OFFICE OF
CHEMICAL SAFETY AND
POLLUTION PREVENTION UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON D.C., 20460

PC Code: 084701 MEMORANDUM DP Barcode: 422819, 422850

DATE: October 22, 2014

SUBJECT: Response to the Initial 60 -Day Public Comment on: “ Registration Review: Draft Problem Formulation for Environmen tal Fate, Ecological Risk, Endangered Species and Human Health Drinking Water Exposure Assessments for Etridiazole (05/06/14; PC Code 084701; DP Barcode 417576) ”

TO: Margaret Hathaway, Chemical Review Manager Tom Myers, Team Leader Risk Management and Implementation Branch II (RMIB II)

Pesticide Re-evalu ation Division (7508P)

FROM: Karen Milians, Ph.D., Chemist Catherine Aubee, Biologist

Environmental Risk Branch IV

Environmental Fate and Effects Division Office of Pesticide Programs

REVIEWED

BY: Jim Carleton, Ph.D., Senior Scientist Thomas Steeger, Ph.D., Senior Science Advisor

Environmental Risk Branch IV

Environmental Fate and Effects Division Office of Pesticide Programs

APPROVED

BY: Sarah Winfield, Acting Branch Chief

Environmental Risk Branch IV

Environmental Fate and Effects Division Office of Pesticide Programs

The Environmental Fate and Effects Division (E FED) has reviewed the public comments on the Preliminary Work Plan for Regi stration Review of etridiazole 1 , including the draft problem

1 Docket ID Number EPA-HQ-OPP-2014-4014Page 2 of 10 formulation 2 for environmental fate, ecological ris k, endangered species and human health drinking water exposure assessments. Comments received from the following stakeholders are addressed in this response:

 MacDermid Agricultural Solutions (formerl y Chemtura Corporation, registrant) (August 19, 2012 3 )

 Physician’s Committee for Responsib le Medicine (PCRM) (August 25, 2013 4 )

Additionally, an upgrade request submitted by MacDermid Agricultural Solutions (MRID 49460901) is addressed in this document.

In the following sections, the specific comment is summarized in italics and is then followed by EFED’s response.

1. MacDermid Agricultural Solutions (former ly Uniroyal Chemical Company, Inc.), regarding MRID 43504305:

a) Upgrade request, submitted in MRID 49460901: “First, the solvent extraction scheme for soil, namely acetonitrile: 1% a mmonium hydroxide in water (4 :1), was able to effectively extract etridiazole from soil. That is, greater than 98% of the applied radioactivity at Day 0 was extractable from the water/soil sy stem and the extracta ble radioactivity corresponded to etridiazole. Only 1% of th e applied radioactivity re mained in the postextracted solids following extraction. Thus, the solvent used in the study was, in fact, appropriate to achieve quantitative extr action of etridiazole from soil.

Hydrosoil-bound residues were indeed signi ficant following extraction. Therefore, bound residues from two representative sampli ng intervals (Day 60 and Day 179) were additionally extracted with "str onger" solvents in an attempt to remove more radioactive residues. These samples represented sampli ng intervals, which were widely, spaced during the incubation period and also represen ted essentially maximum values for bound residues. Initially, the samples were extra cted with acetonitrile:water:acetic acid (80:20:2.5) for 4 hours. Less than 3.5% of the applied dose was extract able from either sample. Analysis of the extracts from this solvent mixture showed less than 0.3% of the applied dose corresponding to etridiazole. The samples were then heated at reflux conditions with 0.25 N hydrochloric acid fo r about 1 hour. Despite this very rigorous extraction attempt, less than 10% of the applied dose was releas ed. Of that released, only about half could be partitioned into ethyl acetat e. Therefore, the 3-step extraction scheme indicated that, (1), etridiaz ole could be extracted from hydrosoil quantitati vely with the initial solvent (acetonitrile :1% ammonium hydroxide in water (4:1) and (2), even stronger extraction solvents using more ri gorous conditions were not able to remove more appreciable amounts of bound radioactive re sidues. Thus, it can be concluded that etridiazole, in an anaerobic and aquatic envi ronment degrades quickly, forms significant

2 US EPA 2014 Registration Review: Draft Problem Formulation for Environmental Fate, Ec ological Risk, and Endangered Species, and Human Health Drinking Water Exposure Assessments for Etridiazole (PC Code 084701; DP Barcode 417576). Fr om: C. Aubee and K. Milians,

Environmental Fate and Effect s Division; To: M. Hathaway and T. Myers, Pesticide Re-evaluati on Division; 05/06/2014.

