UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON D.C., 20460

PC Code: 061402

DP Barcode: D418766

Date: April23, 2014

MEMORANDUM

SUBJECT: Response to Public Comments on the Acibenzolar-S-methyl Registration Review

Problem Formulation

TO:

FROM: Dana Friedman, Chemical Review Manager Cathryn Britton, Team Leader

Risk Management and Implementation Branch II

Pesticide Re-Evaluation Division

Office ofPesticide Programs (7508P)

# MichaelLowit,Ph.D.,Ecologist**/~ ~i;/f**  Stephen Wente, Ph.D.,

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Meghan Radtke, Ph.D., Acting RAPL

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Environmental Risk Branch I 

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Environmental Fate and Effects Division (7507P)

Office ofPesticide Programs

In response to the "Registration Review: Preliminary Problem Formulation for Environmental
Fate, Ecological Risk, Endarigered Species, and Drinking Water Exposure Assessments for Acibenzolar-S-methyl" (DP413831), the registrant, Syngenta Crop Protection, and the Center for Biological Diversity submitted comments during the public comment period. The purpose of

this memorandum is to address these comments.

Comments by Syngenta Crop Protection

Comment#l:

The preliminary work plan issued in December 2013 requests an Environmental Chemistry

Method for analysis of acibenzolar-S-methyl and CGA-21007 in water and a corresponding independent laboratory validation (ILV) of the method(s). Presumably, the origin of this requirement stems from Guideline Number 835.6200 for Aquatic Field Dissipation Studies.

Guideline Number 835.6200 states that an independent laboratory validation should be provided

for the method used to actually generate the aquatic dissipation data submitted. However, no aquatic dissipation studies were conducted or submitted based upon the use pattern; therefore, provision of a water method and an independent laboratory validation (IL V) should not apply.2 Therefore, Syngenta respectfully re quests a waiver of the requirem ent to provide an applicable Environmental Chemistry Method and ILV for an alysis of acibenzolar-S-methyl and CGA21007 in water. (Syngenta Crop Protection, p. 2).

EPA Response #1:

Both the soil and water environmental chemistr y methods (ECMs) are required for monitoring and enforcement purposes. If, for example, a spil l of acibenzolar-S-methyl were to occur, a responsible agency would have an immediate n eed for methods for measuring residues in

affected soils and surface and/ or groundwater. The methods that registrants submit can be found

at: http://www.epa.gov/pesticides/methods/ecm-a.html . This website has soil ECMs for acibenzolar-S-methyl and CGA-2100007, but no water ECMs for either chemical. The independent laboratory validation (IL V) studies ensure that the methods can be used as written in

the ECM.

Comment #2: EPA statements: Anticipated Da ta Needs for the CGA-210007 Degradate Avian reproduction test (bobwhite quail) (P WP Page 5, Table 1)

“For instance, recent risk assessments stated th at there would be a chronic risk concern if CGA210007 is about 2-15X more toxic than acibenzolar-S- methyl which caused effects to birds in one of the available reproduction studies. On the other hand, chemical structures suggest that CGA210007 is more likely than acibenzolar-S-methyl to be excreted in urine.” (PWP Page 21, Paragraph 2)

Animal metabolism data for birds (Rumbeli 1996) and mammals (MRID 44014250) indicate that once ingested, acibenzolar-S-met hyl is rapidly metabolized to CGA-210007 and therefore data from experiments conducted with acibenzolar-S -methyl are applicable for evaluating the biological effects of CGA-210007. This conclusion is based on the fact th at internal exposure would be expected to be the same whether birds and mammal s directly ingest CGA-210007 or alternatively ingest acibenzol ar-S-methyl and then rapidly metabolize it to CGA-210007. The similar metabolic pathways and rapid brea kdown of acibenzolar-S-methyl to CGA-210007 in birds and mammals, coupled with consistent findi ngs that demonstrate markedly lower biological activity of CGA-210007 relative to ac ibenzolar-S-methyl in aquatic organisms (Table 4 of PPF), provide a strong basis that CGA-210007 poses no greater potential risk to birds and mammals compared to acibenzolar-S-methyl.

