Bispyribac-sodium Human-Health Risk Assessment DP# 361116 

Page 1 of 31 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

 OFFICE OF CHEMICAL SAFETY AND 

 POLLUTION PREVENTION 

 

MEMORANDUM

DATE: 18-AUG-2010 

SUBJECT: Bispyribac-sodium; Human-Health Risk Assessment for New Product 

Registration for Aquatic Uses on Freshwater Fish. 

PC Code: 078906 DP Barcodes: D361116, D361118 

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

Petition No.: 8F7509 Regulatory Action: Section 3 

Risk Assessment Type: Single Chemical/Aggregate Case No.: 7258 

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

MRID No.: NA 40 CFR: §180.577

FROM: Sarah J. Levy, Chemist 

 Robert J. Mitkus, Ph.D., DABT, Toxicologist 

 Kelly M. Lowe, Environmental Scientist 

 Risk Assessment Branch 1 (RAB1) 

Health Effects Division (HED; 7509P) 

 THROUGH: Dana M. Vogel, Branch Chief 

 George F. Kramer, Ph.D., Senior Chemist 

 RAB1/HED (7509P) 

 

TO: Hope Johnson/James Tompkins, Risk Manager 25 

 Herbicide Branch/RD (RD; 7505P) 

The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human 

health from exposure to pesticides. The RD of OPP has requested that HED evaluate hazard and 

exposure data and conduct dietary, occupational, residential, and aggregate exposure 

assessments, as needed, to estimate the risk to human health that will result from the proposed 

(and registered) aquatic bispyribac-sodium (sodium, 2,6-bis[(4,6-dimethoxy-pyrimidin-2-

yl)oxy]benzoate) uses on freshwater fish. The most recent HED human-health risk assessment 

for bispyribac-sodium was conducted for a new use on rice (Memo, J. Tyler, et al., 25-SEP2001; DP# 276557). 

A summary of the findings and an assessment of human-health risk resulting from the proposed 

and registered uses of bispyribac-sodium are provided in this document. The risk assessment, 

residue chemistry review, and dietary exposure assessment were provided by Sarah Levy 

(RAB1); the occupational/residential exposure assessment was provided by Kelly Lowe (RAB1); 

the toxicology review was provided by Robert Mitkus (RAB1); and the drinking water 
Bispyribac-sodium Human-Health Risk Assessment DP# 361116 

Page 2 of 31 

assessment was provided by Cheryl Sutton of the Environmental Fate and Effects Division 

(EFED). 

TABLE OF CONTENTS 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

6.0 Aggregate Risk Assessments and Risk Characterization............................................ 21

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

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

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

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

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

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

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

8.2 Occupational Postapplication Exposure/Risk.................................................. 27 

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

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

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

9.3 Occupational and Residential Exposure........................................................... 27 

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

Attachment 1b. Toxicity Profile of Bispyribac-sodium Technical and Metabolites............ 28
Bispyribac-sodium Human-Health Risk Assessment DP# 361116 

Page 3 of 31 

1.0 Executive Summary 

Bispyribac-sodium is a herbicide formulated as a soluble powder (SP) and is currently registered 

for use on rice and on golf courses and sod farms. The mode of action is the inhibition of the 

plant enzyme acetolactate synthetase. Tolerances for residues of bispyribac-sodium are 

established under §180.577(a) on rice grain and straw (each at 0.02 ppm). 

Under Section 3 of the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), as 

amended, Valent U.S.A. Corporation is requesting a Section 3 registration for TradewindTM

Herbicide (EPA Reg. No. 59639- RAL), an 80% SP formulation of bispyribac-sodium, for 

aquatic uses restricted to slow-moving or quiescent bodies of water with minimal or no outflow, 

such as bayous, canals, drainage ditches, lakes, marshes, non-irrigation canals, ponds, and 

reservoirs. The product is proposed for surface applications to water at 0.05-0.1 lb 

ai/A/application, with a maximum rate of 0.4 lb ai/A/year, using ground or aerial equipment, and 

for subsurface applications to water at a concentration of 30-45 ppb, with a maximum 

cumulative rate of 180 ppb per year. The proposed label prohibits application to flowing water, 

intertidal, or estuarine areas or to water utilized for crayfish farming, and prohibits the use of 

treated water to irrigate food crops until the concentration of bispyribac-sodium in water is ≤1 

ppb. 

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

“Tolerances are established for residues of the herbicide bispyribac-sodium, including its 

metabolites and degradates, in or on the commodities in the table below. Compliance with the 

tolerance levels specified below is to be determined by measuring only bispyribac-sodium, (2,6-

bis[(4,6-dimethoxy-2-pyrimidinyl)oxy]benzoic acid, sodium salt), in or on the following raw 

agricultural commodities: 

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

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

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

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

Milk......................................................................................0.01 ppm 

Poultry, meat byproducts .....................................................0.50 ppm 

Egg .......................................................................................0.01 ppm 

Poultry, fat............................................................................0.01 ppm 

Poultry meat.........................................................................0.01 ppm” 

Hazard Assessment 

Bispyribac-sodium has a low acute toxicity profile and is not a dermal sensitizer. The liver and 

bile duct were identified as the target organs in the subchronic and chronic toxicity studies in 

rats, mice, and dogs, and the reproductive toxicity study in rats. Repeated dermal applications at 

the limit dose did not elicit systemic toxicity or dermal irritation. Bispyribac-sodium was 

negative for carcinogenicity in feeding studies in rats and mice and is classified as a “not likely 

human carcinogen” and mutagenicity studies conducted with the parent and three major 

metabolites were negative. There was no evidence of fetal toxicity or offspring susceptibility in 

the developmental toxicity studies in rats and rabbits or in the reproductive toxicity study in rats. 

Bispyribac-sodium has shown no indications of central or peripheral nervous system toxicity in 

any study and does not appear to be structurally related to any other chemical that causes adverse 

nervous system effects. 
Bispyribac-sodium Human-Health Risk Assessment DP# 361116 

Page 4 of 31 

Dose-Response Assessment 

The acute reference dose (aRfD) for the general population, including infants and children, was 

not established because an endpoint of concern attributable to a single dose was not identified. 

Therefore, this assessment is not necessary. The chronic reference dose (cRfD) of 0.027 

mg/kg/day was determined on the basis of the chronic carcinogenicity study in mice. An 

uncertainty factor (UF) of 100 (10X for interspecies extrapolation and 10X for intraspecies 

variability) was applied to the NOAEL of 2.7 mg/kg/day to derive the cRfD. No short- or 

intermediate-term dermal points of departure were identified; therefore, quantification of shortand intermediate-term dermal risks is not required. A NOAEL of 100 mg/kg/day from a 

developmental study in rabbits was selected as the point of departure for short-term inhalation 

exposure. A NOAEL of 100 mg/kg/day from a 90-day feeding study in dogs was selected as the 

point of departure for intermediate-term inhalation. A body weight of 70 kg was used for the 

short- and intermediate-term exposure assessment. Since no inhalation absorption data are 

available, toxicity by the inhalation route is considered to be equivalent to the estimated toxicity 

by the oral route of exposure. 

FQPA Decision 

The Agency’s level of concern for risks [i.e., target level for margins of exposure (MOEs)] is 

defined by UFs. The Agency applies a factor of 10X to account for interspecies extrapolation to 

humans from the animal test species and another factor of 10X to account for intraspecies 

sensitivity. HED has concluded that the FQPA Safety Factor (SF) for bispyribac-sodium can be 

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

assessments is 100X. 

Dietary Exposure and Risk

An acute dietary assessment was not performed for bispyribac-sodium because there were no 

adverse effects that could be attributable to a single dose. Thus, an endpoint of concern was not 

identified to quantitate acute dietary risk to the general population or any population subgroup. 

An unrefined chronic dietary risk assessment was conducted using the Dietary Exposure 

Evaluation Model software with the Food Commodity Intake Database (DEEM-FCIDTM; ver. 

2.03) model. Estimated drinking water concentrations (EDWCs) from EFED, based on the 

highest application use rate (aquatic use), were also included in the dietary assessment. The 

resulting food and drinking water exposure estimates are not of concern to HED [<100% chronic 

population-adjusted dose (cPAD)]; all infants <1 year old were the most highly exposed 

population (12.5% cPAD). A cancer dietary exposure assessment was not conducted because 

bispyribac-sodium was classified as “not likely to be carcinogenic to humans.” 

