Bispyribac-sodium Human-H ealth Risk Assessment DP# 361116

Page 1 of 31 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

DATE: 18-AUG-2010

SUBJECT: Bispyribac-sodium ; Human-Health Risk Assessment for New Product Registration for Aquatic Us es on Freshwater Fish.

PC Code: 078906 DP Barcodes: D361116, D361118

Decision Nos.: 404448, 404450 Registration No.: 59639-RAL

Petition No.: 8F7509 Regulatory Action: Section 3 Risk Assessment Type: Single Chemical/Aggregate Case No.: 7258

TXR No.: NA CAS No.: 125401-92-5

MRID No.: NA 40 CFR: §180.577

FROM: Sarah J. Levy, Chemist Robert J. Mitkus, Ph.D., DABT, Toxicologist Kelly M. Lowe, Environmental Scientist Risk Assessment Branch 1 (RAB1) Health Effects Division (HED; 7509P)

THROUGH: Dana M. Vogel, Branch Chief George F. Kramer, Ph.D., Senior Chemist RAB1/HED (7509P)

TO: Hope Johnson/James Tompkins, Risk Manager 25 Herbicide Branch/RD (RD; 7505P)

The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides. The RD of OPP has requested that HED evaluate hazard and exposure data and conduct dietary, occupati onal, residential, and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from the proposed (and registered) aquatic bis pyribac-sodium (sodium, 2,6-bis[(4,6-dimethoxy-pyrimidin-2- yl)oxy]benzoate) uses on freshwater fish. The most recent HED human-health risk assessment for bispyribac-sodium was conducted for a new use on rice (Memo, J. Tyler, et al ., 25-SEP2001; DP# 276557).

A summary of the findings and an assessment of human-health risk resulting from the proposed and registered uses of bispyribac-sodium are pr ovided in this document. The risk assessment, residue chemistry review, a nd dietary exposure assessment were provided by Sarah Levy (RAB1); the occupational/residen tial exposure assessment was provided by Kelly Lowe (RAB1); the toxicology review was provided by Robert Mitkus (RAB1); and the drinking waterBispyribac-sodium Human-H ealth Risk Assessment DP# 361116

Page 2 of 31 assessment was provided by Cheryl Sutton of th e Environmental Fate and Effects Division (EFED).

TABLE OF CONTENTS

1.0 Executive Summary.......................................................................................................... 3

2.0 Ingredient Profile............................................................................................................. . 7

2.1 Summary of Proposed Uses .................................................................................. 7

2.2 Structure and Nomenclature ............................................................................... 8

2.3 Physical and Chemical Properties ....................................................................... 9

3.0 Hazard Characterization/Assessment............................................................................. 9

3.1 Mammalian Toxicology ........................................................................................ 9

3.2 Dose-Response Assessment ................................................................................ 10

3.3 FQPA Considerations ......................................................................................... 12

3.4 Endocrine Disruption ......................................................................................... 13

4.0 Dietary Exposure/Risk Characterization ..................................................................... 13

4.1 Residue Profile .................................................................................................... 13

4.2 Environmental Degradation .............................................................................. 16

4.3 Pesticide Metabolites and Degradates of Concern ........................................... 16

4.4 Drinking Water Residue Profile ........................................................................ 17

4.5 Dietary Exposure and Risk ................................................................................ 17

4.5.1 Acute Dietary Exposure/Risk ................................................................. 17

4.5.2 Chronic Dietary Exposure/Risk ............................................................. 17

4.5.3 Cancer Dietary Risk ............................................................................... 18

5.0 Residential (Non-Occupational ) Exposure/Risk Pathway .......................................... 18

5.1 Residential Handler Exposures and Risks ........................................................ 18

5.2 Residential Postapplication Exposures and Risks ........................................... 18

5.3 Residential Bystander Inhalation Exposure ..................................................... 20

5.4 Spray Drift ........................................................................................................... 20

6.0 Aggregate Risk Assessments a nd Risk Characterization............................................ 21

6.1 Acute Aggregate Risk ......................................................................................... 21

6.2 Short-and Intermediate-Term Aggregate Risks .............................................. 21

6.3 Chronic (Long-Term) Aggregate Risk .............................................................. 22

6.4 Cancer Aggregate Risk ....................................................................................... 22

7.0 Cumulative Risk Characterization/Assessment........................................................... 22

8.0 Occupational Exposure/Risk Pathway.......................................................................... 22

8.1 Occupational Handler Exposure/Risk .............................................................. 22

8.2 Occupational Postappl ication Exposure/Risk .................................................. 27

9.0 Data Needs and Label Recommendations .................................................................... 27

9.1 Toxicology ............................................................................................................ 27

9.2 Residue Chemistry .............................................................................................. 27

9.3 Occupational and Residential Exposure ........................................................... 27 Attachment 1a. Acute Toxicity Data for Bispyribac-sodium Technical. .............................. 28 Attachment 1b. Toxicity Profile of Bisp yribac-sodium Technical and Metabolites............ 28Bispyribac-sodium Human-H ealth Risk Assessment DP# 361116

Page 3 of 31 1.0 Executive Summary

Bispyribac-sodium is a herbicide formulated as a soluble powder (SP) and is currently registered for use on rice and on golf courses and sod farms. The mode of action is the inhibition of the plant enzyme acetolactate synthetase. Tolera nces for residues of bispyribac-sodium are established under §180.577(a) on rice gr ain and straw (each at 0.02 ppm).

Under Section 3 of the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), as amended, Valent U.S.A. Corporation is reque sting a Section 3 regi stration for Tradewind TM
Herbicide (EPA Reg. No. 59639- RAL), an 80% SP formulation of bispyribac-sodium, for aquatic uses restricted to slow-moving or quies cent bodies of water with minimal or no outflow, such as bayous, canals, drainage ditches, la kes, marshes, non-irrigation canals, ponds, and reservoirs. The product is proposed for su rface applications to water at 0.05-0.1 lb ai/A/application, with a maximum ra te of 0.4 lb ai/A/year, using ground or aerial equipment, and for subsurface applications to water at a concentration of 30-45 ppb, with a maximum cumulative rate of 180 ppb per year. The proposed label prohibits applica tion to flowing water, intertidal, or estuarine areas or to water utilized for crayfish farming, and prohibits the use of treated water to irrigate food crops until the c oncentration of bispyrib ac-sodium in water is ≤ 1 ppb.

In conjunction with the petition, Valent U.S. A. Corporation has proposed the following:

“Tolerances are established for residues of the herbicide bispyribac-sodium, including its metabolites and degradates, in or on the commoditi es in the table below. Compliance with the tolerance levels specif ied below is to be determined by measuring only bispyribac-sodium, (2,6- bis[(4,6-dimethoxy-2-pyrimidinyl)oxy ]benzoic acid, sodium salt), in or on the following raw agricultural commodities:

Fish, freshwater....................................................................0.01 ppm Cattle, goat, hog, horse, and sh eep, meat byproducts..........0.03 ppm Cattle, goat, hog, horse and sheep, meat..............................0.01 ppm Cattle, goat, hog, horse, and sheep, fat ................................0.01 ppm Milk......................................................................................0.01 ppm Poultry, meat byproducts .....................................................0.50 ppm Egg .......................................................................................0.01 ppm Poultry, fat............................................................................0.01 ppm Poultry meat.........................................................................0.01 ppm”

Hazard Assessment Bispyribac-sodium has a low acute toxicity profile and is not a dermal sensitizer. The liver and bile duct were identified as the target organs in the subchronic and chroni c toxicity studies in rats, mice, and dogs, and the reproductive toxicity st udy in rats. Repeated dermal applications at the limit dose did not elicit systemic toxicity or dermal irritation. Bispyribac-sodium was negative for carcinogenicity in feedin g studies in rats and mice and is classified as a “not likely human carcinogen” and mutageni city studies conducted with the parent and three major metabolites were negative. There was no evidence of fetal toxicity or offspring susceptibility in the developmental toxicity studies in rats and rabbits or in the reproductive toxicity study in rats. Bispyribac-sodium has shown no indications of central or peripheral nervous system toxicity in any study and does not appear to be structurally re lated to any other chemical that causes adverse nervous system effects.Bispyribac-sodium Human-H ealth Risk Assessment DP# 361116

Page 4 of 31 Dose-Response Assessment The acute reference dose (aRfD) for the genera l population, including in fants and children, was not established because an endpoint of concern a ttributable to a single dose was not identified. Therefore, this assessment is not necessary. The chronic referen ce dose (cRfD) of 0.027 mg/kg/day was determined on the basis of the chronic carcinogenicity study in mice. An uncertainty factor (UF) of 100 (10X for inters pecies extrapolation and 10X for intraspecies variability) was applied to the NOAEL of 2.7 mg/kg/day to derive the cRfD. No short- or intermediate-term dermal points of departure were identified; therefore, quantification of shortand intermediate-term dermal risks is not required. A NOAEL of 100 mg/kg/day from a developmental study in rabbits was selected as th e point of departure for short-term inhalation exposure. A NOAEL of 100 mg/kg/da y from a 90-day feeding study in dogs was selected as the point of departure for intermediate-term inha lation. A body weight of 70 kg was used for the short- and intermediate-term exposure assessmen t. Since no inhalation absorption data are available, toxicity by the inhalati on route is considered to be equi valent to the estimated toxicity by the oral route of exposure.

FQPA Decision The Agency’s level of concern for risks [i.e., ta rget level for margins of exposure (MOEs)] is defined by UFs. The Agency applies a factor of 10X to account for interspecies extrapolation to humans from the animal test species and anot her factor of 10X to account for intraspecies sensitivity. HED has concluded th at the FQPA Safety Factor (SF) for bispyribac-sodium can be

reduced to 1X. The total UF that has been applied to occupational and residential risk

assessments is 100X.

Dietary Exposure and Risk An acute dietary assessment was not performed for bispyribac-sodium because there were no

adverse effects that could be attributable to a si ngle dose. Thus, an endpoint of concern was not identified to quantitate acute di etary risk to the general popula tion or any population subgroup. An unrefined chronic dietary risk assessm ent was conducted using the Dietary Exposure

Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID TM ; ver. 2.03) model. Estimated drinking water concen trations (EDWCs) from EFED, based on the highest application use rate (aqua tic use), were also included in the dietary assessment. The resulting food and drinking water exposure estimat es are not of concern to HED [<100% chronic population-adjusted dose (cPAD)]; all infants <1 year old were the most highly exposed population (12.5% cPAD). A cancer dietary expo sure assessment was not conducted because bispyribac-sodium was classified as “ not likely to be carcinogenic to humans.”

