Docket Number EPA-HQ-OPP-2014-0262 

www .regulations. gov 

Spirodiclofen Preliminary Work Plan 

Registration Review: Initial Docket 

Case Number 7443 

Approved by: 

Date: 

March 2015 

~col.P~/b 

Richard P. Keigwin, Jr. 

Director 

Pesticide Re-evaluation Division 
Spirodiclofen Preliminary Work Plan - Table of Contents 

OVERVIEW ................................................................................................................................... 3 

ANTICIPATED DATA NEEDS ..................... : .............................................................................. 3 

STATUTORY AND REGULATORY AUTHORITY ................... ........... ..................................... 5 

CHEMICAL FACTS .................................................................. .................................................... 5 

USE AND USAGE INFORMATION ................................ ............................................................ 6 

RECENT ACTIONS ...... ..... ........ .................................................................................................... 7 

ANTICIPATED RISK ASSESSMENTS FOR REGISTRATION REVIEW ..... ............... ....... ..... 7 

TIMELINE ...................... ....................................................................... .......................................... 9 

NEXT STEPS .. ............................................................................. .................................................. 9 

Appendix - Additional Areas Considered in the Spirodiclofen Registration Review ............. 10 

References: 

This Preliminary Work Plan summarizes the Environmental Protection Agency's current position 

based on the following documents: 

1. Registration Review - Problem Formulation for the Ecological Risk Assessment and 

Drinking Water Exposure Assessment to be Conducted for Spirodiclofen. 

Justin Housenger and Larry Liu. Ph.D. January 28,2015. 

2. Spirodiclofen. Human Health Assessment Scoping Document in Support of Registration 

Review. Kelly Lowe, Thomas Bloem, and Monique M. Perron, Sc.D. January 7, 2015. 

3. Spirodiclofen: Tier I Review of Human Incidents. Elizabeth Evans and Shanna Recore. 

October23, 2014. 

4. BEAD Chemical Profile (BCP) for Registration Review: Spirodiclofen (PC Code: 124871). 

Nikhil Mallampalli, Claire Paisley-Jones, and Michelle Ranville. November 17, 2014. 

5. Spirodiclofen (124871) Screening Level usage Analysis (SLUA). June 9, 2014. 

These and other supporting documents for the spirodiclofen registration review case may be 

found in the docket EPA-HQ-OPP-2014-0262 at http://www.regulations.gov. 

2 
OVERVIEW 

The docket for spirodiclofen is now open, initiating the first public comment period for this 

registration review (docket number EPA-HQ-OPP-2014-0262). Spirodiclofen is an 

insecticide/miticide in the tetronic and tetramic acid chemical class that acts by interfering with 

development in eggs, and nymphal and adult female growth stages (adult males are not affected). 

Products containing spirodiclofen are registered for use to control mites, leafhoppers, and San 

Jose scale on crops including citrus, grapes, stone fruit, pome fruit, and tree nuts. There are no 

residential uses for spirodiclofen. This Preliminary Work Plan (PWP) document explains what 

EPA's Office of Pesticide Programs knows about spirodiclofen, highlighting anticipated data and 

assessment needs, identifying the types of information that would be especially useful to the 

Agency in conducting the review, and providing an anticipated timeline for completing the 

registration review for spirodiclofen. 

The registration review process was designed to include a public participation component to 

solicit input from interested stakeholders. The Agency intends, by sharing this information in the 

docket, to inform the public of what it knows about spirodiclofen and what types of new data or 

other information would be helpful for the Agency to receive as it moves toward a decision on 

spirodiclofen. The Agency encourages all interested stakeholders to review the PWP and 

Appendix and to provide comments and additional information that will help the Agency's 

decision-making process for this chemical. In addition to general areas on which persons may 

wish to comment, there are some areas identified in the PWP and Appendix about which the 

Agency specifically seeks comments and information. Interested stakeholders could include: 

environmental non-profit or interest groups; pesticide manufacturers; agricultural labor or 

commodity groups; commercial, institutional, residential, and other users of pesticides; or the 

public at large. 