Aggregate Risk

An acute aggregate risk assessment was not necessary since an appropriate endpoint for the 

assessment of acute dietary risk was not identified (no acute hazard is present). Chronic 

aggregate risk is made up only of dietary sources; therefore, the chronic exposure estimates 

provided in the chronic dietary exposure analysis represents chronic aggregate exposure. An 

aggregate cancer risk assessment was not performed because bispyribac-sodium was classified as 

“not likely to be carcinogenic to humans.” 

Only a short-term aggregate risk assessment was conducted since the residential use pattern is 

expected to only result in short-term exposures; however, since the short- and intermediate-term 

points of departure are the same, the short-term aggregate assessment is protective of 

intermediate-term exposures. Short- and intermediate-term aggregate risks are made up of 
Bispyribac-sodium Human-Health Risk Assessment DP# 361116 

Page 5 of 31 

dietary and non-dietary sources of exposure. Dietary (food + drinking water) exposure estimates 

are based on a conservative, unrefined chronic dietary exposure assessment. Non-dietary 

(residential) exposure estimates are conservative estimates due to the standard assumptions that 

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

course and sod farm turf and there is no dermal endpoint, the non-dietary (residential) aggregate 

exposures for adults and children include only incidental oral exposure from the aquatic uses. 

Post-application inhalation exposure is not expected and was not included in the aggregate risk 

estimates. The short- and intermediate-term aggregate MOEs for all population subgroups were 

assessed, and are not of concern to HED (MOEs >100). 

Occupational Exposure

Occupational exposures and risks resulting in MOEs greater than or equal to 100 are not of 

concern to HED. Short- and intermediate-term dermal occupational handler exposures and risks 

were not assessed for bispyribac-sodium, since no dermal points of departure were identified. 

The short- and intermediate-term inhalation risks to handlers do not exceed HED’s level of 

concern at baseline (no respirator) for any of the handler scenarios where baseline data are 

available. Only engineering control (enclosed cockpit) data are available to assess inhalation 

risks to handlers operating aircraft. The inhalation risks do not exceed HED’s level of concern 

for pilots using enclosed cockpits and wearing no respirator. Even though dermal exposures 

were not assessed due to lack of a dermal point of departure, handlers should still wear label 

prescribed personal-protective equipment (PPE; long-sleeved shirt and long pants, chemicalresistant gloves, and shoes plus socks). 

Occupational postapplication exposures following bispyribac-sodium application to aquatic areas 

is likely limited to persons who contact the treated water to perform tests, such as testing the 

levels of bispyribac-sodium. Short- and intermediate-term dermal postapplication exposures and 

risks were not assessed for bispyribac-sodium, since no dermal points of departure were 

identified. Based on the Agency's current practices, a quantitative occupational postapplication 

inhalation exposure assessment was not performed for bispyribac-sodium at this time. However, 

there are multiple potential sources of postapplication inhalation exposure to individuals 

performing postapplication activities in previously treated areas, including volatilization of 

pesticides. If new policies or procedures are put into place, the Agency may revisit the need for 

a quantitative occupational postapplication inhalation exposure assessment for bispyribacsodium. 

Residential Exposure and Risk 

In addition to the proposed aquatic use, bispyribac-sodium is also currently registered for use on 

golf courses and sod farms. No residential handler exposure is expected from the proposed and 

registered uses of bispyribac-sodium. For the proposed aquatic use, the label indicates that 

bispyribac-sodium may only be applied to water by Federal or State agencies, the U.S. Army 

Corps of Engineers, and licensed applicators authorized by Federal or State agencies. 

Residential postapplication exposure following use of bispyribac-sodium on golf courses and sod 

farms is possible. A dermal postapplication assessment was not performed since there is no 

short-term dermal point of departure. Based on the Agency's current practices, a quantitative 

postapplication inhalation exposure assessment was not performed for bispyribac-sodium. 

However, volatilization of pesticides may be a potential source of postapplication inhalation 

exposure to individuals nearby to pesticide applications. If new policies or procedures are put 

into place, the Agency may revisit the need for a quantitative postapplication inhalation exposure 

assessment for bispyribac-sodium. 
Bispyribac-sodium Human-Health Risk Assessment DP# 361116 

Page 6 of 31 

HED determined there is a potential for residential postapplication exposure from swimming in 

water bodies that have been previously treated with bispyribac-sodium. Postapplication 

exposure and risks were developed for the non-competitive adult and child swimmer. Exposure 

is expected to be short-term; however, since the short- and intermediate-term points of departure 

are the same, the short-term assessment is protective of intermediate-term exposures. Only oral 

postapplication exposure to recreational swimmers was assessed in this document. Dermal 

postapplication exposures were not assessed, since no dermal points of departure were identified. 

Short-term incidental ingestion MOEs were greater than 100 for noncompetitive adult and child 

swimmers and; therefore, do not exceed HED’s level of concern. 

Review of Human Research 

Past bispyribac-sodium risk assessments rely in part on data from studies in which adult human 

subjects were intentionally exposed to a pesticide to determine their dermal and inhalation 

exposure. Many such studies, involving exposure to many different pesticides, comprise generic 

pesticide exposure databases such as the Pesticide Handlers Exposure Database (PHED), the 

Outdoor Residential Exposure Task Force (ORETF) Database, and the Agricultural Reentry Task 

Force (ARTF) Database. EPA has reviewed all the studies supporting these multi-pesticide 

generic exposure databases, and has found no 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. 

Environmental Justice Considerations

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

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," 

(http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf). 

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, HED estimates 

risks to population subgroups from pesticide exposures that are based on patterns of that 

subgroup’s food and water consumption, and activities in and around the home that involve 

pesticide use in a residential setting. Extensive data on food consumption patterns are compiled 

by the U.S. Department of Agriculture (USDA) under Continuing Surveys of Food Intakes by 

Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a 

pesticide. These data are analyzed and categorized by subgroups based on age, season of the 

year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary 

exposure to smaller, specialized subgroups and exposure assessments are performed when 

conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on 

home use of pesticide products and associated risks for adult applicators and for toddlers, youths, 

and adults entering or playing on treated areas post-application are evaluated. Further 

considerations are currently in development as OPP has committed resources and expertise to the 

development of specialized software and models that consider exposure to bystanders and farm 

workers as well as lifestyle and traditional dietary patterns among specific subgroups. 
Bispyribac-sodium Human-Health Risk Assessment DP# 361116 

Page 7 of 31 

Regulatory Recommendations 

Pending submission of revised Sections B and F, HED recommends in favor of the proposed use 

and the requested tolerance for freshwater fish as follows: “Tolerances are established for 

residues of the herbicide bispyribac-sodium, including its metabolites and degradates, in or on 

the commodity listed below. Compliance with the tolerance level specified below is to be 

determined by measuring only bispyribac-sodium, (2,6-bis[(4,6-dimethoxy-2-

pyrimidinyl)oxy]benzoic acid, sodium salt), in or on the following raw agricultural commodity: 

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

Registration should be conditional pending resolution of:

Toxicology

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

• Acute neurotoxicity study. 

• Subchronic neurotoxicity study. 

• 28-day inhalation study. 

2.0 Ingredient Profile 

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

and broadleaf weeds. The mode of action is the inhibition of the plant enzyme acetolactate 

synthetase. Bispyribac-sodium is formulated as a SP and is registered in the U.S. for the control 

of aquatic weeds in rice fields. Tolerances for residues of bispyribac-sodium are established 

under §180.577(a) on rice grain and straw (each at 0.02 ppm). 

TradewindTM Herbicide is labeled for use on surface, submerged and emergent aquatic weeds in 

bayous, canals, fresh water ponds, lakes, marshes and reservoirs. It may be applied as a 

subsurface application for control of submerged aquatic weeds or as a surface application for 

control of floating and emergent aquatic weeds. According to the proposed label, applicators and 

other handlers must wear a long-sleeved shirt and long pants, chemical-resistant gloves, and 

shoes plus socks. 

2.1 Summary of Proposed Uses

Table 2.1. Proposed Occupational Uses of Bispyribac-sodium.

Crop/Use 

Site 

Product, 

Formulation 

Target of 

Application 

Maximum 

Application 

Rate 

Application Equipment Treatment 

Interval 

Surface 

weeds 0.1 lb ai/A 

Aerial (airplane or helicopter), 

Boat-Mounted Boom, Handgun 

Sprayer, Low-Pressure Handwand 

Sprayer, Backpack Sprayer 

30 days; do not 

apply more than 

8 oz product (0.4 

Aquatic lb ai)/A/year* 

weeds 

TradewindTM 

Herbicide 

(EPA Reg. #: 59639-

RAL) 

Soluble powder 

formulation packaged 

in water-soluble bags 

(80% a.i.) 