Aggregate Risk An acute aggregate risk assessment was not necessary since an appropriate endpoint for the assessment of acute dietary risk was not identified (no acute ha zard is present). Chronic aggregate risk is made up only of dietary sour ces; therefore, the chr onic exposure estimates provided in the chronic dietary exposure analysis represents ch ronic aggregate exposure. An aggregate cancer risk assessment was not performe d because bispyribac-sodium was classified as “not likely to be car cinogenic to humans.”

Only a short-term aggregate risk assessment was conducted since the residential use pattern is expected to only result in short- term exposures; however, since th e short- and intermediate-term points of departure are the same, the short- term aggregate assessment is protective of intermediate-term exposures. Short- and inte rmediate-term aggregate risks are made up ofBispyribac-sodium Human-H ealth Risk Assessment DP# 361116

Page 5 of 31 dietary and non-dietary sources of exposure. Dietary (food + dri nking water) exposure estimates are based on a conservative, unrefined chroni c dietary exposure assessment. Non-dietary (residential) exposure estimates ar e conservative estimates due to the standard assumptions that

were built into the calculations. Since bi spyribac-sodium only has commercial use on golf

course and sod farm turf and there is no dermal endpoint, the non-dietary (residential) aggregate exposures for adults and children include only inci dental oral exposure fr om the aquatic uses. Post-application inhalation exposur e is not expected and was not included in the aggregate risk

estimates. The short- and intermediate-term aggregate MOEs for all population subgroups were assessed, and are not of c oncern to HED (MOEs >100).

Occupational Exposure Occupational exposures and risks resulting in MO Es greater than or equal to 100 are not of

concern to HED. Short- and intermediate-term dermal o ccupational handler exposures and risks were not assessed for bispyribac-sodium, since no dermal points of departure were identified.

The short- and intermediate-term inhalation ri sks to handlers do not exceed HED’s level of concern at baseline (no respirat or) for any of the handler scen arios where baseline data are available. Only engineering control (enclosed co ckpit) data are available to assess inhalation risks to handlers operating aircraft. The inha lation risks do not exceed HED’s level of concern for pilots using enclosed cockpits and weari ng no respirator. Even though dermal exposures were not assessed due to lack of a dermal point of departure, handlers sh ould still wear label prescribed personal-protective equipment (PPE; long-sleeved shirt and lo ng pants, chemicalresistant gloves, and shoes plus socks).

Occupational postapplication exposur es following bispyribac-sodium application to aquatic areas is likely limited to persons who contact the treated water to perform tests, such as testing the levels of bispyribac-sodium. S hort- and intermediate-term derm al postapplication exposures and risks were not assessed for bispyribac-sodium , since no dermal points of departure were identified. Based on the Agency's current prac tices, a quantitative occupational postapplication inhalation exposure assessment was not performed for bispyribac-sodium at this time. However, there are multiple potential sources of postappl ication inhalation exposure to individuals performing postapplication activitie s in previously treated area s, including vol atilization of pesticides. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational pos tapplication inhalation exposur e assessment for bispyribacsodium.

Residential Exposure and Risk In addition to the proposed aquatic use, bispyribac -sodium is also currently registered for use on golf courses and sod farms. No residential hand ler exposure is expected from the proposed and registered uses of bispyribac-sodium. For the proposed aquatic use, th e label indicates that bispyribac-sodium may only be applied to water by Federal or State agencies, the U.S. Army Corps of Engineers, and licen sed applicators authorized by Federal or State agencies. Residential postapplication exposure following use of bispyribac-sodium on golf courses and sod farms is possible. A dermal postapplication assessment was not perfor med since there is no short-term dermal point of departure. Based on the Agency's current practices, a quantitative postapplication inhalation exposure assessment was not performed for bispyribac-sodium. However, volatilization of pestic ides may be a potential source of postapplication inhalation exposure to individuals nearby to pesticide applications. If new policies or procedures are put into place, the Agency may revisit the need fo r a quantitative postapplic ation inhalation exposure assessment for bispyribac-sodium.Bispyribac-sodium Human-H ealth Risk Assessment DP# 361116

Page 6 of 31 HED determined there is a potential for reside ntial postapplication expos ure from swimming in water bodies that have been previously treated with bispyribac-sodium. Postapplication exposure and risks were developed for the non-co mpetitive adult and child swimmer. Exposure is expected to be short-term; however, since the short- and intermediate-term points of departure are the same, the short-term assessment is protec tive of intermediate-term exposures. Only oral postapplication exposure to recr eational swimmers was assessed in this document. Dermal postapplication exposures were not assessed, since no dermal points of departure were identified. Short-term incidental ingestion MOEs were greater than 100 for noncompetitive adult and child swimmers and; therefore, do not exceed HED’s level of concern.

Review of Human Research Past bispyribac-sodium risk assessments rely in part on data from studies in which adult human subjects were intentionally exposed to a pest icide to determine their dermal and inhalation exposure. Many such studies, i nvolving exposure to many different pesticides, comprise generic pesticide exposure databases such as the Pest icide Handlers Exposure Database (PHED), the Outdoor Residential Exposure Task Force (ORETF ) Database, and the Agricultural Reentry Task Force (ARTF) Database. EPA has reviewed all the studies supporting these multi-pesticide generic exposure databases, and has found no cl ear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantly deficient relative to the ethical standards prevailing at the time the research wa s conducted. All applicab le requirements of EPA’s Rule for the Protection of Human Subject s of Research (40 CFR Part 26) have been satisfied, and there is no re gulatory barrier to continue d reliance on these studies.

Environmental Justice Considerations Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human-health risk assessment, in accordance w ith U.S. Executive Order 12898, "Federal Actions

to Address Environmental Just ice in Minority Populations an d Low-Income Populations," ( http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf ).

As a part of every pesticide risk assessment , OPP considers a large variety of consumer subgroups according to well-esta blished procedures. In line with OPP policy, HED estimates risks to population subgroups fr om pesticide exposures that ar e based on patterns of that subgroup’s food and water consumption, and activ ities in and around the home that involve pesticide use in a residential se tting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture (US DA) under Continuing Surveys of Food Intakes by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categ orized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when

conditions or circumstances warrant. Whenever appropriate, non-diet ary exposures based on home use of pesticide products and associated ri sks for adult applicators and for toddlers, youths, and adults entering or playing on treated ar eas post-application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditi onal dietary patterns among specific subgroups.Bispyribac-sodium Human-H ealth Risk Assessment DP# 361116

Page 7 of 31 Regulatory Recommendations

Pending submission of revised Sections B and F, HED recommends in favor of the proposed use and the requested tolerance for freshwater fish as follows: “Tolerances are established for residues of the herbicide bispyribac-sodium, in cluding its metabolites and degradates, in or on the commodity listed below. Compliance with the tolerance level specified below is to be determined by measuring only bispyr ibac-sodium, (2,6-bis[(4,6-dimethoxy-2- pyrimidinyl)oxy]benzoic acid, sodi um salt), in or on the followi ng raw agricultural commodity:

Fish, freshwater............................................................................................0.01 ppm”.

Registration should be conditional pending resolution of:

Toxicology

• An immunotoxicity study is now a data re quirement in the 40 CFR revised Part 158.

• Acute neurotoxicity study.

• Subchronic neurotoxicity study.

• 28-day inhalation study.

2.0 Ingredient Profile

Bispyribac-sodium is a broad-spectrum, posteme rgence contact herbicide which controls grass

and broadleaf weeds. The mode of action is the inhibition of the plant enzyme acetolactate synthetase. Bispyribac-sodium is formulated as a SP and is register ed in the U.S. for the control of aquatic weeds in rice fields. Tolerances fo r residues of bispyribac -sodium are established under §180.577(a) on rice grain and straw (each at 0.02 ppm).

Tradewind TM Herbicide is labeled for use on surface, submerged and emergent aquatic weeds in bayous, canals, fresh water ponds, lakes, marshes and reservoirs. It may be applied as a subsurface application for control of submerged aquatic weeds or as a surface application for control of floating and emergent aquatic weeds. According to th e proposed label, applicators and

other handlers must wear a l ong-sleeved shirt and long pants, chemical-resistant gloves, and shoes plus socks.

2.1 Summary of Proposed Uses

Table 2.1. Proposed Occupational Uses of Bispyribac-sodium.

Crop/Use

Site Product,

Formulation Target of Application Maximum Application

Rate Application Equipment Treatment

Interval

Surface

weeds 0.1 lb ai/A Aerial (airplane or helicopter), Boat-Mounted Boom, Handgun Sprayer, Low-Pressure Handwand Sprayer, Backpack Sprayer 30 days; do not apply more than 8 oz product (0.4

lb ai)/A/year* Aquatic

weeds Tradewind TM

Herbicide (EPA Reg. #: 59639- RAL)

Soluble powder formulation packaged in water-soluble bags (80% a.i.) Subsurface

weeds 0.12 lb ai/Afoot Boat-Mounted Trailing Hose Not provided

* Number of applications at the maximum rate = 4 (0.4 lb ai/A/year ÷ 0.1 lb ai/A = 4 applications/year).Bispyribac-sodium Human-H ealth Risk Assessment DP# 361116

Page 8 of 31 Conclusions: The proposed label recommends that wh en the product is to be applied to the foliage of floating or emerged aquatic weeds, an adjuvant approved for us e in aquatic habitats should be included in the spray mix. The pr oduct may be tank mixed with other aquatic herbicides, such as 2,4-D or diquat dibromide. The label specifies th at there is no postapplication holding restriction ag ainst use of treated water for drinking or recreational purposes (e.g., swimming, fishing).

The proposed label specifies the following: • application is not to be made into flow ing water, intertidal, or estuarine areas; • application is not to be made to water utilized for crayfish farming;

• treated water is not to be us ed to irrigate food or ornamental crops until the concentration of bispyribac-sodium in water is ≤ 1 ppb [water may be anal yzed using Enzyme-Linked Immunoassay (ELISA) or other a pproved analytical methods]; • subsurface applications are not be made to water bodies subject to rapid dilution.

Conclusions: The proposed label is adequate to allow evaluation of the residue data relative to the proposed use. The petitioner should propose a minimum retreatment interval (RTI) for the subsurface application. Furthermore, the label shoul d be revised to indicate that the treated water may not be used as a water source for livestock until the concentration of bispyribac-sodium in

water is ≤ 1 ppb.

HED recommends that the product label be made cl earer with respect to the application rate. The label indicates the product is packaged in 2- oz bags; however, the application rates provided are 1 to 2 oz of formulated product/A for su rface weeds and from 0.8 oz to 2.4 oz product/A-ft for subsurface weeds. If a handler must open pa ckages to obtain fractions of an ounce to mix, the advantage of water-sol uble packaging is lost. A revised Section B should be submitted.

2.2 Structure and Nomenclature

Table 2.2. Test Compound Nomenclature.

