibromide through intact rat skin is considered very low. OPPTS 870.7800 immunotoxicity
- no study

3.1.3 Hazard Character ization   14   44

The toxicity

data base for diquat is complete and clearly defines the toxicity

of the compound. Subchonic and chronic studies in several species indicate multiple target sites for diquat dibromide toxicity . In subchronic dermal exposure studies in rats, diquat dibromide showed evidence of severe sy stemic toxicity , i.e. high mortality and clinical signs. While a dermal study was available, the dermal endpoint is based on a rabbit developmental gavage study because the dermal study

was determined to be inappropriate for endpoint selection. Route specific endpoints are available for all other exposure pathway s. In a subchronic inhalation study in rats, the lung was determined to be the primary target site for inhalation toxicity . Chronic feeding studies in dogs, rats, and mice indicate that target sites include the eyes and kidney s in both males and females and the adrenals and epididy

mides in males. Developmental toxicity was observed in rat, rabbit, and mouse studies, and reproductive toxicity was observed in the rat in both generations. Rat and rabbit studies provided evidence of maternal toxicity . The acute and subchonic neurotoxicity studies in rats provided no evidence of neurotoxicity . Available data provide no evidence of endocrine disr

uption following exposure to diquat dibromide. Carcinogenicity studies in rats and mice provided no evidence of increase tumor incidence and diquat dibromide was classified as a Category E (evidence of non
- carcinogenicity to humans) by

the HED Reference D ose (RfD)/Peer Review Committee based on the 1999 EPA Draft Proposed Guidelines for Carcinogen Risk Assessment . The weight of the evidence was predominantly negative for mutagenicity . The data provided no indication of increased sensitivity of rats, mice, or rabbits to in utero and/or early postnatal exposure to diquat dibromide. The terminal residue of concern is the parent compound, diquat cation. There is no indication that metabolites are present in significant quantities. 3.2 FQPA Considerations HED’s FQPA committee determined that the FQPA safety factor could be removed (1x) in assessing the risk posed by this chemical because the toxicological database is complete for FQPA assessment, there is no indication of quantitative or qualitative i ncreased susceptibility of rats or rabbits to in utero and/or postnatal exposure, a developmental neurotoxicity study is not required, and the dietary

(food and drinking water) and residential exposure assessments will not underestimate the potential expos ures for infants and children. The HIARC and FQPA Committee determined that a developmental neurotoxicity study was not required for diquat dibromide based on the fact that (1) there is no indication of abnormalities in the development of the fetal nervous sy stem in prenatal developmental toxicity studies in rats, mice, and rabbits at oral dose levels that were maternally

toxic, (2) there was no evidence of neuropathology in either the acute or subchronic neurotoxicity

studies, (3) the clinical and function al observational battery observations in the acute neurotoxicity study , which could not be unequivocally correlated to an effect on the nervous sy stem, were not observed in the subchronic neurotoxicity study , and (4) no neurotoxic effects were observed in the brain weights or histopathology of the nervous sy stem in the chronic toxicity studies with diquat in several species. 3.3 Dose Response Assessment Doses and toxicological endpoints selected for various exposure scenarios are summarized in Table 3. Table 3. Sum ma ry of Toxicological Dose and Endpoints for Diquat for Use in Hum an Risk Assessm ent   15   44

Exposure Scenario Dose Endpoint Study Acute Dietary general population incl infants and children NOAEL= 75 mg/kg

UF = 100 LOAEL of 150 mg/kg based on clinical signs and

decreased body
- we ight gain. Acute neurotoxicity rat FQPA = 1x Acute RfD = 0.75 m g/kg Acute PAD = 0.75 m g/kg Chronic Dietary NOAEL = 0.5 mg/kg/day UF = 100 LOAEL of 2.5 mg/kg/day based on cataracts in

females and dec reased adrenal and epididymides we ights in males. chronic toxicity dog FQPA = 1x Chronic RfD = 0.005 m g/kg/day Chronic PAD = 0.005 m g/kg/day Short
- Term

Oral (1day
- 1 month) NOAEL = 1 mg/kg/day MOE = 100 LOAEL of 3 mg/kg/day based on body
- we ight loss

and decreased food consumption. Developmental toxicity
- rabbit Short
- Term Dermal a (1 day
- 1 month) NOAEL = 1 mg/kg/day MOE = 100 LOAEL of 3 mg/kg/ day based on body
- we ight loss

and decreased food consumption. Developmental toxici ty - rabbit Short
- Term Inhalation (1 day
- 1 month) NOAEL = 0.1 ug/l

(0.024 mg/kd/d male, 0.026 mg/kd/d female) MOE = 100 LOAEL of 0.49 ug/L (0.117 mg/kg/day male,

0.128female) due to increased mean lung weight in males, mottling and reddening of lungs in females, and lung lesions. 21
- day inhalation toxicity rat a Since an oral value was selected, route
- to - route extrapolation should be followed. A dermal absorption factor is required for this risk assessments. 3.3.1 Dietary Exposure End points 3.3.1.1 Acute Reference Dose The HI ARC selected an acute RfD of 0.75 mg/kg based on an acute neurotoxicity gavage study in the rat which showed clinical signs of sy stemic toxicity (e.g., piloerection, diarrhea, urinary incontinence, upward curvature of the spine, subdued behavior) and decreased body
- weight gains at the sy stemic L owest Observed Adverse Effect Level (LOAEL). The study is considered appropriate for selection of an acute endpoint because effects were seen after a single dose. The H IA RC recommended a (UF) of 100x (10x for interspecies and 10x for intraspecies is extrapolation) for calculation of the RfD. The acute endpoint selected by the HI ARC for the current risk assessment differs from that used in assessments conducted for the 1995 RED and 1998 assessment of risk based new and revised uses. The acute dietary endpoint used in previous assessments was based on a rat developmental study , which showed transitory decrease in mean body
- weight gain of the maternal rat following four d ay s of exposure to diquat dibromide. The HI ARC concluded that this endpoint was not a single dose effect and so was not appropriate for use in an acute risk assessment. The rabbit and mouse developmental toxicity studies were also re
- evaluated by the HI A RC for the current analy sis. The rabbit study was deemed inappropriate because the maternal body
- weight loss observed during gestation was not a single dose effect. The mouse study was rejected for   16   44

endpoint selection because of poor dosing technique whic h caused inappropriate introduction of test material into the lungs.

3.3.1.2 Chronic Reference Dose The HI ARC selected a chronic RfD of 0.005 mg/kg/day from a chronic oral dog toxicity study . The endpoint is based on unilateral cataracts in males and females and decreased adrenal and epididy

mides weights in males at the L OAEL of 2.5 mg/kg/day . The study is considered appropriate for selection of an endpoint for a chronic exposure sce nario because cataracts and decreased adrenal and epididy mides weights are found consistently in repeat exposure studies in both the dog and the rat. The rat chronic toxicity /carcinogenicity

study which also showed evidence of cataracts, was considered co
- critical for this endpoint. The HIARC recommended a UF of 100 (10 interspecies; 10 intraspecies). The chronic endpoint selected for the current analy sis was used in both of the previous diquat risk assessments.

3.3.2 Residential Exposure Endpoints 3.3.2.1 Short
- Term Oral Exposure (1 day
- 1 month) A short
- term oral NOAEL of 1 mg/kg/day was selected from a rabbit developmental gavage study which showed maternal body
- w eight loss during gestation day s (GD) 7
- 10 and decreased food consumption during dosing (GD 7
- 10) at the L OAEL of 3 mg/kg/day . The study is considered appropriate as a basis for endpoint selection for infants and children, the population of concern for in cidental oral exposure. A target MOE of 100 was determined to be adequate for this exposure pathway

by the HI ARC. A short
- term oral endpoint was not included in previous HIARC or risk assessment documents for this chemical. 3.3.2.2 Short
- Term Dermal E xposure (1 day
- 1 month) The HI ARC selected a short
- term dermal NOAEL of 1 mg/kg/day . The endpoint is based on a rabbit developmental gavage study which resulted in maternal body
- weight loss during Acute RfD = 75mg/kg (NOAEL = 0.75 mg/kg

100 (UF)

Chronic RfD = 0.5mg/kg/day (NOAEL) = 0.0 05 mg/kg/day 100 (UF)   17   44

gestation day s (GD) 7
- 10 and decreased food consumptio n during dosing (GD 7
- 10) at the L OAEL of 3 mg/kg/day . The rat chronic toxicity /carcinogenicity

study was considered co
- critical for this endpoint. The recommended target MOE was 100. For the diquat risk assessment conducted for the 1995 RED, and endpoi nt from a 20 day dermal toxicity

study in rabbits was selected for use in assessing risk from dermal exposure. For the 1998 revised assessment, the HIARC determined that the 21
- day

rat dermal toxicity

study was more appropriate for use in selecting a derm al endpoint because the rabbit study

is a non
- guideline study . Only 3 rabbits/group were used and hematology , clinical chemistry , and urinaly sis parameters were not monitored. The guideline states that ten animals/sex/dose are needed for a NOAEL for risk assessment. The HI ARC then re
- evaluated the rat dermal toxicity

study for this TRED. Based on the most recent review, the HIARC concluded that the rat study

was inappropriate for use in endpoint selection because the animal’s skin was compromised result ing in increased severity of effects and an artificially low NOAEL
. 3.3.2.3 Dermal Absorption Since the dermal exposure endpoints were selected from oral toxicity studies, a dermal absorption factor is required to convert the oral dose to an equivalent dermal dose for the risk assessment. In an acceptable/guideline in vivo per cutaneous absorption study , three aqueous doses of [ 14 C] diquat dibromide were applied dermally to 12 Sprague
- Dawley

rats (four rats per dose). The rats were dermally

dosed at l evels of 0.05, 0.5, and 5 mg diquat cation/rat for exposure periods of 2, 10 and 24 hours. The respective 2, 10, and 24 hour absorption rates were 4.1, 5.5, and 7.4% at the low dose (0.05 mg/rat), absorption was 2.8, 5.3, and 4.7% at the middle dose (0.5 mg/rat), and 2.6, 2.5, and 3.3% at the high dose (5 mg/rat). (Total percent absorbed = percent absorbed + percent remaining in/on the skin.) The 4.1% (dermal absorption factor corresponding to the 2 hour, low dose (0.05 mg/rat) exposure was used for th e non - occupational handler and postapplication exposure scenarios where children and adults are assumed to have a 2 hour exposure duration. This is a conservative assumption in which total percent absorbed = percent absorbed (1.2%) + percent remaining in/ on the skin (3.9%).   18   44

