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OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

October 9, 2014

PC Code: 078906

MEMORANDUM DP Barcode: D422689

SUBJECT: Response to 60-Day Comments on and addendum to Registration Review: Preliminary 

Problem Formulation for Environmental Fate, Ecological Risk, Endangered Species, and 

Human Health Drinking Water Exposure Assessments for Bispyribac-Sodium

FROM: Edward Scollon, Ph.D., Toxicologist

Cheryl Sutton, Ph.D., Environmental Scientist

Environmental Risk Branch IV

Environmental Fate and Effects Division (7507P)

REVIEWED

BY: Jim Carleton, Ph.D., Senior Fate Scientist

Elyssa Arnold, Ph.D., Acting Risk Assessment Process Leader

Environmental Risk Branch IV

Environmental Fate and Effects Division (7507P)

THROUGH: Sarah Winfield, Acting Branch Chief

Environmental Risk Branch IV

Environmental Fate and Effects Division (7507P)

TO: Moana Appleyard, Chemical Review Manager

Jill Bloom, Team Leader

Linda Arrington, Branch Chief

Risk Management and Implementation Branch V

Pesticide Re-evaluation Division (7508P)

The Environmental Fate and Effects Division (EFED) has completed its review of the comments received 

on the preliminary problem formulation for the ecological risk, environmental fate, endangered species, 

and drinking water assessments to be conducted as part of the Registration Review of bispyribac-sodium 

(CAS No. 125401-92-5; PC code 078906). Comments were received from the registrant, Valent U.S.A. 

Corporation, acting on its own behalf and as an agent on behalf of K-I Chemical U.S.A., Inc. As detailed 

below, this document also serves as addendum to the problem formulation with regard to 

recommendations on additional data needed for the registration review risk assessment of bispyribacsodium.
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ENVIRONMENTAL FATE COMMENTS

The Agency received a single comment relevant to the environmental fate characterization of bispyribacsodium, specifically with regard to the aerobic soil metabolism data gap. The problem formulation 

identified the need for three additional aerobic soil metabolism studies (OCSPP guideline 835.4100). In 

response, the registrant identified available aerobic soil metabolism data which were obtained from two 

aged leaching column studies in which the soils (Arkansas sandy loam and North Dakota silt loam) were

treated with bispyribac-sodium and aerobically incubated for 30 days prior to the leaching phase. Based 

on parent data obtained during the studies, reported half-lives (for two radiolabels) were 14.0 and 14.1 

days in the sandy loam soil, and 16.1 and 20.7 days in the silt loam soil. The registrant concluded that 

“...there is sufficient scientific information to conclude that bispyribac-sodium and its significant 

degradates (degradates found at ≥ 10% of applied dose – DesMe-2023, Me2BA, MeBA, BX-180 and 2,6-

DBA) degrade readily in soils under aerobic conditions and undergo ultimate transformation 

(incorporation into soil natural products and 14CO2)” based on the availability of the cited data. 

In response, EFED acknowledges that, based on a cursory review of the information as stated in the 

registrant’s comments, the additional data (upon full review) may provide supplemental information on 

the aerobic soil metabolism of the parent compound in two different types of soil. However, as noted in 

the problem formulation, 

“In the single aerobic soil metabolism study submitted, up to 57% of the applied was mineralized 

to CO2, and high levels of unextracted residues were formed (26-54%) by study termination. 

Recovery of degradates from initially unextracted residues was only accomplished with harsh 

base extraction. Additional aerobic soil metabolism data are needed to adequately determine the 

fate of this compound in soil...”

In the single submitted study (MRID 44929931), including unextracted residues (up to 62%), the half-life 

of bispyribac-sodium was determined to be 267 days. In the aerobic phase of the aged leaching studies 

the registrant is proposing to use in lieu of new aerobic soil metabolism data, unextracted residues were 

also at high levels (23-41% of total radiolabeled residues in the sandy loam soil and 30-37% in the silt 

loam soil). Thus, the issue of high unextracted residues may not be resolved by the data from the aerobic 

aging phase of the two aged leaching studies. 