Compound

O O

N N

N N O O

OCH 3

OCH 3 OCH 3 H

3 CO Na +

Common name Bispyribac-sodium

Company experimental name KIH-2023

IUPAC name sodium 2,6-bis(4,6-dimethoxypyrimidin-2-yloxy)benzoate

CAS name 2,6-bis[(4,6-dimethoxy-2-pyrimidinyl)oxy]benzoic acid, sodium salt

CAS registry number 125401-92-5

End-use product (EP) TradewindTM Herbicide (80% SP; EPA Reg. No. 59639-RAL)Bispyribac-sodium Human-H ealth Risk Assessment DP# 361116

Page 9 of 31 Table 2.2. Test Compound Nomenclature.

Compound

O O

N N

N N O O

OCH 3

OCH 3 OCH 3 OH Na +

Common name Des-methyl KIH-2023 (also identified as Des-Me-2023)

Chemical name sodium 2-(4,6-dimethoxypyrimidin-2-yl)oxy-6-(4-hydroxy-6-methoxypyrimidin2-yl)oxybenzoate

2.3 Physical and Chemical Properties

Table 2.3. Physicochemical Properties of the Technical Grade Test Compound Bispyribac-Sodium.

Parameter Value Reference

Melting range 223-224°C (pure active ingredient); decomposes at 219oC (technical grade)

pH 6.45 (5 % w/v in water, 25°C)

Density 1.29 g/mL (20°C)

Water solubility 6.75 g/100 mL (25°C)

Solvent solubility Shake flask method (25oC) : ethyl acetate 1.98 x 10 -4 g/100 mL dichloromethane 5.13 g/100 mL methanol 2.5 g/100 mL Column generator method (25°C) : acetone 1.4 x 10 -4 g/100 mL ethyl acetate 6.1 x 10 -6 g/100 mL

n-hexane 8.34 x 10 -7 g/100 mL methyl chloride 1.3 x 10 -4 g/100 mL

n-octanol 2.1 x 10 -3 g/100 mL

toluene <1 x 10 -5 g/100 mL

Vapor pressure 3.79 x 10 -11 mm Hg (25°C)

Dissociation constant, pK

a 3.05

Octanol/water partition coefficient K OW = 0.0932; Log(K OW ) = -1.03

UV/visible absorption spectrum Not available RD Memorandum, S. Malak, 26- APR-2001; DP# 267318

3.0 Hazard Characterization/Assessment

3.1 Mammalian Toxicology

The acute toxicity battery of te sts shows that bispyrib ac-sodium has a low acute toxicity profile (Categories III & IV) and is not a dermal sensitizer. The liver and bile duct were identified as the target organs in the subchr onic and chronic toxici ty studies in rats, mice, and dogs and the reproduction toxicity study in rats. Males appear to be slightly more sensitive than females. Repeated dermal applications at the limit dose did not elicit systemic toxicity or dermal irritation. Bispyribac-sodium is negative for carcinogenicity in feeding studies in rats and mice and was classified as a “not likely human carcinogen” by HED’s Hazar d Identification Assessment Review Committee [(HIARC); Memo, G. Reddy, 02-AUG-2001; HED Doc. No. 014647). Bispyribac-sodium was negative for fetal toxi city and showed no evidence of offspringBispyribac-sodium Human-H ealth Risk Assessment DP# 361116

Page 10 of 31 susceptibility in both the developmental studies in rats and rabbits and in the reproduction study

in rats.

The battery of mutagenicity studies with the parent and three major metabolites were all negative. In the last risk assessment, the requirement of an in vitro mammalian cell gene mutation assay (OPPTS 870.5300) was cited as a da ta gap. Since then, the corresponding study (MRID# 46076601) has been submitted and reviewed by the agency. The results of the study were deemed equivocal due to the lack a con centration-related respons e in the induction of mutant colonies over background at the high con centrations. Thus, ther e is no evidence that bispyribac sodium is mutagenic.

Acute and subchronic neurotoxicit y studies are not available for bispyribac-sodium. There were clinical signs of potentia l neurotoxicity (i.e., piloerection, su bnormal temperature, and decreased spontaneous motor activity) in the combined rat chronic/carcinogenicity study. However, these clinical signs occurred at a low incidence in the high dose group and were not dose-dependent. The primary effects of the study were based on m acro- and microscopic ch anges in the liver and choldedochus, decreased body weight s, and decreased food efficiency. There are no other signs of neurotoxicity in the database.

In the rat metabolism study, pretreatment, dose le vel, sex and position of radiolabel had little effect on the absorption, distribut ion, elimination and metabolism. It was readily absorbed by male and female rats following intravenous or oral dosing. The to tal recovery of the administered radioactivity was 95.8-101.6% for all treatment groups. Most of the administered dose (>43%) was excreted in feces within 48 ho urs and elimination was essentially complete within 5 days. Less than 2% of the administer ed dose remained in the carcass and tissues and <0.1% of the dose was recovered in air. The pa rent and five metabolites were identified in the excreta of male and females following administration of [ 14 C-Py]-bispyribac-sodium, whereas the parent and three metabolites were identified following administration of [ 14 C-Bn]-bispyribacsodium.

3.2 Dose-Response Assessment

Table 3.2 summarizes the toxicol ogical doses and endpoints for bi spyribac-sodium for use in

human-health risk assessment.

Table 3.2. Summary of Toxicological Dose and Endpoints for Bispyribac-sodium for Use in Human-Health

Risk Assessments.

Exposure

Scenario Dose Used in

Risk Assessment,

UF FQPA SF and

LOC for Risk

Assessment Study and Toxicological Effects

Acute Dietary all populations Not Applicable Not Applicable No appropri ate endpoint attributable to a single exposure was identified.

Chronic Dietary all populations NOAEL = 10 mg/kg/day

UF = 100 FQPA SF = 1X

cPAD = cRfD = 0.1 mg/kg/day Chronic Toxicity Study - Dog LOAEL = 100 mg/kg/day based on dose-related increases in hyperplasia of the intrahepatic bile ducts in males and females and granulation of the liver in

the females.Bispyribac-sodium Human-H ealth Risk Assessment DP# 361116

Page 11 of 31 Exposure

Scenario Dose Used in

Risk Assessment,

UF FQPA SF and

LOC for Risk

Assessment Study and Toxicological Effects

Short-Term

Incidental Oral (1-30 days)

(Residential) NOAEL = 100 mg/kg/day LOC for MOE =

100

(includes FQPA SF = 1X) Developmental Toxicity Study - Rabbit Maternal LOAEL = 300 mg/kg/day based on lethargy, diarrhea and decreased body-weight gain in the range-finding study.

IntermediateTerm Incidental

Oral (1-6 months)

(Residential) NOAEL = 100 mg/kg/day LOC for MOE =

100

(includes FQPA SF = 1X) 90-Day Feeding Study - Dog LOAEL = 600 mg/kg/day based upon salivation and slight proliferation of intrahepatic bile duct.

Dermal,

All Durations

(Occupational/ Residential) Not Applicable Not Applicable No hazard via the dermal route was identified; therefore, risk quantifica tion is not required. No systemic toxicity was seen at the limit dose in the 21- day dermal toxicity study in rats. In addition no developmental toxicity was seen. Further, based on the physical and chemical properties (large molecular weight = 452.36, and log Kow = 0.092), this compound is not likely to be significantly absorbed through the skin.

Short-Term

Inhalation (1-30 days)

(Occupational/ Residential) Oral study

NOAEL= 100 mg/kg/day (inhalation absorption rate = 100%) LOC for MOE = 100 (Occupational)

LOC for MOE = 100 (Residential, includes the FQPA SF = 1X) Developmental Toxicity Study - Rabbit Maternal LOAEL = 300 mg/kg/day based on lethargy, diarrhea and decreased body-weight gain in the range-finding study.

IntermediateTerm Inhalation (1-6 months)

(Occupational/ Residential) Oral study

NOAEL= 100 mg/kg/day (inhalation absorption rate = 100%) LOC for MOE = 100 (Occupational)

LOC for MOE = 100 (Residential, includes the FQPA SF = 1X) 90-Day feeding study - Dog LOAEL = 600 mg/kg/day based upon salivation and slight proliferation of intrahepatic bile duct.

Long-Term

Inhalation (>6 months)

(Occupational/ Residential) Oral study

NOAEL= 10 mg/kg/day (inhalation absorption rate = 100%) LOC for MOE = 100 (Occupational)

LOC for MOE = 100 (Residential, includes the FQPA SF = 1X) Chronic Toxicity Study - Dog LOAEL = 100 mg/kg/day based on dose-related increases in hyperplasia of the intrahepatic bile ducts in males and females and granulation of the liver in

the females.

Cancer (oral, dermal, inhalation) “not likely” Not Applicable No evidence of carcinogenic or mutagenic potential. A cancer risk assessment is not required.

Abbreviations: UF = uncertainty fact or, FQPA SF = FQPA Safety Factor, NOAEL = no-observed adverse-effect level, LOAEL = lowest-observed adverse-effect level, cPAD = chronic population-adjusted dose, RfD = reference dose, MOE = margin of exposure, LOC = level of concern.

Based on the available toxicity da tabase and the Agency's current practices, the inhalation risk for bispyribac-sodium was assessed using an or al toxicity study. The Agency sought expert advice and input on issues related to this route-to-route extrapolat ion approach (i.e., the use ofBispyribac-sodium Human-H ealth Risk Assessment DP# 361116

Page 12 of 31 oral toxicity studies for inhalati on risk assessment) from its Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scien tific Advisory Panel (SAP) in December 2009. The Agency

received the SAP’s fina l report on March 2, 2010 ( http://www.epa.gov/scipoly/SA P/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, re-examine and develop new policies and procedures for conducting inhala tion risk assessments, including route-to-route extrapolation of toxicity data.

3.3 FQPA Considerations

The toxicological database for bispyribac-so dium is complete with the exception of immunotoxicity, acute neurotoxic ity, and subchronic neurotox icity studies, which are new (2007) regulatory requirements under 40 CFR Part 158, as well as a 28-day inhalation study. A 28-day inhalation toxicity study was requested previously by HE D’s HIARC in 2001 (HED Doc. No. 014647). Consistent with the previous risk assessment for bispyribac-sodium (2001), the RAB1 bispyribac-sodium risk assessment team reco mmends that the FQPA SF be reduced to 1X. This decision is based on the following:

• There is no indication of quantit ative or qualitative increased susceptibility of rats or

rabbits to in utero or postnatal exposure to bispyribac-sodium.

• A developmental-neurotoxicity st udy (DNT) study is not required.

• The level of concern for neurotoxicity is low. Although there were clinical signs indicative of neurotoxicity (e.g., piloerecti on, subnormal temperature, and decreased spontaneous motor activity) in the combined rat chroni c/carcinogenicity study, these occurred at a low incidence in the high-dos e group and were not dose-dependent. The primary effects of the study were based on m acro- and microscopic changes in the liver and choldedochus, decreased body weights, and decreased food efficiency. Although acute and subchronic neurotoxicity studies are now re quired as part of the revisions to 40 CFR Part 158, bispyribac-sodium has shown no indications of central or peripheral nervous system toxicity in any study and does not appear to be struct urally related to any

other chemical that causes adve rse nervous system effects.

