2

Prometryn Preliminary Work Plan – Table of Contents

Overview 3

Anticipated Data Needs 3

Statutory and Regulatory Authority 5

Chemical Facts 6

Use and Usage Information 6

Recent Actions 7

Anticipated Risk Assessments for Registration Review 7

Timeline 9

Next Steps 10

Appendix – Additional Areas Considered in Prometryn’s Registration Review 11

References:

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

based on the following documents:

1. EFED Registration Review Preliminary Problem Formulation for Prometryn. Ruhman 

and Mastrota. March 19, 2013.

2. Prometryn. Human-Health Assessment Scoping Document in Support of Registration 

Review. Lowe et al. February 28, 2013. 

3. Prometryn: Review of Human Incidents. Recore and Evans. November 13, 2012.

4. BEAD Chemical Profile for Registration Review: Prometryn. Phillips et al. December 13, 

2012. 

5. Prometryn Screening Level Usage Report. Biological and Economic Analysis Division. 

September 10, 2012.

6. PRD Label Data Report: Food/Feed & Non-Food/Non-Feed Uses Considered in 

Registration Review Work Planning for Prometryn. August 22, 2012.

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

in the docket EPA-HQ-OPP-2013-0032 at http://www.regulations.gov.
3

OVERVIEW

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

registration review (docket number EPA-HQ-OPP-2013-0032). Prometryn is a substituted 

triazine herbicide registered for use on vegetable crops for control of broadleaf grasses and 

weeds. Prometryn is not registered for residential use. This Preliminary Work Plan (PWP) 

document explains what EPA's Office of Pesticide Programs knows about prometryn,

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 prometryn.

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 prometryn and what types of new data or 

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

prometryn. 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 decisionmaking 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 the 

following: 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 PWP begins by listing the anticipated data needs for prometryn. It then discusses the 

statutory and regulatory authority for registration review, followed by the chemical facts, use and 

usage information, recent actions, anticipated risk assessments, and a projected registration 

review timeline for prometryn. 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 summarizes anticipated data needs for prometryn. For additional discussion of the 

anticipated data needs, see the March 19, 2013 memo, EFED Registration Review Preliminary 

Problem Formulation for Prometryn, and the February 28, 2013 memo, Prometryn. HumanHealth Assessment Scoping Document in Support of Registration Review. Table 2 summarizes 

outstanding conditional data requirements from a 2010 registration action for prometryn. 
4

Table 1: Anticipated Data Needs for Prometryn’s Registration Review1

Guideline 

Number Study Title Test Material

Estimated 

Timeframe

(Months from 

receipt of 

DCI)

Anticipated Data Needs for Prometryn (parent)2

835.4100 Aerobic soil metabolism3 TGAI or 

PAIRA 24

835.4300 Aerobic aquatic metabolism4 TGAI or 

PAIRA 24

835.4400 Anaerobic aquatic metabolism TGAI or 

PAIRA 24

850.6100

Environmental Chemistry Methods and Associated 

Independent Laboratory Validation in Water and 

Soil

TGAI 12

860.1480 Magnitude of the Residue –Meat/Milk TGAI 24

870.3465 90-day Inhalation Study – Rat5 TGAI 12

875.2100 Dislodgeable Foliar Residue Study TEP 12

Non 

GDLN

ORD Study Method EPA 600/R-099-064. Chronic 

Freshwater Sediment Testing (Chironomus dilutus

or C. tentans

TGAI 24

Non 

GDLN

ORD Study Method EPA 600/R-099-064. Chronic 

Freshwater Sediment Testing (Hyallela azteca) TGAI 24

Non 

GDLN

ORD Study Method EPA 600/R-099-020. Chronic 

Estuarine/Marine Sediment Testing (Leptocheirus 

plumulosus)

TGAI 24

Anticipated Data Needs for the Prometryn Degradate Hydroxypropazine (GS-11526)

850.1010 Acute toxicity freshwater invertebrates Degradate 12

850.4400 Aquatic plant toxicity test using Lemna spp Degradate 12

850.5400 Algal toxicity6 Degradate 12

TGAI = technical grade active ingredient; TEP = typical end-use product 1 On June 27, 2012, EPA announced certain revisions in harmonized guideline series 850 – Ecological Effects Data

Requirements – 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, 2012. 

http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0154-0028 2 The anticipated data requirements for registration review do not include studies already required by EPA as a 

condition of registration or by a previous Data Call-In notice. 3 Data are anticipated to be required for two soils representing major cotton growing areas. 4 A study has been submitted to EPA and is in review, but the data requirement will be considered outstanding until 

the review is completed and the study found to be acceptable.

