*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 1 of 56 [RIN 2070-AJ76] 

EO12866_HumanSubjectsRevisions_NPRM_2010-09-172011-01-18.docx

Revised to address Interagency Comments received under EO 12866 Review.

BILLING CODE 6560–50–P 

ENVIRONMENTAL PROTECTION AGENCY 

40 CFR Part 26 

[EPA–HQ–OPP–2010–0785; FRL–XXXX–X] 

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 forwith pesticides 

involving intentional exposure of human subjects and to persons who submit the results of 

human research forwith pesticides to EPA. EPA agreed to propose these amendments as a result 

of a settlement agreement resolving a judicial challenge to the promulgation of these rules in 

2006, and is now seeking comment on these proposed amendments. The proposed amendments 

would broaden the applicability of the rules to cover human testing forwith 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 theythe

proposed amendments would identify specific considerations to be addressed in EPA science and 

ethics reviews of proposed and completed human research forwith 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 from the Nuremberg 

Code.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 [insert date 60 days after date of publication 

in the Federal Register]. 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 2 of 56 [RIN 2070-AJ76] 

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 e-mail. The regulations.gov website 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 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 3 of 56 [RIN 2070-AJ76] 

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 forwith 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 forwith pesticides. 

 • Other entities (NAICS code 541710) that sponsor or conduct human research forwith

pesticides, and Institutional Review Boards who review human research forwith 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) to EPA 

through regulations.gov or e-mail. 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 redacted 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: 

i. Identify the document by docket ID number and other identifying information (subject 

heading, Federal Register date and page number). 

ii. 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. 

iii. Explain why you agree or disagree; suggest alternatives and substitute language for 

your requested changes. 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 4 of 56 [RIN 2070-AJ76] 

iv. Describe any assumptions and provide any technical information and/or data that you 

used. 

v. If you estimate potential costs or burdens, explain how you arrived at your estimate in 

sufficient detail to allow for it to be reproduced. 

vi. Provide specific examples to illustrate your concerns and suggest alternatives. 

vii. Explain your views as clearly as possible, avoiding the use of profanity or personal 

threats. 

viii. Make sure to submit your comments by the comment period deadline identified. 

II. Background 

A. What wWould the proposed amendments doProposed Amendments Do? 

The proposed amendments would change the 2006 rule, published in the Federal 

Register onissue 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 the NAS in theirits 2004 rReport 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 of Research (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 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 5 of 56 [RIN 2070-AJ76] 

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 the 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. 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 6 of 56 [RIN 2070-AJ76] 

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 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 “thirdparty 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 rReport 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.nationalacademies.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 will serve this 

end.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 iensure 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 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 7 of 56 [RIN 2070-AJ76] 

A. Overarching pPrinciples 

EPA is committed to relying on scientifically sound research that is ethically conducted, 

and to transparency in its review processes and decisionmaking.decision-making. EPA issued 

the 2006 rule to further these commitments. As is discussed later in this Unit, experience since 

2006 has shown clearly that the rule has contributed to the soundness of EPA decisions, the 

scientific soundness of new human research, and the ethical treatment of the subjects of new 

research. This experience has also demonstrated the fundamental compatibility of sound science 

and high ethical standards. 

Thenothing in the amendments proposed in this document will not alter the Agency’s 

fundamental commitment to reliance on sound science that is ethically conducted, nor will they 

change the essential substantive provisions of the 2006 rule for protecting human subjects of 

research. 

that. These proposed amendments, however, will increase can be seen as increasing the 

transparency of EPA decisionmaking,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, and refining the 

standards that human research with pesticides must meet to be relied upon by EPA in its actions 

under any of the regulatory statutes it administers to protect health and the environment. 

B. EPA’s Implementation of the Common Rule

EPA adopted the Common Rule when it was initially promulgated in 1991. It was 

codified by EPA at 40 CFR part 26. The Common Rule defines the core protections for human 

subjects in any research conducted, supported, or otherwise subject to regulation by any Federal 

department or agency that has adopted the Common Rule. 

The ethical basis for the Common Rule is the April 18, 1979 report of the National 

Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, a 

commission established by the National ResearchAppropriations Act (Public Law 93-348), 

signed into law on July 12, 1974. The report, entitled “Ethical Principles and Guidelines for the 

Protection of Human Subjects of Research” and widely known as the Belmont Report, put forth 

three basic principles governing the use of humans as research subjects: respect for persons, 

beneficence, and justice. In the years since the publication of the Belmont Report, its principles 

have gained wide international and cross-cultural acceptance. 

The regulatory application of the Belmont principles in the Common Rule rests on two 

pillars of protection: the informed consent process and oversight of the research by an 

independent body known as an institutional review board (IRB). The Common Rule applies to 

all human research conducted or supported by EPA.