3.3.2.4 Short Term Inhalation Exposure (1 day
- 1 month) The selected NOAEL for inhalation exposure is 0.1 μg/L (0.023 mg/kd/day male, 0.027 mg/kg/day

female) based on a repeated dose 21
- day inhalation toxicity

study in rats which resulted in on increased lung weights and microscopic lesions in the lungs at the L OAEL of 0.49 μg/L (0.113 mg/kg/day

male, 0.134 female). The route and duration of exposure are appropriate for selecting a short term inhalation endpoint. 3.3.2.5 In terme diate and L ong - Term Endpoints
- The HI ARC also selected endpoints for intermediate
- term oral, and intermediate, and long
- term dermal and inhalation exposure scenarios. However, since only

short
- term exposures are anticipated for residential uses, endpoint s for longer term exposures were not used in the exposure and risk assessments for this TRED. 3.3.2.6 Common Toxicological Endpoints for Exposure Routes A common toxicological endpoint (decrease in maternal body weight and food consumption) was selected for assessment of short
- term incidental oral and dermal (oral equivalent) exposures. Therefore, these exposure routes can be aggregated. The toxicological endpoint (increased lung weight and microscopic lung lesions) observed via the inhalation route is unique. Therefore, this exposure route cannot be aggregated with the oral and dermal exposures. 3.4 Endocrine Disruptor Effects Available toxicity

data suggest that there is no evidence of endocrine disruption following exposure to diquat dibromide. EP A is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances (including all pesticide active and other ingredients) "may have an effect in humans that is similar to an effect produced by a natura lly

occurring estrogen, or other such endocrine effects as the Administrator may designate." Following the recommendations of its Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC), EPA determined that there was scientific bases for inc luding, as part of the program, the androgen and thy roid hormone sy stems, in addition to the estrogen hormone sy stem. EPA also adopted EDSTAC’s recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FI FRA and, to the extent that effects in wildlife may

help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone sy stems may be added to the Endocrine Disruptor Screening Program (EDSP). When the appropriate screening and/or testing protocols being considered under the Agency ’s EDSP have been developed, diquat dibromide may be subjected to additional screeni ng and/or testing to better characterize effects related to endocrine disruption.   19   44

4.0 EXPOSURE ASSESSMENT 4.1 Summary of Registered Uses Currently registered uses are summarized in Table 4. Table 5 summarizes the volume of diquat dibromide usage by cr op. Table 4. Diquat Dibrom ide Use Groups and Sites Use Group Use Sites Aquatic Food Crop agricultural drainage & irrigation systems; lakes/ponds/reservoirs with human or wildlife use Aquatic Non
- food Industrial drainage systems, lakes/ponds/re servoirs without human or wildlife use Aquatic Non
- food Outdoor aquatic and intermittently flooded areas, streams/rivers/channeled water Aquatic Non
- food Residential ornamental ponds/aquaria Greenhouse Food Crop in
- use greenhouse Indoor Food s torage areas - empty and full Indoor Non
- food empty greenhouse Outdoor Residential residential lawns, household/domestic dwellings outdoor premises Terrestrial Feed Crop alfalfa, Bermuda grass, clover Terrestrial Non
- Food Crop carrot, cucumber, melons, pepper, radish, squash, turnip, tomato Terrestrial Food & Feed Crop potato, sorghum, soybeans Terrestrial Non
- food Crop agricultural fallow/idleland, structures/equipment, rights
- of way/fence rows/hedge rows, and uncultivated areas; airports /landing fields; commercial/industrial lawns, premises and equipment (outdoor); golf course turf; nonagricultural outdoor structures/rights
- of
wa y/fence rows/hedge rows
Table 5. Volum e of Diquat Dibrom ide Usage by Crop Crop % Treated Pounds A.I. (10 00) Application Rate (lbs

A.I) Major States Alfalfa/Seed 50 25 0.4 CA, OR, WA Potatoes 30 170 0.3 ME, ND, NY Soybeans <1 1 0.4
- Sorghum <1 2 0.4
- Dry Beans <1 1 0.3
-   20   44 Table 5. Volum e of Diquat Dibrom ide Usage by Crop Crop % Treated Pounds A.I. (10 00) Application Rate (lbs

A.I) Major States Grapes <1 1 0.4
- Home & Garden <1 100 0.3
- Aquatic Uses <1 200 1.5 CA, FL Total 500 4.2 Dietary Exposure/Risk Pathway 4.2.1 Residue Profile 4.2.1.1 Nature of the Residue
- Plants and L ivestock Plants The reregistration requirements for plant metabolism are fulfille d (T. Morton, 11/20/01, D277710). The qualitative nature of the residue in plants 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, 11/8/01, D277765). The established tolerance expression for residues of diquat dibromide in/on plant commodities is appropriate and no changes are required. The potato metab olism study indicated that no metabolism of diquat occurred in potato tubers following preharvest application of [ 14 C]diquat as a desiccant to potato stalks and stems. Previously

submitted soy

bean and wheat metabolism studies were deemed marginal because of inadequate characterization and identification of 14 C
- residues in the commodities of concern. In lieu of additional crop metabolism studies, the Agency recommended several alternatives for this requirement. The registrant opted to conduct a bioavaila bility study . The results of the bioavailability

study showed that diquat 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. The retention of diquat residues in tissues was negligible (  0.004 ppm diquat equivalents) following dosing at  25x the maximum human dietary intake. Li vestock The reregistration requirements for animal metabolism are fulfilled. The qualitative nature of the residue in livestock is adeq uately understood based on acceptable poultry , ruminant, and fish metabolism studies. The HED Metabolism Assessment Review Committee (MARC) has concluded the residue of concern for livestock is the diquat cation (T. Morton, 11/8/01, D277765).   21   44

The establis hed tolerance expression for residues of diquat dibromide in animal commodities is appropriate and no changes are required. Inthe poultry

metabolism study , laying hens were dosed with ring
- labeled [ 14 C]diquat at 32 ppm in the diet for 4 day s. The total radioactive residues (TRR; expressed as diquat equivalents) ranged from <0.001
- 0.004 ppm in egg y olks, egg whites, fat, and muscle, 0.042
- 0.058 ppm in kidney , and 0.030
- 0.045 ppm in liver. The predominant metabolites identified were diquat cation (48% of TRR in liver), and diquat monopy ridone (15.1% of TRR in kidney ) The metabolism of diquat dibromide in ruminants has been extensively investigated. Ruminant data confirm that the residue of concern in ruminant milk and tissues is diquat cation. Ethylene b ridge
- labeled [ 14 C]diquat dibromide was administered at 5 ppm to three cows. In addition, one cow was dosed with ethylene bridge
- labeled [ 14 C]diquat at 20 ppm and with by py ridyl
- labeled [ 14 C]diquat at 5 ppm. The highest TRR value in milk was 0.077 ppm in the 72
- hour milk sample from the cow dosed at 20 ppm. In milk samples from the high
- dose cow, residues of diquat per se were quantitated at <0.002 ppm and did not concentrate in the fat, casein or whey . No residues (<0.01 ppm) were found in the leg musc le samples from one of the cows dosed at 5 ppm. A bull calf was administered ethylene bridge
- labeled [ 14 C]diquat dibromide at 8 ppm and sacrificed 24 hours after dosing. The TRR were 1.071 ppm in kidney , 0.033 ppm in liver and <0.04 ppm in other tissues. Residues of diquat cation were 0.03 ppm and <0.01 ppm in the kidney and liver samples, respectively
. Inthe fish metabolism study , trout and carp were exposed to an initial concentration of 1 ppm of bridge
- labeled [ 14 C]diquat in the water for 7 day s. T he TRR (expressed as diquat equivalents) in carp head and tail, viscera, and body with skin were 0.025
- 0.077 ppm, 0.135
- 0.946 ppm, and 0.013
- 0.024 ppm, respectively . The TRR in skin and flesh without skin were 0.015
- 0.023 ppm and 0.006
- 0.016 ppm, respecti vely . The TRR in trout head, tail, and flesh were 0.025
- 0.051 ppm, 0.059
- 0.239 ppm, and 0.008
- 0.01 ppm, respectively . Approximately 65% of the radioactivity

in carp flesh and trout viscera was identified as diquat. 4.2.1.2 Residue Analy

tical Method
- P lants and L ivestock Enforcement methods The Pesticide Analy

tical Manual (PAM) Vol. I I. lists a spectrophotometric method, designated as Method A as available for the enforcement of tolerances for residues of diquat in/on plant and in livestock commoditi es. The limit of detection is 0.01 ppm. The registrant has proposed new enforcement methods, RM
- 5B
- 1 and RM
- 5C, for plant and livestock commodities, respectively . The stated limit of detection is 0.005 ppm for RM
- 5B
- 1; the limit of detection for RM
- 5C i s not clearly