5 A 28-day study is expected to be sufficient. 6

EPA expects to require a study on freshwater algae, Pseudokirchneriella subcapita.
5

Table 2: Outstanding Data Requirements for Prometryn1

Guideline 

Number Study Title Status 

850.1350 Aquatic Invertebrate Life Cycle (Saltwater) In Review 

860.1300 Nature of the Residue in Plants (Carrot or Other Root 

Crop)

Due 4/1/2016

870.6200 Acute & Subchronic Neurotoxicity In Review 

870.7800 Immunotoxicity In Review 1 These data requirements will be considered to be outstanding until they have been submitted to EPA, reviewed, 

and found to be acceptable. Studies in review have been submitted to the Agency as part of an ongoing registration 

action. 

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 website1

.

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 prometryn. Table 3 provides a summary of the current regulatory 

status of prometryn.

 1 http://www.epa.gov/oppsrrd1/registration_review/
6

Table 3: Prometryn Chemical Facts

PC code 080805

Case Number 0467

CAS Number 7287-19-6

Year first registered 1974

Pesticide Type Herbicide 

Chemical class Thiomethyl Triazine 

Reregistration Eligibility 

Decision (RED)

1996

Cumulative group Not applicable. Prometryn does not share the toxicity profile of 

the triazines in the common mechanism group. 

40 CFR Citation Tolerances for prometryn are established in 40 CFR §180.222.

Dual use No, conventional pesticidal uses only

Non-pesticidal uses None

Pesticide Re-evaluation Division, 

Chemical Review Manager

Christina Scheltema, Scheltema.christina@epa.gov, (703)308-

2201

Registration Division, Product 

Manager

Kable “Bo” Davis, davis.kable@epa.gov, (703)306-0415

USE AND USAGE INFORMATION

Table 4 summarizes the use and usage information for prometryn. Please see the December 13, 

2012 memo, BEAD Chemical Profile for Registration Review: Prometryn, in the registration 

review docket for more details.

Table 4: Use and Usage Information

Summary of Use Herbicide registered for use to control of broadleaf grasses and 

weeds 

Use Sites* Carrots, celery, celeriac, celtuce, cilantro, cotton, dill, fennel, okra, 

parsley, pigeon peas, rhubarb, and leafy vegetables; fallow ground

Summary of Usage The greatest use of prometryn is on cotton, celery (85% of crop 

treated), carrots, and fallow ground, based on use data from 1998 

to 2011. 

Formulation Type(s) Dry flowable or water dispersible granular, emulsifiable and 

soluble liquid concentrates 

Application Method(s) Ground, aerial, irrigation systems 

Technical Registrant(s) Syngenta Crop Protection, Verolit Chemical Manufacturer’s LTD

No. of Registrations 8 FIFRA Section 3 Registrations, numerous Section 24(c) Special 

Local Need Registrations

Restricted Use No

*This includes both Federal FIFRA Section 3 and Special Local Need Section 24(c) Registrations. 
7

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.

• Certain prometryn labels are unclear with respect to application parameters like the 

maximum yearly rate for each application type, use site, soil type, plant height, weed 

size, and the types of applications that may be applied to the same field within a year’s 

time. In the absence of such information, EPA expects to approximate these parameters 

in order to conduct a quantitative assessment for prometryn. EPA will work with 

registrants to make sure prometryn labels do not include any missing or ambiguous use 

parameters.

• Confirmation of the following label information: sites of application; formulations; 

application methods and equipment; maximum application rates; frequency of 

application, application intervals, and 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 ai/A) from usage data – national, state, 

and county.

• 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.

• Foreign technical registrants not listed above who supply technical prometryn to the US 

market.

RECENT ACTIONS

• EPA has received a petition for new food uses on snap beans and dill2

. This action is 

currently pending. 

• Prometryn is the subject of an ongoing formal consultation with National Marine 

Fisheries Service under Section 7 of the Endangered Species Act. This is described in 

more detail in the appendix to this document. 

• EPA granted conditional registrations for the prometryn products Caparol® 4L (EPA 

Registration Number 100-620) and Prometryn Technical (100-542) in January 2010. 

Outstanding conditional data requirements for this action are summarized in Table 2. 

