Page 1 of 21 **UNITED STA TES ENVIRONMENTA**  **L PROTECTION A GENCY**  WA SHINGTON, D.C. 20460

**OFFICE OF CHEMICAL SAFETY AND**  **POLLUTION PREVENTION MEMORANDUM**  **Date:** 04 - JUN - 2014 **SUBJECT: Bispyribac**  **- sodium**  **.** Human - Health Assessment Scoping Document in Support

of Registration Review. **PC Code:** 078906 **DP Barcode:** D417912 **Decision No.:** 487556 **Registration No.:** N/A **Petition No.:** N/A **Regulatory Action:** Registration Review Scoping Document **Risk Assessment Type:**  N/A **Case No.:** 7258 **TXR No.:** N/A **CAS No.:** 125401 - 92 - 5 **MRID No.:** N/A **40 CFR:** §180.577 **FROM:** Kelly

M. Lowe, Environmental Scientist Anwar Y. Dunbar, Ph.D., Pharmacologist Sarah J. L ev y, Chemist Risk Assessment Branch 1 (RAB1) Health Effects Division (HED, 7509P) **THROUGH:** Charles W. Smith III , Branch Chief

George F. Kramer, Ph.D., Senior Chemist RAB1/HED (7509P) **TO:** Moana R. Appleyard

Pesticide Re - Evaluation Division (PRD) (7508P) Attached is HED ’s human - health risk assessment scoping document for bispy ribac - sodium to support R egistration R eview.Bispyribac - sodium Registration Review Human - Health Assessment Scoping Document

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Page 2 of 21 **Table of Contents**  Executive Summary ................................ ................................ ................................ ........................ 3 1.0 Introduction ................................ ................................ ................................ .............................. 4 2.0 Hazard Characterization/Assessment ................................ ................................ ....................... 5 3.0 Residue Chemistry ................................ ................................ ................................ ................... 6 4.0 Dietary

Exposure ................................ ................................ ................................ ..................... 8 5.0 Residential Exposure ................................ ................................ ................................ ............... 9 6.0 Aggregate - Risk Assessment ................................ ................................ ................................ .. 10 7.0 Occupational Exposure ................................ ................................ ................................ .......... 10 8.0 Public Health and Pesticide Epidemiology Data ................................ ................................ ... 11 9.0 Tolerance Assessment and International Harmonization ................................ ...................... 11 10.0 Environmental Justice ................................ ................................ ................................ .......... 11 11.0 Cumulative ................................ ................................ ................................ ........................... 12 12.0 Human Studies ................................ ................................ ................................ ..................... 12 13.0 Ri sk Assessment Updates, Data Deficiencies, and Label Revisions ................................ ... 12 14.0 References ................................ ................................ ................................ ............................ 13 Attachment 1: Chemical I dentity Table. ................................ ................................ ...................... 14 Attachment 2: Bisp yribac - sodium Acute, Subchronic, and Chronic Toxicity Profile ................ 15 Attachment 3: Bisp yribac - sodium Endpoint Selection Tables (from 2010 Risk Assessment). .. 19 Attachment 4: Summary of Registered Uses ................................ ................................ ............... 20 Attachment 5: Bisp yribac - sodium International Residue L imit Status Sheet. ............................ 21Bispyribac - sodium Registration Review Human - Health Assessment Scoping Document

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Page 3 of 21 **Executive Summary** HED has prepared a scoping document to support Registration Review of bispy ribac - sodium (sodium, 2,6 - bis[(4,6 - dimethoxy- py rimidin - 2 - yl )oxy]benzoate) . B ispy ribac - sodium is a postemergence contact herbicide belonging to the py rimidinyl oxy

benzoic acid group. Its mode of action is through inhibition of acetolactate sy nthase (ALS) and the bios ynthesis of three branched amino acids: valine, leucine, and isoleucine. This inh ibition interferes with cell division and causes cessation of plant growth. Plant chlorosis, necrosis, and death of sensitive plants follows. Herbicidal selectivity is determined by absorption and translocation and differential metabolism. In sensitive plants, bispy ribac - sodium is a

b sorbed through the leaf surface and translocated throughout the plant. Bispy ribac - sodium is formulated as dry flowables (DF) and wettable powders in water - soluble bags (WSB) , and is currently registered for use on rice , go lf courses , sod farms , and aquatic areas . There are currently four registered Section 3 labels for bispy ribac - sodium, as well as six active Speci al Local Needs (SL N) r egistration s for specific uses on golf courses and sod farms . The most recent quantitat ive human - health risk assessment was performed in 20 10 , and was for the aquatic use of bispy

ribac - sodium ( Memo, S. Levy et al. , 1 8 - AUG - 20 10 ; D 311161 ). There is currentl y one pending PRIA action for bispy ribac - sodium for a new use on turf, including athlet ic fields, commercial and residential turf . HED has evaluated the status of the human - health assessments for bispy ribac - sodium to determine whether sufficient data are available and whether any updates are needed to support Registration Review. HED has considered all available data and human - health risk assessments for bispy ribac - sodium with respect to its toxicity , exposure, and usage databases, and the most updated Agency

science policy

and risk assessment methodologies to determine the scope of work necessary

to support Registration Review. The toxicity database for bispy ribac - sodium is adequate for risk assessment as specified b y the 2007 revised 40 CFR Toxicology Data Requirements. HED’s Hazard and Science Policy Council ( HASPOC ) has determined that an i mmunotoxicity study , the n eurotoxicity s creening b atteries, and a s ubchronic i nhalation toxicity study are all not required for bispy ribac - sodium at this time. During R egistration R eview, the endpoints, doses, and safety factors u sed in the most recent human - health risk assessments will be evaluated based on current HED policy . The residue chemistry

