Document ID: EPA-HQ-OPP-2014-0074-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2014-06-25T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, 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. Levy, 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 bispyribac-sodium to support Registration Review.

                                       
                               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  Risk Assessment Updates, Data Deficiencies, and Label Revisions	12
14.0  References	13
Attachment 1:  Chemical Identity Table.	14
Attachment 2:  Bispyribac-sodium Acute, Subchronic, and Chronic Toxicity Profile	15
Attachment 3:  Bispyribac-sodium Endpoint Selection Tables (from 2010 Risk Assessment).	19
Attachment 4:  Summary of Registered Uses	20
Attachment 5:  Bispyribac-sodium International Residue Limit Status Sheet.	21
EXECUTIVE SUMMARY

HED has prepared a scoping document to support Registration Review of bispyribac-sodium (sodium, 2,6-bis[(4,6-dimethoxy-pyrimidin-2-yl)oxy]benzoate).  Bispyribac-sodium is a postemergence contact herbicide belonging to the pyrimidinyl oxybenzoic acid group.  Its mode of action is through inhibition of acetolactate synthase (ALS) and the biosynthesis of three-branched amino acids: valine, leucine, and isoleucine.  This inhibition 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, bispyribac-sodium is absorbed through the leaf surface and translocated throughout the plant.  

Bispyribac-sodium is formulated as dry flowables (DF) and wettable powders in water-soluble bags (WSB), and is currently registered for use on rice, golf courses, sod farms, and aquatic areas.  There are currently four registered Section 3 labels for bispyribac-sodium, as well as six active Special Local Needs (SLN) registrations for specific uses on golf courses and sod farms.  The most recent quantitative human-health risk assessment was performed in 2010, and was for the aquatic use of bispyribac-sodium (Memo, S. Levy et al., 18-AUG-2010; D311161).  There is currently one pending PRIA action for bispyribac-sodium for a new use on turf, including athletic fields, commercial and residential turf.  

HED has evaluated the status of the human-health assessments for bispyribac-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 bispyribac-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 bispyribac-sodium is adequate for risk assessment as specified by the 2007 revised 40 CFR Toxicology Data Requirements.  HED's Hazard and Science Policy Council (HASPOC) has determined that an immunotoxicity study, the neurotoxicity screening batteries, and a subchronic inhalation toxicity study are all not required for bispyribac-sodium at this time.  During Registration Review, the endpoints, doses, and safety factors used 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 crops), 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 additional residue chemistry data (ruminant and poultry feeding studies) were waived based on the aquatic use label (Tradewind[(TM)]) being revised to indicate that treated water may not be used as a water source for livestock until the concentration of bispyribac-sodium in water is <=1 ppb.  This restriction has not been put on the Tradewind(TM) 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. Levy, 07-JUL-2010; D363348).  Chronic dietary (food +drinking water) risk estimates were not of concern to HED [<100% chronic population-adjusted dose (cPAD); all infants <1 year old were the most highly exposed population (12% cPAD)].  As part of Registration Review, a revised dietary-exposure analysis 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 points 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 inhalation exposure is considered negligible.  A post-application assessment for incidental ingestion of treated water was conducted for bispyribac-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 based on a review of the registered labels for bispyribac-sodium, except for (1) aerial applications to golf courses and sod farms allowed for several SLN registrations and (2) aerial applications to rice (mixer/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 for all scenarios.  Since there is no dermal POD chosen for bispyribac-sodium, a quantitative occupational post-application assessment is not necessary.  Updated occupational and residential assessments for all uses may be necessary if toxicological PODs are revised.  

No data deficiencies were identified for bispyribac-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 data (ruminant and poultry feeding studies) were waived based on the aquatic use label (Tradewind[(TM)]) being revised to indicate that treated water may not be used as a water source for livestock until the concentration of bispyribac-sodium in water is <=1 ppb.  This restriction has not been put on the Tradewind(TM) label and should be addressed during Registration Review.
         o A revised dietary-exposure analysis 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 Assessments for all uses may be updated if toxicological PODs are revised.  