OSCPP Guideline 860.1500, Magnitude of the Residue in Carrots, which was listed as an 

outstanding data requirement in the human health scoping document, is now fulfilled. 

EPA completed its review of the submitted study (MRID 48727501) and found it to be 

acceptable. 

ANTICIPATED RISK ASSESSMENTS FOR REGISTRATION REVIEW

The most recent comprehensive human health and ecological risk assessments for prometryn 

were completed in 2009 for the US registration of prometryn use on carrots as well as new food 

 2 Pesticide Registration Improvement Extension Act (PRIA) petition number 2E8052.
8

registrations for use on celeriac, cilantro, okra, parsley, and leafy greens (petioles, crop subgroup 

4B). The findings and conclusions from these risk assessments are summarized in the March 19, 

2013, document, EFED Registration Review Preliminary Problem Formulation for Prometryn

and the February 28, 2013, document, Prometryn Human-Health Assessment Scoping Document 

in Support of Registration 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

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

occupational risk assessments during registration review. If toxicological endpoints or points of 

departure are revised based on the data that are anticipated to be required for registration review, 

they will be considered in the new assessments, as well as any changes to the standard operating 

procedures or default exposure assumptions. Table 5 summarizes the anticipated registration 

review risk assessments based on the EFED Problem Formulation and HED Scoping Document.

Table 5: Anticipated Risk Assessments for Prometryn’s Registration Review

Type of Risk Assessment Conduct? Notes

Ecological and Environmental Fate

Comprehensive ecological 

(species to be assessed 

include terrestrial and 

aquatic organisms), 

including endangered 

species 

Yes EPA expects to include prometryn, its unextracted 

residues, and the degradate hydroxypropazine (GS11526) in the anticipated ecological risk assessment. 

EPA expects to consider slightly different residues for 

plants and animals. See page 32 of the problem 

formulation for details. 

Incidents Will check for 

updates

EPA has received reports of crop damage, other 

incidents to nontarget plants, and fish kills associated 

with exposure to prometryn; these are summarized on 

pages 29 and 30 of the Problem Formulation.

Human Health

Dietary

Food Yes EPA expects to revise the 2009 dietary risk assessment 

for food and drinking water as part of a pending 

registration decision. The Agency may rely on this 

revised dietary assessment for registration review. 

Drinking water Yes EPA anticipates revising estimates of prometryn 

residues in drinking water. Because there is limited 

information regarding the toxicity of a major 

degradate, hydroxypropazine (GS-11526), EPA intends 

to include it as a residue of concern for drinking water 

along with the parent compound.

Occupational

Handlers (mixers, loaders, 

applicators)

Yes EPA may evaluate occupational risks associated with 

dry flowable (DF) formulations of prometryn. EPA 

expects to evaluate post-application risks for all 

formulations. 

Post-application Yes 
9

Type of Risk Assessment Conduct? Notes

Residential

Handlers No No residential uses are currently registered for 

prometryn; therefore, no residential handler or postapplication assessments are necessary. 

Post-application No

Other

Aggregate Yes Evaluates the combined risk from dietary and 

residential exposures. Any aggregate assessment for 

prometryn would be limited to residues in food and 

water.

Cumulative No Although prometryn is a triazine, and certain triazine 

pesticides were identified as a common-mechanism 

group (CMG), it has been excluded from the triazine 

CMG because it does not share the toxicity profile of 

the CMG triazines. 

Tolerances Yes The tolerance expression for prometryn in 40 CFR 

§180.222 needs to be updated to reflect current Agency 

policies and to ensure that it covers the prometryn 

metabolites and degradates of concern. 

Incidents Will check for 

updates

At this time, there does not appear to be a concern for 

human poisonings, based on the low frequency and 

severity of incident cases reported for prometryn3. 

Guidance for Commenters: Additional ecological information requested for this registration 

review, and of particular interest to EPA, is described below.

• Registrants are requested to check the detailed/summary label information provided in the 

Prometryn Problem Formulation document, Tables 1-3 and Appendix A, for accuracy and 

to then comment accordingly.

• Ecological incidents (non-target plant damage and avian, fish, reptilian, amphibian, and 

mammalian mortalities) not already reported to the Agency.

• Water quality monitoring data (see the Appendix of this document for further details).

TIMELINE

EPA has created the following estimated timeline for the completion of prometryn’s registration

review in Table 6.