specified. Both methods have been adequately validated by

the registrant; however, an independent laboratory validation must be conducted followed by validation by

the Agency 's Analy

tical Chemistry

Branch before they

can be considered fully adequate for   22   44

enforcement purposes. Once a successful EPA method validation has been performed, these methods will be sent to FDA for inclusion in PAM Vol. I I. Data collection Residue data submitted for tolerance reassessment were collected using the cur rent (PAM Vol. 2 Method A) or proposed (RM
- 5B and RM
- 5C) enforcement methods. The registrant provided adequate method validation data to verify the suitability

of these methods for data collection. 4.2.1.3 Multiresidue Methods The FDA's PESTDATA dated 1 1/6/90 (PAM Vol. I , Appendix) indicates that recovery of diquat dibromide using Multiresidue Protocols is unlikely . The updated PESTDATA dated 08/93 does not have an entry

for diquat dibromide. 4.2.1.4 Storage Stability

Data The requirements for storage stability data are fulfilled for purposes of tolerance reassessment. Adequate storage stability data on diquat dibromide are available to support the storage conditions and intervals of samples from magnitude of the residue studies in plants and livestoc k. Residues of diquat are stable under frozen (
- 20  C) storage conditions for: up to six months in/on bell pepper, carrot roots, clover (hay and seed), lettuce, potato, rice (grain and straw), sorghum grain, soy

bean, tomato and tomato processed fractions, and wheat (grain and straw); up to 8 months in processed fractions of sorghum grain and soy bean; and up to 2 months in water and seafood samples. 4.2.1.5 Magnitude of the Residue in Crop Plants All data for magnitude of the residue in plants have been ev aluated and deemed adequate except for the following deficiencies: residue data required for sorghum aspirated grain fractions, soy bean aspirated grain fractions. All field residue data have been re
- evaluated and plant commodity

tolerances reassessed (whe re residue data are available) for TRED purposes. There are no registered uses of diquat dibromide on sugarcane and vetch. Therefore, field residue data for these crops are no longer required and the established tolerance for residues in/on sugarcane sho uld be revoked. 4.2.1.6 Magnitude of the Residue in Processed Food/Feed The data for magnitude of the residue in processed food/feed have been evaluated and deemed adequate to determine the extent to which residues of diquat concentrate in food/feed ite ms upon processing of raw agricultural commodities. Acceptable potato, soy bean, and sorghum processing studies have been submitted and evaluated. Acceptable processing data are also   23   44

available for tomato wet pomace, tomato juice, and tomato paste. Howeve r, additional residue data are required for sorghum and soy bean aspirated grain fractions and tomato puree. 4.2.1.7 Magnitude of the Residue in Meat, Milk, Poultry , and Eggs The reregistration data requirements for magnitude of the residue in livestock a re fulfilled. The HED MARC has concluded that the residue of concern for livestock is the diquat cation (T. Morton 11/08/01) and acceptable animal feeding studies have been submitted and evaluated. A new maximum dietary

burden (MDB) estimate has been ca lculated based on reassessed established/proposed tolerances of feed commodities and revised Table I I of OPPTS 860 Guidelines. (T. Morton, 11/20/01, D277710). The established tolerances of 0.02 ppm for diquat residues in the fat, meat, and meat by product s of cattle, goats, hogs, horses, and sheep may be raised to 0.05 ppm to achieve compatibility with the Codex maximum residue limit (MRL ). The established 0.02
- ppm tolerance level for diquat residues in poultry fat, meat, meat by

products and eggs may be r aised to 0.05 ppm to achieve compatibility with the Codex MRL
. 4.2.1.8 Magnitude of the Residue in Fish and Shellfish All data requirements for magnitude of the residue in fish and shellfish have been evaluated and deemed adequate to reassess the toler ances for diquat; no additional data are required regarding this topic. The available data indicate that residues of diquat in fish and shellfish will exceed the established tolerances following tests reflecting the current maximum registered use patterns . The registrant must submit a petition requesting tolerance increases from 0.1 ppm to 2.0 ppm for fish and 20 ppm for shellfish to cover all residues of diquat which may occur as a result of the currently

registered uses. 4.2.1.9 Magnitude of the Resid ue in Irrigated Crops The available data concerning diquat residues following irrigation of carrot, corn (sweet), cowpea, peach, and rice are adequate to support the established 0.02 ppm tolerances for diquat residues in/on all members of the crop groups containing these commodities. However, the data also indicate that residues in/on cowpea, blackberry , strawberry , orange, mustard greens, pasture grass, and tomato may

exceed the tolerances for the respective crop groups. The registrant must propose a hi gher tolerance level of 0.05 ppm for citrus fruit, small fruits, fruiting vegetables, legume vegetables, and Brassica leafy vegetables. The registrant is required to propose a higher tolerance level of 0.20 ppm for forage grasses. No data are available f

or the commodities avocado, cottonseed, hops, and sugarcane for which tolerances currently exist. However, data for other crops can be translated to these commodities. Based on the highest residues found in other crops irrigated with water containing diquat residues, HED recommends that the registrant propose tolerances of 0.20 ppm for these crops. I f lower tolerances are desired, additional data will be required.   24   44

4.2.1.10 Confined and Field Accumulation in Rotational Crops The data requirements for confined rotational crops have been reviewed and deemed adequate by

the Environmental Fate and Effects Division (EFED). The requirements for field rotational crop studies have been waived at this time. 4.2.1.11 Codex/International Harmonization Several maximum residue limits (MRL s) for diquat have been established by Codex in various commodities. Tolerance levels for some commodities with an MRL have been revised in the TRED to achieve compatibility with Codex. The U.S. tolerance for eggs, poultry , me at, and offal (mammalian) may

be raised to 0.05 ppm to achieve harmonization. Further harmonization of U.S. tolerances and Codex MRL s on other commodities are not feasible at this time because of differences in agricultural practices. 4.2.2 Dietary Exp osure/Risk Assessment 4.2.2.1 Consumption Data and Dietary Risk Analy sis Diquat acute and chronic dietary exposure assessments were conducted using the Dietary Exposure Evaluation Model (DEEM  ) software Version 7.73, which incorporates consumption data f rom USDA’s Continuing Survey s of Food I ntake for Individuals (CSFI I), 1989
- 1992. The 1989
- 92 data are based on the reported consumption of more than 10,000 individuals over three consecutive day s, and in total represent more than 30,000 unique “person day s” of data. Foods “as consumed” (e.g., apple pie) are linked to raw agricultural commodities and their food forms (e.g., apples
- cooked/canned or wheat
- flour) by recipe translation files internal to the DEEM software. Consumption data are averaged for the entire US population and within population subgroups (e.g., children one to six y ears old) for chronic exposure assessment, but are retained as individual consumption items for acute exposure assessment. For chronic exposure and risk assessment, estimate s of average residues for foods (e.g., orange) or food
- forms (e.g., orange
- juice) of interest are multiplied by the averaged consumption estimate of each food/food
- form of each population subgroup. Exposure estimates are expressed in mg/kg body weight/day and as a percent of the cPAD. For acute exposure assessments, individual one - day consumption data are used on an individual - by - individual basis. The reported consumption amounts of each food item can be multiplied by a residue point estimate and summed to obtain a total daily pesticide exposure for a deterministic (Tier 1 or Tier 2) exposure assessment, or “matched” in multiple random pairings with residue values and then summed in a probabilistic (Tier 3/4) assessment. The resulting distribution of ex posures is expressed as a percentage of the aPAD on both a user (i.e., those who reported eating relevant commodities/food forms) and a per
- capita basis.   25   44

4.2.2.2 Acute Dietary

Exposure/Risk Assessment An acute dietary

exposure analy sis was conducted for diquat dibromide using the DEEM  software (B. Daiss, D277766, 12/11/01). The acute dietary exposure/risk analy sis was conducted using a conservative deterministic (Tier I ) methodology . The Tier Ianaly sis assumes that; 1) residues are present at publishe d tolerances for registered uses and at recommended tolerances for proposed new uses, and 2) 100% crop treated (CT) for all commodities with existing and/or recommended tolerances. Tier I acute dietary

analy ses were conducted for the general U.S. populati on and all population subgroups. Based on this analy ses, acute dietary risk associated with exposure to diquat from existing and proposed uses are below the Agency ’s level of concern for the general US population and population subgroups. The 95 th percen tile acute exposure estimates were < 100% of the acute Population Adjusted Dose (aPAD). The highest acute exposure ( 0.0054 mg/kg/day

) was in children 1
- 6 y ears old (<1% aPAD). The results are presented in Table 6. Table 6. Acute Dietary (Food) Expos ure Estim ate and Percent of Acute RfD at the 95 th Percentile - Tier 1

Exposure Analysis (Assum es 100% Crop Treated and Tolerance Level Residues) Subgroups 95 th Percentile Exposure (mg/kd/day) % aPAD at 95 th Percentile Exposure US Population (total ) 0.0039 < 1 All Infants (<1 year old) 0.0035 < 1 Children 1
- 6 years old 0.0054 < 1 Children 7
- 12 years old 0.0033 < 1 Females 13
- 50 years old 0.0032 < 1 Males 13
- 19 years old 0.0030 < 1 Males 20+ years old 0.0035 < 1 Seniors 55+ years old 0.0023 < 1 4.2.2.3 Chronic Dietary