1.0  Introduction

Bispyribac-sodium is a herbicide whose mode of action is the inhibition of the plant enzyme ALS.  It is formulated as DFs and WSBs, and is currently registered for use on rice, golf courses, sod farms, and aquatic areas.  There are currently four registered Section 3 labels for bispyribac-sodium, as well as six active SLN registrations for specific uses on golf courses and sod farms.  The most recent quantitative human-health risk assessment was performed in 2010 and was for the aquatic use of bispyribac-sodium (Memo, S. Levy et al., 18-AUG-2010; D311161).  There is currently one pending PRIA action for bispyribac-sodium for a new use on turf, including athletic fields, commercial and residential turf.  

2.0  Hazard Characterization/Assessment

In the rat metabolism study for bispyribac-sodium, pretreatment, dose level, sex, and position of radiolabel had little effect on the absorption, distribution, elimination, and metabolism.  It was readily absorbed by 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 essentially complete within 5 days.  Less than 2% of the 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]-bispyribac-sodium, whereas the parent and three metabolites were identified following administration of [[14]C-Bn]-bispyribac-sodium.

The acute toxicity battery of tests shows that bispyribac-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 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.  Bispyribac-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 systemic 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.  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 of a concentration-related response in the induction of mutant colonies over background at the high concentrations.  Thus, there is no evidence that bispyribac-sodium is mutagenic.

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 Hazard Identification 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 immunotoxicity study, (2) an acute neurotoxicity study, (3) a subchronic neurotoxicity study, and (4) a subchronic inhalation toxicity 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 0056389 (08-FEB-2013) and 0056840 (26-NOV-2013)].  

Conclusions:  The toxicity database for bispyribac-sodium is adequate for risk assessment as specified by the 2007 revised 40 CFR Toxicology Data Requirements.  HED's HASPOC has determined that an immunotoxicity study, the neurotoxicity screening batteries, and a subchronic inhalation toxicity study are all not required for bispyribac-sodium at this time.  During Registration Review, the endpoints, doses, and safety factors used in the most recent human-health risk assessments will be evaluated based on current HED policy.   

3.0  Residue Chemistry

Permanent tolerances are established for residues of bispyribac-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 bispyribac-sodium in/on livestock commodities or for indirect/inadvertent residues in rotational crops. 

The nature of the residue in rice and livestock is adequately understood based on the available rice, ruminant, and poultry metabolism studies.  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.  Adequate ruminant and poultry metabolism studies are available depicting the metabolism of [[14]C]bispyribac-sodium; separate ruminant 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, 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.  

When HED evaluated the use of bispyribac-sodium on rice, it was noted that if additional uses were requested in the future which significantly increased the poultry dietary burden, then a poultry metabolism study with benzene-labeled bispyribac-sodium may be required.  In the HED risk assessment for the use in aquatic areas, it was noted that this use resulted in significantly increased dietary burdens to livestock and that HED could no longer conclude that there is no expectation of finite residues of bispyribac-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 (Tradewind[(TM)]) was 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 (minutes of HED's ChemSAC meeting held 16-JUN-2010).  This restriction has not been put on the Tradewind[(TM)] 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 analyzed for bispyribac-sodium and its metabolite des-methyl KIH-2023, a major residue in the anaerobic aquatic metabolism study (minutes of HED's Science Advisory Council for Chemistry (ChemSAC) meeting held 30-MAY-2007).  The fish residue study did analyze for these residues, and the available data demonstrated that bispyribac-sodium residues in water remained consistent throughout the study period, and residues of bispyribac-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 (oysters and clams), shrimp, crayfish and/or other crustaceans for the rice and aquatic uses, however, a waiver for these data was previously 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 study indicated that there is a possibility of detectable residues of bispyribac-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 water 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 bispyribac-sodium.  The method determines residues of bispyribac-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 analyte in fish tissue and 0.001 ppm for each analyte in tank water.  An acceptable independent laboratory validation (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 demonstrates an additional cleanup step as an option for the confirmation technique and an addition of alternate analytical conditions for LC-MS/MS analysis which can serve as an enforcement method.  Bispyribac-sodium is not likely to be recovered through the U.S. Food and Drug Administration (FDA) MRM protocols.  

An adequate gas chromatography (GC) method RM-35R-2 for the enforcement of tolerances on rice grain and straw is available for bispyribac-sodium.  The reported method limit of detection (LOD) and LOQ for residues of bispyribac-sodium are 0.01 ppm and 0.02 ppm, respectively, 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 Analytical Chemistry Branch (ACB) of the Biological Economic Analysis Division (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 residues (analysis using a different GC column, and/or analysis 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 bispyribac-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 analyzed for residues of bispyribac-sodium using GC method RM-35R-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 collection.

