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EO12866_HumanSubjectsRevisions_NPRM_2010-09-17.docx 

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 for pesticides 

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

human research for 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 for pesticides submitted to EPA 

under any regulatory statute. They would also disallow participation in pesticide studies by 

subjects who cannot consent for themselves. Finally they would identify specific considerations 

to be addressed in EPA science and ethics reviews of proposed and completed human research 

for pesticides, drawn from the recommendations of the National Academy of Sciences (NAS) 

and from the Nuremberg Code. 

DATES: Comments must be received on or before [INSERT DATE 60 DAYS AFTER DATE 

OF PUBLICATION IN THE FEDERAL REGISTER]. 

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 
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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 

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 for pesticides involving human subjects. Potentially affected entities may 

include, but are not limited to: 

 • Pesticide and other agricultural chemical manufacturers (NAICS code 325320) who 
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sponsor or conduct human research for pesticides. 

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

pesticides, and Institutional Review Boards who review human research for 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. 

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. 
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II. Background 

A. What would the proposed amendments do? 

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

on 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 their 2004 report to EPA, and from 

the Nuremberg Code. 

The amendments proposed here would make no changes to the Federal Policy for the 

Protection of Human Subjects 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 

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). 
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 • 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. 

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. 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 Appropriations Act directly mandates that EPA promulgate a rule on “third-party 

intentional dosing human toxicity studies for pesticides . . .” without limiting the rule to pesticide 
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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) absent compliance with the applicable rules in 40 

CFR part 26, as proposed. The importance of these rules to the protection of human subjects is 

demonstrated in the 2004 report from the NAS titled “Intentional Human Dosing Studies for 

EPA Regulatory Purposes: Scientific and Ethical Issues.” 

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. 

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 

insure that these provisions regarding use of registered pesticides in a manner that does not cause 

unreasonable risk and full and free consent in human testing with pesticides are effectuated. 

III. EPA’s Human Subjects Protection Rules 

A. Overarching principles 

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

and to transparency in its review processes and decisionmaking. 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. 

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. 

These proposed amendments, however, will increase the transparency of EPA 

decisionmaking, by clarifying the scope and applicability of the requirements in 40 CFR part 26, 
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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 Research 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 

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 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 
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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 

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 
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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 

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: 
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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 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. The 2006 

rule, as subsequently amended on June 23, 2006 to extend special protections to nursing women 

as well (71 FR 36171) (FRL 8071-6), is discussed in the next Unit and is now being further 

amended by this proposed rule. 

E. 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 for pesticides. (In 

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

(“second-party”) by EPA or another Federal Common Rule 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. 

The 2006 rule also extends the ethical protections in the Common Rule to non-pregnant, 

non-nursing adult subjects of research involving intentional exposure to pesticides. The 2006 

rule significantly strengthens and expands on these protections for participants in third-party 

research by: 

 • Requiring 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 of the 2004 NAS’ report. 

2. Implementation experience. Because EPA’s experience in implementing the 2006 rule 
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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-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 risk assessments. 

 • 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. 

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 science reviewers 

proposed to rely on 17 of these 29 studies; the HSRB found 13 of these 17 studies scientifically 

acceptable. 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 
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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, 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. 

EPA science reviewers also proposed to reject the remaining 12 studies, all published 

reports concerning 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 

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 8 post-FQPA toxicity studies to the HSRB. These 8 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, 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 risk assessments were not the main objective of the research, but were 

side effects of treatment with the material used as a medication. The HSRB concurred with the 

EPA science reviews in four of these cases, 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 HSRB concurred with EPA’s scientific assessments of these 42 studies in all but a 

handful of instances. Whenever the HSRB has recommended against acceptance of any of these 

pre-rule studies for either scientific or ethical reasons, EPA has accepted and acted on the 

HSRB’s recommendation, and has not relied on any studies found unacceptable by the HSRB. 

ii. New research involving intentional exposure of human subjects. The second broad 
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category of topics addressed by the HSRB since 2006 is 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. 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 NAS report 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. 

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 

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 
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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 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. 

Since that initial review, the overall designs of the monitoring programs of the 

Antimicrobial Exposure Assessment Task Force (AEATF II) and the Agricultural Handlers 

Exposure Task Force (AHETF) have been fully documented and 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 
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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 

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. 

F. 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 
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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. 