database is adequate to support current Registration Review requirements. Adequate metabolism (crops, livestock, and rotational c rops), storage stability , magnitude of the residue, and processing data are available to support the registered uses. Adequate methods are available for enforcement of the currently established tolerances. It was noted during review that a dditional resid

ue chemistry

data (ruminant and poultry feeding studies) were waived based on the aquatic use label (TradewindTM ) being revised to indicate that treated water may not be used as a water source for livestock until the concentration of bispy ribac - sodium in water is ≤1 ppb. This restriction has not been put on the TradewindTM label and will need to be addressed during Registration Review. The dietary - exposure database is adequate to support current registration requirements. The most recent risk assessment provided an unrefined chronic dietary (food + drinking water) exposure estimates that are below HED’s level of concern (LOC) for the general U.S. population and all population subgroups (Memo, S. L ev y, 07 - JUL - 2010; D363348). Chronic dietary (food +drinking water) risk estimates were not of concern to HED [<100% chronic population - adjustedBispyribac - sodium Registration Review Human - Health Assessment Scoping Document

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Page 4 of 21 dose (cPAD); all infants <1 year old were the most highly exposed population (12% cPAD) ] . As part of Registration Review, a revised dietary - exposure ana ly sis will be required to reflect the most recent dietary - exposure models, revised estimated drinking water concentrations (EDWCs) (including the revised aquatic use EDWC), and/or changes to the toxicological point s of departure (PODs) . There is sufficient information available to assess occupational and residential exposure and risk from the registered uses. No quantitative residential assessment is necessary for the golf course use since there is no dermal POD and post - application inha lation exposure is considered negligible. A post - application assessment for incidental ingestion of treated water was conducted for bispy

ribac - sodium; however, this assessment will need to be updated during Registration Review based on revised inputs and assumptions , and a residential handler assessment will also need to be completed . It appears that the previous occupational assessments cover most of the occupational handler scenarios anticipated for all registered uses b ased on a review of the registere d labels for bispy ribac - sodium , except for (1) aerial applications to golf courses and sod farms allowed for several SL N registrations and (2) aerial applications to rice (mixer/loader assessed, but not applicator). Updated assessments will be necessary d uring Registration Review to reflect these exposure scenarios, as well as updated policies and exposure data for all scenarios . Since there is no dermal POD chosen for bispy ribac - sodium, a quantitative occupational post - application assessment is not neces sary . Updated occupational and residential assessments for all uses may be necessary if toxicological POD s are revised. No data deficiencies were identified for bisp yribac - sodium. EPA notes the following label revisions and risk assessment updates will need to be completed during Registration Review: o Toxicology : Reevaluate toxicity endpoint/dose selection, along with the Food Quality Protection Act (FQPA) Safety Factor s (SF s ) based on current HED policy . o Residue Chemistry

/Dietary Exposure: o A dditi onal residue chemistry data (ruminant and poultry feeding studies) were waived based on the aquatic use label (TradewindTM ) being revised to indicate that treated water may

not be used as a water source for livestock until the concentration of bispy

ribac - so dium in water is ≤1 ppb . This restriction has not been put on the TradewindTM label and should be addressed during Registration Review. o A revised dietary - exposure anal ys is will be required to reflect the most recent dietary - exposure models, revised EDWCs ( including the revised aquatic use EDWC), and/or changes to the toxicological PODs. o Occupational/Residential Exposure: o Revised residential post - application assessment for the registered aquatic use will be necessary

to reflect revised inputs and assumptions , and a residential handler assessment will also need to be completed . o Revised occupational handler inhalation assessments will be necessary to reflect all potential exposure scenarios, as well as updated policies and exposure data. o A ssessments for all uses may be updated if toxicological PODs are revised. **1.0 Introduction**  Bispy ribac - sodium is a herbicide whose mode of action is the inhibition of the plant enzy me AL S . It is formulated as DFs and WSBs, and is currentl y registered for use on rice, golf courses, sod farms, and aquatic areas. There are currentl y four registered Section 3 labels for bisp yribac sodium, as well as six active SL N r egistrations for specific uses on golf courses and sod farms.Bispyribac - sodium Registration Review Human - Health Assessment Scoping Document

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Page 5 of 21 The most recent quantitative human - heal th risk assessment was performed in 2010 and was for the aquatic use of bispy

ribac - sodium ( Memo, S. Levy et al. , 18 - AUG - 2010; D311161 ). There is currentl y one pending PRIA action for bispy ribac - sodium for a new use on turf, including athletic fields, comm ercial and residential turf. **2.0 Hazard Characterization/Assessment** In the rat metabolism study for bispy ribac - sodium , pretreatment, dose level, sex, and position of radiolabel had little effect on the absorption, distribution, elimination, and metabolism. It was readil y absorbed b y male and female rats following intravenous or oral dosing. Most of the administered dose (>43%) was excreted in feces within 48 hours , and elimination was essentiall y complete within 5 days. Less than 2% of th e administered dose remained in the carcass and tissues and <0.1% of the dose was recovered in air. The parent and five metabolites were identified in the excreta of male and females following administration of [ 14 C - Py] - bispy ribac sodium, whereas the pare nt and three metabolites were identified following administration of [ 14 C - Bn] - bispy

ribac - sodium. The acute toxicity

battery of tests shows that bispy ribac - sodium has a low acute toxicity profile (Categories III & IV) and is not a dermal sensitizer. The l iver and bile duct were identified as the target organs in the subchronic and chronic toxicity studies in rats, mice, and dogs , and in the reproduction toxicity

