Federal Register / Vol. 76, No. 22 / Wednesday, February 2, 2011 / Proposed Rules 5735 

ENVIRONMENTAL PROTECTION 

AGENCY 

40 CFR Part 26 

[EPA–HQ–OPP–2010–0785; FRL–8862–7] 

RIN 2070–AJ76 

Revisions to EPA’s Rule on 

Protections for Subjects in Human 

Research Involving Pesticides 

AGENCY: Environmental Protection 

Agency (EPA). 

ACTION: Proposed rule. 

SUMMARY: EPA proposes to amend the 

portions of its rules for the protection of 

human subjects of research applying to 

third parties who conduct or support 

research with pesticides involving 

intentional exposure of human subjects 

and to persons who submit the results 

of human research with pesticides to 

EPA. The proposed amendments would 

broaden the applicability of the rules to 

cover human testing with pesticides 

submitted to EPA under any regulatory 

statute it administers. They would also 

disallow participation in third-party 

pesticide studies by subjects who 

cannot consent for themselves. Finally 

the proposed amendments would 

identify specific considerations to be 

addressed in EPA science and ethics 

reviews of proposed and completed 

human research with pesticides, drawn 

from the recommendations of the 

National Academy of Sciences (NAS). In 

seeking comments on these proposed 

amendments, EPA does not imply that 

the current Federal Policy for the 

Protection of Human Subjects (the 

‘‘Common Rule’’), which governs 

research with human subjects 

conducted or supported by EPA and 

many other Federal departments and 

agencies, is inadequate. Indeed, the 

amendments proposed here would make 

no changes to the Common Rule or 

EPA’s codification of the Common Rule. 

Rather, EPA is proposing these 

amendments to other portions of its 

regulation as a result of a settlement 

agreement, and is now seeking comment 

on these proposed amendments. The 

settlement agreement makes clear that 

EPA retains full discretion concerning 

what amendments are proposed, and 

what, if any, amendments are finalized. 

Furthermore, no research has been 

identified that is outside the scope of 

EPA’s current rule, but that would be 

within the scope of these proposed 

amendments. EPA seeks comments on 

the need for and value of the proposed 

changes. 

DATES: Comments must be received on 

or before April 4, 2011. 

ADDRESSES: Submit your comments, 

identified by docket identification (ID) 

number EPA–HQ–OPP–2010–0785, by 

one of the following methods: 

• Federal eRulemaking Portal: http:// 

www.regulations.gov. Follow the on-line 

instructions for submitting comments. 

• Mail: Office of Pesticide Programs 

(OPP) Regulatory Public Docket (7502P), 

Environmental Protection Agency, 1200 

Pennsylvania Ave., NW., Washington, 

DC 20460–0001. 

• Delivery: OPP Regulatory Public 

Docket (7502P), Environmental 

Protection Agency, Rm. S–4400, One 

Potomac Yard (South Bldg.), 2777 S. 

Crystal Dr., Arlington, VA. Deliveries 

are only accepted during the Docket 

Facility’s normal hours of operation 

(8:30 a.m. to 4 p.m., Monday through 

Friday, excluding legal holidays). 

Special arrangements should be made 

for deliveries of boxed information. The 

Docket Facility telephone number is 

(703) 305–5805. 

Instructions: Direct your comments to 

docket ID number EPA–HQ–OPP–2010– 

0785. EPA’s policy is that all comments 

received will be included in the docket 

without change and may be made 

available on-line at http:// 

www.regulations.gov, including any 

personal information provided, unless 

the comment includes information 

claimed to be Confidential Business 

Information (CBI) or other information 

whose disclosure is restricted by statute. 

Do not submit information that you 

consider to be CBI or otherwise 

protected through regulations.gov or email. The regulations.gov Web site is an 

‘‘anonymous access’’ system, which 

means EPA will not know your identity 

or contact information unless you 

provide it in the body of your comment. 

If you send an e-mail comment directly 

to EPA without going through 

regulations.gov, your e-mail address 

will be automatically captured and 

included as part of the comment that is 

placed in the docket and made available 

on the Internet. If you submit an 

electronic comment, EPA recommends 

that you include your name and other 

contact information in the body of your 

comment and with any disk or CD–ROM 

you submit. If EPA cannot read your 

comment due to technical difficulties 

and cannot contact you for clarification, 

EPA may not be able to consider your 

comment. Electronic files should avoid 

the use of special characters, any form 

of encryption, and be free of any defects 

or viruses. 

Docket: All documents in the docket 

are listed in the docket index available 

at http://www.regulations.gov. Although 

listed in the index, some information is 

not publicly available, e.g., CBI or other 

information whose disclosure is 

restricted by statute. Certain other 

material, such as copyrighted material, 

is not placed on the Internet and will be 

publicly available only in hard copy 

form. Publicly available docket 

materials are available either in the 

electronic docket at http:// 

www.regulations.gov, or, if only 

available in hard copy, at the OPP 

Regulatory Public Docket in Rm. S– 

4400, One Potomac Yard (South Bldg.), 

2777 S. Crystal Dr., Arlington, VA. The 

hours of operation of this Docket 

Facility are from 8:30 a.m. to 4 p.m., 

Monday through Friday, excluding legal 

holidays. The Docket Facility telephone 

number is (703) 305–5805. 

FOR FURTHER INFORMATION CONTACT: 

Kelly Sherman, Immediate Office of the 

Director (7501P), Office of Pesticide 

Programs, Environmental Protection 

Agency, 1200 Pennsylvania Ave., NW., 

Washington, DC 20460–0001; telephone 

number: (703) 305–8401; fax number: 

(703) 308–4776; e-mail address: 

sherman.kelly@epa.gov. 

SUPPLEMENTARY INFORMATION: 

I. General Information 

A. Does this action apply to me? 

You may be potentially affected by 

this action if you sponsor, conduct, 

review, or submit to EPA research with 

pesticides involving human subjects. 

Potentially affected entities may 

include, but are not limited to: 

• Pesticide and other agricultural 

chemical manufacturers (NAICS code 

325320) who sponsor or conduct human 

research with pesticides. 

• Other entities (NAICS code 541710) 

that sponsor or conduct human research 

with pesticides, and Institutional 

Review Boards who review human 

research with pesticides to ensure it 

meets applicable standards of ethical 

conduct. 

This listing is not intended to be 

exhaustive, but rather provides a guide 

for readers 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) codes are provided to assist 

you and others in determining whether 

this action might apply to certain 

entities. If you have any questions 

regarding the applicability of this action 

to a particular entity, consult the person 

listed under FOR FURTHER INFORMATION

CONTACT. 

B. What should I consider as I prepare 

my comments for EPA? 

1. Submitting CBI. Do not submit 

confidential business information (CBI) 

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5736 Federal Register / Vol. 76, No. 22 / Wednesday, February 2, 2011 / Proposed Rules 

to EPA through regulations.gov or email. Clearly mark the part or all of the 

information that you claim to be CBI. 

For CBI information in a disk or CD– 

ROM that you mail to EPA, mark the 

outside of the disk or CD–ROM as CBI 

and then identify electronically within 

the disk or CD–ROM the specific 

information that is claimed as CBI. In 

addition to one complete version of the 

comment that includes information 

claimed as CBI, a copy of the comment 

that does not contain the information 

claimed as CBI must be submitted for 

inclusion in the public docket. 

Information so marked will not be 

disclosed except in accordance with 

procedures set forth in 40 CFR part 2. 

2. Tips for preparing your comments. 

When submitting comments, remember 

to: 

a. Identify the document by docket ID 

number and other identifying 

information (subject heading, Federal 

Register date and page number). 

b. Follow directions. The Agency may 

ask you to respond to specific questions 

or organize comments by referencing a 

Code of Federal Regulations (CFR) part 

or section number. 

c. Explain why you agree or disagree; 

suggest alternatives and substitute 

language for your requested changes. 

d. Describe any assumptions and 

provide any technical information and/ 

or data that you used. 

e. If you estimate potential costs or 

burdens, explain how you arrived at 

your estimate in sufficient detail to 

allow for it to be reproduced. 

f. Provide specific examples to 

illustrate your concerns and suggest 

alternatives. 

g. Explain your views as clearly as 

possible, avoiding the use of profanity 

or personal threats. 

h. Make sure to submit your 

comments by the comment period 

deadline identified. 

II. Background 

A. What would the proposed 

amendments do? 

The proposed amendments would 

change the 2006 rule, published in the 

Federal Register issue of February 6, 

2006 (71 FR 6138) (FRL–7759–8), 

subsequently amended on June 23, 2006 

(71 FR 36171) (FRL–8071–6), and 

codified at 40 CFR part 26, in the 

following substantive respects: 

• By broadening the applicability of 

40 CFR part 26, subparts K, L, M, and 

Q, so these subparts would apply not 

only to research submitted to or 

considered by EPA under the pesticide 

laws, but also to research involving a 

‘‘pesticide’’ (as defined in the Federal 

Insecticide, Fungicide, and Rodenticide 

Act (FIFRA) (7 U.S.C. 136(u)) which is 

submitted to or considered by EPA 

under any other regulatory statute it 

administers. 

• By incorporating the definition of 

‘‘pesticide’’ from FIFRA, as a substance 

or mixture of substances intended for 

pesticidal effect. 

• By deleting from 40 CFR part 26, 

subpart K, all references to consent on 

behalf of a subject in research involving 

intentional exposure to a pesticide by a 

subject’s ‘‘legally authorized 

representative.’’ 

• By incorporating into 40 CFR part 

26, subparts P and Q, factors to be 

considered by EPA and the Human 

Studies Review Board (HSRB) in their 

review of proposed and completed 

research, derived from the 

recommendations of NAS in its 2004 

Report to EPA, and from the Nuremberg 

Code. 

The amendments proposed here 

would make no changes to the Federal 

Policy for the Protection of Human 

Subjects (the ‘‘Common Rule’’), which 

governs research with human subjects 

conducted or supported by EPA and 

many other Federal departments and 

agencies. EPA’s codification of the 

Common Rule appears as subpart A in 

40 CFR part 26. 

Subparts B, C, and D of 40 CFR part 

26 would also be unchanged by these 

proposed amendments. These subparts 

categorically prohibit any EPA research 

involving intentional exposure to any 

substance of human subjects who are 

children or pregnant or nursing women 

(40 CFR part 26, subpart B), and provide 

extra protections for pregnant women 

and for children who are the subjects of 

observational research conducted or 

supported by EPA (40 CFR part 26, 

subparts C and D). 

The proposed amendments would 

retain without substantive change the 

core provisions of the 2006 rule 

applying to the conduct of human 

pesticide research by third parties—i.e., 

research neither conducted nor 

supported by EPA or another Common 

Rule Federal department or agency. 

These substantively unchanged 

provisions: 

• Categorically prohibit new research 

involving intentional exposure of 

pregnant or nursing women or of 

children to a pesticide (40 CFR part 26, 

subpart L). 

• Apply the provisions of the 

Common Rule to third-party human 

research involving intentional exposure 

of non-pregnant, non-nursing adults to a 

pesticide (40 CFR part 26, subpart K). 

• Require submission to EPA of 

proposals for new covered research 

before it is initiated (40 CFR part 26, 

subpart K, § 26.1125). 

• Require persons who submit to EPA 

reports of completed human research on 

pesticides to document the ethical 

conduct of that research (40 CFR part 

26, subpart M). 

• Establish an independent HSRB to 

review and advise EPA concerning both 

proposals for new human research 

involving intentional exposure to a 

pesticide and reports of completed 

research on which EPA proposes to rely 

in its actions (40 CFR part 26, subpart 

P). 

The proposed amendments would 

make only minor editorial revisions to 

40 CFR part 26, subpart O, which 

defines administrative actions available 

to EPA to address non-compliance with 

40 CFR part 26, subparts A through L. 

The proposed amendments would 

retain the essential structure of 40 CFR 

part 26, subpart P, which defines the 

processes of EPA and HSRB review of 

proposed and completed research. The 

amendments, however, would also add 

substantial new clarifying language to 

40 CFR part 26, subpart P, as discussed 

in detail in Unit IV.C. of this document. 

The proposed amendments would 

retain the essential structure of 40 CFR 

part 26, subpart Q, which defines the 

standards to be applied when EPA 

proposes to rely on data from completed 

research involving intentional exposure 

of human subjects to a pesticide. The 

amendments, however, would also add 

substantial new clarifying language to 

40 CFR part 26, subpart Q, as discussed 

in detail in Unit IV.D. of this document. 

The proposed amendments would not 

change the provision in 40 CFR part 26, 

subpart Q, forbidding EPA to rely on 

any otherwise unacceptable research 

involving intentional exposure of 

human subjects to a pesticide, except 

under extremely restrictive conditions. 

These conditions require a public 

review by HSRB, an opportunity for 

public comment, and a showing by EPA 

that to do so would result in a more 

protective regulatory standard than 

could be justified without reliance on 

the unethical research. 

B. What is the agency’s authority for 

taking this action? 

The legal authority for the 2006 rule 

on human research is set forth in the 

preamble to that final rule (71 FR 6138, 

February 6, 2006) (FRL–7759–8). These 

proposed amendments to that rule rest 

upon the same legal authority. In 

particular, the legal authority for 

expanding the 2006 rule to cover 

research involving the intentional 

exposure of a human subject to a 

pesticide submitted under any EPA 

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Federal Register / Vol. 76, No. 22 / Wednesday, February 2, 2011 / Proposed Rules 5737 

regulatory statute is provided by section 

201 of the Department of the Interior, 

Environment, and Related Agencies 

Appropriations Act, 2006, Public Law 

109–54 (2006 Appropriations Act), and 

FIFRA. 

The 2006 Appropriations Act directly 

mandates that EPA promulgate a rule on 

‘‘third-party intentional dosing human 

toxicity studies for pesticides * * *’’ 

without limiting the rule to pesticide 

studies submitted under FIFRA or 

section 408 of the Federal Food, Drug, 

and Cosmetic Act (FFDCA) (21 U.S.C. 

346a). 

Additionally, under FIFRA, EPA has 

the authority to issue regulations as to 

both unregistered and registered 

pesticides used in research involving 

the intentional exposure of a human 

subject, whether or not that research is 

conducted for submission under FIFRA. 

Section 3(a) of FIFRA authorizes EPA 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’’). EPA concludes that there 

would be an unreasonable risk to 

humans if unregistered pesticides were 

used in research involving intentional 

exposure of human subjects (or sold and 

distributed for such use) that is not 

already covered by the Common Rule 

absent compliance with the applicable 

rules in 40 CFR part 26, as proposed. 

The importance of these rules to the 

protection of human subjects is 

demonstrated in the 2004 Report from 

the National Research Council of the 

NAS, entitled ‘‘Intentional Human 

Dosing Studies for EPA Regulatory 

Purposes: Scientific and Ethical Issues’’ 

(2004 NAS Report) (http:// 

www.national-academies.org). 

Section 25(a) of FIFRA authorizes 

EPA to ‘‘prescribe regulations to carry 

out the provisions of [FIFRA].’’ (7 U.S.C. 

136w(a)). Regulations protecting human 

subjects in research involving the 

intentional exposure of human subjects 

to registered pesticides fall within that 

purview. FIFRA provides that a 

pesticide may not be registered unless 

use of the pesticide under its labeling 

will not cause unreasonable risks to 

humans or the environment, that a 

pesticide may not be used inconsistent 

with its label, and that a pesticide may 

not be used in human testing unless the 

subjects are fully informed regarding the 

nature, purpose, and physical and 

mental health consequences of the 

testing and freely volunteer. (See 7 

U.S.C. 136(bb), 136a(c)(5), 136j(a)(2)(G), 

136j(a)(2)(P)). The 2006 rule and the 

amendments proposed in this document 

ensure that these provisions regarding 

use of registered pesticides in a manner 

that does not cause unreasonable risk 

and full and free consent in human 

testing with pesticides are effectuated. 

III. EPA’s Human Subjects Protection 

Rules 

A. Overarching Principles 

EPA is committed to relying on 

scientifically sound research that is 

ethically conducted, and to 

transparency in its review processes and 

decision-making. EPA issued the 2006 

rule to further these commitments and 

nothing in the amendments proposed in 

this document will change that. These 

proposed amendments can be seen as 

increasing the transparency of EPA’s 

decision-making process by clarifying 

the scope and applicability of the 

requirements in 40 CFR part 26, 

codifying the scope and approach used 

in EPA’s science and ethics reviews of 

human research involving pesticides. 

B. Appropriations Act of 2006 

In August 2005, in the 2006 

Appropriations Act, which appropriated 

funds for EPA and other Federal 

departments and agencies for FY 2006, 

Congress included at section 201 the 

following provision: 

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. 

In response, EPA published a 

proposed rule in the Federal Register 

issue of September 12, 2005 (70 FR 

53838) (FRL–7728–2), accepted public 

comment until December 12, 2005, and 

promulgated on February 6, 2006, a 

final rule which took effect on April 7, 

2006 (71 FR 6138) (FRL–7759–8). The 

2006 rule, as subsequently amended on 

June 23, 2006, to extend special 

protections to nursing women as well 

(71 FR 36171) (FRL–8071–6), is 

discussed in Unit III.E. and is now being 

further amended by this proposed rule. 