Exposure/Risk Assessment A chronic dietary

exposure analy sis was conducted for diquat dibromide using the DEEM  software. The chronic dietary analy sis was conducted using a conservative deterministic (Tier I ) methodology

(i.e., residues present at tolerance levels and 100 %CT). Tier I chronic dietary analy ses were conducted for the general U.S. population and all population subgroups. Based on this analy ses, chronic dietary risk associ ated with exposure to diquat from existing and proposed uses are below the Agency ’s level of concern for the general US population and population subgroups. The chronic exposure estimates were < 100% of the chronic PAD (cPAD) with the highest chronic expo sure (0.0031 mg/kg/day ) occurring in children 1
- 6 y ears old (62% cPAD). Results are presented in Table 7.   26   44

Table 7. Chronic Dietary (Food) Exposure Estim ate and Percent of Chronic RfD - Tier 1 Exposure Analysis

(Assum es 100% Crop Treated and Tolerance Level Residues) Subgroups Mean Exposure (mg/kd/day) % cPAD at Mean Exposure US Population (total) 0.0019 38 All Infants (<1 year old) 0.0017 33 Children 1
- 6 years old 0.0031 62 Children 7
- 12 years old 0.0021 42 Females 13
- 50 years old 0.0017 34 Males 13
- 19 years old 0.0018 26 Males 20+ years old 0.0019 38 Seniors 55+ years old 0.0015 31 4.3. Drinking Water Exposure/Risk Pathway 4.3.1. Environmental Fate Assessment 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 primary route of environmental dissipation of diquat used in terrestrial settings is strong adsorption to soil. When used as an aquatic h erbicide, diquat is removed from the water column by adsorption to sediment, aquatic vegetation, and organic matter. Based on acceptable guideline studies, diquat does not hy droly ze or photodegrade and is resistant to microbial degradation under aerobic a nd anaerobic conditions. There were no major degradates isolated from any of the environmental fate studies. Environmental fate data indicate that diquat is miscible in water (7 x 10 5 ppm), is stable to hy droly sis and photoly sis, and metabolism, but is e ssentially immobile in soil and sediment. The extent of adsorption appears to be related to soil pH, with is consistent with cation exchange in soil. 4.3.2 Estimated Environmental Concentrations/Monitoring Results The Environmental Fate and Effects Div ision (EFED) performed a Tier Idrinking water assessment for diquat dibromide for both terrestrial uses and aquatic uses (D281199, J. Breithaupt, 3/5/01). EFED used both computer models and monitoring data to estimate environmental concentrations of diqu at in surface and ground water. For terrestrial uses, EFED assessed preharvest application to potatoes, alfalfa, and clover with aerial and ground equipment and application to clover trees, vines, small fruits, and vegetables using directed spray from gro und equipment. The assessed aquatic uses include application to lakes and flowing streams.   27   44

4.3.2.1 Terrestrial Uses Surface Water The FQPA Index Reservoir Screening Tool (FI RST) model was used to estimate environmental concentrations in drinking wate r from surface water contaminated by terrestrial use of diquat. FI RST is based upon the linked Pesticide Root Zone Model (PRZM) which simulates pesticides in field run
- off and Exposure Analy sis Modeling Sy stem (EXAMs) which simulates pesticide fate and tr ansport in an aquatic environment. However, where previous PRZM
- EXAMs models used a standard field pond scenario, FI RST uses an Index Reservoir which is based on Shipman City

L ake in I llinois ( 13 acres in area, 9 feet deep, and a watershed area of 427 a cres). Inaddition, FI RST uses a Percent Cropped Area (PCA) factor which translates to reduction of area within the reservoir that is planted to modeled crop. Due to the change from the standard pond to In dex Reservoir, the phy sical scenario as well as th e treatment of spray drift is different in FI RST. FIRST is designed to produce more realistic estimates of pesticides in surface water that is used as a source of drinking water. FIRST was used to model the following diquat scenarios: trees/vines/small fruits/vegetables (maximum use rate of 1 lb a.i./A, single application, 87 PCA); potatoes (0.5 lb a.i./A, 2 applications, 14 day application interval, 87 PCA); and alfalfa/clover/non
- crop (0.5 lb a.i./A, 1 application, single application, 87 PCA) . The s urface water estimated environmental concentrations (EECs) generated by FIRST ranged from 6.3
- 13.2 ppb (ug/L ) for peak exposure and 0.2
- 0.4 ppb for annual average exposure. Groundwater EFED used the Screening Concentration in Ground Water (SCI
- GROW) m odel to estimate diquat concentrations in groundwater contaminated by terrestrial uses. SCI
- GROW is a regression
based model that uses few input parameters: pesticide’s organic carbon partition coefficient (Koc), aerobic soil degradation half
- life, and pr oduct label application rate and frequency (Barrett, 1997). Itprovides a groundwater screening concentration for use in determining potential risk to human health from drinking water contaminated with a pesticide. The groundwater concentration is estima ted based on the maximum application rates in areas where groundwater is exceptionally vulnerable to contamination. These vulnerable areas are characterized by high rainfall, rapidly permeable soil, and shallow aquifer. The SCI
- GROW model estimated terres trial use groundwater EECs of 0.006 ppb. However, EFED recommends that monitoring data be used in lieu of the SCI
GROW results because higher concentrations were observed from monitoring data. The sources of available monitoring data include the South Florida Water Management District (SFWMD), and potable water modeling studies from the registrant, and monitoring data from the EPA Office of Water (OW). The SFWMD data contained a total of 42 samples that were taken from April 1992 to November 2000 on a pproximately

a 1
- 3 month interval. For diquat, the only detection observed in surface water was 0.0045 ppm in 1994. Further monitoring beyond   28   44

1994 has not shown any

detections in surface water. Also in the SFWMD, diquat was detected in 9 sediment sampl es from canals with a maximum concentration of 3.1 ppm (L OD of 2.5 ppm, Miles and Pfeuffer, Pesticides in Canals of South Florida, Arch. Environ. Contam. Toxicol. 32:337
- 345, 1997). Inthe potable water modeling studies, highly variable estimates of wat er concentrations have been observed. The modeling concentrations at reservoir pumps ranged from non
- detections (LOD of 0.003 ppm) to 0.26 ppm. These modeling estimates were not used in this assessment because of available monitoring data obtained by OW. OW has monitored for diquat at intake pumps at drinking water utilities that use surface water and ground water. Data from eight states in the y ears 1993
- 1997 were included in the report. In these eight states, 0.06 percent of combined surface water an d ground water sy stems reported exceedences of the 0.02 ppm (mg/L ) Maximum Contaminate level (MCL ) set by OW, resulting in a population exceedence of 0.27 % (Occurrence of Regulated Contaminants in Drinking Water: First Stage Occurrence and Exposure Report for Six
- Year Regulatory

Review, Working Draft 5/12/2000). Based on municipal monitoring data, EFED recommends use of the MCL of 0.02 ppm (20 ppb) for both peak and average terrestrial use EECs for groundwater. 4.3.2.2 Aquatic Uses EFED also relied on monitoring data to estimate surface water and ground water concentrations from aquatic uses of diquat. For the aquatic use, EFED also included use information from the U.S. Corp of Engineers and the states of Florida, Minnesota, and Michigan. For aquat ic use, EFED recommends use of the MCL of 0.02 ppm (20 ppb) for both peak and annual average EECs. EFED recommends use of the same annual average EECs for both surface and groundwater contaminated by aquatic uses of diquat because diquat is used near well s located next to lakes and ponds resulting in interaction between surface water and ground water. EFED notes that, while concentrations in excess of 20 ppb in private wells cannot be ruled out, they are unlikely because of the tendency

of diquat to sorb nearly

irreversably

to soil and sediment. EECs for surface and groundwater terrestrial and aquatic uses are provided in the Tables 8 and 9 respectively
. Table 8. FIRST EEC’s for Diquat for Drinking Water Assessm ent fromSurface Water Ty pe of Use Use Site Peak (ppb) Average Annual (ppb) Terrestrial Trees, vines, small fruits, vegetables 13.2 0.4

Alfalfa, Clover 6.3 0.2 Non
- Crop (fallow

land) 6.6 0.2 Potatoes 12.7 0.4 Aquatic Ditches, reservoirs, and rivers 20 1 20 1 MCL from Office of Water   29   44

Table 9. Monitoring EEC’s for Diquat for Drinking Water Assessm ent fromGround Water Ty pe of Use Use Site Peak (ppb) Average Annual (ppb) Terrestrial Trees, vines, small fruits, vegetables, alfalfa, clover,

non - crop (fallow land), and potatoes 20 20 Aquatic Ditches, reservoirs, and rivers 20 20 4.4 Residential Exposure/Risk Assessment A regulatory

review of residential exposure to diquat dibromide was conducted for this TRED because there is potential exposure to n on - occupational (residential) handlers (mixers, loaders, applicators, etc.) during handling and application of diquat and/or to persons entering treated sites after its application (T. Brennan, 12/14/01, D279507). Only short
- term exposures are expected/as sessed for residential exposure scenarios. 4.4.1 Home Uses 4.4.1.1 Handler Handler Exposure Scenarios Diquat dibromide can be applied to turf and backyard ponds for general weed control and can be used in and around home & garden sites for weed control and landscape uses by residential handlers. Diquat dibromide is applied to residential turf grass at application rates ranging from 0.25 to 0.5 lb ai/acre. Therefore, for this assessment both low end and high end MOEs were assessed based on the range of application rates. Diquat dibromide is formulated for residential uses both as a L iquid Ready to Use, and as a Soluble Concentrate/L iquid that can be mixed with water and then applied with a low pressure handwand or backpack spray er. This TRED estimates exposure and risk for four residential handler scenarios: 1) Mixing, loading, and applying with a low pressure handwand
- This residential handler scenario estimates exposure and risk to a mixer, loader, applicator apply ing diquat dibromide with a lo w pressure handwand to control weeds in and around lawns, gardens, around buildings, driveway s, fence lines and other such edge areas. The dermal and inhalation unit exposures for this scenario were obtained from the Outdoor Residential Exposure Task Forc e (ORETF) chemical handler exposure studies. 2) Mixing, loading, applying with a backpack spray er - This scenario estimates exposure and risk to a mixer, loader, applicator applying diquat dibromide with a backpack spray er to control residential weeds in edge areas.   30   44