Subsurface 

weeds 

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

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

Page 8 of 31 

Conclusions: The proposed label recommends that when the product is to be applied to the 

foliage of floating or emerged aquatic weeds, an adjuvant approved for use in aquatic habitats 

should be included in the spray mix. The product may be tank mixed with other aquatic 

herbicides, such as 2,4-D or diquat dibromide. The label specifies that there is no postapplication holding restriction against use of treated water for drinking or recreational purposes 

(e.g., swimming, fishing). 

The proposed label specifies the following: 

• application is not to be made into flowing water, intertidal, or estuarine areas; 

• application is not to be made to water utilized for crayfish farming; 

• treated water is not to be used to irrigate food or ornamental crops until the concentration of 

bispyribac-sodium in water is ≤1 ppb [water may be analyzed using Enzyme-Linked 

Immunoassay (ELISA) or other approved analytical methods]; 

• subsurface applications are not be made to water bodies subject to rapid dilution. 

Conclusions: The proposed label is adequate to allow evaluation of the residue data relative to 

the proposed use. The petitioner should propose a minimum retreatment interval (RTI) for the 

subsurface application. Furthermore, the label should be revised to indicate that the treated water 

may not be used as a water source for livestock until the concentration of bispyribac-sodium in 

water is ≤1 ppb. 

HED recommends that the product label be made clearer with respect to the application rate. 

The label indicates the product is packaged in 2-oz bags; however, the application rates provided 

are 1 to 2 oz of formulated product/A for surface weeds and from 0.8 oz to 2.4 oz product/A-ft 

for subsurface weeds. If a handler must open packages to obtain fractions of an ounce to mix, 

the advantage of water-soluble packaging is lost. A revised Section B should be submitted. 

2.2 Structure and Nomenclature 

Table 2.2. Test Compound Nomenclature.

Compound 

O O

N

N

N

N

O O

OCH3

OCH3 OCH3

H3CO

Na+

Common name Bispyribac-sodium 

Company experimental name KIH-2023 

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

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

CAS registry number 125401-92-5 

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

Page 9 of 31 

Table 2.2. Test Compound Nomenclature.

Compound 

O O

N

N

N

N

O O

OCH3

OCH3 OCH3

OH

Na+

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

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

2.3 Physical and Chemical Properties 

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

Parameter Value Reference 

Melting range 223-224°C (pure active ingredient); 

decomposes at 219oC (technical grade) 

pH 6.45 (5 % w/v in water, 25°C) 

Density 1.29 g/mL (20°C) 

Water solubility 6.75 g/100 mL (25°C) 

Solvent solubility Shake flask method (25oC): 

ethyl acetate 1.98 x 10-4 g/100 mL 

dichloromethane 5.13 g/100 mL 

methanol 2.5 g/100 mL 

Column generator method (25°C): 

acetone 1.4 x 10-4 g/100 mL 

ethyl acetate 6.1 x 10-6 g/100 mL 

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

methyl chloride 1.3 x 10-4 g/100 mL 

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

toluene <1 x 10-5 g/100 mL 

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

Dissociation constant, pKa 3.05 

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

UV/visible absorption spectrum Not available 

RD Memorandum, S. Malak, 26-

APR-2001; DP# 267318

3.0 Hazard Characterization/Assessment 

3.1 Mammalian Toxicology 

The acute toxicity battery of 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 the 

reproduction toxicity study in rats. Males appear to be slightly more sensitive than females. 

Repeated dermal applications at the limit dose did not elicit systemic toxicity or dermal irritation. 

Bispyribac-sodium is negative for carcinogenicity in feeding studies in rats and mice and was 

classified as a “not likely human carcinogen” by HED’s Hazard Identification Assessment 

Review Committee [(HIARC); Memo, G. Reddy, 02-AUG-2001; HED Doc. No. 014647). 

Bispyribac-sodium was negative for fetal toxicity and showed no evidence of offspring 
Bispyribac-sodium Human-Health Risk Assessment DP# 361116 

Page 10 of 31 

susceptibility in both the developmental studies in rats and rabbits and in the reproduction study 

in rats. 

The battery of mutagenicity studies with the parent and three major metabolites were all 

negative. In the last risk assessment, the requirement of an in vitro mammalian cell gene 

mutation assay (OPPTS 870.5300) was cited as a 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 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. 

Acute and subchronic neurotoxicity studies are not available for bispyribac-sodium. There were 

clinical signs of potential neurotoxicity (i.e., piloerection, subnormal temperature, and decreased 

spontaneous motor activity) in the combined rat chronic/carcinogenicity study. However, these 

clinical signs occurred at a low incidence in the high dose group and were not dose-dependent. 

The primary effects of the study were based on macro- and microscopic changes in the liver and 

choldedochus, decreased body weights, and decreased food efficiency. There are no other signs 

of neurotoxicity in the database. 

In the rat metabolism study, 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. The total recovery of the 

administered radioactivity was 95.8-101.6% for all treatment groups. Most of the administered 

dose (>43%) was excreted in feces within 48 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]-bispyribac-sodium, whereas 

the parent and three metabolites were identified following administration of [14C-Bn]-bispyribacsodium. 

3.2 Dose-Response Assessment 

Table 3.2 summarizes the toxicological doses and endpoints for bispyribac-sodium for use in 

human-health risk assessment. 

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

Risk Assessments. 

Exposure 

Scenario 

Dose Used in 

Risk 

Assessment, 

UF 

FQPA SF and 

LOC for Risk 

Assessment Study and Toxicological Effects 

Acute Dietary 

all populations

Not Applicable Not Applicable No 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. 
Bispyribac-sodium Human-Health Risk Assessment DP# 361116 

Page 11 of 31 

Exposure 

Scenario 

Dose Used in 

Risk 

Assessment, 

UF 

FQPA SF and 

LOC for Risk 

Assessment Study and Toxicological Effects 

Short-Term 

Incidental Oral 

(1-30 days) 

(Residential) 

NOAEL = 100 

mg/kg/day 

LOC for MOE = 

100 

(includes FQPA SF 

= 1X) 

Developmental Toxicity Study - Rabbit 

Maternal LOAEL = 300 mg/kg/day based on 

lethargy, diarrhea and decreased body-weight gain in 

the range-finding study. 

IntermediateTerm Incidental 

Oral 

(1-6 months) 

(Residential) 

NOAEL = 100 

mg/kg/day 

LOC for MOE = 

100 

(includes FQPA SF 

= 1X) 

90-Day Feeding Study - Dog 

LOAEL = 600 mg/kg/day based upon salivation and 

slight proliferation of intrahepatic bile duct. 

Dermal, 

All Durations 

(Occupational/ 

Residential) 

Not Applicable Not Applicable No hazard via the dermal route was identified; 

therefore, risk 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. 

IntermediateTerm Inhalation 

(1-6 months) 

(Occupational/ 

Residential) 

Oral study 

NOAEL= 100 

mg/kg/day 

(inhalation 

absorption rate 

= 100%) 

LOC for MOE = 

100 (Occupational) 

LOC for MOE = 

100 (Residential, 

includes the FQPA 

SF = 1X) 

90-Day feeding study - Dog 

LOAEL = 600 mg/kg/day based upon salivation and 

slight proliferation of intrahepatic bile duct. 

Long-Term 

Inhalation 

(>6 months) 

(Occupational/ 

Residential) 

Oral study 

NOAEL= 10 

mg/kg/day 

(inhalation 

absorption rate 

= 100%) 

LOC for MOE = 

100 (Occupational) 

LOC for MOE = 

100 (Residential, 

includes the FQPA 

SF = 1X) 

Chronic Toxicity Study - Dog 

LOAEL = 100 mg/kg/day based on dose-related 

increases in hyperplasia of the intrahepatic bile ducts 

in males and females and granulation of the liver in 

the females. 

Cancer (oral, 

dermal, 

inhalation) 

“not likely” Not Applicable No evidence of carcinogenic or mutagenic potential. 

A cancer risk assessment is not required. 

Abbreviations: UF = uncertainty 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. 

Based on the available toxicity database and the Agency's current practices, the inhalation risk 

for bispyribac-sodium was assessed using an oral toxicity study. The Agency sought expert 

advice and input on issues related to this route-to-route extrapolation approach (i.e., the use of 
Bispyribac-sodium Human-Health Risk Assessment DP# 361116 

Page 12 of 31 

oral toxicity studies for inhalation risk assessment) from its Federal Insecticide, Fungicide, and 

Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009. The Agency 

received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report and may, as appropriate, re-examine and develop new 

policies and procedures for conducting inhalation risk assessments, including route-to-route 

extrapolation of toxicity data. 