study in rats. Males appear to be slightly more sensitive than females. Bispy ribac - sodium was negative for fetal toxicity and showed no evidence of offspring susceptibility

in both the developmental studies in rats and rabbits and in the reproduction study . Repeated dermal applications at the limit dose did not elicit sy stemic toxicity or dermal irritation. 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 data gap. Sin ce then, the corresponding study (MRID# 46076601) has been submitted and reviewed by the A gency . The results of the study were deemed equivocal due to the lack of a concentration - related response in the induction of mutant colonies over background at the high concentrations. Thus, there is no evidence that bispy ribac - sodium is mutagenic. Bispy ribac - sodium is negative for carcinogenicity in feeding studies in rats and mice and was classified as a “not likely human carcinogen” b y HED’s Hazard Identificatio n Assessment Review Committee [(HIARC); Memo, G. Reddy , 02 - AUG - 2001; HED Doc. No. 014647). In the last risk assessment, four toxicity data gaps were identified : (1) an i mmunotoxicity study , (2) an a cute n eurotoxicity study , (3) a s ubchronic n eurotoxici ty study , and (4) a s ubchronic i nhalation t oxicity

study . Using a weight - of - evidence approach for each of the four studies, HED’s Hazard and Science Policy Council (HASPOC) concluded that none were required at this time at this time [ TXR #’s 005 6389 (08 - FEB - 2013) and 0056840 (26 - NOV - 2013)] . Conclusions: The toxicity database for bisp yribac - sodium is adequate for risk assessment as specified by

the 2007 revised 40 CFR Toxicology Data Requirements. HED ’s HASPOC has determined that an i mmunotoxicity study , the n eurotoxicity s creening b atteries, and a s ubchronic i nhalation toxicity

study are all not required for bispy ribac - sodium at this time. During R egistration R eview, the endpoints, doses, and safety factors used in the most recent human health ri sk assessments will be evaluated based on current HED policy .Bispyribac - sodium Registration Review Human - Health Assessment Scoping Document

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Page 6 of 21 **3.0 Residue Chemistry**  Permanent tolerances are established for residues of bispy ribac - sodium, including its metabolites and degradates in/on freshwater fish at 0.01 ppm, and rice grain and straw at 0.02 ppm (40 CFR §180.577). There are currently no tolerances established for bispy ribac - sodium in/on livestock commodities or for indirect/inadvertent residues in rotational crops. The nature of the residue in rice and livestock is adequatel y understood based on the available rice, ruminant, and poultry metabolism studies. Adequate plant metabolism studies are available depicting the metabolism of [ 14 C]bispy ribac - sodium in rice. Based on these studies, HED prev iously

determined that the parent compound is the only residue of concern for purposes of both risk assessment and the tolerance expression in rice. Adequate ruminant and poultry metabolism studies are available depicting the metabolism of [ 14 C]bispy ribac - sodium; separate ruminant studies were conducted with bispy ribac - sodium labeled in the benzene ring or in both py rimidine rings, and the poultry study was conducted with bispy ribac - sodium labeled in both py rimidine rings. Based on these studies, HED prev iously determined that the parent compound is the only

residue of concern for purposes of both risk assessment and the tolerance expression in livestock commodities. When HED evaluated the use of bisp yribac - sodium on rice, it was noted that if additiona l uses were requested in the future which significantl y i ncrease d the poultry dietary burden, then a poultry metabolism study with benzene - labeled bispy ribac - sodium may

be required. In the HED risk assessment for the use in aquatic areas, it was noted that this use resulted in significantl y increased dietary

burdens to livestock and that HED c ould no longer conclude that there is no expectation of finite residues of bispy ribac - sodium in livestock commodities. This conclusion required the submission of additional data (ruminant and poultry feeding studies ) to support the proposed use. However, the Registrant requested a waiver for these studies ; the basis of which was that quantifiable residues would not be expected at the 1X dietary burden and that there was a low likelihood of livestock consuming treated water at the maximum labeled concentration. HED’s ChemSAC recommended granting the waiver , provided the aquatic use label ( TradewindTM ) wa s revised to indicate that the treated water may not be used as a water source for livestock until the concentration of bispy ribac - sodium in water is ≤1 ppb (minutes of HED’s ChemSAC meeting held 16 - JUN - 2010). This restriction has not been put on the TradewindTM label and should be addressed during Registration Review . For the aquatic use, HED concluded that a fish metabolism study would not be required, as long as samples from the submitted fish residue study were anal yz ed for bisp yri bac - sodium and its metabolite des - methyl KIH - 2023, a major residue in the anaerobic aqu atic metabolism study (minutes of HED’s Science Advisory Council for Chemistry

(ChemSAC) meeting held 30 - MAY - 2007). The fish residue study did anal yz e for these residues , and the available data demonstrate d that bispy

ribac - sodium residues in water remaine d consistent throughout the study period, and residues of bispy ribac - sodium and des - methyl KIH - 2023 were nonquantifiable in fish tissue over the 28 - day exposure period. Magnitude of the residue studies are normally also required in mollusks (oy sters and c lams), shrimp, crayfish and /or other crustaceans for the rice and aquatic use s , however, a waiver for these data was previousl y submitted and HED recommended in favor of the requested waivers (minutes of HED’s ChemSAC meeting held 30 - MAY - 2007). For the rice use, an irrigated crop study was previously submitted that also satisfied the requirement for the aquatic use . After review, HED concluded that the irrigated crop studyBispyribac - sodium Registration Review Human - Health Assessment Scoping Document