• The toxicology database for bi spyribac-sodium does not show any evidence of treatmentrelated effects on the immune system. The overall weight of evidence suggests that this chemical does not directly target the i mmune system. An immunotoxicity study is required as a part of new data requireme nts in the 40 CFR Part 158 for conventional pesticide registration; however, the Agency does not believe that conducting a functional immunotoxicity study will result in a lower point of departure than that currently used for overall risk assessment, and therefore, a database uncertainty factor (UF DB ) is not needed to account for lack of this study.

• A 28-day inhalation study is not available; however, the EPA has determined that the additional FQPA SF is not needed. Based on the very low vapor pressure of bispyribacsodium (3.79 x 10 -11 at 25 0 C) and because the residential use pattern is limited to golf courses and swimming areas, minimal potential for inhalation exposure is expected. Therefore, the risk estimate is conserva tive and is considered protective and the additional FQPA SF is not needed.

• The dietary food and drinking water exposure assessments are conservative and will not underestimate the potential exposu res for infants and children.

• The residential exposure assessment was c onducted using high-end estimates of use and potential exposure providing a conservati ve, health-protective estimate of risk.Bispyribac-sodium Human-H ealth Risk Assessment DP# 361116

Page 13 of 31 3.4 Endocrine Disruption

As required under FFDCA section 408(p), EP A has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (inc luding pesticide active and other ingredients) may have an effect in humans or wildlife si milar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two-tiered ap proach to making the statutorily required

determinations. Tier 1 consists of a battery of 11 scr eening assays to identify the potential of a chemical substance to interact with the estrog en, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go th rough Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stag e of the EDSP where EPA will determine which, if any, of th e Tier 2 tests are necessary base d on the available data. Tier 2 testing is designed to identify a ny adverse endocrine related eff ects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticid e active ingredients and 9 inert ingredients.

This list of chemicals was selected based on th e potential for human exposure through pathways such as food and water, residen tial activity, and certain post-applic ation agricultural scenarios.

This list should not be construed as a lis t of known or likely endocrine disruptors.

Bispyribac-Sodium was not among the group of 58 pe sticide active ingredie nts on the initial list

to be screened under the EDSP. Under FFDCA sec. 408(p) the Agen cy must screen all pesticide chemicals. Accordingly, EPA anticipates issuin g future EDSP test orders/data call-ins for all pesticide active ingredients.

For further information on the status of the ED SP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, pleas e visit our website: http://www.epa.gov/endo/

4.0 Dietary Exposure/Risk Characterization

The residue chemistry data submitted in support of proposed petitions were evaluated by HED on 07-JUL-2010 (Memo, S. Levy, DP# 363347). The drinking water assessment was completed by EFED on 27-OCT-2009 (Memo, C. Sutton, DP # 362285). The dietary exposure assessment was completed by HED on 07-JUL-2010 (Memo, S. Levy, DP# 363348).

4.1 Residue Profile

Nature of the Residue

Plants: Adequate plant metabolism studies are available depicting the metabolism of [ 14 C]bispyribac-sodium in rice. Based on these studies, HED previously determined that the parent compound is the only residue of concern for purposes of both risk assessment and the tolerance expression in rice. The decision was based on the following considerations: (1) all metabolites identified were present at low levels in the plant and livestock metabolism studies; (2) bispyribac-sodium has a low toxicity profile a nd the metabolites are not expected to be more toxic than the parent; and (3) the identified meta bolites are also metabolites in rats and their toxicity was assessed in the rat metabolism studies.Bispyribac-sodium Human-H ealth Risk Assessment DP# 361116

Page 14 of 31 Livestock: Adequate ruminant and poultry me tabolism studies are av ailable depicting the metabolism of [ 14 C]bispyribac-sodium; separate rumi nant studies were conducted with bispyribac-sodium labeled in the benzene ring or in both pyrimidine rings, and the poultry study was conducted with bispyribac-sodium labeled in both pyrimidine rings. Based on these studies,

and the considerations listed a bove for plant metabolism, HED previously determined that the parent compound is the only residue of concern for purposes of both risk assessment and the tolerance expression in livestock commodities. HE D noted that if additional uses are requested in the future which significan tly increase the poultr y dietary burden, a poultry metabolism study with benzene-labeled bispyr ibac-sodium may be required.

Fish: HED previously concluded that a fish metabolism study would not be required to support the proposed use associated with DP# 361116, but re quired that samples from the fish residue study be analyzed for bispyribac-sodium a nd its metabolite des-methyl KIH-2023, a major residue in the anaerobic aqua tic metabolism study [minutes of 30-MAY-2007 meeting of the HED Chemistry Science Advi sory Council (ChemSAC)]. For purposes of this petition , HED recommends that the requirement for a fish me tabolism study be waived, but that samples from the fish magnitude of the residue study shoul d be analyzed for bispyribac-sodium and its metabolite des-methyl KIH-2023, a major residue in the anaerobic aquatic metabolism study.

Residue Analytical Methods Valent has submitted a high-performance liquid chromatography (HPLC) method with tandem mass spectroscopy detection (MS/MS), Method GPL-MTH-068. The method determines residues of bispyribac-sodium and des-methyl KI H-2023 in water and fish tissue and was used as the data collection method in the fish accumulation study. The limit of quantitation (LOQ) was 0.010 ppm for each analyte in fish tissue and 0.0 01 ppm for each analyte in tank water. An acceptable independent laboratory validation (IL V) study was conducted. This method is adequate for use as a data-collection method. Th e petitioner has also submitted a slightly-revised version of the data-collection method, GPL-MTH-068a which demonstrated an additional cleanup step as an option for the confirmation tec hnique and an addition of alternate analytical conditions for LC-MS/MS analysis whic h can serve as an enforcement method.

Multiresidue Methods (MRM) Data pertaining to the MRM testing of bispyribac-sodium were previously submitted in conjunction with PP#9F6044 (Memo, J. Tyler, 23-AUG-2001; DP# 267306). The study results indicate that bispyrib ac-sodium is not likely to be rec overed through the U.S. Food and Drug Administration (FDA) MRM protocols.

Magnitude of Residues in Fish The submitted fish magnitude of the residue stud y is adequate and supports the proposed aquatic use. The study investigated residues of bis pyribac-sodium and its des-methyl metabolite in freshwater fish (bluegill or cat fish) for up to 28 days following application of bispyribac-sodium to water at 0.090 mg/L (90 ppb). Residues were determined using the proposed enforcement method (GPL-MTH-068). The method was adequa tely validated in conjunction with the analysis of the study samples.

The available data demonstrate that bispyribac- sodium residues in water remained consistent throughout the study period, and residues of bis pyribac-sodium and des-methyl KIH-2023 were nonquantifiable in fish tissue over the 28-day exposure period. Ba sed on the results of the study,

HED concludes that the residues of concern in fish for tolerance enforcement and riskBispyribac-sodium Human-H ealth Risk Assessment DP# 361116

Page 15 of 31 assessment consist of bispyribac-sodium only. The data support a to lerance for bispyribacsodium residues in fish tissue at the LOQ, 0.01 ppm.

The proposed aquatic uses prohibit a pplications into flowing water, intertidal or estuarine areas, or areas where crayfish farming is practiced. No residue studies with shellfish or mollusks are needed to support the proposed use.

A residue study with irrigated crops has been su bmitted previously which indicates the potential for quantifiable residues in/on irri gated crops treated with irriga tion water contai ning bispyribacsodium at 64 ppm. Tolerances for irrigated crops will not be needed to support the proposed use because the proposed label prohibits use of tr eated water to irriga te food crops until the concentration of bispyribac-sodium in water is ≤ 1 ppb.

Magnitude of Residues in Meat, Milk, Poultry and Eggs (MMPE) As livestock may be exposed to bispyribac-sodium through the cons umption of treated water, the proposed aquatic use results in si gnificantly increased dietary bur dens to livestock. HED can no longer conclude that there is no expectation of fi nite residues of bispyr ibac-sodium in livestock commodities. HED would normally recommend th at the petitioner subm it ruminant and poultry feeding studies to support the proposed use. However, Valent requested a waiver for ruminant and poultry feeding studies. The basis for this request was that (1) quan tifiable residues would not be expected at the 1X dietary burden, (2) the low likelihood of livestock consuming treated water, and (3) the low likelihood that the water would contain the maximum labeled

concentration. HED’s ChemSAC recommended granting the waiver provided that the

Tradewind TM label is revised to indicate that the treat ed water may not be used as a water source for livestock until the concentration of bispyribac-sodium in water is ≤ 1 ppb (minutes of HED’s ChemSAC meeting held 16-JUN-2010). A revised Section B should be submitted.

Tolerance Summary Valent has proposed the establishment of toleran ces for residues of th e herbicide bispyribacsodium, including its metabolites and degradates, in or on the commodities listed below in Table 4.1. Compliance with the tolerance levels specified below is to be determined by measuring only bispyribac-sodium, (2,6-bis[(4,6-dimethoxy-2-pyrimidinyl)oxy]benzoic acid, sodium salt), in or

on the RACs listed below.

The available data will support a to lerance for bispyribac-sodium in fish at the LOQ (0.01 ppm). The petitioner should submit a revised Section F , removing the proposed tolerance levels for livestock and poultry commodities.

There are currently no establ ished Codex, Canadian, or Mexican maximum residue limits (MRLs) for residues of bispyribac-sodium in/on fish matrices. Therefore, no compatibility issues exist with regard to th e proposed U.S. tolerance.Bispyribac-sodium Human-H ealth Risk Assessment DP# 361116

Page 16 of 31 Table 4.1. Tolerance Summa ry for Bispyribac-Sodium.

Commodity Proposed Tolerance (ppm) HED-Recommended Tolerance (ppm) 1 Comments; Correct Commodity Definition

Fish, freshwater 0.01 0.01

Cattle, goat, hog, horse, and sheep, meat byproducts 0.03

-

Cattle, goat, hog, horse and sheep, meat 0.01

-

Cattle, goat, hog, horse and sheep, fat 0.01

-

Milk 0.01

- Poultry, meat byproducts 0.01

- Egg 0.01

- Poultry, fat 0.01

- Poultry meat 0.01

-

1 Tolerances for livestock commodities are not needed as long as the Tradewind TM label is revised to indicate that the treated water may not be used as a water sour ce for livestock until the concentratio n of bispyribac-sodium in water is ≤ 1 ppb (minutes of HED’s ChemSAC meeting held 16-JUN-2010).