3.3 FQPA Considerations

The toxicological database for bispyribac-sodium is complete with the exception of 

immunotoxicity, acute neurotoxicity, and subchronic neurotoxicity studies, which are new 

(2007) regulatory requirements under 40 CFR Part 158, as well as a 28-day inhalation study. A 

28-day inhalation toxicity study was requested previously by HED’s HIARC in 2001 (HED Doc. 

No. 014647). Consistent with the previous risk assessment for bispyribac-sodium (2001), the 

RAB1 bispyribac-sodium risk assessment team recommends that the FQPA SF be reduced to 1X. 

This decision is based on the following: 

• There is no indication of quantitative or qualitative increased susceptibility of rats or 

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

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

• The level of concern for neurotoxicity is low. Although there were clinical signs 

indicative of neurotoxicity (e.g., piloerection, subnormal temperature, and decreased 

spontaneous motor activity) in the combined rat chronic/carcinogenicity study, these 

occurred at a low incidence in the high-dose group and were not dose-dependent. The 

primary effects of the study were based on macro- and microscopic changes in the liver 

and choldedochus, decreased body weights, and decreased food efficiency. Although 

acute and subchronic neurotoxicity studies are now required as part of the revisions to 40 

CFR Part 158, bispyribac-sodium has shown no indications of central or peripheral 

nervous system toxicity in any study and does not appear to be structurally related to any 

other chemical that causes adverse nervous system effects. 

• The toxicology database for bispyribac-sodium does not show any evidence of treatmentrelated effects on the immune system. The overall weight of evidence suggests that this 

chemical does not directly target the immune system. An immunotoxicity study is 

required as a part of new data requirements in the 40 CFR Part 158 for conventional 

pesticide registration; however, the Agency does not believe that conducting a functional 

immunotoxicity study will result in a lower point of departure than that currently used for 

overall risk assessment, and therefore, a database uncertainty factor (UFDB) is not needed 

to account for lack of this study. 

• A 28-day inhalation study is not available; however, the EPA has determined that the 

additional FQPA SF is not needed. Based on the very low vapor pressure of bispyribacsodium (3.79 x 10-11 at 250

C) and because the residential use pattern is limited to golf 

courses and swimming areas, minimal potential for inhalation exposure is expected. 

Therefore, the risk estimate is conservative and is considered protective and the 

additional FQPA SF is not needed. 

• The dietary food and drinking water exposure assessments are conservative and will not 

underestimate the potential exposures for infants and children. 

• The residential exposure assessment was conducted using high-end estimates of use and 

potential exposure providing a conservative, health-protective estimate of risk. 
Bispyribac-sodium Human-Health Risk Assessment DP# 361116 

Page 13 of 31 

3.4 Endocrine Disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor 

Screening Program (EDSP) to determine whether certain substances (including pesticide active 

and other ingredients) may have an effect in humans or wildlife similar to an effect produced by 

a “naturally occurring estrogen, or other such endocrine effects as the Administrator may 

designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect. 

Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first 

group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. 

This list of chemicals was selected based on the potential for human exposure through pathways 

such as food and water, residential activity, and certain post-application agricultural scenarios. 

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

Bispyribac-Sodium was not among the group of 58 pesticide active ingredients on the initial list 

to be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide 

chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all 

pesticide active ingredients. 

For further information on the status of the EDSP, the policies and procedures, the list of 67 

chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: 

http://www.epa.gov/endo/

4.0 Dietary Exposure/Risk Characterization 

The residue chemistry data submitted in support of proposed petitions were evaluated by HED 

on 07-JUL-2010 (Memo, S. Levy, DP# 363347). The drinking water assessment was completed 

by EFED on 27-OCT-2009 (Memo, C. Sutton, DP# 362285). The dietary exposure assessment 

was completed by HED on 07-JUL-2010 (Memo, S. Levy, DP# 363348). 

4.1 Residue Profile

Nature of the Residue

Plants: Adequate plant metabolism studies are available depicting the metabolism of 

[

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. The decision was based on the following considerations: (1) all 

metabolites identified were present at low levels in the plant and livestock metabolism studies; 

(2) bispyribac-sodium has a low toxicity profile and the metabolites are not expected to be more 

toxic than the parent; and (3) the identified metabolites are also metabolites in rats and their 

toxicity was assessed in the rat metabolism studies. 

 
Bispyribac-sodium Human-Health Risk Assessment DP# 361116 

Page 14 of 31 

Livestock: 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, 

and the considerations listed above for plant metabolism, HED previously determined that the 

parent compound is the only residue of concern for purposes of both risk assessment and the 

tolerance expression in livestock commodities. HED noted that if additional uses are requested 

in the future which significantly increase the poultry dietary burden, a poultry metabolism study 

with benzene-labeled bispyribac-sodium may be required. 

Fish: HED previously concluded that a fish metabolism study would not be required to support 

the proposed use associated with DP# 361116, but required that samples from the fish residue 

study be analyzed for bispyribac-sodium and its metabolite des-methyl KIH-2023, a major 

residue in the anaerobic aquatic metabolism study [minutes of 30-MAY-2007 meeting of the 

HED Chemistry Science Advisory Council (ChemSAC)]. For purposes of this petition, HED 

recommends that the requirement for a fish metabolism study be waived, but that samples from 

the fish magnitude of the residue study should be analyzed for bispyribac-sodium and its 

metabolite des-methyl KIH-2023, a major residue in the anaerobic aquatic metabolism study. 

Residue Analytical Methods

Valent has submitted a high-performance liquid chromatography (HPLC) method with tandem 

mass spectroscopy detection (MS/MS), Method GPL-MTH-068. The method determines 

residues of bispyribac-sodium and des-methyl 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. The petitioner has also submitted a slightly-revised 

version of the data-collection method, GPL-MTH-068a which demonstrated an additional 

cleanup step as an option for the confirmation technique and an addition of alternate analytical 

conditions for LC-MS/MS analysis which can serve as an enforcement method. 

Multiresidue Methods (MRM)

Data pertaining to the MRM testing of bispyribac-sodium were previously submitted in 

conjunction with PP#9F6044 (Memo, J. Tyler, 23-AUG-2001; DP# 267306). The study results 

indicate that bispyribac-sodium is not likely to be recovered through the U.S. Food and Drug 

Administration (FDA) MRM protocols. 

Magnitude of Residues in Fish

The submitted fish magnitude of the residue study is adequate and supports the proposed aquatic 

use. The study investigated residues of bispyribac-sodium and its des-methyl metabolite in 

freshwater fish (bluegill or catfish) for up to 28 days following application of bispyribac-sodium 

to water at 0.090 mg/L (90 ppb). Residues were determined using the proposed enforcement 

method (GPL-MTH-068). The method was adequately validated in conjunction with the 

analysis of the study samples. 

The available data demonstrate that bispyribac-sodium residues in water remained consistent 

throughout the study period, and residues of bispyribac-sodium and des-methyl KIH-2023 were 

nonquantifiable in fish tissue over the 28-day exposure period. Based on the results of the study, 

HED concludes that the residues of concern in fish for tolerance enforcement and risk 
Bispyribac-sodium Human-Health Risk Assessment DP# 361116 

Page 15 of 31 

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

The proposed aquatic uses prohibit applications into flowing water, intertidal or estuarine areas, 

or areas where crayfish farming is practiced. No residue studies with shellfish or mollusks are 

needed to support the proposed use. 

A residue study with irrigated crops has been submitted previously which indicates the potential 

for quantifiable residues in/on irrigated crops treated with irrigation water containing bispyribacsodium at 64 ppm. Tolerances for irrigated crops will not be needed to support the proposed use 

because the proposed label prohibits use of treated water to irrigate food crops until the 

concentration of bispyribac-sodium in water is ≤1 ppb. 

Magnitude of Residues in Meat, Milk, Poultry and Eggs (MMPE)

As livestock may be exposed to bispyribac-sodium through the consumption of treated water, the 

proposed aquatic use results in significantly increased dietary burdens to livestock. HED can no 

longer conclude that there is no expectation of finite residues of bispyribac-sodium in livestock 

commodities. HED would normally recommend that the petitioner submit ruminant and poultry 

feeding studies to support the proposed use. However, Valent requested a waiver for ruminant 

and poultry feeding studies. The basis for this request was that (1) quantifiable residues would 

not be expected at the 1X dietary burden, (2) the low likelihood of livestock consuming treated 

water, and (3) the low likelihood that the water would contain the maximum labeled 

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

TradewindTM label is 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). A revised Section B should be submitted. 