In addition to oversight by a duly constituted IRB, all human research conducted or 

supported by EPA is reviewed by the EPA Human Subjects Research Review Official (HSRRO) 

to ensure compliance with the Common Rule’s requirements. The HSRRO is an independent, 

senior EPA official with responsibility for overseeing all EPA activities involving research with 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 8 of 56 [RIN 2070-AJ76] 

human subjects. It is EPA policy that no human subject may be recruited or enrolled in any 

research conducted or supported by the Agency until that research has been reviewed by the EPA 

HSRRO and either approved or determined to be exempt from the Common Rule.

When EPA promulgated the of 2006 rule adding new subparts to 40 CFR part 26, EPA’s 

codification of the Common Rule was redesignated—without change—as 40 CFR part 26, 

subpart A. The amendments to 40 CFR part 26 proposed in this document would again make 

no changes to 40 CFR part 26, subpart A, EPA’s codification of the Common Rule.

C. Research Sponsored or Supported by EPA 

EPA maintains an active research program to support its regulatory programs. In 

addition to conducting its own intramural research, the Agency makes grants to academic and 

not-for-profit scientific institutions to conduct research under its STAR (Science To Achieve 

Results) program. See http://www.epa.gov/ncer/grants. The Agency also conducts research 

jointly with other Federal agencies. Although it represents only a portion of EPA’s overall 

research effort, some of this research involves human subjects, and is thus governed by the 

Common Rule. Since promulgation of the Common Rule in 1991, EPA has worked diligently to 

ensure its human research complies fully with all requirements of the Common Rule.

In 2006 EPA defined new regulatory requirements in 40 CFR part 26, subparts B, C, and 

D that provide additional safeguards for specific groups of vulnerable subjects. These 

regulations complement longstanding internal operating procedures designed to ensure the 

interests of human participants in research that EPA conducts or supports are fully protected.

Subpart B of 40 CFR part 26 categorically prohibits EPA research involving the 

intentional exposure of children or of pregnant or nursing women to any substance. Subpart C 

defines additional protections for pregnant women (and indirectly their fetuses) involved as 

subjects in EPA observational research. Subpart D of 40 CFR part 26 defines additional 

protections for children involved as subjects in EPA observational research. The major thrust of 

these subparts is to limit the risk to which the subjects covered by the subparts may be exposed. 

Taken together, the provisions in the Common Rule (40 CFR part 26, subpart A) and in subparts 

B, C, and D of 40 CFR part 26 establish the strongest regulatory protections for participants in 

human research in force by any Federal agency or department.

EPA’s internal operating procedures require a further level of review to complement that 

mandated by these regulations. Under EPA Order 1000.17, “Policy and Procedures on 

Protection of Human Research Subjects in EPA Conducted or Supported Research,” all research 

involving human subjects proposed to be conducted or supported by EPA must receive approval

(or be determined to be exempt from Common Rule and 40 CFR part 26, subpart B, C, and D 

requirements) not only from an IRB, but also from EPA’s HSRRO. 

Finally, EPA recognizes that its observational research into how behavior and other 

factors may influence human exposure to environmental substances raises scientific and ethical 

issues differing from those raised by other types of human research. The Agency has developed 

a guidance document for investigators designing and conducting observational exposure studies 

that identifies and recommends approaches for addressing these issues. The HSRB reviewed a 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 9 of 56 [RIN 2070-AJ76] 

draft of this document favorably in October 2007; its report is available at 

http://www.epa.gov/osa/hsrb/files/october2007hsrbfinaldraftreport3608.pdf. EPA subsequently 

revised the document to incorporate the HSRB’s recommendations and published it in final form

in May 2008, titled: “Scientific and Ethical Approaches for Observational Exposure Studies.” 

Available online at http://www.epa.gov/nerl/sots/SEAOES_doc20080707.pdf. EPA strongly 

encourages investigators conducting observational research to consider and apply this guidance.

D. Past Controversy over Third-Party Human Research with Pesticides 

Amendments to FFDCA made by the Food Quality Protection Act of 1996 (FQPA)

required EPA, when evaluating the safety of pesticide residues in food, to employ a new, 

additional tenfold uncertainty factor to increase protection of children. Soon after passage of 

FQPA a pesticide industry group issued a white paper noting that the toxic effect serving as the 

point of departure for most risk assessments of the widely used organophosphate and carbamate 

pesticides—cholinesterase inhibition—was reversible and easily measured. This white paper 

recommended testing to directly measure cholinesterase inhibition in humans. Such data, the 

paper suggested, could be used by EPA in risk assessments without employing another tenfold 

uncertainty factor that EPA customarily applies when estimating safe exposures for humans 

based on animal toxicity endpoints. A few studies of cholinesterase inhibition in humans had 

already been conducted or initiated when the 1996 amendments were enacted, and several more 

were initiated soon afterward.