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Page 7 of 21 indicate d that there is a possibility of detectable residues of bispy ribac - sodium in crops irrigated with water from treated aquatic areas or drained from treated rice fields . However , tolerances for residues in/on irrigated crops were not established because the rice label includes a restriction against the use of water from treated fields for irrigation purposes (Memo, J. Tyler, 23 - AUG 2001; DP#: 267306) and the aquatic label includes a restriction against the use of treated wat er for purposes of irrigation unless the concentration is less than 1 ppb . A high - performance liquid chromatography (HPLC) method with tandem mass spectroscopy detection (MS/MS), Method GPL - MTH - 068 was previously submitted for bispy

ribac - sodium . The method determines residues of bispy ribac - sodium and des - methyl KIH - 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 analy te in fish tissue and 0.001 ppm for each anal yt e in tank water. An acceptable independent laboratory v alidation (ILV) study

was conducted. This method is adequate for use as a data - collection method. A slightly - revised version of the data - collection method, GPL - MTH - 068a , has also been submitted which demonstrate s an additional cleanup step as an option f or the confirmation technique and an addition of alternate analy tical conditions for L C - MS/MS analysis which can serve as an enforcement method. Bispy ribac - sodium is not likely to be recovered through the U.S. Food and Drug Administration (FDA) MRM protoc ols. An adequate gas chromatography (GC) method RM - 35R - 2 for the enforcement of tolerances on rice grain and straw is available for bispy ribac - sodium . The reported method limit of detection (LOD) and LOQ for residues of bispy ribac - sodium are 0.01 ppm and 0.02 ppm, respectivel y, in/on rice grain and straw. Adequate radiovalidation and ILV data have been submitted for this method. The GC method RM - 35R - 2 was also forwarded to the Anal yt ical Chemistry Branch (ACB) of the Biological Economic Anal ys is Divis ion (BEAD) for a petition method validation ( PMV ) (Memo, J. Tyler, 05 - MAR - 2001; D272600). BEAD stated that this method was an acceptable enforcement method (Memo, J. Tyler, 08 - JUN - 2005; D317734). The method includes procedures for confirmation of residue s (anal ys is using a different GC column, and/or anal ys is by

GC with mass - selective detection). HED concludes that the requirements for a plant enforcement method have been fulfilled for the purpose of permanent tolerances for residues of bispy ribac - sodium per se in/on rice commodities. Rice commodity

samples collected from the field trials and processing studies and beet tops and roots, bok choy , and tomato from the irrigated crop trials were anal yz ed for residues of bispy ribac - sodium using GC method RM - 3 5R - 3. Method RM - 35R - 3 is the same as the proposed enforcement method (RM - 35R - 2), except that diazomethane was substituted for TMS diazomethane as the methylating agent. The concurrent method recoveries indicate that the GC method is adequate for data col lection. Adequate field trial data are available to support the use of bisp yribac - sodium on rice. An adequate number of trials were conducted in the appropriate geographical regions using the appropriate formulation applied at the maximum use rate. Thes e studies are also supported by adequate storage stability data and processing data. The submitted data indicate that residues of bispy ribac - sodium do not concentrate in polished grain, rice hulls, or bran. Conclusions : The residue chemistry database is adequate to support current Registration Review data requirements. Adequate metabolism (crops, livestock, and rotational crops), storage stability , magnitude of the residue, and processing data are available to support the registered uses. Adequate me thods are available for enforcement of the currently established tolerances. ItBispyribac - sodium Registration Review Human - Health Assessment Scoping Document

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Page 8 of 21 was noted during review that additional residue chemistry data (ruminant and poultry feeding studies) were waived based on the aquatic use label (TradewindTM ) being revised to indicate that treated water may

not be used as a water source for livestock until the concentration of bispy ribac - sodium in water is ≤1 ppb. This restriction has not been put on the TradewindTM label and will need to be addressed during Registration Review . **4.0 Dietary Exposure**  No toxic effects attributable to a single exposure to bispy ribac - sodium have been identified; therefore, an acute reference dose (aRfD) was not established for bisp yribac - sodium, and an acute dietary - exposure assessment was not required. HED had conducted a chronic dietary exposure anal ys is, which considered all currently registered uses ( Memo, S. L ev y, 07 - JUL - 2010; D363348 ). The anal ys is was conducted using the Dietary Exposure Evaluation Model

