Monday, 

February 6, 2006 

Part II 

Environmental 

Protection Agency 

40 CFR Parts 9 and 26 

Protections for Subjects in Human 

Research; Final Rule 


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ENVIRONMENTAL PROTECTION 

AGENCY 

40 CFR Parts 9 and 26 

[EPA–HQ–OPP–2003–0132; FRL–7759–8] 

RIN 2070–AD57 

Protections for Subjects in Human 

Research 

AGENCY: Environmental Protection 

Agency (EPA). 

ACTION: Final rule. 

SUMMARY: With this final rule, EPA bans 

research for pesticides involving 

intentional exposure of human subjects, 

when the subjects are pregnant women 

or children. The rule further strengthens 

existing protections for subjects in 

research conducted or supported by 

EPA, by prohibiting such research if it 

would involve intentional exposure of 

human subjects who are pregnant 

women or children. The rule also 

extends new protections to adult 

subjects in research for pesticides 

conducted by others who intend to 

submit the research to EPA, when it 

involves intentional exposure of human 

subjects who are non-pregnant adults, 

and creates a new, independent Human 

Studies Review Board to advise the 

Agency on the ethical and scientific 

issues arising in such research. This 

final rule focuses on third-party 

intentional dosing human studies for 

pesticides and sets the stage for further 

Agency actions. In addition, in order to 

display the OMB control number for the 

information collection requirements 

contained in this final rule, EPA is 

amending the table of OMB approval 

numbers for EPA regulations that 

appears in 40 CFR part 9. 

DATES: This rule is effective on April 7, 

2006. 

ADDRESSES: EPA has established a 

docket for this action under docket 

identification (ID) number EPA–HQ– 

OPP–2003–0132. All documents in the 

docket are listed in the index for the 

docket. Although listed in the docket 

index, some information is not publicly 

available, i.e., Confidential Business 

Information (CBI) or other information 

whose disclosure is restricted by statute. 

Certain other material, such as 

copyrighted material, is not available 

through the electronic docket and will 

be publicly available only in hard copy 

form. Publicly available docket 

materials are available either 

electronically at http:// 

www.regulations.gov or in hard copy at 

the Public Information and Records 

Integrity Branch (PIRIB), Rm. 119, 

Crystal Mall #2, 1801 S. Bell St., 

Arlington, VA. This Docket Facility is 

open from 8:30 a.m. to 4 p.m., Monday 

through Friday, excluding legal 

holidays. The Docket telephone number 

is (703) 305–5805. 

FOR FURTHER INFORMATION CONTACT: 

William L. Jordan, Mailcode 7501C, 

Office of Pesticide Programs, 

Environmental Protection Agency, 1200 

Pennsylvania Ave., NW., Washington, 

DC 20460; telephone number: (703) 

305–1049; fax number: (703) 308–4776; 

e-mail address: jordan.william@epa.gov. 

SUPPLEMENTARY INFORMATION: 

I. General Information 

A. What Does this Final Rule Do? 

With this final rule EPA significantly 

strengthens and expands the protections 

for subjects of ‘‘third-party’’ human 

research (i.e., research that is not 

conducted or supported by EPA) by: (1) 

Prohibiting new research involving 

intentional exposure of pregnant women 

or children, intended for submission to 

EPA under the pesticide laws; (2) 

extending the provisions of the Federal 

Policy for the Protection of Human 

Subjects of Research (the ‘‘Common 

Rule’’) to other human research 

involving intentional exposure of nonpregnant adults, intended for 

submission to EPA under the pesticide 

laws; (3) requiring submission to EPA of 

protocols and related information about 

covered human research before it is 

initiated; and (4) establishing an 

independent Human Studies Review 

Board to review both proposals for new 

research and reports of covered human 

research on which EPA proposes to rely 

under the pesticide laws. 

The final rule also: (1) Categorically 

prohibits any EPA research involving 

intentional exposure of human subjects 

who are pregnant women or children to 

pesticides or any substances; and (2) 

adapts regulations of the Department of 

Health and Human Services providing 

additional protections beyond those of 

the Common Rule to pregnant women 

and children as subjects in EPA 

observational research—i.e., research 

which does not involve intentional 

exposure to any substance. (Research 

conducted by EPA is referred to as 

‘‘first-party’’ research, and ‘‘secondparty’’ research refers to research 

supported by EPA but performed by 

others.) 

Finally, this rule forbids EPA to rely, 

in its actions under the pesticide laws, 

on intentional-exposure human research 

that either involves pregnant women or 

children or is otherwise considered 

unethical, except in narrowly defined 

circumstances. For example, if children 

were at risk from unsafe exposure to a 

substance, the Agency would be 

permitted to rely on otherwise 

unacceptable research to justify setting 

a more restrictive standard to protect 

them. 

B. Legal Authority 

EPA is promulgating this final rule to 

effectuate the express mandate of the 

United States Congress as set forth in 

section 201 of the Department of the 

Interior, Environment, and Related 

Agencies Appropriations Act, 2006, 

Public Law No. 109–54 (Appropriations 

Act), which provides appropriated 

funds for EPA and other federal 

departments and agencies. In addition, 

today’s final rule is authorized under 

provisions of the following statutes that 

EPA administers: Section 3(a) of the 

Federal Insecticide, Fungicide, and 

Rodenticide Act (FIFRA), which 

authorizes the Administrator to regulate 

the distribution, sale, or use of any 

unregistered pesticide in any State ‘‘[t]o 

the extent necessary to prevent 

unreasonable adverse effects on the 

environment’’ (defined at FIFRA section 

2(bb), in pertinent part, as ‘‘any 

unreasonable risk to man or the 

environment, taking into account the 

economic, social, and environmental 

costs and benefits of the use of any 

pesticide’’); section 25(a) of FIFRA, 

which authorizes the Administrator to 

‘‘prescribe regulations to carry out the 

purposes of [FIFRA],’’ and section 

408(e)(1)(C) of the Federal Food, Drug, 

and Cosmetic Act (FFDCA), which 

authorizes the Administrator to issue a 

regulation establishing ‘‘general 

procedures and requirements to 

implement [Section 408].’’ In addition, 

EPA’s expansion of its human subject 

protection regulations to include 

additional subparts supplementing 

EPA’s codification of the Common Rule 

regarding first- and second-party 

research are authorized pursuant to 5 

U.S.C. 301 and 42 U.S.C. 300v–1(b). 

C. Does this Action Apply to Me? 

You may be potentially affected by 

this action if you conduct human 

research on substances regulated by 

EPA. Potentially affected entities may 

include, but are not limited to, entities 

that conduct or sponsor research 

involving intentional exposure of 

human subjects that may be submitted 

to EPA under FIFRA or FFDCA. 

Although EPA has in the past received 

such third-party research from pesticide 

registrants, other entities could submit 

such information to EPA. 

• Pesticide and other Agricultural 

Chemical Manufacturing (NAICS code 

325320). 


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This listing is not intended to be 

exhaustive, but rather provides a guide 

regarding entities likely to be affected by 

this action. Other types of entities not 

listed in this unit could also be affected. 

The North American Industrial 

Classification System (NAICS) code has 

been provided to assist you and others 

in determining whether this action 

might apply to certain entities. To 

determine whether you or your business 

may be affected by this action, you 

should carefully examine the 

applicability provisions of 40 CFR part 

26. If you have any questions regarding 

the applicability of this action to a 

particular entity, consult the person 

listed under FOR FURTHER INFORMATION

CONTACT. 

D. How Can I Access Electronic Copies 

of this Document and Other Related 

Information? 

You may access an electronic copy of 

this Federal Register document and the 

associated electronic docket at http:// 

www.regulations.gov, or you may access 

this Federal Register document 

electronically through the EPA Internet 

under the ‘‘Federal Register’’ listings at 

http://www.epa.gov/fedrgstr/. A 

frequently updated electronic version of 

the Code of Federal Regulations (CFR) is 

available at http://www.gpoaccess.gov/ 

ecfr/ . 

II. Background 

A. Summary of EPA Goals for this Final 

Rule 

EPA’s most important statutory 

responsibility is to protect public health 

and the environment by regulating air 

and water pollutants, pesticides, 

hazardous wastes, industrial chemicals, 

and other environmental substances. To 

meet this responsibility the Agency 

considers a wide range of information 

about each substance, including its 

potential to cause harm—i.e., its 

toxicity—and how and at what levels 

people may be exposed to it—i.e., their 

exposure. By linking information about 

toxicity with estimates of exposure, EPA 

can estimate the risk a substance poses 

to exposed populations, and then decide 

whether and how best to regulate 

releases of the substance into the 

environment. 

EPA believes that in general it can 

best protect public health by 

considering all available, relevant, 

scientifically sound information, 

including information developed 

through research with human subjects. 

But at the same time, EPA wants to take 

action to ensure that research conducted 

by EPA or for EPA, submitted to EPA, 

and relied on by EPA—especially 

research with human subjects—has been 

conducted ethically. 

B. The Role of Human Research in EPA 

Risk Assessments 

The Agency’s understanding of 

potential risks to people is usually 

based on many tests performed with 

laboratory animals. These tests differ in 

the kinds of animals used, the duration 

of exposure, the age of test animals, and 

the pathway of exposure–through food, 

air, or the skin. When they are 

considered together, the results of all 

these studies provide a good general 

understanding of a pesticide’s potential 

effects. 

Animal studies, however, are not the 

only source of relevant information for 

characterizing potential risks of a 

substance. Epidemiological studies, for 

example, provide valuable information 

about the relationship between chemical 

exposure and effects of concern. 

Monitoring studies that measure 

concentrations of a substance in air, 

water, food, or on surfaces also provide 

valuable insights into chemical 

exposures. Sometimes, however, the 

relationship between environmental 

concentrations of a substance and 

potential human exposure is unclear, 

and can be understood only through 

research involving human subjects. For 

example, a farmer’s actual exposure to 

a pesticide he or she is applying will 

depend on his or her equipment, the 

kind and quantity of pesticide he or she 

uses, what protective clothing or 

equipment he or she uses, and how 

many hours he or she works each day. 

To be able to take these factors into 

account, workers will often wear 

monitors in the field to measure 

exposure levels in their routine work. 

Research like this provides critical data 

for defining protective standards for 

pesticide handlers and applicators. 

Without these and similar studies 

characterizing the exposures received by 

individuals in the normal course of their 

work and daily life, the Agency would 

not understand adequately either what 

types of application equipment and 

protective clothing to require for a 

pesticide, or how soon harvesters or 

other workers could safely enter 

pesticide-treated areas. 

Some human research, however, 

involves intentional exposure of human 

subjects—defined in this rule as 

exposure they would not have 

experienced had they not participated 

in the research. One kind of research 

involves exposing subjects to low doses 

of a substance to measure how it is 

absorbed, distributed, metabolized, and 

excreted. Humans process some 

substances differently from animals, and 

studies of this kind can provide 

essential support for safety monitoring 

programs, such as those which measure 

the known metabolites of a substance in 

the blood or urine of workers to estimate 

their exposure to the substance. 

Although EPA has not required or 

encouraged it, some third parties have 

occasionally conducted and submitted 

to EPA reports of research involving 

intentional exposure of human subjects 

to a substance to identify or measure its 

toxic effects. These studies occur in a 

controlled laboratory or clinical setting. 

Animal data alone can sometimes 

provide an incomplete or misleading 

picture of a substance’s safety or risks. 

Sometimes human research shows 

people to be more susceptible than 

animals to the effects of a chemical, and 

supports regulatory measures more 

protective than could be justified by 

animal data alone. This has been the 

case, for example, for arsenic, certain air 

pollutants, and the pesticide ingredients 

methyl isothiocyanate (MITC) and 

hexavalent chromium. Even when 

human research does not show people 

to be more sensitive than animals, 

scientifically sound human data 

developed under strict ethical standards 

can strengthen the basis for EPA 

regulatory actions. 

C. Societal Concern over the Ethics of 

Human Research 

Scientific experimentation with 

human beings has always been 

controversial. The history of human 

research contains well-known examples 

of unethical behavior in the name of 

science, which have led to reforms in 

the way the government and others 

carry out and oversee human research. 

Through these reforms, the standards for 

ethical human research have evolved to 

become progressively more stringent 

and protective of the subjects of the 

research. In the United States the 

‘‘Common Rule,’’ a regulation followed 

by EPA and 17 federal departments and 

agencies, contains a widely accepted set 

of standards for conducting ethical 

research with human subjects, together 

with a set of procedures designed to 

ensure that the standards are met. See 

Unit V. 

For several years EPA has been at the 

center of an intense debate about the 

acceptability of intentional dosing 

human toxicity studies for pesticides, 

and about what to do with human 

studies that are ethically deficient. In 

this debate some have argued that all 

research involving intentional exposure 

of human subjects to pesticides is 

fundamentally unethical and should 

never be conducted or accepted. Others, 

while acknowledging the possibility of 


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ethical human research with pesticides, 

have argued that EPA should simply 

refuse to consider data from ethically 

problematic research in its regulatory 

decisions. Those who hold this view 

interpret Agency reliance on an 

ethically flawed study as an 

endorsement of the investigators’

behavior, and as encouragement to 

others to engage in similarly unethical 

research. Some also argue that EPA’s 

reliance on ethically deficient human 

data could directly benefit the wrongdoer. For example, if EPA based a 

regulatory decision on a human study 

that shows humans to be less sensitive 

than animals, the result might be a less 

stringent regulatory measure, 

advantageous to the company that 

conducted the study. If the key study 

was unethical, the company could 

benefit from its own misconduct. 

On the other hand, human research 

has contributed enormously to scientific 

understanding of the risks posed by 

many substances in the environment, 

and to some of EPA’s past regulatory 

actions. With this in mind, others argue 

that the Agency should consider all 

relevant and scientifically sound 

information—not excluding ethically 

deficient human data—because to do so 

will lead to better decisions, based on 

assessments that better reflect actual 

risks. Holders of this view argue that the 

ethical deficiencies of the research are 

the responsibility of the researchers, not 

of EPA. They further argue that EPA can 

do no additional harm to the subjects of 

the research by relying on scientifically 

valid and relevant data from an ethically 

deficient study, whereas EPA’s refusal 

to rely on such data could do nothing 

to benefit the subjects of the research. 

Moreover, they assert that while the 

Agency cannot undo what has already 

happened, EPA can clearly express its 

disapproval of past unethical conduct. 

Holders of this view also stress the 

importance of strengthening protections 

for volunteers who participate in future 

studies, while taking advantage of all 

that past research can offer to benefit 

society. 

D. EPA’s Solicitation of Expert Advice 

In response to public concerns over 

human research with pesticides, EPA 

convened an advisory committee under 

the joint auspices of the EPA Science 

Advisory Board (SAB) and the FIFRA 

Scientific Advisory Panel (SAP) to 

address issues of the scientific and 

ethical acceptability of such research. 

This committee, known as the Data from 

Testing of Human Subjects 

Subcommittee (DTHSS), met in 

December 1998 and November 1999, 

and completed its report in September 

2000. Their report is available in the 

public docket for this rulemaking, and 

on the web at: http://www.epa.gov/ 

science1/pdf/ec0017.pdf. 

The DTHSS advisory committee 

agreed unanimously on several broad 

principles, including the following: 

• Any policy adopted should reflect 

the highest standards, and special 

concern for the interests of vulnerable 

populations. 

• The threshold of justification for 

intentional exposure of human subjects 

to toxic substances should be very high. 

• The justification cannot be to 

facilitate commercial interests, but only 

to safeguard public health. 

• Not only the nature and magnitude 

of risks and benefits but their 

distribution must be considered in 

assessing research protocols. 

• Bad science is always unethical. 

No clear consensus, however, 

emerged from the committee on many 

other points, including either the 

scientific merit or the ethical 

acceptability of studies to identify or 

measure toxic effects of pesticides in 

human subjects. A vigorous public 

debate continued about the extent to 

which EPA should accept, consider, or 

rely on third-party intentional dosing 

human studies for pesticides. 

In December 2001, EPA asked the 

advice of the National Academy of 

Sciences (NAS) on the many difficult 

scientific and ethical issues concerning 

intentional human dosing studies. At 

EPA’s request, the NAS convened a 

committee to provide the requested 

advice. The committee met publicly in 

December 2002, and again in January 

and March 2003. After long and 

thoughtful consideration of the full 

range of issues, the committee released 

its final report, ‘‘Intentional Human 

Dosing Studies for EPA Regulatory 

Purposes: Scientific and Ethical Issues,’’

in February 2004. Their report is 

available at: http://www.nap.edu/books/ 

0309091721/html/. 

The NAS recommendations addressed 

what standards should guide the 

conduct of future human research and 

whether or not EPA should rely on the 

results of ethically deficient human 

studies. The NAS Report concluded that 

the answers to these questions should 

start from the existing standards for the 

ethical treatment of human research 

embodied in the Common Rule. The 

NAS Report then offered numerous 

recommendations, supported by 

detailed rationales, for how to apply the 

principles of the Common Rule to the 

particular issues confronting EPA. EPA 

has relied heavily on the advice of this 

committee in developing this rule. The 

NAS Report discusses the full range of 

types of human studies available to EPA 

and the full breadth of statutory 

programs under which they might be 

considered. 

E. Balancing Conflicting Societal Goals 

EPA’s mission is to make the best 

possible regulatory decisions to protect 

public health and the environment. EPA 

does not want to ignore potentially 

important information that might 

benefit its assessments and decisionmaking. At the same time, the Agency’s 

conduct should encourage high ethical 

standards in research with human 

subjects. If all research with human 

subjects always met the highest 

contemporary ethical standards, these 

goals could all be pursued together. But 

sometimes they conflict. 

Two salient issues illustrate the 

difficulty in striking an appropriate 

balance between societal goals in 

conflict. First, the Agency must decide 

what standard to apply to assess the 

ethical acceptability of research 

performed before the new rule takes 

effect. The choices are: To apply today’s 

standards of ethical conduct to research 

performed in the past, or to judge past 

research against the ethical norms 

prevailing when it was conducted. 

Codes of ethical research conduct 

regulate the behavior of investigators 

before and during the research. It is 

reasonable to expect investigators to 

follow ethical codes that prevail when 

they do their work; but EPA believes it 

is unreasonable to expect them to 

anticipate and follow standards that 

may be developed after their work is 

done. EPA believes that scientifically 

meritorious research that adhered to 

accepted high ethical standards when it 

was conducted should not be set aside 

because ethical standards have 

subsequently changed. EPA also 

believes that ethical standards are likely 

to continue to change in the future and 

that if and when they do, such a change 

should not invalidate or make 

unacceptable otherwise meritorious 

research conducted now, in conformity 

with high ethical standards of today. 

Other parts of the U.S. government, and 

other countries, have arrived at a similar 

position. 

In the final rule, EPA has 

implemented the applicable 

recommendation of the NAS, and will 

accept scientificatiated before the rule 

becomes effective unless there is clear 

and convincing evidence that it was 

fundamentally unethical or significantly 

deficient with respect to the ethical 

standards prevailing when the research 

was conducted. 

The second salient issue concerns 

whether it is ever justified to rely on a 


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report of scientifically sound research 

judged to be unethical. To illustrate this 

problem, assume that EPA received a 

report of scientifically valid research 

involving intentional exposure of 

children, which is defined by this rule 

as unacceptable. But assume this study 

shows that the level of exposure to the 

tested substance safe for children is 5 

parts per billion (ppb), whereas all other 

information available from animal 

studies and ethical human studies 

suggests that children would be safe if 

exposed at levels up to 90 ppb. A 

regulatory standard of 5 ppb based on 

the unacceptable study would 

adequately protect exposed children; a 

standard which did not rely on the 

unacceptable study would be set at 90 

ppb, and would not adequately protect 

exposed children. 

In such a situation, what should the 

Agency do? If EPA refused to rely on the 

unethical research in this example, it 

would set its standard at 90 ppb and 

would not adequately protect exposed 

children. Moreover, if the final rule 

always prohibited reliance on data from 

research involving intentional exposure 

of children, even in this exceptional 

case, using the data to justify a level at 

5 ppb would be a plain violation of a 

regulation that could be subject to legal 

challenge. 

The ethical and responsible course, 

EPA believes, would be to rely on the 

data to set a fully protective standard, 

while strongly condemning unethical 

research conduct and imposing 

appropriate administrative sanctions. 

Moreover, the number of people who 

would benefit from EPA’s regulatory 

intervention could be far greater than 

the number of subjects involved in the 

research. Thus EPA has retained the 

proposed exception, to permit it to take 

legally defensible action to protect 

public health in this kind of exceptional 

situation. 

EPA expects a circumstance like this 

example to arise only rarely, if at all. 

But however rarely it might occur, any 

decision to rely on unacceptable data, 

should only be made with great care, 

with full opportunity for public 

discussion, and in reliance on expert 

advice. As discussed further later, the 

final rule both provides for the essential 

public health protection exception, 

narrowly defined, and meets all these 

additional criteria. 

III. EPA’s Proposed Human Studies 

Rulemaking and General Public 

Comments 

Summary: This unit reviews the 

general public comments on EPA’s 

proposed rulemaking. The detailed 

comments are addressed in subsequent 

units of this preamble. 

An extensive review of the historical 

development of ethical standards for the 

conduct of human research and the 

events leading up to the promulgation of 

this final rule appeared in the preamble 

to the proposed rule, available in the 

public docket for this action. 

Today’s final rule is the first to 

emerge from the process which began 

with publication of an Advance Notice 

of Proposed Rulemaking in the Federal 

Register on May 7, 2003 (68 FR 24410) 

(FRL–7302–8). On February 8, 2005 (70 

FR 6661) (FRL–7695–4), EPA published 

and invited public comment on a 

Federal Register notice announcing its 

plan to establish a comprehensive 

framework for deciding whether to 

consider or rely on certain types of 

research with human subjects. 

On September 12, 2005 (70 FR 53838) 

(FRL–7728–2), EPA published in the 

Federal Register a notice of proposed 

rulemaking to strengthen the protections 

for people who participate as subjects in 

human research. The Agency proposed 

to ban intentional dosing human testing 

for pesticides when the subjects are 

pregnant women or children, to 

formalize and further strengthen 

existing protections for subjects in 

human research conducted or supported 

by EPA, and to extend new protections 

to adult subjects in human research for 

pesticides, involving intentional 

exposure of human subjects and 

conducted by others who intend to 

submit the research to EPA. The 

proposal also contained provisions to 

establish an independent Human 

Studies Review Board responsible for 

reviewing proposals to conduct new, 

intentional-exposure human research 

under the pesticide laws and EPA 

decisions to rely on the results of certain 

types of completed human research in 

its actions under the pesticides laws. 

EPA received approximately 50,000 

comments during the 90–day public 

comment period. The vast majority of 

the comments were submitted by 

private individuals as part of e-mail and 

letter-writing campaigns. The remaining 

unique comments came from 

individuals and organizations 

representing a range of stakeholders 

including pesticide companies, farm 

groups and other pesticide users, and 

environmental and public health 

advocacy groups. EPA has reviewed, 

summarized, and responded to these 

comments in the Response to Comments 

document available in the docket for 

this rule. In addition, this unit 

summarizes the major themes raised by 

the comments on the proposal, and 

explains how EPA has addressed them 

in the final rule. 

Comment: All human research with 

pesticides is fundamentally unethical. 

Response: EPA agrees with the advice 

it has received, as discussed in Unit II., 

from its advisory committees. The SAB/ 

SAP Data from Testing of Human 

Subjects Subcommittee agreed that 

although ethical human research with 

pesticides was possible, the threshold of 

justification should be set very high. 

The NAS Committee likewise counseled 

care, recommending many specific 

conditions which should be satisfied, 

but nonetheless acknowledged the 

possibility of ethical research when 

those conditions were met. On that basis 

EPA has gone forward with this final 

rule. 

Comment: Comments objected to the 

Agency’s rulemaking on the ground that 

it would promote unethical research on 

human subjects by pesticide companies. 

Response: EPA expects its tougher 

new rules will eliminate all unethical 

research and will decrease the overall 

number of future intentional dosing 

studies conducted for pesticides. The 

additional science and ethics reviews by 

EPA and the Human Studies Review 

Board should eliminate any proposed 

unethical research. 

Over the period 1996 to 2001, EPA 

received approximately 33 intentional 

dosing studies of all types annually. 

These included studies measuring 

worker exposure; the efficacy of insect 

repellents; studies of absorption, 

distribution and excretion that help EPA 

assess exposure; and studies of systemic 

toxicity. Of these 33, only 4 a year, on 

average, involved intentional exposure 

of human subjects to measure minor, 

reversible systemic toxic effects. 

(Systemic effects are those that occur 

within the body, such as trembling, 

nausea, or headaches resulting from 

chemical changes in the nervous 

system.) See the Economic Analysis, 

Appendix B. 

Since 1996 we have received about 26 

intentional dosing, systemic toxicity 

studies on humans. After this rule is 

finalized, we expect that number to 

decrease from an average of 3 a year to 

as few as 0 or 1 per year. We expect that 

number of non-toxicity intentional 

dosing studies to remain about the 

same. 

Comment: The proposal was unclear. 

Response: Many comments on the 

proposed rule reflected confusion about 

which provisions applied to EPA and 

which to regulated third parties, and 

about how the standards applying to the 

conduct of new research by EPA or third 

parties differed from the standards 

applying to EPA decisions to consider 


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completed research. These different 

elements were mingled in some 

subparts of the proposed rule, 

contributing to this confusion. A 

concerted effort has been made in the 

final rule to eliminate these potential 

causes of confusion, by sharpening the 

focus of each subpart and grouping 

subparts in three broad groups: 

• Rules applying to EPA’s conduct 

and support of new research with 

human subjects. 

• Rules applying to certain types of 

new third-party research for pesticides 

with human subjects. 

• Rules applying to EPA in its 

regulatory capacity. 

Comment: Ethical standards can be 

evaded simply by denying intent to 

submit the results of the research to 

EPA. 

Response: The final rule, like the 

proposal, extends the Common Rule 

requirements only to third-party 

research intended for submission to 

EPA under the pesticide laws, FIFRA 

and FFDCA. EPA believes this is 

appropriate because there has not been 

adequate consideration of the policy 

consequences of extending the 

provisions of the final rule to 

investigators who have no intent to 

provide their research results to EPA 

and would otherwise have no reason to 

be aware of these requirements. 

EPA also disagrees that the approach 

used in the final rule makes it easy to 

evade ethical standards for research by 

denying the intent to submit. Several 

elements in the final rule interact to 

ensure the application of appropriate 

standards. First is the explicit 

presumption in the rule that all research 

submitted by a pesticide registrant was 

intended for submission to EPA. 

Specific, credible documentation would 

have to be provided to rebut this 

presumption; a denial of intent, 

standing alone, could not serve as a 

rebuttal. 

Second, if a submitter successfully 

rebutted the presumption of intent, it 

would make little practical difference, 

and would certainly not compel the 

Agency to accept unethically conducted 

research. Under the final rule, whether 

or not it was intended for submission to 

EPA when research was initiated, and 

whether or not it was otherwise subject 

to the requirements of subpart K: (1) 

After the effective date of the rule, all 

reports of human research submitted to 

EPA under the pesticide laws are 

required by subpart M to be 

accompanied by documentation of 

ethical conduct of the research, (2) all 

completed post-rule intentionalexposure research, on which the Agency 

intends to rely in actions under the 

pesticide laws, is required by subpart P 

to be reviewed by the Human Studies 

Review Board, and (3) all post-rule 

intentional-exposure research 

considered under the pesticide laws is 

subject under subpart Q to the Common 

Rule as the ethical standard of 

acceptability. 

Consequently, the likelihood that 

unethical research will be used by EPA 

in actions under its pesticide laws is 

very small—only when it is determined 

that the data are crucial to support more 

protective public health actions would 

the Agency consider such data. 

Comment: Limitation to research 

involving intentional exposure of 

human subjects excludes many kinds of 

studies. 

Response: Most third-party human 

research for pesticides conducted by or 

for EPA, or intended for submission to 

EPA, meets the rule’s definition of 

research involving intentional exposure, 

and thus will be subject to the 

requirements of subpart K. But whether 

or not research is subject to subpart K, 

all reports of all post-rule human 

research submitted to EPA are required 

by subpart M to be accompanied by 

documentation of ethical conduct. 

Comment: Prohibitions of new 

research involving intentional exposure 

of pregnant women, fetuses, and 

children are subject to exceptions. 

Response: The rule provides for no 

exceptions under any circumstances to 

the bans on the conduct of new research 

involving intentional exposure of 

pregnant women, fetuses, and children 

as subjects. The final rule has been 

revised for clarity; the prohibitions have 

been moved to subparts B (applying to 

EPA) and L (applying to third parties,) 

where they stand alone, and they have 

been reworded to emphasize that they 

apply notwithstanding any other 

provisions anywhere in 40 CFR part 26. 

Comment: The prohibition on 

considering human subjects research 

involving intentional exposure of 

pregnant women, fetuses, and children 

applies only to regulatory decisions, and 

not to such non-regulatory agency 

actions as risk assessments. 

Response: The final rule has been 

changed from the proposal to make this 

prohibition applicable to all Agency 

actions taken under the pesticide laws. 

Comment: The proposed exception 

permitting EPA to consider unethically 

obtained data when to do so would be 

‘‘crucial to protection of public health’’

undermines all other provisions of the 

rule. Anything from a more accurate risk 

assessment to increased agricultural 

production could be interpreted as 

‘‘crucial to protection of public health,’’

and used to justify reliance on unethical 

data. 

Response: Such a broad interpretation 

was never intended by the Agency, but 

EPA acknowledges that its intentions 

were not perfectly clear from the 

language of the proposal. The final rule 

retains a ‘‘public health exception,’’ but 

it is reworded to make it very clear that 

it could never be invoked to support a 

less stringent regulatory outcome than 

could be justified without consideration 

of the unethical research. 

Comment: Many provisions of the 

Common Rule allow for exceptions to 

its requirements at the discretion of the 

Administrator or Institutional Review 

Boards (IRBs); these exceptions should 

not be allowed for third-party research. 