Tolerance Summary

Valent has proposed the establishment of tolerances for residues of the herbicide bispyribacsodium, including its metabolites and degradates, in or on the commodities listed below in Table 

4.1. Compliance with the tolerance levels specified below is to be determined by measuring only 

bispyribac-sodium, (2,6-bis[(4,6-dimethoxy-2-pyrimidinyl)oxy]benzoic acid, sodium salt), in or 

on the RACs listed below. 

The available data will support a tolerance for bispyribac-sodium in fish at the LOQ (0.01 ppm). 

The petitioner should submit a revised Section F, removing the proposed tolerance levels for 

livestock and poultry commodities. 

There are currently no established Codex, Canadian, or Mexican maximum residue limits 

(MRLs) for residues of bispyribac-sodium in/on fish matrices. Therefore, no compatibility 

issues exist with regard to the proposed U.S. tolerance. 
Bispyribac-sodium Human-Health Risk Assessment DP# 361116 

Page 16 of 31 

Table 4.1. Tolerance Summary for Bispyribac-Sodium. 

Commodity Proposed Tolerance 

 (ppm) 

HED-Recommended 

Tolerance (ppm)1

Comments; 

Correct Commodity Definition

Fish, freshwater 0.01 0.01 

Cattle, goat, hog, horse, and 

sheep, meat byproducts 

0.03 - 

Cattle, goat, hog, horse and 

sheep, meat 

0.01 - 

Cattle, goat, hog, horse and 

sheep, fat 

0.01 - 

Milk 0.01 - 

Poultry, meat byproducts 0.01 - 

Egg 0.01 - 

Poultry, fat 0.01 - 

Poultry meat 0.01 - 1 Tolerances for livestock commodities are not needed as long as the TradewindTM label is 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).

4.2 Environmental Degradation

Bispyribac-sodium is a moderately persistent, mobile compound on most soils. In soil, 

bispyribac-sodium is stable to abiotic degradation. The primary degradation pathways in soil 

and aquatic environments are aerobic and anaerobic metabolism, with the formation of multiple 

major metabolites: sodium 2-(4,6-dimethoxypyrimidin-2-yl)oxy-6-(4-hydroxy-6-

methoxypyrimidin-2-yl) benzoate (DesMe-2023); 2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-

hydroxybenzoate (Bx-180); 2-hydroxy-6-[(4-hydroxy-6-methoxypyrimidin-2-yl)oxy] benzoic 

acid (DesMe-180); 2,6-dihydroxybenzoic acid (2,6-DBA); 4,6-dihydroxy-2-methoxypyrimidine 

(MeBa); and 4,6-dimethoxy-2-hydroxypyrimidine (Me2Ba). Bispyribac-sodium residues further 

degrade in soil, eventually mineralizing to carbon dioxide. When applied directly to water, 

bispyribac-sodium is stable to abiotic degradation by hydrolysis and aqueous photolysis. It is 

likely to partition predominantly to the water column. Bispyribac-sodium is subject to microbial 

degradation under aerobic and anaerobic conditions, with slower degradation observed in 

anaerobic aquatic environments (half-lives of 88-109 days) relative to aerobic soil (half-life of 62 

days) or aerobic aquatic environments (half-lives of 46-82 days). 

In an aquatic field dissipation study conducted at one site in Florida, bispyribac-sodium degraded 

with a half-life of 25 days after being directly applied to the surface water via subsurface 

injection. However, the study was not conducted at the maximum label rate, but used only a 

single application targeted to achieve an aqueous concentration of 45 ppb. The major degradate, 

and only degradate monitored in the study, was DesMe-2023, which was present at a maximum 

of 4.3 ppb (day 28) and degraded with a half-life of 36 days. 

4.3 Pesticide Metabolites and Degradates of Concern

The nature of the residue in rice, hen, and goat metabolism studies is adequately understood 

based on acceptable metabolism studies conducted on these commodities. Based on these 

studies, the residues of concern in rice and livestock commodities, as well as drinking water, are 

as follows (Memo, J. Tyler, 23-AUG-2001; DP# 267306): 
Bispyribac-sodium Human-Health Risk Assessment DP# 361116 

Page 17 of 31 

Rice: bispyribac-sodium (risk assessment and tolerance expression) 

Livestock: bispyribac-sodium (risk assessment and tolerance expression) 

Drinking water: bispyribac-sodium (risk assessment) 

4.4 Drinking Water Residue Profile 

The drinking water residues used in the dietary risk assessment were provided by EFED (Memo, 

C. Sutton, 27-OCT-2009; DP# 362285) and incorporated directly into this dietary assessment. 

Monitoring data are not unavailable for bispyribac-sodium. Because currently used Tier 1 

aquatic exposure models to simulate agricultural uses and are not appropriate for determining 

EDWCs for aquatic uses of pesticides applied directly to surface water bodies, EFED 

recommended using the maximum annual label target rate of 180 ppb for subsurface injection of 

bispyribac-sodium into water. This value represents the maximum cumulative concentration in 

water based on four applications (assumed, not specified on the label), at unspecified intervals, 

needed to achieve a 45-ppb level of bispyribac-sodium in the water column. Because this 

chemical is only moderately persistent and will undergo degradation in the environment between 

applications, this value can be considered conservative. The water residue value of 180 ppb was 

incorporated in the DEEM-FCIDTM into the food categories “water, indirect, all sources,” and 

“water, direct, all sources.” 

4.5 Dietary Exposure and Risk

A chronic dietary exposure assessment was conducted using DEEM-FCIDTM Version 2.03, which 

incorporates consumption data from USDA’s CSFII, 1994-1996 and 1998. The 1994-96, 98 data 

are based on the reported consumption of more than 20,000 individuals over two nonconsecutive survey days. For chronic exposure assessment, consumption data are averaged for 

the entire U.S. population and within population subgroups, but for acute exposure assessment 

are retained as individual consumption events. 

For chronic dietary exposure assessments, an estimate of the residue level in each food or foodform (i.e., orange or orange juice) on the food commodity residue list is multiplied by the 

average daily consumption estimate for that food/food form to produce a residue intake estimate. 

The resulting residue intake estimate for each food/food form is summed with the residue intake 

estimates for all other food/food forms on the commodity residue list to arrive at the total 

average estimated exposure. Exposure is expressed in mg/kg body weight/day and as a percent 

of the PAD. This procedure is performed for each population sub group. 

4.5.1 Acute Dietary Exposure/Risk

No toxic effects attributable to a single exposure to bispyribac-sodium have been identified; 

therefore, an aRfD has not been established for bispyribac-sodium and an acute dietary exposure 

assessment is not required. 

4.5.2 Chronic Dietary Exposure/Risk

An unrefined, chronic dietary exposure assessment was conducted assuming tolerance-level 

residues (for all registered and proposed new uses), DEEMTM 7.81 default processing factors, and 

100% crop treated (CT). Drinking water was incorporated directly into the dietary assessment. 

The use of anticipated residues (ARs), empirical processing factors, and %CT data would refine 
Bispyribac-sodium Human-Health Risk Assessment DP# 361116 

Page 18 of 31 

further HED’s exposure and risk estimates. However, refinement of the dietary exposure 

estimates is not needed at this time. 

Bispyribac-sodium chronic dietary (food + drinking water) exposure estimates using the DEEMFCIDTM software are not of concern for the U.S. population or any of the population subgroups. 

Dietary exposure was estimated at 0.003800 mg/kg/day for the U.S. population (3.8% of the 

cPAD) and 0.012453 mg/kg/day (12.5% of the cPAD) for the most highly exposed population 

subgroup (all infants, <1 year old). The estimated exposures/risks from food and water are 

summarized in Table 4.5.2 for all populations. 

Table 4.5.2. Summary of Dietary (Food and Drinking Water) Exposure Risk for Bispyribac-sodium.

Chronic Dietary 

Population Subgroup Dietary Exposure (mg/kg/day) % cPAD 

General U.S. Population 0.003800 3.8 

All Infants (<1 year old) 0.012453 12.5 

Children 1-2 years old 0.005646 5.6 

Children 3-5 years old 0.005285 5.3 

Children 6-12 years old 0.003645 3.6 

Youth 13-19 years old 0.002748 2.7 

Adults 20-49 years old 0.003548 3.5 

Adults 50+ years old 0.003731 3.7 

Females 13-49 years old 0.003533 3.5 1 Chronic dietary endpoint of 0.1 mg/kg/day applies to the general U.S. population and all population subgroups. The 

population subgroup with the highest estimated chronic dietary (food + drinking water) exposure and risk is indicated by 

bold text. 