4.2 Environmental Degradation

Bispyribac-sodium is a moderately persiste nt, mobile compound on most soils. In soil, bispyribac-sodium is stable to abiotic degrada tion. The primary degradation pathways in soil and aquatic environments are aerobic and anaerobic metabolism, with the formation of multiple major metabolites: sodium 2-(4,6-di methoxypyrimidin-2-yl)oxy-6-(4-hydroxy-6- methoxypyrimidin-2-yl) benzoate (DesMe-2023 ); 2-[(4,6-dimethoxypyrim idin-2-yl)oxy]-6- hydroxybenzoate (Bx-180); 2-hyd roxy-6-[(4-hydroxy-6-methoxypyr imidin-2-yl)oxy] benzoic acid (DesMe-180); 2,6-dihydroxybenzoic acid (2,6-DBA); 4,6-dihydroxy-2-methoxypyrimidine (MeBa); and 4,6-dimethoxy-2-hydroxypyrimidine (Me 2 Ba). Bispyribac-sodium residues further degrade in soil, eventually mine ralizing to carbon dioxide. When applied directly to water, bispyribac-sodium is stable to abiotic degrada tion by hydrolysis and aque ous photolysis. It is likely to partition predominantly to the water colu mn. Bispyribac-sodium is subject to microbial degradation under aerobic and an aerobic conditions, with slow er degradation observed in anaerobic aquatic environm ents (half-lives of 88-109 days) relati ve to aerobic soil (half-life of 62 days) or aerobic aquatic environments (half-lives of 46-82 days).

In an aquatic field dissipation study conducted at one site in Flor ida, bispyribac-sodium degraded with a half-life of 25 days afte r being directly applied to th e surface water via subsurface injection. However, the study was not conducted at the maximum label rate, but used only a single application targeted to ach ieve an aqueous concentration of 45 ppb. The major degradate, and only degradate monitored in the study, was DesMe-2023, which was present at a maximum of 4.3 ppb (day 28) and degraded with a half-life of 36 days.

4.3 Pesticide Metabolites and Degradates of Concern

The nature of the residue in rice, hen, and goat metabolism studies is adequately understood based on acceptable metabolism studies conducted on these commodities. Based on these studies, the residues of concern in rice and lives tock commodities, as well as drinking water, are as follows (Memo, J. Tyler, 23-AUG-2001; DP# 267306):Bispyribac-sodium Human-H ealth Risk Assessment DP# 361116

Page 17 of 31 Rice: bispyribac-sodium (risk a ssessment and tolerance expression) Livestock: bispyribac-sodium (risk assessment and tolerance expression) Drinking water: bispyribac- sodium (risk assessment)

4.4 Drinking Water Residue Profile

The drinking water residues used in the dietar y risk assessment were provided by EFED (Memo, C. Sutton, 27-OCT-2009; DP# 362285) and incorporated directly into this dietary assessment. Monitoring data are not unavailable for bispyr ibac-sodium. Because currently used Tier 1 aquatic exposure models to simulate agricultura l uses and are not appropriate for determining EDWCs for aquatic uses of pe sticides applied directly to surface water bodies, EFED recommended using the maximum annual label target rate of 180 ppb for subsurface injection of bispyribac-sodium into water. This value repr esents the maximum cumulative concentration in water based on four applications (assumed, not sp ecified on the label), at unspecified intervals, needed to achieve a 45-ppb level of bispyribac-sodium in the water column. Because this chemical is only moderately persistent and will undergo degradation in the environment between applications, this value can be considered cons ervative. The water residue value of 180 ppb was incorporated in the DEEM-FCID TM into the food categories “water , indirect, all sources,” and “water, direct, all sources.”

4.5 Dietary Exposure and Risk

A chronic dietary exposure assessmen t was conducted using DEEM-FCID TM Version 2.03, which incorporates consumption data from USDA ’s CSFII, 1994-1996 and 1998. The 1994-96, 98 data are based on the reported consumption of more than 20,000 indi viduals over two nonconsecutive survey days. For chronic exposure assessment, consumption data are averaged for the entire U.S. population and within population subgroups, but for acute exposure assessment are retained as individual consumption events.

For chronic dietary exposure assessments, an es timate of the residue leve l in each food or foodform (i.e., orange or orange juice) on the f ood commodity residue list is multiplied by the average daily consumption estimate for that food/ food form to produce a residue intake estimate. The resulting residue intake estimate for each f ood/food form is summed w ith the residue intake

estimates for all other food/food forms on the comm odity residue list to arrive at the total average estimated exposure. Exposure is expres sed in mg/kg body weight/day and as a percent of the PAD. This procedure is performed for each population sub group.

4.5.1 Acute Dietary Exposure/Risk

No toxic effects attributable to a single exposure to bispyribac -sodium have been identified; therefore, an aRfD has not been established for bispyribac-sodium and an acute dietary exposure assessment is not required.

4.5.2 Chronic Dietary Exposure/Risk

An unrefined, chronic dietary exposure assessm ent was conducted assuming tolerance-level residues (for all registered and proposed new uses), DEEM TM 7.81 default processing factors, and 100% crop treated (CT). Drinking wa ter was incorporated directly into the dietary assessment. The use of anticipated residues (A Rs), empirical processing factor s, and %CT data would refineBispyribac-sodium Human-H ealth Risk Assessment DP# 361116

Page 18 of 31 further HED’s exposure and risk estimates. Ho wever, refinement of the dietary exposure

estimates is not needed at this time.

Bispyribac-sodium chronic dietary (food + drin king water) exposure estim ates using the DEEMFCID TM software are not of concern for the U.S. population or any of the population subgroups. Dietary exposure was estimated at 0.003800 mg/ kg/day for the U.S. population (3.8% of the cPAD) and 0.012453 mg/kg/day (12.5% of the cPAD) for the most highly exposed population subgroup (all infants, <1 year old). The esti mated exposures/risks from food and water are summarized in Table 4.5.2 for all populations.

Table 4.5.2. Summary of Dietary (Food and Drinking Water) Exposure Risk for Bispyribac-sodium. Chronic Dietary Population Subgroup Dietary Exposure (mg/kg/day) % cPAD
General U.S. Population 0.003800 3.8 All Infants (<1 year old) 0.012453 12.5 Children 1-2 years old 0.005646 5.6 Children 3-5 years old 0.005285 5.3 Children 6-12 years old 0.003645 3.6 Youth 13-19 years old 0.002748 2.7 Adults 20-49 years old 0.003548 3.5 Adults 50+ years old 0.003731 3.7 Females 13-49 years old 0.003533 3.5

1 Chronic dietary endpoint of 0.1 mg /kg/day applies to the general U.S. population and all populat ion subgroups. The population subgroup with the highest estimated chronic dietary (food + drinking water) exposure and risk is indicated by

bold text.

4.5.3 Cancer Dietary Risk

There is no evidence that bispyribac-sodium is carcinogenic to humans; therefore, a cancer dietary exposure assessment is not required.

5.0 Residential (Non-Occupational) Exposure/Risk Pathway

Bispyribac-sodium is currently registered fo r use on golf courses and sod farms (Memo, M. Dow, 09-OCT-2003, DP# 289929; M. Dow, 27-M AR-2008; DP# 349324); and is proposed for aquatic use. Residential exposure may occur as a result of the regist ered and proposed uses.

5.1 Residential Handler Exposures and Risks

No residential handler exposure is expected from the proposed and registered uses of bispyribacsodium. For the proposed aquatic use, the labe l indicates that bispyr ibac-sodium may only be applied to water by Federal or State agencies, U.S. Army Corps of Engineers, and licensed applicators authorized by Fe deral or State agencies.

5.2 Residential Postapplication Exposures and Risks

Residential postapplication exposure following use of bispyribac-sodium on golf courses and sod farms is possible. A dermal postapplication assessment was not perfor med since there is no short-term dermal point of departure. Based on the Agency's current practices, a quantitative postapplication inhalation exposure assessment was not performed for bispyribac-sodium at this time primarily because the vapor pressure of bispyribac-sodium is low (3.79 x 10 -11 mm Hg atBispyribac-sodium Human-H ealth Risk Assessment DP# 361116

Page 19 of 31 25°C). However, volatilization of pesticides may be a potential sour ce of postapplication inhalation exposure to individuals nearby to pesticide applicati ons. The Agency sought expert advice and input on issues rela ted to volatilization of pesticides from its FIFRA SAP in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/ meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to inco rporate postapplication in halation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a qu antitative postapplication inhalati on exposure assessment for bispyribacsodium.

For the proposed aquatic use, bispyribac-sodi um can treat water bodies (e.g., lakes) at concentrations up to 45 ppb. Therefore, there is a potential for exposure to recreational users (i.e., swimmers) in these water bodies. Postapplicati on exposure and risks were developed for the non-competitive adult and child swimmer. E xposure is expected to be short-term; however,

since the short- and intermed iate-term points of departure are the same, the short-term assessment is protective of intermediate-term exposures.

A series of assumptions and exposure factors serv ed as the basis for completing the residential postapplication risk assessment. The assumptions and factors used in the risk calculations are consistent with current Agency policy for comp leting residential exposure assessments (i.e., Standard Operating Procedures (SOPs) for Resi dential Exposure Assessment, 1997). Only oral postapplication exposure to recr eational swimmers is assessed in this document. Dermal postapplication exposures were not assessed since no short-term dermal point of departure was selected. The values and assumptions used in this assessment include:

• Maximum concentration in water = 45 ppb in acc ordance with label re strictions. It is assumed that 100% of the application concentr ation is available in the water for oral ingestion.

• Duration of exposure = 5 hours a day -- assume d for both adults (18-64 years old) and children (6 years old). This exposure durat ion is based on the 90th percentile value for time spent at home in a swimming pool from the 1996 Exposure Factors Handbook.

• Mean ingestion rate for adu lt and children swimmers is 0.05 L/hour. This ingestion rate is based on HED’s swimmer model typically used to assess competitive swimmers in pools who tend to swim with th eir heads partially immersed in the water and can ingest larger amounts of water. It is anticipated that recreationa l swimmers in weed infested

waters would not immerse their heads as of ten and, therefore, would ingest smaller

amounts of water.

• Average body weight is 70 kilograms for adults and 22 kilograms for a 6-year-old child.

• Permeability coefficient (Kp) of bispyribac-sodium is 2.44 x 10 -6 cm/hr.

Risks were calculated using the MOE approac h, which is a ratio of the body burden to the toxicological point of departur e. The following calculations and equations were used to determine oral exposure as a resu lt of swimming in aquatic areas treated with bispyribac-sodium.

Incidental Ingestion Dose = (Cw x IgR x ET) / BW

Where:Bispyribac-sodium Human-H ealth Risk Assessment DP# 361116

Page 20 of 31 Cw = concentration in water (mg/L), IgR = ingestion rate of water (L/hr), ET = exposure time (hr/day), and BW = body weight (kg).