– Fo od Consumption Intake Database (DEEM - FCID, ver. 2.03), which incorporates the food consumption data from the United States Department of Agriculture (USDA) Continuing Survey s of Food Intakes by Individuals (CSFII; 1994 - 1996 and 1998) and assumed tolerance level residues and 100% crop treated. Dietary risk estimates were determined considering exposures from food plus drinking water using EDWCs for surface water sources provided in a 2009 memo from the Environmental Fate and Effects Division (EFED; Memo, C. Sutton, 27 - OCT - 2009; D362285). In this 2009 document, the maximum proposed application rate for subsurface aquatic applications was based on the proposed label which indicated a maximum target concentration in the water column of 45 ppb, with a maximum cumulative concentration of 180 ppb per ye ar in a single treatment area. Thus, the annual use rate was assumed to be four applications at the single rate to produc e a concentration of 45 ppb, for a total annual application of 180 ppb. In 2010, EFED prov ided a revised memo based on an amended proposed aquatic use label. The amended label indicated that the total annual application rate was still 180 ppb, but that applications at any point in time must not exceed 45 ppb. Therefore, EFED revised its recommendation to a maximum annual target rate of 45 ppb for subsurface applications as the recommended maximum EDWC. In the 2010 HED risk assessment, the EDWC was based on the aquatic area use, using the more conservative value of 180 ppb. The water residue value of 180 ppb was incorporated in the DEEM - FCID into the food categories “water, indirect, all sources,” and “water, direct, all sources.” In the 2010 assessment, the resulting chronic exposure estimates were not of concern to HED [ 3.8% of chronic popu lation - adjusted dose ( cPAD) ] . The most highly exposed population subgroup was all infants (<1 ye ar old) utilizing 12% of the cPAD. For future dietary exposure assessments, if applicable, HED will use the revised EDWC of 45 ppb which reflects the amended label. In a meeting on 31 - JUL - 2001, the HED Metabolite Assessment Review Committee (MARC) concluded that the residue of concern in drinking water is bispy ribac - sodium (Memo, J. Tyler, 20 - AUG - 2001; D276560). All metabolites identified were present at lo w levels, and are not expected to be more toxic than the parent. Conclusions: The dietary- exposure database is adequate to support current registration requirements. In the most recent risk assessment, chronic dietary exposures were not of concern to HED. However, as part of Registration Review, a revised dietary - exposure anal ys is will be required to reflect the most recent dietary- exposure models, revised EDWCs (including the revised aquatic use EDWC), and/or changes to the toxicological PODs.Bispyribac - sodium Registration Review Human - Health Assessment Scoping Document

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Page 9 of 21 **5.0 Residential Exposure**  Bispy ribac - sodium is currently registered for use on golf c ourse turf and in aquatic areas . Registered formulations include DFs and WSBs . Attachment 4 includes a summary of the use sites for bispy

ribac - sodium , including those related to residential areas. Previous occupational and residential exposure (ORE) assessments have been conducted for the golf course (D 349324 , M. Dow, 27 - MAR - 2008; D289929, M. Dow, 09 - OCT - 2003) and aquatic area (D363349, K. Lowe, 21 - JU L - 2010) uses. Since there are no dermal PODs for bispy ribac - sodium , only

inhalation and incidental oral exposures/risk estimates were assessed previously. A quantitative residential assessment for the use on golf course s has not been conducted because there are no dermal PODs and post application inhalation exposure is expected to be negligible. In addition, incidental oral post application exposure is not expected from the golf course use. For the aquatic use, only pos t application incidental ingestion of water was assessed for both adults and children . The proposed label that was reviewed for the use indicated that bispy ribac - sodium may

onl y be applied to water b y Federal or State agencies, U.S. Army Corps of Engineer s, and licensed applicators authorized b y Federal or State agencies ; therefore, a residential handler assessment was not conducted . No post - application risk estimates of concern were identified. For Registration Review, it is anticipated that the post - application exposure assessment for the aquatic use will need to be updated to reflect current exposure assumptions and data for aquatic assessments . The current aquatic use product label does not indicate that bispy ribac - sodium can only be applied by

li censed applicators; therefore, a residential handler assessment will need to be completed . Spray Drift/By stander Exposure Residential exposures resulting from off - site transport (e.g., spray drift or volatilization) may occur as a result of applications of bispy ribac - sodium . The Agency is in the process of evaluating these types of exposures and may, as appropriate, develop policies and procedures to identify the need for and, subsequently , the way to incorporate these post - application exposures into th e Agency's risk assessments. The need for spray drift and volatilization risk assessment for bispy ribac - sodium will be examined during registration review . Conclusions : The residential exposure database is adequate to support the Registration Review process for bispy

ribac - sodium . Since there is no dermal POD and post - application inhalation exposure is considered negligible, no quantitative residential assessment is neces sary for the golf course use. A post - application assessment for incidental ingestion of treated water was conducted for bispy

ribac - sodium ; however, this assessment will need to be updated during Registration Review based on revised inputs and assumptions , and a residential handler assessment will also need to be completed . New assessments may also be necessary

if toxicological PODs change during Registration Review.Bispyribac - sodium Registration Review Human - Health Assessment Scoping Document

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Page 10 of 21 **6.0 Aggregate**  **- Risk Assessment**  The most recent aggregate - risk assessment was performed i n conjunction with the 20 10 HED human - health risk assessment ( Memo, S. L ev y et al. , 18 - AUG - 2010; D311161 ). Since an acute dietary endpoint was not identified, an acute aggregate assessment was not performed. A short term aggregate assessment was conducte d, and since the short - and intermediate - term PODs are the same, the short - term aggregate assessment is protective of intermediate - term exposures. The s hort - and intermediate - term aggregate risks were made up of dietary and non - dietary (residential aquatic use) sources of exposure , and were not of concern to HED. Chronic (long - term) aggregate risk is made up only of dietary

sources; therefore, the chronic dietary - exposure estimates represents chronic aggregate exposure , and were not of concern to HED . Aggregate cancer risk was not calculated because bisp yribac - sodium was classified as “not likely to be carcinogenic to humans.” Conclusions: A new aggregate risk assessment will be required during Registration Review to incorporate revis ed dietary - exposure anal ys es and/or revised residential exposure assessments . **7 .0**  **Occupational Exposure** Occupational handler and post - application exposures are expected b ased on the registered agricultural and commercial uses of bispy ribac - sodium . Attachment 4 provides a summary of the occupational use pattern. The current registrations include some SL N registrations. Current formulations include DFs and WSBs . The application rates range from 0.0 34