4.5.3 Cancer Dietary Risk

There is no evidence that bispyribac-sodium is carcinogenic to humans; therefore, a cancer 

dietary exposure assessment is not required. 

5.0 Residential (Non-Occupational) Exposure/Risk Pathway 

Bispyribac-sodium is currently registered for use on golf courses and sod farms (Memo, M. 

Dow, 09-OCT-2003, DP# 289929; M. Dow, 27-MAR-2008; DP# 349324); and is proposed for 

aquatic use. Residential exposure may occur as a result of the registered and proposed uses. 

5.1 Residential Handler Exposures and Risks 

No residential handler exposure is expected from the proposed and registered uses of bispyribacsodium. For the proposed aquatic use, the label indicates 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. 

5.2 Residential Postapplication Exposures and Risks 

Residential postapplication exposure following use of bispyribac-sodium on golf courses and sod 

farms is possible. A dermal postapplication assessment was not performed since there is no 

short-term dermal point of departure. Based on the Agency's current practices, a quantitative 

postapplication inhalation exposure assessment was not performed for bispyribac-sodium at this 

time primarily because the vapor pressure of bispyribac-sodium is low (3.79 x 10-11 mm Hg at 
Bispyribac-sodium Human-Health Risk Assessment DP# 361116 

Page 19 of 31 

25°C). However, volatilization of pesticides may be a potential source of postapplication 

inhalation exposure to individuals nearby to pesticide applications. The Agency sought expert 

advice and input on issues related to volatilization of pesticides from its FIFRA SAP in 

December 2009. The Agency received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the process of 

evaluating the SAP report and may, as appropriate, develop policies and procedures to identify 

the need for and, subsequently, the way to incorporate postapplication inhalation exposure into 

the Agency's risk assessments. If new policies or procedures are put into place, the Agency may 

revisit the need for a quantitative postapplication inhalation exposure assessment for bispyribacsodium. 

For the proposed aquatic use, bispyribac-sodium can treat water bodies (e.g., lakes) at 

concentrations up to 45 ppb. Therefore, there is a potential for exposure to recreational users 

(i.e., swimmers) in these water bodies. Postapplication exposure and risks were developed for 

the non-competitive adult and child swimmer. Exposure is expected to be short-term; however, 

since the short- and intermediate-term points of departure are the same, the short-term 

assessment is protective of intermediate-term exposures. 

A series of assumptions and exposure factors served as the basis for completing the residential 

postapplication risk assessment. The assumptions and factors used in the risk calculations are 

consistent with current Agency policy for completing residential exposure assessments (i.e., 

Standard Operating Procedures (SOPs) for Residential Exposure Assessment, 1997). Only oral 

postapplication exposure to recreational swimmers is assessed in this document. Dermal 

postapplication exposures were not assessed since no short-term dermal point of departure was 

selected. The values and assumptions used in this assessment include: 

• Maximum concentration in water = 45 ppb in accordance with label restrictions. It is 

assumed that 100% of the application concentration is available in the water for oral 

ingestion. 

• Duration of exposure = 5 hours a day -- assumed for both adults (18-64 years old) and 

children (6 years old). This exposure duration is based on the 90th percentile value for 

time spent at home in a swimming pool from the 1996 Exposure Factors Handbook. 

• Mean ingestion rate for adult and children swimmers is 0.05 L/hour. This ingestion rate 

is based on HED’s swimmer model typically used to assess competitive swimmers in 

pools who tend to swim with their heads partially immersed in the water and can ingest 

larger amounts of water. It is anticipated that recreational swimmers in weed infested 

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

amounts of water. 

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

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

Risks were calculated using the MOE approach, which is a ratio of the body burden to the 

toxicological point of departure. The following calculations and equations were used to 

determine oral exposure as a result of swimming in aquatic areas treated with bispyribac-sodium. 

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

Where: 
Bispyribac-sodium Human-Health Risk Assessment DP# 361116 

Page 20 of 31 

Cw = concentration in water (mg/L), 

IgR = ingestion rate of water (L/hr), 

ET = exposure time (hr/day), and 

BW = body weight (kg). 

The total UF that has been applied to the residential postapplication risk assessment for 

bispyribac-sodium is 100. Short-term incidental ingestion risks were greater than 100 for 

noncompetitive adult and child swimmers and, therefore, do not exceed HED’s level of concern. 

A summary of the short-term postapplication risks for adults and children is provided in Table 

5.2. 

Table 5.2. Short -Term Postapplication Exposure for Adults and Children Swimmers to Bispyribacsodium. 

Exposure 

Scenario 

Cw1 

(mg/L) 

IgR2 

(L/hr) 

ET3 

(hr/day) BW4

 (kg) Oral Dose5

(mg/kg/day) Adult MOE6 Child MOE7

70 1.61E-04 Oral 0.045 0.05 5 

22 5.11E-04 620,000 200,000 

1 Cw = concentration in water (45 ppb = 0.045 mg/L). 

2 IgR = ingestion rate of water (0.05 L/hr). 

3 ET =exposure time (5 hr/day). 

4 BW = body weight = 70 kg for adults and 22 kg for children. 

5 Oral Dose = (Cw x IgR x ET)/BW. 

6 Adult MOE = NOAEL (100 mg/kg/day)/Adult Dose (mg/kg/day). 

7 Child MOE = NOAEL (100 mg/kg/day)/Child Dose (mg/kg/day). 

5.3 Residential Bystander Inhalation Exposure 

Based on the Agency's current practices, a quantitative postapplication inhalation bystander 

exposure assessment was not performed for bispyribac-sodium at this time. However, 

volatilization of pesticides may be a potential source of postapplication inhalation exposure to 

individuals nearby to pesticide applications. The Agency sought expert advice and input on 

issues related to volatilization of pesticides from its FIFRA SAP in December 2009. The 

Agency received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the process of 

evaluating the SAP report and may, as appropriate, develop policies and procedures to identify 

the need for and, subsequently, the way to incorporate postapplication inhalation exposure into 

the Agency's risk assessments. If new policies or procedures are put into place, the Agency may 

revisit the need for a quantitative postapplication inhalation exposure assessment for bispyribacsodium. 

5.4 Spray Drift 

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for bispyribacsodium. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices 

and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices. The Agency is now requiring interim mitigation measures for aerial 

applications that must be placed on product labels/labeling. The Agency has completed its 

evaluation of the new data base submitted by the Spray Drift Task Force, a membership of U.S. 

pesticide registrants, and is developing a policy on how to appropriately apply the data and the 

AgDRIFT® computer model to its risk assessments for pesticides applied by air, orchard airblast 
Bispyribac-sodium Human-Health Risk Assessment DP# 361116 

Page 21 of 31 

and ground hydraulic methods. After the policy is in place, the Agency may impose further 

refinements in spray drift management practices to reduce off-target drift and risks associated 

with aerial as well as other application types where appropriate. 

6.0 Aggregate Risk Assessments and Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

risks from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard, or the risks themselves can be aggregated. When aggregating exposures and 

risks from various sources, HED considers both the route and duration of exposure. Since there 

are residential uses registered, HED conducted a residential aggregate assessment for bispyribacsodium. 

6.1 Acute Aggregate Risk

An endpoint of concern was not identified to quantify acute-dietary risk to the general population 

or to any population subgroup. Since an acute dietary endpoint was not identified, an acute 

hazard does not exist and an acute aggregate assessment was not performed. 

6.2 Short-and Intermediate-Term Aggregate Risks

Only a short-term aggregate risk assessment was conducted since the residential use pattern is 

expected to only result in short-term exposures; however, since the short- and intermediate-term 

points of departure are the same, the short-term aggregate assessment is protective of 

intermediate-term exposures. Short- and intermediate-term aggregate risks are made up of 

dietary and non-dietary sources of exposure. Dietary (food + drinking water) exposure estimates 

are based on a conservative, unrefined chronic dietary exposure assessment (see Table 4.5.2). 

Non-dietary (residential) exposure estimates are conservative estimates due to the standard 

assumptions that were built into the calculations (see Section 5.0). Based on the 

proposed/registered bispyribac-sodium uses, HED anticipates only incidental oral exposures to 

adults and children. The populations included in Table 6.2 represent the adult and children 

populations with the highest dietary (food + drinking water) exposures (the U.S. population was 

included as well). 