An environmental advocacy group learned of this testing and published a report in 1998 

charging that the new studies of cholinesterase inhibition in human subjects were scientifically 

weak and fundamentally unethical. Over the next few years fewer than a dozen new studies of 

this type were completed by pesticide companies and submitted to EPA to support re-registration 

of their products. 

As critics became aware of these new studies the controversy grew. Some argued that all 

human testing with pesticides was inherently unethical, and EPA should never consider it. 

Others argued that although some human testing was ethical, EPA should never consider 

unethical data. Still others argued that it would be unethical not to rely on the best and most 

relevant scientific data, regardless of how they were obtained.

EPA sought guidance from an advisory panel convened under the joint auspices of the 

EPA Science Advisory Board and the FIFRA Scientific Advisory Panel. The final report of this 

group, “Comments on the Use of Data from the Testing of Human Subjects: A Report by the 

Science Advisory Board and The FIFRA Scientific Advisory Panel,” was issued in September 

2000, but left important issues unresolved. In December 2001, EPA asked NAS to conduct “an 

expeditious review of the complex scientific and ethical issues posed by EPA’s possible use of 

third-party studies which intentionally dose human subjects with toxicants to identify or quantify 

their effects.” At the same time EPA promised that, while the NAS review was underway and 

until a policy was in place, it would not “consider or rely on any such human studies in its 

regulatory decision making, whether previously or newly submitted.”

A trade association for agricultural pesticide companies sued EPA in early 2002, seeking 

to overturn the Agency’s interim commitment not to consider or rely on human studies, arguing 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 10 of 56 [RIN 2070-AJ76] 

that this policy statement had the effect of a rule without having been issued through notice-andcomment rulemaking. In its June 2003 decision, the United States Court of Appeals for the 

District of Columbia vacated the policy and directed EPA to reinstate “the agency’s previous 

practice of considering third-party human studies on a case-by-case basis, applying statutory 

requirements, the Common Rule, and high ethical standards as a guide . . . unless and until it is 

replaced by a lawfully promulgated regulation.” CropLife America v. EPA, 329 F.3d 876, 879 

(D.C. Cir. 2003).

By the time of the CropLife decision, EPA had already begun the rulemaking process, 

publishing on May 7, 2003 an Advance Notice of Proposed Rulemaking on the matter, soliciting 

public comment on a wide range of issues (68 FR 24410) (FRL 7302-8). In April 2004, the NAS 

issued its report, “Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific 

and Ethical Issues.”

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 on 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 (71 FR 6138) (FRL 7759-8),, a final rule which took 

effect on April 6, 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) (FRL8071-6), is discussed in the next Unit III.E. and is now being further amended by this proposed 

rule. 

EC. EPA’s 2006 Rule 

1. Summary of contents. The 2006 rule established a comprehensive set of new

protections for people participating as subjects in third-party human research forwith pesticides. 

(In this context “third-party” research is research neither conducted (“first-party”) nor supported 

(“second-party”) by EPA or another Federal 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.
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 11 of 56 [RIN 2070-AJ76] 

The 2006 rule also extends the ethical protections in the Common Rule to third-party 

studies of non-pregnant, non-nursing adult subjects of research involving intentional 

exposureintentionally exposed to pesticides. The key provisions of the 2006 rule significantly 

strengthens and expands on these protections for participants in third-party research byinclude: 

 • 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 ofin the 2004 NAS’ reportNAS Report. 

2. Implementation experience. Because

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 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, that history is recounted in 

some detail. 

. The public meetings of the 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 the HSRB has been called upon to review. 

The 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

the, HSRB has reviewed both reports of completed research and proposals for new research. 

Specifically, the 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 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. 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 12 of 56 [RIN 2070-AJ76] 

 • Proposals for and reports of new research involving intentional exposure to materials 

used in the research as pesticides. 

Since issuance of the 2006 rule, all proposals for new research involving intentional 

exposure to pesticides have fallen into one of two categories. Some have been studies of the 

performance of skin-applied repellents intended to keep mosquitoes, ticks and other pests away 

from treated skin; others have been studies monitoring occupational exposure of pesticide 

handlers as they mix, load, or apply pesticides in well-defined use scenarios. 

All but one of the repellent studies reviewed as a proposal by the HSRB has subsequently 

been amended to incorporate EPA and HSRB recommendations, executed, reported, submitted to 

EPA, and found both scientifically and ethically acceptable by both EPA and the HSRB. 