Screening level evaluations usi ng T-REX v.1.5.2 for foliar applicati ons indicate that the avian chronic reproduction NOEC value for CGA-210007 woul d have to be markedly lower to cause any screening level exceedances for ecological risk assessment. For instance, output from TREX v.1.5.2 indicated that the hi ghest predicted exposure on diet ary items for foliar labelled uses is based on 4 applications at 0.0625 lb/A w ith 7-day intervals (defau lt foliar half-life of 35 days assumed). Relative to the avian reproduc tion NOEC value for bobwhite quail exposed to acibenzolar-S-methyl (600 mg/kg-diet; MRID 44 537009), estimates of screening level exposure

for this use indicate that the NOEC value fo r CGA-210007 would have to be 12 – 100 X lower (more sensitive) in order to ex ceed listed species LOC values.3 The highest predicted exposure based on a screen ing level evaluation of seed treatments is

associated with the sunflower seed treatment . Using the seed treatment module of T-REX v.1.5.2, calculations indicate that the NOEC valu e for bobwhite quail with CGA-210007 would have to be 2 X lower (more sensitive) than th e respective value for the parent acibenzolar-Smethyl (600 mg/kg-diet; MRID 44537009). It is important to note that assumptions of exposure

associated with the seed treatment module of T-REX v.1.5.2 are highly conservative as it assumes terrestrial organisms ingest the entire seed treatment dose (mg ai/kg seed), and subsist for 5 months exclusively on a diet treated with the test item. Literature studies demonstrate that many small birds and mammals display a dehusking be havior, in which only the internal fruit is extracted and ingested, whereas the outer fibrous prot ective seed coat of sunflower seeds are discarded (Avery et al. 1997, Bruhl , et al. 2011). Minimal exposure may occur as animals handle treated seeds during the dehusking process, studies reported in the peer-reviewed literature

indicate that the amount of active ingredient ingested is only a sm all fraction of that applied to a sunflower seed. During studies ex amining potential exposure associ ated with seed treatments to granivourous birds, Avery et al. 1997 determined th at > 65% of the chemical that is applied to

sunflower seed is left on the hus ks after birds handle the seed.

The rapid metabolism of ingested acibenzola r-S-methyl to CGA-210007 by birds provides strong evidence that additional toxicity testing with CGA-210007 is unlikel y to prove valuable to the ecological risk assessment of acibenzolar-S-methyl. Available data for acute oral (MRID 44537005, MRID 44537004) and acute dietary t oxicity studies (MRID 44537006, MRID 44537008) indicate that acibenzola r-S-methyl is practically n on-toxic to birds. Chronic reproductive studies with acibenzolar-S-methyl al so show no effects to mallard ducks at 1000 mg/kg-diet, the highest concentration tested (MRID 44537010). Effects to bobwhite quail were reported only at the highest dietary exposure concentration tested (1000 mg/kg-diet; MRID 44537009), with a NOEC of 600 mg/kg-diet. While these studies were all initiated with acibenzolar-S-methyl, data from metabolism studi es provide strong evid ence that the test material is rapidly converted to CGA-210007 after birds were administered doses or consumed

treated-diets. Given the transient nature of acibe nzolar-S-methyl in birds, coupled with the fact

that avian NOEC values for CGA-210007 would ha ve to be markedly lower than those for acibenzolar-S-methyl in order to demonstrate ri sk based on highly conservative screening level assessments, there is strong evidence that av ian chronic reproductiv e studies with CGA-210007 will not provide additional information of valu e for the acibenzolar-S-methyl ecological risk assessment. Syngenta respectiv ely requests that the Agency not include the bobwhite reproduction study with CGA-210007 as a data gap on the GDCI. (Syngenta Crop Protection, p. 3-4).