3) Applying with an aerosol spray er - This scenario estimates exposure and risk to an applicator applying diquat with an aerosol spray can to control residential weeds in edge areas. 4) Applying with a trigger pump spray er - This scenario es timates exposure and risk to an applicator applying diquat dibromide with an trigger pump spray er to control residential weeds. The dermal and inhalation unit exposures for this scenario were obtained from a carbaryl Occupational and Residential Exposure Task Force (ORETF) study on ready
- to use insect spray er application to home garden vegetables. The handler assessment was developed using standard residential application techniques and PHED unit exposure data. I t is the policy of the HED to use data fro m the Pesticide Handlers Exposure Database (PHED) Version 1.1 to assess handler exposures for regulatory actions when chemical
- specific monitoring data are not available. PHED was designed by a task force of representatives from the US. EPA, Health Canada , the California Department of Pesticide Regulation, and members of the American Crop Protection Association. PHED is a software sy stem consisting of two parts; 1) a database of measured exposure values for workers involved in the handling of pesticides under actual field conditions, and 2) a set of computer algorithms used to subset and statistically

summarize the selected data. Currently , the database contains values for over 1,700 monitored individuals (i.e., replicates). For the handler scenarios fe male adult applicators were assessed for dermal exposures because the dermal toxicity endpoint was based on developmental toxicity

effects. A complete summary of the handler dermal exposure and risk calculations, critical assumptions, and results is provi ded in Table 10. Handler exposure assumptions are summarized below. Handler Exposure Assumptions The following assumptions were made in the exposure calculations:

· Average body

weight of an adult handler is 70 kg/day
.

· Application rates range from a l ow - end rate 0.009 to a high
- end 0.018 lb ai/gallon of spray er.

· Backpack spray ers and low pressure handwands were applied at a rate of 5 gallons per day . Aerosol cans and triggers spray ers were applied at a rate of 0.125 gallons per day
.

· No protectiv e clothing was factored into the assessment for these residential handler exposure/risk scenarios. Clothing assumptions include short pants, short
- sleeved shirt, and no gloves.

· Exposure frequency
- The residential handlers are expected to have a short
- te rm exposure duration (less than 30 day s). Handler Exposure and Risk Estimates   31   44

A target MOE of 100 for the dermal and inhalation routes are considered adequate for the handler risk assessment. Results of handler exposure assessment are presented in Table 10 and are summarized below. 1) Lo w pressure handwand scenario
- The adult applicator dermal MOEs were 670 for the low end scenario and 330 for the high end scenario. The inhalation MOEs were 8,800 for the low end scenario and 4,400 for the high end sc enario. 2) Backpack spray er scenario
- The adult applicator dermal MOEs were 7,500 for the low end scenario and 3,700 for the high end scenario. The inhalation MOEs were 1,400 for the low end scenario and 720 for the high end scenario. 3) Aerosol can scenario
- The adult applicator dermal MOEs were 6,900 for the low end scenario, and 3,500 for the high end scenario. The inhalation MOEs were 720 for the low end scenario, and 360 for the high end scenario. 4) Trigger pump spray

scenario
- The adult ap plicator dermal MOEs were 24,390 for the low end scenario, and 14,000 for the high end scenario. The inhalation MOEs were > 24,000,000 for the low end scenario, and > 12,000,000 for the high end scenario. Table 10: Diquat Dibrom ide Residential Handler S hort Term Exposure and Risk Assessm ent Exposure Scenario (Scenario #) Dermal Unit Exposure (mg/lb ai) Inhalation

Unit Exposure (ug/lb ai) Crop

(rate) Applicati

on Rate (lb ai per gal) Amount

Treated (gal per day) Dermal

Absorbed Dose c (mg/kg/d) Dermal

MOE d Inhalation

Dose e (mg/kg/d) Inhalation

MOE f

Mixer/Loader/App Mixing/Loading/Applying Liquids for Low Pressure Handwand application (1) a 100 30 high end 0.018 5 0.003 330 0.0000055 4400 Mixing/Loading/Applying Liqu ids for Low Pressure Handwand application (2) a 100 30 low end 0.009 5 0.0015 670 0.0000028 8800 Mixing/Loading/Applying Liquids for Backpack sprayer application (3) b 5.1 30 high end 0.018 5 0.00027 3700 0.000038 720 Mixing/Loadi ng/Applying Liquids for Backpack sprayer application (4) b 5.1 30 low end 0.009 5 0.00013 7500 0.000019 1400
Applicator Aerosol can application (5) b 220 2400 high end 0.018 0.125 0.00029 3500 0.000077 360 Aerosol can applicatio n (6) b 220 2400 low end 0.009 0.125 0.00014 6900 0.000039 720 Trigger Sprayer (7) a 53 0.067 high end 0.018 0.125 0.00007 14000 2E
- 09 12000000 Trigger Sprayer (8) a 53 0.067 low end 0.009 0.125 0.000041 24390 1E
- 09 2400 0000 Footnotes : a Baseline dermal and inhalation exposure derived from the ORETF chemical handler exposure studies. b Baseline dermal unit exposure represents short pants, short
- sleeved shirt, no gloves, open mixing/ loading, open cab/tractor. Values fr om PHED V1.1. Baseline inhalation unit exposure represents no respirator. Values from PHED V1.1. c Dermal daily dose (mg/ kg/ day) = daily unit exposure (mg/ lb ai) x application rate (lb ai/ acre) x amount handled per day (acres) / bw (60 kg). d Derma l MOE = NOAEL (1 mg/kg) / [daily dose (mg/ kg/ day) x dermal absorption factor (4.1%)].   32   44

e inhalation daily dose (mg/ kg/ day) = inhalation unit exposure (μg/ lb ai) x application rate (lb ai/ acre) x amount handled per day (acres) x conversion factor (1 mg/ 1,000 μg) / body weight (70 kg). f Inhalation MOE = NOAEL (0.1 u g/L) / daily dose (mg/ kg/ day). 4.4.1.2 Postapplication Diquat dibromide is used on dormant turf grass for weed control. Diquat dibromide will kill all ty pes of vegetation and can be used to kill turf grass. Based on this and a review the labels, HED conducted a lawn post
- application analy sis. Diquat dibromide is specifically labeled to be applied on dormant Bermuda and zoy sia grass. Therefore re
- entry must be addressed. Only short
term exposures (1 to 30 day period of exposure) are assessed because residents can have post
application exposure to treated lawns in the initial hours and day s following treatment. Diquat dibromide is applied to residential turf grass at applicati on rates ranging from 0.25 to 0.5 lb ai/acre. Therefore, for this assessment both low end and high end MOEs were assessed based on the range of application rates. Postapplication Exposure Scenarios Four post
- application scenarios were assessed: 1) D ermal exposure to treated turf grass
- adults and children
- This post
- application scenario estimates the dermal exposures and risk to adults and toddlers from dermal contact with turf treated with diquat dibromide. This scenario assumes that diquat dibro mide residues are transferred to the skin of adults/toddlers who enter treated y ards for recreation, yard work, or other homeowner activities. 2) Toddler ingestion of treated turf grass via object
- to - mouth activities
- This post
application scenario esti mates doses among toddlers from incidental ingestion of residential turf grass that has been previously treated with pesticides. This scenario assumes that turf is ingested (or just mouthed) by toddlers who play

in the treated areas. 3) Toddler ingesti on of residue via hand
- to - mouth activity while on treated turf grass
- This post - application scenario estimates potential ingestion of pesticide residues from previously treated turf. This scenario assumes that pesticide residues are transferred to the sk in of toddlers playing on treated y ards and are subsequently ingested as a result of hand
- to - mouth transfer. 4) Toddler ingestion of soil from treated area
- This post
- application scenario estimates doses among toddlers from incidental ingestion of soil c ontaining pesticide residues. This scenario assumes that pesticide residues in soil are ingested by toddlers who play

in treated areas. The turf, post
- application assessments were developed using the Residential SOP guidance. The exposure and risk ca lculations, critical assumptions, and results are provided in Table 11 for postapplication dermal scenarios and in Table 12 for postapplication incidental oral exposure. Post
- application exposure assumptions are summarized below. Postapplication Exposure Assumptions   33   44

The following assumptions were made in the dermal postapplication exposure calculations:

· Application rates range from a low
- end rate of 0.25 to a high
- end rate of 0.50 lbs ai/acre.

· Turf transferable residue is equal to 5 % of the applicatio n rate.

· Turf transfer coefficient is 14,500 cm 2 /hr for adult and 5,200 cm 2 /hr for children.

· Exposure duration is 2 hours for exposure to residential lawns, and 4 hours for exposure to golf course turf.

· Body weight is 70 kg for adults, and 15 kg for tod dlers. The following assumptions were made in the oral postapplication exposure calculations:

· Application rates range from a low
- end rate of 0.25 to a high
- end rate of 0.50 lbs ai/acre.