– 0. 133 lb ai/A, and applications can be made us ing aerial, groundboom or handheld equipment depending on the use site . Occupational Handlers There is the potential for dermal and inhalation exposure to occupational handlers from the currentl y registered use pattern of bispy ribac - sodium . Previous ORE assessments have been conducted for the rice ( D276686 , M. Dow, 24 - AUG - 2001), golf course (D349324, M. Dow, 27 - MAR - 2008; D289929, M. Dow, 09 - OCT - 2003) and aquatic - area (D363349, K. L owe, 21 - JUL 2010) uses. The assessment s w ere based on exposure data from the Pesticide Handlers Exposure Database (PHED) , assumptions for area treated from the Science Advisory Council for Exposure (ExpoSAC) Policy

#9 , and maxi mum application rates. Handler's exposure and risk were calculated at baseline (long pants, a long - sl eeved shirt, no chemical - resistant gloves, and no respirator) and with personal - protective equipment (PPE) when necessary (e.g., chemical resistant gloves, respirators, and engineering controls). Quantitative dermal risk estimates were not calculated sinc e there is no dermal POD for bispy ribac - sodium; and i nhalation risk estimates were not of concern (i.e., MOEs ≥ 100) for all registered uses .Bispyribac - sodium Registration Review Human - Health Assessment Scoping Document

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Page 11 of 21 Based on a review of the registered labels for bispy ribac - sodium , it appears that the previous assessment s cove r most of the occupational handler scenarios antic ipated for all registered uses , except for (1) aerial applications to golf courses and sod farms allowed on several SLN label s and (2) aerial applications to rice (mixer/loader assessed, but not applicator) . In addition, since the previous reviews, there have been several updates to HED ’s exposure policies, including u pdated exposure data for oc cupational handler assessments and u pdates to body - weight assumptions. These assessments will need to be revised during Registration Review to reflect current Agency

policy and data. Updated assessments may also be necessary if toxicological PODs change. Occupational Post - Application There may

be the potential for post - application dermal exposure to workers following applications of bispy

ribac - sodium to agricultural crops and commercial use sites ; however, there is no dermal POD for bispy ribac - sodium , therefore a quantitative dermal po st - application exposure assessment was not performed . Conclusions: The occupational exposure database is adequate to support the Registration Review process for bispyribac - sodium . Based on a review of the registered labels for bispy ribac - sodium, it ap pears that the previous assessments cover most of the occupational handler scenarios anticipated for all registered uses, except for (1) aerial applications to golf courses and s od farms allowed on several SLN label s and (2) aerial applications to rice (mi xer/loader assessed, but not applicator). Updated assessments will be necessary during Registration Review to reflect these exposure scenarios, as well as updated policies and exposure data . Updated assessments may also be necessary

if toxicological PODs change. **8.0 Public Health and Pesticide Epidemiology Data**  The Agency

has reviewed the available incident data for bispy ribac - sodium (Memo, S. Recore and E. Evans, D XXXXXX , XX - JAN - 201 4 ) and concludes that since there were no incidents involving bispy

ribac - sodium reported to either ID S or SENSOR - Pesticides , there does not appear to be a concern at this time that would warrant further investigation. The Agency will continue to monitor the incident information and if a concern is triggered, additio nal analy sis will be included in the risk assessment. **9 .0**  **Tolerance Assessment and International Harmonization** U.S. permanent tolerances (listed in 40 CFR 180. 577 ) are summarized in Attachment 5. There are no Codex or Mexican maximum residue limits (MRLs ) in/on the registered crops. **10 .0**  **Environmental Justice** Potential areas of environmental justice concerns, to the extent possible, were considered in the most recent bispy

ribac - sodium human - health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Low - Income Populations 1

. ” The OPP ty pically considers the highest potential exposures from the legal use of a pesticide when conducting human - health risk assessment s, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability

1 http://www.epa.gov/compliance/environmentaljustice/resources/policy/exec_order_12898.pdfBispyribac - sodium Registration Review Human - Health Assessment Scoping Document

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Page 12 of 21 of diets within the U.S., and people who may be exposed when harvesting crops. Should these highest exposures indicate potential risks of concern, OPP further refines the risk assessments to ensure that the risk estimates are based on the best available information. **11.0 Cumulative**  Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanis m of toxicity , EPA has not made a common mechanism of toxicity finding for bispy ribac - sodium and any

other substances; and bispy ribac - sodium does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance act ion, therefore, EPA has assumed that bispy ribac - sodium does not have a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulat ive effects of such chemicals, see the policy statements released b y EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/. **1 2**  **. 0**  **Human Studies** Past bispy

ribac - sodium risk assessments rel y in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure. Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as 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 clear and convincing evidence that the conduct of any of them was either fundamentall y unethical or significantly deficient relative to the ethical standards prevailing at the time the research was conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory

barrier to continued re liance on these studies. **1 3**  **.0 Risk Assessment Updates, Data Deficiencies, and Label Revisions**  No data deficiencies were identified for bisp yribac - sodium. EPA notes the following label revisions and risk assessment updates will need to be completed during Registration Review: o Toxicology : Reevaluate toxicity endpoint/dose selection, along with the Food Quality Protection Act (FQPA) Safety Factors (SFs) based on current HED policy . o Residue Chemistry

/Dietary Exposure: o Additional residue chemistry dat a (ruminant and poultry feeding studies) were waived based on the aquatic use label (TradewindTM ) being revised to indicate that treated water may

not be used as a water source for livestock until the concentration of bispy

ribac - sodium in water is ≤1 ppb. This restriction has not been put on the TradewindTM label and should be addressed during Registration Review. o A revised dietary - exposure anal ys is will be required to reflect the most recent dietary - exposure models, potential revised EDWCs (including the re vised aquatic use EDWC), and/or changes to the toxicological PODs. o Occupational/Residential Exposure:Bispyribac - sodium Registration Review Human - Health Assessment Scoping Document