EPA Response #2: The registrant suggests that inte rnal exposure would be expected to be the same whether birds and mammals directly ingest CGA-210007 or altern atively ingest acibenzo lar-S-methyl and then rapidly metabolize it into CGA-210007. This as sumes that acibenzolar-S-methyl is rapidly

metabolized to CGA-210007 relative to the CG A-210007 excretion rate (alternatively, slow metabolism and rapid excretion would lead to lower exposure to CGA-210007). The cited rat metabolism study (MRID 44014250) and the physical -chemical properties of acibenzolar-Smethyl support the idea that acibenzolar-S-methyl should be metabolized to CGA-210007. However, blood concentrations were reported in terms of total radioactivity rather than

individual chemicals and a time series was not presented showing the formation of CGA-210007.4 This type of information or other lines of evidence ( e.g. , the rate of hydrolysis of the thiol ester) would be useful for evaluating the amount of exposure to CGA-210007 from direct ingestion of acibenzolar-S-methyl. If the registrant has other da ta pertinent to this issue then EFED will take

it into consideration.

Mammals and birds may show differences in meta bolism so EFED will consider whether or not the avian metabolism study (Rumbeli, 1996) provides sufficient information about avian exposure to CGA-210007 from direct ingestion of acibenzolar-S-methyl.

The seed treatment exposure scenario does not a ssume that terrestrial organisms subsist for 5 months exclusively on a diet trea ted with the test item. The e xposure scenario assumes the peak concentration and that reproducti ve effects could occur from e ither a short or long duration exposure (reproductive effects may occur from a short duration exposure based on the timing of the exposure within the reproductive period) . EFED acknowledges that some birds and mammals may de-husk seeds; however , this may not be the case for all species and the degree to which exposure may be reduced will va ry by species and perhaps individual.

Comment #3: EPA statement: Referenced endpoi nt for aquatic non-vascular plant studies was presented as cell density. (PF Page 11, Table 3)

Effect concentrations (ECx) calculated based on growth rate are considered more robust than those based on standing crop (cell density and biom ass) for a given time-point because growth rate is independent of exposure time (US EPA 2012). For aquatic plants, study duration, conditions of temperature, light, and nutrients , and reported endpoints can vary considerably among studies. In addition, other resource-limiting factors, such as nutrient depletion and selfshading, can complicate the interpretation of reported plant EC x values. These factors may affect study results, which could result in misleading es timates in certain cases for some species (US EPA 2012). Using cell density or absolute biom ass can potentially result in particularly misleading ECx values when growth rates are m odest, and a departure from exponential growth will be most pronounced in the treatments with the highest growth rates (US EPA 2012). With respect to toxicity tes ting, differences in design of the study can result in complicated growth dynamics and relationships that are difficult to interpret (US EPA 2012).

As indicated by Bergtold and Dohmen (2011), grow th rate is the approp riate endpoint in the Lemna and algal toxicity test guidelines (OECD 2006a,b). Specifically, in the OECD 221 guideline for testing growth inhibition in fres hwater alga and cyanobacteria (OECD 2006a), it

states:

“ECx values based upon average specific grow th rate (ErCx) will generally be higher than results based upon yield (EyC x) if the test conditions of this Guideline are adhered to, due to the mathematical basis of the respective approaches. This should not be interpreted as a difference in sensitivity between the two resp onse variables, simply that the values are different mathematically. The co ncept of average specif ic growth rate is based on the general exponential growth patte rn of algae in non-limited cultures, where toxicity is estimated on the basis of the effects on the growth rate, without being5 dependent on the absolute level of the specifi c growth rate of the control, slope of the concentration-response curve or on test dura tion. In contrast, resu lts based upon the yield response variable are dependent upon all these other variables. Yiel d is dependent on the specific growth rate of the algal species us ed in each test and on the maximum specific growth rate that can vary betw een species and even different algal strains. This response variable should not be used for comparing the sensitivity to toxican ts among algal species

or even different strains.”

Based on the aforementioned information, Syngenta s uggests that relative grow th rate results are more scientifically appropriate and should be us ed for ecological risk assessment of aquatic plants. (Syngenta Crop Protection, p. 4-5).

EPA Response #3: EFED will consider this approach in future risk assessments.