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 NAS report. The 2006 Appropriations Act required EPA’s rule 

to be consistent with the principles proposed in the 2004 NAS report. Petitioners argued that in 

citing the “principles” of the NAS report, Congress was referring to the 17 recommendations in 

that report. Petitioners further argued that the 2006 rule was inconsistent with several specific 

recommendations in the report. 

First, Petitioners argued that the 2006 rule did not incorporate NAS Recommendations 3-

1 and 5-1, which recommend factors to be considered in the scientific evaluation of human 

research, including that such studies should have “adequate statistical power” and involve 

“representative populations for the endpoint in question.” 

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

4-1 and 4-2, 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, EPA made it inconsistent with the 

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 recommendation. 

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. 

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 

this 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 by a legally 

authorized representative of the subject. 
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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 Rule consent requirements were inadequate to ensure fully 

informed consent. 

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 Code’s requirement that human studies be “designed and 

based on the results of animal experimentation.” 

Finally, Petitioners argued that the 2006 rule was inconsistent with the Nuremberg Code 

principle that human testing “should be such as to yield fruitful results . . . unprocurable by other 

methods or means of study, and not random and unnecessary in nature.” Petitioners argued that 

the 2006 rule requires no inquiry into whether human testing is necessary given other methods of 

research. 

G. Settlement of 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 Appeals on June 18, 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 

Appeals and that EPA will take final action on the amendments within 18 months of this filing. 

The settlement, however, makes clear that EPA retains full discretion concerning what 

amendments are proposed, and what, if any, amendments are finalized. 

Although they differ in a few details of construction and wording, the amendments 

proposed in this document are substantially consistent with the regulatory language negotiated 
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with Petitioners, and these amendments address the Petitioners’ major arguments outlined in 

Unit III.F. 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 

Recommendations cited by Petitioners in their challenge to the 2006 rule, as well as other 

pertinent recommendations from the 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 emerge from a settlement agreement, EPA is 

proposing these amendments because they are consistent with the language and purposes of the 

applicable statutes and because they further the 2006 rule’s goal of ensuring that EPA does not 

rely on research involving intentional exposure of human subjects to pesticides that is not 

ethically conducted or that is not scientifically sound. 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. EPA will fully re-evaluate the appropriateness of the proposed 

amendments in light of all comments received in response to this proposed rule. 

IV. Provisions of this Proposed Rule and Rationale 

A. Redefining Scope and Applicability 

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. 

In general, the proposed revisions would shift the focus from whether the research 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 
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focus in the 2006 Appropriations Act on intentional dosing human toxicity studies for pesticides. 

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. If studies involving intentional 

exposure of humans to a pesticide are submitted or considered under other EPA regulatory 

statutes, EPA believes such studies should be subject to the same requirements that would have 

applied had they been submitted or considered under FIFRA or FFDCA. 

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. Subparts K and L – basic ethical requirements and prohibitions applying to thirdparty research involving intentional exposure of human subjects to a pesticide. 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 was initiated after April 6, 2006 (the effective date of the rule). 

 • It is “research involving intentional exposure of a human subject” as defined at 

§26.1102(i). 

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

 • It was intended by any person conducting or supporting the research to be submitted to 

EPA, or to be held for later inspection by EPA, under the pesticide laws (FIFRA or FFDCA). 

The two cited definitions are critical to understanding the scope and applicability of 

subparts K and L of 40 CFR part 26. “Research involving intentional exposure of a human 

subject,” is defined at §26.1102(i) as “a study of a substance in which the exposure to the 

substance experienced by a human subject participating in the study would not have occurred but 

for the human subject’s participation in the study.” In applying this definition, EPA considers 

whether a test subject would have experienced equivalent exposure to a test material had the 

subject not participated in the research. If not, the research is deemed to involve intentional 

exposure of the subject. Notably this definition encompasses all classes of test substances—not 

only pesticides. 

A “person” is defined at §26.1102(j) to have the same meaning as in FIFRA section 2(s) 

(7 U.S.C. 136(s)), except that it excludes Federal agencies subject to the Common Rule and any 

person when performing research supported by a Common Rule agency. 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 (“firstparty”) nor supported (“second-party”) by EPA or another Federal Common Rule department or 

agency. 

Finally, §26.1101(g) explains how EPA will approach determination of the intent of 
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sponsors or investigators to submit research to EPA under the pesticide laws, or hold it for 

inspection by EPA under the pesticide laws. 

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 

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 

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. 