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

Population 

Dietary (Food + 

Drinking Water) Exposure1

(mg/kg/day) 

Residential 

Exposure2, 3

(mg/kg/day) 

Aggregate 

MOE4

U.S. Population 0.003800 0.000161 25,000 

Adults 50+ years olds 0.003731 0.000161 26,000 

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

1

 Average dietary (food + drinking water) exposure for the respective populations from Table 4.5.2. 2

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

 Post-application exposure for children swimmers (See Table 5.2). 4

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

100. 
Bispyribac-sodium Human-Health Risk Assessment DP# 361116 

Page 22 of 31 

As can be seen in Table 6.2, the short- and intermediate-term aggregate MOEs for the general 

U.S. population, as well as the population subgroups children and adults are not of concern to 

HED. 

6.3 Chronic (Long-Term) Aggregate Risk

Chronic (long-term) aggregate risk is made up only of dietary sources; therefore, the chronic 

exposure estimates provided in the chronic dietary exposure analysis represents chronic 

aggregate exposure. 

6.4 Cancer Aggregate Risk

Aggregate cancer risk was not calculated because bispyribac-sodium was classified as “not likely 

to be carcinogenic to humans.” 

7.0 Cumulative Risk Characterization/Assessment

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to bispyribac-sodium and any other substances and spirotetramat does not appear to produce a 

toxic metabolite produced by other substances. For the purposes of this tolerance action, 

therefore, EPA has not assumed that bispyribac-sodium has 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/.

8.0 Occupational Exposure/Risk Pathway

The occupational exposure and risk assessment was performed by HED (Memo, K. Lowe, 21-

JUL-2010; DP# 363349). It is anticipated that there will be occupational handler and 

postapplication exposure from the proposed uses of bispyribac-sodium. Based on label 

information (a maximum of 4 applications per year; 30 days apart), exposure is expected to occur 

for short- and intermediate-term durations. 

8.1 Occupational Handler Exposure/Risk 

Application methods, maximum application rates and use sites for the proposed use of 

bispyribac-sodium are summarized in Table 2.1. No chemical-specific data were available with 

which to assess potential exposure to pesticide handlers. Where applicable, the estimates of 

exposure to pesticide handlers are based upon surrogate study data available in PHED (August, 

1998). There are no exposure data in PHED specific to application of sprays from a boat, 

application of sprays from a helicopter, or from the use of water-soluble bags with handheld 

equipment; therefore, the following surrogate unit exposures from PHED were used: 

• The inhalation unit exposure for aerial application (fixed wing) was used for 

rotary (helicopter) applications. 
Bispyribac-sodium Human-Health Risk Assessment DP# 361116 

Page 23 of 31 

• The inhalation unit exposure for open-cab groundboom applications was used for 

boat-mounted boom (surface) and boat-mounted trailing hose (subsurface) 

applications. 

• The inhalation unit exposure for mixing/loading/applying liquids with a backpack 

sprayer was used for mixing/loading/application of water-soluble bags with a 

backpack sprayer. 

• The inhalation unit exposures for mixing/loading/applying wettable powders with 

a handgun and low-pressure handwand sprayer were used for mixing/loading/ 

application of water-soluble bags with a handgun and low-pressure handwand 

sprayer. 

NOTE: The product label could be made clearer with respect to the application rate. The label 

indicates the product is packaged in 2-oz bags; however, the application rates provided are 1 to 2 

oz of formulated product/A for surface weeds and from 0.8 oz to 2.4 oz product/A-ft for 

subsurface weeds. If a handler must open packages to obtain fractions of an ounce to mix, the 

advantage of water-soluble packaging is lost. Therefore, this assessment assumes open 

mixing/loading of a wettable powder (used as surrogate for SP formulation). 

The following exposure scenarios have been assessed for occupational handlers: 

Mixer/Loaders

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

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

Applicators

• Applying sprays with aircraft, 

• Applying sprays with groundboom equipment, 

Flaggers 

• Flagging to support aerial spray applications,

Mixer/Loader/Applicators

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

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

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

For pesticide handlers, HED presents estimates of dermal exposure for “baseline” (i.e., workers 

wearing a single layer of work clothing consisting of a long-sleeved shirt, long pants, shoes plus 

socks, and no protective gloves), as well as for “baseline” and the use of protective gloves or 

other PPE, as might be necessary. The bispyribac-sodium product labels direct applicators and 

other handlers must wear a long-sleeved shirt and long pants, chemical-resistant gloves, and 

shoes plus socks. 

The daily areas treated were based on information from (1) HED Exposure Science Advisory 

Committee (ExpoSAC) SOP No. 9.1, (2) a previous endothall assessment for aquatic uses 

(Memo, S. Tadayon, 12-AUG-2005, DP# 319373), (3) a SRRD memo from a meeting between 

the Agency and the Army Corp Of Engineers to discuss assumptions used in aquatic risk 

assessment (SRRD, Mika Hunter, 27-JUL-2005), and (4) registrant-proposed values. 
Bispyribac-sodium Human-Health Risk Assessment DP# 361116 

Page 24 of 31 

For surface applications, the area treated in a day was assumed to be: 

• 150 and 350 acres for mixing/loading to support aerial applications, applying sprays with 

aircraft, and flagging to support aerial applications, 

• 30 acres for mixing/loading to support groundboom applications and applying sprays 

with groundboom equipment, and 

• 10 acres for mixing/loading/applying with handgun, low-pressure handwand and 

backpack sprayer. 

For subsurface applications, the area treated in a day was assumed to be 30 acres for 

mixing/loading to support groundboom applications and applying sprays with groundboom 

equipment. An eight foot depth was assumed for subsurface applications. 

Daily inhalation handler exposures are estimated for each applicable handler task with the 

application rate, the area treated in a day, and the applicable inhalation unit exposure using the 

following formula: 

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

Where: 

Daily Exposure = amount (mg ai/day) inhaled that is available for inhalation absorption; 

UE = unit exposure value (mg ai/lb ai); 

AR = application rate (e.g., lb ai/A); and 

A = application area (e.g., A/day). 

The daily inhalation dose is calculated by normalizing the daily exposure by body weight and 

adjusting, if necessary, with an appropriate inhalation absorption factor using the following 

formula: 

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

Where: 

Average Daily Dose = absorbed dose received from exposure to a pesticide in a given scenario (mg 

ai/kg body weight/day); 

Daily Exposure = amount (mg ai/day) inhaled that is available for inhalation absorption; 

AF = absorption factor which is a measure of the amount of chemical that crosses a 

biological boundary such as the skin or lungs (% of the total available 

absorbed); and 

BW = body weight determined to represent the population of interest in a risk 

assessment (kg). 

Non-cancer inhalation risks for each applicable handler scenario are calculated using a MOE, 

which is a ratio of the NOAEL to the daily dose. All MOE values were calculated using the 

formula below: 

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

Table 8.1 presents the short- and intermediate-term estimated inhalation risks for occupational 

handlers. The inhalation risks to handlers do not exceed HED’s level of concern at baseline (no 

respirator) for any of the handler scenarios where baseline data are available. Only engineering 
Bispyribac-sodium Human-Health Risk Assessment DP# 361116 

Page 25 of 31 

control (enclosed cockpit) data are available to assess inhalation risks to handlers operating 

aircraft. The inhalation risks do not exceed HED’s level of concern for pilots using enclosed 

cockpits and wearing no respirator. Even though dermal exposures were not assessed due to lack 

of a dermal point of departure, handlers should still wear label prescribed PPE (long-sleeved 

shirt and long pants, chemical-resistant gloves, and shoes plus socks). 
Bispyribac-sodium Human-Health Risk Assessment DP# 361116 

Page 26 of 31 

Table 8.1. Short- and Intermediate-Term Handler Exposures and Risks for Bispyribac-sodium.