3 EFED presumes that the actual date of correspondence is Augus t 19, 2014, since it was submitted in response to the Preliminary Work Plan (June 25, 2014).

4 EFED presumes that the actual date of correspondence is Augus t 25, 2014, since it was submitted in response to the Preliminary Work Plan (June 25, 2014).Page 3 of 10 amounts of soil-bound residues, and slowly those residues are microbially mineralized to

carbon dioxide.

A table summarizing the pH, redox and dissolv ed oxygen values is provided by the laboratory that conducted this study (Table 1) . Collection of these data were mentioned in the report (p. 15) but not actually provided per se. These data i ndicate that dissolved oxygen concentrations are quite low, rangi ng from 0 - 0.7 mg/L (ppm), and clearly are indicative of an anaerobic environment. Furthermore, the redox measurements throughout the incubation period ranged from 14-109 mv, also indicative of a reducing environment. For instance, microbially medi ated iron reduction (transformation of ferric ion to ferrous ion) indicative of environm ents that are anaerobic, become prominent when the oxidation-reduction potential fa lls below about 200 mV (see Introduction to Soil Microbiology, Martin Alexander, Second Edition, Krieger Publishing Co., Malabar, Florida, 1991, p.375 -- 376). Thus, these two par ameters, namely, dissolved oxygen and redox potential, indicate that anaerobic conditions we re maintained during the incubation period.”

EFED’s response: In preparing its data evaluation record (D ER), the Environmenta l Fate and Effects Division (EFED) considered the information referred to in this comment, which was provided with the study report. The commen t itself provides no new information, and

EFED concludes that there is a lack of a compelling rationale for upgrading the study.

The following deficiencies of the study are reiterated:

1. EFED agrees that at day zero 98% of et ridiazole was effectively extracted from soil. However, there is a concern with extractions at other sampling times when the recovery of etridiazole was consid erably lower (sampling day 7-179 days post-treatment, 40.8-58.1% of the applied, respectively). Addi tional extractions should have been performed with sodi um hydroxide and with other solvent systems in an attempt to rec over a greater portion of the [ 14 C] residues for

characterization. In the absence of su ch an effort, it cannot necessarily be
concluded that, as asserted in the comme nt, etridiazole in an anaerobic aquatic environment degrades quickly to form soil-bound residues, wh ich are in turn ultimately mineralized.

2. The redox potential in the study (range: 14 - 109 mV) was relatively high, thus it cannot be concluded that the test system constituted an anaerobic aquatic environment as specified per OCSPP Guideline 835.4400 5

, i.e ., “the sediment and water are regarded as anaerobic once th e redox potential (Eh) is lower than -

100mV.”

Further deficiencies of the study are su mmarized in the DER for the study (MRID 43504305).

5 USEPA. 2008. Fate, Transport and Transformation Test Guid elines. OCSPP 835.4400. Anaerobic Aqua tic Metabolism. Office of Ch emical Safety and Pollution Prevention formerly th e Office of Prevention, Pesticides and Toxic Substances (7101) EFA 712-C-08-019. http://www.regulations.gov/#!documen tDetail;D=EPA-HQ- OPPT-2009-0152-0039Page 4 of 10 2. MacDermid Agricultural Solutions, Inc.

a) Guideline No, 850.1350 Mysid Chronic Toxicity Test MacDermid Agricultural Soluti ons Inc. is evaluating the et ridiazole labels to update the language to avoid application near est uarine/marine invertebrate habitat.