The total UF that has been applied to the residential postapplicati on risk assessment for bispyribac-sodium is 100. Short-term incidental ingestion risks were greater than 100 for noncompetitive adult and child swimmers and, therefor e, do not exceed HED’s level of concern. A summary of the short-term pos tapplication risks for adults a nd children is provided in Table

5.2.

Table 5.2. Short -Term Postapplication Exposure fo r Adults and Children Sw immers to Bispyribacsodium.

Exposure

Scenario Cw 1
(mg/L) IgR 2
(L/hr) ET 3
(hr/day) BW 4 (kg) Oral Dose 5
(mg/kg/day) Adult MOE 6 Child MOE 7

70 1.61E-04 Oral 0.045 0.05 5 22 5.11E-04 620,000 200,000

1 Cw = concentration in water (45 ppb = 0.045 mg/L). 2 IgR = ingestion rate of water (0.05 L/hr). 3 ET =exposure time (5 hr/day). 4 BW = body weight = 70 kg fo r adults and 22 kg for children. 5 Oral Dose = (Cw x IgR x ET)/BW. 6 Adult MOE = NOAEL (100 mg/kg/ day)/Adult Dose (mg/kg/day). 7 Child MOE = NOAEL (100 mg/kg/day)/Child Dose (mg/kg/day).

5.3 Residential Bystander Inhalation Exposure

Based on the Agency's current practices, a qua ntitative postapplication inhalation bystander exposure assessment was not performed for bispyribac-sodium at this time. However, volatilization of pesticides may be a potential source of pos tapplication inhalation exposure to individuals nearby to pesticide applications. The Agency sought expert advice and input on

issues related to vola tilization of pesticides from it s FIFRA SAP in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/ meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to inco rporate postapplication in halation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may

revisit the need for a quantitative postapplication inhala tion exposure assessment for bispyribacsodium.

5.4 Spray Drift

Spray drift is always a potential source of expos ure to residents nearby to spraying operations. This is particularly the case with aerial appl ication, but, to a lesser ex tent, could also be apotential source of exposure from the ground application method employed for bispyribacsodium. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation a nd other parties to devel op the best spray drift management practices. The Agency is now re quiring interim mitigation measures for aerial applications that must be placed on product la bels/labeling. The Agency has completed its evaluation of the new data base submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is de veloping a policy on how to appr opriately apply the data and the AgDRIFT ® computer model to its risk assessments for pesticides app lied by air, orchard airblastBispyribac-sodium Human-H ealth Risk Assessment DP# 361116

Page 21 of 31 and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift and risks associated with aerial as well as other applic ation types where appropriate.

6.0 Aggregate Risk Assessment s and Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking wate r, and residential exposu res. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard, or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. Since there are residential uses registere d, HED conducted a residential aggr egate assessment for bispyribacsodium.

6.1 Acute Aggregate Risk

An endpoint of concern was not id entified to quantify acu te-dietary risk to the general population or to any population subgroup. Since an acute dietary endpoint was not identified, an acute hazard does not exist and an acute ag gregate assessment was not performed.

6.2 Short-and Intermediate-Term Aggregate Risks

Only a short-term aggregate risk assessment was conducted since the residential use pattern is expected to only result in short- term exposures; however, since th e short- and intermediate-term points of departure are the same, the short- term aggregate assessment is protective of intermediate-term exposures. Short- and inte rmediate-term aggregate risks are made up of dietary and non-dietary sources of exposure. Dietary (food + dri nking water) exposure estimates are based on a conservative, unrefined chroni c dietary exposure assessment (see Table 4.5.2). Non-dietary (residential) exposur e estimates are conservative es timates due to the standard assumptions that were built into the cal culations (see Section 5.0). Based on the proposed/registered bispyribac-sodium uses, HED an ticipates only incidental oral exposures to adults and children. The populations included in Table 6.2 represent th e adult and children populations with the highest dietary (food + drin king water) exposures (t he U.S. population was included as well).

Table 6.2. Short- and Intermediate-Term Aggregate Risk Calculations.

Population Dietary (Food +
Drinking Water) Exposure 1

(mg/kg/day) Residential Exposure 2, 3 (mg/kg/day) Aggregate

MOE 4

U.S. Population 0.003800 0.000161 25,000

Adults 50+ years olds 0.003731 0.000161 26,000

All infants (<1 years old) 0.012453 0.000511 7,700

1 Average d ietary (food + drinking water) exposure for the respective populations from Table 4.5.2.

2 Post-application exposure for adult swimmers (See Table 5.2).

3 Post-application exposure for children swimmers (See Table 5.2).

4 Aggregate MOE = Short-term NOAEL (100 mg/kg/day)/(food + water exposure) + (residential exposure). LOC =

100.Bispyribac-sodium Human-H ealth Risk Assessment DP# 361116

Page 22 of 31 As can be seen in Table 6.2, the short- and in termediate-term aggregate MOEs for the general U.S. population, as well as the population subgroups children and a dults are not of concern to

HED.

6.3 Chronic (Long-Term) Aggregate Risk

Chronic (long-term) aggregate ri sk is made up only of dietary sources; therefore, the chronic exposure estimates provided in the chronic di etary exposure analysis represents chronic

aggregate exposure.

6.4 Cancer Aggregate Risk

Aggregate cancer risk was not calc ulated because bispyribac-sodium was classified as “not likely to be carcinogenic to humans.”

7.0 Cumulative Risk Characterization/Assessment

Unlike other pesticides for which EPA has fo llowed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to bispyribac-sodium and any other substances and spirotetramat does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that bispyrib ac-sodium has a common mechanism of toxicity

with other substances. For in formation regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to eval uate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and proc edures for cumulating effects from substances found to have

a common mechanism on EPA’s website at http://www.epa.gov/pestic ides/cumulative/.

8.0 Occupational Exposure/Risk Pathway

The occupational exposure and risk assessm ent was performed by HED (Memo, K. Lowe, 21- JUL-2010; DP# 363349). It is an ticipated that there will be occupational handler and postapplication exposure from the proposed us es of bispyribac-sodium. Based on label information (a maximum of 4 applications per year ; 30 days apart), exposure is expected to occur

for short- and intermediate-term durations.

8.1 Occupational Handler Exposure/Risk

Application methods, maximum application rate s and use sites for the proposed use of bispyribac-sodium are summarized in Table 2.1. No chemical-speci fic data were available with which to assess potential exposure to pesticide ha ndlers. Where applicable, the estimates of exposure to pesticide handlers are based upon surr ogate study data available in PHED (August, 1998). There are no exposure data in PHED spec ific to application of sprays from a boat, application of sprays from a helicopter, or from the use of water-soluble bags with handheld equipment; therefore, the following surrogate unit exposures from PHED were used:

• The inhalation unit exposure for aerial a pplication (fixed wing) was used for rotary (helicopter) applications.Bispyribac-sodium Human-H ealth Risk Assessment DP# 361116

Page 23 of 31 • The inhalation unit exposure for open-cab groundboom applications was used for boat-mounted boom (surface) and boat -mounted trailing hose (subsurface) applications.

• The inhalation unit exposure for mixing/lo ading/applying liquids with a backpack sprayer was used for mixing/loading/app lication of water-soluble bags with a backpack sprayer.

• The inhalation unit exposures for mixing/loading/applying wettable powders with a handgun and low-pressure handwand spra yer were used for mixing/loading/ application of water-soluble bags with a handgun and low-pressure handwand

sprayer.

NOTE: The product label could be ma de clearer with respect to the application rate. The label indicates the product is packaged in 2-oz bags; ho wever, the application ra tes provided are 1 to 2 oz of formulated product/A for surface weed s and from 0.8 oz to 2.4 oz product/A-ft for subsurface weeds. If a handler must open packag es to obtain fractions of an ounce to mix, the advantage of water-soluble packaging is lost . Therefore, this assessment assumes open mixing/loading of a wettable powder (use d as surrogate for SP formulation).

The following exposure scenarios have been assessed for occupational handlers:

Mixer/Loaders

• Mixing/loading water-soluble bags to support aerial applications,

• Mixing/loading water-soluble bags to support groundboom applications,

Applicators

• Applying sprays with aircraft,

• Applying sprays with groundboom equipment,

Flaggers

• Flagging to support aerial spray applications,

Mixer/Loader/Applicators

• Mixing/loading/applying wetta ble powders with low-pressure handwand equipment,

• Mixing/loading/applying liquids with backpack sprayer, and

• Mixing/loading/applying wettable powders with handgun equipment.

For pesticide handlers, HED presents estimates of dermal exposure for “baseline” (i.e., workers wearing a single layer of work clothing consisting of a long-sleeved shirt, long pants, shoes plus socks, and no protective gloves), as well as fo r “baseline” and the use of protective gloves or other PPE, as might be necessary. The bispyribac-sodium product labels direct applicators and

other handlers must wear a l ong-sleeved shirt and long pants, chemical-resistant gloves, and shoes plus socks.

The daily areas treated were based on informa tion from (1) HED Exposure Science Advisory Committee (ExpoSAC) SOP No. 9.1, (2) a previous endothall assessment for aquatic uses (Memo, S. Tadayon, 12-AUG-2005, DP# 319373), (3) a SRRD memo from a meeting between the Agency and the Army Corp Of Engineers to discuss assumptions used in aquatic risk assessment (SRRD, Mika Hunter, 27-JUL-2005) , and (4) registrant-proposed values.Bispyribac-sodium Human-H ealth Risk Assessment DP# 361116

Page 24 of 31 For surface applications, the area trea ted in a day was assumed to be:

• 150 and 350 acres for mixing/loading to support ae rial applications, applying sprays with aircraft, and flagging to s upport aerial applications,

• 30 acres for mixing/loading to support gr oundboom applications and applying sprays with groundboom equipment, and

• 10 acres for mixing/loading/applying w ith handgun, low-pressure handwand and backpack sprayer.

For subsurface applications, the area treated in a day was assumed to be 30 acres for mixing/loading to support groundboom applicatio ns and applying sprays with groundboom equipment. An eight foot depth wa s assumed for subsurface applications.

Daily inhalation handler exposures are estimate d for each applicable handler task with the application rate, the area treated in a day, and the applicable inhalation unit exposure using the following formula:

Daily Exposure (mg ai/day) = UE (mg ai/lb ai handled) * AR (lbs ai/area) * A (area/day)

Where:

Daily Exposure = amount (mg ai/day) inhaled that is available for inhalation absorption; UE = unit exposure value (mg ai/lb ai); AR = application rate (e.g., lb ai/A); and A = application area (e.g., A/day).