Additionally, from “EFED Risk Assessment for Section 3 Registration of Bispyribac-Sodium (Sodium 2,6-

bis[(4,6-dimethoxypyrimidin-2-yl)oxy]benzoate)(Regiment) (8/6/2001; DP Barcodes: D267285; 

D267289; D268683)”, there are available data indicating that the degradation rate of bispyribac-sodium 

may be more rapid initially, then decrease with time:

“Uniformly benzene-labeled bispyribac-sodium and bispyribac-sodium labeled in the 2 position 

of the pyrimidine ring (nominal application rate of 0.6 mg/g; combined data) degraded through 

a two-step model, with half-lives of 18.9 days for the first 55 days, and 97 days from day 55 to 

study termination (MRID #449299-31). Specifically, in a Gridley series (clay loam soil at pH 6.1 

adjusted to 75 % of the moisture content at 0.33 bar and incubated in darkness at 25C for 348 

days) a half-life of 18.9 days (18 to 20 days at 95% confidence interval; r2 = 0.995) fits the data 

well for up to the first 55 days. From 55 days to study termination, a half-life of 97.0 days (83 to 

118 days at 95% confidence interval; r2 = 0.958) fits the data well. The bi-phasic degradation 

curve characterized by two half-lives, fits the data better than a single first-order half-life.” 

Based on the high levels of unextracted residues and the available data which indicate that a 30-day 

aerobic soil metabolism may not sufficiently demonstrate the degradation rate over time in aerobic soil, it 
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is unclear if the proposed submissions could be used to fulfill the data gap as identified in the Registration 

Review Problem Formulation. As noted in the OCSPP 835.4100 guidelines, 

For transformation rate studies at least three additional soils should be used representing a 

range of relevant soils. Those soils should vary in their organic carbon content, pH, clay content 

and microbial biomass (see paragraph (j)(11) of this guideline).

And (bold added for emphasis): 

Test duration. The rate and pathway studies should normally not exceed 120 days (see

paragraphs (j)(4), (j)(7), (j)(9) of this guideline) because thereafter a decrease of the soil 

microbial activity with time would be expected in an artificial laboratory system isolated from 

natural replenishment. Aerobic studies might be terminated much before 120 days provided 

that ultimate transformation pathway and ultimate mineralization are clearly reached at that 

time. Termination of the test is possible after 120 days, or when at least 90% of the test 

substance is transformed, but only if at least 5% CO2 is formed. When necessary to 

characterize the decline of the test substance and the formation and decline of major 

transformation products, studies can be continued for longer periods (e.g., 6 or 12 months) (see 

paragraph (j)(9) of this guideline). Longer incubation periods should be justified in the test 

report and accompanied by biomass measurements during and at the end of these periods.

For these reasons, EFED recommends that the lack of sufficient information on the aerobic soil 

metabolism of bispyribac-sodium still be considered a data gap at this time. 

ECOLOGICAL EFFECTS COMMENTS

The Agency received a single comment relevant to the ecological effects of bispyribac-sodium, 

specifically with regard to the request for a honey bee larval development study. Recently, the Agency 

has issued guidance1for assessing the potential risks of pesticides to bees and the data needed to support 

such assessments. The guidance document indicates that if exposure of bees to a pesticide is expected, a 

Tier I screening-level risk assessment should be conducted. The Tier I assessment is intended to be 

sufficiently conservative such that chemicals which pass the screen represent a relatively low risk of 

adverse effects to bees. Tier I toxicity data that are generally needed to complete screening-level risk 

assessments include a suite of laboratory-based studies of individual bees and consist of the following 

tests: acute contact toxicity data to adult honey bees (honey bees serving as a surrogate for other Apis and 

non-Apis bees and other insect pollinators), acute and chronic oral toxicity to adult honey bees, and acute 

and chronic oral toxicity to honey bee larvae. If risk concerns are identified in the screening-level 

assessment, the assessment may be refined using data that further define exposure or through additional 

data including Tier II semi-field or full-field toxicity tests conducted with whole colonies.