Adequate field trial data are available to support the use of bispyribac-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.  These studies are also supported by adequate storage stability data and processing data.  The submitted data indicate that residues of bispyribac-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 methods are available for enforcement of the currently established tolerances.  It was noted during review that additional residue chemistry data (ruminant and poultry feeding studies) were waived based on the aquatic use label (Tradewind[(TM)]) being revised to indicate that treated water may not be used as a water source for livestock until the concentration of bispyribac-sodium in water is <=1 ppb.  This restriction has not been put on the Tradewind(TM) label and will need to be addressed during Registration Review.  

4.0  Dietary Exposure

No toxic effects attributable to a single exposure to bispyribac-sodium have been identified; therefore, an acute reference dose (aRfD) was not established for bispyribac-sodium, and an acute dietary-exposure assessment was not required.  HED had conducted a chronic dietary-exposure analysis, which considered all currently registered uses (Memo, S. Levy, 07-JUL-2010; D363348).  The analysis was conducted using the Dietary Exposure Evaluation Model  -  Food Consumption Intake Database (DEEM-FCID, ver. 2.03), which incorporates the food consumption data from the United States Department of Agriculture (USDA) Continuing Surveys 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 year in a single treatment area.  Thus, the annual use rate was assumed to be four applications at the single rate to produce a concentration of 45 ppb, for a total annual application of 180 ppb.  In 2010, EFED provided 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 population-adjusted dose (cPAD)].  The most highly exposed population subgroup was all infants (<1 year 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 bispyribac-sodium (Memo, J. Tyler, 20-AUG-2001; D276560).  All metabolites identified were present at low 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 analysis 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.

5.0  Residential Exposure

Bispyribac-sodium is currently registered for use on golf course turf and in aquatic areas.  Registered formulations include DFs and WSBs.  Attachment 4 includes a summary of the use sites for bispyribac-sodium, including those related to residential areas.  Previous occupational and residential exposure (ORE) assessments have been conducted for the golf course (D349324, M. Dow, 27-MAR-2008; D289929, M. Dow, 09-OCT-2003) and aquatic area (D363349, K. Lowe, 21-JUL-2010) uses.  

Since there are no dermal PODs for bispyribac-sodium, only inhalation and incidental oral exposures/risk estimates were assessed previously.  A quantitative residential assessment for the use on golf courses 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 post-application incidental ingestion of water was assessed for both adults and children.  The proposed label that was reviewed for the use indicated that bispyribac-sodium may only be applied to water by Federal or State agencies, U.S. Army Corps of Engineers, and licensed applicators authorized by 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 bispyribac-sodium can only be applied by licensed applicators; therefore, a residential handler assessment will need to be completed.  

Spray Drift/Bystander Exposure
Residential exposures resulting from off-site transport (e.g., spray drift or volatilization) may occur as a result of applications of bispyribac-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 the Agency's risk assessments.  The need for spray drift and volatilization risk assessment for bispyribac-sodium will be examined during registration review.

Conclusions:  The residential exposure database is adequate to support the Registration Review process for bispyribac-sodium.  Since there is no dermal POD and post-application inhalation exposure is considered negligible, no quantitative residential assessment is necessary for the golf course use.  A post-application assessment for incidental ingestion of treated water was conducted for bispyribac-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.

6.0  Aggregate-Risk Assessment

The most recent aggregate-risk assessment was performed in conjunction with the 2010 HED human-health risk assessment (Memo, S. Levy 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 conducted, and since the short- and intermediate-term PODs are the same, the short-term aggregate assessment is protective of intermediate-term exposures.  The short- 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 bispyribac-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 revised dietary-exposure analyses and/or revised residential exposure assessments.  

7.0  Occupational Exposure

Occupational handler and post-application exposures are expected based on the registered agricultural and commercial uses of bispyribac-sodium.  Attachment 4 provides a summary of the occupational use pattern.  The current registrations include some SLN registrations.  Current formulations include DFs and WSBs.  The application rates range from 0.034  -  0.133 lb ai/A, and applications can be made using 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 currently registered use pattern of bispyribac-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. Lowe, 21-JUL-2010) uses.  The assessments were 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 maximum application rates.  Handler's exposure and risk were calculated at baseline (long pants, a long-sleeved 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 since there is no dermal POD for bispyribac-sodium; and inhalation risk estimates were not of concern (i.e., MOEs >= 100) for all registered uses.  