The Preliminary Work Plan begins by listing the anticipated data needs for spirodiclofen. Next, 

it discusses the statutory and regulatory authority for Registration Review. Then the document 

provides chemical facts, use and usage information, recent actions, the anticipated risk 

assessments, and a projected registration review timeline for spirodiclofen. Finally, the 

Appendix to this document includes identification and discussion of some areas that are 

considered generally in Registration Review along with some additional chemical case-specific 

information. 

ANTICIPATED DATA NEEDS 

Table 1 below summarizes anticipated data needs for spirodiclofen. For additional discussion of 

the anticipated data needs, see the Registration Review - Problem Formulation for the 

Ecological Risk Assessment and Drinking Water Exposure Assessment to be Conducted for 

Spirodiclofen and Spirodiclofen. Human Health Assessment Scoping Document in Support of 

Registration Review. 

3 
Table 1: Anticipated Data Needs for the Spirodiclofen Registration Review 

Estimated 

Guideline Timeframe Study Title1 Test Number (Months from Material receipt of DCI) 

Anticipated Data Needs for the Parent Spirodiclofen 

835.4200 Anaerobic Soil Metabolism TGAI 24 

835.4400 Anaerobic Aquatic Metabolism TGAI 24 

850.6100 Environmental Chemistry Methods and Associated TGAl 12 Independent Laboratory Validations for Water 

850.1350 Aquatic Invertebrate Life Cycle (Saltwater) TGAI 12 

850.1735 Whole Sediment: Acute Toxicity Freshwater TGAI 12 Invertebrates with Chironomus dilutus1

•

3 

850.1735 Whole Sediment: Acute Toxicity Freshwater TGAI 12 Invertebrates with Hyalella azteca1.4 

850.1740 Whole Sediment: Acute Toxicity Marine Invertebrates TGAI 12 with Leptocheirus plumulosus5

•

6 

850.2100 Avian Oral Toxicity (Passerine Speciesf TGAI 12 

850.3040 Field Testing for Pollinators TEP 24 

Special Study 

(OECD TG 237): Honey Bee Larvae Acute Oral TGAI 12 Toxicity& 

Special Study Honey Bee Larvae Chronic Oral Toxicity TGAI 12 

Special Study Honey Bee Adult Chronic Oral Toxicity TGAI 12 

Special Study Field Trial of Residues in Pollen and Nectar TEP 36 

Special Study 

Semi-Field testing for Pollinators (Tunnel or Colony TEP 24 Feeding Studies) 

Anticipated Data Needs for Spirodiclofen Degradates 

850.6100 Environmental Chemistry Methods and Associated Oegradates9 12 Independent Laboratory Validations for Water 

TGAI = techmcal grade acttve mgredtent; TEP = typtcal end-use product 1 On June 27,201 2, EPA announced certain revisions in harmonized guideline series 850 - Ecological Effects Tests 

- including renumbering and other designations or changes for some guideline studies. See "Final Test 

Guidelines; OCSPP 850 Series; Notice of Availability" 77 FR 38282, June 27,20 12. 

http://www.regulations.gov1#!documentDetaii:D=EPA-IfQ-OPPT-2009-0154-0028 

2 Also known as "Whole Sediment: Subchronic Freshwater Invertebrates," as per EFED Guidance Document 

Entitled "Toxicity Testing and Ecological Risk Assessment Guidance for Benthic Invertebrates." April20 14. 3 A I 0-day study is anticipated to be requested. 4 A I 0-day study is anticipated to be requested. 

s Also known as "Whole Sediment: Subchronic Marine Invertebrates," as per EFED Guidance Document Entitled 

"Toxicity Testing and Ecological Risk Assessment Guidance for Benthic Invertebrates." April 2014. 

6 A 1 0-day study is anticipated to be requested. 7 A protocol does not need to be submitted for Agency approval prior to study initiation provided that the study 

adheres to the parameters outlined in the guidance available at: 

http://www.epa.gov/pesticideslscience/efed/policy guidance/team authors/terrestrial biology tech teamlpasserin 

e ocspp850 21 00 avian oral tox.pdf 

8 Depending on the design of the "Honey Bee Larvae Chronic Oral Toxicity," study, a 72-hour LDso value may be 

derived. If this endpoint is able to be derived, then it would obviate the anticipated need for the (OECD TG 237) 

(Tier I) Honey Bee Larvae Acute Oral Toxicity (Tier I) study. 