Bispyribac-sodium is registered for several agricultural (e.g., rice) and non-agricultural (e.g., ornamental 

lawns and turf, including golf courses and sod farms, as well as aquatic sites such as canals, drainage 

ditches, marshes, lakes, ponds, and reservoirs) uses and may be applied via ground and aerial sprayers. 

These use patterns may result in exposure to blooming non-target plants and could result in residues in 

pollen and nectar (which could then be transported to the hive by adult forager bees). Additionally, 

bispyribac-sodium is moderately persistent, systemic, and can be absorbed through the foliage and roots. 

Therefore, in addition to direct contamination of pollen and/or nectar through foliar applications, 

 

1 USEPA et al.. 2014. Guidance for Assessing Pesticide Risks to Bees. http://www2.epa.gov/sites/production/files/2014-

06/documents/pollinator_risk_assessment_guidance_06_19_14.pdf
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bispyribac-sodium residues may be translocated to pollen and nectar either through transport from leaf 

tissues affected by spray drift or from root uptake in plants grown where bispyribac-sodium was 

previously applied. Residues can in turn be brought back to bee colonies where in-hive bees including 

young adult and developing brood (i.e., eggs, larvae and pupae) may be exposed. Therefore, exposure at 

all bee life stages would be expected. 

Since exposure of bees to bispyribac-sodium residues is expected, Tier I honey bee laboratory toxicity 

data are needed to conduct the screening-level risk assessment. Acute contact toxicity data are available 

that indicate bispyribac-sodium residues are practically non-toxic to honey bees on an acute contact 

exposure basis. However, no data are available to evaluate bispyribac-sodium’s oral toxicity to either 

adult or larval bees from either acute or chronic exposure. 

Therefore, EFED is recommending that additional data be submitted to support the ecological risk 

assessment of bispyribac-sodium. The full complement of Tier I laboratory toxicity data on the technical 

grade active ingredient (TGAI) for acute and chronic oral toxicity for both adult and larval honey bees is 

needed to complete the risk assessment for bees, as further detailed in the attached data rationale tables. 

The identification of these additional data needs should be considered as an addendum to the problem 

formation for bispyribac-sodium. Should the screening level risk assessment based on the submitted data 

indicate that there are risk concerns for bees, mitigation measures may need to be considered or the 

Agency may require additional studies under semi-field or full-field conditions (e.g. 850.30402 guideline 

studies) that reduce uncertainty by characterizing bispyribac-sodium’s effects at the whole-colony level.

 

2 USEPA. 2012. Ecological Effects Test Guidelines OCSPP 850.3040: Field Testing for Pollinators. Office of Chemical Safety and Pollution 

Prevention (7101). EPA 712-C-017 January 2012. file:///C:/Users/tsteeger/Downloads/EPA-HQ-OPPT-2009-0154-0018%20(3).pdf
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Guideline Number: Non-Guideline

Study Title: Adult Honey Bee Acute Oral Toxicity

Rationale for Requiring the Data

This study is needed to evaluate potential effects to adult honey bees from acute oral exposure to technical 

grade active ingredient (TGAI). Bispyribac-sodium is registered for several agricultural (e.g., rice) and 

non-agricultural (e.g., ornamental lawns and turf, including golf courses and sod farms, as well as aquatic 

sites such as canals, drainage ditches, marshes, lakes, ponds, and reservoirs) uses and may be applied via 

ground and aerial sprayers. Some of these uses may result in exposure to blooming non-target plants and 

could result in residues in pollen and nectar (which could then be transported to the hive). Additionally, 

bispyribac-sodium is moderately persistent, systemic, and can be absorbed through the foliage and roots. 