C. EPA’s 2006 Rule 

1. Summary of contents. The 2006 

rule established a set of protections for 

people participating as subjects in thirdparty human research with pesticides. 

(In this context ‘‘third-party’’ research is 

research neither conducted (‘‘firstparty’’) nor supported (‘‘second-party’’) 

by EPA or another Common Rule 

Federal department or agency.) The 

2006 rule bans all third-party research 

on pesticides involving intentional 

exposure of children or of pregnant or 

nursing women. It further forbids EPA 

itself to conduct or support any research 

involving intentional exposure of 

pregnant or nursing women or of 

children to any substance. EPA was 

required to promulgate the 2006 rule by 

the 2006 Appropriations Act. 

The 2006 rule also extends the ethical 

protections in the Common Rule to 

third-party studies of non-pregnant, 

non-nursing adult subjects intentionally 

exposed to pesticides. The key 

provisions of the 2006 rule include: 

• Requiring pre-implementation 

submission to EPA of protocols and 

related information about proposed 

research to ensure any future studies 

meet high ethical standards. 

• Establishing an independent HSRB 

to obtain expert peer review of both 

proposals for new research intended for 

submission to EPA and reports of 

completed human research involving 

intentional exposure on which EPA 

proposes to rely in an action taken 

under the pesticide laws. 

• Prohibiting EPA from relying on the 

results of research in its actions under 

the pesticide laws unless EPA 

determines that the research meets 

acceptance standards derived from the 

recommendations in the 2004 NAS 

Report. 

2. Research with pesticides since 

promulgation of the 2006 rule. Contrary 

to some predictions, the 2006 rule has 

not led to an upsurge in human research 

with pesticides for submission to EPA 

under FIFRA or FFDCA. Since 

promulgation of the 2006 rule EPA has 

received no proposals at all for research 

on the toxicity of a pesticide to human 

subjects, and has received significantly 

fewer than were projected proposals for 

new research of other kinds (e.g., insect 

repellent studies). In the analyses 

supporting the 2006 rule, EPA estimated 

33 new intentional exposure studies 

would be submitted each year; in fact, 

only 26 proposals for new research on 

pesticides for submission to EPA under 

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5738 Federal Register / Vol. 76, No. 22 / Wednesday, February 2, 2011 / Proposed Rules 

1For more details on this finding, see the study 

report available on the HSRD Web site at http:// 

www.epa.gov/hsrb/index.htm. 

FIFRA and FFDCA have been submitted 

over a span of approximately 5 years, or 

just over 5 per year. 

3. Overview of HSRB reviews. EPA’s 

experience in implementing the 2006 

rule is critical to understanding the 

amendments proposed in this 

document. The public meetings of 

HSRB have served as key milestones in 

the implementation of the 2006 rule, 

and the implementation of the 2006 rule 

can be best characterized by 

summarizing what HSRB has been 

called upon to review. HSRB met for the 

first time in April 2006, immediately 

after the 2006 rule became effective, and 

has met 14 times since then, most 

recently in October 2010. At these 

meetings, HSRB has reviewed both 

reports of completed research and 

proposals for new research. Specifically, 

HSRB has reviewed: 

• Completed reports of pre-2006 rule 

research reporting toxic endpoints. 

These have included intentional 

exposure toxicity tests initiated both 

before and after passage of the Food 

Quality Protection Act (FQPA) in 1996, 

as well as therapeutic trials of 

substances used both as drugs and as 

pesticides, reporting side effects 

relevant to EPA pesticide risk 

assessments. 

• Proposals for and reports of new 

research involving intentional exposure 

to materials used in the research as 

pesticides. 

a. Pre-rule research reporting toxic 

endpoints. At its first two meetings in 

April and May 2006, HSRB reviewed 28 

reports of pre-rule research conducted 

with 11 substances. At all its subsequent 

meetings combined the Board has 

reviewed 14 more such reports. Half of 

these 42 reports were published; the rest 

were unpublished reports submitted 

directly to EPA by pesticide companies. 

Of the 42 reports, 37 reported nontherapeutic research, and 5 were 

published reports of therapeutic trials 

that described side effects relevant to 

pesticide risk assessments. We 

summarize the disposition of each of the 

42 studies in the following paragraphs, 

and additional details may be accessed 

in the study specific reports available on 

the HSRB Web site at http:// 

www.epa.gov/hsrb/index.htm. 

Twenty-nine of the 37 nontherapeutic studies reviewed by HSRB 

were initiated before the passage of 

FQPA in 1996; all reported toxic 

endpoints. EPA conducted both science 

and ethic reviews of these studies prior 

to submission of the studies to HSRB. 

EPA science reviewers proposed to rely 

on 17 of these 29 studies. HSRB found 

13 of these 17 studies scientifically 

acceptable under the applicable 

standards of the 2006 rule. EPA ethics 

reviewers found 5 of the 17 clearly 

acceptable, and deferred to HSRB 

concerning whether the shortcomings 

noted in the conduct of the remaining 

12 studies rose to the level of 

‘‘significant’’ deficiencies relative to 

prevailing standards of ethical research 

conduct. HSRB found 15 of those 17 

studies ethically acceptable under the 

applicable standards of the 2006 rule— 

§ 26.1703 and § 26.1704. HSRB found 1 

study ethically unacceptable because of 

deficiencies in risk minimization 

procedures that could have led to 

serious harm to subjects, and another 

unacceptable because incomplete 

information provided to subjects 

concerning previous studies seriously 

impaired their informed consent. These 

2 studies found by HSRB to be ethically 

unacceptable were among those also 

found by HSRB to be scientifically 

unacceptable. EPA has not subsequently 

relied on any studies deemed either 

scientifically or ethically unacceptable 

by HSRB. 

The 12 remaining pre-FQPA studies 

that EPA science reviewers had 

proposed to reject concerned dichlorvos 

(DDVP). These reports on the effects of 

dichlorvos had been submitted by the 

registrant to support a proposal to 

reduce the inter-species uncertainty 

factor in EPA’s DDVP risk assessment. 

EPA reviewers found all 12 to be 

scientifically unacceptable to reduce the 

inter-species factor since a dose 

response could not be calculated due to 

numerous technical weaknesses. HSRB 

concurred. Because the reported 

research was deemed scientifically 

unacceptable for the proposed use, 

neither EPA nor HSRB explicitly 

reviewed its ethical conduct. EPA has 

not relied on any of these 12 studies. 

Turning to the 8 post-FQPA toxicity 

studies that EPA presented to HSRB, we 

note that they were among a group of 

about 20 studies at the center of 

controversy before promulgation of the 

2006 rule. Other post-FQPA human 

toxicity studies were deemed by EPA 

science reviewers to be irrelevant to 

EPA’s risk assessments, and have not 

been considered further. 

Of the eight relevant post-FQPA 

toxicity studies, EPA science reviewers 

found six scientifically acceptable and 

proposed to rely on them, found one 

more to be clearly scientifically 

unacceptable to set a point of departure 

because no effect was measured from 

the single dose level tested 1, and 

deferred to HSRB with respect to the 

scientific acceptability of the last one. 

HSRB concurred that the first six 

studies were scientifically acceptable, 

and found both the others unacceptable. 

EPA ethics reviewers found four of the 

eight studies clearly acceptable, one 

clearly unacceptable, and deferred to 

HSRB’s judgment whether the 

shortcomings noted in the conduct of 

the remaining three rose to the level of 

‘‘significant’’ deficiencies relative to 

prevailing standards of ethical conduct. 

HSRB found all but one of these eight 

studies ethically acceptable under the 

applicable standards in the 2006 rule. 

Studies found either scientifically or 

ethically unacceptable by HSRB have 

not subsequently been relied on by EPA 

in any actions. 

EPA also proposed to rely on five 

published reports of therapeutic trials of 

materials that may be used as either 

drugs or as pesticide active ingredients. 

In these studies the reported toxic 

endpoints relevant to EPA pesticide risk 

assessments were not the main objective 

of the research, they were reported side 

effects of treatment when a test material 

(which is sometimes used as a pesticide) 

was administered as a medication. 

HSRB concurred with the EPA science 

reviews that these four studies were 

scientifically unacceptable, but found 

one study scientifically unacceptable for 

the purpose EPA proposed. EPA ethics 

reviewers and HSRB both found all five 

of these studies to be ethically 

acceptable under the standards of the 

2006 rule. 

In summary, EPA and HSRB worked 

through the backlog of pre-rule studies 

of pesticide toxicity awaiting review 

when the 2006 rule was promulgated. 

EPA and HSRB agreed about the 

acceptability of these studies in most 

cases; when there was disagreement, 

EPA has accepted HSRB 

recommendation. Some pre-rule studies 

that met the scientific and ethical 

standards defined in the 2006 rule have 

been relied upon by EPA in actions 

under the pesticide laws, although EPA 

has not relied on any studies found 

unacceptable by HSRB. Meanwhile, as 

EPA completed the reassessment of 

tolerances mandated by FQPA, it found 

human toxicity testing to be relevant to 

only a handful of those assessments. 

b. New research involving intentional 

exposure of human subjects. In addition 

to reviewing pre-2006 rule research, 

HSRB has reviewed proposals for new 

research involving intentional exposure 

of human subjects. EPA developed a 

detailed ‘‘framework’’ for its reviews of 

these proposals (see the HSRB Web site 

at http://www.epa.gov/hsrb/index.htm). 

This framework has been used to guide 

all subsequent EPA reviews, and has 

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been refined in detail to incorporate 

suggestions from HSRB. A completed 

framework addressing concerns 

identified in the 2004 NAS Report and 

subsequently by HSRB has been 

attached to each EPA review of a 

proposal for new research under the 

2006 rule. 

Since promulgation of the 2006 rule 

EPA has received no proposals at all for 

new research concerning pesticide 

toxicity or metabolism in human 

subjects. All submitted proposals for 

new research have been for research 

involving intentional exposure of 

human subjects to registered pesticides 

used for pesticidal purposes in the 

research itself. This has included 

proposals for research to measure the 

duration of effectiveness of skin-applied 

repellents intended to keep mosquitoes, 

ticks, and other pests away from the 

treated skin of human subjects, and for 

research monitoring occupational 

exposure of pesticide handlers as they 

mix, load, or apply pesticides in a 

variety of agricultural and nonagricultural use scenarios. 

Close scrutiny by both EPA and HSRB 

of proposals for new repellent 

performance testing and worker 

exposure monitoring studies has led to 

steady and substantial improvement 

both in the scientific design of these 

studies and in their provision for ethical 

treatment of subjects. These reviews 

have led to some delays in field research 

costly to the study sponsors, but the 

sponsors and investigators proposing 

these studies have learned how to 

design and execute them efficiently and 

in full compliance with the standards of 

the 2006 rule. These studies provide 

essential information about repellent 

performance and worker exposure that 

is not available except from well 

designed, ethically conducted research 

involving intentional exposure of 

human subjects to pesticides. 

i. Repellent performance studies. 

Repellent performance studies using 

human subjects have been required by 

EPA for many years to support 

registration of pesticide products 

bearing claims to keep mosquitoes, 

ticks, or other pests away from treated 

human skin. Since 2006, HSRB has 

reviewed proposals for 13 new repellent 

performance studies testing a total of 29 

repellent formulations. EPA and HSRB 

identified enough scientific and ethical 

deficiencies in their initial review of the 

first 2 such proposals that a second 

review was required. After they were 

revised and resubmitted, both proposals 

were reviewed favorably by EPA and 

HSRB. All subsequent proposals for new 

repellent performance studies have been 

found acceptable, with identified 

needed refinements, upon their first 

review by EPA and HSRB. 

Five of the 13 proposals have been for 

laboratory research with caged insects 

or ticks reared in the laboratory and 

known to be disease-free. The remaining 

studies have been for field studies of 

repellency against wild populations of 

insects. Three of the 13 studies have 

measured the duration of tick repellency 

in the laboratory—2 of them 

concurrently testing repellency to 2 

species of ticks. Two more have 

measured the duration of repellency to 

biting flies—1 in the laboratory with 

laboratory-reared stable flies, and 

another in the field measuring 

repellency against black flies. The 

remaining 8 studies have measured the 

duration of repellency against 

mosquitoes—7 of them in the field, in 

areas where previous monitoring has 

not found evidence of infection of 

potential disease vectors among the 

wild insects present, and 1 in the 

laboratory with laboratory-reared, 

pathogen-free mosquitoes. 

In all these cases, HSRB has 

concurred with the EPA science and 

ethics reviews, in some cases 

recommending further refinements. One 

proposal was abandoned by its sponsor 

after a favorable HSRB review; 11 more 

have been amended consistent with 

EPA and HSRB recommendations and 

executed. Reports of these 11 have been 

submitted to EPA and reviewed by EPA 

and HSRB. The most recent proposal is 

expected to be executed in the field in 

2011. 

In one case EPA and HSRB found the 

execution of a completed field mosquito 

repellency test to have been noncompliant with 40 CFR part 26, subparts 

A–L. This study protocol was 

subsequently revised and re-executed; 

the report of the re-executed study was 

found acceptable by EPA and HSRB. 

Reports of all the other ten completed 

repellent performance studies were 

found both scientifically and ethically 

acceptable by EPA and HSRB as first 

submitted. 

ii. Studies of occupational exposure 

of pesticide handlers. All other 

proposals for new research submitted to 

EPA since promulgation of the 2006 rule 

have been for research monitoring 

exposure of professional pesticide 

handlers as they mix, load, or apply 

pesticides in well-defined agricultural 

and non-agricultural use scenarios. In 

such research, experienced workers 

performing their usual tasks are 

typically monitored at different sites, 

representing the range of variation in 

use practices, equipment, and other 

factors likely to affect exposure. 

Potential dermal exposure of the 

workers is measured by analyzing 

residues in special ‘‘long underwear’’ 

worn under their normal work clothing, 

and by rinsing their hands, face and 

neck. Potential inhalation exposure is 

measured with a portable air sampler 

worn in the breathing zone of each 

worker. This type of research has also 

long been required by EPA to support its 

assessments of worker risk. 

Five proposals for field monitoring of 

worker exposure submitted to EPA by 

an industry consortium were presented 

to HSRB in June 2006. These proposals 

were from the Agricultural Handlers 

Exposure Task Force (AHETF). HSRB 

review was highly critical, and called 

for substantially greater information 

from both the consortium and from EPA 

concerning the overall design of the 

research program, the statistical design 

of the proposed studies, the uses to 

which the resulting data would be put 

by EPA, and many other aspects of the 

proposed research. All five of these 

proposals were subsequently withdrawn 

so that HSRB criticisms could be 

addressed prior to resubmission. 

Since that initial review, the overall 

designs of the umbrella monitoring 

programs of AHETF and the designs 

from the Antimicrobial Exposure 

Assessment Task Force (AEATF II) have 

been fully documented and presented to 

HSRB. HSRB continues to review the 

design of individual monitoring studies, 

but the soundness of the overall 

approaches of both the AEATF II and 

AHETF programs have been established. 

Monitoring studies for four 

antimicrobial exposure scenarios 

submitted by the AEATF II have been 

presented to HSRB and approved with 

suggestions for refinements by both EPA 

and HSRB. These four scenarios involve 

common methods of application of 

antimicrobial pesticide products, 

including mopping, wiping down 

surfaces with a pre-soaked ready-to-use 

wipe, spraying surfaces with a pump 

spray and wiping them down with a 

cloth, and spraying surfaces with an 

aerosol product that does not need to be 

wiped off. For each scenario, monitoring 

of workers at three distinctive locations 

was proposed. After amendment of the 

protocols consistent with EPA and 

HSRB recommendations, the first three 

of these four studies have been 

executed; the first complete scenario 

report was submitted to EPA and 

reviewed by HSRB in October 2010. The 

remaining reports of completed AEATF 

II exposure research were submitted to 

EPA in the fall of 2010, and are 

scheduled for presentation to HSRB in 

early 2011. 

Monitoring studies for four 

agricultural exposure scenarios 

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submitted by the AHETF have been 

presented to HSRB and approved, again 

with suggestions for refinements by both 

EPA and HSRB. These scenarios involve 

application of liquid pesticides to trellis 

and orchard crops using ‘‘air-blast’’ 

spray equipment with closed cabs, 

application of liquid pesticides using 

air-blast spray equipment with open 

cabs, mixing and loading pesticides sold 

in water-soluble packaging into a wide 

variety of application equipment, and 

application of herbicides to rights-ofway. Each of these scenarios calls for 

monitoring workers in five different 

regions of the United States, working 

with different kinds of equipment and 

crops. The first two of these four studies 

have been executed; the first complete 

scenario report was submitted to EPA 

and reviewed by HSRB in October 2010. 

Reports of the remaining research 

scenarios will be submitted to EPA and 

presented to HSRB in 2011. 

D. Legal Challenge to the 2006 Rule 

In early 2006, the Natural Resources 

Defense Council, Inc., Pesticide Action 

Network North American, Pineros y 

Campesinos Unido Del Noroeste, 

Physicians for Social Responsibility— 

San Francisco, Farm Labor Organizing 

Committee, ALF–CIO, and Migrant 

Clinicians Network petitioned for 

review of the 2006 rule in the United 

States Court of Appeals for the Second 

Circuit (Second Circuit Court of 

Appeals). (NRDC v. EPA, No. 06–0820- 

ag (2d Cir.)). The Petitioners argued that 

the 2006 rule violated the 2006 

Appropriations Act because it did not 

bar all pesticide research with pregnant 

women and children, was inconsistent 

with the 2004 NAS Report, and was 

inconsistent with the Nuremburg Code. 