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 
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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 is 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 is sulfur dioxide (SO2)—a registered pesticide active ingredient used as 

a fungicide in grape culture, and also a common air pollutant. Thousands of tons of SO2 are 

released yearly into the atmosphere by burning of coal and other fossil fuels. In promulgating 

National Ambient Air Quality Standards (NAAQS) for SO2 under the Clean Air Act (CAA) in 

2010, EPA relied on numerous human studies involving intentional exposure of subjects to SO2. 

Most of these studies on their face indicate clearly that they tested SO2 as an industrial air 

pollutant and not as a pesticide. The few that do not expressly state they tested SO2 as an air 

pollutant are, nonetheless, easily classified as not involving exposure to a pesticide, because the 

testing was not conducted 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. 

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 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 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 
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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. 

As an example, EPA’s Office of Water has, in the past, set Maximum Contaminant 

Levels (MCLs) under the SDWA for pesticides found in drinking water. Under the proposed 

amendment to the scope of 40 CFR part 26, subpart K, any new third-party study involving 

intentional exposure of a human to a pesticide, and intended for submission to the Office of 

Water for consideration in setting a MCL, would now be subject to 40 CFR part 26, subpart K, 

including the requirement of §26.1125 for submission of the proposal for prior review by EPA 

and the HSRB. 

EPA actions not taken under the authority of regulatory statutes would not satisfy this 

fourth criterion. For example, an EPA comment on another Federal 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 an 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, or clean-up standards 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 subpart L applies to all 

research subject to 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. 
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2. Subpart M – requirement for documentation of the ethical conduct of completed 

human research submitted to EPA. 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. 

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 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. 

EPA proposes to broaden the applicability of 40 CFR part 26, subpart M 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 
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pesticide registration or a party petitioning for a pesticide tolerance should have to exercise 

reasonable efforts to obtain records of the ethical conduct of research relied on to support the 

EPA action sought, whether or not the research happens to be described in a scientific journal. 

Reasonable efforts in these circumstances may include seeking relevant records from the 

research administrator or the overseeing IRB. On the other hand, if a member of the public 

responds to an EPA request for information on a pesticide by citing or submitting a published 

study, EPA believes that certification that the submitter did not sponsor, participate in, or 

otherwise have personal knowledge of or responsibility for the referenced research would satisfy 

the submitter’s obligation under 40 CFR part 26, subpart M. 

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. Subpart P – EPA and HSRB review of proposed and completed human research. 

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. EPA proposes to make 

explicit the applicability of 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.” 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. Subpart Q – ethical standards for assessing whether to rely on the results of human 

research in EPA actions. 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, 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. 

For the same reasons it is proposing to broaden the applicability of 40 CFR part 26, 

subpart K (discussed in Unit IV.A.1.) EPA proposes to amend §26.1701 to broaden the 

applicability of 40 CFR part 26, subpart Q. Proposed §26.1701(a) would retain without change 

the applicability of 40 CFR part 26, subpart Q to research involving intentional exposure of 
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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 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. 

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. 

B. Disallowing Consent by a Surrogate (Subpart K) 

In its 2004 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 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, EPA proposes to amend 40 CFR part 26 by deleting from subpart K all 

references permitting consent by a subject’s legally authorized representative. The sections 

affected are the definition of “legally authorized representative” at §26.1102(c), the “Criteria for 

IRB approval of research” at §26.1111; the “General requirements for informed consent” at 

§26.1116; and the requirements for “Documentation of informed consent” at §26.1117. 

EPA proposes to disallow consent by a representative because it thinks that investigators 

will never need such a procedure for the research covered by 40 CFR part 26, subpart K—

research involving intentional exposure of non-pregnant, non-nursing adults to a pesticide or 

research involving intentional exposure of non-pregnant, non-nursing adults intended for 

submission under FIFRA or FFDCA. 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 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, for which parental consent on behalf of a child subject is entirely 

appropriate.
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C. Revised Standards for EPA and HSRB Reviews (Subpart P) 

In 40 CFR part 26, subpart P defines in largely procedural terms how EPA is to review 

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 all proposed amendments to 40 CFR part 26, subpart P became final, it would include: 

 • A 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 new §26.1602 incorporating by reference the definitions in 40 CFR part 26, subpart 

K. 

 • An expanded 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 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 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 redesignated as §26.1605, defining the 

membership and responsibilities of the HSRB. 