EFED’s response: There are currently no data available to address uncertainties associated with the potential for

adverse effects to estuarine/marine fish and i nvertebrates since chronic data are not available

for estuarine/marine invertebrates. As stated in 40 CFR Part 158.660 6 , aquatic invertebrate life cycle data for a saltwate r species are required if a pr oduct meets any of the following

conditions:

i. Intended for direct application to th e estuarine or marine environment,

ii. Expected to enter this environment in significant concentrations because of its expected use or mobility patterns.

iii. If the acute LC 50 or EC 50 < 1 milligram/liter (mg/L).

iv. If the estimated environmental concentration (EEC) in water is >1% of the acute

EC 50 or LC 50 or if any of the following conditions exist:

A. Studies of other organisms indicate the reproductive physiology of fish and/or invertebrates may be affected.

B. Physicochemical properties indicate bioaccumulation of the pesticide.

C. The pesticide is persistent in water ( e.g ., half-life in water >4 days).

EFED has considered the following data in determ ining that an estuarine/marine invertebrate life cycle study is necessary for the ecological risk assessment, with consideration to sections (ii), (iv), (iv)(B), and (iv)(C) above:

 The currently labeled use patterns of etridi azole, particularly the use on golf course turf, indicate that etridiazole use may occu r in close proximity to estuarine/marine

environments.

 A Tier I analysis in the support of the Reregistration Eligibility Decision (RED) 7 for etridiazole determined that surface water EECs may reach 0.44 mg a.i./L.

 Etridiazole is moderately toxic to estuarin e/marine invertebrates on an acute exposure basis (LC 50 =2.5 mg a.i./L, MRID 42834603).

 Based on these data, the peak surface wate r EEC = 0.18 of the acute toxicity endpoint

for estuarine/marine invert ebrates (EEC 0.44 mg a.i./L  LC 50 2.5 mg a.i./L = 0.18) and therefore is 18 times gr eater than the 0.01 threshold identified in 40 CFR Part

158.660.

 The log octanol-water part ition coefficient (log K ow ) for etridiazole is 3.37, which indicates a potential to bioaccumulate.

 The half-life for etridiazole in water, base d on hydrolysis, ranges from 81-83 days at pH values of 5 to 7 and suggests that the compound may persist in water (Accession

6 CFR. 2014. Title 40 (Protection of the E nvironment), Chapter 1 (Environmental Protec tion Agency), Subchapter E (Pesticide Pro grams), Part 158 (Data Requirements for Pesticides), S ubpart G (Ecological Effects), §158.660 (Non-t arget plant protection data requirements table). http://www.ecfr.gov/cgi-bin/text -idx?SID=b9b5a7025cc818a6d42deb818e 657b83&node=se40.24. 158_1660&rgn=div8

7 USEPA, 2000. Revised EFED Risk Assessment for the Reregist ration Eligibility Decision on 5-ethoxy -e tricholoromethyl-1,2,4-thi adiazole (Etridiazole; Terrazole ® ) Environmental Protection Agency (USEPA). From Environm ental Fate and Effects Division to Special Review and Reregistration Division. Memorandum issued: May 22, 2000.Page 5 of 10 Number 00001650). Additional data are needed to evaluate biotic (aerobic and anaerobic aquatic) metabolism.

EFED will evaluate any proposed label change s that may be submitted in accordance with a Pesticide Registration Improvement Act (PRIA) action or Registration Review and which may have an impact on ecological risks. Ho wever, although changes in labeled use patterns may result in lower exposure potential, the need still exists for estuarine/marine invertebrate life cycle data, particularly give n etridiazole’s potential to bioaccumulate and its persistence

in water.

b) Guideline No. 850.4400 Aquatic Plan t Toxicity Test (Using Lemna ssp.) The test material required for the Aquatic Plan t Toxicity Test (Lemna spp.) is for an End-Use Product (TEP). MacDermid Agricultural Solutions , Inc. requests that the study be done on the TGAI using a study design that would be mo re suitable to the physical chemistry of the

active.