Response: EPA agrees that some 

exceptions in the Common Rule are not 

appropriate for the kinds of third-party 

human research covered by this rule. In 

mirroring the core protections of the 

Common Rule as they apply to third 

parties in subpart K of the final rule, 

EPA has eliminated or narrowed many 

of these exceptions, as discussed in 

detail in Unit VII. 

IV. Reorganization of the Rule 

Structure 

Summary: To clarify the various 

requirements in the proposal and how 

they apply to first, second, and third 

parties, the Agency has extensively 

reorganized the final rule. The new 

organization regroups the provisions of 

the proposal into several new subparts. 

In this final rule, EPA’s codification of 

the Common Rule remains in force with 

no changes except to designate it as 

subpart A of part 26. Following today’s 

action, the text of 40 CFR 26.101 

through 26.124 remains identical to the 

codifications of the Common Rule by 

the other federal departments and 

agencies that have promulgated it. 

The remaining subparts in the final 

rule, each discussed in a later unit of 

this preamble, are grouped as follows: 

• Subparts A through D apply to EPA 

as an investigator or sponsor of new 

research with human subjects, and to 

second-party investigators whose 

research EPA supports. Subpart A 

contains the basic policy for human 

research (the unchanged Common Rule). 

Subpart B prohibits EPA human 

subjects research on any substance 

involving intentional exposure of 

pregnant women, fetuses, or children. 

Subparts C and D provide additional 

protections for pregnant women, 

fetuses, and children when they are 

subjects of observational studies 

conducted or supported by EPA. 

• Subparts K and L apply to third 

parties as investigators or sponsors of 


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new research involving intentional 

exposure of human subjects and 

intended for submission to EPA under 

the pesticide laws. Subpart K 

establishes the basic protections for 

non-pregnant adult subjects in covered 

third-party research, corresponding in 

substance to subpart A. Subpart L 

prohibits covered third-party human 

subjects research for pesticides 

involving intentional exposure of 

pregnant women or children. 

• Subpart M applies to all third 

parties who submit reports of any 

research with human subjects to EPA 

under the pesticide laws, whether or not 

the research is covered by subpart K, 

and requires concurrent submission of 

information documenting the ethical 

conduct of such research. 

• Subparts O—Q apply to EPA in its 

regulatory capacity. Subpart O identifies 

potential actions for noncompliance 

with subparts A through L. Subpart P 

addresses the establishment and 

operation of the Human Studies Review 

Board, and subpart Q defines the ethical 

standards EPA will use to decide 

whether to rely on data from human 

research in EPA actions. 

Because this reorganization causes 

extensive changes in the numbering of 

the provisions of the final rule, EPA 

provides the following table to make it 

easier to follow how the reorganization 

affects the location of specific 

provisions. 

TABLE 1.—LOCATION IN PROPOSED AND FINAL RULE TEXT OF RULES APPLYING TO EPA AS AN INVESTIGATOR OR

SPONSOR OF RESEARCH WITH HUMAN SUBJECTS

Location in Final Rule 

Title/Description 

Location in Proposed Rule 

Subpart Section Subpart Section 

A §§ 26.201 thru 

26.124 

Basic Policy for Protection of Subjects in Human Research 

Conducted or Supported by EPA 

A §§ 26.101 thru 

26.124 

B §§ 26.201 thru 

26.203 

Prohibition of Human Subjects Research Conducted or 

Supported by EPA Involving Intentional Exposure of 

Pregnant Women, Fetuses, or Children 

B and D §§ 26.220 and 

26.420 

B § 26.201 To what does this subpart apply? n/a n/a 

B § 26.202(a) Definition of research involving intentional exposure of a 

human subject 

A § 26.102(k) 

B § 26.202(b) Definition of child D § 26.402(a) 

B § 26.203 Prohibition of EPA human subjects research involving intentional exposure of pregnant women, fetuses, or children B and D §§ 26.220 and 

26.420 

C §§ 26.301 thru 

26.305 

Additional Protections for Pregnant Women or Fetuses Involved as Subjects in Observational Research Conducted or Supported by EPA B §§ 26.201 thru 

26.206 

D §§ 26.401 thru 

26.406 

Additional Protections for Children Involved as Subjects in 

Observational Research Conducted or Supported by 

EPA 

D § 26.401 thru 

26.408 

TABLE 2.—LOCATION IN PROPOSED AND FINAL RULE TEXT OF RULES APPLYING TO THIRD PARTIES AS INVESTIGATORS OR

SPONSORS OF RESEARCH WITH HUMAN SUBJECTS

Location in Final Rule 

Title/Description 

Location in Proposed Rule 

Subpart Section Subpart Section 

K §§ 26.1101 

thru 26.1125 

Basic Ethical Requirements for Third-Party Human Subjects 

Research for Pesticides Involving Intentional Exposure of 

Non-Pregnant Adults 

A §§ 26.101 thru 

26.124 

K § 26.1101(a) To what does this subpart apply? A § 26.101(j) 

K § 26.1101(b) Exemption of research involving only the collection or study 

of existing data . . . 

A § 26.101(b)(4) 

K § 26.1101(c) Administrator retains final judgment as to whether a particular activity is covered by this subpart A § 26.101(c) 

K § 26.1101(d), 

(e), and (f) 

Relation to other Federal, State, Tribal, Local, or foreign 

laws or regulations 

A § 26.101(e), (f), 

and (g) 

K § 26.1101(g) For purposes of determining a person’s intent under paragraph (a) of this section . . . A § 26.101(k) 


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TABLE 2.—LOCATION IN PROPOSED AND FINAL RULE TEXT OF RULES APPLYING TO THIRD PARTIES AS INVESTIGATORS OR

SPONSORS OF RESEARCH WITH HUMAN SUBJECTS—Continued 

Location in Final Rule 

Title/Description 

Location in Proposed Rule 

Subpart Section Subpart Section 

K §§ 26.1102(a) 

thru 

26.1102(h) 

Definitions A §§ 26.102(a) thru 

26.102(i) 

K § 26.1102(i) Definition of research involving intentional exposure . . . A § 26.102(k) 

K § 26.1102(j) Definition of person n/a n/a 

K §§ 26.1107 

thru 26.1117 

IRB and informed consent requirements A §§ 26.107 thru 

26.117 

K § 26.1123 Early termination of research A § 26.123(a) 

K § 26.1125 Prior submission to EPA of proposed human research A § 26.124(b) 

L §§ 1201 thru 

26.1203 

Prohibition of Third-Party Human Subjects Research for 

Pesticides Involving Intentional Exposure of Pregnant 

Women, Fetuses, or Children 

B and D §§ 26.220 and 

26.420 

M §§ 1301 thru 

26.1303 

Requirements for Submission of Information on the Ethical 

Conduct of Completed Human Research 

A § 26.124(c) 

TABLE 3.—LOCATION IN PROPOSED AND FINAL RULE TEXT OF RULES APPLYING TO EPA IN ITS REGULATORY CAPACITY

Location in Final Rule 

Title/Description 

Location in Proposed Rule 

Subpart Section Subpart Section 

O §§ 26.1501 thru 

26.1503 

Administrative Actions for Noncompliance E §§ 26.501 thru 

26.506 

P §§26.1601 thru 

26.1603 

Review of Proposed and Completed Human Research A § 26.124(b) 

P § 26.1601(c) Determination of Equivalence of Foreign Ethical Standards A § 26.101(h) 

P § 26.1603 Operation of the Human Studies Review Board A § 26.124(b)(5) 

Q §§ 26.1701 thru 

26.1703 

Ethical Standards for Assessing Whether to Rely on the 

Results of Human Subjects Research in EPA Actions 

B, D, and F §§ 26.221, 26.421, 

26.601, 26.602, 

and 26.603 

Q §§ 26.1701 and 

26.1702 

Applicability and Definitions n/a n/a 

Q § 26.1703 Prohibition of reliance on research involving intentional exposure of pregnant women, fetuses, or children B and D §§ 26.221 and 

26.421 

Q § 26.1704 Prohibition of reliance on unethical human research conducted before the effective date of the final rule F § 26.601 

Q § 26.1705 Prohibition of reliance on unethical human research conducted after the effective date of the final rule F § 26.602 

Q § 26.1706 Criteria and procedures for decisions to protect public 

health by relying on otherwise unacceptable research 

F § 26.603 

V. Subpart A—Basic Ethical Protections 

for Subjects of Human Research 

Conducted or Supported by EPA 

Summary: This unit describes the 

basic ethical protections that apply to 

human research conducted or supported 

by EPA. Unit V.A. discusses the 

comprehensive system of ethical 

protections created by the ‘‘Basic 

Federal Policy for Protection of Human 

Research Subjects,’’ generally referred to 

as the Common Rule. The Common Rule 

applies to all human research conducted 

or supported by EPA and 17 other 

federal departments and agencies. Unit 

V.B. discusses the proposed rule, Unit 

V.C. discusses public comments, and 

Unit V.D. discusses the final rule. 

A. The Common Rule 

The Common Rule defines the core 

protections for human subjects of 

research, and it is important to 

understand just what those protections 

are. 

First, the Common Rule requires that 

research with human subjects be 

overseen by a qualified, independent 


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IRB meeting specific requirements laid 

out in the rule governing membership, 

procedures, decision-making, 

recordkeeping, and avoidance of 

conflicts of interest. The IRB is vested 

with responsibility to review proposed 

research, and with authority to approve 

or disapprove it. The IRB is also 

responsible for overseeing the conduct 

of approved research, and investigators 

are required to report any unanticipated 

events to the responsible IRB. IRB 

members must be trained, and must 

remain current with extensive guidance 

promulgated by the Office for Human 

Research Protections in HHS. 

Under the Common Rule an IRB may 

approve proposed human subjects 

research only when it concludes that all 

of the following conditions are satisfied: 

• Risks to subjects have been 

minimized. 

• Risks to subjects are reasonable in 

relation to anticipated benefits, if any, to 

subjects, and the importance of the 

knowledge that may reasonably be 

expected to result. 

• Selection of subjects is equitable. 

• Informed consent will be sought 

from each prospective subject or the 

subject’s legally authorized 

representative. 

• Informed consent will be 

appropriately documented. 

• The research plan makes adequate 

provision for monitoring the data 

collected to ensure the safety of 

subjects. 

• There are adequate provisions to 

protect the privacy of subjects and to 

maintain the confidentiality of data. 

• Additional safeguards have been 

included in the study to protect the 

rights and welfare of subjects who are 

likely to be vulnerable to coercion or 

undue influence, such as children, 

prisoners, pregnant women, mentally 

disabled persons, or economically or 

educationally disadvantaged persons. 

The Common Rule also requires each 

IRB to maintain records of everything it 

reviews, of its discussion of 

controversial issues, and of its decisions 

and their rationale. 

The second major element in the 

Common Rule is its requirement that no 

investigator involve a human being as a 

subject in research without the informed 

consent of the subject or the subject’s 

legally authorized representative. The 

Common Rule further specifically 

requires that: 

• An investigator shall seek such 

consent only under circumstances that 

provide the prospective subject 

sufficient opportunity to consider 

whether or not to participate and that 

minimize the possibility of coercion or 

undue influence. 

• The information given to the subject 

must be in language understandable to 

the subject. 

• No informed consent, oral or 

written, may include any exculpatory 

language through which the subject is 

made to waive or appear to waive any 

of the subject’s legal rights, or releases 

or appears to release the investigator, 

the sponsor, the institution or its agents 

from liability for negligence. 

The Common Rule defines the 

following mandatory elements in 

informed consent: 

• A statement that the study involves 

research, an explanation of the purposes 

of the research and the expected 

duration of the subject’s participation, a 

description of the procedures to be 

followed, and identification of any 

procedures which are experimental. 

• A description of any reasonably 

foreseeable risks or discomforts to the 

subject. 

• A description of any benefits to the 

subject or to others which may 

reasonably be expected from the 

research. 

A disclosure of appropriate 

alternative procedures or courses of 

treatment, if any, that might be 

advantageous to the subject. 

• A statement describing the extent, if 

any, to which confidentiality of records 

identifying the subject will be 

maintained. 

• For research involving more than 

minimal risk, an explanation as to 

whether any compensation and any 

medical treatments are available if 

injury occurs and, if so, what they 

consist of, or where further information 

may be obtained. 

• An explanation of whom to contact 

for answers to pertinent questions about 

the research and research subjects’

rights, and whom to contact in the event 

of a research-related injury to the 

subject. 

• A statement that participation is 

voluntary, refusal to participate will 

involve no penalty or loss of benefits to 

which the subject is otherwise entitled, 

and that the subject may discontinue 

participation at any time without 

penalty or loss of benefits to which the 

subject is otherwise entitled. 

The Common Rule specifies 

additional elements of informed consent 

that are sometimes required, and defines 

standards for documenting informed 

consent by use of a written consent form 

approved by the IRB and signed by the 

subject. The Common Rule requires that 

a copy be given to the person signing 

the form. 

The Common Rule extends these core 

protections to all human subjects of 

covered research, including those in 

vulnerable populations. It is to this base 

of core protections for all subjects that 

‘‘additional protections’’ for pregnant 

women, fetuses, and children as 

subjects of observational research 

conducted or supported by EPA, as 

contained in subparts C and D of this 

final rule, are added. Vulnerable 

populations for which no ‘‘additional 

protections’’ are provided by rule are 

not left defenseless or exploited; they 

are covered by these core protections of 

the Common Rule, including its 

requirement that IRBs ensure, on a caseby-case basis, that additional safeguards 

are employed in any study involving 

vulnerable populations to protect their 

rights and welfare. 

In addition to these substantive 

protections for research subjects, the 

Common Rule as it applies to research 

conducted or supported by EPA or any 

other signatory department or agency 

also contains many administrative 

provisions intended to accommodate 

the wide range of circumstances in all 

the departments and agencies to which 

it applies. Among others, these 

administrative provisions include: 

• Authority for the agency head to 

extend coverage of the rule to research 

‘‘otherwise subject to regulation’’

(§ 26.101(a)) and to determine what is 

within its scope (§ 26.101(c) and (d)). 

• Provision that only certain sections 

apply to third-party research subject to 

regulation (§ 26.101(a)(2)). 

• A list of six kinds of human 

research exempted from coverage by the 

rule (§ 26.101(b)). 

• Provision for approving research 

conducted under foreign standards that 

‘‘afford protections that are at least 

equivalent to those provided in’’ the 

Common Rule (§ 26.101(h)). 

• A grant of discretion to the agency 

head to waive provisions of the rule, 

with public notice in the Federal 

Register and to the DHHS Office for 

Human Research Protections 

(§ 26.101(i)). 

• A grant of discretion to IRBs to 

waive or alter requirements for informed 

consent (§ 26.116(c) and (d)) or 

documentation of informed consent 

(§ 26.117(c)). 

B. The Proposed Rule 

The September 12 proposal to extend 

EPA’s Common Rule to third-party 

research involved extending all the 

provisions of subpart A, §§26.101 

through 26.124, to covered third-party 

research. It also would have altered the 

shared text of the Common Rule by 

adding: 

• A new paragraph defining the scope 

of third-party research to which it 

applied (proposed § 26.101(j)). 


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• A new paragraph defining how a 

party’s intent to submit research to EPA 

would be determined (proposed 

§ 26.101(k)). 

• A new definition of research 

involving intentional exposure of a 

human subject (proposed § 26.102(k)). 

• A new requirement for prior 

submission to EPA of proposals for 

covered third-party research (proposed 

§ 26.124(b)). 

• A new requirement for submission 

to EPA of documentation of the ethical 

conduct of completed research 

(proposed § 26.124(c)). 

As noted in the preamble to the 

proposal, HHS requested EPA not to 

make any alterations in the text of the 

shared Common Rule, and to codify the 

extension of the Common Rule 

standards to third-party research in the 

final rule in a way that left subpart A—

the Common Rule—intact and 

unchanged. EPA agreed that the 

Common Rule should not be altered, 

and committed to making this change in 

the final rule. 

C. Public Comment 

Comment: The proposed extension of 

the entire Common Rule, including its 

provisions for administrative waivers of 

many requirements, alarmed many 

commenters. These administrative 

provisions were perceived as loopholes 

which could be exploited to undermine 

the whole purpose of extending the 

Common Rule. 

Response: Such exploitation of these 

provisions was never the Agency’s 

intent, and EPA agrees with the 

commenters who argued that many of 

these administrative provisions were 

not appropriate in a rule applying to 

third-party research. Thus, while 

subpart K in the final rule does extend 

all the substantive core protections of 

the Common Rule to non-pregnant adult 

subjects of covered research, it also 

eliminates or narrows the exceptions in 

the Common Rule. Unit VII. discusses 

each change from the Common Rule to 

subpart K in detail. 

D. The Final Rule 

In the final rule subpart A is the 

unaltered Common Rule, exactly as 

promulgated in 1991 except for its 

designation as ‘‘Subpart A.’’ It applies to 

all research with human subjects 

conducted or supported by EPA. 

VI. Subpart K—General Provisions 

Applying to Third Party, Intentional 

Exposure Human Research under the 

Pesticide Laws 

Summary: Subpart K extends the 

basic protections of the Common Rule to 

subjects in certain research conducted 

or supported by third parties. It applies 

to third-party human research involving 

intentional exposure of non-pregnant 

adult subjects and that is intended to be 

submitted to EPA under the pesticide 

laws. In addition to the basic procedures 

and protections contained in the 

Common Rule, it also requires 

researchers who propose to conduct 

new research covered by the rule to 

submit protocols and other materials for 

science and ethics review by both EPA 

and a newly created Human Studies 

Review Board (HSRB). Unit VI.A. 

summarizes EPA’s proposal, Unit VI.B. 

discusses public comment, and Unit 

VI.C. discusses the provisions of the 

final rule. 

A. EPA’s Proposed Rule 

EPA’s proposal added to the ‘‘Scope’’

section of the Common Rule additional 

paragraphs, proposed § 26.101(j) and (k), 

to make the provisions of the Common 

Rule applicable to certain third-party 

human research. Thus, the Agency’s 

proposal would have extended the 

Common Rule requirements to third 

parties, without substantive or editorial 

modification. 

The scope of the third-party human 

research covered by the proposal was 

defined as: 

[A]ll research involving intentional 

exposure of a human subject if, at any time 

prior to initiating such research, any person 

who conducted or supported such research 

intended: 

(1) To submit results of the research to EPA 

for consideration in connection with any 

regulatory action that may be performed by 

EPA under the Federal Insecticide, 

Fungicide, and Rodenticide Act (7 U.S.C. 136 

et seq.) or section 408 of the Federal Food, 

Drug, and Cosmetic Act (21 U.S.C. 346a); or 

(2) To hold the results of the research for 

later inspection by EPA under the Federal 

Insecticide, Fungicide, and Rodenticide Act 

(7 U.S.C. 136 et seq.) or section 408 of the 

Federal Food, Drug, and Cosmetic Act (21 

U.S.C. 346a). 

In effect, this provision would have 

included all intentional-exposure 

human research conducted with the 

intent to submit the results to the 

Agency under the pesticide laws. The 

proposal also established a rebuttable 

presumption that any information 

submitted by a person regulated under 

the pesticide laws was generated with 

the intent to submit it to EPA. 

In § 26.102(k), the proposal defined 

‘‘research involving intentional 

exposure of a human subject’’ to mean 

‘‘a study of a substance in which the 

exposure to the substance experienced 

by a human subject participating in the 

study would not have occurred but for 

the human subject’s participation in the 

study.’’ The preamble to the proposed 

rule explained that this term did not 

include a study that ‘‘monitored 

agricultural workers (such as 

professional fruit thinners or harvesters 

or other workers) who perform their 

usual work in areas that have been 

treated with pesticides at rates and 

using methods registered and approved 

by EPA’’ (70 FR 53846). The preamble 

also explained that intentional exposure 

studies did not include ‘‘most 

occupational exposure studies, and 

studies involving use of registered 

pesticides for approved uses according 

to label directions’’ (70 FR 53845). 

In addition, the proposed rule 

included a new section, proposed 

§ 26.124, that would have required any 

person proposing to conduct a new 

human study covered by the rule to 

submit the protocol and other materials 

for a science and ethics review by EPA. 

The same proposed section also created 

a new independent panel of experts, 

called the Human Studies Review 

Board, to review all proposed new 

research covered by the rule. The HSRB 

would also review all completed human 

research that EPA intended to rely on 

under the pesticide laws. 

B. Public Comments 

The major public comments 

applicable to subpart K of the final rule 

are discussed in Unit III. 

C. The Final Rule 

The final rule establishes new 

requirements for third-party research in 

a separate subpart K, and the rule text 

defining the scope of the types of thirdparty research covered by the proposed 

rule remains unchanged in the final 

rule. The Agency, however, has decided 

that the types of research captured by 

the definition of ‘‘research involving 

intentional exposure of a human 

subject’’ is broader than suggested by 

the preamble to the proposal. Although 

the text of the definition remains the 

same, EPA thinks it is important to 

clarify that the term covers any research 

on a substance, unless the subjects of 

the research retain complete control 

over whether, when, and how they are 

exposed to the substance. Thus, if the 

researcher decides a particular 

compound will be studied in the 

research and determines the manner in 

which subjects will be exposed, the 

research falls within the scope of 

‘‘research involving intentional 

exposure.’’

The substantive requirements 

applicable to covered third-party 

research are similar to the requirements 

contained in the Common Rule. In most 

cases the text is identical, and the 

sections employ a parallel numbering 


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system. The sections in subpart K are 

designated as §§ 26.1101 through 

26.1125 and correspond to the sections 

of the Common Rule designated 

§§ 26.1xx. For example, § 26.1107 in 

subpart K corresponds to § 26.107 of the 

Common Rule. 

EPA also made a number of minor 

modifications to the text of the Common 

Rule in order to reflect the applicability 

of subpart K to a particular subset of 

human subjects research studies 

involving intentional exposure of nonpregnant adults intended for submission 

under the pesticide laws. These 

modifications are discussed in 

paragraph 1 below. 

1. Modifications to the text of the 

Common Rule in subpart K. In a number 

of its provisions the Common Rule 

refers to itself as a ‘‘policy.’’ Throughout 

subpart K, EPA has replaced the word 

‘‘policy’’ with ‘‘subpart,’’ to remove any 

doubt about whether the provisions of 

subpart K create binding requirements. 

Throughout subpart K, EPA replaced 

references to ‘‘department or agency 

head’’ with ‘‘the Administrator.’’

Section 26.1102 includes a definition 

stating that Administrator refers to the 

Administrator of EPA or any officer or 

employee to whom authority has been 

delegated. 

Section 26.101(b) of the Common 

Rule exempts research in six categories 

from the requirements of the Common 

Rule. These exemptions generally cover: 

(i) Research on educational practices 

conducted in an educational setting. 

(ii) Research involving surveys, 

educational tests, observation, or 

interviews that involve no collection of 

sensitive personal information on 

identifiable individuals. 

(iii) Research involving surveys, 

educational tests, observation, or 

interviews that involve public officials 

or candidates for public office. 

(iv) Research involving the collection 

or study of existing data, documents, 

specimens, etc. from publicly available 

sources or sources that do not disclose 

the identity of individual subjects. 

(v) Research examining the delivery of 

public benefit programs. 

(vi) Research involving taste and food 

quality evaluation and consumer 

acceptance. 

Subpart K, however, covers only 

third-party research for pesticides 

involving intentional exposure of nonpregnant adults. Because five of these 

exemptions describe types of research 

that either could not possibly or should 

not involve ‘‘intentional exposure’’ to a 

pesticide, EPA deleted them from 

subpart K. Because the fourth category, 

above, could encompass the 

examination of results from research 

involving intentional exposure, the 

Agency did retain exception number 4 

in subpart K. See § 26.1101(b) of the 

regulatory text. 

Section 26.101(d) of the Common 

Rule states that, without prior notice, an 

agency head may extend the 

requirements of the Common Rule to 

specific research activities or classes of 

research. As a legal and policy matter, 

EPA believes that the public should 

receive notice of and an opportunity for 

public comment on any extension of 

these requirements to additional 

categories of third-party research. 

Accordingly, subpart K does not contain 

a provision comparable to § 26.101(d). 

Section 26.101(f) of the Common Rule 

indicates that State and local laws may 

contain additional requirements 

governing the conduct of human 

research and that the Common Rule 

does not supersede those requirements. 

Recognizing that Native American 

governmental entities also have legal 

authority to regulate the conduct of 

human research, EPA has added Tribal 

authority to the list of legal sources that 

may establish additional requirements 

beyond those in the final rule. See 

§ 26.1101(e) of the regulatory text. 

Section 26.101(h) of the Common 

Rule authorizes the head of an agency 

to allow human research conducted in 

a foreign country to proceed in 

accordance with the requirements of 

that country, even if foreign authorities 

require behavior that does not fully 

comply with the Common Rule, so long 

as the agency head determines that the 

requirements of the foreign country 

provide protections ‘‘at least equivalent 

to those [of the Common Rule.]’’ This 

section further provides that when an 

agency head makes such a decision, he 

must publish a notice of the action in 

the Federal Register. In promulgating 

subpart K, EPA retained a comparable 

provision, but with several changes. 

First, EPA moved this provision to 

subpart P of the final rule, which 

addresses EPA’s decisions on the 

acceptability of proposed research, 

where it appears as § 26.1601(c). 

Second, EPA did not adopt the Common 

Rule’s requirement to publish a Federal 

Register Notice announcing such a 

decision on proposed third-party 

research. The Agency concluded that 

such a procedure was redundant with 

the HSRB process, which will involve 

both a transparent presentation of EPA’s 

positions regarding proposed research 

and public meetings about such 

positions and an opportunity for the 

public to comment on them. 

Section 26.101(i) contains language 

allowing the Administrator to waive any 

of the requirements of the Common 

Rule. While every other federal 

Common Rule agency and department 

has such discretion, and while such 

discretion seems appropriate for firstand second-party research, EPA has 

never exercised this authority under the 

Common Rule and sees no need for such 

discretion under subpart K. 

Accordingly, subpart K does not contain 

a provision comparable to § 26.101(i). 

The definitions in the Common Rule 

include the term research subject to 

regulation; see § 26.102(e). Subpart K 

omits this definition because the types 

of third-party research covered by the 

rule are specified by the paragraphs in 

§ 26.1101 delineating the scope of 

subpart K. 

Section 26.102(j) contains a definition 

of the term certification. Because this 

definition actually establishes a 

substantive obligation to submit 

documentation of IRB approval, the 

substantive requirement appears in 

§ 26.1125 as one of the items that must 

be submitted to EPA in connection with 

review of proposed research. See 

§ 26.1125(f) of the regulatory text. 

EPA added a new definition of person 

in § 26.1102(j) of the final rule to clarify 

that the requirements of subpart K (as 

well as subparts L and M) do not apply 

to first-party and second-party human 

research by other federal departments 

and agencies that are subject to the 

Common Rule. Having operated under 

the Common Rule for many years, these 

agencies and departments are very 

familiar with its meaning and 

application and have well developed 

procedures for assuring compliance. 

Therefore, EPA sees no reason either to 

promulgate requirements that duplicate 

regulations already in force, or to 

impose on these agencies the new 

requirements of subpart K concerning 

submission of proposals for future 

research for EPA and HSRB review. Of 

course, the Agency will, on request, 

work with other agencies intending to 

submit the results of human research to 

EPA to ensure that the results may be 

considered under subpart Q. 

Several sections of the Common 

Rule—§§ 26.107(a), 26.111(a)(3), 

26.111(b), and 26.116(b)(1)—refer to 

additional measures required when 

research involves pregnant women, 

children, or other special populations as 

subjects. Subpart L, however, prohibits 

third-party research involving 

intentional exposure of human subjects 

who are pregnant women (and therefore 

their fetuses) or children. Thus subpart 

K covers only third-party research 

involving intentional exposure of nonpregnant adults. To be consistent with 

this scope, EPA removed from subpart 


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K all references to pregnant women, 

fetuses, newborns, or children. 

The first sentence of § 26.107 of the 

Common Rule states: 

Each IRB shall have at least five members, 

with varying backgrounds to promote 

complete and adequate review of research 

activities commonly conducted by the 

institution. 

This provision reflects the assumption 

that IRBs are always associated with an 

‘‘institution.’’ It also arguably would 

excuse an IRB from having adequate 

expertise to assess studies beyond those 

‘‘commonly conducted’’ at the 

institution. EPA believes that IRBs 

should acquire whatever expertise they 

need to evaluate the types of studies 

they agree to review. Accordingly, EPA 

has revised that sentence to read: 

Each IRB shall have at least five members, 

with varying backgrounds to promote 

complete and adequate review of research 

activities which are presented for its 

approval. 

Section 26.108(a) of the Common Rule 

contains a cross-reference to certain 

earlier sections of the Common Rule. 

For greater clarity, and consistent with 

FDA’s approach in its similar rules. EPA 

simply repeated the substantive 

requirements of the referenced sections 

in § 26.1108(a) of subpart K. This led to 

redesignation of some paragraphs. 

Section 26.109(c) of the Common Rule 

includes a reference to § 26.117(c), 

which gives IRBs the authority, under 

certain circumstances, to waive the 

requirement for written documentation 

of informed consent. Since EPA has not 

included in subpart K a paragraph 

comparable to § 26.117(c) of the 

Common Rule, the Agency has deleted 

the cross-reference in § 26.1109(c) of 

subpart K. 

Section 26.114 of the Common Rule 

contains a provision designed to 

facilitate cooperative research among 

multiple investigators in different 

institutions. This section authorizes the 

head of an agency to accept a joint 

review or review by a single IRB to 

avoid duplication of effort. Rather than 

use the text of the Common Rule 

provision, EPA has adopted in § 26.1114 

a similar but clearer provision from FDA 

regulation; see 21 CFR 56.114. 

Section 26.115(a)(5) of the Common 

Rule cites another provision of the 

Common Rule that specifies the 

information about the members of an 

IRB which the IRB is required to 

provide in its records. In the parallel 

section of subpart K, § 26.1115(a)(5), 

EPA followed the approach FDA used in 

its regulations and repeated the 

substantive provisions of the referenced 

sections. 