9 Degradates of concern spirodiclofen-enol (BAJ 2740-enol), spirodiclofen-dihydroxy (BAJ 2740-dihydroxy), and 

spirodiclofen-ketohydroxy (BAJ 2740-ketohydroxy). 

4 
STATUTORY AND REGULATORY AUTHORITY 

The Food Quality Protection Act (FQPA) of 1996 mandated a registration review program. All 

pesticides distributed or sold in the United States (U.S.) generally must be registered-by the 

Environmental Protection Agency (EPA or the Agency), based on scientific data showing that 

they will not cause unreasonable risks to human health or the environment when used as directed 

on product labeling. The registration review program is intended to make sure that, as the ability 

to assess risk evolves and as policies and practices change, all registered pesticides continue to 

meet the statutory standard of no unreasonable adverse effects to human health or the 

environment. Changes in science, public policy, and pesticide use practices will occur over time. 

Through the registration review program, the Agency periodically reevaluates pesticides to make 

sure that as change occurs, products in the marketplace can be used safely. Information on this 

program is provided on EPA's website. 1 

The Agency is implementing the registration review program pursuant to Section 3(g) of the 

Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), and will review each registered 

pesticide every 15 years to determine whether it continues to meet the FIFRA standard for 

registration. The regulations governing registration review begin at 40 CFR 155.40. The 

Agency will consider benefits information and data as required by FIFRA. The public phase of 

registration review begins when the initial docket is opened for each case. The docket is the 

Agency's opportunity to state what it knows about the pesticide and what additional risk analyses 

and data or information it believes are needed to make a registration review decision. After 

reviewing and responding to comments and data received in the docket during this initial 

comment period, the Agency will develop a Final Work Plan (FWP) and anticipated schedule for 

the registration review of spirodiclofen. 

CHEMICAL FACTS 

Table 2 provides a summary of the chemical facts for spirodiclofen. 

Table 2: Chemical Facts for Spirodiclofen 

PC code 124871 

Case Number 7443 

CAS Number 148477-71-8 

Year first registered 2005 

Pesticide Type Insecticide/miticide 

Chemical class Tetronic and tetramic acid family 

Reregistration Eligibility Because it was registered after November 1984, spirodiclofen 

Decision (REDi was not subject to reregistration. 

Tolerance Reassessment Because it was registered after November 1984, spirodiclofen 

Eligibility Decision (TRED) was not subject to tolerance reassessment. 

Cumulative group Not applicable. Spirodiclofen has not been identified as a 

member of a cumulative group that shares a common 

mechanism oftoxicity. 

1 http://www.epa.gov/oppsrrd 1/registration_review/ 

5 
Table 2: Chemical Facts for Spirodiclofen 

40 CFR Citation Tolerances for spirodiclofen are established at 

40 CFR § 180.608. 

Dual-use Spirodiclofen is registered for conventional pesticidal uses only 

and has no registered antimicrobial or biopesticidal uses. 

Non-pesticidal uses There are no identified non-pesticidal uses of spirodiclofen. 

Pesticide Re-evaluation Julia Stokes 

Division, Chemical Review Stokes.julia@.epa.gov 

Manager (703) 347-8966 

Registration Division, Mark Suarez 

Product Manager Suarez.Mark@epa.gov 

(703) 305-0120 

USE AND USAGE INFORMATION 

Table 3 summarizes the use and usage information for spirodiclofen. Please see the BEAD 

Chemical Profile (BCP) f or Registration Review: Spirodiclofen (PC Code: 124871) in the 

registration review docket for more details. 

Table 3: Spirodiclofen Use and Usage Information 

Summary of Use Spirodiclofen is an insecticide/miticide that acts by interfering 

with growth regulation and lipid biosynthesis. 