Comment #4: EPA statement: “CGA-210007 toxicity to birds and mammals is unknown and w ill be assumed equal to that of acibenzolar-S-methyl in the absence. However, there is no basis at this time for characterizing a level of confidence in the assumption that CGA-2100 07 is not more toxic than acibenzolar-S-methyl to birds and mammals.” (PF Page 17, Paragraph 3)

It is important to consider the available anim al metabolism data while evaluating the ecological risk associated with environmental exposur e of CGA-210007 to bird s and mammals. CGA210007 has been identified as a degradate in bot h environmental fate and animal metabolism studies. Once ingested, acibenzo lar-S-methyl parent is rapi dly metabolized to CGA-210007, and therefore data from experiments conducted with acibenzolar-S-methyl are applicable for evaluating the biological eff ects of CGA-210007. This conclusion is based on the fact that internal exposure would be expected to be the same whether birds and ma mmals directly ingest CGA-210007 or alternatively ingest acibenzolar-S-methyl and th en rapidly metabolize it to

CGA-210007.

A previously-submitted study on the metabolism of acibenzolar-S-methyl (MRID 44014250) is particularly relevant for evalua ting dietary routes of exposures as the results demonstrate that acibenzolar-S-methyl is rapidly and completely abso rbed in the gastrointestinal tract of rats. In this metabolism study with adult rats, 99+% of acibenzolar-S-methyl is absorbed, while small amounts, not exceeding 1% of the dose, are ex creted unchanged with the feces. The dose absorbed is hydrolyzed to yield the corres ponding carboxylic acid de rivative (CGA-210007) and readily excreted (82-96% of th e dose received) renally. A small amount of the acid, less than 3% of the dose, is eliminated via feces. A second minor portion (<2%) of the acid is conjugated with glycine and then renally eliminated. The metabolic fate of acibenzolar-S-methyl is quantitatively independent of gender and dose level and is not influenced by pretreatment of the compound.

In a metabolism study with birds (Rumbeli 1996), laying hens administer ed oral doses of acibenzolar-S-methyl demonstrated the same ra pid metabolism of acibenzolar-S-methyl to CGA210007 as rats. Syngenta will submit the laying hen metabolism study for EPA review. The aforementioned similar metabolic pathways an d rapid breakdown of acibenzolar-S-methyl to CGA-210007 in birds and mammals, coupled with consistent findings that demonstrate markedly6 lower biological activity of CGA-210007 relative to acibenzolar-S -methyl in aquatic organisms (Table 4 of PPF), provide a str ong basis that CGA-210007 poses no grea ter potential risk to birds and mammals compared to acibenzolar-S -methyl. (Syngenta Crop Protection, p. 5-6).

EPA Response #4: Please see EPA Response #2.

Comment #5:

EPA statement: “This assessment will be conducted in accordance with the Overview Document (USEPA, 2004), provisions of the ESA, and the Services’ Endangered Species Consultation Handbook (USFWS and NMFS, 1998).” (Page 18)

Simple deterministic screening level assessmen ts, which are highly conservative by design, can facilitate rapid initial screening/exclusion criteri a for a pesticide active ingredients’ potential to adversely affect listed (threatened or endangere d species) and non-listed sp ecies. If a pesticide exposure results in a risk quotient (RQ) below a predefined level of concern (LOC), which are additionally conservative with re spect to endangered (listed) sp ecies assessments (e.g. 5x to 10x lower than already conservative non-listed LOCs), then the pote ntial risks are considered de minimis and unlikely to jeopardize the existe nce of a listed species. Thus by design, such compounded layers of conservatism are intended to minimize potential type II errors (failure to reject a false null hypothesis of de minimu s risk) but correspondingly compound unrealistic conditions and assumptions. If, however, an RQ is generated that exceeds the highly conservative LOC, additional higher- tier scientific information must be incorporated in order to refine the risk assessment and more accurately an d realistically reflect potential exposures and effects, and reducing potential t ype I errors (falsely rejecting the null hypothesis of de minimus risk). This information includes community-level effects data, environm ental fate and exposure data, monitoring data, geospatial location and pr oximity data, species biology data, and a variety of refined modelling and assessment analysis, an d other pertinent species-specific and pesticidespecific data. Given that ‘risk’ requires estimation of likeliho od, higher tier risk assessments need to consider and employ probabilistic technique s in order to more accurately and realistically characterize risk. Moreover, wher e possible and appropriate, risk assessments should consider assemblage level effects (populations, communitie s, and ecosystems) rather than singular deterministically oriented single species approach es. A summary of the types of higher-tier data

and assessment refinements available to more accura tely and realistically evaluate potential risks to endangered species is provided in MRID# 49200601. (Syngenta Crop Protection, p. 6).