· Hand and object transfer efficiency is equal to 5 % of the application rate available for transfer from treated turf to wet hands and objects.

· Surface portion of hand put in mouth is 20 cm 2

.

· Hand
- to - mouth exposure frequency is 20/times per hour.

· Body weight is 15 kg for toddlers.

· Exposure time 2 hours.

· Saliva extra ct factor (for hand
- to - mouth only ) is 50 percent. Postapplication Exposure and Risk Estimates A target MOE of 100 for both the dermal and incidental oral routes is considered adequate for the postapplication risk assessment. Results of post application assessment are presented in Tables 11 and 12 and are summarized below. 1) Dermal exposure to treated turf grass
- adults and children
- The adult MOEs for re
entering treated lawns were not a risk concern with a low end MOE of 480, and a high end MOE of 220. The toddler MOEs for this scenario were also not a risk concern with a low end MOE of 270 and a high end MOE of 130. 2) Toddler ingestion of treated turf grass via object
- to - mouth activities
- The toddler MOEs for ingesting (or mouthing) of treat ed turf grass were not a risk concern with the low end MOE of 1,110, and a high end MOE of 560.   34   44

3) Toddler ingestion of residue via hand
- to - mouth activity while on treated turf grass
- The toddler MOEs from incidental exposure arising from hand
- to - mouth transfer of diquat dibromide were not a risk concern with the low end scenario MOE of 290 and the high end scenario MOE of 145. 4) Toddler ingestion of soil from treated area
- The toddler MOEs for ingesting (or mouthing) of treated soil were not a risk of concern with the low end MOE of 83,300, and a high end MOE of 41,670.
Table 11. Derm al Post - application Risks to Toddlers and Adults When Reentering Treated Lawns on Day 0 after Sprays have Dried Scenario Range

Finder 1 Application

Rate (lb ai/ acr e) Fraction

of Residue Retained Transfer

Coefficient (cm2 /hr) Exposure

Duration (hours) Body

Wt (kg) Daily Dermal Dose 2 (mg/kg/ d) Dermal

MOE 3

Toddler Low End 0.25 0.05 5,200 2 15 0.09 270

High End 0.5 0.05 5,200 2 15 0.19 130 Adult Low End 0.25 0.05 14,500 2 70 0.051 480

High End 0.5 0.05 14,500 2 70 0.11 220 1 Low end ranges are derived from the lowest labeled application rates, while the high end ranges are derived from the highest labeled rates

EPA Reg. No. 10182
- 404. These application rates represent broadcast application to dormant, established turf grass. 2 Dermal potential dose rates are calculated as follows: PDR t = DFR

t * CF1 * Tc * ET where: PDR t = potential dose rate on day “t ” (mg/day). DFR t = dislodgeable foliar residue on day “t” (ug/cm 2 ). CF1 = weight unit conversion factor to convert ug units in the DFR to mg for the daily dose (0.001 mg/ug) Tc = transfer coefficient (cm 2 /hr). ET = exposure time (hr/day). and DFR t + AR * F * (1
- D) t * CF2 * CF3 where: AR = application rate (lbs ai/ft2 or lb ai/acre).

F = fraction of ai retained on foliage (unitless). D = fraction of residue that dissipates daily (unitless). t = post - application day on which exposure is being assessed. CF2 = weight unit conversion factor to convert the lbs ai in the application rate to ug for the DFR value (4.54E8 ug/lb) CF3 = area unit conversion factor to convert the surface area units (ft2 ) in the application rate to cm 2 for the DFR valu e (1.08E
- 3 ft 2 /cm 2 or 24.7E
- 9 acre/cm 2 if the application rate is per acre) 3 Post
- application Dermal MOE = Oral NOAEL (1 mg/kg/ day)/ [Daily Dermal Dose (mg/ kg/ day) x Dermal Absorption Value (4.1%)]. MOEs are reported to two significant figures.

Table 12. Oral Post - application Risks to Toddlers fromOral Exposures When Reentering Treated Lawns Type of Exposure Range

Finder 1 Application

Rate (lb ai/ acre) Fraction

of Residue Available on Foliage Ingestion Rate or

Other Assumptions Saliva Extraction Factor Exposure

Duration (hours) Body

Wt (kg) Daily Oral Dose 2 (mg/kg/ d) MOE 3

Exposure to Low End 0.25 0.20 NA 2 15 0.0009 1,110   35   44

Table 12. Oral Post - application Risks to Toddlers fromOral Exposures When Reentering Treated Lawns Type of Exposure Range

Finder 1 Application

Rate (lb ai/ acre) Fraction

of Residue Available on Foliage Ingestion Rate or

Other Assumptions Saliva Extraction Factor Exposure

Duration (hours) Body

Wt (kg) Daily Oral Dose 2 (mg/kg/ d) MOE 3

Treated Turf Grass via object
- to - mouth activities 5 High End 0.5 25 cm 2 / day ingestion 0.0018 560
Hand
- to - Mouth Activity While on Treated Turf Grass Low End 0.25 0.05 20 hand
- to - mouth events per hour; 20 cm 2 / day exposed surface area per event 50% 0.0035 290 High End 0.5 0.007 145
Soil 6 Low End 0.25 NA 100 mg/ day ingestion NA 0.000012 83,330

High End 0.5 0.000024 41,670 1 Low end ranges are derived from the lowest labeled application rates, while the high end ranges are derived from the highest labeled rates

EPA Reg. No. 10182
- 404. These application rates represent broadcast application to dormant, established turf grass.
2 Object - to - mouth exposure to treated turf grass potential dose rates from ingestion are calculated as follows : PDR t = GR

t * I gR * CF1 where: PDR t = potential dose rat e on day “t” (mg/day) GR t = grass (and plant matter) residue on day “t” (ug/cm 2 ) IgR = ingestion rate of grass (cm 2 /day) CF1 = weight unit conversion factor to convert ug units in the DFR to mg for the daily dose (0.001 mg/ug) Hand - to - mouth potential dos e rates from ingestion are calculated as follows :

PDR t = DFR

t * SA * FQ * SEF * ET * CF1 where: PDR t = potential dose rate on day “t” (mg/day). DFR t = dislodgeable foliar residue on day “t” (ug/cm 2 turf). SA = surface area of the hands (cm 2 /event). SEF = s aliva extraction factor (%) FQ = frequency of hand
- to - mouth activity (events/hr). ET = exposure time (hr/day). CF1 = weight unit conversion factor to convert ug units in the DFR value to mg for the daily exposure (0.001 mg/ug) Ingestion of soil from treat ed area potential dose rates from ingestion are calculated as follows : PDR t = SR t * Ing * CF1 where: PDRt = potential dose rate on day ‘t” (mg/day)

SRt = soil residues on day “t” (ug/g) IgR = ingestion rate of soil (mg/day) CF1 = weight unit conversion f actor to convert ug units in the residues on the soil to g for the daily dose (1.0E
- 6 g/ug)
3 Postapplication oral MOE = Oral NOAEL (1 mg/kg/ day)/ Daily Oral Dose(mg/ kg/ day). Oral NOAEL

determined from a rabbit developmental study. MOEs are reported to two significant figures ; an acceptable MOE is at least 100. Aggregate Post
- Application Exposure and Risk Estimate The short term aggregate post
- application risk is the estimated risk associated with combined risks from the short term dermal and o ral post
- application exposures. Given the observed effects at the recommended NOAELs for oral and dermal pathway s, HED believes that risk from these exposure routes can be reasonably added. The inhalation risks are not aggregated because the NOAEL for th is exposure pathway is based on a distinct target organ effect. Aggregate post
- application risk is estimated for the child exposure scenario only since the child   36   44

may be exposed via both oral and dermal pathway s while the adult exposure is from the dermal route only . The short term aggregate MOE for the child is calculated by adding exposure estimates from the oral and dermal pathway s using the formula presented below. The child aggregate risk combines the highest exposures from the post
- application scen arios (i.e., high
- end oral and dermal post
- application reentry exposure). The calculated short
- term aggregate MOE is presented in Table 13. The short
- term aggregate post - application MOE for the high
- end exposure scenario for 1
- 6 y ear old children is 70 . The residential aggregate risk combines screening level risk estimates from individual exposure pathway s and should be viewed as a highly conservative estimate which is certain to over
- estimate risk. The estimated risk from the individual pathway s is b ased on high
- end assumptions, i.e., highest application rates, child reentry /play on the day

of treatment, and a high
- end turf transferable residue factor of 5%. In addition, based on a human dermal absorption study

cited by the registrant which shows der mal absorption of 0.3%, use of a 4.1% dermal absorption factor is likely to result in a further overestimation of risk. A refined analy sis would result in lower exposure estimates and higher MOEs. MOE Post
- Application CHILD = 1 1 + 1 MOE DERMAL MOE ORAL where: MOE DERMAL = Short Term Dermal NOAEL (mg/kg/day)  (Short Term Dermal Exposure (mg/kg/day) x Dermal Absorption Fa ctor) MOE ORAL = Short Term Oral NOAEL (mg/kg/day)  Short Term Oral Exposure (mg/kg/day) Table 13. Short TermAggregate Post - Application Risk to Child Populatio n Subgroup Short Term

Oral NOAEL mg/kg/d Short Term

Dermal NOAEL mg/kg/d Short Term Der mal

Re - entry Exposure mg/kg/d 1 Short Term Oral

- Hand to Mouth - Exposure mg/kg/d Oral MOE Dermal MOE Post Application Aggregate MOE Child 1
- 6 1 1 0.0078 0.007 145 130 70 1 Includes Dermal Absorption Factor of 4.1% (0.19 mg/kg/d x 0.041 = 0.0078) 4.4.2 Recreational Two recreational post
- application exposure scenarios were assessed: 1) Recreational golfer exposure from playing on treated turf grass (adults)
- This post
application scenario estimates dermal exposures and risk to adult golfers from dermal contact with turf grass on golf courses that has been previously treated with diquat dibromide. The scenario assumes that a golfer re
- enters the course after diquat dibromide spray s have dried and then play a four hour round o f golf. 2) Swimming exposure to treated ponds and lakes
- This post
- application scenario estimates dermal exposures and risk to adult and 7
- 10 y ear old swimmers who re
- enter treated ponds and lakes. Several of the diquat dibromide labels intended for aq uatic weed   37   44

control uses have swimming re
- entry intervals of 0 day s (example: EPA Reg. No. 10182
- 404). The exposure and risk calculations, critical assumptions, and results for the recreational golfer exposure scenarios are provided in Table 14. Exposure assumptions for the golfer scenario are summarized below. Recreational Golfer Exposure Assumptions The following assumptions were made in the dermal exposure calculations for recreational golfer exposure:

· Application rates range from a low
- end rate of 0 .25 to a high
- end rate of 0.50 lbs ai/acre.

