Page 1 of 8 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

O ctober 9 , 2014

PC Code: 078906 MEMORANDUM DP Barcode: D 422689

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

Chery l 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 B loom, Team Leader Linda Arrington, Branch Chief Risk Management and Implementation Branch V Pesticid e 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 re ceived 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 ad ditional data needed for the registration review risk assessment of bispyribac

sodium.Page 2 of 8

ENVIRONMENTAL FATE COMMENTS

The Agency received a single comment relevant to the environmental fate characterization of bispyribac

sodium, 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 soil s ( Arkansas sandy loam and North Dakota silt loam ) w ere 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 co ncluded 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 f

ormulation,

“ In the single aerobic soil metabolism study submitted, up to 57% of the applied was mineralized to CO 2, and high levels of unextracted residues were formed (26

- 54%) by study termination. Recovery of degradates from initially unextracted resi dues was only accomplished with harsh base extraction. Additional aerobic soil metabolism data are needed to adequately determine th e 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 res idues were also at hi gh 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.

Additi onally, fr om “ 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 degra dation 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; r 2 = 0.995) fits the data well for up to the first 55 days. From 55 da ys to study termination, a half

- life of 97.0 days (83 to 118 days at 95% confidence interval; r 2 = 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.”

Ba sed 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, itPage 3 of 8

is unclear if the proposed submissions could be u sed 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).

A n d (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 o

f the test is possible after 120 days, or when at least 90% of the test substance is transformed, but only if at l east 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 guideli ne). 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 de velopment study. Recently, the Agency has issued guidance 1 for 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. T he 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

assessme nts 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 ad ditional 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 s od 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.pdfPage 4 of 8

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

- s odium 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 ar e 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 re commend ing 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 s ubmitted 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 cond itions ( e.g. 850.3040 2 guideline studies) that reduce uncertainty by characterizing bispyribac

- sodium’s effects at the whole

- colony level.

2 USEPA. 2012. Ecolo gical 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).pdfPage 5 of 8

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 law ns 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 bloo ming 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, bisp yribac

- 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 co lonies 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 guidance 3 for assessing risks to bees and now requ ires 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 a cute oral toxicity study with adult honey bees (OECD TG213 4 ) 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 850.3020 5 to estimate the acute toxicity of technical grade active ingredient (TGAI) to individual young adult honey bees. The stud ies 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 assum e 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 21 st Septe mber 1998. http://www.oecd

ilibrary.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

- 0016Page 6 of 8

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 be e 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 has finalized its guidance 6 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 devel op 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 thes e 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 endangere d 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 neede d. 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 endang ered 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.Page 7 of 8

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 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 ex posure 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. T herefore, 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.

T he Agency finalized its guidance 7 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, the 21

- day larval toxicity study currently under development by OECD 8 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 determin e 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 pollin ators) 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 expo sed.

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.pdfPage 8 of 8

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 reservo irs) 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, bispyriba c

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 uptak e 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 guidance 9 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, the 21

- day larval toxicity study currently under development by OECD provides both acute and chronic oral t oxicity 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) larv al 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 est imates 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 pollin ators) 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 expo sed.

9 Ibid USEPA et al . 2014.