Sections 26.116(c) and (d) of the 

Common Rule authorize an IRB to waive 

or alter the requirement for informed 

consent in certain circumstances for 

research conducted or supported by 

EPA. EPA deleted these paragraphs from 

subpart K because of the central 

importance of informed consent to 

ensuring ethical treatment of subjects in 

human research. In addition, EPA 

concluded that the types of human 

research covered by subpart K—research 

involving intentional exposure of nonpregnant adults intended for submission 

under the pesticide laws—would not 

meet any of the Common Rule criteria 

for waiving or altering the informed 

consent procedures. 

EPA added a new paragraph to 

§ 26.1116 to clarify that the informed 

consent materials for research covered 

by subpart K must include ‘‘the identity 

of the pesticide and the nature of its 

pesticidal function.’’ While implicit in 

the requirements of § 26.1116(a)(1), 

which is derived from § 26.116(a)(1) of 

the Common Rule, the Agency thought 

that the final rule should make this 

obligation explicit. 

In a provision that parallels the 

waiver authority discussed above, 

§ 26.117(c) of the Common Rule 

authorizes an IRB to waive the 

requirement for an investigator to obtain 

a signed consent form from each subject 

for research conducted or supported by 

EPA. Because of the importance of being 

able to demonstrate that each subject 

was fully informed and freely 

volunteered to participate in the types 

of research covered by subpart K, EPA 

decided not to adopt this Common Rule 

provision in subpart K. The Agency also 

made minor editorial changes to 

§ 26.1117(a) and (b) to reflect the 

deletion of paragraph (c). 

Section 26.101(a)(2) identifies the 

sections of the Common Rule which 

apply to ‘‘research that is neither 

conducted nor supported by a Federal 

department of agency but is subject to 

regulation as defined in § 26.102(e).’’

These sections include §§ 26.107 

through 26.117, but not § 26.103 or 

§§ 26.118 through 26.124. Sections 

26.118 through 26.124 generally apply 

to procedures associated only with firstparty and second-party research, but 

which would not be relevant to thirdparty research. Consistent with the 

thrust of § 26.101(a)(2) and in order to 

reduce confusion, EPA has not created 

parallel sections for § 26.103 or, with 

two exceptions, any of the sections after 

§ 26.117. 

The first of these exceptions is to 

include in subparts K and P of the final 

rule two passages parallel to § 26.123 of 

the Common Rule. Section 26.1123, 

which corresponds to § 26.123(a) in 

subpart A, authorizes the Administrator 

to suspend or terminate research if EPA 

determines that a sponsor, IRB, or 

investigator has materially failed to 

comply with the terms of subpart K. 

(FDA’s regulations contain a similar 

provision at 21 CFR 56.113.) In 

addition, EPA has included the 

substance of § 26.123(b)—authorizing 

EPA to consider an investigator’s record 

in past ethical (or unethical) human 

research when reviewing proposals for 

new research—in § 26.1601(b) of 

subpart P, which governs EPA’s review 

of proposed new research. 

The second exception is to include in 

subpart P of the final rule a § 26.1601, 

parallel to § 26.124 of subpart A. This 

provides that, in its review of proposed 

new research, EPA may, on a case-bycase basis, impose additional conditions 

applicable to the conduct of a study that 

are necessary for the protection of 

human subjects. 

2. Revisions to the requirements for 

information concerning proposed 

research. In reorganizing the final rule, 

EPA has moved the substantive content 

of proposed § 26.125, which would have 

required third parties to submit 

proposals for new human research for 

EPA review, to § 26.1125 of subpart K. 

In addition, EPA has revised this section 

in the final rule in two ways. A new 

§ 26.1125(d) adds ‘‘a description of the 

circumstances and methods for 

presenting information to potential 

human subjects for the purpose of 

obtaining their informed consent’’ to the 

list of what information must be 

included with a submitted proposal for 

new research, and § 26.1125(f) adds an 

explicit requirement for documentation 

of IRB approvals. 

VII. Intentional Exposure Research: 

Subparts B and L—Prohibitions of 

Human Research Involving Intentional 

Exposure of Pregnant Women, Fetuses, 

and Children 

Summary: Subpart B of the final rule 

categorically prohibits EPA from 

conducting or supporting human 

subjects research on a substance that 

involves intentional exposure of 

pregnant women, fetuses, and children 

to the substance. See 40 CFR 26.203 of 

the regulatory text. 

Subpart L of the final rule prohibits 

human subjects research for pesticides 

conducted or supported by third parties 

that involves intentional exposure of 

pregnant women, fetuses, or children. 

See 40 CFR 26.1203 of the regulatory 

text. 

Unit VII.A. summarizes EPA’s 

proposal, Unit VII.B. discusses public 

comments, and Unit VII.C. discusses the 

provisions of the final rule. 


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A. The Proposed Rule 

The September 12 proposal 

contained, in § 26.220 of proposed 

subpart B, a clear prohibition of any 

future EPA research involving 

intentional dosing of pregnant women, 

fetuses or certain newborns. Section 

26.420 of proposed subpart D contained 

an equally clear prohibition of any 

future EPA research involving 

intentional dosing of children. 

The same sections of the proposal—

§ 26.220 in subpart B and § 26.420 in 

subpart D—also prohibited any new 

third-party research intended for 

submission to EPA under the pesticide 

laws, and involving intentional dosing 

of pregnant women, fetuses, or children. 

The proposed prohibition would, as a 

practical matter, have applied to any 

research conducted by pesticide 

companies or by investigators working 

on their behalf. 

B. Public Comments 

Almost without exception, comments 

on the prohibitions contained in the 

proposed rule drew no distinction 

between third-party research and firstand second-party research. Therefore, 

unless otherwise indicated, the 

following discussion applies both to the 

proposed prohibitions against human 

subjects research conducted or 

supported by EPA that involves 

intentional exposure of pregnant 

women, fetuses, or children and to the 

prohibitions against such research by 

third parties who intend to submit the 

results to EPA under the pesticide laws. 

In addition, comments generally made 

the same recommendations regarding 

the prohibition on research involving 

intentional exposure of children as for 

the prohibition on research involving 

intentional exposure of pregnant women 

and fetuses. Again, unless otherwise 

indicated, the discussion below refers to 

both sets of prohibitions. 

Comment: Some commenters argued 

that the proposed prohibitions were too 

narrow and should be expanded in 

order that all potentially affected test 

subjects received protection. 

Specifically, these comments 

recommended that: (1) The prohibition 

on research with children should not be 

limited to research involving intentional 

exposure, but should cover all types of 

human research (including scientific 

observation of public behavior of 

children); (2) the prohibition on 

research with pregnant women should 

be similarly broad; and (3) additional 

groups should be protected under the 

ban on intentional exposure research, 

including prisoners, all women of 

childbearing age, the elderly, and 

people with chronic diseases or 

developmental disabilities. 

Response: EPA believes that 

‘‘observational research,’’ i.e., research 

that does not involve intentional 

exposure of human subjects, often 

provides a great deal of valuable 

scientific information that can be 

critical for effective environmental and 

public health regulation. To adopt the 

commenters’ approach would mean, for 

example, that EPA could not collect, 

through research involving little or no 

risk to the subjects, information on the 

amount of time that children spend 

outdoors, the types of food consumed by 

pregnant women, or the possible 

correlation between air pollution and 

asthma in newborns. Therefore, EPA has 

decided not to accept the comments 

recommending expansion of the 

prohibitions to cover all types of human 

research. 

EPA agrees with the commenters who 

point out that other groups deserve 

special consideration if they are to be 

included in research as test subjects. 

The Common Rule and EPA’s extension 

of it to certain types of third-party 

research already direct IRBs to pay 

particular attention to the issues 

involved with research on several of 

these groups. See § 26.111(b) and 

§ 26.1111(b) of the regulatory text. EPA 

believes that the approach created by 

the final rule—which requires both EPA 

and HSRB review of all future thirdparty research covered by the rule—will 

successfully identify those studies that 

may proceed ethically and those for 

which it would not be ethical to involve 

individuals from the identified groups. 

Comment: Some commenters argued 

that the proposed prohibitions were too 

broad and that certain kinds of research 

should be excluded from the bans on 

conduct of future research involving 

intentional exposure of human subjects. 

Specifically, these comments 

recommended exclusion of: (1) 

Pharmaceutical studies, particularly 

products for control of head and body 

lice; (2) nutrition studies with 

micronutrients that may also be 

pesticides; (3) research on the efficacy of 

insect repellents; (4) research involving 

only use of registered pesticides for 

approved uses, or ‘‘product-in-use’’

studies; and (5) research on the efficacy 

of swimming pool and spa sanitizers 

and disinfectants; 

Response: For a variety of reasons, 

EPA is not persuaded by these 

comments to modify the scope of its 

proposed prohibitions. 

EPA notes that it does not conduct or 

support pharmaceutical studies and 

nutritional studies with any human 

subjects, and therefore there is no need 

to modify the proposed prohibitions for 

first- and second-party research. 

Further, EPA did not intend its 

proposed prohibitions to apply to third 

parties when conducting 

pharmaceutical or micronutrient 

research, and believes that such thirdparty research generally would fall 

outside the scope of the prohibitions 

because they would not meet the ‘‘intent 

to submit’’ criterion in § 26.1201. In fact, 

EPA thinks it would be contrary to the 

public interest to ban research of the 

effects on pregnant women and children 

of drugs, like streptomycin, or 

micronutrients, like copper or iodine, 

simply because these compounds also 

have approved uses as pesticides. Given 

that it is unlikely an investigator would 

undertake such research for submission 

to EPA in support of a pesticide action, 

these types of studies would not be 

prohibited. 

EPA believes that there is no need to 

perform research on the efficacy of 

insect repellents with pregnant women 

or children. The efficacy of a repellent 

depends primarily on the properties of 

the pesticide formulation and does not 

vary with the age of the person to whom 

it is applied. Therefore, studies using 

non-pregnant adults should provide 

adequate information to assess how well 

insect repellents work, and there is no 

reason to exclude this type of research 

from the prohibition. 

Similarly, EPA does not believe that 

comments have presented a compelling 

argument for recommending the Agency 

exclude from the prohibitions ‘‘productin-use’’ research on pesticides. The 

Agency agrees with comments that such 

product-in-use research will generally 

pose relatively little risk to test subjects, 

because the exposures occurring during 

the research would correspond to 

exposures authorized by the Agency 

under its pesticide regulatory program—

exposures that EPA has found cause no 

unreasonable adverse effects on human 

health or the environment. But these 

comments contain no satisfactory 

explanation of why it is necessary to 

conduct such product-in-use research 

with pregnant women, fetuses, or 

children. Like research on insect 

repellents, the Agency believes that 

general product-in-use research with 

non-pregnant adults should provide 

sufficient information to meet legitimate 

scientific needs. 

Finally, research on the efficacy of 

antimicrobial agents used in swimming 

pools, spas, and hot tubs raises unusual 

and difficult issues. The Agency issues 

experimental use permits for these 

studies to determine whether, under 

typical use conditions, the antimicrobial 

can successfully control the additional 


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microbial load introduced by bathers. 

The Agency, however, does not approve 

such field research until the Agency can 

conclude that both the experimental use 

is likely to be effective and the levels of 

the antimicrobial in water will pose no 

risk to the bathers. 

EPA, however, does not regard such 

studies as ‘‘research with human 

subjects’’ under the definitions in the 

Common Rule at §§ 26.102 and 26.1102, 

and therefore does not believe they are 

subject to the prohibitions or any other 

provisions in part 26. The definitions of 

‘‘research’’ and ‘‘human subject’’ make 

clear that the phrase ‘‘research with a 

human subject’’ applies to a systematic 

investigation in which an investigator 

collects information through an 

intervention or interaction with an 

individual for the purpose of developing 

generalizable knowledge about humans. 

In the case of these antimicrobial 

efficacy studies, the research does not 

involve interactions with, or collection 

of information on, identifiable 

individuals for the purpose of 

producing generalizable knowledge. 

Comment: A number of comments 

objected to what they perceived to be 

‘‘loopholes’’ in the proposed rule’s 

prohibition on research involving 

intentional exposure of children. 

Specifically, they argued that: (1) 

Proposed § 26.401(a)(1) permitted EPA 

to waive the prohibition when research 

was conducted outside the United 

States; (2) proposed § 26.401(a)(2) 

permitted EPA to waive any provision 

of proposed subpart D, including the 

prohibition; and (3) proposed § 26.408, 

which authorized an IRB to waive the 

requirement for assent from children 

lacking the capacity to give it, and to 

waive the requirement for permission 

from abusive or neglectful parents, 

meant that EPA intended to allow 

research on mentally retarded, abused, 

or neglected orphans. 

Response: Many commenters 

misinterpreted EPA’s proposed 

language. Contrary to public comments, 

none of the alleged ‘‘loopholes’’ ever 

existed, because the prohibition in 

proposed § 26.420 stated 

‘‘Notwithstanding any other provision 

of this part, under no circumstances 

shall EPA or a person when covered by 

§ 26.101(j) conduct or support research 

involving intentional dosing of any 

child.’’ The words, ‘‘Notwithstanding 

any other provision of this part,’’ mean 

that the provisions in proposed § 26.420 

override all other provisions of the 

entire regulation, including §§ 26.401 

and 26.408. Even though those two 

sections would have given EPA 

authority to waive certain requirements, 

they would not have authorized any 

departure from the ban in proposed 

§ 26.420. 

Nonetheless, in order to remove any 

doubt about the scope of the 

prohibitions, EPA has made several 

changes in the final rule. The 

prohibitions appear in separate subparts 

so that there is less chance someone will 

misread the provisions intended to 

confer flexibility in the approach to 

observational research as applying to 

research involving intentional exposure. 

In subpart D, which addresses 

observational research with children 

conducted or supported by EPA, EPA 

has removed or revised the text of 

§§ 26.401 and 26.408 to make clear that 

they do not create an opportunity to 

relax the protections for children. 

C. The Final Rule 

After careful consideration of public 

comments—particularly the thousands 

of comments expressing strong 

opposition to EPA’s ever conducting 

human subjects research that involves 

intentional exposure of pregnant 

women, fetuses, or children, the Agency 

has retained in the final rule the 

proposed prohibitions, essentially 

without change. Subpart B contains the 

proposed prohibitions against EPA 

conducting or supporting new research 

involving intentional exposure of 

pregnant women, fetuses, and children. 

This prohibition applies to EPA’s firstand second-party research with any 

substance, and is not restricted to 

pesticides. 

Subpart L of the final rule contains a 

parallel prohibition of new third-party 

human subjects research for pesticides 

involving intentional exposure of 

pregnant women, fetuses, or children. 

Subpart L applies to research conducted 

or supported by any person who intends 

to provide the results of the research to 

EPA under FIFRA or the FFDCA. The 

final rule retains the text from the 

proposal establishing how EPA will 

determine a person’s intent for purposes 

of applying the prohibition. 

The Agency recognized that the 

wording of the proposed prohibitions 

and other requirements could be 

interpreted to apply to studies, which 

do not constitute ‘‘research’’ with 

‘‘human subjects,’’ as these terms are 

defined in the Common Rule, but in 

which humans who are not subjects of 

the research may be incidentally 

exposed. The Agency did not intend, for 

example, that the proposal would affect 

animal research on a pesticide simply 

because a person might be intentionally 

exposed to a test material as a 

consequence of working as a lab 

technician. Accordingly, EPA has 

revised the rule text in subparts B, C, L, 

and Q to clarify that the prohibitions 

and other provisions apply only to 

research with human subjects and not to 

other types of research. 

The Agency hopes that the 

reorganization of the final rule gives 

greater prominence to these 

prohibitions, and clarifies EPA’s intent 

that there be no exceptions to or 

loopholes in these prohibitions. Both 

subparts B and L begin by expressly 

stating the universe of research 

activities to which they apply. To 

further reinforce the point that the bans 

on these types of testing are not subject 

to any exceptions, the prohibitory 

provisions use the introductory phrase 

‘‘Notwithstanding any other provision 

of this part, under no circumstances 

....’’ This language means that this 

provision is to be enforced over all other 

provisions of every other subpart of part 

26. 

VIII. Observational Research: Subparts 

C and D—Additional Protections for 

Pregnant Women, Fetuses, and 

Children Involved as Subjects in 

Observational Research Conducted or 

Supported by EPA 

Summary: This unit discusses 

protections additional to the core 

protections provided by the Common 

Rule (subpart A), which are established 

by the final rule for pregnant women 

and fetuses (subpart C) and children 

(subpart D) when they are subjects in 

observational research conducted or 

supported by EPA. The final rule 

defines observational research as 

research not involving intentional 

exposure. The provisions of the final 

rule are similar to regulations 

promulgated by HHS to govern studies 

with these populations when conducted 

or supported by HHS. Unit VIII.A. 

summarizes the proposal, Unit VIII.B. 

discusses public comment, and Unit 

VIII.C. describes the position taken in 

the final rule. 

A. The Proposed Rule 

Most of the provisions of proposed 

subparts B and D would have defined 

additional protections for individuals 

from vulnerable populations when they 

were subjects in observational research 

conducted or supported by EPA—i.e., 

studies that do not involve intentional 

exposure. Proposed subpart B contained 

protections for pregnant women, 

fetuses, and certain newborns, and 

proposed subpart D contained 

protections for children. The protections 

in both proposed subparts were in 

addition to the basic protections created 

by the Common Rule, 40 CFR part, 26 

subpart A. Because the HHS regulations 

affording additional protections for 


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pregnant women and fetuses and for 

children had been in existence for over 

20 years and enjoyed widespread 

acceptance by the research ethics 

community, EPA proposed to adopt the 

HHS rules without substantive change, 

except as noted below. 

1. Proposed subpart B. EPA proposed 

to adopt by reference much of the 

content of subpart B of the HHS rule, 45 

CFR part 46, with only a few changes. 

Thus, EPA proposed to adopt several 

sections from the HHS rule: 

• In proposed § 26.201, EPA adapted 

the text of 45 CFR 46.201, thereby 

defining the scope of the subpart—

research conducted or supported by 

EPA that involved research with 

pregnant women, fetuses, or certain 

newborns. 

• Proposed § 26.202 cross referenced 

several paragraphs of 45 CFR 46.202 

defining such terms as delivery, fetus, 

neonate, and pregnancy. 

• Proposed § 26.203 cross referenced 

the requirement of 45 CFR 46.203 that 

assigns to IRBs the primary 

responsibility for ensuring that 

investigators follow the requirements of 

the subpart. 

• Proposed § 26.204 cross referenced 

the requirements of 45 CFR 46.204 

defining the findings an IRB must make 

(in additional to those required by the 

Common Rule at § 26.111) before 

approving proposed research with 

pregnant women or fetuses. (Because of 

the prohibition in proposed § 26.220, 

the provisions in proposed §§ 26.204 

and 26.205 would have applied only to 

EPA’s observational research.) In 

summary, these include findings that: 

Adequate preliminary research exists to 

characterize potential risk, the risks to 

pregnant women and fetuses have been 

minimized, either the risks are minimal 

or the research holds out the prospect of 

direct benefit, and appropriate informed 

consent is obtained, in some cases from 

both the father and the pregnant 

woman. 

• Proposed § 26.205 cross referenced 

the requirements of 45 CFR 46.205 

defining the findings an IRB must make 

before approving observational research 

with certain newborns, including, 

where applicable, that the observational 

research has the prospect of improving 

the chances of survival of neonates of 

uncertain viability or that the 

observational research will develop 

important biomedical knowledge which 

could not otherwise be obtained. 

• Proposed § 26.206 cross referenced 

the requirements of 45 CFR 46.206 

concerning observational research 

involving, after delivery, the placenta, 

the dead fetus, or fetal material. 

The major substantive change EPA 

made to the HHS rule in proposed 

subpart B was the choice not to propose 

adopting the provisions in 45 CFR 

46.207, which provide a special 

procedure for approving in exceptional 

cases observational research which does 

not meet the standards of 45 CFR 46.204 

or 46.205. EPA considered such a 

provision both inappropriate and 

unnecessary for observational research 

with environmental substances. 

2. Proposed subpart D. EPA proposed 

to adopt much of the content of subpart 

D of the HHS rule, 45 CFR part 46, 

specifically: 

• In proposed § 26.401, EPA adopted 

the text of 45 CFR 46.401, thereby 

defining the scope of the subpart—

research conducted or supported by 

EPA involving children as subjects. The 

proposed rule text contained the same 

exceptions that appear in the HHS rule. 

• Proposed § 26.402 contained the 

same definitions that appear in the HHS 

rule in 45 CFR 46.402, except that EPA 

proposed to define a child as a person 

younger than 18 years old, in contrast to 

the HHS definition, which relies on 

local law to determine when a person 

becomes an adult. 

• Proposed § 26.403 cross referenced 

the requirement of 45 CFR 46.403 that 

assigns to IRBs the primary 

responsibility for ensuring that 

investigators follow the requirements of 

the subpart. 

• Proposed § 26.404 adapted, 

essentially verbatim, the text of the HHS 

regulation in 46 CFR 46.404 that 

authorizes IRBs to approve 

observational research with children 

(which also meets the criteria in 

§ 26.111), which involves ‘‘no more than 

minimal risk’’ only if there are adequate 

procedures, as specified in § 26.408, for 

soliciting the assent of the children and 

the permission of their parents or 

guardians. (Because of the prohibition 

in proposed § 26.420, the provisions in 

proposed §§ 26.404, 26.405, and 26.408 

would have applied only to EPA’s 

observational research.) 

• Proposed § 26.405 adopted, 

essentially verbatim, the text of the HHS 

regulation in 46 CFR 46.405 that 

authorizes IRBs to approve 

observational research with children 

(which also meets the criteria in 

§ 26.111), which involves ‘‘greater than 

minimal risk’’ only if the IRB finds the 

observational research offered the 

prospect of direct benefit to the 

individual subjects or would otherwise 

contribute to their well-being, and there 

are adequate procedures, as specified in 

§ 26.408, for soliciting the assent of the 

children and the permission of their 

parents or guardians. 

• Proposed § 26.408 adopted, 

essentially verbatim, the text of the HHS 

regulation in 45 CFR 46.408 establishing 

special requirements for obtaining 

permission by parents or guardians and 

for assent by children. Among other 

provisions this section provided that in 

some cases an IRB could determine that 

a child was not capable of assent, in 

light of their age, maturity, or 

psychological state. If so, the inability of 

the investigator to obtain assent could 

not be a basis for excluding a child from 

research that held out the prospect of 

benefit to the child. The proposal also 

allowed an IRB to waive assent on the 

same grounds that it could waive 

informed consent by adults (see 

§ 26.116(d)). This proposed section also 

granted to IRBs discretion to determine 

that, in some cases, it would not be 

reasonable to require the permission of 

a child’s parent or guardian because, for 

example, the adult abused or neglected 

the child. In such instances, this section 

authorizes the IRB to approve an 

alternative mechanism of obtaining 

permission from an adult who would 

better represent the child’s interests. 

As noted above, most of the proposed 

rule text came directly from the existing 

HHS regulations establishing additional 

protections. The Agency did propose a 

few revisions. In addition to minor 

editorial changes necessary to reflect 

that the proposed rule would be 

implemented by EPA, the most notable 

substantive changes were: (1) Defining a 

child as a person under the age of 18 

years, (2) choosing not to propose 

adopting the provisions in 45 CFR 

46.406 and 46.407, and (3) choosing not 

to propose adopting the provisions in 45 

CFR 46.409. 

In 45 CFR 46.406 and 46.407, HHS 

establishes special standards and 

procedures for approving in exceptional 

cases research which does not meet the 

standards of 45 CFR 46.404 or 46.405—

i.e., research which poses more than 

minimal risk to the children in the 

study but which offers no prospect of 

direct benefit to them. EPA considers 

such provisions both inappropriate and 

unnecessary for research with 

environmental substances, particularly 

observational studies. Consistent with 

the choice not to adopt those two 

sections, EPA chose to omit 45 CFR 

46.409 of the HHS rule as well, since it 

specifies measures which are required 

only when the children in a study 

approved under the authority of 45 CFR 

46.406 or 46.407 were wards of the 

state. 

B. Public Comment 

Most comments on proposed subparts 

B and D addressed the proposed 


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prohibitions on research involving 

intentional exposure of pregnant 

women, fetuses, or children. These 

comments are addressed in Unit VIII. 

This unit covers the public comments 

which addressed the adoption of 

additional protections for pregnant 

women and children as subjects in 

observational research conducted or 

supported by EPA. 

Comment: Some commenters 

supported EPA’s proposal to adopt only 

some of the provisions of the HHS 

regulations in 45 CFR part 46, subparts 

B and D that create additional 

protections for pregnant women, 

fetuses, and children in observational 

research. Other comments 

recommended the Agency adopt these 

HHS regulations in their entirety. By 

doing so, EPA and HHS would follow 

consistent approaches. These comments 

also noted HHS has operated under 

these regulations for over 20 years 

without significant debate over their 

ethical adequacy. 

Response: The Agency agrees there is 

considerable value in employing 

consistent approaches in similar areas of 

research. Consistency makes it easier for 

affected researchers to comply and 

helps to build a broader consensus on 

what constitutes ethical behavior. 

Accordingly, EPA is adopting large parts 

of the HHS regulations from 45 CFR part 

46, subparts B and D essentially 

verbatim. The Agency, however, is not 

promulgating all of these HHS rules 

because, in EPA’s judgment, the omitted 

provisions would never apply to 

observational research. Specifically, 

EPA has not adopted the following 

sections from the HHS rules: 45 CFR 

46.205, 46.207, 46.406, 46.407, and 

46.409. These sections would apply 

only when proposed research would 

present more than a minimal risk to the 

subjects and would have no prospect for 

direct benefit to the subjects. EPA 

simply cannot conceive of observational 

research that could not meet such 

criteria, and in the unlikely event that 

an investigator proposed such research, 

EPA would not expect to approve it. 

Comment: Some comments objected 

to the inclusion in the proposed rule of 

provisions that allowed observational 

research if an IRB judged the potential 

risks to subjects as ‘‘minimal.’’ These 

comments claimed that the concept of 

‘‘minimal risk’’ was not adequately 

defined and potentially subject to abuse. 

These comments recommended that no 

observational research be allowed 

unless there was ‘‘no risk’’ to subjects. 

(Many of these comments further argued 

that no human research was totally risk 

free and therefore no human research 

should be allowed.) 

Response: The Common Rule and 

subpart D of the final rule define 

minimal risk as ‘‘the probability and 

magnitude of harm or discomfort 

anticipated in the research are not 

greater in and of themselves than those 

ordinarily encountered in daily life or 

during the performance of routine 

physical or psychological examinations 

or tests.’’ 40 CFR 26.402. The Agency 

agrees that this definition leaves room 

for the exercise of expert judgment by a 

person reviewing a proposed protocol, 

and that different people may disagree 

on whether a particular research 

technique poses minimal risk. 

Nonetheless, this definition has been 

part of the Common Rule since 1991, 

and this provision has been in the HHS 

regulations since 1983. Based on its long 

history of application and the benefits of 

consistency with HHS, EPA has decided 

to retain proposed § 26.404 without 

change. In addition, EPA thinks the 

prospects for abuse are extremely small 

since all research allowed using these 

criteria would need approval both from 

a local IRB and from EPA’s Human 

Subjects Research Review Official 

(HSRRO). 

Comment: Some comments objected 

to EPA’s proposal to adopt 45 CFR 

46.405, which would allow an IRB to 

approve observational research with 

children if the IRB found the risks to 

children were ‘‘greater than minimal,’’

but presented ‘‘the prospect of direct 

benefits to the individual subjects.’’

These comments argued that 

observational research would never 

meet such criteria. 

Response: EPA rarely expects 

observational research to pose ‘‘greater 

than minimal risk.’’ By its very nature, 

observational research leaves all 

decisions regarding exposure to the 

subjects. Thus, an investigator 

ordinarily just measures and records 

information about exposure and effects 

that the subjects, in their own 

discretion, choose to experience. EPA, 

nonetheless, believes its final rule 

should include a provision comparable 

to 45 CFR 46.405. Although unlikely, 

EPA thinks some measurement 

techniques used in observational 

research could theoretically involve 

more than minimal risk to subjects and 

therefore would fail to meet the criteria 

for approval under § 26.304 of the final 

rule. Consistent with the HHS approach 

in 45 CFR 46.205, EPA believes that, if 

such risks exist, the research should not 

be allowed unless an IRB finds that the 

‘‘greater than minimal risks’’ were 

justified by the prospect of direct 

benefits to the subjects. Because EPA 

does not want to prevent potentially 

valuable research that requires nonstandard measurement techniques, EPA 

has adopted in § 26.305 of its final rule 

the content of the provision of the HHS 

regulations. 

Comment: Although most comments 

agreed with EPA’s proposal to define 

child as a person younger than 18 years 

old, some comments recommended 

using the text in the HHS rule, which 

defers to the legal standards defining 

children and adults in the local 

jurisdictions where the research is 

conducted. These comments pointed 

out that EPA’s proposed definition 

could lead to the exclusion of an 

emancipated minor, typically an older 

teenager who has married. Excluding 

these potential subjects could deny 

them the benefits of participating in the 

research simply because of their age. 

Other comments favored raising the age 

to 21 years old because the human body, 

particularly the brain, continues to 

mature after the age of 17 years and 

research might adversely affect 18–21 

year olds during this developmental 

period of potentially increased 

sensitivity. 

Response: EPA is not persuaded that 

the potential increased sensitivity of 

people between the ages of 18 and 20 

years to some effects warrants defining 

a child as a person under 21 years old. 

The Agency notes that such sensitivity 

is not likely to exist for all chemicals. 

If, however, a proposal to perform 

observational research did raise 

concerns about an increased sensitivity 

of subjects, those concerns can be 

addressed on a case-by-case basis by the 

IRB and EPA’s HSRRO. It is not 

necessary, in EPA’s view, to deal with 

these theoretical concerns by redefining 

who is a child. 

While EPA sees benefit to using a 

definition consistent with HHS, the 

Agency is concerned about the added 

complexity for investigators who are 

conducting research in multiple 

jurisdictions. In addition, EPA questions 

whether youngsters no older than 15 

years, as an adult is defined in some 

states, are sufficiently mature to make 

decisions about whether to volunteer to 

participate in human research. In light 

of these concerns and the broad support 

for EPA’s proposal, EPA has decided to 

retain the proposed definition of child 

as a person younger than 18 years old. 