EFED’s response:

EFED is limited in its ab ility to provide a response to this comment without clarification of what is meant by “ a study design that would be more suit able to the physical chemistry of the

active .” The 40 CFR Part 158.660 indicates that e ither a typical end-use product (TEP) or the technical grade active ingred ient (TGAI) may be used for a quatic plant testing. However, EFED policy, as stated in a 1994 guidance memo 8 and in the 850 test guidelines for aquatic plants, is that TEP is the pref erred test substance for aquatic plant toxicity studies. General guidance from the EFED Plant Technical Team is that TEP testing shou ld be used in these studies. There may be instances where aquatic plant testing with TGAI would be acceptable,

such as cases where runoff from a treated field is expected to be the predominant route of exposure and solubility is not an issue. However, in cases where spray drift exposure may affect water bodies, solubility of the test substance is limite d or the pesticide is applied directly to water, TEP may still need to be requested if only T GAI studies are available. The use of a TEP is preferred to use of a TGAI with a standard solvent.

c) Nonguideline Honey Bee Larval Toxicity A guideline compliant study will be s ubmitted. Requires protocol submission.

EFED’s response: EFED appreciates the registrant’s communica tion that it will submit data to fulfill the requirements for acute toxicity to honey bee ( Apis mellifera ) larvae and for acute oral and contact toxicity to young adult honey bees. We look forward to reviewing a protocol for the larval toxicity test prior to initiation of the experiment.

Recently, the Agency has issued guidance 9 for assessing the potential risks of pesticides to bees and the data needed to support such asse ssments. The guidance document indicates that

8 Maciorowski, A. F. 1994. Closure on Nontarget Plant Phytotoxic ity Policy Issues. Support Document #19. In: U.S. EPA. 2004. Ov erview of the Ecological Risk Assessment Process in the Office of Pesticid e Programs. Office of Prevention, Pesticides, and Toxic Substan ces. Office of Pesticide Programs. Washington, D.C. January 23, 2004.

9 USEPA et al .. 2014. Guidance for Assessing Pesticide Risks to Bees. http://www2.epa.gov/s ites/production/files/2014- 06/documents/pollinator_risk_a ssessment_guidance_06_19_14.pdfPage 6 of 10 if exposure of bees to a pesticide is expecte d, a Tier I screening-leve l risk assessment should
be conducted. The Tier I assessment is in tended to be sufficiently conservative that chemicals which pass the screen can be assumed to represent a relativel y 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 on individual bees, and consist of the following tests: acute contact toxicity data to adult honey be es (honey bees serving as a surrogate for other Apis and non- Apis bees), acute and chronic or al 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 assessm ent may be refined using data that further define exposure or through additi onal data including Tier II semi -field or full-field toxicity
tests conducted with whole colonies.

Consistent with the guidance 9 that was issued shortly after the draft Problem Formulation for etridiazole, Tier I honey bee la boratory toxicity data are ne eded to conduct the screeninglevel risk assessment because e xposure of bees to etridiazole residues is expected. The registrant has since submitted a nonguideline stu dy testing acute and oral contact toxicity to the bumblebee ( Bombus terrestris L.) (MRID 49460902) 10 . This study is in review and may provide useful information for risk characte rization, particularly since bumblebees are ground-dwelling insects and are lik ely to be exposed to soil -incorporated etridiazole. Additionally, the registrant has indicated that it will submit guideline-compliant data for acute contact and oral toxicity for adult honey be es, and for acute larval toxicity. In support of the Final Work Plan for etridiazole, EFED further recommends the submission of toxicity data for chronic oral exposure to larval and adult honey bees, as described in the Pollinator
Guidance. These additional recommendations ar e detailed in the following data rationale
tables.

Should the screening-level risk assessment id entify risk concerns for bees, mitigation measures may need to be considered or th e registrant may be required to conduct more refined studies under semi-field or full-field conditions ( e.g. , 850.3040 11 guideline studies) that reduce uncertainty by char acterizing etridiazole’s effect s at the whole-colony level.