· Turf transferable residue is equal to 5 % of the application rate.

· Turf transfer coefficient is 14,500 cm 2 /hr for adult

· Exposure duration 4 hours for exposure to golf course turf.

· Body weight is 70 kg for ad

ults
Table 14. Derm al Post - application Risks Adults When Reentering Golf Courses on Day 0 after Sprays have Dried Scenario Range

Finder 1 Application

Rate (lb ai/ acre) Fraction

of Residue Retained Transfer

Coefficient (cm2 /hr) Exposure

Duratio n (hours) Body

Wt (kg) Daily Dermal Dose 2 (mg/kg/ d) Dermal

MOE 3

Adult Golfer Low End 0.25 0.05 500 4 70 0.0034 7,100

High End 0.5 0.05 500 4 70 0.0077 3,200 1 Golfer durations are assumed to be 4 hours for an 18
- hole round of golf. 2 Dermal potential dose rates are calculated as follows: PDR t = DFR

t * CF1 * Tc * ET 3 Post
- application Dermal MOE = Oral NOAEL (1 mg/kg/ day)/ [Daily Dermal Dose (mg/ kg/ day) x Dermal Absorption Value (4.1%)]. MOEs are reported to two significant figures. Swimmer Exposure Assumptions Inorder to assess potential exposures to swimmers who re
- enter treated ponds and lakes, HED used the Swimmer Exposure Assessment Model (SWI MODEL). The SWI MODEL was developed for estimating the human exposure do ses to the pesticides and toxic pollutants in swimming pools. This model is a modification of a study used by J. A. Beech (1980) for estimating exposure to Trihalomethanes (THM) in swimming pools. Clearly swimming in ponds and lakes is different than poo ls in many way s; however, the basic exposure to chemicals in the water column are similar enough to warrant using this model for this TRED.   38   44

The model is based on exposure routes and age
- specific contact factors, exposure duration and frequency , chemical/

phy sical properties of the pollutant, and pollutant concentration, total exposure doses can be approximated by the model. For this TRED child (age 7
- 10) and adult swimmers were modeled. One diquat dibromide concentration in the lake was modeled for this analy sis: 20 ppb

– the maximum contaminant goal which was reported by EFED as a high end, monitoring data endpoint. The exposure and risk calculations, critical assumptions, and results for the swimmer scenario are provided in Table 15.
Table 15. Chil d and Adult Exposure and Risk to Swim mi ng in Treated Lakes on Day 0 Exposed Population Concentration

in Lake (ppm) 1 Total Exposure

(mg/event) 2 Body Weight (kg) 3 Total Dose

(mg/kg/day) 4 MOE 5 Child (age 7
- 10) 20 0.062 37.8 0.0016 630 Adult 20 0.0087 84.4 0.0001 10,000 1 The concentration in the lake was run at 20 ppb (the maximum contaminant goal reported by EFED as a high end, mo nitoring data endpoint). 2 Total exposure is a combination of exposures via the following routes: oral, der mal, buccal/sublingual, orbital/nasal, aural, and inhalation. 3 Body w eights represent the 90% for the population being modeled. 4 Total dose (mg/kg/day) = Total exposure (mg/event) / body weight (kg) 5 MOE = Oral NOAEL 1 mg/kg/day / Total dose (mg/kg/day) Recreational Exposure and Risk Estimates A target MOE of 100 for both the dermal and incidental oral routes is considered adequate for the recreational risk assessment. Results of the recreational exposure assessment are presented in Tables 14 and 15 and are summarized below. 1) The MOEs for an adult playing a round of golf on a treated golf course were not a risk concern. MOEs ranged from 7,100 for the low
- end exposure scenario to 3,200 for the high
end scenario. 2) Estimated MOEs were not a risk o f concern for child or adult swimmers. MOEs for children age 7
- 10 ranged from 630 to 180. MOEs for adults ranged from 10,000 to 770. 4.5 Incident Reports The vast majority

of incident reports for diquat fall into one of two categories: (1) people ex posed while handling the product for its intended purpose; and, (2) people who drank the pesticide either by

accident or on purpose (i.e., in order to harm themselves) (M. Spann and J. Blondell, 10/15/01, D278482). According to a several of pesticide inc ident sources, diquat dibromide ranked relatively high on the list of pesticides with reported incidents. Detailed descriptions of 112 cases submitted to the California Pesticide I llness Surveillance Program (1982
-   39   44

1999) were reviewed. In 76 of these case s, diquat was used alone or was judged to be responsible for the health effects. Only cases with a definite, probable or possible relationship were reviewed. Diquat ranked 50 th as a cause of sy stemic poisoning in California based on data for 1982 throug h 1999. Similarly , on the list of the top 200 chemicals for which National Pesticide Telecommunications Network received calls from 1984
- 1991 inclusively , diquat was ranked 54 th with 74 incidents in humans reported. From the review of California data, it appears that a majority of cases involved sy stemic, ey e, and skin illnesses such as ey e irritation/pain, skin rash, chemical burns, chemical conjunctivitis, nausea, and vomiting. Poison Control Center data tend to support the California data, ey e irritat ion/pain, ery thema, rash, skin itching, corneal abrasion, lacrimation, dy spnea, coughing, and choking were the most common effects reported due to exposure. Oral exposure to even modest amounts can lead to severe poisoning and even death. 4.5.1 Residenti al Handler Incidents Of all the handler incident reports, “applicator” was associated with more exposures than any other category . These illnesses included sy mptoms of burning and itching ey es, dizziness, nausea, dy spnea, rashes, chemical conjunctivitis , vomiting, dermatitis, and chemical burns. 4.5.2 Postapplication and Recreational Incidents Not many cases of post
- application exposures have been reported, however there was one incident involving swimmers. In this case, two boy s swam in a lake that had been treated with diquat three day s prior to the activity . Both boy s developed a rash, one much more severe than the other. The nine y ear old boy with the more serious rash was treated by a phy sician while the other boy was treated at home. No info rmation was provided on levels of diquat in the treated lake. 5.0 AGGREGATE RISK ASSESSMENT AND RISK CHARACTERIZATION The aggregate risk assessment integrates the assessments conducted for dietary and residential exposure. Since there is potential for concurrent exposure via the food, water and residential pathway s, the combined exposures are estimated using the methodology described below and are compared with monitoring
- based estimates of drinking water contamination determined by

EFED. All routes of diquat dibromide exposure have been considered. Aggregate exposure pathway s for adults include dietary , drinking water, and dermal and inhalation exposures from application and post
- application activities. Aggregate exposure pathway s for children includ e dietary , drinking water, and dermal and oral exposures from post
- application exposure. 5.1 Acute Aggregate Risk Assessment The acute aggregate risk is the estimated risk associated with combined acute food and drinking water exposure. The acute agg regate MOE is calculated by adding acute dietary

exposure estimates with drinking water levels obtained from monitoring data using the formula presented below. The target MOE for acute aggregate risk is 100. The calculated acute aggregate   40   44

MOEs are prese nted in Table 16. Acute aggregate risk MOEs are below EPA’s level of concern (i.e.,  to 100) for all population subgroups. Since the estimated risk from the individual pathway s are considered to be screening level, the aggregates should be considered as a highly conservative estimate of risk. MOE Aggregate acute = 1 1 + 1 MOE FOOD MOE WATER where: MOE FOOD = Acute Dietary NOAEL (mg/kg/day)  Acute Die tary Exposure (mg/kg/day) MOE WATER = Acute Dietary NOAEL (mg/kg/day)  Acute Water Exposure (mg/kg/day) and: Acute Water Exposure = Acute Water EEC (mg/L) x Drinking Water Consumption (L/day)

(mg/kg/d) Body Weight (kg) Table 16. Acute Aggregate Ri sk Population Subgroup Acute Dietary NOAEL (mg/kg/day) Acute

Dietary Exposure (mg/kg/day) Acute Water

EEC (mg/L) DW

Consumption (L/day) Body

Weight (kg) Acute Water

Exposure (mg/kg/day) Acute

Aggregate MOE US Population (total) 75 0.0039 0. 02 2 70 0.00057 16773 All Infants (<1 year old) 75 0.0035 0.02 1 10 0.002 13636 Children 1
- 6 years old 75 0.0054 0.02 1 10 0.002 10135 Children 7
- 12 years old 75 0.0033 0.02 1 10 0.002 14151 Females 13
- 50 years ol d 75 0.0032 0.02 2 60 0.00067 19397 Males 13
- 19 years old 75 0.0030 0.02 2 70 0.00057 21000 Males 20+ years old 75 0.0035 0.02 2 70 0.00057 18421 Seniors 55+ years old 75 0.0023 0.02 2 70 0.00057 26119