Comment: Some comments found 

unclear the provisions in proposed 

subpart D allowing the waiver, under 

narrow conditions, of the requirements 

for permission of parents and assent of 

children to participate in observational 

research conducted or supported by 

EPA. Other comments objected to these 

proposed provisions asserting that 

children should never become subjects 


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in research without their parent’s 

permission and without their own 

assent. Still other commenters asserted 

that the rule should not allow parents to 

permit their children’s participation in 

human research unless the children will 

benefit directly from doing so. 

Response: EPA’s final rule has 

retained the proposed rule text, with 

only minor changes. EPA believes that 

these provisions give the Agency 

needed flexibility to protect the interests 

of the child when either the child or the 

parent(s) cannot. For example, the 

proposal would allow waiver of assent 

when the child is too young or 

otherwise unable to make responsible 

choices, and where the child’s refusal to 

assent would cause his or her exclusion 

from research that provides a direct 

benefit. The proposal also allows waiver 

of parental permission from a parent 

who abuses or neglects their children; 

clearly such parents do not have 

adequate concern for the child’s welfare 

to make decisions about whether the 

child should participate in research. 

(This provision strengthening the 

protections for children was widely 

misinterpreted as indicating EPA’s 

intention to authorize or conduct 

research involving intentional exposure 

of mentally retarded, abused, and 

neglected children.) 

To clarify the operation of the 

provision allowing waiver of parental 

permission, EPA has modified the text 

to make clear that any alternative 

procedure must be ‘‘equivalent’’ to the 

process of parental permission. By 

‘‘equivalent’’ EPA means that the child’s 

participation must be approved by an 

adult who by position or relationship 

puts the child’s well being foremost and 

who will exercise sufficient diligence to 

make a considered and informed 

decision. Otherwise, EPA has decided 

not to accept the changes recommended 

by the commenters. EPA relies on the 

facts that the concepts in this provision 

comport with the generally accepted 

legal principles defining the scope of 

parental authority and that HHS has 

operated successfully under these 

provisions for over 20 years. Finally, as 

noted above, EPA sees considerable 

benefit from using an approach 

consistent with that of HHS. 

C. The Final Rule 

Subpart C of the Agency’s final rule 

retains most of the rule text appearing 

in proposed subpart B. The most 

significant changes from the proposal 

are the isolation in subparts B and L of 

the prohibition of new research 

proposed at § 26.220, and removal to 

subpart Q of the restriction on EPA 

reliance on completed research 

proposed at § 26.221. To make the 

applicability of the remaining 

provisions of subpart C as clear as 

possible, EPA has revised the titles of 

the subpart and of § 26.301, and 

reworded the text to emphasize 

repeatedly that these provisions apply 

only to observational research, and only 

to research conducted or supported by 

EPA. In the final rule observational 

research is defined in § 26.302 as 

research that does not involve 

intentional exposure of research 

subjects. In addition, EPA has deleted 

from the final rule proposed § 26.205 

(which referenced 45 CFR 46.205) 

because its provisions would never 

apply to the kinds of observational 

research that this subpart permits. 

Subpart D of the Agency’s final rule 

retains most of the rule text appearing 

in proposed subpart D. The most 

significant change from the proposal is 

the isolation in subparts B and L of the 

prohibition of new research proposed at 

§ 26.420, and the removal to subpart Q 

of the restriction on EPA reliance on 

completed research proposed at 

§ 26.421. To make the applicability of 

the remaining provisions of subpart D as 

clear as possible, EPA has revised the 

titles of the subpart and some of its 

sections, and reworded the text to 

emphasize repeatedly that these 

provisions apply only to observational 

research, not involving any intentional 

exposure to any substance, and only to 

research conducted or supported by 

EPA. 

In addition, EPA has made the 

following revisions in subpart D to the 

proposed rule text: 

• In § 26.401(a)(2), EPA clarified that 

the authority to waive requirements 

related only to the sections of subpart D 

and did not confer broad authority on 

the Agency to waive any requirement in 

any other subpart. 

• In § 26.402(a) and (f), EPA added 

definitions of Administrator and 

observational research. 

• In § 26.403, the text from 45 CFR 

46.403 of the HHS regulation is 

incorporated explicitly, rather than by 

reference as was done in the proposal. 

• In § 26.405, EPA reordered the text 

to make its applicability clearer. The 

revision was not intended to make a 

substantive change. 

• In § 26.406(c), EPA has revised the 

text to clarify that if an IRB determines 

that it is not appropriate to require the 

permission of the parent or guardian for 

a child to participate in a study, the IRB 

must approve an equivalent, alternative 

procedure for obtaining permission from 

another adult who will appropriately 

represent the interests of the child. 

IX. Additional Protections Pertaining to 

Research Involving Prisoners Involved 

as Subjects 

Summary: Research with prisoners 

conducted or supported by EPA is 

subject to basic ethical requirements in 

the Common Rule; the parallel 

requirements in subpart K of the final 

rule apply to the conduct of research by 

third parties involving intentional 

dosing of prisoners, if the research is 

intended to be submitted under the 

pesticide laws. The Agency has not 

reached a final position on either the 

need or the most appropriate form for 

any additional protections for prisoners 

beyond these basic requirements. The 

Agency may, in a future action, issue a 

final rule to address the aspects of its 

September 12, 2005, proposal that relate 

to establishing standards for the ethical 

protections of imprisoned subjects of 

research. Unit IX.A. summarizes EPA’s 

proposal and Unit IX.B. explains EPA’s 

decision not to adopt additional 

protections for prisoners in this final 

rule. 

A. The Proposed Rule 

In its September 12, 2005, proposal, 

EPA noted that HHS has promulgated 

regulations that provide additional 

protections for prisoners in research 

conducted or supported by HHS, 

codified at 45 CFR part 46, subpart C. 

The proposal explained that EPA had 

decided not to propose adoption of the 

HHS subpart C rules for a number of 

reasons, among them that HHS and its 

advisory committee, the Secretary’s 

Advisory Committee on Human 

Research Protections (SACHRP), were 

actively considering revisions to the 

HHS subpart C, unchanged since its 

adoption in 1978. 

In addition, the proposal noted that 

EPA has never conducted or supported 

any human studies with prisoner 

subjects, and has no intention to do so 

in the future. It also noted that some 

third-party research with prisoner 

subjects was submitted to the Agency 

some 30 or more years ago; since HHS 

adopted subpart C, this type of research 

has essentially disappeared, and none 

has been submitted to EPA for many 

years. Finally, the proposal noted if 

either EPA or third parties should 

consider performing studies with 

prisoner subjects, such research would 

be subject to the requirements of the 

Common Rule and EPA’s final rule. 

B. The Final Rule 

All provisions of the Common Rule 

would apply to any EPA research with 

imprisoned subjects. In particular, any 

such research would be subject to the 


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Common Rule requirements for IRB 

review and approval and written 

informed consent. Sections 26.111(a)(3) 

and 26.111(b) require an IRB to 

determine that selection of research 

subjects is equitable and free from 

coercion or undue influence, and note 

that particular attention to these aspects 

of subject selection is needed when 

prisoners are involved. Implicit in other 

sections, e.g., §§ 26.102(i), 26.116, and 

26.117, is the concept that research 

must treat each subject involved 

ethically, taking into account their 

particular circumstances. 

In addition, the prohibitions in 

subpart B and the additional protections 

in subparts C and D would also apply 

to imprisoned pregnant women or 

children under the age of 18 years if 

EPA were to conduct observational 

research with subjects from those 

populations. 

EPA does not expect third parties to 

submit to EPA any new studies on 

prisoners. In the unlikely event that a 

third party wished to conduct or 

sponsor research involving intentional 

exposure of prisoners for submission 

under the pesticide laws, it would be 

covered under subparts K and L. Unless 

prohibited by subpart L, such research 

would have to meet the requirements of 

subpart K, which parallel the provisions 

of the Common Rule. In addition, an 

investigator would also be required to 

submit for EPA and HSRB review a 

proposal describing in detail how the 

study would be carried out in an ethical 

manner. Should such a study proposal 

involve prisoners, it would receive 

extremely close review, and EPA almost 

certainly would not approve it, absent a 

compelling justification. 

The Agency has concluded that the 

requirements of this final rule should 

provide adequate protections for 

prisoners, especially since there are not 

likely to be any such studies. 

Nonetheless, the Agency is still 

considering the recommendation from 

public comments to prohibit both EPA 

and third-parties to conduct certain 

types of research with prisoners. EPA 

may, at a later date, adopt such a 

provision, if it determines that such a 

measure is needed and cannot be 

effectuated under existing regulations. 

In addition, EPA will continue to 

monitor the work of the SACHRP 

committee on prisoner protections, and 

will reconsider adopting additional 

protections for prisoners as subjects of 

research when its recommendations are 

known. 

X. Subpart M—Requirements for 

Submission of Information on the 

Ethical Conduct of Completed Human 

Research 

Summary: Subpart M of the final rule 

requires third parties who submit the 

results of completed human research to 

EPA for consideration under the 

pesticide laws to document the ethical 

conduct of that research. Subpart M 

specifies the range of information 

required, including documentation of 

any IRB reviews, documentation of 

informed consent by subjects, and other 

information required to support thirdparty proposals to conduct new human 

research for pesticides involving 

intentional exposure of non-pregnant 

adults. The final rule directs submitters 

to provide this information about 

completed research to the extent it is 

available, and if any of it is not 

available, to describe the efforts made to 

obtain it. Unit X.A. describes the 

proposed rule, Unit X.B. addresses the 

major public comments, and Unit X.C. 

discusses the final rule. 

A. The Proposed Rule 

In the September 12 proposal, 

§ 26.124(c) required ‘‘any person who 

submits to EPA data derived from 

human research covered by this 

subpart’’ to provide information 

documenting compliance with the 

requirements of the subpart. The 

required information included records 

required of the IRBs that approved the 

research; copies of sample informed 

consent documents; and copies of 

correspondence between EPA and the 

investigator or sponsor about the 

proposed protocol. 

In addition, although the proposal 

contained no provision directed at data 

submitters requiring documentation of 

ethical conduct of completed research, 

the proposal indicated that EPA would 

not rely on the results of research 

conducted after the effective date of the 

final rule unless the Agency had 

‘‘adequate information to determine the 

research was conducted in a manner 

that substantially complied’’ with the 

requirements of the rule. 

B. Public Comments 

EPA received no major public 

comments on the proposed provisions 

addressing the content of reports of 

completed human research. 

C. The Final Rule 

EPA has created a new subpart M that 

requires people who submit data from 

completed human research to EPA to 

accompany that submission with 

information documenting the ethical 

conduct of the research. The final rule 

requires that reports on completed 

human research contain essentially the 

same range of information concerning 

the ethical conduct of the research as 

would have been required by the 

proposal. 

The final rule, however, differs from 

the proposal in several respects. First, 

the final rule clarifies that it applies 

only to reports of completed human 

research submitted after the effective 

date of the final rule. 

Second, EPA has broadened the scope 

of the proposed requirement to apply to 

reports on all types of human research 

submitted to the Agency for 

consideration under the pesticide laws, 

FIFRA and FFDCA. This provision of 

the final rule is broader than the 

proposal in two ways: It applies to all 

persons who submit data, whether or 

not they developed the data with the 

intent to provide it to EPA; and it 

applies to all types of human research, 

not only to research involving 

intentional exposure of human subjects. 

The Agency decided to extend the scope 

of this reporting requirement because it 

expects to make ethical assessments of 

all human research it receives under the 

pesticide laws, irrespective of who did 

it, who submitted it, or what type of 

human research was involved. 

Obtaining the information specified by 

subpart M as part of the initial 

submission will improve the efficiency 

and quality of such ethical assessments. 

Under FIFRA sections 3(c)(2)(A) and 

3(c)(2)(B), EPA has the authority to 

require information necessary to 

support both applications for new 

registration and for continued 

registration of a pesticide. Since the 

Agency regards information about the 

ethical conduct of human research as 

relevant to the assessment of the 

acceptability of such research, the 

Agency concludes that the reporting 

provision is consistent with these 

sections of FIFRA. 

Finally, the Agency made two 

changes to minimize the burden of 

reporting information on the ethical 

conduct of completed research. First, 

the final rule provides that information 

need not be resubmitted if it has 

previously been provided to the Agency, 

for example as part of the submission 

required for protocol review under 

§ 26.1125. Second, recognizing that not 

all of the information specified by 

subpart M may be available to the data 

submitter in some cases—for example, if 

the research were conducted in the past, 

or if the submitter did not conduct the 

study, § 26.1303 states that the specified 

information should be provided ‘‘to the 

extent available’’ and asks the submitter 

to describe the efforts made to obtain 


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information which he or she was unable 

to provide. 

XI. Subpart O—Administrative Actions 

for Noncompliance 

Summary: Subpart O contains 

provisions, adapted from similar 

regulations issued by FDA, that describe 

the range of administrative actions EPA 

could take to address noncompliance by 

third parties with the requirements of 

part 26. These actions include: 

Withdrawal or suspension of a research 

institution’s Federal wide assurance; 

disqualification of an institution or an 

IRB; debarment; and public censure. 

This subpart describes procedures EPA 

would follow in reaching a decision to 

take any of these administrative actions. 

Other than the addition of a new section 

explaining the scope of research to 

which these actions could be applied, 

the final rule is unchanged from the 

proposal. 

A. The Proposed Rule 

In proposed subpart E the Agency 

identified a number of specific 

administrative actions that could be 

taken, as circumstances warrant, against 

any person or organization that failed to 

comply with requirements of the rule. 

These actions included: (1) Withdrawal 

or suspension of a research institution’s 

FWA; (2) disqualification of a research 

institution or its IRB; (3) debarment of 

an entity from receiving federal funds 

for research; or (4) public censure—

presenting for public review an 

objective analysis of the ethical 

deficiencies of any human research 

relied upon by EPA for regulatory 

decision-making under any statutory 

authority. The provisions in proposed 

§§ 26.501 through 26.504 and § 26.506 

closely follow FDA’s existing 

regulations in 21 CFR 56.120 through 

56.124. 

B. Public Comment 

EPA received only a few public 

comments on this subpart, most 

supporting the appropriate use of the 

actions identified in proposed subpart E 

to promote compliance. EPA also agreed 

with several commenters that refusal to 

rely on completed research provided the 

strongest incentives for investigators to 

follow the new requirements. Other 

major comments, discussed below, 

addressed the operation of EPA’s 

compliance oversight program. 

Comment: One comment complained 

that the proposal gives EPA discretion 

not to impose any of these sanctions at 

all, even for the most egregiously 

unethical research, and argued that only 

mandatory sanctions could effectively 

deter unethical human research. 

Another commenter recommended that 

EPA explain what types of actions it 

would apply to different types of 

violations. 

Response: EPA generally believes that 

enforcement programs work best when 

they employ a system of graduated 

penalties that increase as the gravity of 

the violation increases. Such an 

approach requires the exercise of 

discretion, but that discretion should 

not operate entirely free from 

constraints. Accordingly, the Agency 

intends to establish policies to guide its 

exercise of discretion about the 

imposition of the sanctions. Although 

EPA does not regard such policies or 

penalty structure as appropriate for 

inclusion in this rulemaking, the 

Agency does intend to explain in 

guidance how it will encourage 

compliance with the new requirements 

in the final rule. 

Comment: Several comments urged 

EPA to adopt procedures similar to 

those of FDA by which it would decide 

whether to disqualify an institution for 

violating the requirement of the final 

rule. 

Response: EPA agrees it should have 

a procedure for deciding whether to 

disqualify an IRB or institution, and that 

it may be appropriate to establish such 

procedures through rulemaking. EPA 

will further consider adopting 

procedures similar to those used by 

FDA and promulgated in 21 CFR part 

16, but has decided not to adopt them 

at this time. 

C. The Final Rule 

Subpart O of the final rule is 

substantively unchanged from subpart E 

of the proposal. EPA has added a new 

§ 26.1501 entitled ‘‘To what does this 

subpart apply?’’ which clarifies that 

EPA will consider using the 

administrative actions identified in the 

subpart only to address instances of 

non-compliance with the requirements 

of the new rule occurring after the new 

rule takes effect. Thus, actions debarring 

an institution from receiving federal 

funds for research or disqualifying an 

institution from performing research 

covered by subpart K could not be taken 

on the basis of events that happened 

before the final rule becomes effective. 

The Agency notes, however, that actions 

which violate the requirements of 

FIFRA section 12(a)(2)(P) would be 

subject to civil or criminal penalties if 

they happened at any time after that 

provision became law in 1972. The 

Agency also made minor wording 

changes in § 26.1502 of the final rule to 

reflect FIFRA terminology and 

enforcement practices. 

EPA recognizes the importance of an 

effective program to ensure compliance 

with the requirements of the final rule. 

The office of the Agency’s Human 

Subjects Research Review Official 

(HSRRO) will have responsibility for 

ensuring compliance with the new rule. 

The HSRRO will also have 

responsibility for managing the 

development of any new guidelines 

needed to explain or implement the 

provisions of the final rule. 

The Agency thinks that one of the 

most important ways to encourage and 

monitor compliance is through the 

review of proposals for new research 

before it is conducted, as required by 

the final rule at § 26.1125. Once such 

studies are initiated, EPA’s Office of 

Enforcement and Compliance 

Assurance, through its laboratory audit 

program, can monitor facilities that 

conduct human research covered by the 

rule. 

EPA inspectors conduct inspections 

and audit studies under EPA’s good 

laboratory practice (GLP) regulations. As 

stated in the GLP regulations (40 CFR 

160.15), EPA will not consider reliable 

for purposes of supporting an 

application for a research or marketing 

permit any data developed by a testing 

facility or sponsor that refuses to permit 

such inspection. In addition, the 

recordkeeping provisions of FIFRA 

which cover records of any tests 

conducted on human beings and records 

containing research data relating to 

registered pesticides including all test 

reports submitted to the Agency in 

support of registration or in support of 

a tolerance petition also apply to studies 

conducted under this rule. 

Finally, the close examination of 

reports on completed research 

represents another important part of the 

compliance program. EPA will train 

scientists who conduct, approve, or 

review human research about the 

provisions of the final rule so they can 

identify possible violations. Throughout 

all of these efforts, the Agency hopes to 

work with the HHS Office for Human 

Research Protections and FDA, to 

ensure that sponsors, investigators, and 

IRBs understand and fulfill their 

responsibilities under the final rule. 

XII. Subpart P—Review of Proposed 

and Completed Human Studies 

Summary: This subpart of the final 

rule provides that EPA will review all 

proposals by third parties to conduct 

research covered by subpart K, i.e., all 

research involving the intentional 

exposure of human subjects, if the 

research is intended for submission to 

EPA under the pesticide laws. The 

subpart also requires EPA to establish 


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an independent group of experts, 

referred to as the Human Studies 

Review Board (HSRB), to assist EPA in 

evaluating such proposals. In addition, 

the subpart requires that EPA review 

reports submitted by third parties on 

completed human research and, if EPA 

decides to rely on information from 

such research in an action under the 

pesticide laws, to submit the results of 

its assessment of the research to the 

HSRB. The HSRB would perform 

science and ethics reviews of proposals 

from third parties to conduct specified 

types of human research and of the 

results of specified types of human 

research if EPA intended to rely on the 

information in its decision-making 

under the pesticide laws. Further, when 

HSRB review is not required by the final 

rule, EPA would nonetheless retain 

discretion to ask the HSRB to review 

studies or to offer advice on other 

issues. 

Finally, although not required by the 

final rule, EPA has decided to establish 

the HSRB under the authority of the 

Federal Advisory Committee Act. By 

operating as a federal advisory 

committee, the HSRB will be required to 

use procedures that ensure transparency 

in its operation and that afford 

opportunities for the public to express 

their views on issues being considered 

by the HSRB. 

A. The Proposed Rule 

Proposed § 26.124 would have 

required third parties to submit to EPA 

detailed information concerning any 

proposed new research covered by the 

new rule at least 90 days before 

initiating of the research. The proposal 

would also have established a HSRB to 

address in an integrated fashion the 

scientific and ethical issues raised by 

human research covered by the 

proposal. Specifically, the Agency 

proposed to convene a small group of 

appropriately qualified experts and to 

enlist their support in reviewing 

covered research proposals, i.e., thirdparty research involving intentional 

exposure of human subjects, when the 

results of such research are intended to 

be submitted to EPA under the pesticide 

laws. 

The same section also provided that 

EPA would review the results of 

completed research covered by the rule. 

This section of the proposal also stated 

that, after completing its initial staff 

assessment of a research proposal or a 

completed study if EPA intended to rely 

on the results in its decision-making 

under the pesticide laws, the Agency 

would send its review and supporting 

materials concerning the study to the 

HSRB for further review and comment. 

EPA’s proposal did not specify any 

details of how the HSRB would 

function, other than to state that the 

members would not be EPA employees, 

would meet the conflict of interest 

standards applying to special 

government employees, and would have 

expertise appropriate for the review of 

human research. The Agency invited 

public comment on whether the final 

rule should specify the functions of the 

HSRB. The preamble also indicated that, 

as recommended by the NAS, EPA 

intended to reexamine the functions of 

the HSRB after 5 years. 

B. Public Comment 

EPA received a great many public 

comments on its proposal to require 

submission of proposed protocols and 

other information relating to proposed 

new human research and to submit its 

assessments of the proposed new 

human research to a new HSRB for 

further review. The Agency’s Response 

to Comments document, in the docket 

for this action, provides a full response 

to these comments. EPA agrees with 

comments that stressed the importance 

of having the HSRB use the substantive 

standards contained in EPA’s final rule 

when reviewing the ethics of proposed 

and completed human research. As an 

entity intended to help the Agency 

make ethical and scientific judgments, 

the HSRB will use the provisions of this 

final rule in the formulation of their 

advice. The major issues raised by the 

comments are discussed below under 

three headings: HSRB procedures; HSRB 

membership and qualifications; and the 

scope of research subject to HSRB 

review. 

1. HSRB procedures. The Agency 

notes that most, if not all, comments on 

the HSRB implicitly accepted EPA’s 

proposal that HSRB review of proposed 

new research would occur following its 

review and approval by a local IRB and 

after EPA developed its review. 

Comment: Many comments addressed 

whether EPA should charter the HSRB 

under the Federal Advisory Committee 

Act (FACA). Environmental and public 

health advocacy groups favored this 

approach because it would assure the 

use of procedures that provided 

opportunities for public comment and 

transparency. Others, primarily 

commenters affiliated with the pesticide 

industry, objected on the grounds that a 

FACA-chartered HSRB would be 

inefficient, and the ensuing delays 

would affect Agency decision-making, 

particularly about new products. These 

comments recommended either staffing 

the HSRB only with EPA employees or 

relying on the HHS Office for Human 

Research Protections (OHRP) for the 

kinds of reviews described in the 

proposed rule. Industry commenters 

also expressed concern that a FACA 

process might lead to public disclosure 

of CBI. 

Response: EPA has decided to charter 

the HSRB under FACA. While operating 

under the requirements for advisory 

committees adds some procedural steps 

to the review process, it is not apparent, 

given the intensity of public concern 

about the use of data from human 

research, that a FACA process would 

necessarily take longer than a process 

involving internal EPA review. More 

important, in EPA’s view, the benefits of 

the transparency and opportunities for 

public participation outweigh any 

potential delays. Given the difficult 

nature of the issues, EPA sees 

significant advantages in ensuring that 

all the considerations influencing the 

Agency’s final position have been 

publicly identified, carefully weighed, 

and commented on by independent 

experts. 

The Agency recognizes the need to 

manage aggressively to ensure both the 

HSRB’s and its own review processes 

operate efficiently. As part of its 

commitment to effective management, 

the Agency intends to acknowledge 

receipt of new research proposals and to 

respond promptly with a projected 

timeline for completing EPA and HSRB 

review. In addition, upon completion of 

its internal reviews, EPA will send 

copies to the submitter of the protocol 

and the schedule for HSRB review. EPA 

expects that it will continue to meet the 

statutory deadlines for reaching 

decisions on new applications for 

pesticide registrations, even if HSRB 

review is required. 

Finally, the Agency notes that under 

FIFRA and FACA, EPA follows 

procedures designed to protect CBI from 

disclosure. Whenever EPA provides CBI 

to a federal advisory committee, that 

information is not placed in a public 

docket or discussed in a public meeting, 

and special steps are taken to maintain 

its confidentiality. 

Comment: Many comments asked 

EPA to clarify in the final rule the 

procedures that the HSRB would use. In 

particular, many suggested that the rule 

require that the HSRB meetings afford 

an opportunity for public comment. 

Response: The Agency believes that, 

at this early stage, the HSRB should 

have the flexibility to adopt procedures 

which best allow it to meet its 

responsibilities. Since the HSRB will 

function as a federal advisory 

committee, FACA will dictate many of 

its procedures, including key 

procedures relating to transparency and 

public participation. Since these were 


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the areas of greatest concern for most 

commenters, EPA believes that its 

decision to establish the HSRB under 

FACA adequately addresses these 

comments. 

Comment: Some comments 

complained that the proposed rule did 

not vest the HSRB with authority to 

disapprove proposed new research or 

EPA decisions to rely on the results of 

completed human studies. Other 

comments supported giving the HSRB 

only an advisory role. 

Response: EPA believes the HSRB 

should have an advisory role. The 

decision to disapprove proposed new 

research or to decide whether or not to 

rely on the results of completed studies 

is inherently governmental. The Agency 

cannot legally confer authority to make 

such decisions on an advisory 

committee. The Agency notes, however, 

that it expects to give considerable 

weight to the advice of the HSRB. 

2. HSRB membership and 

qualifications. 

Comment: Many comments 

emphasized that the HSRB must be 

independent, that its members must 

have no conflicts of interest, including 

any financial relationships with the 

pesticide industry. 

Response: EPA agrees. Chartering the 

HSRB as a federal advisory committee to 

provide expert advice means that all 

candidates for membership on the HSRB 

must meet the federal requirements 

governing conflicts of interest. Although 

other requirements relating to the 

operation of the HSRB as an advisory 

committee are not specified in the final 

rule, EPA did retain in the final rule a 

requirement that members have no 

conflicts of interest. Specifically, the 

final rule provides that HSRB members 

must ‘‘meet the ethics and other 

requirements for special government 

employees.’’ See § 26.1603(a) of the 

regulatory text. 

Comment: Several comments stressed 

the importance of having HSRB 

members with sufficient expertise in the 

substantive disciplines raised by the 

types of human research covered under 

the rule. They specifically identified the 

disciplines of clinical toxicology, 

research ethics and the Common Rule, 

and public health. Comments also noted 

that the Agency might need to 

supplement the HSRB to obtain 

expertise to address particular types of 

research covered by the rule. 

Response: EPA generally agrees with 

the comment and on January 3, 2006, 

issued a Federal Register Notice 

inviting nominations of experts to serve 

on the HSRB (71 FR 116). The Notice 

described the following areas of 

expertise: Bioethics, human toxicology, 

biostatistics, and human risk 

assessment. Under FACA, EPA has the 

authority to appoint consultants to the 

HSRB who can provide additional 

expertise when needed. 

Comment: Several comments 

recommended that the members of the 

HSRB include non-scientists who are 

members of the community and who 

could represent the views of special 

populations that could be the focus of 

proposed human research. 

Response: EPA does not believe that 

it is necessary to include non-expert 

community members on the HSRB. 

However, under FACA, the public, 

including non-expert community 

representatives have opportunities to 

provide both written and oral public 

comment to the HSRB. In addition, the 

HSRB has the flexibility under FACA to 

ask representatives of community 

groups to make presentations to the 

committee on specific topics. EPA also 

notes that, before a proposal reaches the 

HSRB, an IRB will have reviewed and 

approved it. Such IRBs are required by 

the new rules (§ 26.1107), to include 

people familiar with the concerns 

arising in research with special 

populations. Thus, EPA expects in most 

cases that the concerns of communitybased representatives will be a part of 

the information before the HSRB. 

3. Scope of research subject to HSRB 

review. 

Comment: Some comments favored 

expanding the scope of studies reviewed 

by the HSRB to include all first-party 

and second-party research, as well as 

third-party research; all types of human 

research, not only research involving 

intentional exposure of human subjects; 

studies performed with any substance 

regulated by EPA, not only studies with 

pesticides; and all human research 

considered by EPA, not only the 

completed studies on which EPA 

intends to rely. 

Response: EPA agrees that it may 

sometimes be appropriate to obtain 

HSRB review of some of these types of 

studies. The final rule gives EPA 

discretion to seek the advice of the 

HSRB on additional types of studies 

beyond those for which HSRB review is 

required. For the reasons explained 

earlier, however, the Agency has 

decided not to expand the scope of 

subpart K now, and therefore sees no 

reason to expand the scope of required 

EPA or HSRB review of proposed new 

research. Similarly, the Agency has 

decided not to extend without further 

analysis and public discussion the 

ethical framework in subpart Q to 

decisions made under statutory 

authorities other than FIFRA or FFDCA. 

It would make no sense to require the 

HSRB to review human research that 

fell outside the scope of the other 

substantive provisions of the rule. 

Finally, EPA has decided that it would 

not be an efficient use of resources to 

require HSRB review of human research 

that the Agency had decided not to rely 

on, typically because it falls short of 

contemporary standards of scientific 

validity. The Agency does not anticipate 

that the HSRB would often disagree 

with such conclusions, and therefore 

EPA will use its discretion to determine 

whether such scientific judgments 

warrant HSRB review. 

Comment: Many comments generally 

supported the proposed review of new 

research and completed research reports 

by both EPA staff and the HSRB, at least 

in some cases. A number of 

commenters, however, suggested ways 

to narrow the scope of the reviews 

performed by the HSRB, including: (1) 

By having the HSRB review only studies 

intended to identify or measure toxic 

effects, (2) by exempting from HSRB 

review consumer acceptance studies, 

insect repellent efficacy tests, or other 

‘‘product-in-use’’ studies; (3) by 

exempting from HSRB review proposals 

to employ protocols for ‘‘routine’’

exposures or other studies that follow 

established EPA guidelines; and (4) by 

exempting from HSRB review the 

results of research which the HSRB had 

previously reviewed and approved as a 

proposal, unless the investigator failed 

to follow the approved protocol. Finally, 

some comments recommended that the 

HSRB be restricted to considering 

ethical issues, but not scientific issues. 