Therefore, bispyribac-sodium residues may be present in pollen and nectar either through transport from 

leaf tissues affected by spray drift or from root uptake in plants grown where bispyribac-sodium was 

previously applied. Residues can in turn be brought back to bee colonies where in-hive bees including 

young adult and developing brood (i.e., eggs, larvae and pupae) may be exposed. Therefore, exposure at 

all bee life stages would be expected. 

The Agency finalized its guidance3for assessing risks to bees and now requires this study for all use sites 

where potential exposure to pollinators may occur. Although EPA has not developed a guideline for this 

study, the Organization for Economic Cooperation and Development (OECD) has developed a formal test 

guideline for an acute oral toxicity study with adult honey bees (OECD TG2134) that may be used to 

assess the acute oral toxicity for adult bees.

Practical Utility of the Data

How will the data be used and how could the data impact the Agency’s future decision-making? 

The acute oral toxicity data are used in conjunction with acute contact data obtained through OCSPP 

850.30205to estimate the acute toxicity of technical grade active ingredient (TGAI) to individual young 

adult honey bees. The studies also provide slopes for the dose-response curves that can in turn be used for 

estimating the likelihood of individual effects, and sublethal effects observed in the study will be used to 

further characterize effects observed following a single exposure to TGAI. Data obtained from this study 

will be used in estimating acute risk to individual adult bees. Risk estimates based on these data will be 

considered along with other lines of evidence to determine whether higher-tier studies are needed at the 

whole colony level.

These data are needed for risk assessments written in support of Registration Review as well as for future 

endangered species assessments. These data would allow the Agency better characterize the potential for 

risk to insects (including beneficial pollinators) from the use of bispyribac-sodium. These data may help 

the Agency determine whether any mitigations are needed. If the Registration Review and any future 

endangered species risk assessments are performed without these data, the Agency would have to assume 

that bispyribac-sodium "may affect" insects, including bees and beneficial pollinators, directly (and 

endangered species from other taxa indirectly), and uses of bispyribac-sodium might need to be restricted 

in areas where pollinators could be exposed.

 

3 USEPA et al.. 2014. Guidance for Assessing Pesticide Risks to Bees. http://www2.epa.gov/sites/production/files/2014-

06/documents/pollinator_risk_assessment_guidance_06_19_14.pdf

4 OECD. 1998. OECD Guidelines for the Testing of Chemicals Honeybees, Acute Oral Toxicity Test. OECD/OCDE 213 Adopted 21st

September 1998. http://www.oecdilibrary.org/docserver/download/9721301e.pdf?expires=1408726996&id=id&accname=guest&checksum=29D93505197D8AB40C63E8F0DFB4

47D0

5 USEPA. 2012. Ecological Effects Test Guidelines OCSPP 850.3020: Honey Bee Acute Contact Toxicity Test. Office of Chemical Safety and 

Pollution Prevention (7101). EPA-712-C-019. January 2012. http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0154-

0016
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Guideline Number: Non-Guideline

Study Title: Adult Honey Bee Chronic Oral Toxicity

Rationale for Requiring the Data

This study is needed to evaluate the potential effects of technical grade active ingredient (TGAI) on young 

adult honey bees from repeat exposure. Bispyribac-sodium is registered for several agricultural (e.g., rice) 

and non-agricultural (e.g., ornamental lawns and turf, including golf courses and sod farms, as well as 

aquatic sites such as canals, drainage ditches, marshes, lakes, ponds, and reservoirs) uses and may be 

applied via ground and aerial sprayers. Some of these uses may result in exposure to blooming non-target 

plants and could result in residues in pollen and nectar (which could then be transported to the hive). 