EPA Response #5:

EFED will conduct the risk assessment on acibenzol ar-S-methyl in accordance with policies and guidelines pertinent at that time; this includes re finements to the screening level assessment, if applicable.

Comment #6: EPA statement: “The most recent drinking water assessment (DWA) in support of human health risk assessment was conducted to support the regi stration of acibenzolar-S-methyl for use on the low growing berry subgroup 13-07G (DP 386365).” (Page 4)7 A more recent EPA DWA was conducted in sup port of human health risk assessment (DP 392519; 12/13/11) to support registra tion of an Experimental Use Permit on grapefruit, apple and pear. Estimated Drinking Water Concentrations from this assessment were used in a 2012

Human Health risk assessment (DP 396885, 4/25/12) which was cited in the 2013 AcibenzolarS-methyl: Human Health Risk Scoping Document in Support of Registration Review (Syngenta Crop Protection, p. 6).

EPA Response #6: EFED should have referred to the drinking wa ter assessment (DWA) referenced by Health Effects Division (HED) and Syngenta. Since th e completion of the Problem Formulation and Human Health Risk Scoping Document, anothe r drinking water assessment was completed – “Tier II Drinking Water Assessment for the Prop osed Seed Treatment Use of Acibenzolar-Smethyl on Sorghum Seed” (DP 414662; 1/27/14). The Agency will use the most recent DWA at the time of the Registration Review risk assessments.

Comment #7: Syngenta provided a list of edits to several ch emical and fate properties listed in the problem formulation (Syngenta Crop Protection, p. 7).

EPA Response #7: Thank you for the corrections and additional references. EFED will include as appropriate.

Comments by the Center for Biological Diversity

Comment #8: EPA Has an Independent Duty Under the Endangered Species Act to Consult with the U.S. Fish and Wildlife Service and National Marine Fisheries Service on the Reregistration of Acibenzolar (Center for Biological Diversity, p. 1).

...the EPA should begin this revi ew process with the Services immediately after the work plan is finalized . (Center for Biological Diversity, p. 2)

The EPA Must Make Defensible “Not Likely to Adversely Affect” and “Likely to Adversely Affect” Determinations as a Prerequisite fo r Defensible “Jeopardy” and “No Jeopardy” Determinations (Center for Biological Diversity, p. 5).

EPA and the Services Must Assess the Adverse Impacts of Acibenzolar in Critical Habitat (Center for Biological Diversity, p. 7).

EPA Has an Independent Duty Under the Endangered Species Act to Consult with the U.S. Fish

and Wildlife Service and National Marine Fisherie s Service on the Approval of All Acibenzolar End-use Product Labels (Center for Biological Diversity, p. 8).

EPA Response #8: EPA plans to address many of the concerns rais ed in the comments from Center for Biological Diversity as part of the implement ation plan for assessing the risks of pesticides to listed species8 based on the recommendations of the April 2013 Na tional Academy of Sciences (NAS) report. EPA will address concerns specific to acibenzola r-s-methyl in connection with the development of its registration review deci sion for acibenzolar-s-methyl.