The following paragraphs describe the 

Petitioner’s arguments in greater detail. 

1. Inadequate bar against research 

with pregnant women and children. 

Petitioners argued that the scope of the 

2006 rule’s ban on research with 

pregnant women and children was 

unlawfully narrow because it was 

limited to studies intended for 

submission to EPA under FIFRA or 

FFDCA—the pesticide regulatory laws 

EPA administers. Petitioners argued that 

Congress’s direction to EPA in the 

Appropriations Act to ‘‘not permit the 

use of pregnant women, infants, or 

children as subjects’’ in ‘‘intentional 

dosing human toxicity studies for 

pesticides’’ did not allow EPA to 

distinguish between studies originally 

intended for publication and those 

intended for submission to EPA, or 

between studies with pesticides 

conducted for consideration under 

FIFRA or FFDCA and those conducted 

for consideration under the Safe 

Drinking Water Act or any other 

regulatory statute. Petitioners argued 

that EPA’s 2006 rule violated the plain 

language of the 2006 Appropriations Act 

on this point. 

2. Inconsistency with the 2004 NAS 

Report. The 2006 Appropriations Act 

required EPA’s rule to be consistent 

with the principles proposed in the 

2004 NAS Report. Petitioners argued 

that in citing the ‘‘principles’’ of the 

2004 NAS Report, Congress was 

referring to the 17 recommendations in 

that report. Petitioners further argued 

that the 2006 rule was inconsistent with 

several specific recommendations in the 

2004 NAS Report. 

First, Petitioners argued that the 2006 

rule did not incorporate 

Recommendations 3–1 and 5–1 from the 

2004 NAS Report, which recommend 

factors to be considered in the scientific 

evaluation of human research, including 

that such studies should have ‘‘adequate 

statistical power’’ and involve 

‘‘representative populations for the 

endpoint in question.’’ 

Second, Petitioners argued that the 

2006 rule did not incorporate 

Recommendations 4–1 and 4–2 from the 

2004 NAS Report, which suggest ethical 

considerations relevant to evaluation of 

human studies. 

Third, Petitioners argued that by 

adding qualifying language to the 

acceptance standard for pre-rule 

research suggested in Recommendation 

5–7 from the 2004 NAS Report, EPA 

made it inconsistent with the 2004 NAS 

Report. Petitioners argued that EPA’s 

addition of the word ‘‘significantly’’ to 

the recommended acceptance standard, 

which permits EPA to rely on research 

not ‘‘significantly’’ deficient relative to 

prevailing standards, made the criterion 

in the 2006 rule unlawfully inconsistent 

with the recommendations in the 2004 

NAS Report. 

Finally, Petitioners argued that the 

2006 rule unlawfully failed to require 

provision of medical care for study 

participants, as suggested by 

Recommendation 5–5 from the 2004 

NAS Report. 

3. Inconsistency with the Nuremberg 

Code. The 2006 Appropriations Act also 

required EPA’s rule to be consistent 

with the principles in the Nuremberg 

Code pertaining to human 

experimentation. Petitioners argued that 

the 2006 rule was inconsistent with 

several principles in the Nuremburg 

Code. 

First, Petitioners argued that although 

the Nuremberg Code specifies that 

consent must be given by the human 

subject, the 2006 rule permits consent to 

be given in certain situations by a 

legally authorized representative of the 

subject. 

Second, Petitioners argued that the 

2006 rule was inconsistent with the 

Nuremberg Code principle that a test 

subject ‘‘should have sufficient 

knowledge and comprehension of the 

elements of the subject matter involved 

as to enable him to make an 

understanding and enlightened 

decision.’’ Petitioners argued that the 

2006 rule consent requirements were 

inadequate to ensure fully informed 

consent in the context of research 

involving pesticides. 

Third, Petitioners argued that the 

2006 rule failed to address adequately 

the Nuremberg Code principle that a 

subject must be ‘‘so situated as to be able 

to exercise free power of choice, without 

the intervention of any element of force, 

fraud, deceit, duress, over-reaching, or 

other ulterior form of constraint or 

coercion.’’ Petitioners argued that the 

requirement of the 2006 rule that 

consent should only be sought in 

circumstances that ‘‘minimize the 

possibility of coercion or undue 

influence’’ did not address the potential 

for fraud, deceit, over-reaching, or 

constraint. Petitioners asserted that 

constraint was a particular problem 

when prisoners are used as subjects in 

human studies, and the 2006 rule did 

not specifically address research with 

prisoners. 

Fourth, Petitioners argued that the 

2006 rule was inconsistent with the 

Nuremberg Code because it did not 

explicitly impose the Nuremburg Code’s 

requirement that human studies be 

‘‘designed and based on the results of 

animal experimentation.’’ 

Finally, Petitioners argued that the 

2006 rule was inconsistent with the 

Nuremberg Code principle that human 

testing ‘‘should be such as to yield 

fruitful results * * * unprocurable by 

other methods or means of study, and 

not random and unnecessary in nature.’’ 

Petitioners argued that the 2006 rule 

requires no inquiry into whether human 

testing is necessary given other methods 

of research. 

E. Settlement of the Litigation 

After briefing and argument, but 

before a decision was rendered by the 

Second Circuit Court of Appeals, EPA 

and Petitioners began negotiations to 

settle the litigation. In the settlement 

agreement finalized on November 3, 

2010, EPA agreed to conduct noticeand-comment rulemaking on the issue 

of whether the 2006 rule should be 

amended. EPA also agreed to propose, at 

a minimum, amendments to the 2006 

rule that are substantially consistent 

with language negotiated between the 

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parties and attached to the settlement 

agreement as Exhibit A. This agreement, 

including Exhibit A, is available in the 

docket for this action as described under 

ADDRESSES. 

The settlement agreement further 

provides that EPA will propose the 

negotiated amendments no later than 

January 18, 2011, and that EPA will take 

final action on the amendments no later 

than December 18, 2011. The settlement 

agreement, however, makes clear that 

EPA retains full discretion concerning 

what amendments are proposed, and 

what, if any, amendments are finalized. 

Although the wording of the 

amendments proposed in this document 

differs in a few details of construction 

and wording, they are substantially 

consistent with the regulatory language 

negotiated with Petitioners, and EPA 

considers these amendments to address 

the Petitioners’ major arguments 

outlined in Unit III.D. Specifically: 

• The proposed amendments would 

retain the scope of the 2006 rule to 

cover research submitted to EPA under 

FIFRA or FFDCA, and extend that scope 

to cover as well research involving 

intentional exposure to a pesticide, 

intended for submission to EPA under 

any other regulatory statute 

administered by EPA. 

• The proposed amendments 

incorporate language from each of the 

recommendations from the 2004 NAS 

Report cited by Petitioners in their 

challenge to the 2006 rule, as well as 

other pertinent recommendations from 

the 2004 NAS Report. 

• The proposed amendments address 

Petitioners’ arguments concerning the 

Nuremberg Code by dropping from 40 

CFR part 26, subpart K, all provisions 

for consent by a representative, and by 

requiring EPA to consider whether 

subjects gave their ‘‘free and fully 

informed consent’’ to participate in a 

study, whether the design of proposed 

new human research takes into account 

the knowledge gained in earlier animal 

testing, and whether proposed new 

human research is necessary. 

Although these proposed 

amendments emerged from a settlement 

agreement, EPA believes that proposing 

these amendments is consistent with the 

language and purposes of the applicable 

statutes and because they further the 

2006 rule’s goal of ensuring that EPA 

does not rely on research involving 

intentional exposure of human subjects 

to pesticides that is not ethically 

conducted or that is not scientifically 

sound. EPA believes that many of the 

changes proposed in this document are 

codifications of the manner in which 

EPA and HSRB have interpreted and 

implemented the 2006 rule, but 

welcomes comment on these 

interpretations. EPA will fully reevaluate the appropriateness of the 

proposed amendments in light of all 

comments received in response to this 

proposed rule before making a final 

determination. In particular, EPA seeks 

comment on the relative merits of the 

proposed changes compared to retaining 

the current scope and content (i.e., 

current wording) of the 2006 rule. 

IV. Proposed Amendments, Rationale, 

and Request for Comment 

This unit provides a description of 

each proposed change, the rationale for 

the proposed change, and the 

anticipated effects of each change 

relative to the current regulatory text 

(i.e., the 2006 rule). EPA specifically 

requests comment on each of these 

proposed changes, as well as on the 

changes in the aggregate. In particular, 

EPA asks for comment on its 

conclusions regarding the effect of these 

proposed changes, including the effect 

of these proposed changes on the 

volume of studies covered by the rule, 

the likely statutes under which studies 

may be submitted, and the impact on 

activities covered by those other 

statutes, relative to the scope of the 2006 

rule. 

A. Redefining the Scope and 

Applicability of 40 CFR Part 26, 

Subparts K, L, M, P, and O 

1. Summary of proposed changes. 

EPA is proposing amendments that 

would modify the scope and 

applicability of several subparts of the 

2006 rule. The proposed changes would 

modify the criteria defining the types of 

research covered by 40 CFR part 26, 

subparts K, L, and M—most notably the 

criteria relating to the intentions of the 

sponsor or investigator in conducting 

the research or the intentions of the 

person submitting the research to EPA. 

The specific changes proposed to the 

scope and applicability sections of 40 

CFR part 26, subparts K, L, M, P, and 

Q, are explained here. Although EPA 

does not propose to change the text of 

the 2006 rule defining the scope of 40 

CFR part 26, subpart O, concerning 

‘‘Administrative Actions for 

Noncompliance,’’ the scope of that 

subpart would change nonetheless, 

because its applicability depends on the 

scope provisions in other subparts that 

EPA is proposing to change. More 

specifically, these changes alter the 

scope as follows: instead of covering 

substances under FIFRA, the proposed 

amendments would cover pesticides 

under all statutes. 

In general, the proposed amendments 

would shift the focus from whether the 

research on the substance was intended 

for EPA’s consideration and use under 

the pesticide laws, FIFRA and FFDCA, 

to whether the research was conducted 

with a pesticide and was intended for 

EPA’s consideration and use in 

connection with an action under any 

regulatory statute administered by EPA. 

The proposed amendments also would 

add a new section to 40 CFR part 26, 

subpart P, defining its scope and would 

change the scope and applicability of 40 

CFR part 26, subpart Q, to parallel the 

changes in 40 CFR part 26, subpart K. 

2. Summary of anticipated effects. 

Although almost all studies with 

pesticides are conducted and submitted 

to EPA for consideration under FIFRA 

or FFDCA, it is possible that some 

pesticide studies may be considered by 

EPA only under other regulatory 

authorities and not be considered under 

FIFRA and FFDCA. If studies involving 

intentional exposure of humans to a 

pesticide are submitted or considered 

under other EPA regulatory statutes, 

with the proposed amendment, such 

studies would be subject to the same 

requirements that would have applied 

had they been submitted or considered 

under FIFRA or FFDCA. In proposing 

these amendments, EPA finds that these 

changes in scope are consistent with the 

focus in the 2006 Appropriations Act on 

intentional dosing human toxicity 

studies with pesticides. 

In sum, EPA does not believe that the 

several changes to the ‘‘scope’’ sections 

of 40 CFR part 26, subparts K and L— 

§ 26.1101 and § 26.1201—and a new 

definition of ‘‘pesticide’’ at § 26.1102(c), 

that expand the range of human 

research to which these two subparts 

apply, will result in a significant 

increase in the number of studies 

reviewed under the rule. However, EPA 

recognizes that this is a possibility and 

requests comment on whether these 

proposed changes are clear about which 

studies would fall under the scope of 

the rule. EPA knows of no third-party 

research involving intentional exposure 

of a human subject to a pesticide that 

has ever been proposed, conducted, or 

submitted to EPA under regulatory 

authorities other than the pesticide 

laws. The proposed expansion of the 

scope of these subparts, however, would 

mean that any such studies that are 

proposed, conducted, or submitted to 

EPA will be governed by the same 

standards as pesticide studies submitted 

under FIFRA or FFDCA section 408. 

3. 40 CFR part 26, subparts K and L— 

basic ethical requirements and 

prohibitions applying to third-party 

research involving intentional exposure 

of human subjects to a pesticide. 

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a. Current rule. Subpart K of 40 CFR 

part 26 extends the basic protections of 

the Common Rule to subjects in certain 

third-party human research; subpart L of 

40 CFR part 26 forbids new third-party 

research involving intentional exposure 

of children or of pregnant or nursing 

women. In the 2006 rule these two 

subparts apply to ‘‘research with a 

human subject’’ which meets four 

criteria. First, it was initiated after April 

7, 2006 (the effective date of the 2006 

rule). Second, it is ‘‘research involving 

intentional exposure of a human 

subject’’ as defined at § 26.1102(i). 

Third, it was conducted or supported by 

a ‘‘person’’ as defined at § 26.1102(j). 

Fourth, it was intended by any person 

conducting or supporting the research to 

be submitted to EPA, or to be held for 

later inspection by EPA, under the 

pesticide laws (FIFRA or FFDCA). 

The two cited definitions are critical 

to understanding the scope and 

applicability of subparts K and L of 40 

CFR part 26. ‘‘Research involving 

intentional exposure of a human 

subject,’’ is defined at § 26.1102(i) as ‘‘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.’’ In applying this definition, EPA 

considers whether a test subject would 

have experienced equivalent exposure 

to a test material had the subject not 

participated in the research. If not, the 

research is deemed to involve 

intentional exposure of the subject. 

Notably this definition encompasses all 

classes of test substances—not only 

pesticides. 

A ‘‘person’’ is defined at § 26.1102(j) to 

have the same meaning as in FIFRA 

section 2(s) (7 U.S.C. 136(s)), except that 

it excludes Federal agencies subject to 

the Common Rule and any person when 

performing research supported by a 

Common Rule Federal department or 

agency. This exclusion is appropriate 

because that research is covered by the 

Common Rule, which provides 

necessary and appropriate protections 

for the research subjects. Thus, research 

already covered by the standards of the 

Common Rule is not also subject to 

subparts K and L. These subparts, in 

short, apply only to ‘‘third-party 

research’’—research that is neither 

conducted (‘‘first-party’’) nor supported 

(‘‘second-party’’) by EPA or another 

Common Rule Federal department or 

agency. 

Finally, § 26.1101(g) explains how 

EPA will approach determination of the 

intent of sponsors or investigators to 

submit research to EPA under the 

pesticide laws, or hold it for inspection 

by EPA under the pesticide laws. 

b. Proposed amendments, rationale, 

and anticipated effect. The amendments 

proposed in this document would not 

change the definitions of ‘‘research 

involving intentional exposure of a 

human subject’’ or of ‘‘person.’’ They 

would add a new definition of 

‘‘pesticide’’ at § 26.1102(c), and would 

modify the applicability provisions in 

§ 26.1101, as explained later in this Unit 

of the document. 

The first of the four criteria for 

application of 40 CFR part 26, subpart 

K, will change to incorporate the 

effective date of a final rule amending 

the 2006 rule. EPA believes it would be 

inappropriate to apply these proposed 

amendments retroactively. For example, 

if post-2006 research newly covered by 

an amended rule as proposed in this 

document were submitted to EPA, its 

acceptability should not be judged by its 

compliance with a rule promulgated 

after it was conducted. Until the 2006 

rule is amended by a final rule, its 

provisions continue to apply fully to 

new research. Hence no sponsor or 

investigator subject to the 2006 rule 

would be relieved by the change in the 

effective date of any obligation to 

comply with 40 CFR part 26, subparts 

K and L, for research initiated between 

April 7, 2006, and the effective date of 

any subsequent amendments. 

The proposal would modify the 

second of the four criteria so that 40 

CFR part 26, subparts K and L, would 

apply to research involving intentional 

exposure of a human subject ‘‘to a 

pesticide’’ when the research is intended 

for submission to EPA under any 

regulatory statute other than FIFRA or 

FFDCA. The definition of ‘‘research 

involving intentional exposure of a 

human subject’’ would not change, nor 

would the applicability of these 

subparts to all new third-party research 

involving intentional exposure of 

human subjects which is intended for 

submission to EPA under FIFRA or 

FFDCA. 

In determining whether research 

involves intentional exposure to a 

pesticide, EPA will focus, as does the 

FIFRA definition of a ‘‘pesticide,’’ on the 

intended use of the substance. EPA 

expects that application of this standard 

will nearly always be straightforward. 

However, EPA recognizes that there may 

be cases where making such a 

determination may not be as 

straightforward. EPA will apply this 

criterion as follows. 

Initially, EPA will examine the study 

on its face. If the study states that it 

involves the testing of a pesticide, or if 

the tested substance is used for 

pesticidal effect in the study, as it is in 

insect repellent efficacy testing or in 

monitoring exposure of pesticide 

applicators, there can be little question 

that the study involves exposure to a 

pesticide. If on the other hand the study 

reports testing of another type of 

substance, such as an industrial 

chemical, waste product, or air 

pollutant, then absent compelling 

evidence to the contrary, EPA will not 

treat the study as involving exposure to 

a pesticide. 