Additionally, bispyribac-sodium is moderately persistent, systemic, and can be absorbed through the 

foliage and roots. Therefore, bispyribac-sodium residues may be present in pollen and nectar either 

through transport from leaf tissues affected by spray drift or from root uptake in plants grown where 

bispyribac-sodium was previously applied. Residues can in turn be brought back to bee colonies where inhive bees including young adult and developing brood (i.e., eggs, larvae and pupae) may be exposed. 

Therefore, exposure at all bee life stages would be expected. 

The Agency has finalized its guidance6 for assessing risks to bees and now requires this study for all use 

sites where potential exposure to pollinators may occur. Although EPA has not developed a guideline for 

this study and OECD has yet to finalize test guidance for chronic studies, efforts are currently underway 

to develop standardized guidelines for assessing effects from chronic (10-day) exposures to adult bees in 

the laboratory. A protocol should be submitted to the Agency for review prior to study initiation.

Practical Utility of the Data

How will the data be used and how could the data impact the Agency’s future decision-making? 

The 10-day toxicity study with young adult bees provides data that will be used in estimating chronic risk 

to individual adult bees. Risk estimates based on these data will be considered along with other lines of 

evidence to determine whether higher-tier studies are needed at the whole colony level.

These data are needed for risk assessments written in support of Registration Review as well as for future 

endangered species assessments. These data would allow the Agency better characterize the potential for 

risk to insects (including beneficial pollinators) from the use of bispyribac-sodium. These data may help 

the Agency determine whether any mitigations are needed. If the Registration Review and any future 

endangered species risk assessments are performed without these data, the Agency would have to assume 

that bispyribac-sodium "may affect" insects, including bees and beneficial pollinators, directly (and 

endangered species from other taxa indirectly), and uses of bispyribac-sodium might need to be restricted 

in areas where pollinators could be exposed.

 

6

Ibid USEPA et al. 2014.
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Guideline Number: Non-Guideline

Study Title: Larval Honey Bee Chronic Oral Toxicity

Rationale for Requiring the Data

This study is needed to evaluate potential effects of technical grade active ingredient (TGAI) to honey bee 

larvae from repeat exposure. Bispyribac-sodium is registered for several agricultural (e.g., rice) and nonagricultural (e.g., ornamental lawns and turf, including golf courses and sod farms, as well as aquatic sites 

such as canals, drainage ditches, marshes, lakes, ponds, and reservoirs) uses and may be applied via 

ground and aerial sprayers. Some of these uses may result in exposure to blooming non-target plants and 

could result in residues in pollen and nectar (which could then be transported to the hive). Additionally, 

bispyribac-sodium is moderately persistent, systemic, and can be absorbed through the foliage and roots. 

Therefore, bispyribac-sodium residues may be present in pollen and nectar either through transport from 

leaf tissues affected by spray drift or from root uptake in plants grown where bispyribac-sodium was 

previously applied. Residues can in turn be brought back to bee colonies where in-hive bees including 

young adult and developing brood (i.e., eggs, larvae and pupae) may be exposed. Therefore, exposure at 

all bee life stages would be expected. 

The Agency finalized its guidance7for assessing risks to bees and now requires this study for all use sites 

where potential exposure to pollinators may occur. Although EPA has not developed a guideline for this 

study, the 21-day larval toxicity study currently under development by OECD8 provides a draft guidance 

protocol for potentially assessing both the acute and chronic toxicity to developing brood (larvae and 

pupae) from repeat exposure to pesticides. A protocol should be submitted to the Agency for review prior 

to study initiation. 

Practical Utility of the Data

How will the data be used and how could the data impact the Agency’s future decision-making? 

The 21-day toxicity study provides data on the effects of technical grade active ingredient (TGAI) on 

developing bees from acute (short-term) and chronic (longer term) exposure and will be used for estimating 

risk to individual (solitary) bees as well as bee colonies (social bees). Risk estimates based on these data 

will be considered along with other lines of evidence to determine whether higher-tier studies are needed at 

the whole colony level.