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Page 13 of 21 o Revised residential post - application assessment for the registered aquatic use will be necessary

to reflect revised inputs and assumptions , and a residential handler assessment will also need to be completed . o Revised occupational handler inhalation assessments will be necessary to reflect all potential exposure scenarios, as well as updated policies and exposure data. Assessments for all uses may be updat ed if toxicological PODs are revised. **1 4**  **.0 References Mem**  **oranda Relevant to Registration Review.** Author Barcode Date Title K. Lowe D363349 21 - JUL - 2010 Bispyribac - sodium: Occupational and Residential Exposure Assessment for Proposed Uses of Bispyribac - sodium on Aquatic Weeds M. Dow D 349324 27 - MAR - 2008 BISPYRIBAC - SODIUM

– Occupational Exposure/Risk Assessment for the Proposed Use of Velocity SG Herbicide For Golf Course Turf and Sod Farms M. Dow D 289929 09 - OCT - 2003 BISPYRIBAC - SODIUM - Exposure/Risk Assessment For the Proposed Uses o f Bispyribac - sodium on Golf Courses and Sod Farm Turfgrasses. M. Dow D 276686 24 - AUG - 2001 Exposure/Risk Assessment from the Proposed New Use of Bispyribac - Sodium on Rice. J. Tyler et al. D276557 25 - SEP - 2001 PP# 9F06044. BISPYRIBAC - SODIUM IN/ON RICE. Health Effects Division (HED) Risk Assessment. S. Levy et al. D361116,

D361118 18 - AUG - 2010 Bispyribac - sodium ; Human - Health Risk Assessment for New Product Registration for Aquatic Uses on Freshwater Fish . S. Levy D363348 07 - JUL - 2010 Bispyribac - sodium. Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Proposed Section 3 Use Registration for Aquatic Use. J. Tyler D267306 23 - AUG - 2001 PP#9F06044. Bispyribac - sodium in/on Rice. Evaluation of Residue Data and Analytical Methods. **Attachments: Attachment 1: Chemical Identity Table.**  **Attachment 2: Bispyribac**  **- sodium**  **Acute, Subchronic, and Chronic Toxicity Profile .**  **Attachment 3: Bispyribac**  **- sodium**  **Endpoint Selection Tables. Attachment 4: Summary of**  **Register ed Uses**  **. Attachment 5:**  **Bispyribac -**  **sodium International Residue Limit Status Sheet.** 

cc: K. Lowe (RAB1), S. Levy (RAB1), A. Dunbar (RAB1) RDI: RAB1 ( 2/5/14 ), D. Vogel ( 2 / 10 /1 4 ) K. Lowe :S109 4 7:PY - S:(703) 347 - 8989 :7509P:RAB1Bispyribac - sodium Registration Review Human - Health Assessment Scoping Document

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Page 1 4 of 21 **Attachment 1: Chemical Identity Table .**  **Table A1. Test Compound Nom enclature.**  Com pound

Common name Bispyribac - sodium Com pany experimental name KIH - 2023 IUPAC name sodium 2,6 - bis(4,6 - dimethoxypyrimidin - 2 - yloxy)benzoate CAS name sodium 2,6 - bis[(4,6 - dimethoxy - 2 - py rimidinyl)oxy]benzoate CAS registry number 125401 - 92 - 5 Com pound

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 - methoxypyrimidin 2 - yl)oxybenzoate **Table A2. 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) RD Memorandum, S. Malak, 26 - APR - 2001; DP# 267318 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, pKa 3.05 Octanol/water partition coefficient KOW = 0.0932; Log(KOW ) = - 1.03 UV/visible absorption spectrum Not available O O N N N N

O O O C H3

O C H3 O C H 3 H3 C O Na +

O O N N N N

O O O C H3

O C H3 O C H3 O H Na +Bispyribac - sodium Registration Review Human - Health Assessment Scoping Document

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Page 15 of 21 **Attachment 2: Bispyribac**  **- sodium**  **Acute, Subchronic, and Chronic Toxicity Profile .**  **Table A3. 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 **Table A4. Toxicity Profile of Bispyribac -**  **sodium Technical and Me**  **tabolites. 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 incid ence 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 slight 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 **Developm ental**  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 body - weight gain in the range - finding study. **Developm enta**  l NOAEL = 300 mg/kg/day. LOAEL was not established. 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/System ic**  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), bas ed on decreased body weights, body - weight gains, andBispyribac - sodium Registration Review Human - Health Assessment Scoping Document

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Page 16 of 21 **Table A4. Toxicity Profile of Bispyribac -**  **sodium Technical and Me**  **tabolites. Guideline No./Study Type**  **MRID No. (year)/ Classification/Doses**  **Results** liver weights, and increased incidence of consolidation and circumscribed areas in the liver. 870.4300 Com bined 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 mi croscopic 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 dose related 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 gen e mutation assay in bacteria 44889210 (1990) **Acceptable/guideline** 0, 333, 667, 1000, 3330, 6670, or 10000 μg/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 evidence of induction of mutant colonies over background at the high concentration. Cy togene tics 870.5375 in vitro mammalian cy togenetic assay 44889208 (1990) **Acceptable/guideline** 0, 250, 500, 750, 1000, 1500, 2000, 3000, or 4000 μg/ml w/o S9 0, 500, 1250, 2500, 3750, or 5000 - 5010 μg/ml w/ S9 Not clastogenic with or without S9 activation, at any dose tested.