Use Sites Agricultural Use Sites: Citrus, grapes, pome fruit, stone fruit, 

tree nuts, tropical fruits, berries, hops, and Christmas tree 

plantations. 

Non-Agricultural Use Sites: Spirodiclofen is not registered for 

any non-agricultural uses. 

Summary ofUsage An average of 85,000 pounds of spirodiclofen was applied 

annually to 315,000 acres (2008-2012). The largest usage of 

spirodiclofen was on oranges (30% of the total pounds applied), 

grapefruit (20%), grapes (18%), and almonds (15%). The 

majority of spirodiclofen was applied in Florida ( 45% of total 

pounds applied) and California (40%). 

Formulation Type(s) Soluble concentrate 

Application Method(s) Product applied once per crop season by airblast equipment for all 

registered crops and by aerial equipment on avocado and 

Christmas trees only. 

Technical Registrant( s) Bayer CropScience LP 

No. of Registrations Two Section 3 products2, one technical and one end-use 

Restricted Use No 

2 Section 3 product labels can be obtained from the Pesticide Product Label System (PPLS) website 

(http:/ /oaspu b.epa. gov /pestlab 1/pp ls.home ). 

6 
Guidance for Commenters: Additional areas of use and usage related information 

requested for this registration review, and of particular interest to EPA, are described below. 

• The following usage information may assist in future Agency assessments for 

Spirodiclofen: Recent reports of pest resistance, information on comparative product 

performance or other aspects that underlie the drop in total spirodiclofen use since 2010, 

and typical application rates. 

• Confirmation of the following label information: sites of application, application 

methods and equipment, maximum application rates, frequency of application, 

application intervals, maximum number of applications per season, and geographic 

limitations on use. 

• Use distribution (e.g., acreage and geographical distribution of relevant use sites). 

• Median and 90th percentile reported use rates (lbs ail A) from usage data - national, state, 

and county. 

• Typical application timing (date of first application and application intervals) - national, 

state, and county. 

• Usage/use information for non-agricultural uses. 

• Typical application interval (days). 

• State or local use restrictions. 

RECENT ACTIONS 

Bayer CropScience requested a tolerance amendment for residues of spirodiclofen in citrus oil 

that was published on June 11 ,2014 (Docket ID: EPA-HQ-OPP-2013-041 1-003). 

ANTICIPATED RISK ASSESSMENTS FOR REGISTRATION REVIEW 

The most recent comprehensive human health risk assessment for spirodiclofen was performed 

for pending uses on bushberries and tropical fruit; however, the applications for amendments to 

add these uses were withdrawn. The most recent human health risk assessment that covers 

currently registered uses for spirodiclofen was completed in October 2009. The most recent 

ecological and environmental fate risk assessment was completed in April 20 11. Findings and 

conclusions from these risk assessments are summarized in the Registration Review - Problem 

Formulation for the Ecological Risk Assessment and Drinking Water Exposure Assessment to be 

Conducted for Spirodiclofen and Spirodiclofen. Human Health Assessment Scoping Document 

in Support ofRegistration Review. 

During registration review, the Agency anticipates the need to conduct a comprehensive 

ecological risk assessment, including an endangered species assessment, for all uses of 

spirodiclofen. For human health, EPA anticipates the need to conduct revised dietary and 

occupational risk assessments during registration review. The need for spray drift and 

volatilization risk assessments will be considered during registration review. 

Table 4 below summarizes the anticipated registration review risk assessments based on the 

EFED Problem Formulation and HED Scoping Document. 

7 
Table 4: Anticipated Risk Assessments for the Spirodiclofen Registration Review 

Type of Risk Assessment Conduct? Notes 

Ecological and Environmental Fate 

Comprehensive ecological y Spirodiclofen will be considered the stressor of concern 

(species to be assessed for the risk assessment. Spirodiclofen and degradates 

include terrestrial and aquatic will be included in the drinking water exposure 

organisms), including assessment. 

endangered species 

Incidents Will check For a discussion of the sole reported ecological incident 

for updates for spirodiclofen, see page 31 of the Problem 

Formulation. 