If it is not clear from the face of the 

study whether it involves exposure to a 

pesticide, EPA will look to other 

objective factors to determine whether a 

substance is being tested as a pesticide. 

Intent to test a substance as a pesticide 

could be indicated by evidence that the 

testing was conducted or supported by 

an entity regulated under FIFRA or 

section 408 of FFDCA; the testing was 

conducted for the purpose of attaining 

a FIFRA registration or FFDCA 

tolerance; there are not significant 

commercial uses for the substance other 

than as a pesticide; or human exposure 

to the substance occurs primarily from 

its use as a pesticide. Absent any such 

evidence, EPA will generally treat the 

study as not involving exposure to a 

pesticide. 

EPA expects that in most cases, the 

question of whether the study involves 

exposure to a pesticide will be quickly 

resolvable without looking to other 

objective factors such as the four 

identified in the previous paragraph. 

EPA believes that this would be true 

even for multiple-use substances that 

may be used as a pesticide and may also 

result in human exposure from other 

commercial uses or as a result of 

deposition in the environment as a 

waste product. 

A good example of how EPA will 

determine if studies on multi-use 

substances are studies on a pesticide is 

presented by sulfur dioxide (SO2)—a 

registered pesticide active ingredient 

used as a fungicide in grape culture, and 

also a common air pollutant. Thousands 

of tons of SO2 are released yearly into 

the atmosphere by burning of coal and 

other fossil fuels. In promulgating 

National Ambient Air Quality Standards 

(NAAQS) for SO2 under the Clean Air 

Act (CAA) in 2010, EPA relied on 

numerous human studies involving 

intentional exposure of subjects to SO2. 

Most of these studies on their face 

indicate clearly that they tested SO2 as 

an industrial air pollutant and not as a 

pesticide. The few that do not expressly 

state they tested SO2 as an air pollutant 

are, nonetheless, easily classified as not 

involving exposure to a pesticide, 

because the testing was not conducted 

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or sponsored by a pesticide registrant, 

the studies do not indicate they were 

performed in support of FIFRA 

registration, and there are clearly other 

major sources of human exposure to SO2

in addition to whatever pesticide 

exposure occurs. Thus, these studies 

would not come within the scope of the 

2006 rule if the scope is modified as 

proposed. 

EPA specifically requests comment on 

the implications of this change for the 

volume of studies that may need to be 

reviewed under such a proposed 

amendment. 

The amendments proposed in this 

document would not change the 

applicability of 40 CFR part 26, subparts 

K and L, to ‘‘persons’’ or the definition 

of that term at § 26.1102(j). Thus the 

third of the four criteria would not be 

affected by these proposed amendments. 

The fourth criterion would be 

broadened by the amendments proposed 

in this document beyond the scope of 

the 2006 rule. The 2006 rule applies to 

research with any substance, conducted 

with intent to submit its results to EPA 

under FIFRA or FFDCA; as proposed 

here, the rule would apply as well to 

research with a pesticide, conducted 

with intent to submit its results to EPA 

‘‘for consideration in connection with 

any action that may be performed under 

any regulatory statute administered by 

EPA’’ other than FIFRA or FFDCA. 

The new element in this fourth 

criterion, putting aside the proposed 

amendment to refer to ‘‘pesticides,’’ is 

the reference to actions taken ‘‘under 

any regulatory statute administered by 

EPA.’’ Research intended for submission 

under FIFRA or FFDCA is covered by 

the 2006 rule and would continue to be 

covered under proposed § 26.1101(a)(1). 

Proposed § 26.1101(a)(2) would broaden 

the scope of subparts K and L of 40 CFR 

part 26 to apply as well to research 

involving intentional exposure of a 

human subject to a pesticide which is 

intended for submission to EPA for 

consideration in connection with any 

action that may be performed under any 

regulatory statute other than FIFRA or 

FFDCA. Such submission could be 

made under CAA, the Safe Drinking 

Water Act (SDWA), the Clean Water Act 

(CWA), the Resource Conservation and 

Recovery Act (RCRA), the 

Comprehensive Environmental 

Response, Compensation and Liability 

Act (CERCLA, or the Superfund law), or 

other similar statutes. EPA specifically 

seeks comment on the scope of this 

proposed change (i.e., the frequency 

with which it might be triggered, 

including other statutes to which the 

proposed change would apply) and the 

implications of the proposed changes on 

the activities governed by those other 

regulations. EPA seeks comment on the 

relative merits of this change compared 

to retaining the current scope of the 

2006 rule. As noted, EPA does not 

expect that these wording changes will 

result in any substantive changes to the 

number or manner in which studies are 

currently reviewed. 

As an example, EPA’s Office of Water 

has, in the past, set Maximum 

Contaminant Levels (MCLs) under the 

SDWA with pesticides found in 

drinking water. Under the proposed 

amendment to the scope of 40 CFR part 

26, subpart K, any new third-party study 

involving intentional exposure of a 

human to a pesticide, and intended for 

submission to the Office of Water for 

consideration in setting a MCL, would 

now be subject to 40 CFR part 26, 

subpart K, including the requirement of 

§ 26.1125 for submission of the proposal 

for prior review by EPA and HSRB. EPA 

would note that this is a theoretical 

example in that it is unaware of any 

such study having been submitted with 

regard to a MCL. 

EPA actions not taken under the 

authority of regulatory statutes would 

not satisfy this fourth criterion. For 

example, an EPA comment on another 

Federal department’s or agency’s 

Environmental Impact Statement would 

not constitute an action taken under a 

regulatory statute, and research 

intended for submission solely for 

consideration in such a context would 

not be subject to 40 CFR part 26, 

subparts K and L. 

EPA interprets the word ‘‘action’’ in 

this context broadly, embracing both 

regulatory and non-regulatory actions. 

Regulatory actions include, for example, 

cancellation or registration of a 

pesticide, establishment of a tolerance 

for a pesticide residue in food, or 

establishing a MCL for a pesticide active 

ingredient under SDWA. Non-regulatory 

actions include, for example, risk 

assessments of pesticide active 

ingredients, recommended (nonbinding) safe levels of exposure such as 

Health Advisory Limits when these 

pertain to pesticides, or clean-up 

standards for pesticides at a Superfund 

site. 

The amendments proposed in this 

document include two additional 

editorial revisions to clarify the scope 

sections of 40 CFR part 26, subparts K 

and L. One change would clarify the 

applicability of 40 CFR part 26, subpart 

K, by moving the exposition of how EPA 

will determine intent to submit from 

§ 26.1101(g), where it appears in the 

2006 rule, to § 26.1101(b), immediately 

following the presentation of the four 

criteria. The other would amend 

§ 26.1201, the scope section of 40 CFR 

part 26, subpart L, to state simply that 

40 CFR part 26, subpart L applies to all 

research subject to 40 CFR part 26, 

subpart K. 

4. 40 CFR part 26, subpart M— 

requirement for documentation of the 

ethical conduct of completed human 

research submitted to EPA. 

a. Current rule. Subpart M of 40 CFR 

part 26 requires those who submit the 

results of human research to EPA for 

consideration under the pesticide laws 

to submit information documenting the 

ethical conduct of the completed 

research. Under the 2006 rule, 40 CFR 

part 26, subpart M, applies when a 

‘‘person’’ as defined at § 26.1102(j) 

submits after the effective date of the 

2006 rule a report containing the results 

of any human research to EPA for 

consideration under the pesticide laws. 

These criteria differ from those 

defining coverage by 40 CFR part 26, 

subparts K and L, in important ways. 

First, unlike other subparts of the 2006 

rule, subpart M applies to submissions 

after the effective date of the rule of any 

and all human research, without regard 

to who conducted it, when, or for what 

purpose, or whether or not the reported 

research involved intentional exposure 

of a human subject. Second, subpart M 

applies only when a person (other than 

a Federal department or agency subject 

to the Common Rule) submits the 

results of human research to EPA. 

Subpart M does not apply when EPA, 

on its own initiative, retrieves published 

articles or otherwise obtains information 

derived from human research. 

b. Proposed amendments and 

rationale. EPA proposes to broaden the 

applicability of 40 CFR part 26, subpart 

M, by amending § 26.1301, while 

leaving the substantive requirements of 

subpart M unchanged. Specifically, EPA 

proposes to include submissions of 

reports of human research on pesticides 

for consideration by EPA under 

regulatory statutes other than FIFRA or 

FFDCA. Under the proposed 

amendments, subpart M would apply 

when a ‘‘person’’ as defined at 

§ 26.1102(j) submits after the effective 

date of the amended rule a report 

containing the results of any human 

research to EPA for consideration under 

FIFRA or FFDCA, or a report containing 

the results of any human research on or 

with a pesticide for consideration under 

any other regulatory statute 

administered by EPA. 

The proposed amendments to 40 CFR 

part 26, subpart M, attempt to balance 

the need for full information on ethical 

issues with a concern that the public not 

be deterred from submitting scientific 

data relevant to EPA information 

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requests. Section 26.1303 requires a 

submitter to provide ‘‘information 

concerning the ethical conduct’’ of the 

human research, including copies of 

relevant IRB records, and copies of 

records relevant to the key ethical 

considerations outlined in § 26.1117 

and § 26.1125(a). This requirement is 

qualified by the provision that such 

records need only be provided ‘‘[t]o the 

extent [the records] are available to the 

submitter and not previously provided 

to EPA,’’ but any submitter not 

providing the information required must 

‘‘describe the efforts made to obtain the 

information.’’ 

To minimize the potential burden on 

commenters, EPA considered excluding 

from the coverage of 40 CFR part 26, 

subpart M, submissions of published 

scientific journal articles reporting 

human research, or of citations to such 

articles. In some circumstances, 

however, EPA believes it is important 

for submitters of even published human 

research to bear the burden of gathering 

the information required by § 26.1303. 

Specifically, EPA believes a submitter of 

published human research who is 

seeking action under a regulatory statute 

from EPA that would directly benefit 

the submitter should be obliged to 

gather records bearing on the conduct of 

the research, even if the research is 

described in the public literature. For 

example, an applicant for a pesticide 

registration or a party petitioning for a 

pesticide tolerance should have to 

exercise reasonable efforts to obtain 

records of the ethical conduct of 

research relied on to support the EPA 

action sought, whether or not the 

research happens to be described in a 

scientific journal. Reasonable efforts in 

these circumstances may include 

seeking relevant records from the 

research administrator or the overseeing 

IRB. On the other hand, if a member of 

the public responds to an EPA request 

for information on a pesticide by citing 

or submitting a published study, EPA 

believes that certification that the 

submitter did not sponsor, participate 

in, or otherwise have personal 

knowledge of or responsibility for the 

referenced research would satisfy the 

submitter’s obligation under 40 CFR 

part 26, subpart M. 

c. Anticipated effect. EPA’s concern 

for the potential burden of 40 CFR part 

26, subpart M, on the public is tempered 

by its experience under the 2006 rule. 

Since promulgation of the 2006 rule 

EPA has received very few submissions 

of reports of human research on or with 

a pesticide for consideration under 

FIFRA or FFDCA, and EPA expects 

submissions of such studies to EPA for 

consideration only under other 

regulatory statutes will be even less 

common. 

EPA specifically requests comments 

on this approach to and interpretation of 

the requirements in 40 CFR part 26, 

subpart M. Such comments should 

address whether the proposed rule 

language is adequate to implement 

EPA’s interpretation. 

5. 40 CFR part 26, subpart P—EPA 

and HSRB review of proposed and 

completed human research. 

a. Current rule. Subpart P of 40 CFR 

part 26 applies to EPA and HSRB 

reviews of proposals for new research 

involving intentional exposure of a 

human subject, and EPA and HSRB 

reviews of reports of completed research 

involving intentional exposure of a 

human subject and on which EPA 

proposes to rely in an action under the 

pesticide laws. Unlike other subparts of 

the 2006 rule, subpart P does not 

include a ‘‘scope’’ section; its 

applicability is defined only indirectly 

by references to other subparts. 

b. Proposed amendments and 

rationale. EPA proposes to make 

explicit the applicability of 40 CFR part 

26, subpart P, in a new § 26.1601. This 

proposed new section provides that 40 

CFR part 26, subpart P, applies to EPA 

and HSRB reviews of (1) ‘‘proposed 

research subject to 40 CFR § 26.1125,’’ 

and (2) ‘‘reviews by EPA after [effective 

date of the amended rule] and, to the 

extent required by § 26.1604, by the 

Human Studies Review Board, of 

reports of completed research subject to 

40 CFR 26.1701.’’ 

c. Anticipated effect. Since 40 CFR 

26.1125 is in subpart K and 40 CFR 

26.1701 is in subpart Q, the broadened 

scope of these subparts as proposed in 

these amendments would indirectly 

broaden the scope of 40 CFR part 26, 

subpart P. 

6. 40 CFR part 26, subpart Q—ethical 

standards for assessing whether to rely 

on the results of human research in EPA 

actions. 

a. Current rule. Subpart Q of 40 CFR 

part 26 defines ethical standards that 

must be met for EPA to rely on the 

results of human research in actions 

taken under the pesticide laws. 

Specifically, 40 CFR part 26, subpart Q, 

applies to EPA decisions to rely on data 

from completed studies involving 

intentional exposure of a human 

subject, when EPA regards the data as 

scientifically valid and relevant to an 

action taken under the pesticide laws. 

b. Proposed amendments and 

rationale. For the same reasons it is 

proposing to broaden the applicability 

of 40 CFR part 26, subpart K (discussed 

in Unit IV.A.1.), EPA proposes to amend 

§ 26.1701 to broaden the applicability of 

40 CFR part 26, subpart Q. Proposed 

§ 26.1701(a) would retain without 

change the applicability of 40 CFR part 

26, subpart Q, to research involving 

intentional exposure of human subjects 

to any substance, in the context of EPA 

actions taken under FIFRA or FFDCA. 

Proposed § 26.1701(b) would extend the 

applicability of 40 CFR part 26, subpart 

Q, to research involving intentional 

exposure of human subjects to a 

pesticide, in the context of EPA actions 

taken under any other regulatory statute 

administered by EPA. 

EPA intends to interpret ‘‘action’’ and 

‘‘regulatory statute administered by 

EPA’’ in 40 CFR part 26, subpart Q, just 

as these terms would be interpreted for 

40 CFR part 26, subpart K. To make this 

scope provision consistent with the 

other scope provisions in this proposal, 

EPA proposes to depart from the 

language negotiated in the settlement 

agreement and define the scope of 40 

CFR part 26, subpart Q, in terms of the 

‘‘research’’ covered rather than the 

‘‘decisions’’ covered. 

c. Anticipated effect. EPA expects this 

change in the scope of 40 CFR part 26, 

subpart Q, to affect few, if any, EPA 

actions. Although such actions may 

occur in the future, EPA cannot identify 

any actions taken since 2006 under any 

regulatory statute other than FIFRA or 

FFDCA that relied on research involving 

intentional exposure of a human subject 

to a pesticide. 

As explained previously, EPA is 

authorized to propose this change 

because it is consistent with the 2006 

Appropriations Act. This proposal 

would mean that all intentional human 

studies involving pesticides submitted 

to EPA would be reviewed under the 

same ethical and scientific criteria. On 

the other hand, EPA has also noted that 

it expects this change will affect few 

additional studies and may create some 

uncertainty as to what studies are 

covered by the rule. 

EPA specifically invites comment on 

the value of making this change and 

whether there are additional factors to 

be considered in evaluating the 

appropriateness of the change, such as 

the frequency with which it might be 

triggered, including other statutes to 

which the proposed change would 

apply, and on the clarity of the 

proposed changes. 

B. Disallowing Consent by a Surrogate 

(40 CFR Part 26, Subpart K) 

1. Current rule. In the 2004 NAS 

Report to EPA, the NAS recommended 

use of the Common Rule as the starting 

point for protecting human subjects in 

research involving intentional exposure. 

Consistent with this recommendation, 

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EPA incorporated much of the text of 

the Common Rule into subpart K of 40 

CFR part 26, including language 

providing for consent for a subject’s 

participation in research by the subject’s 

‘‘legally authorized representative’’ 

when the subject lacks the capacity to 

consent for himself or herself. The 

Common Rule, drafted to protect 

subjects in a wide variety of research 

settings, included these provisions to 

permit research in various situations, 

including, for example, research into 

emergency procedures to save lives of 

unconscious patients, into improved 

care for people suffering psychosis or 

schizophrenia, and to collect valuable 

data from research with other subjects 

who lacked the legal capacity to provide 

fully informed, fully voluntary consent. 

2. Proposed amendments and 

rationale. EPA proposes to amend 40 

CFR part 26 by deleting from subpart K 

all references permitting consent by a 

subject’s legally authorized 

representative. The sections affected are 

the definition of ‘‘legally authorized 

representative’’ at § 26.1102(c); the 

‘‘Criteria for IRB approval of research’’ at 

§ 26.1111; the ‘‘General requirements for 

informed consent’’ at § 26.1116; and the 

requirements for ‘‘Documentation of 

informed consent’’ at § 26.1117. 

EPA proposes to disallow consent by 

a representative in third-party studies 

because the types of research that are 

conducted on pesticides would not use 

subjects for whom such a procedure is 

needed. (The research covered by 40 

CFR part 26, subpart K includes 

research involving intentional exposure 

of non-pregnant, non-nursing adults to a 

pesticide or research involving 

intentional exposure of non-pregnant, 

non-nursing adults intended for 

submission under FIFRA or FFDCA.) 