Guideline Number: Non-Guideline Study Title: Larval Hone y Bee Chronic Oral Toxicity

Rationale for Requiring the Data

This study is needed to evaluate the p otential effects of technical grade active ingredient (TGAI) to honey bee larvae from repeat exposure. Etridiazole is used as a soil-incorporated fungicide, an d is currently registered for use on tobacco, tomato, turf (golf-course tees, greens and fairways), on ornamental plants, and commercial nurseries. These use patterns may result in exposure to blooming plants and could result in residues in pollen and nectar (which could then be transported to the hive by adult forager bees). Additionally, etridiazole is moderately persistent, at least locally systemic in plants, and can be absorbed through th e foliage and roots. Theref ore, in addition to direct contamination of pollen and/or nectar through foliar applica tions, etridiazole residues may be translocated to pollen and nectar from root uptake in plants grown where etridiazole has been 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.

10 Verge, E. 2012. Terrazole 48EC (UBI 8142.00): Acut e Oral and Contact Toxicity to the Bumblebee, Bombus terrestris L. (Hymenoptera, Apidae) under Laboratory Conditions (Multi Dose Test). Submitted September 26, 2014. MRID 49460902.

11 USEPA. 2012. Ecological Effects Test Gu idelines OCSPP 850.3040: Field Testing for Po llinators. Office of Chemical Safety and Pollution Prevention (7101). EPA 712-C-017 January 2012.Page 7 of 10 The Agency finalized its guidance 12 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 13 provides a draft guidance protocol for potentially assessing both the acute and chronic toxicity to developi ng brood (larvae and pupae) from repeat exposure to pesticides. A protocol should be submitted to the Agency for review and approval 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 larval 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 Revi ew as well as for future endangered species assessments. These data would allow th e Agency to better characterize the potential for risk to insects (including beneficial pollinators) from the use of etridiazole. These data may help the Agency determine whether any mitigations are needed. If the Registration Re view and any future endangered species risk assessments are performed without these data, the Agency would have to assume that etridiazole "may affect" insects, including bees and beneficial pollinators, directly (and endangered speci es from other taxa indirectly ), and uses of etridiazole might need to be restricted in areas where pollinators could be exposed.

Guideline Number: Non-Guideline Study Title: Adult Honey Bee Chronic Oral Toxicity

Rationale for Requiring the Data

This 10-day study is needed to evaluate the potential effects of technical grade active ingredient (TGAI) on young adult honey bees from repeat exposure. Etridiazole is used as a soil-incorporated fungicide, and is currently registered for use on tobacco, tomato, turf (golf-cours e tees, greens and fairways), on ornamental plants, and commercial nurseries. These use patterns may result in exposure to blooming plants and could result in residues in pollen and nectar (which could then be transported to the hive by adult forager bees). Additionally, etridiazole is moderately persistent, at least locally systemic in plan ts, and can be absorbed through the foliage and roots. Therefore, in addition to direct contamination of pollen and/ or nectar through foliar applications, etridiazole residues may be translocated to polle n and nectar from root uptake in plants grown where etridiazole has been 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 has finalized its guidance 14 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 and approval 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 Revi ew as well as for future endangered species assessments. These data would allow the Agency better characteriz e the potential for risk to insects (including beneficial pollinators) from the use of etridiazole. These data may help the Agency determine whether any mitigations are needed. If the Registration Re view and any future endangered species risk assessments

12 Ibid USEPA et al . 2014.

13 OECD. 2013. OECD Draft Gu idance 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/tes ting/Draft_GD_honeybees_rep_exp_f or_2nd_CR_25_November_2013.pdf

14 Ibid USEPA et al . 2014.Page 8 of 10 are performed without these data, the Agency would have to assume that etridiazole "may affect" insects, including bees and beneficial pollinators, directly (and endangered speci es from other taxa indirectly ), and uses of etridiazole might need to be restricted in areas where pollinators could be exposed.