The NAS report, available at http://www.nap.edu/cat alog.php?record_id=18344 , outlines recommendations on specific scientific and tech nical issues related to the development of pesticide risk assessments that are compliant w ith the Endangered Species Act and the Federal Insecticide, Fungicide, and Roden ticide Act. In November, the EP A, along with the U.S. Fish & Wildlife Service (USFWS), the National Marine Fisheries Service (NMFS) (collectively, the Services), and the U.S. Department of Agricultu re (USDA), released a summary of their joint Interim Approaches for assessing risks to listed species from pesticides. The Interim Approaches were developed in response to the NAS’ reco mmendations and reflect a common approach to risk assessment shared by the Agencies as a wa y of addressing scientif ic differences between EPA and the Services. The joint Interim Appro aches were released pr ior to the stakeholder workshop held on November 15, 2013. EPA presente d the joint Interim Approaches at the December 2013 PPDC and SFIREG meetings, allowi ng additional opportunities for stakeholders to comment on the Interim Approaches. The Ag encies will consider public comments on the Interim Approaches prior to implementing them. The Agencies intend to jointly implement these approaches as part of a phased iterative proc ess. EPA will refine its listed species risk assessments based on these interim approaches. Th e details of the joint Interim Approaches are contained in the white paper “Interim Appro aches for National-Leve l Pesticide Endangered Species Act Assessments Based on the Recommenda tions of the National Academy of Sciences April 2013 Report,” dated November 1, 2013, available at http://www.epa.gov/espp/2013/nas.html

.

Regarding the Center for Biologi cal Diversity's request for EPA to begin informal consultation with the Services immediately after the workplan for acibenzol ar-s-methyl is finalized, EPA plans to follow the March 2013 stakeholder engage ment paper (“Enhancing Stakeholder Input in the Pesticide Registration Review and ESA Consultation Processes and Development of Economically and Technologically Feasible Reasona ble and Prudent Alternatives”) to identify the appropriate time for initiation of consultation, either formal or inform al, with the Services. The stakeholder engagement paper, jointly deve loped by the EPA, USDA, and the Services and

available at http://www.regulations.gov/#!docum entDetail;D=EPA-HQ-OPP-2012-0442-0038

, allows for early interaction with the Services un der informal consultation. EPA and the Services acknowledge that early interaction as part of informal consultati on may result in refinements to EPA’s effects determinations that can improve th e efficiency of the ESA compliance process. For example, EPA may involve the Services at th e earliest stages of registration review. In general, EPA plans to initiate formal ESA consulta tion, if necessary, at the final decision stage in the registration review process. Consulting later in the process allows the EPA to develop more refined ecological risk assessments and to engage stakeholders in discussions that should result in more focused consultation packages that may include risk mitigation for listed species.

References

Avery, M.L., D.L. Fischer, and T.M. Primus. 199 7. Assessing the hazard to grainivorous birds feeding on chemically treated s eeds. Pestic. Sci. 49: 362-366.9 Bruhl, C.A., B. Guckenmus, M. Ebeling, and R. Barfknecht. 2011. Exposur e reduction of seed treatments through dehusking behaviour of the wood mouse (Apodemus sylvaticus).

Environ. Sci. Pollut. Res. 18: 31-37.

Bergtold, M. and G.P. Dohmen. 2011. Biomass or growth rate endpoint for algae and aquatic plants: Relevance for the aquatic risk assessm ent of herbicides. In tegr Environ Assess Manag 7(2) 237-247.

OECD (Organization for Economic Cooperation and Development). 2006a. OECD Guideline 201: Freshwater alga and cyanobacteria, gr owth inhibition test. Adopted 23 March 2006.

Paris.

OECD (Organization for Economic Cooperatio n and Development). 2006b. OECD Guideline 221: Lemna sp. growth inhibition te st. Adopted 23 March 2006. Paris.

Rumbeli, R. 1996. Metabolism of [Phenyl-(U) 14 C]CGA 245705 after multiple oral administration to laying hens. Unpublis hed report by Ciba-Geigy Ltd., Basel,

Switzerland.

US EPA, 2012. Proposed Methodology for Specifying Atrazine Levels of Concern for Protection of Plant Communities in Freshwater Ecosystems. Report To: Environmental Fate and Effects Division, Office of Pesticide Program s, U.S. Environmental Protection Agency, Washington, DC. EPA/600/R-12/ 019. Mid-Continent Ecology Division, National Health and Ecological Effects Laboratory, Office of Research and Development, U.S. Environmental Protection Agen cy, Duluth, MN. March 5, 2012.