The daily inhalation dose is ca lculated by normalizing the daily exposure by body weight and adjusting, if necessary, with an appropriate inhalation absorption factor using the following

formula:

Average Daily Dose (mg/kg/day) = [Daily Exposure (mg ai/day) * AF (%/100)] / BW (kg)

Where:

Average Daily Dose = absorbed do se received from exposure to a pe sticide in a given scenario (mg ai/kg body weight/day); Daily Exposure = amount (mg ai/day) inhaled that is available for inhalation absorption; AF = absorption factor which is a measure of the amount of chemical that crosses a biological boundary such as the skin or lungs (% of the total available absorbed); and BW = body weight determined to represent the population of interest in a risk assessment (kg).

Non-cancer inhalation risks for each applicable handler scenario are calculated using a MOE, which is a ratio of the NOAEL to the daily dose . All MOE values were calculated using the

formula below:

MOE = NOAEL (mg/kg/day) / Average Daily Dose (mg/kg/day)

Table 8.1 presents the short- a nd intermediate-term estimated i nhalation risks fo r occupational

handlers. The inhalation risks to handlers do not exceed HED’s level of concern at baseline (no respirator) for any of the handler scenarios where baseline data are available. Only engineeringBispyribac-sodium Human-H ealth Risk Assessment DP# 361116

Page 25 of 31 control (enclosed cockpit) data are available to assess inhalation risk s to handlers operating

aircraft. The inhalation risks do not exceed HED’ s level of concern for pilots using enclosed cockpits and wearing no respirator . Even though dermal exposures were not assessed due to lack of a dermal point of departure, handlers shoul d still wear label prescribed PPE (long-sleeved shirt and long pants, chemical-resist ant gloves, and shoes plus socks).Bispyribac-sodiumHuman-Health RiskAssessmentDP# 361116Page 26 of 31Table 8.1. Short- and Intermediate-Term Handler Exposures and Risks for Bispyribac-sodium.Inhalation UnitExposure (ug/lb ai)3Inhalation Dose(mg/kg/day)4Short- andIntermediate-termInhalation MOE5Exposure ScenarioCrop orTargetApplicationRate1ApplicationRate UnitsAreaTreatedDaily(acres)2WaterDepth(feet)BaselineEngineeringControlBaselineEngineeringControlBaselineEngineeringControlMixer/LoaderSurface weeds0.1lb ai/acre350NANA0.240.0220.000124,700830,000Mixing/Loading Water-Soluble Bags for AerialApplicationsSurface weeds0.1lb ai/acre150NANA0.240.00920.00005111,0001,900,000Surface weeds0.1lb ai/acre30NANA0.240.00180.0000154,0009,700,000Mixing/Loading Water-Soluble Bags forGroundboom ApplicationsSubsurfaceweeds0.12lb ai/acre-foot308NA0.240.0180.0000125,7008,100,000ApplicatorSurface weeds0.1lb ai/acre350NANo Data0.068No Data0.000034No Data2,900,000Applying Sprays via AerialEquipmentSurface weeds0.1lb ai/acre150NANo Data0.068No Data0.000015No Data6,900,000Subsurfaceweeds0.1lb ai/acre30NA0.74NA0.000032NA3,200,000NAApplying Sprays viaGroundboom EquipmentSubsurfaceWeeds0.12lb ai/acre-foot3080.74NA0.0003NA330,000NAFlaggerFlagging for Aerial SpraysApplicationsSurface weeds0.1lb ai/acre150NA0.35NA0.000075NA1,300,000NAMixer/Loader/ApplicatorMixing/Loading/ApplyingWettable Powders withLow-Pressure Handwand(PHED)Surface weeds0.1lb ai/acre10NA1,100NoData0.016No Data6,400No DataMixing/Loading/ApplyingLiquids with a Backpack(PHED)Surface weeds0.1lb ai/acre10NA30No Data0.00043No Data230,000No DataMixing/Loading/ApplyingWettable Powders with aHandgun Sprayer(LCO ORETF data)Surface weeds0.1lb ai/acre10NA64No Data0.00091No Data110,000No Data1 Application Rates based on proposeduses on label for bispyribac-sodium TradewindTM Herbicide.2 The daily areas treated were based on information from (1) HEDExpoSAC SOP No. 9.1, (2) a previous endothall assessment for aquatic uses (Memo, S.Tadayon, 12-AUG-2005, DP#319373), (3) a SRRD memo from a meeting between the Agency and theArmy Corp Of Engineers to discuss assumptions used in aquatic risk assessment (SRRD, M. Hunter, 27-JUL-2005),and (4) registrant-proposed values.3 Unit Exposures based on PHED Version 1.1. Baseline: no respirator. Engineering control: water-soluble bags or enclosed cockpit.4 Inhalation Dose (mg/kg/day) = unit exposure (μg/lb ai) * 1E-03 mg/ug * application rate(lb ai/acre) * acres treated * inhalation absorption (100%) / body weight (70 kg).5 Inhalation MOE = NOAEL (100 mg/kg/day)/inhalation daily dose (mg/kg/day). LOC = 100.Bispyribac-sodium Human-Health Risk Assessment DP# 361116

Page 27 of 31 8.2 Occupational Postappl ication Exposure/Risk

Postapplication occupational exposures following bispyribac-sodium applic ation to aquatic areas is likely limited to persons who contact the treated water to perform tests, such as testing the levels of bispyribac-sodium. S hort- and intermediate-term derm al postapplication exposures and risks were not assessed for bispyribac-sodium , since no dermal points of departure were identified. Based on the Agency's current prac tices, a quantitative occupational postapplication inhalation exposure assessment was not performed for bispyribac-sodium at this time. However, there are multiple potential sources of postappl ication inhalation exposure to individuals performing postapplication activitie s in previously treated area s, including vol atilization of pesticides. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational pos tapplication inhalation exposur e assessment for bispyribacsodium.

9.0 Data Needs and Label Recommendations

9.1 Toxicology

• An immunotoxicity study is now a data re quirement in the 40 CFR revised Part 158.

• Acute neurotoxicity study.

• Subchronic neurotoxicity study.

• 28-day inhalation study.

9.2 Residue Chemistry

• The petitioner should submit a revised S ection B proposing a minimum RTI for the subsurface application. Furthermore, a revi sion should be made to the label indicating that the treated water may not be used as a water source for livestock until the concentration of bispyribac-sodium in water is < 1 ppb.

• The petitioner should submit a revised Secti on F which states that “Tolerances are established for residues of the herbicide bispyribac-sodium, including its metabolites and degradates, in or on the commodity listed be low. Compliance with the tolerance level specified below is to be determined by m easuring only bispyribac-sodium, (2,6-bis[(4,6- dimethoxy-2-pyrimidinyl)oxy]benzoic acid, so dium salt), in or on the following raw agricultural commodity:” Fish, freshwater....................................................................0.01 ppm

9.3 Occupational and Residential Exposure

• HED recommends that the product label coul d be made clearer with respect to the application rate. The label indicates the pr oduct is packaged in 2-oz bags; however, the application rates provided are 1 to 2 oz of formulated product/A for surface weeds and from 0.8 oz to 2.4 oz product/A-ft for subsurf ace weeds. If a handler must open packages to obtain fractions of an ounce to mix, the adva ntage of water-soluble packaging is lost.

Attachments Attachment 1a: Acute Toxicity Data for Bispyribac-Sodium Technical. Attachment 1b: Toxicity Profile of Bi spyribac-sodium Technical and Metabolites.

RDI: D. Vogel (14-JUL-2010); G. Kramer (16-AUG-2010) S. Levy: S-10953: PY1: (703)305-0783: 7509P: RAB1 DP#s: 361116, 361118

PC Code: 078906Bispyribac-sodium Human-Health Risk Assessment DP# 361116

Page 28 of 31 Attachment 1a. Acute Toxicity Data for Bispyribac-sodium Technical.

Guideline No./Study Type MRID# Results Toxicity Category

870.1100 Acute Oral - Rat 44889127 LD 50 = 4111 (male), 2365 (female), 3565 (combined) mg/kg III

870.1200 Acute Dermal - Rabbit 44889128 LD 50 > 2000 mg/kg III

870.1300 Acute Inhalation - Rat 44889130 LC 50 > 4.48 mg/L IV 870.2400 Primary Eye Irritation -

Rabbit 44929911

44929912 Moderate irritant (unwashed) Not an irritant (washed) III

IV 870.2500 Primary Skin Irritation

- Rabbit 44929913 Not an irritant IV

870.2600 Dermal Sensitization 44929914 Not a sensitizer NA

Attachment 1b. Toxicity Profile of Bi spyribac-sodium Technical and Metabolites.

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

Classification/Doses Results

870.3100 90-Day oral toxicity rodents (rat) 44929916 (1991) Acceptable/guideline 0, 100, 1000, 10,000, or 20,000

ppm
M : 0, 8.1, 79.7, 790.8, or 1582.5 mg/kg/day F: 0, 7.2, 71.9, 724.0, or 1456.5 mg/kg/day NOAEL = 71.9/79.9 mg/kg/day (M/F). LOAEL = 724.0/790.8 mg/kg/day (M/F), based on decreased body-wt. gain, increased absolute and relative liver weights, increased alkaline phosphatase and gamma -GTP, and increased incidence of grossly dilated bile duct lumen in males, and microscopic lesions in the liver, biliary system and urinary bladder in both sexes.

870.3100 90-Day oral toxicity rodents (mouse) 44929917 (1991) Acceptable/guideline 0, 35, 350, 3500, or 7000 ppm M: 0, 6.8, 68.6, 699.1, or 1478.9 mg/kg/day F: 0, 8.0, 79.0, 806.1, or 1590.5 mg/kg/day NOAEL = 68.6/79.0 mg/kg/day (M/F). LOAEL = 699.1/806.1 mg/kg/day (M/F), based on liver cell swelling and slight liver cell granulation in

females.

870.3150 90-Day oral toxicity in nonrodents (dog) 44889132 (1992) Acceptable/guideline M & F: 0, 30, 100, or 600 mg/kg/day NOAEL = 100 mg/kg/day LOAEL = 600 mg/kg/day (M/F), based on

increased salivation and s light proliferation of intrahepatic bile duct.

870.3200 21/28-Day dermal toxicity (rat) 44889133 (1996) Acceptable/guideline M & F: 0, 10, 100, or 1000 mg/kg/day NOAEL = 1000 mg/kg/day (M/F). LOAEL >1000 mg/kg/day (M/F). No systemic toxicity or dermal irritation noted.

870.3700a Prenatal developmental in rodents (rat) 44929921 (1991) Acceptable/guideline F: 0, 100, 300, or 1000 mg/kg/day Maternal NOAEL = 1000 mg/kg/day LOAEL > = 1000 mg/kg/day Developmental NOAEL = 1000 mg/kg/day LOAEL > 1000 mg/kg/day.