Human Health 

Dietary 

Food y May be required to reflect the most recent dietaryexposure models and revised estimated drinking water 

concentrations (EDWCs). 

Drinking water y May be revised to reflect the most recent dietaryexposure models (specifically, use of PRZM-GW). 

Occupational 

Handlers (mixers, loaders, y Updated inhalation assessments may be conducted to 

applicators) reflect maximum application rates, using current 

occupational exposure policies and updated inhalation 

toxicological points of departure. 

Post -application y A post-application inhalation assessment may be 

conducted to reflect maximum application rates, the 

highest exposure post-application activities, current 

exposure policies, and updated inhalation toxicological 

points of departure. 

Residential 

Handlers N There are no residential uses of spirodiclofen. 

Post-application y The need for spray drift and volatilization risk 

assessments will be examined. 

Other 

Aggregate y Evaluates the combined risk from dietary and residential 

exposures and may be required to reflect potentially 

revised EDWCs. 

Cumulative N Spirodiclofen has not been identified as a member of a 

cumulative group that shares a common mechanism of 

toxicity, and spirodiclofen does not appear to produce a 

toxic metabolite produced by other substances. 

Tolerances y Decisions concerning harmonization of the U.S. 

tolerance values with either the Canadian and/or Codex 

MRLs will be made as part of Registration Review. 

8 
Table 4: Anticipated Risk Assessments for the Spirodiclofen Registration Review 

Type of Risk Assessment Conduct? Notes 

Incidents Will check For a discussion of the small number of reported human 

for updates incidents for spirodiclofen, see page 1 0 of the Scoping 

Document and the Spirodiclofen: Tier I Review of 

Human Incidents. 

TIME LINE 

The estimated timeline for the completion of the spirodiclofen registration review appears in 

Table 5 below. 

Table 5: Projected Spirodiclofen Registration Review Timeline 

Activities Estimated Date 

Opening the Docket 

Open Docket and 60-day Public Comment Period 2015- March 

Close Public Comment 2015- May 

Case Development 

Final Work Plan 2015- August 

Issue DCI 2015- October- December 

Data Submission 2018- October-December 

60-day Public Comment Period for Draft Risk 2020- April- June 

Assessments3 

Registration Review Decision 

60-day Public Comment Period for Proposed 2021 - January- March 

Registration Review Decision 

Registration Review Decision and Begin Post-Decision 2021 

Follow-up 

Total (years) 6 

NEXT STEPS 

After the 60-day public comment period closes, the Agency will review and respond to any 

comments received in a timely manner and then issue a Final Work Plan for the registration 

review of spirodiclofen. 

3 The regulations governing Registration Review generally require the Agency to provide a public comment period 

of at least 30 calendar days for draft risk assessments; see 40 CFR Part 155.53(c). For conventional pesticides, the 

Agency plans to provide a 60 calendar day public comment period generally for draft risk assessments. 

9 
Appendix - Additional Areas Considered in the Spirodiclofen Registration 

Review 

PUBLIC COMMENTS AND FEEDBACK: 

Guidance for Commenters: The areas below highlight topics of special interest to the Agency 

where your comments, data submissions, or reference to sources of additional information could 

be of particular use. 

Trade Irritants: 

Through the registration review process, the Agency intends to solicit information on trade 

irritants and, to the extent feasible, take steps toward facilitating irritant resolution. The Agency 

will work to harmonize tolerances and international maximum residue limits (MRLs) and may 

modify tolerance levels to do so, whenpossible. Growers and other stakeholders are asked to 

comment on any trade irritant issues resulting from lack ofMRLs or disparities between U.S. 

tolerances and MRLs in key export markets, providing as much specificity as possible regarding 

the nature of the concern. 