 3

See the November 13, 2012 memo, Prometryn: Review of Human Incidents, for details. 
10

Table 6: Projected Registration Review Timeline

Activities Estimated Date

Opening the Docket

Open Docket and 60-day Public Comment Period 2013 – March

Close Public Comment 2013 – May

Case Development

Final Work Plan 2013 – August

Issue DCI 2014 – April - June

Data Submission 2016 – April - June

60-day Public Comment Period for Draft Risk Assessments 2017 – Oct - Dec.

Registration Review Decision

60-day Public Comment Period for Proposed Registration 

Review Decision

2018 – April - June

Registration Review Decision and Begin Post-Decision Followup2019

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 prometryn.
11

Appendix – Additional Areas Considered in Prometryn’s 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, when possible. Growers and other stakeholders are asked to 

comment on any trade irritant issues resulting from lack of MRLs 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:

Prometryn has been identified as a cause of impairment for 10 miles of the Salt Slough, an 

upstream tributary of the San Joaquin River in California, as defined under section 303(d) of the 

Clean Water Act. Prometryn has not been identified as the cause of impairment for any other 

water body; no additional listings were found on EPA’s website4. Aquatic benchmarks have 

been established for prometryn, based on information from the 1996 RED, and may be found on 

EPA’s website5

. However, no Total Maximum Daily Loads (TMDL) have been developed for 

prometryn, according to information provided on the website6. More information on impaired 

water bodies and TMDLs can be found on EPA’s website.

7

 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 Process8 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 of the 

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

 4 http://iaspub.epa.gov/tmdl_waters10/attains_nation_cy.cause_detail_303d?p_cause_group_id=885

5 http://www.epa.gov/oppefed1/ecorisk_ders/aquatic_life_benchmark.htm

6

http://iaspub.epa.gov/tmdl_waters10/attains_nation.tmdl_pollutant_detail?p_pollutant_group_id=885&p_pollutant_

group_name=PESTICIDES

7 http://www.epa.gov/owow/tmdl/

8 http://www.epa.gov/oppsrrd1/registration_review/water_quality_sop.htm
12

atypical, unusually high exposure to prometryn 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.

ENDANGERED SPECIES:

EPA has not conducted a risk assessment that supports a complete endangered species 

determination for prometryn. The ecological risk assessment planned during registration review 

will allow the Agency to determine whether prometryn’s use 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.

EPA completed a regional, species-specific endangered species risk assessment evaluating the 

potential effect of prometryn on Pacific Salmonids in 2002 and is currently in consultation with 

the National Marine Fisheries Service (NMFS). This assessment and subsequent consultation 

are in response to litigation (Washington Toxics Coalition vs. EPA) concerning the effects of –

pesticides on Pacific salmon and steelheads in Washington, Oregon, and California. NMFS is 

currently scheduled to complete a biological opinion on prometryn and Pacific Salmonids by 

June 2013. In 2009, the Agency also completed an endangered species risk assessment 

evaluating the potential effects of prometryn on the California red-legged frog, in response to 

litigation concerning the direct and indirect effects of several pesticides on the California redlegged frog (Center for Biological Diversity vs. EPA). EPA initiated formal consultation with 

the US Fish and Wildlife Services (USFWS) on prometryn in 2009. For more details, please see 

EPA’s endangered species website, 

http://www.epa.gov/oppfead1/endanger/litstatus/wtc/index.htm. 

On January 19, 2011, the Center for Biological Diversity and the Pesticide Action Network 

North America filed a lawsuit in the United States District Court for the Northern District of 

California, against the Environmental Protection Agency (EPA) for allegedly failing to undergo 

consultation with the United States Fish and Wildlife Service and the National Marine Fisheries 

Service regarding the effects of over 350 pesticides, including prometryn, on over 200 

endangered and threatened species throughout the United States (Center for Biological Diversity, 

et al. v. EPA, et al., No. C 11-00293 (N.D.Cal.).

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 prometryn, EPA reviewed 
13

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), prometryn 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 with E, A, or T hormonal systems will proceed to the next stage of the 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 of 67 

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Prometryn is 

not among the group of 58 pesticide active ingredients on the initial list to be screened under the 

EDSP. Accordingly, as part of registration review, EPA will issue future EDSP orders/data callins, requiring the submission of EDSP screening assays for prometryn. For further information 

on the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the 

test guidelines and the Tier 1 screening battery, please visit the EPA website9

.

HUMAN STUDIES:

Past prometryn 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 PHED 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/