5.2 Short - Term Aggregate Risk Assessment The short term aggregate risk is the estimated risk associated with combined risks from the following pathway s: chronic dietary intake, average annual drinking water exposures, and short term dermal and oral (if applicable ) exposures. Given the observed effects at the recommended NOAELs for each of these pathway s, HED believes that risk from these exposure routes can be reasonably

added. The inhalation risks are not aggregated because the NOAEL for this exposure pathway i s based on a distinct target organ effect. The short term aggregate MOE is calculated by adding exposure estimates from each of these pathway s using the formula presented below. The adult aggregate risk combines the highest exposures from the various app lication and post
application scenarios (i.e., high
- end, low pressure handwand applicator exposure, and high
- end   41   44

adult reentry

exposure). L ikewise, the highest dermal and oral exposures from the assessed scenarios are added for the estimated child risk ag gregate. The calculated short
- term aggregate MOEs are presented in Table 14. The short term aggregate MOE for the high
- end exposure scenario for the adult applicator is 100. The short
- term aggregate MOE for the high
- end toddler exposure scenario is 55. The short
- term aggregate risk combines screening level risk estimates from individual exposure pathway s and should be viewed as a highly conservative estimate, certain to over
estimate risk. A refined analy sis would result in lower exposure estimates and higher MOEs. Possible refinements include: 1) revising the dietary assessment to account for actual percent crop treated (i.e., no use involves 100% crop treated; most involve <1% CT) and to reflect residues based on field trial data, which are general ly much lower than tolerance levels; 2) revising estimated environmental concentrations in drinking water sources to reflect lower concentrations in a sizeable majority

of monitoring samples (i.e., monitoring data from 1993
- 1997 showed an MCL exceedence rate of < 1%); and 3) refining the residential exposure scenarios to include more plausible assumptions regarding a) the use of protective clothing for applicators (i.e., no protective clothing was factored into assessments of residential exposure), b) appli cation rates (i.e., highest rates are assumed), c) day of reentry

(i.e., children and adults are assumed to reenter and work/play on the lawn on the day

of treatment), d) turf transferable residue (i.e., TTR is assumed to be 5% of the application rate
- a high
- end assumption), and e) dermal absorption factor (i.e., dermal absorption is assumed to be 4.1% based on a rat study ; a human dermal absorption study cited by the registrant estimates dermal absorption to be about 0.3% (Feldman RJ and Maibach HI , “Pe rcutaneous penetration of some pesticides and herbicides in man” Tox. Appl. Pharm. 28 126
- 132, 1974)). MOE Aggregate SHORT TERM = 1 1 + 1 + 1 + 1 MOE FOOD MOE WATER MOE DERMAL MOE ORAL * * If applicable where: MOE FOOD = Short Term Oral NOAEL (mg/kg/day)  Chronic Dietary Exposure ( mg/kg/day) MOE WATER = Short Term Oral NOAEL (mg/kg/day)  Chronic Water Exposure (mg/kg/day) MOE DERMAL = Short Term Dermal NOAEL (mg/kg/day)  (Short Term Dermal Exposure (mg/kg/day) x Dermal Absorption Factor) MOE ORAL = Short Term Oral NOAEL (mg/kg/day)  Short Term Oral Exposure (mg/kg/day) and: Water Exposure = Chronic Water EEC (mg/L) x Drinking Water Consumption (L/day)

(mg/kg/d) Body Weight (kg) Table 17. Short TermAggregate Risk Population Subgroup Short Term

Oral NOAEL mg/kg /d Chronic

Dietary Exposure mg/kg/d Annual

Avg W ater Exposure mg/kg/d Short Term

Dermal NOAEL mg/kg/d Short Term Dermal

Exposure - Handwand Applicator mg/kg/d 1 Short Term Dermal Exposure Re entry mg/kg/d 1 Short Term Oral

- Hand to Mouth - Exposure mg/kg/d Short

Term Aggregate MOE Male 20+ 1 0.0018 0.00057 1 0.003 0.0045 NA 100 Child 1
- 6 1 0.0031 0.002 1 NA 0.0078 0.007 55 1 Includes Dermal Absorption Factor of 4.1% (0.11 mg/kg/d x 0.041 = 0.0045; 0.19 mg/kg/d x 0.041 = 0.0078 )   42   44

5.3 Chronic Aggregate Risk Assessment The chronic aggregate risk is the estimated risk associated with combined chronic food and drinking water exposure. The chronic aggregate MOE is calculated by adding chronic dietary exposures and estimated avera ge annual drinking water concentrations using the formula presented below. The target MOE for chronic aggregate risk is 100. The calculated chronic aggregate MOEs are presented in Table 18. Chronic aggregate risk MOEs are below EPA’s level of concern ( i.e.,  to 100) for all population subgroups. Again, since the aggregate combines screening level risks from individual exposure pathway s, the chronic aggregate risk estimate is highly conservative. MOE Aggregate CHRONIC = 1 1 + 1 MOE FOOD MOE WATER where: MOE FOOD = Chronic Dietary NOAEL (mg/kg/day)  Chronic Dietary Exposure (mg/kg/day) MOE WATER = Chronic Dietary NOAEL (mg/kg/day)  Chronic Water Expo sure (mg/kg/day) and: Chronic Water Exposure = Chronic Water EEC (mg/L) x Drinking Water Consumption (L/day)

(mg/kg/d) Body Weight (kg) Table 18. Chronic Aggregate Risk Population Subgroup Chronic Dietary NOAEL (mg/kg/day) Chronic

Dietary E xposure (mg/kg/day) Chronic

Water EEC (mg/L) DW

Consumption (L/day) Body

Weight (kg) Annual Avg

Water Exposure (mg/kg/day) Chronic

Aggregate MOE US Population (total) 0.5 0.0019 0.02 2 70 0.00057 202 All Infants (<1 year old) 0.5 0.0017 0.02 1 10 0.002 135 Children 1
- 6 years old 0.5 0.0031 0.02 1 10 0.002 98 Children 7
- 12 years old 0.5 0.0021 0.02 1 10 0.002 122 Females 13
- 50 years old 0.5 0.0017 0.02 2 60 0.00067 211 Males 13
- 19 years old 0.5 0.0018 0.02 2 70 0.00057 211 Males 20+ years old 0.5 0.0019 0.02 2 70 0.00057 202 Seniors 55+ years old 0.5 0.0015 0.02 2 70 0.00057 241

6.0 CUMULATIVE RISK The Food Quality

Protection Act (1996) stipulates that when determining the saf ety of a pesticide chemical, EPA shall base its assessment of the risk posed by the chemical on, among other things, available information concerning the cumulative effects to human health that may   43   44

result from dietary , residential, or other non
- occupationa l exposure to other substances that have a common mechanism of toxicity . The reason for consideration of other substances is due to the possibility

that low
- level exposures to multiple chemical substances that cause a common toxic effect by a common mechanism could lead to the same adverse health effect as would a higher level of exposure to any

of the other substances individually . A person exposed to a pesticide at a level that is considered safe may in fact experience harm if that person is also expose d to other substances that cause a common toxic effect by a mechanism common with that of the subject pesticide, even if the individual exposure levels to the other substances are also considered safe. HED did not perform a cumulative risk assessment as p art of this TRED for diquat dibromide because HED has not y et initiated a review to determine if there are any other chemical substances that have a mechanism of toxicity common with that of diquat dibromide. For purposes of this TRED, EPA has assumed th at diquat dibromide does not have a common mechanism of toxicity

with other substances. On this basis, the registrant must submit, upon EPA’s request and according to a schedule determined by

the Agency , such information as the Agency directs to be submit ted in order to evaluate issues related to whether diquat dibromide shares a common mechanism of toxicity with any other substance and, if so, whether any tolerances for diquat dibromide need to be modified or revoked. I f HED identifies other substances that share a common mechanism of toxicity with diquat dibromide, HED will perform aggregate exposure assessments on each chemical, and will begin to conduct a cumulative risk assessment once the final guidance HED will use for conducting cumulative risk ass essments is available. HED has recently

developed a framework that it proposes to use for conducting cumulative risk assessments on substances that have a common mechanism of toxicity . This guidance was issued for public comment on June 30, 2000 (65 FR 40644
- 40650) and is available from the OPP Website at: http://www.epa.gov/fedrgstr/EPA
- PEST/2000/June/Day
- 30/6049.pdf Inthe draft guidance, it is stated that a cumulative risk assessment of substances that cause a common toxic effect by a common mech anism will not be conducted until an aggregate exposure assessment of each substance has been completed. The proposed guidance on cumulative risk assessment of pesticide chemicals that have a common mechanism of toxicity is expected to be finalized by Dec ember 2001. Before undertaking a cumulative risk assessment, HED will follow procedures for identifying chemicals that have a common mechanism of toxicity as set forth in the “ Guidance for Identifying Pesticide Chemicals and Other Substances that Have a C ommon Mechanism of Toxicity ” (64 FR 5795
- 5796, February 5, 1999). 7.0 DATA NEEDS/LABEL REQUIREMENTS   44   44

All product chemistry

data are required for the Sy ngenta 41.1% and 37.3% Formulation In termediates (EPA Reg. Nos. 10
- 1062 and 100
- 1063). Magnitude of th e residue in plants studies are required for sorghum aspirated grain fractions and soy bean aspirated grain fractions.