Although several of the more complex exposure studies have been executed in the field, final 

reports have not yet been reviewed by the HSRB.

i. Pre-rule research reporting toxic endpoints. At its first two meetings in April and 

May 2006 the, 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 non-therapeutic 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 website at http://www.epa.gov/hsrb/index.htm. 

Twenty-nine of the 37 non-therapeutic studies reviewed by the 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; the. 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 the 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. The HSRB found 15 of 

those 17 studies ethically acceptable under the applicable standards of the 2006 rule—§26.1703 

and §26.1704. The 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 the HSRB to be ethically 

unacceptable were among those also found by the HSRB to be scientifically unacceptable. EPA 

has not subsequently relied on any studies deemed either scientifically or ethically unacceptable 

by the HSRB. 

The 12 remaining pre-FQPA studies that EPA science reviewers alsohad proposed to 

reject the remaining 12 studies, all published reports concerningconcerned 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; the to reduce the inter-species factor 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 13 of 56 [RIN 2070-AJ76] 

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 the HSRB explicitly reviewed its ethical conduct. EPA has not 

relied on any of these 12 studies. 

In addition, EPA has presented Turning to the 8 post-FQPA toxicity studies that EPA 

presented to the HSRB. These 8, 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 tested1, and deferred to the HSRB with respect to the scientific acceptability of 

the last one. The 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 the 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. The 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 the 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, 

butthey were reported side effects of treatment with thewhen a test material (which is sometimes 

used as a pesticide) was administered as a medication. The HSRB concurred with the EPA 

science reviews in four ofthat these casesfour studies were scientifically unacceptable, but found 

one study scientifically unacceptable for the purpose EPA proposed. EPA ethics reviewers and 

the HSRB both found all five of these studies to be ethically acceptable under the standards of 

the 2006 rule. 

The In summary, EPA and HSRB concurred with EPA’s scientific assessments of these 

42 studies in all but a handful of instances. Wheneverworked through the HSRB has 

recommended against acceptance of any of these backlog of pre-rule studies for either scientific 

or ethical reasonsof 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 and acted on the HSRB’sHSRB recommendation, and has . 

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 

 

1

 For more details on this finding, see the study report available on the HSRD website at 

http://www.epa.gov/hsrb/index.htm.
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 14 of 56 [RIN 2070-AJ76] 

those assessments.

the HSRB. 

ii. New research involving intentional exposure of human subjects. The second broad 

category of topics addressed by the HSRB since 2006 isIn addition to reviewing pre-2006 rule 

research, HSRB has reviewed proposals for new research involving intentional exposure of 

human subjects. To ensure the thoroughness of its scientific and ethics reviews of these 

proposals, and to ensure as well that the applicable recommendations of the NAS in its 2004 

report were taken fully into consideration, EPA developed a detailed “framework” for its reviews 

of these proposals. (see the HSRB website at http://www.epa.gov/hsrb/index.htm). This 

framework has been used to guide all subsequent EPA reviews, and has been refined in detail to 

incorporate suggestions from the HSRB. A completed framework addressing concerns identified 

in the 2004 NAS rReport and subsequently by the 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 non-agricultural 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.

a. 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 the,

HSRB has reviewed proposals for 13 new repellent performance studies testing a total of 29 

repellent formulations. EPA and the 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 the HSRB. 

All subsequent proposals for new repellent performance studies have been found acceptable, 

with identified needed refinements, upon their first review by EPA and the 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 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 15 of 56 [RIN 2070-AJ76] 

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 the, 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 the HSRB. The most recent proposal is expected to be executed in the field in 2011. 

In one case EPA and the HSRB found the execution of a completed field mosquito 

repellency test to have been non-compliant 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 the HSRB. 

Reports of all the other ten completed repellent performance studies were found both 

scientifically and ethically acceptable by EPA and the HSRB as first submitted. 

b. 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 the HSRB in June 2006. The 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) 

and the Agricultural Handlers Exposure Task Force (AHETF) have been fully documented and 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 16 of 56 [RIN 2070-AJ76] 

presented to the HSRB. The 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 the HSRB and approved with suggestions for refinements by both EPA 

and the 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 

the 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 the HSRB in 

early 2011. 

Monitoring studies for four agricultural exposure scenarios submitted by the AHETF 

have been presented to the HSRB and approved, again with suggestions for refinements by both 

EPA and the 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 watersoluble packaging into a wide variety of application equipment, and application of herbicides to 

rights-of-way. 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 the HSRB in October 2010. Reports of the remaining research scenarios will be 

submitted to EPA and presented to the HSRB in 2011. 