870.3700b Prenatal developmental in nonrodents (rabbit) 44889201 (1992) 44889136 (1990) Acceptable/guideline F: 0, 30, 100, 300, or 500 Range-finding F: 0, 75, 150, 300, or 500 Materna l NOAEL = 100 mg/kg/day. LOAEL = 300 mg/kg/day, based on lethargy, diarrhea, and decreased bod y-weight gain in the range-finding study. Developmenta l NOAEL = 300 mg/kg/day.

LOAEL was not established.Bispyribac-sodium Human-Health Risk Assessment DP# 361116

Page 29 of 31 Guideline No./Study Type MRID No. (year)/

Classification/Doses Results

870.3800 Reproduction and fertility effects (rats) 44929923 (1994) Acceptable/guideline 0, 20, 1,000, or 10,000 ppm M: 0, 1.5, 75.7, or 759.0 mg/kg/day F: 0, 1.72, 86.3, or 874.0 mg/kg/day Parental/Systemic NOAEL = 1.5 mg/kg/day. LOAEL = 75.7 mg/kg/day (M/F), based on trace to mild choledocus (bile duct) hyperplasia. Reproductive NOAEL = 759.0 mg/kg/day LOAEL >759 mg/kg/day. Offspring NOAEL = 75.7 mg/kg/day. LOAEL = 759 mg/kg/day (M/F), based on decreased body weights, body-weight gains, and liver weights, and increased incidence of

consolidation and circumscribed areas in the liver.

870.4300

Combined chronic toxicity/carcinogenicity rodents (rat) 44929924 (1995) Acceptable/guideline M: 0, 20, 200, 3500, or 7000

ppm (0, 1.1, 10.9, 194.5, or 404.5 mg/kg/day, respectively) F: 0, 20, 200, 5000, or 10,000 ppm (0, 1.4, 13.8, 352.2, or 714.9 mg/kg/day, respectively) NOAEL = 10.9 mg/kg/day. LOAEL = 194.5 mg/kg/day (M), based on macroscopic and microscopic changes in the liver and choldedochus and clinical signs. The LOAEL is 714.9 mg/kg/day for females based on reduced body weight, body weight gains, food efficiency, clinical signs and microscopic changes in the liver

and choldedochus.

No evidence of carcinogenicity.

870.4100b Chronic toxicity (dog) 44889134 (1998) Acceptable/guideline M & F: 0, 10, 100, or 750 mg/kg/day NOAEL = 10 mg/kg/day.LOAEL = 100 mg/kg/day (M/F), based on doserelated increase in intrahepatic bile duct hyperplasia and liver granulation in females.

870.4300 Carcinogenicity (mouse) 44929920 (1995) Acceptable/guideline 0, 10, 100, 2,500, or 5,000 ppm M: 0, 1.4, 14.1, 353.0, 728.9 mg/kg/day F: 0, 1.7, 17.4, 447.8, or 902.9 mg/kg/day NOAEL = 14.1/17.4 (M/F) mg/kg/day. LOAEL = 353.0/447.8 mg/kg/day (M/F), based on decreased body-weight gain , and food efficiency, and increased incidence of microscopic lesions in the liver and gall bladder (M).

No evidence of carcinogenicity.

Gene Mutation

870.5100 reverse gene mutation assay in bacteria 44889210 (1990) Acceptable/guideline 0, 333, 667, 1000, 3330, 6670,

or 10000 μ g/plate There was no evidence of induced mutant colonies over background.

Gene Mutation

870.5300

in vitro mammalian cell mutation assay 46076601 (2003) Acceptable/guideline 0, 250, 500, 750, 1000, or 1500 μg/ml without metabolic activation and 0, 250, 500, 600, 750, or 1000 with S-9 mix There was equivocal evid ence of induction of mutant colonies over background at the high

concentration.

Cytogenetics

870.5375

in vitro mammalian cytogenetic assay 44889208 (1990) Acceptable/guideline 0, 250, 500, 750, 1000, 1500, 2000, 3000, or 4000 μ g/ml w/o

S9 0, 500, 1250, 2500, 3750, or

5000-5010 μ g/ml w/ S9 Not clastogenic with or without S9 activation, at any dose tested.

Other Effects

870.5395

in vivo mammalian cytogenetic assay 44889211 (1991) Acceptable/guideline 0, 1250, 2500, or 5000 mg/kg Did not induce micronucleated polychromatic erythrocytes (PCEs) in bone marrow at any dose.Bispyribac-sodium Human-Health Risk Assessment DP# 361116

Page 30 of 31 Guideline No./Study Type MRID No. (year)/

Classification/Doses Results

Other Genotoxic Effects

870.5500 bacterial DNA damage and repair test 44929925 (1997) Acceptable/guideline 0, 50, 150, 500, 1500, or 5000

μ g/ml No zones of inhibition and the differential killing index suggesting potential DNA damage.

Other Genotoxic Effects

870.5550 UDS synthesis in

mammalian cell culture 44889209 (1990) Acceptable/guideline 0, 0.5 to 5000 μ g/ml Did not induce UDS at any dose.

870.7485

Metabolism and pharmacokinetics (rat) 44889216 (1993) 44889213 (1991) 44889214 (1991) 44889215 (1994) Acceptable/guideline M & F: 30 or 600 mg/kg single oral dose, -single gavage dose of 30 mg/kg for 14 days followed by labeled 30 mg/kg, -single IV dose of 30 mg/kg, -in bile duct cannulated, single dose of 10 or 100 mg/kg A series of rat metabolism studies with [ 14 CPy]- bispyribac-sodium and [ 14 C-Bn]-bispyribac-sodium indicated that pretreatment, dose level, sex and position of the radiolabel made little effect on the absorption, distribution, elimination and metabolism. It was readily absorbed by male and female rats following intravenous or oral dosing. The total recovery of the administered radioactivity was 95.8-101.6% for all treatment groups. Most of the dose (>43%) of the administered dose was excreted in feces within 48 hours and essentially complete within 5 days. Less than 2% of the

administered dose rema ined in the carcass and

tissues and <0.1% of the dose was recovered in air.

Parent and 5 metabolites were identified in the

excreta of male and female s following administered [ 14 Cpy]-bispyribac-sodium and parent and 3 metabolites identified with [ 14 C-Bn]-bispyribacsodium administration. The parent compound, bispyribac-sodium, was the major component identified in the feces (3 7-69% of the dose) and urine (5-41%of the dose), in both sexes.

Metabolites identified in the excreta constituted 8.3-

14.6% and unknown metabolites constituted 0.7-

5.2% of the dose.

Non-guideline - mouse

serum bile acids 44929929 (1995) Acceptable/nonguidline 0, or 7000 ppm equivalent to 0 or 1050 mg/kg/day in males Bile acids increased 115% and slight cecal enlargement in 9/10 treated mice.

Non-guideline - mouse reversibility 44929930 (1994) Unacceptable/guideline 0, 100, or 5000 ppm M: 0, 15.3, or 854.1 mg/kg/day F: 0, 19.6, or 1025.9 mg/kg/day Bispyribac-sodium was a ssociated with liver lesions, bile duct hyperplasia and dilated gall bladders in subchronic and oncogenicity studies were not replicated in this reversibility study.

Non-guideline - rat

serum bile acids 44979001 (1995) Acceptable/nonguideline 0, or 20,000 ppm equivalent to 0, or 1792 mg/kg/day in males Total bile acids increased 1072% (12X). The concentration of glycocholic acid, taurocholic acid, deoxycholic acid increased 2127%, 2991% and 138%, respectively, where as chenodeoxy cholic

acid levels were similar to controls. Hyodeoxycholic acid was reduced from 34.0% to

3.3 of the total bile acids. Treatment altered the degree of conjugation; hyodeoxycholic acid increased 84% and deoxycholic acid increased

1133%.Bispyribac-sodium Human-Health Risk Assessment DP# 361116

Page 31 of 31 Guideline No./Study Type MRID No. (year)/

Classification/Doses Results

Non-guideline - rat reversibility 44979002 (1994) Acceptable/nonguideline M: 0, 200, or 7000 ppm (0, 12.3, or 446.8 mg/kg/day) F: 0, 200, or 10000 ppm (0, 13.8, or 724.2 mg/kg/day) Bispyribac-sodium was a ssociated with urinary bladder epithelial hyperplasia in subchronic study and bile duct hyperplasia, en larged bile ducts, and liver cell hypertrophy and fibrosis in chronic study. Upon removal of bispyribac-sodium from the diet, complete recovery in liver enzymes, food consumption, food efficiency, body weights were observed. Muscular hypertrophy of choledocus was still evident. The study did not duplicate urinary bladder lesions noted in the subchronic study.

Metabolites

Gene Mutation

870.5100 reverse gene mutation assay in bacteria 44889203 (1991) Acceptable/guideline 0, 66.7, 100, 333, 667, 1000, 3330, or 6670 μg/plate DesMe-2023 did not induce mutant colonies over background.

Gene Mutation

870.5100 reverse gene mutation assay in bacteria 44889204 (1995) Acceptable/guideline 0, 50, 158, 500, 1580, or 5000 μg/plate 2,4-dihydroxy-6-methoxy pyrimidine did not induce mutant colonies over background.

Gene Mutation

870.5100 reverse gene mutation assay in bacteria 44889205 (1995) Acceptable/guideline 0, 50, 158, 500, 1580, or 5000 μg/plate KIH-2023-M-8-Na did not induce mutant colonies over background.

Gene Mutation

870.5100 reverse gene mutation assay in bacteria 44889206 (1995) Acceptable/guideline 0, 50, 158, 500, 1580, or 5000 μg/plate KIH-2023-M-9-Na did not induce mutant colonies over background.

Gene Mutation

870.5100 reverse gene mutation assay in bacteria 44889207 (1991) Acceptable/guideline 0, 100, 333, 667, 1000, 3330, 6670, or 10,000 μg/plate BIX-180 did not induce mutant colonies over background.

Gene Mutation

870.5100 reverse gene mutation assay in bacteria 44889212 (1991) Acceptable/guideline 0, 100, 333, 667, 1000, 3330, or 5000 μg/plate Me 2 BA did not induce mutant colonies over background.

Gene Mutation

870.5100 reverse gene mutation assay in bacteria 44929926 (1992) Acceptable/guideline 0, 8, 40, 200, 312.5, 625, 1000, 1250, 2500, or 5000 μg/plate KIH-2023-I-1 did not induce mutant colonies over background.

Gene Mutation

870.5100 reverse gene mutation assay in bacteria 44929927 (1995) Acceptable/guideline 0, 50, 150, 500, 1500, or 5000 μg/plate KIH-2023-I-2 did not induce mutant colonies over background.

Gene Mutation

870.5100 reverse gene mutation assay in bacteria 44929928 (1995) Acceptable/guideline 0, 50, 150, 500, 1500, or 5000 μg/plate KIH-2023-I-4 did not induce mutant colonies over background.