Response: EPA disagrees with the 

comments suggesting a narrowed scope 

for HSRB review. EPA agrees that each 

of the categories described above may 

contain at least some studies that 

present no difficult scientific or ethical 

issues. To the extent EPA’s review 

indicates that a study presents no 

difficult science or ethics issues, the 

Agency would expect the HSRB to agree 

and quickly conclude its review. But 

any research involving intentional 

exposure may present risks to 

individual human subjects greater than 

those they would receive in their 

normal activities, and therefore warrants 

careful examination, even if the purpose 

of the study is not to identify or measure 

toxic effects. Similarly, while EPA 

anticipates that many consumer 

acceptance tests, insect repellent 

efficacy tests, and other ‘‘product-inuse’’ studies will raise no difficult 

scientific or ethical issues, the Agency 

has relatively little experience with 

assessing explicitly the ethical attributes 

of such research. Therefore the Agency 

thinks it would be imprudent to exclude 


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HSRB review of these studies. EPA 

likewise recognizes that following 

established guidelines may reduce the 

chances of scientific deficiencies in a 

study, but EPA’s guidelines do not 

address the full range of potential 

ethical issues that should be considered 

on a case-by-case basis. Finally, EPA 

believes that even if a study follows an 

established protocol, unanticipated 

scientific and ethical issues may arise 

that will warrant expert advice. 

C. The Final Rule 

As a result of the reorganization of the 

final rule, all provisions relating to EPA 

and HSRB review of proposals for new, 

third-party research or reports of 

completed studies, or to the 

establishment of the HSRB, now appear 

in subpart P. 

The final rule reflects one significant 

change from the proposal. Under the 

final rule, the HSRB will review all 

research involving intentional exposure 

conducted after the effective date of the 

final rule, as well as all research 

involving intentional exposure 

performed before the rule takes effect, if 

the purpose of the research was to 

identify or measure a toxic effect. But 

the final rule grants to the Agency 

discretion to decide whether studies 

performed before the effective date of 

the final rule that do not measure 

toxicity should undergo HSRB review. 

After publishing the proposal, EPA 

examined how the proposal would 

affect its plans to complete tolerance 

reassessment by August 2006, as 

required by the 1996 FQPA 

amendments to FFDCA. The Agency 

reviewed the existing toxicity and 

exposure databases for upcoming 

tolerance reassessment decisions and 

determined that as many as several 

hundred studies relevant to the risk 

assessments for these actions appeared 

to meet the definition of ‘‘research 

involving intentional exposure of 

human subjects.’’ Only a relative few of 

these intentional exposure studies 

measure the toxicity of a pesticide; the 

great majority of them measure the 

levels of potential human exposure 

resulting from pesticide use, the efficacy 

of insect repellents, or the absorption, 

distribution, metabolism, and excretion 

of pesticides. 

Since the enactment of the Food 

Quality Protection Act in 1996 EPA has 

relied on many of these non-toxicity, 

intentional-exposure human studies in 

its registration and reregistration 

decisions. Moreover, the Agency has 

afforded multiple opportunities for 

public comment on several hundred 

draft and final Reregistration Eligibility 

Decision (RED) documents and Interim 

RED (IRED) documents, but has never 

received any public comment on a RED 

or IRED concerning the ethics of 

intentional-exposure human studies 

other than a toxicity study. Taking all of 

these non-toxicity, intentional-exposure 

studies to the HSRB would significantly 

increase its workload and expand the 

number of pending regulatory decisions 

affected. Accordingly, EPA has decided 

that while the final rule should require 

the Agency to send to the HSRB all 

completed toxicity studies on which it 

intends to rely, it need not require all 

non-toxicity studies in its existing 

databases to undergo HSRB review. 

Thus, under the final rule, the Agency 

will retain the discretion to submit 

additional types of old studies to the 

HSRB, and will consider public 

comments on its upcoming pesticide 

actions for tolerance reassessment in 

deciding which of the non-toxicity 

studies raise significant ethical or 

scientific issues warranting HSRB 

review. 

In addition, subpart P in the final rule 

reflects a few other minor revisions to 

the proposal. The provisions governing 

Agency review of proposals for new 

third-party research were placed in 

subpart P in preference to subpart K, so 

that subpart P would apply only to EPA, 

and subpart K would apply only to 

regulated third parties. 

To help ensure effective 

implementation of the final rule, EPA 

has made several administrative 

decisions affecting the HSRB. Most 

important, the Agency has decided to 

establish the HSRB as a separately 

chartered advisory committee under the 

Federal Advisory Committees Act 

(FACA). FACA requires the HSRB, as a 

federal advisory committee, to follow 

certain basic procedures designed to 

promote transparency and to ensure 

public participation. These include 

timely public notice of meetings, public 

access to meetings, and opportunity for 

the public to comment; public 

availability of documents considered by 

the HSRB and meeting minutes; and a 

Federal officer or employee attending 

each meeting. Of course, the HSRB will 

be required to protect materials 

designated as confidential from public 

disclosure. Finally, EPA is also 

committing to aggressive management of 

the process to promote efficient use of 

resources and timely decisions, and to 

ensure affected stakeholders have 

complete information about the status of 

ongoing reviews. 

XIII. Subpart Q—Ethical Standards for 

Assessing Whether to Rely on the 

Results of Human Research in EPA 

Regulatory Decisions 

This unit discusses the ethical 

standards EPA will use to guide its 

decisions whether to rely in its actions 

under the pesticide laws on the results 

from completed human research. Unit 

XIII.A. summarizes EPA’s proposal, 

Unit XIII.B. discusses public comment, 

and Unit XIII.C. describes the positions 

taken in the final rule. 

Summary: The final rule is 

substantively unchanged from the 

proposal, although the provisions have 

been revised to make them clearer. One 

new section (§ 26.1701) clarifies the 

applicability of this subpart to EPA 

decisions to rely on relevant, 

scientifically valid ‘‘data from research 

involving intentional exposure of 

human subjects to a pesticide’’ in its 

actions under the pesticide laws, FIFRA 

and FFDCA. A second new section 

(§ 26.1702) provides needed definitions 

of terms. The remaining four sections in 

the final rule together delineate the 

framework within which EPA will 

decide whether to rely on the results of 

certain types of human research. 

This framework rests on the basic 

principle that EPA will not rely in its 

actions on data derived from unethical 

research. Section 26.1703 forbids EPA to 

rely on data from any study involving 

intentional exposure of pregnant 

women, fetuses, or children. Section 

26.1704 forbids EPA to rely on data 

from ‘‘old’’ research—i.e., covered 

studies initiated before the effective date 

of the final rule—concluded to be 

fundamentally unethical or significantly 

deficient with respect to the ethical 

standards prevailing when it was 

conducted. Section 26.1705 forbids EPA 

to rely on data from any ‘‘new’’

research—i.e., research initiated after 

the effective date of the final rule—

unless EPA finds that the research 

complied with the new requirements. 

Finally, § 26.1706 creates a very narrow 

exception to the Agency’s general 

refusal to rely on unethical data, one 

that allows reliance on unethical data 

when it is crucial to supporting more 

stringent regulatory measures to protect 

public health. 

A. The Proposed Rule 

In proposed subpart F of 40 CFR part 

26, EPA set out ethical standards for its 

decisions to rely on or not to rely in its 

regulatory decisions under FIFRA or 

FFDCA on reports of completed 

intentional-dosing research with human 

subjects. For covered research initiated 

after the effective date of the rule, EPA 


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proposed to refuse to rely on data from 

scientifically sound and relevant human 

research unless EPA had adequate 

information demonstrating that the 

research complied with the Common 

Rule. For covered research initiated 

before the effective date of the rule, EPA 

proposed to rely on data from 

scientifically sound and relevant human 

research unless there was clear evidence 

to show the conduct of the research was 

fundamentally unethical or was 

significantly deficient relative to the 

ethical standards prevailing when it was 

conducted. EPA also proposed a formal 

exception to these standards when to 

rely on scientifically sound but ethically 

deficient research would give crucial 

support to a regulatory action more 

protective of public health than could 

be justified without relying on the 

ethically deficient research. 

B. Public Comments 

EPA received many public comments 

on proposed subpart F. The major issues 

raised by the comments are grouped and 

summarized below under these four 

headings: 

• Comments advocating a broader or 

narrower scope for this subpart—a 

change to the kinds of research and the 

range of EPA decisions the framework 

should cover. 

• Comments questioning the 

proposed framework itself, including 

arguments to include standards for 

scientific validity of human research, 

and arguments that EPA should never 

reject scientifically sound data for 

ethical reasons. 

• Comments on the substantive 

ethical standard to be applied to ‘‘old’’

research initiated before this final rule 

takes effect. 

• Comments on the proposed ‘‘public 

health exception’’ to the general refusal 

to rely on unethical research. 

The Agency notes that, although some 

comments favored more specificity in 

EPA’s final rule, many comments 

expressed support for EPA’s proposal to 

rely on the Common Rule as the ethical 

benchmark for judging the acceptability 

of research conducted after the effective 

date of the final rule. 

1. The scope of application of EPA’s 

ethical framework. 

Comment: Some comments advocated 

expanding the application of the ethical 

framework beyond research involving 

intentional exposure of human subjects 

to cover all types of human subjects 

research considered by the Agency, or to 

embrace consideration of human 

subjects research conducted with 

pesticides under EPA statutes other than 

the pesticide laws, or to cover research 

involving intentional exposure of 

human subjects to any environmental 

substance, not only to pesticides. 

Response: The Agency has decided 

not to expand the application of the 

ethical standards in this subpart to 

encompass all types of human subjects 

research relied on by EPA, to research 

involving substances other than 

pesticides, or to actions taken under 

authorities other than the pesticide 

laws. In the future, the Agency will 

consider further actions to address these 

and other issues beyond the scope of 

this final rule. 

The Agency believes an initial focus 

on research involving intentional 

exposure is warranted in that potential 

risks to research subjects are generally 

greater when exposure is intentional 

than in other types of studies. It is 

reasonable to scrutinize such research 

closely to ensure that research subjects 

are fully protected and the research is 

ethical. EPA has not fully considered, 

and public comments have not 

thoughtfully addressed, what protective 

measures would be appropriate for 

research that does not involve 

intentional exposure. Thus, the Agency 

thinks it premature to conclude that all 

of the provisions applying to research 

involving intentional exposure should 

apply more widely. 

EPA thinks there has also been 

inadequate consideration of the 

consequences of expanding the scope of 

the ethical framework to embrace 

research with substances other than 

pesticides. Most of the comments 

favoring expansion of the rule beyond 

pesticides came primarily from 

stakeholders affiliated with the 

pesticide industry, and EPA received 

essentially no meaningful response to 

its requests for comment from other 

stakeholder interests, including those 

likely to be affected by such an 

expansion. Given the mandate of the 

2006 Appropriations Act to address 

research ‘‘for pesticides,’’ the final rule 

retains the proposed focus on human 

research for pesticides. 

Finally, the Agency has decided to 

retain the proposed applicability of the 

framework to actions taken under the 

pesticide laws. Although EPA 

recognizes the theoretical possibility 

that human research with a pesticide 

may be considered under other statutes, 

the Agency notes that the 2006 

Appropriation Act does not require the 

adoption of a broader scope than 

decisions under FIFRA and FFDCA. 

Also, the Agency has not received 

meaningful public comment on whether 

its authorities under other statutes 

permit it to refuse to rely on relevant, 

scientifically sound data which were 

derived from an unethical study. 

Because of the questions about the 

Agency’s legal authorities and the 

absence of a clear mandate, EPA has 

decided not to require the application of 

the ethical framework to actions taken 

under its other laws. 

Comment: Other comments argued for 

restricting the application of the ethical 

framework to only certain kinds of 

human research—to research intended 

to identify or measure toxic effects, to 

research conducted in a laboratory or 

clinical setting, or to exclude research 

involving only exposures that EPA had 

already approved (e.g., studies of 

registered pesticides used in accordance 

with their approved labeling). Two 

general reasons were offered for these 

recommendations: (i) Public controversy 

has focused exclusively on a narrower 

set of studies than those falling within 

the scope of proposed subpart F, and (ii) 

there is so little risk from the types of 

studies suggested for exclusion that no 

additional measures would be needed to 

protect subjects. 

Response: Because EPA finds these 

reasons unpersuasive, the Agency has 

decided to retain, at this time, the scope 

of the proposal for its final rule. Thus, 

EPA is not narrowing the scope of its 

framework in any of the ways 

recommended above. 

Although recent controversy has 

focused on ‘‘intentional dosing, human 

toxicity testing for pesticides’’ (see the 

Appropriations Act discussed in Unit 

XIV.A.), there has also been public 

debate about other kinds of human 

research, including product-in-use 

studies using registered pesticides, 

studies performed outside the laboratory 

setting, and studies which do not 

measure toxicity. To promote public 

confidence in its operations and 

judgments EPA must address this larger 

universe of research. Second, EPA 

thinks that it is important to examine 

the risks of studies involving intentional 

exposure of research subjects—even 

when comparable exposures have 

already been approved for the general 

public under a pesticide registration. 

While the risks experienced by the 

research subjects and the general public 

may not differ, the risks experienced by 

the particular subjects may exceed what 

they would otherwise receive, and 

therefore researchers must provide each 

potential subject a full explanation of 

the potential for any additional risk they 

might assume by volunteering for a 

study. For its part, EPA should ensure 

that, in their interactions with subjects, 

the sponsors and investigators have 

acted ethically. 

2. The adequacy of the ethical 

standards. 


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Comment: Although nearly all 

comments supported EPA’s application 

of an explicit ethical standard in 

deciding whether or not to rely on data 

from completed human research, one 

significant line of comment argued that 

EPA should never refuse to rely on 

relevant, scientifically sound research 

even if it were conducted unethically. 

This conclusion rested on three 

arguments: (i) Rejecting scientifically 

sound data would deprive decisionmakers of information that would serve 

the mission of protecting public health; 

(ii) applying a new standard of ethical 

acceptability retroactively to completed 

research would be unfair; and (iii) 

refusing to rely on data from unethical 

research could do nothing to remedy 

any harm done to the subjects in the 

research. 

Response: While EPA sees some merit 

in each of these arguments, the Agency 

disagrees with the conclusion. EPA 

believes that rejecting unethical data is 

an appropriate and powerful means of 

promoting compliance with ethical 

standards, and that rejecting unethical 

data generally meets public expectations 

about conduct of the government. 

First, EPA agrees that it is important 

to consider all available information in 

carrying out its mission to protect 

public health. This is especially 

important when reliable data show 

humans to be more sensitive than 

animals. Sometimes, however, data from 

human research will show that humans 

are less sensitive—or no more 

sensitive—than animals, and that a less 

restrictive regulatory measure may 

provide adequate protection for public 

health. This is important to know 

because the Agency is interested in costefficient regulations. Finally, human 

research often confirms a risk 

assessment based on animal toxicity 

data. Such confirmation increases 

confidence in the Agency’s decisions. 

Therefore, the Agency agrees that it is 

always important to assess data from 

available human research. 

The Agency also agrees that it is 

generally inappropriate to apply current 

ethical standards to judge the 

acceptability of research completed 

before such standards were articulated. 

Not only could that lead to declaring 

unethical much completed research 

which was considered ethical when it 

was conducted, it would also set a 

standard for ethical conduct—adherence 

to standards not yet articulated—that 

even the most ethically concerned 

investigators and sponsors could never 

meet. To avoid such an outcome EPA 

will generally judge the ethical 

acceptability of research initiated before 

the effective data of this rule in terms of 

the ethical standards prevailing when it 

was performed. 

The Agency also agrees that no 

actions taken after research is completed 

can undo any harm experienced by the 

human subjects in the research. But this 

point ignores the deterrent value of 

government actions that ‘‘punish’’

unacceptable conduct. EPA believes that 

by refusing to rely on unethical data it 

creates a strong incentive for the 

scientific community to conduct future 

research ethically. If investigators and 

sponsors understand that EPA will not 

rely on the results of their research 

unless it is performed ethically, they 

will not wish to risk losing either their 

direct investment in the research or any 

benefit its use might bring to them. 

Finally, EPA believes that the public 

expects its government to apply a clear 

standard of ethical acceptability in 

deciding whether to rely on the results 

of completed research. Such an 

expectation, evident in thousands of 

public comments on the proposed rule, 

provides additional reason for 

establishing an explicit ethical 

framework for making these decisions, 

and for refusing to rely on unethically 

obtained data. (As discussed below, 

EPA believes that in certain very limited 

circumstances the ethical course of 

conduct may require reliance on 

ethically deficient research when to do 

so is crucial to supporting more 

stringent regulatory measures to protect 

public health.) 

Comment: Some comments, noting 

that scientifically unsound research is 

always unethical, argued that the 

proposed framework should articulate 

explicit standards of scientific validity. 

Response: EPA agrees that its ethical 

framework should exclude data which 

are not scientifically sound, and thus 

the final rule clarifies that subpart Q 

applies only to ‘‘scientifically valid and 

relevant data.’’ The Agency has not, 

however, attempted to define a standard 

for scientific validity and relevance, 

because this is necessarily a case-bycase judgment. EPA has long had in 

place policies and procedures to ensure 

rigorous scientific review of research it 

is considering, including procedures for 

formal peer review of research and 

assessments critical to Agency actions. 

In addition, § 26.1603(b) of the final rule 

provides that the HSRB ‘‘shall review 

and comment on the scientific and 

ethical aspects of research proposals 

and reports of completed intentional 

exposure research. . . .’’ Over time the 

results of HSRB review of the scientific 

aspects of both proposed and completed 

human research will support 

articulation of general principles for the 

scientifically sound and ethical conduct 

of different types of human research. 

3. The ethical standard for accepting 

‘‘old’’ research. Opinions about research 

conducted before the final rule varied 

widely, and are summarized below 

under these headings: 

• The proposed standard is too weak; 

the Common Rule should be applied to 

all research, regardless of when it was 

conducted; 

• The rule should define such terms 

as ‘‘standards prevailing when research 

was conducted’’; ‘‘fundamentally 

unethical’’; and ‘‘significantly 

deficient.’’

• Rejection of any research involving 

intentional exposure of pregnant 

women, fetuses, or children is 

inconsistent with ‘‘standards prevailing 

when research was conducted.’’

• The standard of ‘‘clear evidence’’

should be different; 

Comment: Many comments favored 

application of the Common Rule to all 

research, regardless of when it was 

performed. These comments argued that 

the standard in proposed § 26.601 was 

unacceptably weak because it failed to 

reflect contemporary ethical standards. 

Response: EPA believes it would be 

unreasonable to apply to completed 

research ethical standards articulated 

after the research was conducted. Thus, 

the final rule retains the proposed 

standard for judging the acceptability of 

completed ‘‘old’’ research—i.e., research 

initiated before the final rule becomes 

effective. 

First, for many years the prevailing 

ethical standard in the U.S. has been the 

Common Rule, and with respect to 

biomedical research, the earlier DHHS 

rules that form the basis for the 

Common Rule. Consequently, as a 

practical matter, the same standard of 

ethical acceptability—the Common Rule 

or its foreign equivalent—would apply 

to research conducted since its 

promulgation in 1991. 

Thus, reference to ethical standards 

prevailing at the time of the research 

makes a practical difference only when 

considering the acceptability of research 

which meets today’s standards of 

scientific validity but which was 

conducted before today’s ethical 

standards were articulated. Codes of 

ethical research conduct require 

investigators to do certain things in 

certain ways before and during the 

research. It is reasonable to expect 

investigators to follow ethical codes that 

prevail when they do their work; it is 

unreasonable to expect them to 

anticipate and follow standards 

developed after their work is done. EPA 

believes that scientifically meritorious 

research which adhered to accepted 


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ethical norms when it was conducted 

should not be set aside because ethical 

standards have subsequently changed. 

EPA also believes that ethical standards 

are likely to continue to change in the 

future and that if and when they do, 

such a change should not invalidate or 

make unacceptable otherwise 

meritorious research conducted now, in 

conformity with the ethical standards of 

today. 

It is sometimes argued that to accept 

‘‘old’’ research falling short of today’s 

standards would encourage others to 

conduct unethical research in the 

future. EPA disagrees. With respect to 

new research, the principal incentive to 

conduct research ethically is the 

prospect that the Agency might refuse to 

rely on research that doesn’t comply 

with contemporary ethical standards. A 

refusal by EPA to rely on new human 

research would carry serious economic 

consequences for the investigator and 

sponsor. Much third-party research is 

conducted by private, for-profit 

organizations in the hope that the 

results will lead to financial benefits, 

often through changes in government 

regulation. For example, the current 

controversy over pesticide studies 

centers on research conducted by 

pesticide companies who hoped to 

demonstrate through human studies that 

their products were safer than was 

indicated by available animal studies, 

and thus that their market could 

expand—or at least need not shrink—

because of concerns about risk. An 

Agency refusal to rely on data would 

deprive the investigator and sponsor of 

such potential financial benefits. 

Importantly, under § 26.1705 of the final 

rule, the Common Rule’s provisions will 

guide EPA’s decisions about reliance on 

the results of new research, i.e., studies 

conducted after the rule takes effect. 

The fact that EPA may apply a different 

standard to ‘‘old’’ studies is irrelevant. 

An investigator conducting a new, 

covered study after these final rules take 

effect would be very foolish to think 

that the Agency will judge its ethical 

acceptability by any standard other than 

the Common Rule. 

Comment: A number of comments 

called for the rule to specify that certain 

documents—the Nuremberg Code, 

various editions of the Declaration of 

Helsinki, the Belmont Report, and the 

Common Rule, among others—would 

serve as the point of reference in 

identifying the ‘‘standards prevailing at 

the time the research was conducted.’’

Other comments asked that the Agency 

explain and give examples of the types 

of ethical deficiencies that it would 

deem ‘‘fundamentally unethical’’ or 

‘‘significantly deficient’’ in the 

provision codified as § 26.1704 of the 

final rule. 

Response: In recent years, EPA has 

reviewed numerous reports of 

completed research on pesticides 

involving intentional exposure of 

human subjects. These studies have 

been conducted over many years, in 

many places, under a variety of ethical 

policies and regulatory schemes; they 

have addressed a wide range of research 

questions, and they have presented a 

wide spectrum of ethical shortcomings, 

from minor flaws to more serious 

deficiencies. Given these variations, the 

Agency believes that its ethical 

framework must retain sufficient 

flexibility to judge each situation on its 

merits, in the context of the time and 

place the research was conducted. 

While the historical documents cited in 

the comments reflected widely shared 

views about what constitutes ethical 

conduct, they were not necessarily 

universal or comprehensive in their 

coverage. Certainly they are among the 

standards which may have prevailed 

when specific research was conducted, 

and EPA will rely on them when they 

are appropriate to the evaluation of a 

particular study. But it adds nothing to 

list them in the final rule. 

EPA also thinks it unnecessary to 

elaborate on the meaning of the 

narrative standards ‘‘fundamentally 

unethical,’’ ‘‘significantly deficient’’ or 

‘‘substantial compliance.’’ The gravity of 

a particular ethical lapse depends not 

only on the details of the deficiency, but 

also on the circumstances in which it 

occurred. EPA agrees with the NAS that 

each study requires case-by-case 

evaluation. EPA expects these terms to 

acquire greater clarity over time, 

through HSRB and public review of 

Agency decisions concerning reliance 

on completed human research. 

Comment: Some comments objected 

to the proposed prohibition of EPA’s 

reliance in its pesticide decisions on 

data from human subjects research 

involving intentional exposure of 

pregnant women, fetuses, or children. 

These comments argued that if such 

research was not considered unethical 

under the standards prevailing when it 

was conducted EPA should accept and 

consider it, and that exclusion of such 

research could deprive EPA of 

potentially valuable information. 

Response: EPA agrees that existing 

research involving intentional exposure 

of pregnant women, fetuses, or children 

may have been considered ethical 

according to the standards prevailing 

when the studies were conducted. 

Nonetheless, in light of the provisions of 

the 2006 Appropriations Act and the 

thousands of public comments on the 

proposal condemning research of this 

kind, the Agency believes it must 

generally refuse to rely on such 

research. The Agency knows of only a 

very few existing studies involving 

intentional exposure of pregnant women 

or children. If it were determined that 

reliance on any of them were crucial to 

a decision that would impose a more 

stringent regulatory restriction to protect 

public health than could otherwise be 

justified, the exception procedure 

defined in § 26.1706 in the final rule 

could be invoked. 

Comment: Several comments 

recommended revising the evidentiary 

standard for accepting ‘‘old’’ studies. 

Some suggested a change from ‘‘clear 

evidence’’ to a less demanding test, such 

as ‘‘any evidence.’’ Others 

recommended adoption of the exact 

wording of the NAS recommendation on 

which EPA based the proposal, 

changing ‘‘clear evidence’’ to ‘‘clear and 

convincing evidence.’’

Response: It is conceivable that the 

standard requiring ‘‘clear evidence’’

could lead the Agency to accept data 

from research which it suspected but 

could not prove had serious ethical 

flaws. The Agency agrees this would be 

unfortunate, but believes a change to a 

standard of ‘‘any evidence’’ would 

likely lead to even more unfortunate 

outcomes. Because reliable information 

about its conduct is often very limited, 

in many cases it is difficult or 

impossible to prove that older research 

was ethical. An unsupported accusation 

of unethical conduct should thus not in 

itself be sufficient to force rejection of 

completed research. Rejection of 

research on the basis of weak or 

suggestive evidence of unethical 

conduct could deprive the Agency of 

information important to sound 

decisions. Because EPA can see no 

benefit that would flow from changing 

the standard to ‘‘any evidence,’’ EPA is 

not accepting this recommendation. 

On the other hand EPA agrees with 

the comments urging a return to the 

exact wording of the evidentiary test in 

NAS Recommendation 5–7. Since the 

Agency did not intend to alter the 

standard, and since ‘‘clear and 

convincing evidence’’ has an accepted 

meaning under administrative law, EPA 

has changed the final rule to read, in 

pertinent part: 

. . . EPA shall not rely on data from any 

research initiated before April 7, 2006 if there 

is clear and convincing evidence that the 

conduct of that the research was 

fundamentally unethical . . . 

4. The exception allowing use of 

unethical data to justify more stringent 

regulatory restrictions to protect public 

health. 


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Comment: One group of comments 

argued that the Agency should, without 

exception, never rely on data derived 

from unethical research because to do 

otherwise would condone unethical 

research. Many of these commenters 

also misunderstood the proposed 

exception as authorizing the conduct of 

unethical future research. 

Response: Although EPA thinks there 

will rarely, if ever, be situations 

requiring the use of this exception, EPA 

can easily imagine a circumstance in 

which ethical behavior could require 

Agency decision-makers to rely on 

unethical data. (See Unit II.) The 

exception would be used when 

scientifically sound but ethically flawed 

data show that the Agency needs to take 

a more protective action than could be 

justified without considering the human 

research. Invoking the exception would 

allow EPA to protect the health of many 

people—perhaps millions; a greater 

public good than any benefits that 

would flow from refusing to rely on the 

data. In EPA’s moral calculus, the 

greater good should and will guide the 

choice whether to use unacceptable 

data. 

The Agency disagrees with the 

argument that the final rule should 

contain no exceptions to the basic 

principle of refusing to rely on unethical 

research, because an exception would 

encourage the conduct of unethical 

research. A public refusal by EPA to rely 

on unethical data brings shame to the 

investigator who acted unethically, and 

in most cases also directly affects the 

financial interests of the investigator, 

sponsor, or both. Such a refusal serves 

as an important deterrent to other 

investigators, discouraging unethical 

research in the future. 

To further ensure that EPA’s 

exceptional use of ethically flawed data 

does not encourage unethical research 

conduct, § 26.1706 expressly requires 

the Agency to publish ‘‘a full 

explanation of its decision to rely on 

otherwise unacceptable data, including 

a thorough discussion of the ethical 

deficiencies of the study ....’’ In 

addition, the Agency will have recourse 

to any of the other measures identified 

in subpart O to promote compliance 

with standards of ethical research. EPA 

believes the exception as defined in the 

final rule, allowing for EPA 

consideration of unethical research 

under well defined and narrow 

conditions and requiring a full public 

discussion of its ethical deficiencies, 

will not in any way encourage other 

investigators to conduct unethical 

research. 

Comment: Some comments argued for 

a broad interpretation of the concept of 

‘‘protection of public health,’’ such that 

it would not be limited to cases 

involving imposition of more stringent 

regulatory restrictions. Some comments 

suggested, for example, that a more 

accurate assessment of risks to humans 

should be interpreted as ‘‘protection of 

public health.’’ Other comments called 

upon EPA to clarify in the final rule that 

‘‘protection of public health’’ does not 

encompass the ability of American 

agriculture to produce more crops at a 

lower cost. 

Response: EPA does not agree that the 

public health exception should be 

interpreted to permit reliance on 

unethical research to support more 

accurate risk assessments or more 

efficient or lower cost agricultural 

production. EPA’s ethical framework is 

built on the principle that unethical 

research should not be relied on in 

Agency actions except in the most 

extraordinary circumstances; such 

interpretations would amount to 

abandoning this principle altogether, 

and could severely undermine 

incentives for compliance with the new 

requirements. 

The Agency does agree, however, that 

the proposal was unclear with respect to 

what would constitute a ‘‘public health’’

benefit justifying invocation of the 

exception. EPA has thus revised the 

final rule to clarify that invoking the 

public health exception would only 

permit the Agency to ‘‘impose a more 

stringent regulatory restriction that 

would improve protection of public 

health ....’’ See § 26.1706 of the 

regulatory text. 

C. The Final Rule 

Subpart Q of the final rule 

corresponds in substance to subpart F of 

the proposal. In this final rule EPA has 

moved the rule text to a new subpart, 

and has rewritten the proposed 

provisions to express the standards 

more clearly. 