3. Summary of implementation of the 2006 rule. EPA’s experience in implementing the 

2006 rule can be summarized in these three points:

• EPA and the HSRB quickly worked through the backlog of pre-rule studies of 

pesticide toxicity awaiting review when the 2006 rule was promulgated. EPA and the HSRB 

agreed about the acceptability of these studies in most cases; when there was disagreement, EPA 

has accepted and acted on the advice of the HSRB. 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. 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.

• Close scrutiny by both EPA and the 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 high standards of the 2006 rule. These 

studies provide essential information about repellent performance and worker exposure that is 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 17 of 56 [RIN 2070-AJ76] 

simply not available except from well designed, ethically conducted research involving 

intentional exposure of human subjects to pesticides.

• Contrary to some predictions, the 2006 rule has not led to an upsurge in human research 

for pesticides. 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 

proposals for new research of other kinds than were projected. 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 have been submitted over a span of approximately 5 

years, or just over 5 per year.

FD. 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 rReport. The 2006 Appropriations Act required 

EPA’s rule to be consistent with the principles proposed in the 2004 NAS rReport. Petitioners 

argued that in citing the “principles” of the 2004 NAS rReport, 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 report2004 NAS Report. 

First, Petitioners argued that the 2006 rule did not incorporate NAS 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.” 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 18 of 56 [RIN 2070-AJ76] 

Second, Petitioners argued that the 2006 rule did not incorporate NAS 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 NAS 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 NAS recommendationrecommendations 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 NAS 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 

thisthe Nuremburg Code. 

First, Petitioners argued that although the Nuremberg Code specifies that consent must be 

given by the human subject, the 2006 rule inconsistently permits consent to be given in certain 

situations by a legally authorized representative of the subject. 

Second, Petitioners argued that, by adopting the Common Rule’s requirements for

informed consent, 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 Common Rule2006 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 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 19 of 56 [RIN 2070-AJ76] 

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. 

GE. 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 filed with the Second Circuit Court of Appealsfinalized on June 

18November 3, 2010, EPA agreed to conduct notice-and-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 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 within seven months of filing the agreement with the Second Circuit Court of 

Appealsno later than January 18, 2011, and that EPA will take final action on the amendments 

withinno later than December 18 months of this filing, 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 they differthe wording of the amendments proposed in this document differs in 

a few details of construction and wording, the amendments proposed in this document 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.FD. 

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 NAS

Recommendationsrecommendations 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 

isbelieves that proposing these amendments because they areis consistent with the language and 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 20 of 56 [RIN 2070-AJ76] 

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. ManyEPA believes that many

of the changes proposed in this document are codifications of the manner in which EPA and the 

HSRB have interpreted and implemented the 2006 rule, but welcomes comment on these 

interpretations. EPA will fully re-evaluate 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. Provisions of this Proposed Rule andAmendments, 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 revisionsamendments 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. 

EPA believes these changes in scope would make the 2006 rule more consistent with the 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 21 of 56 [RIN 2070-AJ76] 

focus in the 2006 Appropriations Act on intentional dosing human toxicity studies for 

pesticides.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, EPA 

believeswith the proposed amendment, such studies shwould 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 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.

1. SubpartsThe 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. 

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 these four criteria:

• It. First, it was initiated after April 6, 2006 (the effective date of the 2006 rule).

• It Second, it is “research involving intentional exposure of a human subject” as defined 

at §26.1102(i).

• It Third, it was conducted or supported by a “person” as defined at §26.1102(j).

• It 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 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 22 of 56 [RIN 2070-AJ76] 

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 agency. ThusFederal 

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 Federal

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(k), a new definition of “initiation” of research 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. 

This proposal includes a new §26.1102(c) defining “Initiation of research involving 

human subjects” as occurring with the enrollment of the first subject in the research. This would 

codify the interpretation expressed in the preamble to the final 2006 rule (71 FR 6165) and 

applied by EPA in implementing the 2006 rule. In guidance issued under the Common Rule 

some other Federal agencies have defined study initiation as occurring when the first 

advertisement for subjects is issued; EPA’s standards of Good Laboratory Practice at 40 CFR 

part 160 define study initiation as occurring when the Study Director signs the protocol. To 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 23 of 56 [RIN 2070-AJ76] 

avoid confusion, EPA is considering recasting this criterion, stating simply that 40 CFR part 26, 

subparts K and L apply to research in which the first subject is enrolled after the effective date of 

a final amendment. Comments on this point are specifically requested.