3. Physician’s Committee for Responsible Medicine (PCRM)

a) Guideline No. 850.2100 Acute Avian Oral Toxicity We recommend that OECD Test Guideline 223, Avi an Acute Oral Toxicity Test, be used as the protocol instead of EPA Guideline 850.2100 in the interest of reducing the numbers of animals used by up to 61%. We also refer th e registrant to the “Guidance for Classifying Studies Conducted Using the OECD Test Guideline 223 (TG223) (Acute Avian Oral Sequential Dose Study)” ava ilable on the Agency’s website.

EFED’s response: EFED encourages careful consideration of the limitations and appropriateness of the Organization for Economic Cooperation and De velopment (OECD) Test Guideline 223 15 for a given test chemical and species. For exampl e, it is important to document that background mortality for the test species is less than 1% in a given laboratory, and that the species has a low propensity to regurgitate. Specific re commendations are outlined in the document referenced by PCRM, “ Guidance for Classifying Studies Conducted Using the OECD Test Guideline 223 (TG223) (Acute Av ian Oral Sequential Dose Study) ” (November 9, 2011). This document is publicly available at the following web address: http://www.epa.gov/pesticides/science/efed/pol icy_guidance/team_authors/terrestrial_biolog y_tech_team/review_avian_ acute_oral_oecd_tg223.pdf

To address the potential for regurgitati on in test birds, EFED has provided “ Guidance for Use When Regurgitation is Observed in Avian Acute Toxicity Studies with Passerine Species ” (April 9, 2012). Note that the OECD 223 test design is not appropriate for use when regurgitation occurs. The guidan ce is publicly available at http://www.epa.gov/pesticides/science/efed/pol icy_guidance/team_authors/terrestrial_biolog y_tech_team/rr_regurg_ acute_passerine.pdf

More recently, EFED publicly shared its inte rnal guidance for reviewers: “Guidance for Reviewing OCSPP 850.2100 Avian Or al Toxicity Studies Conduc ted with Passerine Birds” 16 (August 20, 2014). This document is specific to studies conducted using OCSPP 850.2100 and does not address studies which may be c onducted using OECD Test Guideline 223.

b) Guideline No. 850.1075 Fish Acute Toxi city Test (3-Carb-T and 3-DCMT degradates) (freshwater and estuarine/marine) We refer the Agency to the following study to be taken into consideration for the fish acute

15 OECD 2009. OECD Guideline for the Testi ng of Chemicals. Avian Acute Oral Toxic ity Test. OECD/OCDE 223 Adopted: 22 July 201 0. http://www.oecd-ilibrary.org/envi ronment/test-no-223-avian-acute-o ral-toxicity-test_9789264090897-en

16 USEPA. 2014. Guidance for Reviewing OCSPP 850.2100 Avian Oral Toxicity Studies Conducted with Passerine Birds. http://www.epa.gov/pesticides/sci ence/efed/policy_guidance/team_authors/terrest rial_biology_tech_team/passerine_ocspp850_2100_a vian_oral_ tox.pdfPage 9 of 10 toxicity test. The study is available in the California Department of Pesticide Regulation records for Terrazole. 2

...
2 http://apps.cdpr.ca.gov/ere glib/, chemical code 580.

EFED’s response: In response to the Preliminary Work Plan, EF ED notes that the registrant has submitted existing study reports on the acute toxicity of the etridiazole degradate 3-Carb-T (also referred to as T-02) to freshwater fish 17 and invertebrates 18 ; these studies are in review (MRIDs 49460903 and -04). The registrant i ndicated that it will submit a guideline compliant study for acute toxicity of the de gradate 3-DCMT to estuarine/marine fish. 19

EFED was unable to obtain any study documen t using the link provided by PCRM. As with other data requirements, a registrant may su bmit non-guideline data fo r consideration by the Agency, along with a rationale explaining how the submitted data may address a given data requirement.

c) Guideline No. 850.1075 Fish Acute Toxi city Test (3-Carb-T and 3-DCMT degradates) (freshwater and estuarine/marine) (continued) If these data are not sufficient then we r ecommend the registrant consider an alternative strategy that can supplement otherwise unac ceptable fish toxicity data or provide information on the concentrations likely to caus e acute fish toxicity. Such a strategy includes the newly-adopted Fish Embyrotoxicity Te st guideline (FET) (OECD TG 236), an acute threshold estimation approach, and QSAR or re ad-across methods. Together these methods may in some cases provide enough information to set safe exposure levels without conducting additional live fish testing.