Section 26.1701 of the final rule 

describes the scope of subpart Q; it 

applies to: 

. . . EPA’s decisions whether to rely in its 

actions under the Federal Insecticide, 

Fungicide, and Rodenticide Act (7 U.S.C. 136 

et seq.) or section 408 of the Federal Food, 

Drug, and Cosmetic Act (21 U.S.C. 346a) on 

scientifically valid and relevant data from 

research involving intentional exposure of 

human subjects. 

The Agency has chosen to retain the 

scope of the proposed rule because it 

believes that the 2006 Appropriations 

Act does not require this rule to address 

a broader scope of issues, and because 

there has not been adequate 

consideration of the consequences of 

adopting a more expansive scope. 

Section 26.1703 prohibits EPA’s 

reliance on data from research involving 

intentional exposures of pregnant 

women, fetuses, or children. Derived 

from proposed §§ 26.221 and 26.421, 

this section states: 

Except as provided in § 26.1706, in actions 

within the scope of § 26.1701, EPA shall not 

rely on data from any research involving 

intentional exposure of any human subjects 

who is a pregnant woman (and therefore her 

fetus) or child. 

This provision makes clear that the 

Agency will not rely in its actions on 

the results of research that EPA and 

third parties are prohibited from 

conducting under subparts B and L, 

except under the narrow exception 

provided by § 26.1706. To clarify that 

this prohibition applies to EPA’s nonregulatory actions (such as issuance of 

a risk assessment or a health advisory 

level) as well as to its regulatory 

decisions, EPA has changed the phrase 

‘‘regulatory decision-making’’ in the 

proposal to ‘‘actions’’ in the final rule. 

Section 26.1704 defines the ethical 

standard EPA will use to decide 

whether to rely on the results of 

research conducted with non-pregnant 

adults before the effective date of the 

rule. It provides: 

Except as provided in § 26.1706, in actions 

within the scope of § 26.1701, EPA shall not 

rely on data from any research initiated 

before April 7, 2006, if there is clear and 

convincing evidence that the conduct of the 

research was fundamentally unethical (e.g., 

the research was intended to seriously harm 

participants or failed to obtain informed 

consent), or was significantly deficient 

relative to the ethical standards prevailing at 

the time the research was conducted. This 

prohibition is in addition to the prohibition 

in § 26.1703. 

The above rule text is derived from 

proposed § 26.601, and follows the 

language of the NAS recommendation 

5–7. In response to public comment, the 

evidentiary standard for concluding 

research was unethical has been 

changed from ‘‘clear evidence’’ to ‘‘clear 

and convincing evidence.’’ The Agency 

made this change to minimize 

confusion, to conform to the wording of 

the NAS recommendation, and to use a 

formulation of the evidentiary standard 

that has an accepted legal meaning in 

administrative law. For purposes of 

clarity, the section also reaffirms that 

the prohibition in § 26.1703 against 

relying on research involving pregnant 

women and children is unaffected by 

this provision. 

Section 26.1705 describes the ethical 

standard EPA will use to decide 

whether to rely on the results of human 

subjects research conducted with nonpregnant adults after the effective date 


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of the rule. It provides that the Agency 

will not rely on data from such research: 

Except as provided in § 26.1706, in actions 

within the scope of § 26.1701, EPA shall not 

rely on data from any research initiated after 

April 7, 2006, unless EPA has adequate 

information to determine that the research 

was conducted in substantial compliance 

with subparts A through M of this part, or if 

conducted in a foreign country, under 

procedures at least as protective as those in 

subparts A through L. This prohibition is in 

addition to the prohibition in § 26.1703. 

This rule text is based on proposed 

§ 26.602. It has been revised to make 

clear that EPA may accept and rely on 

data from human research conducted in 

a foreign country if EPA has adequate 

information to determine the research 

was ‘‘conducted . . . under procedures 

at least as protective as those in subparts 

A through L.’’ Allowing the use of 

foreign research provided the research 

meets ethical norms equivalent to those 

of the Common Rule is consistent with 

the Common Rule at § 26.101(h). Like 

§ 26.1704, § 26.1705 reaffirms, for the 

sake of clarity, that the prohibition in 

§ 26.1703 against relying on research 

involving pregnant women and children 

is unaffected by this provision. 

Finally § 26.1706 provides for an 

exception to the general refusal to rely 

on the results of unethical research. 

This section defines the specific 

circumstance in which the Agency will 

use data from research judged 

unacceptable under § 26.1703, 

§ 26.1704, or § 26.1705, and the 

procedures EPA must follow in reaching 

that decision, as follows: 

EPA may rely on such data only if all the 

conditions in paragraphs (a) through (d) of 

this section are satisfied: 

(a) EPA has obtained the views of the 

Human Studies Review Board concerning the 

proposal to rely on the otherwise 

unacceptable data, 

(b) EPA has provided an opportunity for 

public comment on the proposal to rely on 

the otherwise unacceptable data, 

(c) EPA has determined that relying on the 

data is crucial to a decision that would 

impose a more stringent regulatory restriction 

that would improve protection of public 

health than could be justified without relying 

on the data, and 

(d) EPA publishes a full explanation of its 

decision to rely on the otherwise 

unacceptable data, including a thorough 

discussion of the ethical deficiencies of the 

study and the full rationale for finding that 

the standard in paragraph (c) of this section 

was met. 

The text of this section of the final 

rule contains a number of minor 

revisions to clarify the substantive and 

procedural requirements. Most notably, 

EPA changed the wording for the 

substantive standard for using the 

exception from ‘‘crucial to the 

protection of public health’’ in the 

proposal to ‘‘crucial to a decision that 

would impose a more stringent 

regulatory restriction that would 

improve protection of public health’’ in 

the final rule. This change reflects the 

Agency’s intent to limit the exception to 

a very narrow circumstance and to 

prevent use of the exception in a way 

that could benefit a person responsible 

for the unethical conduct. 

XIV. EPA’s 2006 Appropriations Act 

and the Final Rule 

This unit discusses how today’s final 

rule meets the requirements of the 

Department of the Interior, 

Environment, and Related Agencies 

Appropriations Act, 2006, Public Law 

No. 109–54 (Appropriations Act), which 

required EPA to promulgate a final rule 

relating to intentional dosing human 

toxicity studies for pesticides within 

180 days of enactment of the Act, and 

included various mandates concerning 

the promulgated final rule. 

A. Section 201 of EPA’s FY 2006 

Appropriations Act 

On August 2, 2005, the President 

signed into law the Department of the 

Interior, Environment, and Related 

Agencies Appropriations Act, 2006, 

Public Law No. 109–54 (Appropriations 

Act), which provides appropriated 

funds for EPA and other federal 

departments and agencies. Section 201 

of the Appropriations Act addresses 

EPA activities regarding intentional 

dosing human toxicity studies for 

pesticides as follows: 

None of the funds made available by this 

Act may be used by the Administrator of the 

Environmental Protection Agency to accept, 

consider or rely on third-party intentional 

dosing human toxicity studies for pesticides, 

or to conduct intentional dosing human 

toxicity studies for pesticides until the 

Administrator issues a final rulemaking on 

this subject. The Administrator shall allow 

for a period of not less than 90 days for 

public comment on the Agency’s proposed 

rule before issuing a final rule. Such rule 

shall not permit the use of pregnant women, 

infants or children as subjects; shall be 

consistent with the principles proposed in 

the 2004 report of the National Academy of 

Sciences on intentional human dosing and 

the principles of the Nuremberg Code with 

respect to human experimentation; and shall 

establish an independent Human Subjects 

Review Board. The final rule shall be issued 

no later than 180 days after enactment of this 

Act. 

B. Compliance of the Final Rule with the 

Appropriations Act 

The first requirement of the 

Appropriations Act is that EPA not 

‘‘accept, consider or rely on third-party 

intentional dosing human toxicity 

studies for pesticides, or . . . conduct 

intentional dosing human toxicity 

studies for pesticides until the 

Administrator issues a final rulemaking 

on this subject.’’ EPA has not accepted, 

considered, or relied on any third-party 

intentional dosing human toxicity 

studies in its actions under FIFRA and 

FFDCA since September 2005. EPA has 

further neither conducted nor supported 

any intentional dosing human toxicity 

study for pesticides during this 

rulemaking period. 

The second requirement of the 

Appropriations Act is to ‘‘allow for a 

period of not less than 90 days for 

public comment on the Agency’s 

proposed rule before issuing a final 

rule.’’ A notice of proposed rulemaking 

addressing both third-party intentional 

dosing human toxicity studies for 

pesticides and EPA’s conduct of 

intentional dosing human studies was 

published in the Federal Register on 

September 12, 2005 (70 FR 53838); the 

public comment period ended on 

December 12, 2005. 

EPA’s proposed rule addressed first-, 

second-, and third-party human subjects 

testing for pesticides. In particular, the 

proposal defined the scope of thirdparty human research covered by the 

proposal as: 

[A]ll research involving intentional 

exposure of a human subject if, at any time 

prior to initiating such research, any person 

who conducted or supported such research 

intended: 

(1) To submit results of the research to EPA 

for consideration in connection with any 

regulatory action that may be performed by 

EPA under the Federal Insecticide, 

Fungicide, and Rodenticide Act (7 U.S.C. 136 

et seq.) or section 408 of the Federal Food, 

Drug, and Cosmetic Act (21 U.S.C. 346a); or 

(2) To hold the results of the research for 

later inspection by EPA under the Federal 

Insecticide, Fungicide, and Rodenticide Act 

(7 U.S.C. 136 et seq.) or section 408 of the 

Federal Food, Drug, and Cosmetic Act (21 

U.S.C. 346a). 

EPA used the act of submitting, or the 

intent to submit, to the Agency under 

FIFRA or FFDCA as a surrogate for the 

Appropriations Act’s requirement that 

EPA promulgate a rule addressing 

‘‘third-party intentional dosing human 

toxicity studies for pesticides.’’ The use, 

sale, and distribution of pesticides are 

exclusively regulated by EPA under 

FIFRA and FFDCA. Moreover, as 

discussed above, the ongoing 

controversy over EPA’s use of human 

research data in its risk assessments has 

focused almost exclusively on the use of 

such data in risk assessments under 

FIFRA and FFDCA. Indeed, the 

Congressional debate that resulted in 

the passage of section 201 of the 

Appropriations Act focused entirely on 


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human subjects research related to 

Agency actions under FIFRA and 

FFDCA. Therefore, EPA believes that 

interpreting the phrase ‘‘third-party 

intentional dosing human toxicity 

studies for pesticides’’ to require either 

submission or intent to submit under 

FIFRA or FFDCA reflects the intent of 

the Congress as expressed in section 201 

of the Appropriations Act. 

The third requirement of the 

Appropriations Act is that the final rule 

‘‘not permit the use of pregnant women, 

infants or children as subjects.’’ Today’s 

final rule effectuates this mandate by: 

(1) Categorically prohibiting EPA from 

conducting or supporting research 

involving intentional exposure to any 

substance of human subjects who are 

pregnant women or children (subpart B 

of the final rule, § 26.203); and (2) 

prohibiting third-party research for 

pesticides involving intentional 

exposure of human subjects who are 

pregnant women or children (subpart L 

of the final rule, § 26.1203). 

The fourth requirement of the 

Appropriations Act is that the final rule 

‘‘shall be consistent with the principles 

proposed in the 2004 report of the 

National Academy of Sciences on 

intentional human dosing.’’ Based on a 

careful review of the NAS report, EPA 

concludes that the underlying 

principles intended by the NAS 

committee to be reflected in its 

recommendations are the three 

‘‘fundamental ethical principles’’

identified by the National Commission 

for the Protection of Human Subjects of 

Biomedical and Behavioral Research 

(National Commission) in its report, 

Ethical Principles and Guidelines for 

the Protection of Human Subjects of 

Research (the ‘‘Belmont Report’’). These 

three fundamental principles are respect 

for persons, beneficence, and justice. 

See NAS Report at pp. 49–50, 98, and 

113–14. 

The NAS committee makes the point 

clearly that they did not propose new 

principles: 

[T]he committee was not required to invent 

the basic standards that govern human 

research in the United States. These 

standards are already embodied in the 

Federal Policy for the Protection of Human 

Subjects (the Common Rule.) NAS Report pp. 

4, 33. 

The NAS committee further stated 

that the fundamental principles 

articulated in the Belmont Report both 

undergird and are made operational by 

the procedural requirements of the 

Common Rule. The following quotations 

express this view: 

Federal regulations incorporate the 

obligation of beneficence by requiring IRBs to 

ensure that risks are minimized to the extent 

possible, given the research question, and are 

reasonable in relation to potential benefits to 

the participant or to the importance of the 

knowledge to be gained through the research 

(40 CFR 26.111(a)(1)–(2)). NAS Report at 56. 

[D]etermining whether the principle of 

beneficence has been satisfied requires 

balancing the anticipated risks to study 

participants against the anticipated benefits 

of the study to society. The risks to 

participants must be reasonable in relation to 

the societal benefit. In the words of the 

Common Rule, the risks must be reasonable 

in relation to the importance of the 

knowledge that may reasonably be expected 

to result (40 CFR 26.111 (a)(2)). NAS Report 

at 107. 

According to the Common Rule, IRBs 

should not approve a research protocol 

involving humans unless ‘‘selection of 

subjects is equitable’’ (40 CFR 26.111(3)). 

This requirement derives from the principle 

of justice identified in the Belmont Report. 

NAS Report at 114. 

Voluntary, informed consent by research 

participants . . . is a major element in the 

system of protection of research participants. 

The consent requirement expresses the 

principle of respect for persons, including 

respect for and promotion of autonomous 

choices. The Common Rule stresses this 

requirement, as do other codes of research 

ethics, including the Nuremberg Code (1949), 

the Declaration of Helsinki, and the Good 

Clinical Practice guidelines. NAS Report at 

120. 

Accordingly, EPA concludes that the 

‘‘principles proposed in the 2004 report 

of the National Academy of Sciences on 

intentional human dosing’’ are, in fact, 

the three fundamental principles of 

respect for persons, beneficence, and 

justice articulated in the Belmont 

Report, and that the Common Rule rests 

on the foundation of those principles. 

Today’s final rule extending the 

substantive requirements of EPA’s 

Common Rule to additional categories 

of regulated third-party research is thus 

consistent with those principles, as 

required by the Appropriations Act. 

The fifth requirement of the 

Appropriations Act is that the final rule 

‘‘shall be consistent with the principles 

. . . of the Nuremberg Code with respect 

to human experimentation.’’

The NAS report (p. 47) explains the 

history of the Nuremberg Code as 

follows: 

Public policies regarding the ethical 

treatment of humans in research began 

forming in the late 1940’s, largely in response 

to the atrocities committed by Nazi 

investigators who were tried before the 

Nuremberg Military Tribunal (United States 

v. Karl Brandt, et al.) In 1946, the American 

Medical Association adopted its first code of 

research ethics, which ultimately influenced 

the Nuremberg Tribunal’s standards for 

ethical research, embodied in the ten ‘‘basic 

principles’’ for human research now known 

as the Nuremberg Code. [Footnotes and 

references omitted] 

Before publishing the NPRM, EPA 

carefully assessed whether the proposed 

provisions were consistent with the 10 

principles of the Nuremberg Code as a 

guide, and concluded that it was 

consistent with such principles. EPA 

believes this final rule remains 

consistent with the principles of the 

Nuremberg Code. An analysis 

explaining this conclusion is in the 

docket for this action, and comments on 

this issue have been addressed in our 

Response to Comments document. 

The sixth requirement of the 

Appropriations Act is that the final rule 

‘‘shall establish an independent Human 

Subjects Review Board.’’ EPA believes 

that the entity required by the 

Appropriations Act is intended to be 

substantially identical to the ‘‘Human 

Studies Review Board’’ recommended 

by Chapter 6 of the NAS Report. 

Consistent with both the requirement of 

the Appropriations Act and the 

recommendations of the NAS, this final 

rule establishes an independent HSRB. 

The HSRB will review proposed human 

subjects research after review by a local 

IRB and EPA staff. This sequence is 

consistent both with EPA’s current 

practice for reviewing first- and secondparty human research proposals and 

with the practice of FDA for reviewing 

human research proposals. Although the 

NAS Report recommended that the EPA 

and HSRB reviews come before the IRB 

review, EPA believes that HSRB review 

after local IRB and EPA review will 

better serve the purposes for which 

HSRB review of proposed research is 

intended. 

The final requirement of the 

Appropriations Act is that the final rule 

‘‘shall be issued no later than 180 days 

after enactment of this Act.’’ This 

requirement was met when EPA 

Administrator Stephen L. Johnson 

signed the final rule before January 29, 

2006, and it was made publicly 

available. 

XV. Effective Date of the Final Rule 

EPA noted in the preamble to the 

proposed rule that it considered the 

expeditious application of the new 

protections in the final rule to be in the 

public interest. Accordingly the Agency 

explained that it would provide no 

longer period than is essential between 

publication of the final rule and its 

effective date. Since the final rule is 

being promulgated under the authority 

of FIFRA, EPA is subject to FIFRA 

section 25(a)(4), 7 U.S.C. 136w(a)(4), 

which provides that: 

Simultaneously with the promulgation of 

any rule or regulation under this Act, the 

Administrator shall transmit a copy thereof 

to the Secretary of the Senate and the Clerk 


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of the House of Representatives. The rule or 

regulation shall not become effective until 

the passage of 60 calendar days after the rule 

or regulation is so transmitted. 

Therefore, EPA proposed that the 

final rule would be effective 60 days 

after its promulgation and transmittal to 

Congress. 

EPA received only one comment on 

the effective date, arguing that the 

requirements of the rule should not 

apply retroactively. EPA agrees that the 

provisions of the final rule should not 

apply retroactively, and the final rule 

contains no retroactive requirements. 

Specifically, the final rule establishes 

standards for the conduct by EPA and 

by third parties, in the future, of certain 

types of research. The Agency notes that 

the actions to promote compliance 

identified in subpart O of the final rule 

would only be applied to those whose 

actions, following the effective date of 

the final rule, did not comply with 

applicable requirements. Actions 

occurring before the final rule takes 

effect would not be subject to direct 

sanctions under subpart O, such as civil 

penalties or debarment. In addition, the 

final rule establishes standards to guide 

future Agency decisions about the 

ethical acceptability of completed 

research. While some of the research 

that EPA will evaluate under the new 

standards for ethical acceptability was 

conducted prior to the effective date of 

the final rule, such studies will be 

judged by the ethical standards 

prevailing when the research was 

performed. Thus, even the standard of 

acceptability is not ‘‘retroactive’’ in the 

sense that conduct would be judged 

using a standard created after the 

conduct occurred. 

The Agency has decided to make the 

final rule effective 60 days after the date 

of publication of its Notice of Final 

Rulemaking in the Federal Register. As 

required by FIFRA section 25(a)(4), the 

Agency has previously transmitted 

copies of the signed final rule to the 

Secretary of the Senate and the Clerk of 

the House of Representatives. Although 

technically the rule could take effect a 

few days earlier, EPA concluded that 

allowing 60 days from the date of 

publication of this Federal Register 

document was appropriate. 

Accordingly, this rule takes effect on 

April 7, 2006. 

The Agency notes that a number of 

the provisions of the rule apply to 

research ‘‘initiated’’ after the effective 

date of this rule. For purposes of 

research conducted or supported by 

EPA, the Agency will consider that an 

investigator has initiated a study once 

the Agency’s HSRRO has approved the 

protocol for the study. For purposes of 

research that is covered by subparts K 

or L or by § 26.1705, a study was 

‘‘initiated’’ when the first subject was 

enrolled. If that date cannot be 

determined, EPA will consider the 

earliest date on which experimental 

activity involved a subject to be the date 

of initiation of the research. 

XVI. FIFRA Review Procedures for the 

Final Rule 

FIFRA section 25(a)(2)(B) provides: 

‘‘[a]t least 30 days prior to signing any 

regulation in final form for publication 

in the Federal Register, the 

Administrator shall provide the 

Secretary of Agriculture a copy of such 

regulation.’’ This section also authorizes 

the Secretary to waive the opportunity 

to review and comment on final 

regulations. FIFRA section 25(d)(1) 

states that ‘‘[t]he Administrator shall 

submit to an advisory panel for 

comment [the] final form of regulations 

issued under section 25(a) within the 

same time periods as provided for the 

comments of the Secretary of 

Agriculture ....’’ This section also 

authorizes the FIFRA Scientific 

Advisory Panel to waive the 

opportunity for review. Both, the FIFRA 

Scientific Advisory Panel (SAP) and the 

U.S. Department of Agriculture (USDA) 

have waived the opportunity under 

FIFRA to review the final rule. 

In addition, FIFRA section 25(a)(3) 

states that ‘‘[a]t such time as the 

Administrator is required under 

paragraph (2) to provide the Secretary of 

Agriculture with . . . a copy of the final 

form of regulations, the Administrator 

shall also furnish a copy of such 

regulations to the Committee on 

Agriculture in the House of 

Representatives, and the Committee on 

Agriculture, Nutrition, and Forestry in 

the United States Senate.’’ Because 

USDA waived review under FIRFA 

section 25(a)(2)(B), EPA is not required 

to furnish a copy of the final regulations 

to the specified committees 30 days 

prior to signature of the final rule. The 

Agency, nonetheless, provided copies of 

the final rule to the Congressional 

committees prior to its publication. 

XVII. Statutory and Executive Order 

Reviews 

A. Executive Order 12866 

Under Executive Order 12866, 

entitled Regulatory Planning and 

Review (58 FR 51735, October 4, 1993), 

the Office of Management and Budget 

(OMB) has determined that this final 

rule is a ‘‘significant regulatory action’’

under section 3(f) of the Executive 

Order because this action might raise 

novel legal or policy issues. 

Accordingly, this action was submitted 

to OMB for review under Executive 

Order 12866 and any changes made 

based on OMB recommendations have 

been documented in the docket for this 

rulemaking as required by section 

6(a)(3)(E) of the Executive Order. 

In addition, EPA prepared an 

economic analysis of the potential costs 

and benefits associated with this action. 

This analysis is contained in a 

document entitled ‘‘Economic Analysis 

of the Human Studies Final Rule’’

(Economic Analysis). A copy of the 

Economic Analysis is available in the 

docket for this rulemaking and is briefly 

summarized here. 

The Economic Analysis describes the 

benefits of the rulemaking in qualitative 

terms. These benefits include greater 

protections for test subjects, and a 

corresponding reduction in their risks, 

to the extent that affected third-party 

researchers are not already following the 

Common Rule. The benefits to sponsors 

of third-party human research include a 

better understanding of the standards 

that EPA will apply in determining 

whether to rely on the results of their 

studies, and thus, the opportunity to 

design and perform studies that are 

more likely to meet EPA standards, 

leading to more efficient Agency 

reviews. The Agency believes the 

general public will also benefit from this 

action because the rule will strengthen 

the protections for human subjects and 

reinforce the Agency’s strong 

commitment to base its decisions on 

scientifically sound information. 

The Economic Analysis also estimates 

the costs of the final rule by focusing on 

the costs to third parties of complying 

with the new requirements and the costs 

to EPA of implementing the new 

requirements. In general, EPA believes 

that most, if not all, recent third-party 

research intended for submission to 

EPA that involves intentional exposure 

of human subjects already complies 

with the Common Rule or an equivalent 

foreign standard. For purposes of this 

analysis, EPA assumed that current 

practice was in full compliance with the 

Common Rule. 

After reviewing the history of EPA’s 

consideration of research involving 

human subjects in its various program 

offices, EPA estimates that this action 

will affect only a limited number of 

third-party studies involving human 

subjects each year. EPA also collected 

data on the cost per study of compliance 

with the Common Rule. These costs 

include preparing documents to support 

review by an IRB and the expense 

associated with the IRB review. These 

costs are very minor relative to the 

overall cost of conducting the studies. 


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For EPA, the costs are associated with 

the review of protocols and the review 

of completed human studies by EPA 

staff and the Human Studies Review 

Board. 

As detailed in the Economic Analysis 

prepared for this final rule, this action 

is estimated to result in a total annual 

incremental cost to third parties of 

approximately $39,000, and an 

estimated annual cost to EPA of 

approximately $808,000. 

B. Paperwork Reduction Act 

The information collection 

requirements contained in this final rule 

have been approved by the Office of 

Management and Budget (OMB) under 

the Paperwork Reduction Act (PRA), 44 

U.S.C. 3501 et seq., under OMB control 

number 2070–0169. In accordance with 

the procedures at 5 CFR 1320.11, EPA 

sought comment on the Information 

Collection Request (ICR) document that 

was submitted to OMB in conjunction 

with the proposed rule (identified under 

EPA ICR No. 2195.01). Revised to reflect 

the provisions in this final rule, the ICR 

document (identified under EPA ICR 

No. 2195.02) was prepared and 

submitted to OMB and serves as the 

basis for OMB’s approval. A copy of this 

ICR document has been placed in the 

docket for this rulemaking. 

Under the PRA, an agency may not 

conduct or sponsor, and a person is not 

required to respond to an information 

collection request unless it displays a 

currently valid OMB control number. 

The OMB control numbers for the EPA 

regulations codified in Chapter 40 of the 

CFR, after appearing in the preamble of 

the final rule, are listed in 40 CFR part 

9, displayed either by publication in the 

Federal Register or by other appropriate 

means, such as on the related collection 

instrument or form, if applicable. The 

display of OMB control numbers in 

certain EPA regulations is consolidated 

in 40 CFR part 9. For this ICR activity, 

in addition to displaying the applicable 

OMB control number in this unit, the 

Agency is amending the table in 40 CFR 

9.1 to list the OMB control number 

assigned to this ICR activity. Due to the 

technical nature of the table, EPA finds 

that further notice and comment about 

amending the table is unnecessary. As a 

result, EPA finds that there is ‘‘good 

cause’’ under section 553(b)(B) of the 

Administrative Procedures Act (APA), 5 

U.S.C. 553(b)(B), to amend this table 

without further notice and comment. 

EPA estimates that respondents may 

submit to the Agency each year under 

FIFRA or FFDCA, approximately 33 

reports of research involving intentional 

exposure of human subjects. The 

Agency expects extremely limited 

submission of toxicity studies per year 

(i.e., 0–4 studies), with the bulk of the 

33 studies being composed of efficacy 

and skin sensitization studies. (See also 

the response to comment on this topic 

that appears in Unit III.) EPA estimates 

that it may receive approximately 29 

reports each year of other types of 

pesticide research involving human 

subjects. EPA estimates that preparation 

of the required information will require 

about 32 hours per study, for a total 

estimated annual burden for affected 

entities of 1,984 hours, at an estimated 

cost of $1,927 per study, or a total 

estimated annual paperwork cost to 

respondents of $84,647. This total 

annual paperwork burden and cost 

estimate includes activities related to 

initial rule familiarization, as well as 

activities that researchers already 

perform and would continue to perform 

even without the Agency’s rulemaking 

in this area (i.e., developing a protocol 

and maintaining records). The average 

annual burden on EPA for reviewing 

this information for each study 

submission is estimated to be 80 hours 

per study (in total 4,960 hours), 

representing a paperwork related labor 

cost of about $14,672 per response and 

a total annual cost of $909,664. 

In the context of the PRA, ‘‘burden’’

means the total time, effort, or financial 

resources expended by persons to 

generate, maintain, retain, or disclose or 

provide information to or for a Federal 

agency. This includes the time needed 

to review instructions; develop, acquire, 

install, and utilize technology and 

systems for the purposes of collecting, 

validating, and verifying information, 

processing and maintaining 

information, and disclosing and 

providing information; adjust the 

existing ways to comply with any 

previously applicable instructions and 

requirements; train personnel to be able 

to respond to a collection of 

information; search data sources; 

complete and review the collection of 

information; and transmit or otherwise 

disclose the information. 

The information collection activity 

imposed by this final rule is planned to 

ensure that sound and appropriate 

scientific data are available to EPA 

when making regulatory decisions, and 

to protect the interests, rights and safety 

of those individuals who are 

participants in the type of research 

activity that is the subject of this rule. 

Specifically, this new information 

collection activity consists of reporting 

and recordkeeping requirements. 

Whenever respondents intend to 

conduct research for submission to EPA 

under the pesticide laws that involves 

intentional dosing of human subjects, 

they will be required to submit study 

protocols to EPA and a cognizant local 

IRB before such research is initiated so 

that the scientific design and ethical 

standards that will be employed during 

the proposed study may be reviewed 

and approved. Respondents will also be 

required to submit information about 

the ethical conduct of completed 

research that involved intentional 

dosing of human subjects when such 

research is submitted to EPA. 

FIFRA sections 3(c)(1)(F) and 

3(c)(2)(B) authorize EPA to require 

various data in support of a pesticide’s 

continued registration or an application 

for a new or amended pesticide 

registration. FIFRA section 12(a)(2)(P) 

forbids any person ‘‘to use any pesticide 

in tests on human beings unless such 

human beings (i) are fully informed of 

the nature and purposes of the test and 

of any physical and mental health 

consequences which are reasonably 

foreseeable therefrom, and (ii) freely 

volunteer to participate in the test.’’

C. Regulatory Flexibility Act 

Pursuant to section 605(b) of the 

Regulatory Flexibility Act (RFA), 5 

U.S.C. 601 et seq., after considering the 

potential economic impacts of today’s 

rule on small entities, the Agency 

hereby certifies that this final rule will 

not have a significant adverse economic 

impact on a substantial number of small 

entities. This determination is based on 

the Agency’s economic analysis 

performed for this rulemaking, 

summarized in Unit XVI.A., and a copy 

of which is available in the docket for 

this rulemaking. The following is a brief 

summary of the factual basis for this 

certification. 

Small entities include small 

businesses, small organizations, and 

small governmental jurisdictions. For 

purposes of assessing the impacts of 

today’s rule on small entities, small 

entity is defined in accordance with the 

RFA as: (1) A small business as defined 

by the Small Business Administration’s 

(SBA) regulations at 13 CFR 121.201; (2) 

a small governmental jurisdiction that is 

a government of a city, county, town, 

school district, or special district with a 

population of less than 50,000; and (3) 

a small organization that is any not-forprofit enterprise which is independently 

owned and operated and is not 

dominant in its field. 