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 thirdparty 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. This isEPA 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 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 24 of 56 [RIN 2070-AJ76] 

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 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 forwith 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, 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 25 of 56 [RIN 2070-AJ76] 

subpart K, including the requirement of §26.1125 for submission of the proposal for prior review 

by EPA and the HSRBHSRB. 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 ana MCL 

for a pesticide active ingredient under SDWA. Non-regulatory actions include, for example, risk 

assessments of pesticide active ingredients, recommended (non-binding) 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. 

In sum, EPA proposes several changes to the “scope” sections of 40 CFR part 26, 

subparts K and L—§26.1101 and §26.1201—and new definitions of “initiation of research” at 

§26.1102(c) and of “pesticide” at §26.1102(k), to expand at the margin the range of human 

research to which these two subparts apply. EPA does not believe this expansion will result in a 

significant increase in the number of studies reviewed under the rule. EPA knows of no thirdparty 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. This expansion of the scope of these subparts, however, insures 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. It is also consistent with the 

Congressional directive in the 2006 Appropriations Act.

2. Subpart4. 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. EPA proposes to broaden the 

applicability of subpart M by amending §26.1301, while leaving the substantive requirements of 

subpart M unchanged. 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 26 of 56 [RIN 2070-AJ76] 

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 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 public 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 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 27 of 56 [RIN 2070-AJ76] 

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 members of 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. 

3. Subpart5. 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. 

4. Subpart6. 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 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 28 of 56 [RIN 2070-AJ76] 

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 itsthe 2004 reportNAS 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, 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. 

In this document,2. Proposed amendments and rationale. EPA proposes to amend 40 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 29 of 56 [RIN 2070-AJ76] 

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 it

thinks the types of research that investigators will never needare conducted on pesticides would 

not use subjects for whom such a procedure for theis needed. (The research covered by 40 CFR 

part 26, subpart K— includes research involving intentional exposure of non-pregnant, nonnursing adults to a pesticide or research involving intentional exposure of non-pregnant, nonnursing 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. Subpart A40 CFR part 26, subpart A, applies to a much broader range of 

research with human subjects conducted or supported by EPA including, for example, 

observational studies with young children, research for which parental consent on behalf ofby a 

child subject is entirelylegally authorized representative may be appropriate. 

C. Revised Standards for EPA and HSRB Reviews (40 CFR part 26, Subpart P) 

In1. Current rule. 40 CFR part 26, subpart P, defines in largely procedural terms how 

EPA is to reviewevaluates 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 the HSRB. 

If all2. Proposed amendments and rationale. a. Revisions to subpart P generally. The

proposed amendments to 40 CFR part 26, subpart P became final, it would, 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 incorporating by referencereferences the definitions in 40 

CFR part 26, subpart K. 

• An expanded • 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 revised discussion of EPA reviews of completed research, 

redesignating §26.1602 in 40 CFR part 26 as §26.1604, and revising paragraph (a) to emphasize 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 30 of 56 [RIN 2070-AJ76] 

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 the HSRB. 

 • A proposed new §26.1606 requiring the 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 the 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. 

The 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 proposed for inclusion 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 arewere derived primarily 

from the 2004 NASfollowing 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 EPA and from the Nuremberg Code. Making these considerations

explicit will codify in a regulation the 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 developed by EPA and 

the HSRB in the course of implementing the 2006 rule, and will 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 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 31 of 56 [RIN 2070-AJ76] 

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;

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 these crucial aspects of the 

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 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 32 of 56 [RIN 2070-AJ76] 

equivalent. Research conducted by EPA scientists should be reviewed by an EPAauthorized IRB.

[Taken from pages 7-14 of the 2004 NAS report and the Nuremberg Code continue to be 

considered in the future by EPA and the HSRB. Report (http://www.national-academies.org).]

c. Science Reviews— §26.1603(b). The provisions in proposed §26.1603(b) will ensure 

include considerations that unnecessary human research is not conducted, EPA must take into 

account when conducting its science reviews of proposed research that any research that is 

conducted is designed so that would be covered by the data collected are likely to answer an 

important research question dispositively,rule. In developing this list of considerations, EPA 

relied on recommendations 3-1 and that5-1 from the conduct of 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 follows. 

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: (i) Address the research question. (ii) 

Include representative study populations for the endpoint in question. (iii) 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 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 33 of 56 [RIN 2070-AJ76] 

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 (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 and practices, including, when appropriate, 

good clinical practices.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 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. One critical consideration for ethical research, reiterated here, is that the subjects’ 

participation “follow[s] free and fully informed consent.” The Nuremburg Code eloquently 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 34 of 56 [RIN 2070-AJ76] 

states the importance of free and fully informed consent and describes the elements of such 

consent: 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. 