3. Anticipated effect. EPA has never 

seen, and cannot envision, any such 

research in which it could be justified 

to enroll subjects lacking the capacity to 

consent for themselves. EPA does not 

propose to modify the provisions of 40 

CFR part 26, subpart A, EPA’s 

codification of the Common Rule. 40 

CFR part 26, subpart A, applies to a 

much broader range of research with 

human subjects conducted or supported 

by EPA including research for which 

consent by a legally authorized 

representative may be appropriate. 

C. Revised Standards for EPA and HSRB 

Reviews (40 CFR Part 26, Subpart P) 

1. Current rule. 40 CFR part 26, 

subpart P, defines in largely procedural 

terms how EPA evaluates proposals for 

new research submitted under § 26.1125 

of 40 CFR part 26, subpart K, and how 

EPA is to review reports of completed 

research. Subpart P of 40 CFR part 26 

also defines the membership and 

responsibilities of HSRB. 

2. Proposed amendments and 

rationale. 

a. Revisions to 40 CFR part 26, 

subpart P, generally. The proposed 

amendments to 40 CFR part 26, subpart 

P, include: 

• A proposed new § 26.1601 

explicitly defining the applicability of 

40 CFR part 26, subpart P, to EPA and 

HSRB reviews of proposals for new 

research submitted under § 26.1125 of 

subpart K and to EPA and HSRB 

reviews of reports of completed research 

covered by subpart Q. This change is 

discussed in Unit IV.A.3. 

• A proposed new § 26.1602 

references the definitions in 40 CFR part 

26, subpart K. 

• A proposal to expand the 

discussion of EPA reviews of proposed 

research in § 26.1603, retaining all 

elements of § 26.1601 from the 2006 

rule, and including a new § 26.1603(b) 

listing considerations to be addressed by 

EPA in its science reviews of proposed 

research, and a new § 26.1603(c) listing 

considerations to be addressed by EPA 

in its ethics reviews of proposed 

research. 

• A proposal to slightly revise 

discussion of EPA reviews of completed 

research, redesignating § 26.1602 in 40 

CFR part 26 as § 26.1604, and revising 

paragraph (a) to emphasize the required 

thoroughness of EPA’s reviews and to 

extend its applicability to reviews of 

completed human research on 

pesticides considered under regulatory 

statutes other than FIFRA or FFDCA. 

• The unchanged text of § 26.1603 in 

the 2006 rule would be redesignated as 

§ 26.1605, defining the membership and 

responsibilities of HSRB. 

• A proposed new § 26.1606 requiring 

HSRB in its reviews of proposed 

research to consider the same range of 

scientific, ethical, and other topics 

addressed by EPA in its reviews under 

§ 26.1603. 

• A proposed new § 26.1607 requiring 

HSRB in its reviews of completed 

research to consider both the scientific 

and ethical merits of the research, and 

to apply the appropriate acceptance 

standards in 40 CFR part 26, subpart Q. 

As indicated previously and again 

throughout this discussion, EPA 

requests comment on each of these 

proposed changes, as well as on the 

changes in the aggregate. EPA also seeks 

comments on particular points as 

provided in the discussion. 

b. Section 26.1603—EPA Review of 

proposed human research. Because the 

most significant changes proposed are 

the new lists in § 26.1603(b) and (c) of 

considerations to be addressed in EPA 

reviews of proposed new research, those 

proposed changes will be discussed in 

greater detail here. These proposed lists 

were derived primarily from the 

following recommendations in the 2004 

NAS Report (reproduced verbatim here 

and referenced in the subsequent 

discussions): 

Recommendation 3–1: Scientific Validity of 

Intentional Human Dosing Studies 

EPA should issue guidelines for 

determining whether intentional human 

dosing studies have been: 

a. Justified, in advance of being conducted, 

as needed and as scientifically appropriate, 

in that they could contribute to addressing an 

important scientific or policy question that 

cannot be resolved on the basis of animal 

data or human observational data; 

b. Designed in accordance with current 

scientific standards and practices to (i) 

address the research question, (ii) include 

representative study populations for the 

endpoint in question, and (iii) meet 

requirements for adequate statistical power; 

c. Conducted in accordance with 

recognized good clinical practices, including 

appropriate monitoring for safety; and 

d. Reported comprehensively to EPA, 

including the full study protocol, all data 

produced in the study (including adverse 

events), and detailed analyses of the data. 

Recommendation 4–1: Value of Studies That 

Seek to Improve the Accuracy of EPA’s 

Decisions But Do Not Provide a Public Health 

or Environmental Benefit 

EPA should consider a human dosing 

study intended to reduce the interspecies 

uncertainty factor (for example, a study of a 

biomarker such as cholinesterase inhibition) 

as conferring a societal benefit only if it was 

designed and conducted in a manner that 

would improve the scientific accuracy of 

EPA’s extrapolation from animal to human 

data. Because the anticipated benefit would 

not be as great as that conferred by studies 

intended to provide a public health or 

environmental benefit, the study could be 

justified ethically only if the participants’ 

exposure to the pesticide could reliably be 

anticipated to pose no identifiable risk or 

present a reasonable certainty of no harm to 

study participants. 

Recommendation 5–1: Criteria for Scientific 

and Ethical Acceptability 

Studies that do not meet the highest 

scientific and ethical standards should not be 

carried out or accepted by EPA as input to 

the regulatory decision-making process. 

Necessary conditions for scientifically and 

ethically acceptable intentional human 

dosing studies include: 

a. Prior animal studies and, if available, 

human observational studies; 

b. A demonstrated need for the knowledge 

to be obtained from intentional human 

dosing studies; 

c. Justification and documentation of a 

research design and statistical analysis that 

are adequate to address an important 

scientific or policy question, including 

adequate power to detect appropriate effects; 

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d. An acceptable balance of risks and 

benefits and minimization of risks to 

participants; 

e. Equitable selection of participants; 

f. Free and informed consent of 

participants; and 

g. Review by an appropriately constituted 

IRB or its foreign equivalent. 

Recommendation 5–2: Participant Selection 

Criteria 

IRBs reviewing intentional human dosing 

studies should ensure that the following 

conditions are met in selecting research 

participants: 

a. Selection should be equitable. 

b. Selection of persons from vulnerable 

populations must be convincingly justified in 

the protocol, which also must justify the 

measures to be taken to protect those 

participants. 

c. Selection of individuals with conditions 

that put them at increased risk for adverse 

effects in such studies must be convincingly 

justified in the protocol, which also must 

justify the measures that investigators will 

use to decrease the risks to those participants 

to an acceptable level. 

Recommendation 5–3: Payment for 

Participation 

IRBs, all relevant review boards, 

investigators, and research sponsors should 

ensure that payments to participants in 

intentional human dosing studies are neither 

so high as to constitute undue inducement 

nor so low as to be attractive only to 

individuals who are socioeconomically 

disadvantaged. Proposed levels of and 

purposes for remuneration (e.g., time, 

inconvenience, and risk) should be 

scrutinized in light of the principles of 

justice and respect for persons. Moreover, 

EPA, in conjunction with other Federal 

agencies, should consider developing further 

guidance on remuneration for participation 

in intentional human dosing studies, 

including guidance regarding whether 

remuneration should reflect the level of risk 

as well as the time and inconvenience 

involved. 

Recommendation 5–5: Compensation for 

Research-Related Injuries 

At a minimum, sponsors of or institutions 

conducting intentional human dosing studies 

should ensure that participants receive 

needed medical care for injuries incurred in 

the study, without cost to the participants. In 

addition, EPA should study whether broader 

compensation for research-related injuries 

should be required. 

Recommendation 6–1: IRB Review of All 

Studies 

EPA should require that all human 

research conducted for regulatory purposes 

be approved in advance by an appropriately 

constituted IRB or an acceptable foreign 

equivalent. Research conducted by EPA 

scientists should be reviewed by an EPAauthorized IRB. 

[Taken from pages 7–14 of the 2004 NAS 

Report (http://www.national-academies.org).] 

c. Science Reviews—§ 26.1603(b). The 

provisions in proposed § 26.1603(b) 

include considerations that EPA must 

take into account when conducting its 

science reviews of proposed research 

that would be covered by the rule. In 

developing this list of considerations, 

EPA relied on recommendations 3–1 

and 5–1 from the 2004 NAS Report to 

identify specific items that would be 

relevant to evaluating the scientific 

merit of proposed human research. How 

EPA developed the specific language for 

each provision follows. 

• Proposed § 26.1603(b)(1): Whether 

the research would be likely to produce 

data that address an important 

scientific or policy question that cannot 

be resolved on the basis of animal data 

or human observational research. 

This language is a combination of 

recommendations 3–1(a) and 5–1(b) and 

(c) from the 2004 NAS Report (see 

verbatim text provided in Unit 

IV.C.2.b.). The language ‘‘address an 

important scientific or policy question’’ 

reflects excerpts taken from 

recommendation 5–1(c). The language 

‘‘that cannot be resolved on the basis of 

animal data or human observation 

research’’ is taken from recommendation 

3–1(a). These recommendations are 

intended to avoid unnecessary exposure 

for human subjects. If animal data or 

human observational research were 

available to address an important 

scientific or policy question, then there 

would be no scientific need for 

additional human research. EPA relied 

primarily on recommendation 5–1 in 

formulating the proposed language 

because that recommendation addresses 

criteria for EPA acceptance of human 

research, whereas recommendation 3– 

1describes topics that should be covered 

in EPA guidelines. 

Based on recommendation 5–1, EPA 

has phrased the proposed language as 

whether the research ‘‘addresses’’ an 

important scientific question rather than 

use the phraseology ‘‘contributes to 

addressing’’ in recommendation 3–1. 

The Agency believes its formulation is 

clearer and intends to interpret this as 

meaning that the research needs to be 

designed to obtain data likely to provide 

significant insight into important 

research questions. 

EPA requests comment on whether its 

reliance primarily on the language of 

recommendation 5–1(c) is appropriate 

here, or whether it should have used the 

‘‘contributes to’’ language from 

recommendation 3–1(a). 

• Proposed § 26.1603(b)(2): Whether 

the proposed research is designed in 

accordance with current scientific 

standards and practices to: Address the 

research question, include 

representative study populations for the 

endpoint in question, and have 

adequate statistical power to detect 

appropriate effects. 

Again, this language is a combination 

of recommendations 3–1(b) and 5–1(c) 

from the 2004 NAS Report (see verbatim 

text provided in Unit IV.C.2.b.). The 

recommendations highlight the need for 

adequate statistical power and 

appropriate representative study 

populations to ensure the scientific 

validity and reliability (and thus ethical 

conduct) of human research. To 

accommodate these recommendations, 

EPA is proposing to adopt language 

from the recommendations 3–1(b) and 

5–1(c). 

For the reason stated in the previous 

discussion on proposed § 26.1603(b)(1), 

EPA placed primary reliance on 

recommendation 5–1. The Agency notes 

that the proposed § 26.1603(b)(2)(iii), 

which reflects the language in 5–1(c), 

differs from the language in 3–1(b), 

which says ‘‘meets requirements for 

adequate statistical power.’’ The Agency 

prefers to propose the language as 

contained in 5–1(c) because it does not 

believe that there is one specific set of 

‘‘requirements’’ with which to evaluate 

statistical power. The Agency intends to 

evaluate the statistical power of a study 

while focusing on the ultimate goal of 

ensuring that appropriate effects are 

detected rather than on some arbitrary 

and undefined set of ‘‘requirements.’’ 

EPA requests comment on whether 

the proposed language is clear and 

specifically on this language as 

compared to using the language directly 

from the recommendation in the 2004 

NAS Report. 

• Proposed § 26.1603(b)(3): Whether 

the investigator proposes to conduct the 

research in accordance with recognized 

good research practices, including, 

when appropriate, good clinical practice 

guidelines and monitoring for the safety 

of subjects. 

This provision reflects excerpts taken 

from recommendation 3–1(c) from the 

2004 NAS Report (see verbatim text 

provided in Unit IV.C.2.b.). Although 

the NAS focused on good clinical 

practice guidelines, the Agency is 

proposing to apply a broader standard 

‘‘recognized good research practices’’, 

which may include good clinical 

practice guidelines when appropriate. 

The rationale for this is that some 

human research—in fact, all human 

research proposed to EPA to be 

conducted since promulgation of the 

2006 rule—is not conducted in clinical 

settings (e.g., field testing of repellents 

or worker exposure) and thus good 

clinical practice guidelines would be 

inappropriate to apply. However, there 

may be other general good research 

practices that the research community 

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employs to ensure scientific integrity of 

their studies and safety of the subjects 

that would be relevant for the Agency to 

consider. One such practice that has 

currently been developed is the 

Guidelines for Performance Testing of 

Skin-Applied Insect Repellent issued in 

October 2008, and incorporated into the 

OCSPP harmonized test guidelines 

library in July 2010, entitled ‘‘Product 

Performance Test Guidelines No. 

810.3700: Insect Repellents to be 

Applied to Human Skin’’ (http:// 

www.epa.gov/ocspp/pubs/frs/ 

publications/Test_Guidelines/ 

series810.htm). 

EPA requests comment on this 

expansion and also welcomes 

suggestions for other good research 

practice documents that could be cited 

here as well. 

d. Ethics Reviews—§ 26.1603(c). The 

provisions in proposed § 26.1603(c) 

address many important ethical 

concerns, including, among other 

things, identification and minimization 

of risks to participants, equitable 

selection of participants, and provision 

of medical care for participants. In 

developing this list of considerations, 

EPA relied on several recommendations 

from the 2004 NAS Report, including 4– 

1, 5–1, 5–2, 5–3, and 5–5 (see verbatim 

text provided in Unit IV.C.2.b.), to 

identify specific considerations that 

would be relevant to evaluating the 

ethics of proposed human research. 

Each proposed consideration is 

discussed below. 

• Proposed § 26.1603(c)(1): Whether 

adequate information is available from 

prior animal studies or from other 

sources to assess the potential risks to 

subjects in the proposed research. 

This provision reflects excerpts taken 

from recommendation 5–1(a) from the 

2004 NAS Report (see verbatim text 

provided in Unit IV.C.2.b.), which 

recommends that animal studies be 

available prior to conducting human 

studies. This NAS recommendation also 

suggests consideration of human 

observational studies if available. When 

EPA conducts its ethics reviews, it does 

and will continue to consider whether 

there is adequate information from prior 

animal and human observational studies 

to understand the level of risk that may 

be presented to subjects of the proposed 

research. Although the NAS does not 

specify in its recommendation the 

specific purpose that the information 

from prior animal studies or from other 

sources, including human observational 

studies if available, serves, EPA believes 

its use of these studies to assess 

potential risks in evaluating the ethics 

of a human research proposal subject to 

this rule is reasonable and an integral 

part of determining whether the benefits 

of the research outweigh the risks of the 

research. The proposed language refers 

to ‘‘information * * * from prior animal 

studies or from other sources.’’ EPA 

intends the reference to ‘‘other sources’’ 

to include human observational studies, 

consistent with recommendation 5–1. 

EPA requests comment on whether 

the proposed language is clear and 

specifically on this language as 

compared to using the language directly 

from the recommendation in the 2004 

NAS Report. 

• Proposed § 26.1603(c)(2): Whether 

the research proposal adequately 

identifies anticipated risks to human 

subjects and their likelihood of 

occurrence, minimizes identified risks 

to human subjects, and identifies likely 

benefits of the research and their 

distribution. 

This provision is based on 

recommendation 5–1(d) from the 2004 

NAS Report (see verbatim text provided 

in Unit IV.C.2.b.), which states that the 

necessary conditions for human 

research include ‘‘an acceptable balance 

of risks and benefits and minimization 

of risks to participants.’’ EPA has 

separated these two conditions and 

addresses minimization of risk in this 

paragraph and the balance of risks and 

benefits in proposed § 26.1603(c)(3). In 

this paragraph, EPA also proposes to 

include a consideration of whether the 

research proposal adequately identifies 

anticipated risks to human subjects and 

their likelihood of occurrence and the 

likely benefits of the research and their 

distribution. These additional 

considerations are important in 

understanding the overall risk/benefit 

picture of proposed human research 

covered by this rule. EPA does not 

believe that adding these considerations 

will impose any additional burden on 

stakeholders since this information is 

typically provided with research 

proposals that are submitted to IRBs and 

to the Agency. EPA currently reviews 

human research proposals submitted to 

it under the 2006 rule with these 

considerations in mind. 

EPA requests comment on whether it 

is appropriate to address minimization 

of risk and the risk-benefit balance in 

separate paragraphs. EPA has chosen 

this approach because it interprets 

recommendation 5–1(d) as setting forth 

separate and independent 

considerations and, given this 

interpretation, believes that repeating 

the risk-benefit balance language in this 

paragraph would be duplicative and 

confusing. EPA also recognizes an 

alternative view of recommendation 5– 

1(d) is that separating the minimization 

of risk consideration from the riskbenefit balance consideration alters the 

collective context intended by 

recommendation 5–1(d) of the 2004 

NAS Report. As such, EPA requests 

comments on both approaches as they 

apply to the proposed §§ 26.1603(c)(2) 

and 26.1603(c)(3). 