Although we cannot predict whether 

or how many small entities might 

engage in the subject matter research in 

the future, as estimated in the Economic 

Analysis, the cost to researchers covered 

by this rule is estimated to be $5,200 per 

study. This is a trivially small portion 

of the overall cost of performing such 


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studies, each of which is estimated to 

cost from $125,000 to $500,000. After 

reviewing the history of EPA’s 

consideration on human research in its 

various program offices, EPA estimates 

that this rule would affect only a limited 

number of third-party human studies 

each year. Because both the number of 

affected studies is relatively small and 

the estimated current costs of 

compliance with the Common Rule are 

low, the potential overall costs from this 

rule to third parties are also estimated 

to be small. 

D. Unfunded Mandates Reform Act 

Under Title II of the Unfunded 

Mandates Reform Act of 1995 (UMRA) 

(Public Law 104–4), EPA has 

determined that this action does not 

contain a Federal mandate that may 

result in expenditures of $100 million or 

more for State, local, and tribal 

governments, in the aggregate, or the 

private sector in any one year. As 

described in Unit XVI.A. the estimated 

total costs associated with this action 

are approximately $38,837 per year. 

This cost represents the incremental 

cost to researchers attributed to the 

additional procedural requirements 

contained in this final rule. Based on 

historical submissions, EPA has 

determined that State, local, and tribal 

governments rarely perform human 

research intended for submission to 

EPA under FIFRA or FFDCA. In 

addition, the final rule is not expected 

to significantly or uniquely affect small 

governments. Accordingly, this action is 

not subject to the requirements of 

sections 202 and 205 of UMRA. 

E. Executive Order 13132 

Pursuant to Executive Order 13132, 

entitled Federalism (64 FR 43255, 

August 10, 1999), EPA has determined 

that this rule does not have ‘‘federalism 

implications,’’ because it will not have 

substantial direct effects on the states, 

on the relationship between the national 

government and the states, or on the 

distribution of power and 

responsibilities among the various 

levels of government, as specified in the 

Order. As indicated earlier, instances 

where a state performs human research 

intended for submission to EPA under 

FIFRA or FFDCA are rare. Therefore, 

this final rule may seldom affect a state 

government. Thus, Executive Order 

13132 does not apply to this rule. 

F. Executive Order 13175 

As required by Executive Order 

13175, entitled Consultation and 

Coordination with Indian Tribal 

Governments (59 FR 22951, November 

6, 2000), EPA has determined that this 

final rule does not have tribal 

implications because it will not have 

substantial direct effects on tribal 

governments, on the relationship 

between the Federal government and 

the Indian tribes, or on the distribution 

of power and responsibilities between 

the Federal government and Indian 

tribes, as specified in the Order. As 

indicated previously, instances where a 

tribal government performs human 

research intended for submission to 

EPA under FIFRA or FFDCA are 

extremely rare. Thus, Executive Order 

13175 does not apply to this rule. 

G. Executive Order 13045 

Executive Order 13045, entitled 

Protection of Children from 

Environmental Health Risks and Safety 

Risks (62 FR 19885, April 23, 1997) does 

not apply to this rule because this action 

is not designated as an ‘‘economically 

significant’’ regulatory action as defined 

by Executive Order 12866. Furthermore, 

this final rule does not establish an 

environmental standard that is intended 

to have a negatively disproportionate 

effect on children. To the contrary, this 

action will provide added protections 

for children with regard to the research 

covered by the rule. 

H. Executive Order 13211 

This final rule is not subject to 

Executive Order 13211, entitled Actions 

Concerning Regulations that 

Significantly Affect Energy Supply, 

Distribution, or Use (66 FR 28355, May 

22, 2001) because this rule does not 

have any significant adverse effect on 

the supply, distribution, or use of 

energy. 

I. National Technology Transfer and 

Advancement Act 

Section 12(d) of the National 

Technology Transfer and Advancement 

Act of 1995 (NTTAA), 15 U.S.C. 272 

note) directs EPA to use voluntary 

consensus standards in its regulatory 

activities unless to do so would be 

inconsistent with applicable law or 

impractical. Voluntary consensus 

standards are technical standards (e.g., 

materials specifications, test methods, 

sampling procedures) that are 

developed or adopted by voluntary 

consensus standards bodies. NTTAA 

directs EPA to provide Congress, 

through OMB, with explanations when 

the Agency decides not to use available 

and applicable voluntary consensus 

standards. This action does not require 

specific methods or standards to 

generate data. Therefore, this final rule 

does not impose any technical standards 

that would require Agency 

consideration of voluntary consensus 

standards. 

J. Executive Order 12898 

This final rule does not have an 

adverse impact on the environmental 

and health conditions in low-income 

and minority communities. Therefore, 

under Executive Order 12898, entitled 

Federal Actions to Address 

Environmental Justice in Minority 

Populations and Low-Income 

Populations (59 FR 7629, February 16, 

1994), the Agency is not required to 

consider environmental justice-related 

issues. Although not directly impacting 

environmental justice-related concerns, 

the provisions of this rule will require 

researchers to use procedures to ensure 

equitable selection of test subjects in 

covered human research. 

XVIII. Congressional Review Act 

The Congressional Review Act, 5 

U.S.C. 801 et seq., generally provides 

that before a rule may take effect, the 

Agency promulgating the rule must 

submit a rule report that includes a copy 

of the rule to each House of the 

Congress and the Comptroller General of 

the United States. EPA will submit a 

report containing this rule and other 

required information to the U.S. Senate, 

the U.S. House of Representatives, and 

the Comptroller General of the United 

States prior to publication of the rule in 

the Federal Register. This rule is not a 

‘‘major rule’’ as defined by 5 U.S.C. 

804(2). 

List of Subjects in 40 CFR Part 9 

Environmental protection, Reporting 

and recordkeeping requirements. 

List of Subjects in 40 CFR Part 26 

Environmental protection, Human 

research subjects, Reporting and 

recordkeeping requirements. 

Dated: January 26, 2006. 

Stephen L. Johnson, 

Administrator. 

■ Therefore, 40 CFR chapter I is 

amended as follows: 

■ 1. Part 9 is amended as follows: 

PART 9—[AMENDED] 

■ a. The authority citation for part 9 

continues to read as follows: 

Authority: 7 U.S.C. 135 et seq., 136–136y; 

15 U.S.C. 2001, 2003, 2005, 2006, 2601–2671, 

21 U.S.C. 331j, 346a, 348; 31 U.S.C. 9701; 33 

U.S.C. 1251 et seq., 1311, 1313d, 1314, 1318, 

1321, 1326, 1330, 1342, 1344, 1345 (d) and 

(e), 1361; E.O. 11735, 38 FR 21243, 3 CFR, 

1971–1975 Comp. p. 973; 42 U.S.C. 241, 

242b, 243, 246, 300f, 300g, 300g–1, 300g–2, 

300g–3, 300g–4, 300g–5, 300g–6, 300j–1, 

300j–2, 300j–3, 300j–4, 300j–9, 1857 et seq., 


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6901–6992k, 7401–7671q, 7542, 9601–9657, 

11023, 11048. 

■ b. In § 9.1 the table is amended by 

adding the following new entries under 

the new heading ‘‘Protection of Human 

Subjects’’ to read as follows: 

§ 9.1 OMB approvals under the Paperwork 

Reduction Act. 

* * * * * 

40 CFR citation OMB Control No. 

* * * * * 

.

Protection of Human Subjects 

26.1125 ..............

26.1303 ..............

2070–0169 

2070–0169 

* * * * * 

* * * * * 

PART 26—[AMENDED] 

■ 2. Part 26 is amended as follows: 

■ a. By revising the authority citation for 

part 26 to read as follows: 

Authority: 5 U.S.C. 301; 7 U.S.C. 

136w(a)(1); 21 U.S.C. 346a(e)(1)(C); section 

201 of Public Law No. 109–54; and 42 U.S.C. 

300v–1(b). 

■ b. By redesignating §§ 26.101 through 

26.124 as subpart A and adding a new 

subpart heading to read as follows: 

Subpart A—Basic EPA Policy for 

Protection of Subjects in Human 

Research Conducted or Supported by 

EPA 

■ c. By adding new subparts B through 

Q as follows: 

Subpart B—Prohibition of Research 

Conducted or Supported by EPA Involving 

Intentional Exposure of Human Subjects 

who are Pregnant Women or Children 

Sec. 

26.201 To what does this subpart apply? 

26.202 Definitions. 

26.203 Prohibition of research conducted or 

supported by EPA involving intentional 

exposure of any human subject who is a 

pregnant woman (and therefore her 

fetus) or child. 

Subpart C—Observational Research: 

Additional Protections for Pregnant Women 

and Fetuses Involved as Subjects in 

Observational Research Conducted or 

Supported by EPA 

26.301 To what does this subpart apply? 

26.302 Definitions. 

26.303 Duties of IRBs in connection with 

observational research involving 

pregnant women and fetuses. 

26.304 Additional protections for pregnant 

women and fetuses involved in 

observational research. 

26.305 Protections applicable, after 

delivery, to the placenta, the dead fetus, 

or fetal material. 

Subpart D—Observational Research: 

Additional Protections for Children Involved 

as Subjects in Observational Research 

Conducted or Supported by EPA 

26.401 To what does this subpart apply? 

26.402 Definitions. 

26.403 IRB duties. 

26.404 Observational research not involving 

greater than minimal risk. 

26.405 Observational research involving 

greater than minimal risk but presenting 

the prospect of direct benefit to the 

individual subjects. 

26.406 Requirements for permission by 

parents or guardians and for assent by 

children. 

Subpart E—[Reserved] 

Subpart F—[Reserved] 

Subpart G—[Reserved] 

Subpart H—[Reserved] 

Subpart I—[Reserved] 

Subpart J—[Reserved] 

Subpart K—Basic Ethical Requirements for 

Third-Party Human Research for Pesticides 

Involving Intentional Exposure of Nonpregnant Adults 

26.1101 To what does this subpart apply? 

26.1102 Definitions. 

26.1103—26.1106 [Reserved] 

26.1107 IRB membership. 

26.1108 IRB functions and operations. 

26.1109 IRB review of research. 

26.1110 Expedited review procedures for 

certain kinds of research involving no 

more than minimal risk, and for minor 

changes in approved research. 

26.1111 Criteria for IRB approval of 

research. 

26.1112 Review by institution. 

26.1113 Suspension or termination of IRB 

approval of research. 

26.1114 Cooperative research. 

26.1115 IRB records. 

26.1116 General requirements for informed 

consent. 

26.1117 Documentation of informed 

consent. 

26.1118—26.1122 [Reserved] 

26.1123 Early termination of research. 

26.1124 [Reserved] 

26.1125 Prior submission of proposed 

human research for EPA review. 

Subpart L—Prohibition of Third-Party 

Research for Pesticides Involving 

Intentional Exposure of Human Subjects 

who are Pregnant Women or Children 

26.1201 To what does this subpart apply? 

26.1202 Definitions. 

26.1203 Prohibition of research involving 

intentional exposure of any pregnant 

woman, fetus, or child. 

Subpart M—Requirements for Submission 

of Information on the Ethical Conduct of 

Completed Human Research 

26.1301 To what does this subpart apply? 

26.1302 Definitions. 

26.1303 Submission of information 

pertaining to ethical conduct of 

completed human research. 

Subpart N—[Reserved] 

Subpart O—Administrative Actions for 

Noncompliance 

26.1501 To what does this subpart apply? 

26.1502 Lesser administrative actions. 

26.1503 Disqualification of an IRB or an 

institution. 

26.1504 Public disclosure of information 

regarding revocation. 

26.1505 Reinstatement of an IRB or an 

institution. 

26.1506 Debarment. 

26.1507 Actions alternative or additional to 

disqualification. 

Subpart P—Review of Proposed and 

Completed Human Research 

26.1601 EPA review of proposed human 

research. 

26.1602 EPA review of completed human 

research. 

26.1603 Operation of the Human Studies 

Review Board. 

Subpart Q—Ethical Standards for 

Assessing Whether to Rely on the Results 

of Human Research in EPA Actions 

26.1701 To what does this subpart apply? 

26.1702 Definitions. 

26.1703 Prohibition of reliance on research 

involving intentional exposure of human 

subjects who are pregnant women (and 

therefore their fetuses) or children. 

26.1704 Prohibition of reliance on unethical 

human research with non-pregnant 

adults conducted before April 7, 2006. 

26.1705 Prohibition of reliance on unethical 

human research with non-pregnant 

adults conducted after April 7, 2006. 

26.1706 Criteria and procedure for 

decisions to protect public health by 

relying on otherwise unacceptable 

research. 

Subpart B—Prohibition of Research 

Conducted or Supported by EPA 

Involving Intentional Exposure of 

Human Subjects who are Pregnant 

Women or Children. 

§ 26.201 To what does this subpart apply? 

(a) This subpart applies to all research 

involving intentional exposure of any 

human subject who is a pregnant 

woman (and her fetus) or a child 

conducted or supported by the 

Environmental Protection Agency 

(EPA). This includes research 

conducted in EPA facilities by any 

person and research conducted in any 

facility by EPA employees. 

(b) The requirements of this subpart 

are in addition to those imposed under 

the other subparts of this part. 

§ 26.202 Definitions. 

The definitions in § 26.102 shall be 

applicable to this subpart as well. In 

addition, the definitions at 45 CFR 


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46.202(a) through (f) and at 45 CFR 

46.202(h) are applicable to this subpart. 

(a) Research involving intentional 

exposure of a human subject means a 

study of a substance in which the 

exposure to the substance experienced 

by a human subject participating in the 

study would not have occurred but for 

the human subject’s participation in the 

study. 

(b) A child is a person who has not 

attained the age of 18 years. 

§ 26.203 Prohibition of research 

conducted or supported by EPA involving 

intentional exposure of any human subject 

who is a pregnant woman (and therefore 

her fetus) or child. 

Notwithstanding any other provision 

of this part, under no circumstances 

shall EPA conduct or support research 

involving intentional exposure of any 

human subject who is a pregnant 

woman (and therefore her fetus) or 

child. 

Subpart C—Observational Research: 

Additional Protections for Pregnant 

Women and Fetuses Involved as 

Subjects in Observational Research 

Conducted or Supported by EPA 

§ 26.301 To what does this subpart apply? 

(a) Except as provided in paragraph 

(b) of this section, this subpart applies 

to all observational research involving 

human subjects who are pregnant 

women (and therefore their fetuses) 

conducted or supported by the 

Environmental Protection Agency 

(EPA). This includes research 

conducted in EPA facilities by any 

person and research conducted in any 

facility by EPA employees. 

(b) The exemptions at § 26.101(b)(1) 

through (b)(6) are applicable to this 

subpart. 

(c) The provisions of § 26.101(c) 

through (i) are applicable to this 

subpart. References to State or local 

laws in this subpart and in § 26.101(f) 

are intended to include the laws of 

federally recognized American Indian 

and Alaska Native Tribal Governments. 

(d) The requirements of this subpart 

are in addition to those imposed under 

the other subparts of this part. 

§ 26.302 Definitions. 

The definitions in §§ 26.102 and 

26.202 shall be applicable to this 

subpart as well. In addition, 

observational research means any 

human research that does not meet the 

definition of research involving 

intentional exposure of a human subject 

in § 26.202(a). 

§ 26.303 Duties of IRBs in connection with 

observational research involving pregnant 

women and fetuses. 

The provisions of 45 CFR 46.203 are 

applicable to this section. 

§ 26.304 Additional protections for 

pregnant women and fetuses involved in 

observational research. 

The provisions of 45 CFR 46.204 are 

applicable to this section. 

§ 26.305 Protections applicable, after 

delivery, to the placenta, the dead fetus, or 

fetal material. 

The provisions of 45 CFR 46.206 are 

applicable to this section. 

Subpart D—Observational Research: 

Additional Protections for Children 

Involved as Subjects in Observational 

Research Conducted or Supported by 

EPA 

§ 26.401 To what does this subpart apply? 

(a) This subpart applies to all 

observational research involving 

children as subjects, conducted or 

supported by EPA. References to State 

or local laws in this subpart and in 

§ 26.101(f) are intended to include the 

laws of federally recognized American 

Indian and Alaska Native Tribal 

Governments. This includes research 

conducted in EPA facilities by any 

person and research conducted in any 

facility by EPA employees. 

(b) Exemptions at § 26.101(b)(1) and 

(b)(3) through (b)(6) are applicable to 

this subpart. The exemption at 

§ 26.101(b)(2) regarding educational 

tests is also applicable to this subpart. 

However, the exemption at 

§ 26.101(b)(2) for research involving 

survey or interview procedures or 

observations of public behavior does not 

apply to research covered by this 

subpart, except for research involving 

observation of public behavior when the 

investigator(s) do not participate in the 

activities being observed. 

(c) The exceptions, additions, and 

provisions for waiver as they appear in 

§ 26.101(c) through (i) are applicable to 

this subpart. 

§ 26.402 Definitions. 

The definitions in § 26.102 shall be 

applicable to this subpart as well. In 

addition, the following terms are 

defined: 

(a) For purposes of this subpart, 

Administrator means the Administrator 

of the Environmental Protection Agency 

and any other officer or employee of the 

Environmental Protection Agency to 

whom authority has been delegated by 

the Administrator. 

(b) Assent means a child’s affirmative 

agreement to participate in research. 

Mere failure to object should not, absent 

affirmative agreement, be construed as 

assent. 

(c) Permission means the agreement of 

parent(s) or guardian to the 

participation of their child or ward in 

research. 

(d) Parent means a child’s biological 

or adoptive parent. 

(e) Guardian means an individual 

who is authorized under applicable 

State, Tribal, or local law to consent on 

behalf of a child to general medical care. 

(f) Observational research means any 

research with human subjects that does 

not meet the definition of research 

involving intentional exposure of a 

human subject in § 26.202(a). 

(g) Minimal risk means that the 

probability and magnitude of harm or 

discomfort anticipated in the research 

are not greater in and of themselves than 

those ordinarily encountered in daily 

life or during the performance of routine 

physical or psychological examinations 

or tests. 

§ 26.403 IRB duties. 

In addition to other responsibilities 

assigned to IRBs under this part, each 

IRB shall review observational research 

covered by this subpart and approve 

only research that satisfies the 

conditions of all applicable sections of 

this subpart. 

§ 26.404 Observational research not 

involving greater than minimal risk. 

EPA will conduct or fund 

observational research in which the IRB 

finds that no greater than minimal risk 

to children is presented, only if the IRB 

finds that adequate provisions are made 

for soliciting the assent of the children 

and the permission of their parents or 

guardians, as set forth in § 26.406. 

§ 26.405 Observational research involving 

greater than minimal risk but presenting the 

prospect of direct benefit to the individual 

subjects. 

If the IRB finds that an intervention or 

procedure presents more than minimal 

risk to children, EPA will not conduct 

or fund observational research that 

includes such an intervention or 

procedure unless the IRB finds and 

documents that: 

(a) The intervention or procedure 

holds out the prospect of direct benefit 

to the individual subject or is likely to 

contribute to the subject’s well-being; 

(b) The risk is justified by the 

anticipated benefit to the subjects; 

(c) The relation of the anticipated 

benefit to the risk is at least as favorable 

to the subjects as that presented by 

available alternative approaches; and 

(d) Adequate provisions are made for 

soliciting the assent of the children and 


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permission of their parents or guardians, 

as set forth in § 26.406. 

§ 26.406 Requirements for permission by 

parents or guardians and for assent by 

children. 

(a) In addition to the determinations 

required under other applicable sections 

of this subpart, the IRB shall determine 

that adequate provisions are made for 

soliciting the assent of the children, 

when in the judgment of the IRB the 

children are capable of providing assent. 

In determining whether children are 

capable of assenting, the IRB shall take 

into account the ages, maturity, and 

psychological state of the children 

involved. This judgment may be made 

for all children to be involved in 

research under a particular protocol, or 

for each child, as the IRB deems 

appropriate. If the IRB determines that 

the capability of some or all of the 

children is so limited that they cannot 

reasonably be consulted or that the 

intervention or procedure involved in 

the observational research holds out a 

prospect of direct benefit that is 

important to the health or well-being of 

the children and is available only in the 

context of the research, the assent of the 

children is not a necessary condition for 

proceeding with the observational 

research. Even where the IRB 

determines that the subjects are capable 

of assenting, the IRB may still waive the 

assent requirement under circumstances 

in which consent may be waived in 

accord with § 26.116(d). 

(b) In addition to the determinations 

required under other applicable sections 

of this subpart, the IRB shall determine, 

in accordance with and to the extent 

that consent is required by § 26.116, that 

adequate provisions are made for 

soliciting the permission of each child’s 

parents or guardian. Where parental 

permission is to be obtained, the IRB 

may find that the permission of one 

parent is sufficient for research to be 

conducted under § 26.404 or § 26.405. 

(c) In addition to the provisions for 

waiver contained in § 26.116, if the IRB 

determines that a research protocol is 

designed for conditions or for a subject 

population for which parental or 

guardian permission is not a reasonable 

requirement to protect the subjects (for 

example, neglected or abused children), 

it may replace the consent requirements 

in subpart A of this part and paragraph 

(b) of this section with provided an 

appropriate, equivalent mechanism for 

protecting the children who will 

participate as subjects in the research is 

substituted, and provided further that 

the waiver is not inconsistent with 

Federal, State, or local law. The choice 

of an appropriate, equivalent 

mechanism would depend upon the 

nature and purpose of the activities 

described in the protocol, the risk and 

anticipated benefit to the research 

subjects, and their age, maturity, status, 

and condition. 

(d) Permission by parents or 

guardians shall be documented in 

accordance with and to the extent 

required by § 26.117. 

(e) When the IRB determines that 

assent is required, it shall also 

determine whether and how assent must 

be documented. 

Subpart E—[Reserved] 

Subpart F—[Reserved] 

Subpart G—[Reserved] 

Subpart H—[Reserved] 

Subpart I—[Reserved] 

Subpart J—[Reserved] 

Subpart K—Basic Ethical 

Requirements for Third-Party Human 

Research for Pesticides Involving 

Intentional Exposure of Non-pregnant 

Adults 

§ 26.1101 To what does this subpart 

apply? 

(a) Except as provided in paragraph 

(b) of this section, subpart K of this part 

applies to all research initiated after 

April 7, 2006 involving intentional 

exposure of a human subject if, at any 

time prior to initiating such research, 

any person who conducted or supported 

such research intended: 

(1) To submit results of the research 

to EPA for consideration in connection 

with any action that may be performed 

by EPA under the Federal Insecticide, 

Fungicide, and Rodenticide Act (7 

U.S.C. 136 et seq.) or section 408 of the 

Federal Food, Drug, and Cosmetic Act 

(21 U.S.C. 346a); or 

(2) To hold the results of the research 

for later inspection by EPA under the 

Federal Insecticide, Fungicide, and 

Rodenticide Act (7 U.S.C. 136 et seq.) or 

section 408 of the Federal Food, Drug, 

and Cosmetic Act 21 U.S.C. 346a). 

(b) Unless otherwise required by the 

Administrator, research is exempt from 

this subpart if it involves only the 

collection or study of existing data, 

documents, records, pathological 

specimens, or diagnostic specimens 

from previously conducted studies, and 

if these sources are publicly available or 

if the information is recorded by the 

investigator in such a manner that 

subjects cannot be identified, directly or 

through identifiers linked to the 

subjects. 

(c) The Administrator retains final 

judgment as to whether a particular 

activity within the scope of paragraphs 

(a) and (b) of this section is covered by 

this subpart. 

(d) Compliance with this subpart 

requires compliance with pertinent 

Federal laws or regulations which 

provide additional protections for 

human subjects. 

(e) This subpart does not affect any 

State or local laws or regulations which 

may otherwise be applicable and which 

provide additional protections for 

human subjects. Reference to State or 

local laws in this subpart is intended to 

include the laws of federally recognized 

American Indian and Alaska Native 

Tribal Governments. 

(f) This subpart does not affect any 

foreign laws or regulations which may 

otherwise be applicable and which 

provide additional protections to human 

subjects of research. 

(g) For purposes of determining a 

person’s intent under paragraph (a) of 

this section, EPA may consider any 

available information relevant to 

determining the intent of a person who 

conducts or supports research with 

human subjects after the effective date 

of the rule. EPA shall rebuttably 

presume such intent existed if: 

(1) The person or the person’s agent 

has submitted or made available for 

inspection the results of such research 

to EPA; or 

(2) The person is a member of a class 

of people who, or whose products or 

activities, are regulated by EPA under 

FIFRA or the FFDCA and, at the time 

the research was initiated, the results of 

the research would be relevant to EPA’s 

exercise of its authority under FIFRA or 

the FFDCA with respect to that class of 

people, products, or activities. 

§ 26.1102 Definitions. 

(a) For purposes of this subpart, 

Administrator means the Administrator 

of the Environmental Protection Agency 

(EPA) and any other officer or employee 

of EPA to whom authority has been 

delegated. 

(b) Institution means any public or 

private entity or agency (including 

Federal, State, and other agencies). 

(c) Legally authorized representative 

means an individual or judicial or other 

body authorized under applicable law to 

consent on behalf of a prospective 

subject to the subject’s participation in 

the procedure(s) involved in the 

research. 

(d) Research means a systematic 

investigation, including research, 

development, testing and evaluation, 


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designed to develop or contribute to 

generalizable knowledge. Activities 

which meet this definition constitute 

research for purposes of this subpart, 

whether or not they are considered 

research for other purposes. For 

example, some demonstration and 

service programs may include research 

activities. 

(e) Human subject means a living 

individual about whom an investigator 

(whether professional or student) 

conducting research obtains: 

(1) Data through intervention or 

interaction with the individual, or 

(2) Identifiable private information. 

(3) ‘‘Intervention’’ includes both 

physical procedures by which data are 

gathered (for example, venipuncture) 

and manipulations of the subject or the 

subject’s environment that are 

performed for research purposes. 

Interaction includes communication or 

interpersonal contact between 

investigator and subject. ‘‘Private 

information’’ includes information 

about behavior that occurs in a context 

in which an individual can reasonably 

expect that no observation or recording 

is taking place, and information which 

has been provided for specific purposes 

by an individual and which the 

individual can reasonably expect will 

not be made public (for example, a 

medical record). Private information 

must be individually identifiable (i.e., 

the identity of the subject is or may 

readily be ascertained by the 

investigator or associated with the 

information) in order for obtaining the 

information to constitute research 

involving human subjects. 

(f) IRB means an institutional review 

board established in accord with and for 

the purposes expressed in this part. 

(g) IRB approval means the 

determination of the IRB that the 

research has been reviewed and may be 

conducted at an institution within the 

constraints set forth by the IRB and by 

other institutional and Federal 

requirements. 

(h) Minimal risk means that the 

probability and magnitude of harm or 

discomfort anticipated in the research 

are not greater in and of themselves than 

those ordinarily encountered in daily 

life or during the performance of routine 

physical or psychological examinations 

or tests. 

(i) Research involving intentional 

exposure of a human subject means a 

study of a substance in which the 

exposure to the substance experienced 

by a human subject participating in the 

study would not have occurred but for 

the human subject’s participation in the 

study. 

(j) Person means any person, as that 

term is defined in FIFRA section 2(s) (7 

U.S.C. 136), except: 

(1) A federal agency that is subject to 

the provisions of the Federal Policy for 

the Protection of Human Subjects of 

Research, and 

(2) A person when performing human 

research supported by a federal agency 

covered by paragraph (j)(1) of this 

section. 

§§ 26.1103 through 26.1106 [Reserved] 

§ 26.1107 IRB membership. 

(a) Each IRB shall have at least five 

members, with varying backgrounds to 

promote complete and adequate review 

of research activities which are 

presented for its approval. The IRB shall 

be sufficiently qualified through the 

experience and expertise of its 

members, and the diversity of the 

members, including consideration of 

race, gender, and cultural backgrounds 

and sensitivity to such issues as 

community attitudes, to promote respect 

for its advice and counsel in 

safeguarding the rights and welfare of 

human subjects. In addition to 

possessing the professional competence 

necessary to review specific research 

activities, the IRB shall be able to 

ascertain the acceptability of proposed 

research in terms of institutional 

commitments and regulations, 

applicable law, and standards of 

professional conduct and practice. The 

IRB shall therefore include persons 

knowledgeable in these areas. If an IRB 

regularly reviews research that involves 

a vulnerable category of subjects, such 

as prisoners or handicapped or mentally 

disabled persons, consideration shall be 

given to the inclusion of one or more 

individuals who are knowledgeable 

about and experienced in working with 

these subjects. 

(b) Every nondiscriminatory effort 

will be made to ensure that no IRB 

consists entirely of men or entirely of 

women, including the institution’s 

consideration of qualified persons of 

both sexes, so long as no selection is 

made to the IRB on the basis of gender. 

No IRB may consist entirely of members 

of one profession. 

(c) Each IRB shall include at least one 

member whose primary concerns are in 

scientific areas and at least one member 

whose primary concerns are in 

nonscientific areas. 

(d) Each IRB shall include at least one 

member who is not otherwise affiliated 

with the institution and who is not part 

of the immediate family of a person who 

is affiliated with the institution. 

(e) No IRB may have a member 

participate in the IRB’s initial or 

continuing review of any project in 

which the member has a conflicting 

interest, except to provide information 

requested by the IRB. 

(f) An IRB may, in its discretion, 

invite individuals with competence in 

special areas to assist in the review of 

issues which require expertise beyond 

or in addition to that available on the 

IRB. These individuals may not vote 

with the IRB. 

§ 26.1108 IRB functions and operations. 

In order to fulfill the requirements of 

this subpart each IRB shall: 

(a) Follow written procedures: 

(1) For conducting its initial and 

continuing review of research and for 

reporting its findings and actions to the 

investigator and the institution; 

(2) For determining which projects 

require review more often than annually 

and which projects need verification 

from sources other than the investigator 

that no material changes have occurred 

since previous IRB review; 

(3) For ensuring prompt reporting to 

the IRB of proposed changes in research 

activity; and 

(4) For ensuring that changes in 

approved research, during the period for 

which IRB approval has already been 

given, may not be initiated without IRB 

review and approval except where 

necessary to eliminate apparent 

immediate hazards to the human 

subjects. 