Inhalation Unit 

Exposure (ug/lb ai)3

Inhalation 

(mg/kg/da

Exposure Scenario Crop or Target Application Rate1 Application Rate Units 

Area 

Treated 

Daily 

(acres)2

Water 

Depth 

(feet) Baseline Engineering Control Baseline E

Mixer/Loader 

Mixing/Loading Water- Surface weeds 0.1 lb ai/acre 350 NA NA 0.24 0.022 

Soluble Bags for Aerial 

Applications Surface weeds 0.1 lb ai/acre 150 NA NA 0.24 0.0092 

Mixing/Loading Water- Surface weeds 0.1 lb ai/acre 30 NA NA 0.24 0.0018 

Soluble Bags for 

Groundboom Applications 

Subsurface 

weeds 0.12 lb ai/acre- foot 30 8 NA 0.24 0.018 

Applicator 

Applying Sprays via Aerial Surface weeds 0.1 lb ai/acre 350 NA No Data 0.068 No Data 

Equipment Surface weeds 0.1 lb ai/acre 150 NA No Data 0.068 No Data 

Subsurface 

weeds 0.1 lb ai/acre 30 NA 0.74 NA 0.000032 

Applying Sprays via 

Groundboom Equipment Subsurface 

Weeds 0.12 lb ai/acre- foot 30 8 0.74 NA 0.0003 

Flagger 

Flagging for Aerial Sprays 

Applications Surface weeds 0.1 lb ai/acre 150 NA 0.35 NA 0.000075 

Mixer/Loader/Applicator 

Mixing/Loading/Applying 

Wettable Powders with 

Low-Pressure Handwand 

(PHED) 

Surface weeds 0.1 lb ai/acre 10 NA 1,100 No Data 0.016 

Mixing/Loading/Applying 

Liquids with a Backpack 

(PHED) 

Surface weeds 0.1 lb ai/acre 10 NA 30 No Data 0.00043 

Mixing/Loading/Applying 

Wettable Powders with a 

Handgun Sprayer 

(LCO ORETF data) 

Surface weeds 0.1 lb ai/acre 10 NA 64 No Data 0.00091 

1 Application Rates based on proposed uses on label for bispyribac-sodium TradewindTM Herbicide. 2 The daily areas treated were based on information from (1) HED ExpoSAC SOP No. 9.1, (2) a previous endothall assessment for aquatic uses (Memo, S. Tad

319373), (3) a SRRD memo from a meeting between the Agency and the Army Corp Of Engineers to discuss assumptions used in aquatic risk assessment (SR

and (4) registrant-proposed values. 

3 Unit Exposures based on PHED Version 1.1. Baseline: no respirator. Engineering control: water-soluble bags or enclosed cockpit. 

4 Inhalation Dose (mg/kg/day) = unit exposure (μg/lb ai) * 1E-03 mg/ug * application rate (lb ai/acre) * acres treated * inhalation absorption (100%) / body we

5 Inhalation MOE = NOAEL (100 mg/kg/day)/inhalation daily dose (mg/kg/day). LOC = 100.
Bispyribac-sodium Human-Health Risk Assessment DP# 361116 

Page 27 of 31 

8.2 Occupational Postapplication Exposure/Risk 

Postapplication occupational exposures following bispyribac-sodium application to aquatic areas 

is likely limited to persons who contact the treated water to perform tests, such as testing the 

levels of bispyribac-sodium. Short- and intermediate-term dermal postapplication exposures and 

risks were not assessed for bispyribac-sodium, since no dermal points of departure were 

identified. Based on the Agency's current practices, a quantitative occupational postapplication 

inhalation exposure assessment was not performed for bispyribac-sodium at this time. However, 

there are multiple potential sources of postapplication inhalation exposure to individuals 

performing postapplication activities in previously treated areas, including volatilization of 

pesticides. If new policies or procedures are put into place, the Agency may revisit the need for 

a quantitative occupational postapplication inhalation exposure assessment for bispyribacsodium. 

9.0 Data Needs and Label Recommendations 

9.1 Toxicology 

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

• Acute neurotoxicity study. 

• Subchronic neurotoxicity study. 

• 28-day inhalation study. 

9.2 Residue Chemistry 

• The petitioner should submit a revised Section B proposing a minimum RTI for the 

subsurface application. Furthermore, a revision should be made to the label indicating 

that the treated water may not be used as a water source for livestock until the 

concentration of bispyribac-sodium in water is <1 ppb. 

• The petitioner should submit a revised Section F which states that “Tolerances are 

established for residues of the herbicide bispyribac-sodium, including its metabolites and 

degradates, in or on the commodity listed below. Compliance with the tolerance level 

specified below is to be determined by measuring only bispyribac-sodium, (2,6-bis[(4,6-

dimethoxy-2-pyrimidinyl)oxy]benzoic acid, sodium salt), in or on the following raw 

agricultural commodity:” 

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

9.3 Occupational and Residential Exposure 

• HED recommends that the product label could be made clearer with respect to the 

application rate. The label indicates the product is packaged in 2-oz bags; however, the 

application rates provided are 1 to 2 oz of formulated product/A for surface weeds and 

from 0.8 oz to 2.4 oz product/A-ft for subsurface weeds. If a handler must open packages 

to obtain fractions of an ounce to mix, the advantage of water-soluble packaging is lost. 

Attachments 

Attachment 1a: Acute Toxicity Data for Bispyribac-Sodium Technical. 

Attachment 1b: Toxicity Profile of Bispyribac-sodium Technical and Metabolites. 

RDI: D. Vogel (14-JUL-2010); G. Kramer (16-AUG-2010) 

S. Levy: S-10953: PY1: (703)305-0783: 7509P: RAB1 

DP#s: 361116, 361118 

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

Page 28 of 31 

Attachment 1a. Acute Toxicity Data for Bispyribac-sodium Technical. 

Guideline No./Study Type MRID# Results Toxicity Category

870.1100 Acute Oral - Rat 44889127 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 

Attachment 1b. 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. 
Bispyribac-sodium Human-Health Risk Assessment DP# 361116 

Page 29 of 31 

Guideline No./Study 

Type 

MRID No. (year)/ 

Classification/Doses Results 

870.3800 

Reproduction and fertility 

effects (rats) 

44929923 (1994) 

Acceptable/guideline

0, 20, 1,000, or 10,000 ppm 

M: 0, 1.5, 75.7, or 759.0 

mg/kg/day 

F: 0, 1.72, 86.3, or 874.0 

mg/kg/day 

Parental/Systemic NOAEL = 1.5 mg/kg/day. 

LOAEL = 75.7 mg/kg/day (M/F), based on trace to 

mild choledocus (bile duct) hyperplasia. 

Reproductive NOAEL = 759.0 mg/kg/day 

LOAEL >759 mg/kg/day. 

Offspring NOAEL = 75.7 mg/kg/day. 

LOAEL = 759 mg/kg/day (M/F), based on 

decreased body weights, body-weight gains, and 

liver weights, and increased incidence of 

consolidation and circumscribed areas in the liver. 

870.4300 

Combined chronic 

toxicity/carcinogenicity 

rodents (rat) 

44929924 (1995) 

Acceptable/guideline

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

ppm 

(0, 1.1, 10.9, 194.5, or 404.5 

mg/kg/day, respectively) 

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

ppm (0, 1.4, 13.8, 352.2, or 

714.9 mg/kg/day, respectively) 

NOAEL = 10.9 mg/kg/day. 

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

macroscopic and microscopic changes in the liver 

and choldedochus and clinical signs. The LOAEL 

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

body weight, body weight gains, food efficiency, 

clinical signs and microscopic changes in the liver 

and choldedochus. 

No evidence of carcinogenicity.

870.4100b 

Chronic toxicity (dog) 

44889134 (1998) 

Acceptable/guideline

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

mg/kg/day 

NOAEL = 10 mg/kg/day. 

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

and liver granulation in females. 

870.4300 

Carcinogenicity (mouse) 

44929920 (1995) 

Acceptable/guideline

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

M: 0, 1.4, 14.1, 353.0, 728.9 

mg/kg/day 

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

mg/kg/day 

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

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

decreased body-weight gain, and food efficiency, 

and increased incidence of microscopic lesions in 

the liver and gall bladder (M). 

No evidence of carcinogenicity.

Gene Mutation 

870.5100 

reverse gene mutation 

assay in bacteria 

44889210 (1990) 

Acceptable/guideline

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

or 10000 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. 
Bispyribac-sodium Human-Health Risk Assessment DP# 361116 

Page 30 of 31 

Guideline No./Study 

Type 

MRID No. (year)/ 

Classification/Doses Results 

Other Genotoxic Effects 

870.5500 

bacterial DNA damage 

and repair test 

44929925 (1997) 

Acceptable/guideline

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

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 [14CPy]-

bispyribac-sodium and [14C-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 5 metabolites were identified in the 

excreta of male and females following administered 

[

14Cpy]-bispyribac-sodium and parent and 3 

metabolites identified with [14C-Bn]-bispyribacsodium 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 chenodeoxy cholic 

acid levels were similar to controls. 

Hyodeoxycholic acid was reduced from 34.0% to 

3.3 of the total bile acids. Treatment altered the 

degree of conjugation; hyodeoxycholic acid 

increased 84% and deoxycholic acid increased 

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

Page 31 of 31 

Guideline No./Study 

Type 

MRID No. (year)/ 

Classification/Doses Results 

Non-guideline - rat 

reversibility 

44979002 (1994) 

Acceptable/nonguideline

M: 0, 200, or 7000 ppm (0, 

12.3, or 446.8 mg/kg/day) 

F: 0, 200, or 10000 ppm (0, 

13.8, or 724.2 mg/kg/day) 

Bispyribac-sodium was 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 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.