Based on a review of the registered labels for bispyribac-sodium, it appears 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 sod farms allowed on several SLN labels 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 updated exposure data for occupational handler assessments and updates 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 bispyribac-sodium to agricultural crops and commercial use sites; however, there is no dermal POD for bispyribac-sodium, therefore a quantitative dermal post-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 bispyribac-sodium, it appears 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 sod farms allowed on several SLN labels and (2) aerial applications to rice (mixer/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 bispyribac-sodium (Memo, S. Recore and E. Evans, DXXXXXX, XX-JAN-2014) and concludes that since there were no incidents involving bispyribac-sodium reported to either IDS 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, additional analysis 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 bispyribac-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."  The OPP typically considers the highest potential exposures from the legal use of a pesticide when conducting human-health risk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability 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 mechanism of toxicity, EPA has not made a common mechanism of toxicity finding for bispyribac-sodium and any other substances; and bispyribac-sodium does not appear to produce a toxic metabolite produced by other substances.  For the purposes of this tolerance action, therefore, EPA has assumed that bispyribac-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 cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.

12.0  Human Studies

Past bispyribac-sodium risk assessments rely 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 fundamentally 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 reliance on these studies.

13.0  Risk Assessment Updates, Data Deficiencies, and Label Revisions

No data deficiencies were identified for bispyribac-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 data (ruminant and poultry feeding studies) were waived based on the aquatic use label (Tradewind[(TM)]) being revised to indicate that treated water may not be used as a water source for livestock until the concentration of bispyribac-sodium in water is <=1 ppb.  This restriction has not been put on the Tradewind(TM) label and should be addressed during Registration Review.
         o A revised dietary-exposure analysis will be required to reflect the most recent dietary-exposure models, potential 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.  Assessments for all uses may be updated if toxicological PODs are revised.

14.0  References

Memoranda 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
D349324

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
D289929
09-OCT-2003
BISPYRIBAC-SODIUM - Exposure/Risk Assessment For the Proposed Uses of Bispyribac-sodium on Golf Courses and Sod Farm Turfgrasses.  
M. Dow
D276686
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 Registered 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 (2/10/14)
K. Lowe:S10947:PY-S:(703)347-8989:7509P:RAB1

Attachment 1:  Chemical Identity Table.

Table A1.  Test Compound Nomenclature.
Compound

Common name
Bispyribac-sodium
Company 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-pyrimidinyl)oxy]benzoate
CAS registry number
125401-92-5
Compound

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

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
LD50 = 4111 (male), 2365 (female), 3565 (combined) mg/kg
                                      III
870.1200 Acute Dermal - Rabbit
44889128
LD50 > 2000 mg/kg
                                      III
870.1300 Acute Inhalation - Rat
44889130
LC50 > 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 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 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
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
Maternal NOAEL = 100 mg/kg/day.
LOAEL = 300 mg/kg/day, based on lethargy, diarrhea, and decreased body-weight gain in the range-finding study.
Developmental 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/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 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 gene 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 ug/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.
Cytogenetics 
870.5375
in vitro mammalian cytogenetic 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 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.
Other Genotoxic Effects 
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)
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 remained in the carcass and tissues and <0.1% of the dose was recovered in air.  Parent and five metabolites 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.  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 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 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%.  
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 associated with urinary bladder epithelial hyperplasia in subchronic study and bile 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.  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 ug/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 ug/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 ug/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 ug/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 ug/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 ug/plate
Me2BA 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 ug/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 ug/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 ug/plate
KIH-2023-I-4 did not induce mutant colonies over background.

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 Assessment, 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 of 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 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.
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 (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 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.

Attachment 4:  Summary of Registered Uses. 

                                 Crop/Use Site
                                  Formulation
                              Application method
                               Maximum App Rate 
                                      REI
Aquatic areas (slow-moving or quiescent bodies of water where there is minimal or no outflow; such as bayous, drainage ditches, lakes, marshes, non-irrigation canals, ponds, reservoirs)
                              Wettable Powder in 
                              Water-Soluble Bags
                   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 hr 

Attachment 5:  Bispyribac-sodium International Residue Limit Status Sheet.

                     Bispyribac-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-pyrimidinyl)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

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