• Proposed § 26.1603(c)(3): Whether 

the proposed research presents an 

acceptable balance of risks and benefits. 

In making this determination for 

research intended to reduce the 

interspecies uncertainty factor in a 

pesticide risk assessment, the 

Administrator must consider 

Recommendation 4–1 in the 2004 

Report from the National Research 

Council of the National Academy of 

Sciences (NAS), entitled ‘‘Intentional 

Human Dosing Studies for EPA 

Regulatory Purposes: Scientific and 

Ethical Issues.’’ 

This provision reflects excerpts taken 

from recommendations 5–1(d) and 4–1 

from the 2004 NAS Report (see verbatim 

text provided in Unit IV.C.2.b.). For 

each human research proposal 

submitted to the Agency that is covered 

by this rule, in addition to considering 

whether a study proposal minimizes 

risks to the human subjects, EPA is 

proposing to consider whether the 

proposed research presents an 

acceptable balance of risks and benefits 

based on, among other things, the 

information it considers under the 

proposed paragraphs (c)(1) and (c)(2) in 

§ 26.1603. 

Recommendation 5–1(d) also refers to 

‘‘the minimization of risks to 

participants.’’ EPA addressed that 

consideration in proposed 

§ 26.1603(c)(2). The Agency requests 

comment on whether another reference 

to minimization of risk is nonetheless 

needed in this paragraph for consistency 

with the 2004 NAS Report. 

For research that is intended 

specifically to reduce the interspecies 

uncertainty factor in a pesticide risk 

assessment, the Agency is proposing to 

consider whether that study presents an 

acceptable balance of risks and benefits 

in accordance with process laid out for 

evaluating that type of study in 

recommendation 4–1 and the attendant 

discussion in the 2004 NAS report that 

informs the application of that 

recommendation. EPA lacks experience 

in reviewing proposals for research 

intended to reduce the interspecies 

uncertainty factor. Since the 

promulgation of the 2006 rule, EPA has 

received no proposals for such research 

and, as noted in Unit IV.A.2. and A.3., 

EPA knows of no third-party research 

involving intentional exposure of a 

human subject to a pesticide that has 

ever been proposed, conducted, or 

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2The Nuremburg Code states the importance of 

free and fully informed consent and describes the 

elements of such consent: ‘‘The voluntary consent 

of the human subject is absolutely essential. This 

means that the person involved should have legal 

capacity to give consent; should be so situated as 

to be able to exercise free power of choice, without 

the intervention of any element of force, fraud, 

deceit, duress, over-reaching, or other ulterior form 

of constraint or coercion; and should have sufficient 

knowledge and comprehension of the elements of 

the subject matter involved as to enable him to 

make an understanding and enlightened decision 

***’’ http://ohsr.od.nih.gov/guidelines/ 

nuremberg.html. 

submitted to EPA under regulatory 

authorities other than the pesticide 

laws. However, EPA recognizes that this 

is a possibility in the future. 

The Agency asks for comment on how 

it should consider NAS 

recommendation 4–1, if this proposed 

amendment were finalized and EPA 

received a study proposal for that 

purpose, and, given the context of the 

proposed expansion to the scope of the 

2006 rule as discussed in Unit IV.A., 

whether the proposed § 26.1603(c)(3) is 

clear about how NAS recommendation 

4–1 might apply to future studies. 

• Proposed § 26.1603(c)(4): Whether 

subject selection will be equitable. 

This provision is taken directly from 

recommendations 5–1(e) and 5–2(a) 

from the 2004 NAS Report (see verbatim 

text provided in Unit IV.C.2.b.). 

• Proposed § 26.1603(c)(5): Whether 

subjects’ participation would follow free 

and fully informed consent. 

This provision reflects excerpts taken 

from recommendations 5–1(f) from the 

2004 NAS Report (see verbatim text 

provided in Unit IV.C.2.b.), which 

mentions free and informed consent, 

and the Nuremberg Code.2

Key aspects or indicators of free and 

fully informed consent or legally 

effective consent are set out in detail in 

§ 26.1116. They include that 

information be provided in a form 

understandable to the subject, including 

information on the purposes and 

duration of the research as well as on 

the procedures, risks, and any 

compensation involved in the research. 

Further, the subject must be made aware 

that participation in the research is 

voluntary, that there is no penalty for 

not participating, and that the subject 

may withdraw from the research at any 

time. The reference in § 26.1603(c)(5) to 

‘‘free and fully informed consent’’ 

emphasizes the centrality of this 

concept to the ethics evaluation process. 

• Proposed § 26.1603(c)(6): Whether 

an appropriately constituted 

Institutional Review Board or its foreign 

equivalent has approved the proposed 

research. 

This provision reflects excerpts taken 

from recommendations 5–1(g) and 6–1 

from the 2004 NAS Report (see verbatim 

text provided in Unit IV.C.2.b.). Section 

26.1125 already requires third-parties 

covered by the 2006 rule to obtain IRB 

approval before submitting proposals to 

EPA under subpart P, and section 

26.1601(c) of the current rule allows the 

Agency to consider whether foreign 

proposed research has undergone 

equivalent protective procedures. 

• Proposed § 26.1603(c)(7): If any 

person from a vulnerable population 

may become a subject in the proposed 

research, whether there is a convincing 

justification for selection of such a 

person, and whether measures taken to 

protect such human subjects are 

adequate. 

This provision reflects excerpts taken 

from recommendation 5–2(b) from the 

2004 NAS Report (see verbatim text 

provided in Unit IV.C.2.b.). EPA 

recognizes that some individuals who 

may become subjects in human research 

may be more vulnerable to coercion or 

undue influence, for example, prisoners, 

persons with mental disabilities, or 

economically or educationally 

disadvantaged persons. As such, for 

proposals in which such individuals 

may become a subject of the research, 

EPA is proposing to consider whether 

the proposal contains a convincing 

justification for the selection of those 

persons as well as whether any 

measures taken to protect those persons 

are adequate. The specific language of 

recommendation 5–2(b) states that ‘‘IRBs 

* * * should ensure that the following 

conditions met in selecting research 

participants * * * (b) Selection of 

persons from vulnerable populations 

must be convincingly justified in the 

protocol, which also must justify the 

measures to be taken to protect the 

participants.’’ In drafting this provision 

EPA rephrased recommendation 5–2(b) 

to convert it to regulatory language. In 

doing so, EPA first made this provision 

conditional (the ‘‘if’’ clause) because 

EPA does not expect that vulnerable 

populations will often be included in 

human research and there is no reason 

to impose a burden on researchers to 

justify a situation when it is 

inapplicable. EPA also substituted the 

requirement that measures taken to 

protect such human subjects be 

‘‘adequate’’ instead of requiring a 

‘‘convincing justification’’ for them. 

EPA requests comment on whether 

the proposed language is clear and 

specifically on this language as 

compared to using the language directly 

from recommendation 5–2(b) in the 

2004 NAS Report. 

• Proposed § 26.1603(c)(8): If any 

person with a condition that would put 

them at increased risk for adverse 

effects may become a subject in the 

proposed research, whether there is a 

convincing justification for selection of 

such a person, and whether measures 

taken to protect such human subjects 

are adequate. 

This provision reflects excerpts taken 

from recommendation 5–2(c) from the 

2004 NAS Report (see verbatim text 

provided in Unit IV.C.2.b.). Although 

EPA anticipates that persons with 

conditions that put them at increased 

risk for adverse effects would likely be 

screened from participating in human 

research subject to this rule, there may 

be circumstances when an exception is 

warranted. In those instances where 

such persons may become subjects in 

research covered by this rule, EPA is 

proposing to consider whether the 

research contains a convincing 

justification for the selection of those 

persons as well as whether any 

measures taken to protect those persons 

are adequate to decrease risks to an 

acceptable level. The specific language 

of recommendation 5–2(b) states that 

‘‘IRBs * * * should ensure that the 

following conditions met in selecting 

research participants * * * (c) Selection 

of individuals with conditions that put 

them at increased risk for adverse effects 

in such studies must be convincingly 

justified in the protocol, which also 

must justify the measures that 

investigators will use to decrease the 

risks to those participants to an 

acceptable level.’’ For this provision, 

EPA followed a similar path in 

converting the NAS recommendation 

into regulatory language as it did with 

proposed § 26.1603(c)(7), i.e., EPA made 

the provision conditional and used an 

adequacy test rather than a convincing 

justification as to evaluating the 

measures to protect the subjects. 

EPA requests comment on whether 

the proposed language is clear and 

specifically on this language as 

compared to using the language directly 

from recommendation 5–2(c) in the 

2004 NAS Report. 

• Proposed § 26.1603(c)(9): Whether 

any proposed payments to subjects are 

consistent with the principles of justice 

and respect for persons, and whether 

they are so high as to constitute undue 

inducement or so low as to be attractive 

only to individuals who are 

socioeconomically disadvantaged. 

This provision reflects excerpts taken 

from recommendation 5–3 from the 

2004 NAS Report (see verbatim text 

provided in Unit IV.C.2.b.). Although 

this provision overlaps slightly with 

proposed §§ 26.1603(c)(4) and 

§ 26.1603(c)(7), EPA is proposing to 

enumerate a specific consideration for 

whether the level of remuneration for 

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participation in any proposal for human 

research covered by this rule is 

appropriate, i.e., consistent with the 

principles of justice and respect for 

persons, and whether it is likely to 

induce participation from individuals 

from vulnerable populations and affect 

the equitable selection of subjects. In 

converting the affirmative statement in 

recommendation 5–3 into a ‘‘whether’’ 

statement for regulatory language, EPA 

dropped the recommendation’s 

‘‘neither—nor’’ phrasing because it is 

potentially confusing. EPA believes that, 

as drafted, this provision requires 

consideration of whether payments are 

either too high or too low but requests 

comment on this point. 

EPA requests comment on whether 

the proposed language is clear and 

specifically on this language as 

compared to using the language directly 

from recommendation 5–3 in the 2004 

NAS Report. 

• Proposed § 26.1603(c)(10): Whether 

the sponsor or investigator would 

provide needed medical care for injuries 

incurred in the proposed research, 

without cost to the human subjects. 

This provision reflects excerpts taken 

from recommendation 5–5 from the 

2004 NAS Report (see verbatim text 

provided in Unit IV.C.2.b.). EPA is 

proposing to consider in its ethics 

review of proposed human research 

subject to this rule whether medical care 

resulting from participation in the 

research will be provided without cost 

to the human subjects. 

As noted throughout this section, EPA 

requests comment on whether the 

provisions of proposed § 26.1603 are 

consistent with the recommendations 

from the 2004 NAS Report and whether 

the regulatory language chosen by EPA 

adequately captures EPA’s intended 

goal and is otherwise clear and easily 

understood. 

D. Revised Acceptance Standards for 

Completed Research (40 CFR part 26, 

subpart Q) 

1. Overview 

a. Current rule. 40 CFR part 26, 

subpart Q, establishes standards 

governing reliance by EPA under the 

pesticide laws on ‘‘scientifically valid 

and relevant data from research 

involving intentional exposure of 

human subjects.’’ Section 26.1703 

forbids EPA to rely on any research 

involving intentional exposure of a 

subject who was a pregnant woman, a 

nursing woman, or a child. Section 

26.1704 forbids EPA to rely on research 

initiated before the effective date of the 

2006 rule in the face of 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.’’ 

Section 26.1705 forbids EPA to rely on 

research initiated after the effective date 

of the 2006 rule unless EPA has 

‘‘adequate information to determine that 

the research was conducted in 

substantial compliance with subparts A 

through L * * *’’ Section 26.1706 

permits EPA to rely on the results of 

human research unacceptable under the 

standards of §§ 26.1703–26.1705 only if 

EPA determines, after public notice and 

comment and consultation with HSRB, 

that reliance on the research is 

necessary to support ‘‘a more stringent 

regulatory restriction that would 

improve protection of public health 

* * * than could be justified without 

relying on the data.’’ The Agency is not 

proposing to amend the substance of 

§ 26.1706. 

b. Summary of proposed changes. In 

addition to broadening the scope of 40 

CFR part 26, subpart Q, to apply to 

research relied on by EPA under 

regulatory statutes other than FIFRA or 

FFDCA, EPA proposes to amend the 

substantive standards in §§ 26.1703, 

26.1704, and 26.1705 for determining 

the acceptability of completed research 

involving intentional exposure of a 

human subject to a pesticide. As noted 

throughout this document, EPA requests 

comment on each of these proposed 

changes, as well as on the changes in 

the aggregate. In particular, EPA seeks 

comment on its conclusions regarding 

the effect of these proposed changes 

relative to the scope of the 2006 rule, 

including the effect of these proposed 

changes on the volume of studies 

covered by the rule, the likely statutes 

under which studies may be submitted, 

and the impact on activities covered by 

those other statutes. 

c. Anticipated effects. If a covered 

study does not meet the applicable 

standards in 40 CFR part 26, subpart Q, 

EPA would be prohibited from relying 

on the data in any action it takes under 

any of its regulatory authorities except 

under the extremely restrictive 

conditions defined in § 26.1706. 

2. § 26.1703: Standards Applicable to all 

Covered Research 

a. Proposed changes and rationale. 

Consistent with the changes proposed in 

40 CFR part 26, subpart P, and 

discussed in Unit IV.C., EPA proposes 

to add in § 26.1703(a) an explicit 

prohibition against reliance on data 

from completed research ‘‘unless EPA 

determines that the data are relevant to 

a scientific or policy question important 

for EPA decision-making, that the data 

were derived in a manner that makes 

them scientifically valid and reliable, 

and that it is appropriate to use the data 

for the purpose proposed by EPA.’’ 

In making this determination, EPA 

would be required to assess these four 

aspects of the research: 

• Whether the research was designed 

and conducted according to 

‘‘appropriate scientific standards and 

practices prevailing at the time the 

research was conducted.’’ 

• The extent to which the test 

subjects represent the population whose 

response the data will be used to 

predict. 

• The statistical power of the data to 

support the scientific conclusions 

drawn by EPA. 

• Whether, in a study that reports a 

No Observed Effect Level (NOEL) or a 

No Observed Adverse Effect Level 

(NOAEL), some dose level elicited a 

biological effect. 

These four aspects of the research are 

derived from Recommendations 3–1 and 

5–1 from the 2004 NAS Report. They do 

not establish fixed criteria for 

acceptance or rejection of a study, but 

they identify specific aspects of a study 

that EPA must consider in determining 

that it is relevant, scientifically valid 

and reliable, and appropriate for a 

particular use. 

b. Anticipated effect. As noted 

previously, 40 CFR part 26, subpart Q, 

applies to EPA decisions to rely on 

‘‘scientifically valid and relevant data’’ 

from covered research. Since 2006, 

EPA’s practice in reviewing reports of 

covered human research has been to 

examine carefully the scientific merit of 

the reported studies and to refuse to use 

research deemed invalid or irrelevant. 

EPA proposes to delete these factors 

from the scope of 40 CFR part 26, 

subpart Q, as defined in § 26.1701, and 

to codify them as factors in § 26.1703(a) 

to ensure that they remain central to 

determinations of scientific validity and 

relevance. If this proposed amendment 

is finalized, EPA would likely make 

minor revisions to its internal review 

procedures to highlight the 

consideration given to these four aspects 

of the research. 

3. § 26.1704: Acceptance Standards for 

Research not Subject to § 26.1705 

a. Proposed changes and rationale. 

The Agency based the ethical 

acceptability standard in § 26.1704 on 

Recommendation 5–7 from the 2004 

NAS Report, which states in relevant 

part: 

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EPA should accept scientifically valid 

studies conducted before its new rules are 

implemented unless there is clear and 

convincing evidence that the conduct of 

those studies was fundamentally unethical 

(e.g., the studies were intended to seriously 

harm participants or failed to obtain 

informed consent) or that the conduct was 

deficient relative to then-prevailing 

standards. 

Section 26.1704 provides in relevant 

part (emphasis added): 

* * * EPA shall not rely on data from any 

research initiated before [the effective date of 

the 2006 rule], 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. 

EPA adopted the recommendation 

from the 2004 NAS Report nearly 

verbatim, with the notable insertion of 

the word ‘‘significantly’’ before 

‘‘deficient.’’ EPA explained in the 

preamble to the 2006 rule (at 71 FR 

6161) that this was to allow it the 

flexibility to consider the impact on 

subjects of any ethical shortcomings in 

the conduct of the research. EPA stated 

in that preamble (at 71 FR 6161) that 

‘‘EPA expects [the meaning of 

‘‘significantly’’] to acquire greater clarity 

over time, through HSRB and public 

review of Agency decisions concerning 

reliance on completed human research.’’ 

EPA believes that greater clarity has, 

indeed, been achieved through the 

application of the 2006 rule by EPA and 

HSRB. EPA now proposes to revise 

§ 26.1704 by deleting the word 

‘‘significantly,’’ proposing instead to 

characterize explicitly the kinds of 

deficiencies that would make a study 

unacceptable. 

This language is derived from the 

advice of HSRB as they have applied the 

standard of § 26.1704 in the 2006 rule. 