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]

 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 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 35 of 56 [RIN 2070-AJ76] 

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 submitted to EPA under regulatory 

authorities other than the pesticide laws. However, EPA recognizes that this is a possibility in 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 36 of 56 [RIN 2070-AJ76] 

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 Code2. 

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 

 

2

 The 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.
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 37 of 56 [RIN 2070-AJ76] 

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. 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 38 of 56 [RIN 2070-AJ76] 

 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 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 (Subpart Q)

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. 

Subpart Q)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 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 39 of 56 [RIN 2070-AJ76] 

of its regulatory authorities except under the extremely restrictive conditions defined in 

§26.1706.

Subpart Q of the 2006 rule established1. 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 the 

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 §26.1706.1. Proposed Changes to §26.1703: Standards Applicable to All Covered Research. 

Consistent with the changes proposed in 40 CFR part 26, subpart P

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 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 40 of 56 [RIN 2070-AJ76] 

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. 

The concern for theseThese four aspects of the research isare derived from NAS

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 of the 2006 rule,

applies to EPA decisions to rely on “scientifically valid and relevant data” from covered 

research. Since 2006 the Agency’s, EPA’s practice in reviewing reports of covered human 

research has been to examine carefully the scientific reliabilitymerit of the reported studies and 

to refuse to rely onuse 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 ruleamendment is finalized, EPA will revise would 

likely make minor revisions to its internal review documentation standardsprocedures to 

highlight the consideration given to these four aspects of the research. 

2. Changes to3. §26.1704: aAcceptance 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 infrom the 2004 NAS rReport, which states in relevant part: 

 

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. 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 41 of 56 [RIN 2070-AJ76] 

EPA adopted the NAS 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 the HSRB. EPA now proposes to revise §26.1704 by deleting the 

word “significantly,” and by characterizingproposing instead to characterize explicitly the kinds 

of deficiencies that would make a study unacceptable. 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.” 

This language is derived from the advice of the Human Studies Review BoardHSRB 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-

public-meeting/april2006mtgfinalreport62606.pdf. For each study they found ethically 

acceptable, the 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. 

3. Changes to §26.1705 standardsb. 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 NAS 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 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 42 of 56 [RIN 2070-AJ76] 

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 as 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 third-party 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 the 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 the 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 of EPA’s rule, 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 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 43 of 56 [RIN 2070-AJ76] 

§26.1705(b)(2), corresponding changes are made applicable to research conducted in foreign 

countries. 

Finally, in a new paragraph (c) in §26.1705(c),, 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 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 the 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 pesticidespecific regulations are found. 

2. Proposed amendments and rationale. EPA is not now proposing such a recodification, but invites public comment on the idea. Although it would necessitate many nonsubstantive revisions—mainly of internal cross-references—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. Subpart 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. 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 44 of 56 [RIN 2070-AJ76] 

V. FIFRA Review Requirements 

[Note to reviewers: this section will be filled in once FIFRA review is completed, which is 

scheduled to occur during the EO 12866 review process.]

In accordance with FIFRA section 25(a), EPA has submitted a draft of the proposed rule 

to the FIFRA SAP,Scientific Advisory Panel (SAP), the Secretary of Agriculture (USDA), and 

appropriate Congressional Committees. The FIFRA SAP waived its review of this proposal on 

[insert date],October 12, 2010, because the significant scientific issues involved have already 

been reviewed by the SAP and additional review isn’tis not necessary. Comments on the draft 

proposal received from USDA have been addressed [or revise to say they did not comment. Or 

say...USDAresponded without comments, but participated fully in the interagency review 

process under Executive Order 12866, during which EPA and USDA discussed [enter major 

topic areas that were raised and resolved]..

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” because it may 

raise novel legal or policy issues..” 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 public 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 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 45 of 56 [RIN 2070-AJ76] 

$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 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 the 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 of the RFA as: 

1. A small business as defined by the Small Business Administration’s (SBA) 

regulations at 13 CFR 121.201. 

2. A small governmental jurisdiction that is a government of a city, county, town, school 

district or special district with a population of less than 50,000. 

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. 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 46 of 56 [RIN 2070-AJ76] 

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 researching involving subjects who are children, or pregnant or nursing 

women. These provisions would not be affected by the proposed amendments.
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 47 of 56 [RIN 2070-AJ76] 

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: _________________ 

____________________________________ 

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 paragraphs (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. 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 48 of 56 [RIN 2070-AJ76] 

§ 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 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, 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 shallmust 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. AmendIn § 26.1102 as follows:

a. Revise paragraph (a);

b. Remove paragraph (c); and

c. Add new, revise paragraphs (ca) and (kc) to read as follows: 

§ 26.1102 Definitions. 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 49 of 56 [RIN 2070-AJ76] 

 (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) Initiation of research involving human subjects is defined as occurring with the 

enrollment of the first subject in the research.