 • A 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 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 most significant changes 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. These lists are 

derived from the 2004 NAS recommendations to EPA and from the Nuremberg Code. Making 

these considerations explicit will codify in a regulation the practices developed by EPA and the 

HSRB in the course of implementing the 2006 rule, and will ensure that these crucial aspects of 

the NAS report and the Nuremberg Code continue to be considered in the future by EPA and the 

HSRB. 
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The provisions in proposed §26.1603(b) will ensure that unnecessary human research is 

not conducted, that any research that is conducted is designed so that the data collected are likely 

to answer an important research question dispositively, and that the conduct of the research 

follows good research and clinical practices. 

The provisions in proposed §26.1603(c) address many important ethical concerns 

including 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 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] 

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. 

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. 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. 

Subpart Q of the 2006 rule established 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 
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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. 

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

Consistent with the changes proposed in 40 CFR part 26, subpart P and discussed in Unit IV.C., 

EPA proposes to add in §26.1703(a) an explicit prohibition against reliance on data from 

completed research “unless EPA determines that the data are relevant to a scientific or policy 

question important for EPA decision-making, that the data were derived in a manner that makes 

them scientifically valid and reliable, and that it is appropriate to use the data for the purpose 

proposed by EPA.” 

In making this determination, EPA would be required to assess these four aspects of the 

research: 

 • Whether the research was 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 Adverse Effect Level, some dose level 

elicited a biological effect. 

The concern for these four aspects of the research is derived from NAS 

Recommendations 3–1 and 5–1. 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. 

As noted previously, 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 practice 

in reviewing reports of covered human research has been to examine carefully the scientific 

reliability of the reported studies and to refuse to rely on research deemed invalid or irrelevant. 

EPA proposes to delete these factors from the scope of 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 rule is finalized, EPA will revise its review 

documentation standards to highlight the consideration given to these four aspects of the 

research. 
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2. Changes to §26.1704 acceptance standards for research not subject to§26.1705. The 

Agency based the ethical acceptability standard in §26.1704 on Recommendation 5-7 in the 2004 

NAS report, 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. 

EPA adopted the NAS recommendation 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 “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 characterizing 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 Board 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. 
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3. Changes to §26.1705 standards for completed research conducted under 40 CFR Part 

26 or another codification of the Common Rule. 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, which states in relevant part (italics in the original; footnote omitted): 

EPA should operate on the strong presumption that data obtained in studies conducted 

after implementation of the new rules that do not meet the ethical standards described in 

this report will not be considered in its regulatory decisions. 

EPA adapted this recommendation in its drafting of §26.1705, which provides in 

relevant part: 

EPA shall not rely on data from any research initiated after [the effective date of the 2006 

rule] unless EPA has adequate information to determine that the research was conducted 

in substantial compliance with subparts A through L of this part, or if conducted in a 

foreign country, under procedures 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 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 
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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 

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

countries. 

Finally, in a new paragraph §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. 

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 decisionmaking. 

E. Request for Public Comment on Possible Re-codification of Subparts K-Q 

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 subparts K-Q were moved to a different section of EPA’s 

regulations, within the range where other pesticide-specific regulations are found. 

EPA is not now proposing such a re-codification, but invites public comment on the idea. 

Although it would necessitate many non-substantive revisions—mainly of internal crossreferences—re-codification would not be difficult to accomplish. 40 CFR part 26 would retain 

current subparts A-D, and at least parts of current 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 subparts K, L, M, O, P, and Q. 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. 
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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, the Secretary of Agriculture (USDA), and appropriate Congressional 

Committees. The FIFRA SAP waived its review of this proposal on [insert date], because the 

significant scientific issues involved have already been reviewed by the SAP and additional 

review isn’t necessary. Comments on the draft proposal received from USDA have been 

addressed [or revise to say they did not comment. Or say...USDA 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 

$45,927 per study, for a total estimated annual burden for affected entities of 20,332 hours at an 
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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 

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. 
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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.

H. Affect on Energy Supply, Distribution or Use 
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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, Human research, Pesticides 

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. 

§ 26.1101 To what does this subpart apply? 
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 (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 shall 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. Amend § 26.1102 as follows: 

 a. Revise paragraph (a); 

 b. Remove paragraph (c); and 

 c. Add new paragraphs (c) and (k) to read as follows: 

§ 26.1102 Definitions. 

 (a) Administrator means the Administrator of the Environmental Protection Agency 
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(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) 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]. 

 4. Amend § 26.1111 by removing from paragraph (a)(4) the phrase “or the subject’s 

legally authorized representative”. 