(b) Follow written procedures for 

ensuring prompt reporting to the IRB, 

appropriate institutional officials, and 

the Environmental Protection Agency 

of: 

(1) Any unanticipated problems 

involving risks to human subjects or 

others; 

(2) Any instance of serious or 

continuing noncompliance with this 

subpart of the requirements or 

determinations of the IRB; or 

(3) Any suspension or termination of 

IRB approval. 

(c) Except when an expedited review 

procedure is used (see § 26.1110), 

review proposed research at convened 

meetings at which a majority of the 

members of the IRB are present, 

including at least one member whose 

primary concerns are in nonscientific 

areas. In order for the research to be 

approved, it shall receive the approval 

of a majority of those members present 

at the meeting. 

§ 26.1109 IRB review of research. 

(a) An IRB shall review and have 

authority to approve, require 

modifications in (to secure approval), or 

disapprove all research activities 

covered by this subpart. 


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(b) An IRB shall require that 

information given to subjects as part of 

informed consent is in accordance with 

§ 26.1116. The IRB may require that 

information, in addition to that 

specifically mentioned in § 26.1116 be 

given to the subjects when, in the IRB’s 

judgment, the information would 

meaningfully add to the protection of 

the rights and welfare of subjects. 

(c) An IRB shall require 

documentation of informed consent in 

accordance with § 26.1117. 

(d) An IRB shall notify investigators 

and the institution in writing of its 

decision to approve or disapprove the 

proposed research activity, or of 

modifications required to secure IRB 

approval of the research activity. If the 

IRB decides to disapprove a research 

activity, it shall include in its written 

notification a statement of the reasons 

for its decision and give the investigator 

an opportunity to respond in person or 

in writing. 

(e) An IRB shall conduct continuing 

review of research covered by this 

subpart at intervals appropriate to the 

degree of risk, but not less than once per 

year, and shall have authority to observe 

or have a third party observe the 

consent process and the research. 

§ 26.1110 Expedited review procedures for 

certain kinds of research involving no more 

than minimal risk, and for minor changes in 

approved research. 

(a) The Secretary, HHS, has 

established, and published as a Notice 

in the Federal Register, a list of 

categories of research that may be 

reviewed by the IRB through an 

expedited review procedure. The list 

will be amended, as appropriate after 

consultation with other departments 

and agencies, through periodic 

republication by the Secretary, HHS, in 

the Federal Register. A copy of the list 

is available from the Office for Human 

Research Protections, HHS, or any 

successor office. 

(b)(1) An IRB may use the expedited 

review procedure to review either or 

both of the following: 

(i) Some or all of the research 

appearing on the list and found by the 

reviewer(s) to involve no more than 

minimal risk, 

(ii) Minor changes in previously 

approved research during the period (of 

1 year or less) for which approval is 

authorized. 

(2) Under an expedited review 

procedure, the review may be carried 

out by the IRB chairperson or by one or 

more experienced reviewers designated 

by the chairperson from among 

members of the IRB. In reviewing the 

research, the reviewers may exercise all 

of the authorities of the IRB except that 

the reviewers may not disapprove the 

research. A research activity may be 

disapproved only after review in 

accordance with the non-expedited 

procedure set forth in § 26.1108(b). 

(c) Each IRB which uses an expedited 

review procedure shall adopt a method 

for keeping all members advised of 

research proposals which have been 

approved under the procedure. 

(d) The Administrator may restrict, 

suspend, or terminate, an institution’s 

or IRB’s use of the expedited review 

procedure for research covered by this 

subpart. 

§ 26.1111 Criteria for IRB approval of 

research. 

(a) In order to approve research 

covered by this subpart the IRB shall 

determine that all of the following 

requirements are satisfied: 

(1) Risks to subjects are minimized: 

(i) By using procedures which are 

consistent with sound research design 

and which do not unnecessarily expose 

subjects to risk, and 

(ii) Whenever appropriate, by using 

procedures already being performed on 

the subjects for diagnostic or treatment 

purposes. 

(2) Risks to subjects are reasonable in 

relation to anticipated benefits, if any, to 

subjects, and the importance of the 

knowledge that may reasonably be 

expected to result. In evaluating risks 

and benefits, the IRB should consider 

only those risks and benefits that may 

result from the research (as 

distinguished from risks and benefits 

subjects would receive even if not 

participating in the research). The IRB 

should not consider possible long-range 

effects of applying knowledge gained in 

the research (for example, the possible 

effects of the research on public policy) 

as among those research risks that fall 

within the purview of its responsibility. 

(3) Selection of subjects is equitable. 

In making this assessment the IRB 

should take into account the purposes of 

the research and the setting in which 

the research will be conducted and 

should be particularly cognizant of the 

special problems of research involving 

vulnerable populations, such as 

prisoners, mentally disabled persons, or 

economically or educationally 

disadvantaged persons. 

(4) Informed consent will be sought 

from each prospective subject or the 

subject’s legally authorized 

representative, in accordance with, and 

to the extent required by § 26.1116. 

(5) Informed consent will be 

appropriately documented, in 

accordance with, and to the extent 

required by § 26.1117. 

(6) When appropriate, the research 

plan makes adequate provision for 

monitoring the data collected to ensure 

the safety of subjects. 

(7) When appropriate, there are 

adequate provisions to protect the 

privacy of subjects and to maintain the 

confidentiality of data. 

(b) When some or all of the subjects 

are likely to be vulnerable to coercion or 

undue influence, such as prisoners, 

mentally disabled persons, or 

economically or educationally 

disadvantaged persons, additional 

safeguards have been included in the 

study to protect the rights and welfare 

of these subjects. 

§ 26.1112 Review by institution. 

Research covered by this subpart that 

has been approved by an IRB may be 

subject to further appropriate review 

and approval or disapproval by officials 

of the institution. However, those 

officials may not approve the research if 

it has not been approved by an IRB. 

§ 26.1113 Suspension or termination of 

IRB approval of research. 

An IRB shall have authority to 

suspend or terminate approval of 

research that is not being conducted in 

accordance with the IRB’s requirements 

or that has been associated with 

unexpected serious harm to subjects. 

Any suspension or termination of 

approval shall include a statement of 

the reasons for the IRB’s action and 

shall be reported promptly to the 

investigator, appropriate institutional 

officials, and the Administrator of EPA. 

§ 26.1114 Cooperative research. 

In complying with this subpart, 

sponsors, investigators, or institutions 

involved in multi-institutional studies 

may use joint review, reliance upon the 

review of another qualified IRB, or 

similar arrangements aimed at 

avoidance of duplication of effort. 

§ 26.1115 IRB records. 

(a) An IRB shall prepare and maintain 

adequate documentation of IRB 

activities, including the following: 

(1) Copies of all research proposals 

reviewed, scientific evaluations, if any, 

that accompany the proposals, approved 

sample consent documents, progress 

reports submitted by investigators, and 

reports of injuries to subjects. 

(2) Minutes of IRB meetings which 

shall be in sufficient detail to show 

attendance at the meetings; actions 

taken by the IRB; the vote on these 

actions including the number of 

members voting for, against, and 

abstaining; the basis for requiring 

changes in or disapproving research; 

and a written summary of the 


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discussion of controverted issues and 

their resolution. 

(3) Records of continuing review 

activities. 

(4) Copies of all correspondence 

between the IRB and the investigators. 

(5) A list of IRB members identified 

by name; earned degrees; representative 

capacity; indications of experience such 

as board certifications, licenses, etc., 

sufficient to describe each member’s 

chief anticipated contributions to IRB 

deliberations; and any employment or 

other relationship between each 

member and the institution, for 

example, full-time employee, a member 

of governing panel or board, 

stockholder, paid or unpaid consultant. 

(6) Written procedures for the IRB in 

the same detail as described in 

§ 26.1108(a) and § 26.1108(b). 

(7) Statements of significant new 

findings provided to subjects, as 

required by § 26.1116(b)(5). 

(b) The records required by this 

subpart shall be retained for at least 3 

years, and records relating to research 

which is conducted shall be retained for 

at least 3 years after completion of the 

research. All records shall be accessible 

for inspection and copying by 

authorized representatives of EPA at 

reasonable times and in a reasonable 

manner. 

§ 26.1116 General requirements for 

informed consent. 

No investigator may involve a human 

being as a subject in research covered by 

this subpart unless the investigator has 

obtained the legally effective informed 

consent of the subject or the subject’s 

legally authorized representative. An 

investigator shall seek such consent 

only under circumstances that provide 

the prospective subject or the 

representative sufficient opportunity to 

consider whether or not to participate 

and that minimize the possibility of 

coercion or undue influence. The 

information that is given to the subject 

or the representative shall be in 

language understandable to the subject 

or the representative. No informed 

consent, whether oral or written, may 

include any exculpatory language 

through which the subject or the 

representative is made to waive or 

appear to waive any of the subject’s 

legal rights, or releases or appears to 

release the investigator, the sponsor, the 

institution or its agents from liability for 

negligence. 

(a) Basic elements of informed 

consent. In seeking informed consent 

the following information shall be 

provided to each subject: 

(1) A statement that the study 

involves research, an explanation of the 

purposes of the research and the 

expected duration of the subject’s 

participation, a description of the 

procedures to be followed, and 

identification of any procedures which 

are experimental; 

(2) A description of any reasonably 

foreseeable risks or discomforts to the 

subject; 

(3) A description of any benefits to the 

subject or to others which may 

reasonably be expected from the 

research; 

(4) A disclosure of appropriate 

alternative procedures or courses of 

treatment, if any, that might be 

advantageous to the subject; 

(5) A statement describing the extent, 

if any, to which confidentiality of 

records identifying the subject will be 

maintained; 

(6) For research involving more than 

minimal risk, an explanation as to 

whether any compensation and an 

explanation as to whether any medical 

treatments are available if injury occurs 

and, if so, what they consist of, or where 

further information may be obtained; 

(7) An explanation of whom to 

contact for answers to pertinent 

questions about the research and 

research subjects’ rights, and whom to 

contact in the event of a research-related 

injury to the subject; and 

(8) A statement that participation is 

voluntary, refusal to participate will 

involve no penalty or loss of benefits to 

which the subject is otherwise entitled, 

and the subject may discontinue 

participation at any time without 

penalty or loss of benefits to which the 

subject is otherwise entitled. 

(b) Additional elements of informed 

consent. When appropriate, one or more 

of the following elements of information 

shall also be provided to each subject: 

(1) A statement that the particular 

treatment or procedure may involve 

risks to the subject (or to the embryo or 

fetus, if the subject may become 

pregnant) which are currently 

unforeseeable; 

(2) Anticipated circumstances under 

which the subject’s participation may be 

terminated by the investigator without 

regard to the subject’s consent; 

(3) Any additional costs to the subject 

that may result from participation in the 

research; 

(4) The consequences of a subject’s 

decision to withdraw from the research 

and procedures for orderly termination 

of participation by the subject; 

(5) A statement that significant new 

findings developed during the course of 

the research which may relate to the 

subject’s willingness to continue 

participation will be provided to the 

subject; and 

(6) The approximate number of 

subjects involved in the study. 

(c) The informed consent 

requirements in this subpart are not 

intended to preempt any applicable 

Federal, State, or local laws which 

require additional information to be 

disclosed in order for informed consent 

to be legally effective. 

(d) Nothing in this subpart is intended 

to limit the authority of a physician to 

provide emergency medical care, to the 

extent the physician is permitted to do 

so under applicable Federal, State, or 

local law. 

(e) If the research involves intentional 

exposure of subjects to a pesticide, the 

subjects of the research must be 

informed of the identity of the pesticide 

and the nature of its pesticidal function. 

§ 26.1117 Documentation of informed 

consent. 

(a) Informed consent shall be 

documented by the use of a written 

consent form approved by the IRB and 

signed by the subject or the subject’s 

legally authorized representative. A 

copy shall be given to the person 

signing the form. 

(b) The consent form may be either of 

the following: 

(1) A written consent document that 

embodies the elements of informed 

consent required by § 26.1116. This 

form may be read to the subject or the 

subject’s legally authorized 

representative, but in any event, the 

investigator shall give either the subject 

or the representative adequate 

opportunity to read it before it is signed; 

or 

(2) A short form written consent 

document stating that the elements of 

informed consent required by § 26.1116 

have been presented orally to the 

subject or the subject’s legally 

authorized representative. When this 

method is used, there shall be a witness 

to the oral presentation. Also, the IRB 

shall approve a written summary of 

what is to be said to the subject or the 

representative. Only the short form itself 

is to be signed by the subject or the 

representative. However, the witness 

shall sign both the short form and a 

copy of the summary, and the person 

actually obtaining consent shall sign a 

copy of the summary. A copy of the 

summary shall be given to the subject or 

the representative, in addition to a copy 

of the short form. 

§§ 26.1118 through 26.1122 [Reserved] 

§ 26.1123 Early termination of research. 

The Administrator may require that 

any project covered by this subpart be 

terminated or suspended when the 


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Administrator finds that an IRB, 

investigator, sponsor, or institution has 

materially failed to comply with the 

terms of this subpart. 

§ 26.1124 [Reserved] 

§ 26.1125 Prior submission of proposed 

human research for EPA review. 

Any person or institution who intends 

to conduct or sponsor human research 

covered by § 26.1101(a) shall, after 

receiving approval from all appropriate 

IRBs, submit to EPA prior to initiating 

such research all information relevant to 

the proposed research specified by 

§ 26.1115(a), and the following 

additional information, to the extent not 

already included: 

(a) A discussion of: 

(1) The potential risks to human 

subjects; 

(2) The measures proposed to 

minimize risks to the human subjects; 

(3) The nature and magnitude of all 

expected benefits of such research, and 

to whom they would accrue; 

(4) Alternative means of obtaining 

information comparable to what would 

be collected through the proposed 

research; and 

(5) The balance of risks and benefits 

of the proposed research. 

(b) All information for subjects and 

written informed consent agreements as 

originally provided to the IRB, and as 

approved by the IRB. 

(c) Information about how subjects 

will be recruited, including any 

advertisements proposed to be used. 

(d) A description of the circumstances 

and methods proposed for presenting 

information to potential human subjects 

for the purpose of obtaining their 

informed consent. 

(e) All correspondence between the 

IRB and the investigators or sponsors. 

(f) Official notification to the sponsor 

or investigator, in accordance with the 

requirements of this subpart, that 

research involving human subjects has 

been reviewed and approved by an IRB. 

Subpart L—Prohibition of Third-Party 

Research for Pesticides Involving 

Intentional Exposure of Human 

Subjects who are Pregnant Women or 

Children 

§ 26.1201 To what does this subpart 

apply? 

Subpart L applies to any person who, 

after April 7, 2006, conducts or supports 

research with a human subject intended: 

(1) For submission to EPA for 

consideration in connection with any 

action that may be performed by EPA 

under the Federal Insecticide, 

Fungicide, and Rodenticide Act (7 

U.S.C. 136 et seq.) or section 408 of the 

Federal Food, Drug, and Cosmetic Act 

(21 U.S.C. 346a); or 

(2) To be held for later inspection by 

EPA under the Federal Insecticide, 

Fungicide, and Rodenticide Act (7 

U.S.C. 136 et seq.) or section 408 of the 

Federal Food, Drug, and Cosmetic Act 

21 U.S.C. 346a). 

(b) For purposes of determining a 

person’s intent under paragraph (a) of 

this section, EPA may consider any 

available information relevant to 

determining the intent of a person who 

conducts or supports research with 

human subjects after the effective date 

of the rule. EPA shall rebuttably 

presume such intent existed if: 

(1) The person or the person’s agent 

has submitted or made available for 

inspection the results of such research 

to EPA; or 

(2) The person is a member of a class 

of people who, or whose products or 

activities, are regulated by EPA under 

FIFRA or the FFDCA and, at the time 

the research was initiated, the results of 

the research would be relevant to EPA’s 

exercise of its authority under FIFRA or 

the FFDCA with respect to that class of 

people, products, or activities. 

§ 26.1202 Definitions. 

The definitions in § 26.1102 shall be 

applicable to this subpart as well. In 

addition, the definitions at 45 CFR 

46.202(a) through (f) and at 45 CFR 

46.202(h) are applicable to this subpart. 

In addition, a child is a person who has 

not attained the age of 18 years. 

§ § 26.1203 Prohibition of research 

involving intentional exposure of any 

pregnant woman, fetus, or child. 

Notwithstanding any other provision 

of this part, under no circumstances 

shall a person conduct or sponsor 

research covered by § 26.1201 that 

involves intentional exposure of any 

human subject who is a pregnant 

woman (and therefore her fetus) or 

child. 

Subpart M—Requirements for 

Submission of Information on the 

Ethical Conduct of Completed Human 

Research 

§ 26.1301 To what does this subpart 

apply? 

This subpart applies to any person 

who submits a report containing the 

results of any human research if: 

(a) The report is submitted after April 

7, 2006, and 

(b) The report is submitted for 

consideration in connection with any 

action that may be performed by EPA 

under the Federal Insecticide, 

Fungicide, and Rodenticide Act (7 

U.S.C. 136 et seq.) or section 408 of the 

Federal Food, Drug, and Cosmetic Act 

(21 U.S.C. 346a). 

§ 26.1302 Definitions. 

The definitions in § 26.102 shall 

apply to this subpart as well. 

§ 26.1303 Submission of information 

pertaining to ethical conduct of completed 

human research. 

Any person who submits to EPA data 

derived from human research covered 

by this subpart shall provide at the time 

of submission information concerning 

the ethical conduct of such research. To 

the extent available to the submitter and 

not previously provided to EPA, such 

information should include: 

(a) Copies of all of the records 

relevant to the research specified by 

§ 26.1115(a) to be prepared and 

maintained by an IRB. 

(b) Copies of all of the records 

relevant to the information identified in 

§ 26.1125(a) through (f). 

(c) Copies of sample records used to 

document informed consent as specified 

by § 26.1117, but not identifying any 

subjects of the research. 

(d) If any of the information listed in 

paragraphs (a) through (c) of this section 

is not provided, the person shall 

describe the efforts made to obtain the 

information. 

Subpart N—[Reserved] 

Subpart O—Administrative Actions for 

Noncompliance 

§ 26.1501 To what does this subpart 

apply? 

This subpart applies to any human 

research subject to subparts A through 

L of this part. References to State or 

local laws in this subpart are intended 

to include the laws of federally 

recognized American Indian and Alaska 

Native Tribal Governments. 

§ 26.1502 Lesser administrative actions. 

(a) If apparent noncompliance with 

the applicable regulations in subparts A 

through L of this part concerning the 

operation of an IRB is observed by an 

officer or employee of EPA or of any 

State duly designated by the 

Administrator during an inspection. 

EPA may send a letter describing the 

noncompliance to the IRB and to the 

parent institution. The agency will 

require that the IRB or the parent 

institution respond to this letter within 

a reasonable time period specified by 

EPA and describe the corrective actions 

that will be taken by the IRB, the 

institution, or both to achieve 

compliance with these regulations. 

(b) On the basis of the IRB’s or the 

institution’s response, EPA may 


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schedule a reinspection to confirm the 

adequacy of corrective actions. In 

addition, until the IRB or the parent 

institution takes appropriate corrective 

action, the Agency may: 

(1) Withhold approval of new studies 

subject to the requirements of this part 

that are conducted at the institution or 

reviewed by the IRB; 

(2) Direct that no new subjects be 

added to ongoing studies subject to this 

part; 

(3) Terminate ongoing studies subject 

to this part when doing so would not 

endanger the subjects; or 

(4) When the apparent noncompliance 

creates a significant threat to the rights 

and welfare of human subjects, notify 

relevant State and Federal regulatory 

agencies and other parties with a direct 

interest of the deficiencies in the 

operation of the IRB. 

(c) The parent institution is presumed 

to be responsible for the operation of an 

IRB, and EPA will ordinarily direct any 

administrative action under this subpart 

against the institution. However, 

depending on the evidence of 

responsibility for deficiencies, 

determined during the investigation, 

EPA may restrict its administrative 

actions to the IRB or to a component of 

the parent institution determined to be 

responsible for formal designation of the 

IRB. 

§ 26.1503 Disqualification of an IRB or an 

institution. 

(a) Whenever the IRB or the 

institution has failed to take adequate 

steps to correct the noncompliance 

stated in the letter sent by the Agency 

under § 26.1502(a) and the EPA 

Administrator determines that this 

noncompliance may justify the 

disqualification of the IRB or of the 

parent institution, the Administrator 

may institute appropriate proceedings. 

(b) The Administrator may disqualify 

an IRB or the parent institution from 

studies subject to this part if the 

Administrator determines that: 

(1) The IRB has refused or repeatedly 

failed to comply with any of the 

regulations set forth in this part, and 

(2) The noncompliance adversely 

affects the rights or welfare of the 

human subjects of research. 

(c) If the Administrator determines 

that disqualification is appropriate, the 

Administrator will issue an order that 

explains the basis for the determination 

and that prescribes any actions to be 

taken with regard to ongoing human 

research, covered by subparts A through 

L of this part, conducted under the 

review of the IRB. EPA will send notice 

of the disqualification to the IRB and the 

parent institution. Other parties with a 

direct interest, such as sponsors and 

investigators, may also be sent a notice 

of the disqualification. In addition, the 

agency may elect to publish a notice of 

its action in the Federal Register. 

(d) EPA may refuse to consider in 

support of a regulatory decision the data 

from human research, covered by 

subparts A through L of this part, that 

was reviewed by an IRB or conducted at 

an institution during the period of 

disqualification, unless the IRB or the 

parent institution is reinstated as 

provided in § 26.1505, or unless such 

research is deemed scientifically sound 

and crucial to the protection of public 

health, under the procedure defined in 

§ 26.1706. 

§ 26.1504 Public disclosure of information 

regarding revocation. 

A determination that EPA has 

disqualified an institution from studies 

subject to this part and the 

administrative record regarding that 

determination are disclosable to the 

public under 40 CFR part 2. 

§ 26.1505 Reinstatement of an IRB or an 

institution. 

An IRB or an institution may be 

reinstated to conduct studies subject to 

this part if the Administrator 

determines, upon an evaluation of a 

written submission from the IRB or 

institution that explains the corrective 

action that the institution or IRB has 

taken or plans to take, that the IRB or 

institution has provided adequate 

assurance that it will operate in 

compliance with the standards set forth 

in this part. Notification of 

reinstatement shall be provided to all 

persons notified under § 26.1502(c). 

§ 26.1506 Debarment. 

If EPA determines that an institution 

or investigator repeatedly has not 

complied with or has committed an 

egregious violation of the applicable 

regulations in subparts A through L of 

this part, EPA may recommend that 

institution or investigator be declared 

ineligible to participate in EPAsupported research (debarment). 

Debarment will be initiated in 

accordance with procedures specified at 

40 CFR part 32. 

§ 26.1507 Actions alternative or additional 

to disqualification. 

Disqualification of an IRB or of an 

institution is independent of, and 

neither in lieu of nor a precondition to, 

other statutorily authorized proceedings 

or actions. EPA may, at any time, on its 

own initiative or through the 

Department of Justice, institute any 

appropriate judicial proceedings (civil 

or criminal) and any other appropriate 

regulatory action, in addition to or in 

lieu of, and before, at the time of, or 

after, disqualification. The Agency may 

also refer pertinent matters to another 

Federal, State, or local government 

agency for any action that that agency 

determines to be appropriate. 

Subpart P—Review of Proposed and 

Completed Human Research 

§ 26.1601 EPA review of proposed human 

research. 

(a) EPA shall review all protocols 

submitted under § 26.1125 in a timely 

manner. With respect to any research or 

any class of research, the Administrator 

may recommend additional conditions 

which, in the judgment of the 

Administrator, are necessary for the 

protection of human subjects. 

(b) In reviewing proposals covered by 

this subpart, the Administrator may take 

into account factors such as whether the 

applicant has been subject to a 

termination or suspension under 

§ 26.123(a) or § 26.1123 and whether the 

applicant or the person or persons who 

would direct or has/have directed the 

scientific and technical aspects of an 

activity has/have, in the judgment of the 

Administrator, materially failed to 

discharge responsibility for the 

protection of the rights and welfare of 

human subjects (whether or not the 

research was subject to Federal 

regulation). 

(c) When research covered by subpart 

K takes place in foreign countries, 

procedures normally followed in the 

foreign countries to protect human 

subjects may differ from those set forth 

in subpart K. (An example is a foreign 

institution which complies with 

guidelines consistent with the World 

Medical Assembly Declaration of 

Helsinki, issued either by sovereign 

states or by an organization whose 

function for the protection of human 

research subjects is internationally 

recognized.) In these circumstances, if 

the Administrator determines that the 

procedures prescribed by the institution 

afford protections that are at least 

equivalent to those provided in subpart 

K, the Administrator may approve the 

substitution of the foreign procedures in 

lieu of the procedural requirements 

provided in subpart K. 

(d) Following initial evaluation of the 

protocol by Agency staff, EPA shall 

submit the protocol and all supporting 

materials, together with the staff 

evaluation, to the Human Studies 

Review Board. 

(e) EPA shall notify the submitter of 

the proposal of the results of the EPA 

and Human Studies Review Board 

reviews. 


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§ 26.1602 EPA review of completed human 

research. 

(a) When considering data under 

FIFRA or FFDCA from research 

involving intentional exposure of 

humans, EPA shall review the material 

submitted under § 26.1303 and other 

available, relevant information and 

document its conclusions regarding the 

scientific and ethical conduct of the 

research. 

(b) EPA shall submit its review of data 

from human research covered by 

subpart Q, together with the available 

supporting materials, to the Human 

Studies Review Board if EPA decides to 

rely on the data and: 

(1) The data are derived from research 

initiated after April 7, 2006, or 

(2) The data are derived from research 

initiated before April 7, 2006, and the 

research was conducted for the purpose 

of identifying or measuring a toxic 

effect. 

(c) In its discretion, EPA may submit 

data from research not covered by 

paragraph (b) of this section to the 

Human Studies Review Board for their 

review. 

(d) EPA shall notify the submitter of 

the research of the results of the EPA 

and Human Studies Review Board 

reviews. 

§ 26.1603 Operation of the Human Studies 

Review Board. 

EPA shall establish and operate a 

Human Studies Review Board as 

follows: 

(a) Membership. The Human Studies 

Review Board shall consist of members 

who are not employed by EPA, who 

meet the ethics and other requirements 

for special government employees, and 

who have expertise in fields appropriate 

for the scientific and ethical review of 

human research, including research 

ethics, biostatistics, and human 

toxicology. 

(b) Responsibilities. The Human 

Studies Review Board shall comment on 

the scientific and ethical aspects of 

research proposals and reports of 

completed research with human 

subjects submitted by EPA for its review 

and, on request, advise EPA on ways to 

strengthen its programs for protection of 

human subjects of research. 

Subpart Q—Ethical Standards for 

Assessing Whether to Rely on the 

Results of Human Research in EPA 

Actions 

§ 26.1701 To what does this subpart 

apply? 

This subpart applies to EPA’s 

decisions whether to rely in its actions 

taken under the Federal Insecticide, 

Fungicide, and Rodenticide Act (7 

U.S.C. 136 et seq.) or section 408 of the 

Federal Food, Drug, and Cosmetic Act 

(21 U.S.C. 346a) on scientifically valid 

and relevant data from research 

involving intentional exposure of 

human subjects. 

§ 26.1702 Definitions. 

The definitions in § 26.1102 and 

§ 26.1202 shall apply to this subpart as 

well. 

§ 26.1703 Prohibition of reliance on 

research involving intentional exposure of 

human subjects who are pregnant women 

(and therefore their fetuses) or children. 

Except as provided in § 26.1706, in 

actions within the scope of § 26.1701, 

EPA shall not rely on data from any 

research involving intentional exposure 

of any human subject who is a pregnant 

woman (and therefore her fetus) or 

child. 

§ 26.1704 Prohibition of reliance on 

unethical human research with nonpregnant adults conducted before April 7, 

2006. 

Except as provided in § 26.1706, in 

actions within the scope of § 26.1701, 

EPA shall not rely on data from any 

research initiated before April 7, 2006, 

if there is clear and convincing evidence 

that the conduct of the research was 

fundamentally unethical (e.g., the 

research was intended to seriously harm 

participants or failed to obtain informed 

consent), or was significantly deficient 

relative to the ethical standards 

prevailing at the time the research was 

conducted. This prohibition is in 

addition to the prohibition in § 26.1703. 

§ 26.1705 Prohibition of reliance on 

unethical human research with nonpregnant adults conducted after April 7, 

2006. 

Except as provided in § 26.1706, in 

actions within the scope of § 26.1701, 

EPA shall not rely on data from any 

research initiated after April 7, 2006, 

unless EPA has adequate information to 

determine that the research was 

conducted in substantial compliance 

with subparts A through L of this part, 

or if conducted in a foreign country, 

under procedures at least as protective 

as those in subparts A through L of this 

part. This prohibition is in addition to 

the prohibition in § 26.1703. 

§ 26.1706 Criteria and procedure for 

decisions to protect public health by relying 

on otherwise unacceptable research. 

This section establishes the exclusive 

criteria and procedure by which EPA 

may decide to rely on data from 

research that is not acceptable under the 

standards in §§ 26.1703 through 

26.1705. EPA may rely on such data 

only if all the conditions in paragraphs 

(a) through (d) of this section are 

satisfied: 

(a) EPA has obtained the views of the 

Human Studies Review Board 

concerning the proposal to rely on the 

otherwise unacceptable data, 

(b) EPA has provided an opportunity 

for public comment on the proposal to 

rely on the otherwise unacceptable data, 

(c) EPA has determined that relying 

on the data is crucial to a decision that 

would impose a more stringent 

regulatory restriction that would 

improve protection of public health, 

such as a limitation on the use of a 

pesticide, than could be justified 

without relying on the data, and 

(d) EPA publishes a full explanation 

of its decision to rely on the otherwise 

unacceptable data, including a thorough 

discussion of the ethical deficiencies of 

the underlying research and the full 

rationale for finding that the standard in 

paragraph (c) of this section was met. 

[FR Doc. 06–1045 Filed 2–3–06; 8:45 am] 

BILLING CODE 6560–50–S 


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