These data are needed for risk assessments written in support of Registration Review as well as for future 

endangered species assessments. These data would allow the Agency better characterize the potential for 

risk to insects (including beneficial pollinators) from the use of bispyribac-sodium. These data may help 

the Agency determine whether any mitigations are needed. If the Registration Review and any future 

endangered species risk assessments are performed without these data, the Agency would have to assume 

that bispyribac-sodium "may affect" insects, including bees and beneficial pollinators, directly (and 

endangered species from other taxa indirectly), and uses of bispyribac-sodium might need to be restricted 

in areas where pollinators could be exposed. 

 

7

Ibid USEPA et al. 2014.

8 OECD. 2013. OECD Draft Guidance Document Honey Bee (Apis mellifera) Larval Toxicity Test, Repeated Exposure. Revision of June 2013 

draft GD, 25 November 2013. http://www.oecd.org/env/ehs/testing/Draft_GD_honeybees_rep_exp_for_2nd_CR_25_November_2013.pdf
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Guideline Number: Non-Guideline

Study Title: Larval Honey Bee Acute Oral Toxicity

Rationale for Requiring the Data

This study is needed for the assessment to evaluate risks to honey bees if the registered uses will result in 

bee exposure. Bispyribac-sodium is registered for several agricultural (e.g., rice) and non-agricultural 

(e.g., ornamental lawns and turf, including golf courses and sod farms, as well as aquatic sites such as 

canals, drainage ditches, marshes, lakes, ponds, and reservoirs) uses and may be applied via ground and 

aerial sprayers. Some of these uses may result in exposure to blooming non-target plants and could result 

in residues in pollen and nectar (which could then be transported to the hive). Additionally, bispyribacsodium is moderately persistent, systemic, and can be absorbed through the foliage and roots. Therefore, 

bispyribac-sodium residues may be present in pollen and nectar either through transport from leaf tissues 

affected by spray drift or from root uptake in plants grown where bispyribac-sodium was previously 

applied. Residues can in turn be brought back to bee colonies where in-hive bees including young adult 

and developing brood (i.e., eggs, larvae and pupae) may be exposed. Therefore, exposure at all bee life 

stages would be expected. 

The Agency finalized its guidance9for assessing risks to bees and now requires this study for all use sites 

where potential exposure to pollinators may occur. Although EPA has not developed a guideline for this 

study, the 21-day larval toxicity study currently under development by OECD provides both acute and 

chronic oral toxicity data on developing bee brood and (when this guidance is finalized) may be used to 

satisfy the requirement for both acute and chronic oral toxicity to honey bee larvae. Registrants are at 

liberty though to submit a separate acute (single dose) larval toxicity study following OECD TG 237 as 

well as the 21-day repeat dose chronic toxicity study. 

Practical Utility of the Data

How will the data be used and how could the data impact the Agency’s future decision-making? 

The acute larval toxicity study provides data on the effects of technical grade active ingredient (TGAI) on 

developing bees from acute (short-term) exposure and will be used for estimating risk to individual 

(solitary) bees as well as bee colonies (social bees). Risk estimates based on these data will be considered 

along with other lines of evidence to determine whether higher-tier studies are needed at the whole colony 

level.

These data are needed for risk assessments written in support of Registration Review as well as for future 

endangered species assessments. These data would allow the Agency better characterize the potential for 

risk to insects (including beneficial pollinators) from the use of bispyribac-sodium. These data may help 

the Agency determine whether any mitigations are needed. If the Registration Review and any future 

endangered species risk assessments are performed without these data, the Agency would have to assume 

that bispyribac-sodium "may affect" insects, including bees and beneficial pollinators, directly (and 

endangered species from other taxa indirectly), and uses of bispyribac-sodium might need to be restricted 

in areas where pollinators could be exposed.

 

9

Ibid USEPA et al. 2014.