* * * * *

(k (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)]. 

§ 26.1111 [Amended].AMENDED]

 4. AmendIn § 26.1111 by removingremove from paragraph (a)(4) the phrase “or the 

subject’s legally authorized representative”. 

 5. AmendIn § 26.1116 by revisingrevise the introductory text of the section and 

paragraph (e) 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 shallmust 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 shallmust 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. 

* * * * *

(e) The subjects of the research must be informed of the identity of the pesticide and the 

nature of its pesticidal function.

 6. Revise § 26.1117 to read as follows: 

§ 26.1117 Documentation of informed consent. 

 (a) Informed consent shallmust 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 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 50 of 56 [RIN 2070-AJ76] 

by § 26.1116. This form may be read to the subject, but in any event, the investigator shallmust

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 

shallmust 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 shallmust sign both the short form and a copy of the summary, and the 

person actually obtaining consent shallmust sign a copy of the summary. A copy of the 

summary shallmust be given to the subject, in addition to a copy of the short form. 

 7. Revise the titleheading 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].AMENDED]

 10. AmendIn § 26.1302 by removingremove the word “shall” from this section..” 

§ 26.1502 [Amended].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
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 51 of 56 [RIN 2070-AJ76] 

b. In the second sentence of paragraph (a) remove the phrase “The aAgency” and add in 

its place “EPA.” 

c. In the last sentence of the introductory text of paragraph (b) remove the phrase “The 

aAgency” and add in its place “EPA.” 

§ 26.1505 [Amended].AMENDED]

12. AmendIn § 26.1505 by removingremove from the last sentence, the phrase “§ 

26.1502(c)” and adding in its place “§ 26.1502(b)(4).” 

§ 26.1507 [Amended].AMENDED]

13. Amend the last sentence ofIn § 26.1507 by removingremove from the last sentence,

the phrase “The aAgency” and adding in its place “EPA”. 

§ 26.1601-26.1603 [Redesignated].REDESIGNATED]

14. Amend subpart P of this part 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 shallmust review all proposals for new human research submitted under § 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 52 of 56 [RIN 2070-AJ76] 

26.1125 in a timely manner. 

 (b) In reviewing proposals for new human research submitted under § 26.1125, the EPA 

Administrator shallmust 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 shallmust 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 shallmust consider Recommendation 4-1 ofin 

the 2004 Report from the National Research Council as contained in its 2004 reportof 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 Institutional Review BoardIRB or its foreign 

equivalent has approved the proposed research. 

 (7) If any person from a vulnerable population may become a subject in the proposed 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 53 of 56 [RIN 2070-AJ76] 

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 shallmust 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 shallmust 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 shallmust 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 shallmust consider the scientific merits and ethical aspects of the 

completed research, and shallmust apply the appropriate standards in subpart Q of this part. 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 54 of 56 [RIN 2070-AJ76] 

 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 §§ 26.1701-26.1705 to read as follows: 

§ 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 shallmust 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 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 such determinations, EPA shallmust 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 shallmust 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. 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 55 of 56 [RIN 2070-AJ76] 

§ 26.1704 Prohibition of reliance on unethical human research with non-pregnant, nonnursing 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 shallmust 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) This prohibition is in addition to the prohibitions in § 26.1703. 

§ 26.1705 Prohibition of reliance on unethical human research with non-pregnant, nonnursing adults initiated after April 76, 2006, and subject to subparts A through L of this 

part or 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 6, 2006. 

 (2) Was subject, at the time it was conducted, either to subparts A through L of this part 

or to another codification of the BasicFederal Policy for the Protection of Human Subjects in 

Human Research Conducted or Supported by a Federal Agency, generally referred to as the 

“Common Rule.” 

 (b) Except as provided in § 26.1706, EPA shallmust 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 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 codification of the 

Common Rule by another Federal department or agency. 

 (c) Except as provided in § 26.1706, EPA shallmust 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 
*** EO 12866 Review Deliberative - Do Not Cite, Quote, or Release During Review *** 

Page 56 of 56 [RIN 2070-AJ76] 

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 shallmust 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) This prohibition is in addition to the prohibitions in § 26.1703. 

 21. Amend § 26.1706 inIn paragraph (d) by removingof § 26.1706, remove the phrase 

“publishes” and adding in its place “has published.” 

[Note to reviewers: We are double checking for any cross references in the CFR that might 

need to be corrected as a result of these amendments. If any are found, amendatory text to 

correct them will be added here.]

[FR Doc. ??–????? Filed ??–??–??; 8:45 am]