Water Quality: 

Spirodiclofen is not identified as a cause of impairment for any water bodies listed as impaired 

under section 303(d) ofthe Clean Water Act.4 In addition, no Total Maximum Daily Loads 

(TMDL) have been developed for spirodiclofen.5 More information on impaired water bodies 

and TMDLs can be found at the Agency's website.6 The Agency invites submission of water 

quality data for this pesticide. To the extent possible, data should conform to the quality 

standards in Appendix A of the OPP Standard Operating Procedure: Inclusion of Impaired 

Water Body and Other Water Quality Data in OPP 's Registration Review Risk Assessment and 

Management Process7 in order to ensure they can be used quantitatively or qualitatively in 

pesticide risk assessments. 

Environmental Justice: 

EPA seeks to achieve environmental justice, the fair treatment and meaningful involvement of all 

people, regardless of race, color, national origin, or income, in the development, implementation, 

and enforcement of environmental laws, regulations, and policies. To help address potential 

environmental justice issues, the Agency seeks information on any groups or segments ofthe 

population who, as a result of their location, cultural practices, or other factors, may have 

atypical, unusually hiigh exposure to spirodiclofen compared to the general population. Please 

comment if you are aware of any sub-populations that may have atypical, unusually high 

exposure compared to the general population. 

4 http://iaspub.epa.gov/tmdl waters I 0/attains nation cy.cause detail 303d?p cause group id=885 . 5http://iaspub.epa.gov/tmdl waters I 0/attains nation.tmdl pollutant detail?p pollutant group id=885&p pollutant 

group name=PESTICIDES 6 http://www.epa.gov/owow/tmdll 7 http://www.epa.gov/oppsrrd !/registration review/water quality sop.htm 

10 
ENDANGERED SPECIES: 

A risk assessment that supports a complete endangered species determination has not been 

conducted for spirodiclofen. The ecological risk assessment planned during registration review 

will allow the Agency to determine whether use of spirodiclofen has "no effect" or "may affect" 

federally listed threatened or endangered species (listed species) or their designated critical 

habitats. When an assessment concludes that a pesticide's use "may affect" a listed species or its 

designated critical habitat, the Agency will consult with the U.S. Fish and Wildlife Service 

and/or National Marine Fisheries Service (the Services), as appropriate. 

ENDOCRINE DISRUPTOR SCREENING PROGRAM: 

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse 

outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and 

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, 

reproductive, and general or systemic toxicity. These studies include endpoints which may be 

susceptible to endocrine influence, including effects on endocrine target organ histopathology, 

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, 

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and 

chronic studies that assess growth, developmental and reproductive effects in different 

taxonomic groups. As part of its most recent registration decision for spirodiclofen, EPA 

reviewed these data and selected the most sensitive endpoints for relevant risk assessment 

scenarios from the existing hazard database. However, as required by FFDCA section 408(p ), 

spirodiclofen is subject to the endocrine screening part of the Endocrine Disruptor Screening 

Program (EDSP). 

EPA has developed the EDSP to determine whether certain substances (including pesticide 

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

produced by a "naturally occurring estrogen, or other such endocrine effects as the Administrator 

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

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

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

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

interact withE, A, or T hormonal systems will proceed to the next stage ofthe EDSP where EPA 

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

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

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

Under FFDCA section 408(p ), the Agency must screen all pesticide chemicals. Between 

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of67 

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list 

of chemicals identified for EDSP screening was published on June 14, 20138 and includes some 

pesticides scheduled for registration review and chemicals found in water. Neither of these lists 

8 See http://www.reg.ulations.gov/#!documentDetaii;D=EPA-HO-OPPT-2009-0477-0074 for the final second list of 

chemicals. 

11 
should be construed as a list of known or likely endocrine disrupters. Spirodiclofen doesn't 

appear on either list. 

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

chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our 

website.9 

HUMAN STUDIES: 

Past spirodiclofen risk assessments rely in part on data from studies in which adult human 

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

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

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

Agricultural Handler Exposure Task Force (AHETF) Database, and the Agricultural Reentry 

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

generic exposure databases, and has found no clear and convincing evidence that the conduct of 

any of them was either fundamentally unethical or significantly deficient relative to the ethical 

standards prevailing at the time the research was conducted. All applicable requirements of 

EPA's Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been 

satisfied, and there is no regulatory barrier to continued reliance on these studies. 

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

12