 5. Amend § 26.1116 by revising 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 shall seek such consent only under circumstances that provide the prospective 

subject sufficient opportunity to consider whether or not to participate and that minimize the 

possibility of coercion or undue influence. The information that is given to the subject shall 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 shall be documented by the use of a written consent form approved 

by the IRB and signed by the subject. A copy shall be given to the subject. 

 (b) The consent form may be either of the following: 

(1) A written consent document that embodies the elements of informed consent required 

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

shall be a witness to the oral presentation. Also, the IRB shall approve a written summary of 

what is to be said to the subject. Only the short form itself is to be signed by the subject. 

However, the witness shall sign both the short form and a copy of the summary, and the person 

actually obtaining consent shall sign a copy of the summary. A copy of the summary shall be 

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

 7. Revise the title for subpart L to read as follows: 

Subpart L—Prohibition of Third-Party Research Involving Intentional Exposure to a 

Pesticide of Human Subjects Who are Children or Pregnant or Nursing Women

 8. Revise § 26.1201 to read as follows: 

§ 26.1201 To what does this subpart apply?

 This subpart applies to any research subject to subpart K of this part. 

 9. Revise § 26.1301 to read as follows: 

§ 26.1301 To what does this subpart apply?

 This subpart applies to any person who submits to EPA after [effective date of final rule] 

either of the following: 

 (a) A report containing the results of any human research for consideration in connection 

with an action that may be performed by EPA under FIFRA (7 U.S.C. 136-136y) or section 408 

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

 (b) A report containing the results of any human research on or with a pesticide for 

consideration in connection with any action that may be performed by EPA under any regulatory 

statute administered by EPA. 

§ 26.1302 [Amended]. 

 10. Amend § 26.1302 by removing the word “shall” from this section. 

§ 26.1502 [Amended]. 

 11. Amend § 26.1502 as follows: 

 a. In the first sentence of paragraph (a) remove the period after the phrase “during an 

inspection” and add in its place a comma; and

b. In the second sentence of paragraph (a) remove the phrase “The agency” and add in its 
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place “EPA.” 

c. In the introductory text of paragraph (b) remove the phrase “The agency” and add in 

its place “EPA.” 

§ 26.1505 [Amended]. 

12. Amend § 26.1505 by removing from the last sentence the phrase “§ 26.1502(c)” and 

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

§ 26.1507 [Amended]. 

13. Amend the last sentence of § 26.1507 by removing the phrase “The agency” and 

adding in its place “EPA”. 

§ 26.1601-1603 [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 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 shall review all proposals for new human research submitted under § 26.1125 in 

a timely manner. 
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 (b) In reviewing proposals for new human research submitted under § 26.1125, the 

Administrator shall 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 Administrator 

shall 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 shall consider Recommendation 4-1 of the 

National Research Council as contained in its 2004 report 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 Board or its foreign 

equivalent has approved the proposed research. 

 (7) If any person from a vulnerable population may become a subject in the proposed 

research, whether there is a convincing justification for selection of such a person, and whether 

measures taken to protect such human subjects are adequate. 
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 (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 Administrator may 

recommend additional conditions which, in the judgment of the Administrator, are necessary for 

the protection of human subjects. 

* * * * * 

 (h) EPA shall provide the submitter of the proposal copies of the EPA and Human 

Studies Review Board reviews. 

 17. Amend 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 shall 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 shall 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 shall consider the scientific merits and ethical aspects of the completed 

research, and shall apply the appropriate standards in subpart Q of this part. 

 19. Revise the heading for subpart Q to read as follows: 
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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 shall 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 shall 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 shall not rely on data from any 

research subject to this subpart involving intentional exposure of any human subject who is a 

pregnant woman (and therefore her fetus), a nursing woman, or a child. 

§ 26.1704 Prohibition of reliance on unethical human research with non-pregnant, nonnursing adults which is not subject to § 26.1705. 
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 (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 shall 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 7, 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 Basic Policy for the Protection of 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 shall 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 shall not rely on data from any research subject 

to this section unless EPA determines that the research was conducted in substantial compliance 

with either: 

 (1) A proposal that was found to be acceptable under § 26.1603(c), and no amendments 

to or deviations from that proposal placed participants at increased risk of harm (based on 

knowledge available at the time the study was conducted) or impaired their informed consent. If 

EPA discovers that the submitter of the proposal materially misrepresented or knowingly omitted 

information that would have altered the outcome of EPA’s evaluation of the proposal under § 

26.1603(c), EPA shall not rely on that data. 
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 (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 in paragraph (d) by removing 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]