EFED’s response: EFED recognizes the importance of reducing anim al testing and will consider multiple lines

of evidence in its risk assessm ent. The methods identified by PCRM may be useful for risk characterization. However, ther e are significant uncertainties a ssociated with each of the methods identified by the registrant and these uncertainties may limit the utility of these studies for quantitatively assessing risk from th e use of etridiazole. The Agency continues to evaluate the Fish Embryo Toxicity (FET) 20 method and its poten tial utility for risk assessment, but the FET method has not been iden tified as a suitable substitute for testing the acute toxicity to fish using OCSPP 850.1075 21 at this time. Similarly, while an acute threshold approach 22 using alga or invertebrates may seem appealing, the biological and

17 Cafarella, M.A. 2000. T-02 acute toxicity to rainbow trout ( Onchorhynchus mykiss ) under static conditions. Submitted September 3, 2014.

MRID 49460904.

18 Cafarella, M.A. 2000. T-02 acute toxicity to daphnids ( Daphnia magna ) under static conditions. Submitted September 3, 2014. MRID

49460903.

19 MacDermid Agricultural Solutions, Inc. 2014. Letter to th e Office of Pesticide Programs Docket (EPA-HQ-OPP-2014-0414).

20 OECD. 2013. Test Guideline 236: Fish Embryo Ac ute Toxicity Test. OECD Guidelines for the Testing of Chemicals. Available at: http://www.oecd-ilibrary. org/environment/test-no- 236-fishembryo-acute-toxicity-fet-test_9789264203709-en. Accessed August 25, 2014.

21 USEPA. 1995. Ecological Effects Test Guid elines OCSPP 850.1075. Fish Acute Toxicity Test, Freshwater and Marine. Office of Chemical Safety and Pollution Prevention formerly the Office of Preventi on, Pesticides and Toxic Substances (7101). EPA 712-C-96-118. April 1996. http://www.epa.gov/ocspp/pubs/frs/publica tions/OPPTS_Harmonized/850_Eco logical_Effects_Test_Gui delines/Drafts/850-1075.pdf

22 OECD. 2010. Series on Testing and Assessment No. 126. Short Guidance on the ThresholdPage 10 of 10 quantitative relevance of effects seen in these ta xonomic groups is difficult to extrapolate to fish, and effects from such studies would do little to inform risk characterization for fish and aquatic amphibians. Finally, the accuracy of Quantitative Structure-Activity Relationships (QSAR) and other inference methods 23,24 is dependent on the quantity and quality of underlying data on chemicals with similar stru ctures and mechanisms of action. It is uncertain to what extent appr opriate data are available for molecules that are chemically similar to etridiazole’s environmental degr adates to support a robust QSAR analysis. However, if the registrant can provide evidence consistent with that identified in the North American Free Trade Agree (NAFTA) guidance 25 on the use of QSARs that etradiazole degradates fall within the range of applicabil ity for these models, EPA will consider this evidence in determining whether additional te sting is needed with the degradates.

Approach for Acute Fish Toxicity. Available at http://ntp.niehs.nih.gov/iccvam/suppdocs/fedd ocs/oecd/oecd-gd126.pdf. Accessed August 25 , 2014.

23 OECD. 2010. (Q)SAR Application Toolbox Versi on 1.1: Strategies for grouping chemicals for data gap filling for acute aquatic toxi city endpoints. Available online at http://www.oecd.o rg/dataoecd/4/47/45133663.pdf

. 24 North American Free Trade Association ( NAFTA). 2012. Quantitative Structure Activit y Relationship [(Q)SAR] Guidance Document

. Technical Working Group on Pesticides. Available online at http://www.epa.gov/oppfead1/in ternational/naftatwg/guida nce/qsar-guidance.pdf

. 25 Ibid NAFTA. 2012.