Other Effects 870.5395 in vivo mammalian cy togenetic 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. Other Genotoxic Effect s 870.5500 bacterial DNA damage and repair test 44929925 (1997) **Acceptable/guideline** 0, 50, 150, 500, 1500, or 5000 μg/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 μg/ml Did not induce UDS at any dose. 870.7485 Metabolism and pharmacokinetics (rat) 44889216 (1993) 44889213 (1991) 44889214 (1991) A series of rat metabolism studies with [ 14 CP y] - bispyribac - sodium and [ 14 C - Bn] - bispyribac sodium indicated that pretreatment, dose level, sexBispyribac - sodium Registration Review Human - Health Assessment Scoping Document

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Page 17 of 21 **Table A4. Toxicity Profile of Bispyribac -**  **sodium Technical and Me**  **tabolites. Guideline No./Study Type**  **MRID No. (year)/ Classification/Doses**  **Results** 44889215 (1994) **Acceptable/guideli ne**  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 and position of the radiolabel made little effect on the absorption, distribution, elimination , and metabolism. It was readily absorbed by male and female r ats 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 withi n 5 days. Less than 2% of the administered dose remained in the carcass and tissues and <0.1% of the dose wa s recovered in air. Parent and five me tabolites were identified in the excreta of male and females following administered [ 14 Cpy] - bispyribac - sodium and parent and three metabolites identified with [ 14 C - Bn ] - bispyribac - sodium administration. The parent compound, bispyribac - sodium, was the major component identified in the feces (37 - 69% of the dose) and urine (5 - 41% of the dose), in both sexes. Metab olites identified in the excreta constituted 8.3 - 14.6% and unknown metabolites constituted 0.7 - 5.2% of the dose. Non - guideline - mo use 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 - mo use 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 - sod ium was associated 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 chenodeoxycholic acid level s 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%. Non - guideline - rat reversibili ty 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 associated with urinary bladder epithelial hyperplasia in subchronic study and bi le duct hyperplasia, enlarged 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. Muscul ar hy

pertrophy of choledocus wa s still evident. The study did not duplicate urinary bladder lesions noted in the subchronic study. **Me tabolites** Bispyribac - sodium Registration Review Human - Health Assessment Scoping Document

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Page 18 of 21 **Table A4. Toxicity Profile of Bispyribac -**  **sodium Technical and Me**  **tabolites. Guideline No./Study Type**  **MRID No. (year)/ Classification/Doses**  **Results** 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 m utant 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 bact eria 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 KI H - 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.Bispyribac - sodium Registration Review Human - Health Assessment Scoping Document

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Page 19 of 21 **Attachment 3: Bispyribac**  **- sodium**  **Endpoint Selection Tables (from 2010 Risk Assessment)**  **. Table**  **A5 . Summary of Toxicological Dose and Endpoints for Bispyribac**  **- sodium for Use in Human**  **- Health**  **Risk Assessments. Exposure**  **Scenario Dose Used in** 

**Risk Assess**  **me nt, UF**  **FQPA SF and LOC**

**for Risk Assessment Study and Toxicological Effects**  Acute Dietary all populations Not Applicable Not Applicable No appropriate 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 o f the liver in the females. 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. Intermediate - Term 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 quantification 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 o n 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. Intermediate - Term 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 (Re sidential, 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 duct s 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 factor, 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.Bispyribac - sodium Registration Review Human - Health Assessment Scoping Document

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Page 20 of 21 **Attachment 4: Summary of Registered Uses .** 

**Crop/Use Site Form**  **ulation Application method**  **Maximum App Rate**  **REI** Aquatic areas ( slow - mo ving or quiescent bodies of water where there is minim al or no outflow ; such as bayous, drainage ditches, lakes, marshes, non - irrigation canals, ponds,

reservoirs) Wettable Powder in W ater - S oluble B ags aerial, ground and/or

handheld equipment 0.1 lb ai/A and

0.12 lb ai/A - foot NA

Golf courses Dry Flowable groundboom only (no

aerial or handheld or chemigation) 0.066 lb ai/A NA Wettable Powder in Water - Soluble Bags groundboom only (no

aerial or handheld or chemigation) 0.1 lb ai/A NA Golf courses (SLN) Wettable Powder in Water - Soluble Bags aerial and groundboom (no chemigation) 0.133 lb ai/A NA Rice (except CA) Wettable Powder in Water - Soluble Bags aerial and groundboom (no chemigation) 0.034 lb ai/A 12 hr Rice (CA only) Wettable Powder in Water - Soluble Bags aerial and groundboom (no chemigation) 0.04 lb ai/A 12 hr

Sod farms Dry Flowable groundboom only (no

aerial or handheld or chemigation) 0.066 lb ai/A 12 hr Wettable Powder in Water - Soluble Bags groundboom only (no

aerial or handheld or chemigation) 0.1 lb ai/A 12 hr Sod farms (SLN) Wettable Powder in Water - Soluble Bags aerial and groundboom (no chemigation) 0.1 lb ai/A 12 hrBispyribac - sodium Registration Review Human - Health Assessment Scoping Document

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Page 21 of 21 **Attachment 5: Bispyribac**  **- sodium**  **International Residue Limit Status Sheet .**  Bispy ribac - sodium (078906; 12/19/13) Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 Codex 40 CFR 180.577: Plant: bispyribac - sodium, (2,6 - bis[(4,6 - dimethoxy - 2 - py

rimidinyl)oxy]benzoic acid, sodium salt) None None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 1 Codex Fish, freshwater 0.01 Rice, grain 0.02 Rice, straw 0.02

Com pleted: M. Negussie; 12/23/13 1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.