See, for example, their comments on 

studies involving aldicarb, methomyl, 

oxamyl, azinphos-methyl, DDVP, 

ethephon, sodium cyanide, and amitraz 

at: http://www.epa.gov/osa/hsrb/files/ 

meeting-materials/apr-4-6-2006-publicmeeting/ 

april2006mtgfinalreport62606.pdf. For 

each study they found ethically 

acceptable, HSRB found ‘‘no evidence of 

significant deficiencies in the ethical 

procedures that could have resulted in 

serious harm (based on the knowledge 

available at the time the study was 

conducted) nor that information 

provided to participants seriously 

impaired their informed consent.’’ 

Finally, EPA proposes to redefine the 

applicability of § 26.1704 in a new 

paragraph (a) as the complement of the 

more detailed scope of § 26.1705, 

thereby eliminating any gaps or overlap 

in the applicability of the two standards. 

b. Anticipated effect. Proposed 

§ 26.1704 would forbid EPA to rely on 

research not covered by 40 CFR part 26, 

subpart K, or the Common Rule in the 

face of clear and convincing evidence 

that its conduct ‘‘placed participants at 

increased risk of harm (based on 

knowledge available at the time the 

study was conducted) or impaired their 

informed consent.’’ EPA specifically 

requests comment on the incremental 

value of this change as well as the 

extent to which this change might 

inappropriately reduce EPA’s access to 

human research. 

4. § 26.1705: Standards for Completed 

Research Conducted Under 40 CFR Part 

26 or Another Codification of the 

Common Rule 

a. Proposed changes and rationale. 

The standard in 40 CFR part 26 

applying to completed research initiated 

after the effective date of the rule is 

§ 26.1705, based on Recommendation 5– 

6 from the 2004 NAS Report, which 

states in relevant part (italics in the 

original; footnote omitted): 

EPA should operate on the strong 

presumption that data obtained in studies 

conducted after implementation of the new 

rules that do not meet the ethical standards 

described in this report will not be 

considered in its regulatory decisions. 

EPA adapted this recommendation in 

its drafting of § 26.1705, which provides 

in relevant part: 

EPA shall not rely on data from any 

research initiated after [the effective date of 

the 2006 rule] 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. 

EPA now proposes to amend both the 

applicability of § 26.1705 and the 

substance of the standard itself. In the 

2006 rule, § 26.1705 applies to any 

scientifically valid and relevant research 

involving intentional exposure of 

human subjects and initiated after the 

effective date of the rule. EPA proposes 

now to limit application of the § 26.1705 

standard to research subject, at the time 

it was conducted, either to subparts A 

through L of 40 CFR part 26 or to 

another Federal department or agency’s 

codification of the Common Rule. 

EPA recognizes that it could in the 

future wish to rely on data from thirdparty research conducted after 2006 but 

which fell outside the scope of 40 CFR 

part 26, subpart K, and for which EPA 

therefore would not have conducted a 

protocol review under 40 CFR part 26, 

subpart P, before the research was 

conducted. For example, as discussed in 

Unit IV.A., 40 CFR part 26, subpart K, 

as now proposed would not apply to a 

new clinical trial evaluating the 

therapeutic efficacy of a drug that was 

also a pesticide. Because this research 

would fall outside the scope of 40 CFR 

part 26, subpart K, investigators would 

not have submitted the protocol to EPA 

under 40 CFR part 26, subpart K, and 

EPA and HSRB would not have 

reviewed it under 40 CFR part 26, 

subpart P. Yet, if data from such 

research were to be relied on by EPA, 

the standards of subpart Q would apply. 

As § 26.1705 is currently worded in 40 

CFR part 26, such a study could only be 

relied on if ‘‘EPA has adequate 

information to determine that the 

research was conducted in substantial 

compliance with subparts A through L.’’ 

But because the protocol would not 

have been submitted for review by EPA 

and HSRB, the research in this example 

would not have been conducted in 

substantial compliance with 40 CFR 

part 26, subpart K. 

EPA believes that it would be 

inappropriate to reject otherwise 

meritorious and ethical research for 

failure to comply with provisions in 40 

CFR part 26, subparts A–L that did not 

apply when the research was 

conducted. Thus EPA proposes to make 

§ 26.1705 applicable only to studies that 

were initiated after the effective date of 

the 2006 rule and that were subject to 

EPA’s rules for the protection of human 

subjects (40 CFR part 26, subparts A 

through L) or another codification of the 

Common Rule. A companion change in 

§ 26.1704(a) would apply the standard 

of § 26.1704 to all other completed 

research considered by EPA under 40 

CFR part 26, subpart Q, without regard 

to when the research was initiated. 

EPA proposes further changes to 

§ 26.1705 to help make this clear. 

Proposed § 26.1705(b)(1) defines the 

applicable standard as either 40 CFR 

part 26, subparts A through L, or 

another Federal department or agency’s 

codification of the Common Rule, 

whichever set of rules covered the 

research when it was conducted. In 

proposed § 26.1705(b)(2), corresponding 

changes are made applicable to research 

conducted in foreign countries. 

Finally, in a new paragraph (c) in 

§ 26.1705, EPA proposes to require 

substantial compliance of covered 

research with its protocol. A study 

reviewed as a proposal under subpart P 

of 40 CFR part 26 could be relied on 

only if it had been conducted in 

substantial compliance with the 

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protocol found acceptable by EPA, and 

if the investigator did not further amend 

or deviate from the protocol in ways 

that placed participants at increased risk 

of harm (based on knowledge available 

at the time the study was conducted) or 

impaired their informed consent. If a 

completed study was not reviewed as a 

proposal under 40 CFR part 26, subpart 

P, the study could only be relied on if 

it had been conducted in substantial 

compliance with a protocol that would 

have been found acceptable, and if the 

investigator did not amend or deviate 

from the protocol in ways that placed 

participants at increased risk of harm 

(based on knowledge available at the 

time the study was conducted) or 

impaired their informed consent. 

b. Anticipated effect. Taken together, 

these proposed changes in § 26.1705 

reflect the interpretations and methods 

used by EPA and HSRB since 2006 in 

reviewing completed, post-rule 

research. Codifying these interpretations 

will ensure consistency and 

transparency in future decision-making 

and is consistent with the 2006 

Appropriations Act. 

E. Request for Public Comment on 

Possible Re-Codification of 40 CFR Part 

26, Subparts K–Q 

1. Current rule. Subparts A–D of 40 

CFR part 26 all apply to research with 

human subjects which is conducted or 

supported by EPA in its role as a 

research agency. Subparts K–Q of 40 

CFR part 26 apply to pesticide research 

with human subjects that is conducted 

by regulated third parties, and to EPA’s 

regulatory oversight of that research. 

Some stakeholders have suggested that 

this important distinction would be 

clearer if 40 CFR part 26 contained only 

those subparts applying to EPA as a 

research agency, and if 40 CFR part 26, 

subparts K–Q, were moved to a different 

section of EPA’s regulations, within the 

range where other pesticide-specific 

regulations are found. 

2. Proposed amendments and 

rationale. EPA is not now proposing 

such a re-codification, but invites public 

comment on the idea. Although it 

would necessitate many non-substantive 

revisions—mainly of internal crossreferences—re-codification would not 

be difficult to accomplish. 40 CFR part 

26 would retain current 40 CFR part 26, 

subparts A–D, and at least parts of 

current 40 CFR part 26, subpart O. A 

previously unused part within 40 CFR, 

within the numerical range of parts 

150–180 where other pesticide-related 

regulations appear, would include 

current 40 CFR part 26, subparts K, L, 

M, O, P, and Q. 40 CFR part 26, subpart 

O, potentially applies to both EPA 

research and to third-party research and 

would need to be adapted to fit into 

both parts of a separated codification in 

40 CFR. 

3. Anticipated effect. Although this 

proposed re-codification may better 

distinguish those requirements applying 

to EPA as a research agency, and those 

applying to third-party studies, it would 

only change the location of the 

regulation within 40 CFR, and would 

not otherwise have any effect on the 

requirements. 

V. FIFRA Review Requirements 

In accordance with FIFRA section 

25(a), EPA has submitted a draft of the 

proposed rule to the FIFRA Scientific 

Advisory Panel (SAP), the Secretary of 

Agriculture (USDA), and appropriate 

Congressional Committees. The FIFRA 

SAP waived its review of this proposal 

on October 12, 2010, because the 

significant scientific issues involved 

have already been reviewed by the SAP 

and additional review is not necessary. 

USDA responded without comments, 

but participated in the interagency 

review process under Executive Order 

12866. 

VI. Statutory and Executive Order 

Reviews 

A. Regulatory Planning and Review 

Under Executive Order 12866, 

entitled Regulatory Planning and 

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

this has been identified as a ‘‘significant 

regulatory action.’’ Accordingly, EPA 

submitted the draft proposed rule to the 

Office of Management and Budget 

(OMB) for review under Executive 

Order 12866 and any changes made in 

response to OMB recommendations 

have been documented in the docket for 

this rulemaking as required by the 

Executive Order. 

The incremental costs of these 

proposed amendments both to industry 

and to EPA are expected to be 

negligible. EPA has not, therefore, 

prepared a new economic analysis for 

this rulemaking. Because no research 

has been identified that is outside the 

scope of the 2006 rule but that would be 

within the scope of these proposed 

amendments, EPA has no basis on 

which to revise the cost estimates that 

were provided in the economic analysis 

for the 2006 rulemaking or those most 

recently provided in the 2008 renewal 

of the Information Collection Request 

(ICR) for the existing regulation at 40 

CFR part 26. The recent estimates 

included in the ICR are summarized in 

Unit VI.B. and a copy of the ICR is 

available in the docket. 

B. Paperwork Reduction Act 

This action does not impose any new 

information collection burden that 

would require additional review or 

approval by OMB under the Paperwork 

Reduction Act (PRA), 44 U.S.C. 3501 et 

seq. OMB previously approved the 

information collection requirements 

contained in the existing regulations at 

40 CFR part 26 under OMB Control No. 

2070–0169 (EPA ICR No. 2195). Burden 

is defined at 5 CFR 1320.3(b). 

In its 2008 analysis supporting the 

most recent renewal of this ICR, EPA 

estimated that respondents would 

submit to the Agency some 34 proposals 

for or reports of research involving 

intentional exposure of human subjects 

each year. EPA estimated that 

preparation of information required by 

the 2006 rule would require about 598 

hours per study at a cost of $45,927 per 

study, for a total estimated annual 

burden for affected entities of 20,332 

hours at an estimated cost of $1,561,518. 

In addition, EPA estimated annual 

submission of 20 reports of research 

requiring only documentation of ethical 

conduct at a cost of 12 hours/$879 per 

report, or 240 hours/$17,580 per year. 

The total estimate of the annual 

respondent burden and cost was the 

sum of these two estimates, or 2,572 

hours/$1,579,098. 

These paperwork burden and cost 

estimates include activities related to 

initial rule familiarization, as well as 

activities that researchers would have to 

perform even without the Agency’s 

rulemaking in this area, such as 

developing a protocol and maintaining 

records. 

The average annual burden on EPA 

for reviewing each of the 34 study 

submissions was estimated to be 178 

hours/$16,850 per study, or 6,052 

hours/$572,900 per year. The average 

annual burden on EPA for reviewing 

each of the 20 additional submissions 

was estimated to be 44 hours/$3,158 per 

study, or 880 hours/$63,160 per year. 

The total estimate of the annual burden 

on EPA was the sum of these two 

estimates, or 6,932 hours/$636,000 per 

year. 

In no year since promulgation of the 

2006 rule have more than 7 protocols 

been submitted to EPA by industry; the 

average annual rate has been just over 

5 for the 5-year period of 2006–2010. 

Somewhat fewer completed reports 

have been submitted during this period, 

so the average of new protocols and 

finished studies has been about 11 per 

year, less than a third of the projected 

34 per year covered by the ICR. There 

is no evidence to suggest an upward 

trend, and nothing in these amendments 

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is believed likely to lead to a significant 

change in the rate of protocol and study 

submissions. 

An agency may not conduct or 

sponsor, and a person is not required to 

respond to, a collection of information 

unless it displays a currently valid OMB 

control number. The OMB control 

numbers for EPA’s regulations in 40 

CFR are listed in 40 CFR part 9. 

C. Small Entity Impacts 

Pursuant to section 605(b) of the 

Regulatory Flexibility Act (RFA), 5 

U.S.C. 601 et seq., the Agency hereby 

certifies that this action will not have a 

significant adverse economic impact on 

a substantial number of small entities. 

Under RFA, small entities include small 

businesses, small organizations, and 

small governmental jurisdictions. For 

purposes of assessing the impacts of this 

proposed rule on small entities, small 

entity is defined in accordance with 

RFA section 601 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. 

3. A small organization that is any 

not-for-profit enterprise which is 

independently owned and operated and 

is not dominant in its field. 

Because no small entities have been 

identified that are directly regulated by 

these proposed amendments, EPA has 

not attempted to reduce the impact of 

this proposed rule on small entities. 

Comments are invited on all aspects of 

the proposal and its impacts on small 

entities. 

D. Unfunded Mandates 

This action does not impose any 

enforceable duty, contain any unfunded 

mandate, or otherwise have any effect 

on small governments subject to the 

requirements of sections 202, 203, 204, 

or 205 of the Unfunded Mandates 

Reform Act (UMRA), 2 U.S.C. 1531– 

1538. These amendments are unlikely to 

affect State, local, and tribal 

governments at all, and are likely to 

affect the private sector only trivially. 

The 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 1 year. 

E. Federalism 

This action does not have federalism 

implications because it is not expected 

to 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 

Executive Order 13132, entitled 

Federalism (64 FR 43255, August 10, 

1999). It makes marginal changes in the 

scope of an existing rule applying to 

sponsors and investigators conducting 

certain kinds of research involving 

human subjects, and refines the 

standards for EPA oversight of and 

reliance on such research. 

In the spirit of Executive Order 13132, 

and consistent with EPA policy to 

promote communications between EPA 

and State and local governments, EPA 

specifically requests comments on this 

proposed action from State and local 

officials. 

F. Tribal Implications 

This action does not have tribal 

implications as specified in Executive 

Order 13175, entitled Consultation and 

Coordination with Indian Tribal 

Governments (65 FR 67249, November 

9, 2000). This action is not expected to 

have substantial direct effects on Indian 

Tribes, will not significantly or uniquely 

affect the communities of Indian Tribal 

governments, and does not involve or 

impose any requirements that affect 

Indian Tribes. Thus, Executive Order 

13175 does not apply to this action. 

G. Children’s Health Protection 

EPA interprets Executive Order 

13045, entitled Protection of Children 

from Environmental Health Risks and 

Safety Risks (62 FR 19885, April 23, 

1997), as applying only to those 

regulatory actions that concern health or 

safety risks, such that the analysis 

required under section 5–501 of the 

Executive Order has the potential to 

influence the regulation. This action is 

not subject to Executive Order 13045 

because it does not establish an 

environmental standard intended to 

mitigate health or safety risks, nor is it 

an ‘‘economically significant regulatory 

action’’ as defined in Executive Order 

12866. The 2006 rule applies to the 

conduct and review of research 

involving intentional exposure of 

human subjects, and prohibits the 

conduct of or EPA reliance on any such 

research involving subjects who are 

children, or pregnant or nursing women. 

These provisions would not be affected 

by the proposed amendments. 

H. Affect on Energy Supply, 

Distribution, or Use 

This action is not a ‘‘significant energy 

action’’ as defined in Executive Order 

13211, entitled Actions Concerning 

Regulations That Significantly Affect 

Energy Supply, Distribution, or Use (66 

FR 28355, May 22, 2001), because this 

action is not likely to have any affect on 

the supply, distribution, or use of 

energy. 

I. Technical Standards 

Because this action does not involve 

any technical standards, section 12(d) of 

the National Technology Transfer and 

Advancement Act of 1995 (NTTAA) (15 

U.S.C. 272 note), does not apply to this 

action. 

J. Environmental Justice 

This action does not entail special 

considerations of environmental justice 

related issues as delineated by 

Executive Order 12898, entitled Federal 

Actions to Address Environmental 

Justice in Minority Populations and 

Low-Income Populations (59 FR 7629, 

February 16, 1994). The strengthened 

protections for human subjects 

participating in covered research 

established in the 2006 rule would not 

be altered by these proposed 

amendments. 

List of Subjects in 40 CFR Part 26 

Environmental protection, 

Administrative practice and procedures, 

Human research, Pesticides and pests. 

Dated: January 18, 2011. 

Lisa P. Jackson, 

Administrator. 

Therefore, it is proposed that 40 CFR 

chapter I be amended as follows: 

PART 26—[AMENDED] 

1. The authority citation for part 26 is 

revised to read as follows: 

Authority: 5 U.S.C. 301; 7 U.S.C. 136a(a) 

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

201, Pub. L. 109–54, 119 Stat. 531; and 42 

U.S.C. 300v–1(b). 

2. Amend § 26.1101 as follows: 

a. Remove paragraphs (a), (c), and (g); 

b. Redesignate paragraph (b) as (c), (f) 

as (g), (e) as (f), and (d) as (e); and 

c. Add new paragraphs (a), (b), and (d) 

to read as follows. 

§ 26.1101 To what does this subpart 

apply? 

