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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.
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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
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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 threebranched 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 (TradewindTM) 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 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. Levy, 07-JUL-2010; D363348). Chronic dietary (food 

+drinking water) risk estimates were not of concern to HED [<100% chronic population-adjusted 
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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 (TradewindTM) 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 TradewindTM 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 bispyribacsodium, as well as six active SLN registrations for specific uses on golf courses and sod farms. 
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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 [14C-Py]-bispyribacsodium, whereas the parent and three metabolites were identified following administration of 

[

14C-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 genemutation 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 humanhealth risk assessments will be evaluated based on current HED policy. 
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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 [14C]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 [14C]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 

(TradewindTM) 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 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 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
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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-AUG2001; 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 TMSdiazomethane 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
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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 

bispyribac-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 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 dietaryexposure 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 tolerancelevel 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.
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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 postapplication inhalation exposure is expected to be negligible. In addition, incidental oral postapplication exposure is not expected from the golf course use. For the aquatic use, only postapplication 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.
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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 shortterm 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-JUL2010) 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., chemicalresistant 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. 
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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 Populations1.” 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

 

1

http://www.epa.gov/compliance/environmentaljustice/resources/policy/exec_order_12898.pdf
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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 (TradewindTM) 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 TradewindTM 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: 
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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
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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-methoxypyrimidin2-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 10-4g/100 mL

dichloromethane 5.13 g/100 mL

methanol 2.5 g/100 mL

Column generator method (25°C):

acetone 1.4 x 10-4g/100 mL

ethyl acetate 6.1 x 10-6g/100 mL

n-hexane 8.34 x 10-7g/100 mL

methyl chloride 1.3 x 10-4g/100 mL

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

toluene <1 x 10-5g/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

OCH3

OCH3

OCH3

H3CO

Na

+

O O

N

N

N

N

O O

OCH3

OCH3

OCH3

HO

Na

+
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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 
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Table A4. Toxicity Profile of Bispyribac-sodium Technical and Metabolites.

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

Combined chronic 

toxicity/carcinogenicity 

rodents (rat)

44929924 (1995)

Acceptable/guideline

M: 0, 20, 200, 3500, or 7000 

ppm

(0, 1.1, 10.9, 194.5, or 404.5 

mg/kg/day, respectively)

F: 0, 20, 200, 5000, or 10,000 

ppm (0, 1.4, 13.8, 352.2, or 

714.9 mg/kg/day, respectively)

NOAEL = 10.9 mg/kg/day.

LOAEL = 194.5 mg/kg/day (M), based on 

macroscopic and microscopic changes in the liver 

and choldedochus and clinical signs. The LOAEL 

is 714.9 mg/kg/day for females based on reduced 

body weight, body-weight gains, food efficiency, 

clinical signs, and microscopic changes in the liver 

and choldedochus. 

No evidence of carcinogenicity.

870.4100b

Chronic toxicity (dog)

44889134 (1998)

Acceptable/guideline

M & F: 0, 10, 100, or 750 

mg/kg/day

NOAEL = 10 mg/kg/day.

LOAEL = 100 mg/kg/day (M/F), based on doserelated increase in intrahepatic bile duct 

hyperplasia and liver granulation in females.

870.4300

Carcinogenicity (mouse)

44929920 (1995)

Acceptable/guideline

0, 10, 100, 2,500, or 5,000 

ppm

M: 0, 1.4, 14.1, 353.0, 728.9 

mg/kg/day

F: 0, 1.7, 17.4, 447.8, or 902.9 

mg/kg/day

NOAEL = 14.1/17.4 (M/F) mg/kg/day.

LOAEL = 353.0/447.8 mg/kg/day (M/F), based on 

decreased body-weight gain, and food efficiency, 

and increased incidence of microscopic lesions in 

the liver and gall bladder (M).

No evidence of carcinogenicity.

Gene Mutation

870.5100

reverse gene mutation assay 

in bacteria

44889210 (1990)

Acceptable/guideline

0, 333, 667, 1000, 3330, 6670, 

or 10000 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.

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)

A series of rat metabolism studies with [14CPy]-

bispyribac-sodium and [14C-Bn]-bispyribacsodium indicated that pretreatment, dose level, sex 
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Table A4. Toxicity Profile of Bispyribac-sodium Technical and Metabolites.

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

Classification/Doses Results

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 

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 [14Cpy]-bispyribac-sodium 

and parent and three metabolites identified with 

[

14C-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
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Table A4. Toxicity Profile of Bispyribac-sodium Technical and Metabolites.

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 mutant colonies 

over background.

Gene Mutation

870.5100

reverse gene mutation assay 

in bacteria

44889206 (1995)

Acceptable/guideline

0, 50, 158, 500, 1580, or 5000 

μg/plate

KIH-2023-M-9-Na did not induce mutant colonies 

over background.

Gene Mutation

870.5100

reverse gene mutation assay 

in bacteria

44889207 (1991)

Acceptable/guideline

0, 100, 333, 667, 1000, 3330, 

6670, or 10,000 μg/plate

BIX-180 did not induce mutant colonies over 

background.

Gene Mutation

870.5100

reverse gene mutation assay 

in bacteria

44889212 (1991)

Acceptable/guideline

0, 100, 333, 667, 1000, 3330, 

or 5000 μg/plate

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 μg/plate

KIH-2023-I-1 did not induce mutant colonies over 

background.

Gene Mutation

870.5100

reverse gene mutation assay 

in bacteria

44929927 (1995)

Acceptable/guideline

0, 50, 150, 500, 1500, or 5000

μg/plate

KIH-2023-I-2 did not induce mutant colonies over 

background.

Gene Mutation

870.5100

reverse gene mutation assay 

in bacteria

44929928 (1995)

Acceptable/guideline

0, 50, 150, 500, 1500, or 5000 

μg/plate

KIH-2023-I-4 did not induce mutant colonies over 

background.
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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 rangefinding 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 rangefinding 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 = lowestobserved 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 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 
Bispyribac-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.

Bispyribac-sodium (078906; 12/19/13)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 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 Mexico1 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.