(a) Except as provided in paragraph 

(c) of this section, this subpart applies 

to all research initiated on or after 

[effective date of final rule] involving 

intentional exposure of a human subject 

to: 

(1) Any substance if, at any time prior 

to initiating such research, any person 

who conducted or supported such 

research intended either 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, 

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Fungicide, and Rodenticide Act (FIFRA) 

(7 U.S.C. 136–136y) or section 408 of 

the Federal Food, Drug, and Cosmetic 

Act (FFDCA) (21 U.S.C. 346a), or to hold 

the results of the research for later 

inspection by EPA under FIFRA (7 

U.S.C. 136–136y) or section 408 of 

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

(2) A pesticide if, at any time prior to 

initiating such research, any person who 

conducted or supported such research 

intended either to submit results of the 

research to EPA for consideration in 

connection with any action that may be 

performed by EPA under any regulatory 

statute administered by EPA other than 

those statutes designated in paragraph 

(a)(1) of this section, or to hold the 

results of the research for later 

inspection by EPA under any regulatory 

statute administered by EPA other than 

those statutes designated in paragraph 

(a)(1) of this section. 

(b) For purposes of determining a 

person’s intent under paragraph (a) of 

this section, EPA may consider any 

available and relevant information. EPA 

must rebuttably presume the existence 

of intent 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 and, at 

the time the research was initiated, the 

results of such research would be 

relevant to EPA’s exercise of its 

regulatory authority with respect to that 

class of people, products, or activities. 

* * * * * 

(d) The Administrator retains final 

judgment as to whether a particular 

activity is covered by this subpart. 

* * * * * 

3. In § 26.1102, revise paragraphs (a) 

and (c) and add paragraph (k) to read as 

follows: 

§ 26.1102 Definitions. 

(a) Administrator means the 

Administrator of the Environmental 

Protection Agency (EPA) and any other 

officer or employee of EPA to whom 

authority has been delegated. 

* * * * * 

(c) Pesticide means any substance or 

mixture of substances meeting the 

definition in 7 U.S.C. 136(u) [Federal 

Insecticide, Fungicide, and Rodenticide 

Act, section 2(u)]. 

* * * * * 

(k) Common Rule refers to the Federal 

Policy for the Protection of Human 

Subjects that was established in 1991 by 

the Office of Science and Technology 

Policy and codified in 1991 by EPA and 

14 other federal departments and 

agencies (see 56 FR 28003, June 18, 

1991) and subsequently codified by 

other Federal departments and agencies. 

The Common Rule 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. Once codified by a Federal 

department or agency, the requirements 

of the Common Rule apply to research 

conducted or sponsored by that Federal 

department or agency. EPA’s 

codification of the Common Rule 

currently appears in 40 CFR part 26, 

subpart A. 

§ 26.1111 [Amended] 

4. In § 26.1111, remove from 

paragraph (a)(4) the phrase ‘‘or the 

subject’s legally authorized 

representative’’. 

5. In § 26.1116, revise the 

introductory text of the section to read 

as follows: 

§ 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. An investigator 

must 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 that is given 

to the subject must be in language 

understandable to the subject. No 

informed consent, whether 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. 

* * * * * 

6. Revise § 26.1117 to read as follows: 

§ 26.1117 Documentation of informed 

consent. 

(a) Informed consent must be 

documented by the use of a written 

consent form approved by the IRB and 

signed by the subject. A copy shall be 

given to the subject. 

(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, but in 

any event, the investigator must give the 

subject 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. When this method is used, there 

must be a witness to the oral 

presentation. Also, the IRB shall 

approve a written summary of what is 

to be said to the subject. Only the short 

form itself is to be signed by the subject. 

However, the witness must sign both the 

short form and a copy of the summary, 

and the person actually obtaining 

consent must sign a copy of the 

summary. A copy of the summary must 

be given to the subject, in addition to a 

copy of the short form. 

7. Revise the heading for subpart L to 

read as follows: 

Subpart L—Prohibition of Third-Party 

Research Involving Intentional 

Exposure to a Pesticide of Human 

Subjects Who Are Children or 

Pregnant or Nursing Women 

8. Revise § 26.1201 to read as follows: 

§ 26.1201 To what does this subpart 

apply? 

This subpart applies to any research 

subject to subpart K of this part. 

9. Revise § 26.1301 to read as follows: 

§ 26.1301 To what does this subpart 

apply? 

This subpart applies to any person 

who submits to EPA after [effective date 

of final rule] either of the following: 

(a) A report containing the results of 

any human research for consideration in 

connection with an action that may be 

performed by EPA under FIFRA (7 

U.S.C. 136–136y) or section 408 of 

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

(b) A report containing the results of 

any human research on or with a 

pesticide for consideration in 

connection with any action that may be 

performed by EPA under any regulatory 

statute administered by EPA. 

§ 26.1302 [Amended] 

10. In § 26.1302 remove the word 

‘‘shall’’. 

§ 26.1502 [Amended] 

11. Amend § 26.1502 as follows: 

a. In the first sentence of paragraph (a) 

remove the period after the phrase 

‘‘during an inspection.’’ and add in its 

place a comma; and 

b. In the second sentence of paragraph 

(a) remove the phrase ‘‘The agency’’ and 

add in its place ‘‘EPA’’. 

c. In the last sentence of the 

introductory text of paragraph (b) 

remove the phrase ‘‘the Agency’’ and add 

in its place ‘‘EPA’’. 

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§ 26.1505 [Amended] 

12. In § 26.1505 remove from the last 

sentence, the phrase ‘‘§ 26.1502(c)’’ and 

add in its place ‘‘§ 26.1502(b)(4)’’. 

§ 26.1507 [Amended] 

13. In § 26.1507 remove from the last 

sentence, the phrase ‘‘The Agency’’ and 

add in its place ‘‘EPA’’. 

§§ 26.1601 through 26.1603 [Redesignated 

as §§ 26.1603 through 26.1605] 

14. Amend subpart P by redesignating 

§§ 26.1601 through 26.1603 as 

§§ 26.1603 through 26.1605. 

15. Add new §§ 26.1601 and 26.1602 

to read as follows: 

§ 26.1601 To what does this subpart 

apply? 

This subpart applies to both of the 

following: 

(a) Reviews by EPA and by the 

Human Studies Review Board of 

proposals to conduct new research 

subject to 40 CFR 26.1125. 

(b) Reviews by EPA after [effective 

date of the final rule] and, to the extent 

required by § 26.1604, by the Human 

Studies Review Board of reports of 

completed research subject to 40 CFR 

26.1701. 

§ 26.1602 Definitions. 

The definitions in § 26.1102 apply to 

this subpart as well. 

16. Amend newly redesignated 

§ 26.1603 as follows: 

a. Remove paragraphs (a) and (e). 

b. Redesignate paragraphs (b) through 

(d) as (e) through (g). 

c. Add new paragraphs (a), (b), (c), (d), 

and (h) to read as follows. 

§ 26.1603 EPA review of proposed human 

research. 

(a) EPA must review all proposals for 

new human research submitted under 

§ 26.1125 in a timely manner. 

(b) In reviewing proposals for new 

human research submitted under 

§ 26.1125, the EPA Administrator must 

consider and make determinations 

regarding the proposed research, 

including: 

(1) Whether the research would be 

likely to produce data that address an 

important scientific or policy question 

that cannot be resolved on the basis of 

animal data or human observational 

research. 

(2) Whether the proposed research is 

designed in accordance with current 

scientific standards and practices to: 

(i) Address the research question. 

(ii) Include representative study 

populations for the endpoint in 

question. 

(iii) Have adequate statistical power to 

detect appropriate effects. 

(3) Whether the investigator proposes 

to conduct the research in accordance 

with recognized good research practices, 

including, when appropriate, good 

clinical practice guidelines and 

monitoring for the safety of subjects. 

(c) In reviewing proposals for new 

research submitted under § 26.1125, the 

EPA Administrator must consider and 

make determinations regarding ethical 

aspects of the proposed research, 

including: 

(1) Whether adequate information is 

available from prior animal studies or 

from other sources to assess the 

potential risks to subjects in the 

proposed research. 

(2) Whether the research proposal 

adequately identifies anticipated risks to 

human subjects and their likelihood of 

occurrence, minimizes identified risks 

to human subjects, and identifies likely 

benefits of the research and their 

distribution. 

(3) Whether the proposed research 

presents an acceptable balance of risks 

and benefits. In making this 

determination for research intended to 

reduce the interspecies uncertainty 

factor in a pesticide risk assessment, the 

Administrator must consider 

Recommendation 4–1 in the 2004 

Report from the National Research 

Council of the National Academy of 

Sciences (NAS), entitled ‘‘Intentional 

Human Dosing Studies for EPA 

Regulatory Purposes: Scientific and 

Ethical Issues.’’ 

(4) Whether subject selection will be 

equitable. 

(5) Whether subjects’ participation 

would follow free and fully informed 

consent. 

(6) Whether an appropriately 

constituted IRB or its foreign equivalent 

has approved the proposed research. 

(7) If any person from a vulnerable 

population may become a subject in the 

proposed research, whether there is a 

convincing justification for selection of 

such a person, and whether measures 

taken to protect such human subjects 

are adequate. 

(8) If any person with a condition that 

would put them at increased risk for 

adverse effects may become a subject in 

the proposed research, whether there is 

a convincing justification for selection 

of such a person, and whether measures 

taken to protect such human subjects 

are adequate. 

(9) Whether any proposed payments 

to subjects are consistent with the 

principles of justice and respect for 

persons, and whether they are so high 

as to constitute undue inducement or so 

low as to be attractive only to 

individuals who are socioeconomically 

disadvantaged. 

(10) Whether the sponsor or 

investigator would provide needed 

medical care for injuries incurred in the 

proposed research, without cost to the 

human subjects. 

(d) With respect to any research or 

any class of research, the EPA 

Administrator may recommend 

additional conditions which, in the 

judgment of the EPA Administrator, are 

necessary for the protection of human 

subjects. 

* * * * * 

(h) EPA must provide the submitter of 

the proposal copies of the EPA and 

Human Studies Review Board reviews. 

17. Amend newly redesignated 

§ 26.1604 by revising paragraph (a) to 

read as follows: 

§ 26.1604 EPA review of completed human 

research. 

(a) When considering, under any 

regulatory statute it administers, data 

from completed research involving 

intentional exposure of humans to a 

pesticide, EPA must thoroughly review 

the material submitted under § 26.1303, 

if any, and other available, relevant 

information and document its 

conclusions regarding the scientific and 

ethical conduct of the research. 

* * * * * 

18. Add §§ 26.1606 and 26.1607 to 

read as follows: 

§ 26.1606 Human Studies Review Board 

review of proposed human research. 

In commenting on proposals for new 

research submitted to it by EPA, the 

Human Studies Review Board must 

consider the scientific merits and 

ethical aspects of the proposed research, 

including all elements listed in 

§ 26.1603(b) and (c) and any additional 

conditions recommended pursuant to 

§ 26.1603(d). 

§ 26.1607 Human Studies Review Board 

review of completed human research. 

In commenting on reports of 

completed research submitted to it by 

EPA, the Human Studies Review Board 

must consider the scientific merits and 

ethical aspects of the completed 

research, and must apply the 

appropriate standards in subpart Q of 

this part. 

19. Revise the heading for subpart Q 

to read as follows: 

Subpart Q—Standards for Assessing 

Whether To Rely on the Results of 

Human Research in EPA Actions 

20. Revise §§ 26.1701 through 26.1705 

to read as follows: 

* * * * * 

Sec. 

26.1701 To what does this subpart apply? 

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26.1702 Definitions. 

26.1703 Prohibitions applying to all 

research subject to this subpart. 

26.1704 Prohibition of reliance on unethical 

human research with non-pregnant, nonnursing adults which is not subject to 

§ 26.1705. 

26.1705 Prohibition of reliance on unethical 

human research with non-pregnant, nonnursing adults initiated after April 7, 

2006, and subject to subparts A through 

L of this part, or the codification of the 

Common Rule by another Federal 

department or agency. 

* * * * * 

§ 26.1701 To what does this subpart 

apply? 

(a) For decisions under FIFRA (7 

U.S.C. 136–136y) or section 408 of 

FFDCA (21 U.S.C. 346a), this subpart 

applies to research involving intentional 

exposure of human subjects to any 

substance. 

(b) For decisions under any regulatory 

statute administered by EPA other than 

those statutes designated in paragraph 

(a) of this section, this subpart applies 

to research involving intentional 

exposure of human subjects to a 

pesticide. 

§ 26.1702 Definitions. 

The definitions in § 26.1102 and 

§ 26.1202 apply to this subpart as well. 

§ 26.1703 Prohibitions applying to all 

research subject to this subpart. 

(a) Prohibition of reliance on 

scientifically invalid research. EPA 

must not rely on data from research 

subject to this subpart unless EPA 

determines that the data are relevant to 

a scientific or policy question important 

for EPA decisionmaking, that the data 

were derived in a manner that makes 

them scientifically valid and reliable, 

and that it is appropriate to use the data 

for the purpose proposed by EPA. In 

making such determinations, EPA must 

consider: 

(1) Whether the research was 

designed and conducted in accordance 

with appropriate scientific standards 

and practices prevailing at the time the 

research was conducted. 

(2) The extent to which the research 

subjects are representative of the 

populations for the endpoint or 

endpoints in question. 

(3) The statistical power of the data to 

support the scientific conclusion EPA 

intends to draw from the data. 

(4) In a study that reports only a No 

Observed Effect Level (NOEL) or a No 

Observed Adverse Effect Level 

(NOAEL), whether a dose level in the 

study gave rise to a biological effect, 

thereby demonstrating that the study 

had adequate sensitivity to detect an 

effect of interest. 

(b) Prohibition of reliance on research 

subject to this subpart involving 

intentional exposure of human subjects 

who are pregnant women (and therefore 

their fetuses), nursing women, or 

children. Except as provided in 

§ 26.1706, EPA must not rely on data 

from any research subject to this subpart 

involving intentional exposure of any 

human subject who is a pregnant 

woman (and therefore her fetus), a 

nursing woman, or a child. 

§ 26.1704 Prohibition of reliance on 

unethical human research with nonpregnant, non-nursing adults which is not 

subject to § 26.1705. 

(a) This section applies to research 

subject to this subpart that is not subject 

to § 26.1705. 

(b) Except as provided in § 26.1706, 

EPA must not rely on data from any 

research subject to this section if there 

is clear and convincing evidence that: 

(1) 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 

(2) The conduct of the research was 

deficient relative to the ethical 

standards prevailing at the time the 

research was conducted in a way that 

placed participants at increased risk of 

harm (based on knowledge available at 

the time the study was conducted) or 

impaired their informed consent. 

(c) The prohibition in this section is 

in addition to the prohibitions in 

§ 26.1703. 

§ 26.1705 Prohibition of reliance on 

unethical human research with nonpregnant, non-nursing adults initiated after 

April 7, 2006, and subject to subparts A 

through L of this part, or the codification of 

the Common Rule by another Federal 

department or agency. 

(a) This section applies to research 

subject to this subpart, that: 

(1) Was initiated after April 7, 2006. 

(2) Was subject, at the time it was 

conducted, either to subparts A through 

L of this part, or to the codification of 

the Common Rule by another Federal 

department or agency. 

(b) Except as provided in § 26.1706, 

EPA must not rely on data from any 

research subject to this section unless 

EPA determines that the research was 

conducted in substantial compliance 

with either: 

(1) All applicable provisions of 

subparts A through L of this part, or the 

codification of the Common Rule by 

another Federal department or agency; 

or 

(2) If the research was conducted 

outside the United States, with 

procedures at least as protective of 

subjects as those in subparts A through 

L of this part, or the codification of the 

Common Rule by another Federal 

department or agency. 

(c) Except as provided in § 26.1706, 

EPA must not rely on data from any 

research subject to this section unless 

EPA determines that the research was 

conducted in substantial compliance 

with either: 

(1) A proposal that was found to be 

acceptable under § 26.1603(c), and no 

amendments to or deviations from that 

proposal placed participants at 

increased risk of harm (based on 

knowledge available at the time the 

study was conducted) or impaired their 

informed consent. If EPA discovers that 

the submitter of the proposal materially 

misrepresented or knowingly omitted 

information that would have altered the 

outcome of EPA’s evaluation of the 

proposal under § 26.1603(c), EPA must 

not rely on that data. 

(2) A proposal that would have been 

found to be acceptable under 

§ 26.1603(c), if it had been subject to 

review under that section, and no 

amendments to or deviations from that 

proposal placed participants at 

increased risk of harm (based on 

knowledge available at the time the 

study was conducted) or impaired their 

informed consent. 

(d) The prohibition in this section is 

in addition to the prohibitions in 

§ 26.1703. 

§ 26.1706 [Amended] 

21. In paragraph (d) of § 26.1706 

remove the word ‘‘publishes’’ and add in 

its place the phrase ‘‘has published’’. 

[FR Doc. 2011–1629 Filed 2–1–11; 8:45 am] 

BILLING CODE 6560–50–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Centers for Medicare & Medicaid 

Services 

42 CFR Parts 416, 418, 482, 483, 484, 

485, 486, and 491 

[CMS–3225–P] 

RIN 0938–AP94 

Medicare and Medicaid Programs; 

Patient Notification of Right To Access 

State Survey Agencies and Medicare 

Beneficiary Notification of the Right To 

Access Quality Improvement 

Organizations 

AGENCY: Centers for Medicare & 

Medicaid Services (CMS), HHS. 

ACTION: Proposed rule. 

mstockstill on DSKH9S0YB1PROD with PROPOSALS